Anti-integrin αvβ6 autoantibodies are a novel predictive biomarker in ulcerative colitis

Background and Aims: Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvβ6 autoantibodies (anti-αvβ6) have been described in UC patients. Here, we tested for the presence of anti-αvβ6 antibodies in the pre-clinical phase of UC and studied their association with disease-related outcomes after diagnosis. Methods: Anti-αvβ6 were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense pre-clinical cohort (PREDICTS). In a distinct, external validation cohort (GEM), we tested 12 pre-UC subjects and 49 matched controls. Further, anti-αvβ6 were measured in 2 incident UC cohorts (COMPASS n=55 and OSCCAR n=104) and associations between anti-αvβ6 and UC-related outcomes were defined using Cox proportional-hazards model. Results: Anti-αvβ6 were significantly higher among individuals who developed UC compared to controls up to 10 years before diagnosis in PREDICTS. The anti-αvβ6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Anti-αvβ6 predicted UC development with an AUC of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvβ6 in pre-clinical UC samples was validated in the GEM cohort. Finally, high anti-αvβ6 was associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in recently diagnosed UC. Conclusion: Anti-integrin αvβ6 auto-antibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes. ### Competing Interest Statement SM reports receiving research grants from Genentech and Takeda; receiving payment for lectures from Takeda, Genentech, Morphic; and receiving consulting fees from Takeda, Morphic, Ferring and Arena Pharmaceuticals. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi,Takeda, TiGenix, Vifor; and holds stock options in Intestinal Biotech Development RCU has served as an advisory board member or consultant for AbbVie, Bristol Myer Squibb, Janssen, Pfizer, and Takeda; research support from AbbVie, Boehringer Ingelheim, Eli Lily, and Pfizer. TD is employee of Prometheus Laboratories and hold stock options. JAM reports receiving grants from Nexpep/ImmusanT, National Institutes of Health, Immunogenix, Takeda Pharmaceutical, Allakos, Oberkotter, Cour; and consultancy fees from Bionix, Lilly Research Laboratory, Johnson & Johnson, Dr. Schar USA, UCB Biopharma, Celimmune, Intrexon Corporation, Dren Bio, Reistone pharma, Chugai Pharma, Kanyos, Boehringer Ingelheim, Equillium and Torax Medical. SG reports other research funding from Genentech, Boehringer-Ingelheim, EMD Serono, Takeda, and Regeneron. JT received grants from Abbvie and Janssen, payment for lectures from Janssen, Abbvie, and Pfizer, and consulting fees from Janssen, Abbvie, Pfizer, and BMS. DS is a founder of Pliant Therapeutics, receives research funding from AbbVie and is on the Scientific Review Board for Genentech and Amgen. The remaining authors have no competing interests to declare.