Multiple ulcers in the small and large intestines occurred during tocilizumab therapy for rheumatoid arthritis

Tocilizumab is a monoclonal antibody against human interleukin-6 receptor which blocks the binding of interleukin-6 to its receptor. Tocilizumab is effective for the treatment of inflammatory disorders including rheumatoid arthritis. We report a case of multiple ulcers in the small and large intestines, which occurred during tocilizumab therapy. A 57-year-old woman started to use tocilizumab for rheumatoid arthritis. Three months later, she complained of hematochezia. Double-balloon endoscopy revealed multiple small aphthoid ulcers in the small and large intestines. One month after the woman had recovered, she was given tocilizumab again. The woman had hematochezia and abdominal pain again 2 weeks later. Colonoscopy revealed multiple round, discrete punched-out ulcers in the terminal ileum, and vast deep ulcers from the cecum to the descending colon. Bioptic histopathology and cultivation showed non-specific findings. Six weeks after discontinuation of tocilizumab, ulcers in the small and large intestine dramatically improved, leaving ulcer scars. This disease course and the results of examination made us strongly suspect that tocilizumab induced multiple ulcers in the small and large intestines. Interleukin-6 is a pleiotropic cytokine and involved in intestinal mucosal wound healing as well as in inflammatory processes. It is possible that tocilizumab inhibited tissue repair of the intestine and caused intestinal ulcers.

References

• 1 Nishimoto N. Clinical studies in patient with Castleman’s disease, Crohn’s disease, and rheumatoid arthritis in Japan.  Clin Rev Allergy Immunol. 2005;  28 221-230
• 2 Nishimoto N, Kishimoto T. Humanized antihuman IL-6 receptor antibody, tocilizumab.  Handb Exp Pharmacol. 2008;  181 151-160
• 3 Lipsky P E. Interleukin-6 and rheumatic diseases.  Arthritis Res Ther. 2006;  8 S4
• 4 Ito H, Takazoe M, Fukuda Y et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease.  Gastroenterology. 2004;  126 989-996
• 5 Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions.  Mod Rheumatol. 2010;  20 222-232
• 6 Smolen J S, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomized trial.  Lancet. 2008;  371 987-997
• 7 Harris Jr E D. Rheumatoid arthritis. Pathophysiology and implications for therapy.  N Engl J Med. 1990;  322 1277-1289
• 8 Smolen J S, Aletaha D, Koeller M et al. New therapies for treatment of rheumatoid arthritis.  Lancet. 2007;  370 1861-1874
• 9 Tebbutt N C, Giraud A S, Inglese M et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice.  Nat Med. 2002;  8 1089-1097