Summary 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).
Objective
To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH‐2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile ...idiopathic arthritis (JIA)–associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection.
Methods
International pediatric rheumatologists and hemato‐oncologists were asked to retrospectively collect clinical information from patients with systemic JIA–associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH‐2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5‐adapted) or 4 of 5 of the remaining items (4/5‐adapted) were present.
Results
The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5‐adapted HLH‐2004 guidelines performed better than the 4/5‐adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5‐adapted HLH‐2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections.
Conclusion
The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH‐2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA.
Objective
To investigate the long‐term outcome and prognostic factors of juvenile dermatomyositis (DM) through a multinational, multicenter study.
Methods
Patients consisted of inception cohorts seen ...between 1980 and 2004 in 27 centers in Europe and Latin America. Predictor variables were sex, continent, ethnicity, onset year, onset age, onset type, onset manifestations, course type, disease duration, and active disease duration. Outcomes were muscle strength/endurance, continued disease activity, cumulative damage, muscle damage, cutaneous damage, calcinosis, lipodystrophy, physical function, and health‐related quality of life (HRQOL).
Results
A total of 490 patients with a mean disease duration of 7.7 years were included. At the cross‐sectional visit, 41.2–52.8% of patients, depending on the instrument used, had reduced muscle strength/endurance, but less than 10% had severe impairment. Persistently active disease was recorded in 41.2–60.5% of the patients, depending on the activity measure used. Sixty‐nine percent of the patients had cumulative damage. The frequency of calcinosis and lipodystrophy was 23.6% and 9.7%, respectively. A total of 40.7% of the patients had decreased functional ability, but only 6.5% had major impairment. Only a small fraction had decreased HRQOL. A chronic course, either polycyclic or continuous, consistently predicted a poorer outcome. Mortality rate was 3.1%.
Conclusion
This study confirms the marked improvement in functional outcome of juvenile DM when compared with earlier literature. However, many patients had continued disease activity and cumulative damage at followup. A chronic course was the strongest predictor of poor prognosis. These findings highlight the need for treatment strategies that enable a better control of disease activity over time and the reduction of nonreversible damage.
Lupus nephritis (LN) strongly affects the outcome in children with systemic lupus erythematosus (SLE). Many patients, however, have renal disease at onset, but lack a sufficient number of criteria to ...be diagnosed as SLE and develop delayed symptoms over time (d-SLE). Data on the clinical course, long-term outcome and predictors of disease progression in children with LN are scant.
The Italian Collaborative Study included 161 paediatric patients with LN who were followed up for a mean of 96 months (range 6-296) in seven paediatric nephrology units. Cox-Mantel regression models were used to identify predictors of disease remission, relapse and progression.
At 1 year, the proportion of patients in remission was 83.2% (partial) and 53.5% (complete). Renal flares occurred in >50% of patients within 10 years. The intensity of induction treatment correlated significantly with the achievement of remission, while d-SLE, class IV LN and younger age were associated with poor response to treatment and/or with progression to chronic renal failure.
The current study provides outcome data on a large paediatric population with LN and underlines the importance of prescribing appropriate induction treatment to all children, regardless of the presence of enough SLE criteria, which may develop several years after the initial diagnosis.
To determine prevalence and complications of juvenile idiopathic arthritis (JIA)-associated uveitis, and to evaluate risk factors for uveitis and its relation to articular disease.
Records of 309 ...patients with JIA (244 female, 65 male, mean age at onset 4.9 yrs) were retrospectively reviewed. Occurrence of uveitis and complications were assessed among oligoarticular-onset JIA (193 patients), polyarticular-onset JIA (66 patients), and systemic-onset JIA (50 patients). The presence of antinuclear antibodies (ANA) was determined in patients with oligoarticular-onset JIA. Therapy and relapses of uveitis and arthritis were recorded at each visit during the followup (mean followup 7.6 yrs).
Sixty-two patients developed uveitis (20.1%); 57 patients had oligoarticular-, 3 polyarticular-, and 2 systemic-onset JIA. Uveitis was asymptomatic in 56/62 cases. Fifty-five of the 62 patients (88.7%) developed uveitis within 4 years from disease onset. In patients with oligoarticular-onset JIA, an early age at disease onset and the presence of ANA (p < 0.05) and DRB1*11 (p < 0.03) were the best predictors of uveitis, while a polyarticular course was not associated to uveitis (p > 0.05). Active arthritis was present at the first episode of uveitis in 46/62 patients. Forty-four of the 62 patients experienced relapses of uveitis: in 20/62, relapses were concomitant to arthritis relapses; in 24/62 relapses presented without active arthritis. Complications of uveitis developed in 35.5% of the patients (22/62), leading to visual impairment in 13 patients.
