A Ravelli

Performance of the preliminary definition of improvement in juvenile chronic arthritis patients treated with methotrexate

OBJECTIVE To investigate the performance of the core set of outcome measures and the preliminary definition of improvement (PDI) in the assessment of response to methotrexate (MTX) treatment in children with juvenile chronic arthritis (JCA). METHODS Data were obtained from an open label, non-controlled trial designed to investigate the efficacy of MTX in children with JCA. All patients had the core set of variables assessed at baseline and after six months of treatment. Variables in the core set are: (1) physician global assessment of disease activity; (2) parent or patient (if appropriate in age) global assessment of overall well being; (3) functional ability; (4) number of joints with active arthritis; (5) number of joints with limited range of motion; (6) erythrocyte sedimentation rate. The PDI specifies that to be classified as improved, a patient must show at least 30% improvement from baseline in three of any six variables in the core set, with no more than one of the remaining variables worsening by more than 30%. RESULTS A total of 111 JCA patients were included in the study. According to the PDI, after six months of MTX treatment 73 patients (66%) were classified as improved and 38 (34%) as not improved. Among the core set variables, parent assessment detected the highest percentage of patients improved (72%) and functional assessment the lowest (37%). CONCLUSION The PDI identifies about two thirds of patients with JCA treated with low dose MTX as improved. This proportion is similar to that expected to improve based upon a previous controlled study of low dose, oral MTX and provides preliminary evidence of the definition’s validity.

Prevalence of anticardiolipin antibodies in juvenile chronic arthritis.

The prevalence of anticardiolipin antibodies was evaluated in 70 children with juvenile chronic arthritis (JCA), in 25 adult patients with rheumatoid arthritis, in 42 healthy children and in 40 adult controls. Thirty seven (53%) patients with JCA were positive for IgG or IgM anticardiolipin antibodies, or both, and 30 (43%) for IgG anticardiolipin antibodies. In contrast, only seven (28%) adult patients with rheumatoid arthritis presented anticardiolipin antibodies, which were of IgG class in four (16%) cases. IgG anticardiolipin antibodies were negative in all control subjects while IgM anticardiolipin antibodies were detected in two (5%) children and in four (10%) adult controls. No correlations were found in patients with JCA between the presence or titres of anticardiolipin antibodies and various clinical or laboratory variables. No patient with anticardiolipin antibodies showed any feature of the anticardiolipin syndrome.

Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial

Objectives To determine whether baseline demographic, clinical, articular and laboratory variables predict methotrexate (MTX) poor response in polyarticular-course juvenile idiopathic arthritis. Methods Patients newly treated for 6 months with MTX enrolled in the Paediatric Rheumatology International Trials Organization (PRINTO) MTX trial. Bivariate and logistic regression analyses were used to identify baseline predictors of poor response according to the American College of Rheumatology pediatric (ACR-ped) 30 and 70 criteria. Results In all, 405/563 (71.9%) of patients were women; median age at onset and disease duration were 4.3 and 1.4 years, respectively, with anti-nuclear antibody (ANA) detected in 259/537 (48.2%) patients. With multivariate logistic regression analysis, the most important determinants of ACR-ped 70 non-responders were: disease duration >1.3 years (OR 1.93), ANA negativity (OR 1.77), Childhood Health Assessment Questionnaire (CHAQ) disability index>1.125 (OR 1.65) and the presence of right and left wrist activity (OR 1.55). Predictors of ACR-ped 30 non-responders were: ANA negativity (OR 1.92), CHAQ disability index>1.14 (OR 2.18) and a parents evaluation of childs overall well-being ≤4.69 (OR 2.2). Conclusion The subgroup of patients with longer disease duration, ANA negativity, higher disability and presence of wrist activity were significantly associated with a poorer response to a 6-month MTX course.

MRI versus conventional measures of disease activity and structural damage in evaluating treatment efficacy in juvenile idiopathic arthritis

