Myositis is a heterogeneous group of autoimmune diseases, with different pathogenic mechanisms contributing to the different subsets of disease. The aim of this study was to test whether the autoantibody profile in patients with myositis is associated with a type I interferon (IFN) signature, as in patients with systemic lupus erythematous (SLE). Patients with myositis were prospectively enrolled in the study and compared to healthy controls and to patients with SLE. Autoantibody status was analysed using an immunoassay system and immunoprecipitation. Type I IFN activity in whole blood was determined using direct gene expression analysis. Serum IFN-inducing activity was tested using peripheral blood cells from healthy donors. Blocking experiments were performed by neutralizing anti-IFNAR or anti-IFN-α antibodies. Patients were categorized into IFN high and IFN low based on an IFN score. Patients with autoantibodies against RNA-binding proteins had a higher IFN score compared to patients without these antibodies, and the IFN score was related to autoantibody multispecificity. Patients with dermatomyositis (DM) and inclusion body myositis (IBM) had a higher IFN score compared to the other subgroups. Serum type I IFN bioactivity was blocked by neutralizing anti-IFNAR or anti-IFN-α antibodies. To conclude, a high IFN score was not only associated with DM, as previously reported, and IBM, but also with autoantibody monospecificity against several RNA-binding proteins and with autoantibody multispecificity. These studies identify IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood and support IFN-α as a possible target for therapy in these patients.

Department of Pathology VU University Medical Center Amsterdam the Netherlands

Department of Pathology VU University Medical Center Amsterdam the Netherlands Department of Rheumatology Amsterdam Rheumatology and immunology Center VU University Medical Center Amsterdam the Netherlands

Department of Rheumatology Amsterdam Rheumatology and immunology Center VU University Medical Center Amsterdam the Netherlands

Institute of Rheumatology Prague Czech Republic

Mary Kirkland Center for Lupus Research Hospital for Special Surgery Weill Cornell Medical College New York NY USA

Mary Kirkland Center for Lupus Research Hospital for Special Surgery Weill Cornell Medical College New York NY USA Department of Experimental Physiology University of Athens Athens Greece

Pharmacy and Pharmacology University of Bath Bath UK

Rheumatology Unit Department of Medicine Karolinska University Hospital Karolinska Institutet Solna Sweden

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