Serum calprotectin (S100A8/9), clinical and ultrasound assessment in patients with juvenile idiopathic arthritis.

OBJECTIVES: To explore the association between serum S100A8/9 (calprotectin), clinical and ultrasound (US) assessment in juvenile idiopathic arthritis (JIA) patients. METHODS: A total of 30 well-characterised consecutive patients (18 female) with non-systemic JIA and 20 age-matched healthy controls were included. Serum and plasma samples obtained the same day of the clinical and sonographical assessment were tested for calprotectin levels by ELISA. Clinical status was defined using Wallace criteria. Ultrasonographic B-mode and power Doppler (PD) assessment of 44 joints for each subject was performed. RESULTS: Clinically active disease was present in 14 patients, while 16 patients were active according to US evaluation. We found no differences in the serum/plasma calprotectin levels in clinically active disease group [29.6 (5.4-198.1) ng/ml; 12.6 (2.8-65.8) ng/ml] as compared with inactive disease group [24.8 (14.1-204.3); 12.7 (3.4-65.1)] (p=0.73; p=0.29). There was also no difference between US active disease [29.8 (5.4-204.3); 12.9 (2.8-65.8)] and US inactive disease [24.8 (12.1-197.1); 11.7 (3.4-44.2)] with regard to the serum/plasma calprotectin levels (p=0.83; p=1.0). Serum/plasma calprotectin levels correlated moderately with C-reactive protein (CRP) (Spearman r=0.44, p=0.01; Spearman r=0.56, p=0.0021). CONCLUSIONS: To our knowledge, this is the first study to simultaneously examine the correlation between serum/plasma calprotectin levels, clinical and US assessment in JIA. Calprotectin was not associated with the disease status in JIA patients with low number of active joints and its levels were moderately correlated with CRP. Our preliminary study needs to be extended with a larger number of patients.

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.

BACKGROUND: Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. METHODS: We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. FINDINGS: Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. INTERPRETATION: Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. FUNDING: Italian Agency of Drug Evaluation.

Baseline ultrasound examination as possible predictor of relapse in patients affected by juvenile idiopathic arthritis (JIA).

OBJECTIVES: To define the correlation between joint ultrasonography and clinical examination in patients with juvenile idiopathic arthritis (JIA) and to assess whether synovitis detected by ultrasonography in clinically inactive patients predicts arthritis flares. METHODS: 88 consecutive patients with JIA-46 (52%) with persistent oligoarthritis, 15 (17%) with extended oligoarthritis, 15 (17%) with rheumatoid factor-negative polyarthritis and 12 (14%) with other forms of JIA, all clinically inactive for a minimum of 3 months-underwent ultrasound (US) assessment of 44 joints. Joints were scanned at study entry for synovial hyperplasia, joint effusion and power Doppler (PD) signal. Patients were followed clinically for 4 years. RESULTS: US was abnormal in 20/88 (22.7%) patients and in 38/3872 (0.98%) joints. Extended oligoarthritis and rheumatoid factor-negative polyarthritis were more frequent in US-positive than in US-negative patients (35.0% vs 11.8% and 30.0% vs 13.2%, respectively; P=0.005). During 4 years of follow-up, 41/88 (46.6%) patients displayed a flare; 26/68 (38.2%) were US-negative and 15/20 (75%) were US-positive at baseline. Abnormality on US examination, after correction for therapy modification, significantly increased the risk of flare (OR=3.8, 95% CI 1.2 to 11.5). The combination of grey scale and PD abnormalities displayed a much higher predictive value of relapse (65%, 13/20) than grey scale alone (33%, 6/18). CONCLUSIONS: US abnormalities are a strong predictor of relapse at individual patient level. Irrespective of treatment, the risk of flare in US-positive versus US-negative patients was almost four times higher. In case of US abnormalities, patients should be carefully followed regardless of both the International League of Associations for Rheumatology and Wallace categories.

Correction to: The Italian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The family name of author Francesco La Torre was incorrect in the published article. The correct family name should read as La Torre F.

The Italian 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 Italian 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 3 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 1296 JIA patients (7.2% systemic, 59.5% oligoarticular, 21.4% RF negative polyarthritis, 11.9% other categories) and 100 healthy children, were enrolled in 18 centres. The JAMAR components discriminated well healthy subjects from JIA patients except for the Health Related Quality of Life (HRQoL) Psychosocial Health (PsH) subscales. All JAMAR components revealed good psychometric performances.In conclusion, the Italian 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.

Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial.

BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. METHODS: We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS: Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION: Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING: Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).

Chronic nonbacterial osteomyelitis may be associated with renal disease and bisphosphonates are a good option for the majority of patients.

