I_MDS: an inflammatory bowel disease molecular activity score to classify patients with differing disease-driving pathways and therapeutic response to anti-TNF treatment

Crohn's disease and ulcerative colitis are driven by both common and distinct underlying mechanisms of pathobiology. Both diseases, exhibit heterogeneity underscored by the variable clinical responses to therapeutic interventions. We aimed to identify disease-driving pathways and classify individuals into subpopulations that differ in their pathobiology and response to treatment. We applied hierarchical clustering of enrichment scores derived from gene set variation analysis of signatures representative of various immunological processes and activated cell types, to a colonic biopsy dataset that included healthy volunteers, Crohn's disease and ulcerative colitis patients. Patient stratification at baseline or after anti-TNF treatment in clinical responders and non-responders was queried. Signatures with significantly different enrichment scores were identified using a general linear model. Comparisons to healthy controls were made at baseline in all participants and then separately in responders and non-responders. Fifty-nine percent of the signatures were commonly enriched in both conditions at baseline, supporting the notion of a disease continuum within ulcerative colitis and Crohn's disease. Signatures included T cells, macrophages, neutrophil activation and poly:IC signatures, representing acute inflammation and a complex mix of potential disease-driving biology. Collectively, identification of significantly enriched signatures allowed establishment of an inflammatory bowel disease molecular activity score which uses biopsy transcriptomics as a surrogate marker to accurately track disease severity. This score separated diseased from healthy samples, enabled discrimination of clinical responders and non-responders at baseline with 100% specificity and 78.8% sensitivity, and was validated in an independent data set that showed comparable classification. Comparing responders and non-responders separately at baseline to controls, 43% and 70% of signatures were enriched, respectively, suggesting greater molecular dysregulation in TNF non-responders at baseline. This methodological approach could facilitate better targeted design of clinical studies to test therapeutics, concentrating on patient subsets sharing similar underlying pathobiology, therefore increasing the likelihood of clinical response. Author summary Patients exhibiting similar phenotypical characteristics, diagnosed with the same disease, exhibit variable response to therapeutics. This is a major health care issue, due to the increased patient suffering and the socioeconomical burden that occurs. Crohn's disease and ulcerative colitis constitute good examples of inflammatory conditions, with sufferers responding differentially to existent therapeutics. Here, we identified disease-driving pathways and classified individuals into subpopulations that differ in their pathobiology and response to treatment. We utilized gene set variation analysis and transcriptomic data from inflammatory bowel disease sufferers to stratify patients at baseline or after anti-TNF treatment in clinical responders and non-responders. We explored gene signatures obtained from the literature, relevant to immune processes, which were significantly enriched in disease compared to healthy controls, as well as before and after treatment. Using these signatures, we established an inflammatory bowel disease molecular activity score, which allowed us to separate clinical responders and non-responders at baseline with high specificity and sensitivity. We validated the proposed approach in an independent data set, demonstrating comparable classification. This methodological approach may lead to better targeted design of clinical studies, allowing the selection of patient sharing similar underlying pathobiology, thus increasing the likelihood of clinical response to treatment.