Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part two

O1 Efficacy and safety of Canakinumab in patients with periodic fever syndromes (colchicine-resistant fmf, hids/mkd and traps): results from a phase 3, pivotal, umbrella trial F. De Benedetti, J. Anton, M. Gattorno, H. Lachmann, I. Kone-Paut, S. Ozen, J. Frenkel, A. Simon, A. Zeft, E. Ben-Chetrit, H.M. Hoffman, Y. Joubert, K. Lheritier, A. Speziale, J. Guido IRCCS Ospedale Pediatrico Bambino Gesú, Rome, Italy; Hospital Sant Joan de Déu, Barcelona, Spain; Pediatric Rheumatology, G. Gaslini Institute, Genoa, Italy; UK National Amyloidosis Centre, University College London Medical School, London, United Kingdom; Hôpital Kremlin Bicetre, University of Paris SUD, Paris, France; 6 Department of Pediatrics, Hacettepe University, Ankara, Turkey; University Medical Center Utrecht, Utrecht, Netherlands; Radboud University Medical Centre, Nijmegen, Netherlands; Pediatrics Rheumatology, Cleveland Clinic, Cleveland, USA; Rheumatology Unit, Hadassah—Hebrew University Medical Center, Jerusalem, Israel; University of California, San Diego, La Jolla, USA; Novartis Pharma AG, Basel, Switzerland Presenting author: F. De Benedetti Pediatric Rheumatology 2017, 15(Suppl 1):O1

Introduction: Within an adult-onset Systemic Lupus Erytematosus (SLE) context, proteinuria has been shown to take a significant period of time to normalise, with 53% of lupus nephritis (LN) patients requiring up to 2 years to recover, and 74% recovering by 5 years [1]. The recovery time from proteinuria in Juvenile-onset SLE (JSLE) has not been well described. Objectives: 1) To describe time to recovery from proteinuria, and to elucidate if clinical/demographic factors at LN onset differentiate patients who do not fully recover. 2) To determine factors at LN onset which influence time to proteinuria recovery. Methods: Participants of the UK JSLE Cohort Study, between 1995-2015, were included if they had biopsy defined LN or active LN based upon the renal domain of the BILAG score (A/B) AND proteinuria of >50 mg/mmol. Univariate logistic regression modelling compared clinical/demographic factors at the time of LN onset in patients who did/did-not recover from proteinuria during the follow-up period. Covariates with p-value <0.2 were included in a multivariable logistic regression model, and backward stepwise variable selection applied. Univariate Cox proportional hazard (Cox PH) regression modelling was used to explore factors associated with time to proteinuria recovery, followed by the same multivariable model selection procedure. Results: 64/350 (18%) JSLE patients fulfilled the inclusion criteria. 25 (39%) recovered from proteinuria within a median of 17 months (min 2.4, max 78). The remaining 39 (61%) had not recovered after a median of 22 months (min 2.3, max 132). The final multivariable logistic regression model showed ethnicity, eGFR, Azathioprine and cardiorespiratory or haematological involvement at time of LN onset to be significant factors differentiating patients who did/did not recover (see Table 2, section A). Using Cox PH regression modelling, age, eGFR and haematological involvement were found to be significantly associated with time to proteinuria recovery (see Table 2, section B).  Table 3). Inputting individual patient AGP/CP values to the model can provide 3, 6 and 12 month probabilities of state transition. Conclusion: Within an internationally derived Markov state-space model of LN urine biomarker disease dynamics, AGP was predictive of active LN flare or remaining active, whereas CP was predictive of remission or remaining in-active. To improve patient outcomes, this model must be tested in a larger, prospective, rigorously conducted clinical trial of biomarker led LN monitoring. Disclosure of Interest None Declared.  Introduction: Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder with different genetic and environmental factors playing role in its pathogenesis. Early onset SLE, familial SLE, and syndromic SLE are rare situations which may lead to identification of monogenic defects responsible for the disease. İdentification of monogenic causes through these cases can help us to understand the pathogenic mechanisms in SLE. Objectives: We aimed to discover monogenic defects causing SLE by performing whole exome sequencing (WES) in familial or early-onset SLE cases. Methods: We enrolled 12 pediatric SLE cases (from 7 different families) who had disease onset before 5 years of age and a family history consistent with an autosomal recessive inheritance (affected siblings or parenteral consanguinity). Whole exome sequencing and bioinformatic analyses were performed in six index cases and the suspected mutations were confirmed by Sanger sequencing. Only C1Q gene was analyzed in patient 4 since he had similar features with the first three cases.
Results: There was consanguinity in all families. The characteristics of index SLE cases are presented in Table 5. We have demonstrated a homozygous nonsense mutation (c.622C > T/p.Gln208Ter) in C1QA gene in two patients; homozygous nonsense mutation (c.79C > T/ p.Gln27Ter) in C1QC gene in one; homozygous missense mutation (c.100G > A/p.Gly34Arg) in C1QC gene in one; homozygous stop codon mutation (c.1945G > C/p.Ala649Pro) in C1S gene in one; homozygous frameshift mutation (c.290_291delCA/p.Thr97Ilefs*2) in DNA-SE1L3 gene in one patient. There was a candidate novel gene in one patient and functional studies on this gene are ongoing. Conclusion: Five of our patients had homozygous mutations in the genes coding for early complement proteins. The risk to develop pediatric SLE is estimated to be 93% for C1q and 66% for C1s/r. There are less than 90 published cases with homozygous C1q deficiency. The clinical presentations are variable; however, they usually had cutaneous involvement, normal C3, C4 levels and negative anti-dsDNA which was the case in our patients. C1s deficiency is much rarer. The nonsense mutation in C1S gene of our patients was novel. DNASE1L3 gene encodes for DNase1 enzyme which functions as an endonuclease cleaving DNA. Deletion in DNASE1L3 gene has been previously reported to be associated with SLE in the study on seven SLE families where it was shown that protein encoded by the mutant DNASE1L3 completely lacked DNase activity. The variant in DNASE1L3 gene detected in our patient was the same as the one reported. We suggest that monogenic causes/associations should be sought for an early-onset SLE.

Disclosure of Interest
None Declared. Introduction: Fatigue is widely recognised as a common, debilitating symptom for patients with systemic lupus erythematosus (SLE) with significant impact on health-related quality of life. The cause of fatigue in SLE patients is poorly understood and likely to be multifactorial. Evidence is conflicting regarding whether fatigue in SLE patients is associated with factors such as disease activity, pain and mood and there are very few studies of fatigue in children with JSLE.
Objectives: To define the prevalence of fatigue and its associations within a large, national cohort of children with JSLE.
Methods: Patients meeting ≥4 ACR criteria in the UK JSLE Cohort Study were included. Data from the paediatric BILAG (p-BILAG) (completed by clinician), Short Form-36 (SF36) (completed by patient) and the Childhood Health Assessment Questionnaire (CHAQ) was analysed. The SF36 includes a vitality domain measuring energy/fatigue which cumulates in a score from 0-100 where higher scores indicate less fatigue; following review of published normative data we used a conservative estimate of 50 as a cut-off for significant fatigue. Associations between variables was assessed using Spearman's rank correlation co-efficients. Correlation co-efficients of 0-0.19, 0.2-0.39,0.4-0.59, 0.6-0.79, 0.8-1 were considered as very weak, weak, moderate, strong and very strong respectively. Results: 350 patients were included, for whom there were 1428 and 355 completed p-BILAGs and SF36s respectively. 81% of patients had suffered with fatigue at some point during their disease course, with patients suffering some degree of fatigue on 42% of all pBILAG scores. Correlation was moderate to strong between fatigue and disease activity where disease activity is recorded by the patient or physician but was weak/very weak when disease activity is measured by ESR as a biochemical indicator of disease activity ( Table 6). Moderate to strong associations are seen when comparing fatigue with pain and physical function. Strong correlations are seen on all correlations between patient-reported fatigue and patient-reported disease activity, pain and physical function. Weak/very weak correlations are seen when comparing fatigue with mood and anaemia. Data from the SF36 vitality scores had a mean score of 56.7 (SD 25.5) which is lower than published normative mean scores in young adults aged 16-19 years (mean 69.5, SD 19.8) with a mean difference of 12.8 (confidence interval 9.8-15.8). Almost half (45.3%) of patients had an SF36 score of less than 50 during their disease course, indicating significant fatigue. Conclusion: Fatigue affects most patients with JSLE and almost half suffer with significant fatigue. Fatigue is associated with increased disease activity, pain and functional disability. Importantly, the strongest associations are seen when these are measured using patientreported outcomes. These associations need further evaluation of their causality in order to consider future treatment strategies for this resistant and problematic symptom. Disclosure of Interest None Declared.  Introduction: Neurocognitive dysfunction is a common manifestation of childhood-onset Systemic Lupus Erythematosus (cSLE). Murine models suggest that loss of the blood-brain barrier (BBB) integrity allows brain-reactive proteins to enter the CNS and contribute to SLEassociated pathology. Contrast magnetic resonance imaging (MRI) can provide a measure of BBB integrity, but has risk associated with gadolinium use. We have previously identified multiple areas of gray matter (GM) loss on structural MRI in cSLE patients with neurocognitive deficits. Our aim was to evaluate safe, non-invasive MRI-methods of measuring regional BBB permeability and its relationship with neurocognitive function and regional GM volume in cSLE.
Objectives: To evaluate safe, non-invasive MRI-methods of measuring regional BBB permeability and its relationship with neurocognitive function and regional GM volume in cSLE.
Methods: Twelve cSLE patients and 12 healthy controls (age, gender, race and socioeconomic status matched) were enrolled. Those with diseases or medications (except prednisone) affecting neurocognitive function were excluded. Cognitive performance was assessed using the cSLE Neurocognitive Battery, which probes four cognitive domains: working memory, psychomotor speed, attention, and visuoconstructional ability. Performance in each of these was standardized and expressed as a Z-score. We almost concurrently performed arterial spin labeling (ASL) and diffusion-weighted imaging to measure regional BBB permeability. Voxel-based morphometric analysis was done to measure regional GM volume. Voxel-wise comparisons of capillary permeability were made between the cSLE and control groups. Correlation analysis was performed between regional BBB permeability and cognitive performance Z-scores, as well as local GM volume for the cSLE group. Results: Among the cSLE patients (11 females, 7 African American, mean age 18 ± 6.8 years), 9 were treated with prednisone (median dose 5 mg/d). None was diagnosed with active neuropsychiatric SLE. Group comparison revealed clusters of voxels with significantly greater BBB permeability for cSLE patients than controls, in three regions: the parahippocampal gyrus, the right fusiform and inferior occipital region, and the caudate head. Correlations between BBB permeability and regional GM volume or overall and individual domain Z-scores for neurocognitive performance were not statistically significant, although locations of significant increases in permeability for cSLE closely match our previously identified areas of GM loss and functional changes associated with clinically overt neurocognitive impairment. Conclusion: We present imaging evidence of altered regional BBB permeability in cSLE, using a novel non-invasive MRI technique. The absence of correlation with GM volume or cognitive performance Zscores, yet similar location to GM loss in previous work in our cSLE cohort suggests that BBB breakdown may precede clinically overt neurocognitive impairment and brain tissue loss. Longitudinal studies are needed to confirm the change in GM volume in relation to BBB permeability over time.

Disclosure of Interest
None Declared.

P187
Imbalance of regulatory immunome influences disease activity of juvenile systemic lupus erythematosus Joo Guan Yeo 1,2 , Jingyao Leong 2 , Loshinidevi D/O Thana Bathi 2 , Thaschawee Arkachaisri 1,3 , Salvatore Albani 1,2,3 1 Rheumatology and Immunology Service, Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore, Singapore; 2 SingHealth Translational Immunology and Inflammation Centre, Singapore Health Services, Singapore, Singapore; 3 Duke-National University of Singapore Medical School, Singapore, Singapore Presenting author: Joo Guan Yeo Pediatric Rheumatology 2017, 15(Suppl 1):P187 Introduction: The pathogenesis of Systemic Lupus Erythematosus (SLE) hinges on multiple disturbances that perturb the fine balance between immunity and regulation. Traditional investigational approaches have largely been focused on the pathogenic or protective role of individual cell types or even individual molecules. For a multifactorial disease like SLE, this mono-dimensional approach is inadequate. A holistic understanding of the immunome is a critical unmet need.
Objectives: Here, we aim to use a multi-pronged and multidimensional approach to study both the regulatory and inflammatory components sides of the immune balance concurrently. This approach may have immediate translational potential as it can lead to the identification of immune cells subsets which are relevant mechanistically and clinically. Methods: Peripheral blood mononuclear cells from 6 juvenile SLE patients, stratified by disease activity (SLE disease activity index), out of a cohort of 58 were studied with multi-parametric, multi-dimensional mass cytometry (Cytometry by time-of-flight). Analysis was performed using a machine learning custom software through an unbiased, unsupervised approach based on dimensional reductions followed by automated cell classification and clustering and subsequent stratifications of cell clusters with disease activity. Results: We found clear differences in the composition of the immunome between active and inactive disease with a prevalence of regulatory immune cells subsets and expansion of the IL-10 secreting cells (of B and monocyte/macrophage lineages) observed in inactive disease. Among these subsets, the regulatory B (CD19 + IL10+) cells appear relevant with a higher percentage of them present in inactive disease (median 5% versus 2.6%). The significance of these changes will be further determined with increasing sample size and functional characterisation of these immune subsets through transcriptome analysis.
Conclusion: In accordance with our original hypothesis, the imbalance between regulatory and effector immune functions is a cross dimensional feature which spans across both the innate and adaptive arms of the juvenile SLE immunome. Mechanistic features found here may hold a dual translational valency as potential signatures predictive of clinical fate as well as potential targets for intervention. Disclosure of Interest None Declared. Objectives: To describe the proportion of patients participating in the UK JSLE Cohort Study that meet the definition criteria of ID and CR. In addition, to identify any association between reaching ID/CR status and the patient's paediatric British Isles Lupus Activity Group (BILAG) disease activity scores at base line and time to diagnosis. Methods: A retrospective data analysis of prospectively collected data from the UK JSLE Cohort Study (collecting data from 21 sites across the UK) was undertaken. Patients fulfilling American College of Rheumatology (ACR) classification criteria for SLE, aged ≤17 years at diagnosis and having a minimum of 12 months follow up were included. Patient status in meeting definitions of ID and CR as defined by Mina et al were assessed at first, 1 year and last follow up clinic visits. Patients failing to achieve ID/CR were considered being active disease (AD). Patients achieving ID at 1 year and last visit were identified and analyzed against BILAG scores on first visit and time to diagnosis. Continuous data presented as mean (range).
Results: 233 patients were included on first visit. Mean age at diagnosis was 12.6 (1.8-17.9) years, mean follow up 4.7 (1-15) years, 82% were females. Data from 93 and 209 patients were available for analysis at 1-year and last visits respectively. 79 patients (85%) at 1 year and 130 (62%) at last follow up were in AD while only 6 (6%) and 18 (9%) achieved ID respectively; the remaining 8 (9%) and 61(29%) patients could not be classified at these time points due to incomplete data. The percentage of AD decreased over time from 91% on the first visit, to 85% at 1 year and to 62% in the last follow up. Ratio of AD:ID disease patients fell from 35:1 in first visit, to 13:1 at 1 year and to 7:1 at last follow up visit. Notably, 20 (25%) at 1 year and 15 (12%) of the patients at last follow up visit were in AD because of isolated low lymphocyte count. No statistically significant difference was found comparing patients in AD to patients in ID at 1 year and last follow up in relation to time to diagnosis and BILAG scores Conclusion: The majority of patients failed to achieve the suggested criteria for ID/CR reflecting the high burden of JSLE despite the expanding use of aggressive treatments. However, a significant proportion of patients had isolated blood tests abnormalities with limited clinical significance, which may suggest some limits of the ID criteria. Some of the laboratory requirements to meet the criteria for ID may be oversensitive and/or not always reflect disease activity state. Larger prospective studies may be required to identify differences between patients achieving and not achieving ID with regards to disease activity at diagnosis, time to diagnosis and treatment received. Introduction: Systemic lupus erythematosus (SLE) is a rare autoimmune disease which can affect any organ system. SLE with an onset in childhood (cSLE) is thought to be more severe than SLE. Only a few small studies address the adult outcomes of patients with cSLE. Objectives: To investigate the clinical outcomes and health-related quality of life (HRQOL) of 111 adults with cSLE. Methods: Adults with cSLE were seen for a single study visit containing a structured history and physical examination. Medical information since disease onset was requested, scrutinized and added to the data obtained during the visit. Disease activity and damage were calculated with SLEDAI-2 K and SLICC Damage Index (SDI). HRQOL was assessed with the SF-36. Outcomes were compared to 40 patients with adult-onset SLE (SLE). Results: Almost all 111 cSLE patients were female (91%) and white (69%). Median age was 33 years, median disease duration was 20 years. A vast majority of patients (87%) used immunosuppressive drugs, of whom 60% still used prednisone. Herewith, disease activity was relatively low (median SLEDAI 4). Many patients (62%) had developed damage (SDI range 1-8), most commonly in the musculoskeletal (41%) and neuropsychiatric system (33%), and kidneys (23%). SDI scores were similar to the SLE patients. We found that 51% of 45 patients who ever had neuropsychiatric (NP) involvement also had NP damage, and 24% of the 67 patients with nephritis ever had developed renal damage. At (very) young age, 7 cSLE patients had a cerebrovascular accident (median 19 yrs), 5 cSLE patients had a myocardial infarction (median 39 yrs), and 6 cSLE patients had replacement arthroplasty (median 33 yrs).
Compared to the Dutch norm data, HRQOL of cSLE patients was impaired in all but one of the eight SF36-domains. Scores of SLE patients were comparable to those of cSLE patients. Remarkably, mental health scores were similar between patients and Dutch norm data. Patients with and without damage had similar HRQOL scores in all but the physical functioning domain. Conclusion: In this large, mainly white cohort of adults with cSLE, the majority had developed damage at a young age. Not many patients had achieved drug-free remission, and prednisone use was common even after a median disease duration of 20 years. Neuropsychiatric involvement led to neuropsychiatric damage in half of the patients, renal involvement led to renal damage in 1/4 of the patients. Overall, HRQOL was impaired, except for patients' mental health. Disclosure of Interest None Declared.
Introduction: SLE predominantly affects women of child bearing age. The effect of SLE on pregnancy and pregnancy on SLE remains controversial. Although most studies on the incidence and prevalence of SLE have been performed using Caucasian cohorts, it appears that individual race and ethnicity may exhibit differences on disease.
Objectives: To determine maternal and neonatal outcomes in pregnancies complicated by SLE compared to those with normal pregnancies in Arab women from Sultanate of Oman. To analyze the effect of clinical and serological variables of SLE on pregnancy outcome and neonatal morbidity. Methods: A retrospective analysis of 147 pregnant mothers with their corresponding infants was conducted in SQUH. 56 pregnancies (38%) in SLE mothers were compared to 91 (62%) pregnancies in healthy control mothers. The extracted data include demographic characteristics, lupus disease activity at onset of pregnancy, disease flares, clinical manifestation, autoantibody profile, medications, obstetric status and complications. In addition, data collected included neonatal outcomes including gestational age, gender, birth weight and Apgar score which was compared to the control group. Results: The mean age of the SLE group and control group were comparable 29 ± 5 years versus 31 ± 5 years. The number of mothers who were nulliparous and grand multiparous were also comparable in the two groups. However, SLE mothers were more likely associated with gestational diabetes (28% vs. 10%; p = 0.004), polyhydramnios (7.1% vs. 0; p = 0.010) and have pre-term labor (29% vs. 1.1%; p < 0.001). The SLE mothers were also more likely to be associated with a worse previous obstetrical history including previous pre-term labor (8.9% vs. 1.1%; p = 0.030) abortions (43% vs. 15%; p < 0.001) and still birth/intrauterine fetal deaths (7.1% vs. 0; p = 0.010). Among the pregnancies, the male female ratio was 1:1.14 which was not significantly different in the two study cohorts. However, infants born to SLE mothers compared to normal health controls, had higher incidence of pre-term births 29% vs 1.1% (P value >0.001), lower mean birth weight 2.69 ± 0.65 versus 3.00 ± 0.29 kg (p < 0.001) and higher incidence of intrauterine growth retardation (birth weight <2500gm) 32% versus 1.1% (P value <0.001) respectively. However, there was not difference in low Apgar scores at birth in both cohorts. The most common clinical feature includes musculoskeletal (48%), cutaneous (38%), hematological (25%) followed by lupus nephritis (18%). The autoantibody profile in the SLE mothers included positive ANA (95%) followed by dsDNA (52%), antiphospholipid antibodies (33%), anti SSA antibody (36%) and anti SSB antibody (8%). The treatment consisted of hydroxychloroquine (n = 41; 73%), prednisolone (n = 38; 68%) and azathioprine (n = 17; 30%). Despite a high percentage of SLE mothers being on steroids during pregnancy, the majority were on low dose prednisolone 5-10 mg (85%). Up to 80% of SLE mothers were in clinical remission or with mild disease activity, SLEDAI score (0-5) at time of pregnancy and only 19% had disease flare during pregnancy. The clinical and laboratory features of infants born to SLE include liver (25%), hematological (11%)and cutanous (3.6%) Of note, none of the neonates developed cardiac manifestation despite 32% and 7% of babies had circulating anti SSA (Ro) antibody and anti SSB (La) antibodies, which is typically associated with congenital heart block. The mean duration of positive circulating maternal antibody profile in neonates is 6.6 ± 2.9 months with range 2-15 months. Conclusion: Arab SLE mothers from Sultanate of Oman were associated with worse maternal outcomes when compared to normal pregnant mothers. This result is comparable to other SLE pregnancy outcomes from around the world. Disclosure of Interest None Declared.
Introduction: Autoimmune hemolytic anemia (AIHA) is an uncommon autoimmune disorder characterized by autoantibodies targeting red blood cells and has been described in 3-20% of childhood-onset systemic lupus erythematosus (cSLE) and in 4-10% of adult-onset SLE. However, no large study evaluated AIHA in both populations. Objectives: The objective of the present study was to determine the overall prevalence of AIHA, and to compare clinical and laboratorial features in a large population of children and adult lupus patients at diagnosis. Methods: This retrospective study evaluated medical charts of 336 cSLE and 1,830 aSLE patients (ACR criteria) followed in the same tertiary hospital. Demographic data, arthritis characteristics, clinical features and disease activity (SLEDAI-2 K) were recorded. AIHA was defined according to the presence of anemia (hemoglobin <10 g/dL) and evidence of hemolysis (reticulocytosis and positive direct antiglobulin test-DAT/Coombs test) at SLE diagnosis. Evans syndrome (ES) was defined by the combination of immune thrombocytopenia (platelet count <100,000/mm 3 ) and AIHA. Results: The frequency of AIHA at diagnosis was significantly higher in cSLE patients compared to aSLE [49/336(14%) vs. 49/1830(3%), p = 0.0001], with similar frequency of ES [3/336(0.9%) vs. 10/1830(0.5%), p = 0.438]. Compared to adults, cSLE patients had more often multiple hemorrhagic manifestations (41% vs. 7%, p = 0.041), constitutional involvement (84% vs. 31%, p < 0.001), fever (65% vs. 26%, p < 0.001), weight loss > 2 kg (39% vs. 6%, p < 0.001), hepatomegaly (25% vs. 0%, p < 0.001) and splenomegaly (21% vs. 2%, p = 0.004). Other major organ involvements were common but with similar frequencies in adult and children (p = 0.05). The median of hemoglobin levels was reduced in cSLE versus aSLE patients [8.3(2.2-10) vs. 9.5(6.6-10)g/dL, p = 0.002] with a higher frequency of erythrocyte transfusion due to bleeding (24% vs. 5%, p = 0.025). Autoantibody profiles and immunosuppressive treatments were similar in both groups (p > 0.05). Median SLEDAI-2 K was also comparable in adults and children (p = 0.161). Conclusion: We identified that AIHA at SLE diagnosis has distinct features characterized in cSLE by high prevalence and severity of this hematological manifestation and an almost universal association with constitutional symptoms. Disclosure of Interest None Declared.

