Dragana Lazarevic

The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis

Objectives To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM). Methods The Paediatric Rheumatology International Trials Organisation (PRINTO) database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physicians and parents global disease activity/damage evaluations, inactive disease criteria derived from the literature and other ad hoc criteria were evaluated for sensitivity, specificity and Cohens κ agreement. Results The individual measures that best characterised inactive disease (sensitivity and specificity >0.8 and Cohens κ >0.8) were manual muscle testing (MMT) ≥78, physician global assessment of muscle activity=0, physician global assessment of overall disease activity (PhyGloVAS) ≤0.2, Childhood Myositis Assessment Scale (CMAS) ≥48, Disease Activity Score ≤3 and Myositis Disease Activity Assessment Visual Analogue Scale ≤0.2. The best combination of variables to classify a patient as being in a state of inactive disease on or off therapy is at least three of four of the following criteria: creatine kinase ≤150, CMAS ≥48, MMT ≥78 and PhyGloVAS ≤0.2. After 24 months, 30/31 patients (96.8%) were inactive off therapy and 69/145 (47.6%) were inactive on therapy. Conclusion PRINTO established data-driven criteria with clearly evidence-based cut-off values to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice.

Therapeutic approaches for the treatment of renal disease in juvenile systemic lupus erythematosus: an international multicentre PRINTO study

Objectives To evaluate therapeutic approaches and response to therapy in juvenile systemic lupus erythematosus (SLE) with renal involvement in a large prospective international cohort from four geographic areas. Methods New onset and flared patients with active renal disease (proteinuria ≥0.5 g/24 h) were enrolled in 2001–2004. Therapeutic approaches and disease activity parameters were analysed at baseline, 6, 12 and 24 months. Response was assessed by the PRINTO/ACR criteria. Results 218/557 (79.8% female subjects, 117 new onset and 101 flared) patients with active renal disease were identified; 66 patients were lost to follow-up and 11 died. Mean age at disease onset for new onset group was higher than for flared group (13.1 vs 10.2 years, p<0.0001). At baseline, both groups had similar renal activity with similar median doses of corticosteroids (1.0–0.76 mg/kg/day). Cyclophosphamide (43.1%) and azathioprine (22%) were the most common immunosuppressive drugs. At baseline, South American patients received higher doses of corticosteroids than in other areas in new onset (median 1.16 vs 0.8–1 mg/kg/day) while cyclophosphamide use was similar in all four regions in the new onset group. There were no differences regarding the use of azathioprine or mycophenolate mofetil worldwide. PRINTO 70 response was reached in a greater percentage of new onset versus flared patients (74.8% vs 53.3%; p=0.005) at 6 months while at 24 months ACR 90 was reached by 69.9% and 56.1%, respectively. Conclusions New onset and flared juvenile SLE improved similarly over 24 months with minimal differences in therapeutic approaches worldwide.

Development and testing of a hybrid measure of muscle strength in juvenile dermatomyositis for use in routine care

To develop and test a hybrid measure of muscle strength for juvenile dermatomyositis (JDM), which is based on the combination of the Manual Muscle Testing in 8 muscles (MMT‐8) and the Childhood Myositis Assessment Scale (CMAS) but is more comprehensive than the former and more feasible than the latter.

The Serbian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR)

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Serbian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach’s alpha, interscale correlations, test–retest reliability, and construct validity (convergent and discriminant validity). A total of 248 JIA patients (5.2% systemic, 44.3% oligoarticular, 23.8% RF-negative polyarthritis, 26.7% other categories) and 100 healthy children were enrolled in three centres. The JAMAR components discriminated healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Serbian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Outcome of Juvenile Idiopathic Arthritis Associated Uveitis in Two Disease Subtypes

Objectives This study aims to evaluate the efficacy of adalimumab as a first line biologic agent in specific subtypes of juvenile idiopathic arthritis (JIA) patients with associated uveitis. Patients and methods We retrospectively analyzed the data of 11 JIA patients (8 males, 3 females; mean age 14.5 years; range 9 to 18 years) with associated uveitis treated with biologic therapy. All patients were diagnosed as oligoarticular/extended oligoarticular or enthesitis-related JIA subtypes, treated with methotrexate, and had active or previous history of uveitis for which adalimumab was prescribed. We tested all patients for anti-nuclear antibody presence and human leukocyte antigen genotype. We assessed disease activity and therapy efficacy by American College of Rheumatology 50%, 70%, and 100% improvement criteria. We evaluated uveitis activity by slit-lamp biomicroscopy and recorded adverse events. Results Of the JIA patients, three (27.27%) had oligoarticular/extended oligoarticular JIA and eight (72.73%) had enthesitis-related arthritis. Anti-nuclear antibody positivity was present in 27.27% (all females) while human leukocyte antigen-B51 was determined in 62.5% and human leukocyte antigen-B27 in 12.5% of patients. Mean uveitis duration before adalimumab introduction was 12.3 months. After two years of follow-up, there were no relapses of uveitis and visual acuity was stable while on adalimumab and methotrexate treatment. All patient were gradually tapered and discontinued treatment with topical steroids. Disease activity improved and seven patients (63.64%) achieved American College of Rheumatology 100% response rate (attained remission), while four patients (36.36%) achieved American College of Rheumatology 70% response rate. Conclusion Anti-nuclear antibody positivity with oligoarticular/extended oligoarticular and enthesitis-related arthritis JIA subtypes, which are known for their high risk to develop uveitis, may benefit from adalimumab as a first line anti-tumor necrosis factor agent.

