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  • Meeting abstracts
  • Open Access

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

Genoa, Italy. 28 September – 01 October 2016
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Pediatric Rheumatology201715(Suppl 1):44

https://doi.org/10.1186/s12969-017-0142-8

Published: 30 May 2017

P178 Features of drug therapy of patients with systemic juvenile idiopathic arthritis, according to the Russian register of the Russian union of pediatricians

Olga Lomakina1, Ekaterina Alekseeva1, Sania Valieva1, Tatiana Bzarova1, Irina Nikishina2, Elena Zholobova3, Svetlana Rodionovskaya2, Maria Kaleda2

1Rheumatology, Scientific Center of Children’s Health, Moscow, Russian Federation; 2Rheumatology, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation; 3Rheumatology, Sechenov First Moscow State Medical University, Moscow, Russian Federation
Presenting author: Olga Lomakina

Introduction: Systemic juvenile arthritis - a rare chronic disease. Register - it's an important tool to monitor the effectiveness and safety of GIBP.

Objectives: Our aim was to study features of the drug therapy of children with systemic juvenile idiopathic arthritis (sJIA)

Methods: We conducted a retrospective data analysis included in the Register of sJIA cases, for the period from 2002 to 2015

Results: The indicators of 384 children with sJIA are studied. Prior to the diagnosis verification, all patients were prescribed to intake antipyretic agents, 98% —antibiotics. After the diagnosis, non-steroidal anti-inflammatory drugs (NSAIDs) were intaken by 282 (73.4%) patients: diclofenac sodium — by 163 (40.1%), nimesulide — by 88 (22.9%) patients. The average duration of NSAID intake from 2002 to 2015 decreased from 81.5 ± 115.3 to 3.3 ± 3.7 months (p < 0.001). Prior to the diagnosis verification, glucocorticoids were received intravenously or intramuscularly by 265 (69.0%) patients, orally — 176 (45.8%). Totally, glucocorticoids were received by 330 (85.9%) patients: methylprednisolone — 300 of 384 (78.1%), prednisolone — 174 (45.3%), there were totally 1855 prescriptions in 668 cases. The average duration of glucocorticoid intake from 2002 to 2015 decreased from 13.7 ± 26.7 to 5.0 ± 3,8 months (p < 0.001). As a disease-modifying drug, methotrexate was intaken by 237 (61.7%), Cyclosporin — by 193 (50.6%) patients. There were totally 809 cases of genetically engineered biological preparations (GIBP) in 430 patients: in 2002–2005–8, in 2011–2015–602 in 397 cases (p = 0.001). Tocilizumab is intaken by 210 (52.9%) of 397 patients, kanakinumab — 37 (9.3%) patients. The disease duration from the manifestation to the prescription of immunosuppressive drugs from 2002 to 2015 decreased from 27.3 ± 23.9 to1.0 ± 0 months (p < 0.001), GIBP prescriptions — from 70.7 ± 26.3 to 0.5 ± 0.7 months, respectively (p < 0.001)

Conclusion: In 13 years there have been positive changes in the antirheumatic therapy in children with sJIA — the duration of NSAIDs and glucocorticoids intake reduced, the period between diagnosis verification and immunosuppressants and GIBP prescription decreased. However, it is still widely used antibiotics, non-selective NSAIDs and glucocorticoids.

Disclosure of Interest

None Declared

P179 Bicipital synovial cyst associated with systemic juvenile idiopathic arthritis: clinical description, sonographic and pathological findings

Yasuo Nakagishi1, Masaki Shimizu2, Mao Mizuta2, Akihiro Yachie2

1Department of Pediatric Rheumatology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan; 2Department of Pediatrics, School of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
Presenting author: Yasuo Nakagishi

Introduction: Bicipital synovial cyst is a rare manifestation of systemic juvenile idiopathic arthritis (s-JIA). It remains unclear how bicipital synovial cysts arise.

Objectives: To describe the presentation and clinical course of bicipital synovial cysts in 2 patients with s-JIA and to assess how bicipital synovial cysts arise.

Methods: We report 2 patients with bicipital synovial cyst associated with s-JIA. We performed sonographic examinations of bicipital synovial cyst. Furthermore, we investigated pathological examination using biopsy specimen.

Results: Patient 1: Eight-year-old boy was diagnosed as s-JIA at the age of 4. His disease course was steroid-dependent and tocilizumab (TCZ) was started from the age of 5. However, his disease relapsed at the age of 7. He presented with fever and swelling of upper left arm. USG revealed a hyperechogenic cyst along the margin of the biceps muscle. The biopsy of the cyst revealed cyst was surrounded by granulation tissue with abundant macrophages infiltrate and there were no synovial tissues. The cyst disappeared with control of disease activity.