P193
B cell-bound complement activation products in the diagnosis and monitoring of systemic lupus erythematosus Jessica Beckmann 1 , Nora Bartholomä 2 , Nils Venhoff 2 , Philipp Henneke 1 , Ulrich Salzer 2 , Ales Janda 1 Introduction: The neuropsychiatric (NP) manifestations are an important cause of morbidity and mortality in patients with pediatriconset systemic lupus erythematosus (pSLE). The prevalence of these manifestations ranges from 29% to 95% in different series, but data in the spanish pediatric population are scarce. Objectives: To analyze the clinical and immunological features of patients with pSLE and NP followed in a Spanish tertiary center.
Methods: We performed a retrospective study of 62 patients with pSLE diagnosed between 1985 and 2015 in our center. The American College of Rheumatology NPSLE case definitions were used to classify the manifestations. The demographic, clinical and immunological data were obtained through review of their medical charts. Continuous variables were analyzed using Student's t-test (or Mann-Whitney U test if the number was < 10 or the sample did not have a normal distribution) and discrete variables by Pearson's χ2 test (or Fisher's exact test when number in the category was < 5). Results: Twenty eight (45%) developed NP manifestations. The mean age of the patientes with NP manifestations was 13.9 years and female:male ratio was 2.5: 1. These manifestations were presented at the beginning of the disease in 7 cases (25%) and in the first 2 years in 65% of the cases. The most common presentations of NPSLE were the cental manifestation (89,2%) with seizures in 13 cases, headache in 8 cases, mood disorder/depression in 5 cases, psychosis in 4 cases, cerebrovascular disease in 5 cases and aseptic meningitis in 4 cases. There was more than one NP manifestation in 48% of the patients, with an average of 2.4 manifestations/patient. The comparison of patients with and without NPSLE demonstrated significant diffences (p <0.05) in the number of males, titers of anti-DNA antibodies, positivity for anti-β2 -glicoprotein I (β2GPI) and consumption of complement (C3, C4).50% of the patients with NP manifestations had cyioglobuline positive. There were 2 cases of mortality in NPSLE (7.1%) during the follow-up period, one as a result of infection of the central nervous system and another due to sepsis associated with intestinal thrombosis. Conclusion: In our series 45% of the patients had NPSLE manifestations and they frequently occured early during the course of the disease. 100% of the male patients presented NP manifestations during the course of the disease. The clinical spectrum of NPSLE was wide in our cases and most of them had more than one manifestation. Patients with NPSLE showed a high disease activity as measured by levels of anti DNA antibodies and hypocomplementemia. Although NPSLE has been associated with positive antiphospholipid antibodies in other series, specifically anticardiolipin antibodies and lupus anticoagulant, we only found significant association with anti-β2GPI IgG antibodies Disclosure of Interest None Declared.
Introduction: Juvenile systemic lupus erythematosus (jSLE) is a chronic multisystemic autoimmune disease characterized with variable clinical course. Vital organ involvement is the most important morbidity and mortality factor of the disease. Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure (PAP) ≥ 25 mmHg at rest or a right ventricular systolic pressure (RVSP) > 40 mmHg. Non-specific clinical features and insignificant findings are the main reasons of the delayed diagnosis in patients with PH. Timely echocardiographic (ECHO) examination enables early diagnosis of the disease. Pulmonary hypertension has been reported to be associated with poor prognosis in several studies among adults with SLE. The prevalence of PH in adult SLE patients is estimated to be 1.8% to 14%. Studies on pulmonary hypertension among patients with jSLE are spare. Objectives: The aim of this study is to explore the right ventricle functions and to determinate the frequency of pulmonary hypertension in patients with jSLE, using non-invasive methods (Pulsed wave and tissue Doppler ECHO).
Methods: Patients with diagnosis of jSLE followed up at our department were included in the study. Pulse wave and tissue Doppler ECHO was performed to all included patients and to healthy controls. Measurements obtained by ECHO include: peak velocity of the tricuspid insufficiency (TRVmax), end diastolic velocity of pulmonary insufficiency (PIV), tricuspid annular plane systolic excursion (TAPSE), right ventricle diastolic function measurement (Lat E, A, E' wave, E/E' ratio). Bernoulli equation (4 × TRVmax2) was used to calculate the estimated PAP. Results: A total of 38 jSLE patients and 40 healthy controls were included in the study. Mean age of patients was 16.0 ± 2.59 years, mean age at diagnosis was 10,63 ± 3,51 years and mean disease duration was 57.02 ± 33.6 months. Mean age of control group was 15 ± 3.49 years. Echocardiographic measurements of patients and healthy controls are shown in Table 8. TRV max and PIV were significantly higher in jSLE patients comparing to healthy controls with p < 0.05 and p < 0.001, respectively. Tissue Doppler ECO measurements of right cardiac diastolic functions (Lat E, E' wave and E/E' ratio) were significantly different in jSLE patients, comparing to healthy controls. Conclusion: This study confirms that pulmonary hypertension is uncommon among patients with jSLE. However, patients with jSLE have a compromised right cardiac contractile functions and higher pulmonary artery pressure comparing to healthy controls. These results point out the importance of echocardiographic examination in patients with jSLE, regarding right cardiac functions and pulmonary hypertension. Introduction: Patients with juvenile systemic lupus erythematosus (JSLE) have more aggressive disease 1 in addition to the improvement on survival in the last decades 2,3 , have led patients to be exposed to the disease for a longer time and to endangering them to develop damage. Objectives: To assess damage in a large cohort of patients, and to identify the main features associated with the development of damage. Methods: An ambispectic cohort was designed, patients aged ≤16 years old were followed up at least for two years. Every 3 to 6 months all patients were assessed for disease activity (DA) with SLEDAI-MEX 4 , and anually for damage with the Pediatric Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SDI) 5 .
Demographic features are reported as median (min-max). A bivariate analysis was performed for Damage ≥2, (dichotomus variable) with U Mann Whitney and Pearson chi square, and for Damage (numeric variable) with Pearson correlation. Statistical analysis was accomplished with SPSS 16.0, Chicago IL. Ethics and Research Committee have approved the protocol. Results: Eigthy five out of 97 identified JSLE patients were included, misclassification issues were found in 5, leading to 80 patients analyzed, 30% correspond to male patients, F:M ratio 2.3:1. At diagnosis: age had a median of 11.87 yr, min-max (2.18 -16.3 yr), and SLEDAI-MEX 12 (2 -29). The main features at diagnosis are: nefritis 64%, hemolytic anemia 53%, lymphopenia 51%, hematuria 51%,proteinuria 48%, malar rash 46%, oral ulceration 35%, fatigue 32%, fotosensitivity 30%, thrombocytopenia 28%, fever 27% and neurolupus 20%. After at least two years of follow up the disease duration was 3.91 yr (2 -9.4) and SDI 2 (0 -6). Regarding the distribution of damage, 62% of patients have damage ≥2. Bivariate Analysis: for Damage, a significant Pearson correlation with (p ≤ .005) proteinuria and SLEDAI-MEX at the diagnosis time was found. Table 9 shows the variables analized for Damage ≥ 2. The highly associated variables with Damage ≥2 are SLEDAI-MEX >6, hemolytic anemia and nephritis, and to a lesser extent, gender, specifically being male. We did not find any association with age group, the presence of thrombocytopenia, lymphopenia nor with the presence of anticardiolipins antibodies. It has been published before 6 that cumulative disease activity over time, cumulative steroid dose, acute thrombocytopenia and presence of antiphospholipid (APL) antibodies are the main risk factors for development of damage, however, in the clinical setting it is not helpful to have to wait several months in order to calculate the first two variables, plus in our population we did not find any association with acute thrombocytopenia nor with the presence of ALP antibodies. Conclusion: The presence of SLEDAI-MEX >6, proteinuria (>0.5 g/d) and hemolytic anemia, identified at the diagnosis time, can be important factors for the development of damage in patients with JSLE. Pediatric rheumatologists must be aware that the presence of those factors should lead to a close follow up in order to reduce the likelihood of damage. Trial registration identifying number:  Introduction: Exposure to outdoor pollutants has been associated with an increase in hospitalizations due to the activation of our pediatric rheumatic diseases and with an elevated risk of disease activity in our childhood-onset systemic lupus erythematosus (cSLE). However individual real-time exposure, evaluating indoor and outdoor pollutants, were not studied in adult and cSLE populations.
Objectives: To investigate the association between daily individual real-time exposure to air pollutants and SLEDAI-2 K parameters of disease activity in cSLE patients. Methods: A longitudinal and observational panel study (repeated measures from April 2013 to June 2015) was carried out in 108 consecutive appointments with 9 cSLE patients without rhinitis and chronic pulmonary diseases. Over four consecutive weeks, daily individual measures of nitrogen dioxide (NO 2 ) by a passive sampler during seven days, fine particulate matter (PM 2,5 ) by a real-time laser photometer, ambient temperature and humidity were obtained. This cycle was repeated every 2.5 months along one year, and disease activity parameters were collected weekly. Generalized estimation equation models were used, considering the fixed effects of repetitive measures, to assess the impact of these pollutants on the risk of increased serum anti-dsDNA, moderate/severe disease activity (SLEDAI-2 K ≥ 8), presence of nephritis and altered urine casts, and decrease in serum levels of complement. The models were adjusted for inflammatory indicators, body mass index, infections, medication, and weather variables.
Results: For an interquartile range (IQR) increase of 18.12 μg/m 3 in PM 2.5 daily concentration, an increase was observed in the risk of: nephritis on the 3rd, 4th, 10th and 14th days after exposure; haematuria only on the 4th day; leukocyturia from 3-7days after exposure; increased anti-dsDNA levels on the 4th, 10th and 11th days after exposure; SLEDAI-2 K ≥ 8 on the 4th and 11th days after exposure. Moreover, for an IQR increase in PM 2.5 daily concentration, an increase was observed in the 24 h-urine protein on the same day of exposure and from the 6th to the 10th day as well as a decrease in C3 serum levels on the same day and on the 4th and on the 6th day after exposure. An IQR increase in PM 2.5 7-day moving average (from lag0 to lag6) was associated with increased risks for: leukocyturia (3.4; 95%IC 2.6-4.3); increased anti-dsDNA levels (3.1; 95%CI 2.1-4.0) and SLEDAI ≥ 8 (1.5 95%CI 1. 1-1.8).
Conclusion: This was the first prospective study suggesting that exposure to outdoor/indoor air pollution may trigger disease activity and may aggravate nephritis in c-SLE patients.
Introduction: Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disease characterized by the presence of autoantibodies and multiorgan system involvement.
Objectives: The aim of this study was to describe the presenting clinical manifestations, clinical course and prognosis of SLE in children.
Methods: We performed a retrospective review of medical records of SLE patients. Between 1995 and 2016, 52 children with SLE were evaluated. Medical records were systematically reviewed, including demographic data, clinical features, and laboratory findings.
Results: The study consisted of 52 patients with childhood SLE. There were 44 female and 8 male patients. The mean age of onset of the disease was 12,2 +/-2,7 years (range 4-17). The mean duration of follow-up was 5,5 years (range [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Table 10 summarizes the frequency of the clinical features of disease noticed in our patients. The most common clinical feature was arthritis (65,4%), followed by constitutional symptoms (48,1%), malar rash (36,5%), weight loss (21,2%), photosensitivity (15,4%), oral ulcers (9,6%), and alopecia (7,7%). Renal involvement accounted 3/4 of the patients (75%). Hematuria and proteinuria were most frequent presenting findings (38% and 36,5% respectively). 13 patients had nephrotic syndrome. Renal biopsy was performed in 40 patients. According to WHO classification: 1 patient had class V nephritis, 16 had class IV, 6 had class III, 15 had class II and 2 had class V nephritis. All patients with class IV nephritis were treated with pulse metilyprednisolon and intravenous cyclophosphamide as an induction therapy then shifted to either azathioprine or mycofenolate mofetil. Neurological involvement was seen in eleven patients (21,2%); 5 patients had headache, 3   Introduction: Cerebrovascular disease is a recognised manifestation of neuropsychiatric SLE in children; however angiogram-positive large vessel vasculitis is uncommon. Objectives: To describe two cases of paediatric systemic lupus erythematousus (SLE) with extensive large-vessel central nervous system (CNS) vasculitis and their response to cyclophosphamide therapy. Methods: We reviewed and summarised two rare cases of large-vessel CNS vasculitis in 2 patients with known SLE and review existing literature on the various forms of CNS vasculitis in paediatric SLE patients. Results: An 11 year old girl was diagnosed with SLE in May 2014. Initial manifestations of polyarthritis and discoid skin lesions showed good response to prednisone, chloroquine and azathioprine. She represented in April 2015 after a six month period of medication noncompliance with a flare of polyarthritis and frequent headaches refractory to simple analgesia. A single-photon emission computerized tomography (SPECT) scan of her brain showed diffuse perfusion abnormalities, and MRI and MR angiogram revealed extensive vasculopathy with marked narrowing of the right internal carotid artery and bilateral carotid siphons, but no features of ischaemia. A lumbar puncture demonstrated a raised opening pressure of 35 cm H20, but a normal cell count and protein. Following pulse dose of IV methylprednisolone and six months of IV cyclophosphamide at 750 mg/m2, her headaches resolved and repeat imaging showed significant interval improvement. She is currently on myfortec maintenance therapy.
A 16 year old boy was diagnosed with SLE in 2009 after presenting with a malar rash, arthritis and bilateral testicular 'torsion'. Histology of a left orchidectomy showed vasculitis and haemorrhagic infarction. He was subsequently lost to follow-up and represented in December 2014 with isolated polyarthritis that responded well to prednisone, methotrexate and chloroquine. One year later he was seen at routine follow-up with a month long history of a refractory frontal headache and loss of vision in his left eye. He was noted to be severely hypertensive. Ophthalmology exam confirmed a retro-bulbar optic neuritis which resolved completely after treatment with IV methylprednisolone. His hypertension proved very difficult to control, requiring multiple agents. Exhaustive renal investigations for a cause were negative. Cardiac evaluation with ECG and ECHO were normal. However his brain MRI and MR angiogram showed extensive vasculitis, with marked attenuation of all the major cerebral vessels, but no evidence of ischaemia. A lumbar puncture demonstrated normal opening pressure and CSF analysis was normal. He is currently receiving monthly IV cyclophosphamide infusions at 750 mg/m2 and his headaches have resolved. The hypertension is presumed to be of central origin. Conclusion: Angiogram-positive large vessel vasculitis is a rare form of neuropsychiatric SLE in children, however it should always be considered in cases of severe recurrent headache with or without accompanying neurological signs. Disclosure of Interest None Declared. Methods: Diagnostic test study. Retrospective evaluation of features present in the first month of diagnosis in patients with jSLE seen in a pediatric rheumatology service in Bogotá, Colombia between May 2007 and March 2016. Controls were included with the following diagnosis: juvenile idiopathic arthritis (n = 24), dermatomyositis (n = 7), autoimmune hematologic disorders (n = 6), antiphospholipid syndrome (n = 6), systemic vasculitis (n = 5), overlapping syndromes (n = 4), undifferentiated connective tissue disease (n = 2) and autoimmune hepatitis (n = 1). Results: n = 110. 55 cases and 55 controls. Mean age at onset in cases was 12,8 years (7-15 years) and in controls was 11,1 years (2-16 years). Sex distribution in cases was 83,6% girls, F:M ratio 5,4:1 and in controls 65,5% girls, F:M 1,8:1. The most prevalent features in cases were lymphopenia < 1500 in 54,5% (vs 10,9%, p = 0,000), arthritis in 47,2% (vs 52,7%, p = 0,352), proteinuria in 41,8% (vs 7,2%, p = 0,000), lymphopenia < 1000 in 36,3% (vs 3,6%, p = 0,000 and malar rash in 34,5% (vs 9%, p = 0,001). Antinuclear antibodies were positive in 94,4% (vs 34,5%, p = 0,000), anti DNA antibodies in 57,4% (vs 3,7%, p = 0,000), IgM anticardiolipin in 29% (vs 12,7%, p = 0,03), anti Smith in 29% (vs 0%, p = 0,000), IgG anticardiolipin in 27,2% (vs 9%, p = 0,012), lupus anticoagulant in 23,6% (vs 10,9%, p = 0,064) and false positive syphilis test in 16,3% (vs 0%, p = 0,001). There was hypocomplementemia of C3 and C4 in 80% and 69% of cases respectively (vs 12,7% and 15,4%, p = 0,000). During the first month of diagnosis 78,1% of cases completed ACR criteria and 89,1% completed SLICC criteria. The sensitivity of SLICC criteria was higher (89% vs 78%) with a lower specificity (87% vs 96%). Objectives: The aim of this study is to define the immune status against HAV in patients with jSLE, prior to commencement of treatment and one and three years after treatment, and compare this to healthy controls. Methods: Single-center prospective study including 21 patients newly diagnosed with SLE and 76 healthy controls. All patients had two doses of the inactivated Hepatitis A vaccine in early childhood. Exclusion criteria were underlying immunodeficiency, recent blood transfusion (<6 months) and previous treatment with immunomodulating agents. Demographic and clinical and laboratory data as well as data regarding immunization status, vaccine history and mean time between the doses of the vaccine were collected. Seroprotection rates (>20 mIU/ml) and anti-HAV IgG titers were measured at enrollment and at timely intervals afterwards. Data were analyzed using SPSS 19.0. Results: The two groups had similar characteristics, vaccination history and immunization status. No significant differences were detected in terms of vaccine type, time interval between the two groups as well as mean time from last vaccination to blood sampling. Seroprotection rates at enrollment were 93% for the SLE and 98% for the control group. Mean anti-HAV IgG antibodies were significantly lower in the SLE compared to the control group(167mIU/ml versus 249mIU/ml) (p < 0.01). Same results were found at 1 and three years' follow up (Table 11). During the follow up period the SLE group had greater decrease in antibody levels as indicated from the significant interaction effect of analysis.

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Conclusion: Although seroprotection rates were similar between the two groups mean anti-HAV IgG titers were significantly lower in the SLE group at enrollment and at one and three years' follow-up. Low antibody titers could be attributed to disease, disease activity or medications. Further studies are required to address the question of long-term immunity conveyed by immunizations given at an early stage in children with rheumatic diseases. However, evaluation of immunization status against all vaccine preventable diseases in such patients may be beneficiary.  Methods: A boy born to a 35-year-old mother with systemic lupus erythemathosus with positivity for anti-SSA and anti-SSB, and a previous child with NLE with congenital heart block who died at the age of two due to myocarditis. The pregnancy was surveilled, the mother was treated with prednisolone and hydroxychloroquine and a prenatal diagnosis of heart block was made. The mother received dexamethasone and salbutamol but refused endovenous immunoglobulin and plasmapheresis. Results: The child was born during the 36th week of gestation, by cesarean, with an Apgar 1´/5´of 9/10, complete heart block was confirmed and he was admitted to the Department of Neonatology. 24 hours after birth a temporary pacemaker was inserted, which was only replaced by a definitive pacemaker when the patient was 14 days old due to concurrent sepsis. Empiric antibiotic intravenous therapy with meropenem and vancomycin was started. At D22 he developed hypoxemic acute respiratory failure requiring mechanical ventilation, with chest radiographs showing diffuse bilateral cotton-like infiltrates. In the following 48 hours there was clinical worsening, despite the broad-spectrum antibiotics, absence of fever and progressive normalization of leukocyte count and C-reactive protein level. At this time pediatric rheumatology evaluation was requested. The neonate had a history of transitory rough skin rash on chest and back after birth; thrombocytopenia probably in the context of neonatal sepsis whithout other hematologic abnormalities; hepatomegaly without elevation of liver enzymes. The immunology panel showed positivity for antinuclear antibodies at titer 1/ 320 (speckled pattern), positivity for antibody anti-SSA and also anti-dsDNA, with absence of anti-SSB, anti-RNP. The clinical picture was interpreted as NLE-related pneumonitis and the patient received intravenous methylprednisolone pulses (30 mg/kg/day) on 3 consecutive days, followed by oral prednisolone in progressively lower doses, with excellent clinical and imagiological response: after the second pulse he started to ventilate spontaneously and after 7 days supplementary oxygen was no longer needed.   Introduction: Colchicine resistant and corticosteroid dependent (unable to withdraw the drugs without relapse) recurrent pericarditis is a major management challenge. Anakinra, an interleukin (IL)-1 beta recombinant receptor antagonist, is promising in this setting. Objectives: To determine the efficacy and safety of anakinra in colchicine resistant and corticosteroid dependent recurrent pericarditis in the first randomized controlled study. Methods: Investigator-initiated, double-blind, placebo 33 controlled, randomized withdrawal trial among 21 consecutive patients with colchicine resistant and corticosteroid dependent recurrent pericarditis enrolled in 3 Italian referral centers between June and November 2014. At enrolment, mean age was 45.4 years (SD 14.3 years), 67% were females. Included patients had recurrent pericarditis (with ≥3 previous recurrences), elevation of C-reactive protein, colchicine resistance and corticosteroid-dependence. Anakinra was administered at 2 mg/kg/day up to 100 mg for 2 months and then patients were randomized to continue anakinra (N = 11) or switched to placebo (N = 10) for 6 months or until a recurrence. The primary outcomes were recurrent pericarditis and time to recurrence after randomization. Introduction: The last 3 decades, since the era of methotrexate and 'dismantling the pyramid' [1], and in particular in the current era of new biologic response modifying agents [2], have brought dramatic improvement in treatment of children with juvenile idiopathic arthritis (JIA); however, a substantial percentage (>30%) still carries on with active disease in adulthood, and a small minority remains refractory to current therapies, with significant morbidity and cumulative side effects, especailly from infections. Objectives: Report treatment failures and significant infectious sideeffect, including deaths, in a cohort of patients with severe, refractory JIA referred for haematopoietic stem cell transplantation (HSCT).

Disclosure of Interest
Methods: Data analysis from our centre, for the period 2000-2016.
Results: In the period 2000-2007, of the 13 referred patients 5 declined HSCT or were deferred after independent assessment; 2 died before HSCT; 6 underwent autologous T cell depleted HSCT [3], of which 3 are in long-term (>10 yrs) complete remission (CR), 1 relapsed within 6 months post-HSCT, and 2 died. All 4 deaths were caused by infections, 3 from central venous catheter related bacterial sepsis (1 during HSCT procedure, and 2 in patients receiving high-dose steroids, methotrexate and TNF-blocking biologics) and 1 from disseminated adenovirus infection (during HSCT procedure).
In the period 2007-2016, 4 of 5 referred patients underwent allogeneic HSCT [4] of which 3 are in long-term (1-4 yrs) CR, and 1 is only 2 months post-HSCT; 1 patient was deferred after independent assessment. Conclusion: Severe infections are emerging as an important mortality risk factor in children with severe, refractory JIA treated with combined and multiple immunosuppressive and anti-inflammatory therapies. In this small group of patients, these risks should be carefully assessed towards the risks (and potential benefits) from allogeneic HSCT.
Introduction: Juvenile Idiopathic Arthritis (JIA) is the most common chronic inflammatory musculoskeletal disease of childhood in the UK. More than 30% of patients will continue to have active disease as adults, with some requiring a biologic for the first time after the age of 18 years. Prior to December 2015, there was no national UK approval for the use of biologics in this older population, albeit they were used in adults with JIA.
Objectives: This mixed-methods study aimed to explore the clinical experience and decision-making of healthcare professionals in relation to the use of biologics in adults with JIA. Methods: Multi-method research was undertaken comprising of an online survey and one-to-one telephone interviews. An online survey of 205 healthcare professionals working in UK hospitals who have recruited adults with JIA to British Society for Rheumatology Biologics Register (BSRBR-RA) (response rate: 81 (39%) including rheumatology consultants (49), rheumatology specialist nurses (29), research nurses (2) and staff associates (1)), ascertained their experience in relation to four distinct areas: (1) education, training and practice; (2) factors suggesting a diagnosis of JIA; (3) use and choice of biologics; and (4) treatment challenges; and this was explored further through followup one-to-one telephone interviews (N = 10). The survey data was analysed using descriptive statistics and free-text comments using qualitative techniques; and the interview data was analysed qualitatively. This study had ethical approval with informed consent from all participants. Results: Most (95%) survey participants currently treat adults with JIA and many (63%) also treat children. Most had not received any education or training in the specific management of adults with JIA (65%) although 56% had received some training in paediatrics (described as formal education, attendance at study days or meetings; in practice learning and team/colleague support). Many stated further need for training in JIA in adults (52%) and children (58%  Results: Overview. Of 315 JIA pts enrolled, 308 provided data for this. The total person-years (p-y) of observation were mean 231.9 y on ABA and 50.0 y post-ABA. In this registry, 35 (11%) of pts were new starts on ABA (≤1 mo of treatment), 207 (67%) had received ABA treatment for 1 mo-1 y, 52 (18%) for 1-2 y and 14 (4%) > 2 y. ABA was continued during follow-up in 224 pts (73%) Baseline. Of 308 pts, 246 (80%) were female, mean/median at enrollment was age: 13.2/13.8 y, disease duration: 5.4/4.4 y, and active joints: 2.7/0. Baseline clinical, functional and HRQoL scores are shown in Table 15: In the treated pts reflecting real world use, 40 had a history of uveitis and 12 had active uveitis (16% history and active uveitis). JIA subtype was systemic 2%, oligoarticular 21%, polyarticular RF-53%, polyarticular RF+ 10%, psoriatic 4%, enthesitis-related 4%, undifferentiated 6%. Of these pts, 265 (86%) were taking a concomitant medication for JIA (64% MTX, 49% NSAIDs, 17% systemic steroids, 5% leflunomide, 5% hydroxychloroquine, 1% cyclosporine, 1% sulfasalazine.) Follow-up safety. A total of 30 AEs were seen (18 serious; all single occurrences) in 25 pts (0.8% of study population) for an AE rate 12.9 per 100 p-y of exposure (95% CI 8.8-18.2). There were 12 infections of special interest (5.0/100 p-y, 95% CI 2.8-8.8); 2 discontinued ABA due to a safety event (anaphylaxis). No new autoimmune diseases, deaths, malignancies or tuberculosis cases were reported. Conclusion: In this JIA cohort with low MD Global, low number of active joints and with CID seen in above 30% at baseline, abatacept demonstrated persistent effectiveness over 2 years. Abatacept was well tolerated and no new safety signals were seen.  Corticosteroids and conventional immunosuppressive agents are not always safe or efficacious. The complex formed by interleukin-6 (IL-6) and soluble IL-6 receptor appears to play a pivotal role in the pathogenesis of TA.
Objectives: Herein, we report a child with TA to share the efficacy and safety of tocilizumab. Methods: Case report Results: A-14-year old girl who fulfilled the classification criteria for TA was identified. The interval from first symptom onset to diagnosis was 7 months. PVAS at presentation was 13; DEI.Tak was 10 and ITAS2010 was 10. She consisting of thickening of the aortic arch, descending aorta and superior mesenteric artery wall, obstruction of the right main carotid artery and superior mesenteric artery failed to respond to corticosteroids, methotrexate, and cyclophosphamide. After 1 year, she had severe manifestations (blurred vision and severe headache) and elevated both CRP and ESR the disease, and stenosis of the left vertebral artery in MRI angio which was considered as relapse. The patient started TCZ infusions (8 mg/kg for 2 weeks), and a rapid clinical remission was observed, associated with a drastic reduction of inflammatory markers. Corticosteroids were withdrawn, the patient's weight and height improved. 2 months later, TCZ infusions were extended, with no significant side effects. Ischemic manifestations resolved, and new lesions were not observed in MRI during 8 months on TCZ. At the last follow-up, PVAS was 0, ITAS2010 was 0 and DEI.Tak was 0. ESR was 5 mm/hr, and CRP was 3 mg/dL. Conclusion: TA in children is a rare but potentially life-threatening condition. The treatment of TA in children is weak, it is essential to treat TA aggressively as soon as the diagnosis is secured to reduce mortality and morbidity. TCZ appears to be effective in the management of patients with TA, in particular in patients refractory to corticosteroids and/ or conventional immunosuppressive drugs. Introduction: Ghosal Hematodiaphysal dysplasia (GHDD) is a rare disease associated with mutation in the TBXAS1 gene encoding thromboxane synthase. It is characterized by pronounced anemia, increased bone density, hypo cellular bone marrow, diaphyseal and metaphyseal widening and splenomegaly. Corticosteroids have been described as a suitable treatment. A 7-years old boy was admitted to the Paediatric Rheumatology unit due to pain in the extremities. He had earlier been evaluated for iron therapy resistant anemia with moderately increased ESR. Pain was recorded as moderate to severe, leading to significant disability together with tiredness. The diagnosis of GHDD was confirmed by the clinical presentation, typical X-ray abnormalities and mutation of TBXAS1. Per oral steroids was effective in reducing pain and disability and improved anemia to some extent. ESR was normalized as a result of treatment.
Objectives: The patient responded well to p.o. steroid therapy although it was deemed as an unsuitable long term solution due to its known adverse effects. TNF blockade by etanercept, was then evaluated as a steroid sparing drug. Etanercept proved to be unsufficient for this purpose since symptoms, primarily pain, markedly increased when tapering p.o. steroids. Thus, our aim was to rapidly identify an effective pharmacological therapy strategy with minor adverse effects that could replace p o steroids by investigating the patients' cytokine profile.
Methods: Blood sampling was performed during a treatment free period, before p.o. steroids treatment initiation. Blood was also collected in parallel from two healthy controls. Fresh whole blood was stimulated with LPS (1 ng/ml) for 4 h together with ATP (3 mM) for 1 hour. ATP was added since low dose LPS is not sufficient to induce IL-1b release alone. Supernatants were collected after centrifugation in 10 min 1000 g and stored in -80°C until analysis. IL-1b, IL-6, IL-8 and TNF levels were recorded with Cytometric Bead Array (CBA) according to manufactures instructions. Results: TNF was not detectable in the unstimulated patient sample nor in the unstimulated healthy control samples. LPS/ATP stimulation induced lower TNF production in the patient as compared to the healthy controls (1144 pg/ml vs 1867, 3531 pg/ml). A similar pattern was evident for IL-1b production, with no detectable levels in unstimulated samples and lower levels in the LPS/ATP stimulated patient sample (11 461 pg/ ml) as compared to the healthy controls (18 786, 25 508 pg/ml). The IL-6 level in the unstimulated patient sample was low (17 pg/ml), as in the control samples (7, 3 pg/ml). LPS/ATP stimulated samples had similar IL-6 levels in patients and controls, with slightly higher levels in patients (11 986 pg/ml) than in controls (8 893, 10 122 pg/ml). Interestingly IL-8 production was increased in the untreated patient sample (1153 pg/ml) as compared to controls (162, 324 pg/ml). Furthermore, LPS/ATP stimulation resulted in markedly increased IL-8 release in the patient sample (13 007 pg/ml) as compared to controls (4 473, 5 830 pg/ml). Conclusion: Cytokine profiling may prove important for characterizing cytokine patterns in single patients with rare inflammatory diseases. Our patient was hypo responsive to LPS/ATP stimulation as compared to two healthy controls with regard to TNF and IL-1b production. In contrast, our patient was hyper responsive with regard to IL-8 production upon stimulation and also exhibited elevated IL-8 production in the unstimulated sample. Thus we are now aiming to institute IL-8 targeted therapy, once available, and are in the meantime opting for IL-6 blockade rather than IL-1 blocking therapy.

Disclosure of Interest
None Declared.
Additionally, in each time period empty and ETN-loaded PCL and PEG-PCL-PEG microspheres injected groups (n = 64) (8 and 12 weeks after IA injection), and also systemic treatment groups (n = 24) (2, 8, 12 weeks after IA injection) was sacrificed. Knee joints were dissected, freed from muscles and removed. Histopathological examination was carried out by a single (blinded) observer, focusing mainly on polymorphonuclear cell infiltration, tissue proliferation, and cartilage deterioration. The severity of the inflammation was graded into four grades: 0 = no change; 1 = mild change; 2 = moderate change, and 3 = serious change.
Results: There was no arthritis in saline injected group. Experimental arthritis was occurred in all CFA injected groups. It was found various grade (Grade1-3) inflammation findings in histopathological evaluation. Both ETN release systems significantly decreased inflammation degrees in rats with chronic arthritis. However, it was found difference between PCL and PEG-PCL-PEG of etanercept release systems. PCL and PEG-PCL-PEG release systems were indicated effective as anti-inflammatory 8 weeks and 12 weeks, respectively. Conclusion: When we used etanercept with the release systems of microspheres, we found that the effectiveness of etanercept were lasting 8 weeks with PCL, and 12 weeks with PEG-PCL-PEG. Our study also showed that TNF-alpha inhibitor release systems had antiinflammatory effects in experimental arthritis rat model.

Disclosure of Interest
None Declared.

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Long-term folow-up on efectiveness and safety of biological treatment in patients with juvenile idiopathic arthritis: Hungarian data from the national institute of rheumatology and physiotherapy, Introduction: Methotrexate (MTX) is the only disease modifying drug used in the treatment of Rheumatic Arthritis in children, other than biologics. However its oral absorption is variable, and nausea and vomiting frequent (which is believed it is due to high bolus drug peaks in blood after drug administration), resulting in discontinuation. Regular subcutaneous injections are painful and very stressful for children causing considerable anxiety. Transdermal delivery is an attractive alternative delivery route and can help in avoiding the above mentioned drawbacks. However, skin form a fierce barrier for delivery of such hydrophilic drug. Objectives: To design and develop a hydrogel forming microneedles (MN) and evaluate their efficiency as a minimally invasive drug delivery system in delivering clinically relevant doses in sustained controlled manner in-vitro. Methods: Hydrogel-forming MN array was fabricated from a hydrogel composed of 20% w/w copolymers of (methyl vinyl ether and maleic acid) and 7.5%w/w poly ethylene glycol (PEG, MW 10,000 Da) by casting method using silicon mould with an array of 121 (11 x11) microneedles. The formed MN arrays were characterised for their mechanical strength, swelling properties, penetration depth after insertion into isolated cadaver full-thickness pig skin. Rapidly dissolving polymeric films containing various concentrations of MTX was prepared and tested. The ability of MN combined with MTX-containing films to deliver MTX was evaluated in-vitro using dermatomed pig skin.
Results: Hydrogel forming MN was formed measuring (729.5 ± 11.2 um) in height and 300 um width at the baseplate and MN interspacing 250-300 um. The fabricated MN were strong enough to pierce the stratum corneum and penetrate through the skin without breaking or bending by applying 20 N/MN array and removed intact without depositing any polymer in the skin. The penetration depth was around 72% of the MN length. These MN can swell without dissolving and the swelling percentage was around 300% of its original weigh after 1 hour from immersion in phosphate buffer saline (pH 7.4). The fabricated MN were able to deliver various substantial amounts of MTX in a sustained and controlled and manner. Conclusion: hydrogel forming MN formed from 20% w/w copolymers of (methyl vinyl ether and maleic acid) and 7.5%w/w poly ethylene glycol (PEG, MW 10,000 Da) can be used as a minimally invasive drug delivery system to deliver clinically relevant various doses of MTX in a sustained control manner and without depositing any polymer residue in the skin after application.
Introduction: In spite of unprecedented effects of biologic disease modifying antirheumatic drugs (DMARDs) over the last 15 years in treating childhood rheumatic and autoinflammatory disorders, a small minority still remain refractory to multiple, combined immunosuppressive and anti-inflammatory therapies, whilst accumulating serious side effects. Objectives: Present results from our centre of curative allogeneic haematopoietic stem cell transplantation (HSCT) in a group of children with such severe, refractory diseases. Introduction: ABIRISK is a project funded by Innovative Medicine Initiative (IMI), which has the aim to investigate anti-drug antibody formation in the treatment of JIA with biologics. A major limitation to the use of biologics is the development of anti-drug antibodies (ADA) in a subset of patients that may decrease the efficacy of biologics by neutralizing them or modifying their clearance.
Objectives: The aim of this project is to improve the capability to predict biologics immunogenicity and to minimize immunization risk against biological drugs in juvenile idiopathic arthritis (JIA) patients. We present herein the baseline and 6-month data of the JIA patients enrolled in the study. Methods: Patients with juvenile idiopathic arthritis (JIA by ILAR criteria) followed by 21 PRINTO centres in 11 countries were prospectively enrolled and treated with anti-TNFα or anti-IL6 drugs (Etanercept, Adalimumab or Tocilizumab). Patient's data were obtained from the Pharmachild registry, a pharmacovigilance data repository for children with JIA treated with methotrexate (MTX) ± biologics. For each patient detailed clinical information and biologic samples (serum and RNA) were collected before therapy start and at periodic visits during biologics regimen until 18 months of follow-up. Results: 116 patients were included in this analysis. Three patients were considered twice because treated with two different sequential biologics. 82/116 (71%) was females, the median onset age was 5.4 years (range 2.4-10.3) and the disease duration at enrolment was 2.6 years (range 1.1-6.2). Distribution of JIA subtypes was as follows: 8 systemic (7%), 30 (26%) oligoarthritis persistent, 49 (42%) polyarthritis or extended oligoarthritis, 6 (5%) polyarthritis RF+, 16 (14%) arthritis with enthesitis and 7 (6%) undifferentiated arthritis. Sixtyfour patients (55%) started treatment with Adalimumab, 33 (28%) with Etanercept, and 19 (16%) with Tocilizumab. Disease activity of the enrolled patients (assessed with JADAS27) decreased significantly at 3 and 6 months after therapy start (p < 0.0001). (Table 16) Conclusion: Preliminary data show an early statistically significant improvement of disease activity at 3 and 6-month after biologics treatment start. Analysis of collected samples and clinical related information will help to develop predictors of immunogenicity risk and to determine which patients will respond best to which biologic. Introduction: Juvenile idiopathic arthritis(JIA) is a chronic autoimmune disease in children and adolescents with primary joints involvement and various manifestations. Treatment with methotrexate or sulfasalazine of early oligoarticular JIA represents a serious challenge.
Objectives: To compare efficacy and safety methotrexate and sulfasalazine treatment in children with early oligoarticular JIA. Methods: It was the prospective observational study. 80 patients with oligoarticular JIA (the disease duration was less than 6 months) were included. They were not treated with DMARDs before. All patients were divided into two groups: the I-st group included patients who were treated with methotrexate 12.5-15 mg/m2/week (13.8 mg/ m2/week): 25 girls and 15 boys; mean age was 4.9 years (4-12); disease duration was 3.1 months (2-6)). The II-nd group included patients who were treated with sulfasalazine 30-40 mg/kg/day (36 mg/kg/day): 26 girls and 14 boys; mean age was 6.7 years (4-13); disease duration was 3.4 months (2-6). Efficacy end points included the American College of Rheumatology (ACR) Pediatric criteria for improvement 30 (ACR30), ACR50, ACR70, ACR90 at 12 and 24 weeks of treatment.
Results: The ACR Pedi 30 improvement were achieved by 92.5% (n = 37) of patients in the I-st group at week 12 (n = 40). At week 12 3 (7.5%) patients were switched to sulfasalazine therapy (2 patients because of insufficient response, 1 -because of bad tolerance). The ACR Pedi 30, 50 and 70 improvement were achieved by 85% (n = 34), 85% (n = 34) and 10% (n = 4) of patients in the I-st methotrexate group at week 24 (n = 37), respectively. At weeks 24 2(5%) patients were also switched to sulfasalazine therapy, 1(2.5%) patient was prescribed anti-tumor necrosis factor alpha therapy. The ACR Pedi 30 improvement were achieved by 87.5% (n = 35) of patients in the II-nd group at week 12 (n = 40). At week 12 5 (12.5%) patients in the II-nd group were switched to methotrexate therapy because of absent ACRpedi-30 response. At weeks 24 3(7.5%) patients were also switched to methotrexate therapy because of absent ACRpedi-30 response and deterioration. The ACR Pedi 50 improvement  was achieved by 80% (n = 32) of patients in the II-nd sulfasalazine group at week 24 (n = 35). There were no serious adverse events(SAE) in both groups. Conclusion: According to the results of our research, treatment with methotrexate and sulfasalazine in children with early oligoarticular JIA has reliably sufficient efficiency, but treatment with methotrexate was more effective in comparison with treatment with sulfasalazine therapy. There were no SAE in both groups.

