Childhood Arthritis and Rheumatology Research Alliance consensus clinical treatment plans for juvenile dermatomyositis with skin predominant disease.

BACKGROUND: Juvenile dermatomyositis (JDM) is the most common form of the idiopathic inflammatory myopathies in children. A subset of children have the rash of JDM without significant weakness, and the optimal treatments for these children are unknown. The goal of this study was to describe the development of consensus clinical treatment plans (CTPs) for children with JDM who have active skin rashes, without significant muscle involvement, referred to as skin predominant JDM in this manuscript. METHODS: The Children's Arthritis and Rheumatology Research Alliance (CARRA) is a North American consortium of pediatric rheumatology health care providers. CARRA members collaborated to determine consensus on typical treatments for JDM patients with skin findings without significant weakness, to develop CTPs for this subgroup of patients. We used a combination of Delphi surveys and nominal group consensus meetings to develop these CTPs. RESULTS: Consensus was reached on patient characteristics and outcome assessment, and CTPs were developed and finalized for patients with skin predominant JDM. Treatment option A included hydroxychloroquine alone, Treatment option B included hydroxychloroquine and methotrexate, and Treatment option C included hydroxychloroquine, methotrexate and corticosteroids. CONCLUSIONS: Three CTPs were developed for use in children with skin predominant JDM, which reflect typical treatment approaches. These are not considered to be specific recommendations or standard of care. Using the CARRA network and prospective data collection, we will be able to apply statistical methods in the future to allow comparisons of JDM patients following these consensus treatment plans.

Association of Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Autoantibodies With DRB1*07:01 and Severe Myositis in Juvenile Myositis Patients.

OBJECTIVE: Autoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are associated with statin exposure, the HLA allele DRB1*11:01, and necrotizing muscle biopsies in adult myositis patients. The aim of this study was to characterize the features of juvenile anti-HMGCR-positive myositis patients. METHODS: The sera of 440 juvenile myositis patients were screened for anti-HMGCR autoantibodies. Demographic and clinical features, responses to therapy, and HLA alleles were assessed. The features of anti-HMGCR-positive patients were compared to those of previously described adult patients with this autoantibody and to children with other myositis-specific autoantibodies (MSAs). RESULTS: Five of 440 patients (1.1%) were anti-HMGCR-positive; none had taken statin medications. Three patients had rashes characteristic of juvenile dermatomyositis and 2 patients had immune-mediated necrotizing myopathies. The median highest creatine kinase (CK) level of anti-HMGCR-positive subjects was 17,000 IU/liter. All patients had severe proximal muscle weakness, distal weakness, muscle atrophy, joint contractures, and arthralgias, which were all more prevalent in HMGCR-positive subjects compared to MSA-negative patients or those with other MSAs. Anti-HMGCR-positive patients had only partial responses to multiple immunosuppressive medications, and their disease often took a chronic course. The DRB1*07:01 allele was present in all 5 patients, compared to 26.25% of healthy controls (corrected P = 0.01); none of the 5 juvenile patients had DRB1*11:01. CONCLUSION: Compared to children with other MSAs, muscle disease appears to be more severe in those with anti-HMGCR autoantibodies. Like adults, children with anti-HMGCR autoantibodies have severe weakness and high CK levels. In contrast to adults, in anti-HMGCR-positive children, there is a strong association with HLA-DRB1*07:01.

Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo.

Increased IFN-alpha signaling is a primary pathogenic factor in systemic lupus erythematosus (SLE). STAT4 is a transcription factor that is activated by IFN-alpha signaling, and genetic variation of STAT4 has been associated with risk of SLE and rheumatoid arthritis. We measured serum IFN-alpha activity and simultaneous IFN-alpha-induced gene expression in PBMC in a large SLE cohort. The risk variant of STAT4 (T allele; rs7574865) was simultaneously associated with both lower serum IFN-alpha activity and greater IFN-alpha-induced gene expression in PBMC in SLE patients in vivo. Regression analyses confirmed that the risk allele of STAT4 was associated with increased sensitivity to IFN-alpha signaling. The IFN regulatory factor 5 SLE risk genotype was associated with higher serum IFN-alpha activity; however, STAT4 showed dominant influence on the sensitivity of PBMC to serum IFN-alpha. These data provide biologic relevance for the risk variant of STAT4 in the IFN-alpha pathway in vivo.