Patient 2: Twelve-year-old boy was diagnosed as s-JIA at the age of 8. His disease course was steroid-dependent and tocilizumab (TCZ) was started from the age of 12. At the time to start TCZ, he presented with swelling of upper right arm. Ultrasonography revealed a hyperechogenic cyst in the fascia of biceps muscle. The biopsy of the cyst revealed cyst was surrounded by granulation and fibrous tissue with abundant macrophages, lymphocytes and neutrophils infiltrate. There were no synovial tissues. The cyst disappeared with control of disease activity.

Conclusion: These findings indicate bicipital synovial cysts arise as follows: the fluid arises within the shoulder joint and then descends into the contiguous bicipital tendon sheath. The tendon eventually ruptures, leading to collection of fluid in the bicipital area and synovial cysts arise from the biceps muscle fasciitis. Bicipital synovial cyst is a rare manifestation of s-JIA but synovial cyst should be considered in the differential diagnosis in all children with s-JIA presenting with swelling of the upper arm.

Disclosure of Interest

None Declared

P180 Systemic juvenile idiopathic arthritis with MEFV gene mutations may have a good response to colchicine: suggestion from 5 cases in our center

Yuko Sugita, Nami Okamoto, Kousuke Shabana, Takuji Murata, Hiroshi Tamai

Osaka Medical and Pharmaceutical University, Takatsuki-city, Japan
Presenting author: Yuko Sugita

Introduction: Systemic juvenile idiopathic arthritis (SJIA) is considered to be an autoinflammatory disease in which the dysregulation of innate immune response is suggested to be the main pathogenesis, and there are some reports that show SJIA patients have a significantly higher frequency of MEFV gene mutations, which is associated to the activation of IL-1β pathway, than healthy control population1,2.

Objectives: Since the effectiveness of colchicine, which is useful in familial Mediterranean fever, in SJIA patients with MEFV gene mutations is not established, we sought to examine whether colchicine is effective in such patients.

Methods: We searched for gene mutations that is responsible for autoinflammatory disease in SJIA patients who had persistent clinical symptoms (e.g., skin rashes and arthritis) or flare even under treatment with glucocorticoid, disease-modifying antirheumatic drugs (DMARDS), and IL-6 receptor inhibitor (tocilizumab). We obtained informed consent from the patient or their caregivers, and the gene mutation analysis was performed at Medicine Department of Pediatrics, Kyoto University (Dr. Ryuta Nishikomori). Patients with MEFV gene mutations were administered colchicine.

Results: The five SJIA patients with MEFV gene mutations are summarized in Table 1. All the cases required treatment with IL-6 receptor inhibitor. Case 1 had multiple gene mutations besides MEFV gene such as NOD2, PSTPIP1, and NLRP12 which is known to be associated with other autoinflammatory diseases. Case 2 once achieved drug free remission, but had a flare and started colchicine during the flare which was not effective to control the activated disease. Case 3 and 4 had recurrent diseases but became stable after the initiation of colchicine administration. In case 5, colchicine was administered after the identification of MEFV gene mutation, and was effective to urticarial rashes. Case 3, 4, and 5 is now stable without glucocorticoid after the initiation of colchicine.

Conclusion: To SJIA patients with MEFV gene mutations who are resistant to standard treatment such as glucocorticoid, DMARDS, and biologic agents, colchicine may be a useful therapeutic options.

References

1. N. A. Ayaz, S. Özen, Y. Bilginer, M. Ergüven, E. Taşkıran, E. Yılmaz, et al. MEFV mutations in systemic onset juvenile idiopathic arthritis. Rheumatology 2009;48:23–25.

2. Hala M. Lotfy, Manal E. Kandil, Marianne Samir Makboul Issac, Samia Salah, Nagwa Abdallah Ismail, Mohamed A. Abdel Mawla. MEFV Mutations in Egyptian Children with Systemic-Onset Juvenile Idiopathic Arthritis. Molecular Diagnosis & Therapy. 2014; 18(5): 549-557.

Disclosure of Interest

None Declared.
Table 1 (abstract P180).

Summary of the five SJIA patients with MEFV gene mutations

 

Sex

Age of onset

MEFV mutations

recurrent disease

Effectiveness of colchicine

Other treatments

case 1

F

6

L110P, E148Q

+

+

TCZ, TAC, PSL

case 2

F

13

L110P, E148Q, P369S, R408Q

+

TCZ, CyA, PSL

case 3

F

3

L110P, E148Q, G304R

+

+

TCZ

case 4

F

7

G304R

+

+

TCZ

case 5

M

2

E148Q

+

TCZ

F female, M male, TCZ tocilizumab, TAC tacrolimus, PSL prednisolone, CyA Cyclosporin A

Poster Session: Systemic lupus erythematosus and antiphospholipid syndrome I

P181 Predictors of recovery from lupus nephritis in children

Eve M. Smith1, Peng Yin2, Andrea L. Jorgensen2, Michael W. Beresford1,3 on behalf of On behalf of the UK JSLE Cohort Study

1Women and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK ; 2Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 3Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
Presenting author: Eve M. Smith

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).