Disclosure of Interest
None Declared.

P227
Blood monitoring in patients with JIAa retrospective survey Navdha R. Introduction: Etanercept is licenced in the UK for use as monotherapy in JIA 1 . The manufacturer advises regular monitoring to detect clinically significant neutropaenia 2 . In our institution, this has meant checking the neutrophil count, alanine aminotransferase (ALT) and creatinine every 3 months.
Objectives: To determine the efficacy of regular blood test monitoring in Etanercept monotherapy in detecting clinically significant neutropaenia or liver function anomalies Methods: We conducted a retrospective survey of our database of JIA patients at the Great North Children's Hospital, a tertiary paediatric rheumatology centre in Newcastle, UK. All current patients were reviewed and those currently or previously taking Etanercept were identified. Data was collected on demographics, diagnosis, date Etanercept started/stopped & number of blood tests. Abnormalities in ALT or white cell count were recorded, including any resulting action. In addition we looked at the reasons for stopping Etanercept.
Results: 137 patients received Etanercept during the study period, with 155 distinct episodes of Etanercept therapy. 75% were female & median age was 9.7 years at the start of therapy. 56% had polyarticular JIA, 12% extended oligoarticular, 13% oligo-articular, 9% psoriatic, 7% ERA, & 4% systemic onset. There was no significant difference in demographics between those on monotherapy and those also on MTX. 72 patients were or had been taking Etanercept as monotherapy, with 77 distinct episodes of monotherapy. 5 episodes were excluded from further analysis as therapy had been started within 3 months with no test yet, leaving 72 episodes in 68 patients. Of these 72 episodes, median duration of Etanercept monotherapy was 18 months (range 3-85). Twenty-four had no detected neutropenia or abnormal ALT. A total of 31 (43%) abnormal results were detected with a median time from onset of treatment of 5 months (range 0-52). 19 patients had similar abnormalities on MTX therapy before starting Etanercept monotherapy and 12 had new onset abnormalities on Etanercept monotherapy. Eight developed neutropaenia, 5 were noted to have a raised ALT and 1 patient had both. All these episodes were asymptomatic and resolved without any intervention. No patient had their Etanercept stopped due to abnormal blood results. 34 of the 72 patients on monotherapy had Etanercept discontinued during the study period. 9 had been in remission for >2 yrs, 9 developed Chronic Anterior Uveitis and were switched to an alternative Biologic, 7 were switched to an alternative Biologic for inefficacy, 5 had MTX added in, 4 stopped for other reasons including parental choice. Conclusion: In our study Etanercept monotherapy is rarely associated with neutropaenia or deranged liver function and no patient had the treatment interrupted or discontinued as a result. It may be reasonable to consider the frequency of such monitoring given the distress and discomfort of regular venepuncture. cases, more often in biologics-naive patients -86 (83%) vs 18 (17%), previously treated with other biologics. Frequency of ID achievement was higher in Poly-RFpos, Oligo and JIA associated with uveitis: in 60%, 100%, 79% respectively. ID frequency depended on the initial active joints count: if it was <5 ID was achieved in 93%; 5-15in 64%, >15 -48%. The achievement of ID status during first year of treatment was observed more often in pts with disease duration less than 5 yrs. Results were comparable at the second year of treatment (52% vs 37% in the first year; 12% vs 37% in the second year). 61(59%) patients continue ABA therapy, in 43 cases ABA was cancelled (in 4 cases due to infusion/allergy reactions, in 27 cases due to the inefficacy, in 11 cases due to some non-medical reasons). 32% patient (33 cases) failed to comply with the infusion schedule due to organization problems in their regional clinic. The correct dose regimen and interval between infusions during the whole course of treatment influenced higher respond, thus ACRpedi70-90% improvement and ID after 12 months were achieved predominantly in patients who had no deviations in infusion regimen. The average survival rate of ABA was higher in biologics-naive (62% vs 56%) and in Poly-RFneg (66%) in comparison to Poly-RFpos (60%), Olygo (43%) and soJIA (33%). As it has appeared, efficiency of ABA significantly increased after 12 months of therapy. Uveitis remission was identified in 57% of cases after 6 months, in 75% of casesafter 12 months, in 62% of casesafter 18 months, in 60% of casesafter 24 four months. 7 pts had adverse events (3 pts had infusion reactions, 2 pts (the both with early ANA-positive oligoarthicular onset) developed uveitis de-novo, 1 patient had verruca vulgaris) but no serious events were observed.
Conclusion: Long-term therapy with ABA is supposed to be highly efficient for JIA, including patients with uveitis despite of frequent expert opinion, that it is less efficient than other Biologics. It was observed, that positive effect under ABA has continued to increase even after 24 month period of therapy. The efficiency of ABA depends on the correct infusion regimen and it is higher in biologicsnaïve patients. Drug survival rate of ABA seemed to be better in biologics-naive pts, especially in Poly-RFneg subtype and the worst in soJIA. ABA showed a good safety profile in real clinical practice.

Disclosure of Interest
None Declared Objectives: Herein, we report a child with HIDS and renal transplant to share the efficacy and safety of canakinumab. Methods: case report Results: A ten year-old boy who followed HIDS since the age of 3, received kidney transplant from a living donor (mother) 2,5 years ago. He was on etanercept before transplant. It was discontinued after transplant due to ineffectiveness. Firstly, Anakinra was started 6 months after renal tx for HIDS attacks. After a short-term remission with anakinra HIDS attacks restarted. He experienced with acute disseminated encephalomyelitis that required plasmapheresis, IVIG and pulse methyl prednisolone. Since, he had severe diarrhea and weight loss due to gastrointestinal amyloidosis, anakinra was switched to canakinumab. Canakinumab markedly reduced the frequency of diarrhea, increased appetite and rapidly normalized the acute phase reactants include CRP and SAA. After 6 months, he has on treatment canakinumab on 6 months. There was not reveal any adverse effects and graft dysfunction on canakinumab.
Conclusion: Canakinumab is a safe biologic agent to maintain disease control in children with HIDS even in renal transplantation course. We think that canakinumab can be successfully and safety used in renal transplant patients.

Disclosure of Interest
None Declared.

P230
Biological therapy in chronic non-bacterial osteitis: experience of two tertiary centers Introduction: Chronic non-bacterial osteitis (CNO) is a rare disease of unkwown etiology, recently considered an autoinflammatory disease. There is considerable heterogenity among centers regarding its management.
Objectives: To describe the clinical and therapeutical characteristics of 12 patients with CNO refractory to conventional therapy (NSAIDs and bisphosphonates) followed at 2 tertiary centres who received biological therapy. Methods: Clinical chart review. Results: 11 patients were included (9 females). Their mean age at onset was 8.7 years and their mean diagnosis delay was 12 months. All of them showed bone pain and 4 presented fever. Involved bone locations are described in the attached table, being femur (involved in 7/ 11), clavicle (4/11), vertebrae (5/11), tibia (4/11) and pelvis (4/11) the most frequently affected bones. C-Reactive Protein (CRP) was elevated in 10 patients (mean 18.8 mg/L) and ESR in 8 (mean 50 mm/h). IgD was determined in 4 cases, being increased in 2. Propionibacterium acnes was isolated in bone biopsy from 1 patient. Six children showed skin lesions, including psoriasis in 4. All patients received NSAIDs, 8 Pamidronate and all eventually received biological therapy with anti-TNF agents. At the last follow-up visit, 8 patients were still on biologicals (6, infliximab, 2 adalimumab) and 10 out of 11 remained asymptomatic. Conclusion: CNO diagnosis is often delayed due to lack of suspicion of the disease. This series suggests that biological therapy may represent an effective alternative in refractory cases. Further research into the disease is needed to ascertain the precise role of biological therapy in its management. Introduction: Treatment of polyarticular juvenile idiopathic arthritis (JIA) requires disease modifying antirheumatic drug (DMARD) therapy as a rule, in most cases initially with methotrexate (MTX). The additional benefit of systemically or locally administered glucocorticoids (GC), however, is controversially discussed.

Disclosure of Interest
Objectives: To investigate the impact of intra-articular or systemically administered GC, in addition to DMARD therapy with MTX, in the firstline treatment of rheumatoid factor negative polyarticular JIA (RF-PA).
Methods: Patients with JIA were enrolled in the German inception cohort ICON at 11 large German pediatric rheumatology units. Laboratory and clinical parameters such as JIA core set criteria, data on the medication used, as well as the Pediatric Quality of Life Inventory (PedsQL) were collected at defined time points. The following three treatment strategies of the first three months of observation were compared: group 1) MTX plus high-dose systemic GC (>0,2 mg/kg body weight) without intra-articular GC in >4 joints, group 2) MTX plus intra-articular GC in >4 joints without high-dose systemic GC, and group 3) MTX without high-dose systemic GC or intra-articular GC in >4 joints. A propensity score was estimated by logistic regression analysis to model potential differences in clinical characteristics at treatment start between the three groups. Weights were calculated as ratios of the estimated probabilities and balanced samples of patients were obtained by using an inverse probability weight in the statistical analyses. Outcome variables were considered at the one-year and two-year follow-up. Results: Of the 954 patients with JIA enrolled in the inception cohort, 181 patients were diagnosed with RF-PA and were almost DMARD naive at study inclusion. Patients had a mean age of 6.7 years and a mean disease duration of 1.5 months at enrolment. The mean clinical Juvenile Arthritis Disease Activity Score (cJADAS-10) was 14.8, the mean C-HAQ 0.96 and the mean PedsQL 61.9 at study inclusion. Almost 90% of the patients were treated according to one of the defined strategies: group 1 n = 41, group 2 n = 57, group 3 n = 61. At one-year and two-years of follow-up there were no significant differences between the three groups with regard to the physicians global assessment of disease activity, the cJADAS-10, and the proportion of patients with inactive disease. Altogether, 49% and 54% of patients had attained inactive disease at the 1-year and 2-year followup, respectively. At one-year of follow-up, patients of group 3 were treated to a higher proportion with biological DMARDs (49.7%) than patients of group 2 (20.4%). At two-years of follow-up, however, the difference was not statistically significant any more. Patients additionally treated with high-dose or multi-local intraarticular GC reported a similar functional status as patients of group 3, patients of group 2 however had a slightly higher health-related quality of life than patients of the other two groups. Regarding growth and body mass index, there was no difference between the patients treated with high-dose systemic GC and the other two groups at one-year and two-years of follow-up. Introduction: Vaccination has contributed greatly to child health and has been considered generally safe. However, existing guidelines recommend withholding patients using biologicals from receiving live-attenuated vaccines, as there is no safety data available.
Objectives: To investigate the safety and efficacy of live-attenuated vaccines in patients using interleukin (IL)-1 or IL-6 blocking agents. Methods: A large number of international (paediatric) rheumatologists were asked to send in cases of patients who received a liveattenuated vaccine while using IL-1 blockade (anakinra, canakinumab or rilonacept) or IL-6 blockade (tocilizumab).
Results: Nine patients have been included in this study so far (6 female, 3 male). The median age at vaccination was 9 years. Six patients suffered from systemic juvenile idiopathic arthritis (sJIA). The tree other patients suffered from Mevalonate Kinase Deficiency (MKD), Familial Mediterranean Fever (FMF) and Chronic Infantile Neurologic Cutaneous and Articular (CINCA) syndrome. Patients were vaccinated with Measles, Mumps and Rubella (MMR) booster, varicella zoster booster or first vaccine, or oral polio vaccine. All characteristics are summarized in Table 17. In all but one patient (pt1, 3-9) the underlying disease was well controlled at the time of vaccination. In one patient (pt2) disease was only partially controlled. Adverse events were noted in three patients, of which one (pt8) was a serious adverse event leading to hospitalization. Two patients suffered from infection after vaccination, of which one was caused by the micro-organism of the vaccine (pt8). Four patients experienced a flare of their disease. In three patients (pt1,2,6) the vaccination did not lead to a flare or adverse events. Anakinra was stopped two or three days before vaccination and restarted days to weeks later in these three patients.
Conclusion: In this small case series, 3/9 patients experienced an adverse event potentally caused by the vaccine strain. Four patients experienced a flare of their disease. There were no adverse events in patients whose anakinra treatment was interrupted around the vaccination, but there's not yet sufficient data to promote such an approach. Before considering any prospective trial, more retrospective data are needed. We therefore invite centers to contribute cases to our study.

Disclosure of Interest
None Declared. The patients' ages ranged from 1-28 years. Caregivers reported an insidious onset of symptoms, but were initially reassured by their healthcare providers (HCPs) that symptoms were related to normal childhood illnesses. Most parents in this study (86%) realised that something was seriously wrong only after medical crises and hospitalisations. The diagnostic path began in earnest then, including many specialist visits (often with long waits for appointments), extensive testing, and many misdiagnoses including Lyme disease, meningitis, H1N1 influenza, systemic lupus erythematosus, systemic juvenile idiopathic arthritis, atypical Kawasaki's disease, leukaemia, lymphoma, bone cancer, and Crohn's disease. Most parents (92%) lost faith in the medical system's ability to find an answer to their children's symptoms, while they also struggled with unsupportive school officials and dismissive friends and relatives. Parents and patients frequently felt a loss of self-confidence and increasing alienation in the face of criticism and disbelief. Patients and caregivers report holding onto a memory of what normal life was like prior to the onset of symptoms, and mourning their subsequent loss of normalcy. Receiving the diagnosis of an autoinflammatory disease provided vindication and relief, as well as a focus for further education and treatment. Even after diagnosis, patients and caregivers reported continuing confusion about what to expect in the future. Many (64%) reported disease symptoms between flares that were rarely recognised as such by their HCPs. Uncertainties about their diseases led patients and caregivers to seek online support communities, but struggled finding patients whose symptoms mirrored their own. Conclusion: Patients with autoinflammatory diseases often encounter long diagnostic delays, causing significant stress and confusion for the patient and their families. Distrust of the medical establishment may persist even after diagnosis. Loss of normalcy is a core tragedy for many families. Confusion and uncertainty continue to mark these families' lives, even after diagnosis. Initiatives that improve the speed and accuracy of diagnosis, provide more comprehensive patient education, and support patients and their families through their illness have the potential to greatly improve the lives of patients with autoinflammatory diseases. Introduction: Cryopyrin-Associated Periodic Syndrome (CAPS), is a rare hereditary auto inflammatory disorder representing 3 phenotypes: familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurologic cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease (CINCA/NOMID) 1 . Canakinumab (CAN), a fully human anti-IL-1β monoclonal antibody has been shown to be effective over 56 weeks in patients with CAPS aged <24 months (core study) 2 . Here we report the results of an extension study (up to 152 weeks) to this core study (NCT01302860). Objectives: To assess the long-term efficacy (in terms of relapse) and safety of CAN in CAPS pts who completed the core study.
Methods: CAPS pts who completed the core study received 2 mg/kg subcutaneous CAN every 8 weeks, in continuation with the core study. Pts who received a dose adjustment in the core study were continued on the same dose in the extension phase. Efficacy was evaluated by investigator clinical assessment of autoinflammatory disease activity, C-reactive protein (CRP) and serum amyloid A (SAA) levels. Safety was assessed in terms of adverse events (AEs).
Results: Of 17 pts (aged ≤6 years), enrolled in the extension study, 12 (70.6%), 4 (23.5%) and 1 (5.9%) had MWS, NOMID and FCAS phenotypes, respectively. All 17 pts were complete responders; 16 (94.1%) had no flare, and 1 (5.9%) NOMID patient had a flare at the end of extension study. Physician global assessment improved over the extension study, with decline in severity from baseline of the core study to the end of extension study (EOS). The number of pts with absent autoinflammatory disease activity improved from 4 (23.5%) to 11 (64.7%); minimal activity increased from 5.9% (1 pt) to 29.4% (5 pts); mild or moderate activity decreased from 47.1% (8 pts) to 5.9% (1 pt); moderate activity decreased from 23.5% (4 pts) to 0 patients. This improvement was also observed in the assessment of skin rash; proportion of patients with no skin disease increased from 29.4% (5 pts) at baseline of core study to 94.1% (16 pts) at EOS. The mean decrease in CRP and SAA levels from core study baseline was −10.4 and −54.36 mg/L, respectively at EOS. Overall, 10 (58.8%) pts had AEs suspected to be related to CAN; the most common were diarrhoea, pneumonia, rhinitis and cough (3 pts each). Eight (47.1%) pts experienced at least 1 serious AE (4 MWS and 4 NOMID pts), with pneumonia being the most common (2 [11.8%]). No deaths occurred during the study. Conclusion: Canakinumab effectively maintained clinical and serological efficacy in CAPS pts in the extension study. No new safety findings were observed, and the safety profile of canakinumab was consistent with previous studies, which corroborates the long-term use of canakinumab in the treatment of CAPS patients. Introduction: Autosomal dominant gain of function mutations in caspase recruitment domain family member 14 (CARD14) were found to cause plaque psoriasis in two families and severe generalized pustular psoriasis as a monogenic form of childhood (CARD14-mediated psoriasis, CAMPS). CARD14 mutations have also been implicated in pityriasis rubra pilaris. The therapeutic approach in CAMPS includes drugs used for the treatment of moderate-to-severe psoriasis, such as, methotrexate, cyclosporine and biological agents, such as anti-TNF antibodies. Ustekinumab is a monoclonal antibody that notably targets the p40 subunit of both IL-12 and IL-23, which are understood to play a role in activation of NFkB pathway. Objectives: i) to describe the case of a family presenting with an unusual form of severe erytrodermic psoriasis without pustulosis in which whole exome sequencing (WES) analysis revealed a novel CARD-14 mutation ii) to report the clinical and immunological response to ustekinumab. Methods: The probands are two 7 year-old twins suffering from nonspecific dermatitis since the age of 9 months with the appearence of localized erythroderma with a gradual diffusion over all the skin surface by the second year of life. These cutaneous lesions are severely itchy and associated with onychodystrophies and fissures in both children, and ectropion in the twin sister. There are three pairs of twins in the family, five of them presenting psoriasis and two of them presenting psoriatic arthritis. Introduction: Provisional evidence-based classification criteria for inherited periodic fever (TRAPS, FMF, MKD and CAPS) have been recently developed based on the Eurofever registry. However, no consensus on how to combine clinical criteria, laboratory test and results of molecular analysis has been reached so far. Objectives: To understand which variables physicians involved in the clinical care of patients with Autoinflammatory diseases (AIDs) consider as the most important for the classification of patients with inherited periodic fever. Methods: Two following Delphi surveys were sent to health professionals (Clinicians and Genetists) working in the field of autoinflammation.
In the first open survey 124 experts involved in the Eurofever registry could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables may be of any type (i.e. clinical features, laboratory or instrumental tests, genetic tests) and each expert could complete the survey for one or more disease on the basis of his expertise. In the second survey 162 experts (including American experts) were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1 in order of importance. There was no possibility to assign the same rank to multiple variables. This process has been conducted in parallel with an analogous process for PFAPA syndrome Results: The overall rate of response to the first and second Delphi surveys, including PFAPA syndrome, was respectively of 86% (107/124 experts) and 87% (141/162 experts). The variables corresponding to the 3rd quartile considering the total score obtained by the variables after the second Delphi survey were respectively: 20 for MKD (with a total score ranging from 637 to 72), 21 for CAPS (with a total score ranging from 554 to 66), 17 for FMF (with a total score ranging from 626 to 80), and 20 for TRAPS (with a total score ranging from 637 to 82). Conclusion: Our process led to the identification of those features that are considered to be the most important as candidate variable to be included in a new set of evidence based classification criteria for monogenic periodic fever. The next step of this project (now ongoing) is the evaluation by a panel of experts of 360 real patients affected by AIDs (PFAPA, monogenic periodic fever and undefined periodic fever) randomly selected from EUROFEVER Registry. Those patients reaching the 80% of consensus among experts in the evaluation process will be used for the subsequent statistical analysis aimed at identify the best evidence-based classification criteria (in term of sensitivity and specificity) for PFAPA and Monogenic periodic fevers.

Disclosure of Interest
None Declared.

P240
Recommendations for genetic testing of NLRP3 mutation-negative CAPS patients through comparison of sequencing methods Introduction: A high percentage of CAPS patients are negative for mutations in NLRP3 exons 3, 4, and 6. Somatic mosaicism has been shown to account for up to 70% of these patients who are 'mutationnegative' by conventional sequencing methods. In addition, there is significant clinical overlap between known autoinflammatory syndromes, and true genetic heterogeneity is also a possibility.
Objectives: The aim of this study was therefore to establish a stepwise approach for further genetic screening of mutation-negative CAPS patients, through comparison of different sequencing methods. Methods: Four different sequencing methods were used for comparison: 1. Sanger sequencing of NLRP3 exons 3, 4, and 6; 2. Massively parallel sequencing (MPS) of NLRP3 exons 3, 4, and 6 (the current gold standard for detection of somatic mosaicism); 3. Our group's targeted gene panel for vasculitis and inflammation (Vasculitis and Inflammation Panel, VIP), which sequences a total of 166 genes including most of the known genes linked to monogenic autoinflammatory diseases (AID); and 4. Whole Exome Sequencing (WES).
Results: Four patients with a clinical diagnosis of CAPS who were NLRP3 "mutation negative" on initial screening were chosen for comparison; the clinical phenotypes were compatible with Muckle Wells syndrome (n = 2); and CINCA (n = 2). Four different possible scenarios were thus available for comparison as Patient 1 had a low level somatic NLRP3 mutation, Patient 2 had a moderate-high level somatic NLRP3 mutation, Patient 3 had a mutation in another exon of the NLRP3 gene, and Patient 4 had a mutation in another known autoinflammatory gene (NOD2), therefore changing the diagnosis to Blau Syndrome. The results are presented in the We collected blood samples from a cohort of more than 40 pediatric rheumatologic patients and scored them according to a qPCR based IFN gene signature assay. An IFN score was calculated for each patient using the median fold change of gene expression related to a healthy control. Patients were selected based on the presence of the following features: i) atypical or incomplete SLE-like symptoms occurring in infancy or in preprepubertal age; ii) vasculopathy (skin ulcers, chilblains, strokes) iii) panniculitis with or without lypodystrophy iv) interstitial lung disease in the context of systemic inflammation. Molecular analysis (targeted or unbiased) was performed in patients with a positive score. A compassionate treatment of the patients with SAVI using Ruxolitinib, a JAK1/2 inhibitor was started. Results: We identified 2 patients with heterozygous mutations in TMEM173 and 1 patient with a homozygous mutation in DNASE1L3. Molecular screening in other patients with a positive signature is currently ongoing. In one patient with SAVI we observed a good response to Ruxolitinib that allowed steroid tapering and clinical control of both skin vasculopathy and lung interstitial disease. Follow up of the second patient with SAVI is on-going. Conclusion: Combination of peripheral blood interferon signature and molecular analysis is an effective strategy for the identification of type I interferonopathies. Furthermore, we believe that targeting interferon receptor signaling represents a promising therapeutic option for these patients.

Disclosure of Interest
None Declared. 5 years and mean time to diagnosis was 2.9 years in the group of patients with age at disease onset ≤2 years. In the group of patients with age at disease onset between 2 and 5 years, which consists of 259 patients, mean patients' age was 3.8 ± 0.9 years, mean age at diagnosis was 6.5 ± 2.9 years and mean time to diagnosis was 2.7 years. There were 192 patients in the patients' group with age at diagnosis between 5 and 10 years. In this patients group, mean age was 7.7 ± 1.5 years, age at diagnosis was 9.7 ± 2.3 years and time to diagnosis was 2 years. Group of patients with age at diagnosis between 10 and 18 years included 53 patients with mean age at disease onset 12.7 ± 1.7, mean age at diagnosis 14. Methods: The medical records of the patients with SAPHO syndrome, children or adults, seen over the last five years (between 2011 and 2016) were studied. In all, the age of onset, the familial history and the types of joint or bone involvement were recorded. After identification, the patients were called again to assess the evolution. Results: We identified 5 cases of juvenile-onset SAPHO, all males, aged 11 to 15 yrs, with acne, enthesitis and arthritis. In all cases clavicular osteitis with pain and deformity was a constant finding. All patients had a familial history of acne (and in one case of SAPHO syndrome) and were HLA B27 -negative. The acne severity in children generally increased with the age as entering adolescence, but conglobated acne was seen as early as the age of 12. In a child with a 2years history of seronegative symmetric arthritis, the onset of severe acne at 14, hydrosadenitis, sternoclavicular arthritis, clavicular osteitis and lower limbs bone pain and periostitis pointed to the diagnosis. Other associated features in this cases series were large vessel vasculitis, erythema nodosum, recurrent streptococcal infections and guttate psoriasis. The therapy consisted generally in NSAIDS, methotrexate and/or sulphasalazine. Glucocorticoids were generally avoided due to acne exacerbation. Clarithromycin courses were employed in all patients. Two former patients, young adults, had only minor flares and scarring acne after the age of twenty. Conclusion: SAPHO may be encountered in children as well, with a clinical picture similar to that in adults; however, vasculitis and erythema nodosum could be more frequently associated. The frequence and intensity of disease flares may regress after adolescence.

Disclosure of Interest
None Declared.

P244
One Introduction: Autoinflammatory diseases are recently recognized disorders that gained great clinical importance in recent years. In immune basis have theoretical absence of T-self-reactive cells and absence or low tittles of self-antibodies. Pathologic inflammation are, or should be in your majority secondary to innate immunity cells as the mutations found. Clinically they are characterized by sterile inflammation attacks. By the time they were well defined only in the pediatric age group.
Objectives: This work proposes to review clinical features, main diagnostics and main drugs used to clinical control since the clinic creation in 2015.
Methods: All the patient's data were collected spontaneously and aleatory since they were followed by us from 2015 on. Data were collected after consent term was assigned.
Results: A total of 28 patients were found followed at our unit of autoinflammatory disase. As a preferential adult service, almost 70% were older than 16 years at the moment they come to our service. Of all, 75% are female and among adults, woman is also majority representing 78% of them.The most common syndrome was FMF, with more than 21% carrying this diagnosis. Just one patient had a long disease history that had stablished lung and renal amyloidosis and now she is on canakinumab with good response.CAPS, NOD2 and Bechet had 10% each one. All the CAPS patients under 16 years are stable with canakinumab. The adult patient with CAPS presented with an atypical clinical manifestation also was submitted to canakinumab injection without new crisis. NOD2 mutations were found in 3 patients, all female and all had a persistent diarrhea, persistent positive calprotectin. Of all, 2 had skin rash, similar to psoriasis and one had arthralgia in crisis with unspecific skin rash. All receiving anti TNF agents. Bechet disease was found in one female under 16 years stable on colchicine. Older than 16 years we have followed 2 patients and one on tocilizumab and other high doses corticosteroids. CRMO was found in two patients and just the children required biologics as a permanent treatment due to the frequency and gravity of crisis.Just one family was diagnosed with TRAPS (TNF receptor associated periodic syndrome), one female adult patient and his son. The children get response to colchicine therapy and the adult required anti-TNF therapy.
Conclusion: The diagnosis of these rare disease is clinical and are a challenge to the general pediatrician and internal medicine. After the spread of genetic tests there have been a false definition that to make sure it's an autoinflammatory disease we need genetic confirmation. That's our fight in teaching to clinical immunology and allergy residents.
In adulthood the presentation is atypical and so many other inflammatory, infectious and neoplastic disease begin at the same age and can be an aid to diagnosis or a false diagnosis. Other consideration is that some patients haven't been recognized for years and are nowadays with a different phenotype what makes the diagnosis more difficult. According to our findings we suggest that adult's patients that present with or without recurrent fever with one of the findings need further investigations to any autoinflammatory disease: recurrent sterile pleural, pericardial and peritoneal effusion; chronic diarrhea with positive calprotectin; cronic inflammatory central nervous system; chronic recurrent osteomyelitis and chronic neutrophilic dermatosis.

Disclosure of Interest
None Declared.

