BackgroundThe Mediterranean fever (MEFV) gene codes for protein pyrin, one of the regulators of inflammasome activity in innate immune cells. Mutations in this gene are considered the primary cause of Familial Mediterranean fever, but are also found in other monogenic and multifactorial autoinflammatory diseases. The aim of the study was to determine if healthy carriers of MEFV gene mutations and R202Q polymorphism have clinical manifestations of inflammation and impaired oxidative stress parameters.MethodsOne hundred DNA samples from healthy volunteers (13.3 ± 8.87 years of age (mean ± SD); range 2–35) were sequenced by ABI PRISM 310 automated sequencer (PE Applied Biosystems, Norwalk, USA). The Eurofever questionnaire was used to collect retrospectively medical history data. Oxidative stress was determined by measuring spectrophotometrically thiobarbituric acid reactive substances (TBARS) in plasma and erythrocytes, as well as advanced oxidation protein products in plasma. Superoxide dismutase (SOD) activity was determined by McCord and Fridovich method in plasma and erythrocytes, while the catalase erythrocyte activity was assessed using a catalase ELISA kit.ResultsWe found heterozygous carriers of K695R/N mutations in 5 %, E148Q/N mutations in 6 %, R202Q homozygous polymorphism in 10 % and heterozygous R202Q alterations in 45 % of healthy volunteers. The MEFV mutation carriers and R202Q polymorphism homozygotes reported significantly more often recurrent febrile episodes (p = 0.009), diffuse abdominal pain (p = 0.025), and malaise (p = 0.012) compared to non-carriers. Erythrocyte TBARS levels and plasma SOD activity were higher in persons with MEFV mutations and R202Q/R202Q (p = 0.03 and p = 0.049, respectively).ConclusionsHealthy individuals may bear E148Q and K695R MEFV gene mutations, as well as R202Q polymorphism in homozygous state. The determined gene alterations contribute to a subtle oxidative stress and may be associated with more frequent episodes of fever and unspecific inflammatory manifestations. An incomplete penetrance or variable expressivity of R202Q in populations of different ethnicity could influence the expression of autoinflammatory diseases phenotype.

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).

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). 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. 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). 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.

Data from Slovene national primary immunodeficiency (PID) registry are presented. Besides clinical and genetic data of patients with PID, quality indicators in patient care are included. Data are systematically collected in Department of Allergology, Rheumatology and Clinical Immunology in collaboration with physicians of different specialities. Increasing number and spectrum of PID are recognised in Slovenia. After establishment of Slovene multidisciplinary group in PID care in 2007 thorough immunological and genetic diagnostics, subcutaneous immunoglobulin replacement and treatment of PID with haematopoietic stem cell transplantation were introduced in routine clinical practice in Slovenia. Increased medium age of PID patients reflects improved survival and better recognition of PID in adults. According to the data in comparable registries percentages of patients with predominantly antibody deficiencies and complement deficiencies are low and high, respectively.

Objective To identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA). Methods A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the 5 laboratory tests in which change was most important for the diagnosis of MAS and to rank the 5 selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at a consensus conference. Results Platelet count was the most frequently selected test, followed by ferritin level, aspartate aminotransferase (AST), white cell count, neutrophil count, and fibrinogen and erythrocyte sedimentation rate. Ferritin was most frequently assigned the highest score. At the end of the process, platelet count, ferritin level and AST were the laboratory tests in which the experts found change over time to be most important. Conclusions We identified the laboratory tests in which change over time is most valuable for the early diagnosis of MAS in sJIA. The dynamics of laboratory values during the course of MAS should be further scrutinised in a prospective study in order to establish the optimal cut-off values for their variation.

BackgroundLiver disease is rare in the course of mixed connective tissue disease. Most commonly liver steatosis or elevated liver function tests are reported and only a few cases of mixed connective tissue disease associated with autoimmune hepatitis were described.Case presentationWe report a case of an 11-year old boy with hepatitis on admission to the hospital and symptoms and signs of mixed connective tissue disease. Autoimmune hepatitis has been confirmed by liver biopsy.ConclusionTo the best of our knowledge this is the youngest patient with autoimmune hepatitis as a presenting manifestation of mixed connective tissue disease.