Current guidelines provide early identification of uveitis in 90% of patients. With the exception of the first episode of uveitis, uveitis and arthritis seem to run different courses; close ophthalmologic scrutiny then should also be maintained during arthritis remission.
Objective
To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA).
Methods
A multistep process, based on a ...combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA–associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference.
Results
Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best‐performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76).
Conclusion
We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.
To evaluate safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of juvenile idiopathic arthritis-related anterior uveitis (JIA-AU).
Starting January 2007, patients with ...JIA-AU treated with IFX and ADA were managed by a standard protocol and data were entered into the National Italian Registry (NIR). At baseline, all patients were refractory to standard immunosuppressive treatment and/or were corticosteroid-dependent. Data recorded every 3 months included uveitis course, number/type of ocular complications, drug-related adverse events (AE), treatment change or withdrawal, and laboratory measures. Data of patients treated for at least 1 year were retrieved from the NIR and analyzed using descriptive statistics. Treatment efficacy was based on change in uveitis course and in number of ocular complications.
Up to December 2009, data for 108 patients with JIA-AU treated with anti-tumor necrosis factor-α agents were recorded in the NIR and data from 91, with at least 12 months' followup, were included in the study. Forty-eight patients were treated with IFX, 43 with ADA. Forty-seven patients (55.3%) achieved remission of AU, 28 (32.9%) had recurrent AU, and 10 (11.8%) maintained a chronic course. A higher remission rate was observed with ADA (67.4% vs 42.8% with IFX; p = 0.025). Ocular complications decreased from 0.47 to 0.32 per subject. Five patients experienced resolution of structural complications. No patient reported serious AE; 8 (8.8%) experienced 11 minor AE (9 with IFX, 2 with ADA).
IFX and ADA appear to be effective and safe for treatment of refractory JIA-related uveitis, with a better performance of ADA in the medium-term period.
Objective
In pivotal trials, canakinumab has been shown to be effective in the treatment of systemic juvenile idiopathic arthritis (JIA), but reported adverse events have included macrophage ...activation syndrome (MAS). This study was undertaken to assess the impact of canakinumab on MAS incidence.
Methods
An independent MAS Adjudication Committee (MASAC), consisting of 3 of the authors, was convened, and a search of databases from clinical studies of canakinumab treatment in systemic JIA was performed using MASAC‐specified adverse event terms to identify potential MAS events. These were then adjudicated as “probable MAS,” “possible MAS,” or “MAS unlikely,” using criteria developed by the MASAC. MAS rates were expressed as numbers of cases per 100 patient‐years.
Results
Of 72 potential MAS cases identified, 21 events (19 with canakinumab treatment; 2 with placebo treatment) in 19 patients were adjudicated as being probable MAS and 10 events in 9 patients as being possible MAS. Systemic JIA was well controlled in the majority of canakinumab‐treated patients at the time of MAS. The time period between initiation of canakinumab treatment and onset of MAS ranged from 3 to 1,358 days (median 292 days). When the rates of probable MAS events were compared between canakinumab‐treated patients (2.8 per 100 patient‐years) and placebo‐treated patients (7.7 per 100 patient‐years), the difference was not significant (−4.9 95% confidence interval −15.6, 5.9). There were 3 deaths due to MAS‐related complications (2 in patients receiving canakinumab; 1 in a patient receiving placebo); full recovery was reported in all other patients. Infections were the most common trigger of MAS, and the clinical features of MAS were not modified by canakinumab.
Conclusion
Canakinumab does not have a significant effect on MAS risk or its clinical features in patients with systemic JIA. Infections are the most common trigger, and MAS occurs even in patients whose systemic JIA is well controlled with this treatment.
Highlights ► MF59-seasonal influenza vaccine was studied in juvenile idiopathic arthritis (JIA). ► A reduced immunogenicity was observed in the etanercept-treated pediatric patients. ► Immunogenicity ...was similar in the DMARD-treated JIA patients and healthy controls. ► Safety and tolerability of the vaccine appeared to be good even in presence of JIA.
PDF
