Normalization of mucosal cytokine gene expression levels predicts long-term remission after discontinuation of anti-TNF therapy in Crohn's disease

Abstract

Objective. To investigate mucosal cytokine gene expression levels in healed mucosa after anti-tumor necrosis factor (TNF) therapy in patients with Crohn's disease (CD) as possible risk factors for relapse after discontinuation of therapy. Design. Thirty-seven CD patients treated with anti-TNF agents until complete mucosal healing, documented by endoscopy, discontinued anti-TNF treatment and entered a follow-up study. Levels of mRNA expression of interleukin (IL)17A (IL17A), IL23, interferon-gamma (IFNG), TNF-alpha (TNF), IL10 and Forkhead Box P3 (FOXP3) were measured in biopsies from healed mucosa and analyzed as possible risk factors of relapse. Mucosal cytokine transcript levels from patients without CD served as controls. Results. Patients were followed after therapy withdrawal until relapse. Median time to relapse was 20 and 68 weeks for patients with elevated and normalized IL17A and TNF expression levels, respectively (p = 0.02 for IL17A and p = 0.003 for TNF, log-rank). Expression levels of TNF, IL17A and FOXP3 were significantly higher in patients who relapsed before 26 weeks than in those who did not relapse, and also higher in patients with relapse before week 52 versus non-relapsers. Elevated expression levels of TNF and IL17A in healed mucosa significantly increased the risk of relapse (HR = 3.4, p = 0.03, sensitivity 80%, specificity 38% and HR = 4.1, p = 0.008, sensitivity 81%, specificity 61%, respectively). Conclusions. Normalization of mucosal gene expression of cytokines after anti-TNF therapy does not occur in all patients with healed mucosa as judged by endoscopy. Normalization of TNF and/or IL17A expression predicts long-term remission.

Key Words::

• cytokines
• IBD
• mucosal healing
• real-time PCR
• relapse

Acknowledgments

The authors would like to thank Marijan Remijn and Line Wilsgård for technical assistance and the colleagues at the Department of Gastroenterology for providing biopsies during endoscopic procedures. Funding: The project was funded by the Northern Norway Regional Health Authority (Helse Nord RHF), the Gastro fund, University Hospital North Norway and Abbott, Oslo, Norway (unrestricted research funds). Ethics Approval: The project was approved by the Regional Committee of Medical Ethics in North Norway (REK).

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.