title: First case report of exacerbated ulcerative colitis after anti-interleukin-6R salvage therapy.
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.
authors.affiliation: Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Raja
authors.initials: R
authors.lastname: Atreya
authors.affiliation: Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Billmeier
authors.affiliation: Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Rath
authors.affiliation: Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Mudter
authors.affiliation: Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.affiliation: Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Neumann
authors.affiliation: Raja Atreya, Ulrike Billmeier, Timo Rath, Helmut Neumann, Markus F Neurath, Medical Clinic 1, Friedrich-Alexander University Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects*; D001706:Biopsy; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D003113:Colonoscopy; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D005765:Gastrointestinal Agents; C508603:IL6R protein, human; D019947:Receptors, Interleukin-6; C502936:tocilizumab
keywords: Anti-interleukin-6R antibody; Apoptosis; Cytokines; Endomicroscopy; Epithelial barrier; Inflammation; Interleukin-6; Ulcerative colitis