AbstractBackgroundAnti-integrin αvβ6 autoantibodies (anti-αvβ6) are present in up to 90% of ulcerative colitis (UC) patients and predate disease development, but there is a paucity of data regarding anti-αvβ6 in Crohn’s disease (CD). We hypothesized that anti-αvβ6 would be present in colonic CD given the shared biological characteristics with UC.MethodsWe measured anti-αvβ6 IgG in peripheral blood samples from seven distinct cohorts representing diverse ethnic backgrounds, geographical locations and stages of disease including preclinical, incident and established IBD as well as non-IBD controls (HC). Seropositivity was defined as greater than the log10 transformed mean + 2 standard deviations of HC. We determined associations with CD disease location (L1: Ileal, L2: colonic, L3: ileocolonic), disease activity, fecal calprotectin and pANCA.ResultsWe assessed for anti-αvβ6 in adult and pediatric subjects from Mount Sinai Hospital (MSH), NY (MSCCR-adult, n=599 and pediatric, n=75). Anti-αvβ6 levels as well as seropositivity were significantly higher in adult CD (16%) compared to HC (2%) (P=0.0330, P<0.0001), but lower than in UC (64%) (Fig. 1A-B). In the Pediatric cohort, we observed similar results with CD seropositivity (22%) greater than HC (0%) (P=0.0073), but lower than UC (79%) (Fig. 1C-D). Next, we examined anti-αvβ6 by CD location. Patients with L2 disease had higher levels than L1 across all cohorts including 2 incident cohorts (MSCCR P<0.0001; Pediatric P=0.0531; COMPASS n=81, P<0.0001; OSCCAR n=167, P=0.0099), while patients with L3 disease had intermediate levels (Fig. E-H). These findings were validated in an independent cohort (Prometheus n=730) using a commercially available ELISA kit (MBL) (Fig. 1I). A significant positive correlation between anti-αvβ6 and pANCA was observed in L2 CD and L3 CD (Spearman r=0.52, P<0.0001; r=0.46, P=0.0012) but not L1 CD (Fig. 1J). In the Leuven cohort (n=163), anti-αvβ6 levels were significantly higher in those with moderate-severe disease activity (SES-CD≥7) and in those with elevated fecal calprotectin (≥150μg/g) (P=0.0024, P=0.0057) (Fig. 1K-L). Finally, in the PREDICTs cohort, anti-αvβ6 were significantly higher in CD subjects compared to HC at all 4 timepoints (n=824) including up to 10 years before diagnosis (Fig. 2A-B) and when stratifying by location, this was primarily driven by patients who develop L2 disease (Fig. 2C).ConclusionIn patients with CD, anti-αvβ6 differentiate colonic from ileal disease and predate clinical disease by up to 10 years, potentially serving as a novel biomarker for clinical and preclinical colonic CD.