The Type I Interferon Signature Reflects Multiple Phenotypic and Activity Measures in Dermatomyositis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2023-10, Vol.75 (10), p.1842-1849
• Main Authors: Tabata, Mika M, Hodgkinson, Luqman Mushila, Wu, Tiffany T, Li, Shufeng, Huard, Christine, Zhao, Shanrong, Bennett, Donald, Johnson, Jillian, Tierney, Cassandra, He, Wen, Buhlmann, Janet E, Page, Karen M, Johnson, Kristen, Casciola-Rosen, Livia, Chung, Lorinda, Sarin, Kavita Y, Fiorentino, David
• Format: Article
• Language: English
• Subjects: Antibodies; Autoantibodies; Chronic conditions; Demographic variables; Dermatomyositis; Gene sequencing; Heterogeneity; Interferon; Lung diseases; Melanoma; Muscles; Skin diseases; Systemic lupus erythematosus
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.42526

The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ = 0.84-0.95). The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.