Conclusion: A significant proportion of children with LN have on-going proteinuria after 2 years. Poor prognostic factors include ethnicity, young age, low GFR, azathioprine use and concomitant haematological involvement. Consideration of such factors may help to improve LN outcomes.

Reference

1. Touma, Zahi, Urowitz, Murray B, Ibanez, Dominique, Gladman, Dafna D. Time to Recovery From Proteinuria in Lupus Nephritis Patients Receiving Standard of Care Treatment. Arthritis Rheum 2011;63 Suppl 10 :599 DOI: 10.3899/jrheum.130005.

Disclosure of Interest

None Declared.
Table 2 (abstract P181).

See text for description

A) Factors differentiating those who do / do not recover during follow up

Odds ratio (95% CI)

p-value

Interpretation

Ethnicity

(Caucasian vs non-Caucasian)

14.19 (2.52, 122.63)

0.007

Non-Caucasians – less likely to recover from proteinuria

eGFR

1.04 (1.02, 1.08)

0.007

Low eGFR at proteinuria onset - less likely to recover

Azathioprine use

0.093 (0.01, 0.78)

0.044

Use of Azathioprine at proteinuria onset – less likely to recover

Haematological involvement

0.13 (0.03, 0.53)

0.007

Haematological involvement – less likely to recover

Cardiorespiratory involvement

11.22 (1.57, 107.54)

0.022

Cardiorespiratory involvement - more likely to recover

B) Factors influencing time to recovery from proteinuria

HR (95% CI)

p-value

 

Age (years)

1.38 (1.1, 1.8)

0.007

Younger patients - less likely to recover

eGFR

1.0 (1.0, 1.1)

0.036

Lower eGFR - less likely to recover

Haematological involvement

0.3 (0.1, 0.8)

0.016

Haematological involvement - less likely to recover

P182 Are urine biomarkers able to predict changes in lupus nephritis disease activity over time? A Markov state-space model of lupus nephritis urine biomarker dynamics

Eve M. Smith1, Antonio Eleuteri1, Beatrice Goilav2, Laura Lewandowski3, Angel Phuti4, Dawn Wahezi2, Tamar Rubinstein2, Caroline Jones5, Paul Newland5, Stephen Marks6, Rachel Corkhill1, Diana Ekdawy1, Clarissa Pilkington6, Kjell Tullus6, Chaim Putterman7, Chris Scott8, Antony C. Fisher1, Michael W. Beresford1,9

1University of Liverpool, Liverpool, UK, 2Albert Einstein College of Medicine, New York, USA, 3National Institute of Health, Maryland, USA, 4University of Cape Town, Cape Town, South Africa, 5Alder Hey Children’s NHS Foundation Trust, Liverpool, UK, 6Great Ormond Street Hospital, London, UK, 7Albert Einstein College of Medicine, New York, UK, 8 University of Cape Town, Cape Town, South Africa, 9Alder Hey Children's NHS Foundation Trust, Liverpool, UK
Presenting author: Eve M. Smith

Introduction: A urine ‘biomarker panel’ comprising alpha-1-acid glycoprotein (AGP), ceruloplasmin (CP), transferrin, vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1) and lipocalin like prostaglandin D synthase (LPGDS) has been shown to perform to an ‘excellent’ level cross-sectionally for identification of active Lupus Nephritis (LN). The ability of this panel to predict LN flare and remission warrants further investigation.

Objectives: To model urine biomarker dynamics in LN, assessing ability to predict flare and remission.

Methods: The six novel urinary biomarkers were quantified by ELISA in participants of the UK JSLE Cohort Study (Cohort 1), the Einstein Lupus Cohort (Cohort 2), and the University of Cape Town Lupus Cohort (Cohort 3). Patients were categorised as having active LN (renal domain BILAG score of A, B or C & previous histological confirmation of LN, State 2) or inactive LN (renal domain BILAG score D or E, State 1). A baseline homogeneous Markov model of state transitions was fitted, quoting a corrected Akaike Information Criterion score (AICc). A lower AICc score suggested better model accuracy. Urine biomarkers were explored as factors predicting state transitions. Bayesian multiple imputation of missing variables was used.

