Volume 15 Supplement 2

Proceedings of the 24th Paediatric Rheumatology European Society Congress

Open Access

Proceedings of the 24th Paediatric Rheumatology European Society Congress: Part one

Athens, Greece. 14-17 September 2017
Pediatric Rheumatology201715(Suppl 2):64

https://doi.org/10.1186/s12969-017-0185-x

Published: 1 September 2017

Clinical aspects and treatment of systemic lupus erythematosus (SLE)

O1 JSLE and the NLRP3 inflammasome – a novel therapeutic target

Jo Gamble1, Michael W. Beresford2,3

1Child Health, Translational Medicine, University of Liverpool, Liverpool UK; 2Child Health, University of Liverpool, Liverpool, UK; 3Alder Hey Children's Hospital, Liverpool, UK
Correspondence: Jo Gamble

Introduction: Juvenile-onset Systemic Lupus Erythematosus (JSLE) is a severe autoimmune disease causing organ damage and long-term morbidity. Impaired clearance of nuclear debris from cells and upregulated circulating damage-associated molecular patterns (DAMPs) and cytokines are thought to trigger cell death and thus, further increase release of pro-inflammatory molecules following the cytosolic assembly of inflammasomes.

Objectives: To investigate the role of pyroptotic cell death in JSLE, which occurs following the assembly and activation of the NLRP3 inflammasome, which may be a promising target in the treatment of JSLE and other inflammatory diseases.

Methods: THP-1 cell line-derived macrophages (Mφs) were primed using lipopolysaccharide (LPS; 10 ng/ml) and interferon (IFN) γ (20 ng/ml) in complete media at 37 °C for 24 hours, and subsequently treated with 10 mM Adenosine triphosphate (ATP) for 30 min. Primed Mφs not treated with ATP were used as a negative control. Some Mφs were incubated with 10% JSLE patient sera or NETosis-derived material (10 ng/ml) from PMA-treated neutrophils. Primed Mφs were tested for cell surface markers, HLA-DR, CD282 (TLR2), and CD68 using flow cytometry. ATP-treated Mφs were collected and either assayed for pyroptosis marker, lactate dehydrogenase (LDH) activity, cleaved caspase-1 with immunofluorescence (IF), or lysed for cleaved caspase-1 using western blotting.

Results: Primed Mφs showed an M1 phenotype with geometric means ± SEM of HLA-DR, TLR2 and CD68 expression respectively of: 1177 ± 1.15, 613 ± 0.9, and 1549 ± 0.9 gMFI, respectively compared with un-primed Mφs of 597 ± 1.0, 122 ± 0.88, and 1225 ± 0.9 gMFI, respectively (n = 3; p < 0.05). ATP-treated Mφs showed increased LDH activity compared to controls (3.4x10-3 ± 0.12x10-3) compared to 0.00 milliunits/mL, respectively; n = 3; p < 0.05). Furthermore, a greater increase in LDH activity was observed in Mφs that were incubated with JSLE serum and NET material (3.7x10-3 ± 0.5x10-3 and 7.6x10-3 ± 0.5x10-3, respectively, compared to 0.00 milliunits/mL; n = 3-6; p < 0.05). IF was positive for cleaved caspase-1 in ATP treated Mφs; and this was confirmed in lysed cells, using western blotting.

Conclusion: Overall, the results indicate that Mφs undergo pyroptosis via the NLRP3 inflammasome when challenged with a two-signal approach of priming and ATP, and that cytokines, nuclear debris and DAMPs may not only trigger, but amplify the inflammatory response of this pathway. The NLRP3 inflammasome is thought to be an important mediator in the pathogenesis of certain inflammatory diseases, and flare episodes associated with JSLE. Further work is planned to investigate the role of the inflammasome in JSLE, using pharmacological interventions with specific known and novel inhibitors of the NLRP3 inflammasome. This work could prove the NLRP3 inflammasome to be a promising target for future therapy for JSLE.

Disclosure of Interest: None Declared

Big data analytics

O2 Persistence of CD4 memory pathogenic subsets in polyarticular juvenile idiopathic arthritis patients who relapse upon withdrawal of biologic therapy

Jing Yao Leong1, Joo Guan Yeo1,2, Phyllis Chen1, Liyun Lai1, Loshinidevi D/O Thana Bathi1, Justin Tan2, Thaschawee Arkachaisri2, 3, Daniel J. Lovell4,5, Salvatore Albani1,3

1Singhealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singhealth, Singapore, Singapore; 2KK Women's and Children's Hospital, Singapore, Singapore; 3Duke-NUS Graduate Medical School, Singapore, Singapore; 4Division of Rheumatology, Cincinnati Children's Hospital Medical Centre, Cincinnati, OH, United States; 5Department of Paediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
Correspondence: Jing Yao Leong

Introduction: Clinical management of polyarticular JIA with anti-TNF-alpha biologics has been met with significant success, with up to 80% of patients demonstrating clinically meaningful efficacy. Concerns about medium/long term drug toxicities and costs have driven the clinical need to find predictors for successful drug discontinuation. Emerging evidence from previous published data indicate that T cells play a crucial role in the disease progression. Defining the pathogenic subsets and mechanisms within the T cell immunome will likely help stratify patients in terms of therapeutic outcomes.

Objectives: We seek to distill this pathogenic signal hidden within the T cell compartment through the utilisation of a high dimensional platform, CyToF, that is capable of phenotyping up to 41 markers at a single cell resolution. JIA patients treated with anti-TNF-alpha biologics were recruited in the Understanding TNF-alpha trial and segregated into flare, active and inactive arms after drug discontinuation. The central aim of this project is to identify pathogenic immune mechanisms of clinical relapse and signatures capable of distinguishing clinical fates.

Methods: Patients treated with anti-TNF-alpha biologics were recruited into the study (Improved Understanding of the Biology and Use of TNF inhibition in Children with JIA Trial) with clinically inactive disease on treatment (Wallace criteria) and initiated with therapy discontinuation. The patients were followed and evaluated as flare, inactive and active based on 6 JIA core set parameters; number of joints with active arthritis and/or loss of motion, MD global assessment of current disease activity, patient/parent global assessment of overall disease severity in prior week, a validated measure of physical function and ESR. Healthy paediatric controls without any inflammatory diseases were recruited from the day surgery during intravenous plug setting pre-operatively after informed consent.

Results: PBMCs from n = 47 JIA patients (Flare n = 18, Active = 11, Inactive n = 18) and n = 10 healthy controls were stained with 37 markers/4 barcodes T cell CyToF Panel after 6 hours stimulation with PMA/Ionmycin. Dimensional reduction cluster analysis was performed with Marvis and unique nodes representing immune subsets enriched in flare or active disease was statistically filtered (Mann Whitney Test, p < 0.05) and manually verified through conventional bivariate gating (FlowJo). In patients destined to flare (vs inactive/healthy) prior to therapy withdrawal, the CD4 memory compartment was strongly dysregulated (p < 0.05), enriched particularly in (a) CD4 CD45RA- TNF-alpha+, (b) CD4 CD45RA- CXCR5+ (TfH), and were skewed towards (c) CD152-/PD1-.When contrasting against only healthy non-disease controls, patients destined to flare additionally were up-regulated for CD4 CD45RA- TNF-alpha+ IL-6+, possibly representing as a sub-clinical disease subset. Intriguingly we noted a migratory subset, that was not evident in earlier flare cohort comparisons, CD4 CD45RA- CXCR3+ CCR6+ that was present in patients destined to develop active disease (vs inactive/healthy). Upon flaring, the sub-clinical subset CD4 CD45RA- TNF-alpha+ IL-6+ surfaces and CD4 memory subsets are now upregulating expression of CD152/PD1 (vs inactive) in response to ongoing inflammation, but when compared to healthy controls are still inadequate.

Conclusion: There exists a group of patients (flare) for which biologic therapy with anti-TNF-alpha is merely controlling the disease activity but not curative. The persistence of CD4 memory cells are likely to play a pivotal role in disease relapse, that may be partially explained by a weaker control through immune checkpoints (CD152/PD1) or interaction with B cells. These results suggest that clinical fate is immunologically predetermined and patients who will develop different clinical fates can be identified from prior biologic sampling.

Disclosure of Interest: None Declared.

O3 A multi-dimensional immunomics approach reveals distinct regulatory and antigen presenting B cell changes associated with childhood onset systemic lupus erythematosus

Joo Guan Yeo1,2, Jingyao Leong1, Thaschawee Arkachaisri2,3, Angela Yun June Tan2, Loshinidevi D/O Thana Bathi1, Xuesi Sim1, Phyllis Zi Xuan Chen1, Liyun Lai1, Lena Das2, Justin Hung Tiong Tan2, Elene Seck Choon Lee2, Yun Xin Book2, Salvatore Albani1,2,3

1Singhealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singapore, Singapore; 2KK Women's and Children's Hospital, Singapore, Singapore; 3Duke-NUS Graduate Medical School, Singapore, Singapore
Correspondence: Joo Guan Yeo

Introduction: Systemic Lupus Erythematosus (SLE) is a multi-factorial autoimmune disease and the conventional oligo-dimensional investigative approach involving one or a few cell types or analyses at a time is inadequate for its study. We hypothesize that abnormalities within multiple components of the immune system contribute to lupus pathogenesis and hence, there is a need for a comprehensive interrogative analysis.

Objectives: We aim to employ a multi-dimensional holistic approach using mass cytometry to study the immunome of childhood onset SLE (cSLE) patients and unravel the immune derangements involved in its pathogenesis. This will address the critical unmet need for a simultaneous and holistic interrogation of the different immune cell subsets in cSLE.

Methods: Peripheral blood mononuclear cells (PBMC) from 14 cSLE patients and 14 healthy paediatric controls, were stained for 37 immune phenotypic markers after 72 hours of culturing with and without Class B CpG oligodeoxynucleotide stimulation followed by interrogation with mass cytometry. Blood from healthy paediatric subjects without any inflammatory diseases were obtained prior to their elective day surgical procedures during intravenous plug setting after informed consent. Subsequent analysis of the data was done using a machine learning approach with dimensional reductions followed by automated cell classification, clustering and visualization. Unique nodes representing immune subsets enriched in cSLE patients were statistically evaluated with reference to the healthy cohort and its clinical and mechanistic significance inferred from their phenotypes (Wilcoxon rank-sum test, p < 0.05).

Results: A statistically significant enrichment of a class-switched memory B cell subset (CD19+CD27+IgG+) with CD11c+CD25+HLA-DR+CD40hiCD86hi was found in the SLE cohort, suggesting its pathologic mechanistic role in lupus. Intriguingly, CD25 (IL-2α chain) expression was found in this population, indicative of its potential responsiveness to IL-2 secreted T cells. This observation was coupled with a reciprocal increase in the transitional/naive B cell population that was negative for CD11c, CD25, CD40 and CD86 in the healthy cohort. Next, a significant enrichment of the memory regulatory T cell population (CD4+CD45RO+CD25+Foxp3+) was present in the diseased cohort with a small population of these cells expressing CXCR5. CXCR5 is a homing chemokine receptor to the lymph node germinal centre, an important lupus related microenvironment, and its presence may signify a potential regulatory role of these cells. In the healthy cohort, a reciprocal enrichment in the naive regulatory T cell population was found instead. Lastly, the B regulatory compartment of the PBMC was interrogated after CpG stimulation demonstrating an enrichment of IL10 secreting B regulatory cells with the naive and transitional B cell phenotypes (IgM+IgD+/-CD27-) in the cSLE patients. These populations of T and B regulatory cells may be involved in the amelioration of the lupus disease activity during different phases of the illness.

Conclusion: A holistic multi-dimensional approach was able to distill multiple derangements in the cSLE immunome with clinical and mechanistic significance. The identification of a B cell subset with phenotypic markers indicative of its ability for antigen presentation (HLA-DR, CD86) and T-B cell interaction (CD25, CD40) in the cSLE cohort highlights that the immunopathogenic role of B cell in SLE goes beyond antibodies production and immune regulation. Additionally, the concurrent demonstration of an increase in memory CD4 regulatory cells and B regulatory cells in the diseased cohort is consistent with our hypothesis that multiple immune abnormalities are involved in SLE pathogenesis. These findings have the translational potential to unravel the pathogenesis of lupus and identify the cellular subsets for further in-depth mechanistic and functional studies for the eventual goal of developing novel therapeutics.

Disclosure of Interest: None Declared.

O4 Using blood transcriptomic data for disease etiology discovery in pediatric ANCA-associated vasculitis

Erin Gill1, Kelly Brown2, Kim Morishita2, David A. Cabral2, Robert E. W. Hancock1

1University of British Columbia, Vancouver, Canada; 2BC Children's Hospital, Vancouver, Canada
Correspondence: Erin Gill

Introduction: Primary vasculitis encompasses a number of life threatening diseases. The different clinical manifestations and classification framework is partly determined by the size (small, medium, large) of the predominantly inflamed blood vessels. Among small vessel vasculitis (SVV) the Anti-Neutrophil Cytoplasmic Antibody (ANCA) -associated vasculitis (AAV) subtype includes, Microscopic Polyangiitis (MPA) and Granulomatosis with Polyangiitis (GPA) that are difficult for physicians to differentiate because of their many overlapping clinical features1. In the absence of biomarkers, classification algorithms (European League Against Rheumatism (EULAR2) and European Medicines Agency (EMA3) algorithms) exist to distinguish these diseases in adults and have been adapted for use in children. Although rare in childhood, the study of AAV in pediatric patients provides opportunity for biomarker discovery in individuals with a relatively naïve immune system and limited comorbidities.

Objectives: Our group has collected blood for RNA-Seq analysis from children diagnosed with AAV from centres around the world. Transcriptome analyses were conducted in an attempt to detect biomarkers for MPA and GPA that will help determine disease etiology and assist physicians in patient classification.

Methods: Briefly, blood was collected in Tempus tubes, RNA was extracted, enriched for mRNA and RNA-Seq libraries were prepared using standard methods. Sequencing was performed on an Illumina HiSeq 2500. fastq reads were mapped to the human genome using STAR4. DESeq25 was used for differential expression analysis while pathway overrepresentation analysis was conducted via innateDB6 using the Reactome7 pathway annotation system. Samples from 32 patients at the point of diagnosis or flare-up at blood draw were included in the analysis. All 32 patients were classified using the EMA algorithm, although the EMA classification was not used in the analysis.

Results: Hierarchical clustering based on Euclidean distances between samples placed samples into three clusters. Cluster one is composed of only three samples, while clusters two and three are composed of 14 and 15 samples, respectively. Cluster two contains primarily samples from individuals who were classified (via the EMA algorithm) as having MPA or unclassifiable SVV (10/14 samples), while cluster three contains primarily samples from individuals who were classified as having GPA or unclassifiable SVV (14/15 samples). DE analysis between clusters two and three showed 3,198 differentially expressed genes. The MPA cluster is enriched for pathways including interferon signaling, the ISG15 antiviral mechanism, TCR signaling and adaptive immunity. Conversely, the GPA cluster is enriched for pathways including interleukin signaling, TLR4 signaling, and phagosomal maturation. These enriched pathways suggest a viral and adaptive immunity signature for MPA and a bacterial and innate immunity signature for GPA.

Conclusion: The identification of preliminary etiologies for GPA and MPA is the first step toward assisting clinicians in developing improved molecular diagnostics for disease classification, and suggest an opportunity for seeking different treatment paradigms for the management of these two diseases.

Disclosure of Interest: None Declared.

References 1. Barut, K. et al. 2016. Curr Opin Rheumatol 28:29.

2. Luqmani, R.A. et al. 2011. Clin Exp Immunol 164:11.

3. Abdulkader, R. et al. 2012. Ann Rheum Dis 72:1888.

4. Dobin, A. et al. 2013. Bioinformatics 29:15.

5. Love, M.I. et al. 2014. Genome Biol. 15:550.

6. Breuer, K. et al. 2013. Nucl Acids Res. 41:D1.

7. Fabregat, A. et al. 2016. Nucl Acids Res. 44:D481.

Remission and outcome of systemic lupus erythematosus (SLE)

O5 Impact of fatigue, depressive symptoms and skin symptoms in adults with childhood-onset sle and the relation with HRQoL – the CHILL-NL study

Ayse Kaynak1, Noortje Groot1,2, Santusja Ramnath1, Marc Bijl3, Radboud Dolhain4, Onno Teng5, Els Zirkzee6, Karina de Leeuw7, Ruth Fritsch-Stork8, Irene Bultink9, Sylvia Kamphuis1 and on behalf of the CHILL-NL study group

1Department of Pediatric Rheumatology, Sophia Children's Hospital – Erasmus University Medical Centre, Rotterdam, Netherlands; 2Department of Pediatric Immunology, Wilhemina Children’s Hospital – University Medical Centre Utrecht, Utrecht, Netherlands; 3Department of Internal Medicine and Rheumatology, Martini Hospital, Groningen, Netherlands; 4Department of Rheumatology, Erasmus University Medical Centre, Rotterdam, Netherlands; 5Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands; 6Department of Rheumatology, Maasstad Hospital, Rotterdam, Netherlands; 7Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, Netherlands; 8Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands; 9Amsterdam Rheumatology and Immunology Center, Location VUmc, Amsterdam, Netherlands
Correspondence: Ayse Kaynak

Introduction: Childhood onset SLE is a lifelong heterogeneous autoimmune disease that follows a more severe clinical course than adult-onset SLE. Previous studies have shown that HRQoL is impaired in cSLE, little is known which factors influence HRQoL. Fatigue, depressive symptoms and skin/mucosal symptoms (leading to changed physical appearance and potential lower self-esteem) may play an important role for a patient’s HRQoL.

Objectives: To determine the prevalence of fatigue, depressive symptoms and skin/mucosal symptoms in adults with cSLE and examine the relation with HRQoL

Methods: 106 adults with cSLE were included in the CHILL-NL (CHILdhood Lupus-NetherLands) study including a single study visit for structured history, physical examination and SLEDAI-2 k. HRQoL was assessed with SF-36. Fatigue was assessed with Fatigue Severity Scale (FSS) with scores range from 1 to 7. FSS score ≥4 defines abnormal fatigue. Beck Depression Inventory (BDI) was used for depressive symptoms. BDI score ≥14 is indicative for major depressive symptoms.

Results: 92% of cSLE patients were female and white (73%). The median age at study visit was 33 yrs, median disease duration was 20 years, 61% had developed damage (SDI ≥1). HRQoL of cSLE patients was impaired (7/8 domains SF36), remarkably mental health was similar between patients and Dutch norm data. Patients with damage (SDI ≥1) scored remarkably similar on all HRQoL domains, except for the domain ‘physical functioning’. 68% of cSLE patients were abnormal fatigued (FSS score ≥4). 15% were depressive (BDI-score ≥ 14). HRQoL (6/8 domains SF36) was lower in all patients with fatigue but also in those with major depressive symptoms. The median SLEDAI-2 k score was 4, 31% of cSLE patients had ≥ 1 skin/alopecia/mucosal ulcers and its presence was associated with lower HRQoL.

BDI: Exel E, Lupus 2013;22(14):1462-FSS::ad hoc committee on SLE response criteria, ArthrRheum2007;57(8):1348

Conclusion: HRQoL in this large cohort of adults with cSLE was not associated with disease damage, but self-reported fatigue- and major depressive symptoms were. Additionally physical appearance (skin/alopecia) and mucosal symptoms had a clear impact on HRQoL.

Disclosure of Interest: None Declared.

O6 Clinical predictors of developing lupus nephritis in children

Eve M. Smith1, Peng Yin2, Andrea L. Jorgensen2, Michael W. Beresford1

1Department of Women and Children’s Health, Institute of Translational Medicine, Liverpool, United Kingdom; 2Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
Correspondence: Eve M. Smith

Introduction: A proportion of patients with Juvenile-onset Systemic Lupus Erythematosus (JSLE) will have lupus nephritis (LN) as part of their initial presentation, but others will go on to develop this manifestation later [1, 2]. Early recognition and appropriate management of LN is important as early response to treatment is known to be associated with better renal outcomes [3]. Identifying those with or at risk of developing LN is important, so that clinicians can be extra vigilant in monitoring for LN development.

Objectives: (1) To characterise patients with LN at baseline, and how they differ from patients without LN in terms of clinical and demographic factors. (2) For those without LN at baseline, who develop it at a later stage, to determine (a) when they develop LN and (b) whether there are clinical and demographic predictors at baseline which can predict subsequent development of LN.

Methods: Participants of the UK JSLE Cohort Study, between 2006-2016, were included if they had active LN at the time of their initial presentation to paediatric rheumatology care (referred to as ‘baseline’ throughout), or subsequently developed LN. Univariate logistic regression modelling compared clinical/demographic factors of patients with/without active LN at baseline. Those without LN at baseline were followed longitudinally, monitoring for LN development. The association between outcome (time from baseline visit to the development of LN) and clinical/demographic variables at baseline was tested univariately using Cox Proportional hazard modelling. Covariates with a p < 0.2 on univariate analysis were included in a multiple regression model and backward stepwise model selection applied. HRs, 95% CIs and p-values were summarised for covariates present in the final model and the results were displayed graphically with Kaplan-Meier curves and risk tables.

Results: 331 JSLE patients were included in the study. A total of 121/331 (37%) of UK JSLE Cohort Study patients were found to have active LN at baseline. Of the 210/331 patients without LN at baseline, 13 only had a single study visit and were therefore excluded from further analyses. A further 34/197 (17%) patients were found to develop LN after a median of 2.04 years [IQR 0.8-3.7]. Six clinical/demographic factors were found to differ significantly between those with/without LN at baseline. These included the patient’s first ACR score (p = 3.6 x10-6), presence of severe hypertension (p = 0.0006), level of proteinuria (p = 5.7x10-12), serum creatinine (p = 0.00024), ESR (p = 0.00075) and C3 (p = 1.3x10-7). Within the multiple regression model, both ACR score (p = 0.014) and C3 levels (p = 0.0082) at baseline were also significant predictors for subsequent LN development. Patients with a higher ACR score and a lower C3 value at baseline were at greater risk of developing LN at any point in time (ACR score: HR 1.45, 95% CI 1.08-1.95 and C3: HR 0.27, 95% CI 0.10-0.68).

Conclusion: Using clinical data from the UK JSLE Cohort Study, this study has explored the ability of basic clinical and demographic factors at baseline for stratifying JSLE patients as ‘high or low risk’ for LN development at baseline or during their subsequent disease course. Consideration of such factors may help the clinician when considering the individual patients LN risk.

Disclosure of Interest: None Declared.

Immunometabolomics

O7 NRF2 enhances metabolic turnover in myeloid cells resulting in expansion of CD11b+Gr-1+MDSCs

Kim Ohl, Patricia Klemm, Klaus Tenbrock

Dept Of Pediatrics, RWTH University of Aachen, Aachen, Germany
Correspondence: Kim Ohl

Introduction: Reactive oxygen species (ROS) were primarily considered as harmful mediators of inflammation due to their ability to damage proteins, lipids, nucleic acids and matrix components. However, accumulating evidence point towards an immune-regulatory role of ROS with inflammation-limiting effects and the ability to prevent autoimmune diseases. Thus, a deeper analysis of ROS induced pathways in different immune cells is crucial to understand the ambivalent role of ROS molecules.

Objectives: The aim of our study was to analyse the effects of ROS and oxidative stress on the immune response by deciphering the role of Nrf2 – the key transcription factor of the oxidative stress response – in immune cells.

Methods: We generated mice with a constitutive activation of Nrf2 in immune cells. Emerging CD11b+Gr-1+ cells were analysed by flow cytometry, whole transcriptome analysis and metabolic assays and compared to wildtype and LPS induced MDSCs. Finally functionality of CD11b+Gr-1+ cells was tested in vivo by means of a transfer colitis model and in an acute lung injury model.

Results: Activation of Nrf2 in immune cells induced a massive expansion of splenic CD11b+Gr-1+ cells, which exhibited characteristics of myeloid derived suppressor cells (MDSCs) such as suppression of T cell proliferation in vitro and amelioration of T-cell mediated colitis in vivo. Whole transcriptome analysis revealed Nrf2 dependent activation of cell cycle and pentose phosphate pathway, which closely resembled pathways in MDSCs induced by the TLR4 ligand LPS resulting in higher metabolic turnover and cell proliferation. In addition constitutive activation of Nrf2 was protective in LPS induced acute lung injury.

Conclusion: Thus Nrf2 is a critical transcriptional regulator for a myeloid cell population that plays a major regulatory role in inflammation and infections. Modulation of MDSCs via targeting of Nrf2-dependent metabolism provides ample opportunities for therapeutic manipulation of MDSCs depending on clinical necessities.

Disclosure of Interest: None Declared

O8 Novel serum broad-based proteomic discovery analysis identifies proteins and pathways dysregulated in juvenile dermatomyositis (JDM)

Hanna Kim1, Angélique Biancotto2, Foo Cheung2, Terrance O’Hanlon3, Ira Targoff 4, Yan Huang5, Frederick W. Miller3, Raphaela Goldbach-Mansky5, Lisa Rider3

1NIAMS, National Institutes of Health, Bethesda, MD, United States; 2CHI, NHLBI; 3EAG, NIEHS, National Institutes of Health, Bethesda, MD, United States; 4Oklahoma University (OUHSC) and Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK, United States; 5TADS, NIAID, National Institutes of Health, Bethesda, MD, United States
Correspondence: Hanna Kim

Introduction: Juvenile dermatomyositis (JDM) is a complex heterogeneous autoimmune disease. Clinical markers are imperfect to correlate with disease activity. Broad proteomic analysis with high sensitivity and reproducibility may be used biomarker discovery. Novel biomarkers from peripheral blood may help characterize pathogenesis and improve disease monitoring and treatment.

Objectives: To define protein biomarkers dysregulated in JDM and better understand JDM pathogenesis using novel aptamer-based proteomic technology proteome in a well-characterized JDM cohort.

Methods: Unbiased internal discovery and validation analysis was done using broad proteomic analysis of 1306 protein targets using SOMAscan assay of slow off-rate modified aptamers (SomaLogic, CO) which generates simultaneous quantitative results with high sensitivity and reproducibility. In a discovery cohort, 27 JDM patient sera (prevalent cases on variable treatment, average physician global activity or PGA mean 3.9/10 visual analog scale, with 14 anti-p155/140 or TIF1, 6 NXP2, and 7MDA5 myositis specific autoantibodies or MSAs) was compared versus 19 age and gender-matched healthy controls or HC sera using Mann Whitney U FDR <0.10 cutoff. Resulting protein targets were subsequently analyzed in validation cohort sera (14 prevalent JDM cases with similar characteristics including MSA distribution vs 9 HC) using the same cutoff. Resulting proteins with expression ratio of >1.3 were analyzed using Ingeunity Analysis or IPA (Qiagen, CA). The top 10 pathways were then manually clustered to minimize protein overlap with at least 1 unique protein per pathway cluster. Exploratory analysis of the same set of significant upregulated proteins in JDM were analyzed for correlation with PGA by Spearman rank test.

Results: 311 protein targets met above criteria from the discovery cohort; 166 unique proteins met criteria after analysis in the validation cohort. 80 of these proteins were upregulated in JDM versus HC and 59 had expression ratio of >1.3. From IPA analysis, 28 proteins fit into 6 pathway clusters: type I IFN notably including IFN beta, granulocyte/agranulocyte adhesion and diapedesis, remodeling/damage, acute phase response, Th1 pathway, and adipokines. There were between 1-7 unique proteins per pathway cluster but many proteins fit into more than 1 pathway cluster. Among the 10 most highly expressed proteins, the most common associated pathway cluster is type I IFN with granulocyte/agranulocyte adhesion as the second most common. 13 proteins had significant moderate correlation with PGA in JDM from varied pathway clusters with Spearman r values of 0.32-0.41. Further analysis by MSA group is ongoing.

Conclusion: Broad quantitative proteomic analysis in a well-characterized JDM cohort identifies key differentiating pathway clusters as above in JDM versus HC including many novel proteins, 13 of which have moderate correlation with PGA. Top upregulated proteins are most commonly associated with type I IFN pathway cluster, with granulocyte-agranulocyte adhesion and diapedesis as the second most common pathway cluster. Further analysis by MSA group is ongoing. While in need of confirmation in other cohorts, these proteins identified through a high-throughput screen bring to light new pathways that may be important in JDM.

This research was supported by the Cure JM Foundation and the Intramural Research Program of the NIH, NIAMS, NIEHS, NHLBI, NIAID, and the CC.

Disclosure of Interest: H. Kim Grant/Research Support from: Cure JM Foundation, A. Biancotto: None Declared, F. Cheung: None Declared, T. O’Hanlon: None Declared, I. Targoff: None Declared, Y. Huang: None Declared, F. Miller: None Declared, R. Goldbach-Mansky: None Declared, L. Rider: None Declared.

Autoinflammatory diseases in practice

O9 A web-based collection of genotype-phenotype correlations in hereditary periodic fevers from the Eurofever registry

Riccardo Papa1, Matteo Doglio1, Helen J. Lachmann2, Seza Ozen3, Joost Frenkel4, Anna Simon5, Benedicte Neven6, Jasmin Kuemmerle-Deschner7, Huri Ozdogan8, Roberta Caorsi1, Silvia Federici1, Martina Finetti1, Nicolino Ruperto1, Isabella Ceccherini9, Marco Gattorno1 and the Paediatric Rheumatology International Trials Organisation (PRINTO) and the Eurofever Project

1UO Pediatria II-Reumatologia, Istituto Giannina Gaslini, Genoa, Italy; 2National Amyloidosis Centre, Royal Free Campus, University College Medical School, London, United Kingdom; 3Department of Pediatric Nephrology and Rheumatology, Hacettepe University, Ankara, Turkey; 4Department of Paediatrics, University Medical Center Utrecht, Utrecht, Netherlands; 5Department of General Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; 6Unité d'immuno-hématologie pédiatrique, Hôpital Necker Enfants Malades, Paris, France; 7Paediatric Rheumatology, University Hospital Tübingen, Tübingen, Germany; 8Ic Hastaliklari ABD, Romatoloji BD, Cerrahpasa Tip Fakultesi, Istanbul, Turkey; 9Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy
Correspondence: Riccardo Papa

Introduction: Because of the large number of common variants or polymorphisms in genes related to hereditary periodic fevers (HPF), genetic results often require an high clinical discrimination. The Infevers database is a large international registry of the different variants described for genes associated to autoinflammatory diseases. Due to the nature of this registry no genotype-phenotype correlation are provided, except for the clinical phenotype of the first patient(s) described for each mutation.

Objectives: Aim of this study was to elaborate a registry of genotype-phenotype correlations derived from the patients with HPF enrolled and validated in the Eurofever registry.

Methods: We created a table for each HPF describing the genotype-phenotype correlations observed in all the patients enrolled in the Eurofever registry. For autosomal dominant diseases (CAPS, TRAPS), all mutations were analyzed individually. For autosomal recessive diseases (FMF, MKD), homozygous and all combinations of compound heterozygous are described. For each mutation or combination, the following items are shown: number of patients, mean age of onset, disease course (recurrent or chronic), mean duration of fever episodes, clinical manifestations associated with fever episodes, atypical manifestations, complications and response to treatment.

Results: We analyzed the genotype-phenotype correlations of 718 patients (313 FMF, 133 CAPS, 114 MKD, 158 TRAPS) already reported in specific papers and validated by at least two experts for each disease. A total of 152 variants were described: 48 variants of TNFRSF1A, 30 NLRP3, 57 different combinations of MVK and 42 MEFV for compound heterozygous are available. For each HPF, a table with all the variables described has been established.

Conclusion: We provide a useful tool for all the physicians, creating a registry of genotype-phenotype correlation of HPF based on the patients enrolled in the Eurofever registry. This tool is complementary to the Infevers database and will be available at the Eurofever and Infevers websites.

Disclosure of Interest: None Declared.

Genetic aspects of pediatric rheumatic diseases

O10 IKZF1 mutation underlines the B cell landscape heterogeneity in mendelian lupus

Cécile Frachette1, Sulliman O. Omarjee1, Anne Laure Mathieu1, Thibault Andrieu2, Paul Mondier3, Gillian Rice4, Heloïse Reumaux5, David Launay6, Marc Lambert7, Guillaume Lefevre8, Nicole Fabien9, Christophe Malcus10, Isabelle Rouvet11, Emilie Chopin11, Anne-Sophie Michallet3, Thierry Defrance3, Thierry Walzer1, Yanick Crow12, Alexandre Belot1

1Inserm U1111, Centre International de Recherche en Infectiologie- International Center for Infectiology Research, LYON, France; 2Inserm SFR Biosciences Gerland, LYON, France; 3Centre International de Recherche en Infectiologie- International Center for Infectiology Research, LYON, France; 4Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; 5Rhumatologie médecine interne pédiatrique, Urgences, Pédiatrie générale et maladies infectieuses Hôpital Salengro, Lille, France; 6Department of Internal medicine and Clinical Immunology, UMR 995 Inserm, University of Lille, Lille, France; 7Service de médecine interne, Hôpital Huriez, Lille, France; 8Lille Inflammation Research International center, Lille, France; 9Service d'immunologie, CHU de Lyon HCL-Groupement Hospitalier Sud, Lyon, France; 10Laboratoire d'immunologie cellulaire, Groupement hospitalier Edouard herriot, Lyon, France; 11Biotechnology Department, Hospices civils de Lyon, Lyon, France; 12Inserm UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France
Correspondence: Cécile Frachette

Introduction: Next generation sequencing (NGS) represents a revolution in the field of molecular medicine, and offers a new approach to deciphering the pathogenesis of complex diseases. Paediatric-onset SLE (pSLE) is a very rare and more severe phenotype than its adult-onset counterpart, and is possibly associated with a greater contribution of genetic aetiological factors. We have in the past described a B cell-related Mendelian form of lupus due to a deficiency of PKCδ. Here, we identified and characterized a new B cell-related Mendelian lupus secondary to IKZF1 mutation and compared this novel monogenic disease with PKCδ deficiency.

Objectives: The aims of the study were to characterize the molecular impact of a new B cell related variant in IKZF1 encoding the protein IKAROS, and to study the B cell landscape of two distinct monogenic forms of SLE using mass cytometry (Cytof®).

Methods: We designed an NGS panel comprising 200 genes including proven disease-associated as well as prospective candidate genes, and analysed 132 patients. We identified a family with three affected individuals carrying a previously unreported mutation in IKZF1. We set up functional assays including oligonucleotide pulldown, B cell phosphorylation and deep B cell immunophenotyping by mass cytometry.

Results: We identified a heterozygous missense mutation in IKZF1 c.359A > T (p. D120V) in three affected patients in a single family. IKZF1 encodes IKAROS, a key transcriptional factor in B cell development. Functional assays showed that protein stability was not impaired, but DNA-binding was partially impacted. We performed mass cytometry comparing SLE patients carrying a homozygous loss-of-function mutation in PRKCD and our newly identified IKZF1 mutation. We identified B cell clusters, and unsupervised analysis underlined the wide differences between two monogenic diseases leading to SLE.

Conclusion: Ikaros and PKCδ dysfunction demonstrate that monogenic lupus can occur as a consequence of distinct anomalies of B cell development underlining the fact that SLE should be considered as a syndrome rather than a single homogenous disease.

Disclosure of Interest: None Declared.

Remission in chronic arthritis

O11 Development of New JADAS and cJADAS cut-offs for disease activity states in oligoarthritis and rf-negative polyarthritis from a large multinational cohort of children with juvenile idiopathic arthritis

Alessandro Consolaro1,2, E.H. Pieter van Dijkhuizen3, Graciela Espada4, Boriana Varbanova4, Sheila K. Oliveira4, Paivi Miettunen4, Gaelle Chédeville4, Michael Hofer4, Pavla Dolezalova4, Ivan Foeldvari4, Gerd Horneff4, Anne Estmann4, Chris Pruunsild4, Rosa Merino4, Inmaculada Calvo Penades4, Pablo Mesa-del-Castillo4, Pekka Lahdenne4, Maka Ioseliani4, Maria Trachana4, Olga Vougiouka4, Miroslav Harjacek4, Ilonka Orban4, Tamàs Constantin4, Nahid Shafaie4, Violeta Panaviene4, Marite Rygg4, Elzbieta Smolewska4, Jose Antonio Melo-Gomes4, Jelena Vojinovic4, Ekaterina Alekseeva4, Tadej Avcin4, Veronika Vargova4, Nuray Aktay Ayaz4, Ozgur Kasapcopur4, Yaryna Boyko4, Sarah Ringold4, Marco Garrone1,4, Nicolino Ruperto1,4, Angelo Ravelli1,2 on behalf of PRINTO and EPOCA Study Group

1Istituto Giannina Gaslini, Genova, Italy; 2University of Genova, Genova, Italy; 3Wilhelmina Children's Hospital, Utrecht, Netherlands; 4PRINTO, Genova, Italy
Correspondence: Alessandro Consolaro

Introduction: The measurement of the level of disease activity plays a pivotal role in the care of patients with ju-venile idiopathic arthritis (JIA). To serve this purpose, the Juvenile Arthritis Disease Activity Score (JADAS) was developed in 2009. More recently, a version excluding the acute phase reactant was tested (cJADAS). Cutoff values for the state of remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) were recently developed for the original JADAS score and for the clinical version. These cutoff values are ideally suited for pursuing tight disease control in a treat-to-target strategy, with treatment escalation if the desired JADAS score is not reached. However, although cut-offs were validated in a large and multinational cohort of patients, they were developed in a dataset of patients from a single pediatric rheumatology center an partly before the advent of the so-called biologic era.

Objectives: To develop the JADAS and cJADAS cut-off values of remission, LDA, MDA, and HDA for oligoarthritis and RF-negative polyarthritis in a large multinational cohort of JIA patients.

Methods: The EPidemiology, treatment and Outcome of Childhood Arthritis (EPOCA) study is aimed to obtain information on the frequency of JIA subtypes in different geographic areas, the therapeutic approaches adopted by pediatric rheumatologists practicing in diverse countries or continents, and the disease and health status of children with JIA currently followed worldwide. More than 9.000 patients with JIA from 118 pediatric rheumatology centres in 49 countries were collected so far. For the development of cut-offs, patients with oligoarthritis and polyarthritis followed in the 20 Centres with the highest frequency of these 2 subtypes were retained. In each centre, the 75th centile of JADAS and cJADAS distribution in patients who were subjectively rated by the attending physician as being in remission and LDA, and the 25th centile of JADAS and cJADAS in patients rated as in HDA, were calculated. The obtained values at each centre were then averaged to obtain the prelimary cut-offs for each disease activity state.

Results: The cut-offs validation cohorts were made of 930 patients with oligoarthritis from 20 pediatric rheumatology Centres and 1.004 patients with RF-neg polyarthritis from 20 pediatric rheumatology Centres. Preliminary cut offs values for each versions of JADAS and cJADAS are presented in Table 1.
Table 1

(Abstract O11). See text for description

 

JADAS10

JADAS27

JADAS71

cJADAS10

cJADAS27

cJADAS71

Oligoarthritis

Remission

1.5

1.5

1.5

1.2

1.2

1.2

LDA

3.9

3.7

3.9

3.4

3.3

3.4

HDA

16.4

16.2

16.4

14.3

14.1

14.3

Polyarthritis

Remission

2.6

2.6

2.6

2.4

2.3

2.4

LDA

5.1

4.9

5.1

5.1

4.9

5.1

HDA

18.9

18.9

22.7

19.0

20.0

25.3

Conclusion: New JADAS and cJADAS temptative cut-offs for remission, LDA, and HDA were calculated. Obtained values will be tested in the validation analysis. The preliminary values are higher than currently available cut-offs.

Disclosure of Interest: None Declared.

New insights into the pathogenesis of systemic lupus erythematosus (SLE)

O12 Interferon-γ plays a role in the pathogenesis of pediatric systemic lupus erythematosus and its activity correlates with disease activity

Gian Marco Moneta1, Claudia Bracaglia1, Ivan Caiello1, Luisa Bracci-Laudiero1,2, Rita Carsetti3, Fabrizio De Benedetti1, Emiliano Marasco1

1Division of Rheumatology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy; 2Institute of Translational Pharmacology, CNR, Rome, Italy; 3B Cell Physiopathology Unit, Immunology Research Area, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
Correspondence: Marco Moneta

Introduction: Pediatric systemic lupus erythematosus (pSLE) is a rare autoimmune disorder with onset before 18 years of age and characterized by heterogeneous clinical manifestations, unpredictable courses and a substantial risk of morbidity. There is no targeted treatment available for pSLE. In the last decade, several gene expression profiling and protein studies showed an up-regulation of genes typicallyinduced by type I interferons (IFNα/β) in the peripheral blood and tissue samples of pSLE patients. Although blood expression levels of IFNα/β-related genes were also correlated with disease activity of pSLE patients, the mechanism by which type I IFN contribute to pathogenesis has not yet been elucidated.

Objectives: In this study, we aim to investigate the role of type II IFN, IFNγ, in the pathogenesis of pSLE evaluating: 1) the expression levels of IFNγ-related genes in the peripheral blood of pSLE patients; 2) the relationship between type II and type I IFNs; 3) the correlations between the expression levels of IFNγ-related genes in peripheral blood and the clinical features of pSLE patients.

Methods: We analysed the expression levels of IFNα/β induced genes (IFI27, IFI44L, IFIT1, RSAD2, ISG15, SIGLEC1) and IFNγ induced genes (CXCL9, CXCL10, IDO1) in the peripheral blood of pSLE patients (n = 19) by real time PCR. For each patient, SLEDAI score was calculated. Human peripheral blood mononuclear cells (PBMCs) obtained by healthy donors (HD) (n = 3) were stimulated in vitro with recombinant human IFNγ and IFNα2b, expression levels of IFN-regulated genes were evaluated by real time PCR. We used non-parametric Mann-Whitney U test and Spearman r for statistical analysis.

Results: Expression levels of both IFNα/β-induced genes and IFNγ-induced genes were increased in the peripheral blood of pSLE patients with active disease (n = 9) compared to HD (n = 10) and pSLE patients with inactive disease (n = 10). We developed a type II IFN score similarly to the type I IFN score described by Crow et al. We calculated the type I IFN score and the type II IFN score for each pSLE patient. As previously reported, the type I IFN score was significantly correlated with the SLEDAI of pSLE patients (r = 0.67, p < 0.01). We found that the type II score was also significantly correlated with the SLEDAI score of pSLE patients (r = 0.64, p < 0.01).

As it is known that some IFN-induced genes can be upregulated by both types of interferons, we asked if IFNγ was able to affect, in human PBMCs, the expression of IFNα/β induced genes (IFI27, IFI44L, IFIT1, RSAD2, ISG15, SIGLEC1) assessed to calculate the type I score: we found that IFNγ treatment induced the expression of type I IFN-related genes in human PBMCs in dose-dependent manner. Interestingly, human PBMC stimulated with recombinant IFNα2b strongly up-regulated the expression of IFNγ.

Conclusion: Taken together, these data indicate a possible role of IFNγ in the pathogenesis of pSLE. Both types of IFNs potentiate each other effect on tissues by affecting their reciprocal biological activity. IFNγ correlates with disease activity in pSLE, IFNγ-induced gene expression may represents a promising biomarker in this autoimmune disease. The potential pathogenic role of IFNγ in SLE remains to be elucidated.

Disclosure of Interest: None Declared.

Scleroderma and related disorders

O13 Reliability and performance of the loscat clinical score for the assessment of activity and tissue damage in a large cohort of patients with juvenile localized scleroderma

Anna Agazzi, Gloria Fadanelli, Fabio Vittadello, Francesco Zulian, Giorgia Martini

Department of Woman and Child Health, University of Padua, Padova, Italy
Correspondence: Anna Agazzi

Introduction: One of the open issues for Juvenile Localized Scleroderma (JLS) is the assessment and monitoring over time of the extent of inflammation and tissue damage. The lack of reliable and standardized outcome measures has represented, over the years, a significant limitation for both clinical monitoring of the disease and development of therapeutic trials.

Objectives: We assessed the reliability of Localized Scleroderma Cutaneous Assessment Tool (LoSCAT) clinical score in comparison with contemporary thermographic analysis. Secondary aim was to evaluate and compare the sensitivity to change of LoSCAT and thermography over time.

Methods: A longitudinal observational analysis of patients with JLS, consecutively evaluated at our Paediatric Rheumatology Unit, has been performed by using the LoSCAT clinical score and infrared thermography.

LoSCAT score is composed of two indexes: the modified Localized Scleroderma Skin Severity Index (mLoSSI) which measures disease activity considering any new/enlarged lesion, erythema and thickening, and the Localized Scleroderma Skin Damage Index (LoSDI) which measures tissue damage as dermal atrophy, subcutaneous atrophy and depigmentation.

Infrared thermography is a non-invasive imaging technique detecting the thermal energy emitted from the skin providing a graphical representation of its distribution on the body surface.

Three examiners with different experience in Paediatric Rheumatology blindly evaluated all patients twice, at baseline and at least three months later. At each visit, thermographic analysis and LoSCAT score were performed by each examiner. The inter-rater reliability was assessed by the Intraclass Correlation Coefficient (ICC) and interpreted as follows: ICC values range 0.75-1 excellent reliability, 0.4-0.74 good reliability, <0.4 poor reliability. All statistical analyses, including the analysis of variance (ANOVA), were performed by using IBM SPSS (Vers. 18.0).

Results: Forty-seven patients (129 lesions) entered the study, and 26 (79 lesions) were reassessed by same examiners with the same modality after 4.5 (+1.5) months. As for LoSCAT, mLoSSI showed excellent inter-rater reliability expressed by ICC 0.895 (95% CI 0.846-0.931); the analysis of variance (ANOVA) confirmed that values indicated by the 3 examiners, were not different from each other (test F = 1.275 and p = 0.283). The inter-rater reliability for LoSDI was excellent too with ICC = 0.880 (95% CI 0.825-0.921), ANOVA test F = 3.030 (p = 0.052).

In the group of 79 lesions examined twice an improvement for all anatomic sites for both evaluations of the three examiners and thermographic detection was observed. Moreover, thermographic analysis showed statistically significant correlation in different anatomic sites with domains of erythema, dermal atrophy and subcutaneous atrophy of LoSCAT.

Conclusion: LoSCAT appears as a promising outcome measure in JLS, distinguishing the different aspects of activity and damage. LoSCAT is not influenced by the experience of the examiner. Infrared thermography confirms to be a very helpful tool for detecting disease activity and reliable in monitoring lesions over time.

Disclosure of Interest: None Declared.

O14 Tocilizumab is a promising treatment option for therapy resistent juvenile localised scleroderma patients

Ivan Foeldvari1, Jordi Anton2, Mark Friswell3, Blanca Bica4, Jaime de Inocencio5, Angela Aquilani6, Nicola Helmus1

1Hamburg Center for Pediatric and Adolescent Rheumatology, AM Schöen Klinik Eilbek, Hamburg, Germany; 2Sant Joan de Déu Hospital, Barcelona, Spain; 3Great North Children’s Hospital, Newcastle, United Kingdom; 4Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 5University Hospital 12 de Octubre, Madrid, Spain; 6Ospedale Bambino Gesù, Rome, Italy
Correspondence: Ivan Foeldvari

Introduction: Juvenile localised scleroderma (jlSc) is an orphan disease. Most patient respond to treatment ot methotrexate or mycophenolate. In case of nonresponse or partial response, based on the promising tocilizumab (TOC) data of adult systemic sclerosis studies, TOC seems to be a promising option. There is no publication regarding the effectiveness of tocilizumab in jLS.

Objectives: To assess the effectivity of TOC in jlSC patients, who had nonresponse or partial response on conventional therapy.

Methods: Participants of the pediatric rheumatology email board were asked, if they follow patients with jlSc, who are treated with TOC. Clinical characteristics and the response to TOC was assessed.

Results: Six centers responded to the survey from the email board, with around 800 participants, and reported 11 patients. The mean age of the patients at disease onset was 5.5 years. Disease duration at time of the initiation of TOC was 53.5. months (range 9 to 109). 5 patients had linear subtype, 3 of them with facial involvement, 2 of them Parry Romberg and one of them coup de sabre. Three had generalized subtype, 2 mixed subtype and 1 limited subtype/morphea. Before starting TOC patients received 10/11 Methotrexate, 7/11 Mycophenolate, 1 abatacept and 1 anti-TNF therapy. Reason to start TOC was in 9 patients increase in Localised Scleroderma Activity Index[1] (mLoSSI). In two patients increased extracutaneous activity was the indication, in one increased activity of arthritis and in the other increased activity of the central nervous system involvement.

The mean duration of tocilizumab therapy was 14.75 months. 2 patients received s.c. according the poly JIA dosing and all other i.v.. There were different i.v doses applied, 5 of them 8 mg/kg every 4 weeks, one of them 8 mg/kg every three weeks, 1 every two weeks and 1 patients received 10 mg/kg every 3 weeks. 3/11 received TOC as monotherapy. 8/11 as combination therapy, 6 of them with Methotrexate and one of each with Mycophenolate or Tacrolimus. Therapy success was reflected by a decreased mLoSSI in 8/11 patients and in 6 patients by a decrease in the Localosed Scleroderma Skin Damage Index[1] (LoSDI). No new lesion occurred during the treatment and in the patients with Parry Romerg subtype(n = 2) no increase in the facial atrophy occurred. In 8/8 patients physician global (VAS 0-100) decreased and in 8/8 the patients global disease activity (VAS 0-100) decreased. In 3/3 patients, were it was applicable, the number of active joints decreased, in one patients the limb discrepancy decreased. The mean modified Rodnan skin score assessed in 8 patients decreased from the mean value of 9.6 to 5.5.

Conclusion: Conclusion:

In this small cohort of patients TOC seems to be a promising rescue medication in methotrexate/mycophenolate nonresponsive patients. A prospective controlled study would be important to prove the seen effect in a controlled way.

1. Arkachaisri T, Vilaiyuk S, Torok KS, Medsger TA, Jr.: Development and initial validation of the localized scleroderma skin damage index and physician global assessment of disease damage: a proof-of-concept study. Rheumatology (Oxford) 2010, 49(2):373-381.

Disclosure of Interest: None Declared.

Pathogenesis of juvenile idiopathic arthritis (JIA)

O15 P75NTR/PRONGF up regulation in synovial tissues activates inflammatory responses in chronic arthritis patients

gaetana minnone1, Melissa Noack2, Pierre Miossec3, Ivan Caiello1, Marzia Soligo4, Luigi Manni4, Antonio Manzo5, Fabrizio De Benedetti1, Luisa Bracci-Laudiero4

1Division of Rheumatology and Immuno-Rheumatology Research Laboratories, Bambino Gesù Children’s Hospital, Rome, Italy; 23 Immunogenomics and Inflammation Research Unit, EA 4130, Edouard Herriot Hospital, Hospices Civils de Lyon and University Claude Bernard Lyon 1, Lyon, France; 3Immunogenomics and Inflammation Research Unit, EA 4130, Edouard Herriot Hospital, Hospices Civils de Lyon and University Claude Bernard Lyon 1,, Lyon, France; 4Institute of Translational Pharmacology, CNR, Rome, Italy; 5Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology,, IRCCS Policlinico S. Matteo Foundation/University of Pavia, Pavia, Italy
Correspondence: gaetana minnone

Introduction: We have recently demonstrated that synovial fluids of JIA patients contain elevated levels of proNGF, the immature form of the Nerve Growth Factor (NGF), and not mature NGF as believed in the past. Moreover, mononuclear cells of JIA patients show a reduced expression of TrkA, the specific receptor of mature NGF, and an enhanced expression of p75NTR, the specific receptor for proNGF. This results in an inverted ratio of TrkA and p75NTR in JIA patients compared to healthy donors. How this altered proNGF/p75NTR axis can influence the inflammatory response is at present unknown.

Objectives: In this study, we focused on the involvement of p75NTR and its ligand proNGF in regulating inflammatory responses in the inflamed synovia and in synoviocytes of arthritis patients.

Methods: Fibroblast-like synoviocytes (FLS) were obtained by synovial tissue of rheumatoid arthritis patients (RA FLS) after enzymatic digestion. Osteoarthritis fibroblasts (OF) and skin fibroblasts (SF) were used as control. Using Realtime-PCR and western blot, we evaluated TrkA, p75NTR, sortilin, NGF mRNA expression and protein levels. Realtime-PCR and ELISA were used to evaluate cytokine production.

Results: Our preliminary data show that, similarly to JIA SFMC, p75NTR is significantly upregulated in FLS of RA patients, while TrkA is much less expressed than p75NTR. Instead, OF and SF showed a higher expression of TrkA than p75NTR. Moreover, FLS express NGF mRNA and release high amounts of proNGF, but not of mature NGF, in the conditioned media. Inflammatory stimuli, such as IL-1b, further upregulate p75NTR expression in FLS and induce the expression of p75NTR in control fibroblasts. In vitro, the addition of proNGF to FLS induces the expression of pro-inflammatory cytokines. This effect is abolished when p75NTR activity was inhibited using LM11A-31, a non-peptide ligand that blocks the binding site of p75NTR for proNGF.

Conclusion: These preliminary data suggest that the proNGF found in synovial fluids of chronic arthritis patients is produced and released principally by FLS. The accumulated proNGF binds to its specific receptor p75NTR, which is highly expressed by both FLS and SFMC, inducing pro-inflammatory cytokine expression. Inflammatory stimuli further enhances the expression of p75NTR in FLS, creating a vicious circle that amplify the inflammatory response. The use of p75NTR inhibitors might represent a new therapeutic approach for the treatment of JIA and RA.

Disclosure of Interest: None Declared.

Oral Presentations 1

O16 Three treatment strategies in recent onset dmard naive juvenile idiopathic arthritis: first results of clinical outcome after 24 months

Petra Hissink Muller1,2, Danielle Brinkman1,3, Dieneke Schonenberg4, Wytse van den Bosch1, Yvonne Koopman-Keemink5, Isabel Brederije1, Peter Bekkering6, Taco Kuijpers4, Marion van Rossum7, Lisette W. van Suijlekom-Smit8, J M. van den Berg4, Stefan Boehringer9, C F. Allaart10, Rebecca ten Cate1

1Pediatric Rheumatology, LUMC, Leiden, Netherlands 2Pediatric Rheumatology, Erasmus MC Sophia, Rotterdam, 3Pediatrics, Alrijne Hospital, Leiderdorp, Netherlands 4Department of Pediatric Hematology, Immunology, Rheumatology and Infectious Diseases, Emma Children’s Hospital AMC, University of Amsterdam, Amsterdam, Netherlands 5Pediatrics, Juliana Children's Hospital, The Hague, Netherlands 6Pediatric Oncology, Princess Máxima Center of Pediatric Oncology, Utrecht, Netherlands 7Pediatric Rheumatology, Amsterdam Rheumatology and Immunology Center location Reade, Amsterdam, Netherlands 8Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital, Rotterdam, Netherlands 9Medical Statistics and Bioinformatics, LUMC, Leiden, Netherlands 10Rheumatology, LUMC, Leiden, Netherlands
Correspondence: Petra Hissink Muller

Introduction

The BeSt treatment strategy for children with juvenile idiopathic arthritis (JIA) has not been determined as of today.

Objectives

The aim of the BeSt for Kids study was to investigate, which of three treatment strategies is most effective and safe, by comparing them directly. The therapeutic target in all arms was inactive disease by rapid reduction of disease activity and repeated monitoring and revision of therapy in case of insufficient response. We hypothesized that early treatment with etanercept and methotrexate (arm 3), compared to initial monotherapy (arm 1) or initial combination therapy with methotrexate and prednisone (arm 2), would lead to significantly earlier clinical inactive disease.

Methods

We conducted a randomized, single blinded, multicenter, treatment strategy study with 24 months of follow up. Disease modifying anti rheumatic drug (DMARD)-naive JIA patients were randomized to 1. sequential DMARD-monotherapy (sulfasalazine (SSZ) or methotrexate (MTX), 2. combination therapy: MTX and prednisolone-bridging, 3. Combination-therapy MTX with etanercept. For all arms, the treatment protocol described a number of subsequent treatment steps in case medication failed. After reaching remission for 3 (oligoarticular) or 6 months (polyarticular) medication was tapered and stopped as dictated per protocol and flare frequency was observed. Missing data were imputed. Primary outcome was time to inactive disease and time to flare after tapering and stopping DMARD therapy, both calculated using Kaplan Meier method with log rank test. Secondary outcomes are adjusted ACRPedi 30/50/70 scores, toxicity, functional ability and quality of life. Generalised Estimating Equations were used for longitudinal data analyses. In this abstract we share the first 24 months results.

