Anti-Microbial Antibodies and Inflammatory Markers Are Present in the Serum of Patients with Ibd Years Before Diagnosis and Can Predict Disease

Background: IBD is preceded by a preclinical period where immunological changes can already be detected. Prior studies have shown that antimicrobial antibodies (Abs) and inflammatory markers can be detected years (Y) before diagnosis (dx), but no study has yet looked into the longitudinal evolution of these markers and their power to predict disease at given time-points (TP) before diagnosis. Methods: Stored pre-dx serum samples from military personnel were obtained from 100 CD, 100 UC, and 100 healthy controls (HC). Cases were identified based on ICD9 codes. Samples were tested for ASCA (IgA, IgG), AntiOmpC, AntiFlaX, antiFla2, antiCbir1, pANCA, and CRP. The distribution of each marker in each subject was treated as a stochastic process, and functional principal component analysis was performed to derive its trajectory along time in CD, UC and HC. A linear mixed effects model was used to compare each marker's differential trajectory. A logistic regression model was used to evaluate the power to predict disease 3Y, 2Y and 1Y before dx. Survival curves were developed for each marker from first seropositivity until dx. Results: 1000 serum samples (400 from CD, 300 from UC and 300 from HC) at different TP before diagnosis were tested. Median time before diagnosis was −797 days (range: −7118, 2355) for CD, and −849 days (−6536, 31) for UC. In UC, pANCA and CRP presented different trajectories as compared to HC (p=10–6, p=0.001, respectively), increasing towards dx. In CD all markers trajectories (except pANCA) were significantly different as compared to HC (p=0.008 for antiOmpC, p≤0.001 for all other markers). Combining the markers with highest predictive accuracy in a multivariate model provided a higher predictive accuracy than each marker alone (estimated AUC based on cross-validation: 0.756, 0.803, and 0.795 at 3Y, 2Y, and 1Y before dx). Specifically, 3 of the 5 markers, anti-Fla2, anti-OmpC and CRP were found to significantly predict CD in the model, with an Odds Ratio of 2.80 (90% CI: 1.8, 4.4), 1.83 (90% CI: 1.2, 2.7) and 1.78 (90% CI: 1.2, 2.5) respectively at 3Y before diagnosis. In the survival analysis, for all markers (except antiOmpC), a pre-clinical positive result was associated with a greater chance of developing IBD (Figure 1). Figure 1. Results from functional principal component analysis. Conclusions: Circulating antibodies and markers of systemic inflammation can be detected in the serum of patients with IBD years before diagnosis, indicating that immune dysfunction precedes detectable tissue injury. Accurate prediction of disease at this preclinical stage could pave the way for preventive strategies.