Juvenile Myositis Pathogenesis and Translational Medicine

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

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. An interferon (IFN) signature has been reported in JDM patients with active disease, but the exact role of IFN in disease pathogenesis remains unclear. IFN has been identified as a key driver of Mendelian autoinflammatory interferonopathies with genetic mutations driving pathogenic IFN signaling. We published a paper in Arthritis Research and Therapy directly comparing the IFN signature or score in JDM versus Mendelian autoinflammatory interferonopathies (CANDLE and SAVI). We also compared these conditions (JDM, CANDLE, SAVI) clinically, identifying unique cutaneous features in each, and areas of overlap, such as more prominent vasculopathy features (interstitial lung disease ulceration) in anti-MDA5 autoantibody JDM and SAVI. JDM was confirmed to have a significantly higher IFN-regulated gene score or IRG-score versus healthy controls, with the top quartile of JDM IRG-scores as high as CANDLE and SAVI. Principal component analysis found that the IRG expression in JDM was closer to SAVI than CANDLE, indicating a potentially greater role for STING and IFN-beta (type I IFN) in JDM, particularly for anti-MDA5 autoantibody JDM. Also, JDM with elevated IRG-scores had a higher IFN-gamma (type II) contribution than CANDLE and SAVI. The IRG-score correlated with multiple clinical disease activity measures of JDM; Multivariable regression analysis found that weakness and joint symptoms were the best predictors of a high IRG-score in JDM. Also, the IRG-score had a higher correlation with skin disease activity in the anti-TIF1 autoantibody group despite not having higher skin disease activity. These findings indicate that JDM has some unique aspects to its IRG-score, with more overlap with SAVI and some differences by MSA group. 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. This was published in Annals of Rheumatic Disease finding 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, IFN signaling gene and protein expression as 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. We evaluated some key validated clinical disease measures after 72 weeks or 18 months of treatment and found continued improvement. This was presented at the Annual American College of Rheumatology Meeting in November 2020 as an oral presentation. Future studies will continue to evaluate dysregulated pathways based on gene and protein expression in JDM patients and novel targeted treatments based on pathogenic mechanisms to improve treatment and lessen side-effects in JDM.