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Cronic non-bacterial osteomyelitis (CNO) and polyarteritis nodosa: a report of 2 cases with an unusual association Introduction: Drug-induced lupus erythematosus is an autoimmune disorder caused by a drug overreaction. To our knowledge only one case of possible correlation between the use of ethosuximide and SLE has been described so far Objectives: To describe a case of drug induced lupus and the use of interferon signature as a marker of disease activity in clinical practice Methods: we describe a case of drug induce lupus followed clinically, with routine immunological work-up and with serial determinations of interferon signature, by means of quantitative reverse transcription PCR, measuring 6 different interferon I stimulated genes (IFI27, IFI44L, IFIT1, ISG15,RSAD2,SIGLEC1), as previously described 1 Results: M.L. is a 16-year-old girl who was suffering since birth from a very mild cognitive delay, focal epilepsy and ESES (continuous spike wave epilepsy during sleep) since 9 y/o. Extensive neurological work-up failed to revealed any underlying disease. The girl was put on Ethosuximide with good seizures control. Two years later she started to complain from generalized arthralgia and myalgia, transient hands and feet swelling, and recurrent, evanescent rash on cheeks. The girl was then referred to our rheumatology unit. Physical exam was normal but lab-works showed ANA 1:640 homogeneous, positive anti ds-DNA antibodies, reduced complement levels and mild proteinuria. We also run an in-house interferon signature assay, revealing a very high expression of IFN-stimulated genes, similarly to children with clear-cut SLE. For this reason a drug-induced lupus was hypothesized and the collegial decision was to stop ethosuximide. In the following 6 months the girl remained free of seizures, the myalgia and rash disappeared, all the laboratory abnormalities normalized. We also found a decrease in the interferon signature, testifying a lower expression level of the 6 interferon-stimulated genes There is evidence that IL-1B secretion in PAPA is increased and correlates with disease activity.
Objectives: To present the case of a child with PAPA syndrome and latent tuberculosis successfully treated with canakinumab.
Methods: An 8-year-old male arrived to our Pediatric Rheumatology Unit diagnosed with juvenile idiopathic arhritis (JIA). The patient presented recurrent arthritis of his knees from the age of 3 years. The first episode was treated as septic arthritis because of elevated acute phase reactants and purulent synovial fluid. Cultures were negative. Subsequently he was treated with intraarticular steroid injections, systemic steroids and methotrexate, persisting activity of the disease. At the age of 4 years the patient developed ulcerated cutaneous lesions in right underarm region and groin that lasted for several months. He also had history of frequent intense local vaccine reactions. His mother was diagnosed with a systemic JIA and his grandmother with a rheumatoid arthritis. Father with psoriasis. When the patient was assessed in our unit, he presented arthritis of his left knee. The synovial fluid was purulent with 131090 leucocytes (94% neutrophils). The blood tests showed elevated acute phase reactants. The Mantoux test was positive with 17 mm of induration. The possibility of a pathergy phenomenon was thought, but IGRA tests were also positive. Chest X-ray and high resolution thoracic tomography did not show pathological findings. Synovial fluid cultures were negative, including mycobacteria, and PCR of Mycobacterium tuberculosis was not detected. In the gastric fluid there was no presence of acid-fast bacilli and cultures were negative. He was treated with isoniazid because of latent tuberculosis infection.
Results: The study of mutations in the PSTPIP1 gene revealed the mutation E250Q in heterozygosity, that was also present in the mother and in the grandmother. An intraarticular steroid injection was performed in the knee and treatment with canakinumab 2 mg/Kg/4 weeks was started after 4 weeks of treatment with isoniazid, with good response. The patient has received treatment with canakinumab now for 34 months with good control of the articular disease. One year after treatment onset he had eczematous recurrent lesions in antecubital flexure at site of puncture for blood test, that were thought to be a clorhexidine contact dermatitis. No other cutaneous lesions apart from dry scaly lesions in the scalp and eczematous psoriasiform lesions in the pinna have appeared during the follow-up. Normal blood tests with no elevation of inflammatory parameters. Good physical growth. The treatment has been well tolerated without significant infections. The patient is currently on canakinumab 2 mg/Kg/8 weeks.
Conclusion: We present a family with PAPA syndrome with one member treated with canakinumab and good control of the disease during 34-month follow-up on treatment. Long-term efficacy and control of cutaneous disease, that is described to appear later on the course of the disease, will be established during follow-up. A particular feature in this case is the difficulty related to the latent tuberculosis infection because of the possible initial interpretation of Mantoux test as pathergy phenomenon and the treatment with isoniazide before starting biological treatment.

Disclosure of Interest
None Declared.

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Successful use to tocilizumab to treat pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome Nadia K. We report the first case of PHID syndrome treated with tocilizumab, with successful outcome in relation to systemic inflammation, cutaneous skin lesions, and overall quality of life. Linear growth and diabetes did not improve; however, no adverse events occurred. Whilst the mechanism of autoinflammation of PHID remains uncertain, we suggest that tocilizumab should be the first choice when considering treatment of the autoinflammatory component of this genetic disease. At the time of writing, her similarly affected sister is now also commencing tocilizumab.
Written informed consent was taken for the publication of this report. Introduction: We describe a cohort of 6 patients in Singapore with Chronic Non-bacterial Osteitis (CNO) and retrospectively calculated their Jansson Score. Objectives: We aim to document the characteristics of CNO in an Asian Paediatric population and describe the utility of the Jansson Clinical Score for these patients. Methods: We looked retrospectively into the case records of six patients who have been undergoing treatment for CNO in the Paediatric Rheumatology Unit of the University Hospital. Inclusion criteria were the diagnosis of CNO, evidence of at least one lesion of osteitis confirmed by imaging and onset of symptoms before age 18 years. Results: Six patients (4 males) with CNO were identified, and their diagnosis confirmed by the exclusion of other conditions and response to therapy for CNO. Age range at diagnosis was 5 to 16 years. Duration of follow-up was 8 months to 8 years. The condition was unifocal in 3 (50%) of the patients. The clavicle was the most frequently affected bone (50%), followed by long bones (femur, tibia), pelvis and small bones of the foot. Fifty percent of the patients had concomitant arthritis. Five had fever at presentation. Three had extra-osseous manifestations in the form of recurrent aphthous ulcers. All patients underwent radio-isotope bone scans and 5 received targeted MRIs. Only one patient underwent a bone biopsy. All received initial therapy with NSAIDs, with 2 patients receiving therapy with NSAIDs alone. The other 4 patients received methotrexate (4), anti-TNF alpha agents (2) and pamidonate (1). Five patients had treatment with prednisolone during the course of their disease. At the last medical encounter, disease was in remission in 2 patients (1 without medicine, 1 while on infliximab). Jansson defines scores of 0-28 as "probably not CNO", 29 to 38 as "uncertain diagnosis" and 39 to 63 as "probably CNO". Our patients had Jansson Clinical Scores of 26 to 54. Based on this score, only one patient would have received the diagnosis of "probably CNO", 4 with "uncertain diagnosis" and 1 with the score of "probably not CNO". The patient who received the diagnosis of "probably not CNO" had a score of 26, mulftifocal disease, received treatment with NSAIDs, prednisolone, methotrexate, pamidronate and entered remission finally with Etanercept alone. Conclusion: The Jansson Clinical Score for CNO predicted the diagnosis only in 1 of 6 of our patients. Majority of the patients received scores within the category of "uncertain diagnosis" while the patient whose clinical course was most consistent with difficult to treat multifocal disease requiring biologics had the lowest score. We propose that in our population, the score limits within each category be lowered in order to more accurately predict patients with CNO, and avoid unnecessary bone biopsies that would otherwise be indicated if this score was applied. Disclosure of Interest None Declared. Introduction: The majority of the Familial Mediterranean Fever (FMF) patients complains about leg pain that induced by exercise and this is also regarded among the minor diagnostic criteria of the disease itself. Restless Leg Syndrome (RLS) is a disorder characterized by irritating feeling in the legs and the uncontrolled stimulation of moving the legs while resting in order to remove this feeling. Growing pain (GP) is also one of the frequently seen pain syndromes of the childhood period. Objectives: As to our knowledge, there is no study evaluating the frequency of RLS and GP in FMF patients. Therefore, the objective of this study was to investigate the frequencies of RLS and GP in children who have FMF and also to evaluate the effects of these symptoms on quality of life and sleeping quality. Methods: Sixty patients with FMF were consecutively included in the study. Demographic characteristics, FMF family history, the onset age, follow-up periods, disease symptoms and findings of the FMF patients were recorded. Seventy healthy children who had no chronic diseases were included in the study as the control group. RLS, GP, quality of life and sleeping habits were evaluated by standard forms and questionnaires in both FMF patients and control group. Results: The mean age was 8.94 ± 3.89 for the FMF patients and 9.8 ± 3.7 for the controls (p = 0.20) and there was no difference in the genders between groups (p = 0.43). No significant differences were detected among patients with FMF and healthy children regarding GP and RLS diagnosis criteria (p = 0.44, p = 0.23, respectively). Total sleeping score was 48.1 ± 8 in FMF group and 45.3 ± 7 in the control group (p = 0.03). There was no significant difference between the sleeping scores of the patients with and without growing pain in both FMF patients and control group (p = 0.18, p = 0.29, respectively). Similarly, there was no significant difference between the sleeping scores of the patients with and without RLS in both FMF patients (p = 0.86) and control group (p = 0.65). Moreover; there was no significant difference between the sleeping scores of the patients with and without exercise induced leg pain complaints in the patient group (p = 0.22). There was a high ratio of GP in patients with exercise induced leg pain. While, 8 of 27 patients with exercise induced leg pain fulfilled GP criteria, this ratio was 2 of 33 patients without exercise induced leg pain (p = 0.015). Quality of life forms of 22 patients were filled by their parents because the patients were under the age of six. Thirty-eight patients filled these surveys both on their own and with their parents. A negative significant correlation was found between total sleeping score and total parent score of quality of life in the FMF group (r = -0.45, p < 0.01). Total parent score of quality of life was significantly and negatively correlated with the age of the patient, dosage of colchicine and disease severity score. Conclusion: It seems that fulfilling RLS and growing pain criteria are similar in FMF patients and healthy children. Also, it was found that the ratio of fulfilling the growing pain criteria in the patients with exercise induced leg pain complaints was significantly higher when compared to the children without exercise induced leg pain. However, no significant relationship was detected between exercise induced leg pain and RLS. Interestingly, RLS, GP and exercise induced leg pain did not have an effect on the sleep quality. Disclosure of Interest None Declared. Introduction: Familial Mediterranean fever (FMF) is a chronic autoinflammatory disease that is inherited in an autosomal recessive manner and characterized with recurrent fever, polyserositis attacks such as abdominal and chest pain. Celiac disease is histologically characterized with villous atrophy as a consequence of overactivation of immune system in genetically susceptible individuals upon exposure to gluten. Some similar symptoms and signs like diarrhea, abdominal pain, arthralgia, and arthritis serve as diagnostic challenges in differential diagnosis of these two diseases. Consequently it is possible to misdiagnose celiac disease as FMF or overlook symptoms and signs of celiac disease during follow-up of FMF patients. Objectives: We aimed to screen celiac disease in children with FMF.
Methods: This prospective study is conducted from October 2015 to March 2016 in pediatric rheumatology and gastroenterology clinic of a tertiary referral center. We have enrolled 303 children with FMF randomly and the same pediatric gastroenterology specialist performed both the face-to-face negotiation and physical examination for celiac disease. Then, serum levels of total immunoglobulin A (Ig A) and anti-tissue transglutaminase Ig A antibody (anti-tTG A) were measured in all of the patients regardless of a symptom or sign that is suspicious for celiac disease. Positive children for anti-tTG A were further searched for IgA antiendomysial antibodies (IgA-EmA). For definitive diagnosis, small intestine biopsy was performed to the patients with positive IgA-EmA results. Results: Mean age, height and weight of the 303 children with FMF were 12.06 ± 4.23 years, 148.23 ± 21.19 cm and 43.64 ± 18.90 kg, respectively. Males were constituting 50.2% (n = 152) and females were 49.8% (n = 151) of the cohort. The mean disease duration was measured as 5.47 ± 3.46 years. While the mean hemoglobin and total Ig A levels were 12.70 ± 1.37 g/dL and 140.72 ± 69.4 mg/dL, respectively; the mean anti-tTG A level was 3.22 ± 18.22 U/mL. Merely 9 patients were positive for anti-tTG A level and these patients further evaluated for IgA-EmA positivity. Only one patient had a positive IgA-EmA result and so, has been deserved advanced diagnostic procedures for celiac disease. Although there has been a suspected history with the complaints of abdominal distension since birth, both the gastroduodenoscopy and histology did not reveal anything predicting celiac disease. Moreover, the patient was not carrying the HLA-DQ2/DQ8 allele. Conclusion: Neither clinical findings nor laboratory results were consistent with celiac disease in our 303 FMF children. Hence, we conclude that there is no association between FMF and celiac disease. Introduction: Blau syndrome (BS) is a rare monogenic disease with autosomal-dominant inheritance resulting from mutations in nucleotide oligomerization domain 2 (NOD2). It is phenotypically characterized by multiorgan granulomatous inflammation classically presenting as arthritis, uveitis, and skin rash. Treatment is empiric and consists of nonsteroidal anti-inflammatory drugs, corticosteroids (CS), and immunosuppressive agents. Activation of NF-kB is involved in its pathogenesis, suggesting that biologic agents targeted at blocking tumor necrosis factor may be efficacious. Objectives: To report the effectiveness and safety of TNF-inhibitors (TNFi) in a cohort of patients with Blau syndrome. Methods: Retrospective review of prospectively collected data. Patients with BS who received treatment with TNFi were included. Demographic, clinical and genetic data were collected. Therapeutic response was evaluated using a (yet unvalidated) composite key symptom score that captures active disease in 13 domains (scored as 0, 1, or 2 according to severity): fever, rash, arthritis, tenosynovitis, uveitis, hepatomegaly/splenomegaly, lymphadenopathy, syaladenitis, interstitial lung disease, arterial hypertension, renal disease, pericarditis, and erythrocyte sedimentation rate. The range of the BS disease activity score (BSDAS) is 0 to 26. Adverse events (AEs) were recorded throughout the observation period, Results: In a cohort of 6 patients with BS 4 children have been treated with TNFi. One of them received only one 5 mg/kg injection of infliximab during his last 24 hours before death due to severe multiorgan failure. The remaining 3 patients (2 boys) are the focus of this report. Mutations in NOD2 were identified in 2 patients (R334Q and 1007 fs), while one was wild type. They all had evidence of noncaseous, giant cell-granulomata and exclusion of infections, Crohn´s disease and primary immunodeficiency. Age of onset was (median) 9 months, age at start of TNFi 24 months. They had all failed to respond to CS and methotrexate (MTX). Etanercept (ETA) up to 1 mg/ kg/dose twice weekly was the initial TNFi in 2 patients (in whom it was switched to adalimumab (ADA) 20 mg every 2 weeks later on), while ADA was the initial TNFi in one patient. Patients received TNFi for 36 months (ETA 15 months, ADA 21 months). TNFi were administered along with MTX and varying doses of CS. At baseline arthritis was present in 3 patients, uveitis and splenomegaly in 2 patients, rash and syaladenitis in 1 patient each; BSDAS was 5. After 12 months of therapy splenomegaly was present in 2 patients, while arthritis, tenosynovitis, fever, rash, and uveitis occurred in 1 patient each; BSDAS was 4. After 24 months BSDAS was 1. Switching to ADA did not result in better outcomes except for remission of uveitis in 1 patient and lesser need for  Introduction: DITRA syndrome is a severe autoinflammatory disease, characterised by pustular psoriasis, due to autosomal recessive mutations in the IL36RN gene, encoding the IL-36 receptor antagonist. Due to the rarity of this severe condition, the response to treatment is still unclear. Objectives: To describe the clinical characteristics and response to treatment in a patient with severe DITRA syndrome. Methods: The clinical hystory of a DITRA patient has been analysed. Results: The child at the age of 3 years, following an upper-airways viral infection, presented generalised pustular lesions associated with fever and poor general conditions, requiring iv antibiotics and high doses of steroids. The diagnosis of pustular psoriasis was confirmed by a skin biopsy and retinoid acid was started, without a good clinical response; it was therefore replaced with high doses of cyclosporine (4 mg/kg/day). However any attempt to reduce the steroidal treatment was followed by a worsening of the skin lesion, even after the association of retinoid acid with cyclosporine. The Sanger analysis of IL36RN revealed a compound heterozygosis (P76L and S113L), confirming the diagnosis of DITRA syndrome. Do to the subsequent worsening of the skin lesion, followed by the appearance of fever and hypovolemic shock, despite high doses of antibiotics and steroids, treatment with anakinra was started at the dosage of 5 mg/kg/ day with a quick amelioration of the clinical conditions allowing a progressive reduction of steroidal treatment. After two months of complete wellbeing, when the steroidal treatment was reduced at the dosage of 0.5 mg/kg/day, following a systemic infection, the child presented the reappearance of the skin manifestations with fever. In spite of the antibiotics and the increase of the dosage of anakinra (3 mg/kg twice a day) the clinical conditions worsened requiring high doses of steroidal treatment. Anakinra was therefore withdrawn. In light of the crucial role of the infections in determining the clinical flares and the detection of a reduction of plasmatic levels of IgG, prophylaxis with antibiotics and substitutive treatment with human immunoglobulins were started. Thalidomide was then started at the dosage of 1 mg/kg/day together with oral steroids; however, few weeks later the skin manifestation worsened and the treatment was withdrawn. Due to the inefficacy of the previous treatment, dapsone was then started. The cutaneous flared that followed the beginning of this treatment were less severe with an erythematous rash not associated to pustular lesions and followed by fine desquamation. In order to achieve a complete control of the clinical manifestation, treatment with ustekinumab was started at the dosage of 0.75 mg/kg. In fact this anti-IL12 and 23 monoclonal antibody has been demonstrated to be effective in the control of severe pustular psoriasis. Moreover, the detection of the lymphocyte populations performed in the patient revealed a higher number of Th17 cells with a higher expression of Il17A and IL22 respect to the healthy donor. Following the beginning of treatment with ustekinumab the patient did not display any cutaneous flare and the steroidal treatment has been progressively reduced. Conclusion: This clinical report enlighten the severity of DITRA syndrome. The treatments usually effective for both psoriasis and autoinflammatory diseases are frequently ineffective. The association of dapsone with ustekinumab is promising in our patient, together with the prevention of infections. However a longer period of observation is required to prove the efficacy of this approach, even after the discontinuation of steroidal treatment. Disclosure of Interest None Declared.

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Nephrotic syndrome as the presenting feature in a child with NLRP3 mutation: more than what meets the eye? Sagar Bhattad 1 , Amit Rawat 1 , Anju Gupta 1 , Deepti Suri 1 , Vignesh Pandiarajan 1 , Ritambhra Nada 2 , Kaara Tiewsoh 1  Introduction: Long standing uncontrolled inflammation is known to result in amyloidosis in children with auto-inflammatory disease. Nephrotic syndrome as the presenting feature of amyloidosis in the absence of systemic inflammatory features is distinctly uncommon Objectives: To report a child with renal amyloidosis due to NLRP3 mutation who presented with steroid resistant nephrotic syndrome and paucity of systemic inflammatory features Methods: A 10-year-old girl first born to a non-consanguineous couple was referred to our institute for the management of steroid resistant nephrotic syndrome. Her illness started at 6.5 years of age with edema and decreased urine output and the urinalysis revealed nephrotic range proteinuria. Biochemical investigations showed hypoalbuminemia and hypercholesterolemia. She was instituted on 2 mg/kg oral prednisolone therapy that was given for 6 weeks which was later tapered. She had relapses whenever her prednisolone doses were stepped down to alternate day regimen. Eight months later, she developed cortical venous thrombosis and was treated with injection heparin followed by oral warfarin. Prior to presentation to our institute, she had received oral cyclophosphamide for 12 weeks followed by mycophenolate mofetil for 6 months. At 10 years of age, she was referred to our Institute. She was noted to have short stature, pallor, grade 3 pan-digital clubbing, and frontal bossing. Her height was 112.5 cm (< -3 WHO Z score) and weight was 17.6 kg (< -3). She also had mild ascites and pitting pedal edema. There was no lymphadenopathy and hepatosplenomegaly. Blood counts revealed white cell counts of 19.5x10 9 /L with neutrophilic predominance (62% polymorphs), anemia (78 g/L), and platelet counts of 567x10 9 /L. She also had an erythrocyte sedimentation rate of 55 mm at first hour and C-reactive protein levels of 19 mg/L (N < 6). Renal functions were deranged at admission (creatinine clearance-26.4 ml/min). Ultrasound abdomen showed normal-sized kidneys and raised cortical echogenicity. Renal biopsy was performed that showed features of AA amyloidosis. Results: Work up for chronic infections (like tuberculosis); cystic fibrosis and celiac disease was non-contributory. Serologies for human immunodeficiency virus (HIV) and hepatitis C virus were negative. Hepatitis B surface antigen and anti-nuclear antibodies were negative. Her previous medical records were reviewed and a note was made of persistently high platelet counts (580x10 9 /L to 821x10 9 /L) in the blood counts done ever since she had nephrosis. Magnetic resonance imaging of the brain was normal. Pure tone audiometry to assess hearing showed loss of air and bone conduction at 8000 Hz suggestive of mild high frequency sensorineural hearing loss. She continued to develop worsening renal functions and ascites in the follow-up. 3 months later, she succumbed to her illness due to uremia, fluid overload, and acute respiratory distress syndrome. Genetic studies revealed a mutation in the exon 3 of NLRP3 gene: c.1055C > T;p.Ala352Val. She was finally diagnosed to have renal amyloidosis due to NLRP3 mutation and Cryopyrin associated periodic fever syndrome (CAPS) Conclusion: Renal amyloidosis in children with CAPS can result in nephrotic syndrome. A high degree of suspicion is required to make a timely diagnosis Disclosure of Interest None Declared.
Introduction: Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory disorders with autosomal dominant inheritance. Although Muckle-Wells Syndrome (MWS) stands in the middle of the CAPS severity spectrum, it is associated with the high risk of severe late complications that include hearing loss, vision impairment and AA amyloidosis affecting about 26% of individuals. Early diagnosis and appropriate treatment with interleukin-1 (IL-1) blockade may prevent their development.
Objectives: Analysis of a single paediatric patient trajectory leading to the revelation of multiple members of his family suffering with MWS, description of evolving disease phenotype in patients from different generations. To stress an importance of disease awareness as well as interdisciplinary collaboration in detecting familiar conditions affecting both children and adults. Methods: Multiple-case study Results: A 3-years old Caucasian boy was referred to the allergology clinic by his primary care paediatrician for recurrent flares of nonpruritic urticarial rash from about 6 months of age. There were no other symptoms of note. Detailed family history suggested presence of rash in other family members. Working together, paediatric and adult rheumatologist detected additional 9 individuals suffering with variable combinations of fever episodes with rash (all), episodic arthritis, eye inflammation, hearing loss, headache and AA amyloidosis. (Table 19, patient 3b). The boy's great grandmother died in 52 years of age from renal failure. Although renal biopsy was not performed at the time, presence of other symptoms as reported by her children made clinical diagnosis of MWS and amyloidosis very likely. Genetic analysis of exon 3 of NLRP3 gene in affected individuals revealed heterozygous mutation c.1322C > T causing change of amino acids p.Ala441Val and prompted referral to the autoinflammatory disease centre for biologic therapy. Conclusion: In this family medical care was not primarily seeked by adults who have got used to their long-term and relatively mild symptoms. The diagnostic procedure was initiated by the paediatric referral. Detailed analysis of the symptoms suggests presence of the high risk of severe complications. Hearing loss, proteinuria and/or AA amyloidosis have only been noticed in individuals older than 50 years of age. Importantly, younger members below 30 years have not yet developed any of these symptoms which may now be prevented with long-term biologic therapy. This multi-case report illustrates importance of the high degree of suspicion as well as close collaboration between paediatric and adult specialists in order to establish timely diagnosis and initiate appropriate investigations and treatment.  Introduction: Familial Mediterranean Fever (FMF) is an autosomal recessive auto inflammatory disease. Long-term effects of sub clinical inflammation in FMF cause cardiac morbidity and mortality. Previous studies showed cardiac autonomic dysfunction in FMF patients. Heart rate recovery (HRR) and systolic blood pressure recovery (SBPR) can be used to evaluate cardiac autonomic function. Objectives: The aim of this study is to evaluate the cardiac autonomic functions in pediatric FMF patients by using HRR and SBPR parameters. Methods: A total of 50 FMF patients and 30 healthy children were included in the study. All patients were evaluated by echocardiography before study in order to eliminate congenital heart defects. All patients underwent a maximal graded exercise test. HRR and SBPR parameters were calculated. Results: There was a significant decrease in HRR1 value in FMF patients (p = 0.03). In addition, SBPR1 and SPBR2 values were obtained higher in the FMF group compared to the control group (0.96 ± 0.12 vs. 0.88 ± 0.12 and 0.95 ± 0.09 vs. 0.91 ± 0.11); and the highness in SBPR1 value was statistically significant (p = 0.02). FMF presence had a negative correlation with HRR1 (r = −0.26, p = 0.03), but a positive correlation with SBPR1 (r = 0.29 p = 0.02). Moreover, there was a negative correlation of the M694V homozygous mutation with HRR1 and HRR2 values (r = -0.43, p = 0.004, r = -0.42, p = 0.005). Conclusion: Cardiac involvement may consist in FMF patients without cardiovascular symptoms. Impaired SBPR and decreased HRR response may indicate increased cardiovascular risk in these patients despite normal exercise test. Disclosure of Interest None Declared. We checked if the response to treatments received anytime correlated with clinical score at follow-up. Tonsillectomy. 10/26 subjects underwent tonsillectomy before the first visit, 8 of whom without any response. Three of them were classified as HPF-like at follow-up. Glucocorticoids. Poor response to glucocorticoids tended to be more common in UPF than in HPF-like (n.s). Colchicine was tried in 12 subjects, with good response in less than half cases. No one of responders had a clinical score supportive of FMF. Conclusion: UPF represent an heterogeneous group of disorders, as concern clinical features, response to treatments and prognosis. A fascinating hypothesis is that classification of UPF by analogy with well defined HPF could help in choosing appropriate treatments and in establishing a correct prognosis. We showed that PRINTO criteria seem not suitable for this purpose. First, PRINTO-scores are not stable uring follow-up of patients with UPF, since in our series most patients changed their score from baseline to last visit. Second, the PRINTO score at last follow-up doesn't correlate with response to any previous treatment received, including tonsillectomy, glucocorticoids and colchicines, and thus seem not useful to classify patients for clinical purposes. Indeed, more than half patients showed poor response to glucocorticoids, tonsillectomy and colchicines and unexpectedly no patient who responded to colchicines had a clinical score supportive of FMF. Results: In 9 pts (5 male and 4 female) aged between 3 and 57 heterozygous Q705K variant was found (7,1% of the patient setting). All these pts had features of autoinflammation: persistent fever (9), rash (7), acutephase markers (8), serositis (3), arthritis (7), most of them polyarticular, nonpersistent, without destruction and functional disability. In 1 case recurrent aseptic meningoencephalitis was observed. In 3 of 9 pts in addition to Q705K pathogenic mutations T350M and V200M in 2pts were detected and diagnosis of CAPS was confirmed.    Introduction: Mevalonate kinase deficiency (MKD) is a multisystemic inflammatory disorder caused by a mutation of MVK gene that severely reduces mevalonate kinase activity. Mevalonic aciduria (MA) is severe phenotype of MKD characterized by serious neurologic abnormalities as well as recurrent fever with poor prognosis. The pathogenesis of neurologic impairment of MA is not yet clear. One hypothesis is that neurodegeneration is linked to intrinsic apoptosis pathway triggered by mitochondrial damage and to pyroptosis. [1] Objectives: To investigate the relationship between neurological aspects of MA and mitochondrial dysfunction. Methods: We present a case of MA with severe neurological involvement, mimicking Leigh encephalopathy, which is neurodegenerative disorder associated with dysfunction in mitochondrial energy metabolism.
Results: A 1-month-old Japanese male of non-consanguineous background was referred to our hospital due to fever of unknown origin. He developed interstitial pneumonia, elevated liver enzymes, and hypertrophy of myocardium with chronic inflammation. Furthermore, he showed severe developemental delay and failure to thrive. Laboratory data showed elevation of blood lactate and pyruvate concentration with mild lactic acidemia. The lactate to pyruvate ratio of blood and cerebrospinal fluid increased suggesting mitochondrial dysfunction. Magnetic resonance imaging of brain showed symmetrical T2 hyperintensity of basal ganglia, severe brain atrophy and thinning of corpus callosum, which resembled to Leigh encephalopathy. However, extremely increased urinary excretion of mevalonic acid was revealed, and molecular analysis showed homozygous mutation c.227-1G > A of the MVK gene. He was diagnosed as having mevalonate kinase deficiency at the age of 14 months. He was treated with oral corticosteroid, resulting in partial improvement of chronic inflammation, but no change was observed for his severe psychomotor retardation. Our plan is to perform allogenic bone marrow transplantation from his father, who is HLA one-antigenmismatched and heterozygous carrier of the mutant gene.
Conclusion: It was suggested that neuropathology of severe phenotype of MA might be related to secondary mitochondrial dysfunction due to deregulation of mevalonate pathway. Introduction: The mechanisms of Polyarteritis Nodosa (PAN) are probably heterogeneous since it has been described in association with cancers and multiple infections. Recently loss-of-function mutations in CECR1 have also been associated with a spectrum of vascular and inflammatory phenotypes, including childhood-onset PAN. Objectives: To report a case of childhood-onset PAN associated with autosomal recessive mutations in CECR1 gene. Methods: This report focus on a single case. Data were collected from the patient clinical registry and we discuss it based on the scientific literature. Results: A female patient, currently 31 years old (y/o), presented at 5 years of age with long-lasting fever, asymmetric polyarthritis and livedo reticularis, leucocytosis, normochromic normocytic anaemia and elevation of ESR (117 mm/hour). Angiographic studies revealed renal and hepatic microaneurysms. Subcutaneous nodules were present and biopsy was compatible with PAN. Infectious causes of PAN were excluded. Throughout her life, she suffered many disease complications such as paresia of the sixth cranial pair (10y/o), ischemic stroke of the left anterior corona radiata and right lateral thalamus, cauda equina syndrome (26y/o), multiple mononeuropathy (29y/o) and two digital amputations due to digital necrosis (27 and 30y/o), all of these occurring despite several treatment strategies, which included long term corticosteroids, aspirin, oral anticoagulants, azathioprine, methotrexate, several cycles of intravenous cyclophosphamide followed by oral cyclophosphamide, intravenous immunoglobulin, iloprost and oral vasodilators. These multiple complications of the disease rendered impossible to tapper corticosteroids and the patient had at a very early age multiple treatment complications including growth restriction, cushingoid habitus, secondary osteoporosis with multiple fractures, metabolic syndrome, recurrent infections and precancerous conditions like Barrett esophagus and cervical intraepithelial dysplasia related to human papillomavirus. Two autosomal recessive heterozygous mutations were found in our patient localized to gene CECR1: p.Gly47Arg and p.Tyr453Cys, both pathogenic. After many years of frustrating disease control, infliximab (5 mg/ kg) was initiated at age 30, moved by successful recent reports. Following the first infusion, there was a mild decreased in ESR from 47 to 27 mm/h, but a major rise of haemoglobin levels from basal 8-10 to 13-15 g/dL; intravenous iron supplementation was discontinued. There was resolution of the patient's fatigue, an important limiting symptom of her quality of life and she hasn't had any relapse in a one-year follow-up. Discussion: This is the first described Portuguese case of childhood onset PAN associated with compound heterozygous mutations in the CECR1 gene, which are associated with lower levels or loss of activity of adenosine deaminase 2, a growth factor for endothelial and leukocyte development and differentiation. These mutations have recently been implicated in the pathogenesis of a few cases of PAN presenting a high variability in the age of onset and clinical presentation. These patients apparently respond well to infliximab, by inhibiting the TNF-alfa, a pro-inflammatory cytokine produced primarily by cells of the macrophage-monocyte lineage and thus thought to participate in the vascular inflammation and endothelial cell death. Introduction: Familial Mediterranean fever (FMF) traditionally has been considered an autosomal recessive disease; however, the diagnosis remains predominantly clinical, since mutations cannot always be identified on both alleles. Objectives: to evaluate cessation of colchicine therapy in selected group of patients with FMF who possess only 1 or none demonstrable MEFV mutation. Methods: We performed a prospective controlled study evaluated cessation of colchicines therapy in patients that were previously diagnosed and treatd for FMF based on clinical features and did not carry any common MEFV mutation or were heterozygote for one of the mutations. Patients were included in the study if they were between the age of 2-18 years and were treated with colchicine, had a normal level of serum amyloid A (SAA)and had at least 6 months free of FMF attacks. SAA levels were evaluated before colchicine cessation and at 3 and 6 months following cessation. Colchicine therapy was resumed in case of FMF attacks reappeared during this period. Results: twelve patients ages 10.7 ± 4 years enrolled in the study. Prior to entering the study patients were treated with colchicine for an average of 36.3 month (7-144 months). The average time with no FMF attacks before enrolment into the study was 12.8 ± 8.6 months and the average follow up after stopping colchicine therapy was 15.3 ± 5.7 months.Five patients were heterozygote for the M694Vmutation. Five patients (41.6%) had an FMF attack during follow up and needed to renew colchicine therapy, the average time to renew colchicine therapy was 5.3 months (range 1.5-11.4 months) 3 of them (60%) carried the M694V mutation. There were no differences between the groups of patients that did not relapse and the groups that needed to renew therapy regarding age (10.7 ± 1.6 vs 10.6 ± 6.3 p-0.97) or levels of SAA at time of enrolment (4 ± 3.6 vs 3.3 ± 2.4 p-0.7). Length of colchicine therapy prior to enrolment showed tendency that didn't reach significance towards longer time in the patients needed to resume therapy (22.3 ± 12.6 vs 53 ± 51 months p-0.18).

