DOP16 Anti-integrin ⍺vβ6 autoantibodies predate Ulcerative Colitis diagnosis by up to 10 years and are associated with adverse disease-related outcomes
Livanos, A.(1)*;Dunn, A.(2);Fischer, J.(2);Ungaro, R.C.(1);Turpin, W.(3);Lee, S.H.(3);Rui, S.(1);Del Valle, D.M.(2);Jougon, J.J.(4);Martinez-Delgado, G.(2);Riddle, M.S.(5);Murray, J.A.(6);Laird, R.M.(7);Torres, J.(8);Agrawal, M.(1);Magee, J.S.(9);Dervieux, T.(10);Gnjatic, S.(2);Sheppard, D.(11);Sands, B.E.(1);Porter, C.K.(7);Croitoru, K.(3);Petralia, F.(12);Colombel, J.F.(1);Mehandru, S.(1);
(1)Icahn School of Medicine at Mount Sinai, Henry D. Janowitz Division of Gastroenterology, New York, United States;(2)Icahn School of Medicine at Mount Sinai, Precision Immunology Institute, New York, United States;(3)Mount Sinai Hospital, Zane Cohen Centre for Digestive Diseases, Toronto- Ontario, Canada;(4)Claude Huriez Hospital- University of Lille, Hepato-Gastroenterology Department, Lille, France;(5)University of Nevada- Reno School of Medicine, Office of Medical Research, Reno, United States;(6)Mayo Clinic, Division of Gastroenterology and Hepatology, Rochester, United States;(7)Naval Medical Research Center, Enteric Diseases Department, Silver Spring, United States;(8)Hospital Beatriz Ângelo, Gastroenterology Division, Loures, Portugal;(9)Walter Reed National Military Medical Center, Gastroenterology, Bethesda, United States;(10)Prometheus Laboratories, Chief Scientific Officer, San Diego, United States;(11)University of California San Francisco, Division of Pulmonary- Critical Care- Allergy and Sleep- Department of Medicine, San Francisco, United States;(12)Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, United States; CCC-GEM Project Research Consortium and OSCCAR Consortium
Background
Biomarkers for predicting the development of Ulcerative Colitis (UC) and disease-related complications are lacking. Anti-integrin ⍺vβ6 IgG autoantibodies (anti-⍺vβ6) have been recently described in patients diagnosed with UC. Here, we sought to determine if anti-⍺vβ6 autoantibodies predate UC development and to study associations between anti-⍺vβ6 and disease outcomes in newly diagnosed UC patients.
Methods
In a unique pre-clinical IBD cohort from the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS), anti-⍺vβ6 were measured in longitudinal pre-diagnosis serum samples from 82 subjects who later developed UC as well as in 82 matched subjects that did not develop IBD (HC). Sample A was at the time of UC diagnosis, Sample B was at a median of 2 years before Sample A, Sample C was at a median of 4 years before Sample A and Sample D was at a median of 10 years before Sample A. In a distinct, external validation cohort (the Crohn’s and Colitis Canada Genetics Environment Microbial (GEM) Project), we tested samples from 12 subjects who later developed UC and compared those with 49 matched subjects who remained asymptomatic. Further, anti-⍺vβ6 were measured in 2 incident IBD cohorts (COMPASS, n=55 and OSCCAR, n=104 UC subjects) and associations between anti-⍺vβ6 and adverse UC-outcomes were defined using Cox proportional-hazards model.
Results
Anti-⍺vβ6 were significantly higher in the PREDICTS cohort among individuals who developed UC compared to HC up to 10 years prior to diagnosis (Figure 1A). The anti-⍺vβ6 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. Additionally, the predictive performance of anti-⍺vβ6 autoantibodies as assessed via area under the receiver operator curves (AUROC) with 10-fold cross validation was at least 0.8 up to 10 years before diagnosis (Figure 1B). Elevated levels of anti-⍺vβ6 in pre-clinical UC samples were further validated in the GEM cohort (Figure 1C). Finally, high anti-⍺vβ6 were associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in both incident cohorts (Figure 1D).
Conclusion
Anti-integrin ⍺vβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.