Expression of interferon-regulated genes in juvenile dermatomyositis versus Mendelian autoinflammatory interferonopathies

Hanna Kim,John A. McGrath,Yan Huang,Adriana A. de Jesus,Wanxia L. Tsai,Massimo Gadina,Terrance P. O’Hanlon,Frederick W. Miller,Lisa G. Rider,Fatima Gunter-Rahman,Ira N. Targoff,Raphaela Goldbach-Mansky,Esther Lee

doi:10.1186/s13075-020-02160-9

Abstract

BackgroundJuvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. The Mendelian autoinflammatory interferonopathies, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) and STING-Associated Vasculopathy with onset in Infancy (SAVI), are caused by genetic mutations and have extremely elevated IFN signatures thought to drive pathology. The phenotypic overlap of some clinical features of CANDLE and SAVI with JDM led to the comparison of a standardized interferon-regulated gene score (IRG-S) in JDM and myositis-specific autoantibody (MSA) JDM subgroups, with CANDLE and SAVI.MethodsA peripheral 28-component IRG-S assessed by NanoString™ in 57 JDM patients subtyped by MSA was compared with IRG-S in healthy controls (HC) and CANDLE/SAVI patients. Principal component analysis (PCA) was performed, and individual genes were evaluated for their contribution to the score. IRG-S were correlated with disease assessments and patient characteristics.ResultsIRG-S in JDM patients were significantly higher than in HC but lower than in CANDLE or SAVI. JDM IRG-S overlapped more with SAVI than CANDLE by PCA. Among MSA groups, anti-MDA5 autoantibody-positive patients’ IRG-S overlapped most with SAVI. The IFI27 proportion was significantly higher in SAVI and CANDLE than JDM, but IFIT1 contributed more to IRG-S in JDM. Overall, the contribution of individual interferon-regulated genes (IRG) in JDM was more similar to SAVI. IRG-S correlated moderately with JDM disease activity measures (rs = 0.33–0.47) and more strongly with skin activity (rs = 0.58–0.79) in anti-TIF1 autoantibody-positive patients. Weakness and joint disease activity (multinomial OR 0.91 and 3.3) were the best predictors of high IRG-S.ConclusionsOur findings demonstrate peripheral IRG expression in JDM overlaps with monogenic interferonopathies, particularly SAVI, and correlates with disease activity. Anti-MDA5 autoantibody-positive JDM IRG-S were notably more similar to SAVI. This may reflect both a shared IFN signature, which is driven by IFN-β and STING pathways in SAVI, as well as the shared phenotype of vasculopathy in SAVI and JDM, particularly in anti-MDA5 autoantibody-positive JDM, and indicate potential therapeutic targets for JDM.

Highlights

Juvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown
Our findings demonstrate peripheral interferon-regulated gene (IRG) expression in JDM overlaps with monogenic interferonopathies, Stimulator of IFN genes (STING)-Associated Vasculopathy with onset in Infancy (SAVI), and correlates with disease activity
Anti-MDA5 autoantibody-positive JDM interferon-regulated gene score (IRG-S) were notably more similar to SAVI. This may reflect both a shared IFN signature, which is driven by IFN-β and STING pathways in SAVI, as well as the shared phenotype of vasculopathy in SAVI and JDM, in anti-MDA5 autoantibody-positive JDM, and indicate potential therapeutic targets for JDM

Summary

Introduction

Juvenile dermatomyositis (JDM) is a systemic autoimmune disease with a prominent interferon (IFN) signature, but the pathogenesis of JDM and the etiology of its IFN signature remain unknown. Mendelian autoinflammatory interferonopathies, which are associated with a strong IRG signature, include Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE) caused by additive loss-of-function mutations in proteasome components [14,15,16] and STING-Associated Vasculopathy with onset during Infancy (SAVI), resulting from gain-offunction mutations in the Stimulator of IFN genes (STING) protein [16, 17]. These conditions have a very strong IRG signature and blocking IFN signaling with a Janus kinase (JAK) inhibitor correlates with clinical improvement and IRG-S decrease in the majority of 18 CANDLE and SAVI patients, with 50% of CANDLE patients achieving persistent clinical remission [16, 18,19,20]. CANDLE is associated with lipodystrophy, joint contractures, and myositis, while SAVI has frequent vasculopathy including distal ulcerations and interstitial lung disease [1, 16, 21]

Objectives

Methods

Results

Discussion

Conclusion