Reference
Conclusion: Cessation of colchicine therapy in selected group of patients who are not homozygous for the common MEFV mutation should be considered. Monitoring SAA levels every 3 months could not predict FMF attacks following cessation of colchicine therapy. Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterised by recurrent, self limited attacks of fever with serositis. Various diseases were reported to be associated with FMF or carriers of MEFV mutations. Objectives: The aim of this study was to investigate the frequency and characteristics of sacroiliitis in children with FMF. Methods: Files of FMF patients who had been seen in two reference hospitals in Ankara, in the last two years, were retrospectively evaluated. Patients with FMF and concomitant sacroiliitis were included to the study. All patients had magnetic resonance imaging evidence of sacroiliitis. Results: Among 600 FMF patients 17 (11 females, 6males; mean age: 13,32 ± 4,24 years) (2.8%) of them were found to have sacroiliitis. Mean age at FMF diagnosis and sacroiliitis diagnosis were 106,76 ± 43,17 and 130,76 ± 39,12 months, respectively. FMF diagnosis was done concurrently or afterwards to sacroiliitis in only 6 (35%) patients. Ten patients had isolated sacroiliitis and 7 had associated diseases (5 enthesitis related arthritis, 1 psoriatic arthritis and 1 ulcerative colitis). Eighty-eight percent of the patients carried at least one M694V mutation. Classical FMF attacks were present in 14 patients; the remaining 3 patients had atypical symptoms but had 2 MEFV mutations. Conclusion: Sacroiliitis can be seen in patients with FMF during childhood. M694V mutation seems to be a susceptibility factor for its development. Objectives: To define the minimal clinically important differences (MCID) of all JADAS versions for worsening and improvement using both parent and physician perspectives. Methods: Changes in the JADAS scores in consecutive visits were calculated in a dataset of 1,874 visits of JIA patients seen at the study Unit. Both parent and attending physician were asked to rate in a 5point Likert scale if the patient was much worsened, slightly worsened, stable, slightly improved, much improved from previous visit. Those visits in which patient was subjectively rated by parents or by the physician as slightly worsened or slightly improved were retained. Subsequent visits with a time interval of more than 6 months were not retained; each patient could contribute for no more than 1 visit for improvement and 1 visit for worsening for each assessor. MCID were defined as the median changes of the JADAS scores of individual patients who had a minimal important improvement or worsening between visits. Results: Table shows calculated MCID for all JADAS versions according to parents and physician. Conclusion: MCID for all JADAS and cJADAS versions were defined according to parent and physician perspective. Differently from the results of previous study, the clinically important change of the score was smaller for improvement than for worsening for both parents and physicians. Parents required a minor change in the score than physician to define both improvement and worsening. Disclosure of Interest None Declared. Objectives: To investigate possible influence of tumor necrosis factor alpha (TNFα-308) and FokI Vitamin D receptor (VDR) gene polymorphism on long term disease outcome in JIA patients treated with biologics. Methods: We have retrospectively analysed data from our registry of JIA patients treated with biologics in whome 6 years follow-up data could be obtained and genomic DNA extracted to test TNFά-308 promoter and FokI VDR polymorphism. Disease activity was evaluated by ACR Pedi core set criteria for inactive disease. Results: We have evaluated 78 JIA patients in whom there was not significant distribution difference of TNFα-308and FokI Vitamin D receptor (VDR) gene polymorphism among different JIA subtypes. Patients with the -308 GG (p = 0,004) and GA (p = 0,026) genotype achieved clinical response significantly more frequently than those  Results: Demographic and clinical features of patients seen in the two study periods were overall comparable. As compared to the older sample, patients treated more recently had received more frequently methotrexate (84.2 vs 64.5%) and biologic medications (61.8% vs 11.3%), and had undergone more commonly intra-articular corticosteroid injections (98% vs 79%). The comparison of disease activity and damage between the two cohorts is presented in the table.

Disclosure of Interest
All items of articular and extra-articular JADI were decreased in the recent sample, with the exception of temporo-mandibular damage and leg-length discrepancy, whose frequency was comparable in the two datasets. Conclusion: Compared with patients treated in the "methotrexate" era, those treated in the "biologic" era have a higher frequency of inactive disease and less articular and extra-articular damage. These findings highlight the improvement in disease outlook achieved with the newer therapeutic modalities.

Disclosure of Interest
None Declared. Introduction: Increasing attention is being paid to parent-/child-reported outcomes in juvenile idiopathic arthritis (JIA). Incorporation of these measures in patient assessment is deemed important as they reflect the parent's and children's perception of the disease course and effectiveness of therapeutic interventions. Objectives: To develop and to validate a composite parent-centered and child-centered versions of the JADAS, named parJADAS and chi-JADAS, respectively. Methods: The parJADAS and chiJADAS include 4 measures: 1) parent/ child assessment of disease activity; 2) assessment of pain intensity; 3) self/proxy assessment of joint disease; 4) assessment of morning stiffness (MS). Disease activity and pain are assessed on a 21-numbered circle VAS (0 = best and 10 = worst). The active joint count is based on the count of any swollen or painful joint, irrespective of its type, up to a maximum of 10 joints. MS duration is assessed on a Likert scale, ranging from no MS (0 points) to > 2 hours of MS (10 points). Validation was conducted on a dataset of 602 children with JIA who underwent 1749 visits at study unit. To account for repeated measurements in a single patient, construct validity was assessed by calculating between-subject and within-subject correlations of parJADAS and chiJADAS with JADAS10, cJADAS10, physician global assessment of disease activity, the number of active joints, parent/ child rating of overall well-being and erythrocyte sedimentation rate (ESR). Discriminant ability was evaluated by comparing parJADAS and chiJADAS levels between patients with active or inactive disease according to current criteria, and between patients who were satisfied or not satisfied with disease outcome. Sensitivity to change was tested using standardized response mean (SRM) in 2 subsequent visits performed no more than 6 months apart. Internal consistency was assessed by means of Cronbach's alpha coefficient and inter-rater reliability was assessed using the intraclass correlation coefficient (ICC).
Results: Between-subject correlations of parJADAS and chiJADAS were high (>0.70) with JADAS10, cJADAS10, parent/child rating of overall wellbeing, and moderate (0.40-0.70) with the other measurements. Moreover, in the same subject, changes over time of the parJADAS and chiJADAS corresponded to changes in disease activity, as indicated by high withinsubject correlations with JADAS10, cJADAS10, physician global assessment of disease activity, parent/child rating of overall well-being, and active joint count. Both parJADAS and chiJADAS discriminated well between inactive and active disease and between satisfied and not satisfied patients (p < 0.001). The responsiveness to clinical change of parJA-DAS was good (SRM = 0.84). The internal consistency was satisfactory, with Cronbach's alpha >0.80 for both parJADAS and chiJADAS. The interrater reliability between the parJADAS and the chiJADAS measured at the same visit was high, with ICC 0.92 (95% CI 0.90-0.93).

Conclusion:
The parJADAS and chiJADAS were found to be valid and reliable for assessment of disease activity in JIA and may, therefore, be suitable for use in clinical practice, observational studies, and therapeutic trials. Both scores may potentially surrogate physician assessments when these are not available.

Disclosure of Interest
None Declared. Introduction: Systemic lupus erythematosus (SLE) is a rare, lifelong autoimmune disease. Childhood-onset SLE (cSLE) often has its onset during puberty, and is thought to be more severe than SLE. Information regarding long term outcomes like fertility and pregnancies is scarce for this population.
Objectives: To investigate effects of cSLE on family planning, fertility and pregnancies in a large cohort of 101 female adults with cSLE. Methods: Adults with cSLE and SLE were seen for a single study visit. Information regarding family planning, fertility and pregnancies were assessed by structured questionnaires and checked with medical records. Results: We studied a cohort of 101 female cSLE patients with median age at study visit of 33 years and median disease duration of 20 years. 26% of patients felt that effects of cSLE limited them in their sexuality. Two third of the patients found the disease to be a restrictive factor in wanting children. They feared complications during pregnancy (51%) and during labour (30%), and problems with raising children (34%). 29% of patients feared their children would be diagnosed with SLE. A total of 85 pregnancies were reported in 36 cSLE patients (median 2 pregnancies per female), of whom 22% had a history of cyclophosphamide use.
Remarkably, time to pregnancy was not delayed, as it was 12 months or less in all but three patients. The 85 pregnancies resulted in 63 live births (76%), 13 miscarriages (15%), and 5 induced abortions (6%). The miscarriage rate in this group was comparable to that of healthy Dutch women. An impressive 37% of the 67 pregnancies with a duration of at least 20 weeks had a complicated course. Four pregnancies (6%) resulted in stillbirth, where only 0,9% of pregnancies have this outcome in healthy Dutch women. Other complications were pregnancy induced hypertension, pre-eclampsia/HELLP, preterm birth (median gestational age of 31 weeks) and placental abruption. The frequency of pregnancy complications was higher in cSLE than in SLE and the Dutch female population. Conclusion: Family planning is affected in a substantial percentage of females with cSLE. Multiple issues complicated their wish to have children. In this cohort, fertility did not seem to be impaired as no delay was found in the time to pregnancy. In contrast, the frequency of pregnancy complications including stillbirth was remarkably high in cSLE patients.

Disclosure of Interest
None Declared. Introduction: Systemic lupus erythematosus (SLE) is a rare autoimmune disease which can affect any organ system. Childhood-onset SLE (cSLE) is thought to be more severe than SLE, with more major    In the whole cohort, 5 patients were lost to follow-up and 10 patients have already achieved adulthood and maintain follow-up in our department. From these, 2 fulfil criteria for Still´s disease, 2 for rheumatoid arthritis and 6 for spondylarthritis (1 PsA, 4 ankylosing spondylitis and 1 arthritis associated with inflammatory bowel disease). When evaluating remission rates, no significant differences were found regarding ILAR categories, with 37.5% of the patients in remission classified as oligoarthritis, 20.8% ERA and 16.7% PsA (p = 0.5). Neither demographic characteristics nor disease activity at presentation or immunological phenotype were associated with clinical remission. Conclusion: In this cohort established in the 21st century, almost half of JIA patients achieved clinical remission after a mean follow-up of 5 years. We could not identify any clinical/ immunological predictors of remission, although the proportion of oligoarthritis JIA achieving remission is higher than the other categories. Development of new therapeutic agents in association with early rehabilitation can explain the trend towards higher remission rates independently from clinical variables, although the small sample does not allow definitive conclusions.

Disclosure of Interest
None Declared.   Introduction: The classical inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate (ESR) often inadequately reflect disease activity, but on the other hand, there are few specific biomarkers that can be helpful in managing the different categories of juvenile idiopathic arthritis (JIA). The search for other biomarkers in JIA is attracting increased interest and a number of biomarkers have shown potential for predicting clinical phenotype, disease activity and severity, clinical remission and relapse, response to treatment and disease course over time. Objectives: To assess the serum levels of DKK1, IL1β, INFγ, IL10 and IL17 in patients with JIA, and detect their relation to disease activity. Methods: Demographical and clinical data from 316 patients with JIA registered in the Reuma.pt were collected and a blood sample from each patient was obtained for cytokine determination. Disease activity was evaluated using the Juvenile Arthritis Disease Activity Score in 27 joints (JADAS27) and the Childhood Health Assessment Questionnaire (CHAQ) score. Serum levels of DKK1, IL1β, INFγ, IL10 and IL17 levels were determined by ELISA. Multivariate linear regression for each JIA category was used for the analysis of the relation between DKK1, IL1β, INFγ, IL10 and IL17 levels and JADAS27 (and its individual components) and CHAQ, adjusting for gender, body mass index, age and disease duration. Results: 316 JIA patients, 65% female, with mean age 17.1 ± 9 years and mean disease duration 8.1 ± 1.4 years. The distribution of JIA categories was: 105 persistent oligoarticular, 51 extended oligoarticular, 51 polyarticular rheumatoid factor (RF) negative, 30 polyarticular RF positive, 26 systemic, 36 enthesitis-related arthritis and 17 psoriatic arthritis. The analysis of the 7 JIA categories revealed no relation between the serum levels of these cytokines and disease activity measured by JADAS27. In patients with polyarticular RF positive we have found an inverse relation between DKK1 levels and CHAQ score (ß = -0.003; adjusted p = 0.025) and, in polyarticular RF negative patients an inverse relation between DKK1 levels and ESR (ß = -0.031; adjusted p = 0.03). In patients with psoriatic arthritis there was a positive relation between IL1β, INFγ and IL17 with CHAQ (ß = 0.012 and adjusted p = 0.007; ß = 0.004 and adjusted p = 0.03; ß = 0.034; adjusted p = 0.04; respectively) and an inverse relation between IL10 levels with CHAQ (ß = -0.011; adjusted p = 0.005). Conclusion: Our data reinforce the need of biomarkers studies of disease activity in the different JIA categories. Interestingly, mostly in JIA psoriatic arthritis patients, we have identified potential biomarkers of disease activity. Larger studies are needed in order to validate these results. The incorporation of effective and reliable biomarkers into routine practice might facilitate adoption of a stratified approach to investigation and management, foster the implementation of research into the design of personalized and targeted therapies, and ultimately lead to more rational and effective clinical care. Introduction: Among the TNF family, receptor activator of nuclear factor kB (RANK), receptor activator of nuclear factor kB ligand (RANKL), and osteoprotegerin (OPG), a soluble receptor that inactivates RANKL, are known to interfere in the immune system, bone metabolism, and endocrine functions. The clinical relevance of observations of serum levels of RANKL and OPG in Juvenile idiopathic arthritis (JIA) is not clear. Objectives: To assess the serum levels of RANKL and OPG in JIA patients and to detect their relation to disease activity in the different JIA categories. Methods: Consecutively recruited JIA patients were clinically examined, the Juvenile arthritis disease activity score in 27 joints (JADAS27) calculated and Childhood Health Assessment Questionnaire (CHAQ) used to measure the functional status. Routine laboratory examinations were recorded and serum RANKL and OPG levels were determined by ELISA.Nonparametric tests and multivariate linear regression were used for analysis the relation between the levels of RANKL and OPG versus JADAS27 and CHAQ, adjusting for gender, body mass index, age, disease duration and JIA categories. Results: 316 JIA patients, 65% female, with mean age 17.10 ± 9.01 years and mean disease duration 8.11 ± 1.41 years. The distribution of JIA categories was: 105 persistent oligoarticular, 51 extended oligoarticular, 51 Introduction: Rheumatic disease (RD) is an important cause of acquired disability in children. The aim of this study was to explore health professionals' (HP) and nurses' confidence in the treatment of paediatric rheumatology patients; the perceived adequacy of their undergraduate and postgraduate paediatric rheumatology education; and perceived utility of a number of forms of educational opportunities for these professional groups.

Disclosure of Interest
Objectives: The aims of this study were to explore: (1) HPs' and nurses' confidence in the treatment of paediatric rheumatology patients; (2)  Introduction: Rheumatic disease (RD) in childhood and adolescence is a significant cause of short and long-term disability. The provision of health care to children with RD is challenging with agreement that a multidisciplinary approach is best practice. Early diagnosis and management by a multidisciplinary team is the gold standard for JIA management and delays in diagnosis may significantly impair the outcomes of children diagnosed with RD with reduced quality of life, increased pain level and worse long-term prognosis for children with RD reported.
Objectives: This survey of parent and carers aims to establish the level of care and services currently provided to children diagnosed with Rheumatic Diseases (RD) in New South Wales (NSW), Australia. Methods: The survey included parents and carers of children presenting to paediatric rheumatology (PR) services in NSW. Subjects attending PR clinics in both public and private settings were invited to complete an online or paper survey. Results: Overall 148 surveys were completed. The process of obtaining the diagnosis of RD was described as being 'difficult' or 'very-difficult' in 56.9% (n = 83) of the surveyed cohort and 41.5% (n = 61) consulted 4 or more different clinicians prior to diagnosis. Between symptom onset and final diagnosis, 42.6% (n = 63) participants reported a delay of 5 months or more, and 16.9% (n = 25) waited longer than 12 months. Ultimately, 91% (n = 134) were referred to a paediatric rheumatologist and 63.6% (n = 94) were seen within 4 weeks from initial referral. More than half of respondents felt that general practitioners and general paediatricians were not aware of RD. Overall, improved knowledge of paediatric rheumatology diseases amongst general practitioners, improved access to PR, improved educational materials for patient's and families, access to specialty rheumatology nurses and coordinated rheumatology teams would have significantly improved the overall experience of their child's disease. Conclusion: Children with RD in NSW still experience significant delays from symptom onset to definite diagnosis through consultations with multiple health-care professionals. Reassuringly, when the referral to PR services is made, patients are usually seen faster than other international standards Disclosure of Interest None Declared.  Results: In the evaluation of children's health; measurement tools and development of these tools which enable an holistic approach to the patient are among the important issues of today as well as the bloodurine tests and radiological examinations. There are two types of measurement tools used for children; general and disease-targeted. General measurement tools are designed to be relevant to everyone and allow for a relative comparison of the different disease patient groups. The development of disease-targeted measurement tools focus on the gaps of the general measurement tools for the specific conditions of the disease. Disease-targeted measurements are more sensitive to detect clinically important changes and thus have more applicability in the clinical study. There are two kinds of health status evaluation scales for the children; the first one is the form that the patient fills the report (patient self-report) and the second one is filled by the family (parent proxy-report) if the child is too small or has cognitive impairment or unable to complete the form due to the severity of the disease. Filling out these two forms either by the child or the family will play an important role in the evaluation of perspectives for the treatment and guide the provision of holistic care of the disease. Conclusion: Activities related to rheumatic diseases in the the past concentrated more on the disease activity measurement than the assessment emphasis of physical, social and mental function of health as it is today. Measurement tools enable healthcare personnel to evaluate their patients and their health without an invasive procedure.

Disclosure of Interest
None Declared.

P283
The physical activity level, pain, well-being and functional abilities in patients with juvenile idiopathic arthritis Ela Tarakci  Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic pediatric rheumatic disease and an important cause of acquired impairment and disability in children and adolescents. Patients with JIA commonly experience acute and chronic pain, decreased mobility, and joint stiffness leading to restrictions on activities and isolation from their peers. Physical activity is essential for the social, emotional, and cognitive development of children and adolescents with JIA.
Objectives: The aim of this study was to investigate physical activity level functional ability, pain, and well-being in children and adolescents with JIA and was to assess relations between this parameters. Methods: Cross-sectional study design including patients with JIA aged between 7 and 18 years and healthy controls was used. Patients were diagnosed by a pediatric rheumatologist using the International League of Associations for Rheumatology criteria. Sociodemographic and clinical features were assessed. Physical activity level and energy expenditure were assessed with a 1-day activity diary. Pain and overall well-being were measured using a visual analog scale (VAS). Functional ability was assessed with the Childhood Health Assessment Questionnaire (CHAQ). Results: Fifty-two patients and 48 controls were included with a mean age of 12.13 ± 2.92 and 11.27 ± 1.59 years, respectively. The mean disease duration was 64 months. The JIA group had significantly less time in physical activity (p = 0.001), decrease in energy expenditure (p = 0.04), and higher CHAQ scores (p = 0.001) compared with the control group. In the JIA group, significant relationships were found between the number of involved joint and disease duration (r = 0.44, p = 0.001) and VAS pain (r = 0.30, p = 0.02). Significant relationships were found between VAS overall well-being, CHAQ (r = 0.37, p = 0.001) and VAS pain (r = 0.41, p = 0.001). Conclusion: This study has shown a significantly lower physical activity level, energy expenditure, and functional ability in patients with JIA compared with healthy controls. The results of our study showed that there was no significant relationship between physical activity and functional ability level in patients with JIA. The likely cause for this relationship may be multifactorial and needs to be revealed to improve assessment strategies.

Disclosure of Interest
None Declared. Conclusion: An international collaboration between clinicians and multiple stakeholders has begun using the OMERACT process to develop an expanded Core Domain Set for assessment of JIA in clinical trials. The initial results of the preliminary phases of the work have supported a need to reconsider the current JIA Core Set to include patient/caregiver-centered outcomes. Data collected thus far will inform the development of the list of domains to be tested in a comprehensive Delphi process for pediatric rheumatology stakeholders: researchers, health care providers and patients/caregivers. Continued participation in the rigorous OMERACT process with broad internationally representative involvement of clinicians, researchers, patients, industry and regulators will help to refine the important outcomes that will ultimately be included in the final JIA Core Set.

Disclosure of Interest
None Declared. Results: A total of 19 patients completed the modified cyclophosphamide pulse therapy (94.7% female, mean age 11.2 + 3.7 years at lupus diagnosis, mean nephritis duration upon completion of treatment 30.6 + 5.2 months), with a minimum follow up duration of one year. At 9 months of treatment, 47.4% (9/19) already reached complete remission, and 52.6% (10/19) were in partial remission. Upon completion of 9 monthly and 5 quarterly pulses, 94.7% (18/19) was with complete treatment response. One patient (5.3%) relapsed during the maintenance phase and was in partial remission at the end of the treatment. The random urine protein:creatinine ratio and disease activity were significantly improved in all 19 patients. Treatment failure was not noted in any of the patients at the end of 9 months and at the completion of treatment. Reported adverse events were gastrointestinal symptoms (100%), mild infections (94.7%), alopecia (89.5%), severe infections (10.5%), menstrual irregularities (33.3%), and hematologic disturbances (26.3%). All of the 19 patients are in remission during their most recent follow up. With the above data, we find that extension of the induction therapy by three months using standard dosing while maintaining the total cumulative dose by shortening the maintenance phase resulted in a favorable shortterm outcome and adverse event occurrence, which is comparable to outcomes of other Asian cohorts. Conclusion: A modified regimen of 9 monthly and 5 quarterly cyclophosphamide pulses may be an effective therapeutic option for childhood-onset LN.

Disclosure of Interest
None Declared.

P286
Assessment of disease activity and prognosis in a group of JIA TL expressed by T/S ratio (amplification telomere product and single copy gene) was significantly reduced between JIA patients and controls (0. 85 ± 0, 34 vs. 1, 67 ± 1, 38, Mann-Whitney test P = 0.025). When age adjusted by ANCOVA, the difference remained significant (P = 0,032). There was no correlation between TL and age (P =0, 449, r = 0, 166), sex (P = 0, 521), disease duration (P =0, 358, r = -0, 318), JADAS (P = 0, 184, r = -0, 287) e VOP (P = 0, 843, r = 0, 044) in patients with AIJ. Conclusion: TL was significantly shorter in long disease duration and high to moderate disease activity with no DCV risk factors AIJ patients and compared to controls.VOP was normal and no significant difference between controls were found. No correlations were observed between TL or VOP and disease duration, age and sex.

Disclosure of Interest
None Declared.  Introduction: Around forty percent of systemic Juvenile idiopathic arthritis (SJIA) in Thailand had steroid dependency or failure to respond to conventional therapy, therefore tocilizumab (TCZ), a humanized anti-IL-6 receptor antibody, was indicated in these patients. However, due to financial problem, some patients could not receive TCZ treatment as soon as a failure of the conventional treatment occurred, leading to disability and poor quality of life. Therefore, this study focused on the outcomes between early and late TCZ treatment in SJIA patients. Objectives: To compare the outcomes between early and late TCZ treatment in SJIA patients.
Methods: This is an observational cohort study. Thirty-three SJIA patients were included in this study. Baseline characteristics and disease severity were collected. Patients were divided into 2 groups; 1) early TCZ treatment, patients who received TCZ as first line therapy or received TCZ as soon as it was indicated, 2) late TCZ treatment, patients who receive TCZ later than 6 months after a failure of conventional treatment. Patients who received only nonsteroidal antiinflammatory drugs (NSAIDs) and/or disease-modifying antirheumatic drugs (DMARDs) were included into the study as controls.  Although the four components assess different disease construct, their relative contribution in determining the total score is unclear. It has been argued that the tendency for parents to provide global ratings higher than those of physicians may artificially inflate the score. Furthermore, because acute phase reactants are frequently normal in JIA, their role may be less relevant than that of the other parameters.
Objectives: To examine the relative contribution of the four component of the JADAS10 in determining the total score. Methods: The clinical information recorded during visits made in children with JIA from January 1987 to March 2012 was retrieved from the study center database. The JADAS10 score as well the score of each of its four components was computed for each visit. The score range of each component ranges from 0 to 10 and the total JADAS10 score ranges from 0 to 40. The following calculations were made: 1) number ( (1). Elevation of sCD25 is consistent with the presence of T cell activation in MAS. Elevation of neopterin and CXCL9, both of which reflects IFNγ production, and their correlation with laboratory parameters, supports the pathogenic role of IFNγ in MAS. Given the fact that circulating CXCL9 levels appear to reflect tissue IFNγ production, presence of high CXCL9 in patients with a history of MAS, but without MAS at sampling, suggests subclinical activation of the IFNγ pathway in these patients.  Values are expressed as p value (r di Spearman).
Introduction: Macrophage activation syndrome (MAS) is a severe complication of autoimmune and autoinflammatory disease. MAS is most strongly associated with systemic juvenile idiopathic arthritis (SJIA) but can also be seen in Kawasaki disease, SLE or IBD. Clinically, MAS is strikingly similar to hemophagocytic lymphohistiocytosis (HLH) and the initial differentiation between SJIAassociated MAS and primary HLH or acquired HLH is difficult. Due to recent advances in the description of HLH-related gene defects, most patients with primary HLH can be identified through genetic or functional analysis. Unfortunately these investigations are not always easily available. Since viral infections such as EBV and CMV can trigger both primary and acquired forms of HLH, the presence of a viral trigger in a patient with HLH does not necessarily allow classification of the disease as acquired HLH. S100A12 is an endogenous TLR4 ligand that induces monocyte activation, thereby acting as an amplifier of innate immunity during early inflammation. S100A12 is highly overexpressed in SJIA, and the assessment of S100A12 serum levels helps distinguish SJIA from other febrile illnesses.
Objectives: The main goal of this study was to determine whether S100A12 might help distinguish SJIA-associated MAS from HLH. Methods: S100A12 serum levels were assessed in 177 samples obtained from 114 unique patients using the in-house ELISA kit. Of 177 samples, 152 samples were also available for a multiplex immunoassay including 53 cytokines and chemokines. Serum samples were obtained from 9 healthy controls, sJIA patients without MAS (17 active/ 19 remission), SJIA patients with MAS (33 active/ 33 remission), acquired HLH (22 active/ 20 remission) and 33 patients with primary HLH at disease onset. Additional data obtained at the time of serum collection included clinical features, conventional laboratory markers (CRP, ESR, differential blood count, fibrinogen, ferritin, triglycerides) and when available, NK cell function test results and sCD25 levels.
Results: Serum levels of S100A12 could differentiate patients with primary or acquired HLH from patients with SJIA-associated MAS. Levels of S100A12 > 1400 ng/ml were only seen in patients with active SJIA, either with MAS (mean ± SD 5470 ± 3042 ng/ml) or without MAS (4150 ± 3251 ng/ml), but not in patients with acquired (451 ± 351 ng/ml) or primary HLH (216 ± 170 ng/ml). Healthy controls were in a lower range (85 ± 44 ng/ml). Although S100A12 levels correlated closely with disease activity in SJIA patients (as determined by JIA core set criteria), no significant difference between SJIA patients with or without MAS was seen. Conclusion: S100A12 serum levels are useful to differentiate between SJIA-associated MAS and inherited or acquired HLH. Introduction: It is common view that macrophage activation syndrome (MAS) bears close similarities with primary hemophagocytic lymphohistiocytosis (pHLH). The resemblance of their clinical and laboratory manifestations may make it difficult to differentiate the two conditions, particularly when pHLH occurs at a later age or MAS develops at onset of systemic juvenile idiopathic arthritis (sJIA), when arthritis is not yet present. However, early discrimination is important because pHLH is often more severe than MAS and the therapeutic approaches are different Objectives: To develop and validate a diagnostic score that discriminates pHLH from sJIA-associated MAS Methods: The clinical, laboratory and histopathologic features of 362 patients with sJIA-associated MAS and of 258 patients with pHLH were collected in a multinational collaborative project involving pediatric rheumatologists and pediatric hematologists. 80% of the study population was used to develop the score and the remaining 20% constituted the validation sample. The features with the strongest association with pHLH in univariate analyses (odds ratio > 5) were further scrutinized in multivariate logistic regression procedures. Each variable that entered the best fitting model was then assigned a score, based on its statistical weight. The MH score was made up with the individual scores of the selected variables. The cut-off in the MH score that discriminated best pHLH from MAS was calculated by means of ROC curve analysis. The sensitivity (SE), specificity (SP), area under the curve (AUC) and kappa value of the MH score were calculated for both the developmental and validation samples Results: The following 6 variables entered the best fitted model of logistic regression analysis, that is, were most closely associated with a diagnosis of pHLH: age at disease onset ≤ 1.6 years, neutrophil count ≤ 1400/μl, fibrinogen ≤ 131 mg/dl, splenomegaly, platelet count ≤ 78000/μl, hemoglobin ≤ 8.3 g/dl. The MH score ranged from 0 to 123. Its median value was 97 (IQR 75-123) in pHLH patients and 12 (IQR 11-34) in MAS patients. The probability of a diagnosis of pHLH ranged from < 1% for a score < 11 to > 99% for a score ≥ 123. A cut-off value > 59 revealed the best performance in discriminating pHLH from MAS (SE = 91%, SP = 93%, AUC = 0.92, kappa = 0.85). The strong diagnostic power of the MH score was confirmed in the validation sample Conclusion: The MH score is a powerful tool that facilitates timely discrimination of pHLH from MAS. Its application in routine clinical care may aid practitioners to identify those patients who are more likely to have pHLH and may, thus, deserve diagnostic confirmation with appropriate genetic and functional testing Disclosure of Interest None Declared. Introduction: Macrophage activation syndrome (MAS) is a term used to identify hemophagocytic lymphohistiocytosis (HLH) secondary to rheumatic diseases. It is a severe and potentially fatal condition that occurs in the context of rheumatic diseases, particularly systemic JIA. It is part of secondary HLH forms. While the triggering mechanism behind pHLH is the defect in cytotoxicity, caused by mutations in genes encoding proteins required for lymphocyte and natural killer cell activity, MAS pathogenesis is not clearly understood. Our recent data on patients with MAS showed that levels of interferon-gamma (IFNγ) and of IFNγ-induced chemokines are markedly increased and are correlated with the severity of laboratory abnormalities of MAS (Bracaglia, 2016). Objectives: Based on our results in patients and on data obtained in animal models of pHLH, showing that IFNγ neutralization reverts the disease, in this study, we aim to demonstrate the role of IFNγ and the efficacy of a treatment with an anti-IFNγ antibody in a murine model of MAS. Methods: A mouse model of MAS (Strippoli R, 2012), relying on an exaggerated response to toll-like receptor ligands in mice transgenic for the pro-inflammatory cytokine interleukin-6 (IL-6TG), has been used to evaluate the activation of the IFNγ pathway and the therapeutic potential of a rat neutralizing IFNγ antibody (XMG1.2, BioXcell, USA). Results: LPS-challenged IL-6TG mice showed significantly higher mRNA levels of Infγ and higher phospho-STAT1 (Tyr701) protein levels in liver and spleen compared to LPS-challenged wild type (WT) mice. Accordingly, in LPS-challenged IL-6TG mice significantly higher mRNA expression levels of IFNγ-induced chemokines, such as Cxcl9 and Cxcl10, were observed both in liver and in spleen. The upregulation in the IFNγ pathway in peripheral tissues resulted in significantly higher circulating levels of CXCL9 and CXCL10 in LPSchallenged IL-6TG mice compared to LPS-challenged WT mice. IFNγ neutralization studies revealed that, in LPS-challenged IL-6TG mice, anti-IFNγ treatment significantly improved survival (p = 0.003) and body weight recovery (p = 0.015), compared to control antibodytreated animals. Furthermore, a significant amelioration in laboratory parameters of MAS, including reduction in ferritin levels and increase in fibrinogen levels, was observed in mice treated with anti-IFNγ Ab. Finally, in IL-6TG mice treated with the anti-IFNγ antibody circulating levels of CXCL9, CXCL10 and, notably, of pro-inflammatory cytokines were significantly reduced. The trend in circulating CXCL9 and CXCL10 levels significantly paralleled the circulating levels of proinflammatory cytokine, as well as the serum ferritin levels (Spearman r = 0.83, p = 0.0008 and Spearman r = 0.76, p = 0.003, respectively). This association of ferritin levels with circulating levels of CXCL9 and CXCL10 was confirmed also in MAS patients followed longitudinally. Conclusion: These results provide insights into the pathophysiology of MAS, further support the hypothesis that IFNγ is the unique and common mediator of all HLH forms and provide the rationale for a targeted therapy against IFNγ in MAS.

