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Anti-TNF nonresponse in ulcerative colitis: correcting for mucosal drug exposure reveals distinct cytokine profiles

Joep van Oostrom1, Jurij Hanzel1,2, Bram Verstockt3,4

  • 1Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands.

Journal of Crohn'S & Colitis
|January 2, 2025
PubMed
Abstract

Insights

Tumor necrosis factor inhibitors (TNFi) fail in many ulcerative colitis (UC) patients. This study found high interleukin-6 (IL-6) levels in non-responders, suggesting it drives inflammation, while Oncostatin M (OSM) parallels it.

Area of Science:

  • Gastroenterology
  • Immunology
  • Pharmacology

Background:

  • Up to 30% of ulcerative colitis (UC) patients do not respond to tumor necrosis factor inhibitors (TNFi).
  • Validated biomarkers for TNFi nonresponse (NR) are lacking.
  • Previous studies often fail to distinguish pharmacokinetic from inflammatory mechanisms of NR.

Purpose of the Study:

  • To develop a framework correcting for mucosal drug exposure (MDE).
  • To apply this framework to mucosal cytokine profiles in UC patients.
  • To identify biomarkers associated with TNFi response or nonresponse.

Main Methods:

  • Prospective international cohort study of moderate-to-severe UC patients starting TNFi.
  • Endoscopy at baseline and follow-up to assess endoscopic response.
  • Measurement of mucosal drug concentrations (TNFi/TNF ratio for MDE).
  • Quantification of mucosal cytokines: IL-6, OSM, IL-10, and IL-12/23p40.

Main Results:

  • 39 of 54 (72%) UC patients were endoscopic responders.
  • Non-responders with high MDE showed elevated IL-6 at both time points.
  • Responders with low MDE had low baseline IL-10.
  • High OSM at follow-up was associated with NR, while high IL-12/23p40 was associated with response.

Conclusions:

  • Incorporating MDE into cytokine research avoids bias from insufficient anti-TNF levels.
  • Elevated IL-6 in the mucosa appears to drive inflammation in TNFi-resistant UC.
  • OSM levels may parallel inflammation but do not appear to cause TNFi refractoriness.
Keywords:
anti-TNFcytokinesinflammatory bowel diseasespharmacokineticsulcerative colitis

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