Results: Ninety-four patients were randomised, 32 in arm 1, 32 in arm 2 and 30 in arm 3. Two patients received a different diagnosis during follow-up and were left out of all analysis. Two patient were lost to follow up but were analysed due to intention to treat principle. Overall baseline median (InterQuartileRange IQR) age was 9.1 (4.6-12.9) years. 37% were ANA positive, 11 patients had oligo-articular disease, 66 patients polyarticular JIA and 15 patients juvenile psoriatic (polyarticular) arthritis. Baseline median (IQR) ACRpedi-scores: VAS physician 50 (39-58) mm, VAS patient 54 (37-70) mm, ESR 6(2-14) mm/hr, active joint count 8 (5-12), limited joint count 2.5 (1-5), CHAQ score 0.9 (0.6-1.5). Inactive disease occurred overall after mean 9.8 months (8.5-11.1). Time to inactive disease was not significantly different in all three arms (log rank test p = 0.23). Outcome measures after 24 months of therapy are summarised in the Table 2.
Table 2

(abstract O16). See text for description

 

Arm 1 n = 31

Arm 2 n = 32

Arm 3 n = 29

3 vs 1 p OR (CI)

2 vs 1 p OR (CI)

3 vs 2 p OR (CI)

ACRPEdi30(%)(CI)

92.2 (82,1-102.4)

84.4 (71.2-97.5)

96.6 (89.8-103.3)

0.1 1.7 (0.8-3.4)

0.8 0.9(0.5-1.7)

0.1 0.9-3.7

ACRPedi50 (%)(CI)

85.5 (72.4-98.6)

83.8 (70.1-97.4)

93.1 (83.7-102.4)

0.3 1.4(0.7-2.8)

0.9 1.1(0.6-2.0)

0.4 1.3(0.7-2.7)

ACRPedi70 (%)(CI)

69.0 (52.1-85.9)

68.8 (51.6-85.9)

82.8 (68.8-96.8)

0.07 1.8(1.0-3.3)

0.7 0.9(0.4-1.7)

0.03 2.1(1.1-4.0)

Inactive disease (%)

61.0 (39.7-82.3)

63.1 (43.6-82.7)

61.0 (40.9-81.2)

0.9 1.0(0.7-1.7)

0.1 0.7(0.4-1.1)

0.09 1.5(0.9-2.5)

JADAS-10 (CI)

2.6(1.4-3.8)

4.0(2.2-5.8)

3.0(1.6-4.4)

0.6 0.6(0.1-3.5)

0.2 3.1(0.5-20.3)

0.09 0.2(0.03-1.3)

Conclusion: Although our study did not meet its primary end point, treat-to-target treatment in this cohort of children with recent-onset JIA resulted in high frequencies of clinical inactive disease and adjusted ACRpedi30/50/70 scores in all three arms. In clinical trials inactive disease seems a feasible goal in juvenile idiopathic arthritis patients.

Trial registration identifying number: NTR1574

Disclosure of Interest: None Declared.

O17 Predictive value of magnetic resonance imaging in patients with juvenile idiopathic arthritis in clinical remission

Marta Mazzoni1, Angela Pistorio2, Stefania Viola3, Alessia Urru1, Emanuela Sacco3, Eleonora Zaccheddu3, Francesca Magnaguagno4, Angelo Ravelli1, Alberto Martini1, Clara Malattia1

1Università degli studi di Genova, Pediatria II-Reumatologia, Genoa, Italy; 2Epidemiologia, Biostatistica e Comitati, Genoa, Italy; 3Pediatria II-Reumatologia, Genoa, Italy; 4Radiologia, G. Gaslini, Genoa, Italy
Correspondence: Marta Mazzoni

Introduction: MRI studies on RA patients showed that subclinical synovitis is often present in patients in clinical remission and is responsible for progression of joint damage. A high frequency of MRI-detected inflammation in JIA patients with clinically inactive disease was also reported. Due to the lack of longitudinal studies in JIA, it is unclear whether this phenomenon entails a risk of progression of joint damage and whether it should affect the therapeutic decisions.

Objectives: To assess the prevalence of subclinical synovitis as detected by MRI in a cohort of JIA patients in clinical remission and to evaluate its association with disease flare and structural damage progression.

Methods: All JIA patients who met the Wallace criteria for clinical remission and underwent contrast-enhanced MRI at the Study Unit between 2007 and 2015 were included. MRIs were scored by two independent readers according to the Outcome Measure in Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Scoring System (RAMRIS). Joint damage progression was assessed by conventional radiography (CR) according to the adapted versions of the Sharp/van der Heijde score and to the Childhood Arthritis Radiographic Score of the Hip. The concordance between the readers was assessed using kappa statistics. Categorical data were analyzed using chi-squared test and Fisher’s exact test. Comparison of quantitative variables was performed by the non-parametric Mann–Whitney U-test. A logistic regression model was applied to perform multivariate analysis of the radiographic damage risk factors.

Results: A total of 90 patients (15 M, 75 F; mean age 13.8 years; mean disease duration 8.5 years; mean follow-up duration 2.9 years) were included. Fourteen out of 90 patients (15.6%) were in remission off medication, while 76/90 patients (84.4%) were in remission on medication. Forty-five patients were assessed by MRI in the wrist, 30 in the hips, 13 in the ankle and 2 in the knee. Fifty-seven patients (63.3%) had evidence of subclinical synovitis on MRI. The inter-observer agreement for presence/absence of synovitis was good (k = 0.74; 95% CI: 0.5-0.9). Forty-three out of 57 patients (75,4%) with subclinical synovitis experienced a disease flare versus 11 out of 33 patients (33.3%) who hadn't any synovial inflammation (P < 0.0001). Radiographic damage progression was assessed in 54/90 patients for whom follow-up CRs were available and was detected in 19/54 patients (35.2%). A significant association between systemic JIA subtype and deterioration of joint damage was found (P = 0.027, Fisher’s exact test). MRI-detected bone marrow oedema (BMO) score and the baseline radiographic damage score were also significantly related to structural progression (P = 0.002, Mann–Whitney U-test). The multivariable logistic regression analysis showed that only baseline BMO score ≥3 independently contributed to explain radiographic damage progression (OR 4.82; 95% CI: 1.0-23.2; P = 0.035).

Conclusion: A sizeable proportion of patients in clinical remission had MRI evidence of persistent joint inflammation. Subclinical synovitis was significantly associated with disease flare, while BMO showed remarkable promise in predicting joint destruction. These findings support the utility of MRI for the assessment of JIA patients in clinical remission and may have important clinical implications for their management.

Disclosure of Interest: None Declared

O18 Baseline predictors of functional disability eight years after disease onset in the nordic juvenile idiopathic arthritis population-based cohort

Veronika Rypdal1, Ellen D Arnstad2, Lillemor Berntson3, Marek Zak4, Kristiina Aalto5, Suvi Peltoniemi5, Susan Nielsen4, Mia Glerup6, Troels Herlin6, Anders Fasth7, Maria Ekelund8, Marite Rygg2, Ellen Nordal1 and Nordic Study Group of Pediatric Rheumatology (NoSPeR)

1Dep of Pediatrics, University Hospital of North Norway, UiT The Arctic University of Norway, Tromsø; 2Dep of Laboratory Medicine, Children’s and Women’s Health, NTNU, Dep of Pediatrics, St.Olavs Hospital, Trondheim, Norway; 3Dep of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden; 4Pediatric Clinic II, Rigshospitalet, Copenhagen, Denmark; 5Dep of Pediatrics, Helsinki University Hospital, Helsinki, Finland; 6Dep of Pediatrics, Århus University Hospital, Århus, Denmark; 7Dep of Pediatrics, University of Gothenburg, Gothenburg, Sweden; 8Dep of Pediatrics, Ryhov County Hospital, Dep of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
Correspondence: Veronika Rypdal

Introduction: Baseline clinical predictors on long-term outcome, not only regarding remission but also on functional ability, may enable assessment of prognosis and guide early treatment decisions in juvenile idiopathic arthritis (JIA).

Objectives: To evaluate potential baseline clinical predictors of functional ability assessed by the Childhood Health Assessment Questionnaire (CHAQ) eight years after disease onset.

Methods: Consecutive cases with newly diagnosed JIA from defined geographical areas in Denmark, Finland, Sweden and Norway were included and followed over eight years. Logistic regression was performed to assess potential baseline predictors of disability in terms of CHAQ (or HAQ for participants ≥18 years of age) score >0 at the final study visit.

Results: At follow-up 98 months (median, IQR 95-102) after disease onset, CHAQ/HAQ was available in 352 (80%) of the total 440 participants. A CHAQ/HAQ score of 0 was found in 239 (68%) of these. The following characteristics at the first study visit 7 months (median, IQR 6-8) predicted CHAQ/HAQ > 0 eight years after disease onset: higher cumulative joint count, symmetric arthritis in wrists, fingers, or ankles, higher score on physician and patient/parent global assessment of disease activity, pain, CHAQ and morning stiffness (Table 3).
Table 3

(abstract O18). Baseline characteristics analysed as predictors of disability eight years after disease onset

Clinical Characteristics

N

CHAQ/HAQ =0

CHAQ/HAQ >0

OR (95%CI)

p

Cumulative active joint count

352

3 (1-6)

5 (2-9)

1.1 (1.0-1.1)

0.001

Physician GA, VAS

210

1.0 (0.3-2.0)

2.0 (0.7-4.3)

2.5 (1.5-4.0)

< 0.001

Symmetric wrist arthritis, n (%)

351

28 (50.0)

28 (50.0)

2.5 (1.4-4.5)

0.002

Symmetric finger arthritis, n (%)*

351

20 (39.2)

31 (60.8)

4.2 (2.3-7.8)

< 0.001

Symmetric ankle arthritis, n (%)

351

50 (57.5)

37 (42.5)

1.9 (1.1-3.1)

0.02

CHAQ- score at baseline

239

0.1 (0.0-0.9)

0.6 (0.0-1.4)

2.0 (1.4-3.0)

0.001

Patient/parent GA, VAS

234

0.7 (0.0-2.3)

2.0 (1.0-4.0)

2.3 (1.5-3.6)

< 0.001

Pain VAS

231

0.7 (0.0-2.3)

2.7 (1.0-5.0)

3.2 (2.0-5.0)

< 0.001

Morning stiffness > 15 min, n (%)

276

41 (41.4)

58 (58.6)

5.2 (3.0-8.9)

<0.001

Values are the median (IQR) unless otherwise indicated; OR, odds ratio; CI, confidence interval. * Symmetric finger arthritis: bilateral arthritis in 1 or more of the 14 finger joints; GA, global assessment; VAS, visual analogue scale range 0-10

Conclusion: A higher cumulative joint count, and specifically symmetric arthritis in finger joints, morning stiffness and higher pain score, higher patient/parent and physician global VAS score at baseline, predicts functional disability eight years after disease onset in a population-based Nordic JIA cohort.

Disclosure of Interest: None Declared.

O19 What is the outcome of juvenile idiopathic arthritis in adulthood? The monocentric experience of 414 patients followed in a transition tertiary clinic of rheumatology

Irene Pontikaki1,2,3, Lorenza Maria Argolini4, Tania Ubiali4, Maria Gerosa2,3, Carolina Artusi4, Marcello Truzzi5, Roberto Viganò6, Antonella Murgo2,3, Orazio De Lucia2,3, Pierluigi Meroni2,3

1Center of Pediatric Rheumatology, Milan, Italy; 2Rheumatology, ASST Pini/CTO, Milan, Italy; 3Chair of Rheumatology, Milan, Italy; 4Rheumatology, University of Milan, Milan, Italy; 5Rheuma Surgery, Milan, Italy; 6Division of Rheumatoid Arthritis Surgery, ASST Pini/CTO, Milan, Italy
Correspondence: Irene Pontikaki

Introduction: Juvenile Idiopathic Arthritis (JIA) is a chronic inflammatory disease that affects children and adolescents and shows many differences in clinical manifestations, assessment and management compared to adult-onset arthritis. The transition from the child-centered to the adult-oriented care is a challenging multidimensional process that emphasizes a lot of aspects that need to be addressed.

Objectives: To describe the long-term outcome of JIA.

Methods: Four-hundred and fifteen patients affected by JIA and referred to a transition care rheumatology tertiary centre were considered between 1999 and 2016. The outcome assessment included disease activity, mean disease duration, medications, number of prosthesis implantation, pregnancies, mortality, social integration (mobility, employment status and educational level).

Results: A hundred and twenty (28.9%) males and 294 (71%) females were included; 58 (14%) patients were lost to follow up. The median age of the patients was 25 (18-57) years, the median age at onset was 9 years and the average disease duration was 17 years. Subtypes of JIA at disease onset included oligoarthritis 212 (51.2%), polyarthritis 98 (23.6%), systemic arthritis 51 (12.3%), psoriatic arthritis 11 (2.7%), enthesitis related arthritis 41 (9.9%) and undifferentiated arthritis 1 (0.2%). Seventy-one (17.1%) patients had persistent uveitis. Eighty-five implant prosthesis and 15 arthrodesis were recorded. Sixty-eight patients (16.4%) were also referred to the ultrasonography-guided infiltration clinic, to receive either intrarticular steroids or hyaluronic acid. At follow up 180 (43.5%) had low active disease activity, 84 (20.3%) had moderate disease activity, 14 (3.4%) had a high disease activity, 72 (17.4%) were on remission on medication and 64 (15.5%) off medication. Among the 350 patients still on medication, 75 (21.4%) were under treatment with oral steroids, 200 (57.1%) with sDMARDs and 225 (64.3%) with bDMARDs. Five deaths (1.2%) occurred in this cohort. A hundred and eighty-one (43.7%) subjects had a higher educational level (university), 294 (71%) had an employment, 243 (58.7%) obtained a driving license. Twenty-one (5.1%) pregnancies were registered. The transition age was considered after the age of sixteen years old. Particular attention was brought to the multidisciplinary approach towards each patient, that was realized with the collaboration of other specialists (ophthalmologist, orthopedic, dermatologist, gastroenterologist, obstetric and psychologist).

Conclusion: In the era of biologic therapy the long-term outcome of JIA underwent an outstanding improvement regarding a lot of variables. Two hundred and twenty-five (54.3%) patients were still on tight control, not only because of the continuation of the biological therapy, but also owing to the multidisciplinary care carried out even during remission. JIA often persists over the adulthood, therefore the long term follow-up and care of these patients needs to be conducted by a rheumatologist expertized in JIA in collaboration with other specialists.

Disclosure of Interest: None Declared.

O20 Identification of novel antibodies predictive of the development of uveitis in jia using high-density nucleic acid programmable protein arrays

Madeleine Rooney1, David Gibson2, Ji Qui3, Sorcha Finnegan1, Joshua Labaer3

1Center Experimental Medicine, Queens University Belfast, Belfast, United Kingdom; 2NI Centre of Stratified Medicine, Ulster University, Londonderry, United Kingdom; 3Center for Personalized Diagnostics, Arizona State University, Tempe, AZ United States
Correspondence: David Gibson

Introduction: Currently all children with oligo and polyarticular JIA have to be screened by ophthalmologists for years in order to ensure that this completely asymptomatic disease is not missed. If missed or inadequately treated, some 50% of these children can go functionally blind. The only useful biological marker currently available is ANA status. However this is neither sensitive nor specific enough to significantly alter regular clinical screening. It does however suggest that autoantibodies, as yet undiscovered, may be important in the pathophysiology of this disease.

We undertook this proof of concept study to see whether a novel technique capable of producing multiple proteins could be used to screen for autoantibodies that are associated with uveitis development in JIA patients. This could enable us to identify children, at the time of diagnosis of arthritis, who are highly likely to develop uveitis.

Objectives: To Identify novel antibodies that predict the development of uveitis in children with JIA.

Methods: Nucleic Acid Programmable Protein Arrays (NAPPA) enable the in situ production of multiple proteins from DNA templates which are immobilised on a solid phase. Methodology is described in detail elsewhere [1]. NAPPA slides with 2200 genes were produced. Pubmed search identified ~60 genes associated with uveitis pathology and ~30 genes associated with arthritis development. The remaining ~2100 genes were randomly identified from a ~12000 human gene collection (http://dnasu.asu.edu). The arrays were then probed using plasma from JIA patients with (n = 20) and without uveitis (n = 20) and from healthy age and sex matched controls (n = 20). Proteins with higher levels of antibody detected were confirmed by ELISA.

Results: NAPPA image analysis revealed distinct signals from plasma antibodies of JIA patients with Uveitis which had reacted with specific array proteins. Hierarchical clustering heat maps were used to visualize clusters of proteins with higher array reactivity for JIA or Uveitis samples, realtive to controls. ELISA's were developed for nine highly reactive proteins including BATF, FO5, PROSAPIP1, CCND1, NOUFV3 and SSB. Antibodies specific for single-stranded DNA-binding proteins (SSB) were confirmed to be at significantly higher concentrations in the plasma of JIA patients with uveitis, relative to JIA patients without eye disease.

Conclusion: These results indicate that the NAPPA technique is a sensitive tool for screening antigens including specific nuclear antigens which distinguish JIA patients with uveitis. We plan on developing a nuclear antigen array with over 2000 features to determine further uveitis patient reactivity. Prospective studies are also required to establish if these immunoglubulins are present at detectable levels in JIA patients prior to development of uveitis and to assess their predictive utility.

Reference

[1]: Bian, X., Wiktor, P., Kahn, P., Brunner, A., Khela, A., Karthikeyan, K., Barker, K., Yu, X., Magee, M., Wasserfall, C. H., Gibson, D., Rooney, M. E., Qiu, J., and LaBaer, J. (2015) Antiviral antibody profiling by high-density protein arrays. Proteomics 15, 2136–2145

Disclosure of Interest: None Declared.

O21 New onset uveitis in patients with juvenile idiopathic arthritis under biological therapy

Irina Nikishina1, Olga Kostareva1, Maria Kaleda1, Svetlana Rodionovskaya1, Svetlana Arsenyeva1, Anna Shapovalenko1, Ekaterina Denisova2

1Pediatric, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation; 2Pediatric, Helmgoltz Moscow Research Institute of Eye Diseases, Moscow, Russian Federation
Correspondence: Irina Nikishina

Introduction: Biological agents (BA), especially TNF inhibitors, are high efficacy options for current therapy for patients (pts) with juvenile idiopathic arthritis (JIA). They are successfully used not only for the arthritis but also for JIA-associated uveitis, however, development of uveitis de novo in pts treated with BA is a well-established paradoxical adverse event.

Objectives: to evaluate the frequency of new onset (no-) uveitis, occurring under BA therapy in JIA pts, to establish clinical features, which may be associated with development of such phenomenone.

Methods: retrospective cohort study involved all JIA pts (760) who were treated with BA in our clinic from 2004 to 2017. All cases of no-uveitis were collected for the describing of their clinical features in disease onset and course, activity level, JIA category, exposure to Methotrexate (MTX) and BA, presence of ANA, HLA B27.

Results: among of 760 pts treated with different BA we identified 22 (2.9%) pts (12 female/10 male) with no-uveitis under BA, mostly during etanercept (ETA) therapy (22 cases from 302 ETA courses, 6.6%), 1/120 - in abatacept (ABA) and 1/249 - in adalimumab (ADA). There are no cases of no-uveitis under other BA Frequency of no-uveitis is much higher in ETA group (2.46 events per 100 patient-year (PY) vs 0.31 in ABA, and 0.15 in ADA. ETA exposure was 14.7 ± 9.7 months (mo).. A case of no-uveitis under ABA was observed after 5 mo of therapy in a girl previously treated with infliximab. 1 boy with early JIA onset (in age of 18 mo) developed no-uveitis after 71 mo of ADA 71 mo simultaneously with general response decreasing and successfully switched to ABA. JIA subtypes were as follows: RF-neg polyarthritis 6 (27%), persistent oligoarthritis 3 (14%), extended oligoarthritis 11 (50%), enthesitis-related arthritis (ERA) - 2 (9%). Average age at JIA onset was 4.5 ± 3.9 yrs. 19/22 patients had high laboratory activity (CRP 54 ± 23 mg/l; ESR 41 ± 19 mm/h) and severe arthritis before BA initiation. However most of pts (18/22) achieved 90-100% ACRpedi-response by the uveitis development. 14/22 pts were ANA-positive, 11/22 pts had HLAB27, including 3 pts who had the both features. Uveitis was occurred earlier in ANA plus HLAB27 positive pts (mean exposure - 10.7 mo) than in only ANA-positive or HLAB27-positive pts (27.4 mo and 21.6 mo accordingly). 19/22 (86%) of pts received methotrexate (MTX) in mean dosage 11.5 mg/m2/week. There are no differences in time of uveitis development depending of MTX. In all cases of no-uveitis BA was switched.

Conclusion: Our study suggested that new onset of uveitis is rare adverse event during BA therapy in JIA without any known predisposing risk factors.. Such paradoxical effects may reflect not so much therapy complications, but the delayed implication of natural character of disease. Development of no- uveitis is more often observed in pts receiving ETA, especially in pts with early age of JIA onset. High activity aggressive manifestations at the disease onset and good initial response to BA are typical features for all pts, who developed this paradoxical effect under BA therapy.

Disclosure of Interest: None Declared

O22 Microparticles as potential biomarkers of disease activity in anti-neutrophil cytoplasmic antibody – associated vasculitis

Milena Kostić1, Fariborz Mobarrez2, Jelena Vojinović1, Iva Gunnarsson2, Aleksandra Antović2

1Department of Pediatrics, Clinical Center, Nis, Serbia; 2Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden
Correspondence: Milena Kostić

Introduction: Microparticles (MPs) are irregularly shaped submicron vesicles, which are released from plasma membrane upon cell activation and during the early phase of apoptosis. Increased levels of circulating MPs (mainly of endothelial cell origin, but also platelet derived) correlates with autoinflammatory disease activity, such as anti-neutrophil cytoplasm antibody (ANCA) – associated vasculitis (AAV).

Objectives: To evaluate levels of activity markers expressed on surface of MPs, during active disease and remission, compared to healthy control subjects.

Methods: Our study included 48 AAV patients (24 with active and 24 with inactive disease) and 23 healthy control subjects (age and gender matched). We analyzed the number and phenotype of MPs in plasma identified by flow cytometry, via labeling with following monoclonal antibodies: CD142 (tissue factor-TF), anti-H3cit (citrulinated H3 directed against neutrophil extracellular traps-NETs), anti-pentraxin3 (pentraxin3), HMGB1 (high mobility group box 1 protein-HMGB1), anti-TWEAK (tumor necrosis factor-like weak inducer of apoptosis-TWEAK), anti-plasminogen (plasminogen), anti-C3a (C3a) and anti-C5a (C5a). The assessment of vasculitis disease activity was performed using the Birmingham Vasculitis Activity Score (BVAS), while active disease was defined as BVAS ≥1 and inactive (remission) as BVAS = 0. Statistical analysis was performed using GraphPed software.

Results: Half of the patients group (24) had active vasculitis (mean BVAS 6,69 ± 8,76) and 24 had inactive disease. Plasma levels of MPs expressing TF, NETs, pentraxin3 and HMGB1 in active patients were significantly higher than in those in remission and healthy controls (p < 0.01, p < 0.0001, respectively). MPs expressing C5a and C3a were significantly higher in both patients groups compared to controls (p < 0.001). Additionally, levels of MPs expressing C5a strongly correlated with BVAS (r = 0.78, p < 0.0001), while there was no significant correlation between other explored markers and BVAS. Data presented in Table 4.
Table 4

(Abstract O22). Microparticles (MPs) levels in AAV patients with active or inactive disease and healthy controls

 

Active AAV

Inactive AAV

Healthy controls

p-value (respectively)

median

IQR

median

IQR

median

IQR

Tissue factor

265

247

174

107

105

84,5

p < 0.01* p < 0.001**

NETs

112

24

103

18

44

35

p < 0.05* p < 0.0001** p < 0.001***

Pentraxin3

1332

1810

347

294,5

184

146,5

p < 0.01* p < 0.0001** ns***

HMGB1

684

452,5

380

258

77

61,5

p < 0.01* p < 0.001** p < 0.001***

TWEAK

131

83

141

102,5

67

53

ns* p < 0.0001** p < 0.05***

Plasminogen

86

23

89

23

44

33,5

ns* p < 0.001** p < 0.01***

C3a

201

91

147

87

89

72

ns* p < 0.001** p < 0.05***

C5a

131

86,5

111

65

51

30

ns* p < 0.001** p < 0.01***

*between active and inactive, ** between active and controls, ***between inactive and controls

Conclusion: Our results support recently postulated potential role of complement system in AAV pathogenesis and disease activity. Evaluated proteins expressed on MPs, especially C5a, could be used as potential biomarkers which might reflect inflammation and disease activity in AAV patients. Further investigations are necessary to confirm our preliminary results and to validate the most promising biomarker in AAV.

Disclosure of Interest: None Declared.

O23 Plasmalemma vesicle-associated protein 1 (pv-1) as a marker of active disease in childhood vasculitis.

Andrea Taddio1, Sarah Abu Rumeileh2, Claudia Bracaglia3, Luigina De Leo4, Rebecca Nicolai3, Fabrizio De Benedetti3, Alberto Tommasini4, Samuele Naviglio4, Serena Pastore4, Alessandro Ventura1, Tarcisio Not1

1Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" - and University of Trieste, Trieste, Italy; 2University of Trieste, Trieste, Italy; 3Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; 4Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" -, Trieste, Italy
Correspondence: Andrea Taddio

Introduction: The endothelial protein Plasmalemma Vesicle-associated protein 1 (PV-1) is the main component of stomatal and fenestral diaphragms of blood vessels. It regulates permeability, leukocyte migration and angiogenesis [1]. Considering the central role of the endothelium in vasculitis pathogenesis and the lack ofspecific biomarkersfor the clinical diagnosis and management of this group of complex disorders, we have investigated the levels of PV-1 among children with vasculitis and their association with disease activity or remission.

Objectives: To determine, for the first time, serum levels of endothelial protein PV-1 in a population of patients with vasculitis and healthy controls and possibly to assess the role of PV-1 to serve as a diagnostic biomarker in vasculitis disorders in childhood and/or to monitor disease activity and severity.

Methods: A case-control matched for age study was conducted including 62 healthy young people and 35 children with active vasculitis and other inflammatory diseases with vascular involvement: 18 patients with Pediatric Systemic Lupus Erythematosus (pSLE), 9 with Juvenile Dermatomyositis (JDM), 2 with Kawasaki Disease, 2 with leukocytoclastic vasculitis, 2 glomerulonephritis, 1 Central Nervous System Vasculitis, 1 Henoch-Schönlein Purpura (HSP). PV-1 serum levels were also measured in 9 children in clinical remission (2 SLE, 2 JDM, 3 HSP, 1 Kawasaki disease, 1 Hughes-Stovin Syndrome). Measurement of PV-1in blood serum (expressed in ng/ml) was performed using ELISA assay following the manufacturer’s (Biomatik) instructions.

Results: Patients with active disease showed significantly higher concentrations of PV-1 than healthy controls (p < 0.001) and patients with inactive disease (p < 0.001) (Table 5). Optimal serum PV-1 cut-off to identify patients with active vasculitis was found to be 0.78 ng/ml, which achieved on receiver operating characteristic (ROC) curve analyses an accuracy of 0.90, with 74% sensitivity and 92% specificity. Different diseases did not show significant differences regarding levels of PV-1.
Table 5

(abstract O23). See text for description

Patients

Controls N = 62

Acute Vasculitis N = 35

Remission vasculitis N = 9

PV – 1 (ng/ml) Median (interquartile range)

0.221 (0.082 – 0.436)

1.818 (0.746– 3.970)

0.316 (0.203 – 0.606)

p value

 

< 0.001

< 0.001

Conclusion: PV-1 could represent a specific marker of disease activity in vasculitis disorders in childhood.

1. Guo L, Zhang H, Hou Y, et al. Plasmalemma vesicle–associated protein: A crucial component of vascular homeostasis (Review). Exp Ther Med 2016; 12:1639–44.

Disclosure of Interest: None Declared.

O24 Takayasu arteritis in childhood: retrospective experience from a tertiary referral center in South India

Sathish Kumar1, Ruchika Goel2, Debashish Danda2

1Pediatric Rheumatology, Department of Pediatrics, Christian Medical College, Vellore, India; 2Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, India
Correspondence: Sathish Kumar

Introduction: Takayasu arteritis (TAK) is an idiopathic large-vessel vasculitis affecting the aorta and its major branches. Although the disease rarely affects children, it does occur, even in infants. The untreated inflammation often leads to narrowing or ectasias of aorta and its direct branches with or without pulmonary and coronary involvement. It’s a rare medical condition but we in our tertiary care center have collected the second largest single center series of patients over the past 16 years.

Objectives: To evaluate the clinical features, disease activity, treatment and outcome of childhood TAK in a tertiary center in South India

Methods: We analyzed a retrospective case series of children fulfilling the TAK classification criteria of the European League against Rheumatism and the Paediatric Rheumatology European Society. Data has been collected in a retrospective manner from our institute’s electronic medical records (EMR) for childhood onset TAK. Data regarding demographics, clinical features, treatments, and outcomes were recorded. Baseline data including age, gender, disease duration, angiographic type, the extent of clinical disease using DEI.Tak, CRP, and ESR were collected. Disease activity was assessed by a composite clinical score namely ITAS-A (CRP). At each visit, active disease was defined as

1. Clinical activity by the presence of any one of the following:

1a. ITAS ≥ 2 (not attributable by in-stent restenosis) or

1b. ITAS-A (CRP) ≥ 3, but at least one point should be contributed by clinical criteria as in ITAS proforma

2. Activity by imaging by presence of de Novo lesion on follow-up angiography or stenosis of the same vessel extending beyond stent margins

3. Laboratory criteria of activity were defined by persistently raised CRP as well as ESR on 2 consecutive visits without any alternative explanation like infection

Results: 100 children with juvenile-onset TAK were included in this study over the past 16 years. Out of 100 children with TAK, 30 were male and 70 were female. Median age at onset was 14 years and mean duration of delay in diagnosis was 7 months (4-24 months). The most common clinical features at presentation were pulse abnormality (67%) followed by arterial hypertension (62%), claudication (40%) and systemic symptoms like fever and fatigue (36%).

Past, present history of tuberculosis or tuberculosis after treatment was seen in 6 patients while 2 patients had been treated empirically for TB. At presentation, median ITAS 2010 score was 9 (4-15), DEI. Tak was 9 (6-13) and TADS was 7 (4-11).

The full angiographic profile was performed for 97 patients. Rest of the patients had limited area imaging. Type 5 was the commonest followed by type 4 and type 1. Aneurysms or ectasias with or without stenosis seen in 7 patients

Treatment included corticosteroids (85%), combined with MMF in most cases (51), azathioprine(15), methotrexate (9) and tocilizumab (5) were reserved for severe and/or refractory cases. Mean follow-up duration was 33 months (12-61). Delta TADS calculated in 75 patients was 0 (0-1) and last visit ITAS and ITAS-A CRP was 0 (0-1). Disease course was persistently stable in 39, relapsing in 16, persistent active in 5 children. 1 child expired during follow-up.

Conclusion: Improved awareness of TAK is essential to secure a timely diagnosis. The initial symptoms and signs are non-specific, and a high index of suspicion is needed if the diagnosis is to be made. The investigation and management of Takayasu’s disease can prove difficult.

Disclosure of Interest: None Declared.

Oral Presentations 2

O25 Single cell RNA-sequencing of bone marrow macrophages identifies a distinct subpopulation in systemic JIA with features of interferon response, endocytic vesicles and phagocytosis

Grant Schulert1, Nathan Salomonis2, Sherry Thornton1, Alexei Grom1

1Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; 2Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Correspondence: Grant Schulert

Introduction: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (SJIA), characterized by activation and expansion of cytolytic lymphocytes and macrophages with hemophagocytic properties. Recent work by us and others has shown that emergence of MAS is associated with a surge in IFN-gamma and IFN-induced chemokines; however, previous gene expression studies failed to demonstrate this IFN-induced signature in peripheral blood cells. However, prior studies in SJIA and MAS have been limited by a failure to examine key myeloid effector cells, specifically activated macrophages or histiocytes which traffic to tissue including bone marrow during MAS.

Objectives: Utilize single-cell RNA-sequencing to identify specific gene expression signatures of bone marrow macrophage populations in SJIA and MAS.

Methods: Cell sources include unused portions of bone marrow aspirates obtained as part of a diagnostic workup and interpreted as normal were obtained from the Cincinnati Children’s Hospital Immunopathology lab, as well as cells obtained from a bone marrow biopsy from a newly diagnosed SJIA patient. Macrophage single cell suspensions were obtained using cell sorting for populations expressing the monocyte and macrophage surface markers CD14 and CD163 while excluding cells expression the granulocyte/monocyte marker CD15, prior to loading onto the Fluidigm C1 Single-Cell Auto Prep System. Extracted RNA was converted into cDNA and sequenced as a pooled library, and aligned to the human Ensembl transcriptome using Kallisto through AltAnalyze version 2.1.1.

Results: Three independent control samples yielded 180 single cells which passed quality-control filtering. While there was substantial inter-individual variability, using principle component analysis and Iterative Clustering and Guide-gene Selection, a core set of approximately 1400 genes were identified that contributed to the heterogeneity of normal bone marrow macrophage population. Control macrophages formed at least three primary cellular clusters, which were distinguished based on expression of genes associated with inflammatory responses, GM-CSF signaling, and aurora B signaling. 61 single bone marrow macrophages were captured from a patient with newly diagnosed SJIA with active systemic features, arthritis, marked anemia and relative thrombocytopenia, but lacking other overt signs of MAS, who underwent bone marrow biopsy as part of the diagnostic evaluation. Expression profiles were broadly similar to control macrophages by PCA, and all macrophage clusters were represented. However, a distinct subpopulation of bone marrow macrophages from the SJIA patient was identified that exhibited markedly altered transcriptional profiles. Compared to other macrophages within the cluster, this SJIA macrophage population showed alterations in gene pathways including cellular response to interferon gamma (adjusted p = 1.35e-14), endocytic vesicle membranes (p = 8.44E-14), phagosome (p = 2.98e-9) and vesicle-mediated transport (p = 1.05E-07). These cells showed a proinflammatory gene expression signature, including significant enrichment for genes regulated by NF-kB and STAT1. This included S100A12, which is highly expressed in patients with SJIA and MAS and was markedly elevated in serum from this patient.

Conclusion: We identify a distinct subpopulation of bone marrow macrophages in an SJIA patient with features associated with emergence of MAS, including interferon response, phagocytosis and vesicular transport. This demonstrates the importance of studying these effector cells at the sites of inflammation, and suggests that tissue macrophages may be a key source of IFN-induced products during MAS. Together, these data show that single cell gene expression profiling of bone marrow macrophages can identify reproducible cellular clusters as well as potential biologically relevant subpopulations and pathways perturbed during inflammatory disorders.

Disclosure of Interest: G. Schulert Consultant for: Novartis, N. Salomonis: None Declared, S. Thornton: None Declared, A. Grom Grant/Research Support from: NovImmune, AB2Bio, Consultant for: Novartis, Juno.

O26 Adjudication of infections from the pharmacovigilance in juvenile idiopathic arthritis patients (pharmachild) treated with biologic agents and/or methotrexate with a focus on opportunistic infections

Gabriella Giancane, Joost Swart, Elio Castagnola, Andreas Groll, Gerd Horneff, Hans-Iko Huppertz, Dan Lovell, Tom Wolfs, Michael Hofer, Ekaterina Alexeeva, Violeta Panaviene, Susan Nielsen, Jordi Anton, Florence Uettwiller, Valda Stanevicha, Maria Trachana, Fabrizio De Benedetti, Constantin Ailioaie, Elena Tsitsami, Sylvia Kamphuis, Troels Herlin, Pavla Dolezalova, Gordana Susic, Berit Flato, Flavio Sztajnbok, Elena Fueri, Francesca Bovis, Francesca Bagnasco, Angela Pistorio, Alberto Martini, Nico Wulffraat, Nicolino Ruperto

Pediatria II, Reumatologia; PRINTO, Istituto Giannina Gaslini, GENOA, Italy
Correspondence: Gabriella Giancane

Introduction: Pharmachild is a pharmacovigilance registry on children with JIA treated mainly with biologics ± methotrexate (MTX). Little evidence exists in literature about the role of JIA or its immunosuppressive therapy in determining infections, especially caused by opportunistic pathogens.

Objectives: To provide an update on opportunistic infections (OI) revised by an independent Safety Adjudication Committee (SAC) (3 pediatric rheumatologists and 2 pediatric infectious disease specialists).

Methods: The participating centres were asked to report all infections encountered by their JIA patients. PRINTO and the medical monitor (MM) classified events based on MedDRA dictionary. Moderate/serious/severe/very severe infections were then revised blindly by the SAC, who were asked to answer 6 questions. The events with consensus of at least 3/5 experts on the first 3 questions (‘Is this an infection?’, ‘Is it common?’, ’Is it opportunistic?’) were retained for the analysis. With referral to the recommendations by Withrop et al. 1, for the first time a list of opportunistic infections in children with JIA on immunosuppressive therapy was elaborated and approved by consensus, through three Delphi steps.

Results: A total of 772 safety events related to 634 patients were submitted to the Safety Adjudication Committee. 689 (89.2%) events received consensus among the experts on the 3 questions and, of these, 682 (99.0%) were considered as infections, corresponding to 53 High Level Term (HLT) including 153 different Preferred Terms (PT), according to MedDRA dictionary. Among the 682 infections, 603 (88.4%) were defined by the experts as common and 119 (17.4%) as opportunistic. For 92 (60%) of the 153 PT, the MM and SAC used the same PT, while the remaining 40% was adjudicated by a third examiner, who analyzed again the case reports and assigned the PT which was the most appropriate taking into account the experts’ opinion. A final number of 52 HLT emerged and, among them, herpes viral infections, tract respiratory infections and EBV were the most frequent (Table 6). Analyzing the infections by PT, 151 different PT resulted. Of them, the experts adjudicated: 22 as OI, 117 as not OI, 8 discordant and 4 not evaluable. Comparing the experts’ adjudication with the approved list of OI by PT, there was full agreement for the 22 PT classified as OI, while 26/117 (22.2%) PT resulted in the list, but were not classified as OI by the experts.
Table 6

(Abstract O26). The most frequent HLT for the 682 infections with agreement of at least 3/5 experts on the first 3 questions. (N: number of infections)

HLT

N

%

Herpes viral infections

265

38.9

Lower and upper respiratory tract and lung infections

93

13.6

Epstein-Barr viral infections

38

5.6

Abdominal and gastrointestinal infections

32

4.7

Tuberculous infections

29

4.3

Candida infections

17

2.5

Influenza viral infections

14

2.1

Streptococcal infections

14

2.1

Salmonella infections

9

1.3

Conclusion: Our preliminary analysis showed a significant number of opportunistic infections in JIA patients on immunosuppressive therapy, which was mostly confirmed in the list of opportunistic infections approved by the experts. Further analysis on the correlation with medications is ongoing.

Disclosure of Interest: G. Giancane: None Declared, J. Swart: None Declared, E. Castagnola: None Declared, A. Groll: None Declared, G. Horneff: None Declared, H.-I. Huppertz: None Declared, D. Lovell: None Declared, T. Wolfs: None Declared, M. Hofer: None Declared, E. Alexeeva: None Declared, V. Panaviene: None Declared, S. Nielsen: None Declared, J. Anton: None Declared, F. Uettwiller: None Declared, V. Stanevicha: None Declared, M. Trachana: None Declared, F. De Benedetti: None Declared, C. Ailioaie: None Declared, E. Tsitsami: None Declared, S. Kamphuis: None Declared, T. Herlin: None Declared, P. Dolezalova: None Declared, G. Susic: None Declared, B. Flato: None Declared, F. Sztajnbok: None Declared, E. Fueri: None Declared, F. Bovis: None Declared, F. Bagnasco: None Declared, A. Pistorio: None Declared, A. Martini Grant/Research Support from: Starting from 1 march 2016 I became the Scientific Director of the G. Gaslini Hospital, therefore my role does not allow me to render private consultancies resulting in personal income. I perform consultancy activities on behalf of the Gaslini Institute for the following companies: Abbvie, Boehringer, Novartis, R-Pharm The money received for these activities are directly transferred to the Gaslini Institute's bank account., N. Wulffraat: None Declared, N. Ruperto Grant/Research Support from: The G. Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from BMS, Hoffman-La Roche, Janssen, Novartis, Pfizer and Sobi for the coordination activity of the PRINTO network. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Speaker Bureau of: Abbvie, Ablynx, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol Myers Squibb,, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, Medimmune, Novartis, Pfizer, Rpharm, Roche, Sanofi.

O27 Use of whole-body magnetic resonance to identify potential diagnostic clues in children with fever of unknown origin (FUO)

Sara Signa1, Giorgio Stagnaro2, Roberta Caorsi1, Francesca Minoia1, Paolo Picco1, Angelo Ravelli1, Gian Michele Magnano2, Maria Beatrice Damasio2, Marco Gattorno1

1U.O. Pediatria II, Instituto Giannina Gaslini, Genova, Italy; 2U.O. Radiologia, Instituto Giannina Gaslini, Genova, Italy
Correspondence: Sara Signa

Introduction: Whole-body magnetic resonance imaging (WBMRI) is a fast and accurate method to detect diseases throughout the entire body without exposure to ionizing radiation. Possible emerging applications for this technique include rheumatologic field and evaluation of fever of unknown origin (FUO).

Objectives: To evaluate the ability of WBMRI to identify significant potential diagnostic clue(PDC) in patients presenting a non specific inflammatory clinical picture.

Methods: We retrospectively collected cases of pediatric patients followed in a single pediatric rheumatology center who underwent WBMRI between January 2010 and December 2015 for the following indications: i) FUO(temperature greater than 38.3 °C for more than three weeks or failure to reach diagnosis after one week of investigations), iii) recurrent fever, iii) persistent low grade fever with evidence of elevation of acute phase reactants and/or other clinical symptoms.WBMRI studies were acquired with coronal and sagittal planes (slice thickness 5 mm) with acquisition of several image sets with automatic direct image realignment after acquisition creating a whole-body scan.Sequences include short τ inversion recovery (STIR) and T1-weighted. All studies have been evaluated twice, the second time according to a predefined checklist, defined by an experienced radiologist, considering systematically single/multifocal bone lesion, bone marrow, joint effusion, soft tissues, adenopathies, parenchymal and vessels looking for PDC.

Results: We collected 105 patients who underwent WBMRI; 24 (23%) of them presenting FUO, 29 (28%) presenting recurrent fever and 52 (49%) presenting persistent low grade fever.The mean age of onset symptoms was 7 years and seven months (range: 2 weeks old- 17 years and 6 months). The mean age of execution of WBMRI was 9 years (range: 5 months old- 19 years and one month). After the whole diagnostic work-out a final diagnosis was achieved in 34 patients (32%).

PDCs were identified at the first evaluation in 72/105 cases (68.5%) and in 29/105 cases (39%)the identified PDC was useful to the achievement of the diagnosis (7 JIA, 8 systemic infections, 4 monogenic inflammatory diseases, 3 ALPS, 2 Goldbloom’s Syndrome,2 Vasculitis,1 eosinophilic fasciitis, 1 hystiocytosis, 1 neuroblastoma).

Blind re-evaluation of WBMRI allowed the identification of additional PDCs in 51 patients (14 of them previously negative).In 8 cases the PDC found after re-evaluation were consistent with the final diagnosis (2 JIA, 2 infectious diseases,,1 neuroblastoma, 1 ALPS, 1 monogenic inflammatory disease, 1Takayasu arteritis).

Conclusion: WBMRI can be a powerful diagnostic tool in patients with FUO. A predefined checklist increase sensitivity of WBMRI in the identification of PDC.

Disclosure of Interest: None Declared.

O28 Usefulness of magnetic resonance imaging in early assesment of low back pain with possible inflammatory cause in children

Lovro Lamot1,2, Mandica Vidovic1, Matej Mustapic1, Mirta Lamot1, Ivana Rados1, Karla Rubelj1, Miroslav Harjacek1,2

1Clinical Hospital center Sestre Milosrdnice, Zagreb, Croatia; 2Univeristy of Zagreb School of Medicine, Zagreb, Croatia
Correspondence: Lovro Lamot

Introduction: Low back pain (LBP) is a common complaint in adults that often begins in childhood. Despite the increasing frequency, it is estimated only 24% of children with LBP visit a doctor. Nevertheless, those patients are often seen in pediatric rheumatology clinic. Although most of the LBP cases after exclusion of trauma are caused by benign musculoskeletal disease, a history of sacroiliac (SI) joint tenderness and/or inflammatory lumbosacral (LS) pain is one of the ILAR classification criteria for enthesitis related arthritis (ErA), a form of juvenile idiopathic arthritis (JIA) that includes most of the patients with juvenile spondyloarthritis (jSpA). Recognition of jSpA particularly early in the course of the disease represents a unique set of challenges and therefore all of the patients with inflammatory back pain (IBP) and arthritis or enthesitis should be suspected for jSpA with possible involvement of SI and other vertebral joints. Since magnetic resonance imaging (MRI) is the preferred method of assessment both for axial inflammation and other possible musculoskeletal, infectious and malignant causes of LBP in children, it might be advisable to use it in the initial assessment of suspected IBP in children.

Objectives: To evaluate the usefulness of early MRI in discovering inflammation of spinal joints and other possible causes of LBP in children with suspected IBP not fulfilling ILAR classification criteria for ErA at the time of investigation.

Methods: Thirty five children referred to our pediatric rheumatology clinic due to LBP lasting for more than three months, who meet ASAS criteria for IBP and had SI joint tenderness and positive FABRE test on physical examination, participated in the study. Their average age was 14.2 years (6-18) and 11 (31.4%) of them were boys. Five study participants (14.3%) had arthritis and 19 (54.3%) had enthesitis confirmed by physical examination and ultrasound, but none of them meet ILAR criteria for ErA at the time. Twelve (out of 15) were HLA-B27 positive and 13 (37.1%) had a history of SpA related disease in a first degree relative. One of the patients had a diagnosis of ulcerative colitis (UC), and one of psoriasis. All of the participants had normal CBC and CRP values, with negative ANA and RF. None had neurological symptoms. Contrast enhanced MRI of SI joints and thoracolumbar spine was performed according to recommended protocols for the assesment of inflammatory changes within one week after initial visit on a 1.5 T machine and interpreted by experienced musculoskeletal radiologist.

Results: Nineteen (54,3%) patients had various pathological findings detected by MRI. Four (11,4%) had signs of inflammation with one having an active sacroiliitis according to ASAS criteria. Schmorl nodes were discovered in six patients and three of them, including one with the signs of inflammation, had Scheuermann disease. Two patients had stress reaction in LS region. Five patients had incipient degeneration of intervertebral discs. Three patients had disc protrusion without and one with radial nerve compression. After three months of follow up, 19 patients (54.3%) meet ILAR criteria for ErA, one for psoriatic arthritis and one, who also had UC, meet criteria for undifferentiated arthritis.

Conclusion: Differential diagnosis of LBP in children is very wide and it is difficult to distinguish inflammatory and other causes upon the first encounter with pediatric rheumatologist based on history and physical examination alone. In our study, all of the patients with LBP had some characteristics of IBP and ErA, while definite diagnosis of jSpA was subsequently established in almost 60% of the patients. Interestingly, 20% of them already had inflammatory changes of LS and SI joints discovered by MRI, while many others had signs of other LBP causes. Therefore, MRI performed early after referral to pediatric rheumatologist, in all children with suspected IBP, can be very useful in elucidating the cause of LBP and differentiation of those who need only symptomatic relief, orthopedic consultation or further follow up in pediatric rheumatology clinic. High cost of this approach can be justified with the benefit of early therapeutic intervention in those with established axial inflammation and the avoidance of unnecessary treatment in those with other causes.

Disclosure of Interest: None Declared.

O29 Efficacy and safety of Canakinumab in patients with HIDS/MKD: results from the pivotal phase 3 cluster trial

Joost Frenkel1, Jordi Anton2, Philip Hashkes3, Marco Cattalini4, Tamas Constantin5, Avi Livneh6, Bernard Lauwerys7, Susanne Bensler8, Paivi Miettunen9, Tillman Kallinich10, Jasmin Kummerle-Deschner11, Yankun Gong12, Eleni Vritzali13, Guido Junge13, Fabrizio De Benedetti14, Anna Simon15

1University Medical Center Utrecht, Utrect, Netherlands; 2Hospital Sant Joan de Déu, Barcelona, Spain; 3Shaare Zedek Medical Center, Jerusalem, Israel; 4Pediatric Clinic, University of Brescia and Spedali Civili di Brescia, Brescia, Italy; 5Department of Pediatrics, Semmelweis Egyetem, Budapest, Hungary; 6Department of Medicine, Sheba Medical Centre, Tel-Hashomer, Ramat-Gan, Israel; 7Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels, Belgium; 8Department of Paediatrics, Alberta Children's Hospital, University of Calgary, Alberta, Canada; 9Alberta Children’s Hospital Research Institute Calgary, Calgary, Canada; 10Charité, Humboldt University, Berlin, Germany; 11University Hospital Tuebingen, Tuebingen, Germany; 12Novartis Pharma, Shanghai, China; 13Novartis Pharma AG, Basel, Switzerland; 14IRCCS Ospedale Pediatrico Bambino Gesú, Rome, Italy; 15Radboud University Medical Centre, Nijmegen, Netherlands
Correspondence: Joost Frenkel

Introduction: Canakinumab (CAN), a fully human, specific, anti-interleukin-1β monoclonal antibody, has been shown to be efficacious in reducing the frequency of flares and improving clinical symptoms in patients (pts) with hyper immunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD)1.

Objectives: Primary objective was to demonstrate that CAN 150 mg every 4 weeks (q4w) was superior to placebo (PBO) in resolving flare by Day 15 with no new flares over 16 weeks (wks). Secondary objectives included: proportion of pts who maintained optimal control of disease activity (absence of new flares) between Wk 16 and Wk 40 after dose prolongation; evaluation of pharmacokinetics (PK), pharmacodynamics (PD) and safety of CAN in the HIDS/MKD pts.

Methods: The study comprised 4 epochs (E1-4): The study design has been reported earlier2. In E2, HIDS/MKD pts were randomised (1:1) to CAN 150 mg every 4 wks (q4w) or PBO. Pts who did not flare in E2 in the CAN group were rerandomised to CAN 150 mg q8w or PBO/CAN withdrawal in E3. In E3, dose could be escalated up to 300 mg q4w for pts with a flare. For PK/PD assessments, CAN concentrations and total IL1β at baseline (Day 1), and trough concentrations at Wk 16 were assessed. Safety assessments included adverse events (AEs) and serious AEs (SAEs).

Results: Of the 72 HIDS/MKD pts randomised to CAN 150 mg q4w (n = 37) or PBO (n = 35) in E2, 3 discontinued the study (2 PBO, 1 CAN). The proportion of responders at Wk 16 was significantly higher with CAN vs PBO (`). In E3, 13 (CAN E2 responders) were re-randomised to CAN 150 mg q8w or PBO while 53 pts completing E2 received open-label CAN treatment. In E3, the proportion of pts who did not present new flares was numerically higher in the CAN vs PBO group (Table 7). 22.7% of the HIDS/MKD pts, including pts treated in open-label maintained disease control with a prolonged dosing interval (q8w) till Wk 40. 22.7% required uptitration back to original dose 150 mg q4w while 28.8% pts required uptitration to 300 mg q4w. No new safety findings or deaths were reported in CAN treated pts through E3 (Table 7). The serum clearance and steady state volume of distribution of CAN (liquid in vial) varied according to body weight, and were estimated to be 0.14 ± 0.04 L/day and 4.96 ± 1.35 L, respectively. The estimated half-life of CAN was 25 ± 6.4 days. Total IL-1β serum concentrations showed dose proportional increase.
Table 7

(Abstract O29). Efficacy results and summary of safety

 

PBO N = 35

CAN 150 mg q4w N = 37

p-value

Proportion of responders at Wk 16 (E2), n (%)

2 (5.7)

13 (35.1)

<0.002*

Proportion of patients with no new flare at Wk 40 (E3), n (%)

PBO N = 7

CAN 150 mg q8w N = 6

p-value

1 (14.3)

3 (50.0)

0.2168

Safety

 

PBO N = 35

Any CAN*, E2 N = 68

Any CAN*, E2 + E3 N = 71

Exposure to CAN, pyr

3.2

19.1

51.0

Number of AEs (AE rate/100 pyr)

59 (1818.5)

251 (1313.6)

613 (1201.2)

Number of SAEs (SAE rate/100 pyr)

4 (123.3)

11 (57.6)

20 (39.2)

*Indicates statistical significance (one-sided) at the 0.025 level. #Any patient who received a dose of CAN during E2 or E3

n = number of patients who responded; N = number of patients evaluated for response. AE, adverse event; CAN, canakinumab; E, epoch; PBO, placebo; q4w, every 4 weeks pyr, patient-years; SAE, serious AE ; Wk, week

Conclusion: CAN (150 mg q4w) was efficacious in resolving flare by Day 15 and preventing new flares in HIDS/MKD patients over 16 weeks. Approximately 23% pts did not flare with a prolonged dose interval (q8w) at the end of E3 compared to 14% pts who did not flare when CAN was completely withdrawn. No new safety issues were reported over 40 weeks of treatment; the safety profile was not distinct from previous controlled studies. The PK/PD results observed with the liquid-in-vial form of CAN were similar to those observed in CAPS and SJIA.

1. Arostegui JI, et al Arthritis Rheumatol. 2015;67(S10). 2. De Benedetti F, et al. Ann Rheum Dis. 2016;75(Suppl2):615.

Trial registration identifying number: NCT02059291

Disclosure of Interest: J. Frenkel Grant/Research Support from: Novartis and SOBI, J. Anton: None Declared, P. Hashkes Grant/Research Support from: Novartis, M. Cattalini: None Declared, T. Constantin: None Declared, A. Livneh: None Declared, B. Lauwerys: None Declared, S. Bensler Consultant for: Novartis, SOBI, AbbVie, P. Miettunen: None Declared, T. Kallinich: None Declared, J. Kummerle-Deschner Grant/Research Support from: Novartis, Consultant for: Novartis, SOBI, Baxalta, Y. Gong Employee of: Novartis, E. Vritzali Employee of: Novartis, G. Junge Employee of: Novartis, F. De Benedetti Grant/Research Support from: Pfizer, AbbVie, Roche, Novartis, Novimmune and BMS, A. Simon Grant/Research Support from: Novartis, Xoma/Servier, CSL Behring, Consultant for: Novartis, Takeda, SOBI, Xoma.

O30 Efficacy, safety, pharmacokinetics and pharmacodynamics of Canakinumab in patients with traps: results from the pivotal phase 3 cluster trial

Marco Gattorno1, Ryoki Hara2, Anna Shcherbina3, Laura Obici4, Segundo Bujan5, Gerd Hoerneff6, Anette Jansson7, Riva Brik8, Itzhak Rosner9, Alberto Tomassini10, Yankun Gong11, Eleni Vritzali12, Guido Junge12, Fabrizio De Benedetti13, Helen Lachmann14

1Pediatric Rheumatology, G. Gaslini Institute, Genoa, Italy; 2Yokohama City University, Yokohama, Japan; 3Clinical immunology Department, Center of Children's Hematology n.a. D. Rogachev, Moscow, Russian Federation; 4Amyloidosis Research and Treatment Centre, Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 5Vall d'Hebron Hospital, Barcelona, Spain; 6Asklepios Clinic, Sankt Augustin, Munich, Germany; 7Department of Rheumatology & Immunology, Dr. von Hauner Childrens Hospital, Ludwig-Maximilians-University, Munich, Germany; 8Meyer Children's Hospital, Rambam Medical Center, Haifa, Israel; 9Rheumatology, Bnai-Zion Medical Center, Rappaport Faculty of Medicine. Technion, Haifa, Israel; 10Institute for Maternal and Child Health- IRCCS “Burlo Garofolo”, Trieste, Italy; 11Novartis Pharma, Shanghai, China; 12Novartis Pharma AG, Basel, Switzerland; 13IRCCS Ospedale Pediatrico Bambino Gesú, Rome, Italy; 14UK National Amyloidosis Centre, University College London, London, United Kingdom
Correspondence: Marco Gattorno

Introduction: Interleukin (IL)–1β is known to be a key cytokine in the pathogenesis of tumour necrosis factor receptor associated periodic syndrome (TRAPS).1 Canakinumab (CAN) is a fully human monoclonal antibody that specifically neutralises the activity of IL–1β.