Disclosure of Interest
None Declared. disease. An ongoing study in primary HLH (pHLH) shows promising efficacy and favourable safety of NI-0501, an anti-IFNγ antibody, in the control of HLH, known to be driven by high production of IFNγ. Objectives: To describe the use of the PK and PD data of NI-0501 obtained from the ongoing clinical trial in pHLH, to define the NI-0501 dosing strategy to be used to investigate the role of IFNγ neutralization in MAS/sJIA. Methods: In active HLH the measurable circulating IFNγ levels do not account for the total amount of the cytokine present in the body. Following the administration of NI-0501 in pHLH patients, the measurement of "total IFNγ", namely free and bound to NI-0501, is used as a surrogate for IFNγ production, revealing the high production of this cytokine, despite the relatively low "free IFNγ" levels at baseline in blood. Extrapolations from these data allowed estimation of IFNγ production in MAS/sJIA patients, based on the levels of IFNγ-related chemokines present at baseline. Results: The measurement of total IFNγ levels in pHLH revealed that the IFNγ concentration to be neutralized by NI-0501 was several hundreds fold higher compared to what indicated by the baseline free IFNγ level (median IFNγ at baseline <50 pg/ml; at peak 17'858 pg/ ml). Total IFNγ at 48 hours post NI-0501 administration tightly correlates with IFNγ-related chemokines levels (CXCL9: r = 0.6264, p = 0.0008; CXCL10: r = 0.6931, p = 0.0001), suggesting that CXCL9 and CXCL10 concentrations are an excellent marker of the presence of biologically active IFNγ. The amount of IFNγ produced in MAS/sJIA patients was then indirectly estimated on the basis of the total IFNγ concentration in pHLH patients with comparable levels of CXCL9 and CXCL10 following the administration of NI-0501. This information, coupled with modelling and simulation techniques, has allowed to i) determine the NI-0501 dose expected to neutralize rapidly the total amount of IFNγ in the majority of MAS/sJIA patients, ii) identify an appropriate frequency of NI-0501 administration to avoid unnecessary drug accumulation. Conclusion: The methodology applied allowed a precise determination of the dosing strategy to be tested in the future trial, significantly reducing the risk of exposing patients to non-therapeutic NI-0501 doses.  . Diagnosis of MAS in sJIA is difficult to distinguish from a flare of sJIA or sepsis. Since vascular endotherial and tissue damage are worsen by the hour in MAS, early diagnosis is crucial and treatment should be promptly initiated. The assessment of changes in laboratory data that indicates tissue damage, hemophagocytic activity, endotherial damage and hyper coagulationfibrinolysis system is necessary. MAS is caused by excessive activation of T cells and macrophages, leading to production of massive pro-inflammatory cytokines, hemophagocytic activity and massive inflammatory responses. The disregulation of the augmentation or degradation of inflammation is considered to be related to the pathology of MAS. Objectives: -To present a case of 2 year old girl diagnosed and treated for sJIA complicated with MAS -To assess changes over time of the laboratory data and serum cytokine and chemokine profiles of Interleukin(IL)-6, IL-18, Interferon(IFN)-γ, IFN-γ inducible protein (IP)-10/CXCL10, and serum High mobility group box (HMGB)-1 concentration. Methods: We retrospectively reviewed the case record and laboratory findings. IL-6, IL-18, IFN-γ, IP-10 and HMGB-1 of frozen serums were measured by ELISA. Results: A 2 year-old girl presented with 5 days of fever, rash, poor appetite, hip and knee joint pain and cervical lymphadenopathy. Blood investigations had shown neutrophilia, thrombocytosis, and raised inflammatory markers (CRP, ESR, Ferritin). She was initially diagnosed with Kawasaki disease and was treated with IV Immunoglobulins. Because she continuously presented remittent fever, she was treated with high dose corticosteroids as sJIA. The 18 days after the onset, her laboratory data showed anemia, low platelet count, significantly elevated LDH (2,075 IU/L) and ferritin (33,359 ng/dL), and high AST, triglycerides and sIL-2R. She was transferred to our hospital. In the view of remittent fever, typical rash, lymphadenopathy, splenomegaly, arthritis, we diagnosed her as sJIA complicated with MAS and started treatment with dexamethasone palmitate and cyclosporine which led her recovery from MAS. Because the reduction of corticosteroids doses was difficult, she was administered tocilizumab. After 5 months of first episode of MAS, fever, and elevated LDH and ferritin were observed again. We initiated treatment for Beginning of MAS. One month after second episode of MAS, her blood cell count and laboratory inflammation markers were back to normal. Next, we investigated changes of her serum cytokines, chemokine, and HMGB-1 over time in the course of treatment. The levels of serum IL-6 and IL-18 were extremely high at the onset of the sJIA, and a significant level of serum IL-18 was persistent. Although concentrations of IFN-γ and IP-10 were low at the time of remittent fever, these levels were remarkably elevated at a few days before the diagnosis of MAS, then decreased to undetectable levels at the recovery from MAS. On the other hand, the level of HMGB-1was increased at the time of remittent fever, and decreased during MAS.  Objectives: To describe all the cases of MAS presenting to a paediatric rheumatology clinical network over a 9 year period, specifically investigating underlying diagnosis, if the episode of MAS was part of the initial presentation or later in the disease course and the applicability of the current published diagnostic and classification criteria. Methods: Retrospective case note review. Results: 19 cases of MAS were identified. 9 were male and 10 female, with an age range of 13 months to 16 years, mean age 10.1 years. All cases had a peak ferritin level of >1070 μg/l. The most common underlying diagnosis was SoJIA in 11, followed by SLE in 4, 1 polyarteritis nodosa, 1 juvenile dermatomyositis, 1 reactive and 1 an immune deficiency. 13 cases of MAS occurred during the initial presenting illness. Only 6 children were known to have an underlying rheumatological diagnosis prior to their MAS episode. Of those 6, 3 had their underlying diagnosis changed during the episode of MAS, 1 from psoriatic arthritis to SoJIA, 1 from polyarticular JIA to SLE and 1 from polyarticular JIA to an underlying MHC class II deficiency. 3 children in the cohort died; 1 directly from MAS, the other 2 from complications of the underlying disorder. Applying the existing diagnostic criteria to our cases; 5 of the 19 cases of MAS fulfilled the HLH criteria 1 , 9/11 of the cases with a final underlying diagnosis of SoJIA fulfilled the original Ravelli et al 2005 criteria 2 , 5/11 fulfilled the latest Ravelli 2016 criteria 3 and all 4 children with SLE fulfilled the Parodi criteria 4 for MAS in association with SLE. Conclusion: 68% of the cases of MAS in our series presented without an underlying diagnosis. As MAS is difficult to diagnose in children with underlying rheumatological disorders, this difficulty is heightened in children without an underlying disease whose clinical and laboratory features cannot be applied to the existing diagnostic criteria, all developed for use with known underlying conditions. It is essential that awareness is raised of this serious disorder amongst general paediatricians to avoid delays in diagnosis and treatment which could potentially increase morbidity and mortality. There is a need for the development of diagnostic criteria which can be used in cases where the episode of MAS is part of the initial presentation of the underlying condition. In our series, the majority of cases of MAS present in this way.
Introduction: Innovative, clinical and translational European research in rare diseases mandates collaborations across national borders. However, researchers funded to conduct these critically important studies struggle with the dramatic heterogeneity within and across European countries in research including ethics approval process, frameworks for data and sample collection and sharing. Currently there is no EU-wide framework enabling paediatric research. Objectives: To systematically review the published evidence for best practice in international paediatric research and to establish European recommendations for collaborative paediatric research in paediatric rheumatology. Methods: Within the defined, innovative SHARE framework a scoping review was conducted identifying barriers for collaborative paediatric research. Subsequently, an international expert panel defined the search keywords and strategies of collaborative paediatric research and biobanking. A systematic literature review was performed and reported according to PRISMA guidelines. Published evidence was evaluated and synthesized, recommendations were drafted. In an iterative process, recommendations were refined following in-depth discussion, revisions and reviews with leading Ethics Board members and European experts for ethical and legal aspects of paediatric research. The refined recommendations were shared with European national leaders, reviewed and revised. At the final face-to-face consensus meeting all proposed recommendations were reviewed by the 17 international members of the SHARE expert committee including patient representatives. Each proposed recommendation was discussed in-depth using Nominal Group Technique and voted on requiring an agreement of 80% for inclusion. Results: The scoping review identified four key domains of barrier for collaborative paediatric research including legal, process, research partner-and patient-related barriers. The comprehensive systematic literature review returned 1286 publications. Stepwise primary and secondary screening using pre-defined criteria resulted in a total of 223 papers, of which 85 papers were included; the evidence levels were determined. A total of 21 recommendations were drafted grouped into the domains of 1) general principles (recommendation 1.  Introduction: Methotrexate (MTX) is the most widely used diseasemodifying anti-rheumatic drug in the treatment of juvenile idiopathic arthritis (JIA); however, no unequivocal predictive single nucleotide polymorphism (SNP) has been found yet [1]. Objectives: The goal of this study was to determine whether the IL6 gene -174G > C (rs1800795) SNP is associated with the response to MTX in patients with JIA. Methods: The study included 276 patients with JIA who were divided into 7 subgroups according to the ILAR classification. The disease was considered more severe if the MTX treatment was required. The response to MTX was analyzed in 176 patients. The response was considered good if patient achieved clinical remission on medication (Wallace), otherwise it was regarded as insufficient. Genotyping was executed using real-time PCR method. Statistical analysis was performed using two-tailed Fisher's exact test (p), odds ratio (OR), 95% confidence interval (95% CI) and logistic regression. Results: The alleles and genotypes distribution of the IL6 gene -174G > C SNP was similar in patients with (n = 257) and without (n = 16) requirement of the MTX treatment (p = 0.692). When analyzed according to the MTX response there was only a trend toward a higher proportion of the GC genotype and a lower proportion of the GG genotype in JIA patients who had not achieved clinical remission on medication (n = 107) than in those who had achieved (n = 69) (55.1% vs. 40.6%, p = 0.065 for the GC genotype and 32.7% vs. 46.4%, p = 0.081 for the GG genotype, respectively). The same analysis was performed separately for the patients with the three most frequent JIA subtypes: persistent oligoarthritis (n = 110), RF-negative polyarthritis (n = 81) and systemic JIA (n = 28). The C allele frequency was significantly higher, while the G allele and the GG genotype frequencies were significantly lower in persistent oligoarthritis patients with an insufficient response to MTX (n = 20), than in those with a good response (n = 32) (55.0% vs. 29.7%, p = 0.013, OR = 2.90, 95%CI 1.23-6.60 for the C allele; 15.0% vs. 53.1%, p = 0.0083, OR = 0.16, 95%CI 0.04-0.66 for the GG genotype; 45.0% vs. 70.3%, p = 0.013, OR = 0.35, 95%CI 0.15-0.81 for the G allele, respectively). The best model of inheritance was dominant, where the presence of the C allele marked an increased risk of an insufficient response to MTX (CC + GC vs. GG, p = 0.0043, OR = 6.42, 95% CI 1.57-26.31). No significant differences were observed for patients with two other subtypes. On the contrary, there was a trend toward a decrease of the frequency of the CC genotype in children with RF-negative polyarthritis and an insufficient response to MTX (p = 0.058). It should be noted, that the C allele and the CC genotype frequencies were significantly higher, and the G allele frequency was significantly lower in patients with persistent oligoarthritis, than in other children with JIA (45.0% vs. 33.7%, p = 0.0094, for the C allele; 21.8% vs. 10.8%, p = 0.016, for the CC genotype; 55.0% vs. 66.3%, p = 0.0094, for the G allele). Smaller sample sizes could partially explain the lack of the association of the IL6 gene -174G > C SNP with the response to MTX in patients with RF-negative polyarthritis and systemic JIA. Conclusion: In this study we revealed that the C allele of the IL6 gene -174G > C SNP may serve as a marker of increased risk of an insufficient response to MTX in patients with persistent oligoarticular JIA. Introduction: A 3 year-old boy was investigated for skin lesions on lower and upper limbs. His family history was unremarkable. He was born by forceps delivery at 42 weeks following a pregnancy with normal antenatal scans. He walked independently at about 19 months of age. Parents reported that he had been previously diagnosed with an autistic spectrum disorder and had suffered from recurrent upper airway infections, including severe episode of croup requiring an admission to intensive care at the age of 2 years. Screening for immunodeficiency only revealed persistent mild lymphopenia. On physical examination he had macrocephaly (head circumference >97.5th centile), and had an unusual vasculitic rash with distinct circinate pattern. Skin biopsy revealed thrombotic lymphocytic vasculitis with absence of immune-complex deposition on immunofluorescence.
Objectives: The presence of both autism, macrocephaly, and unusual vasculitic rash prompted us to screen him using a targeted next generation sequencing gene panel, called the "vasculitis and inflammation" (VIP) panel, described more detail in a separate abstract.
Methods: The Agilent SureDesign tool was used to design an NGS panel targeting 113 genes, grouped into 9 broad clinical phenotypes: autoinflammatory disease; monogenic vasculitis/vasculopathy; complement defects; monogenic lupus; HLH; early-onset inflammatory bowel disease; autoimmune lymphoproliferative syndromes; monogenic stroke; and hereditary amyloidosis. The targeted region includes coding exons, conserved non-coding exons, upstream promoter regions, and splice sites. Captured and indexed libraries (QXT Target Enrichment System) were sequenced as a multiplex of 16 samples on an Illumina MiSeq sequencer in paired-end mode. Read alignment, variant calling, and annotation were performed using Agilent SureCall v3.0 software. Validation of the VIP gene panel is described in a separate abstract.

Results:
The results showed a mutation in the PTEN gene, c.650 T > A, p.V217D, which encodes for Phosphatase and tensin homolog protein, mutation of which is associated with Cowden Syndrome (CS), and related entities. CS, also known as "Multiple hamartoma syndrome" is a rare autosomal dominant inherited disorder characterized by hamartomas in the skin, mucous membranes, thyroid gland, and breast tissue. Patients with CS are at increased risk of cancer including breast, thyroid, endometrial, and renal cancers. Mutations in PTEN, a tumour suppressor gene, lead to hyperactivity of the mTOR pathway. Clinical clues for possible diagnosis are macrocephaly, and at least one of autism, dermatologic features, vascular features and gastrointestinal polyposis. The association between CS and immune dysregulation has been described in a few cases, and was the reason we included this gene in our VIP gene panel. PTEN is an important regulator of T-cell maturation, and we speculate that lymphocytic vasculitis could be linked to this genetic mutation, although the exact mechanism remains uncertain Conclusion: We conclude that our targeted VIP panel revealed a diagnosis that we hitherto had not considered, and provides a further evidence of the diagnostic utility of this approach. Disclosure of Interest None Declared. Introduction: Down's Arthropathy (DA) was first reported in the literature in 1984. Crude estimates suggest higher incidence and prevalence rates of DA compared with Juvenile Idiopathic Arthritis (JIA), (JIA prevalence 1/1000, estimated DA prevalence 8.7/1000). Despite this fact, there remains a paucity of data on this condition. DA is rarely recognised at onset, & remains under-diagnosed. As a direct consequence children with DA are presenting with significant joint damage and disability at diagnosis. Objectives: · Perform a musculoskeletal examination on children with Trisomy 21 (T21) aged 0-20 years Methods: Children with T21 were invited to attend a screening clinic. Screening involved completion of a health questionnaire & a comprehensive musculoskeletal examination. DA cases detected were investigated & managed as per normal clinical practice. Data on a convenience sample of 33 newly diagnosed children with JIA was collected to create a comparison group. Results: 503 children with T21 have been screened for DA, 22 new cases have been diagnosed. All of these children had poor language skills or were non-verbal. Only 11% of the parents suspected that their child may have arthritis prior to attending our screening clinics, and this was only after reading our recruitment literature. In total, we now have 33 children attending our centre with DA (combining cases attending pre-dating the start date of the study). This suggests the prevalence of DA in Ireland is 18-21/1000. The majority of children presented with a polyarticular pattern of disease. No cases of uveitis have been observed to date. 88% of the DA cohort had small joint involvement of the hands, significantly higher than that observed in the JIA comparison group. Erosive changes were reported on X-Ray in 29.2% of the DA cohort (9.5% in the JIA Cohort). Methotrexate-associated nausea was a significant barrier to treatment with this DMARD in DA. There was a significant delay in diagnosis of DA, 1.7 years v 0.7 years in the JIA cohort. Conclusion: Children with T21 are at increased risk of developing arthritis. There is a lack of awareness of this risk among health care professionals & the general public at large. This almost certainly contributes to poor recognition of the disease and a delay in diagnosis. The predominant pattern of disease is polyarticular small joint arthritis. Treatment with standard protocols used in JIA is complicated by drug-associated side effects in children with T21. However, a good response to treatment with steroid intra-articular joint injections has been observed. Our study has raised a number of questions. Future research to accurately define this disease & identify best practice with regards to treatment would be invaluable. We advocate that all children with T21 should have annual musculoskeletal examination as part of their health surveillance programme. Disclosure of Interest None Declared. Introduction: Musculoskeletal complications of Trisomy 21 (T21) are common. Almost all children with T21 have muscle hypotonia and joint laxity. The combination of this ligamentous laxity and low muscle tone contribute to an increased risk of a number of musculoskeletal disorders, a delay in acquisition of motor milestones and lower levels of physical activity. Inappropriately low expectations of physical activity and motor function from family, health care workers and self, and over-attributing motor difficulties to low tone and hypermobility may lead to missed pathology and misdiagnoses. Objectives: 1. To describe the musculoskeletal anomalies observed in a national cohort of children with T21 2. To calculate the average age children with T21 walked unaided in our cohort. Methods: Over an 18-month period, children with T21 were invited to attend for a musculoskeletal assessment by a paediatric doctor. Relevant musculoskeletal history and clinical findings were documented. Results: 503 children with T21 were examined (56% male). Median age 8.1 years (0.6-19.2 years). Musculoskeletal Anomalies and Trisomy 21. Pes Planus was the most common musculoskeletal anomaly detected, occurring in 91.1% of the children with T21 examined. Just under a quarter of these children did not avail of orthoses (23.6%). A range of other anomalies were observed, inflammatory arthritis (7.1%) and scoliosis (4.8%) occurring most frequently after pes planus. Other spinal abnormalities included the well-documented T21 associated c-spine instability, absent C2 vertebra and spondylolisthesis. Common hip and foot pathologies included dislocations, Perthes disease, slipped upper femoral epiphysis (SUFE) and hallux valgus. Ambulation and Trisomy 21. The median age our cohort walked was 28 months (12-84 months). This is comparable to the literature that reports children with T21 walk at 23 months (range 13-48), compared with 12 months (range 9-17) for the general paediatric population. Conclusion: Children with T21 are at increased risk of a number of potentially debilitating musculoskeletal problems. Early, regular and continuous musculoskeletal assessment of children with Down syndrome is paramount to management of musculoskeletal conditions. The aim is to avoid children presenting with irreversible, preventable joint damage and disability due to delayed or incorrect diagnosis and management of these very treatable conditions. Key Message(s) -Pes planus is common in children with Trisomy 21, therefore early consideration of orthotics and life-long appropriate supportive footwear is advised.
-When a child with Down syndrome presents with a limp they should always be referred for a hip x-ray.
-A high index of suspicion for pathology should be employed when assessing a child with Down syndrome presenting with change and/ or deterioration in function and mobility.
-Inflammatory arthritis in children with Down syndrome is common and potentially erosive and debilitating if left untreated.
-Significantly delayed ambulation is noted in children with T21. Variability exists in the basic biomechanics of the musculoskeletal system in children with Down syndrome in terms of motor control, coordination, and skill. Multidisciplinary team assessment and management should be early, regular and ongoing to ensure these children reach their potential with regards to motor function. -Compulsory annual musculoskeletal assessment for all children with T21 would enable early detection of potential problems, allowing for timely intervention and in-turn better clinical outcomes. Disclosure of Interest None Declared. Introduction: Coffin-Siris (CSS) and Nicolaides-Baraitser (NBS) are two overlapping syndromes caused by mutations in genes associated with the chromatin remodeling complex, which are associated with multiple malformations and intellectual disability. Musculo-skeletal changes, such as prominence of inter-phalangeal joints in hands, feet, and knee joints are very common in NBS (up to 75%), and also reported in CSS. These changes are usually considered to be dysplastic in nature rather than inflammatory, however. Objectives: To identify the genetic cause in a child with some clinical features suggestive of NBS and diffuse polyarthritis. Methods: We performed Whole Exome Sequencing (WES) on the proband and immediate family members. WES results were confirmed by conventional Sanger sequencing. Results: Case report-We present the case of a 7 year old boy with a long standing boggy polyarthritis, a previous history of developmental delay, microcephaly (<4th centile), and distinct dysmorphic features that were reminiscent of Nicolaides-Baraitser Syndrome. However, Sanger sequencing of the SMARCA2 gene was negative (wild-type). There were no signs of uveitis. Laboratory tests showed normal inflammatory markers, negative autoantibody screen, and normal complement levels. Synovial biopsy confirmed the presence of a chronic inflammatory synovitis consistent with juvenile idiopathic arthritis. Brain MRI revealed a dysgenetic corpus callosum. Treatment was started with methotrexate (15 mg/m 2 /week, subcutaneously), which failed to control the polyarthritis; etanercept was subsequently added, leading to significant improvement. Whole exome sequencing (WES) was performed on the patient and immediate family members, revealing a novel, de novo heterozygous missense mutation in exon 20 of the ARID1B gene, resulting in a premature stop codon at amino acid position 1802 (c.C5404T; p.R1802X), thus confirming the diagnosis of CSS. Sanger sequencing confirmed the presence of the mutation in the patient and segregation with disease within the family. Conclusion: This case illustrates yet again the power of nextgeneration sequencing to provide molecular confirmation of a rare diagnosis, CSS caused by a heterozygous mutation in ARID1B. The absence of significantly raised inflammatory markers, in addition to a suspected clinical diagnosis of a genetic syndrome known to be associated with skeletal dysplasia almost certainly contributed to this patient's polyarthritis not being recognized for several years. We propose that inflammatory arthritis may be an important feature of CSS and related syndromes. In general, it is increasingly recognized that some patients with skeletal dysplasia may also have inflammatory arthritis, and early recognition of this and appropriate treatment may reduce morbidity and long-term damage. Objectives: The objective of this study was a longitudinal whole transcriptome analysis of children with sJIA during the early phase of treatment with IL-1 antagonists to identify novel targets that predict response to therapy. Methods: From the database of the German AIDnet database, patients with sJIA and active systemic disease treated with anakinra and subsequent remission were identified. Clinical data was obtained by retrospective chart review. Whole blood was drawn during active disease before initiation of anakinra and after achievement of remission. RNA was extracted and subjected to Affymetrix HTA 2.0 Arrays followed by intraindividual analysis of regulated genes in each patient and combined analysis of the genes in all the patients including GO analysis of differentially expressed genes. In addition regulatory genomics toolbox motif enrichment analysis was performed to identify transcription factors and pathways that are redulated during therapy. Results: Six children with sJIA with active systemic disease were included in the study. Using a p-value of <0.01 and a fold change of 2 or greater, 742 genes were identified of which most were associated with immune mediated processes. Using a fold change of higher than 3 as a more stringent criterium, still more than 100 genes remained. Our analysis revealed HLADRB1 as the most strongly upregulated gene in remission compared to active disease (FC 6.8). This gene has been recently identified as a risk factor in an association study of 982 children with sJIA and 8,010 healthy control subjects. Moreover besides e.g. S100A8 as known disease marker an upregulation of CD177 during active disease was identified, which is a molecule engaged in neutrophil activation and transmigration and has not been described in previous studies. Motif analysis revealed upregulation of promoters bound by STAT3 and STAT4 in active disease, transcriptionfactors downstream of IL-6 and IL-12 signaling respectively. Conclusion: Our study identifies the strong up-regulation of HLA-DRB1 in patients with sJIA in remission upon treatment with IL-1 antagonists. This provides a functional confirmation of a previous study, which identified HLA-DRB1 as a risk factor in sJIA. Additionally CD177 was observed as a possible new marker in sJIA. Studies with larger patient cohorts are necessary to confirm these results. Disclosure of Interest None Declared. Introduction: In recent years S100A8 and S100A9 proved to be reliable biomarkers in chronic inflammatory disorders especially in systemic and non-systemic forms of juvenile idiopathic arthritis (JIA). They are highly expressed and released at local sites of synovial inflammation. On a molecular level these proteins function as damageassociated molecular pattern molecules (DAMPs), which amplify inflammation by binding to Toll-like receptor-4 (TLR-4). Released from activated phagocytes or necrotic cells the physiologically relevant S100A8/A9 heterodimers stimulate surrounding cells in order to promote pro-inflammatory processes in innate immunity. Activation of dendritic cells (DCs) via TLR-4 is believed to further trigger adaptive immunity. Interestingly, we now identified a novel immuneregulatory function of S100 proteins in monocyte-derived DCs.
Objectives: This study aims to demonstrate the underlying mechanisms of immune regulation by S100 proteins in DCs on a molecular as well as functional level. Methods: Human monocyte derived DCs are differentiated with or without exposure to S100A8 for six days prior to activation with LPS. After characterization and determination of the activation status using flow cytometry, the ability of these cells to induce autologous CD4 + , CD8 + , and γδ T-cell proliferation is investigated in co-cultures in vitro. In addition cytokines and chemokines, secreted during DC differentiation and DC/T-cell co-culture, where analyzed by Luminex cytokine arrays. The metabolic state of DCs was further examined by using Seahorse XFp Analyzer assays. To identify the molecular mechanisms leading to the observed phenotype the mRNA expression of human DCs at various stages of differentiation was screened by genome-wide gene expression arrays. Results: Our results demonstrate that S100A8 exposure to developing monocyte-derived DCs impairs differentiation and subsequent activation of DCs and therefore leads to an unresponsive, immunesuppressive DC phenotype. This phenotype is characterized by significantly reduced surface expression of cell-type specific activation markers and diminished cellular glycolysis and mitochondrial respiration. Furthermore, suppressive DCs secrete reduced amounts of proinflammatory IL-1β and IL-6, IL-12 and IL-18 and chemo-attractant CCL19 and CXCL10 whereas the secretion of many other cytokines and chemokines is not affected. In co-cultures with autologous Tcells, suppressive DCs show significantly reduced potential to induce T-cell proliferation in CD4 + , CD8 + , and γδ T-cells. Genome-wide gene expression analysis on RNA level and subsequent studies of the affected transcription factor networks indicated a novel role of the well-known master regulator of LPS-induced genes C/EBPδ for the induction of S100-induced suppressive DCs. We already confirmed the differential S100-induced expression of C/EBPδ on protein level.
Conclusion: Taken together, our results represent a novel regulatory mechanism of S100A8 in innate immunity to prevent overwhelming immune responses. A disturbed balance of this regulatory mechanism of S100A8/S100A9 on adaptive immunity and the well-known TLR-4-dependent pro-inflammatory effects of these potent DAMPs on innate immune cells may play a significant role in the inflammatory process of JIA. Disclosure of Interest None Declared. Introduction: The potential of expanded flow cytometric analysis of peripheral blood lymphocytes (PBLs) has not been yet been fully exploited to study JIA heterogeneity neither to monitor JIA patients' on biological treatments. Objectives: To analyze in depth lymphocyte subpopulations in treated JIA patients stratified by age and gender. Methods: 101 patients, 69 pediatric and 32 adult fulfilling JIA (ILAR) criteria attending HUVH rheumatology clinic were included. All patients were treated with either MTX, anti-TNFα, or a combination of both. Controls were sex/age matched volunteers either healthy or attending the clinics of HUVH for non inflammatory conditions (59 controls, 29 pediatric and 30 adult). Demographical, clinical and analytical variables were recorded. Extended immunophenotype following a protocol based on the Human ImmunoPhenotyping Consortium (HIP-C) protocol that discerns 57PBL subpopulations was applied. Bonferrroni's correction indicated that the cut off for significance was p < 0.00041667. Human ImmunoPhenotyping Consortium (HIP-C)FITMaN protocol that discerns 57PBL subpopulations was applied. Bonferrroni's correction indicated that the cut off for significance was p < 0.00041667. Results: Changes common to each group of patients irrespective of treatment are as follows: pediatric patients showed lower percentage of CD8 effector cells (CD45RA + CCR7-) when compared to controls (10.53 ± 5.71 vs 16.92 ± 5.71). Percentage of total CD4 cells was higher on JIA children than in controls (42.21 ± 7.40 vs 36.04 ± 5.22). No differences were found on percentages nor in absolute number of Th1 (CXCR3 + CCR6-), Th2 (CXCR3-CCR6-), or Th17 (CXCR3-CCR6-) CD4 cells. Interestingly all Th subpopulations showed decreased expression of HLA-DR in JIA children when compared with controls (6.06 ± 3.08 vs 10.49 ± 5.02; 0.81 ± 0.51 vs 1.48 ± 0.64; 8.57 ± 3.81 vs 12.6 ± 4.95; respectively). JIA adults presented no significant differences in T cells subpopulations compared to HC, but showed higher percentage of CD21-switch-memory B cells (IgD-IgM-CD27-) than controls (10.82 ± 5.33 vs 4.29 ± 4.33). Regarding the treatment followed just in JIA patients few differences were observed. Pediatric patients treated with MTX (n = 27) showed a lower proportion of the effector memory (CD45RA-CCR7-) cells both CD4+ and CD8+, when compared to controls, anti-TNF, and anti-TNF plus MTX groups (20.01 ± 7.76 vs 27.64 ± 9.27; 20.01 ± 7.76 vs 27.84 ± 4.27; 20.01 ± 7.76 vs 27.07 ± 10.05; for CD4s and 26.42 ± 7.23 vs 37.10 ± 12.38; 26.42 ± 7.23 vs 42.08 ± 11.59; 26.42 ± 7.23 vs 37.27 ± 12.54 for CD8s, respectively). Percentage of CD25+ lymphocytes was higher in the anti-TNF plus MTX group. The Th1-17 (CCR6 + CXCR3+) CD4 cell subpopulation was significantly increased in anti-TNF and anti-TNFα plus MTX groups compared with controls and MTX (10.45 ± 3.14 vs 6.38 ± 3.89; 10.45 ± 3.14 vs 4.78 ± 2.56 and 9.43 ± 4.63 vs 6.38 ± 3.89; 9.43 ± 4.63 vs 4.78 ± 2.56, respectively). Adult patients treated with anti-TNFα + MTX and MTX presented higher levels of CD21-naïve B cells compared to HC and to anti-TNF groups (4.86 ± 3.24 vs 2.32 ± 1.69; 4.86 ± 3.24 vs 2.95 ± 1.94 and 5.38 ± 1.54 vs 2.32 ± 1.69; 5.38 ± 1.54 vs 2.95 ± 1.94). Conclusion: In depth phenotypic analysis of PBL in JIA showed alterations in cell subpopulations that seem dependent on age group, and also can be a valuable tool for monitoring and comparing JIA treatments. Disclosure of Interest None Declared. In the I group included 115 children with JIA (mean age 11,9 ± 3,4 years), II group consisted of 34 children with JS (mean age 12,4 ± 2,8 years), III -18 children with SLE (mean age 13,1 ± 1,7 years). All the children were identified content tumor necrosis factor alpha (TNF-alpha), content of primary and secondary lipid peroxidation products, as well as levels of water-soluble and fat-soluble antioxidant capacity of substances in the serum. Results: According to the results of the study found a significant increase in TNF-α in serum in children with JIA, SLE (P <0.01) and JS (P <0.001) when compared with the control group. The individual values of serum TNF-α were elevated in 27 (79.4%) patients with JS, in 98 (85.2%) of children with JIA, all children with SLE. The maximum value of this index were observed in patients with JS with rapidly progressive course of the disease (298,6 ± 19,3 pg/ml) and in children with systemic JIA option (273,98 ± 24,7 pg/ml). Correlation analysis revealed the relationship between TNF-α level and disease activity (r = 0,73; P < 0.001), between TNF-α and CRP (r = 0,64; P < 0.01). The content of TNF-α was significantly higher in patients with high values of rheumatoid factor (RF) than in children with normal RF levels (P < 0.05). A significant role in the development and progression of RD plays acceleration of lipid peroxidation and antioxidant system inconsistency. The study found a significant (P < 0.05-0.001) increasing of lipid peroxidation products in the blood serum of patients of all clinical groups compared with the control group. Oxidized lipids have antigenic properties, triggering autoimmune processes of tissue damage. During the correlation analysis found a positive correlation between the levels of dienketones and dienkonyugates serum and erythrocyte sedimentation rate (r s = 0,287, P < 0.001). The study in children of all clinical groups found significant (P < 0.001) reduction in serum ACW and ACL substances when compared to the control group, suggesting disturbance antioxidant protection. A negative correlation between the level of TNF-α and ACL in the blood serum (r s = -0,346, P < 0.05) between the content of ACW and TNF-α in the serum (r s = -0,54, P < 0.001) established.