AIM: The aim of this Italian study was to describe the clinical features, treatment options and outcomes of a cohort of patients with chronic nonbacterial osteomyelitis (CNO). METHODS: This was a retrospective cohort study. Laboratory data, diagnostic imaging, histological features and clinical course are reported. RESULTS: We enrolled 47 patients diagnosed with CNO. Bone pain was the leading symptom, and multifocal disease was present in 87% of the patients. The majority of the bone lesions were located in the appendicular skeleton (58%). Extraosseous manifestations were present in 34% of the patients, and renal involvement was detected in four patients. Inflammatory indices were increased in 80%, and bone x-rays were negative in 15% of the patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the first therapy for all patients, achieving clinical remission in 27%. A good response to NSAIDs was significantly associated with a better prognosis. Bisphosphonates were used in 26 patients, with remission in 73%. Only six patients (13%), all with spine involvement, developed sequelae. CONCLUSION: We found a possible association between CNO and renal disease. Bisphosphonates were more likely to lead to clinical remission when NSAIDs and corticosteroids had failed. Vertebral localisation was the only risk factor for potential sequelae.

Defining criteria for high disease activity in juvenile idiopathic arthritis based on the juvenile arthritis disease activity score.

OBJECTIVE: To determine cutoff values for defining the state of high disease activity (HDA) in juvenile idiopathic arthritis (JIA) using the Juvenile Arthritis Disease Activity Score (JADAS). METHODS: For the selection of cutoff values, data from a clinical database including 609 patients were used. Optimal cutoff values were determined against external criteria by calculating the 25th and 10th centile of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria were based on the therapeutic decision made by the attending doctor. Cross-validation was performed using five patient samples that included 1421 patients. RESULTS: The optimal cutoff values were those obtained through the 90% fixed sensitivity method. The selected JADAS cutoff values were the following: 4.2 and 8.5 for JADAS27 in oligoarthritis and polyarthritis, respectively; 4.2 and 10.5 for both JADAS10 and JADAS71 in oligoarthritis and polyarthritis, respectively. In cross-validation analyses, the cutoff values showed strong ability to discriminate between different levels of American College of Rheumatology paediatric response in two clinical trials and could predict worse functional and radiographic outcome. CONCLUSIONS: Cutoff values for classifying HDA in JIA using the JADAS were developed. In cross-validation analyses, they proved to have good construct and discriminant validity and ability to predict disease outcome.

A long-term follow-up study of methotrexate in juvenile localized scleroderma (morphea).

BACKGROUND: Recent studies report that methotrexate (MTX) is beneficial in the treatment of juvenile localized scleroderma (JLS) but little is known about its long-term effectiveness. OBJECTIVE: We assessed the therapeutic role of MTX in children with JLS who were followed up for a prolonged period. METHODS: A cohort of patients with JLS, previously enrolled in a double-blind, randomized controlled trial and treated with oral MTX (15 mg/m(2)/wk) and prednisone (1 mg/kg/d, maximum 50 mg) for the first 3 months, were prospectively followed up. Lesions were evaluated clinically, with infrared thermography, and by a computerized skin score. Response to treatment was defined as: (1) no new lesions; (2) skin score rate less than 1; and (3) decrease in lesion temperature by at least 10% compared with baseline. Clinical remission (CR) on medication was defined when response was maintained, on treatment, for at least 6 months, and complete CR when response was maintained, without treatment, for at least 6 months. RESULTS: Of 65 patients treated with MTX, 48 (73.8%) were responders, 10 (15.4%) relapsed by 24 months since MTX start, and 7 (10.8%) were lost to follow-up. Among the responders, 35 (72.9%) maintained CR for a mean of 25 months and 13 (27.1%) were in CR on medication. Adverse effects seen in 28 patients (48.3%) were generally mild and never required treatment discontinuation. LIMITATIONS: The use of objective measures not widely available, such as infrared thermography and computerized skin score, makes it difficult to compare data from previous studies. CONCLUSIONS: Long-term MTX therapy is beneficial and well tolerated for JLS.