Objectives: The primary objective was to demonstrate that canakinumab (CAN)150 mg every 4 weeks (q4w) is superior to placebo (PBO) in achieving a clinically meaningful response [resolution of flare at Day 15 and no new disease flares over 16 weeks (wks) of treatment] in TRAPS patients (pts). Secondary objectives included: the proportion of pts who maintained optimal control of disease activity (absence of new flares) between Wk 16 and Wk 40 after dose reduction; evaluation of pharmacokinetics (PK), pharmacodynamics (PD) and safety of CAN in TRAPS pts.

Methods: The study comprised 4 epochs: a 12-wk screening epoch (E1), a 16-wk randomised treatment epoch (E2), a 24-wk randomised withdrawal epoch (E3) and a 72-wk open-label treatment epoch (E4). TRAPS pts with a flare during E1 were randomised in E2 to receive CAN 150 mg q4w or PBO. Pts who did not flare in E2 in the CAN group were re-randomised to CAN 150 mg q8w or PBO/CAN withdrawal in E3. In E3, for pts with a flare, dose could be escalated up to 300 mg q4w. For PK/PD assessments, CAN concentrations and total IL-1β at baseline (Day 1), and trough concentrations at Wk 16 were assessed. Safety assessments included adverse events (AEs) and serious AEs (SAEs).

Results: Of the 46 TRAPS pts randomised to CAN 150 mg q4w (n = 22) or PBO (n = 24) in E2, 2 pts in the PBO group discontinued the study. The proportion of responders at Wk 16 was statistically higher with CAN vs. PBO (Table 8). In E3, 9 (CAN E2 responders) were re-randomised to CAN 150 mg q8w or PBO while remaining pts completing E2 received open-label treatment. In E3, the proportion of pts with no new flare was numerically higher in the CAN vs PBO group (Table 8). 53.3% of the TRAPS pts, including pts treated in open-label maintained disease control with a prolonged dosing interval (q8w) till Wk 40. While 8.3% pts were up-titrated to 300 mg q4w. No new safety findings or death were reported in CAN treated pts through E3 (Table 8). The serum clearance and steady-state volume of distribution of CAN varied according to body weight, and were estimated to be 0.14 ± 0.04 L/day and 4.96 ± 1.35 L, respectively. The estimated half-life of CAN was 25 ± 6.4 days. Total IL-1β serum concentrations showed dose proportional increase.
Table 8

(Abstract O30). Efficacy and summary of safety

 

CAN 150 mg q4w N = 22

PBO N = 24

p-value

Proportion of responders at Wk 16 (E2), n(%)

10 (45.5)

2 (8.3)

0.005*

Proportion of patients with no new flare at Wk 40 (E3), n(%)

CAN 150 mg q8w N = 4

PBO N = 5

p-value

3 (75.0)

2 (40.0)

0.3571

Safety

 

PBO (N = 24)

Any CAN*, E2 (N = 43)

Any CAN*, E2 + E3 (N = 61)

Exposure to CAN, pyr

2.0

12.1

39.2

Number of AEs (AE rate/100 pyr)

34 (1698.8)

112 (925.7)

265 (676.2)

Number of SAEs (SAE rate/100 pyr)

1 (50.0)

3 (24.8)

5 (12.8)

*Indicates statistical significance (one-sided) at the 0.025 level. #Any patient who received a dose of CAN during E2 or 3.

n = number of patients who responded; N = number of patients evaluated for response. AE, adverse event; CAN, canakinumab; E, epoch; PBO, placebo; q4w, every 4 weeks pyr, patient-years; SAE, serious adverse event; W, week

Conclusion: CAN (150 mg q4w) was efficacious in resolving flare by Day 15 and preventing new flares in TRAPS patients over 16 weeks. The prolonged dose interval (150 mg q8w) was sufficient to maintain disease control in approximately 50% TRAPS patients at the end of epoch 3. No new safety issues were reported over 40 weeks of treatment; the safety profile was not distinct from previous controlled studies. The PK/PD results observed with the liquid-in-vial form of CAN were similar to those observed in CAPS and SJIA.

1.Gattorno M, et al. Ann Rheum Dis. 2016;76(1):1738

Trial registration identifying number: NCT02059291

Disclosure of Interest: M. Gattorno Grant/Research Support from: Novartis and SOBI, Consultant for: Novartis and SOBI, R. Hara: None Declared, A. Shcherbina: None Declared, L. Obici: None Declared, S. Bujan: None Declared, G. Hoerneff Grant/Research Support from: AbbVie, Chugai, Novartis, Pfizer, Roche, A. Jansson: None Declared, R. Brik: None Declared, I. Rosner: None Declared, A. Tomassini: None Declared, Y. Gong Employee of: Novartis, E. Vritzali Employee of: Novartis, G. Junge Employee of: Novartis, F. De Benedetti Grant/Research Support from: Pfizer, AbbVie, Roche, Novartis, Novimmune and BMS, H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speaker Bureau of: Novartis, SOBI.

O31 Evidence based recommendations for corticosteroid tapering/discontinuation in new onset juvenile dermatomyositis patients from the PRINTO trial

Gabriella Giancane, Claudio Lavarello, Angela Pistorio, Francesco Zulian, Bo Magnusson, Tadej Avcin, Fabrizia Corona, Valeria Gerloni, Serena Pastore, Roberto Marini, Silvana Martino, Anne Pagnier, Michel Rodiere, Christine Soler, Valda Stanevicha, Rebecca Ten Cate, Yosef Uziel, Jelena Vojinovic, Elena Fueri, Angelo Ravelli, Alberto Martini, Nicolino Ruperto

Pediatria II, Reumatologia; PRINTO, Istituto Giannina Gaslini, GENOA, Italy
Correspondence: Gabriella Giancane

Introduction: At present no clear evidence based guidelines exist to standardize the tapering and discontinuation of corticosteroids (CS) in juvenile dermatomyositis (JDM).

Objectives: To provide evidence-based recommendations for CS tapering/discontinuation through the analysis of the patients in the PRINTO new onset JDM trial. Secondary objective of the study was to identify predictors of clinical remission and CS discontinuation.

Methods: New onset JDM children were randomized to receive either prednisone (PDN) alone or in combination with MTX or CSA. All children were given initially intravenous methylprednisolone, and then PDN starting with 2 mg/kg/day. Gradual tapering according to a specific protocol could lead to the safe dose of 0.2 mg/kg/day by month 6, then discontinued at month 24. Major therapeutic changes (MTC) were defined as the addition or major increase in the dose of MTX/CSA/other drugs or any other reasons for which patients were dropped from the trial. Patients were divided according to clinical remission (CMAS = 52 and MD global = 0 for 6 continuous months) into two major groups. Group 1 included those on clinical remission, who could discontinue PDN, with no MTC, and represented the reference standard for the best clinical outcome. Group 1 was compared with those who did not achieve clinical remission, without or with MTC (group 2 and 3, respectively). JDM core set measures (CSM) were compared in the 3 groups. We also calculated the gold standard group (group 1) median change in the CSM in the first 6 and over 24 months and applied a logistic regression model to identify the predictors of clinical remission with PDN discontinuation.

Results: 139 children were enrolled in the trial: 47 on PDN, 46 on PDN + CSA and 46 on PDN + MTX. We identified 30 (21.6%) patients for group 1, 43 (30.9%) for group 2 and 66 (47.5%) for group 3. At baseline all 3 groups had a high level of disease activity with no differences in the CSM. Already in the first 2 months a clear differential trend in disease activity measures, according to clinical remission status and PDN discontinuation, could be identified. From the observation of the median change in the CSM of group 1 in the first 6 months, the following recommendations could be extrapolated: decrease corticosteroids from 2 to 1 mg/kg/day in 2 months if the MD-global, parent-global, CHAQ, DAS, CMAS, MMT or Phs measures have a change of at least 50%; from 1 to 0.5 mg/kg/day in the following 2 months if the MD-global, CHAQ, DAS, CMAS have a change of at least 20%; in the following 2 months (month 4-6) corticosteroids can be tapered up to the safe dose of 0.2 mg/kg/day, if the disease activity measures remain at low/normal values. We finally ran a logistic regression model that showed that the achievement of PRINTO criteria 50-70-90 at 2 months from disease onset, an age at onset >9 years and the combination therapy PDN + MTX, increase the probability of clinical remission from 4 to 7 times. (Table 9).
Table 9

(Abstract O31). Logistic regression model for the outcome: achievement of remission (n/tot: 28/130; 21.5%)

 

OR (95% CI)

P#

Responder at 2 months:

Printo-50 (vs. not responder/Printo-20)

5.41 (1.37 - 21.32)

0.0076

Printo-70 (vs. not responder/Printo-20)

6.90 (1.91 - 24.99)

 

Printo-90 (vs. not responder/Printo-20)

4.46 (1.08 - 18.38)

 

Age at onset > 8.53 years (£ 8.53 years)

4.64 (1.69 - 12.71)

0.0017

Treatment group: PDN + MTX (vs. PDN/PDN + CSA)

3.63 (1.30 - 10.09)

0.0116

AUC of the model: 0.80

  

OR: Odds Ratio; 95% CI: 95% Confidence Interval; P#: Likelihood Ratio test

Conclusion: We propose evidence based specific cut-offs for corticosteroid tapering/discontinuation based on the change in JDM CSM of disease activity, and to identify the best predictors for clinical remission and corticosteroid discontinuation.

Trial registration identifying number: NCT00323960

Disclosure of Interest: G. Giancane: None Declared, C. Lavarello: None Declared, A. Pistorio: None Declared, F. Zulian: None Declared, B. Magnusson: None Declared, T. Avcin: None Declared, F. Corona: None Declared, V. Gerloni: None Declared, S. Pastore: None Declared, R. Marini: None Declared, S. Martino: None Declared, A. Pagnier: None Declared, M. Rodiere: None Declared, C. Soler: None Declared, V. Stanevicha: None Declared, R. Ten Cate: None Declared, Y. Uziel: None Declared, J. Vojinovic: None Declared, E. Fueri: None Declared, A. Ravelli Grant/Research Support from: BMS, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi, Speaker Bureau of: AbbVie, BMS, Pfizer, Hoffman LaRoche, Novartis, Centocor., A. Martini Grant/Research Support from: Starting from 1 march 2016 I became the Scientific Director of the G. Gaslini Hospital, therefore my role does not allow me to render private consultancies resulting in personal income. I perform consultancy activities on behalf of the Gaslini Institute for the following companies: Abbvie, Boehringer, Novartis, R-Pharm The money received for these activities are directly transferred to the Gaslini Institute's bank account., N. Ruperto Grant/Research Support from: The G. Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from BMS, Hoffman-La Roche, Janssen, Novartis, Pfizer and Sobi for the coordination activity of the PRINTO network. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Speaker Bureau of: Abbvie, Ablynx, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol Myers Squibb,, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, Medimmune, Novartis, Pfizer, Rpharm, Roche, Sanofi.

O32 Evaluation of varicella zoster immune status in children with rheumatic diseases treated with biologic agents

Elena Moraitis1,2, Lucy Backhouse1, Ian Macdonald1, Jennifer Crooks1, Muthana Al-Obaidi1

1Rheumatology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom; 2Infection, Inflammation, Rheumatology, UCL GOS Institute of child Health, London, United Kingdom
Correspondence: Elena Moraitis

Introduction: In immunocompromised patients, varicella zoster virus (VZV) infection can have a very severe clinical course. There is scarce evidence that in adult and paediatric population with rheumatoid or juvenile idiopathic arthritis and other rheumatic diseases the treatment with biologic agents may impair the antibody response to vaccines. However, there is no evidence on whether the use of biologic agents affects in children the VZV IgG levels acquired after natural infection.

Objectives: The aim of the study is to investigate whether children with a rheumatic condition treated with biologic agents have a change in their VZV immune status.

Methods: We performed retrospective case notes review of children presenting with any rheumatic diagnosis requiring treatment with a biologic agent to the Paediatric Rheumatology services at Great Ormond Street Hospital NHS Foundation Trust between 2009 and 2017, identified from the biologic database. We included in the study the children with positive VZV IgG prior to the treatment with a biologic agent and with a minimum of one repeat VZV IgG measurement post initiation of the treatment. A sensitive VaccZyme

VZV glycoprotein IgG Low Level Enzyme Immunoassay Kit (Binding Site) was used to measure VZV IgG.

Results: Sixty four patients treated with biologic agents and with two measurements of VZV IgG prior and post biologic were identified. Forty three patients had positive VZV IgG acquired prior to treatment and were included in the study. None had received the VZV vaccine, which is not part of the routine childhood vaccination schedule in the United Kingdom. After initiation of treatment with biologics, 10/43 (23%, 2 males and 8 females) had a change in VZV IgG, of which 5/43 (11.6%) had negative VZV IgG, and 5/43 (11.6%) equivocal. Four had a diagnosis of JIA, 2 systemic vasculitides, and 4 other rheumatic conditions. Seven patients were treated with anti-TNF agents, 2 patients with Tocilizumab and 1 received Abatacept. Nine patients received concomitant treatment with other disease-modifying anti-rheumatic drugs (7/9 Methotrexate, 2/9 Azathioprine). For the 10 patients, the median age at the measurement of a positive VZV IgG pre-biologic was 7 years (range 1-12), median time between the two assessments was 40.5 months (range 9-105), and the median time between the initiation of the biologic agent and the post-biologic measurement of VZV IgG was 24 months (range 11-68).

Conclusion: We describe the changes in the VZV immune status post treatment with biologics in the first cohort of paediatric patients with initial seroconversion following natural infection. Although limited by the size of the study population, observational nature and other concomitant medications, our results indicate that biologic agents can affect the VZV immune status of patients with rheumatic conditions, making them susceptible to re-infection. Therefore we suggest that all patients on biologic agents should have the VZV IgG levels re-tested regularly to identify whether the VZV IgG levels are protective and give prophylaxis as required in the event of varicella contact.

Disclosure of Interest: None Declared.

O33 Prolonged reduced aerobic fitness in adolescents and young adults with juvenile idiopathic arthritis

Philomine Van Pelt1,2, Tim Takken3, Marco V. Brussel3, Radboud Dolhain4, Johannes Bijlsma5, Aike Kruize5, Nico Wulffraat1

1rheumatology and pediatric rheumatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands; 2rheumatology and pediatric rheumatology, ErasmusMC University Rotterdam, Rotterdam, Netherlands; 3Child Development and Exercise Center, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands; 4rheumatology, ErasmusMC University Rotterdam, Rotterdam, Netherlands; 5rheumatology and immunology, University Medical Center Utrecht, Utrecht, Netherlands
Correspondence: Philomine Van Pelt

Introduction: Aerobic fitness may serve as an important health-related outcome measure in Juvenile Idiopathic Arthritis (JIA). Reduced aerobic fitness is associated with cardiovascular morbidity, mortality and osteoporosis in adult patients with chronic diseases. However, in adolescents and young adults, long-term outcome of aerobic fitness is unknown. Reduced aerobic fitness was described previously in cross-sectional studies in children and adolescents with JIA and was more impaired in active disease.

Objectives: Our objectives are to describe the course of aerobic fitness in a longitudinal cohort of adolescents and young adult JIA-patients who are intensively treated and to identify the association of clinical variables.

Methods: In a longitudinal cohort, all consecutive patients aged 10-24 years were included after informed consent. Annual examinations were obtained from demographic and disease-related items. At baseline and at study-end, aerobic fitness (VO2peak) was assessed using a graded cardiopulmonary exercise test (CPET) to volitional exhaustion performed on a cycle ergometer. Absolute and relative VO2peak values were measured and related to reference values of healthy controls (Z-scores), using one-sample T-tests. Non-parametric tests were used to evaluate results.

Results: Paired Z-scores were available from 35 patients. 40% were male, median age at baseline was 13,0 yrs (IQR 4,1), disease duration 7,8 yrs (6,4), JADAS27 3,7 (6,4), DAS28 1,8 (1,0). 79% of the patients were in DAS28-remission. 17% had systemic JIA, 6% persistent oligoarticular and 74% had a polyarticular course. Baseline and end Z-scores were reduced compared to healthy controls (ZAbs_base -0,68, IQR2,3 p = 0,01; Zrel_base -1,33, IQR 2,0, p < 0,01; Zabs_end -1,33, IQR 1,7, p < 0,01; Zrel_end -0,70, IQR 1,8, p = 0,01) and did not change significantly over time (change Zabs_change 0,65, p = 0,34; Zrel_change 0,63, p = 0,31). At baseline, a higher DAS28 (p = 0,01), higher JADAS27 (p < 0.01), ESR (p < 0,01), higher thrombocytes (p < 0.01) and the use of MTX (p = 0.01) were associated with a worse outcome of aerobic fitness. The greatest improvement of aerobic fitness over time was seen in male patients (p < 0.01) at baseline. Multivariate analysis showed that a higher DAS28 and male gender were the most important variables for worse aerobic fitness at baseline, a higher ESR at baseline was the most important predictor for improving aerobic fitness over time.

Conclusion: Aerobic fitness is significantly reduced in adolescents and young adults with JIA and does not improve over time, despite intensive treatment. Be aware of a reduced health outcome into adulthood due to a persistent reduced aerobic fitness during disease course of JIA, despite low disease activity.

Disclosure of Interest: None Declared.

Autoinflammatory diseases

P1 PFAPA syndrome in large pediatric population: a single center experience

Esra Pehllivan, Amra Adrovic, Sezgin Sahin, Kenan Barut, Ovgu Kul, Ozgur Kasapcopur

Pediatric Rheumatology, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey
Correspondence: Amra Adrovic

Introduction: Periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome is an auto-inflammatory condition of unknown etiology. It is the second most common auto-inflammatory disease in our country, following familial Mediterranean fever. The strong familial clustering suggest a potential genetic origin of the syndrome but none of single genetic variants seem to be relevant for the disease etiology. Previous studies showed that tonsillectomy represents efficient treatment options.

Objectives: Our aim was to explore the main clinical features, response to tonsillectomy and long–term outcome of PFAPA pediatric patients in a single cohort. We assessed association of MEFV gene mutation with disease characteristics and treatment response.

Methods: We reviewed medical records of patients who were diagnosed with PFAPA syndrome between the January 2010 and June 2016. All of the recorded 562 patients were called by the telephone and 359 (64%) of them were reached. Demographic, clinical and therapeutically features were taken from the patients’ medical records. Data on clinical course and the disease outcome were collected by using a structured questionnaire, which was fulfilled during the phone conversation between investigator and patient’s parents.

Results: A total of 359 patients with PFAPA were examined: 155 (43%) of them were female. The mean age at disease onset, at diagnosis and at the investigation was 22.79 ± 18.8, 41.7 ± 21.7 and 77.14 ± 31.35 months, respectively. The most common disease feature at the disease onset was: recurrent fever in 359 (100%), cryptic tonsillitis in 359 (100%) and aphtous stomatitis in 317 (88%). Sixty-three (17%) patients met the criteria for both PFAPA and FMF. MEFV gene mutation analysis was performed in 93 (25%) patients and 51 of them (54%) had a heterozygous mutation in exon 10. Surgical treatment was performed in 158 (43%) patients. Complete clinical remission was achieved in 127 (80.3%) patients. Six (3%) showed no response to surgical treatment while 25 (15.8%) patients had a partial response. In patients with partial clinical response, frequency of fever attacks decreased significantly from 17.5 to 7.3 attack per year (p < 0.05). Among patients who did not respond to tonsillectomy, 11 (52.4%) were carrier of MEFV heterozygous mutation in exon 10. There was a statistically significant difference between patients with and without coexistence of FMF features, according to surgical treatment response (p < 0.05). The mean age of resolution of PFAPA symptoms in patients who underwent tonsillectomy was 52 ± 22.4 months and in patients without tonsillectomy 66 ± 22.6 months (Table 10).
Table 10

(Abstract P1). Clinical characteristics of patients according to coexistence of FMF

 

Patients with coexistence of FMF (n = 63)

Patients without coexistence of FMF(n = 296)

p

Mean age at disease onset (months ± SD)

27 ± 23

22 ± 16.6

0.562

Mean age at diagnosis (months ± SD)

44 ± 23

43 ± 21

0.274

Male/Female ratio

36/27

168/128

1.0

Mean time interval between fever episodes (weeks ± SD)

3 ± 0.9

3.2 ± 1.4

0.61

Mean duration of fever (days ± SD)

3.6 ± 1.4

3.9 ± 3.6

0.94

Cryptic tonsillitis

63 (100%)

296 (100%)

1.0

Abdominal pain

20 (31.7%)

83 (28%)

0.54

Response to colchicum treatment

18/27 (66%)

6/18 (33%)

0.03

Clinical response to surgical treatment

18/36 (50%)

113/146 (77.4%)

0.002

Conclusion: Although PFAPA symptoms usually resolve before age of eight, some patients’ complaints persist. FMF should be considered in tonsilloadenoidectomy unresponsive PFAPA patients, especially in endemic regions like Turkey. Tonsilloadenoidectomy seems to be an effective treatment option for pediatric PFAPA patients.

References:

1. Marshall GS, Edwards KM, Butler J, Lawton AR (1987) Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr 110:43–46

2. Vanoni F, Theodoropoulou K, Hofer M. PFAPA syndrome: a review on treatment and outcome. Pediatr Rheumatol Online J 2016;14:38.

3. Batu ED, Kara Eroğlu F, Tsoukas P, et al. Periodic Fever, Aphthosis, Pharyngitis, and Adenitis Syndrome: Analysis of Patients From Two Geographic Areas. Arthritis Care Res (Hoboken) 2016;68:1859-1865.

4. Celiksoy MH, Ogur G, Yaman E, et al. Could familial Mediterranean fever gene mutations be related to PFAPA syndrome? Pediatr Allergy Immunol. 2016;27:78-82.

Disclosure of Interest: None Declared.

P2 through new classification criteria for inherited periodic fevers and PFAPA. An integrated approach among clinicians and geneticists.

Silvia Federici1, Federica Vanoni2, Francesca Bovis3, Maria Pia Sormani3, Nicola Ruperto4, Marco Gattorno4 and on behalf of the Expert Committee for the Classification Criteria in periodic fever

12° Division of Pediatric, Gaslini Institute, Genova, Italy; 2Pediatric Rheumatology Unit, CHUV, University of Lausanne, Lausanne, Switzerland; 3Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy; 42° Division of Pediatric, Gaslini Institute, Genoa, Italy
Correspondence: Silvia Federici

Introduction: Provisional Eurofever evidence-based classification criteria for inherited periodic fever (TRAPS, FMF, MKD and CAPS) have been recently developed and other diagnostic criteria are available for FMF, CAPS and PFAPA. However, no consensus on how to combine clinical criteria and results of molecular analysis has been reached so far. We have recently identified, through a process based on the Delphi techniques (2 subsequent Delphi surveys), those variables the expert, clinicians and geneticists, consider as important for the diagnosis of each monogenic periodic fever syndrome and PFAPA. We also obtained, trough a web-based evaluation a consensus >80% among clinicians and geneticists on the diagnosis for 269 over 360 patients with monogenic periodic fever, PFAPA and undefined periodic fever (UPF) randomly selected from the Eurofever Registry.

Objectives: To identify candidate set of classification criteria for monogenic periodic fever and PFAPA and to test their sensibility and specificity on the subset of patients having reached a consensus among experts. To select the best sets of criteria for each disease to be discussed in a Consensus Conference

Methods: We selected for each disease the clinical variables corresponding to the 3rd quartile considering the total score obtained after the second Delphi survey. Performing univariate statistical analysis, we subsequently assess the ability of these variables to classify individual patients as having or not FMF, MKD, TRAPS, CAPS, PFAPA or UPF according to consensus classification of experts. These variables could be associated both in a positive or negative way to each disease. At the same time we assigned to each genotype presented by our patients a score from 5 to 1 on the basis of the evaluation done by the experts to be able to include the results of genetic testing in the statistical analysis. In a second step, multivariate statistical analysis has been performed to obtain different sets of criteria including only positively associated or positively and negatively associated clinical variables with and without genetic data. For each criteria the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under the curve (AUC) were calculated. The best performing criteria for each disease have been selected and presented to the expert for voting in a consensus Conference held in Genova in march 2017.

Results: A total of 98 clinical variables derived from the second Delphi survey has been tested. The univariate analysis identified 15 variables significantly associated with FMF (6 positively and 9 negatively), 20 with CAPS (12 positively and 8 negatively), 9 with TRAPS (6 positively and 3 negatively), 13 with MKD (11 positively and 2 negatively) and 15 with PFAPA (5 positively and 10 negatively). 193 criteria derived from the statistical analysis have been selected (45 for FMF, 50 for CAPS, 44 for TRAPS, 32 for MKD and 22 for PFAPA) to be discussed and voted at the consensus. In addition criteria already published in the literature and criteria directly proposed by experts were included for discussion.

Conclusion: Our process led to the identification of the best variables to be included in the multivariate analysis for the identification of the candidate criteria for monogenic periodic fever and PFAPA. Next, the ability of candidate criteria to classify individual patients as having FMF, MKD, TRAPS CAPS or PFAPA have been assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The best classification criteria for each disease in term of sensibility and specificity have been shown and voted by a panel of Experts during the Consensus Conference held in Genoa. For CAPS, FMF and MKD a consensus >80% has been reached for the best genetic/clinical criteria and for the best clinical criteria while for TRAPS the consensus has been reached only for the best clinical/genetic criteria. A new round of web-based evaluation is now ongoing to try to reach a consensus on the clinical criteria for TRAPS as well. Moreover a consensus has been reached for PFAPA clinical criteria.

Disclosure of Interest: None Declared.

P3 Chronic recurrent multifocal osteomyelitis: case report

Maria Francesca Gicchino1, Mario Diplomatico1, Daniela Capalbo1, Carmela Granato1, Alma Nunzia Olivieri1

1Department of Women, Child and General and Specialistic Surgery, Università della Campania Luigi Vanvitelli, Naples, Italy
Correspondence: Maria Francesca Gicchino

Introduction: Chronic recurrent multifocal osteomyelitis (CRMO), also known as chronic nonbacterial osteomyelitis, is a rare, noninfectious inflammatory disorder that causes multifocal lytic bone lesions with swelling and pain characterized by periodic exacerbations and remissions of unclear/unknown pathogenesis.

Objectives: To describe a case of CRMO in a 10 years old girl.

Methods: A 10 years old girl came to our department because of pain in her right shoulder since the age of 9 years. She did not recall a precipitating event or a trauma, reported no fever or weakness. There was no relevant personal or family history. Before coming to our observation an X-ray of her right shoulder revealing an osteolytic lesion and a PET-CT showing the presence of a pathological high-uptake of the lesion were performed, and a biopsy of the lesion of the right shoulder was done to exclude a neoplastic lesion, a bone infection, or a Langerhans cells histiocytosis (LCH). Patient’s bone biopsy showed infiltration by lymphocytes and neutrophils. No neoplastic cells were identified. All cultures were negative. LCH was excluded since immunohistochemical evaluation of bone marrow for CD1a and S100 expression was negative. When she was admitted to our department she had pain in her right arm and shoulder. Laboratory results showed a modest increase of inflammation parameters (ESR 34 mm/h, CRP 0,88 mg/dL) with normal complete blood count, liver and renal function. The abdominal ultrasound and the chest X-ray were normal so we performed an MRI. On MRI the lesion was hypointense in T1 and hyperintense in T2 and STIR, suggesting an inflammatory process.Suspecting a CRMO, anti-inflammatory treatment with naproxen was prescribed and the symptomatology disappeared. Five months later the patient came back to our department because of pain and swelling in her right clavicle. The physical examination showed a painful swelling of the sternal end of the right clavicle. Laboratory results indicated a modest increase of inflammation parameters (ESR 29 mm/h, CRP 0,98 mg/dL). Clavicle X-ray showed an osteolytic lesion, ultrasound of sternoclavicular joint revealed articular effusion. On MRI this lesion was hyperintense in T2 and STIR.

Results: Clinical history, physical signs, instrumental investigations and histopathological pattern were highly suggestive of CRMO. Anti-inflammatory treatment with naproxen was started again and the symptoms disappeared. After six months was performed a whole-body MRI to evaluate the status of disease. The MRI did not show new lesions and previous bone lesions disappeared.

Conclusion: In a patient with recurrent bone pain CRMO should be considered. The diagnosis is of exclusion and it is based on the clinical and radiological data. Biopsy is needed to exclude infectious osteomyelitis, malignancy, LCH. Some authors suggest that biopsy is not necessary if a patient has classical radiological findings of CRMO, or comorbidities, such as Crohn's disease. Skeletal manifestations are unifocal or multifocal, and the involvement of clavicle, sternum or mandible suggest a CRMO diagnosis. Extra-articular manifestation are gastrointestinal and skin involvement (acne, pustolsis, psoriasis).The SAPHO syndrome seems to be an advanced state of CRMO. The treatment of CRMO has been mostly empiric; NSAIDs are the first choice for CRMO treatment. When disease activity is high or there are complications therapy with bisphosphonates or biologic drugs such as TNF antagonists (etanercept) or inhibitors of IL-1 (anakinra) should be considered.

Disclosure of Interest: None Declared.

P4 Pluripotent stem cell models of Blau syndrome reveal an IFN-γ-dependent inflammatory response in macrophages

Yuri Kawasaki1, Sanami Takada2, Naotomo Kambe3, Ryuta Nishikomori4, Tatsutoshi Nakahata1, Megumu K. Saito1

1Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan; 2Department of Dermatology, Chiba University Graduate School of Medicine, Chiba, Japan; 3Department of Dermatology, Kansai Medical University, Hirakata, Japan 4Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
Correspondence: Yuri Kawasaki

Introduction: Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in nucleotide-binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome.

Objectives: To elucidate the mechanisms of autoinflammation in Blau syndrome, we sought to clarify the relation between disease associated-mutant NOD2 and the inflammatory response in human samples.

Methods: Blau syndrome-specific induced pluripotent stem cells (iPSCs) lines were established. To precisely evaluate the in vitro phenotype of iPSC-derived cells, the disease-associated NOD2 mutation of iPSCs was corrected using a CRISPR-Cas9 system. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the status of NF-κB pathway and proinflammatory cytokine secretion were investigated.

Results: IFN-γ acted as a priming signal through the up-regulation of NOD2. In iPSC-derived macrophages with mutant NOD2, IFN-γ treatment induced ligand-independent, NF-κB activation and proinflammatory cytokine production. RNA-seq analysis revealed distinct transcriptional profiles of mutant macrophages both before and after IFN-γ treatment. Patient-derived macrophages demonstrated a similar IFN-γ-dependent inflammatory response.

Conclusion: Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of Blau syndrome patients.

Disclosure of Interest: None Declared.

P5 Transcriptional regulatory gene variations could influence expression patterns and inflammatory propagation in clavicular cortical hyperostosis

Lovro Lamot1,2, Kristina Gotovac Jercic2, Antonela Blazekovic2, Mandica Vidovic1, Mirta Lamot1, Fran Borovecki2, MIroslav Harjacek1,2

1Clinical Hospital Center Sestre Milosrdnice, Zagreb, Croatia; 2University of Zagreb School of Medicine, Zagreb, Croatia
Correspondence: Lovro Lamot

Introduction: Clavicular cortical hyperostosis (CCH) is a rare inflammatory bone disorder of unknown aetiology represented by pain and swelling of the clavicle. Although similar to chronic nonbacetril/recurrent multifocal osteomyelitis (CNO/CRMO), due to lack of recurrence and additional inflammatory sites, it can be considered separate disease in the spectrum. In our previous study microarray gene expression profiling of CCH patients revealed 974 differentially expressed genes involved in various inflammatory processes (1). Subsequent qRT-PCR in additional number of patients confirmed significantly lower expression of ERBB2 gene and higher expression of TRPM3 and TPRM7 transient receptor potential (TRP) channel genes. Additionally, immunofluorescence microscopy showed high signal of TRPM3 in blood cells of one CCH patient. Based on described findings and other studies which showed TRP channels are involved in inflammasome activation, while ERBB activation promotes protective cellular outcomes during inflammation, we hypothesized CCH could be autoinflammatory disease, but the mechanisms responsible for observed expression alterations remained unclear.

Objectives: Identify possible disease causing gene variants in CCH patients using whole exome sequencing (WES).

Methods: Genomic DNA was extracted from peripheral whole blood samples of three CCH patients. Targeted exome sequencing was performed using the Nextera Rapid Capture Exome Kit (Illumina). The sequence library was constructed with 50 ng of genomic DNA and 100-bp paired-end reads were sequenced on HiSeq 2000 next-generation sequencer (Illumina). The extracted variants were annotated and filtered using the Variant Studio software (Illumina) and Variant Interpreter (Illumina).

Results: WES analysis identified 428 shared identical variants among affected individuals. Thirty of these variants were not associated with a gene, 121 were in ZNF717 gene and 277 were distributed in 63 other genes. One heterozygous variant in CTBP2 gene, one in HYDIN gene and six in ZNF717 were classified as likely pathogenic (Table 11).
Table 11

(Abstract P5). Shared identical variants classified as likely pathogenic

Gene

Variant

Coordinate

Transcript

Consequence

dbSNP ID

CTBP2

T > T/A

126727602

  

rs76555439

HYDIN

GA > GA/G

70896015

NM_032821.2

frameshift_variant, feature_truncation

rs77276171

ZNF717

A > A/T

75786827

NM_001128223.1

stop_gained

rs79635065

ZNF717

C > C/A

75786916

NM_001128223.1

stop_gained

rs78906544

ZNF717

G > G/T

75787127

NM_001128223.1

stop_gained

rs74740396, rs148624740

ZNF717

T > T/TA

75787352

NM_001128223.1

frameshift_variant, feature_elongation

 

ZNF717

GAA > GAA/G

75787645

NM_001128223.1

frameshift_variant, feature_truncation

rs67117547, rs141065192

ZNF717

G > G/C

75788028

NM_001128223.1

stop_gained

rs77971486, rs150689808

Conclusion: In this comprehensive study “bottom-up” approach was used in order to elucidate the molecular disease mechanisms of what we believe could be a new disease entity. Previously performed diligent transcriptome analysis and proof-of-concept experiment which confirmed the results on a protein level indicated CCH could be induced by sternoclavicular joint overuse, TRP channel overexpression, inflammasome activation and reduced protection during inflammation. Interestingly, WES analysis identified majority of likely pathogenic variants in ZNF717 gene. This gene encodes a Kruppel-associated box (KRAB) zinc-finger protein, which belongs to a large group of transcriptional regulators and is therefore involved in the regulation of crucial physiological and pathological processes (2). Many aspects of these proteins are still essentially unknown, as is their role in the inflammation, yet it is speculated they increase DNA accessibility and inflammatory gene transcription (3). Together with possible influence on observed expression patterns, all of these processes could contribute to CCH evolution.

References

1. Lamot L et al. TRP channels overexpression contributes to inflammasome activation in clavicular cortical hyperostosis? Ann Rheum Dis 2015;74(Suppl2):146.

2. Lupo A et al. KRAB-Zinc Finger Proteins: A Repressor Family Displaying Multiple Biological Functions. Current Genomics 2013;14(4):268–278.

3. Chinenov Y et al. Glucocorticoid Receptor Coordinates Transcription Factor-Dominated Regulatory Network in Macrophages. BMC Genomics 2014;15(1):656.

Disclosure of Interest: None Declared.

P6 A novel phenotype associated with ADAM17 mutations

Sonia Melo Gomes1,2, Ebun Omoyinmi1, Ying Hong1, Glenn Anderson3, William Mufzud3, William Moore4, Clive Edelsten4, Louise Wilson5, Paul Brogan2

1Rheumatology, GOSH UCL Institute of Child Health, London, United Kingdom; 2Rheumatology, Great Ormond Street Hospital, London, United Kingdom; 3Pathology, Great Ormond Street Hospital, London, United Kingdom; 4Ophthalmology, Great Ormond Street Hospital, London, United Kingdom; 5Genetics, Great Ormond Street Hospital, London, United Kingdom
Correspondence: Sonia Melo Gomes

Introduction: ADAM17 is an important shedding enzyme that regulates the response to tissue injury and inflammation. Only 2 cases of ADAM17 mutations in humans have been described thus far: siblings with a homozygous ADAM17 deletion resulting in a severely truncated protein causing autosomal recessive neonatal inflammatory bowel and skin disease.

Objectives: The aim of this study was to discover the genetic cause affecting a child with a novel inflammatory phenotype.

Methods: Whole Exome sequencing was performed using DNA extracted from peripheral blood for a trio analysis. The Nextera Exome Capture and Hiseq sequencing platforms were used in this process.

Results: A four-year- old girl presented with extreme photophobia, bloody diarrhoea, anal fissures from the first weeks of life, and intermittent fevers. Examination revealed blepharitis, perioral rash and gingival inflammation with hyperthrophy. Feeding difficulties attributed to gastro-oesophageal reflux led to oral aversion and poor weight gain. Inflammatory markers were moderately elevated (mean CRP-22 mg/L and ESR-32 mm/h) in between fevers, and higher (CRP > 150 mg/L) during fevers. Upper gastrointestinal endoscopy at 10 months of age showed gastritis and duodenitis. Brain MRI showed cerebellar hypoplasia; corneal biopsy revealed an abnormal cornea and conjunctival epithelium. Extensive neuro-metabolic investigations performed were normal. Whole exome sequencing revealed 2 rare heterozygous missense mutations in the ADAM17 gene (p.I50V and p.R215V). Sanger sequencing confirmed these results, and carrier status in the parents. Both these mutations were absent from our in-house exome database of 120 exomes; were not seen in homozygous state in population databases; and were predicted damaging in silico. Biopsies of oral mucosa, tonsillar and skin tissue were then assessed by electron microscopy showing patchy structural changes in hemidesmosomes.

Conclusion: We describe the third case of human disease associated to ADAM17, but with a novel phenotype, similar to conditional knock-out mouse models with severely reduced ADAM17 sheddase activity, which develop opaque eyes, skin and heart defects as well as increased susceptibility to dextran sulfate induced colitis. This is in-keeping with the mutations found in our proband, since they are unlikely to result in the complete absence of the protein described in the other human cases.

Ongoing functional work will provide further information on how these mutations affect ADAM17 activity and impact on hemidesmosome structure.

Disclosure of Interest: None Declared.

P7 The impact of gastrointestinal clinical manifestations in autoinflammatory diseases (AID): lessons from the international Eurofever registry

Alessia Omenetti1, Francesca Bovis2, Joost Frenkel3, Helen J. Lachmann4, Seza Ozen5, Nicolino Ruperto6, Marco Gattorno6 on behalf of PRINTO and Eurofever Registry

1DINOGMI, Genoa, Italy; 2Biostatistics Unit, Department of Health Sciences,, University of Genoa, Genoa, Italy; 3University Medical Center Utrecht, Utrecht, Netherlands; 4Division of Medicine, University College London, London, United Kingdom; 5Department of Paediatric Rheumatology, Hacettepe University, Ankara, Turkey; 6Pediatria II, Gaslini IRCCS, Genoa, Italy
Correspondence: Alessia Omenetti

Introduction: The spectrum of autoinflammatory diseases (AID) is continuosly expanding and significant delay in diagnosis may occur if those rare entities are not promptly identified.

Objectives: To assess the impact and significance of gastrointestinal (GI) clinical manifestations in a broad cohort of AID patients.

Methods: The web-based international Eurofever registry containing data retrospectively collected about patients enrolled by 108 partecipating centres from November 2009 to June 2016 was evaluated. When present, each GI manifestation was ranked as occasionally or persistently present during flares. Development of severe GI complications was also assessed. To then identify subsets of patients featured by homogeneous patterns of clinical features, the unsupervised Latent Class (LC) analysis was applied to the cohort featured by GI manifestations (GI cohort) in the attempt to assign mutually exclusive class membership based on latent patterns among the observed variables.

Results: The cohort included 1655 patients with confirmed diagnosis of AID. At least 1 GI manifestation was reported in 52.32%. Interestingly, the latter had earlier onset compared to cohort that did not show GI involvement (5.18 ± 8.18 vs 9.11 ± 10.25, mean years ± SD). As expected, the majority of FMF, MVK and TRAPS were affected by GI symptoms whereas CAPS and CRMO were mainly represented in the subset lacking GI involvement. In the GI cohort (Table 12), during flares LC1 (13%) displayed persistent abdominal pain together with prolonged diarrhea, and it mainly included majority of MVK. LC2 (7%) was affected by occasional abdominal pain together with occasional vomiting, diarrhea and hepatosplenomegaly. LC3 represented the majority of GI cohort (72%) and presented only occasional abdominal pain while LC4 (8%) was characterized by persistent abdominal pain occasionally associated with vomiting, diarrhea, and sometime developing complications such as septic peritonitis and peritoneal adhesions. As expected, the latter was mostly represented by FMF.
Table 12

(abstract P7). See text for description

n=

LC1

LC2

LC3

LC4

Tot GI Cohort

Total not GI Cohort

Total AID

Total

87

52

666

61

866

789

1655

CAPS

4

7

31

2

44

134

179

CRMO

0

0

28

1

29

323

352

FMF

17

15

274

43

349

28

378

MVK

39

15

56

8

118

4

122

PFAPA

11

2

99

0

112

158

271

TRAPS

7

7

101

5

120

37

158

Undefined

9

5

57

1

72

63

135

Others

0

1

20

2

23

38

60

Conclusion: These data unveiled the unforeseen significance of GI involvement in AID with implications in the daily clinical management. GI specialists should be aware of these rare diseases in order to avoid delayed diagnosis and joined work-up protocols should be developed in order to monitor these signs and prevent potential complications. A prospective analysis is needed in order to delineate the disease history and potential evolutions (if any) into more defined GI diseases in the contest of autoinflammation.

Disclosure of Interest: None Declared.

P8 Next generation sequencing-based panel screening in patients with undifferentiated autoinflammatory diseases: friend or foe?

Abstract withdrawn

P9 Monogenic diseases masquerading as Behçet’s disease in the young

Charalampia Papadopoulou1, Ebun Omoyinmi1, Ariane Standing1, Jessica Macwilliam2, Clare Pain2, Despina Eleftheriou1,3, Paul Brogan1

1Infection, Inflammation and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; 2Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom; 3 Centre for Adolescent Rheumatology, Arthritis Research UK, London, United Kingdom
Correspondence: Charalampia Papadopoulou

Introduction: Monogenic autoinflammatory disorders (AID) and some primary immunodeficiencies can present early in life with Behçet-like symptoms, and may be mistaken for Behçet’s disease (BD). Most of these monogenic conditions require alternative treatments than typically required for BD, and are associated with high morbidity and mortality if diagnosis and appropriate treatment are delayed. Next generation sequencing (NGS) undoubtedly offers the opportunity to screen for these diseases more efficiently, and greatly facilitates diagnosis in this context.

Objectives: To retrospectively describe the clinical and laboratory features, and molecular diagnoses of 11 paediatric cases referred for suspected BD.

Methods: Retrospective, two-centre, case series. A combination of NGS or conventional candidate gene screening approaches were utilised to ascertain genetic diagnoses, facilitated in some cases by functional immunological screening assays. NGS approaches utilised included targeted exome sequencing (the “Vasculitis and Inflammation Panel”, VIP); or whole exome sequencing (WES).

Results: Eleven children referred with suspected BD underwent further molecular testing because of incomplete or atypical BD features, and presentation under the age of 5 years. Seven/11 patients (58%) were Caucasian; the remaining 4/11 were Asian; 64% were female. Two cases were siblings from a consanguineous kindred with “familial” BD; and another had a maternal history of BD. The median age of disease onset was 1.0 (range 0.5-3.0) years. All had systemic inflammation and oral ulceration; 4/11 had genital ulceration; 4/11 had ocular involvement; and 8/11 had cutaneous manifestations. Nine out of 11 were considered to have a monogenic cause: the final genetic diagnoses were: A20 haploinsufficiency (n = 1); Hyper IgE syndrome (n = 1); LYN associated AID (n = 1); TRAPS (n = 1), Chronic Granulomatous Disease (n = 2), Periodic Fever Immunodeficiency and thrombocytopenia Syndrome (PFIT; n = 2), and pustular psoriasis caused by mutation in AP1S3 (n = 1). The remaining two cases had a suspected atypical AID caused by a novel variant in MEFV (n = 1); and a STAT1 variant, as the suspected but as yet unproven monogenic cause (n = 1).

Conclusion: Rare monogenic disorders can mimic BD, particularly when the presentation is under the age of 5 years. These data are now informing a strategy to begin to explore screening for genetic mimics of BD in a UK cohort of children and adults to better understand the proportion of UK BD patients who may in fact have an underlying genetic diagnosis.

Disclosure of Interest: None Declared.

P10 Proteomic profile of patients with different autoinflammatory diseases: an approach to identify new biomarkers

Federica Penco1, Andrea Petretto2, Chiara Lavarello2, Elvira Inglese2, Ilaria Gueli3, Alessia Omenetti3, Martina Finetti3, Federico Tomasi4, Annalisa Barla4, Arinna Bertoni1, Claudia Pastorino1, Marco Gattorno3

1Laboratorio di Immunologia delle Malattie Reumatiche Pediatria II, Università degli Studi di Genova, Genova, Italy; 2Core Facilities, Università degli Studi di Genova, Genova, Italy; 3U.O. Pediatria II, Instituto Giannina Gaslini, Università degli Studi di Genova, Genova, Italy; 4Dibris, Università degli Studi di Genova, Genova, Italy
Correspondence: Federica Penco

Introduction: Autoinflammatory diseases are a group of inherited diseases characterized by early onset and systemic inflammation, often manifesting with unexplained fevers. These pathologies are usually caused by mutations in genes involved in the regulation of innate immune response with consequent inflammatory phenotype. The mechanism that lead to the development of this diseases are not still clear and part are however genetically undefined.

Objectives: Our aim is to evaluate the differences in the expression of proteins or pathway in monocytes, and plasma metabolites of patients with some of the best-known autoinflammatory diseases (CAPS, TRAPS, FMF and MKD) and healthy subjects. The purpose is clusterize the different disorders to better characterize each pathology and try to distinguish the genetically undefined pathologies.

Methods: Monocytes (purified form peripheral blood and incubated for 4 hours with or without LPS) and plasma were collected from patients and healthy donors. The samples were processed and proteins or metabolites expression evaluated by an High Resolution/Mass Accuracy Liquid Chromatography Tandem Mass Spectrometry (HR/MA LC MS/MS). PCA analysis and Person’s correlation were used as quality control of experimental design, while the statistical analysis was performed with the Perseus software.

Results: We analyze the monocytes and plasma of patients with CAPS, TRAPS, FMF and MKD. We identified about 4000 proteins of each 3500 are quantified by LFQ approach. PCA analysis and Person’s correlation show a good reproducibility of data and a good separation between the different groups. In synchronous way using a cluster analysis and heatmap, based on a machine learning protein selection, we observed a protein signature specific for each group of pathology and for each condition of monocytes treatment. Furthermore we used a supervised multivariate analysis to try to identify a more specific list of proteins for each pathology: at the moment we obtained a list of about 40 protein per disease, significantly modulated if compared with healthy controls and comparing each pathology with the other.

Conclusion: Here, we addressed how an high resolution proteomics approach could be used to better understand the biology of autoinflammatory diseases. The characterization of a broad spectrum of proteins and metabolites and their interaction network will allow us to identify new biomarkers for the different pathologies and better comprehend and recognize the genetically undefined disorders.

Disclosure of Interest: None Declared.

P11 Through new classification criteria for inherited periodic fevers and PFAPA syndrome: the patient validation phase

Federica Vanoni1,2, Silvia Federici3, Francesca Bovis4, Mariapia Sormani5, Nicola Ruperto3, Marco Gattorno3, Michaël Hofer2 and on behalf of the Expert Committee for the Classification Criteria in periodic fever

1Departement of Pediatric of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland; 2Pediatric Rheumatology Unit, CHUV, Lausanne, Switzerland; 3Pediatria II - Reumatologia, Istituto G. Gaslini, University of Genoa, Genoa, Italy; 4Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy; 5Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy
Correspondence: Federica Vanoni

Introduction: Provisional evidence-based classification criteria for inherited periodic fever (TRAPS, FMF, MKD and CAPS) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory test and results of molecular analysis has been reached so far. Moreover, no validated evidence based set of classification criteria for PFAPA has been established so far. We conducted a multistep process, based on a combination of expert consensus and analysis of real patient, to develop new criteria for inherited periodic fevers and PFAPA syndrome.

Objectives: To obtain a consensus > 80% among experts on the diagnosis of a group of patients with inherited periodic fevers, PFAPA and undefined periodic fevers.

Methods: A panel of experts (25 clinicians and 8 geneticists) was asked to evaluate, via a web-based system on the basis of clinical and laboratory data, 360 real patients affected by AIDs (60 FMF, 60 TRAPS, 60 MKD, 60 CAPS, 60 PFAPA and 60 undefined periodic fever) randomly selected from the EUROFEVER Registry. PFAPA patient were evaluated only by clinicians. Experts were asked to classify each patient as having FMF, TRAPS, MKD, CAPS, PFAPA or undefined periodic fever syndrome. The criterion for agreement used was 80% consensus among raters.

Results: After four round of evaluation, 281 over 360 patients (78%) were classified with a consensus > 80% for a specific disease: 36 as FMF, 32 as CAPS, 56 as MKD, 39 as TRAPS, 37 as PFAPA and 81 as undefined periodic fever. In 50 cases the diagnosis changed respect to the diagnosis of the enrolling center. 25 over 36 FMF patients were homozygous or compound heterozygous for high penetrance variants while 4 over 36 patients were compound heterozygous with one high penetrance mutation associated with E148Q variant. 6 over 36 were heterozygous for high penetrance mutations and 1over 36 patients carried only the E148Q variant. Over the 32 CAPS patients, 28 had a genotype consistent with the disease while 4 patients carried a variant of unknown significance (V198M). None of the patients showing the Q703K variant or with negative genetic test was classified as CAPS by the experts. Regarding TRAPS only 1 over 15 patients carrying a low penetrance variants (R92Q, P46L) reached the consensus; none of the 2 patients with negative genetic analysis reached the consensus. Among MKD patients, 4 carried the V377I variant in heterozygous date and among these 2 reached the consensus.

Conclusion: Our process led to a consensus on the diagnosis for 281 patients affected by inherited periodic fevers and PFAPA. In the subsequent phase we had performed statistical analysis in which variables coming from the EUROFEVER Delphi survey will be tested on these patients, to identify the best sets of classification criteria (in term of sensitivity and specificity) for inherited periodic fever and PFAPA that have been discussed in the consensus conference held in Genoa in March 2017.

Disclosure of Interest: None Declared.

P12 A preliminary study regarding to the levels of vitamin B12 and folate during colchicine treatment in children with FMF

Özge Kaba1, Mustafa Çakan2, Şerife Gül Karadağ2, Betül Sözeri3, Gonca Keskindemirci1, Nuray Aktay Ayaz2

1Pediatrics, Kanuni Sultan Süleyman Research And Training Hospital, İstanbul, Turkey; 2Pediatric Rheumatology, Kanuni Sultan Süleyman Research And Training Hospital, İstanbul, Turkey; 3Pediatric Rheumatology, Ümraniye Research And Training Hospital, İstanbul, Turkey
Correspondence: Nuray Aktay Ayaz

Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterized by irregular periodic attacks of serosal inflammation. The gold standard in treatment is colchicine and it is very potent both in preventing attacks and subsiding inflammation and by that way avoiding emergence of amyloidosis.

Objectives: There is a hypothesis pointing out to the negative influence of colchicine on the intestinal absorption of vitamin B12. As colchicine treatment should be used lifelong, vitamin B12 deficiency due to malabsorption may ensue during the course of treatment. Although there is an adult study, there is no data for children with FMF under colchicine treatment.

Methods: Forty-six children with newly diagnosed FMF were enrolled to this prospective study. They were all started colchicine according to their age (0-5 years:0.5 mg, 5-10 years:1 mg, >10 years: 1.5 mg - maximum 2 mg). Vitamin B12 and folic acid levels were obtained at the first day of colchicine treatment, 3rd month and 6th month of the treatment. Mutation analysis of the patients and their clinical findings were also reported.

Results: Of 46 children involved to the study 18 (39.1%) were females and 28 (60.9%) were males. The mean age of beginning of the symptoms was 65.3 ± 45.5 months, the mean age of diagnosis was 97.13 ± 50.2 months. There was family history of FMF in 25 patients (54.3%). Fever was present in 40 (86.9%), peritonitis was in 35 (76%), pleuritis was in 11 (23.9%), arthritis was in 6 (13%) patients. The mean vitamin B12 values and folate values were significantly decreased during colchicine treatment. Vitamin B12 levels were 436.28 ± 174.43, 411.63 ± 196.70, 361.67 ± 142.58 at the beginning, on the 3rd and 6th months of the colchicine treatment respectively. Folate levels were 10.91 ± 3.45, 9.29 ± 4.37, 9.76 ± 5.64 at the beginning, on the 3rd and 6th months respectively.

Conclusion: There was significant vitamin B12 and folate level decrease on the 6th month of colchicine therapy in the children with newly diagnosed FMF. This may be related to ileal malabsorption of vitamin B12 and jejunal malabsorption of folate. Although the study was performed among a small number of children with FMF and a limited time period was reported, prolonged periods may show more significant decrements in the levels of vitamin B12 and folate.

Disclosure of Interest: None Declared

P13 Longitudinal assessment of iron homeostasis in patients with newly diagnosed familial Mediterranean fever

Özge Kaba1, Nuray Aktay Ayaz2, Şerife Gül Karadağ2, Mustafa Çakan2

1Pediatrics, Kanuni Sultan Süleyman Research and Training Hospital, İstanbul, Turkey; 2Pediatric Rheumatology, Kanuni Sultan Süleyman Research and Training Hospital, İstanbul, Turkey
Correspondence: Nuray Aktay Ayaz

Introduction: Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease, characterized by recurrent fever and self-limited paroxysmal attacks of serosal inflammation.

Objectives: The aim of this study was to evaluate whether iron homeostasis parameters in patients with AAA was improved by treatment with colchicine or not.

Methods: Forty-six pediatric patients with newly diagnosed FMF were included into the study. All patients were assessed in the attack-free periods for hemoglobin, hematocrit, platelet, serum amyloid A, iron, total iron binding capacity, and ferritin before the colchicine treatment, and on the 3rd and 5th months of colchicine treatment.

Results: We have found that there was a significant increase in mean hemoglobin values when compared the results of hemoglobin levels before the treatment and on the 5th month of the treatment (p = 0,048; <0,05). Also, we have observed the same increase in iron levels (p═0,004). We have seen that there was a significant decrease in ferritin and SAA levels and platelet counts, reflecting the control of ongoing inflammation. However, no significant difference was found between mean total iron binding capacity value, mean hematocrit values (Table 13).
Table 13

(abstract P13). See text for description

 

Before treatment

3th month of treatment

5th month of treatment

p*

HGB

12,11 ± 1,16 (12,08)

12,20 ± 1,03 (12,05)

12,38 ± 1,02 (12,31)

0,027*

HCT

38,05 ± 3,19 (38,02)

38,63 ± 3,45 (38,30)

38,82 ± 2,81 (38,27)

0,135

PLT

350.932 ± 110.096 (334.600)

310.671 ± 85.475 (309.850)

303.202 ± 81.570 (296.700)

<0,001*

SAA

192,19 ± 295,14 (38,95)

20,26 ± 46,58 (3,85)

9,68 ± 25,81 (3,30)

<0,001*

IRON

53,47 ± 29,56 (50,85)

66,76 ± 35,61 (56,50)

67,41 ± 31,15 (64,00)

<0,001*

TIBC

361,09 ± 52,93 (362,50)

364,78 ± 55,12 (365,00)

372,91 ± 48,92 (366,00)

0,163

FERRITIN

56,63 ± 42,46 (45,00)

34,69 ± 21,34 (30,55)

32,74 ± 23,80 (25,55)

0,002*

Conclusion: In conclusion, we think that colchicine may be effective in balancing the iron homeostasis that is disturbed by chronic inflammation in FMF.

