Crohn's Patient Serum Proteomics Reveals Response Signature for Infliximab but not Vedolizumab

Background: Crohn's disease is a chronic inflammatory bowel disease that affects the gastrointestinal tract. Common biologic families used to treat Crohn's are tumor necrosis factor (TNF)-α blockers (infliximab and adalimumab) and immune cell adhesion blockers (vedolizumab). Given their differing mechanisms of action, the ability to monitor response and predict treatment efficacy via easy-to-obtain blood draws remains an unmet need. Methods: To investigate these gaps in knowledge, we leveraged 2 prospective cohorts (LOVE-CD, TAILORIX) and profiled their serum using high-dimensional isobaric-labeled proteomics before treatment and 6 weeks after treatment initiation with either vedolizumab or infliximab. Results: The proportion of patients endoscopically responding to treatment was comparable among infliximab and vedolizumab cohorts; however, the impact of vedolizumab on patient sera was negligible. In contrast, infliximab treatment induced a robust response including increased blood-gas regulatory response proteins, and concomitant decreases in inflammation-related proteins. Further analysis comparing infliximab responders and nonresponders revealed a lingering innate immune enrichments in nonresponders and a unique protease regulation signature related to clotting cascades in responders. Lastly, using samples prior to infliximab treatment, we highlight serum protein biomarkers that potentially predict a positive response to infliximab treatment. Conclusions: These results will positively impact the determination of appropriate patient treatment and inform the selection of clinical trial outcome metrics.