Results: The study included 184 observations from 57 Cohort 1 patients, 27 from 13 Cohort 2 patients, and 33 from 10 Cohort 3 patients. Across the data set there were 10 transitions from inactive to active LN (1-2 transition), 18 from active to inactive LN (2-1 transition), with 93 and 43 remaining inactive and active respectively. A baseline homogeneous multi-state Markov model of LN activity was fitted, producing a AICc score of 149.0. Each urine biomarker was individually added to the model, identifying AGP and CP as covariates producing the lowest AICc’s. Addition of both biomarkers as predictors of all state transitions led to a worsening of AICc, 157.2. The confidence intervals of hazard ratios for CP on the 1-2 transition and for AGP on the 2-1 transition included the value 1. Re-fitting of the model, whereby AGP only had an effect on 1-2 transitions, and CP on 2-1 transitions, produced a lower AICc, 135.0, favouring this model (see 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.
Table 3 (abstract P182).

See text for description

Model characteristics

LN state transition

Baseline

Log AGP

Log CP

AICc

Hazard ratios for changing state for each covariate and 95% confidence intervals

AGP and CP as predictors of all LN state transitions

1-2

0.25 (0.03, 1.89)

1.80 (1.08, 3.01)

0.46 (0.17,1.28)

157.2

2-1

0.19 (0.03, 1.41)

1.22 (0.78, 1.91)

0.33 (0.18, 0.62)

AGP as predictor of 1-2 transition & CP for 2-1

1-2

0.59 (0.24, 1.45)

1.49 (1.10, 2.02)

-

135.0

2-1

2.11 (0.90, 4.94)

-

0.60 (0.39, 0.93)

P183 Growing international evidence for urine biomarker panels identifying lupus nephritis in children – verification from the South African Western Cape lupus cohort

Eve M. Smith1, Laura Lewandowski2, Angel Phuti3, Andrea Jorgensen4, Chris Scott5, Michael W. Beresford6

1Department of Women and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 2Pediatric Rheumatology, National Institute of Health, Maryland, USA; 3Paediatric Rheumatology, University of Cape Town, Cape Town, South Africa; 4Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 5Paediatric Rheumatology, University of Cape Town, Cape Town, South Africa; 6Department of Women’s & Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
Presenting author: Eve M. Smith

Introduction: The Paediatric Lupus Erythematosus in South Africa (SA) Cohort has collected clinical data in the Western Cape since 2013. They have demonstrated that their patients often initially present with severe lupus nephritis (LN). Monitoring of such patients can be problematic due to geographical, economic and social constraints faced by families. A range of urine biomarkers for LN have been explored within the UK JSLE Cohort study, with a panel of four (alpha-1-acid glycoprotein (AGP), lipocalin like prostaglandin D synthase (LPGDS), transferrin and ceruloplasmin) demonstrating an ‘excellent’ ability to identify active LN.

Objectives: To assess whether the same/different biomarker combinations are of importance for identifying active LN in the Paediatric Lupus Erythematosus in SA Cohort.

Methods: Participants of the Paediatric Lupus Erythematosus in SA Cohort attending Red Cross Memorial and Groote Schuur Hospital Hospitals, Cape Town, aged <18 years at diagnosis, were recruited between January 2015-16. Healthy controls (HC’s) with non-inflammatory non-infective diagnoses were also recruited. Patients were categorised as having active LN (renal domain of the BILAG score of A/B & previous histological confirmation of LN) or in-active LN (renal domain of the BILAG score of D/E). Novel urinary biomarkers; AGP, LPGDS, transferrin, ceruloplasmin, vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein 1 (MCP-1) were quantified by ELISA. Measurements were standardized to urinary creatinine. The Mann Whitney-U test was used to compare biomarker levels between groups. Binary logistic regression modeling and receiver operating curve analysis was used to assess combinations of biomarkers for active LN identification.

Results: 23 JSLE patients (20 females, 3 males) with a median age of 13.5 years [IQR 12.7-14.9] and disease duration of 2.6 years [IQR 1.8-4.0] were included. 18 HC’s (14 females, 4 males) had a median age of 11 years [IQR 10-12]. All novel urine biomarkers were significantly higher in active than in-active LN patients (corrected p-values, p c all <0.01), with no difference seen between in-active LN patients and HC’s (all p c = 1.0, see Table below). Inclusion of all novel biomarkers in a binary logistic regression model and application of step AIC function to get a final model identified VCAM-1, MCP-1 and LPGDS to be the best combination of biomarkers identifying active LN within the SA cohort, with a combined area under the curve (AUC) of 0.96.

Conclusion: This is the first study to look at urine biomarkers in an African JSLE population, highlighting their potential utility in this population. The optimal panel of biomarkers may differ to that of the UK, but requires further investigation in a prospective longitudinal study given the samples size. In SA, it is anticipated that use of a point of care testing device to monitor LN activity in the home or local clinic could help to improve patient monitoring, treatment and outcomes.

Disclosure of Interest

None Declared.
Table 4 (abstract P183).

