OP32Preclinical Anti-Integrin αvβ6 Autoantibodies in Ulcerative Colitis: Validation of Predictive Performance, Early Life Emergence and Environmental Modifiers across Multiple Population-Based Cohorts

Abstract Background IgG autoantibodies against integrin αvβ6 have been associated with preclinical ulcerative colitis (UC),1,2 but data on their emergence and validation are still scarce. Therefore, we aimed to establish and validate a cutoff of anti-αvβ6 for predicting future UC across two independent preclinical cohorts. Additionally, we examined their development in early-life, assessed the influence of genetic-, environmental risk factors and inflammation on anti-αvβ6. Methods Within large population-based cohorts (n 180,000), prediagnostic blood samples from individuals who later in life were diagnosed with UC were compared with age- and sex-matched controls who remained UC-free during follow-up (Figure 1). To explore early-life presence and genetic and shared environmental influences, we analysed serum from ABIS, a population-based birth cohort (n = 17,055) and the Swedish Twin Registry (n 97,000). Anti-αvβ6 levels were measured using an in-house automated fluorescence enzyme immunoassay. Relative estimates of proteins were measured on the Olink platform3. Results In the discovery cohort (Table 1), anti-αvβ6 antibodies differentiated preclinical UC from controls (area under the curve AUC=0.68). Applying the model to the validation cohort yielded an AUC of 0.79, with a sensitivity of 46% and a specificity of 93%, at the optimal cut-off (109 UA/l) derived from the discovery cohort. Predictive capacity increased closer to diagnosis but remained significant for samples collected ≥20 years before UC diagnosis (AUC=0.67). In the birth cohort, anti-αvβ6 levels at birth appeared elevated in children who later developed UC (OR = 2.13; 95%CI, 0.84-5.38), likely reflecting transplacental antibody transfer, but also after 5 years (OR = 2.58; 95%CI, 0.83-8.03) and 8 years (OR = 2.50; 95%CI, 0.30-21.00). When assessing the level of agreement within twin pairs, low intra-class correlation coefficients were observed irrespective of zygosity and disease status, suggesting limited influence of genetic and shared environmental exposures. However, anti-αvβ6 levels differed across smoking categories in the preclinical cohorts, but inclusion of smoking status added little to model performance (AUC=0.82). By calculating a composite proteomic score, a progressive increase in the score was observed from the lowest to highest quartile of αvβ6 levels in preclinical UC, whereas most controls were found in the lowest quartiles for both the proteomic score and autoantibody levels. Conclusion Anti-αvβ6 autoantibodies represent a reproducible biomarker for preclinical UC. Their early-life presence, environmental modulation, and correlation with immuno-inflammatory proteins highlight their potential utility for risk stratification. References: 1.Livanos AE, Dunn A, Fischer J, et al. Anti-Integrin alphavbeta6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis. Gastroenterology. Apr 2023;164(4):619–629. doi:10.1053/j.gastro.2022.12.042 2.Sawahashi M, Kakuta Y, Naito T, et al. Autoantibodies against endothelial protein C receptor and integrin alphavbeta6 predict the development of ulcerative colitis. J Gastroenterol. Sep 2025;60(9):1108–1117. doi:10.1007/s00535-025-02263-7 3.Grännö O, Bergemalm D, Salomon B, et al. Preclinical Protein Signatures of Crohn’s Disease and Ulcerative Colitis: A Nested Case-Control Study Within Large Population-Based Cohorts. Gastroenterology. Apr 2025;168(4):741–753. doi:10.1053/j.gastro.2024.11.006 Conflict of interest: Pertsinidou, Eleftheria: Employed by Thermo Fisher Scientific Grännö, Olle: No conflict of interest Bergemalm, Daniel: Daniel Bergemalm has received fees for lectures and/or advisory board from Abbvie, Bristol Mayers Squibb, Johnson and Johnson, Pharmacosmos, Pfizer, Takeda, Tillots Pharma and Sandoz. Salomon, Benita: No conflict of interest Salihovic, Samira: No conflict of interest Eriksson, Carl: Carl Eriksson received grant support from Takeda. Lindqvist, Carl Mårten: No conflict of interest Moverare, Robert: Employed by Thermo Fisher Scientific. Rydell, Niclas: Employed by Thermo Fisher Scientific Hultdin, Johan: No conflict of interest Repsilber, Dirk: No conflict of interest Grip, Olof: Olof Grip served as speaker and/or advisory board member for Abbvie, Bristol Mayer Squibb, Eli Lilly, Ferring, Janssen, Pfizer Takeda, Tillotts Pharma and Vifor Pharma. Ludvigsson, Johnny: No conflict of interest Karling, Pontus: Advisory board participant for Johnson and Johnson, Abbvie Halfvarson, Jonas: Grant support: Swedish Foundation for Strategic Research (RB13-0160 to J.H.), the Swedish Research Council (2020-02021 to J.H.), the Örebro University Hospital research foundation (OLL-890291 to J.H.), NordForsk (90569 to J.H.) and Vinnova (2019-01185 to JH and 2024-01155 co-applicant), IHI, EU, INTERCEPT (Grant agreement number 101194780, co-applicant), miGut-Health, HORIZON-HLTH-2022, EU (Grant Agreement 101095470, Co-applicant), 3TR, IMI 2, EU, (Grant agreement number 831434, Co-applicant), Janssen, MSD, and Takeda. Consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Hospira, Index Pharmaceuticals, Janssen, Johnson & Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and speaker’s fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma and research grant support from Janssen, Merck Sharp & Dohme and Takeda.