Juvenile Myositis Pathogenesis and Translational Medicine

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications & trials

Abstract

Juvenile dermatomyositis (JDM) is a rare complex systemic vasculopathy with prominent involvement of muscle and skin with inflammation involving adaptive and innate immunity. JDM generally causes weakness and disability with significant morbidity sometimes involving organs which can be life-threatening. Myositis-specific autoantibody (MSA) groups define clinical subgroups within JDM. Most patients have a chronic or polycyclic disease course often requiring multiple empiric potent immunosuppressive medications long-term. Although risk factors have been identified, the pathogenesis of JDM is still not fully understood. We co-authored one clinical review of JDM including features, outcomes, treatment and pathogenesis (Rheum Dis Clinics North Am, 2021). Our goal is to further study pathogenic mechanisms and evaluate novel treatments. An interferon (IFN) signature has been reported in JDM patients with active disease, but the exact role of IFN in disease pathogenesis remains unclear. Given that baricitinib, a janus kinase or JAK inhibitor that can block type I and II IFN signaling, was clinically efficacious in CANDLE and SAVI, we assessed baricitinib in a cohort of refractory JDM as part of a compassionate use program (NCT01724580) and found significant improvement in multiple validated disease activity measures by 24 weeks or 6 months, though improvement was noted as early as 4 weeks. This included improvement in skin disease and weakness as well as improvement in muscle edema or inflammation on MRI. As a proof-of-concept, we showed that IFN signaling gene and protein expression was decreased. There were no serious adverse events and none of the subjects had to hold or discontinue baricitinib. This importantly identifies JAK inhibition with blockade of IFN-signaling as an exciting promising therapy in juvenile dermatomyositis (Ann Rheum Dis, 2021). Current studies are evaluating gene and protein expression in JDM patients (both presented at the Global Conference on Myositis, 2024) and cell-type specific differences in response to baricitinib. We will also be opening a prospective open-label study to systematically evaluate deucravacitinib (TYK2 inhibitor) in adults with dermatomyositis or JDM, the first study of a TYK2 inhibitor in DM or JDM. Broad use of JAK inhibitors for JDM by clinicians was further assessed by an international survey, identifying that JAK inhibitor use for JDM is relatively widespread, primarily for refractory disease, with barriers based on access and limited clinical data (Rheumatology, 2025) Updates in pathogenesis, biomarkers, and current therapies in JDM were presented at an international myositis meeting and in a peer-reviewed review article (Global Conference on Myositis, 2024; Paediatr Drugs, 2025). Commentary on broader use of an IFN response gene score in JDM was also provided (J Rheumatol, 2025). Consensus treatment plans for biologic treatments in refractory JDM as part of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) were also developed (Arthritis Care Res, 2024). The first use of a monoclonal anti-IFN beta treatment (dazukibart) in a refractory JDM patient was also reported, with impressive clinical response (Pediatrics, 2025). We are continuing to evaluate peripheral blood protein and gene expression in JDM and myositis-specific autoantibody groups to further evaluate for activity-related biomarkers and identify other dysregulated biologic pathways, which may or may not be related to the IFN dysregulation. We are also exploring other treatment options for JDM including B-cell depletion via chimeric antigen receptor on T-cells or CAR-T- cell therapy, targeting B-cell markers such as CD19.