See text for description

Marker

(ngmgCr)

Active LN

[med, IQR], n = 9

Inactive LN

[med, IQR], n = 14

HC

[med, IQR], n = 18

Act vs Inact (p c )

Inact vs HC (p c )

VCAM-1

59 [42-119]

4 [2-11]

4 [2-6]

0.0003

1.0

MCP-1 (pgmgCr)

1020 [410-3642]

219 [150-334]

296 [186-448]

0.0258

1.0

LPGDS

2683 [1640-3602]

601 [151-900]

577 [314-765]

0.0054

1.0

AGP

145435 [54746-250367]

680 [394-2985]

605 [408-1458]

0.0002

1.0

CP

51714 [34861-177503]

1901 [1140-3276]

1700 [1324-2999]

0.00003

1.0

TF

63630 [38071-156026]

433 [221-1020]

425 [234-928]

0.00003

1.0

P184 Whole exome sequencing in early onset systemic lupus erythematosus

Ezgi Deniz Batu1, Can Kosukcu2, Ekim Taskiran2, Sema Akman3, Kubra Ozturk4, Betul Sozeri5, Erbil Unsal6, Zelal Ekinci4, Yelda Bilginer1, Mehmet Alikasifoglu2, Seza Ozen1

1Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Department of Medical Genetics, Hacettepe University Faculty of Medicine, Ankara, Turkey; 3Department of Pediatrics, Division of Nephrology-Rheumatology, Akdeniz University Faculty of Medicine, Antalya, Turkey; 4Department of Pediatrics, Division of Rheumatology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey; 5Department of Pediatrics, Division of Rheumatology, Erciyes University Faculty of Medicine, Kayseri, Turkey; 6Department of Pediatrics, Division of Rheumatology, Dokuz Eylul University Faculty of Medicine, İzmir, Turkey
Presenting author: Ezgi Deniz Batu

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 DNASE1L3 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.
Table 5 (abstract P184).

Characteristics of pediatric patients with early-onset systemic lupus erythematosus

 

Pt 1

Pt 2

Pt 3

Pt 4

Pt 5

Pt 6

Pt 7

SLE in sibling

+

+

-

-

+

-

+

Mutant genes

C1QA

C1QC

C1QC

C1QA

C1S

DNASE1L3

Novel gene (?)

Malar/discoid rash/photosensitivity

+

+

+

+

+

+

-

Oral ulcers

+

+

+

-

+

-

-

Arthritis

+

+

-

-

+

+

-

Nephritis

-

-

-

-

+

+

-

Hematologic involvement

+

+

+

-

+

+

-

Decrease in C3, C4

-

-

-

-

+

+

+

Autoantibodies*

Anti-SM

RF

Anti-SM, anti-SSA, LA

Anti-SM, U1RNP

AntidsDNA, Anti-SSA, U1RNP, anti-histon

AntidsDNA, Anti-CL

AntidsDNA, DC

Pt patients, SLE systemic lupus erythematosus, CL cardiolipin, LA lupus anticoagulant, RF rheumatoid factor

* ANA was positive in all patients

P185 Fatigue in JSLE: analysis of prevalence and associations in a large, national cohort of patients

Hanna Lythgoe1,2, Michael W. Beresford2

1Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 2NIHR Alder Hey Clinical Research Facility, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
Presenting author: Hanna Lythgoe

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 patient-reported 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.
Table 6 (abstract P185).

Associations of BILAG fatigue scores and SF36 vitality scores

 

Spearman’s rank correlation coefficients

Assessed association

Measure used as comparator

BILAG fatigue

SF36 vitality

Disease activity

Physician global activity VAS score

0.53

-0.5

Patient global VAS score

0.48

-0.72

ESR

0.25

-0.12

Pain

SF36 bodily pain

-0.45

0.69

Physical function

CHAQ

0.45

0.62

Anaemia

Haemoglobin

0.18

-0.21

Mood

Mood disorder, anxiety disorder or organic depressive illness on p-BILAG

0.17

-0.23

VAS visual analogue scale, ESR erythrocyte sedimentation rate. Strong correlations are shown in bold. All correlation co-efficients were statistically significant (P < 0.05)

P186 Evidence of altered blood brain barrier permeability in systemic lupus erythematosus using magnetic resonance imaging

Hermine I. Brunner1, Gaurav Gulati2, Jordan T. Jones3, Mekibib Altaye4, Jamie Eaton5, Mark Difrancesco6

1Pediatrics, Cincinnati Children's Hosptial Medical Center, Cincinnati, USA; 2Internal Medicine, University of Cincinnati, Cincinnati, USA; 3Pediatrics, University of Kansas, Kansas, USA; 4Pediatrics, Cinccinnati Children's Hospital Medical Center, Cincinnati, USA; 5Pediatrics, Cincinnati Children'sHosptial MEdical Center, Cincinnati, USA; 6Radiology, University of Cincinnati, Cincinnati, USA
Presenting author: Hermine I. Brunner