Conclusion:
The results indicate that an increase in TNF-α level at RD reflects inflammatory activity of the disease. The observed increase in the content of primary and secondary products of lipid peroxidation in the serum, as well as reducing the level of water-soluble and fat-soluble antioxidant capacity in serum substances in children with JIA, JS and SLE indicates an increase in activity of lipid peroxidation and a decrease in antioxidant defense mechanisms. Disclosure of Interest None Declared. Introduction: For rheumatic diseases (RD) is characterized by the frequent combination with comorbid infection, mainly respiratory and urinary systems. Attention to this issue is primarily due to the fact that infectious complications are a leading cause of adverse outcomes in RD. Early inclusion in the treatment of immunosuppressive drugs and genetic engineering of biological drugs has significantly changed the course and outcomes of the disease and at the same time causes the activation of latent fear of current comorbid infections. In this connection the question arises about how to prevent the emergence and worsening of chronic infections, especially bronchopulmonary and urinary systems, complicating the course of the underlying disease and require additional treatment costs. Objectives: to determine the frequency and the role of comorbid infections in children with rheumatic diseases. Methods: The rheumatology department of the 4th City Children's Clinical Hospital of Minsk were examined 167 patients with RD, among them 115 children with juvenile idiopathic arthritis (JIA) (mean age 11,9 ± 3,4 years), 34 children with juvenile scleroderma (JS) (mean age 12,4 ± 2,8 years) and 18 children with systemic lupus erythematosus (SLE) (mean age 13,1 ± 1,7 years). Results: Infection as a cause of the disease most often referred to patients with JIA and SLE. The most common respiratory diseases observed patients with JIA (55,6%) and SLE (61,1%). Patients with JIA often enough noted the presence of nasopharyngeal infections (sinusitis, pharyngitis and bronchitis -18, 29 and 14 patients respectively), and patients with a JS (24, 15 and 21 patients respectively). Often sick colds 21,7% of children with JIA and 38.9% of children with SLE, as well as 17,6% of children with JS. Sore throat worried children with RD, on average 2 times a year. More than half of the children observed the occurrence of arthralgias against a background of infections this location. About 1/3 of patients responded positively to the question about the relationship of acute illness with acute respiratory viral infection (35,6% with JIA, SLE 38,9 and 17,6% with JS). Among the 16 children with JIA treated with MTX and adalimumab, respiratory tract infection occurred in 18,7%, including serious -at 6,3%. Cold sores on the lips, nose, wings and other parts of the face, most children appear 2-3 times a year, in some cases up to 7-8 times a year. The most prone to relapse of viral infection were patients with SLE (61,1%), less frequently such episodes occurred in children with JIA (42,6%) and JS (32,8%). Urinary tract infection was observed in 17,3% of children with JIA, 27,8% of children with SLE and 23,5% JS. The frequency of urinary tract infection in children with JIA treated with methotrexate and TNF-alpha inhibitors was 4,1% with methotrexate, 6,3% with TNF-alpha. At the same time in the presence of patients in the history of this disease is the risk of infection is significantly increased. Conclusion: The findings suggest first of all about the importance of infection in the initiation of a number of rare-earth and the need for careful history in patients with RD, which will reveal their comorbid infections that can complicate the course of the underlying disease, and to select the optimal treatment strategy. Disclosure of Interest None Declared. Introduction: Juvenile idiopathic arthritis (JIA) summarizes a group of phenotypically heterogeneous chronic inflammatory disease of childhood. The innate immunity is playing a role in the pathogenesis of JIA. Complement is activated by three pathways (classical pathway (CP), lectin pathway (LP) and alternative pathway (AP)). In RA a high turnover of C3, C4 and C5 in inflamed joints is discussed. The role of the complement system in the pathogenesis of JIA is still unclear.
Objectives: This is a controlled prospective observational study. It is focused on the three pathways of complement system (CS) and its effector, the membrane attack complex (MAC), associated with disease activity and inflammation markers in all subgroups of JIA. (Trial numberUN373). Methods: Peripheral blood samples (PB) (n = 158) of 57 pediatric JIA patients (partially also in longitudinal visits), were analyzed for specific complement pathway activation (COMPL300 ELISA), complement factor H (CFH)-autoantibodies (CFHAb ELISA) and the soluble MAC (sC5b-9 ELISA) in serum (S) and EDTA-plasma (P)-The JIA subgroups were persistent Oligoarthritis (perOA, n = 19), extended Oligoarthritis (extOA, n = 8), rheumatoid factor positive Polyarthritis (PARF+, n = 4) and negative Polyarthritis (PARF-, n = 12) polyarthritis, Enthesitis related arthritis (ERA, n = 4); Psoriatic arthritis (PsA, n = 3) and systemic JIA (sJIA, n = 7). As control group We tested s(n = 118) healthy adults (n = 100) and children (n = 18) without inflammatory diseases were tested. JADAS10 Score defined acute phase of disease. Conclusion: Special groups of JIA showed increased CS activation with elevated levels of MAC in PB in acute phase of disease. The additional decreased capacity in the CP and AP suppose that the complement system as an additional contributor in pathogenesis and/or course of the acute disease. Therefore the testing of COMPL300 in combination with sMAC could be a helpful biomarker for acute JIA disease and furthermore the pharmaceutical blockage of parts of the complement system might be a therapeutical option in therapy resistant patients. Disclosure of Interest None Declared. Introduction: JMML (juvenile myelomonocytic leukemia) is a clonal proliferation of hematopoietic stem cells that is characterized by the absence of Philadelphia chromosome and affects usually children younger than 2 years. To set the diagnosis the three major criteria (absence of Bcr-Abl translocation, peripheral monocytosis and presence of less than 20% of blast cells in peripheral blood) are needed and they have to be associated with at least two of the five minor criteria (fetal hemoglobin increased for age, immature granulocytes in the peripheral blood, white blood cell count greater than 1 × 109/L, clonal chromosomal abnormality, granulocyte-macrophage colony-stimulating factor hypersensitivity of myeloid progenitors in vitro). Objectives: We describe the case of one patient affected with JMML with homozygous Cbl mutation who develops a severe steroid dependent uveitis. Methods: A 7-year-old male patient came to our attention because of a severe steroid dependent uveitis. The boy had been diagnosed at the age of two with JMML due to hepatosplenomegaly, persistent monocytosis, presence of blast cells in the bone marrow and Cbl homozygous mutation: the disease showed an indolent behavior, and was therefore controlled on a strict follow-up, without any treatment. At the age of three he developed a severe left uveitis, that was treated with topical and systemic corticosteroid with complete resolution after one year. Metotrexhate was started as steroid-sparing agent but it was discontinued because of an infectious pneumonia. One year after ocular remission, bilateral uveitis developed and orally steroid therapy was reinitiated. The boy showed a good response to steroids but every prednisone tapering led to uveitis relapse, configuring the disease as corticosteroid-dependent. Moreover the patient developed different adverse effects such as hypertension and cataract. When he came to our attention, he was on corticosteroid treatment (prednisone 10 mg/day) and he presented bilateral uveitis (Tyndall +1 and cells +1), with an initial cataract of the right eye. His physical examination was remarkable for Cushing-like habitus and for hepatosplenomegaly. His blood count demonstrated 1100/mmc monocytes. Emphasizing the indolent behavior of his hematological disease and the fact that Cbl is strictly linked with Ras-mTOR the disorder could be considered similar to Ras-associated autoimmune leukoproliferative disorder (RALD). On this basis, to treat patient's uveitis, we proposed a trial with sirolimus, a mTOR inhibitor that showed its efficacy both in primitive uveitis and in autoimmune manifestations associated with JMML. Topical treatment with steroidal and mydriatic eye drops was associated. We started with the dosage of 0.5 mg/day and we slowly increased the dosage to 1.5 mg/day, in order to maintain the blood level of the drug between 5 to 15 ng/ml. Results: After two months of treatment the uveitis did not show any improvement, despite the achievement of an adequate blood concentration of the drug, neither the monocyte count decreased; for this reason sirolimus was suspended and methotrexate was reinitiated. Conclusion: In conclusion, we present the case of a JMML patient with a Cbl mutation that developed a severe steroid dependent uveitis that did not respond to sirolimus. Treatment with sirolimus was attempted emphasizing the common pathway of Cbl and Ras, but its inefficacy might imply that this pathway is not involved in the uveitis pathogenesis. Disclosure of Interest None Declared.

Results
Poster Session: JIA (oligo, poly, psoriatic) II Introduction: Over the last decade implementation of targeted therapy has improved the functional ability in children with JIA considerably. Evidence-based benefits of physical activity (PA) have led to less restriction in participation of JIA patients in PA and sports. However, JIA patients still seem to be less physically active, have lower physical capacity, and are more challenged in PA than healthy peers. Subjective assessments of PA are commonly used but often biased in children but only few data exist on objectively measured PA in children with JIA. Objectives: To objectively monitor daily free-living PA and relate to self-reported exercise habits in gym-classes and club-sports in 10-16 year-old children with JIA compared to healthy peers. Methods: 61 patients (females 60.7%), mean age 13.2 (±1.7) years, mean disease duration 70 (±49) months and 118 controls (females 50.8%), mean age 12.4 (±1.7) years completed the questionnaire: Patterns of Physical Activity in Leisure-time, Education and Sports (PPA-LES). Accelerometer monitoring was assessed using the GT1M Acti-Graph, monitoring daily PA during wakening hours for one week. Accelerometry assessments of JIA patients were compared to age and gender related normative Danish reference values (n = 2055) and expressed as mean counts per minute (meanAcc), minutes per days with > 1000 counts/min (Acc1000) and minutes per day >2500 counts/min (Acc2500). Results: Significantly fewer patients participated fully in gymclasses compared to healthy controls (51.5% vs. 76.3%, p < 0.01) and fewer patients reported participation in sport club activities (62% vs. 76%). Of those in the JIA cohort participating in sport 29.5% spent >3 hours per week compared to 48.3% in the control group. But overall no significant difference was found between sport-active patients and controls in the reported time spent in sports (p = 0.202). As previously reported (1) patients had decreased PA as assessed by accelerometry (PA-Acc) compared to healthy controls, both regarding meanAcc (p < 0.004), Acc1000(p < 0.001) and Acc2500 (p < 0.002). We found no relation when comparing Z-scores of age and gender controlled values of PA-Acc to the reported participation in gymclasses (Fig. 3). However, when reporting activites in sports we found an increasing level of Z-scores of PA-Acc proportional to the number of hours spent per week in sports (Fig. 3). In fact, patients were even more active than normative controls, when spending more than 5 hrs/week in sports. Conclusion: Patients with JIA were less physically active than healthy controls both when assessing participation in gym-classes and sport club activities by self-reported questionnaire (PPA-LES) and when objectively assessing PA by accelerometry (PA-Acc). However, the reported participation in gym-classes and sports differently reflected the activity recorded by objectively measured PA-Acc. Our results may emphasize the need for accurate measures when assessing PA in children with JIA. Introduction: Juvenile idiopathic arthritis (JIA) is a group of chronic rheumatic diseases in childhood. For some children it is a mild disease, but for others it is a long-lasting and potentially disabling disease. Unfortunately, our insight into prognostic risk factors is still limited and although several predictive markers of outcome have been proposed, results have been inconsistent. In a large proportion of patients, the level of the standard inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), is within the normal range despite clinical signs of disease activity. Objectives: To evaluate whether C-reactive protein (CRP), including variation within the normal range, is predictive of long-term disease outcome in juvenile idiopathic arthritis (JIA). Methods: Consecutive patients with newly diagnosed JIA were included prospectively from defined geographic areas of the Nordic countries from 1997-2000. Inclusion criteria were availability of a baseline serum sample within 12 months after disease onset and eight-year clinical assessment data. Systemic onset JIA was not included. CRP was measured by high sensitive ELISA (detection limit of 0.2 mg/l). Results: One hundred and thirty participants with a median followup time of 97 months (range 95-100) were included. At follow-up, 38% of the patients were in remission off medication. Absence of remission was associated with elevated level of CRP at baseline (odds ratio (OR): 1.33, confidence interval (CI): 1.08-1.63, p = 0.007). By applying a cutoff at the normal upper limit (>10 mg/l) the risk of not achieving remission was increased to an OR of 8.60 (CI: 2.98-24.81, p < 0.001). Variations of CRP within the normal range had no predictive impact on disease activity at follow-up. Baseline levels of ESR were available in 80 patients (61%) and elevated ESR was associated with absence of remission in a multivariable logistic regression analysis (OR: 2.32, CI: 1.35-4.00, p = 0.002).
Conclusion: This results of this study indicate that baseline CRP concentrations above 10 mg/l are predictive of a poor outcome at eightyear follow-up. We could not demonstrate any predictive value of CRP variations within the normal range. Disclosure of Interest None Declared.

P319
Single nucleotide polymorphisms in survivin gene are associated to response to methotrexate in juvenile idiopathic arthritis Mojca Zajc Avramovič 1 , Vita Dolžan 2 , Nataša Toplak 1 , Tadej  The disease activity was measured using JADAS 71 score. Nonresponders 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: BIRC 5 G692C rs8073069, BIRC5 T241C rs17878467 and BIRC G31C rs9904341. Two-tailed Fisher exact test was used for statistical analysis. Results: At 6 months 30/116 (25.8%) of patients were defined as non-responders. BIRC5 T241C rs17878467 (p < 0.0001) and BIRC G31C rs9904341 (p = 0.0272) were associated with achieving 30% improvement in JADAS 71 after 6 months. BIRC G31C rs9904341 was also associated with 70% improvement in JADAS 71 score (p < 0.0001) after 6 months of treatment. Introduction: JIA is the most common chronic inflammatory rheumatic diseases of childhood. Objectives: To evaluate 6-year (y) safety and 2 y effectiveness profile of Adalimumab with or without methotrexate (ADA ± MTX) when used in current clinical practice for treatment of moderately to severely active pJIA. Methods: This is a 6 y interim analysis of an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA with up to10 y safety follow-up. Included pts are treated with ADA ± MTX or MTX alone as part of their routine clinical care enrolled in US, EU, and Australia. MedDRA observational adverse events (AEs) were recorded from first day in registry through last contact, irrespective of duration of registry treatment. Effectiveness was assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. Results: As of Jan 2014, enrollment was complete. As of June 1, 2015 cut-off date, 846 pts (ADA ± MTX: 543 and MTX: 303) were treated in the registry; 39 pts rolled over from MTX to ADA ± MTX arm. At registry entry mean pJIA disease duration was 1.4 y and 3.7 y for MTX and ADA ± MTX arms, respectively. At baseline (BL), mean AJC71 was 5.8 and 5.3 for MTX and ADA ± MTX arms, respectively; Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI) was 0.6 for both arms. At data cutoff, mean duration of study exposure was Introduction: Etanercept (ETN) is approved in the EU for the treatment of children with juvenile idiopathic arthritis (JIA) categories of polyarticular, extended oligoarticular (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA), but little evidence is currently available regarding predictors of clinical remission. Objectives: To evaluate characteristics that may have predicted the achievement of clinical remission with ETN in the CLIPPER study. Methods: In this ongoing, Phase 3b, open-label study, paediatric patients with eoJIA (2-17 y), ERA (12-17 y), or PsA (12-17 y) received ETN 0.8 mg/kg once weekly (maximum, 50 mg) for up to 96 weeks. Baseline demographic and disease characteristics that were significantly different (p < 0.05) between children in remission or with active disease were analysed post hoc as categorical predictors (i.e., dichotomized continuous characteristics) in univariate logistic regression models; response and disease activity status after 12 weeks of   (Table 34). There was relatively high agreement between scores, with the highest agreement between the two CHAQ tools (78%) and lowest between the HAQ and P-CHAQ (71%). Where discordant, the majority of HAQ scores fell below those from either CHAQ. Discordance between CHAQ scores was more evenly distributed with 12% P-CHAQ scores falling below and 10% exceeding C-CHAQ scores, respectively (Table 34).
Conclusion: There was strong correlation and good concordance between the P-CHAQ, A-CHAQ and HAQ in adolescents with JIA. The strong correlations and concordances between the HAQ and either CHAQ tool indicate the utility of HAQ in adolescents with JIA. Further work is needed to understand which domains drive the lower HAQ scores in this population.

Disclosure of Interest
None Declared. Introduction: Musculoskeletal pain is a common complaint in children, but the differential diagnosis may cover a wide range of diseases, and only a minority of patients will turn out to have a chronic inflammatory condition. Objectives: We recently developed a score (CASco) to calculate the probability a patients with musculoskeletal complaints will receive a diagnosis of chronic arthritis 1 . To validate this score we performed this study. As a secondary objective we analyzed the distribution in our cohort of the different causes and manifestations of musculoskeletal pain. Methods: 199 patients referred for muskuloskeletal complaints in a time frame of 6 months were recruited. At the time of recruitment we applied a standardized questionnaire to collecte detailed clinical information, focusing on the joint swelling pattern, the precipitating factors of pain, the duration of morning stiffness and the frequency of pain, which are the variables that had previously been shown to be significantly associated with a positive CASco. The score was calculated by I.P. while the other investigators were blinded to the results of the score. Once the final diagnosis was confirmed we compared the result of the CASco score with the clinical diagnosis, to calculate the sensibility and sensitivity of the score. Results: The final diagnosis were distributed as follows: chronic inflammatory arthritis (17%), infections-related arthritis (17%) and noninflammatory disorders (66%). Pain frequency: Joint pain was recorded in 92% of patients. The patients with chronic arthritis showed a dichotomic pain distribution (persistent pain: 62%; absence of pain: 23%), while the presence of recurrent pain with more than one episode per month was significantly associated with non-inflammatory disorders and the single episode of pain resulted the typical presentation of children with infections-related arthritis. Pain precipitating factors: rest was associated with chronic arthritis, a prior infection with children with infections-related arthritis and activity with non-inflammatory disorders. Joint swelling pattern: 74% of children with chronic arthritis had daily persistent joint swelling in one or more joints. By contrast, in the other groups the clinical presentation at onset was characterized in most cases by the absence of joint swelling (56% of children with infectionsrelated arthritis and 80% of children with non-inflammatory disorders).
Morning stiffness: was reported more frequently in patients with chronic arthritis (53% of patients) compared with the other two groups (15% and 8%). All the mentioned differences were statistically significant (p < 0.001). Among children with chronic arthritis who suffered from morning stiffness, this symptom usually lasted for less than one hour (33%). In this data set the predictive score correctly identified 185/199 patients with a precision of 93%. The Score revealed high sensitivity (88%) and specificity (94%). Conclusion: we confirmed the CASco score as an instrument with good sensitivity and specificity. Of course, the CASco is not intended as a substitute of a clinical evaluation, still its use in the daily clinical routine may help the pediatrician to correctly address the differential diagnosis in a child with musculoskeletal complaints, rationalizing time and resources and promptly identifying those patients who would benefit the most from a pediatric rheumatology evaluation.
Introduction: Musculoskeletal pain is one of the most common complaints in the pediatric population, affects between 10% and 20% of children and it is one of the leading reasons of referring to pediatric rheumatologist. The most common origin of the pain is a non inflammatory condition, including orthopedic diseases, hypermobility, "growing pains" and postural disorders. Recently, we developed a score, called CASco 1 , that can determine the probability a child with musculoskeletal complaints will receive a final diagnosis of inflammatory arthritis.
Objectives: The aim of our study was to verify if a pediatric rheumatologist would be able to correctly diagnose those patients with musculoskeletal complaints secondary to postural abnormalities Methods: All children referred for musculoskeletal complaints, with a medical history suggestive for a "mechanical" origin of the pain were recruited. The CASco score was calculated and the patients went through a standardazied evaluation to detect postural problems. All the patients were then referred to the physiatrist, who was considered the "gold standard" for the diagnosis of postural problems Results: We enrolled 14 children referred to our pediatric rheumatology department for musculoskeletal. The postural examination confirmed the presence of postural alterations in 10/14 children. The CASco score was negative (i.e. not indicative for inflammatory arthritis) in 12/14 patients. All these patients were finally referred to the physiatrist that found alterations at physical evaluation and reach a final diagnosis of postural disorders in 14/14 children.

Conclusion:
The study is still in progress, but the preliminary results suggest that pediatricians still need to develop proper skills to identify postural problems, that may be a cause of musculoskeletal complaints. The use of the CASco score, as a support instrument to rule out inflammatory disorders, may be of valuable help to the pediatrician. With all the proper instruments pediatricians, and pediatric rheumatologists among them, will be able to precociously differentiate patients with musculoskeletal complaints due to postural problem, and refer them to the physiatrist. 1   Introduction: Although nearly 20,000 Canadian children are affected by juvenile idiopathic arthritis (JIA), little awareness for this condition exists in the community. JIA is often a life-long disease, and children suffer from "invisible challenges"-chronic pain and fatigue, limited participation in sports and extracurricular activities, daily medications, blood tests and other painful procedures. There is a knowledge gap about how children cope with such stresses. Art therapy decreases patients' stress and storytelling results in psychosocial benefits for patients. This combined approach has not been previously studied in JIA.
Objectives: An innovative art/ visual story telling program for children with JIA consisted of the children creating an individual art work followed by "illness experience narrative" as a digital story. The specific aims were: 1) To understand if such an expressive opportunity improves children's health status; 2) To publicize children's art/stories to increase community education about JIA. Methods: Participants: A prospective cohort of 10 children and adolescents (8 -18 years), affected by JIA (Alberta Children's Hospital, Calgary, Canada) participated in one-day art workshop(s) that were not illness specific, but focused on visual art skills. Each child subsequently produced a digital story about their illness experience using art, talking, writing and videoclips, assisted by a research assistant. To assess health related quality of life (HRQL), Pediatric Quality of Life Inventory-Rheumatology Module (Peds QL-R) was used. The higher scores indicate better HRQL, with "0" indicating the worst and "100" the best HRQL. It was administered 1 week prior and 1 week post completion of the project. Individual structured interviews with the children were conducted following the creation of digital story. Social media/public venues were used to exhibit children's expressive creations. This mixed methods study used philosophical hermeneutics for the qualitative methodology, which has been successfully used in healthcare situations where knowledge is expected to emerge from dialogue in a form of an unpredictable discovery rather than a controlled outcome.
Results: A total of 10 children and adolescents were included (4 males and 6 females). Each child created an individual art work (a sculpture, painting or collage) that was subsequently used as a point of discussion in the digital story narrative. The pre-project PedsQL-R mean (range) scores for the 5 subsections were as follows: 1) Pain Introduction: Juvenile idiopathic arthritis (JIA) is the most common childhood inflammatory rheumatological condition. It is a heterogenous condition with variability in clinical presentation and response to treatment. One of the most challenging aspects of management is identifying true disease remission and when to stop medication. The Wallace Criteria are the current gold standard in clinical practice. Unfortunately, many patients meeting these criteria still have disease flare after stopping treatment. Myeloid related protein (MRP8/14), a calcium binding protein, member of the S100 family, has previously been shown to be a useful biomarker of subclinical disease activity with good correlation between concentration in synovial fluid and serum. It has also been proposed to predict which patients will respond to Methotrexate. The test remains a research test but is now available in a clinical setting in some centres.  . 20 patients were included in group A (34%), 5 in groups B and C respectively (9% each) and 28 in group D (48%). TMJ involvement (I+ and/or D+) was reported in 30/58 patients (52%), from which 25/58 (43%) had active inflammatory arthritis (group A and B). Treatment in these 2 groups were intra-articular physiological serum (10/25, 40%) and intraarticular corticosteroids (9/25, 36%). No TMJ treatment was administrated in 38/58 patients (65%). Conclusion: The majority of patients were referred to our multidisciplinary consultation because of pain, and a TMJ active arthritis was found in a large number of them. Moreover, more than half of the patients referred to the TMJ consultation had consistent treatment with at least one BA. No correlation was found between TMJ involvement and a specific JIA subtype, nor with history of uveitis; on the contrary, a significant association with ANA+ was described in our cohort. TMJ involvement should be screened even in case of minor symptoms or signs in JIA patients, particularly those with severe disease; when TMJ arthritis is suspected, MRI should be performed rapidly.

Disclosure of Interest
None Declared.

