Case Report
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2015; 21(45): 12963-12969
Published online Dec 7, 2015. doi: 10.3748/wjg.v21.i45.12963
First case report of exacerbated ulcerative colitis after anti-interleukin-6R salvage therapy
Raja Atreya, Ulrike Billmeier, Timo Rath, Jonas Mudter, Michael Vieth, Helmut Neumann, Markus F Neurath
Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany
Jonas Mudter, Medical Department, Hospital Ostholstein, 23701 Eutin, Germany
Michael Vieth, Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany
Author contributions: Atreya R and Neurath MF designed the study; Atreya R, Billmeier U, Rath T, Mudter J, Vieth M, Neumann H and Neurath MF acquired the data; Atreya R, Billmeier U, Vieth M, Neumann H, Neurath MF analyzed the data; Atreya R, Billmeier U, Rath T, Mudter J, Vieth M, Neumann H and Neurath MF interpreted the data and wrote the paper.
Supported by Clinical Research Group 257 CEDER of the Deutsche Forschungsgemeinschaft.
Institutional review board statement: Ethics approval has been granted by the Ethics Committee of the Friedrich-Alexander Universität Erlangen-Nürnberg. It has approved analysis of the mucosal biopsies. The anti-IL-6R antibody (tocilizumab) was applied as compassionate use therapy in a patient with treatment refractory ulcerative colitis.
Informed consent statement: The patient provided informed written consent prior to study enrolment.
Conflict-of-interest statement: The authors declare no conflict-of-interest
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Markus F Neurath, MD, Professor of Medicine, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, Ulmenweg 18, D-91054 Erlangen, Germany. markus.neurath@uk-erlangen.de
Telephone: +49-9131-8535000 Fax: +49-9131-8535209
Received: March 29, 2015
Peer-review started: March 30, 2015
First decision: June 2, 2015
Revised: June 30, 2015
Accepted: September 14, 2015
Article in press: September 14, 2015
Published online: December 7, 2015
Processing time: 252 Days and 6.6 Hours
Abstract

We present the case of a 53-year-old woman with long-standing ulcerative colitis and severe, steroid-dependent disease course unresponsive to treatment with azathioprine, methotrexate, anti-TNF antibodies (infliximab, adalimumab) and tacrolimus, who refused colectomy as a therapeutic option. As the pro-inflammatory cytokine interleukin-6 (IL-6) had been identified as a crucial regulator in the immunopathogenesis of inflammatory bowel diseases, we treated the patient with biweekly intravenous infusions of an anti-IL-6R antibody (tocilizumab) for 12 wk. However, no clinical improvement of disease activity was noted. In fact, endoscopic, histological and endomicroscopic assessment demonstrated exacerbation of mucosal inflammation and ulcer formation upon anti-IL-6R therapy. Mechanistic studies revealed that tocilizumab treatment failed to suppress intestinal IL-6 production, impaired epithelial barrier function and induced production of pro-inflammatory cytokines such as TNF, IL-21 and IFN-γ. Inhibition of IL-6 by tocilizumab had no clinical benefit in this patient with intractable ulcerative colitis and even led to exacerbation of mucosal inflammation. Our findings suggest that anti-IL-6R antibody therapy may lead to aggravation of anti-TNF resistant ulcerative colitis. When targeting IL-6, the differential responsiveness of target cells has to be taken into account, as IL-6 on the one side promotes acute and chronic mucosal inflammation via soluble IL-6R signaling but on the other side also strongly contributes to epithelial cell survival via membrane bound IL-6R signaling.

Keywords: Ulcerative colitis; Interleukin-6; Epithelial barrier; Anti-interleukin-6R antibody; Inflammation; Endomicroscopy; Apoptosis; Cytokines

Core tip: Interleukin (IL)-6 is regarded as a pro-inflammatory cytokine in the immunopathogenesis of inflammatory bowel diseases. Unexpectedly, this first reported case describes that anti-IL-6R antibody treatment led to aggravated inflammation in a severe ulcerative colitis patient. Mechanistic studies revealed that anti-IL-6R treatment failed to suppress intestinal IL-6 production, impaired epithelial barrier function and induced production of pro-inflammatory cytokines. Our case report demonstrates that differential responsiveness of target cells has to be taken into account in therapeutic approaches, as IL-6 promotes mucosal inflammation via soluble IL-6R signaling, but also strongly contributes to epithelial cell survival via mIL-6R signaling.