Inflence of clinical and genetic characteristics on ability to achive and maintain remission in JIA patients on etanercept treatment

There are no official published recommendations how and when to stop treatment with biologics when remission achieved.

Influence of TNFα–308 and T676G TNF-RII polymorphism on response to etanercept and posibility to discontinue tretment

Results Average duration of etanercept therapy was 34.61±12.11 months. Disease subtype distribution was 6.78% systemic, 54.24% poly RFand extended-oligo, 18.64% poly RF+, 16.95% ERA and 3.38 PsA. The distribution of TNFὰ308 and T676G genotypes was not significantly different among JIA subtypes. TNFὰ308 genotypes distribution was 6.78% AA, 30.51% GG and 62.71% GA while T676G genotypes were 59.3% TT, 8.3% GG and 26.4% TG. T676G genotype polymorphism did not significantly influenced outcome. ACR Pedi 30,50,70 and 100 improvement was significantly faster and sustained in TNFὰ308 GG-genotype patients compared to GA genotype (results shown in table:*significant compared to 1 year; a-significant compared to GG). Treatment induced remission in 35.14%, had to be reintroduced due to disease worsening in 16.22%, disease was in remission under medication in 21.62% or still active in 24.32% GA patients and in 38.9%, 16.7%, 27.8% and 11.1% in GG patients, respectively. Patients with systemic or RF+ disease course were mostly treatment resistant in both genotypes. (Table 1)

DNase I levels and disease outcome in JIA patients treated with etanercept

Methods The study was performed in 25 JIA patients who donated paired serum samples prior and one year after continous etanercept therapy. Basic clinical data (six core set variables defined in ACR PEDI outcome score) were recorded along with alkalyne DNase I serum levels using the method where acid soluble nucleotides are determined spectrophotometrically at 260 nm. Treatment schedule of etanercept was 0,4mg/kg body weight subcutaneously twice weekly.

Development and initial validation of a new functional ability tool for juvenile dermatomyositis

Methods The MyoFun assesses the ability of the child to perform 15 activities that require the use of all skeletal muscles and muscle groups. Each item is scored from 0 to 3 (0=with no difficulty; 1=with some difficulty; 2=with much difficulty; 3=unable to do). The total score ranges from 0 (normal physical function) to 45 (worst physical function). A parent of 27 children with JDM was asked to complete the MyoFun and the Childhood Health Assessment Questionnaire (C-HAQ) and to rate the child’s overall well-being and pain intensity on a 21numbered circle visual analog scale (VAS). The attending physician assessed the child’s muscle strength/function with the Kendall’s Manual Muscle Testing (MMT) and the Childhood Myositis Assessment Scale (CMAS). Laboratory tests included creatine phosphokinase (CK) and lactic dehydrogenase (LDH). Construct validity of the MyoFun was examined by calculating its Spearman’s correlations with the other JDM outcome measures on both cross-sectional data and change between 2 consecutive visits. Correlations were considered high, moderate or low when >0.7, 0.4-0.7, or <0.4, respectively

The PRINTO provisional definition of remission in juvenile dermatomyositis

Methods 275 patients in active phase of JDM <18 years, median disease duration 7.7 months, were evaluated at baseline and 24 months. Out of 275 patients, all patients (39/ 275) who were off treatment at 24 months were defined as being in clinical remission and were included as the “gold standard” group. A random sample of patients (n=78) who were in an active phase of JDM at baseline and on medications at 24 months, were selected as the “comparison group”. Literature was reviewed for definitions of remission and in addition other definitions were tested which included PRINTO core set variables, muscle enzymes, and other JDM activity measures. Accuracy measurements were calculated: sensitivity, specificity, Youden index, Cohen’s kappa (≥0.8 almost perfect).