Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer

Scleroderma is a chronic autoimmune rheumatic disease associated with widespread tissue fibrosis and vasculopathy. Approximately two-thirds of all patients with scleroderma present with three dominant autoantibody subsets. Here, we used a pair of complementary high-throughput methods for antibody epitope discovery to examine patients with scleroderma with or without known autoantibody specificities. We identified a specificity for the minor spliceosome complex containing RNA Binding Region (RNP1, RNA recognition motif) Containing 3 (RNPC3) that is found in patients with scleroderma without known specificities and is absent in unrelated autoimmune diseases. We found strong evidence for both intra- and intermolecular epitope spreading in patients with RNA polymerase III (POLR3) and the minor spliceosome specificities. Our results demonstrate the utility of these technologies in rapidly identifying antibodies that can serve as biomarkers of disease subsets in the evolving precision medicine era.