Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Abstract

Objectives JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). Methods This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Results Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. Conclusion This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.

Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry

“…A recent French multicenter study identified 13 patients with Juvenile myositis and positive anti-MDA5 antibodies, and this group was constituted equally by Juvenile Dermatomyositis (JDM) and Juvenile Overlap Myositis. They confirmed the presence of ulcerative skin disease and arthritis in frequencies similar to those previously reported; in addition, they identified that a lupuslike rash was present in half of the subjects, and aseptic abscesses in 20% [40].…”

“…The cytokine profile in patients with anti-MDA5 DM further supports an upregulated interferon axis (IFN-γ, IFN-α, and IFN-induced protein, IP-10) alongside other proinflammatory cytokines [39,40]. A hierarchical cluster analysis of the cytokine profiles in DM revealed two distinct clusters, with predominance of IFN-related cytokines in cluster one, 75% of which was constituted by anti-MDA5 DM and strong correlation with cutaneous vasculitis [39].…”

“…Four-gene interferon signature, serum interferon levels and interferon expression in cutaneous biopsies are elevated in both adults and children with anti-MDA5 IMIM and correlate with response to treatment [40].…”

“…Thus, it seems plausible that anti-MDA5 DM may represent an acquired form of the same type of condition [42,43]. However, in a recent French study, no obvious pathogenic mutations were observed in genes associated with recognized monogenic interferonopathies in 21 anti-MDA5 JDM patients [40].…”

Clinical Images: A not so common overlap presentation in systemic lupus erythematosus

“…Melanoma differentiation–associated gene 5 (MDA‐5) is associated with dermatomyositis and often presents with a distinct cutaneous presentation and progressive interstitial lung disease (ILD) (1–3). MDA‐5 signaling often leads to increased interferon signaling, which contributes to atypical vasculopathy, leading to atypical, and at times ulcerative or necrotic, cutaneous manifestations, which are challenging to diagnose and treat (2).…”