Claudia Bracaglia

Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty‐eight patients

OBJECTIVE To describe the clinical and laboratory features of macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus (SLE). METHODS Cases of juvenile SLE-associated macrophage activation syndrome were provided by investigators belonging to 3 pediatric rheumatology networks or were found in the literature. Patients who had evidence of macrophage hemophagocytosis on bone marrow aspiration were considered to have definite macrophage activation syndrome, and those who did not have such evidence were considered to have probable macrophage activation syndrome. Clinical and laboratory findings in patients with macrophage activation syndrome were contrasted with those of 2 control groups composed of patients with active juvenile SLE without macrophage activation syndrome. The ability of each feature to discriminate macrophage activation syndrome from active disease was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve. RESULTS The study included 38 patients (20 with definite macrophage activation syndrome and 18 with probable macrophage activation syndrome). Patients with definite and probable macrophage activation syndrome were comparable with regard to all clinical and laboratory features of the syndrome, except for a greater frequency of lymphadenopathy, leukopenia, and thrombocytopenia in patients with definite macrophage activation syndrome. Overall, clinical features had better specificity than sensitivity, except for fever, which was highly sensitive but had low specificity. Among laboratory features, the best sensitivity and specificity was achieved using hyperferritinemia, followed by increased levels of lactate dehydrogenase, hypertriglyceridemia, and hypofibrinogenemia. Based on the results of statistical analysis, preliminary diagnostic guidelines for macrophage activation syndrome in juvenile SLE were developed. CONCLUSION Our findings indicate that the occurrence of unexplained fever and cytopenia, when associated with hyperferritinemia, in a patient with juvenile SLE should raise the suspicion of macrophage activation syndrome. We propose preliminary guidelines for this syndrome in juvenile SLE to facilitate timely diagnosis and correct classification of patients.

Safety and efficacy of infliximab and adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year followup data from the Italian Registry.

Objective. To evaluate safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of juvenile idiopathic arthritis-related anterior uveitis (JIA-AU). Methods. 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. Results. 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). Conclusion. 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.

EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical characterisation

Objectives To report methodology and overall clinical, laboratory and radiographic characteristics for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) classification criteria. Methods The preliminary Vienna 2005 consensus conference, which proposed preliminary criteria for paediatric vasculitides, was followed by a EULAR/PRINTO/PRES - supported validation project divided into three main steps. Step 1: retrospective/prospective web-data collection for HSP, c-PAN, c-WG and c-TA, with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a subgroup of 280 cases (128 difficult cases, 152 randomly selected) enabling expert diagnostic verification. Step 3: Ankara 2008 Consensus Conference and statistical evaluation (sensitivity, specificity, area under the curve, κ-agreement) using as ‘gold standard’ the final consensus classification or original treating physician diagnosis. Results A total of 1183/1398 (85%) samples collected were available for analysis: 827 HSP, 150 c-PAN, 60 c-WG, 87 c-TA and 59 c-other. Prevalence, signs/symptoms, laboratory, biopsy and imaging reports were consistent with the clinical picture of the four c-vasculitides. A representative subgroup of 280 patients was blinded to the treating physician diagnosis and classified by a consensus panel, with a κ-agreement of 0.96 for HSP (95% CI 0.84 to 1), 0.88 for c-WG (95% CI 0.76 to 0.99), 0.84 for c-TA (95% CI 0.73 to 0.96) and 0.73 for c-PAN (95% CI 0.62 to 0.84), with an overall κ of 0.79 (95% CI 0.73 to 0.84). Conclusion EULAR/PRINTO/PRES propose validated classification criteria for HSP, c-PAN, c-WG and c-TA, with substantial/almost perfect agreement with the final consensus classification or original treating physician diagnosis.

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 Friedmans 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).

Inhibition of Natural Killer Cell Cytotoxicity by Interleukin-6: Implications for the Pathogenesis of Macrophage Activation Syndrome

Systemic juvenile idiopathic arthritis (JIA) is associated with high levels of interleukin‐6 (IL‐6) in the serum and synovial fluid, and impairment of natural killer (NK) cell function is often observed. This study was undertaken to evaluate a possible link between these 2 biologic findings and whether they may be associated with the development of macrophage activation syndrome, a condition frequently observed in systemic JIA.

