Discontinuation of Infliximab Increases the 1-Year Relapse Rate of Ulcerative Colitis in Remission - A Prospective, Multicentre, Randomised Controlled Trial

Abstract

Background and Aims: Anti-tumour necrosis factor (TNF)- a agents are the mainstay of long-term treatment for refractory ulcerative colitis (UC). However, there has been no prospective randomised controlled trial evaluating whether anti-TNFa agents can be discontinued in UC patients in remission. Methods: This prospective, multicentre, randomised controlled trial enrolled UC patients from 23 specialist centres treated with infliximab (IFX) who were in remission. Patients who were confirmed to be: 1) in remission for > 6 months, 2) steroid-free, and 3) with a Mayo endoscopic subscore (MES) of 0 or 1, were randomised into two groups (continued IFX or discontinued IFX) in a 1:1 ratio stratified according to the use of immunomodulators and MES, using computer-generated stratified randomisation. The remission rate at week 48 in the full analysis set (FAS) was the primary endpoint in this trial. As secondary objectives, risk factors for relapse, and efficacy of re-treatment with IFX after relapse were also evaluated. Findings: A total of 95 patients were randomised, and 92 were included in the FAS. The remission rate at week 48 was 80.4% (n = 37/46; 95% CI: 66.1% to 90.6%) and 54.3% (n = 25/46; 95% CI: 39.0% to 69.1%) in the IFX-continued and IFX-discontinued groups, respectively (between-group difference: 26.1% [7.7% to 44.5%], p = 0.008). C-reactive protein and histological severity index were associated with future non-remission. Neither clinical nor endoscopic remission was predictive of remission. Retreatment with IFX upon relapse was safe, and two-thirds of patients achieved remission in 8 weeks. Interpretation: Discontinuing IFX resulted in a significantly increased relapse rate at 1 year. Residual subtle inflammation, as estimated based on CRP and histological inflammation seemed to be predictive of future relapse. Trial Registration:This study was registered at the University Hospital Medical Information Network Center Trials Registry (UMI12092). Funding Statement: This study was supported in part by a Grant-in-Aid for the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan, and Mitsubishi- Tanabe Pharmaceuticals. Co. Declaration of Interests: Dr. Nakamura reports grants and personal fees from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from EA Pharamaceutical Co Ltd, grants and personal fees from AbbVie Inc, personal fees from Janssen Pharmaceutical Co Ltd, grants and personal fees from Mochida Pharamaceutical Co Ltd, personal fees from Takeda Pharmaceutical Co Ltd, grants from Kyorin Holdings Inc, grants from JIMRO Co Ltd, grants from ZERIA Pharmaceutical Co Ltd, outside the submitted work. Dr. Motoya reports grants from Takeda pharmaceutical Co. Ltd, grants from Mitsubishi Tanabe Pharma Coporation, grants from Janssen Pharma coporation, during the conduct of the study. Dr. Hisamatsu reports grants and personal fees from EA pharma Co. Ltd., grants and personal fees from AbbVie GK, personal fees from Celgene K.K., personal fees from Janssen Pharmaceutical K.K., grants and personal fees from Pfizer Inc., grants and personal fees from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from Kyorin Pharmaceutical Co. Ltd., grants and personal fees from JIMRO Co.Ltd, grants and personal fees from Mochida Pharmaceutical Co., Ltd, personal fees from Nichi-lko Pharmaceutical Co., Ltd., grants from Daiichi-Sankyo, grants and personal fees from Takeda Pharmaceutical Co. Ltd., outside the submitted work. Dr. Abe reports personal fees from EA Pharma Co.,LTD., personal fees from Kissei Pharmaceutical Co.,LTD., personal fees from Mochida Pharmaceutical Co.,LTD., personal fees from Mitsubishi Tanabe Pharma Corporation, outside the submitted work. Dr. Hibi reports personal fees from Aspen Japan K.K, grants and personal fees from Abbvie GK, personal fees from Ferring, personal fees from Gilead Sciences, personal fees from Janssen, grants and personal fees from JIMRO, personal fees from Kisse Pharmaceutical, grants and personal fees from Mitsubishi-Tanabe Pharma, grants and personal fees from Mochida Pharmaceutical, personal fees from Nippon Kayaku, personal fees from Pfizer, grants and personal fees from Takeda Pharmaceutical, grants and personal fees from Zeria Pharmaceutical, personal fees from Bristol-Myaers Squibb, personal fees from Celltrion, personal fees from EA Pharma, personal fees from Eli Lilly, grants and personal fees from kyorin, personal fees from Nichi-Iko Pharmaceutical, grants from Otuska Holdings, outside the submitted work. Ethics Approval Statement: The protocol was approved by the institutional review board of each participating institution. Written informed consent was obtained from all patients included in the study.