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 SLE-associated 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 Z-scores, 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 Yeo1,2, Jingyao Leong2, Loshinidevi D/O Thana Bathi2, Thaschawee Arkachaisri1,3, Salvatore Albani1,2,3

1Rheumatology and Immunology Service, Department of Paediatric Subspecialties, KK Women’s and Children’s Hospital, Singapore, Singapore; 2SingHealth Translational Immunology and Inflammation Centre, Singapore Health Services, Singapore, Singapore; 3Duke-National University of Singapore Medical School, Singapore, Singapore
Presenting author: Joo Guan Yeo

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 multi-dimensional 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.

P188 Disease activity status in juvenile systemic lupus erythematosus

Nagla Abdelrahman1, Michael W Beresford2, Valentina Leone1 and UK JSLE study group supported by the National Institute of Health Research Clinical Research Network

1Leeds Teaching Hospitals, Leeds, UK; 2NIHR Alder Hay clinical research facility, Liverpool, UK
Presenting author: Nagla Abdelrahman

Introduction: A key aim in the management of Juvenile-onset Systemic Lupus Erythematosus (JSLE) is to achieve inactive disease (ID) and clinical remission (CR). There are no universally agreed definitions of ID & CR; however an evidence based, internationally-accepted consensus process to define ID & CR was reached and published in May 2012 (Mina R, Klein-Gitelman MS, Ravelli A, et al. Arthritis Care Res)

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 over-sensitive 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.

Disclosure of Interest

None Declared

P189 Adult outcomes in a large cohort of childhood-onset SLE patients: clinical outcome and quality of life - the CHILL-NL study

Noortje Groot, D. Shaikhani, I. E. M. Bultink, M. Bijl, R. J. E. M. Dolhain, Y. K. O. Teng, E. Zirkzee, K. de Leeuw, R. Fritsch-Stork, S. S. M. Kamphuis

Sophia Children's Hospital - Erasmus University Medical Centre, Rotterdam, Netherlands
Presenting author: Noortje Groot

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.
Table 7 (abstract P189).

Patient characteristics

 

cSLE

n = 111

SLE

n = 40

p*

Female

91% (101/111)

93% (37/40)

 

Ethnicity

White

69% (77/111)

68% (27/40)

 

Non White

31% (34/111)

32% (13/40)

 

Age at study visit (median (range))

33 (18 – 65)

40 (25 – 76)

p = 0.000

Age at diagnosis in yrs (median (range))

14 (4 – 17)

28 (18 – 69)

p = 0.000

Disease duration in yrs (median (range))

20 (1 – 55)

11 (1 – 34)

p = 0.000

Current SLEDAI-2 K score (median (range))

4 (0 – 14)

4 (0 – 10)

 

SDI-score (median (range))

1 (0 – 8)

1 (0 – 7)

 

Patients with SLICC-DI ≥ 1

62% (69/111)

60% (24/40)

p = 0.05

Musculoskeletal

41% (28/69)

46% (11/24)

p = 0.027

Renal

23% (16/69)

8% (2/24)

Neuropsychiatric

33%(23/69)

13% (3/24)

Cardiovascular

13% (9/69)

33% (8/24)

Patients currently using any immunosuppressive drug

87% (97/111)

93% (37/40)

 

Current prednisone use

60% (58/97)

59% (22/37)

Renal involvement (ever)

60% (67/111)

48% (19/40)

 

Renal damage on SDI

24% (16/67)

11% (2/19)

n.s.

Neuropsychiatric involvement (ever)

41% (45/111)

30% (12/40)

n.s.

Neuropsychiatric damage on SDI

51% (23/45)

25% (3/12)

Myocardial infarction

5% (5/111)

3% (1/40)

Cerebrovascular accident

6% (7/111)

3% (1/40)

p < 0.05 compared to Dutch norm; *if no p-values are given, differences between cSLE and SLE were not statistically significant

P190 Urinary biomarker production in juvenile lupus nephritis – role of the podocytes

Rachael D. Wright1, Eve M. Smith1, Michael W. Beresford1, 2

1Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 2Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK
Presenting author: Rachael D. Wright

Introduction: Lupus nephritis (LN) is a severe manifestation of juvenile-onset systemic lupus erythematosus (JSLE); it occurs in up to 80% of patients and can lead to end-stage renal disease (ESRD) in 10-15% requiring dialysis or transplantation. LN is relapsing-remitting in character and each flare increases the risk of ESRD. LN is caused by the binding of autoantibodies present in the circulation to antigens expressed on native kidney cells leading to an inflammatory response.