Objective To compare the American College of Rheumatology paediatric (ACRp) response criteria and conventional radiography with MRI findings in a cohort of patients with juvenile idiopathic arthritis. Methods Forty consecutive patients (30 girls, 10 boys; median age 10.8 years) with arthritis of the wrist starting treatment with disease-modifying antirheumatic drugs or biological agents were recruited. At 1-year follow-up the treatment response was assessed by ACRp criteria and radiographic progression using the adapted Sharp/van der Heijde method. Wrist MRIs were evaluated using both the paediatric-MRI and the OMERACT rheumatoid arthritis MRI scores. Sensitivity to change of clinical and imaging variables was assessed by standardised response mean (SRM) and relative efficiency (RE) was used to compare SRMs. Results ACRp90 responders showed a significantly higher decrease in MRI synovitis score (median change −4) than non-responders (median change 0), ACRp30–50 responders (median change 0) and ACRp70 responders (median change −1) (p=0.0006, Kruskal–Wallis test). Non-responders showed significantly higher radiographic progression than ACRp90 responders (pB=0.016). The MRI synovitis score showed a greater responsiveness to change (SRM 1.69) compared with the majority of ACR core set of variables. MRI erosion scores were less responsive than conventional radiography in detecting destructive changes (RE <1). MRI follow-up revealed no signs of inflammation in four out of 24 wrists with clinically inactive disease. Conclusion Only ACRp90 responders showed a significant decrease in synovitis and the halting of structural damage, suggesting that levels of response higher than ACRp30 are more appropriate for assessing drug efficacy. The excellent responsiveness of MRI and its ability to detect subclinical synovitis make it a promising outcome measure.

OP0059 A Randomized Trial in New Onset Juvenile Dermatomyositis: Prednisone Versus Prednisone Plus Cyclosporine Versus Prednisone Plus Methotrexate

Background Data regarding the safety and efficacy of treatment regimens for juvenile dermatomyositis (JDM) tends to be from anecdotal, small, uncontrolled, non-randomized case series. Objectives This randomized trial was aimed to find out the treatment regimen associated with the lowest occurrence of flare and the lowest drug related toxicity. Methods Children with newly diagnosed JDM were randomized in an open fashion to receive one of 3 different therapeutic approaches: prednisone (PDN) versus PDN plus methotrexate (MTX) versus PDN plus Cyclosporine A. The overall hypothesis to be tested in this trial was that the early introduction of combination therapy of corticosteroids and either MTX or CsA will prove more effective and safe than corticosteroids alone in the treatment of JDM. Primary outcome measures after 6 months of treatment: response rate according to the Paediatric Rheumatology International Trials Organisation (PRINTO) provisional definition of improvement in the 3 arms (20% improvement in at least 3 core set variables with no more than 1 of the remaining variables, (muscle strength excluded), worsened by > 30%). The PRINTO JDM core set variables are: 1) muscle strength by the mean of the Childhood Myositis Assessment Scale (CMAS); 2) physician’s global assessment of disease activity on a 10 cm VAS ; 3) global disease activity assessment by the mean of the Disease Activity Index (DAS); 4) parent’s/patient’s global assessment of overall well-being on a 10 cm VAS; 5) functional ability assessment by the mean of the Childhood Health Assessment Questionnaire (CHAQ); 6) health-related quality of life assessment. Primary outcome measures after 24 months of treatment: a) time to inactive disease; b) time to major therapeutic changes because of inefficacy/flare/adverse events. Results 138/139 randomized patients were included in the efficacy dataset. There were 81/138 females (59%) with a median age at onset of 7.4 years (1st-3rd quartiles 1.1-15.4) and a median disease duration of 2.8 months (1.4-5.3). Frequency of response at 6 months was for 24/46 (52.2%) for PDN, 31/46 (67.4%) for PDN+CSA and 34/46 (73.9%) for PDN+MTX (p 0.082). Time to inactive disease in the combination group (PDN+CSA or PDN+MTX) was significantly shorter than that of PDN alone (p 0.031). Time to major therapeutic changes in the combination group (PDN+CSA or PDN+MTX) was significantly longer than that of PDN alone (p 0.009). Total number of adverse events were 57/276 (20.7%) in the PDN group, 141/276 (51.1%) in PDN+CSA and 78/276 (28.3%) in PDN+MTX (p < 0.0001). Skin and subcutaneous tissue disorders, and nervous system disorders were statistically more frequent in PDN+CSA (p 0.0015, p 0.039 respectively). Conclusions Combined therapy with PDN and either CSA or MTX was more effective than with PDN alone. However the safety profile favour the combination with MTX toward that with CSA. Disclosure of Interest None Declared

Use of the JADAS criteria to assess efficacy of canakinumab in patients with SJIA – an analysis of 12-week pooled data

The composite score JADAS1, 2 27-CRP (J27), 10-CRP (J10), and cut-off values for inactive (ID), low (LDA), moderate (MDA) and high disease activity (HDA) were designed to monitor the level of disease activity in all JIA subtypes1. The efficacy of canakinumab (CAN), a selective, human, anti-IL-1β monoclonal antibody, was previously demonstrated in SJIA in phase III trials using aACR-JIA response criteria3.