Methotrexate treatment in juvenile localized scleroderma: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Juvenile localized scleroderma is a chronic progressive fibrotic disorder of the skin that causes permanent disability and aesthetic damage. This study was undertaken to assess the safety and efficacy of methotrexate (MTX) in the treatment of juvenile localized scleroderma. METHODS: In this double-blind study, patients with active juvenile localized scleroderma were randomized (2:1) to receive oral MTX (15 mg/m², maximum 20 mg) or placebo once weekly, for 12 months or until treatment failure. Both groups received oral prednisone (1 mg/kg/day, maximum 50 mg) for the first 3 months. A target lesion was evaluated clinically, with infrared thermography and using a computerized scoring system with skin score rate (SSR) evaluation. Response to treatment was defined as the absence of new lesions, SSR ≤ 1, and a decrease in lesion temperature of at least 10% compared to baseline. Treatment failure was defined as the occurrence of new lesions, SSR > 1, or increased lesion temperature. All analyses were done on the intent-to-treat population. RESULTS: Of the 85 patients screened, 70 (ages 6-17 years) were randomized (46 to the MTX group, 24 to the placebo group). The mean disease duration was 2.3 years. After an initial response in all patients, disease relapsed in 15 MTX-treated patients (32.6%) and 17 placebo-treated patients (70.8%) (P < 0.005). New lesions appeared in 3 MTX-treated patients (6.5%) versus 4 placebo-treated patients (16.7%). The mean SSR decreased from 1 to 0.79 in the MTX group and increased from 1 to 1.1 in the placebo group, and the mean target lesion temperature decreased by 44.4% in the MTX group versus 12.1% in the placebo group. Twenty-six patients in the MTX group (56.5%) and 11 patients in the placebo group (45.8%) developed mild side effects related to treatment. None of the side effects were severe enough to necessitate treatment discontinuation. CONCLUSION: Our findings indicate that MTX is efficacious in the treatment of juvenile localized scleroderma and is well tolerated.

Adalimumab with or without methotrexate in juvenile rheumatoid arthritis.

BACKGROUND: Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. METHODS: Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. RESULTS: Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients. CONCLUSIONS: Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542.)

Treatment of severe uveitis associated with juvenile idiopathic arthritis with anti-CD20 monoclonal antibody (rituximab).

OBJECTIVE: Rituximab (RTX), a chimeric mAb directed against the B-cell marker CD20, was investigated for its anti-inflammatory effect in treating refractory uveitis associated with JIA. METHODS: Case series, retrospective multicentre. JIA patients with severe uveitis with vision-threatening complications (n = 10) and with insidious onset. All patients were treated with RTX for active uveitis refractory to topical and systemic CSs, immunosuppressives and at least one of the TNF-α inhibitors. All had active arthritis. Uveitis and arthritis course were assessed before and after RTX treatment. RESULTS: After one RTX cycle (mean follow-up 11 months, range 7-18 months), uveitis inactivity was achieved in seven oligoarthritis patients (ANA⁺, HLA-B27⁻) for a prolonged period of time (mean 7.5 months, range 6-9 months). Therefore, CSs and immunosuppression could be spared. In three of four patients responding to RTX, uveitis recurred thereafter, and RTX re-treatment led to inactivity again. In another three patients (ANA⁺ polyarthritis, n = 1; ANA⁺ HLA-B27⁺ oligo- or polyarthritis, n = 2) uveitis activity persisted after RTX therapy. In seven patients, arthritis improved or was inactive after RTX treatment (PedACR30/50/70). CONCLUSION: RTX may represent a rescue therapy option for severe JIA-associated uveitis refractory to CSs, immunosuppression and TNF-α inhibitors.

Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis.

OBJECTIVE: We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. METHODS: This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. RESULTS: Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. CONCLUSION: Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.

Absence of Association Between Abatacept Exposure and Initial Infection in Patients With Juvenile Idiopathic Arthritis.

OBJECTIVE: To assess the relationship between infection risk and abatacept (ABA) exposure levels in patients with polyarticular-course juvenile idiopathic arthritis (pJIA) following treatment with subcutaneous (SC) and intravenous (IV) ABA. METHODS: Data from 2 published studies (ClinicalTrials.gov: NCT01844518, NCT00095173) of ABA treatment in pediatric patients were analyzed. One study treated patients aged 2-17 years with SC ABA and the other treated patients aged 6-17 years with IV ABA. Association between serum ABA exposure measures and infection was evaluated using Kaplan-Meier plots of probability of first infection vs time on treatment by ABA exposure quartiles and log-rank tests. Number of infections by ABA exposure quartiles was investigated. RESULTS: Overall, 343 patients were included in this analysis: 219 patients received SC ABA and 124 patients received IV ABA. Overall, 237/343 (69.1%) patients had ≥ 1 infection over 24 months. No significant difference in time to first infection across 4 quartiles of ABA exposure levels was observed in the pooled (P = 0.45), SC (2-5 yrs: P = 0.93; 6-17 yrs: P = 0.48), or IV (P = 0.50) analyses. Concomitant use of methotrexate and glucocorticoids (at baseline and throughout) with ABA did not increase infection risk across the ABA exposure quartiles. There was no evidence of association between number of infections and ABA exposure quartiles. No opportunistic infections related to ABA were reported. CONCLUSION: In patients aged 2-17 years with pJIA, no evidence of association between higher levels of exposure to IV ABA or SC ABA and incidence of infection was observed.

