Molecular Predictors of Biologic Therapy Response in Mucosal Biopsies from Patients with Crohn's Disease: A Review

Abstract

Roughly two in five patients with Crohn's disease do not respond to anti-tumour necrosis factor therapy, and at present there is no way to identify the before treatment begins. Mucosal biopsies taken at diagnosis contain signals that separate responders from non- responders, and the question is whether any of them is reliable enough to act on. Objectives: To review the published evidence on molecular markers measured in mucosal biopsies that predict response to biologic therapy in Crohn's disease: which markers have been reported for each drug class, how accurate they are, how well they replicate, and why so few have entered practice.  Material and Methods: Narrative review of transcriptomic profiling studies, single-cell analyses, prospective cohorts and meta-analyses indexed in
PubMed and the major gastroenterology and immunology journals. Studies were eligible if they reported the association between a molecular measurement in intestinal tissue and subsequent response to a biologic agent. No new patient data were generated; every accuracy estimate and effect size quoted is one published by the original investigators. Results: High mucosal oncostatin M expression separated patients sharply: complete mucosal healing on infliximab was achieved by 85 per cent of those with low expression against 10 to 15 per cent of those with high expression. A five-gene mucosal panel comprising TNFRSF11B, STC1, PTGS2, IL13RA2 and IL11 predicted endoscopic remission after infliximab with 95 per cent sensitivity and 85 per cent specificity, and in Crohn's colitis a related five-gene signature separated responders from non-responders completely. Single-cell analysis of ileal lesions identified a cellular module of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells and stromal cells whose presence at diagnosis, confirmed across four independent cohorts totalling 441 patients, correlated with failure to achieve durable corticosteroid-free remission on anti-TNF therapy. Markers for other classes are more preliminary: a four-gene colonic panel for vedolizumab and mucosal IL23A expression for ustekinumab. Conclusion: The signal is real and reproducible in direction, but the reported accuracy figures come from small derivation cohorts with cut-offs set in the same data, and the gene sets identified in different studies barely overlap. The obstacle is not the absence of a marker but the absence of a common endpoint and of independent prospective validation.
Abbreviations: CD – Crohn's Disease, UC – Ulcerative Colitis, IBD – Inflammatory Bowel Disease, TNF – Tumour Necrosis Factor, OSM – Oncostatin M, OSMR – On costatin M Receptor, TREM1 – Triggering Receptor Expressed on Myeloid Cells 1, GIMATS – IgG Plasma Cells, Inflammatory Mononuclear Phagocytes, Activated T and Stromal Cells, SES-CD – Simple Endoscopic Score for Crohn's Disease, scRNA-seq – Single-Cell RNA Sequencing, mRNA – Messenger Ribonucleic Acid, qPCR – Quantitative Polymerase Chain Reaction.