Disclosure of Interest: None Declared

P14 Population based study of frequency of carrying FMF mutation among Armenian females

Artashes Tadevosyan1, Tigran Avagyan1, Gayane Amaryan2,3,4, Hasmik Hayrapetyan5, Anush Budumyan1

1Public Health, YEREVAN STATE MEDICAL UNIVERSITY, Yerevan, Armenia; 2Pediatrics, YEREVAN STATE MEDICAL UNIVERSITY, Yerevan, Armenia; 3National Pediatric Centre for Familial Mediterranean fever, Yerevan, Armenia; 4Arabkir” Joint Medical Centre - Institute of Child and Adolescent Health, Yerevan, Armenia; 5Centre of Medical Genetics - Primary Health Care, Yerevan, Armenia,
Correspondence: Tigran Avagyan

Introduction: The Familial Mediterranean fever (FMF; OMIM 249100) is the most common autoinflammatory syndrome in the group of hereditary periodic fever syndromes, widespread in Armenia. The existing information on frequency of carrying the mutations of FMF gene is hospital based data with subsequent recalculations. To our best knowledge this is first epidemiological population based study in Armenia.

Objectives: The objective is revealing the frequency of MEFV gene mutations and genotypes in Armenian female population in Republic of Armenia.

Methods: The proportionate random sampling technique was performed to select 173 females aged 18-19 years from Yerevan and all marzes (regions) of Armenia. Absence of history or clinical manifestation of FMF or any autoimmune inflammatory disease/syndrome was the premium inclusion criteria. Venous blood samples were taken in EDTA containing vials. Genomic DNA was isolated by means of “Puregene kit” (Gentra System, USA). Molecular-genetic testing performed in the laboratory of auto inflammation diseases of the Center of Medical Genetics and Primary Health Care that has an international certificate and is the best in the region. The most common for Armenian ethnicity 12 mutation were analyzed: M694V, M694I, M680I (G/C), M680I (G/A), V726A, E148Q, K695R, F479L, R761H, A744S, P369S, 1692del.

Results: 53 (30.6%) of females from total 173 carry at least one mutation of FMF gene. From tested 12 mutations only 9 were detected: M694V, M680I, V726A, E148Q, K695R, F479L, R761H, A744S, and P369S. The most frequent finding was M694V: 19 cases (38.8%), followed by V726A: 11cases (22.4%) and E148Q: 9 cases (18.4%). These three mutations cumulatively comprised almost 80% of all. Out of 53 carriers 49 were heterozygous and four carries two mutations. No homozygous were observed. E148Q mutation was presented in all four compound heterozygote carriers, two in combination with V726A and two with P369S.

Conclusion: The frequency of carrying of FMF gene mutation in Armenian non-symptomatic female population is 30.6%. The most common mutations are M694V, V726A, and E148Q. The M694V reported as the most frequent mutation in hospital settings as well, causing the most sever course of disease. Asymptomatic carrier of compound heterozygous genotype is rare, 2.3% only.

Disclosure of Interest: None Declared

P15 Is routine periodic laboratory work-up necessary for paediatric MEFV (mediterranean fever) carriers

Balahan Balahan, Nesrin Gülez

Behçet Uz Children s Hospital, Izmir, Turkey
Correspondence: Balahan Balahan

Introduction: Familial Mediterranean fever (FMF) is the most common hereditary auto-inflammatory disease in the world. Although FMF is inherited autosomal recessively, some heterozygotes may express disease phenotype and require therapy. On the other hand, some of the patients presenting manifestations evocative of FMF might happen to be heterozygotes coincidentally due to the high frequency of MEFV variants in at-risk populations.To date, there is no study in the literature about how to follow-up MEFV heterozygotes who do not fulfil FMF criteria.

Objectives: To share a single-center experience of the long-term clinical and laboratory follow-up of paediatric MEFV carriers.

Methods: The hospital charts of 240 children who were heterozygous for MEFV variants were retrospectively reviewed. Among them, 119 heterozygous patients fulfilled paediatric FMF diagnostic criteria and were started colchicine in the first 6 months of follow-up. Ten patients who fulfilled PFAPA syndrome with one MEFV mutation were excluded. 42 patients did not continue to be followed-up at our unit. So, the rest 69 heterozygotes were included in this study. Families were advised to record an FMF diary; including presence of fever, abdominal pain, chest pain, arthritis, arthralgia, myalgia, and erysipelas like erythema and also were asked to record the duration of these symptoms. Patients were asked to admit to hospital in case of any advocative FMF symptom lasting at least 6 hours in order to check acute phase reactants. The children were also followed-up with their routine analysis and serum amyloid A (SAA) levels every 6 months. The data of the visits in which an infection was reported were not included. The averages of all laboratory parameters were then calculated.

Results: 39 children had pathogenic mutations and 30 children had MEFV variants of unknown significance. The most common MEFV variants were M694V (n = 24) and E148Q (n = 16). The mean age at admission was 7.3 ± 3 years. The mean follow-up was 3.2 ± 1.6 years (min:2 max:6 years).

The median of average SAA level was 3.5 (3-38) mg/L and the median of average CRP level was 0.1 (0.01-1.8) mg/dl and mean of average ESR was 11.3 ± 5.4 (5-27) mm/hour. The children with pathogenic mutations had significantly higher mean SAA levels than the children with variants of unknown significance (p = 0.018), however; the mean CRP and ESR were similar. Besides, the children with pathogenic mutations had significantly more fever episodes than the children with variants of unknown significance (p = 0.04). None of the children had persistent proteinuria in the follow-up. We started colchicine in only 2 patients who were M694V heterozygous because of initiation of typical disease symptoms accompanied by at least one increased acute phase protein during an attack. Both patients had family history for FMF and fulfilled the disease criteria after 2 years of follow-up. Neither of these patients had persistently elevated acute phase reactants in their routine follow-up.

Conclusion: The results of this study suggested that routine clinical follow-up is useful; however, routine periodic laboratory work-up is not necessary among MEFV carriers. To the best of our knowledge, this is the first study about the long-term periodic clinical and laboratory follow-up of MEFV carriers in the literature.

Disclosure of Interest: None Declared

P16 Increased psoriasis frequency in patients with familial Mediterranean fever

Ezgi D. Batu1, Abdulsamet Erden2, Emrah Seyhoğlu3, Alper Sarı2, Hafize E. Sönmez1, Berkan Armagan2, Selcan Demir1, Emre Bilgin3, Levent Kılıç2, Ömer Karadağ2, Ali Akdoğan2, Yelda Bilginer1, Ihsan Ertenli2, Sedat Kiraz2, Sule A. Bilgen2, Umut Kalyoncu2, Seza Özen1

1Division of Rheumatology, Department of Pediatrics, HACETTEPE UNIVERSITY FACULTY OF MEDICINE, Ankara, Turkey; 2Division of Rheumatology, Department of Internal Medicine, HACETTEPE UNIVERSITY FACULTY OF MEDICINE, Ankara, Turkey; 3Department of Internal Medicine, HACETTEPE UNIVERSITY FACULTY OF MEDICINE, Ankara, Turkey
Correspondence: Ezgi D. Batu

Introduction: Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by MEFV mutations. FMF may be associated with psoriasis in some cases. The prevalence of psoriasis in normal Turkish population is 0.40%.

Objectives: We aimed to investigate the prevalence of psoriasis among FMF patients and their relatives.

Methods: FMF patients followed at Hacettepe University Adult and Pediatric Rheumatology Departments between January and August 2016 were included. FMF patients/their relatives were accepted to have psoriasis if the diagnosis was made by a dermatologist.

Results: 351 FMF patients (177 adults; 174 children) were included. The median (min-max) age of adult and pediatric patients was 35 (19-63) and 10 (2-18) years, respectively. Thirteen (3.7%) FMF patients (11 adults, 2 children) had psoriasis. Psoriasis was more common in adult than pediatric patients (p = 0.02). Psoriasis was present in 22 (12.4%) of adult and 9 (5.2%) of pediatric patients’ relatives (p = 0.023). The frequency of psoriasis in ≥1 relatives of FMF patients was found to be 8.8%. Abdominal pain and fever were significantly higher and arthralgia, arthritis, pleural chest pain, pericarditis, and erysipelas-like erythema were significantly less frequent in the pediatric group than adults (p < 0.05).

Conclusion: In our study, psoriasis was more common in FMF patients than the normal population. Thus, FMF patients should be questioned and carefully examined for psoriasis lesions and psoriasis family history. Prospective multicenter studies may be important to find the incidence of psoriasis in FMF.

Disclosure of Interest: None Declared

P17 Periodic fever, aphtous stomatitis, pharyngitis and cervical adentitis (PFAPA) syndrome. A qualitative study of parent's experiences and strategies

Carina Sparud-Lundin1, Stefan Berg2, Anders Fasth3, Anna Karlsson4, Per Wekell5

1Institute of Health and Care Sciences, Sahgrenska Academy, Goteborg, Sweden; 2Pediatric Immunology and Rheumatology, The Queen Silvia Children's Hospital, Goteborg, Sweden; 3Dept of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Goteborg, Sweden; 4Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Instutute of Medicine, Goteborg, Sweden; 5NU-Hospital Organisation, Dept of Pediatrics, Uddevalla, Sweden
Correspondence: Stefan Berg

Introduction: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a fairly common autoinflammatory disease. Still, knowledge of the effects of the recurrent fever episodes on the child and its family situation are limited.

Objectives: To examine the experiences of parents regarding the impact of the disease on the child's general well-being, the family's situation and how the family handles the associated challenges.

Methods: A qualitative approach was used, applying a modified version of Grounded theory for design, data collection and analysis. Data was collected from two different sources:

· Face-to face interviews with one of the parents of children diagnosed with PFAPA (n = 10, 6 mothers and 4 fathers)

· Communication between parents of children with PFAPA in a closed Facebook group

Results: The child´s well-being was highly affected by the symptoms during episodes. Parents experienced increased stress with constant fatigue, social constraints of family life and restricted career opportunities. Hope of a recovery was constantly present. Parents described a lengthy process, depicted in the following Grounded Theory core category: From uncertainty to gradually managing and awaiting recovery.

Subcategories (below) describes illness trajectory, illness representation and the experiences/impacts of the periodic condition:

Uncertainty (Harmlessness - severity)

·Worries · Fear · Frustration

Assurance (Establishment of diagnosis)

·Relief · Reassuring · Explaining · Guilt reducing

Gradually managing (Regularity - unpredictability)

·Suffering · Exhaustion · Isolation · Work-related limitations

Recovery

·Outgrowing PFAPA · Surgery (tonsillectomy)

Conclusion: Getting a diagnosis becomes very important for parents since this reduces uncertainty and feelings of guilt

Disclosure of Interest: None Declared

P18 Aicardi-Goutières syndrome with a novel mutation in the SAMHD1 gene

Sorina Boiu1, Adrianos Nezos2, Isabelle Melki3, Argirios Dinopoulos4, Erato Atsali1, Clio Mavragani2, Vana Papaevangelou5, Dimitrios Boumpas6

1Pediatric Rheumatology Unit, Third Department of Pediatrics, "Attikon" University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 2Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; 3Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR1163, Institut Imagine, Paris, France; 4Pediatric Neurology Unit, Third Department of Pediatrics, "Attikon" University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 5Third Department of Pediatrics, "Attikon" University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 6Joint Rheumatology Program, Fourth Department of Medicine, “Attikon” University Hospital, National and Kapodistrian University of Athens, Athens, Greece
Correspondence: Sorina Boiu

Introduction: Type I interferonopathies are a clinically heterogeneous group of Mendelian disorders characterized by constitutive upregulation of type I interferon activity. Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy and sometimes mimics a congenital viral infection. Over time, as many as 40% of patients develop chilblain skin lesions on the fingers, toes, and ears. Classical AGS phenotype was associated with mutations in seven genes encoding proteins involved in nucleotide metabolism and/or sensing: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7). Mutations in these genes result in the induction of type I interferon production and upregulation of interferon stimulated genes. However, the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.

Objectives: To identify the genetic cause for a phenotype associating severe encephalopathy and chilblain skin lesions in a twenty years old male.

Methods: A twenty years old male presented since early infancy with violaceous, scaling lesions of the fingers and toes, resorption of distal phalanges, dystrophic nail changes and, violaceous lesions on the nose that worsened during the cold season. He was diagnosed at the age of 7 years with Cornelia de Lange syndrome (CdLS) based on the phenotype associating severe somatic and psychomotor retardation, microcephaly, hypertrichosis, synophrys, arched palate, strabismus, hearing loss, cryptorchidism and unilateral vesicoureteral reflux with kidney scarring. Laboratory investigations showed mild thrombocytopenia and positive anti-thyroid antibodies. No cerebral imaging was ever performed. The patient consulted in our Clinic because of his severe peripheral vasculopathy. The interferon type I signature was determined in the peripheral blood of the patient and four age/sex matched healthy controls by quantitative PCR for 3 interferon-stimulated genes (ISGs) (MX-1, IFIT-1 and IFI44); a type I interferon score was calculated as previously described (Nezos et al. J. Autoimmunity, 2015). For disease gene identification, a next-generation sequencing (NGS) panel followed by Sanger sequencing were performed.

Results: The type I interferon score was markedly higher (98 times higher) in our patient compared to healthy controls. Using a next-generation sequencing panel, followed by Sanger confirmation, the patient was found to be homozygous for a novel c.66delC/p.SerGlnfs*43 variant in SAMHD1. Although not seen before, considering that this lesion is predicted to act as a biallelic nonsense mutation, and in light of the clinical features, this result confirmed the diagnosis of an Aicardi-Goutières syndrome. A cerebral MRI will be performed to evaluate the cerebrovascular involvement in this patient, considering the risk of intracerebral large vessel involvement with catastrophic cerebral vascular accidents associated with mutations in SAMHD1.

Conclusion: We describe a novel mutation in SAMHD1 in a patient with AGS, previously diagnosed with CdLS. It is important to consider the diagnosis of AGS in patients with neurologic symptoms in the presence of chilblain lesions.

Disclosure of Interest: None Declared

P19 The challenges to diagnose and treat a rare patient with candle syndrome

Martin Boyadzhiev1, Veselin Boyadzhiev1, Lachezar Marinov1, Violeta Iotova1, Sophie Hambleton2, Ivona Aksentijevich3

1Dept. of Pediatrics, Medical University, Varna, Bulgaria; 2Instituste of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom; 3National Human Genome Research Institute, National Institutes of Health, Washington D.C., United States
Correspondence: Martin Boyadzhiev

Introduction: Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) is a rare recessively inherited autoinflammatory syndrome, characterized by early-onset recurrent fevers, skin lesions, periorbital swelling, lipodistrophy, arthritis, myositis, short stature and hepatomegaly. It is caused by defects in assembly of the proteasome complex. Thus far, mutations have been identified in 5 genes although most commonly they are found in the PSMB8 gene.

Objectives: We present a 4 year old boy with a genetically confirmed diagnosis of CANDLE after presenting to our clinic with the typical clinical and laboratory features of the syndrome.

Methods: The patient was born at full-term and after uneventful pregnancy, to unrelated parents. At 20 days postnatal age a maculopapular rash appeared, initially confined to the extremities, and accompanied by fever. Over the next two years the rash spread to involve the face and body. He developed periorbital swelling, splenomegaly, leucocytosis, iron-deficiency anemia and thrombocytopenia. Fever, reaching up to 40 °C, was a consistent features of disease flares. Three skin biopsies were performed and showed evidence for perivascular and periadnexial infiltrations, consisting mainly of neutrophils. Bone marrow biopsy and immunologic investigations were unremarkable. Treatments with Hydroxychloroquine, Methotrexate and short courses of corticosteroid were tried with little to no effect.

At the age of 2 years and 10 months, the boy presented to our Clinic. Lipodystrophy, short stature (-4 SDS), typical facial features, longer IV-th and V-th fingers of both hands and hepatomegaly were noted in addition to the above features and a clinical diagnosis of CANDLE syndrome was made. Blood samples from the child and both parents were sent to NIH for genetic testing, revealing compound heterozygous mutations in the patient’s PSMB8 gene. The two mutations, p.A92V and p.K105Q, were previously associated with CANDLE. Each parent is heterozygous for one mutation.

Results: The patient has since been on treatment with oral Methylprednisolone that proved to be effective in controlling his skin rash and systemic inflammation at the cost of systemic side effects. Regular follow-up during the next two years showed nephrocalcinosis, which resolved with symptomatic therapy, and arterial hypertension, controlled by dual antihypertensive therapy. Preliminary reports in the literature showed that JAK-inhibitors might be very effective in controlling the disease activity and we hope to obtain this therapy for our patient.

Conclusion: CANDLE should be considered in patients who present with early-onset severe inflammation, typical skin rash, and lipodystrophy. Genetic testing is already available and although therapy is currently challenging, treatment with JAK-inhibitors holds promise for the future.

Disclosure of Interest: None Declared

P20 Complement endorse the pathogenesis in autoinflammation

Juergen Brunner1, Wilfried Posch2, Evelyn Rabensteiner1, Doris Wilflingseder2

1Pediatrics, Medical University Innsbruck, Innsbruck, Austria; 2Division of Hygiene and Medical Microbiology, Medical University Innsbruck, Innsbruck, Austria
Correspondence: Juergen Brunner

Introduction: The complement system represents a major part of the innate immune system, consisting of more than 30 different proteins in plasma and on cell surfaces and can be activated through three different pathways. Inflammasomes are also part of the innate immune system. A group of disorders in inflammasomes have been associated with autoinflammatory diseases (AIDs). Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease (CINCA/NOMID) were originally described as three distinct diseases. After the identification of their common genetic origin, i.e. mutations in the NLRP3 gene on chromosome 1q44, they are perceived as a continuum of one disease entity and labelled cryopyrin-associated periodic syndromes (CAPS). Aim of this preliminary study in a patient with MWS was to find a correlation between the complement system and a disorder of autoinflammation.

Objectives: Aim of this preliminary study in a patient with MWS was to find a correlation between the complement system and a disorder of autoinflammation.

Methods: PBMCs (peripheral blood mononuclear cells) were isolated from blood of a healthy donor and of an individual suffering from MWS by density gradient centrifugation using a Ficoll Paque Premium (GE Healthcare). After washing, PBMCs were incubated with anti-human CD14 Magnetic Beads (BD) to obtain CD14+ monocytes. These were stimulated by addition of cytokines (IL-4 and GM-CSF) for five days to generate immature moDCs (iDCs), which were used for cytokine ELISAs and flow cytometric analyses. IL-6 and IL-1β cytokine ELISAs were performed according to the manufacturer (Biolegend) following stimulation of cells using either LPS or differentially complement opsonized HIV-1. Phenotypical characterization of pathogen-exposed DCs was performed by analyzing characteristic surface markers (CD11c, DC-SIGN (C-type lectin receptor on DCs, characteristic marker for iDCs), CD86) by multi-color flow cytometry.

Results: IL-1β production of iDCs is higher in the patients cells than in the cells of the healthy donor. However, the most significant difference was shown in complement opsonized iDCs. DC-SIGN is higher expressed in complement opsonized iDCs in patient cells compared to cells of a healthy donor (37,12% v28,64%). DC-SIGN is also higher expressed in the iDCs of the MWS patient after stimulation with LPS.

Conclusion: The complement system may play an important role in the development of an proinflammatory milieu in patients with disorders of autoinflammation. The phenomenon shown in a patient with MWS has to be reproduced in more MWS patients a well as in patients with other disorder of autoinflammation.

Disclosure of Interest: None Declared

P21 Recurrent pericarditis: clinical course and treatment in pediatric patients

Camilla Celani1, Diala Khraiche2, Pierre Quartier3, Damien Bonnet2, Brigitte Bader-Meunier1

1Unité d'Immunologie-Hématologie et Rhumatologie Pédiatriques, Hopital Necker, Paris, France2Cardiologie pediatrique, Hopital Necker, Paris, France3Unitè d'Immunologie-Hématologie et Rhumatologie Pédiatriques, Hopital Necker, Paris, France
Correspondence: Camilla Celani

Introduction: Recurrent pericarditis is a common complication of acute pericarditis and affects 15-30% of patients after an initial attack. The etiology is poorly understood and about 80% of these recurrent pericarditis are "idiopathic". However, some data suggest an autoimmune or autoinflammatory mechanism. Colchicine associated with nonsteroidal anti-inflammatory drugs (NSAIDs) is the treatment of choice and the use of other treatments remains exceptional.

Objectives: To analyze the clinical findings, course and treatment of pediatric patients with recurrent pericarditis.

Methods: Retrospective monocentric study. Inclusion Criteria :1) patients with at least twice recurrence of recurrent pericarditis (RP) ; 2) followed at Necker hospital between 2006 and 2016. Exclusion Criteria : 1)Known history of autoimmune or autoinflammatory disease.

Results: Thirteen patients (10 F and 3 M) with recurrent pericarditis were included. The median age at disease onset (first episode of pericarditis) was 11.3 years (range 8 - 17). Two groups of patients could be identified: In group 1 (6 patients), the recurrent pericarditis occurred after surgical correction of cardiac malformations; in group 2 (7 patients), there was no history of cardiac disease. During the episodes of pericarditis, all patients showed fever, chest pain, electrocardiographic changes and increased white blood cell counts and C reactive protein (CRP median 181 mg/l, polymorphonuclear cells 13619 g/l,) without differences between the two groups. A family history of recurrent pericarditis was noted in 2 patients from the first group. Six patients had pleuritis and/or pneumonia with concomitant pleural effusion (3 patients in each group). Patients in group 1 had more recurrences than in group 2 (median 2.8 vs 1.5) during the same follow-up period (one year). ANA > 1/640 (Anti-nuclear autoantibodies) and anti-DNA were present in 2 patients of each groups. The pericardial biopsy was performed in 5 patients and displayed fibrosis and showed[an inflammatory tissue with predominance of neutrophils. Initial treatments was aspirin with anti-inflammatory dose, alone (5 patients) or in combination with Colchicine (4 patients), colchicine alone (1 patients) or in combination with ibuprofen (1 patient) and antibiotic therapy (2 patients). To prevent recurrence, six of patients were treated with NSAIDs associated to colchicine or indomethacin alone. Corticotherapy was required in 2 patients in group 2 . Anakinra was introduced in one of them because of corticodependence. Clinical remission was obtained in all patients after discontinuation of the treatment (10 patients) or under treatment (3patients). A heterozygous mutation of R92Q for the TRAPS gene was found in 1 of the 6 patients studied. No mutation in the MEFV gene was found.

Conclusion: Recurrent pericarditis can develop after cardiac surgery or can be isolated. The presence of fever, inflammatory syndrome, pericardial neutrophilic infiltrate, and the efficacy of anti-IL1 in some patients suggests that some recurrent pericarditis could be considered as auto-inflammatory disease. Furthermore the existence of familial cases in two patients suggests a genetic susceptibility. In conclusion early anti inflammatory treatment should be considered in recurrent pericarditis associated with an inflammatory syndrome, after rulling out an infection.

Disclosure of Interest: None Declared

P22 Sinogenic subdural empyema in two girls treated with Adalimumab for chronic recurrent multifocal osteomyelitis (CRMO)

Anne Estmann Christensen, Peter Toftedal

Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
Correspondence: Anne Estmann Christensen

Introduction: Sinusitis is a rare cause of intracranial infection in children. The morbidity and mortality remains high in reported series.

Objectives: We report two cases of sinusitis complicated with intracranial empyema in patients treated with tumor necrosis factor-alfa monoclonal antibody (Adalimumab) for CRMO.

Methods: Case report

Results: The two girls were 11 years old when the infectious complication developed.

Patient 1 had been treated with adalimumab for 15 months, as she developed fever, acute pansinusitis and orbital cellulitis and abscesses during vacation. She was treated with intravenous antibiotics and drainage. The treatment was continued after returning home, and clinical improvement and normalisation of C-reactive protein (CRP) was achieved. Mild and unspecific symptoms of headache, double vision and swelling of the forehead remained and was initially thought of as sequela after surgery. Upon further investigation papilloedema was recognised and a CT scan of the brain showed subdural empyema, intra cerebral oedema located in the frontal lope, abscesses intra orbital and in the forehead, continued sinusitis and subperiosteal abscess and osteomyelitis (Potts puffy tumor). An aggressive rhino- and neuro-surgical approach combined with long-term broad-spectrum antibiotic treatment was initiated. Despite this, osteomyelitis in the frontal bone reoccurred several times, latest 1½ year after the initial infection. Immunosuppressive drugs have been discontinued at the beginning of the infectious period.

Patient 2 was treated with methotrexate for a year and received adalimumab for a period of 3 months. In these months she developed chronic rhinitis and allergy was suspected but not confirmed. When psoriasis appeared adalimumab was stopped, but the chronic sinusitis persisted. Two months later she was admitted with high fever and convulsions. She had discrete increased white cell count in the spinal fluid and a CT scan showed pansinusitis but no ostitis or intra cerebral changes. Broad-spectrum antibiotic treatment was started together with drainage of the sinuses. She improved clinically but CRP remained elevated. A MRI of the head was planned, but before it was performed another convulsion occurred. MRI showed pansinusitis, osteitis and subdural empyema. Functional endoscopic sinus surgery (FESS) was performed and the girl is now improving on long-term antibiotic treatment. Methotrexate treatment was stopped at the initial symptoms of meningitis.

Conclusion: Tumor necrosis factor-alfa monoclonal antibody is an efficient anti-inflammatory drug used in treatment of several inflammatory diseases. The increased risk of infections is well known. Special attention should be drawn towards symptoms of chronic rhinitis/sinusitis, as severe intra cerebral complications, such as subdural empyema, may develop. Children with sinusitis and any neurologic finding, signs of complicated sinusitis such as Pott's puffy tumor or orbital cellulitis, or persistent headache, fever, or nausea and vomiting should have additional evaluation for sinogenic subdural empyema.

Written consent for publication has been obtained from the parents.

Disclosure of Interest: None Declared

P23 Spectrum of chronic recurrent multifocal osteomyelitis in a Belgian cohort of 25 children: clinical presentation, imaging, treatment and outcome

Lien De Somer1, Sara Kaut2, Ine Van den Wyngaert2, Davy Christiaens3, Carine Wouters1, Steven Pans3

1Department of Pediatric Rheumatology, UZ Leuven, Leuven, Belgium; 2Pediatrics, UZ Leuven, Leuven, Belgium; 3Radiology, UZ Leuven, Leuven, Belgium
Correspondence: Lien De Somer

Introduction: Chronic Recurrent Multifocal Osteomyelitis (CRMO) is a rare auto-inflammatory disorder, characterized by recurrent episodes of bone pain. Diagnosis can be challenging and is based on exclusion. Laboratory investigations, radiology and histology are necessary to make a differential diagnosis with malignancy, infectious osteomyelitis and juvenile idiopathic arthritis.

Objectives: To document clinical characteristics of pediatric patients diagnosed with CRMO. To collect data on outcome and management of the disease.

Methods: We reviewed clinical characteristics, radiological data and treatment in pediatric CRMO patients, followed at the pediatric rheumatology department of the University Hospital of Leuven.

Results: Twenty-five patients were enrolled, with a mean age of 10.1 years at onset of the disease. The mean age at diagnosis was 11.2 years, with a mean diagnostic delay of 14 months. Bone pain was the leading symptom (24/25 patients). On imaging, 148 lesions were identified with an average of 5,9 lesions per patient. The most common sites of involvement were the vertebrae (37%) and lower limbs (31%), followed by the pelvis (10%) and clavicle (9%). In almost half of patients (12/25) monotherapy with NSAIDs was sufficient to obtain remission. The remaining 13 patients received bisphosphonates as 2nd-line therapy. Methotrexate was prescribed in 5 patients. Two patients needed further therapy with biologicals: etanercept (n = 2) and tocilizumab (n = 1). Disease was in remission in 15/25 after a mean time of 22.7 months. The prognosis was worse in patients with spinal involvement, resulting in more long-term sequelae

Conclusion: We present a unique pediatric cohort of 25 CRMO patients. A typical pattern of bone involvement could be found on MRI. Lesions presented as areas of bone marrow edema, with an abnormal hyperintensity on STIR images and/or abnormal hypointensity on T1-weighted images and/or areas of contrast enhancement. NSAIDs were administered as first-line treatment. Second-line strategies included bisphosphonates, glucocorticosteroids, methotrexate, etanercept and tocilizumab

Disclosure of Interest: None Declared

P24 Clinical characteristics of familial Mediterranean fever patients according to their MEFV mutation

Pelin Esmeray1, Zehra S. Arıcı2, Hafize E. Sönmez2, Yelda Bilginer2, Seza Özen2

1Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey
Correspondence: Pelin Esmeray

Introduction: Familial Mediterranean fever (FMF) is the most common autoinflammatory disease in the world. It is an autosomal recessive disease caused by mutations in MEFV.

Objectives: The aim of this study is to evaluate the clinical characteristics of FMF patients in relation with their MEFV mutations.

Methods: 378 patients (0-18 years), who were followed up at the Department of Pediatric Rheumatology in Hacettepe University, Ankara, Turkey, between January 2005 and October 2016, were included in the study. Mutations in MEFV were evaluated in all of the patients. The clinical characteristics, disease activity, need for additional treatment and acute phase reactants were compared according to the mutations of the patients. We have also compared after dividing patients into two groups as patients with high-risk mutations (M694V/M694V, M680I/M680I, M694V/M680I) and others.

Results: 36.7% of the patients were homozygous for M694V. 14.3% M694V/M680I, 10% M694V/V726A, 9% M694V/-, 6% M694V/E148Q, 3.7% M680I/V726A, and 2.9% were M680I/M680I. The patients with M69V/M694V were significantly younger at disease onset than other patients (3 years vs 4 years, respectively; p = 0,021). In addition, the disease duration, disease activity, acute phase reactants, and AIDAI(auto-ınflammatory disease activity index) values were higher and need for additional therapy was more frequent among patients with M694V/M694V compared to others.The disease activity, acute phase reactants were higher and need for additional therapy was more frequent in patients with high-risk mutations than others (Table 14).
Table 14

(abstract P24). Clinical characteristics and laboratory findings of M694V homozygote patients

 

Others (n = 240)

M694V-Homozygote (n = 138)

p

Age of diagnosis (years),

5 (0-17)

4 (1-15)

0,098*

Disease duration (years),

6 (0-17)

7 (1-17)

0,004*

Attack status in last 6 months, n (%)

72 (30,0)

65 (47,1)

0,001**

Attacks frequency in last 6 months

2 (1-19)

2 (1-15)

0,722*

Disease activity score

0 (0-5)

1 (0-6)

<0,001*

AIDAI,

0 (0-14)

1 (0-9)

<0,001*

Regular drug use (n = 192), n (%)

86 (64,7)

38 (64,4)

0,973**

Need for addditional treatment (n = 192), n (%)

7 (5,3)

13 (22,0)

<0,001**

n: number of patient; %: Column percentage; *Mann-Whitney U Test; **Pearson chi-Square Test

Conclusion: The disease phenotype is more severe in patients with high-risk mutations. Therefore, close follow-up is critical for these patients.

Disclosure of Interest: None Declared

P25 Infection status in children with familial Mediterranean fever (FMF) according to MEFV

Pelin Esmeray1, Ezgi D. Batu2, Zehra S. Arıcı2, Hafize E. Sönmez2, Yelda Bilginer2, Seza Özen2

1Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey
Correspondence: Pelin Esmeray

Introduction: Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease which is characterized by recurrent, self-limited flares of fever associated with polyserositis. The association with infectious disease is not clear except for the association with helicobacter pylori infection.

Objectives: In this study, the aim was to assess whether there was a tendency to infections.

Methods: 197 children with FMF who were followed at the Department of Pediatric Rheumatology in Hacettepe University, Ankara, Turkey between May 2016 and October 2016 were included in the study. In immunodeficiencies, the tendency for infections are defined as acute otitis media, sinusitis and pneumonia frequencies in a year, intravenous antibiotic requirement, presence of abscess, presence of recurrent urinary tract infections and acute gastroenteritis. We have assessed these frequencies in our patient groups according to mutations and attack frequencies.

Results: 30.4% of the patients were in the M694V homozygote group and 42.1% were in high-risk mutation(M694V/M694V, M680I/M680I, M694V/M680I) group. When examining M694V homozygous patients; 3% of patients had more than 4 acute otitis media per year, 6.7% had sinusitis more than 4 per year, and 1.7 had more than 4 per month of upper respiratory tract infection. All of the patients had less than 2 pneumonia per year. Only 6.7% of patients needed intravenous antibiotics. Recurrent urinary tract infection was present in 3.3% and abscess was 1.7% of patients. 13.4% of the patients had a history of acute gastroenteritis.

When examining high-risk mutations patients; 3.6% of patients had more than 4 acute otitis media per year, 4.8% had sinusitis more than 4 per year, and 2.4% had more than 4 per month of upper respiratory tract infection. All of the patients had less than 2 pneumonia per year. 4.8% of patients needed intravenous antibiotics. Recurrent urinary tract infection was present in 3.6% and abscess was 1.2% of patients. 14.4% of the patients had a history of acute gastroenteritis.

There was no statistically significant difference in the incidence of infection between mutation groups.

When the patients who had an attack in the last 6 months were examined, there was no significantly difference in infection status.

When the patients, who had increase in any infection frequency, were evaluated according to the mutation groups and attack status in the last 6 months, there was no significantly difference between the groups.

Conclusion: FMF patients are not inclined to develop infections as in immunodeficiencies. It may be speculated that the abnormality in the innate immune system in these patients does not significantly inpair host defense. More extensive work on this issue may be needed.

Disclosure of Interest: None Declared

P26 Clinical characteristics of FMF patients according to age groups

Pelin Esmeray1, Ezgi D. Batu2, Hafize E. Sönmez2, Selcan Demir2, Yelda Bilginer2, Seza Özen2

1Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey
Correspondence: Pelin Esmeray

Introduction: Familial Mediterranean fever (FMF) is the most common autoinflammatory disease in the world. The disease course could be different in different age groups.

Objectives: In this study, we aimed to study the disease characteristics, treatment compliance and need for additional treatment according to age groups of FMF patients.

Methods: 378 FMF patients (0-18 years) followed at the Department of Pediatric Rheumatology in Hacettepe University, Ankara, Turkey, between January 2005 and October 2016 were included in the study. The patients were evaluated in three groups according to their age at disease onset; 0-5, 6-11, 12-18 years. The treatment compliance was evaluated in 199 out of 378 patients according to their present ages.

Results: The disease onset was ≤5 years in 69%, 6-11 years in 26%, and ≥12 years in 5% of patients. Fever symptom was significantly less frequent in the ≥12 years group than the other age groups. The characteristics of patients according to age groups (at symptom onset) are presented in Table 15. The disease onset was significantly younger in patients homozygous for M694V mutation than patients who were negative for M694V (p = 0.021). 64,6% of 199 patients were compliant to colchicine treatment. When we grouped these patients according to their present age, ≤5 years group was the most compliant and the adolescent patients (≥12 years of age) was the less compliant to treatment (p < 0.05).
Table 15

(abstract P26). See text for description

  

Onset age

 

p

 

≤5 yaş (n = 261)

6-11 yaş (n = 98)

≥12 yaş (n = 19)

 

Age (year), median (min-max)

10 (2-18)

13 (7-18)

17 (14-18)

<0,001*

Sex, n (%) Male

Girl

143 (54,8)

118 (45,2)

56 (57,1)

42 (42,9)

10 (52,6)

9 (47,4)

0,897**

Attack Status in Last 6 Months n (%)

100 (38,3)

29 (29,6)

8 (42,1)

0,237**

Attack frequency in the last 6 months median (min-max)

2 (1-19)

2 (1-6)

1,5 (1-3)

0,226*

ISSF, median (min-max)

1 (0-6)

1 (0-5)

1 (0-4)

0,103*

Treatment compliance (n = 192), n (%)

84 (66,7)

31 (57,4)

9 (75,0)

0,363**

Need for additional treatment (n = 192), n (%)

12 (9,5)

7 (13,0)

1 (8,3)

0,764**

Conclusion: The disease course may be different in different age groups in FMF. FMF may present with less typical phenotype when the symptoms start at an older age (less fever symptom in adolescent. Treatment compliance is very critical in FMF patients and our results have emphasized that poor compliance is an important problem in especially adolescent patients.

Disclosure of Interest: None Declared

P27 Oral findings in children with familial Mediterranean fever

Pelin Esmeray1, Ezgi D. Batu2, Zehra S. Arıcı2, Tülin I. Keçeli3, Yelda Bilginer2, Meryem Tekçiçek3, Seza Özen2

1Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Dentistry, Ankara, Turkey; 3Deparment of Pediatrics Pedodontology, Hacettepe University Faculty of Dentistry, Ankara, Turkey
Correspondence: Pelin Esmeray

Introduction: Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease which is characterized by recurrent, self-limited flares of fever associated with polyserositis. Oral apthosis and periodontitis may be seen in the course of the disease. However we lack studies on the dental care in pediatric FMF patients.

Objectives: In this study, the aim was to report the oral findings and to check the effects of tooth decay on disease course in children with FMF.

Methods: 199 children with FMF who were followed at the Department of Pediatric Rheumatology in Hacettepe University, Ankara, Turkey between May 2016 and October 2016 were included in the study.

Results: The characteristics of patients are presented in Table 16. The mean age of patients was 11.24 ± 4.04 years. Tooth decay was observed in 182 (91.5%) patients. Tongue abnormalities in 65 (32.8%), lip abnormalities in 13 (6.6%), buccal abnormalities in 6 (3%). Oral aphthosis occured in 21 (10.6%), and recurrent oral aphthosis in 67 (33.8%) patients. The median (min-max) dental plaque index was 1.26 (0-2.25), and the median gingival index was 0.87 (0-1.81). Erythrocyte sedimentation rate and the attack frequency at the last six months were both higher in the patients with tooth decay than patients who did not have decay. Tooth decay was more common away M694V homozygous patients (98.3% vs 88.6%, p = 0.025; respectively).
Table 16

(Abstract P27). The demographic and laboratory features of the patients

 

All patients (n = 199)

Patients with tooth decay (n = 182)

Patients who did not have tooth decay (n = 17)

 

median (minimum-maximum)

  

The status of attack at the last six months, n (%)

115 (57.7)

75 (97.4)

2 (2.6)

The frequency of attacks at the last six months (n = 115)

0.96 ± 2.08/0 (0-19)

2 (1-19)

2.5 (2-3)

 

n (%)

  

Deciduous tooth decay

166 (83,4)

  

Permanent tooth decay

104 (52,3)

  

Tooth decay

182 (91,5)

  

Dental plaque index

1.26/198 (0-2.25)

  

Gingival index

0.87/198 (0-1.81

  

Conclusion: The frequency of the tooth decay was higher in our patient group compared to previously reported Turkish figures(91.5% vs 69.8-73.1%; respectively). The attack frequency at the last six months was higher away patients with tooth decay. Our results may suggest that dental problems may be a trigger for inflammatory attack in FMF. On the other hand, the chronic inflammation itself may be a risk factor for tooth decay in FMF.

Disclosure of Interest: None Declared

P28 Successful use of tocilizumab, interleukin-6 (IL-6) inhibitor, in a child with TRAPS

Abstract withdrawn

P29 The Eurofever project: an update on the longitudinal stage

Martina Finetti, Silvia Federici, Joost Frenkel, Seza Ozen, Helen Lachmann, Fabrizio De Benedetti, Joost Swart, Luca Cantarini, Romina Gallizzi, Marco Cattalini, Rolando Cimaz, Donato Rigante, Jordi Anton, Maria Alessio, Alma Nunzia Olivieri, Pavla Dolezalova, Annette Jansson, Giovanna Fabio, Judith Sanchez Manubens, Eric Hachulla, Rita Consolini, Karoline Krause, Zelal Ekinci, Jurgen Brunner, Isabelle Koné-Paut, Giovanni Filocamo, Maria del Carmen Pinedo, Efimia Papadopoulou-Alataki, Liliana Bezrodnik, Alberto Martini, Nicola Ruperto, Marco Gattorno and on behalf of Eurofever Project

Pediatria II - Reumatologia, Istituto Giannina Gaslini on behalf of Eurofever Project, Genoa, Italy
Correspondence: Martina Finetti

Introduction: In 2008 the Paediatric Rheumathology European Society (PReS) promoted an International Project (EAHC, Project No2007332) for the study of Autoinflammatory Diseases (AIDs) named Eurofever, whose main purpose is to create a web-based registry for the collection of clinical, laboratory, instrumental and response to treatment information in patients with AIDs.

Objectives: To implement the Registry with the new recently described AIDs and to increase the collection of longitudinal data, particularly regarding treatment and safety.

Methods: The data analysed in the study were extracted from the Eurofever registry, which is hosted in the PRINTO website (http://www.printo.it). From February 2015 we started the longitudinal collection of follow-up data for the patients already included in the Registry with particular focus on treatment, modification of the clinical picture, onset of complication/sequelae/adverse events.

Results: Up to date 3648 patients (M:F = 1799:1849) have been enrolled in the Registry from 60 different countries (all of them with available baseline demographic information). In 3183 pts (87%) complete clinical information and response to treatment data from disease onset to diagnosis are also available. For each disease the number of enrolled patients is: FMF 1012 pts (877 with complete clinical data); CAPS 289 pts (268 with complete clinical data); TRAPS 272 pts (254 with complete clinical data); MKD 203 pts (188 with complete clinical data); Blau’s disease 50 pts (26 with complete clinical data); PAPA 35 pts (all of them with complete clinical data); NLRP-12 mediated periodic fever 13 pts (10 with complete clinical data); DADA2 10 pts (6 with complete clinical data); SAVI 3 pts (all of them with complete clinical data); DIRA 3 pts (all of them with complete clinical data); Majeed 3 pts (all of them with complete clinical data); CANDLE 1 pt (with complete clinical data). Among multifactorial autoinflammatory diseases: PFAPA 653 pts (530 with complete clinical data); CRMO 535 pts (513 with complete clinical data); 340 pts with undefined periodic fever (269 with complete clinical data); Bechet disease 215 pts (186 with complete clinical data) and Schnitzler syndrome 11 pts (all of them with complete clinical data).

Longitudinal data are available for 393 pts (11%, M:F = 190:203). For each disease, the number of patients with at least one follow-up visit is: FMF 72 pts, CAPS 36 pts, TRAPS 32 pts, MKD 29 pts, PAPA 6 pts, DADA2 3 pts, SAVI 1 pt, DIRA 1 pt. Among multifactorial diseases: CRMO 99 pts, Bechet disease 67 pts, undefined periodic fever 29 pts, PFAPA 14 pts, Schnitzler syndrome 4 pts.

Conclusion: The enrolment in Eurofever Registry is still ongoing. The longitudinal collection and analysis of data coming from the Registry will improve our knowledge both on the natural history of the single disease and on the efficacy/safety of treatment commonly used in the clinical practice.

Disclosure of Interest: M. Finetti: None Declared, S. Federici: None Declared, J. Frenkel: None Declared, S. Ozen: None Declared, H. Lachmann: None Declared, F. De Benedetti: None Declared, J. Swart: None Declared, L. Cantarini: None Declared, R. Gallizzi: None Declared, M. Cattalini: None Declared, R. Cimaz: None Declared, D. Rigante: None Declared, J. Anton: None Declared, M. Alessio: None Declared, A. N. Olivieri: None Declared, P. Dolezalova: None Declared, A. Jansson: None Declared, G. Fabio: None Declared, J. Sanchez Manubens: None Declared, E. Hachulla: None Declared, R. Consolini: None Declared, K. Krause: None Declared, Z. Ekinci: None Declared, J. Brunner: None Declared, I. Koné-Paut: None Declared, G. Filocamo: None Declared, M. D. C. Pinedo: None Declared, E. Papadopoulou-Alataki : None Declared, L. Bezrodnik: None Declared, A. Martini Grant/Research Support from: Starting from 1 march 2016 I became the Scientific Director of the G. Gaslini Hospital, therefore my role does not allow me to render private consultancies resulting in personal income. I perform consultancy activities on behalf of the Gaslini Institute for the following companies: Abbvie, Boehringer, Novartis, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute's bank account., N. Ruperto Grant/Research Support from: The G. Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from BMS, Hoffman-La Roche, Janssen, Novartis, Pfizer and Sobi for the coordination activity of the PRINTO network. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Speaker Bureau of: Abbvie, Ablynx, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol Myers Squibb,, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, Medimmune, Novartis, Pfizer, Rpharm, Roche, Sanofi., M. Gattorno Grant/Research Support from: Unrestricted grant from SOBI and NOVARTIS

P30 Mevalonate-kinase deficiency in the Czech Republic

Abstract withdrawn

P31 Eye manifestations of patients with Muckle-Wells syndrome

sukru cekic1, ozgur yalcinbayır2, Sara Sebnem Kilic1

1Pediatric Rheumatology, Uludag University Medical Faculty, Bursa, Turkey; 2ophthalmatology, Uludag University Medical Faculty, Bursa, Turkey
Correspondence: Sara Sebnem Kilic

Introduction: CAPS is a rare autoinflammatory disease associated with mutations in the CIAS1 gene, encoding for NLRP3 that result in overactivation of the inflammasome and systemic inflammation. Muckle-Wells syndrome (MWS) is a rare autosomal dominant disease which causes episodic fever attacks, sensorineural deafness, recurrent hives, arthritis and eye involvement.

Objectives: Here we present the findings of eye involvement in a family whose 11 members have MWS.

Methods: Clinical data was collected during the course of ongoing patient care.

Results: We evaluated the clinical features of 11 patients who were referred to a tertiary care center. The median age of the patients was 25 years (range: 9-65). The ratio of females/males was 1.2 (6/5). All patients had arthritis with exacerbation on exposure to cold and recurrent episodes of pink eye. The median age of onset of ocular involvement was 8 years (2-45). We observed severe eye involvement in 27% of our cases, including band keratopathy, severe damage of corneal stroma and neovascularization. Corneal involvement and clouding was detected in four patient. Two of those had the diagnosis of keratoconus as well. Patients with keratoconus had corneal scarring due to corneal hydrops verified with corneal topography. The other two patients with corneal clouding had bant keratopathy. One of those patient was a 17 year old girl who had recurrent uveitis with hypopyon which necessiated the use of intravitreal dexamethasone implant. She also had posterior synechia of the iris to the lens. The other eye of that patient had signs of phthisis bulbi. The other patient with bant keraopathy was 46 years old male who had optic atrophy and tractional fibrovascular membranes at the posterior pole of the eye. Anakinra was used for treatment of 5 cases, and canakinumab of 3 cases. It was observed that the frequency of conjunctivitis decreased after anti IL-1 therapy. There was no mutation detected in the study of MEFV (all exons), TNFRSF1A (exons 2 to 7), MVK (all exons), NLRP3 (all exons), NOD2 (exons 4, 8 and 9) and PSTPIP1 (exons 10 and 11) genes.

Conclusion: In this study, it has been shown that eye findings related to MWS can vary from conjunctivitis to severe uveitis. We want to emphasize that ocular involvement in MWS should be carefully assessed, since it can lead to visual impairment.

Trial registration identifying number:

Disclosure of Interest: None Declared

P32 Clinical comparison of patients with unifocal and multifocal chronic recurrent multifocal osteomyelitis in an Irish cohort

Daire O'Leary1, Anthony Gerard Wilson2, Emma-Jane MacDermott3, Orla Killeen3

1Paediatric Department, RCSI, Dublin, Ireland; 2School of Medicine, UCD, Dublin, Ireland; 3National Centre for Paediatric Rheumatology, Our Lady's Children's Hospital, Dublin, Ireland
Correspondence: Orla Killeen

Introduction: Chronic recurrent multifocal osteomyelitis (CRMO) is an auto-inflammatory condition primarily affecting children with an estimated prevalence of 1 per 106. The umbrella term CRMO includes patients unifocal and multifocal disease that meet the diagnostic criteria.

Objectives: To describe clinical phenotype of an Irish cohort of patients with CRMO and compare those with unifocal and multifocal disease.

Methods: This study was a retrospective chart review of a prospectively gathered cohort of patients attending a single paediatric rheumatology centre.

Results: Since 2006, 42 patients have been diagnosed with CRMO at the National Centre for Paediatric Rheumatology (NCPR) and 5 of these have unifocal disease. Patients with unifocal disease had a single site involved throughout the disease. Three patients with unifocal disease had a single symptomatic episode. All patients met the diagnostic criteria proposed by Jansson et al and are ethnically Irish. Overall the mean age at diagnosis was 10.4 years, diagnostic delay was 0.78 years and number of physicians seen prior to referral to paediatric rheumatology was 3.5. All patients with unifocal disease and 68% of patients with multifocal disease were female (overall F:M = :1). The distribution of lesions was similar in both groups. In patients with unifocal disease, all underwent biopsy to confirm the diagnosis, none had systemic symptoms at presentation, synovitis at any stage or a personal history/first-degree relative with an associated autoimmune disease. In patients with multifocal disease, 81% underwent biopsy, 24% had systemic symptoms at presentation, 21% had synovitis and 38% had a personal history/first-degree relative with autoimmune disease. 1 patient (20%) with unifocal disease was refractory to NSAID treatment and received methotrexate. 14 patients (38%) with multifocal disease were refractory to NSAID treatment and received methotrexate, corticosteroids, anti-TNF, pamidronate or a combination of these.

Conclusion: The clinical phenotype of patients with unifocal CRMO appears to be different to those with multifocal disease. It may be less frequently associated with other autoimmune or autoinflammatory conditions and more frequently responsive to NSAID treatment alone. However, the number of patients with unifocal disease in this cohort was low.

Disclosure of Interest: None Declared

Bone in rheumatic diseases

P33 Magnetic resonance imaging bone marrow oedema in children: insight to comprehension and clinical significance

Federico Caldonazzi1, Sara Pieropan2, Maddalena Maschio3, Gloria Dallagiacoma2, Daniela Degani3, Giorgio Piacentini3, Diego A. Ramaroli3, Domenico Biasi2, Maurizio Rossini2

1UOC di Pediatria, Universita' degli Studi di Verona, Verona, Italy; 2UOC di Reumatologia, Università degli Studi di Verona, Verona, Italy; 3UOC di Pediatria, Università degli Studi di Verona, Verona, Italy
Correspondence: Federico Caldonazzi

Introduction: Bone marrow oedema in a child is a rare and uncommon condition associated with joint and bone pain exacerbated by weight bearing.

Objectives: We re-evaluated in the period of 2015-2016 seven pediatric patients referred to our Rheumatology Clinic for persistent foot pain with MRI oedema of the feet bones (interpreted commonly as algodystrophic syndrome manifestation); they had all been misdiagnosed in other institutions as affected by algodystrophy of the ankle/feet or complex regional pain syndrome (CRPS).

Methods: All the patients were re-evaluated with clinical examination, blood samples of bone turnover and vitamin D levels.

Results: Mean age of the 7 patients (F:M 6:1) was 11 years. 3 of the patients (43%) had a previous diagnosis of oligoarticular juvenile idiopathic arthritis ANA+ with the disease in complete remission at the moment of the clinical evaluation; 4 patients did not suffer from any chronic disease.

Physical examination did not reveal any skin color change (rubor) but intense pain limited to the skeletal sites of feet and ankles; only two patients (28%) had a slight swelling of the feet.

6 of the patients suffered from joint hypermobility with recall of minor ankle strain prior to the symptoms onset as precipitating event after meticulous history; 1 was a football player and reported recurrent feet microtrauma.

1 patient had been treated in another institution with bisphosphonates without any improvement. Bone turnover markers were normal in the 6 patients not treated previously with bisphosphonates; vitamin D was below the lower limits in all patients (72% < 20 ng/mL).

All Patients were treated with an adequate daily vitamin D intake and symptomatic pain relief was achieved with low dose NSAIDs (ibuprofen) or a short course of steroid treatment (prednisone); rest and physical therapy were recommended; vitamin C was added when diet intake was too low according to minimal daily diet recommendations. Clinical improvement appeared within a 2 to 3 month treatment period in all patients; MRI performed in the 3 patients with over 6 month of treatment documented complete regression of bone marrow oedema.

Conclusion: Symptoms and disability out of proportion to the clinical findings is a clinical key feature of MRI bone oedema of painful skeletal sites in children; differential diagnosis with the multifacet pediatric CRPS is possible when bone oedema is associated with limited clinical findings; it may be secondary to underestimated articular microtraumatisms in a bone turnover milieu of vitamin D deficiency; we underline the importance of supplementing vitamin D until the age of 18 as daily drops, in order to avoid its deficiency, which, in combination with other environmental and predisposing factors, could be the cause of invalidating clinical complaints.

Disclosure of Interest: None Declared

P34 Performance of bone scan compared to whole body-MRI in evaluation of chronic non-bacterial osteomyelitis

Pei Ling Ooi1, Gemma Buckley2, Lorenzo Biassoni2, Marina Easty2, Sandrine Compeyrot-Lacassagne1

1Department of Rheumatology, Great Ormond Street Hospital for Children, London, United Kingdom; 2Department of Radiology, Great Ormond Street Hospital for Children, London, United Kingdom
Correspondence: Pei Ling Ooi

Introduction: Chronic non-bacterial osteomyelitis (CNO) is a rare non-infectious inflammatory bone disorder that affects young children and adolescents. It usually affects multiple sites and most commonly the metaphyseal regions of long bones in the lower limbs, pelvis and clavicles.

There is presently no approved guideline for evaluation of bone inflammation in chronic non-bacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO). Bone scan (BS) has been the conventional imaging modality used to evaluate this rare inflammatory bone disease. While recent literature suggests whole body-magnetic resonance imaging (WB-MRI) as the imaging modality of choice, limited resources and high costs are often prohibitive.

Objectives: We aimed to compare the diagnostic yield of bone scan to WB-MRI in CRMO in relation to clinical symptoms and location of lesions on imaging.

Methods: A retrospective review of clinical notes of children with CNO/CRMO was performed. 7 patients with paired BS and WB-MRI performed less than 9 weeks apart between September 2009 and October 2015 were analysed. Patients were excluded if both scans were done more than 9 weeks apart or if there was treatment change between scans.

Results: Four sets of scans were performed at diagnosis and 3 sets after initiation of treatment. BS and WB-MRI detected a total of 29 and 40 lesions respectively. 6 out of 7 patients had asymptomatic lesions. 17/29 (58.6%) and 27/40 (67.5%) were found on BS and WB-MRI respectively.

Symmetrical lesions were detected in 4/7 patients with no significant difference between both modalities (BS 43% vs MRI 57%). All symmetrical lesions occurred in the pelvis and lower limbs. BS was superior in detecting lesions in the spine (85.7% vs 57.4%) and feet (42.8% vs 14.29%), whereas WB-MRI was better for upper limb (0% vs 14.29%) and lower limb (57.1% vs 71.4%) lesions. Both performed equally in detecting lesions in the pelvis and clavicles, with an incidence of 85.7% and 28.6% respectively.

None of the differences in results reached statistical significance but our cohort of patients was small.

Conclusion: Whole body bone scan performs comparably to MRI in detecting inflammatory bone lesions in CRMO, both symptomatic and asymptomatic. Bone scan remains an appropriate and accessible imaging modality in the evaluation of CRMO, particularly in institutions where resources are limited.

Disclosure of Interest: None Declared

P35 The status of bone metabolism in children with juvenile idiopathic arthritis

Yury M. Spivakovskiy1, Anna Spivakovskaja1, Youri Chernenkov1, Natalya Zacharova2

1Department of Hospitality Pediatrics, SARATOV STATE MEDICAL UNIVERSITY, Saratov, Russian Federation; 2SARATOV STATE MEDICAL UNIVERSITY, Saratov, Russian Federation
Correspondence: Yury M. Spivakovskiy

Introduction: The decrease in mineral bone density (BMD) is one of the main manifestations of juvenile idiopathic arthritis (JIA).

Objectives: To evaluate indicators of bone metabolism in patients with articular JIA.

Methods: The study included 66 patients with articular variant of JIA (36 oligoarticular variant of the disease, 30 - with polyarticular), whose average age of 9.74 + 3.56 years, boys – 28, girls - 38. All patients by ELISA in the serum was assessed level: beta crosslaps c-terminal telopeptide (CL), osteoprotegerin (OPG), a membrane protein RANKLand 25-hydroxycholecalciferol (25(Oh)D), carried out ultrasonic densitometry. The obtained data were compared with the results defined in the group of children without signs of inflammatory diseases (comparison group).