Correction to: Proposal for a definition for response to treatment, inactive disease and damage for JIA associated uveitis based on the validation of a uveitis related JIA outcome measures from the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC).

Following publication of the original article [1], we have been notified that the author Joan Calzada should not have been included to the team of authors. The authors' team, thus, should be as follows.

Growth and Puberty in Juvenile Dermatomyositis: A Longitudinal Cohort Study.

OBJECTIVE: To study growth and puberty in a multinational longitudinal prospective cohort of children with juvenile dermatomyositis (DM). METHODS: Children from 31 countries who were ages <18 years and had juvenile DM in active phase were studied, and analyses of height, weight, and pubertal development were conducted in those who had follow-up visits during a 2-year period and for whom anthropometric data was available. RESULTS: A total of 196 of 275 children (71%) were included. We found a significant reduction in parent-adjusted height Z score over time in female patients (P < 0.0001) and male patients (P = 0.001), but with catch-up growth at the final study visit. Median body mass index Z score peaked at 6 months (P < 0.0001) and was still significantly above baseline at the final study visit, which was at a median of 26 months after baseline (P = 0.007), with no difference between sexes. Female patients with a disease duration ≥12 months after onset had significantly lower parent-adjusted height Z score (P = 0.002) and no 2-year catch-up growth. At the final study visit, growth failure was seen in 20 of 97 female patients (21%) and in 11 of 73 male patients (15%). Height deflection (∆height Z score less than -0.25/year) was observed in 29 of 116 female patients (25%) and 25 of 80 male patients (31.3%). Delayed puberty was seen in 20 of 55 female patients (36.4%) and in 11 of 31 male patients (35.5%). Children in early pubertal stage at baseline had the highest risk of growth failure. CONCLUSION: Juvenile DM in the active phase and/or its treatment has a significant impact on growth and puberty in affected children. Children with recent onset of puberty or previous growth failure have the highest risk of delayed pubertal development and further growth retardation.

Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial.

BACKGROUND: Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. METHODS: We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6-17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. FINDINGS: Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0.0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0.0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0.31, 95% CI 0.16-0.95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0.47); only two serious adverse events were reported, both in controls (p=0.50). INTERPRETATION: Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. FUNDING: Bristol-Myers Squibb.

Proposal for a definition for response to treatment, inactive disease and damage for JIA associated uveitis based on the validation of a uveitis related JIA outcome measures from the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC).

BACKGROUND: JIA-associated uveitis (JIAU) is a serious, sight-threatening disease with significant long-term complications and risk of blindness, even with improved contemporary treatments. The MIWGUC was set up in order to propose specific JIAU activity and response items and to validate their applicability for clinical outcome studies. METHODS: The group consists of 8 paediatric rheumatologists and 7 ophthalmologists. A consensus meeting took place on November 2015 in Barcelona (Spain) with the objective of validating the previously proposed measures. The validation process was based on the results of a prospective open, international, multi-centre, cohort study designed to validate the outcome measures proposed by the initial MIWGUC group meeting in 2012. The meeting used the same Delphi and nominal group technique as previously described in the first paper from the MIWGUC group (Arthritis Care Res 64:1365-72, 2012). Patients were included with a diagnosis of JIA, aged less than 18 years, and with active uveitis or an uveitis flare which required treatment with a disease-modifying anti-rheumatic drug. The proposed outcome measures for uveitis were collected by an ophthalmologist and for arthritis by a paediatric rheumatologist. Patient reported outcome measures were also measured. RESULTS: A total of 82 patients were enrolled into the validation cohort. Fifty four percent (n = 44) had persistent oligoarthritis followed by rheumatoid factor negative polyarthritis (n = 15, 18%). The mean uveitis disease duration was 3.3 years (SD 3.0). Bilateral eye involvement was reported in 65 (79.3%) patients. The main findings are that the most significant changes, from baseline to 6 months, are found in the AC activity measures of cells and flare. These measures correlate with the presence of pre-existing structural complications and this has implications for the reporting of trials using a single measure as a primary outcome. We also found that visual analogue scales of disease activity showed significant change when reported by the ophthalmologist, rheumatologist and families. The measures formed three relatively distinct groups. The first group of measures comprised uveitis activity, ocular damage and the ophthalmologists' VAS. The second comprised patient reported outcomes including disruption to school attendance. The third group consisted of the rheumatologists' VAS and the joint score. CONCLUSIONS: We propose distinctive and clinically significant measures of disease activity, severity and damage for JIAU. This effort is the initial step for developing a comprehensive outcome measures for JIAU, which incorporates the perspectives of rheumatologists, ophthalmologists, patients and families.