Previous data have identified urinary biomarkers (α1-acid glycoprotein (AGP), caeruloplasmin (CP), transferrin (Tf), lipocalin-type prostaglandin D2 synthase (L-PGDS) and vascular cell adhesion molecule (VCAM)-1) in JSLE patients that indicate when a flare of LN is occurring without the need for an invasive biopsy. A deeper understanding of the pathways leading to biomarker release in the kidney and the effects these have on native kidney cells may identify new kidney specific targets for therapy.

Podocytes are specialised epithelial cells of the glomerulus that play important roles in selective filtration. They constitutively express toll-like receptors and the expression of receptors for TNF-α increase following inflammatory activation indicating they are potentially able to respond to cytokine stimulation.

Objectives: This study aimed to determine the role of podocytes in the production of urinary biomarkers following exposure to pro-inflammatory cytokines, in particular those known to be involved in JSLE, or urine/serum from LN patients.

Methods: Conditionally immortalised human podocytes (n = 3/group) were cultured at 33 °C until 70% confluent and then thermoswitched to 37 °C for 10-14 days for differentiation to occur; these were then incubated with TNF-α, IL-1β, IFN-α, IFN-γ (10 ng/mL) or LPS (1 μg/mL) for 48 hours and RNA was collected for analysis. Podocytes were also cultured with 10% urine (n = 5/group) or 10% serum (n = 8-9/group) from BILAG defined inactive and active LN patients, and age- and sex-matched healthy controls for 48 hours and RNA collected. Samples were analysed for a modulation in the genes involved in biomarker production by qRT-PCR, normalised to the geometric mean of housekeeping genes – β-actin, TBP and YWHAZ.

Results: Increased mRNA expression for CP was seen in response to IFN-α (0.593 ± 0.227; p = 0.05), a cytokine known to be increased in JSLE, compared to healthy controls (0.019 ± 0.02); no significant changes in mRNA expression were noted of the other biomarkers were present following stimulation with the other cytokines. Podocytes treated with urine from all groups’ demonstrated markedly increased cell death compared to untreated podocytes. Although initially attributed to the acidity of the urine, increased cell death was still noted despite titration as low as 1%. Expression of mRNA for all biomarkers were unchanged following treatment with 10% sera from any of the patient groups.

Conclusion: These data demonstrate that podocytes play a role in the production of CP following treatment with pro-inflammatory stimuli but this cannot be replicated using patient sera. It can therefore be hypothesised that the role played by podocytes in LN is not in biomarker production but perhaps loss of the podocytes resulting in decreased barrier function and thus passive loss of biomarkers into urine. Further work is required into the role that podocytes do play and into the roles played by other native kidney cells in urinary biomarker production in JSLE.

Disclosure of Interest

None Declared.

P191 Neonatal outcomes of pregnancies complicated by systemic lupus erythematosus

Reem Abdawani1, Laila Al Shaqshi2, Ibrahim Al Zakwani3

1Child Health, Sultan Qaboos University Hospital, Muscat, Oman; 2Child Health, OMSB, Muscat, Oman; 3Pharmacy, Sultan Qaboos University, Muscat, Oman
Presenting author: Reem Abdawani

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.

P192 Autoimmune hemolytic anemia in systemic lupus erythematosus at diagnosis: distinct features in 336 pediatric and 1,830 adult patients

Natali W. Gormezano1, David Kern1, Oriany L. Pereira1, Gladys C. C. Esteves1, Adriana M. Sallum2, Nadia E. Aikawa1, Rosa M. Pereira1, Clovis A. Silva1, 2, Eloisa Bonfa1

1Pediatric Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil; 2Pediatric Rheumatology Unit, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
Presenting author: Adriana M. Sallum

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/mm3) 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 Beckmann1, Nora Bartholomä2, Nils Venhoff2, Philipp Henneke1, Ulrich Salzer2, Ales Janda1

1Center for Pediatric and Adolescent Medicine, University Medical Center, Freiburg im Breisgau, Germany; 2Rheumatology and Clinical Immunology, University Medical Center, Freiburg im Breisgau, Germany
Presenting author: Ales Janda

This abstract is not included here as it has already been published.

P194 Neuropsychiatric manifestations in pediatric-onset systemic lupus erythematosus: experience of a tertiary center

Alina Lucica Boteanu1, Sandra Garrote Corral2, Alberto Sifuentes Giraldo1, Mariluz Gámir Gámir1, Antonio Zea Mendoza2

1Rheumatology Pediatric Unit, University Hospital Ramón y Cajal, Madrid, Spain; 2Rheumatology, University Hospital Ramón y Cajal, Madrid, Spain
Presenting author: Alina Lucica Boteanu

Introduction: The neuropsychiatric (NP) manifestations are an important cause of morbidity and mortality in patients with pediatric-onset 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.