Results: The results of densitometry showed a reduction in BMD in the range Z = -1,1 -2,6 SD up to 40% of cases with oligoarticular the form of JIA and in 57,7% of cases, polyarticular JIA variant. Deficiency of 25(Oh)D in blood serum of examined children with oligoarthritis and polyarthritis detected at 23.3% and 50%, respectively, and the failure is at 76,7% and 50%, respectively. In the control group, these figures were 10% and 75%, respectively. The ratio of RANKL/OPG in children with oligoarthritis were 0.17 and polyarthritis - 0,22 in the control group - 0,07. Indicators of CL, indicating bone resorption in the group of oligoarthritis was increased at 93.3%, in the group of polyarthritis in 100%.

Conclusion: Thus, in patients with JIA is a decrease in BMD, with changes in biochemical parameters outstrip the capabilities of the method of instrumental diagnosis (densitometry) and can be recommended for research on early stages of osteopenia providing for timely correction of bone metabolism.

Disclosure of Interest: None Declared

P36 Tocilizumab (ANTI-IL6R MOAB) achieves complete and sustained remission in a patient with refractory CRMO

Abstract withdrawn

Disease outcome

P37 Intraarticular corticosteroid injections (IACI) of temporo-mandibular joints (TMJ) in juvenile idiopathic arthritis (JIA): the patients’ perspective

Alessia Arduini1, Denise Pires-Marafon2, Rebecca Nicolai2, Aurora Pucacco2, Fabrizio De Benedetti2, Silvia Magni-Manzoni2

1Pediatrics, Policlinico Umberto I, “La Sapienza” University, Rome, Italy 2Rheumatology, IRCCS Bambino Gesù Hospital, Rome, Italy
Correspondence: Alessia Arduini

Introduction: Several studies investigated the accuracy and efficacy of IACI for the treatment of TMJ involvement in JIA. However, the impact on patients’ daily activities and patients’ acceptance of TMJ IACI has been scarcely studied.

Objectives: To detect variations in daily activities involving TMJs in patients with JIA, before and after TMJ IACI, through a Juvenile Arthritis TMJ self-reported Assessment (JATA) questionnaire, developed for the purpose. Second aim: to assess the patients’ acceptance of the TMJ IACI procedure at the study center.

Methods: Patients with JIA and clinical involvement of TMJ consecutively seen at the study center in September-December 2016, with at least 8 years of age, were asked to identify the daily activities most affected by TMJ arthritis. From the collected items, we asked them to select the most relevant and representative of “TMJ well-being/worsening” in their daily life. We included in the JATA the items most frequently selected and a patient’s global assessment (GA) of their TMJs (VAS 0-10; 0 = worst; 10 = best). Then, a subgroup of patients, who underwent to intraarticular corticosteroid injection (IACI) of one or both TMJ, was asked to complete the questionnaire (VAS 0-10; 0 = totally unable, 10 = fully able) and TMJ-GA, before and after the therapeutic intervention. Further, we asked the patients to provide a global assessment of the TMJ IACI procedure performed at the study center (VAS 0-10; 0 = worst; 10 = best). Statistical analysis was performed using GraphPad Prism 5 software. Scores of each item and JATA-score were compared between pre- and post-TMJ IACI (Wilcoxon matched pairs test, statistical significance: p <0.05).

Results: Twenty (77%) out of the 26 eligible JIA patients identified daily activities most relevantly affected by TMJ involvement. Thereafter, the items most frequently selected were included in the JATA: 1.ability to bite a sandwich/an apple/a “bombolone”; 2.ability to eat a pizza or a steak; and 3.ability to accurately wash the teeth. Eight patients (100% female, 62.5% with persistent oligoarthritis and 12.5% with extended oligoarthritis, polyarticular RF-negative, and polyarticular RF-positive, respectively) filled the JATA questionnaire, reporting their abilities and global assessment of TMJ before and after TMJ IACI. Each questionnaire was completed in about 3-5 minutes. We observed a statistically significant improvement in the scores, both of the single items and the TMJ-GA, prior and after TMJ IACI (Table 17). The procedure was evaluated with a median score of 8 (IQR: 7.8-10).
Table 17

(Abstract P37). Comparison between JATA single-item scores and JATA TMJ-GA before and after TMJ intraarticular corticosteroid injection (IACI); VAS 0-10 (0 = worst;10 = best). Values are expressed as median (IQ). Wilcoxon test; statistical significance: p < 0.05.

 

Pre-TMJ IACI

Post-TMJ IACI

p

Ability to bite a sandwich/an apple/a “bombolone”

5,0 (4,8-6,0)

9,0 (8,0-10,0)

0,022

Ability to eat a pizza or a steak

5,0 (4,0-7,0)

9,0 (8,5-10,0)

0,036

Ability to accurately wash the teeth

4,0 (4,0-7,3)

10,0 (9,5-10,0)

0,035

TMJ global assessment

5,0 (3,0-5,3)

9,0 (8,5-9,5)

0,022

Conclusion: The JATA questionnaire demonstrated to be easily applicable and showed significant improvement of each item, after TMJ IACI. TMJ IACI procedure at the study center was well accepted. Further studies are planned to confirm these results and investigate the applicability of JATA in clinical practice and research.

Disclosure of Interest: None Declared

P38 Early pain report in oligoarticular juvenile idiopathic arthritis is related to long-term outcome

Ellen D. Arnstad1,2, Veronika G. Rypdal3,4, Suvi Peltoniemi5, Ellen Nordal3,4, Lillemor Berntson6, Kristiina Aalto5, Anders Fasth7, Troels Herlin8, Susan Nielsen9, Marek Zak9, Pål R. Romundstad10, Marite Rygg2,11 and Nordic Study Group of Pediatric Rheumatology (NoSPeR)

1Department of Pediatrics, Levanger Hospital, Levanger, Norway; 2Department of Laboratory Medicine, Children’s and Women’s Health, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; 3Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway; 4Department of Clinical Medicine, UIT The Arctic University of Norway, Tromsø, Norway; 5Department of Pediatrics, Children’s Hospital, Helsinki University Hospital, Helsinki, Finland; 6Department of Women`s and Children`s Health, Uppsala University, Uppsala, Sweden; 7Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden; 8Department of Pediatrics, Århus University Hospital, Århus, Denmark; 9Pediatric Rheumatology Department, Pediatric Clinic II, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 10Department of Public Health and General Practice, NTNU - Norwegian University of Science and Technology; 11Department of Pediatrics, St. Olavs Hospital, Trondheim, Norway
Correspondence: Ellen D. Arnstad

Introduction: Persistent course oligoarticular juvenile idiopathic arthritis (JIA) has the best prognosis of all JIA categories. One third of children with oligoarticular onset will, however, develop oligoarticular extended JIA or other JIA categories during the course of the disease with outcome similar to polyarticular disease (1). Therefore it is important to look for early predictive factors to define long-term outcome for these children. Pain is a frequent complaint, and knowledge of pain and its relevance for disease outcome is limited.

Objectives: To study if self-reported pain early in disease course can predict long-term disease outcome among children with oligoarticular JIA.

Methods: Consecutive cases of JIA from defined areas of Norway, Denmark, Sweden and Finland with onset in 1997 to 2000 were prospectively included in a population-based cohort study (1). Self-reported pain was measured on a 10 cm visual analogue scale (VASpain). The Finnish participants were excluded due to lack of pain scores. Remission at 8 years follow-up was defined according to Wallace (2). We used binomial regression in STATA for multivariable analyses.

Results: The final study population consisted of 243 children, and of these 120 (49%) had oligoarticular disease 6 months after disease onset. Median age at onset in the oligoarticular group was 5.0 years, 73% were girls and 67% reported VASpain >0 six months after disease onset. At 8 years follow-up 43% had developed oligoarticular extended or other JIA categories, 49% reported VASpain >0 and 53% were not in remission off medication.

In the oligoarticular onset group, we analyzed associations between early pain reports and outcome at 8 years follow-up. Children reporting pain 6 months after disease onset developed oligoarticular extended or other JIA categories more often compared to those reporting no pain at 6 months (percent point difference 19%, 95% CI [1-37%]). Among those reporting pain at 6 months, a higher proportion reported pain also at 8 years, compared to children with no pain at 6 months (percent point difference 35%, 95% CI [16-53%]. Pain at 6 months was associated with not being in remission off medication at 8 years compared to no pain at 6 months (percent point difference 36%, 95% CI [19-54%]. After adjustments for age and sex, the results were similar.

Conclusion: Early pain report among children with oligoarticular JIA seems to predict development into prognostically more unfavourable JIA categories, more pain persistence and more severe long-term disease outcome.

References:

1. Nordal E, et al. Arthritis Rheum 2011;63:2809-18

2. Wallace CA, et al. J Rheumatol 2004;31:2290-4

Trial registration identifying number:

Disclosure of Interest: None Declared

P39 HLA II class alleles in juvenile idiopathic arthritis patients with and without chronic arthritis signs in temporomandibular joints evaluated with contrast enhanced MRI

Zane Davidsone1,2, Elena Eglite3, Aleksandrs Kolesovs4, Ruta Santere1, Valda Stanevica1

1Rheumatology, Childrens university hospital, Riga, Latvia; 2Pediatric, Riga`s Stradins University, Riga, Latvia; 3Laboratory of clinical immunology and immunogenetics, Riga Stradins University, Riga, Latvia; 4University of Latvia, Riga, Latvia
Correspondence: Zane Davidsone

Introduction: Temporomandibular joint (TMJ) involvement with both active and chronic signs of arthritis is seen very often (17-87%) in children with juvenile idiopathic arthritis. Contrast enhanced MRI is the golden standart for diagnosis of TMJ arthritis. There are data that specific HLA II class alleles can be asociated with more severe disease course and radiologic progression in patients with rheumatoid arthritis.

Objectives: To identify HLA II class alleles of risk and protection in JIA patients with chronic arthritis signs in temporomandibular joints evaluated with contrast enhanced MRI.

Methods: We performed retrospective study with 72 JIA patients treated at Childrens university hospital in whom TMJ MRI was performed and acute or chronic or both signs of arthritis were detected. Patients were genotyped for HLA- DRB1; DQB1; DQA1- using RT-PCR with sequence-specific primers. Associations of DRB1; DQB1; DQA1 alleles in patients were examined individually using the Chi-square test and Cochran-Mantel-Haenszel test.

Results: 72 JIA patients with mean age of 13.9 years (range 6.0-17.9 yr); 48 (77%) girls and 14 (23%) boys. The mean duration of the disease from the time of diagnosis till performing TMJ MRI was 1.5 years (range 0.2-8.0 yr). JIA subtypes were as follows: seronegative polyarthritis 60%, seropositive polyarthritis 8%, peristant olygoarthritis 2%, arthritis with enthesitis 9%, undifferentiated 3% and 2%for systemic arthritis.

Two groups were separated on the basis of presence of chronic arthritis signs (n = 62) or absence of them (n = 10). Alleles DRB1*14 (OR = 0.19, 95% CI from 0.04 to 0.92, p = 0.039) and DQA1*05:01 (OR = 0.29, 95% CI from 0.11 to 0.80, p = 0.016) were less often observed in the group with chronic arthritis signs than in the group without them. There were no longer duration of disease in the group with chronic arthritis signs (1,47 ± 1,98) compared with 2nd group (2,71 ± 3,30) (p = 0,173).

Conclusion: Alleles DRB1*14 and DQA1*05:01 are possibly protective for development of structural damage in temporomandibular joints in JIA patients and is not dependent on duration of the disease.

Disclosure of Interest: None Declared

P40 The role of antinuclear antibodies positivity in predicting clinical remission in juvenile idiopathic arthritis

Raquel M. Ferreira, Francisca Aguiar, Mariana Rodrigues, Iva Brito

São João Hospital Centre, Porto, Portugal
Correspondence: Raquel M. Ferreira

Introduction: Juvenile idiopathic arthritis (JIA) consists of an auto-immune condition with several subgroups with distint clinical, laboratory features and therapy response. Although antinuclear antibody (ANA) positivity can be found in all subtypes, a higher prevalence in the oligoarticular form is well known. Recently, its association with the remission rate has been studied, but few data are available.

Objectives: To evaluate the clinical response based on ANA status in JIA patients.

Methods: We performed an observational retrospective study with all children diagnosed with JIA followed in our Rheumatology Pediatric Unit until april 2017. Demographic and clinical data were colleted from medical records. JIA subtypes were categorized according to the classification of the International League of Associations for Rheumatology 2001. ANA were considered positive when at least 2 titers were ≥ 1/100. Remission status at follow-up was defined using the Wallace preliminary criteria. Parametric and non-parametric test were used for statistic analysis (SPSS 20.0). P-values <0.05 were considered statistically significant.

Results: A total of ninety-four patients were enrolled. Sixty-three were female (67%). The mean age at time of diagnosis was 7.2 years (SD 4.4) and the mean follow-up was 8.9 years (SD 6.6). The most common subgroup was oligoarticular persistent JIA (38.3%), followed by polyarticular (25.5%), systemic (13.8%), psoriatic (10.6%), enthesitis-related arthritis (7.4%) and oligoarticular extended JIA (4.3%). Extra-articular manifestation as uveitis was seen in 14 patients. Both rheumatoid factor and anti-citrullinated peptide antibody were positive in 37.5% of the polyarticular JIA. ANA positivity was presented in 41.5% of all patients, in which was found a significant predominance of the oligoarticular form, female gender, earlier onset of disease and increased risk of developing chronic anterior uveitis during the course of the disease (p = 0.001, p = 0.025, p = 0.001, p = 0.015, respectively). The mean joint count at diagnosis was 3.9 (SD 5.0). At the last follow-up evaluation the mean joint count was 0.32 (SD 0.7), almost 59% of the patients were in remission (25.5% on medication for at least 6 months and 33% off medication for ≥ 12 months) and 41.5% had active disease. 6.4% of the patients were treated with biologic monotherapy, 37.2% were receiving classic DMARDs while 14.9% were under combination therapy. In the group of patients in remission on medication >6 months, 8.3% and 45.8% of the patients were treated with biologic and classic DMARDs respectively, and combination therapy was observed in 37.5% of them. In the group with active disease, biologic monotherapy, classic DMARDs or combination therapy use was seen in 10.3%, 61.5% and 12.8% of the patients, respectively. No significant diferences were found in what concerns clinical outcome when comparing ANA-positive and ANA-negative patients (p = 0.091).

Conclusion: Our study demonstrates once again the association between the ANA positivity and the oligoarticular subtype, female predominance and the presence of uveitis. It also supports the late literature that didn’t find a relationship between the remission rate and ANA status.

Disclosure of Interest: None Declared

P41 Evaluation of knee joint Q angle and balance in juvenile idiopathic arthritis patients with pesplanovalgus deformity

Eylul Pinar Kisa1, Serap Inal2, Ela Tarakci3, Nilay Arman3, Ozgur Kasapcopur4

1Division of Physiotherapy and Rehabilitation, Faculty of Health Science, Yeditepe University, Istanbul, Turkey; 2Division of Physiotherapy and Rehabilitation, Faculty of Health Science, Bahcesehir University, Istanbul, Turkey; 3Division of Physiotherapy and Rehabilitation, Faculty of Health Science, Istanbul, Turkey 4Department of Pediatric Rheumatology, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
Correspondence: Eylul Pinar Kisa

Introduction: Juvenile idiopathic arthritis (JIA) is the childhood disability from a musculoskeletal disorder. It generally affects large joints such as the knee and the ankle. JIA combine with muscle weakness, poor flexibility, atrophy, pain, and decreased proprioception of the affected joints, abnormal biomechanics, articular cartilage damage.

Objectives: We aimed to observe the effects of knee Q deformity on postural stability of children with pes planovalgus having JIA.

Methods: Twenty participants as age range 4-16 years (4 female,16 male) were enrolled this study. New York Posture Rating Scale were used to evaluate the posture of participants. Hand held dynamometry was used to assess the strength of the lower extremity muscles. Their static balance evaluated with Flamingo balance test. Their dynamic balance evaluated with Prokin balance system. Q angle was calculated by Universal desktop ruler. Universal Desktop Ruler allows you to measure not only a straight-line distance but any curved distance on the screen. For statistical analysis SPSS Version 21.0 program was used.

Results: For our statistical evaluations, abduction, adduction, knee flexion and extension negatively, knee flexion angle and addiction angle positively may affect static balance(p < 0,05). In addition to that, dynamic balance related to power of plantar flexion positively, knee extension, inversion, abduction angle positively. The results of this study showed that knee flexion angle and plantar flexion angle may affect Q angle negatively. There is statistically significant effect between Q angle and posture deformity (p < 0.05).

Conclusion: In this study, power of hip flexion structure and function of the foot and ankle, and there is preliminary evidence that foot problems impair balance. Balance has often been used as a measure of lower extremity function and is defined as the process of maintaining the center of gravity within the body's base of support. These results are supported by evaluating more children with juvenile idiopathic arthritis with pesplanovalgus.

Disclosure of Interest: None Declared

P42 Development of a unique platform for pediatric immuno-rheumatologic diseases (JIRCOHORTE): inclusion of 3266 patients.

M. Mejbri1, R. Carlomagno1, F. Hofer1, V. Hentgen2, B. Bader-Meunier3, B. Fonjallaz4, S. Georgin- Lavialle5, Y. Guex-Crosier6, P. Scolozzi7, A. Woerner8, E. Cannizzaro9, D. Kaiser10, G. Berthet11, W. Baer12, F. Vanoni1, K Theodoropoulou1, A. Belot13, M. Hofer1

1Consultation Romande d’immuno-rhumatologie pediatrique CHUV, HUG, Lausanne, Geneva, Switzerland, 2Centre Hospitalier de Versailles, Versailles, France 3Hôpital Universitaire Necker, Paris, France, 4Ligue Genevoise contre le Rhumatisme, Geneva, Switzerland, 5Hôpital Tenon, Paris, France, 6Hôpital Ophtalmique Jules-Gonin, Lausanne, Switzerland 7HUG, Geneva, Switzerland 8Kinderspital Beider, Basel, Switzerland 9Kinderspital, Zürich, Switzerland 10Kinderklinik, LUCERNE, Switzerland 11Kinderklinik, Aarau, Switzerland 12Kantonspital, Graubunden, Switzerland, 13Hôpital Femme Mère Enfant, Lyon, France
Correspondence: M. Mejbri

Introduction: Pediatric immune-rheumatologic diseases are rare, characterized by chronic course and significant impact on patient’s life. Recent developments have significantly improved the prognosis of these diseases, but a close follow-up of patients’ cohorts is essential to evaluate the long- term outcome. The JIRcohorte is an international platform developed to follow pediatric immune- rheumatologic diseases, and evaluate the long-term tolerance and efficacy of immunosuppressive and biological therapies. The challenge was to develop a tool with items both common for all patients and specific for each disease.

Objectives: Describe the multi-module tool implemented in the JIRcohorte platform and the collective of patients included in the different modules.

Methods: For each of the eCRF, an expert group has defined the items to be collected for prospective follow-up of patients with a specific disease. A first comparison was done to highlight the identical items from the different eCRF and the items specific to each one. For all the items reported in more than one module in a similar but not identical way, a negotiation between the experts made it possible either to find a common item or to clearly define the difference between them. We describe the patients of 45 centers (in Belgium, France, Maroc and Switzerland) included in the JIRcohorte between 2014 and 2017.

Results: Thanks to the development of a multi-module tool, we were able to reduce the number of items to insert in the JIRcohorte from 3860 to 2188, by keeping the same level of information. A total of 3266 patients and 10733 visits were collected. The number of patients and visits per module are as follows: Juvenile Idiopathic Arthritis (1371 patients, 4782 visits), Temporomandibular Arthritis (64, 156), Juvenile Dermatomyositis (18, 61), Juvenile Systemic Lupus (121, 369), Juvenile Periodic Fever Syndrome (450, 803), Still Disease (54, 176), Uveitis (142, 1409) and Vaccination (2251, 6924).

Conclusion: JIRcohorte collects follow-up data on pediatric patients with different immuno- rheumatologic pathologies. Thanks to its structure, with both common and specific items in each module, it can be used as a valuable tool to compare pediatric patients with different inflammatory rheumatic diseases.

Disclosure of Interest: None Declared

Genetics and environment

P43 Progressive pseudorheumatoid dysplasia resolved by whole exome sequencing: a novel mutation in WISP3 and review of the literature

Aviva Eliyahu1,2, ben pode-shakked3,4,5, Asaf Vivante5,6, Ortal Barel7, Shai Padeh8,9, Dina Marel-Yagel9,10, Alvit Veber11, Shachar Abudi12, Irit Tirosh2,13, Shiri Shpilman2,14, Shirlee Shril15, gideon rechavi7,16,17, Friedhelm Hildebrandt18, Mordechai Shohat7,19, yair anikster3,20,21

1 Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, tel hashomer, Israel; 2Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; 3Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; 4Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; 5The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel; 6Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States; 7Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel; 8Pediatric Rheumatology Unit and Department of Pediatrics, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; 9Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 10Metabolic Disease Unit Israel, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; 11Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; 12Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; 13Pediatric Rheumatology Unit and Department of Pediatrics, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; 14Pediatric Rheumatology Unit and Department of Pediatrics, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel; 15Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States; 16Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 17The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Israel; 18 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston MA, United States; 19Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 20Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 21The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel
Correspondence: Aviva Eliyahu

Introduction: Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, non-inflammatory arthropathy, shown to be caused by mutations in the WNT1-inducible signaling pathway protein 3 (WISP3) gene. Although several hundred cases were reported worldwide, the diagnosis remains challenging. Subsequently, the syndrome is often unrecognized and misdiagnosed, leading to unnecessary procedures and treatments.

Objectives: We present here a multiply affected consanguineous family of Iraqi-Jewish descent with PPRD. The proband, a 6.5 years old girl, presented with bilateral symmetric bony enlargements of the 1st interphalangeal joints of the hands, without signs of synovitis.

Methods: Molecular analysis by Whole Exome Sequencing and homozygosity mapping was performed on the proband and other affected and non affected relatives.

Results: Molecular analysis by Whole Exome Sequencing and homozygosity mapping identified a novel homozygous missense mutation (c.257G > T, p.C86F) in the WISP3 gene. Following this diagnosis, an additional 53 years old affected family member was found to harbor the mutation. Two other individuals in the family were reported to have had similar involvement however both had died of unrelated causes.

Conclusion: The reported family underscores the importance of recognition of this unique skeletal dysplasia by clinicians, and especially by pediatric rheumatologists and orthopedic surgeons.

Disclosure of Interest: None Declared

P44 Cytokines genes and the severity of juvenile idiopathic arthritis

Liliia S. Nazarova1, Kseniia V. Danilko1, Tatiana V. Viktorova1,2, Viktor A. Malievsky1

1Bashkir State Medical University, Ufa, Russian Federation; 2Institute of Biochemistry and Genetics, Ufa, Russian Federation
Correspondence: Viktor A. Malievsky

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and an important cause of short-term and long-term disability [1]. It is essential to know the prognosis for the individual patient early in the course of disease and preferentially at the time of diagnosis in order to start the right treatment immediately [2].

Objectives: The goal of the study was to determine whether the TNFA gene -308A > G, IL1B gene -511C > T and IL6 gene -174G > C single nucleotide polymorphisms (SNPs) are associated with the disease severity in patients with JIA.

Methods: The study included 255 patients with JIA who were divided into 4 subgroups according to the severity of the disease course: mild (N = 33), moderate (N = 58), severe (N = 68) and very severe (N = 96). The grouping was performed depending on the number of affected joints, the presence or absence of high laboratory activity, systemic features, uveitis, early radiologic progression, functional disability and the need for early "aggressive" therapy. Genotyping was performed using real-time PCR method. Statistical analysis was performed using two-tailed Fisher's exact test (p), odds ratio (OR) and 95% confidence interval (CI).

Results: The IL6 -174G allele was significantly more frequent in patients with a very severe disease course, than in other patients (p = 0.040, OR = 1.498, 95%CI 1.033-2.167). At the same time, there was a significantly higher proportion of the IL1B -511CT genotype in a mild disease course subgroup in comparison to other subgroups (p = 0.024, OR = 2.427, 95%CI 1.109-5.160). Then the analysis was performed separately for girls and boys. The association mentioned above for the IL6 -174G allele was confirmed only for boys (p = 0.026, OR = 2.108, 95%CI 1.131-3.883) and for the IL1B -511CT genotype – only for girls (p = 0.0004, OR = 10.079, 95% CI 2.656-44.857). In addition, it was found that the IL1B -511 T allele marks a very severe JIA course in boys (p = 0.019, OR = 2.231, 95% CI 1.135-4.215) and that the TNFA -308A allele marks a mild JIA course in boys (p = 0.007, OR = 4.778, 95% CI 1.731-14.256).

Conclusion: In this study we revealed gender-specific associations of the IL6 gene -174G > C, IL1B gene -511C > T and TNFA gene -308A > G SNPs with an altered risk of a very severe or mild JIA course.

References. [1] Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007 Mar 3;369(9563):767-78.

[2] van Dijkhuizen EH, Wulffraat NM. Early predictors of prognosis in juvenile idiopathic arthritis: a systematic literature review. Ann Rheum Dis. 2015 Nov;74(11):1996-2005.

Disclosure of Interest: None Declared

P45 Single nucleotide polymorphisms in survivin gene are associated to response to methotrexate in juvenile idiopathic arthritis

Mojca Zajc Avramovič1, Vita Dolzan2, Natasa Toplak1, Tadej Avcin1

1Department of Allergology, Rheumatology and Clinical Immunology, Children’s Hospital, University Medical Centre Ljubljana, Slovenia, Ljubljana, Slovenia 2Institute of Biochemistry, Medical faculty, Ljubljana, Slovenia
Correspondence: Mojca Zajc Avramovič

Introduction: Survivin is an anti-apoptotic protein and its circulating levels were associated with joint destruction and erosions in rheumatoid arthritis (RA). Recently it was suggested to be a marker of severe disease course in adult patients with RA as well as juvenile idiopathic arthritis (JIA). Three single nucleotide polymorphisms (SNPs) can affect the normal protein and its concentration. Methotrexate (MTX) is an important drug in treating JIA, but markers to predict its efficacy are needed.

Objectives: To evaluate the effect of SNPs in survivin gene on methotrexate efficacy in JIA.

Methods: The data of 119 consecutive patients with JIA treated with MTX at the University Children’s Hospital Ljubljana from June 2011 to January 2015 have been retrospectively reviewed. The disease activity was measured using JADAS 71 score. Non-responders were defined as patients not reaching 30% improvement in JADAS 71 score 6 months after the beginning of treatment with MTX. Genotyping of SNPs in the genes for survivin was performed using real time PCR methods. The following SNPs were analyzed: BIRC5 G692C rs8073069, BIRC5 T241C rs17878465 and BIRC5 G692C rs8073069. Two-tailed Fisher exact test was used for statistical analysis.

Results: A total of 119 patients were included in the analysis, 91 (76.5%) girls and 28 (23.5%) boys. Ten (8.4%) patients had systemic arthritis, 41 (34.5%) RF negative polyarthritis, 5 (4.2%) RF positive polyarthritis, 24 (20.2%) persistent oligoarthritis, 24 (20.2%) extended oligoarthritis, 11 (9.2%) juvenile psoriatic arthritis, 2 (1.7%) patients suffered from enthesitis related arthritis and 2 (1.7%) had undifferentiated arthritis. Mean time of disease duration before MTX was started was 13 months in the whole cohort and 6.9 months in the subgroup of patients with polyarticular disease (RF positive and RF negative). Mean starting dose of MTX was 10.3 mg/m2 and mean dose at 6 months was 12.0 mg/m2. Forty-two (35%) patients were switched to subcutaneous MTX to achieve higher efficacy. At 6 months 30/116 (25.8%) of patients were defined as non-responders. BIRC5 rs17878465 (p < 0.0001) and BIRC5 rs9904341 (p = 0.0272) were associated with achieving 30% improvement in JADAS 71 after 6 months. BIRC5 rs9904341 was also associated with 70% improvement in JADAS 71 score (p < 0.0001) after 6 months of treatment.

Conclusion: Our results suggest that SNPs in survivin gene, BIRC5 rs17878465 and BIRC rs9904341 could be markers of MTX response in JIA.

Disclosure of Interest: None Declared

Imaging - Vasculitides

P46 Henoch schonlein purpura nephitis: initial risk factor and outcomes in a tertiary center of Latin America

Izabel M. Buscatti, Beatriz B. Casella, Nadia E. Aikawa, Andrea Watanabe, Sylvia C. Fahrat, Lucia M. Campos, Clovis A. Silva

Pediatric Rheumatology Division, CHILDREN’S INSTITUTE, HOSPITAL DAS CLINICAS HCFMUSP, FACULDADE DE MEDICINA, UNIVERSIDADE DE SAO PAULO, São Paulo, Brazil
Correspondence: Izabel M. Buscatti

Introduction: European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) proposed validated classification criteria for Henoch-Schönlein purpura (HSP). However, there are rare studies reporting initial risk factors to HSP nephritis (HSPN) and outcomes using these new criteria. In addition, these studies generally included small samples, and none of them were evaluated in Latin American population.

Objectives: To evaluate risk factors associated with HSPN and outcomes in children and adolescents of a tertiary center in Latin America.

Methods: Two hundred ninety six patients with HSP were retrospectively assessed by demographic data, and initial clinical manifestations, laboratory exams and treatments evaluating in the first three months of disease. All of them fulfilled validated EULAR/PRINTO/PRES criteria for HSP. They were also divided in two groups: with and without nephritis. Additional, persistent non-nephrotic proteinuria, nephrotic proteinuria and renal insufficiency were also evaluated at 1, 5, 10 and 15 years after diagnosis.

Results: Nephritis was detected in 139/296 (47%) at first 3 months. The median of age at diagnosis was significantly higher in HSPN patients compared to those without this complication [6.6(1.5-17.7) vs. 5.7(0.9-13.5) years, p = 0.022]. The frequencies of persistent purpura (31% vs. 10%, p < 0.0001), recurrent abdominal pain (16% vs. 7%, p = 0.011), gastrointestinal bleeding (25% vs. 10%, p < 0.0001) and corticosteroid use (54% vs. 41%, p = 0.023) were significantly higher in the former group. In the multivariate analysis, logistic regression demonstrated that the independent variables that predicted HSNP were persistent purpura (OR = 3.601; 95%CI 1.605-8.079; p = 0.002) and gastrointestinal bleeding (OR = 2.991; 95%CI 1.245-7.183; p = 0.014). Of 139 HSPN, further analysis revealed that persistent non-nephrotic proteinuria, nephrotic proteinuria and renal insufficiency occurred during follow-up: at 1 year [46/88 (52%), 1/88 (1%) and 2/88 (2%)], at 5 year [25/47 (53%), 1/47 (2%) and 1/47 (2%)], at 10 year [9/20 (45%), 1/20 (5%) and 1/20 (5%)] and at 15 years [1/6 (17%), 0/6 (0%) and 0/6 (0%)]. In addition, in patients without HSPN at disease onset: 29/118 (25%) had persistent non-nephrotic proteinuria and/or hematuria only at 1 year of follow-up, 19/61 (31%) at 5 years, 6/17 (35%) at 10 years and 4/6 (67%) at 15 years of follow-up.

Conclusion: Persistent purpura and gastrointestinal bleeding were initial predictors for HSPN. Persistent non-nephrotic proteinuria and/or hematuria may occur during the disease follow-up, even in patients without previous HSPN, and rigorous monitoring of renal involvement should be performed.

Disclosure of Interest: I. Buscatti: None Declared, B. Casella: None Declared, N. Aikawa: None Declared, A. Watanabe: None Declared, S. Fahrat: None Declared, L. Campos: None Declared, C. Silva Grant/Research Support from: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 472155/2012-1)

P47 Toward the development of a new radiographic score for diagnosis and monitoring of temporomandibular joint disease in children with juvenile idiopathic arthritis

Gabriella Giancane, Giacomo Chiappe, Fiammetta Sertorio, Veronica Incarbone, Alessandro Consolaro, Nicola Laffi, Gian Michele Magnano, Angelo Ravelli

Istituto Giannina Gaslini, Genoa, Italy
Correspondence: Gabriella Giancane

Introduction: Arthritis of the temporo-mandibular joint (TMJ) is often responsible for severe osteo-articular damage in patients with juvenile idiopathic arthritis (JIA). Early diagnosis of TMJ involvement remains difficult, due to the lack of reliable clinical or imaging parameters. However, magnetic resonance imaging (MRI) is regarded as the most sensitive tool for the detection of TMJ involvement in JIA.

Objectives: To develop and validate a MRI score for early detection of TMJ disease activity and damage in children with JIA.

Methods: After a review of the most recent literature on MRI of the TMJ in JIA and based on their experience, three specialists in different fields (a rheumatologist, a dentist and a radiologist) devised the score for the assessment of activity and damage of TMJ shown in Table 18. The score consists of 3 parameters of arthritis activity (joint effusion, contrast enhancement (CE) and bone edema), and 4 parameters of joint damage (erosion/irregularities of the mandibular condyle, disc abnormalities, flattening of the condyle, mandibular asymmetry). The activity score ranges from 0 to 6 and the damage score from 0 to 9. After a series of training sessions aimed to reach consensus on the definition of the score features, each specialist assigned independently the MRI score to an unselected sample of TMJ MRIs of JIA patients followed at our center. The inter- and intra-observer reliability were calculated through the weighted kappa. The CE parameter was also compared with a recently validated score calculated on a specific region of interest (ROI) of the TMJ MRI in JIA patients1. Agreement was considered acceptable for a k value > 0.60.
Table 18

(Abstract P47). MRI score (CE: contrast enhancement)

TMJ ACTIVITY PARAMETERS

 

Right

Left

Total score

Joint effusion

YES □ NO □

YES □ NO □

0-2

Contrast enhancement (CE)

YES □ NO □

YES □ NO □

0-2

Bone edema/bone marrow CE

YES □ NO □

YES □ NO □

0-2

Total activity score

0-3

0-3

0-6

TMJ DAMAGE PARAMETERS

Erosions/irregularities of the condyle

YES □ NO □

YES □ NO □

0-2

Disc abnormalities

YES □ NO □

YES □ NO □

0-2

Flattening of condyle

MODERATE/SEVERE □ MILD□

NO□

MODERATE/SEVERE □ MILD□

NO□

0-4

Mandibular asimmetry

YES □ NO □

IF YES: RIGHT < □ LEFT < □

0-1

Total damage score

0-5

0-9

Results: A total of 35 TMJ MRIs performed between December 2013 and December 2016 were evaluated. The analysis of the absolute agreement in score assignment among specialists revealed substantial agreement, with greater concordance between the dentist and the radiologist. The rheumatologist tended to assign lower scores. Among disease activity parameters, the lowest agreement was seen for bone edema, whereas the most challenging joint damage parameter was disc abnormalities. There was a moderate agreement between the CE recorded by the study assessors and that obtained through the ROI calculation, especially for the rheumatologist and the dentist.

Conclusion: We have developed a new simple and feasible MRI score for the detection and quantification of disease activity and damage of the TMJ in children with JIA. Although the overall score proved reliable across different specialists, further work is needed to increase concordance for assessment of bone edema and disc abnormalities.

Reference: 1. Resnick CM et al. Quantifying Temporomandibular Joint Synovitis in Children With Juvenile Idiopathic Arthritis. Arthritis Care Res (Hoboken). 2016;68:1795-1802.

Disclosure of Interest: None Declared

P48 Determining disease activity in CIA by optical imaging of phagocyte migration

Sandra Gran1, Lisa Honold2, Olesja Fehler1, Stefanie Zenker1, Sven Hermann2, Michael Schäfers2, Thomas Vogl1, Johannes Roth1

1Institute of Immunology, Münster, Germany; 2European Institute for Molecular Imaging, Münster, Germany
Correspondence: Sandra Gran

Introduction: Phagocyte recruitment and migration to the site of inflammation are key events in the early phase of inflammation. They are indispensable for pathogen elimination, tissue repair and restoration of tissue homeostasis. However, dysregulated phagocyte infiltration and a subsequently overwhelming immune response can also cause severe inflammatory disorders. Therefore, targeting and modulation of phagocyte infiltration represents a promising new approach to fight inflammatory disorders and diseases, such as rheumatoid arthritis. Furthermore, non-invasive tracking of phagocyte migration to the site of inflammation could extend both scientific knowledge as well as the repertoire of diagnostic strategies in clinical use.

Objectives: Within this study we aimed to establish a Fluorescence reflectance imaging (FRI) based system to visualize and analyze migration properties of different cell populations in inflammatory disease models, like experimental arthritis, in vivo.

Methods: Immortalized murine myeloid progenitor ER-HoxB8 cells were differentiated to neutrophils or monocytes (Wang et al., 2006). Differentiated cells were labeled in vitro with the membrane-selective fluorescent dyes DIR (Eisenblätter et al., 2009) or DID, respectively. Viability and functionality of labeled cells were confirmed by in vitro assays. In several mouse models - particularly in a collagen induced arthritis (CIA) mouse model - we investigated the ability and specific properties of different cell populations to migrate to sites of inflammation in vivo via fluorescence reflectance imaging (FRI). Using CRISPR-Cas9 technology we introduced targeted gene deletions for main adhesion molecules.

Results: ER-HoxB8 monocytes and neutrophils could effectively be labeled with DIR or DID. In vitro assays confirmed that viability and functionality of ER-HoxB8 cells was not affected by cell labeling. Subsequent in vivo imaging experiments allowed the visualization of migrated labeled phagocytes in different murine disease models, thereby cells could be detected at sites of inflammation with high sensitivity and specificity. In a CIA mouse model the amount of immigrated cells could even be associated closely to disease score and disease severity. Thus, the detection of immigration of labeled cells might also give hints about new inflammatory spots that are about to settle up before they can be detected macroscopically. Furthermore, differential cell labeling allowed direct quantitative comparison of differences in migration rates of wildtype and CD18 or CD49d knockout cells in vivo.

Conclusion: Specific and distinguishable labeling of diverse cell types allows in vivo tracking and subsequent quantification of migrated cells within the same animal. Targeted gene deletion allows analysis of molecular mechanisms relevant for leukocyte recruitment during different stages of arthritis. Correlation of the amount of immigrated cells to disease severity offers new opportunities to non-invasively detect and monitor inflammatory sites in vivo.

Disclosure of Interest: None Declared

P49 Juvenile Sjögrens syndrome (JSS): comparing glandular ultrasound in primary and secondary JSS

Johannes-Peter Haas, Manuela Krumrey-Langkammerer

German Center for pediatric and adolescent rheumatology, Garmisch-Partenkirchen, Germany
Correspondence: Manuela Krumrey-Langkammerer

Introduction: Diagnosis of juvenile Sjögrens syndrome (jSS) although rare seems to be underestimated in pediatric patients. Especially in patients with undifferenciated mixed connective tissue disease (MCTD) secondary jSS is frequently present but missed in the diagnostic work-up.

Objectives: Our intend was to characterize distinct, ultrasonographic (US) findings in a cohort of primary- and secondary jSS patients, the latter with a focus on MCTD and attribute these findings to US scores defined in adult SS.

Methods: A single-center study collected data from clinical charts of jSS-patients admitted to the GCPAR. According the EULAR/ACR criteria 8 patients with primary jSS, 8 patients with secondary jSS and MCTD and 9 patients with secondary jSS and other collagenoses were included. All ultrasonographic (US) findings were performed by two experienced investigators between 5/2014 and 3/2017 using a GE logic 8 system. Different scoring systems from the literature were compared for accuracy for gland echostructural abnormalities.

Results: A total of 25 patients (22 females, 3 males) with a mean age of 15,8 years have been included. All 9 pjSS patients had sicca symptoms, this was present in only 56,3% of sjSS. Swelling or pain in major salivary glands occurred in 7 of 9 pjSS but only 5 of 16 sjSS (including MCTD). US scoring of salivary glands according to Hocevar [1] which had been proven to be accurate in jSS as well [2] showed a mean score of 26 in pjSS and 18,28 in sjSS patients. We could not correlate US score (Hocevar) with the duration of the disease (Pearsons r =0.197) (Table 19).
Table 19

(Abstract P49). Salivary gland US-scores according Hocevar´s classification

 

pjSS (n = 9)

sjSS other (n = 8)

sjSS in MCTD (n = 8)

All (n = 25)

Decrease in echogenity

3 (33,3%)

3 (37,5%)

2 (25%)

18 (72%)

Inhomogenous parenchyma

9 (100%)

7 (87,5%)

6 (75%)

22 (88%)

Hypoechoic areas

9 (100%)

8 (100%)

7 (87,5%)

24 (96%)

Hyperechoic reflexes

7 (77,7%)

6 (75%)

6 (75%)

19 (76%)

Disturbed border

4 (44,4%)

2 (25%)

0

6 (24%)

Conclusion: In patients with pjSS and sjSS salivary gland ultrasound is a helpful, first-line tool not only to detect salivary gland involvement but to score the severity of inflammation as well. As sjSS is supposed to be underestimated in collagenoses and MCTD, screening of salivary gland by US is usefull even in patients without sicca-symptoms to identified typical, inhomogeneous parchenchymal appearance with hypoechoic lesions suggestive for jSS.

References:

1. Hocevar A. et al;. Rheumatology 2005; Vol 44; pp 768

2. Krumrey-Langkammerer M. et al. 2015: Ultraschall in Med 2015; 36 - A349

Disclosure of Interest: None Declared

P50 Toward the achievement of an agreement between clinical and ultrasound assessment of the ankle region

Stefano Lanni1, Alessandra Alongi1, Adele Civino2, Alessandro Consolaro1,3, Giovanni Filocamo4, Angelo Ravelli1,3

1IRCCS Istituto Giannina Gaslini, Genova, Italy; 2Pia Fondazione di Culto e Religione Card. G. Panico, Tricase, Italy; 3Università degli Studi di Genova, Genova, Italy; 4Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
Correspondence: Stefano Lanni

Introduction: The ankle is a complex anatomical structure owing to the multiple joint recesses and surrounding tendons. The clinical examination of this joint is a challenging task even for the expert physician. Ultrasound (US) is becoming a useful adjunctive tool to clinical evaluation for the assessment of children with juvenile idiopathic arthritis (JIA). Disagreement between clinical and US examinations in the assessment of the ankle region has been shown in some studies.

Objectives: The aims of the study were: 1) to assess the frequency of clinical signs of articular and periarticular involvement and of US abnormalities in the different joint recesses and tendon compartments of the ankle region; 2) to investigate the correlation between clinical signs of articular involvement and US abnormalities in the different joint recesses of the ankle region.

Methods: Twenty-seven ankles of 19 patients with JIA with a clinical suspicion of disease involvement were included in the study. At the same consultation, the ankles were scanned by a physician with experience in the US assessment of children with JIA, who was blinded to clinical findings. Clinical and US evaluations focused on tibiotalar and subtalar joints, the tarsal area and on tendon compartments. For each of the joint recesses the presence of swelling, pain on motion and restricted motion and the detection of joint effusion (JE), synovial hypertrophy (SH) and power Doppler (PD) signal inside the area of SH were recorded on clinical and on US evaluation, respectively. US abnormalities were graded on a 4-point semiquantitative scale. Correlation between clinical signs of articular involvement and US abnormalities in the different joint recesses of the ankle region was estimated using the Kendall’s tau (τ) coefficient.

Results: Overall, on clinical assessment swelling was found more frequently in the tibiotalar joint (52%), whereas both pain and restricted motion were documented more commonly in the subtalar joint (44% and 41%, respectively). On US assessment JE and SH were detected more frequently in the tibiotalar joint (56% and 67%, respectively); PD signal was displayed more commonly in the subtalar joint (44%). Among tendon compartments, both clinical and US assessments documented a more frequent involvement of flexor tendons (11% and 52%, respectively). Correlation was found between presence of pain or restricted motion on clinical evaluation and detection of PD signal on US in the tibiotalar joint (τ = 0,58, p = 0,002 and τ = 0,57, p = 0,002, respectively). In the tarsal area correlation was found between presence of restricted motion on clinical assessment and detection of PD signal on US (τ = 0,43, p = 0,024) and between presence of pain on clinical assessment and detection of SH on US (τ = 0,41, p = 0,033). No correlation was found in the subtalar joint between any clinical sign of articular involvement and US abnormalities.

Conclusion: Tibiotalar and subtalar joints are more commonly affected than the tarsal area on both clinical and US assessment in case of ankle involvement in JIA. Flexor tendons are more frequently inflamed than the anterior and lateral tendon compartments. On clinical examination, pain or restricted motion, but not swelling, in the tibiotalar joint and in the tarsal area seem to correlate with the presence of synovitis on US in these joint recesses of the ankle region. The assessment of the subtalar joint remains a challenging task for the physician without the use of US.

Disclosure of Interest: None Declared

P51 Kawasaki disease: initial echocardiogram predicts subsequent coronary disease and immunoglobuline resistance

Dima Chbeir1, Jean Gaschinard1, Ronan Bonnefoy1, Constance Beyler2, Isabelle Melki1, Albert Faye1, Ulrich Meinzer 1

1Pédiatrie générale, maladies infectieuses et médecine interne, Paris, France 2Service de cardiologie pédiatrique, Hôpital Robert Debré, Paris, France
Correspondence: Ulrich Meinzer

Introduction: Kawasaki disease (KD) is an acute febrile systemic vasculitis that affects blood vessels of small and medium calibre. With the availability of intensified treatments for most severe patients, it is crucial to early identify patients at high risk for coronary artery aneurysms (CAA). However, the available risk scoring systems from Japan have not been validated in European populations. There is little data concerning the link between initial echocardiogram findings and cardiac prognosis.

Objectives: To investigate the first echocardiogram can predict resistance to conventional therapy and/or subsequent development of CAA

Methods: We retrospectively analysed demographic, clinical, biological, echocardiographic and therapeutic data from children diagnosed with KD between 2006 and 2016 at the Robert-Debré University Hospital, Paris, France.

Results: A total of 157 children with KD were included. Initial echocardiogram was performed after a median of 6 days of fever and was abnormal in 48 cases (31%). The initial presence of any echocardiographic abnormality was strongly associated with resistance to intravenous immunoglobulin (p = 0.005) and development of coronary artery lesions within the first six weeks of disease (p = 0.01). All patients (n = 7) with persistent coronary abnormalities at one year already had an abnormal initial echocardiogram. In contrast, severity scores had low sensitivity (24-33%) and low specificity (72-81%) to predict immunoglobulin resistance or cardiac involvement.

Conclusion: Abnormalities in the initial echocardiogram can be used to early identify patients with severe Kawasaki disease in populations with mixed ethnic backgrounds.

Disclosure of Interest: None Declared

P52 Childhood-onset Takayasu arteritis: a referral center experience in Turkey

Sezgin Sahin1, Duhan Hopurcuoglu1, Sule Bektas1, Ezgi Belhan1, Amra Adrovic1, Kenan Barut1, Nur Canpolat2, Salim Calıskan2, Lale Sever2, Ozgur Kasapcopur1

1Pediatric Rheumatology, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey 2Pediatric Nephrology, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey
Correspondence: Sezgin Sahin

Introduction: Takayasu arteritis is a chronic granulomatous vasculitis that effects primarily aorta and its main branches and rarely seen before the age of 18. Delay in diagnosis and treatment is a common feature due to the nonspecific systemic features. There is limited data on clinical features and long-term outcome of Takayasu arteritis. Also, there is need to evaluate efficacy of current therapies, since the spectrum of treatment options have been increased compared to the past.

Objectives: We aimed to report our referral center experience on the clinical features and treatment options of Takayasu arteritis. In addition, we have evaluated the correlation of various activity and damage scores with eachother

Methods: We performed a retrospective chart review for Takayasu arteritis between October 2002 and October 2017 at our tertiary referral pediatric rheumatology center. In addition to the current cases that are followed-up, we have comprehensively searched the hospital database for the ICD-9 code 446.7 and ICD-10 code M31.4 to identify Takayasu arteritis patients.

Results: Overall, 16 patients (12 female) have been diagnosed with Takayasu arteritis in last 15 years. Mean age of the patients at disease onset and diagnosis were 10.9 ± 4.8 years and 11.5 ± 4.7 years, respectively. While the median duration from the onset of first symptom until the diagnosis was 2.4 months (range 0.1-65 months), the mean disease duration was 6.1 ± 5.9 years. The most frequent manifestation at admission was nonspecific systemic features (fever, fatigue, anorexia, weight loss) (n = 13, 81.2%) followed by hypertension (n = 10, 62.5%) and neurologic findings (n = 4, 25%). Tuberculosis disease was also detected in 4/16 subjects (25%) at disease onset and anti-tuberculosis therapy initiated concomitantly with immunosuppressive drugs. All patients had met the ACR 1990 criteria for the classification of Takayasu arteritis. The most common angiographic type was Numano’s type IV seen in 5 patients, followed by type V in 4, type III in 4, type IIa in 2, type IIb and type I one patient each. Subjects had extensive disease at presentation with mean DEI.Tak (±SD) of 13.8 (±6); All of the subjects had elevated acute-phase reactants, and were active at presentation [mean ITAS2010 score (±SD): 18.7 (±7.1) and mean PVAS score (±SD): 14.0 (±4.4)). These three activity scores correlated with each other both at disease onset and last visit (p < 0.05). The most frequently used immunosuppressive drug in therapy was corticosteroids (n = 16/16, 100%), followed by azathioprine (n = 15/16, 93.7%), cyclophosphamide (n = 10/16, 62.5%), methotrexate (n = 6/16, 37.5%) and tocilizumab (n = 6/16, 37.5%). The rate of angioplasty and/or bypass was not rare (n = 7/16, 43.7%). Despite the high frequency of surgical procedure, there was no deceased patient with Takayasu arteritis in the last 15 years.

Conclusion: There is no deceased Takayasu patient in the last 15 years. Fairly good clinical outcomes compared to the past may be due to new biologic drugs and/or improved surgical techniques. Three different disease activity scores were in a great concordance with each other.

References

1. Brunner J, Feldman BM, Tyrrell PN, et al. Takayasu arteritis in children and adolescents. Rheumatology (Oxford) 2010; 49(10): 1806-14.

2. Eleftheriou D, Varnier G, Dolezalova P. Takayasu arteritis in childhood: retrospective experience from a tertiary referral centre in the United Kingdom. Arthritis Res Ther 2015; 17: 36.

3. Misra DP, Aggarwal A, Lawrence A, Agarwal V, Misra R. Pediatric-onset Takayasu's arteritis: clinical features and short-term outcome. Rheumatol Int 2015; 35: 1701-6.

Disclosure of Interest: None Declared

P53 Low dose CT coronary angiography and calcium scoring in patients with Kawasaki disease in convalescent phase- a preliminary study

Rajkumar Chakraborty1, Surjit Singh2, Manphool Singhal1, Deepti Suri2

1Radiodiagnosis and Imaging, Post Graduate Institute of Medical Education and Research, Chandigarh, India, Chandigarh, India; 2Allergy immunology Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India, Chandigarh, India
Correspondence: Surjit Singh

Introduction: Development of coronary artery abnormalities (CAA) is the hallmark of Kawasaki disease (KD) and accounts for most of the morbidity and mortality associated with the disease. Concerns have been raised as to whether patients with KD are really at risk for premature atherosclerosis later in adulthood. With advancements in technology, dual-source computerized tomography (DSCT) coronary angiography can be developed as a low radiation imaging paradigm for patients with KD. Advantages over echocardiography include the ability to visualize middle and distal coronary segments with little or no inter-observer variability. Unlike catheter angiography, DSCT angiography is non-invasive and clearly delineates calcification and intraluminal abnormalities.

Objectives: This study is designed to evaluate whether KD is a risk factor for premature atherosclerosis by calcium scoring (Agatson’s algorithm) and to detect the CAA (aneurysm/thrombus/stenosis/ectasia) using DSCT with low radiation protocols.

Methods: In this prospective study, 21 patients (male: female- 15:6) with KD in convalescence for more than 10 years were enrolled (mean: 15.76 years). Diagnosis of KD was based on the 2004 American Heart Association (AHA) Criteria for KD. Written informed consent was taken from all the patients prior to the enrolment. Patients were scanned during a single breath-hold with a customized protocol designed to minimize the administered radiation dose. Non-ionic contrast (Omnipaque 350, GE Healthcare, Ireland) 2-4 ml/kg was injected at a rate of 4-5 ml/s (through 20G cannula), in the right antecubital vein, followed by a saline push (1-2 mL/kg at a rate of 1.5 mL/second) with a dual head power injector. An 128 slice SOMATOM Definition flash DSCT scanner (SIEMENS HEALTH CARE; Germany) was used for coronary angiography. The data acquisition parameters were 80-100 KVp voltage, tube current (mAs) (care dose 4D), detector configuration 128x0.6 mm, gantry rotation time 0.28 seconds, and the scan length was adjusted from the scout image to encompass the entire heart. The scan was taken from carina till the apex of heart. Images were analyzed on dedicated work station using proprietary soft ware (Syngovia). Coronary arteries was evaluated using the 13 segment model proposed by the AHA. The calcium score was calculated by determining the density of the highest density pixel in each plaque taking the threshold of 130 HU and applying a weighting factor to each plaque, depending upon the peak density in the plaque. Heart rate at which data was acquired, was recorded along with electrocardiogram tracing.

Results: Mean age of the patients at the time of diagnosis was 3.21 years and mean time interval time interval between diagnosis and imaging 12.59 yrs. At the time of data acquisition the mean heart rate of the patients were 80 beat/min, mean tube current 2417.66 mAs, median scan time 2.5 seconds and median effective dose 2.52 mSv. CAAs are seen in the form of aneurysms and ectasias in two patients (9.52%) in our study. No patient with significant stenosis was seen. The aneurysms were detected in proximal segments of RCA (Saccular, medium sized) and LAD (fusiform, small sized). The ectasias were detected in one patient (4.76%) in LAD and LCx. Raised calcium score is seen only one (4.76%) patient with abnormal coronary arteries. The calcium deposition is seen in only in abnormal segments.

Conclusion: Our study suggests that KD itself may not be a cause for premature atherosclerosis unless the coronary arteries are involved in form of aneurysms. However, the results of this preliminary study done in a small population size has to be replicated in larger cohorts to make a firm conclusion.

Disclosure of Interest: None Declared

P54 Low dose dual source CT coronary angiography and calcium scoring in children with Kawasaki disease not treated with intravenous immunoglobulin– a preliminary study

Santosh Dusad1, Surjit Singh1, Manphool Singhal2, Deepti Suri1

1Allergy immunology Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India, Chandigarh, India 2Radiodiagnosis and Imaging, Post Graduate Institute of Medical Education and Research, Chandigarh, India, Chandigarh, India
Correspondence: Surjit Singh

Introduction: Coronary artery abnormalities (CAA) develop in 20-25% of untreated cases and 3-5% of treated cases of Kawasaki disease (KD), that accounts for most of the morbidity and mortality associated with the disease. Although, transthoracic 2-D Echocardiography (2DE) is the initial preferred modality for imaging coronary arteries, it has several inherent limitations- unclear views of middle and distal segments of coronaries, chances of inter-observer variation, and poor acoustic windows in older children to view the coronaries. Dual source CT (DSCT) coronary angiography has recently emerged as an non-invasive tool that has low radiation exposure and can accurately demonstrate the coronary wall anatomy and intraluminal abnormalities like thrombosis, stenosis, calcification. It has several advantages over echocardiography including the ability to visualize middle and distal coronary segments with little or no inter-observer variability.

Objectives: To evaluate the role of DSCT coronary angiography in detecting CAAs in children with KD who were not treated with intravenous immunoglobulin during acute stage and its comparison with 2DE.

Methods: Nineteen (19) children (M:F = 15:4) with KD who did not receive intravenous immunoglobulin and are on regular follow up in Pediatric Rheumatology Clinic were enrolled (median age: 11.03 years; range: 3.7-23 years). Diagnosis was based on diagnostic criteria given by AHA. All of the patients were the cases of incomplete KD and were not given IVIg because they either presented late in convalescent phase or when then presented to us, they were afebrile and ESR, CRP were not raised. Mean duration since diagnosis of KD to the time when study was conducted was 3.84 ± 2.27 years. The study was approved by the Ethics Committee of the Institute. A written informed consent from the parents was obtained prior to enrolment. Children underwent both SOMATOM 128-slice Definition flash DSCT coronary angiography (SIEMENS HEALTH CARE; Germany) and 2DE on the same day. Diameters of major coronary arteries were measured and presence of any coronary artery lesions was looked for. Results of 2DE carried out at the time of diagnosis were also taken into account. Student paired T test was used to compare the average diameter of coronaries obtained by two imaging modalities.

