Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in dermatomyositis patients with anti-TIF1γ autoantibodies
Authors: Hosono Yuji , Sie Brandon , Pinal-Fernandez Iago , Pak Katherine , Mecoli Christopher A. , Casal-Dominguez Maria , Warner Blake M. , Kaplan Mariana J. , Albayda Jemima , Danoff Sonye K. , Lloyd Thomas E. , Paik Julie , Tiniakou Eleni , Milisenda Jose C. , Grau-Junyent Josep M. , Selva-O’Callaghan Albert , Christopher-Stine Lisa , Larman H. Benjamin , Mammen Andrew L. 
Published: March 2022

ABSTRACTObjectivesIn dermatomyositis (DM), different autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with a substantially increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.MethodsPhage ImmunoPrecipitation Sequencing using sera from 67 DM patients suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins myositis patients (255 with DM, 28 with antisynthetase syndrome [ASyS], 40 with immune-mediated necrotizing myopathy [IMNM], 29 with inclusion body myositis [IBM], and 19 with polymyositis [PM]), 75 rheumatologic disease controls (25 with Sjogren’s syndrome, 25 with systemic lupus erythematosus, and 25 with rheumatoid arthritis), and 200 healthy comparators were screened for anti-SP4 autoantibodies by an enzyme-linked immune absorption assay. Serum from 23 Spanish TIF1γ-positive DM patients was also screened for anti-Sp4 autoantibodiesResultsAnti-Sp4 autoantibodies were present in 11.4% of DM and 8% of rheumatoid arthritis patients but not in any other clinical group. Among DM patients, 90% of anti-Sp4 autoantibodies were detected in patients with anti-TIF1γ autoantibodies. Among anti-TIF1γ-positive DM patients from Johns Hopkins and Spain, those with coexisting anti-Sp4 autoantibodies had a decreased risk of cancer (0% vs. 31%; p=0.001, Chi-squared test).ConclusionsAnti-Sp4 autoantibodies are enriched in anti-TIF1γ-positive DM patients without cancer, suggesting that the development of an anti-Sp4 immune response may correlate with a relatively low risk of cancer in these patients.KEY MESSAGESWhat is already known about this subject?Dermatomyositis patients with anti-TIF1γ autoantibodies have an increased risk of cancer.What does this study add?Anti-Sp4 autoantibodies are enriched in dermatomyositis patients with anti-TIF1γ autoantibodies.Anti-Sp4 autoantibodies are only found in dermatomyositis patients without cancer.Muscle strength is greater in dermatomyositis patients with anti-Sp4 autoantibodies.Anti-Sp4 autoantibodies are not present in patients with antisynthetase syndrome, immune-mediated necrotizing myopathy, or inclusion body myositis.Autoantibodies against Sp4 are absent in those with systemic lupus erythematosus or Sjogren’s syndrome and present in 8% of those with rheumatoid arthritis.How might this impact on clinical practice?Testing for anti-Sp4 autoantibodies may define a population of anti-TIF1γ-positive dermatomyositis patients without a substantially increased risk of cancer.