P195 Pulmonary hypertension in patients with juvenile lupus erythematosus

Amra Adrovic1, Reyhan Dedeoglu2, Sezgin Sahin2, Kenan Barut1, Aida Koka2, Funda Oztunc2, Ozgur Kasapcopur1

1Pediatric Rheumatology, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey; 2Pediatric Cardiology, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey
Presenting author: Amra Adrovic

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.

Disclosure of Interest

None Declared
Table 8 (abstract P195).

Echocardiographic measurements in jSLE patients and healthy controls

Pulsed wave and tissue Doppler echocardiographic measurements

jSLE patients

N = 38

Healthy controls

N = 40

MW

p

Lat E wave (cm/s)

13,441 ± 1,463

16,767 ± 2,605

164,000

0,000

Lat A wave (cm/s)

7,963 ± 2,039

8,667 ± 1,857

416,000

0,079

Lat S wave(cm/s)

10,471 ± 1,986

11,340 ± 2,256

417,000

0,112

Lat E’wave (cm/s)

6,772 ± 1,297

5,875 ± 0,720

272,000

0,002

Lat E/E’ ratio

5,227 ± 1,192

5,841 ± 0,677

260,000

0,001

TRV max (m/s)

2,340 ± 0,277

2,044 ± 0,411

299,000

0,011

PIV (m/s)

1,469 ± 0,295

1,214 ± 0,128

250,000

0,000

TAPSE (mm)

23,018 ± 3,422

21,800 ± 1,701

269,000

0,214

P196 Associated features to damage in 80 juvenile systemic lupus erythematosus patients from a tertiary pediatric centre

Ana Luisa Rodriguez-Lozano1, Francisco Rivas-Larrauri1, Silvestre García de la Puente2

1Immunology, Instituto Nacional de Pediatria, Mexico City, Mexico; 2Research Methodology, Instituto Nacional de Pediatria, Mexico City, Mexico
Presenting author: Ana Luisa Rodriguez-Lozano

Introduction: Patients with juvenile systemic lupus erythematosus (JSLE) have more aggressive disease1 in addition to the improvement on survival in the last decades2,3, 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-MEX4, 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 before6 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:

References

1. Tucker LB, Uribe AG, Fernández M, Vilá LM, McGwin G, Apte M, Fessler BJ, et al. Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case - control study within LUMINA, a multiethnic US cohort (LUMINA LVII). Lupus 2008;17:314-22.

2. Lee PY, Yeh KW, Yao TC, Lee WI, Lin YJ, Huang JL.The outcome of patients with renal involvement in pediatric-onset systemic lupus erythematosus--a 20-year experience in Asia. Lupus. 2013;22:1534-40.

3. Blancas-Galicia L, Guevara-Cruz M, Berrón-Pérez R, Berrón-Ruiz L, Gutiérrez-Castrellón P, Espinosa-Rosales FJ. Survival of Mexican patients with paediatric-onset systemic lupus erythematosus and abnormal electroencephalogram. Allergol Immunopathol. 2013;41:108-13.

4. Uribe GA, Vilá ML, McGwin Jr G, Sánchez ML, et al. The systemic lupus activity measurement-revised, the Mexican systemic lupus erythematosus disease activity index (SLEDAI), and a modified SLEDAI-2 K are adequate instruments to measure disease activity in systemic lupus erythematosus. J Rheumatol 2004; 31: 1934-40

5. Gutierrez –Suárez R, Ruperto N, Gastaldi R, et al., A proposal for a pediatric version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index based on the analysis of 1015 patients with Juvenile-Onset Systemic Lupus Erythematosus. Arthritis and Rheumatism 2006; 54: 2989-96

6. Brunner H, Silverman E, To T, Bombardier C, Feldman B. Risk factors for damage in childhood onset systemic lupus erythematosus. Arthritis and Rheumatism 2002; 42: 436-444.

Disclosure of Interest

None Declared.
Table 9 (abstract P196).

Variables tested for association with Damage ≥2

Variable

Damage ≥ 2

Pearson* p Value

Gender:

 Fem / Male

51.8% / 54.2%

1.281 .038

Adolescent

 No / Yes

57.1% / 47.4%

.764 .382

SLEDAI-MEX

  < 6 / >6

20% / 63.3%

11.295 .001

Hemolytic anemia

 No / Yes

36.8% / 66.7%

7.116 .008

Trombocytopenia

 No / Yes

54.1% / 47.4%

.263 .608

APL

 Neg / Pos

42.9% / 61.0%

2.486 .115

*Pearson chi square

P197 Can individual exposure to air pollution trigger disease activity and aggravate nephritis in childhood-onset systemic lupus erythematosus patients?

Andressa G. F. Alves1, Maria F. D. A. Giacomin1, Juliana Farhat2, Alfésio L. F. Braga3, Adriana M. E. Sallum