DOP017Unique serological signatures enable the diagnosis and stratification of Inflammatory Bowel Disease

Abstract Background Accurate, early diagnosis of Inflammatory Bowel Disease (IBD) and stratification into Crohn’s disease (CD) and Ulcerative Colitis (UC) is crucial to limit delays in diagnosis and improve IBD management. Given the increasing recognition of humoral perturbations in IBD, we aimed to characterize and potentially utilize serological profiling of anti-microbial and auto-antibodies for the diagnosis and clinical classification of patients with IBD. Methods Sera from an adult (training n = 512; validation n = 1,596 IBD=1,039; nonIBD=557) and a pediatric (n = 240; 189 IBD, 51 non IBD) (validation) cohort of IBD and non-IBD subjects were profiled using a panel of well characterized, putative anti-microbial (ASCA IgA/IgG, anti-OmpC IgA, anti-CBir1 IgG, anti-Fla2 IgG and anti-FlaX IgG) and autoantibodies (atypical perinuclear anti-neutrophil cytoplasmic antibodies pANCA with DNAse sensitive pattern, anti-proteinase 3 PR3 IgG, and anti-αvβ6 IgG MBL, Tokyo, Japan). Cutoffs for positive antibody status were defined as the 95th percentile of values observed in healthy adults for all anti-microbial antibodies, or according to manufacturer (pANCA and PR3). Cutoff for anti-αvβ6 was set at 3.1 U/mL. We summed positive serological signals and trained logistic models to distinguish IBD from non-IBD controls (step 1) and to stratify UC vs CD (step 2). Model parameters from training cohort were applied to validation cohorts. The sensitivity, specificity and area under the curve (AUC) of the receiver operating characteristic curve were determined. Results In the training cohort, AUCs were 0.85 (IBD vs non-IBD) and 0.86 (CD vs UC). In the adult validation cohort, the sensitivity to distinguish IBD from non-IBD was 80% (834/1,039) and specificity was 79% (442/557) (AUC=0.85). Among the IBD-derived samples (n = 834; 420 UC and 414 CD), discrimination between UC and CD achieved a sensitivity of 91% (383/420) and specificity of 73% (301/414) (AUC=0.87). Anti-microbial antibody positivity strongly supported CD classification, while a combination of pANCA/PR3/avβ6 antibodies were enriched UC and colonic CD (Figure 1). Performance in the pediatric cohort revealed the sensitivity of IBD vs non-IBD as 80% (152/189) and specificity as 67% (34/51) (AUC=0.80). In the IBD derived pediatric samples (n = 152), the sensitivity of distinguishing UC from CD was 93% (42/45) while the specificity was 83% (89/107) (AUC=0.96). Performances in the adult and pediatric cohorts are presented in Figure 2. Conclusion Unique serological signatures identify IBD from controls and permit the classification of specific clinical phenotypes. Validation in prospective cohorts will enable the adoption of serological profiling to help for early diagnosis and classification of IBD. References: 1.Livanos AE, Dunn A, Fischer J, et al. Anti-Integrin alphavbeta6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis. Gastroenterology 2023;164:619-629. 2.Livanos A, Ganjian DY, Acharya AA, et al. OP28 Anti-integrin αvβ6 autoantibodies are detected in preclinical, incident and established colonic Crohn’s disease. Journal of Crohn’s and Colitis 2025;19:i56-i58 Conflict of interest: Colombel, Jean-Frédéric: Grant: AbbVie, Janssen Pharmaceuticals, Takeda, Prometheus and Bristol Myers Squibb Lectures from: AbbVie, Roche and Takeda Other: AbbVie, Amgen, AnaptysBio, Allergan, Apini, Arena Pharmaceuticals, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, candidrx Celgene, Celltrion, Clearview Curogen, Eli Lilly, Envision Pharma Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Roche, Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Iterative Scopes, Landos, Microba Life Science, Merck, Mirador, Novartis, Otsuka Pharmaceutical, Owkin, Pfizer, Protagonist Therapeutics, Sanofi, Sun Pharma, Takeda, Teva, TiGenix, and is holding stock options in Intestinal Biotech Development Mehandru, Saurabh: Grant: Genentech, Brystol Myers Squib (BMS) Personal Fees: AbbVie, Adacyte, Alimentiv, Atticus, Brystol Myers Squib (BMS), Cabaletta, Georgia Immune, Merck, Novartis Livanos, Alexandra: No conflict of interest Ungaro, Ryan: Personal Fees: AbbVie, Bristol Myers Squibb, Genentech, Lilly, Pfizer, Janssen, Takeda Spencer, Elizabeth: No conflict of interest Everts-van der Wind, Annelie: employment, Prometheus Ibarra, Claudia: Prometheus Laboratories, employment Schwalbe, Michael: employment, Prometheus Targan, Stephan: No conflict of interest Dervieux, Thierry: Employment, Prometheus Laboratories