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The Introduction: Juvenile idiopathic arthritis (JIA) frequently affects also the temporomandibular joints (TMJ), potentially leading to condylar lesions. Condylar erosion can progress insidiously and alter the masticatory function and, in some cases, also the craniofacial profile. Even though bone alterations are best detected by Computed Tomography (CT), such investigation should be prescribed carefully, since it exposes the patient to ionizing radiation. In the last years, surface electromyography (SEMG) has been increasingly used to evaluate temporomandibular disorders, but its diagnostic accuracy is still questioned.
Objectives: Our aim is to assess whether, in patients affected by JIA, SEMG findings of masticatory muscles correlate with condylar erosion as documented by cone beam CT scans of the TMJ.
Methods: We retrospectively reviewed the medical records of JIA patients who were addressed to an orthodontist due to the presence of signs and symptoms of temporomandibular involvement. Patients who performed both a cone beam CT scan of the TMJ and a SEMG of masseter and temporal muscles within a 6 month period were included in the study. Severity of TMJ condylar erosion was classified from grade 0 (absence of erosion) to grade 4 (extensive erosion). Each of the masseter and temporal muscles was classified as normotonic, hypotonic or hypertonic. Cone beam CT scan was considered pathologic if the grade of erosion was > 0. SEMG was considered pathologic if at least three of the examined muscles showed altered tone. Using CT as the gold standard to detect condylar lesions, we calculated sensitivity and specificity of SEMG examination. Results: Eighteen patients were included in the study, 13 females and 5 males. Mean age at onset of JIA was 5,9 ± 3,8 years. The most represented JIA category was polyarticular JIA (39%). Mean disease duration when CT scan was performed was 9,1 ± 6,1 years; mean disease duration when SEMG was performed was 9,6 ± 6,3 years. Cone beam CT scan of TMJ showed different grades of bone erosion in 14 patients out of 18. SEMG was completely normal only in one patient, while the other patients presented hypertonus or hypotonus in at least one of the masticatory muscles. Results are summarized in Table 36. Neither increased nor decreased muscle tone in any of the masticatory muscles examined showed a clear association with the severity of bone erosion of ipsilateral or contralater condyle. Considering cone beam CT scan as the gold standard, SEMG showed low sensitivity (57%) and specificity (25% Conclusion: Overall, patients with JIA who are treated with abatacept are similar to patients treated with other BDMs, with the exception of slight differences observed in a few co-morbid conditions. Patients with JIA treated with abatacept in the US HCC database are slightly younger, with less uveitis at baseline, compared with a population of abatacept-treated patients in a JIA registry (mean age 13 years and 15% history of uveitis). 1 Healthcare claims data are another source of data to monitor the use of medications in the real world.   were controlled on medication. Restrictive pattern in PFT was less common in controlled group in comparison 2 other groups (P = 0.05). All pulmonary parameters were significantly lower in case group in comparison to control group (P < 0.01) except FEV1 ratio (P = 0.3). (Table 38). Conclusion: PFT should be considered in all new patients with JIA before started medication and after medication in regular interval, if treatment last more than 6 months. Disclosure of Interest None Declared. Introduction: Juvenile dermatomyositis (JDM) is a rare, but severe chronic systemic autoimmune disease in children, characterized by muscle weakness and a typical skin rash. Clinical evaluation of disease activity remains challenging. Recently, we identified and validated three proteins as robust biomarkers for disease activity in JDM, in two independent cohorts from the Netherlands and the United Kingdom: Galectin-9 (Gal-9), CXCL10 and TNFRII.(1) Endothelial cells are known to be important producers of these three proteins, and endothelial dysfunction has been implicated in the pathogenesis of JDM. We therefore further investigated endothelial function and activation, as reflected in peripheral blood serum, in patients with JDM compared to other pediatric and adult systemic autoimmune diseases.
Objectives: To assess the disease specificity of the biomarker potential of Gal-9, CXCL10 and TNFRII and investigate the peripheral profile of endothelial function and activation in JDM compared to related systemic autoimmune diseases.  The panel of 28 analytes comprised previously identified biomarkers for JDM and a combination of proteins reflecting endothelial function and activation. Data were analyzed using principal component analysis, hierarchical clustering and non-parametric ANOVA.
Results: Measurement of Gal-9, TNFRII and CXCL10 in this third JDM cohort confirmed their strength as biomarkers for disease activity.
Comparison with other diseases revealed that their potential to discriminate between active disease and remission is specific for (J)DM. Principal component analysis of all measured analytes, including endothelial markers, separated the cohort into three main clusters of patients: myositis patients, SLE/APS patients and pediatric Morphea patients. Interestingly, all patients with myositis clustered together, regardless of their principal diagnosis ((S)LE, MCTD, JDM). The proteins mainly responsible for this separation were Gal-9, CXCL10, TNFRII, soluble VCAM-1 and ICAM-1, and CCL2. This indicates that the combination of these proteins is specific for myositis in general, rather than for JDM or systemic inflammation alone. In addition, we found evidence for a highly activated endothelial state and a disturbed balance between angiogenic (VEGF, angiopoeitin-1) and angiostatic (soluble VEGF-R1 and angiopoietin-2) proteins in JDM patients with active disease. Conclusion: We confirmed the biomarker potential of Galectin-9, CXCL10 and TNFRII, which highly correlate with disease activity in juvenile dermatomyositis and seem specific for myositis, independent of the background disease. Introduction of these biomarkers into clinical practice will help to personalize treatment. The high levels of these proteins combined with the endothelial activation profile in patients with active disease points toward the involvement of both endothelial activation and dysfunction in the pathogenesis juvenile dermatomyositis. Introduction: Juvenile dermatomyositis (JDM) is a rare systemic autoimmune vasculopathy that affects mainly skin and muscles. Calcinosis is a dystrophic calcification which occurs in 20-40% of JDM patients. It is an important sequelae of JDM which may cause significant morbidity and mortality and can be difficult to treat. There is no standard curative treatment for calcinosis but different agents were used with variable efficacy. We report the favorable outcome of rituximab on severe calcinosis in 4 JDM patients and present their clinical data Objectives: To report the observed effectivness of riuximab on JDM and associated calcinosis Methods: A retrospective chart review of 4 children with JDM and severe calcinosis who were diagnosed at King Abdul aziz University Hospital,Jeddah,Saudi Arabia and received rituximab for relapsing or polycyclic JDM course. Diagnosis and follow up of calcinosis was clinically and by X-ray. Review data included :age of patients at onset of JDM symptoms and diagnosis,clinical and laboratory criteria at diagnosis,disease course and duration of follow up. Data about calcinosis onset,sites,severity and its progression were also included. Further data about rituximab therapy included :dosage,side effects,other treatment used before,during or after this drug and outcome and duration of follow up of calcinosis after therapy.
Results: 4 patients(2 male,2 female),interval between onset of symptoms was 6-12 months,course of JDM was polycyclic or relapsing,duration of follow up was 5-7 years. Calcinosis was present in one patient at diagnosis,at 9,13 and 16 months after diagnosis.All patients had calcinosis affecting elbows,hands,thighs,knees,ankles and buttocks. Calcinosis was severe causing ulceration, recurrent skin infections, joint limitation,severe disability and inability to walk.It was not improving despite improvement in muscle and skin function with different DMARDs and /or biphosphnates, colchicine and warfarin Reason to start rituximab was inadequate disease control, disability and recurrent relapses. Only one patient given 2 courses of rituximab; others given one course. All patients received steroids and more than one DMARD before starting rituximab and were continued thereafter, follow up after rituximab was 3 to 5 years. All patients had improvement in disease activity and frequency of admission especially due to complications of calcinosis. One patient had complete clearance of calcinosis for the last 5 years, others had significant improvement in calcinosis with no new lesions,decreased sites and density and decreased calcinosis related contractures. There was no serious side effects to rituximab. Conclusion: In our cohort of 4 patients with JDM and severe calcinosis,there was significant improvement and/or clearance of calcinosis after rituximab therapy when used with other DMARDs as well as improvement in disease activity.Further clinical studies are required to evaluate the efficacy of rituximab in JDM and associated calcinosis. Methods: Data were available from an ongoing national longitudinal cohort study, enrolling newly diagnosed cases of JDM from across the UK. The model was developed in 340 subjects, contributing 2725 visits. A Bayesian multivariate and multivariable linear mixed regression model was developed, using as outcome the disease activity parameters creatine kinase level (CK), childhood myositis activity score (CMAS), manual muscle testing in 8 muscle groups (MMT) and the physician's global assessment of disease activity (PGA). Clinical signs and symptoms were used as covariates. The goodness of fit of the model was tested in a random sample of subjects, whereas the out-of-sample predictions were tested in a random sample of subjects not used for the model development.
The model's goodness of fit and out-of-sample predictions were accurate and followed observed patterns over time well. Various clinical signs and symptoms were shown to be associated with the disease activity parameters. Of signs and symptoms at diagnosis, only arthritis was associated with a higher CMAS and MMT score. Presence of myalgia and dysphonia at the visit was associated with higher disease activity with regard to all outcome parameters, as expected. Several cutaneous and soft tissue signs and symptoms, such as periorbital rash, rash on the trunk, rash over large joints, nail fold changes and facial swelling, were associated with higher disease activity with regard to various outcome parameters. In addition, presence of contractures was associated with a higher disease activity with regard to the CMAS, MMT and PGA. Joint swelling was associated with higher disease activity regarding the CMAS and PGA, but there was a tendency for CK levels to be lower. Patients with haematuria had higher CK values, but tended to have a lower PGA. Calcinosis was mostly seen as long-term outcomes of the disease, as evidenced by an association with higher CMAS scores. However, the PGA was higher in these patients too. Patients with a higher CMAS value tended to have a higher MMT value as well, since the estimated correlation between the by-patient intercepts for CMAS and MMT was 0.54 (95% credible region [CR] 0.42-0.65). Correlations among other outcome parameters were low (≤0.23). Given that a visit was estimated to be in remission according to PRINTO criteria, the estimated median probability that PGA was pathological, whereas the other three outcome parameters were non-pathological, was 51% (95% CR 0-99%). It was 6% (95% CR 0-92%), 1% (95% CR 0-35%) and 1% (95% CR 0-64%) for CK, CMAS and MMT, respectively. Conclusion: The model elucidated various clinical signs and symptoms associated with disease activity, which can be used to stratify patients according to their prognosis and guide treatment decisions accordingly. Furthermore, the model brought to light similarities and dissimilarities among the four outcome parameters, useful in the discussion of the set of outcome parameters for JDM.

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Audit of intravenous immunoglobulin protocols used for the treatment of juvenile dermatomyositis Qiong Wu 1 , Tania Amin 1 , Stefania Simou 2 , Lee Dossetter 1 , Lucy R. Introduction: Children with poorly controlled Juvenile Dermatomyositis (JDM) can develop permanent loss of muscle function and skin scarring. For some children with severe disease, after failure of 2nd line medications, Intravenous Immunoglobulin (IVIG) can successfully control inflammation. However, in certain cases, it can precipitate serious side effects including aseptic meningitis and renal impairment. Various IVIG infusion protocols have been trialled at a number of tertiary Paediatric Rheumatology centres, and in 2010, the Children's Arthritis and Rheumatology Research Alliance (CARRA) recommended loading IVIG at 0, 2 and 4 weeks before stretching to monthly infusions. However, little data comparing the complication rate of different protocols have been published. Objectives: We audited protocols which have been used at Great Ormond Street Hospital, and compare complications profile of these protocols.
Methods: Children with JDM treated with IVIG were identified using the UK JDM Cohort and Biomarker Study (JDCBS) database. Dates of IVIG infusions, complications and disease activity measures during first 24 months of IVIG were collected. Results: Twenty children who received IVIG between 2008 and 2015 were identified. Ten were treated using the CARRA protocol (age range 2-14 years, median age 7 years, M:F ratio 1:2.3), while 10 were treated with less intensive protocols, most commonly monthly infusions (age range 3-13 years, median age 7 years, M:F ratio 1:2.3). Prior to 2010, no children were treated with the CARRA protocol, but since 2010, 56% of children have been treated with this protocol. At baseline, CARRA-treated group had mean physician visual analogue scale (phyVAS) of 5/10, parent VAS (parVAS) of 8/10 and MMT8 of 28/80. 70% of children had skin rash, 75% had nailfold abnormalities, 0% had calcinosis and 20% had ulceration. There was a mean of 5 months from diagnosis prior to first IVIG infusion. The less intensive protocol group had physVAS of 4/10, parVAS of 3/10 and MMT8 of 67/80. All children had skin rash, 89% had nailfold abnormalities, 33% had calcinosis and 18% had ulceration. There was a mean of 32 months from diagnosis prior to first IVIG infusion. In both groups, children were treated with a range of disease modifying antirheumatic drugs prior to and/or alongside IVIG infusions. A number of children were also pulsed with IV steroids in combination with IVIG. Two out of the 10 children on CARRA protocol experienced complications, while 7 out of the 10 children on less intensive regimens reported complications. At 24 months, both groups showed improvements in physVAS, parVAS, MMT8, skin rash and nailfold abnormalities. Conclusion: These preliminary data do not suggest an increased complication rate of 0, 2, 4 week IVIG loading in the treatment of JDM compared to monthly infusions. A larger multi-centre study to audit the complication profile of various IVIG regimens is warranted.

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Efficacy and safety of tumour necrosis factor-αlfa antagonists in a large cohort of juvenile dermatomyositis patients Raquel Campanilho-Marques 1,2,3,4 , Claire Deakin 1 , Stefania Simou 1 , Lucy R. Wedderburn 1,5 , Clarissa A. Pilkington 2 on behalf of Juvenile Dermatomyositis Research Group (JDRG) diagnosis was 7.31 ± 4.04 years old and the mean disease duration was of 9.6 ± 4.6. Mean disease duration at the beginning of anti-TNF treatment was 3.49 ± 2.80 years and mean duration of anti-TNF therapy was of 2.76 ± 2.09 years. . Sixteen patients (24%) switched their anti-TNF treatment. 62.5% of the switches were due to therapy failure, 25% due to adverse events and 12.5% for patient preference in subcutaneous administration. Of 21 adverse reactions registered, 7 were considered severe (anaphylactic reactions on infliximab infusion). One patient died due to small bowel perforation (not felt to be related to the use of TNF antagonists). The remaining adverse reactions were not severe and 77% (n = 10) of them were due to infections causes. In 4 of the mild to moderate adverse reactions the drug had to be discontinued and switched to another TNF antagonist, while in the remaining patients temporarily withholding the drug proved sufficient. No tuberculosis case was registered.
Conclusion: This study is one of the largest to explore the efficacy and safety of TNF antagonist treatment in a large independent cohort of JDM patients. Both muscle and skin involvement appeared to improve after anti-TNF treatment. Introduction: Juvenile dermatomyositis (JDM) is a multisystem vasculopathic disease that primarily affects the skin and muscles. Most tools for assessment of disease activity in JDM are centered on physician's evaluation, whereas parent's or child's views are largely neglected. Furthermore, existing instruments are frequently lengthy and complex. Objectives: To develop a composite disease activity score for JDM and provide preliminary evidence of its validity. Methods: A panel of experts devised the composite disease activity score, named Juvenile DermatoMyositis Activity Index (JDMAI), based on their clinical experience and a literature review. The JDMAI is composed of 4 clinical measures or domains: 1) physician's global assessment of overall disease activity on a 0-10 VAS; 2) parent's/child's global assessment of child's wellbeing on a 0-10 VAS; 3) muscle strength/endurance; 4) skin disease activity. Eight versions of the JDMAI were tested, which differed in the tools used to assess items 3 and 4. For item 3, two versions included the hybrid MMT/CMAS (hMC) with score in deciles (0-10), two the hMC with its original score (0-100), two the MMT-8 (0-80), and two the CMAS (0-52). For item 4, four versions included physician's global rating of skin disease activity on a 10-cm VAS (0 = no activity, 10 = maximum activity) and four included the cutaneous domain of the Disease Activity Score (DAS) (0-9). Validation was conducted on 275 patients included in a multinational dataset, evaluated at baseline and at 6, 12, and 24 months. Construct validity was assessed by calculating between-subject and within-subject correlations with JDM outcome measures not included in the JDMAI; internal consistency was assessed with Cronbach α and responsiveness to change with standardized response mean (SRM). Discriminant ability was determined in a different multinational dataset of 136 patients, by assessing the JDMAI score in patients rated in remission, low, moderate, or high disease activity by the attending physician. Results: In between-subject exercise, all JDMAI versions showed strong (r > 0.7) correlations with CHAQ (0.72-0.82), physician's global rating of muscle disease activity on a 10-cm VAS (0.77-0.87), muscle DAS (0.76-0.86) and total DAS (0.68-0.90), and moderate correlations (r = 0.4-0.7) with pain VAS (0.50-0.57) and Myositis Damage Index (MDI) (0.51-0.60). Owing to the interrelatedness of longitudinal data from an individual patient, within-subject correlations were higher and were all strong (r = 0.76-0.97). SRM was good (1.09-1.57) and was higher for JDMAI 1 and 2. Cronbach's alpha was fair (0.70 and 0.69) for JDMAI 1 and 2, and poor for other JDMAI versions. All JDMAI versions discriminated strongly between patients in different disease activity states (Kruskal-Wallis test, p < 0.001). Conclusion: Overall, the JDMAI1 and JDMAI2 revealed the best measurement properties in validation analyses. The JDMAI1 (score range: 0-40) may be preferred over the JDMAI2 as it weights equally its 4 components, whereas in the JDMAI2 (score range: 0-39) items 1 to 3 are scored on a 0-10 scale and skin disease on a 0-9 scale. Disclosure of Interest None Declared Patients were excluded if they were in groups with insufficient numbers for statistical analysis, incomplete records, follow-up period less than 2 years, or intolerance with adverse events from the treatment. Linear regression analysis was performed to assess MSA and  See text for abbreviations. *: scores were reversed for consistency with other parameters demographic variables as predictors of the treatment course. The strength of the association was described by the standardised coefficient (β). Kaplan-Meier survival analysis was used to compare the proportion of patients being off treatment over time across MSA subgroups. Results: 81 and 80 patients fulfilled criteria for analysis of corticosteroid and methotrexate treatment, respectively. The median age at disease onset was 5.6 years (IQR 3.7-8.9) and the median follow up period was 79.3 months (IQR 51.9-112.7). Anti-TIF1ɣ-positive patients tended to have a longer duration of corticosteroid usage and a higher cumulative dose of corticosteroids and methotrexate compared to other MSA subtypes. However, the differences were not statistically significant. To illustrate, anti-TIF1ɣ autoantibodies appeared to be associated with longer duration of corticosteroid and methotrexate usage than other MSA subgroups. In contrast, patients with anti-MDA-5 autoantibodies appeared to have a trend towards shorter duration of corticosteroid usage and lower cumulative dose of corticosteroids. Only age at disease onset and gender were found to be predictors of treatment outcome. These findings may improve clinicians awareness of which patients need higher doses and longer term treatment and provide clinicians with a stratified approach to counseling patients and family.

Disclosure of Interest
None Declared

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The relationship between myositis specific autoantibodies and disease phenotypes (and capillaroscopy findings) in patients with juvenile dermatomyositis: case series Zehra S. Arıcı 1 , Gökçen D. Introduction: Juvenile dermatomyositis (JDM) is a heterogeneous disease. It is believed that autoantibodies are important markers to predict prognosis. It has been reported that anti-NXP2 autoantibodies are associated with calsinosis and anti-MDA5 autoantibodies are associated with interstitial lung disease Objectives: In this study, we investigated the relationships among JDM specific autoantibodies, phenotype and capillaroscopy findings in a single center. Methods: In our 37 JDM patients, clinical and laboratory data were collected. Specific autoantibody panel was viewed. Capillaroscopy was performed in all patients. All patients were evaluated by a specialist pulmonologist and required examinations were performed. Results: In this study, 22 girls (59,5%) and 15 boys (40,5%) with JDM were evaluated. The mean age of onset symptoms was 8,4 years (2,4-15 years). The mean time from disease onset to treatments was 7 months (1-25 months). The mean duration of patient follow-up was 4,8 years (0,7-15,5 years). Anti-MDA5 was found in four patients (10,8%). Interstitial lung disease was observed in one patient with strong positive anti-MDA5 and led to treatment change. There was no interstitial lung disease in other three patients with mild to moderate positive anti-MDA5. None of the patients with anti-MDA5 negative had lung disease. Anti-NXP2 was found in six patients (16,2%). One patient with Anti-NXP2 positive had deep skin ulcers at the disease initial. Four patients with Anti-NXP2 positive had calcinosis. There were 9 patients with calcinosis (25%). Two of them had anti-MDA5 antibodies. Five patients had NXP2 antibodies. Anti-TIF1γ was found one patient with calcinosis. No antibodies were positive in one patient. The mean time from disease onset to treatments was significantly longer patients with calcinosis (10-27 months) than without (1-4 months).
In five of seven patients with anti-TIF1-γ positive, there were persistent skin findings. These were heliotrope rash and Gottron's papules.
In one of patient with anti-TIF1-γ negative, there were serious skin ulcers. This patient had anti-NXP2 positivity. There was no significant relationship between autoantibodies and capillaroscopy findings.
Conclusion: This study indicates that the most important factor in preventing calcinosis is early and effective treatment. Anti-NXP2 was the most common autoantibody in our small JDM patients with calcinosis. It has been shown that the relationship between Anti-TIF1-γ and resistant skin lesions in our patients.

Disclosure of Interest
None Declared

Poster Session: Miscellaneous rheumatic diseases
Introduction: Polyautoimmunity is defined as the presence of more than one autoimmune disease (AiD) in a single patient and multiple auto immune syndrome when three or more autoimmune diseases coexist. The fact that many AiDs share a similar pathogenic mechanisms including: susceptibility genes, epigenetic factors and aberrant immune responses may explain the development of multiple AiDs in a host. AiDs may cause similar symptoms, determine important morbidity and have the tendency to developed in clusters is important for clinicians to have an high index of clinical suspiction and search periodically clinical and serological test to identify those associations of AIDs. Objectives: From de clinical observation of several juvenile patients developed more than one AIDs during follow up at pediatric rheumatology clinics, the members of the GRIP study group developed a registry and study the data obtained to determine their demographic and clinical features Methods: GRIP study group developed a registry of patients followed at 10 pediatric rheumatology clinics in 4 Colombian cities who developed more than one AiD according to international validated diagnostic criteria for organ specific and systemic AIDs.The clinical charts were reviewed and the demographic, family history, clinical, serological and histopathological data were collected in an electronic database. Patients with features of undefined auto immune disease, overlap syndrome or mixed connective tissue disease were excluded to avoid bias. AiDs were reported on a chronologic order and the first one was named Heralding AiD. The intervals between them were calculated on months or defined as simultaneous when were identified with a interval less than 4 weeks. The information is updated as needed if the patient developed additional AiD after was included at the registry. Data was studied using a program SSPS 15 version. Results: N = 216 . The sex ratio was female 9.3: male 1 and was similar on patients who developed 2,3 or 4 AiDs. 166/216 patients develop two AiDs at the time of the data analysis. 46/216 3 diseases and four patients associated four AiDs.The age of onset varies from 0-16 years for the first AiDs and were also similar in the three groups. The interval between AiDs were longer between 1o to 2o with a shorter period to develop additional AiDs. 27% develop simultaneously the first two AiDs, 28% the 2o and 3o and 50% the 3o and 4o. 32% had a positive history of familial autoimmunity and it was similar between groups. 22 AiDs were identified in different associations. The most common systemic AiD was SLE while Hashimoto disease was the most frequent organ specific disease but uncommon diseases as Myasthenia gravis, Rupus, Kikuchi Fujimoto or autoimmune pancreatitis were also present.The most common heralding diseases were:  Caesarean section, most were breastfed. All had a normal weight, height and psychological development. 8/333 pts were adopted children. The clinical onset was dramatically sudden and unexpected in all pts. The early symptoms, tics/OCD were underestimated and endorsed to the birth of brother/sister, family events, school pressure. Histories were characterized by remissions and recurrences of symptoms. Inflammatory parameters: ESR, CRP, fibrinogen were in all normal, both at onset, at our first clinical evaluation, and at follow-up. Thyroid function (except 1 pt), coeliac disease screening, EEG, ECG and echocardiography were regular. Brain MRI was normal in all tested patients. ASLO and antiDNasiB titers were evaluated in all pts at onset and at the first assessment, both were increased in PANDAS pts. ANAs were positive at a low titer in two PANDAS pts, negative in PANS. Anti-dsDNA, anti-ENA, anti-cardiolipin antibodies, and LAC were negative in PANDAS and in PANS pts. Most pts have a good performance both at primary and high level school. Therapy: all pts received amoxicillin + clavulanic acid 80/ 100 mg/Kg for 2-4 weeks and then Benzathine benzylpenicillin 600.000/1.200.000 every 21 days, magnesium and Vit D supplementation. All were evaluated by a Psycologist and 25 were treated by a Psychotherapist. Psychotropic drugs were used in 28/333 pts before our first assessment, all ineffective before starting antibiotic therapy. Eight pts received IVIg according to schedule suggested by S. Sweedo with different results. All pts have been evaluated every 6 months. In the group with only tics we observed a remission of symptoms by 2 to 6 months while OCD had amelioration by 6-12 months. Conclusion: Our data show that PANDAS/PANS affect mainly males with higher familiar predisposition. The age at onset is comparable in both groups, while OCD are more common and severe in PANS than in PANDAS. PANS pts have different triggers: Mycoplasma, Borrelia burgdorferi and VZV, and all responded to the specific therapy. The knowledge of PANDAS/PANS is mandatory to early recognize children at the disease onset avoiding to delay diagnosis and therapy. Doctors have a moral obligation to know and to identify these two entities, so that patients and their families can avoid unnecessary calvary through numerous specialists with progressive worsening of clinical symptoms.

Disclosure of Interest
None Declared

P364
Type I interferon score in peripheral blood of patients with pediatric rheumatic diseases Introduction: Type I interferons (IFNs) are proteins that provide protection from viral infections, through induction of hundreds of genes implicated in antiviral response, the so-called "IFN signature". In the last years, the term "type I interferonopathy (IFNpathy)" has been used to identify a group of monogenic diseases in which the causative mutation determines a constitutive up-regulation of type I IFN activity directly relevant for pathogenesis. A restricted set of 6 genes has been proposed and widely used to identify patients with potential type I IFNpathies, which is commonly referred to as type I IFN score. Objectives: In this study, we aim to investigate the type I IFN score in peripheral blood of patients affected by paediatric rheumatic diseases characterized by the presence of systemic inflammation.

Methods:
We evaluated the expression of type I interferonstimulated genes (ISGs) (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1), by real time PCR in patients with systemic lupus erythematosus (SLE) (n = 14), juvenile dermatomyositis (JDM) (n = 7), systemic juvenile idiopathic arthritis (sJIA) (n = 2), chronic recurrent multifocal osteomyelitis (CRMO) (n = 3), adenosine deaminase deficiency (DADA2) (n = 3), CANDLE syndrome (n = 1), NLRC4-related disease (n = 1), familial mediterranean fever (FMF) (n = 2), undefined autoinflammatory diseases (UAD) (n = 11) and in healthy donors (HDs) (n = 4). The median fold change of the ISGs, when compared with the median of the combined HD, was used to create the type I IFN score. The mean interferon score of the controls plus two SD above the mean was calculated. Scores higher than this value (1,61) were defined as positive. Results: We found that a significant up-regulation of the type I IFN score characterized the peripheral blood of SLE, DADA2 and UAD patients compared to HDs (p < 0.05). In SLE patients the type I IFN score was significantly related to the disease activity as measured by the SLEDAI score (p < 0.01). In JDM, 2 patients with active disease had high type I IFN score. As expected, the CANDLE patient had elevated type I IFN score. We analysed the expression levels of the ISGs in other rheumatic disorders such as sJIA, CRMO, FMF but did not find significant differences with HDs. Interestingly, type I IFN score was elevated in the NLCR4 patient. Some of the UAD patients showed a strong up-regulation of the type I IFN score and clinical manifestations in common with the typical IFNpathies including variable combination of cerebral calcifications, lipodystrophy, interstitial lung disease, cerebral stroke, recurrent fever, low levels of C3 and mild positivity of antinuclear antibodies. Also variable expression of the ISGs was observed: in 2 patients a fold change of IFI27 of 937 and 530 compared to controls, while the expression of the other 5 genes was much lower. We found that one UAD patient with a high type I IFN score carried a de novo undescribed gain of function mutation in the STAT1 gene. Conclusion: Up-regulation of type I IFN score characterized different systemic inflammatory disorders, in addition to classical type I IFNpathies. In the group of UAD we found patients with high expression of the ISGs and characterized by clinical manifestations in common with the typical interferonopathies.   recurring fever. The clinical similarity between moderate Farber phenotypes and polyarticular juvenile idiopathic arthritis (JIA) suggests that Farber disease is likely to be misdiagnosed as JIA. A partial response to anti-inflammatory treatment in Farber patients may also contribute to misdiagnosis. Differential diagnosis can be assisted in most cases by the presence of comparatively early-onset, progressive symmetric arthritis, even a small number of subcutaneous nodules, and an unusual, hoarse cry or voice (due to nodule formation on the larynx) in Farber patients. Currently, Farber disease can be treated with hematopoietic stem cell transplantation, which has shown variable results and carries a severe burden for the patients. Enzyme replacement therapy is currently being developed for Farber disease.
Objectives: Here we report the clinical response of 5 patients with biochemically and genetically confirmed Farber disease to treatment with an interleukin 6 receptor inhibitor.
Methods: Data was gathered retrospectively by chart review. The patients vary in age from infancy to 10 years. Results: All patients demonstrated some clinical response to interleukin-6 receptor (IL-6R) inhibition measureable by changes in standard inflammatory markers (e.g., ESR), and/or improvement of symptoms such as pain, physical impairment, feeding ability and general medical condition. The degree to which each patient responded was variable, in large part due to the difference in disease severity, and in no case has the disease ceased to progress. One patient, severely affected from infancy including CNS involvement, died in spite of treatment.
Conclusion: The information gathered from this cohort, along with the knowledge of the pro-inflammatory role of ceramide, indicates that Farber disease patients who are severely affected or show signs of arthritis, pain, or progressive physical impairment can benefit from anti-inflammatory therapy (preferably IL-6R inhibition), even though it cannot halt the progression of the disease or resolve disease symptoms. Farber disease should be included in the differential diagnosis of JIA, especially in patients with early-onset polyarticular subtype or inadequate response to conventional therapies. Other challenges remain, so collaborating partners must be conscious of their cultural, economic and legal differences. Sharing new ideas, knowledge and study protocols, as well as teaching and learning new techniques are important in these projects. Fellowship programs aimed at teaching care and research are excellent stepping stones to initiate a high quality long-lasting collaboration. The two following projects between The Netherlands and Brazil were born after a fellowship program. Results: The inclusion of a sufficient amount of patients to study of immunogenicity and safety of Human Papilloma Virus (HPV) and Varicella vaccines in childhood-systemic lupus erithematosus (cSLE) and juvenile dermatomyositis (JDM) is a challenge. Both diseases are rare, and the rates of HPV vaccination are still low in Europe. These difficulties were reflected by the numbers of inclusion for the HPV project, even after United Kingdom and Slovenia were involved. However, when 15 Brazilian centers adopted the study protocol, they had included 304 patients (260 jSLE, 44 JDM) within a year's time. The data and samples collected in Brazil are shipped to the Netherlands, where analysis will take place. A previous project, initiated in Brazil, involved varicella vaccination in patients with pediatric rheumatic diseases. Over a period of 5 years, 54 patients (42 Juvenile Idiopathic Arthritis (JIA), 5 juvenile Systemic Scleroderma (jSScl) and 7 JDM) had been included. The samples were shipped to the Netherlands, where the cellular responses after varicella vaccination were analyzed.
Conclusion: The collaboration between The Netherlands and Brazil has resulted in two fruitful projects involving many patients. Sharing study protocols and data, good communication, as well as training scientists in laboratory techniques have shown to be essential in its success. The results of this collaboration may be extremely beneficial for the science, as well as for the participating countries.

Disclosure of Interest
None Declared  Introduction: Multiple epiphyseal dysplasia (MED) is a genetically and phenotypically heterogeneous disease resulting in disorganized epiphyseal ossification of the long bones. So far six different subtypes have been described, among them only one with recessive inheritance (1, 2). All subjects are at risk of developing early osteoarthritis (OA) but inflammatory arthritis has also been described in patients with MED (3). Only four cases of recessive MED (rMED) with homozygosity for the mutation c.1957 T > A p.Cys653Ser in SLC26A gene have been described (4,5). Objectives: To describe a case of inflammatory arthritis in a nine year old girl with rMED Methods: Description of a case according to the data of medical records. Results: The patient was on a regular orthopaedic observation because of congenital hip dysplasia which was diagnosed at the age of three months and was treated with cast immobilisation until the age of 1 year and 7 months. First episode of arthritis (right knee joint) developed at the age of 8 years with normal inflammatory markers in blood. The episode was managed with nonsteroidal anti-inflammatory drugs (NSAID). Repeated episodes of arthritis with morning stiffness developed during next month affecting left hip, knees, ankles and talonacivular joints. The joint aspirate from left knee also showed inflammation (leukocyte count 6900 x10 6 /L). The effect of NSAID treatment was insufficient and oral methotrexate (MTX) was started 4 months after the first arthritis episode. During the differential diagnosis process x-ray investigations revealed double-laired patella and symmetric flattened epiphyses of long bones which led to the suspicion of MED. The diagnosis was genetically confirmed with the detection of homozygotic mutation in SLC26A gene (c.1957 T > A p.Cys653Ser). After the diagnosis of rMED patient's brother (age 16 years) was also diagnosed with the same disease showing characteristic radiological changes in long bones but without any serious joint complaints and arthritis episodes. The girl continues treatment with MTX with positive effect and regular physiotherapy. Conclusion: Although OA is the most common form of arthritis in patients with MED, inflammatory arthritis may also develop, needing adequate treatment to prevent long term joint damage. Written informed consent has been obtained from the parent for the case report.
Introduction: Non-bacterial and acute hematogenous osteomyelitis (NBO and AHO, relatively) are inflammatory diseases of the musculoskeletal system, especially encountered with children and teenagers. In some cases the diseases may have a similar clinical manifestation, therefore require a differential diagnostics, due to fundamentally different plan of approach for treatment. Objectives: To compare clinic-laboratory features of NBO and AHO. Methods: The study includes data of 52 patients with NBO and 47 with AHO under the age of 18 years old. The NBO diagnosis based of clinical finding, laboratory changes, the presence of foci of bone destruction discovered during radiological methods of research, bone biopsy, negative results of bacteriological research of biopsy samples. The AHO diagnosis based in the presence of positive results of bacteriological research of bone biopsy samples. A comparative analysis was performed on the basis of estimating the number of bone lesions, laboratory data -hemoglobin level, WBC, platelets, ESR, CRP level, identification of infectious agent and the time of diagnosis. Results: The onset age disease of patients is 8,4 (5,4; 11,0) and 11,0 (6,2; 12,9) with NBO and AHO relatively (p = 0,08). NBO took place with equal frequency in both boys and girls, while AHO patients boys