Preliminary validation of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) in 403 clinic patients

Methods The JAMAR includes: Juvenile Arthritis Functionality Scale (JAFS) (0 = normal; 30 = worst), Pediatric Rheumatology Quality of Life (PRQL) questionnaire (0 = best; 30 = worst); visual analogue scales (0 = best; 10 = worst) for parent/patient rating of well-being (WB), pain (P), disease activity (DA); parent/patient assessment of morning stiffness, disease status, satisfaction about disease outcome.

Variation of serum IgG subclass concentrations with disease activity in juvenile chronic arthritis.

Nineteen patients with juvenile chronic arthritis were followed up and serum IgG subclass concentrations measured at different stages of disease activity. Patients were divided into three groups according to clinical activity of the disease: active disease, partial remission, and remission. The results were compared with normal values obtained in 448 healthy children aged 6 months to 18 years with a homogeneous distribution for each year of age. Serum IgG subclass concentrations of each child were first log transformed and then age corrected, taking the deviation of the log transformed value from that expected for a child of the same age. It was found that patients with partial remission had increased concentrations of IgG2 and decreased concentrations of IgG1 compared with patients with active disease. This suggests that the remission inducing process, at least in juvenile chronic arthritis, is accompanied by a switch of IgG subclass production.

High levels of interferon-gamma (IFNγ) in macrophage activation syndrome (MAS) and CXCL9 levels as a biomarker for IFNγ production in MAS

Objectives Given the similarities between primary and secondary HLH (sec-HLH), including MAS, we measured levels of IFNg, IFNg-related chemokines (CXCL9, CXCL10, CXLC11), and IL-6 in patients with sec-HLH, and in patients with systemic Juvenile Idiopathic Arthritis (sJIA) with or without MAS at sampling and evaluated their relation to disease activity. In addition, we evaluated the correlation between serum levels of IFNg and of the three IFNg related chemokines with themselves and with laboratory parameters of disease activity in patients with active MAS.

FRI0271 Final Evidence-Based Recommendations for Diagnosis and Treatment of Paediatric Vasculitides

Background The paediatric vasculitides are a group of rheumatic diseases characterized by blood vessel inflammation. Several vasculitic syndromes can be distinguished based on the size of the involved vessels as well as the specific symptoms. Incidence of these syndromes is low and evidence-based paediatric guidelines are lacking. SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) is a project that aims to develop European evidence-based guidelines for diagnosis and treatment of these and other rare paediatric rheumatic diseases (PRD). Objectives To develop evidence-based recommendations for diagnosis and treatment of paediatric vasculitides, i.e. Kawasaki Disease (KD), Henoch Schönlein Purpura (HSP), Polyarteritis Nodosa (PAN), Granulomatosis with Polyangiitis (GPA), Eosinophilic granulomatosis with Polyangiitis (EGPA) and Takayasus Arteritis (TA). Methods A systematic review of literature was conducted (results presented at PReS 2014), from which evidence-based recommendations were derived. A European expert committee evaluated these recommendations, both by online surveys and by discussion using the nominal group technique1 during several in-person consensus meetings in Genoa (Italy, March ’14, results presented at PReS 2014), Utrecht (the Netherlands, January ’15) and Barcelona (Spain, March ’15). Recommendations were accepted for the final guidelines if more than 80% agreement was reached. Results Evidence from literature and expert opinion led to the formulation of recommendations for the different paediatric vasculitides. Adding to the 44 statements accepted with more than 80% consensus in Genoa, an additional 78 statements were accepted in Utrecht. Included statements ranged across different topics, including criteria for diagnosis, referral indications, clinical and laboratory parameters, imaging and treatment of the different vasculitic syndromes. Statements for discussion in Barcelona will focus on general and interdisciplinary aspects of care for children with vasculitis and other PRDs. Conclusions SHARE aims to provide minimal standards of care for PRD. We present the final recommendations for diagnosis and treatment of paediatric vasculitides. These recommendations will contribute to a more uniform and evidence-based foundation for diagnosis and treatment of KD, HSP, PAN, GPA, EGPA and TA in children. References Harvey N, Holmes CA. Nominal group technique: an effective method for obtaining group consensus. Int J Nurs Pract. 2012; 18:188-94 Acknowledgements This project is supported by a grant from European Agency for Health and Consumers (EAHC), grant number 2011 1202. Disclosure of Interest None declared