Safety and Efficacy of Etanercept in a Cohort of Patients with Juvenile Idiopathic Arthritis Under 4 Years of Age

Objective. To evaluate safety, tolerability, and efficacy of etanercept in a cohort of patients with juvenile idiopathic arthritis (JIA) under 4 years of age. Methods. Data were collected at every visit during treatment with etanercept in 25 children who began treatment at a mean age of 3 years (range 18–48 months). Safety endpoints included the incidence of any adverse events. Efficacy endpoints included the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 criteria for improvement. Results. Data from 25 patients with JIA treated with etanercept for a mean period of 23 months were analyzed. All patients received concomitant medications: 24 methotrexate, 3 cyclosporin A, and 10 corticosteroids. After the first 6 months of treatment, 15 (71.4%) patients achieved an ACR Pedi30 response and at the last observation 20 (80%) achieved ACR Pedi30. ACR Pedi50 and 70 responses were, respectively, 62% and 43% at 6 months and 72% and 64% at the last followup. Five patients (20%) discontinued etanercept for lack of efficacy. Two (8%) developed adverse events, both primary varicella zoster virus (VZV) infections (both not vaccinated). One was hospitalized because of a necrotizing fasciitis secondary to VZV infection. No cases of tuberculosis, opportunistic infections, or malignancies were reported. Conclusion. In our cohort of patients etanercept proved to be safe and efficacious in the majority of children. The response in toddlers was similar to that in older children. We observed only 1 case of severe infection that required hospitalization and stopped treatment temporarily.

Infliximab therapy in pediatric Takayasu’s arteritis: report of two cases

Takayasu arteritis (TA) is a chronic vasculitis of unknown etiology. Experience with anti-tumor necrosis factor alpha (anti-TNF) agents in difficult-to-treat patients with TA is limited and refers to adult patients. Here, we present two cases of pediatric TA treated with infliximab, in which clinical remission was observed. Anti-TNF treatment represents a useful therapy in pediatric Takayasu arteritis too, especially to avoid the risk of long-term corticosteroids toxicity.

Prognostic Impact of Atypical Presentation in Pediatric Systemic Lupus Erythematosus: Results from a Multicenter Study

OBJECTIVES The aim of the study is to assess the rate of atypical manifestations at onset in pediatric systemic lupus erythematosus (SLE) and to evaluate their effect on disease outcome. STUDY DESIGN This is a multicenter retrospective cohort study. A manifestation was considered atypical if it was not included in the American College Rheumatology classification criteria for SLE but was reported in literature as associated with SLE. Unfavorable outcome was considered presence of organ damage in the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index at the last available evaluation. RESULTS One hundred patients were enrolled in the study; 24% presented atypical clinical features at onset. Univariate analysis showed a significant association of worse outcome variables with the presence of atypical manifestations at onset (P = .004), as well as renal involvement (P = .027). A multivariate logistic regression analysis showed that atypical manifestations at onset (P = .018), renal involvement at onset or during follow up (P = .024), and central nervous system disease involvement during follow up (P = .021) were independent predictors of poor prognosis. CONCLUSIONS Our data support a relatively high rate of atypical onset in pediatric SLE. Presence of atypical manifestations at presentation and early kidney disease correlate with poor outcome. Similarly, during follow-up, kidney and central nervous system diseases are associated with worse outcome.

MRI of the wrist in juvenile idiopathic arthritis: proposal of a paediatric synovitis score by a consensus of an international working group. Results of a multicentre reliability study

BackgroundMRI is a sensitive tool for the evaluation of synovitis in juvenile idiopathic arthritis (JIA).ObjectiveThe purpose of this study was to introduce a novel MRI-based score for synovitis in children and to examine its inter- and intraobserver variability in a multi-centre study.Materials and methodsWrist MRI was performed in 76 children with JIA. On postcontrast 3-D spoiled gradient-echo and fat-suppressed T2-weighted spin-echo images, joint recesses were scored for the degree of synovial enhancement, effusion and overall inflammation independently by two paediatric radiologists. Total-enhancement and inflammation-synovitis scores were calculated.ResultsInterobserver agreement was poor to moderate for enhancement and inflammation in all recesses, except in the radioulnar and radiocarpal joints. Intraobserver agreement was good to excellent. For enhancement and inflammation scores, mean differences (95 % CI) between observers were −1.18 (−4.79 to 2.42) and −2.11 (−6.06 to 1.83). Intraobserver variability (reader 1) was 0 (−1.65 to 1.65) and 0.02 (−1.39 to 1.44).ConclusionIntraobserver agreement was good. Except for the radioulnar and radiocarpal joints, interobserver agreement was not acceptable. Therefore, the proposed scoring system requires further refinement.

Elicitation of Expert Prior Opinion: Application to the MYPAN Trial in Childhood Polyarteritis Nodosa

Objectives Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa). Methods A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis. Results A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available. Conclusions We suggest that the methodological template we propose could be applied to trial design for other rare diseases.