Results: None of the patients showed any coronary artery abnormalities by both DSCT and 2DE. All coronary arteries were well visualized by DSCT and even LCX branches and distal RCA was also well visualized. However, coronary artery could not be visualized in 7 patients out of 19 by 2DE. In 3 patients, even main arteries were also not seen due to poor acoustic window. However, in 4 cases, RCA and LMCA were well visualized, but it was difficult to visualize left circumflex artery clearly. The 2DE and DSCT had almost the same results of proximal coronary artery especially LMCA, proximal RCA, and LAD. However, DSCT provided the more accurate visualization of distal coronary artery than 2DE. The average diameter of coronary artery measured by 2DE and CT angiography was almost similar. 2DE at the time of diagnosis showed dilatation of coronaries in 3 children (2 LMCA, 1 LAD) which were not seen in current echo and DSCT.

Conclusion: DSCT coronary angiography more accurately delineated the anatomy and lumen of coronary arteries especially in older children with KD when compared with 2DE. DSCT is superior to echo for distal coronary artery visualization. It can reveal coronary artery lesions in patients with KD in timely manner and help with therapeutic decision making to improve the prognosis.

Disclosure of Interest: None Declared

P55 Flow mediated dilatation of brachial artery during the acute and convalescent stages of Kawasaki disease-a preliminary study

Santosh Kumar1, Surjit Singh1, Manphool Singhal2, Vivek Kumar3, Deepti Suri1

1Allergy immunology Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India, 2Radiodiagnosis and Imaging, Post Graduate Institute of Medical Education and Research, Chandigarh, India, 3Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India,
Correspondence: Surjit Singh

Introduction: Kawasaki disease (KD) is usually considered as an acute, self-limited vasculitis of childhood. However, of late, several long-term complications including development of major coronary events and premature atherosclerosis have been recognized in patients with KD. The evaluation of vascular endothelial function is important in predicting several long-term complications in patients with KD. Flow mediated dilatation (FMD) of the brachial arteries is considered one of the non-invasive ways to study the vascular endothelial dysfunction.

Objectives: To study the FMD of brachial artery (BA) and evaluate for endothelial dysfunction in children with KD in both acute and convalescent phases.

Methods: Sixteen (16) children with KD and an equal number of controls were enrolled. The diagnosis of KD was based on the standard clinical diagnostic criteria enunciated by the 2004 American Heart Association (AHA). FDA approved automated edge detection software program (Brachial artery analyserTM) combined with high resolution ultrasound images were used to study the BA. Ultrasonography (USG) on a standard Philips Medical system was performed by a trained and expert radiologist. The software provided the diameter measurement every second. A 10-MHz multifrequency linear array probe attached to a high-resolution ultrasound machine was used to acquire images of the right BA. Baseline images of the right brachial artery were obtained for 2 minutes. A forearm cuff was positioned 1 cm under the antecubital fossa and inflated to 250 mm Hg for 5 minutes to induce forearm-reactive hyperemia. The cuff was then released and images of BA were recorded continuously for next 5 minutes. The basal diameter was taken as the average of measures collected during the first minute, and FMD was calculated as the maximum percentage change in the brachial artery diameter compared with the basal value. The USG was repeated in convalescent stage, at least three months later the diagnosis.

Results: Mean age of the study population was 4.8 years in cases (n = 16; M:F- 12:4) and 5.75 years in control population (n = 16; M:F- 10:6). The baseline BA diameter in acute phase of KD children is 2.3 ± 0.34 mm and that of convalescent phase is 2.49 ± 0.35 mm. Healthy control population had a mean baseline BA diameter of 2.35 ± 0.46 mm. Maximum dilatation was 2.56 ± 0.36 mm in the group of acute KD, 2.93 ± 0.31 mm in the group of convalescent KD and 2.95 ± 0.56 mm in healthy controls (p- 0.02). Children with KD had FMD of 12.32 ± 6.2% in acute phase and 17.99 ± 8.13% in convalescent phase, whereas, the control population had FMD of 26.88 ± 12.76% (p <0.01).

Conclusion: Our results suggest that FMD is significantly reduced in children with KD in acute phase and convalescent phase as compared to healthy controls. To the best of our knowledge, ours is the first study done in both phases of KD and suggests that endothelial dysfunction starts as early as in the acute phase of KD.

Disclosure of Interest: None Declared

P56 Discrepancies between clinical assessment and MR imaging in JIA

E. Charlotte van Gulik1, Robert Hemke1, Mendy M. Welsink-Karssies2, Dieneke Schonenberg1, Koert M. Dolman3, Anouk M. Barendregt1, Charlotte M. Nusman1, Taco W. Kuijpers1, Mario Maas1, J. Merlijn van den Berg1

1AMC, Amsterdam, Netherlands; 2OLVG, Amsterdam, Netherlands; 3Reade, Amsterdam, Netherlands
Correspondence: E. Charlotte van Gulik

Introduction: With the increased use of imaging as a supportive tool for starting or intensifying treatment in JIA patients, discrepancy between the MR imaging and clinical assessment will pose a dilemma.

Objectives

To evaluate patient characteristics and disease activity parameters in a single tertiary center cohort of JIA patients, both with and without synovial hypertrophy upon MRI, in order to explore frequency of mismatching results.

Methods

Clinical, laboratory, and contrast-enhanced MRI data of the knee of prospectively enrolled JIA patients from 2008-2014 were analyzed. JIA was diagnosed according to the ILAR criteria. The Wallace criteria for inactive disease were used. The validated Juvenile Arthritis MRI Scoring (JAMRIS) system for the knee was used to evaluate the presence of synovial hypertrophy (1). Clinically active and inactive patients were, as separate groups, divided into two groups based on the JAMRIS (four groups in total): JAMRIS score ≥1, meaning synovial hypertrophy, or JAMRIS score 0. Patient characteristics and disease activity parameters were then compared using the Chi-square and Fishers exact test if data were categorical and with the Mann–Whitney U if continuous.

Results

The MRI showed contradictory findings with reference to the clinical assessment in 43 of 124 patients (34.7%) (Table 20). The clinically active patients with discordant findings ((i.e. no synovial hypertrophy seen on MRI; n = 25) were significantly older and had been more often diagnosed with polyarticular JIA, compared to the clinically active patients with concordant findings (n = 47) (median age 13.2 years vs 10.9; p = 0.006 and 72% vs 34%; p = 0.003, respectively). The clinically inactive patients with discordant findings (i.e. synovial hypertrophy seen on MRI; n = 18) were significantly younger than the clinically inactive patients with concordant findings (median age 10.7 years vs 14.4; p = 0.008). Other clinical parameters, including CHAQ, laboratory results and medication usage were, however, not significantly different between the discordant and concordant groups (Table 20).
Table 20

(Abstract P56). See text for description

 

Clinically Active

Clinically Inactive

Variable

Concordant n = 47

Discordant n = 25

p-value

Concordant n = 34

Discordant n = 18

p-value

Female gender, n(%)

26 (55.3)

18 (72.0)

0.209

23 (44.2)

10 (19.2)

0.389

Age, years

10.9 (8.6-13.7)

13.2 (11.3-15.6)

0.006

14.4 (12.1-16.3)

10.7 (9.3-13.6)

0.008

Oligoarticular JIA, n(%)

21 (44.7)

2 (8.0)

0.001

11 (32.4)

11 (61.1)

0.076

Polyarticular JIA, n(%)

16 (34.0)

18 (72.0)

0.003

19 (55.9)

4 (22.2)

0.038

Other subtypes, n(%)

10 (21.3)

5 (20)

1.000

4 (11.8)

3 (16.7)

0.682

Conclusion

Nearly 35% of the JIA patients showed discordant findings between clinical assessment and MRI. Clinically active patients without synovial hypertrophy on MRI were significantly older at the time of MRI than the clinically active patients with synovial hypertrophy on MRI.

In the clinically inactive JIA patients, the discrepancy between clinical assessment and MRI was especially seen in younger patients. The meaning of synovial hypertrophy in the clinically inactive patient is still unknown, but it might indicate an incomplete disease remission.

References

1. Hemke R, van Rossum MA, van Veenendaal M, Terra MP, Deurloo EE, de Jonge MC, et al. Reliability and responsiveness of the Juvenile Arthritis MRI Scoring (JAMRIS) system for the knee. European radiology. 2013;23(4):1075-83.

Disclosure of Interest: None Declared

P57 Flow cytometry based assay of platelet reactivity in children with Kawasaki disease- a preliminary study

Pandiarajan Vignesh1, Surjit Singh1, Amit Rawat1, Man Updesh S. Sachdeva2, Jasmina Ahluwalia2

1ALLERGY IMMUNOLOGY UNIT, PEDIATRICS, POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH, Chandigarh, India; 2Hematology, POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH, Chandigarh, India
Correspondence: Pandiarajan Vignesh

Introduction: The acute phase of Kawasaki disease (KD) involve endothelial damage and activation of platelets. Markers of platelet activation were found to be elevated in adults with coronary artery disease (CAD) and venous thromboembolism. The actual evidence for platelet activation in KD, however, is limited to platelet aggregation studies and few studies on platelet activation markers and circulating microparticles. Monocyte-platelet aggregates (MPA), one of the most sensitive markers for activated platelets has not been studied in the acute phase of KD.

Objectives: To assess platelet reactivity by flow cytometry based measurement of MPA in children with KD.

Methods: Fourteen (14) children with KD, 15 age-matched febrile controls, and 13 age-matched healthy controls were enrolled in this prospective study. Diagnosis of KD was based on the American Heart Association (AHA) 2004 criteria. Samples were collected at three different phases of illness in patients with KD- acute stage prior to administration of IVIg and aspirin, 24 hours after administration of IVIg, and 3 months after onset of illness. Immediate fixation of the sample and lysis of red blood cells (RBC) were carried out at the room temperature with the use of BD FACS lysing solution. The washed samples were immunolabeled with a saturating concentration of PerCP-conjugated CD14 (lipopolysaccharide-protein receptor, BD PharmingenTM, Catalogue no. 555398) and fluorescein isothiocyanate (FITC) conjugated GP IIb (CD41, BD PharmingenTM, Catalogue no. 555466). Following incubation for 20 minutes at room temperature, the cells were acquired on the flow cytometry (Beckman coulter, Navios). The monocytes were gated from the lymphocyte side scatter plot and MPAs was identified from the monocyte population that had expressed both CD14 (monocyte marker) and CD41 (platelet marker) using the Kaluza software.

Results: The median age group (inter-quartile range) in the cases, febrile controls, and normal controls were 6 (3.0, 7.25), 5 (3.6, 9.0), and 5.5 years (4.15, 6.5), respectively. Male to female ratio among the groups were 12:2, 13:2, and 11:2 respectively. Echocardiographic abnormalities were detected in 3 children (2- transient abnormalities such as coronary wall brightness and coronary ectasia, 1- giant coronary aneurysms). Percentage of MPA% values were significantly high in children with KD [Median (IQR)- 41.3% (26.6, 52.7)] compared to the febrile [Median (IQR)- 5.98% (2.98, 9.72)] and normal controls [Median (IQR)- 4.48% (2.57, 5.59)], p < 0.01. A consistent drop in serial MPA% was observed from the diagnosis of KD to the end of third month follow-up [Table 21]. The MPA% values at 3 months post diagnosis of KD [Mean (SD)- 9.59% (7.65)] were significantly higher compared to the normal controls [Mean (SD)- 4.3% (2.03)], p-0.004.
Table 21

(Abstract P57). See text for description Median percentage values of MPA (CD14 + CD41+) in children with KD in follow-up: at diagnosis, 24 hour after completion of IVIg infusion and 3 months after diagnosis

S no

Category

Median MPA% (IQR)

P value

1

At enrolment (n = 14)

41.31 (26.6, 52.69)

<0.001*

2

24 hours after IVIg (n = 14)

18.55 (9.2, 22.99)

3

Follow-up at 3rd month (n = 11)

7.55 (4.15, 14.6)

*p < 0.05 considered significant

Conclusion: MPA% as an objective measure of platelet activation was significantly elevated in children with acute stages of KD when compared with age and sex-matched febrile and normal controls. Elevated levels of MPA% in patients with KD 3 months post diagnosis suggest that the endothelial inflammation or damage in KD persists for a longer duration even after control of symptoms and signs of systemic inflammation. Long-term studies on platelet activation markers in a larger multicentric cohort would conclusively establish the role of platelets in acute and long-term cardiac morbidity in KD.

Disclosure of Interest: None Declared

Immunodeficiency and infection related arthritis

P58 Deficiency of CD70 is responsible of a case of chronic active EBV (CAEBV) infection presenting as periodic fever

Roberta Caorsi1, Marta Rusmini2, Stefano Volpi1, Sabrina Chiesa1, Caludia Pastorino1, Francesca Minoia1, Alice Grossi2, Sara Signa1,3, Paolo Picco1, Angelo Ravelli1,3, Isabella Ceccherini2, Marco Gattorno1

1Second division of Pediatrics, G. Gaslini Institute, Genova, Italy; 2Division of Human Genetics, G. Gaslini Institute, Genova, Italy’; 3DINOMGI, University of Genova, Genova, Italy
Correspondence: Roberta Caorsi

Introduction: Chronic active EBV (CAEBV) infection is a rare condition associated to a chronic activation of Epstein Barr virus and therefore to a chronic and potentially life-threating lymphoproliferation. The prognosis is poor: most of the patients not treated with bone marrow transplantation die for lymphatic malignancies and the common immunosuppressive and antiviral therapy are usually not effective. Even if with a wide heterogeneity, most of the patients with CAEBV present severe clinical manifestations with early onset and poor prognosis; the presence of an underlying immunodeficiency causing an unusual EBV replication is therefore reasonable.

Objectives: To describe the clinical course and the genetic characterization of a patient with CAEBV mimicking PFAPA at disease onset.

Methods: In a patient with CAEBV infection a whole exome sequencing (WES) approach was undertaken and variants were prioritized with a custom pipeline to identify the genetic cause of his condition that was validated through Sanger Sequencing in the trio.

Results: The patient, born of consanguineous parents, at the age of 15 months presented, in complete wellbeing, a not-complicated infectious mononucleosis; in the following months he presented recurrent episodes of high fever with exudative tonsillitis, adenitis, splenomegaly and sweating, lasting 3-5 days and treated with NSAIDS or antibiotics. Blood examinations revealed neutrophilic leukocytosis and elevation of acute phase reactants; plasmatic immunoglobulins were within the normal range. An autoinflammatory condition with periodic fever was suspected and therefore on-demand steroidal treatment was suggested, with good response. The child continued to present periodic fever, associated to the occurrence of respiratory infections requiring antibiotics, and recurrent episodes of cheratitis. Several destructive dental caries were found as well as hyper sensibility to mosquitoes bite.

Immunologic test revealed then a reduction in the level of plasmatic immunoglobulins. The detection of EBV DNA with quantitative PCR revealed 21935 copies for 100000 leucocytes with prevalence of infection in the B cells. Whole body positron emission tomography revealed a retroperitoneal formation of about 35 mm with an increased metabolism that, at biopsy, revealed a reactive lymphadenopathy with paracortical involvement associated with EBV infection.

Genetic conditions associated to chronic EBV infection and immunodeficiency were ruled out: the genetic tests for SAP, XIAP, BAFF-R and ICOS were negative and the cytofluorimetric analysis of perforin, CD107 and 2B4 receptor were normal. In light of these findings a CAEBV was suspected.

Being the patient in good general conditions and in light of the prevalent involvement of CD20+ lymphocytes, on demand treatment with rituximab was started. The clinical response to treatment was initially very satisfying; however after two years the child presented severe infections requiring prolonged hospitalisation; stem cell transplantation was then performed with a complete normalization of both clinical and immunological features.

Among variants identified through a WES analysis of the patients and his parents, a homozygous mutation of the CD70 gene appeared to fit the recessive model of inheritance. The variantc.163-2A > G affects the exon2AG-acceptor splice site of the CD70 gene (NM_001252) leading to a deficiency in CD70, the ligand of CD27, a gene involved in isolated immunodeficiency. In the meantime our analysis was ongoing, CD70 mutations were reported in a few patients with a similar condition.

At the protein level, the anti-CD70 antibody failed to detect CD70 by flow cytometry at the cell surface of PHA-stimulated T and EBV-trasformed B cells of the patient. In contrast, expression of CD70 was detectable on cells from healthy donors.

Conclusion: This case describe a new case of a newly identified genetic cause of CAEVB presenting with recurrent periodic fever.

Disclosure of Interest: None Declared

P59 Clostridium difficile enterocolitis and reactive arthritis: a case report ad re-view of the literature

Lorenzo Mambelli1, Michela Cappella2, Martina Mainetti1, Federico Marchetti1

1Pediatrics, S. Maria delle Croci Hospital, Ravenna, Italy; 2Pediatric and Adolescence Rheumatology, S.Maria Nuova Hospital, Reggio Emilia, Italy
Correspondence: Lorenzo Mambelli

We report the case of a 6-year-old boy with pain in the right knee and both ankles after a 10-day course of oral amoxicillin-clavulanate completed three weeks earlier; at the same time he developed diarrhea with positive culture for Clostridium difficile (CD). Three days later the knee and ankles arthritis resolved spontaneously but appeared in the right shoulder and homolateral hip with a migratory pattern and with fever. Synovial fluid and blood cultures, rheumatoid factor, ANA and HLA-B27 antigen were negative. The improvement of colitis and the negativity of fecal calprotectin at follow-up allowed to exclude an inflammatory bowel disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) and metronidazole completely resolved pain, joint swelling and diarrhea. After 24 months of follow-up there has been no recurrence.

Reactive Arthritis (ReA) is an aseptic acute inflammatory arthritis occurring after an intercurrent infection in which the causative organism is outside from the joint. It is typically an asymmetrical oligo/polyarthritis predominantly in the lower limbs large joints (knee, ankle, hip) and present approximately 2-4 weeks following infection. Several patients present a migratory pattern and acute arthritis is often characterized by severe pain and sometimes erythema over the affected joints; enthesitis/tenosynovitis may occur. Most frequent causes are Salmonella, Shigella, Yersinia, C. jejuni, group A Streptococcus and C. trachomatis.

CD is the most common cause of diarrhea after antibiotic therapy but CD ReA is rare and its pediatric epidemiology is poorly known; it was generally migratory and polyarticular, involving large joint and tipically with a good outcome and self-limiting course.

For the diagnosis of ReaA following CD enterocolitis there are criteria established by Putterman and Rubinow [1], but basically a history of diarrhoea after a course of antibiotic with the exclusion of other causes of gastroenteritis or noninfectious arthritis is essential.

Jacobs et al [2] documented until 2001 35 cases of CD ReA in adults; epidemiology in child instead is rare and unknown, but incidence of CD infection has increased among children. We performed a literature search of MEDLINE, Google Scholar, and Cochrane Reviews computerized databases using the keywords “Clostridium difficile”, “arthritis”, and “child” to identify all papers reporting CD enterocolitis-associated ReA in childhood. Six papers met our review's inclusion criteria with a total of 32 pediatrics cases of CD ReA. The most recent study identified, from 2004 to 2013, 26 cases with acute arthritis/tenosynovitis after CD infection and authors estimate that CD ReA affected 1.4% of child with CD infection; only 35% of CD ReA were correctly diagnosed, occasionally misdiagnosed as septic arthritis [3].

Conclusion: CD infection should be suspected in children presenting with an acute inflammatory arthritis following an episode of diarrhea, especially when culture for common enteric infection are negative and the patient has received antibiotic therapy before the onset of diarrhea.

Written informed consent for the publication of patient details was obtained.

Disclosure of Interest: None Declared

References

[1]Putterman et al,Reactive arthritis associated with Clostridium difficile pseudomembranous colitis.Seminars in Arthritis and Rheumatism;22(6),pp 420-6,1993

[2]Jacobs et al,Extracolonic manifestations of Clostridium difficile infections:Presentation of 2 cases and review of the literature.Medicine;80(2),pp 88-101,2001

[3]Horton et al,Epidemiology of Clostridium difficile Infection–Associated Reactive Arthritis in Children.An Underdiagnosed,Potentially Morbid Condition.JAMA Pediatr. 2016;170(7)

Juvenile idiopathic arthritis (JIA) in practice

P60 The effect of task-oriented training with video-based games on activity performance and participation in children with juvenile idiopathic arthritis

Nilay Arman1, Ela Tarakci1, Devrim Tarakci2, Ozgur Kasapcopur3

1Division of Physiotherapy and Rehabilitation, Faculty of Health Science, Istanbul University, Istanbul, Turkey; 2Division of Ergotherapy, Istanbul Medipol University, Istanbul, Turkey; 3Department of Pediatric Rheumatology, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
Correspondence: Nilay Arman

Introduction: Juvenile idiopathic arthritis (JIA) is most common chronic rheumatic disease in childhood. The upper extremity involvement in JIA causes muscle imbalance, joint destruction, pain, stiffness and limitations on activities of daily living (ADL) in varying degrees. However, the information about prevalence of symptoms, disorders, ADL limitations, participation restriction and options of treatments for upper extremity involvement in JIA are limited. It has been reported that improvements of upper extremity functions were achieved by video-based games (VBG) in various disease groups. However, in the literature, no study has been found about effectiveness of VBG in children with arthritis.

Objectives: The aim of the study was to investigate the effects of two different task-oriented activity training to activity performance and participation in children who have involved upper limb with JIA.

Methods: 62 patients included in the study were randomized into two groups as group I (patient-centered task-oriented activity training in daily living conditions) and group II (patient-centered task-oriented activity training with VBG). The patients’ pain, by “Numeric Rating Scale (NRS)”, range of motion (ROM) by “goniometer”, muscle and grip strengths by “dynamometer”, activity performance and participation by “Childhood Health Assessment Questionaire (CHAQ)”, “Duruoz Hand Index (DEI)”, “Jebsen-Taylor Hand Function Test (JTHFT)” and “Nine Hole Peg Test (NHPT)” were evaluated. In group I, ADL were trained with real materials used in daily life and various rehabilitation products. In group II, ADL were trained with VBG. We have created training protocol with Xbox 360 games for patient-centered task-oriented activity training with VBG. We prefered ‘Dance Central2’, one of the Xbox 360 games, for warming (macerana dancing, 10 minutes). Other games, ‘Fruit Ninja’, ‘Table Tennis’, ‘Boxing’, ‘Volleyball’, ‘Darts’ and ‘Bowling’ were selected appropriately according to patients performance. All the patients completed 8 weeks (45 minutes for every session, 3 times in a week) of client-centered treatment.

Results: After treatment in both groups, significant changes were found in NRS, ROM, muscle strength, grips strength, CHAQ, DEI, JTHFT and NHPT (p < 0,05). Table 1 shows comparison between the groups for the activity performance, pain severity, hand grip and pinch grip strengths. After the treatment, group II was statistically more superior than group I in changes of wrist extension ROM and DEI (p <0.05). In addition to, almost all changes of muscles strength in group II were statistically more superior than changes of group I (p < 0.001).

Conclusion: In our study, two different task-oriented activity training provided significant changes in pain, ROMs of upper extremity, muscle strength, grip strength, activity performance and participation and patient-centered task-oriented activity training with video-based games has been proved as an alternative treatment in children who have involved upper limb with JIA.

Trial registration identifying number: Clinical Trial Number: NCT02954718

This work was supported by Research Fund of Istanbul University. Project No: 51144

Disclosure of Interest: None Declared

P61 Analysis of activity performance problems in patients with juvenile idiopathic arthritis

Nilay Arman1, Ela Tarakci1, Ozgur Kasapcopur2

1Faculty of Health Sciences, Division of Physiotherapy and Rehabilitation, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey; 2Department of Pediatric Rheumatology, Medical Faculty of Cerrahpasa, Istanbul University, Istanbul, Turkey
Correspondence: Nilay Arman

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and is an important cause of short-term and long-term disability. Many children appeared to have elbow, hand- and/or wrist-related symptoms and impairments, with resulting moderate to severe levels of activity limitations and participation restrictions at daily living. However, in the literature, no study has been found about variety of activity performance problems in patients with JIA. The Canadian Occupational Performance Measure (COPM) is a client-centered, patient reported outcome measure with which clients evaluate their activity performance and satisfaction with performance in areas of self-care, productivity and leisure. COPM is generally used for analyzing activity performance problems in many chronic diseases.

Objectives: The aim of the study was to analyze the activity performance problems of patients with JIA.

Methods: 50 patients with JIA (42 Female, 8 Male) were included in the study. Inclusion criteria consisted of a diagnosis of JIA according to the International League of Associations for Rheumatology criteria, being aged between 6–18 years, having at least one affected joint in upper extremity (shoulder, elbow, wrist, and finger joints). Activity performance problems as perceived by the individual were measured using face to face interview by the Canadian Occupational Performance Measure (COPM). During the interviews, the patients were encouraged to identify any daily activity that they would like or need to do but found difficult to complete because of their rheumatic diseases. Patients then identified the five most important daily activities and rated, first, their current level of performance, and then, how satisfied they were with this current level of performance. These performance and satisfaction scores were rated by on a 10-point scale, with higher scores indicating better performance and satisfaction. The statistical software SPSS 21.0 was used for the analyses.

Results: The mean age was 12,76 ± 3,16 and the mean disease duration was 5,92 ± 3,82 years. 8% of patients had involvement shoulder joint, 74% of them had involvement elbow joint, 88% of them had involvement wrist joint and also 64% of them had involvement finger joint. The patients with JIA described 36 different types of problematic activities and identified 30 of them as the five most important daily activities. Table 22 shows frequencies of five most important daily activities of patients with JIA. The five most identified problems were “carrying something” (66%), “writing” (50%), “opening a bottle cap” (48%), “dressing” (38%) and “opening a door with handle/knob” (38%) according to COPM. The mean of COPM-performance scores was 3,99 ± 1,72 and the mean disease COPM-satisfaction scores was 2,56 ± 1,70.
Table 22

(Abstract P61). Frequencies of five most important daily activities of patients with JIA

Activity

%

Activity

%

Activity

%

Activity

%

Carrying something

66

Using a knife

20

Drinking

8

Gripping small objects

4

Writing

50

Buttoning

18

Cutting nail

8

Using a scissors

4

Opening a bottle cap

48

Taking a bath

16

Washing dishes

6

Stirring a soup

2

Dressing

38

Peeling a fruit

14

Pushing something

6

Opening a zipper

2

Opening a door with handle/knob

38

Washing hair

14

Removing a sock

4

Acclaiming

2

Combing

28

Tying a shoelace

12

Reaching to grab something

4

Using a fork

2

Unlocking

28

Brushing teeth

10

Unpacking

4

  

Tapping

26

Eating

10

    

Conclusion: Our results showed that patients with JIA, who have at least one affected joint in upper extremity, reported problems with a wide range of activities. We suppose that the COPM can be a useful tool for identifying activity performance problems as a patient-focused outcome measure and also, it could provide information about patient centered management for patients with JIA.

Disclosure of Interest: None Declared

P62 Vaccination coverage in children with rheumatic diseases

Maša Bizjak1, Tadej Avčin1,2, Nataša Toplak1,2

1Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; 2Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Correspondence: Maša Bizjak

Introduction: The evidence of vaccine safety and efficacy in patients with rheumatic diseases is increasing. However, the data on vaccination status in children with rheumatic diseases remain scarce. So far, only few smaller studies were published that found suboptimal vaccination coverage in patients with rheumatic diseases.

Objectives: To assess vaccination status in a cohort of children with rheumatic diseases followed at the University Children's Hospital Ljubljana and to evaluate the most common reasons for vaccination dropout.

Methods: All consecutive patients with rheumatic diseases evaluated at the rheumatology outpatient clinic between 1 January 2015 and 15 January 2017 received a questionnaire about their vaccination status and reasons for potential vaccination dropout. Descriptive statistics were used to analyse the proportion of children with full vaccination status at 5, 10, 18 years and at their last clinic visit. The study was approved by the national ethics committee.

Results: By May 2017 the data were received from 125 out of 422 enrolled patients (29.6%). Among included patients 64.8% were female, median age was 12.3 (1.5-22.9) years and median age at diagnosis 5.8 (0.7-16.6) years. The majority of included children had JIA (n = 114), followed by SLE (n = 5), CRMO (n = 2), JDM (n = 2), MCTD (n = 1) and systemic sclerosis (n = 1). Vaccination coverage was complete in 92.1%, 81.3%, 72.2% and 71.2% of patients at 5, 10, 18 years and at their last clinic visit, respectively. Most commonly omitted vaccines were Hepatitis B (22.9%) and second dose of Measles, Mumps and Rubella vaccine (18.3%). Most common additional vaccine was against tick-borne encephalitis (26.4%), which is an endemic disease in Slovenia. Most common reasons for vaccination dropout were suggestion of the treating rheumatologist and active disease.

Conclusion: We experienced a low initial response rate of 30%, which might be due to increasing parents' vaccine hesitancy. In our sample we found an approximately 10% decrease in complete vaccination coverage between consecutive age cohorts. Overall vaccination coverage in children with rheumatic diseases is lower than in general population in Slovenia. Parent and patient education on vaccination remains crucial and when possible, vaccination catch-up plans and booster vaccinations should be advocated on an individual basis.

Disclosure of Interest: None Declared

P63 Quality of referral letters to pediatric rheumatology and its impact on access to care

Abstract withdrawn

P64 Contextualizing guidelines for the management of juvenile idiopathic arthritis in developing countries: a needs assessment

Mercedes O. Chan1, Ricardo Russo2, Lawrence Okong'o3, Christiaan Scott4

1Pediatrics (Rheumatology), University of Alberta, Edmonton, Canada; 2Immunology and Rheumatology, Hospital de Pediatría Garrahan, Buenos Aires, Argentina; 3Paediatrics and Child Health, University of Nairobi, Nairobi, Kenya, 4University of Cape Town, Cape Town, South Africa
Correspondence: Mercedes O. Chan

Introduction: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood (4/1000 children) and untreated, can lead to significant morbidity including joint deformities, loss of function and blindness (uveitis). Guidelines for the management of JIA have been created for use in the developed world. Challenges in diagnosis and management arise when these guidelines are applied in low-resource settings given different endemic diseases, access to care, and sociocultural practices.

Objectives: We performed a needs assessment of clinicians managing JIA in low-resource settings with a view to applying our findings to recommendations for JIA management in developing countries.

Methods: An anonymous needs assessment regarding the management of JIA in developing countries was developed based on four areas of attention identified by rheumatologists in the developing world: patient management (access to care and medications, clinical work-up, transition); education (to the health professions and the public); advocacy, networks and policy; and research. The survey (available in English and Spanish) was tested, validated and electronically circulated to healthcare practitioners who see children with JIA in developing countries. Contacts were acquired through pediatric rheumatology professional networks

Results: The survey was distributed to 502 practitioners, with 116 responses from clinicians in South America (50%), Africa (28%), Asia (12%), the Middle East (1.5%), Central America (1.5%) and other countries (7%). Respondents were pediatric rheumatologists (66%), adult rheumatologists (22%), allied health professionals (7%), general pediatricians (4%) and general practitioners (1%); median age 40-50 years, median 10-15 years in practice. The percentage of time devoted by these clinicians to pediatric rheumatology in their practice was: <25% (29%), between 26-50% (19%), between 51-75% (13%), >75% (17%) and 100% (22%).

Barriers to accessing care for children with JIA identified by respondents were: insufficient training in JIA among pediatricians (74%), lack of awareness of JIA in the healthcare community (73%), long referral pathways (67%) and few pediatric rheumatologists (63%). Endemic diseases that complicate the management of JIA in participants’ settings were: tuberculosis (84%), HIV (41%), sickle cell anemia (31%), malaria (19%) and diarrheal disease (19%). Transition planning was not a programmed strategy in >40%; and non-adherence to uveitis screening guidelines was reported in >40%.

Education on JIA was available to 71% of pediatrics trainees, 50% of adult rheumatology trainees and <50% of medical students in participants’ settings. Established pediatric rheumatology training programs were unavailable to 40%; access to educational resources and educating the public on JIA was available to only one third of respondents.

Policy and advocacy interventions felt to potentially improve access to care for JIA patients were: increasing the availability of pediatric rheumatologists (79%) and jobs for them (50%), better training on managing JIA (74%), formulation of clear referral channels (65%), formation of patient support groups (62%) and availability of management guidelines (49%).

One third of participants were not involved in research. Epidemiological and clinical research were felt to be research priorities in JIA by 75% and 62% of participants to ascertain local burdens of disease. Major barriers to performing research include: lack of funding (79%), lack of time (58%), lack of support systems, e.g., laboratory (52%), lack of trained personnel (46%) and lack of experience (26%).

Conclusion: Management of JIA remains a challenge in the developing world; is rooted in educational gaps in the medical and general community; and complicated by endemic disease and insufficient access to resources. Guidelines specific to low-resource settings, and informed by research exploring the local burdens of disease and experiences of stakeholders, may serve as a powerful educational document to advocate for policy change and best practices.

Disclosure of Interest: M. Chan Grant/Research Support from: International League Against Rheumatism Grant, R. Russo Grant/Research Support from: International League Against Rheumatism Grant, L. Okong'o Grant/Research Support from: International League Against Rheumatism Grant, C. Scott Grant/Research Support from: International League Against Rheumatism Grant

P65 Evaluation of the diagnostic delay and access to remission in JIA patients of the JIR cohorte

Caroline Freychet1, Natalia Cabrera2, Lega Jean Christophe2, Michael Hofer3, Alexandre Belot4 and JIR cohorte

1Laboratory HESPER (Health Services and Performance Research), University Claude Bernard Lyon 1, Lyon, France; 2Team Evaluation et Modélisations des Effets Thérapeutiques, University Claude Bernard Lyon 1, Lyon, France; 3Paediatric Rheumatology, University hospital of Lausanne, Lausanne, Switzerland; 4Paediatric Rheumatology, University hospital of Lyon, Lyon, France
Correspondence: Caroline Freychet

Introduction: Many studies in pediatric rheumatology underline the concept of « window of opportunity », early in the disease course to prevent joint or ocular damage in the context of juvenile idiopathic arthritis (JIA). In Europe, despite facilitated access to health care, children with JIA are referred to pediatric rheumatology centres with significant delay. This delay is closely linked to the organization of the country’s health care delivery system. In France and Switzerland nothing is known about diagnostic delay and little about access to remission in JIA.

Objectives: To assess the diagnostic delay and the rate of remission at one year and 2 years in JIA patients of the JIR cohorte.

Methods: The JIRcohorte is an international network dedicated to collect prospective and retrospective data on juvenile inflammatory rheumatic diseases. Data collection started in 2013. We included all French and Swiss JIA patients according to the ILAR classification. We focused on the relationship between (i) diagnostic delay (defined by the number of weeks between the first symptoms and the diagnosis), (ii) distance between parent’s home and the place of the diagnosis, and (iii) remission rate at one year, two years and treatments.

Results: We included 709 JIA patients (50% oligoarthritis, 17% RF– polyarthritis, 15% enthesitis-related arthritis [ERA], 10% systemic JIA [sJIA], 3% RF+ polyarthritis, 3% psoriatic arthritis, and 2% undifferentiated arthritis).

The median diagnostic delay of the whole cohort was 17 weeks (interquartile range (IQR) 9-48). The patients with ERA had the longest delay: 45 weeks (13-104), whereas children with sJIA had the shortest delay: 9 weeks (4-21). The median diagnostic delay was not correlated with parents’ home distance from the diagnostic center. 59% and 57% of the patients were in remission and 57% at 1 and 2 years of follow-up, respectively.

The median delay between diagnosis and treatment onset was 3 weeks (IQR 0-34) for oral corticosteroids, 8 weeks (IQR 0.3- 30) for intra-articular corticosteroids, 9 weeks (IQR 0-52) for DMARDS and 52 weeks (IQR 19-147) for biologics.

The diagnostic delays for the whole cohort and for the different JIA subtypes are in line with the international literature. JIA with indolent symptoms as ERA had the longest diagnostic delay whereas sJIA associated to overt manifestations including fever had the shortest delay. In France and Switzerland, there are no guidelines about diagnostic delay but UK guidelines advocate a diagnostic delay inferior to 10 weeks. According to these guidelines, 68% of our patients exceed this delay, which is shlighly lower than previous studies. The absence of correlation with parents’ home distance from the diagnostic center is also described in other countries. Our remission rate at 1 year is higher than described in other studies but it decrease at 2 years. The treatment delay is longer in our cohort than in other studies.

Conclusion: The diagnostic delay and treatment delay in France and Switzerland are too long. Strong efforts have to be made to understand the underlying factors to suggest improvements in care pathway organization and practices by the elaboration of care course management guidelines. The JIR network permit to design a prospective study to identify these factors and improve the short-term prognosis of JIA, in the context of national and European rare disease health programs.

Disclosure of Interest: None Declared

P66 Performance of disease activity measures in pediatric patients with enthesitis-related arthritis

Abstract withdrawn

P67 Teaching adult rheumatology fellows to help young adult patients ‘stick the landing’ when transferring from pediatric to adult rheumatology care

Rebecca E. Sadun1, Gary R. Maslow2, Lisa G. Criscione-Schreiber3

1Internal Medicine and Pediatrics, Duke University, Durham, NC, United States; 2Pediatrics and Psychiatry, Duke University, Durham, NC, United States; 3Internal Medicine, Duke University, Durham, NC, United States
Correspondence: Rebecca E. Sadun

Introduction: The transition from pediatric to adult healthcare is a vulnerable time for adolescents and young adults (AYA) with chronic conditions. Thie year the European League Against Rheumatism (EULAR) and the Pediatric Rheumatology European Society (PReS) jointly offered expert-opinions regarding transitional care of AYA with juvenile-onset rheumatic diseases and the American College of Rheumatology (ACR) developed a toolkit. For these guidelines to be implemented or for these resoures to be utilized, adult and pediatric rheumatologists need to understand their application. Nevertheless, there are no published curricula for teaching transition skills to rheumatologist-in-training.

Objectives: We sought to develop and assess the impact of a workshop designed to help adult rheumatology fellows learn key skills for providing effective transition care to transferring young adult patients.

Methods: A 1-hour skills-based workshop on transition and transfer best practices was developed alongside an objective standardized clinical examination (OSCE) station in which trainees were given 12 minutes to welcome a young adult with lupus – and her parent – to a first visit in an adult clinic and perform a full history. The OSCE evaluation rubric assessed five transition/transfer skills (skills 1-5) and one “control skill” (skill 6), on a Likert scale of 1-5, with 5 being the best performance. Adult rheumatology fellows (n = 19) from 5 institutions were evaluated with the OSCE; 12 were tested with the OSCE de novo, whereas 7 were tested with the OSCE after participating in the workshop. Unpaired, aggregated OSCE scores were complemented with unpaired pre- & post-survey data in which fellows reported their self-assessed level of preparation for 12 transition and transfer skills.

Results: Fellows’ self-assessed proficiency with 12 key transition/transfer skills increased significantly with participation in the workshop and accompanying OSCE, including fellows’ confidence in their ability to discuss the needs of the transferring patient with the pediatric rheumatologist (p < 0.01). In addition, OSCE performance (see Table 23) was greater in the group of fellows that participated in the workshop prior to the OSCE (“post-workshop” - average score of 4.3) than in the group that took the OSCE de novo (“pre-workshop” - average score of 3.3, p = 0.01). The skills demonstrating statistically significantly higher scores post-workshop were: skill 1) highlighting differences between adult and pediatric care and setting expectations (p < 0.01); skill 2) placing the patient in the primary role and utilizing the parent for corroboration (p < 0.05); and skill 4) performing a confidential adolescent social history. There was a trend towards improved performance for skill 3, assessing self-management skills, whereas there was no significant change in skill 5, assessing barriers to transition and medication adherence. Performance on skill 6, the control skill of assessing patient and parent understanding of the disease process, was lower in the group of fellows’ that participated in the workshop prior to being tested with the OSCE (p = 0.01).
Table 23

(Abstract P67). See text for description

 

Skill 1

Skill 2

Skill 3

Skill 4

Skill 5

Total/Avg

Skill 6

Pre-workshop (n = 12)

3.5

4.3

3.8

2.8

2.3

16.7/3.3

3.5

Post-workshop (n = 7)

4.6

5.0

4.4

4.7

2.6

21.3/4.3

2.0

p-value

<0.01

<0.05

0.18

0.01

0.86

0.01

0.01

Conclusion: A brief educational intervention successfully increased adult rheumatology fellows’ perception of their proficiency with key transition/transfer skills. In addition, fellows who participated in the educational intervention had significantly higher scores on their OSCE performance. It is likely that the “control skill” score was lower in the post-workshop group owing to more time being spent on newly acquired peri-transfer skills: during the 12-minute OSCE scenario, discussing disease pathogenesis took a backseat to conversations about expectations in the adult care model, self-management skills, and goal setting. Making this curriculum available to all rheumatologists-in-training would likely improve the care young adult rheumatology patients receive when transferring from pediatric to adult rheumatology. A complementary curriculum for pediatric rheumatology fellows could further improve the care of AYA rheumatology patients.

Disclosure of Interest: None Declared

P68 No radiographic damage after early aggressive treatment in juvenile idiopathic arthritis

Dieuwke Schreurs1,2, Willemieke van Braak2, Petra Hissink Muller1, Charlotte Nusman2

1Pediatric Rheumatology, LUMC, Leiden, Netherlands; 2Radiology, AMC, Amsterdam, Netherlands
Correspondence: Dieuwke Schreurs

Introduction: Juvenile idiopathic arthritis (JIA) is characterized by chronic inflammation of the joints which can lead to structural bone damage.

Objectives: The primary objective of this study was to evaluate response of newly diagnosed JIA patients to an early aggressive treatment by conventional radiography. Secondary objective was to compare Poznanski and BoneXpert methods to evaluate presence and progression of radiological damage in wrists of JIA patients.

Methods: JIA patients participating in the BeSt for Kids study (NTR 1574) were eligible in case of wrist involvement at inclusion if conventional radiographs were available at baseline or within 6 months before/after study inclusion. Follow-up radiographs after 12-36 months were available for comparison. Radiographic bone damage as reflected by carpal length was assessed using Poznanski score. BoneXpert method was used to determine bone age and bone mineral density (BMD).

Results: Forty JIA (27 female) patients were evaluated for Poznanski score and BMD (mean age 7.2 ± 3.4 years), 26 patients (15 female) were evaluated for bone age (mean age 9.3 ± 2.2). At baseline mean Z-score of RM/M2 was 0.047. At follow-up mean Z-score changed to 0.055 (p = 0.937). Baseline and follow-up Z-scores were not different from a healthy population. Bone age did not significantly differ at baseline (Z-score 0.08) and follow-up (Z-score 0.25). At baseline BMD was significantly diminished compared to healthy controls (Z-score -0.71) and improved significantly (Z-score -0.44 (p = 0.032)).

Conclusion: In this cohort of JIA patients treated early and aggressively we have detected no radiographic damage in the wrist at baseline or follow up. BMD was significantly diminished at baseline but improved significantly after follow-up.

Disclosure of Interest: None Declared

P69 The characteristic of the undifferentiated arthritis in juvenile idiopathic arthritis

Betul Sozeri1, Eylem Topaktas1, Duygu Kurtulus2

1Pediatric Rheumatology, University of Health Sciences, Istanbul, Umraniye Training and Research Hospital, Istanbul, Turkey; 2Physical Medicine and Rehabilitation, University of Health Sciences, Istanbul, Umraniye Training and Research Hospital, Istanbul, Turkey
Correspondence: Betul Sozeri

Introduction: Juvenile idiopathic arthritis, JIA, is classified into seven categories; systemic-onset type, persistent and extended oligoarthritis, polyarthritis with rheumatoid factor negative, polyarthritis with rheumatoid factor positive, psoriatic arthritis, enthesitis-related arthritis and undifferentiated arthritis classified by the International League of Associations for Rheumatology. As each category of JIA has different features in clinical phenotypes, precise subtyping is required for research and management. Due to inclusion and exclusion criteria, some patients is ended up in the undifferentiated category. Undifferentiated arthritis includes patients who do not meet criteria for any category. Or, they meet the criteria for more than 1 category but with either a close relative who has psoriasis or the presence of RF. The prevalence of subtypes of JIA was reported; Oligoarticular JIA occurs most frequently (50% to 60% of cases), followed by polyarticular JIA. However, there is not enough information in the literature about the undifferentiated arthritis group.

Objectives: We aimed to analysis the characteristic findings of the undifferentiated arthritis group in JIA patients.

Methods: This was a retrospective longitudinal cohort study of patients with JIA at a tertiary care pediatric rheumatology clinic. Subjects were included if they were evaluated at our pediatric rheumatology clinic between June 2016 and May 2017, had a diagnosis of JIA according to ILAR criteria.

Demographics (sex, age at diagnosis, ANA, RF, HLA B27 status), clinical disease elements (active joint count, tender enthesis count) and current medication use at each visit were identified by querying the electronic medical record. All available visits were included in the analysis. All analyses were performed using SPSS 16.0

Results: During the study period there were 215 JIA patients evaluated at 640 visits. 180(84%) of patients had newly-diagnosed JIA.

There were 21 (84%) girls and 4 (16%) boys. Mean age at disease onset was 13.4 ± 2.2 years.The median duration of disease was 8 years.The median duration prior to treatment was 1 months. Among 25 patients with undifferentiated arthritis, 11 (48%) patients had enthesitis, 15 (60%) had sacroiliitis. Joints mainly affected in the undifferentiated arthritis group with were knees (16, 64%) and 2 patients were RF-positive and 7patients had positive ANA had undifferentiated arthritis. 6 patients (24%) of undifferentiated JIA patients used more than one DMARD.Methotrexate was the mainstay of treatment (52%), with an initial dose of 10–15 mg/m2/week and a maximum dose of 20– 25 mg/m2/week or 25 mg/week. Sulfasalazine was used in36 % of undifferentiated JIA patients. 2 of the patients received biologic agents.

Conclusion: Since distribution of the JIA category is different upon ethnicity, this study showed that percentage of undifferentiated JIA patients in our cohort was found higher reported from other studies in the literature. This is a single center, referral-based cohort study. As such, it might not represent the entire population of Turkey. In our conclusion, to clarify characteristics of undifferentiated JIA patients, need large cohort and multicenter study.

Disclosure of Interest: None Declared

Juvenile idiopathic arthritis

P70 Time of onset of ocular disease in 336 children with juvenile idiopathic arthritis-associated uveitis: evidence-based data to refine current ophthalmologic screening guidelines

Serena Calandra1, Valentina Muratore2, Valentina Ravaschio1, Gabriella Giancane1, Alessandra Alongi1, Angela Pistorio1, Alessandro Consolaro1, Angelo Ravelli1

1Istituto Giannina Gaslini, Genova, Italy; 2Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Correspondence: Serena Calandra

Introduction: Uveitis is the most common form of extraarticular organ involvement in juvenile idiopathic arthritis (JIA). The onset of chronic anterior uveitis in JIA is insidious and often entirely asymptomatic. Children with JIA must be subjected to periodic eye examinations with slit lamp according to the different risk of developing this complication. The decision to undertake a screening program depends on the cost-benefit balance. To date, however, there is uncertainty about the optimal frequency of eye examinations. Although guidelines for ophthalmologic surveillance have been proposed, none of them is universally embraced.

Objectives: To evaluate the time of the occurrence of uveitis after the onset of arthritis in children with JIA

Methods: The clinical charts of 1425 patients with JIA by ILAR criteria followed at study centers from January 1987 to October 2016 and with a follow-up of at least 6 months after disease onset were reviewed to identify those who had uveitis. In all patients, the diagnosis of chronic anterior uveitis was confirmed by an ophthalmologist and was defined according to the Standardization of Uveitis Nomenclature Working Group criteria. Children with systemic arthritis, rheumatoid-factor positive polyarthritis and enthesitis-related arthritis were excluded. Patients who developed uveitis before the onset of arthritis were also excluded. Patients who developed uveitis at the same time of the arthritis onset were included. Through the construction of a cumulative frequency curve, we defined the risk of developing uveitis for each year of disease, starting with the onset of arthritis.

Results: A total of 336 patients (23.6%) had uveitis a median of 1.1 years after onset of arthritis. The cumulative frequency curve showed that 47.6% and 67.3% of patients developed uveitis in the first 1 and 2 years of illness, respectively, and that less than 5% of all instances of uveitis occurred after 7 years from the onset of arthritis (Table 24).
Table 24

(Abstract P70). Cumulative frequency of uveitis

Follow-up (years)

0 to 1

1 to 2

2 to 4

4 to 6

6 to 8

8 to 9

> 9

N.

160

66

51

31

15

6

7

Cumulative %

47.6

67.3

82.4

91.7

96.1

97.9

100

Conclusion: Our study shows that nearly half of JIA patients with uveitis developed this complication in the first year after onset of arthritis and around two-third within two years. Less than 5% of patients had uveitis after 7 years from disease onset. These findings underscore the need for tight ophthalmologic monitoring in the first 2 years of disease and support the recommendation of current guidelines to lengthen ophthalmologic screening after 7 years of disease without ocular involvement.

Disclosure of Interest: None Declared

P71 An open-label extension study to assess the long-term safety and clinical benefit of etanercept in pediatric patients with extended oligo, enthesitis related, and psoriatic JIA: 6-year data from the clipper studies

Ivan Foeldvari1, Tamas Constantin1, Jelena Vojinovic1, Gerd Horneff1, Joke Dehoorne1, Gordana Susic1, Katarzyna Kobusinska1, Violeta Panaviene1, Zbigniew Zuber1, Valda Stanevica1, Vyacheslav Chasnyk1, Ronald Pedersen2, Jack Bukowski2, Tina Hinnershitz2, Bonnie Vlahos2, Alberto Martini1, Nicolino Ruperto1 on behalf of the Paediatric Rheumatology International Trials Organisation (PRINTO)

1PRINTO, Genoa, Italy; 2Pfizer, Collegeville, PA, United States
Correspondence: Ivan Foeldvari

Introduction: A Phase 3b, open-label (OL), multicenter study (CLIPPER) has shown efficacy of etanercept (ETN) in pediatric patients (pts) with extended oligoarticular (eo) juvenile idiopathic arthritis (JIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA). CLIPPER2 is an ongoing OL extension study assessing long-term safety and clinical benefits of ETN in this population.

Objectives: Describe safety and clinical benefit of 6 yr of ETN treatment in CLIPPER (2 yr) and CLIPPER2 (4 yr) studies.

Methods: 127 pts with eoJIA (2–17 yr), ERA, or PsA (12–17 yr) who received ≥1 ETN dose (0.8 mg/kg QW [max, 50 mg]) in CLIPPER were eligible to enter CLIPPER2. Efficacy endpoints included proportions of pts achieving JIA ACR30/50/70/90/100 and Wallace/Juvenile Arthritis Disease Activity Score (JADAS) inactive disease/clinical remission criteria. Time to disease flare for pts who met predefined study criteria for withdrawing from ETN treatment was assessed by Kaplan-Meier (KM) analysis. Safety was assessed from CLIPPER baseline (BL) to month (m) 72.

Results: 109/127 (86%) pts entered CLIPPER2. At m72, 46/127 (36%) were taking ETN (39 [31%] ongoing, 7 [6%] restarted treatment), 44 (35%) had stopped ETN treatment, and 37 (29%) had discontinued the study. Improvements in disease activity seen in CLIPPER (m0–24) were largely maintained at m72 (Table; observed cases). Proportion of pts achieving JIA ACR30/50/70 responses at m24 (% = 99/98/93) was maintained to m72 (% = 96/96/88). Proportion of pts achieving JIA ACR90/100/Wallace inactive disease at m24 (% = 65/54/34) was maintained to m60 (% = 71/51/31) but afterwards decreased (% = 50/26/10 at m72). Sustained remission (≥12 continuous months) was achieved by 7/98 (7%) pts. 22/127 (17%) pts withdrew from ETN treatment due to low/inactive disease; 13/22 (59%) experienced disease flare (median time to flare [KM] = 190 days).

Most frequently reported treatment-emergent adverse events (TEAEs) were (no. events [N], events per 100 pt-yr [EP100PY]), headache (28, 5.34), arthralgia (24, 4.58), and pyrexia (20, 3.81) (Table 25). Number and frequency (N, EP100PY) of TEAEs (excluding infections/injection site reactions [ISR]) decreased over the 6-yr study period from 193, 173.81 in yr1 to 37, 61.34 in yr6. Most commonly reported treatment-emergent (TE) infections were (N, EP100PY) upper respiratory tract infection (66, 52.0), pharyngitis (58, 45.7), and gastroenteritis (31, 24.4). 1 case of malignancy (Hodgkin’s lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported.
Table 25

(Abstract P71). See text for description

Clinical Outcomes

Mean (95% CI)

Safety Summary (to m72)

N (EP100PY) unless otherwise stated

 

BL1(n = 127)

m241(n = 109)

m482(n = 64)

m722(n = 47)

 

eoJIAEXP = 245.607 PY

ERAEXP = 158.888 PY

PsAEXP = 119.945 PY

TotalEXP = 524.441 PY

PtGA

4.96 (4.6,5.4)

0.97 (0.7,1.2)

1.32 (0.9,1.8)

1.29 (0.9,1.7)

TEAEs*

244 (99.35)

151 (95.04)

90 (75.03)

485 (92.48)

PGA

5.02 (4.7,5.3)

n = 108 0.62 (0.5,0.8)

n = 63 0.67 (0.5,0.9)

0.76 (0.5,1.0)

TE infections

351 (142.91)

93 (58.53)

117 (97.54)

561 (106.97)

CRP, mg/L

8.26 (5.7,10.8)

n = 103 2.76 (1.7,3.8)

2.85 (1.6,4.1)

n = 46 1.58 (1.2,2.0)

TEAEs* causing withdrawal, n (%)

5 (2.04)

8 (5.03)

0

13 (2.48)

JADAS 73 joints

n = 119 17.16 (15.9,18.4)

n = 102 2.28 (1.7,2.9)

n = 61 2.48 (1.8,3.1)

n = 29 3.12 (2.2,4.1)

TE infections causing withdrawal, n (%)

2 (0.81)

0

1 (0.83)

3 (0.57)

No. active joints

6.74 (5.9,7.6)

0.61 (0.2,1.0)

n = 63 0.49 (0.3,0.7)

n = 30 0.60 (0.2,1.0)

Serious TEAEs

11 (4.48)

17 (10.70)

4 (3.33)

32 (6.10)

No. active joints (LOM)

5.72 (5.0,6.5)

1.06 (0.5,1.6)

n = 63 1.02 (0.6,1.4)

n = 30 1.10 (0.5,1.8)

Serious TE infections

5 (2.04)

4 (2.52)

4 (3.33)

13 (2.48)

Opportunistic infections

0

1 (0.63)

1 (0.83)

2 (0.38)

Data from patients taking ETN (full analysis set)

1CLIPPER study

2CLIPPER2 study

*Excluding infections/ISR

All herpes zoster

CRP, C-reactive protein; EXP, exposure to ETN; LOM, limitation of motion; PGA, physician’s global assessment; PtGA, patient/parent global assessment; PY, pt-yr

Conclusion: OL ETN treatment to m72 was effective and well tolerated in pts with eoJIA, ERA, and PsA. Majority of pts who withdrew from ETN treatment experienced disease flare. TEAE frequency decreased over time.

Trial registration identifying number: NCT00962741/NCT01421069

Disclosure of Interest: I. Foeldvari: None Declared, T. Constantin: None Declared, J. Vojinovic Speaker Bureau of: Abbvie, G. Horneff Grant/Research Support from: Pfizer, Abbvie, Roche, Novartis, J. Dehoorne Consultant for: Abbvie, Speaker Bureau of: Abbvie, G. Susic Grant/Research Support from: Pfizer, K. Kobusinska: None Declared, V. Panaviene: None Declared, Z. Zuber: None Declared, V. Stanevica Grant/Research Support from: Pfizer, Consultant for: Abbvie, V. Chasnyk: None Declared, R. Pedersen Shareholder of: Pfizer, Employee of: Pfizer, J. Bukowski Employee of: Pfizer, T. Hinnershitz Employee of: Pfizer, B. Vlahos Shareholder of: Pfizer, Employee of: Pfizer, A. Martini Consultant for: Abbvie, Boehringer, Novartis, R-Pharm, N. Ruperto Grant/Research Support from: BMS, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi, Speaker Bureau of: Abbvie, Ablynx, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol Myers Squibb, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, Medimmune, Novartis, Pfizer, Rpharm, Roche, Sanofi

P72 Successful treatment of methotrexate intolerance in juvenile idiopathic arthritis using eye movement desensitization and reprocessing (EMDR)

Lea Höfel1, Bruno Eppler1, Elisabeth Schnöbel-Müller1, Johannes-Peter Haas2, Boris Hügle2

1Psychology, German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany; 2Rheumatology, German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany
Correspondence: Lea Höfel

Introduction: Methotrexate (MTX) is commonly used in the treatment of children with juvenile idiopathic arthritis (JIA). Frequently it is discontinued due to intolerance with anticipatory and associative gastrointestinal symptoms. Eye Movement Desensitization and Reprocessing (EMDR) is a therapy where non-processed and dysfunctional experiences and memories are reprocessed by intensive recall combined with eye movements. This leads to selective processing of the negative affect.

Objectives: Objective of this study was to investigate effectiveness of EMDR in the treatment of MTX intolerance in JIA patients, with the underlying hypothesis that intolerance occurs due to dysfunctional memories and expectations.

Methods: An open prospective study on consecutive JIA patients with MTX intolerance was performed. Intolerance was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire and health-related quality of live was determined using the PedsQL, at 3 time points: directly before and after treatment (after treatment: MISS only), and 4 months after treatment. Patients were treated using a standardized EMDR protocol with 8 sessions over a time period of 2 weeks. Changes in MISS and PedsQL were compared using descriptive and non-parametric methods.

Results: 14 patients with MTX intolerance (median MISS at inclusion: 13.5, range: 6-26) were included. Directly after treatment, all patients reported marked improvement of MTX intolerance symptoms (median MISS: 0.5, range: 0-3, p = 0.001). After 4 months, lasting reduction of MTX intolerance symptoms was observed (n = 5, median MISS: 5, range: 0-10, p = 0.068). However, 2/5 patients (40%) showed MISS >6. The health-related quality of life showed a trend towards improvement 4 months after treatment (n = 5, median pedsQL prior to treatment 84.4%, 4 months after treatment 92.4%, p = 0.46).

Conclusion: MTX intolerance in children with JIA can effectively be treated using an EMDR protocol, with lasting effect over 4 months. This intervention could potentially increase quality of life in affected patients and enable continued treatment with MTX.

Disclosure of Interest: None Declared

P73 The comparison characteristic between patients with systemic onset of juvenile idiopathic arthritis with and without lung involvement.

Mikhail M. Kostik1, Eugenia Isupova1, Irina Chikova1, Margarita Dubko1, Vera Masalova1, Ludmila Snegireva1, Olga Kopchak1,2, Tatyana Kornishina1, Natalia Abramova1, Maria Rumyantseva1, Daria Dzhilkaidarova1, Maria Kaneva1, Olga Kalashnikova1, Vyacheslav Chasnyk1

1Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation; 2Kirov’s regional children’s hospital, Kirov, Russian Federation
Correspondence: Mikhail M. Kostik

Introduction: Juvenile idiopathic arthritis with systemic onset (soJIA) is the most striking form of JIA with combination of arthritis and systemic features. The acute lung involvement (ALI) is not frequent manifestation of soJIA but often influence on disease course, outcomes and treatment. The mechanisms of lung involvement are still unclear.

Objectives: The aim of our study was to compare clinical and laboratorial features of patients with soJIA with and without ALI.

Methods: In the study were included retrospective data of 82 children with soJIA. ALI was described if patient had at least one: dyspnoe, shortness of breath, signs of respiratory distress syndrome, interstitial lung disease, pulmonary arterial hypertension.

Results: ALI was detected in the onset of soJIA in 18 (22.0%) of patients. Patients with ALI had more severe soJIA disease course (data in Table 26).
Table 26

(Abstract 73). See text for description

Parameter

ALI (n = 18)

W\o ALI (n = 67)

p

Hemoglobin, g/l

86,5 (80,0; 108,0)

105,0 (94,0; 116,0)

0,003

Platelets, x109/l

201,0 (95,0; 492,0)

454,0 (361,0; 588,0)

0,006

CRP, mg/l

104,8 (37,5; 154,0)

47 (18,0; 104,0)

0,07

LDH, U/l

1042,0 (543,0; 1230,0)

516,0 (395,0; 676,0)

0,012

Ferritin, ng/ml

1759,0 (1144,0; 11300,0)

321,0 (139,0; 1278,0)

0,0009

Prothrombin, %

71,1 (63,0; 79,0)

91,0 (79,0; 98,0)

0,0009

Fibrinogen, g/l

1,8 (0,8; 4,0)

4,7 (3,2; 5,7)

0,012

Total protein, g/l

64,6 (55,0; 70,3)

71,2 (67,0; 77,0)

0,002

Albumin, %

24,1 (23,0; 25,6)

39,0 (31,8; 43,2)

0,00001

Patients with ALI more frequently had MAS (p = 0,0006), pericarditis (p = 0,0006), transient proteiunuria, attributed to MAS (p = 0,015), concomitant sepsis (p = 0,005) and morphological evidence of hemophagocytosis in bone marrow (p = 0,02).

The main predictors of development ALI were presence of macrophage activation syndrome (OR = 6.6 [2.1; 21.0], p = 0.0006), bone marrow hemophagocytosis (OR = 13.9 [0.7; 269.2], p = 0.02), heart involvement (OR = 6.4 [2.1; 19.7], p = 0.0006), kidney involvement (transient proteinuria) (OR = 6.1 [1.2; 30.3], p = 0.0015), evidence of concomitant sepsis (OR = 21.2 [1.0; 466.0], p = 0.005), albumin ≤ 25.6 g/l (OR = 73.3 [10.9; 495.0], p = 0.0000001), AST > 37.3 U/l (OR = 5.3 [1.4; 20.2], p = 0.008), CRP > 125.0 g/l (OR = 5.6 [1.7; 18.6], p = 0.003), ferritin > 690 ng/ml (OR = 22.7 [2.7; 191.4], p = 0.0002), hemoglobin ≤ 89 g/l (OR = 7.1 [2.3; 22.6], p = 0.0001), LDH > 882 U/l (OR = 4.8 [1.4; 16.4], p = 0.002), platelets ≤ 211x109/l (OR = 10.1 [3.1; 32.9], p = 0.00002), prothrombin ≤ 74.6% (OR = 12.6 [2.8; 57.3], p = 0.0003), total protein ≤ 65.0 g/l (OR = 8.7 [2.7; 27.8], p = 0.00008).

Conclusion: The identified predictors of ALI in soJIA have to check to evaluation of prognosis and choosing treatment plans.

Disclosure of Interest: None Declared

P74 Decreasing prevalence of uveitis in children with juvenile idiopathic arthritis seen over a 30-year period

Valentina Ravaschio1, Valentina Muratore2, Serena Calandra1, Gabriella Giancane1, Alessandra Alongi1, Angela Pistorio1, Alessandro Consolaro1, Benedetta Schiappapietra1, Angelo Ravelli1

1Istituto Giannina Gaslini, Genova, Italy; 2Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Correspondence: Valentina Ravaschio

Introduction: Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA). In recent years, there has been a major advance in the management of both JIA and of uveitis. Non-controlled studies have suggested that some medications, particularly methotrexate and anti-TNF antibodies, are potentially capable to prevent the occurrence of uveitis. However, whether the recent therapeutic progress had led to a reduction in the prevalence of uveitis is unknown.

Objectives: To investigate the temporal trend in the prevalence of uveitis in JIA patients seen over a 30-year period.

Methods: A retrospective analysis of the medical records of all children with JIA by ILAR criteria who were seen at authors’ units between January 1987 to October 2016 was carried out. The prevalence of uveitis in patients with onset of JIA in different time periods (before 1997, between 1997 and 2005 and after 2005) was evaluated. Patients without uveitis who had a disease duration of less than 6 months were excluded.

Results: A total of 1.425 patients with JIA, 336 (23.6%) of whom had developed uveitis were identified. The prevalence of uveitis was 60/211 (28.4%) among patients with onset before 1997, 149/602 (24.8%) among patients with onset between 1997 and 2005, and 127/612 (20,8%) among patients with onset after 2005. The follow-up of patients seen in the three time periods was comparable (Table 27).
Table 27

(Abstract P74). See text for description

 

Before 1997 (n = 211)

1997-2005 (n = 602)

After 2005 (n = 612)

number of Uveitis

60 (28,4%)

149 (24,8%)

127 (20,8%)

Age at onset <3

96 (45,5%)

273 (45,3%)

302 (49,3%)

Age at onset 3-7

80 (37,9%)

203 (33,7%)

169 (27,6%)

Age at onset >7

35 (16,6%)

126 (20,9)

141 (23,0%)

Extended oligoarthritis

35 (16,6%)

84 (14,0%)

97 (15,8%)

Persistent oligoarthritis

117 (55,5%)

317 (52,7%)

348 (56,9%)

FR-negative poliarthritis

35 (16,6%)

139 (23,1%)

138 (22,5%)

Psoriatic arthritis

11 (5,2%)

21 (3,5%)

10 (1,6%)

Undifferentiated arthritis

13 (6,2%)

41 (6,8%)

19 (3,1%)

Conclusion: Our study shows a decrease in the prevalence of uveitis over time, which might be, at least partially, related to the increased tendency toward earlier use of methotrexate and the introduction of biologic agents. This finding should to be confirmed in patient series seen in other pediatric rheumatology centers.

Disclosure of Interest: None Declared

P75 Comparison of patients with familial Mediterranean fever accompanied with sacroiliitis and patients with juvenile spondyloarthropathy

Hafize E. Sönmez, Ezgi D. Batu, Selcan Demir, Yelda Bilginer, Seza Özen

Department of Pediatrics, Division of Rheumatology, HACETTEPE UNIVERSITY FACULTY OF MEDICINE, Ankara, Turkey
Correspondence: Hafize E. Sönmez

Introduction: Familial Mediterranean fever (FMF) is the most common autoinflammatory disease manifesting with self-limited recurrent febrile attacks and polyserositis. Acute recurrent monoarthritis is the most common form of musculoskeletal involvement in FMF; however, up to 5% of FMF patients may develop chronic joint diseases including sacroileitis. It is difficult to distinguish whether sacroiliitis is a musculoskeletal finding of FMF or whether this is the coexistence of two diseases; FMF and SpA.

Objectives: In this study, we aimed to evaluate FMF patients with sacroiliitis, and compare their features with juvenile spondyloarthropathy (SpA) patients all of whom had sacroiliitis.

Methods: 15 pediatric FMF patients with sacroiliitis and 30 patients with juvenile SpA followed between 2014-2016 at the Department of Pediatric Rheumatology at Hacettepe University, Ankara, were included in the study.

Results: The median (min-max) age at diagnosis of sacroiliitis was 11 (7-15) for FMF + sacroiliitis, and 11.5 (7-16) years for juvenile SpA patients. All patients suffered from hip pain and morning stiffness. Only two FMF + sacroiliitis patients had enthesitis, while nearly half of juvenile SpA patients (46.7%) had enthesitis. Four FMF patients suffered from lower back pain, although none of them had spinal involvement. On the other hand, approximately one third of juvenile SpA patients had spinal involvement. The median white blood cell count, erythrocyte sedimentation rate, and C reactive protein values in FMF + sacroiliitis patients were higher (10.1x103/mm3 vs 7.8x103/mm3, p = 0.002; 41 vs 28 mm/h, p < 0.001; 4.6 vs 1.3 mg/dl, p < 0.001; respectively) than juvenile SpA patients. HLA B27 positivity was more common in juvenile SpA than FMF + sacroiliitis patients (86.6% vs 26.7%, respectively, p = 0.001). The most common MEFV (MEditerranean FeVer) mutation was M694V in FMF patients. All juvenile SpA patients but one were negative for MEFV mutations. One juvenile SpA patient was heterozygous for E148Q.

Conclusion: We demonstrated that pediatric patients with FMF + sacroiliitis showed different characteristics (higher inflammatory markers, less frequent spinal and enthesitis involvement and HLA-B27 positivity) from patients with juvenile SpA. The jury is out to decide whether FMF is a triggering factor for SpA or whether this is a feature of FMF per se.

Disclosure of Interest: None Declared

P76 Epidemiology, clinical manifestations and treatment of systemic-onset juvenile idiopathic arthritis (SOJIA): a multicentric study through the international platform JIRcohorte.

Katerina Theodoropoulou1, Alexandre Belot2, Véronique Hentgen3, Isabelle Kone-Paut4, Carine Wouters5, Kenza Bouayed6, Elvira Cannizzaro7, Aurélia Carbasse8, Etienne Merlin9, Claire Ballot10, Daniela Kaiser11, Pascal Pillet, Andreas Woerner 13, Walter Bär14, Sylvaine Poignant15, Véronique Despert16, Caroline Freychet17, Gerald Berthet18, Laetitia Higel19, Tu Tran20, Federica Vanoni21, Sophie Georgin-Lavialle22, Michaël Hofer1

1Pediatric Rheumatology, CHUV, Lausanne, Switzerland; 2Hospices Civils de Lyon, Lyon, France; 3CH de Versailles - Hôpital André Mignot, Paris, France; 4Centre Hospitalier Universitaire Kremlin-Bicêtre, Paris, France ; 5UZ Leuven, Leuven, Netherlands ; 6Hôpital d’Enfants Ebnou Rochd Casablanca, Casablanca, Morocco; 7Kinderspital Zürich, Zürich, Switzerland; 8CHU Arnaud de Villeneuve Montpellier, Montpelier, France; 9Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France; 10CHRU Besançon, Besançon, France; 11Luzerner Kantonspital, Lucerne, Switzerland; 12CHU de Bordeaux, Bordeaux, France; 13Universitäts-Kinderspital beider Basel, Basel, Switzerland; 14Kantonspital Graubünden, Graubünden, Switzerland; 15CHU Nantes, Nantes, France; 16CHU Rennes, Rennes, France; 17CHU St-Etienne, St-Etienne, France; 18Kantonspital Aarau, Aarau, Switzerland; 19Hôpital Hautepierre Strasbourg, Strasbourg, France; 20CHU Nîmes, Nîmes, France; 21L’Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland; 22Hôpital TENON, Paris, France
Correspondence: Katerina Theodoropoulou

Introduction: Systemic-onset juvenile idiopathic arthritis (SoJIA) is a rare paediatric rheumatic condition with unclear pathogenesis, challenging diagnosis and treatment.

Objectives: The aim of our study is to describe the epidemiology, clinical presentation and biologic treatment of SoJIA patients registered in the JIRcohorte.

Methods: This is a multicentre, observational, retrospective and inception cohort study, through an international platform: JIRcohorte. Patients with SoJIA, diagnosed and followed in one of the participating centres in the JIRcohorte project in Switzerland, France, Belgium and Morocco are enrolled in the registry.

Results: 212 patients with SoJIA have been included; 119 were girls with a female: male ratio of 1.3:1. The median age at diagnosis was 5.4 years and the median diagnostic delay was 40 days. Data for initial systemic manifestations were available in 57 patients: 96% presented with typical fever (55/57), 56% with rash (32/57), 32% with lymphadenopathy (18/57), 21% with splenomegaly (12/57), 21% with hepatomegaly (12/57), and 16% with serositis (9/57). Data for joint involvement were available in 46 patients: arthritis was reported in only 61% of them during the first year of disease evolution, with a poly-articular predominance (61%). 169 out of 212 patients (80%) had a biologic treatment at least once during their disease course. Before 2008, anti-TNFa agents were more frequently used (69%), followed by anti-IL-1 agents (30%), with a very few patients receiving anti-IL-6 agent (1%). Since 2008, anti-IL-1 agents became the most common biologic treatment (46%), followed by tocilizumab (36%), with fewer patients under anti-TNFa agents (18%). Higher rate of infectious adverse effects was reported with Tocilizumab, while Anakinra was associated with skin and administration site effects.

Conclusion: We describe here the main epidemiologic and clinical characteristics, as well as the treatment of patients with SoJIA included in our international JIRcohorte platform. Biologic therapies, in particular anti-IL1 agents, are widely used in the treatment of this disease throughout the last years. Further prospective data analysis is required to evaluate the long-term efficacy and the safety of these treatments.

Disclosure of Interest: None Declared

P77 Autoinflammatory mechanisms via NF-KB and caspase-1/IL-1 inflammasome pathways in ana negative juvenile idiopathic arthritis

Andrea Zacarias1, Anna Mensa2, Estibaliz Iglesias1, Rosa Bou1, Joan Calzada1, Jordi Anton1, Juan Ignacio arostegui2, Juan Manuel Mosquera1, Violeta Bittermann1

1Rheumatology, Hospital Sant Joan de Deu, Barcelona, Spain; 2Inmunology, Hospital Clinic, Barcelona, Spain
Correspondence: Andrea Zacarias

Introduction: Classification criteria of Juvenile Idiopathic Arthritis (JIA) are clinical and of exclusion. Autoinflammatory Inherited Diseases (AID) are innate immune system disorders with clinical similarity with JIA that have been considered in differential diagnosis of this disease. Patients with AID previously wrongly diagnosis as JIA has been described

Objectives: To evaluate presence of variations on genes implicated in AID in a group of JIA patients attended at our center between January 2000-2015. To compare clinical and laboratory data between patients with and without variations on these genes.

Methods: Transversal (January 2000-2014) and prospective (January 2014-2015) study. Clinical, demographics and laboratory (erythrocyte sedimentation rate (ESR), C reactive protein (CRP), ANA, blood cell count) data were collected. Next-generation sequencing test of MEFV, TNFRSF1A, MVK, NLRP3, NOD2 and PSTPIP1 were done.

Results: One hundred and one patients were included (76 girls). 61 oligoarticular JIA, 20 rheumatoid factor (RF) negative polyarticular JIA, 19 extended oligoarticular JIA and 1 RF positive polyarticular JIA. Fifty patients were ANA positive. At least one variation was identified in 26.7% of our patients. Accumulated probability of having some variation in these genes in our JIA series was statistical significant greater than healthy Iberian population (20 vs 8.2% respectively, p = 0.01). Table 28 describes identified genetic variations. Variations in all searched genes were detected except for MVK. Oligoarticular extended JIA was the more affected subtype (47.4%, p = 0.082). We did not find differences according to ANA.
Table 28

(Abstract P77). See text for description

Genes

MEFV

MEFV

MEFV

TNFRSF1A

NLRP3

NOD2

NOD2

NOD2

PSTPIP1

Mutation

E148Q

I591T

M694I

P46L

V198M

D925G

N289S

E778K

G258a

JIA Patients

7/101 6,9%

4/101 3,9%

3/101 2,9%

1/101 0,9%

4/101 3,9%

1/101 0,9%

4/101 3,9%

1/101 0,9%

1/101 0,9%

Iberian Population

0/107 0%

2/107 1,8%

18/69.706 0,03%

0/107 0%

1/107 1,8%

1/107 1,8%

1/107 1,8%

0/107 0%

1/6498 0,01%

Based on the presence of a genetic variation we did not find differences in age at onset disease, presence of extra-articular symptoms, laboratory parameters at diagnosis.

Conclusion: Variations on all AID studied genes were detected except for MVK. We found greater prevalence of genetic variations in JIA patients than described in healthy Iberian population. We did not find differences according ANA. We did not find clinical nor laboratory predictors of presence of a genetic variation

Disclosure of Interest: None Declared

Juvenile idiopathic arthritis (JIA) (oligo, poly, psoriatic)

P78 The lull before the TMJ storm: identifying a window of opportunity for early identification of TMJ arthropathy

Clare Marie Adams1, Clarissa Pilkington2

1Rheumatology, Great Ormond Street Hospital for Children, London, United Kingdom; 2Consultant Paediatric Rheumatologist, Great Ormond Street Hospital, London, United Kingdom
Correspondence: Clare Marie Adams

Introduction: Temporomandibular joint (TMJ) arthritis is common in children with Juvenile Idiopathc Arthritis (JIA); it confers significant functional and psychological morbidity to young people suffering with pain, functional impairment and facial asymmetry, as a result of TMJ destruction. Gadolinium-enhanced MRI is the gold-standard imaging modality for detection of synovitis, however early recognition of TMJ arthritis is challenging: clinical assessment is insensitive and early findings on MRI overlap with non-inflammatory synovial enhancement of normal children. With the expense and relative scarcity of MRI, coupled with challenging interpretation of results in early disease, there is an absence of international consensus with regard to screening in TMJ arthritis. Reducing the burden of deforming TMJ disease in young people would undoubtedly be aided by effective early detection of joint involvement.

Objectives: This observational study aims to understand the characteristics of the JIA patient cohort undergoing TMJ MRI in our centre. It aims to identify opportunities for improved clinical practice with a view to early detection of TMJ arthritis, and to contribute to discussion regarding development of consensus based local guidance for TMJ surveillance in children with JIA.

Methods: The electronic clinical records of 30 consecutive patients undergoing TMJ MRI between March 2014 and April 2016 were retrospectively reviewed. They were split into two age groups, 0-4 years (n = 15) and 5-12 years (n = 15). Baseline characteristics including age, sex, JIA subtype, time lag between JIA diagnosis and MRI-TMJ involvement, indications for MRI, MRI reports and whether the MRI changed clinical management were assessed. All TMJ MRIs (n = 56) performed on these 30 patients were assessed.

Results: Children developed TMJ involvement aged 8-10 years old, regardless of age of onset of JIA. Following diagnosis of JIA, TMJ involvement was identified after 6.75 years (median, range 1.25–9.33 years. Mean 5.92 years) in 0-4 age group, and 1 year (median, range 0-9year. Mean 1.83 years) in 5-12 group. 40% (6 children, aged 7-11years) in 5-12 group had TMJ involvement at diagnosis. Most common indications for MRI were pain and restriction (0-4 group), with deviation and asymmetry (5-12 group). The 5-12 group had more bony erosions on MRI report (13/15) and more unilateral disease compared to 0-4 group. The burden of TMJ disease occurs predominantly over the age of 5 (28/30). MRI changed clinical management (18/30).

Conclusion: Irrespective of age of onset of JIA, children developed TMJ involvement between 8-10 years of age. This indentifies a group upon which to focus targetted MRI surveillance with the aim of detecting early TMJ disease. This is a small study, but it contributes to the ongoing discussions regarding formation of pragmatic consensus guidance in TMJ surveillance in asymptomatic children with JIA. Further study is required.

Disclosure of Interest: None Declared

P79 Burden of disease in the pediatric rheumatology clinic at Alain Hospital: the UAE experience

Amal A. Alhosani

child health institute, Alain Hospital, alain, abu dhabi, United Arab Emirates

Introduction: Introduction: The subspeciality of pediatric rheumatology is the newest discipline established at child health institution in Alain hospital, in 2013. The service provides tertiary care for children with rheumatic diseases from all over United Arab Emirates. Currently there are no data that describe the epidemiology of rheumatic diseases in children.

Objectives: The aim of this study is to describe the demographics and diagnostic classification of children with rheumatic conditions followed up in the clinic.

Methods: Methods: a retrospective cohort was conducted. All the files from August 2013 to July April 2017 were reviewed. Case description and diagnosis were captured. Standardized description of diagnosis was used. All patients were screened for uveitis by ophthalmologist using slit lamp examination

Results: Results: rheumatic conditions were diagnosed in 130 subject. JIA was the most frequently encountered rheumatic condition 44% (n = 58), followed by FMF 10% (n = 14) and SLE 9% (n = 12). Among JIA group oligoarticular JIA was the most common subtype 60% (n = 35), 10% (n = 10) of the cases were complicated by anterior uveitis. The remaining 37% of patients had a variety of other conditions. MTX was used to treat 38% (n = 51) of the cases. Biologics were started in 20% (n = 25) cases.

Conclusion: Conclusion: this is the first cohort that describes the epidemiology of rheumatic conditions among UAE children, it highlights the rheumatologist conditions and their frequencies among pediatric population, however continuos prospective data is needed to confirm our initial observation.

Disclosure of Interest: None Declared

P80 Investigating longitudinal course of ankle involvement in relation to treatment in children with JIA using a multistate markov model approach

Alessandra Alongi1,2, Alessandro Consolaro2, Angelo Ravelli2

1Università degli Studi di Genova; 2Instituto Giannina Gaslini, Genova, Italy
Correspondence: Alessandra Alongi

Introduction: The ankle-foot complex (AFC) is a commonly involved joint site in children with Juvenile Idiopathic Arthritis (JIA) that requires special attention from clinicians due to the complexity of its anatomical structure and the recognized association with a more severe disease course. Some patients experience recurrent, treatment refractory involvement of this region, posing unique challenges for therapeutic management. Little information concerning the longitudinal course of AFC arthritis in relation to treatment and its predictors is available to date to guide treatment strategies for JIA patients.

Objectives: To describe trajectories of AFC involvement in a cohort of JIA patients in relation with received treatments, and identify subgroups of patients at risk of recurrent or treatment resistant AFC arthritis over time.

Methods: Records of oligoarticular and polyarticular RF-negative JIA patients followed in a single tertiary center and diagnosed between 2005 and 2012 were retrospectively evaluated for the occurrence of clinically assessed tibiotalar, subtalar and tarsal arthritis. 143 patients with at least one episode of AFC involvement in the first 5 years from disease onset and complete records were identified. Data collected during a total of 2288 visits - at baseline and at intervals of 3-4 months during the first 5 years of follow-up - were included in the analysis. Specifically, time-varying variables such as disease status, patterns of joint involvement, and current treatments including intra-articular steroid injections were analyzed. Probabilities of AFC arthritis and of being treated with methotrexate (MTX), etanercept (ETN), other TNFa inhibitors or systemic steroids at each evaluation from the second to the fifth year of follow-up were evaluated through multistate Markov modeling, which allows detecting transitions among different clinical states. The relationship between the identified states and clinical-demographical features at onset and in the first year of follow-up was then assessed through regression modeling.

Results: The model identified 6 latent states, defined by the combination of AFC activity and treatment status at each time point: absence of AFC involvement in patients currently off medication (State 1, 906 observations); absence of AFC involvement while receiving MTX treatment (State 2, 622 observations); low probability of AFC arthritis and during treatment with both MTX and ETN (State 3, 316 observations); AFC arthritis in patients currently off medication (State 4, 158 observations); State 5 (197 observations) and State 6 (89 observations) are associated with AFC arthritis during MTX therapy but with high and low probability respectively. After adjusting for active joints count, the number of relapses involving the tibiotalar joint during the first year from onset predicted the transition from State 1 to State 4 - relapse off therapy - and were inversely correlated with probability of transition from State 3 to State 1, namely maintaining remission after therapy withdraw (p = 0.014 and p = 0.035, respectively). Tarsal joints arthritis in the first year of disease was negatively associated with transition from State 5 to State 2, namely AFC response to MTX therapy (p = 0.030). A negative correlation between the occurrence of subtalar involvement in the first year of disease and State 1 was also observed (p = 0.021).

Conclusion: Analysis of longitudinal data provides insight for the identification of patients at risk of recurrent AFC involvement and their clinical management. Further studies are needed to assess the potential value of such information in guiding therapeutic strategies for JIA patients.

Disclosure of Interest: None Declared

P81 Novel mutations in PRG4 gene in one Greek family with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome

Sorina Boiu1, Mouna Barat2, Isabelle Touitou3, David Geneviève4, Vasileios Kontogeorgakos5, Erato Atsali6, Dimitrios Boumpas7, Vana Papaevangelou8

1Pediatric Rheumatology Unit, Third Department of Pediatrics, "Attikon" University Hospital, National and Kapodistrian University of Athens, Athens, Greece, 2Laboratoire de Génétique, Hôpital Arnaud de Villeneuve, CHRU Montpellier Montpellier, France, 3Laboratoire de Génétique, Hôpital Arnaud de Villeneuve, CHRU Montpellier, Montpellier, France 4Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Unité Inserm U1183, CHU Montpellier, Université Montpellier, Montpellier, France, 5First Department of Orthopedics, “Attikon” University Hospital, National and Kapodistrian University of Athens, Athens, Greece 6Pediatric Rheumatology Unit, Third Department of Pediatrics, “Attikon” University Hospital, National and Kapodistrian University of Athens, Athens, Greece 7Joint Rheumatology Program, Fourth Department of Medicine, “Attikon” University Hospital, National and Kapodistrian University of Athens, Athens, Greece 8Third Department of Pediatrics, “Attikon” University Hospital, National and Kapodistrian University of Athens, Athens, Greece
Correspondence: Sorina Boiu

Introduction: Camptodactyly-Arthropathy-Coxavara-Pericarditis (CACP) syndrome is a rare autosomal recessive disorder caused by mutations in the PRG4 (proteoglycan 4) gene located on chromosome 1q31.1 (OMIM:*604283). Hallmarks of the syndrome include congenital or early-onset camptodactyly and arthropathy with synovial hyperplasia, progressive coxa vara deformity and non-inflammatory pericarditis. Patients affected by CACP syndrome lack the glycoprotein lubricin, a major lubricant expressed mainly in joints and in pericardial and pleural cavities. Features of CACP syndrome mimic juvenile idiopathic arthritis (JIA) and children with CACP are often misdiagnosed as JIA. To date, twenty-two homozygous mutations and 1 case of CACP syndrome resulting from uniparental disomy of chromosome 1 have been reported in different ethnic populations, none from Greece.

Objectives: To report the mutations in the PRG4 gene in 2 siblings with CACP syndrome in one family from Greece.

Methods: A 6 years old boy suffered from congenital camptodactyly and progressive non-inflammatory arthropathy from the age of 2 years (knees, ankles, elbows, wrists, and cervical spine). Radiographs, ultrasound and MR images revealed features of CACP syndrome. He was diagnosed with juvenile idiopathic arthritis at the age of 3 years and received corticosteroids, methotrexate, and anti-TNF treatment without efficacy. The patient's younger brother, aged 2 years, had a similar history, albeit more severe, starting at the age of 2 months. The family consulted in our Clinic for a second opinion at the age of 6 years. Molecular genetic studies were done for all coding exons and the exon-intron boundaries of the PRG4 gene. NGS was performed on hybridization-captured region of interest. All variants were confirmed by Sanger sequencing.

Results: The 2 siblings were found to be compound heterozygotes for c.[957del];[3254_3260del] p.[(Asp320Ilefs*2)];[(Ser1085*)]. These rearrangements lead to a shift of the reading frame and the appearance of a premature stop codon. This type of mutations is likely to lead to the synthesis of a non-functional truncated protein.

Conclusion: To our knowledge, this is the first report of PRG4 mutations from Greece as well as the first case of CACP syndrome phenotype caused by novel heterozygous mutations. The presence of arthropathy with camptodactyly, especially if familial, should alert the clinician to the possibility of CACP syndrome and avoid misdiagnosis of JIA and unnecessary treatment with potentially harmful drugs.

Disclosure of Interest: None Declared

P82 Dental anxiety and oral health in juvenile idiopathic arthritis

Christina Boros1, Jason Armfiled2

1Discipline of Paediatrics, University of Adelaide, Adelaide, Australia; 2Australian Research Centre for Population Oral Health, University of Adelaide, Adelaide, Australia
Correspondence: Christina Boros

Introduction: Previous studies suggest that children with Juvenile Idiopathic Arthritis (JIA) have poorer oral health compared to their healthy peers despite adequate knowledge of appropriate dental care. We hypothesised that this may be due to dental anxiety and that there may be specific dental and/or disease related factors which predict dental fear in this population

Objectives: We aimed to determine the prevalence and predictors of dental fear in a single centre population of JIA patients.

Methods: JIA patients aged 5–18 years attending the rheumatology clinic at the Women’s and Children’s Hospital in Adelaide, South Australia completed a questionnaire regarding dental visit frequency, past dental experiences, oral health behaviour, self-rated dental health, assessment of dental anxiety using the Modified Child Dental Anxiety Response Scale (MCDASf), their cognitive vulnerability-related perceptions of dental treatment-related events and the degree of pain and reduced movement in upper limb and temporo-mandibular joints (TMJs). Clinical data relating to JIA subtype, medications, arthritis activity in upper limbs and TMJs and JADAS score on the day of questionnaire completion were also documented.

Results: Ninety four patients, (24 boys, 25.5%) participated. Average age was 12.3 years (SD = 4.3), average disease duration 5.6 years (SD = 4.3) and median JADAS score 1 (range 0–17.2). Thirty eight (40.4%) had oligoarticular and 33 (35.1%) had polyarticular onset disease. Nine (9.6%) had examination findings of TMJ involvement and four (4.3%) had active arthritis in upper limb joints of the dominant hand. Mean MCDASf score (Cronbach’s alpha = 0.93) was 2.97 with 50.5% of children having a score above the cut point for classifiable high dental fear. While dental fear was not related to having received any specific previous dental treatment, those who had not received any treatment had higher dental fear than those who had experienced at least one treatment (3.61 cf 2.87, p = 0.002). There was no statistically significant association between having had a previously unpleasant dental experience and dental fear (F = 2.06, p = 0.112). However, dental fear was associated with anxiety related to receiving blood tests (r = 0.32, p = 0.002) and injectable medications (r = 0.34, p = 0.001). Vulnerability-related cognitions, ie perceptions of the dental visit as dangerous, disgusting, uncontrollable and unpredictable were significantly correlated with dental fear (r = 0.44, p < 0.001) and in a multivariable stepwise regression model accounted for a statistically significant amount of variance in dental fear (adjusted R 2 = 31.1%) after controlling for participant demographics, medically-related fears, and having received a past dental treatment.

Conclusion: In a single-centre cohort of JIA, approximately 50% reported high levels of dental fear associated with procedures related to their arthritis care rather than a previously unpleasant dental experience. Those who had not yet visited a dentist had higher dental fear with vulnerability-related cognitions of the dental visit contributing most significantly to dental fear. These results may explain poorer dental health reported in JIA patients.

Disclosure of Interest: None Declared

P83 Characterization of a Colombian cohort with juvenile idiopathic arthritis: a single multicenter experience

Miguel Cañola1, Maria A. Alzate2, Deicy Hernandez-Parra2, Diana Echeverry2, Juan C. Uribe-Salazar3, Javier Alvarez4, Lorena Londoño1, Paula Ortiz-Salazar2, Ricardo Pineda2

1Rheumatology division, Artmedica, IPS, Medellin, Colombia; 2Clinical information group, Artmedica, IPS, Medellin, Colombia; 3School of Statistics, Faculty of Sciences, National University of Colombia, Medellin, Colombia; 4Medical student, Universidad CES, Medellin, Colombia
Correspondence: Miguel Cañola

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatologic disease in children (1). Artmedica is one of the main medical facilities specialized in pediatric rheumatology.

Objectives: To describe a large cohort of patients with JIA from several regions of Colombia that are followed in a specialized private medical center.

Methods: A cross-sectional study was conducted in 366 patients who were enrolled in the registry between December of 2011 and August of 2016. There were 342 patients who met the International League of Statistical Associations for Rheumatology criteria who were included in the analysis. Association was examined by means of Chi-square tests, Kruskal-wallis test, and logistic regression analyses (to adjust for possible confounders).

Results: Analysis of clinical characteristics by subtypes showed differences in gender, rheumatoid factor positivity, bone erosions, axial and peripheral involvement (Table 29). Hand and/or feet deformities were present in 21,3% of the patients, bone ankylosis of the wrist in 9,6%, asymmetric extremities in 2,9%, and ankylosis of the hip in 1,2%. Complications such as uveitis, delayed growth and osteoporosis presented in 4,7%, 7,9% and 5,5%, respectively. Three cases of avascular necrosis and one case of macrophage activation syndrome were registered during follow up. No significant differences in DMARD and biologic therapy were found among groups, but less use of steroid therapy in oligoarthritis (OR 0,24 95%CI 0,09-0,91) and enthesitis related arthritis (OR 0,05 95%CI 0,02-0,16).
Table 29

(Abstract P83). Clinical characteristics of patients with JIA by subtypes

 

All N = 342

Oligoarthritis N = 91

Polyarthritis N = 120

Systemic N = 28

Enthesitis related – Psoriatic N = 83

Un classified N = 20

p-value

Age at onset (median)

7

8

10

6

10

9

<.0001

Duration of disease (median)

4

3

7

6,5

3

33

<.0001

Gender

Male:Female

4:6

4:6

2:8

4:6

7:3

4:6

<.0001

 

N %

N %

N %

N %

N %

N %

p-value

RF (+)

92/252 36,5

17/63 26,9

62/112 55,3

3/15 20

5/50 10

5/12 41,6

<.0001

HLA-B27

26/126 20,6

7/34 20,5

3/23 13,1

0/4 0

15/61 24,6

1/4 25

0,648

Bone erosions

33/147 22,4

4/38 10,5

17/66 25,7

4/7 57

2/27 7,4

6/9 66,6

0.0002

Axial involvement

60 17,5

10 10,9

14 11,6

4 14,2

30 36,4

2 10

<.0001

Peripheral involvement

285 83,3

80 87,9

103 85,8

22 78,5

72 86,7

8 40

<.0001

Conclusion: Polyarthritis was more common in preadolescent females while enthesitis related arthritis in preadolescent males. Bone erosivity was particularly conspicuous in polyarticular and systemic JIA, which implies a great risk of deformities and ankylosis, and could justify a more agressive and early management. The definition of regional epidemiological profiles in JIA helps to understand differences in disease patterns, that allow both the development of personalized interventions and resources optimization.

Disclosure of Interest: None Declared

References

1. Ravelli A, Martini A, Villa L, Al. E, Lenko H, Wulffraat N. Juvenile idiopathic arthritis. Lancet (London, England). Elsevier Saunders, Philadelphia; 2007;369(9563):767–78.

P84 Effectiveness and safety of tocilizumab in juvenile idiopathic arthritis (JIA) in clinical practice.

Gisela Díaz-Cordovés1,2, Natalia Mena1, Esmeralda Nuñez-Cuadros2, Sara Manrique1, Rocio Galindo-Zavala2

1Department of Rheumatology, at the University Regional Hospital of Malaga (HRUM), MÁLAGA, Spain; 2Pediatric Rheumatology Unit, at the University Regional Hospital of Malaga (HRUM), MÁLAGA, Spain
Correspondence: Gisela Díaz-Cordovés

Introduction: Tocilizumab, an anti-interleukin 6-receptor, its an effective treatment in the juvenile idiopathic arthritis, but there is not so much date about the use in clinical practice in subcuteneous administration and what happens when we optimize it.

Objectives: To study the effectiveness and safety of tocilizumab (TCZ intravenous and subcutaneous) in JIA patients in clinical practice

Methods: Design:Case series. Population:Consecutive patients with JIA treated with TCZ in HRUM. Inclusion criteria: Patients with JIA, infant-juvenile and adult, followed in the Maternal and Child Hospital and Civil Hospital respectively. Exclusion criteria: Missing data on primary outcome variable. Protocol: Patients with infant-juvenile AIJ treated with TCZ. They are reviewed during every infusion of TCZ. Before age of 14 years old, patients are derived to Rheumatology Unit to be reviewed in adult unit and then they are followed each time they receive an infusion of the drug in day-hospital or every three months if they are in sc therapy (sc biological therapy clinic). Outcomes: Mean changes from baseline in DAS28, HAQ and activity level at 3rd month from change to sc TCZ and at 6 months from the reduction; count and description of serious and non-serious side effects during the follow-up. Other variables: Demographics, therapeutic and clinical-analytical data: tenderness joint count (TJC), swollen joint count (SJC), CRP, ESR, physician VAS, patient VAS, adverse events. Statistical analysis: Paired t test or Wilcoxon signed rank between the first and last TCZ administration, between the dose reduction and after 6 months, and between switching to sc administration and after 3 months

Results: The main baseline characteristics of patients with JIA during last administration of TCZ are shown in Table. The mean of DAS28 was higher in JIA adults in the last administration of TCZ (p = 0.028).During the exposure to TCZ three non-severe adverse events were recorded. Three patients switched to sc. At 3 months after to start sc TCZ, no differences were observed in effectiveness outcomes and any adverse effect with sc TCZ was recorded. There was not any switch to sc TCZ in patients with infant-juvenile JIA, compared to patients older than 14 years where 70% of them changed to sc TCZ (p = 0.022).Seven patients reduced doses: 6 with iv and 1 sc. Six months after the reduction, no difference was observed in effectiveness outcomes; only trend to fewer non-severe adverse effects in patient with reduced doses (3 with full doses versus none patient in dose reduction;p = 0.07). Only one patient returned to full dose because inefficiency.

Conclusion: Conclusions: TCZ in JIA patients seem an effective option in daily clinical practice. The switch from iv to sc TCZ in JIA patients seems effective in clinical practice. Reduction in TCZ dose in JIA may possible, maintaining good control of the disease and possibly with fewer side effects

Disclosure of Interest: None Declared

P85 Fat mass in juvenile idiopathic arthritis. Should we think about it?

Gisela Díaz-Cordovés1,2, Esmeralda Nuñez-Cuadros1, Rocio Galindo-Zavala1, Sara Manrique2, Mena Natalia2

1PEDIATRIC RHEUMATOLOGY UNIT, HOSPITAL REGIONAL UNIVERSITARIO DE MÁLAGA, MÁLAGA, Spain; 2Rheumatology D., HOSPITAL REGIONAL UNIVERSITARIO DE MÁLAGA, MÁLAGA, Spain
Correspondence: Gisela Díaz-Cordovés

Introduction: Various studies have shown that the excess of adiposity is a proinflamatory state that conditions worse response to treatment. There are few studies on the subject in arthritis juvenile idiopathic (JIA).

Objectives: OBJECTIVE: To describe the body composition and anthropometric parameters of patients with JIA, and evaluate the possible relationship with the activity of the disease.

Methods: PATIENTS and methods: Observational, cross-sectional, in children aged 4-15 years with JIA (excluding forms monoarticular), study in a tertiary hospital pediatric Rheumatology unit. It collected data anthropometric, clinical and of treatment. Also held dual absorptiometry of x-rays (DEXA) body total with assessment of body composition.

Define the index of mass fat (MFI) as the mass fat divided by the mass total and (MFFI) fat-free mass index as lean mass (kg)/height (m2).

The JADAS27 index was used for the evaluation of the activity of the disease.

Results: RESULTS: We analyzed 80 patients, whose characteristics are shown in Table 30. The most frequent subtype was oligoarticular JIA (16.3% extended, 47.5% persistent) followed by polyarticular JIA (25.1%). Twenty-five percent had uveitis. Fifty percent had inactive disease with treatment, 26% had activity and 23% were inactive without treatment. 52.5% had methotrexate and 30% had a biological drug (22.5% antiTNFα, 5% antiIL-1, 2.5% antiIL-6), with an average disease duration of 6.6 years (±3.7DE).They had mean scores of JADAS27 of 2 (± 4DE), PCR of 4.7 mg/l (± 9,5DE), VSG of 8.7 mm (± 7,2DE) and CHAQ of 0.17 (± 0,38DE). The anthropometric parameters are shown in Table 30. The mean of JADAS27 in patients with normal BMI, was lower than 1.7 (± 3.6 SD) for those who were overweight or with obesity 3.3 (± 6.0 SD), although not significant (p = 0.255). In simple linear regression, an increase of 0.3 JADAS27 was observed for each unit of IMG increase (p = 0.03). This relationship was maintained in the multivariate analysis (B 0.015; p 0.01) independently of the JIA subtype and the treatment received during the evolution.
Table 30

(Abstract P85). See text for description

VARIABLE

n = 80

Age in years, median (±DE)

10,7 (3,3)

Sex, female; n (%)

56 (70)

BMI

Median en kg/m2 (±DE)

18,2 (4,2)

Percentile, median (±DE)

42,0 (29,9)

Index waist/hip (±DE)

0,84 (0,06)

Total fat (kg), media (±DE)

11,36 (8,9)

Total Lean (kg), media (±DE)

26,1 (8,9)

Total mass (kg), media (±DE)

38,8 (16,7)

MFI (%) media (±DE)

7,5(5,3)

MFFI (%) media (±DE)

17,8 (3,8)

Conclusion

CONCLUSION: In JIA patients, there is a linear relationship between IMG and disease activity measured by JADAS, but most patients had a normal BMI. The establishment of this relationship (fat-inflammatory activity) would be transcendental because of the need to optimize the recommendations in the JIA approach

Disclosure of Interest: None Declared

P86 Hypovitaminosis D in juvenile idiopathic arthritis: prevalence and involved factors

Rocio Galindo Zavala1, Laura Martín Pedraz2, Esmeralda Núñez Cuadros1, Gisela Díaz-Cordovés Rego3, Antonio L. Urda Cardona2

1Paediatric Rheumatology, Universitary Regional Malaga Hospital, MALAGA, Spain; 2Paediatrics, Universitary Regional Malaga Hospital, MALAGA, Spain; 3Rheumatology, Universitary Regional Malaga Hospital, MALAGA, Spain
Correspondence: Rocio Galindo Zavala

Introduction: 25hydroxi-vitamin D has antiinflammatory and immunomodulatory properties. Hypovitaminosis D prevalence in Juvenile Idiopathic Arthritis (JIA) patients ranges from 6% to 30%

Objectives: Evaluate hypovitaminosis D in JIA pediatric patients in Spain and assess involved factors.

Methods: Observational cross-sectional study in JIA Spanish patients from 4 to 15 years old, monitored by a Pediatric Rheumatology Unit. Monoarticular forms and patients with other chronic diseases were excluded.

Anthropometric, clinical and treatment data were recorded. Blood test with bone metabolism parameters and validated diet (KIDMED- Mediterranean Diet Quality Index) and exercise (PAQ-C/PAQ-A-Physical Activity Questionnaire for Children) questionnaires were obtained.

Hypovitaminosis D was defined as 25hydroxi-vitamin D plasma levels lower than 30 ng/ml

Results: 76 children were enrolled. Their characteristics are included in Table 31.
Table 31

(Abstract P86). See text for description

PATIENTS` CHARACTERITICS (N = 76)

Gender (Male),

23 (30,3)

Age (years), median (IR) n (%)

10,83 (8,52-13,54)

25OH-Vitamin D (ng/mL), mean (+/-SD)

34,04 ng/mL (8,90 ng/mL)

DISEASE CHARACTERISTICS (N = 76)

JIA subtype, n (%)

Systemic

9 (11,8)

Oligoarticular

47 (61,9)

Polyarticular

20 (26,3)

Inflammatory activity duration (days), median (IR)

385,0(246,75-761,25)

RECEIVED TREATMENTS (N = 76)*

Systemic GC, n (%)

61 (80,2)

Synthetic DMARDs treatment, n (%)

39 (51,3)

Biological DMARDs treatment subtype, n(%)

Anti-TNFα

15 (19,7)

Anti-IL1

4 (5,2)

Anti-IL6

2 (2,6)

JIA: Juvenile idiopathic arthrtis; RF: Rheumatic factor; GC: glucocorticoids;

DMARD: Disease-modifying antirheumatic drug; Anti- TNFα: anti- tumoral necrosis factor α;

Anti-IL1: anti-interleukin 1; Anti-IL6; anti-interleukin 6

The population's prevalence estimation of hypovitaminosis D was 16 - 35% (CI 95%).

We found no relationship between 25 hydroxi vitamin D levels and sex, JIA subtype nor duration or dose of systemic glucocorticoids.

In bivariate analysis we found direct association between hypovitaminosis D and Body Mass Index percentile (BMIp)(p = 0,05), received dose of prednisone (p = 0,03) and clinical activity duration (p = 0,04); and an inverse relation with physical activity level (p = 0,04).

In multivariate analysis, relationship between hypovitaminosis D and BMIp (B 0,024; p 0,016) and with disease activity (B 0,015; p 0,01) were maintained. Moreover, we found an inverse association with biological disease-modifiying antirheumatic drugs (B-4,69; p 0,048), specifically with anti tumoral necrosis factor α (antiTNFα) (B -4,7; p 0,042)

Conclusion: Hypovitaminosis D prevalence in our population is similar to previously described.

JIA patients with higher BMIp have more hypovitaminosis D, as it has been reported in other inflammatory diseases.

A direct relationship exists between inflammatory activity and hypovitaminosis D, but we need more studies to asses if one is cause or consecuence of the other.

Patients treated with antiTNF have higher plasma levels of 25 hydroxi-vitamin D, this can be explained because these drugs may increase 25 hydroxi-vitamin D levels or due to a better response to antiTNF of those patient with higher plasma levels of 25 hydroxi-vitamin D.

Disclosure of Interest: None Declared

P87 Neuropsychological assessment in juvenile idiopathic arthritis - Part I: cross-sectional study in a single Hungarian centre

Diana Garan1, Gyurgyinka Gergev1, Wouter Wijker2, Imre Bozi2, Tamás Constantin1

1Rheumatology, 2nd Department of Pediatrics Semmelweis University, Budapest, Hungary; 2Auxiliis-Pharma Kft., Budapest, Hungary
Correspondence: Diana Garan

Introduction: Juvenile idiopathic arthritis (JIA) is one of the most common pediatric chronic illnesses. A remarkable number of patients need long term or lifelong treatment. In ‘biological era’ many publications have strengthened the safety and effectiveness of TNF inhibitors and some of them noticed psychological or neuropsychological (NP) adverse events (AE). The relationship of these AEs with the treatment is unclear. There is no evidence available if these skills vary in different therapy and change during JIA therapy.

Objectives: Our aims are to estimate NP state in JIA treatment groups and specify NP state influencing factors. The next step was to compare NP state in different treatment groups.

Methods: Descriptive statistics and exploratory analysis were completed. 120 patients were examined at the Paediatric Rheumatology Unit (Semmelweis University, Budapest) between 01.01.2015 - 31.12.2016. 68 patients received combined therapy (TNF inhibitor + methotrexate (MTX) and/or salazopyrin (SSZ)), 42 patients received DMARD: MTX +/-SSZ, 18 patients were on only TNF inhibitor therapy. After a formal psychological assessment, all patients were tested with age specific questionnaires as well: Infant Behaviour Questionnaire, Children’s Behaviour Questionnaire, Child Behaviour Checklist. Furthermore, by using Woodcock Johnson III Tests of Achievement, three NP variables were compared in treatment groups: attention, learning, and working memory. In addition, current and baseline disease activity, duration of therapy and demographic parameters were assessed in each group. These parameters were stratified, and NP variables were compared in these strata. Comparison of NP variables of different treatment groups were age-, age at diagnosis-, gender-, duration of treatment-, current and baseline JADAS disease activity-matched.

Results: In the analysis of each treatment groups we did not observe any significant deviation of all NP variables based on age, gender, duration of treatment, current JADAS disease activity. All NP variables were the highest in patients whose JIA was diagnosed between 3,1-5,25 years of age. In combined therapy group attention was significantly (p < 0,05) higher in patients whose baseline disease activity was low. In the analysis of comparison of treatment groups the following differences were observed: learning score was significantly lower (p < 0,05) in male patients in MTX group than in the combined therapy group. Working memory score was significantly (p < 0,05) higher in patients whose JIA was diagnosed between 3,1-5,25 year of age, and whose treatment duration was longer than 3 years in combined therapy group. Attention score remained stable in age-, age at diagnosis-, gender-, JADAS disease activity-matched treatment groups. There was no significant discrepancy in all three NP variables between disease activity-matched treatment groups.

Conclusion: We have not observed any clinically significant difference in the neuropsychological state in different treatment groups assessed only at a definite date. Age, age at diagnosis, gender, duration of treatment, current and baseline JADAS disease activity were not clinically influencing factors of NP variables in this study. The analysis of cognitive function has already been assessed, but has not been analysed yet. In a prospective study we will follow patient’s psychological changes before and during therapy in order to observe if different therapies have any effect on psychological functions in JIA patients.

Disclosure of Interest: None Declared

P88 Characteristics of TNF inhibitor treatment in juvenile idiopathic arthritis - 2-year-follow-up in a Hungarian centre

Diana Garan, Anita P. Juhász, Andrea Ponyi, Tamás Constantin

Rheumatology, 2nd Department of Pediatrics Semmelweis University, Budapest, Hungary
Correspondence: Diana Garan

Introduction: TNF inhibitors have been widely used in the therapy of juvenile idiopathic arthritis (JIA) since the early 2000s.

Objectives: We assessed the efficacy, change in efficacy, reason for treatment discontinuation, relapse rate of TNF inhibitor treatments for JIA started between 2012-2016 at the Unit of Pediatric Rheumatology, Semmelweis University, Budapest.

Methods: 146 treatments were started for 116 patients with polyarticular course JIA. The following variables were assessed: Giannini improvement and JADAS-71 score every 3 months, the time for achieving at least 90% Giannini improvement, reason for treatment discontinuation, relapse rate. We estimated the alteration of Giannini improvement and JADAS-71 disease activity in patients treated for at least 24 months. Finally, we analysed the features of patients achieved inactive disease. Paired Wilcoxon test, Kaplan-Meier survival analysis, log rank test, chi square test, Fisher’s test, T test were used with SPSS statistics program.

Results: Statistically significant (p < 0,05) alteration was detected in achieving ever higher improvement of the Giannini’s criteria in the first 12 months of treatment, afterwards this alteration remained in tendency but not statistically. The JADAS-71 disease activity significantly decreased in the first 6 months of the treatment, afterwards the decline remained in tendency. Giannini 90% improvement was achieved significantly more frequently in those who received etanercept treatment, first-line TNF inhibitor treatment and any first-line biological. Among those who achieved inactive disease, there were significantly more of those, who started treatment with fewer active joints, lower JADAS score and CHAQ values, and were significantly younger at diagnosis. Biological therapy was discontinued due to inefficacy in 50,8%, remission 28% and adverse events 10,5% of cases. In addition, 37,5% of patients had relapse whose treatment was discontinued due to remission, all within the first 3 months on off-medication.

Conclusion: Giannini’s criteria improved significantly over the first 12 months, the disease activity decreased significantly in the first 6 months, afterwards these observations remained in tendency in our cohort. Approximately one-third of treatments were discontinued due to remission almost two-third of these patients have not experienced relapse during our observation period.

Disclosure of Interest: None Declared

P89 Body composition measured by DEXA in children with juvenile idiopathic arthritis. do they have sarcopenia?

Pilar Guarnizo1,2,3, Sally Pino2,4, Adriana Diaz-Maldonado2,5,6, Juan Manuel Reyes2

1Fundacion Cardio Infantil, Bogota, Colombia; 2Care for Kids, Bogota, Colombia; 3Cayre, Bogota, Colombia; 4Hospital Universitario Infantil de San Jose, Bogota, Colombia; 5Hospital de La Misericordia, Bogota, Colombia; 6Instituto Roosevelt, Bogota, Colombia
Correspondence: Pilar Guarnizo

Introduction: Juvenile Idiopathic Arthritis (JIA) is the most frequent disease in pediatric rheumatology. There are few studies about body composition in these population, most of them suggest they have excess fat.

Sarcopenia in children and young adults is pathologic and constitute a risk factor of morbi-mortality due to its association with alteration in immunologic function, decrease strength muscle and thermoregulation capacity, exercise tolerance and functionality, all of them affect articular function and preservation. Additionally, bone mass accretion and bone mineral density are related proportionally direct to muscle mass.

Also patients with sarcopenia could present an increase in the fat mass known as sarcopenic-obesity.

Objectives: To describe body composition alterations in a cohort of children diagnosed with JIA in Bogota, Colombia.

Methods: Cross-sectional study where a cohort of children with JIA was assessed the anthropometry and densitometry measured by dual-energy X-ray absorptiometry (LUNAR iDXA). It was evaluated stature and weight. The fat mass was evaluated through Fat Mass Index (FMI): Kg/m2, subtotal percentage body fat for age and gender, and subtotal trunk fat mass. To measure lean mass was used: lean mass index (LMI): Kg/m2, appendicular lean mass (arm and leg lean): Kg/m2, and total bone mineral density less head (TBLH)

The statistical analysis was only descriptive where it involved measurement of central tendency and dispersion.

Results: Thirty children were included in the study. Fifty three percentage were female with average age of 13.8 years (ranked from 5 to 22 years).All subtypes of arthritis were included, 56% had systemic and polyarticular subtypes.

The average of onset of the disease was 5 year (ranked from 2 to 14 years).

In this cohort 33% of the patients had short stature.

36% patients had compromise in fat mass. FMI median z-score was -0.57 (ranked from -1.66 to 1.11), 26% of children presented fat deficiency (12.5% of them had severe fat deficit), and 10% excess fat - obese. In 20% of patients the percentage of fat was above of expected and trunk fat mass was higher in 16% of the studied children; the last measure is related to cardiovascular risks.

80% of the patients had low LMI z-score that is considered as low lean mass- sarcopenia. LMI z score median was -2.17 (ranked from -4.56 to 0.36). 58.6% presented low appendicular lean mass.

30% of patients had compromise in two compartments (FMI and LMI). 100% of patients with Fat deficit had low lean mass –sarcopenia, while 33% of patients had sarcopenic-obesity (fat excess with sarcopenia) which is associated to decrease in life- expectancy.

The median z score for Total bone mineral density less head (TBLH) was -1.25 (ranked from -3,8 to 1,5 . The TBLH density was low in a 30% of patients, from which 100% had low lean mass-sarcopenia.

Conclusion: The included children diagnosed with JIA presented high percentage of disorders of body compositions characterized by sarcopenia 80% followed by fat mass compromise in 36% (low fat mass 26% and excess fat 10%) and low bone density in 30%.

The abnormalities in the lean mass could be explained due to the increase in metabolic rate and catabolism which lead to skeletal muscle consumption. It has been described “rheumatic cachexia” in 67% of adults with rheumatoid arthritis, affecting bone mineralization, strength muscle loss, and is associated with cardiovascular risk increase, but there is not any data in children with JIA.

This is the first study which measure sarcopenia by DEXA in this population, additional studies including more patients are necessary to validated these results and establish opportune interventions to improve their nutritional status and quality of life.

Disclosure of Interest: None Declared

Reference

1. Evaluacion del estado nutricion en una población mexicana de pacientes adultos con artritis reumatoide. L. Puentes, G. F. Hurtado, C. Abud, A. Bravo. NutrHosp. 2009:24:233-238

P90 Clinical TMJ involvement in JIA patients according to the ILAR categories : preliminary study in 137 children.

Severine Guillaume Czitrom, Gianpaolo de Filippo

Service de Medecine des Adolescents, Chu Bicetre, Kremlin-Bicetre, France
Correspondence: Severine Guillaume Czitrom

Introduction: Temporo-manidibular joint (TMJ) involvement in juvenile idiopathic arthritis (JIA) is the subject of many unanswered questions.

Objectives: We here wonder if the ILAR categories might help identifying JIA patients at risk of TMJ involvement.

Methods: In single cohort of consecutive JIA patients, TMJs were systematically examined at each follow-up visit of JIA patients according to the European recommendations. Clinical involvement of TMJs over time was longitudinally recorded during JIA follow-up. JIA categories were defined according to ILAR definitions.

Results: There were 137 JIA patient, comprising 89 girls and 44 boys aged 14.13 years +/- 4.99 at the time of the analysis. Mean age at disease onset was 7.84 years +/- 4.89 and mean follow-up was 4.41 years +/- 3.83 [0.2-23.9 years]. There were 63 ERAs, 33 oligoarticular JIAs with 26 persistent and 7 extended diseases, 27 polyarticular JIAs, 6 being RF positive, 10 psoriatic arthritis and 4 systemic JIAs.

44 JIA children had clinically detectable TMJ involvement (32%), but the percentages were rather different across the ILAR sub-groups : TMJs were symptomatic in 12 ERAs (19%), in 9 oligoarticular JIAs (27.3%), in 18 polyarticular JIAs (66.7%), in 3 psoriatic arthritis (30%) and in 2 systemics (50%) ; moreover, within the oligoarticular group, the most affected category was the oligo-extended group with 6 out of 7 patients having TMJs involved (85.7%).

Interestingly, the clinical manifestations were not the same since half of the oligoextended JIA patients reported no pain, no chewing difficulty, no evidence of mouth opening limitation but insidiously developped facial asymetry due to unilateral TMJ inflammation. In all cases, the spreading of the arthritic process happened before 5 of age. In contrast, ERA patients manifested pain and reduced mouth opening much more frequently and at a later age, prompting to a quick therapeutic answer.

Conclusion: In conclusion, TMJ arthritis might have severe consequences in those patients starting agressive disease early in life, as many extended-oligoarticular as well as part of polyarticular JIAs and systemics. Detecting the patients at high risk for structural damage in TMJs should be a major goal in the coming years. This preliminary study also shows that a significant proportion of ERA patients suffer from TMJ inflammation during the course of their disease. The limited number of patients is the drawback of this preliminary study and larger prospective studies are required to validate these data.

Disclosure of Interest: None Declared

P91 MRP8/14 and conventional inflammatory markers explaining physician’s global assessment of disease activity in new-onset juvenile idiopathic arthritic patients

Paula Keskitalo1, Salla Kangas2, Paula Vähäsalo1

1Department of Children and Adolescents, University of Oulu, Oulu, Finland; 2Medical Research Center Oulu, Oulu University Hospital and PEDEGO Research Unit, University of Oulu, Oulu, Finland
Correspondence: Paula Keskitalo

Introduction: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory joint disease affecting children. In clinical practice it is occasionally difficult to assess the real inflammatory activity. Physician’s assessment of global disease activity (PGA) is a holistic assessment and it is always available. The myeloid-related protein complex 8/14 (MRP8/14, calprotectin) secreted by infiltrating phagocytes in synovial inflammation has been suggested to function better than conventional acute-phase reactants as a marker of low inflammatory activity and to be more sensitive and reliable indicator of disease activity.

Objectives: The aim of our prospective, observational cohort study was to analyze whether the MRP8/14 levels in serum (S-MRP8/14) or plasma (P-MRP8/14) and conventional inflammatory markers, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), leucocytes (leuc) and neutrophils (neutr), correlate with disease activity assessed by physician.

Methods: Serum and plasma MRP8/14 concentrations from 88 concecutive new-onset JIA patients collected before starting DMARDs were measured by human calprotectin ELISA kit (Hycult biotech). Clinical data of the patients with median age of 6.6 yrs (range 1 – 15.3 yrs) were collected during the visits in the pediatric rheumatology outpatient clinic in Oulu University Hospital between October 2011 and November 2014. Median PGA was 21 with the scale 0-100 (range 3 – 85), median patients/parents global assessment of wellness 31 (range 0 – 88), median patients/parents assessment of pain 31 (range 1 – 45), and median number of joints with active arthritis (AJC) 3 (range 1 – 45). Correlations were analyzed by Spearman’s coefficient. Multiple linear regression was used to quantify the strength of the relationship between laboratory inflammatory markers and to assess which parameter has the most powerfull coefficient of determination of PGA.

Results: Median P-MRP8/14 concentration was 184.9 ng/ml (range 1.2 – 685.9 ng/ml) and in S-MRP8/14 255.0 ng/ml (67.4 – 553.5 ng/ml). Median CRP was 1.5 mg/l (1.5 – 193 mg/l), ESR 13 mm/h (2 – 98 mm/h), leuc 7.4 x 10E9/l (3.4 – 15.2 x 10 E9/l) and neutr 3.9 x 10E9/l (1 – 10.5 x 10E9/l).

We found positive correlations between PGA and the laboratory parameters. PGA weakly correlated with leuc (Spearman’s Rho 0.281, P = 0.008) and neutr (0.313, P = 0.007). Association was better with ESR (0.432, P < 0.001), CRP (0.582, p < 0.001), P-MRP8/14 (0.682, P < 0.001) and S-MRP8/14 (0.409, P < 0.001).

PGA has stronger association with P-MRP8/14 than with the other inflammatory parameters (Table 32.). Multiple linear regression analysis showed leuc, ESR, CRP, neutr, S-MRP8/14 and P-MRP8/14 explaining 55% of PGA. When analyzed the standardized B the strongest relationship was found between P-MRP8/14 and PGA (B = 0.084 (95% CI: 0.045 – 0.123) P < 0.001, standardized B = 0.733), but association between S-MRP8/14 and PGA remained weak (B = -0.032 (95% CI: -0.074 – 0.010), P = 0.14, standardized B = -0.203).
Table 32

(Abstract P91). Relationships between PGA and laboratory parameters analyzed by linear regression

 

B

95% CI

P-value

R2

ESR

0.358

0.194 – 0.523

<0.001

18.3%

CRP

0.345

0.227 – 0.463

<0.001

28.7%

Leucocytes

1.387

0.064 – 2.710

0.040

4.9%

Neutrophils

1.849

-0.289 – 3.986

0.089

4%

MRP8/14 in serum

0.056

0.024 – 0.087

0.001

12.9%

MRP8/14 in plasma

0.075

0.056 – 0.094

<0.001

47.8%

R2 coefficient of determination, B regression coefficient

Conclusion: P-MRP8/14 seemed to be much better than the other conventional inflammatory laboratory markers or MRP8/14 serum concentration when assessing disease activity in JIA patients. P-MRP8/14 concentration might be useful indicator to be used in clinical practice when making evalution of disease activity.

Disclosure of Interest: None Declared

P92 Chronic arthritis as the only manifestation of FMF in Armenian children

Gayane Khloyan

ARABKIR JMS ICAH, Yerevan, Armenia

Introduction: Familial Mediterranean Fever (FMF) is the most common inherited auto inflammatory disease, characterized by recurrent, self–limited attacks of fever and aseptic polyserositis.FMF is widespread in Armenia and there is a higher than expected frequency of FMF-associated arthritis in children. Chronic arthritis can be the first, and sometimes the only manifestation of FMF.

Objectives: To the importance of genetic investigation for MEFV gene mutations in patients of high-FMF-prevalence ethnicities with chronic arthritis.

Methods: Case reports of two patients with chronic arthritis as their first symptom of FMF.

Results: 1-st case: A 6 year-old boy was admitted to the hospital with complaints of weakness and limping during the last 1.5 years. He had also self- limited episodes of knee and foot pain. The physical examination revealed pain on flexion of the left knee, painful palpation of both sacroiliac joints, but no visible or palpable changes of the joints. Initial laboratory examination showed elevation of ESR– 49 mm/h and CRP-48 mg/l. WBC, RBS, PLT were in normal range. An extensive diagnostic work up including biochemical examination, serology tests, urine test, chest X-ray, Echo-CG revealed no changes. Splenomegaly was found on abdominal sonography. MRI of the pelvic bones and hip joints indicated signs of bilateral sacroiliitis. Chronic arthritis was diagnosed. Despite of absence of clinical features of FMF, genetic analysis for MEFV gene mutations was done and homozygous genotype for M694V mutation (M694V/M694V) was found. Treatment with colchicine and sulfasalazine was started and both his clinical condition and laboratory findings improved significantly. Only occasionally the patient still has gait abnormalities.

2-nd case. A 1.8 year-old girl was admitted to the hospital because of pain, swelling and deformity of the left wrist, which had started 5 months earlier. In her past history 2 episodes of unexplained fever of 1 day duration were noticed. The physical examination revealed swelling, pain and limitation of motions of the left wrist. ESR was elevated within 53 mm/h, but CRP was negative. Thorough diagnostic work up (CBC, biochemical examination, serology tests, urine test, chest X-ray, Echo-CG, abdominal sonography) revealed no pathologies. MRI of the left wrist indicated signs of arthritis. Chronic arthritis was diagnosed. But also genetic analysis of MEFV mutations was done and 2 mutations (M694V/R761H) in compound-heterozygous state were found. Intraarticular injection of triamcinolone acetonide to the left wrist was done and colchicine treatment was started with significant improvement: during 4 months of follow up the girl had no complaints and no inflammatory activity with normal level of ESR.

Conclusion: In ethnicities with high prevalence of FMF, screening for MEFV gene mutations is recommended for patients with chronic arthritis even in the absence of FMF symptoms.

Disclosure of Interest: None Declared

P93 The efficacy of etanercept in non-systemic juvenile idiopathic arthritis in Saint-Petersburg: the preliminary data of 148 patients from biologic registry.

Mikhail M. Kostik, Irina Chikova, Eugenia Isupova, Margarita Dubko, Vera Masalova, Ludmila Snegireva, Ekaterina Gaidar, Olga Kalashnikova, Vyacheslav Chasnyk

Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation
Correspondence: Mikhail M. Kostik

Introduction: Etanercept was the first biologic drug approved in children. Russian rheumatologist received the access to etanercept only in 2009 after infliximab, adalimumab, abatacept. Currently etanercept reach the first position in the biologics, used in JIA in Saint-Petersburg.

Objectives: The aim of our study was to evaluate the efficacy of etanercept in the tertial hospital in Saint-Petersburg using the registry.

Methods: The data about all patient (n = 148) who received etanercept were included into the registry. We evaluated all routine JIA measures, ESR, CRP, achievement the remission every 6 months, dynamics of height, weight and side effects. The duration of study was more than 30 months.

Results: The demographic of study population was: girls were 92/148 (62.2%), onset age - 4.9 (2.4; 9.6), age of etanercept initiation: 9.8 (5.9; 13.9) time between JIA onset and etanercept was 2.4 (1.2; 5.8). Duration of etanercept treatment was 3.5 (2.3; 4.3) years. The distribution of JIA categories was: persistent oligoarthritis 6/148 (4.1%), extended oligoarthritis 11/148 (7.4%), RF-negative polyarthritis 84/148 (56.8%), RF-positive polyarthritis - 3/148 (2.0%), enthesitis-related arthritis - 32/148 (21.6%), psoriatic arthritis - 9/148 (6.1%), non-differentiated arthritis 3/148 (2.0%). ANA-positivity was in 33/120 (27.5%), HLA B27 - 24/80 (30%) and RF-positivity - 5/148 (3.4%).

During the trial the etanercept shows high efficacy in the main JIA measures and laboratorial tests (Table 33). Also we have observed decreasing of WBC (p = 0.03), PLT (p = 0.000001), ESR (p = 0.03), increasing the hemoglobin (p = 0. 006), body mass index (p = 0.02). Frequency of morning stiffness decreased from 62.8% to 4.6% (p = 0.0001). The achievement of remission (ACRPedi100) reached 69.3% patients.
Table 33

(Abstract P93). See text for description

Parameter

Baseline

End of study

p

Morning stiffness, minutes

60.0 (30.0; 120.0)

20.0 (10.0; 20.0)

0.03

Global disease activity, mm

48.0 (35.0; 68.0)

0.0 (0.0; 28.0)

0.000001

MD VAS, mm

43.5 (30.0; 60.0)

0.0 (0.0; 18.0)

0.000001

Patient’s VAS, mm

20.0 (10.0; 20.0)

0.0 (0.0; 10.0)

0.000001

Painful joints, n

2.0 (1.0; 5.0)

0.0 (0.0; 0.0)

0.000001

Swollen joints, n

4.0 (2.0; 11.0)

0.0 (0.0; 0.0)

0.000001

Joints with LOM, n

4.0 (1.0; 9.0)

0.0 (0.0; 0.0)

0.000001

Active joints, n

7.0 (3.0; 15.0)

0.0 (0.0; 0.0)

0.000001

CRP, mg/l

1.9 (1.0; 5.5)

0.5 (0.2; 1.3)

0.000001

Etanercept was discontinued in 12/148 (8.1%) due to primary or secondary inefficacy or new onset of uveitis, injection site reactions were rare and lead to discontinuation of etanercept in 1/148 (0.7%). No serious infections, tuberculosis, malignancy were observed during the study.

Conclusion: Etanercept show high efficacy in non-systemic JIA patients. Serious side effects were rare and comparative to literature data. Registry of biologics is a good tool for collection data about patients. Future investigations required.

Disclosure of Interest: None Declared

P94 The treatment of 40 polyarticular juvenile idiopathic arthritis children with tocilizumab: single center experience.

Mikhail M. Kostik, Irina Chikova, Eugenia Isupova, Margarita Dubko, Vera Masalova, Ludmila Snegireva, Ekaterina Gaidar, Olga Kalashnikova, Vyacheslav Chasnyk

Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russian Federation
Correspondence: Mikhail M. Kostik

Introduction: Juvenile idiopathic arthritis (JIA) – is a chronic inflammatory joint diseases, which affects the children under the age 16. Methotrexate (MTX) is a basis of treatment of patients with polyarticular JIA (pJIA). Patients, who fall or intolerance MTX required in biologic treatment.

Objectives: The aim of our study was evaluate the efficacy and safety of tocilizumab (TCZ) in children with pJIA.

Methods: In the present retrospective study with maximal duration 42 months were included 40 children (82,5% girls) with active pJIA, resistant to previous therapy with MTX alone or combination with others non-biologic DMARDs, whom were treated with TCZ every 4 weeks 8 mg/kg (weight ≥ 30 kg) and 10 mg/kg (weight < 30 kg). Onset JIA age was 4,8 (2,9; 8,1) years, time between JIA onset and start of TCZ was 5,7 (1,8; 8,5) years. Duration of TCZ treatment was 1109 (452; 1542) days. TCZ monotherapy was in 13,2% children.

Results: During TCZ course NSAID were discontinued in all studied population, decreased part of children who were treated with combination of non-biologic DMARDs from 37.5% to 2.5% and proportion of whom were treated with MTX from 92.5% to 75.0%, and leflunomide up to 2.5%. The discontinuation of the second DMARD, corticosteroids, cyclosporine and NSAIDs were due to achievement of remission and rare due to intolerance. In first 6 months of therapy was revealed impressed decreasing of ESR (p = 0.000002), CRP (p = 0.00002), WBC and (p = 0.001) PLT (p = 0.00002) up to normal ranges during whole TCZ course. Number of active joints decreased gradually (p = 0,00002), reached the median = 0 to 24th month, 15.3% obtained inactive disease status in 6 months and 80% in 42 months. During the study inactive disease status was reached totally in 60.5% patients and in 3 patients TCZ was discontinued due to persistent remission. The main predictors of achievement inactive disease were WBC < 9.0 x 109/l (HR = 1,92, p = 0.16), absence of previous biologic treatment (HR = 1.92, p = 0.16). The absence of previous biologic treatment was also predictor of low disease activity status (HR = 2.4, p = 0.01).

Among adverse effects were transient hypercholesterolemia and hypertriglyceridemia and single episode of grade II neutropenia which not lead to TCZ discontinuation infection side effects and antibiotic treatment.

Conclusion: The safety and efficacy of TCZ was demonstrated in children with pJIA. Serious adverse events were not revealed.

Disclosure of Interest: None Declared

P95 Atypical oligoarticular juvenile arthritis in children: elbow chronic monoarthritis

Aleksey Kozhevnikov1,2, Nina Pozdeeva1, Michael Konev1, Maxim Nikitin1, Anastasia Bryanskaya1, Evgeniy Prokopovich1, Konstantin Afonichev1, Gennadiy Novik2

1Orthopedic and rheumatology department, Federal state budget institution “The Turner Scientific and Research Institute for Children's Orthopedics”, Saint-Petersburg, Russian Federation; 2Pediatric department n.a. prof. I.M. Voroncov, Federal state budget institution of higher professional education “Saint-Petersburg State Pediatric Medical University”, Saint-Petersburg, Russian Federation
Correspondence: Aleksey Kozhevnikov

Introduction: Juvenile arthritis is a broad term that describes heterogeneous group of a chronic inflammatory joint disease which characterized by progressive course leading reduced mobility and function. Progressive chronic arthritis of an unknown cause lasting for at least more than three months are the main diagnostic criteria of JIA. A typical classic variant of oligoarticular JIA (oligo-JIA) is well known. Monoarthritis of the elbow joint is atypical onset oligo-JIA. It’s difficult to differentiate of elbow chronic synovitis due to clinically heterogeneous. The instrumental and specific diagnostic tests are great assistance to determine cause of synovitis.

Objectives: Chronic synovitis in children arises from several causes. There are inflammatory, infectious, traumatic, reactive, hemorrhagic, neoplastic and undifferent etiologies of synovial diseases. Usually chronic elbow monoarthritis associated with tumor-like conditions (pigmented villonodular synovitis, synovial haemangioma and chondromatosis), osteomyelitis, tuberculosis arthritis, osteochondropathy and rare JIA. The aim of the present study was to determine diagnostic and treatment strategies of elbow monoarthritis manifested like oligo-JIA.

Methods: We carried out a retrospective review of sixteen children with chronic undifferentiated elbow monoarthritis which were hospitalized at Children Orthopedics Institute, Saint-Petersburg (rheumatology department) between 2011 and 2016. The data of clinical, serological, x-ray, ultrasound, MRI, arthroscopy and synovial fluid were analyzed. Detected atypical/diffuse form synovial proliferation or limited to a well-defined single nodule were recommended for arthroscopy and biopsy. Six children were excluded from study due to verification of cause elbow monoarthritis: 6-yr-old girl - PVNS, 10-yr-old boy cavernous haemangioma and 17-yr-old boy - synovial chondromatosis, 2 small girls and 1 boy - osteoid osteoma. Ten children were study group (median age 5,8 ± 2,5, range 3-11 years; female 90%, male 10%). Children with post-traumatic elbow joint transient effusion were controls.

Results: Trauma of elbow joint related to onset chronic arthritis, progressive flexure contracture with dry synovitis, low activity and the long-term period absence of clinical involvement of other joints were occurred in all children. Asymptomatic early-stage, progressive flexure/combined contracture less joint effusion and morning stiffness were cause of late diagnosis of oligo-JIA. Only seven children (all girls) were ANF positive ≥ 1:160, two HLA-B27 positive. Radiographic finding of early-stage JIA were accelerated cartilage model ossification of distal humeral epiphysis and trochlear, osteoporosis with subchondral bone sclerosis and cyst-like deformation. The MR imaging were non-specific inflamed elbow synovium. Overgrowth of epiphysis and trochlear with joint space narrowing, deformation articular surfaces with erosive changes were radiographic findings of late-stage JIA. MR imaging revealed significance multiple erosive synovitis with bone cyst-like deformation. Ultrasound wasn’t show elbow synovitis at half of the study children. 70% children were negative effect of monotherapy NSAID. Positive treated effect was achieved after intra-articular triamcinolone injection (20-40 mgs) and methotrexate therapy (15 mg/m2/week) > 6 months, splinting and physiotherapy. After 2-3 years 30% children were persistence oligo-JIA (involved wrist or knee), 40% - extended oligo-JIA, 30% - isolated monoarthritis. Children with post-traumatic elbow joint deformation haven’t revealed chronic synovitis.

Conclusion: Monoarthritis of elbow joint are rare atypical manifestation of pauciarticular JIA. Non-specific clinical signs and instrumental imaging may contribute to diagnostic problems of elbow chronic synovitis. Therapy of elbow chronic idiopathic monoarthritis must be coincide treat-to-target strategy in juvenile arthritis. Ultrasound can’t be the decisive diagnostic method of chronic elbow pathology.

Disclosure of Interest: None Declared

P96 Platelet microparticles level in juvenile idiopathic arthritis

Sathish Kumar, Naresh Kumar

Rheumatology, Department of Pediatrics, Christian Medical College, Vellore, India
Correspondence: Sathish Kumar

Introduction: Juvenile idiopathic arthritis (JIA) encompasses a complex group of disorders comprising several entities in children. Multiple biomarkers have been used to detect the disease activity. Platelet Microparticles(PMP) are small vesicles released from plasma membrane upon platelet activation. Several studies stated that PMP has been associated with the thrombotic event and inflammatory process in adults. This is the first study in literature to estimate PMP in JIA.

Objectives: To estimate the level of plasma PMP in children with JIA and to study the relationship with disease activity of JIA.

Methods: Study design: Cross-sectional study

Inclusion criteria: Children with JIA who fulfilled the International League of Associations for Rheumatology (ILAR) classification criteria for juvenile idiopathic arthritis were included.They were categorized into active disease group and inactive disease as assessed by Wallace criteria. Complete Blood count, ESR, CRP, and PMP were estimated in all children. PMP level was calculated by Flow Cytometry.Blood investigations and baseline demographics were analyzed

Results: Out of 26 children with JIA, 12 had active disease group and 14 had an inactive disease as assessed by Wallace criteria. Mean PMP level was 83507 cells/μland 34904 cells/μlin active and inactive disease respectively (p = 0.06). There was no significant correlation between PMP level in JIA patients with corresponding ESR, CRP, and platelets

Conclusion: Our study states that level of PMP is significantly elevated in disease activity of JIA and could represent a new biomarker reflecting the state of cell activation in JIA. PMP role in the inflammatory processes needs to be further elucidated

Disclosure of Interest: None Declared

Miscellaneous rheumatic diseases

P97 The need for dedicated paediatric rheumatology services: retrospective review of a clinic service at Tygerberg Hospital, South Africa

Deepthi R. Abraham1, Monika M. Esser2

1Dept of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, NHLS Immunology Unit Tygerberg Hospital, Division Medical Microbiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; 2Department of Pathology, NHLS Immunology Unit Tygerberg Hospital, Division Medical Microbiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
Correspondence: Deepthi R. Abraham

Introduction: Paediatric Rheumatology in South Africa competes with limited health care resources allocated to epidemic diseases. Data on prevalence, incidence, disease categories, delay in diagnosis and management are crucial for defining the need for specialized services. Available literature is limited in South and sub-Saharan Africa. Major challenges include lack of awareness; lack of trained staff, facilities and support services.1 Education in Paediatric Rheumatology is neglected at undergraduate and postgraduate levels with a shortage of paediatric rheumatologists.1 Tygerberg Hospital offers a dedicated clinical service since 1995 with an accredited subspecialty training post since 2005.

Objectives: The primary aim is to document demography, disease profile and medical management of patients attending the Tygerberg Paediatric Rheumatology clinic. The secondary aim, based on these findings, will address the need of specialized services and subspecialty training posts.

Methods: Retrospective folder review, electronic data search and use of bivariate and multivariate statistical tools used for analysis to outline the disease profile of JIA (Juvenile Idiopathic Arthritis), other autoimmune (AI) or auto-inflammatory diseases and miscellaneous musculoskeletal conditions and management thereof.

Results: 450 patients were reviewed between March 1995 and March 2017. Referrals were derived from secondary and tertiary hospitals (68%), general and private practitioners (13%) and 8.2% by primary healthcare centers. 60% of referred patients resided in the greater Cape Town region and 40% in rural-country regions, depending on availability of public health transportation services. Most of the patients (74%) were from a family income bracket of less than 7700 USD per year.

Gender distribution reflected 56% female and 44% male. The most common age of presentation was between 10-14 years (46%) with a range of 0 to19 years. Racial distribution was Mixed Racial 79%, Blacks 16%, Whites 4% and Asians 1%. JIA (38%) was most common rheumatological condition. Reactive Arthritis (23%), autoimmune and autoinflammatory conditions (11%), vasculitides (2%) and miscellaneous musculoskeletal conditions (39%) e.g. growing pains, Raynaud's, infection related arthritis, malignancies etc. comprised the rest.

Common presenting symptoms were tender joints (71%), stiffness after rest (46%) and swollen joints (44%). Uveitis was present in 9% at initial diagnosis or during follow up. Delay in diagnosis was up to 9 years.

Ibuprofen (42%) was the most commonly used NSAID. Most frequently used DMARD's were methotrexate and hydroxychloroquine. Intra articular steroid injections were frequently indicated and biological therapy accessed by selected patients.

Referral to ancillary services included physiotherapy (51.6%), imaging predominantly X-rays (41%), ophthalmology (47.1%), orthopedics (37%), occupational therapy (27%) and dermatology (16.7%).

46.5% were offered social grants. 14.7% recorded, achieved remission. Remission could not be established in most patients due to high rate of patients lost to follow up (50%). 3.5% transitioned to adult Rheumatology services.

Conclusion: Patients reviewed were mainly of mixed racial origin from low-income homes. JIA was the most common paediatric rheumatological condition seen. Delay in diagnosis and late referrals were frequent. Increased awareness, education and training, early diagnosis of disease and appropriate funding for these neglected diseases could dramatically improve outcome. Addressing challenges unique to a developing country and resultant complexities of management are essential for advocacy and planning of such services.

Disclosure of Interest: None Declared

P98 Raynaud phenomenon secondary to the use of illicit drugs

Abstract withdrawn

P99 Unilateral recurrent ear chondritis in spondylarthritis does not always progress to polychondritis

Laura Damian1,2, Simona Rednic2,3,4, Cristina Pamfil5,6, Linda Ghib3, Maria-Magdalena Tamas3, Siao-Pin Simon2,5, Calin Lazar7, Laura Muntean5, Alma Maniu3,8

1Rheumatology, Centre for Rare Musculoskeletal Autoimmune and Autoinflammatory Diseases, Cluj-Napoca, Romania; 2Emergency Clinical County Hospital, Cluj-Napoca, Romania; 3Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 4Centre for Rare Musculoskeletal Autoimmune and Autoinflammatory Diseases, Cluj-Napoca, Romania; 5Rheumatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 6Centre for Rare Musculoskeletal Autoimmune and Autoinflammatory Diseases, Emergency Clinical County Hospital, Cluj-Napoca, Romania; 7Pediatrics, Emergency Clinical County Hospital, Cluj-Napoca, Romania; 8ENT, Emergency Clinical County Hospital, Cluj-Napoca, Romania
Correspondence: Laura Damian

Introduction: Ear perichondritis can be caused by trauma, relapsing polychondritis (RP), vasculitis, infections etc. Irrespective of etiology, cartilage deformity and necrosis may occur. Chondrodermatitis nodularis helicis (Winkler’s disease) is a localized cartilage inflammation, often with crusting, resulting from trauma or bland vascular impaiment.

Objectives: Long-term assessment of recurrent unilateral perichondritis in patients with systemic diseases, for the development of RP diagnostic criteria.

Methods: We retrospectively identified the cases of unilateral recurrent ear perichondritis in the patients with suspected polychondritis in the last 15 years in a tertiary referral adult Rheumatology department. The patients then fulfilled a questionnaire and were seen prospectively for two years. All chondritis episodes and the Mc Adam and Damiani-Levine polychondritis criteria were assessed. Laboratory tests for inflammation, immunology, uric acid, ENT examination, cartilage biopsy whenever accepted and an extensive search for infection,vasculitis, hematologic malignancies, as well as complications of other organs classically involved by polychondritis were recorded, as part of the regular screening for polychondritis.

Results: We identified 3 cases of recurrent unilateral chondritis, all occuring in spondylarthritis patients, that were followed up for 3 to 12 years for other polychondritis features, without development of RP criteria. None of these patients developed ulcerations or crusting to suggest Winkler’s disease, either.

Case 1: A 26-years female patient with a juvenile extensive oligoarthritis since the age of 5 and psoriasis since 11, on methotrexate, presented with recurrent episodes of right ear swelling and inflammation, healing within three days, not altered by empiric antibiotic short courses, accompanied by transient mild leukocytosis with neutrophilia. An active follow-up for 12 years did not reveal other chondritis sites. NSAIDs helped to alleviate the attacks, which became less frequent with time.

Case 2: A 48-year male patient with aseptic abscesses syndromes, Crohn’s disease and spondylarthritis with bilateral coxitis diagnosed for 3 years had a recurrent left ear upper lobe inflammation since the first visit. The nodular chondritis, with low-level local inflammation generally lasting for one week, independent from the joint flares, responded to the addition of NSAID and sulfasalazine to adalimumab and azathioprine. No progression to polychondritis was noted in 3 years.

Case 3: A patient with undifferentiated spondylarthritis and a history of treated medullar thyroid carcinoma presented with recurrent right ear painful inflammation. No signs of tumoral dissemination or relapse were detected in 6 years. The cartilage biopsy was normal. The attacks' frequency decreased after leflunomide.

Conclusion: Unilateral recurrent ear perichondritis may not always herald polychondritis, at least in spondylarthritides. It can be speculated that local triggers (pressure on the ear, etc) may activate the innate immunity through danger-associated molecular patterns, however, the progression to polychondritis probably requires activation of certain Toll-like receptors. An active search for an RP is nevertheless worthed in the unilateral chondritis, as RP requires a more aggressive therapy. Informed consent to publish has been obtained from the patient/parent/guardian.

Funding:PN-II-RU-TE-2014-4-2708

Disclosure of Interest: None Declared

P100 Evaluation of the dental and temporomandibular joint status in children with generalized joint hypermobility

Ferhat Demir1, Tamer Tüzüner2, Özgül Baygın2, Mukaddes Kalyoncu1

1Department of Pediatric Rheumatology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey; 2Department of Pediatric Dentistry, Karadeniz Technical University Faculty of Dentistry, Trabzon, Turkey
Correspondence: Ferhat Demir

Introduction: Generalized joint hypermobility (GJH) is characterized by deficiency of collagen and changes in the proportion of collagen subtypes. It is a clinical feature associated with excessive laxity of joints. Oral mucosa, teeth and temporomandibular joint (TMJ) can be affected in these condition.

Objectives: It was aimed to evaluate the dental and temporomandibular status in children with GJH.

Methods: Sixty two children with GJH and age-sex match sixty two healthy children as a control group were enrolled to the study. The GJH was assessed by the Beighton Hypermobility Score (BHS). The subjects screened for dental and TMJ status. Assesment included index for ‘Decayed’, ‘Missing’ and ‘Filled Teeth’ (DMFT), visual plaque index (VPI) and gingival bleeding index (GBI) scores, tooth mobility and TMJ evaluation. The Mann–Whitney U and chi-square tests were used to evaluate the data.

Results: Mean BHS score was found 6.3 ± 1.2 in GJH group. VPI and GBI scores were found significantly higher in children with GJH then control group (p < 0.05). No differences were found regarding the DMFT scores between GJH and control groups (p > 0.05). Temporomandibular disease (TMD) frequency was significantly higher in children with GJH compared to the control group (p < 0.001) (Table 34). The most frequent TMD obtained as clicking while maximum active mouth opening. By the way, combined TMJ problems observed in approximately one third of the GJH children.
Table 34

(Abstract P100). Comparison of dental status, MT and TMD between in GJH and control groups

 

GJH group

Control group

p

Age (median (min-max))

8 (5-17)

9 (5-17)

0.43*

Gender (M/F)

36/26

36/26

0.57#

VPI positivity (%)

88.7

74.2

0.03#

GBI positivity (%)

64.5

45.2

0.02#

DMFT score (median(min-max))

0.062 (0-0.23)

0.080 (0-0.23)

0.27*

MT positivity (%)

3.2%

1.6%

0.50#

TMD positivity (%)

48.4%

14.5%

<0.001#

*Mann-Whitney U test and #Chi-square test was used for analysis. VPI: Visual plaque index, GBI: Gingival bleeding index, DMFT: decayed, missing and filled teeth, MT: Mobility of tooth, TMD: temporomandibular disease.

Conclusion: High frequency of TMD in GJH group may demonstrate that TMJ is also affected in GJH. The higher VPI and GBI scores indicating the poor oral hygiene in children with GJH may point out that, this children can not perform properbly toothbrushing.

Trial registration identifying number: Ethical approval was obtained from the Ethics Committee of Karadeniz Technical University, Faculty of Medicine (Approval number: 2016/102).

Disclosure of Interest: None Declared

P101 Successful treatment of pediatric IGG4 related ophthalmic disease with mycophenolate mofetil: case report and a review of the pediatric autoimmune dacryoadenitis literature

Talia Diaz, Yuridiana Ramirez, Sofia Osorio, Maria Teresa Braña, Luis Aparicio, Andres Rodriguez, Enrique Faugier, Rocio Maldonado

Pediatric Rheumatology, Hospital Infantil de Mexico Federico Gomez, Ciudad de Mexico, Mexico
Correspondence: Talia Diaz

Introduction: IgG4-related disease (IgG4-RD) is relatively a new growing entity of immune mediated origin, characterized by a unique pathological feature that affect a wide variety of organs with infiltration of IgG4-positive plasma cells and occasionally elevated serum IgG4. It is both a systemic inflammation and a sclerosing disease. The most common manifestations are parotid (14-26%) and lacrimal swelling (4-13%), lymphadenopathy and autoimmune pancreatitis. Several studies have examined orbital adnexal IgG4-related disease or IgG4-related orbital inflammation. The diagnosis should be proven histopathologically but other conditions such as lymphoma should be carefully excluded. Patients with IgG4-RD respond beneficially to glucocorticoid therapy especially when administered at early onset stages. In some cases, the combination of immunosuppressive agents is required.

Objectives: To describe a pediatric clinical case with orbital IgG4 related disease with an excellent response after immunosuppresive treatment.

Methods: We present a 16-year-old girl with IgG4-RD during one year with left ocular pain and eye inflammation, diagnosed as bacterial conjunctivitis and trated with ophtlamic antibioticoteraphy, with no improvement. Weight loss and increased acute phase reactants (erythrocyte sedimentation rate and C-reactive protein). On ocular computed tomography. Histopathology clearly defined the mass to be IgG4 related fibrosis with focally arranged fibrosis in a storiform pattern, and positive CD20 deposit ++++, positive IgG4 +++ in plasmatic cells and lymphocytes, positive CD38 deposit ++. Biopsy report: Autoimmune Dacryoadenitis Associated with IgG4 Disease. IgG4 serum normal level 9 mg/dl.

Ocular Magnetic resonance imaging was performed in which volume and lacrimal gland intensity is identified, which displaces the rectus and oblique muscle causing proptosis, the lacrimal gland presented an increase in it’s dimensions with measures of 23x8x10mm in its posterior axes, posterior No abnormal reinforcement is identified in the contrast medium. Infectious serological test were negative (EBV, CMV, HBV, HCV, toxocara and toxoplasma).

Results: The patient was started on oral corticosteroids and mycophenolate mofetil, which resulted in significant clinical improvement after 3 months of treatment, the mass became smaller and the patient was asymptomatic.

Conclusion: IgG4-RD remains a field not yet fully explored or understood. Early and efficient therapies aiming to achieve a beneficial outcome, and to improve prognosis are still required.

Disclosure of Interest: None Declared

P102 Rheumatic fever and post-streptococcal arthritis in a tertiary hospital from Paraguay.

Jorge Garcete1, Luz Galeano1, Carla Montiel2, Dong Chin2, Maria del Carmen Cabrera2, Milagros Vargas Peña2, Carlos Verón2, María Lezcano3, Alicia Aldana3, Ana Campuzano de Rolón1, Zoilo Morel Ayala4

1Pediatric Service, Hospital de Clinicas. Facultad de Ciencias Medicas.Universidad Nacional de Asuncion., San Lorenzo, Paraguay; 2Pediatric Cardiology, Hospital de Clinicas. Facultad de Ciencias Medicas.Universidad Nacional de Asuncion., San Lorenzo, Paraguay; 3Pediatric Neurology, Hospital de Clinicas. Facultad de Ciencias Medicas.Universidad Nacional de Asuncion., San Lorenzo, Paraguay; 4Pediatric Rheumatology, Hospital de Clinicas. Facultad de Ciencias Medicas.Universidad Nacional de Asuncion., San Lorenzo, Paraguay
Correspondence: Jorge Garcete

Introduction: Rheumatic fever (RF) and post-streptococcal arthritis (PSA) are characterized by autoantibodies secondary to beta hemolytic streptococcus group A infection. In our country, the cardiac sequelae acquired by the RF generate substantial costs for the State and family, becoming a public health problem.

Objectives: To assess the clinical characteristics and outcome of patients with RF and PSA from a Paraguayan referral hospital.

Methods: Retrospective and descriptive study of patients under the age of 18 years, diagnosed with RF and PSA between January 2009 and April 2017.

Results: 32 cases of RF and 8 PSA (all misdiagnosed as originally RF) were found. The population is distributed similarly by all states of the Eastern Region from Paraguay. The average monthly income per household is 18% with 2 minimum wages, 37% with a minimum salary, 30% less than 1 minimum wage, and 15% without data. 62% of children with RF sleeps with 3 or more family members in the same room. Mean age at diagnosis: 10.5 (3-17) years. The female to male ratio is 4:6. Only 5% are Native patients. During the acute phase, 52% had polyarthritis, 43% had carditis, 13% had chorea, 2% had subcutaneous nodules, and 2% had erythema marginatum. Jones minor criteria: arthralgia 20%, fever 14%, elevated ESR 21%, CRP positive 16%, EKG altered 13%. The most affected heart valve is the mitral (45%), followed by mitral and aortic simultaneously (10%), 8% aortic and 5% tricuspid alone; 32% with no affected heart valves. In 93% of patients not throat culture was done. ASO + in 21% of cases, performed in all patients. Treatment: all received benzathine penicillin G, 35% NSAID, 18% corticosteroids, 10% haloperidol, 14% valproic acid. Eleven patients discontinued treatment. Only 10% of patients with RF has required heart surgery (valve replacement), with one death.

Conclusion: RF remains a major cause of acquired heart disease in our country, perhaps by inadequate management of streptococcal infections, in addition to late diagnosis of the disease and household overcrowding.

Disclosure of Interest: None Declared

P103 Immunoglobulin therapy in the treatment of cerebral consequences of neonatal lupus erythematosus

Abstract withdrawn

P104 Validaty and reliability study for the Korean version of the haemophilia activity list in pediatric and adult patients with haemophilic arthropathy

Seonghoon Park, Hwajeong Lee, Jung-Yoon Choe

Department of mediciane, Catholic university of Daegu School of medicine, Daegu, Korea, Republic Of
Correspondence: Seonghoon Park

Introduction: There has been increasing interest in the patient’s perspective on outcome of treatment. The Haemophilia Activity List (HAL) has been developed as a disease-specific questionnaire for haemophilia patients and is a validated self-report measure of function developed according to WHO’s International Classification of Functioning, Disability and Health.

Objectives: In this study, we performed a cross-cultural adaptation and linguistic validation of the HAL questionnaire to assess the health-related quality of life in hemophilia patients in the future.

Methods: To validate HAL in Korean, the English versions of HAL were translated into Korean using ‘the forward–backward translation’ method and merged into a final Korean version. Validation was performed against the Korean version of the multidimensional health assessment questionnaires (MDHAQ) as general tool and Routine Assessment of Patient Index Data (RAPID3) as similar arthritis-specific tool. All processes were done with permission of the developer and according to WHO guidelines.

Results: Eighty-six patients with severe and moderate forms of haemophilia A and B with haemophilic arthropathy were invited to participate in the study. Spearman’s rank correlation test was used for validation and internal consistency of the HAL was calculated with Cronbach’s alpha. Seventy-five patients (86.2%) (15–62 years old) answered the questionnaires. The internal consistency of the Korean version of HAL was high, with Cronbach’s alpha being 0.80–0.95. Upper extremity function had the highest consistency and leisure activities and sport had the lowest. The correlation was good between the HAL overall score and MDHAQ overall (r = 0.78), MDHAQ pain (r = 0.79), and RAPID3 physical function (r = 0.82).

Conclusion: The Korean version of HAL has both internal consistency and convergent validity and may complement other functional tests to gather information on the patient’s self-perceived ability. This questionnaire of Korean version can be useful as a disease-specific instrument for evaluation of the health-related quality of life in Korean patients with haemophilic arthropathy.

Disclosure of Interest: None Declared

P105 Inflammatory pseudotumor: T helper cell subtypes and relation to IGG4-related disease?

Erdal Sag1, Gulsev Kale2, Beril Talim2

1Pediatric Basic Sciences, Pediatric Autoinflammatory Disease Programme, Hacettepe University Faculty of Medicine, Institution of Child Health, Ankara, Turkey; 2Department of Pediatrics, Pathology Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey
Correspondence: Erdal Sag

Introduction: IgG4-related disease is a fibroinflammatory condition characterized by tumefactive lesions, dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and often elevated serum IgG4 concentration. On microscopic examination, presence of IgG+ plasma cells (>10-50/HPF), IgG4+/IgG+ plasma cell ratio (>50%) and typical histopathologic pattern confirm the diagnosis. Inflammatory pseudotumor (inflammatory myofibroblastic tumor) is a mass lesion composed of myofibroblasts, plasma cells, lymphocytes and eosinophils.

Objectives: The aim of this study is to analyze the pediatric patients with inflammatory pseudotumor (inflammatory myofibroblastic tumor) of various organs for the diagnosis of IgG4 related disease, and to investigate the composition of T helper subsets.

Methods: 20 patients who were diagnosed as inflammatory pseudotumor (inflammatory myofibroblastic tumor) of various organs at Hacettepe University Faculty of Medicine, Department of Pediatrics, Pathology Unit were included in the study. Immunohistochemical expression of IgG, IgG4, CD3, CD20, CD68, IL-10, IL-17, Foxp3, IFN-gamma, IFN-alpha and IL-4 were studied from archived paraffin blocks.

Results: The mean age of the patients at the time of biopsy was 7,36 ± 3.85 yr. The biopsies were taken from orbita (2 patients), mediastinum (7 patients; 3 from lungs, 3 from mediastinal wall, 1 from bronchi), and abdomen (10 patients; 2 liver, 1 spleen, 2 intestinal, 4 intraabdominal, 1 retroperitoneal wall). Out of the 20 patients, 3 had more than 50 IgG4+ cells per HPF but none of them did fulfil the diagnostic criteria for IgG4-related disease. In terms of inflammatory milieu, all the biopsies were positive for CD3, CD20 and CD68. As for T helper cell subtypes, all of the biopsies were IL-10 positive, 85% of the biopsies were IL-4 positive, 95% were IL-17 positive, 80% were Foxp3 positive, 50% were IFN-alpha and 35% were IFN-gamma positive.

Conclusion: In our cohort, none of the inflammatory pseudotumors (inflammatory myofibroblastic tumors) fulfilled the diagnostic criteria for IgG4-related disease. B cells, macrophages and T cells are present in the inflammatory pseudotumor and all T helper cell subtypes such as Th1, Th2, Th17 and Treg are included in the inflammatory milieu.

Disclosure of Interest: None Declared

P106 Hyperbaric oxygen therapy in a livedoid vasculopathy: a case report

Nihal Sahin1, Aysenur Pac Kisaarslan1, Sümeyra Ozdemir Cicek1, Betül Sözeri2, Mehmet E. Akcin3, Zubeyde Gunduz1, Ruhan Dusunsel1, Muammer H. Poyrazoglu1

1Pediatric Rheumatology, Erciyes University Faculty of Medicine, Kayseri, Turkey 2Pediatric Rheumatology, Umraniye Research and Training Hospital, İstanbul, Turkey 3Underwater and Hyperbaric Medicine, Kayseri Research and Training Hospital, Kayseri, Turkey
Correspondence: Nihal Sahin

Introduction: Livedoid vasculopathy is characterized disease with recurrent ulceration and thrombosis. Its pathogenesis has been found to be related to occlusion of the cutaneous microcirculation leading to thrombosis, ischemia and minimal inflammation in the vascular wall. There is still no definitive treatment for this disease. Hyperbaric oxygen therapy (HBO) facilitates wound healing by affecting the fibrinolytic pathway. We used HBO in a patient resistant to other treatments.

Methods: A girl aged 15 years was admitted to the Erciyes University Faculty of Medicine Pediatric Rheumatology Department at the first time in May 2016 complaining of painful ulceration in the ankles and foot.

Results: A fifteen-year old female presented with a one year- old history of recurrent multiple painful ulcer, purpuric macule and porcelain – white stellate scars on the ankle and the foot. Patient did not give any history of any other medical illness, or any systemic complaints. There was no remarkable feature in baseline laboratory examinations. Doppler ultrasonography of the lower extremities did not find any vascular insufficiency in the major vessels. Skin biopsy from the lesion site revealed featured of focal necrosis of the epidermis, subepithelial focal hemorrhage, hyalinization of the capillary walls and thrombosis in some vessels. The tests containing C3, C4, RF, ANA, ANCAs, ACA IgM and IgG, lupus anti-coagulant, anti-thrombin III, protein C, protein S, homocysteine were normal. Factor V Leiden, prothrombin and methylenetetrahydrofolate reductase (MTHFR) gene mutation analysis were performed. Heterozygous mutation was detected in nucleotide region 1298 of the MTHFR gene. Anti-platelet, immunosuppressive, immunomodulatory drugs and systemic steroid were given to the patient with diagnosis of livedoid vasculopathy. Hyperbaric oxygen therapy was applied on frequent relapses with these treatments. The patient completely relieved from pain and ulcers showed marked improvement.

Conclusion: Treatment of livedoid vasculopathy is very challenging due to low incidence and unclear pathogenesis. Hyperbaric oxygen therapy is well tolerated, with few side-effects compared with the other treatment regime. We treated resistant livedoid vasculopathy with hyperbaric oxygen therapy.

Disclosure of Interest: None Declared

P107 Echocardiographic findings in children with osteogenesis imperfecta

Shahrzad Fallah1, Mohammad Reza Alaee2, Reza Shiari3, Saeed Mojtahed zadeh2, Behnam Sobouti4

1pediatrician, Shahid Beheshti Univesity of Medical Sciences Tehran, Iran, Islamic Republic Of’; 2Pediatric Cardiologist, Shahid Beheshti Univesity of Medical Sciences Tehran, Iran, Islamic Republic Of; 3Pediatric Rheumatology, Shahid Beheshti Univesity of Medical Sciences Tehran, Iran, Islamic Republic Of; 4pediatrician, Iran Medical Universuty, Tehran, Iran, Islamic Republic Of
Correspondence: Reza Shiari

Introduction: Osteogenesis imperfecta, an inherited connective tissue disorder with remarkable clinical variability, is caused by a quantitative or qualitative defect in collagen synthesis. Exact prevalence of cardiac involvement in Osteogenesis imperfecta is indistinct.

Objectives: The aim of this study was to determine the prevalence of cardiac involvement in children with Osteogenesis imperfect by Echocardiography.

Methods: During one year, Sixty five patients were referred to Out-patient Clinic of Musculoskeletal and endocrinology in Mofid Children’s Hospital. All of them were consulted with our Pediatric Cardiologist and echocardiography was performed.

Results: Among 65 patients (60% male, 40% female), mean age was 6.95 ± 4.36 year-old (ranging from 2 months to 17 years old). Twenty percent of patients were belong to subtype one, 47.7% to subtype III, and 32.3% to subtype IV according to silence category.

Prevalence of aortic root dilatation, mitral valve prolapse (MVP), mitral regurgitation (MR), and tricuspid regurgitation (TR) were 13.8%, 15.38%, 7.6%, and 15.38% respectively. We found a significant relationship between MVP and female gender, however, no relation with patient’s subgroups.

Conclusion: Because of the importance of cardiac involvement in our study, we suggest to perform echocardiography in all children with osteogenesis imperfecta.

Disclosure of Interest: None Declared

P108 Acid ceramidase deficiency (Farber disease) causes symptoms resembling JIA and is likely underdiagnosed: we present a unique cross-sectional natural history study design to address the lack of clinical data on this rare disease

Alexander Solyom1, Boris Hügle2, Dustin Tetzl3, Edward H. Schuchman4

1Enzyvant, Basel, Switzerland; 2German Center for Pediatric Rheumatology, Garmisch-Partenkirchen, Germany; 3Enzyvant, New York, NY, United States; 4Genetic and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, NY, United States
Correspondence: Alexander Solyom

Introduction: Acid ceramidase deficiency (Farber disease; Farber lipogranulomatosis) is caused by mutations in both alleles of the ASAH1 gene, resulting in deficiency of acid ceramidase and accumulation of the pro-apoptotic and pro-inflammatory sphingolipid, ceramide. It is considered an ultra-rare disease, with only 109 cases reported in the medical literature since 1952. However, since 2014, we have identified a cohort of 45 patients (some of whom are since deceased) from 30 countries on 6 continents, which indicates a much broader phenotypic spectrum and potentially higher incidence than previously thought. The information collected from this cohort demonstrates that there are patients diagnosed in late adulthood with attenuated forms, as well as patients for whom years elapse between the appearance of the three typical Farber symptoms: joint disease (arthritis and/or contractures), subcutaneous nodules, and hoarseness (due to laryngeal involvement). Moreover, there is wide intra- and inter-patient variability of symptom severity.

Objectives: To develop a natural history study structure and design that would enable systematic collection of information on deceased patients using medical records, as well as on living patients who have or have not undergone hematopoietic stem cell transplantation (HSCT). In addition, the study will evaluate clinical assessment tools used for other diseases with similar symptoms, as well as those developed specifically for Farber disease.

Methods: We designed a cross-sectional cohort study with a unique data collection instrument, including sections for the collection of retrospective data on disease-specific and general medical history, as well as data from clinical assessments to be performed at prospective visits.

Results: The pre-existing clinical assessment tools include (among others) the Childhood Health Assessment Questionnaire (CHAQ), and Wong-Baker Faces Pain Rating Scale, 6-minute Walk Test, Pulmonary Function Testing, and Joint Range of Motion measurements. We also developed a unique patient reported outcome measure related to Farber disease symptoms including physical impairment, pain, and emotional distress, and a method for the assessment of change in size of subcutaneous nodules.

Conclusion: Consideration of the broad spectrum of ages and heterogeneous phenotypes in a small population of patients available to participate in a study of the natural history of acid ceramidase deficiency led to the design of a cross-sectional cohort study with retrospective and prospective components. By including deceased patients and patients having undergone HSCT in the study design, the amount of data that can contribute to the understanding of this very rare disease is substantially increased. Furthermore, the specific prospective assessments will allow us to follow disease progression over time, and to evaluate the degree to which the assessment tools and techniques may be appropriate measures to use to register change in certain symptoms. It is our hope that this unique design will provide data which is sufficiently robust to serve as the basis for preventing misdiagnosis of acid ceramidase deficiency as JIA, provide an indication of the most appropriate methods for measuring efficacy in future therapeutic trials, and serve as a potential point of reference in the design of similar studies in rare disease populations.

Disclosure of Interest: A. Solyom Employee of: Enzyvant, B. Hügle: None Declared, D. Tetzl Employee of: Enzyvant, E. Schuchman Shareholder of: Enzyvant

P109 Involving patients, parents and carers in paediatric rheumatology research: best practices examples from lay representatives of the United Kingdom's clinical studies group

Simon Robert Stones1,2, Catherine Wright2,3 on behalf of Lay/Consumer CSG Representatives

1School of Healthcare, University of Leeds, Leeds, United Kingdom; 2Paediatric Rheumatology CSG, NIHR CRN: Children/Arthritis Research UK, Liverpool, United Kingdom; 3Arthritis Care Northern Ireland, Arthritis Care, Belfast, United Kingdom
Correspondence: Simon Robert Stones

Introduction: The lived experiences and opinions of patients, parents and carers (PPCs) living with rheumatic and musculoskeletal diseases (RMDs) must inform and influence all aspects of research, from prioritisation through to dissemination. For example, contributing to grant applications, designing studies, identifying the most suitable outcomes to include in a clinical trial, facilitating study recruitment and sharing findings with the wider community. In turn, it is possible that involving PPCs may enhance expectations and subsequent levels of satisfaction with research.

Objectives: The aim of the PPC representatives on the clinical studies group is to provide strategic guidance for the paediatric rheumatology community about the most effective ways of engaging and involving PPCs in clinical and health services research.

Methods: To effectively represent PPCs living with RMDs, it is critical to have a means of ensuring that PPC representatives encapsulate the range of views within the PPC community. The paediatric rheumatology clinical studies group PPC representatives aim to do this through networking, linking with external rheumatology stakeholder groups and through hosting consumer research meetings. In addition, PPC representatives comment on various documents as part of their role, including trial protocols, ethics applications and and participant information sheets. They have also been involved in formulating three research questions as part of the clinical studies group research strategy. The top three research priorities were informed by a patient-led research study with young people and their families. With much delight, one research priority has informed the current development of a study to improve treatment tolerability for young people with RMDs.

Results: Activities of PPC representatives include attendance several face-to-face and teleconference meetings each year. This is an essential activity that enables researchers and healthcare professionals to actively interact with PPCs as equal partners, in order to shape ongoing and future research activities. This approach also emphasises the importance of physical meetings in fostering collaborative and participatory approaches to research. In addition, PPC represenatives bridge the gap between the research community, patient groups and charities, facilitating communication between individuals and teams.

Conclusion: By widely accepting and embracing the PPC voice as a catalyst for high quality, young person- and family-focused research, it is hoped that the often negative experiences of living with an RMD can be used positively to shape research, so as to be able to provide the best possible care, treatment and support for young people and their families living with RMDs in the future.

Disclosure of Interest: None Declared

P110 Defining the clinical impact of symptoms in a diverse population of patients with a rare disease: a qualitative research study in acid ceramidase deficiency (Farber disease)

Alexander Solyom1, Brendan Johnson2, Karoline Ehlert3, Dustin Tetzl4, Karin Coyne5