Reply to Hagiwara

We sincerely thank Dr. Hagiwara for his letter regarding our article on multiple intestinal ulcers during tocilizumab therapy for rheumatoid arthritis [1]. Dr. Hagiwara described his experience of an adverse event of bleeding from multiple colonic diverticula after tocilizumab administration and re-administration. Nishimoto et al. reported that the adverse effects of tocilizumab included gastrointestinal perforation, apparently related to diverticulitis [2]. As we pointed out [1], interleukin-6 plays an important role not only in the inflammatory process, but also in intestinal tissue repair. It is therefore possible that tocilizumab administration could exacerbate diverticulitis, leading to subsequent perforation or bleeding. In our case, as we suggested previously [1], tocilizumab might have delayed wound healing and thus augmented mucosal injury due to other factors, rather than acting as a direct cause of intestinal ulcers. The possible causes of intestinal mucosal damage in our patient included infection and nonsteroidal anti-inflammatory drugs (NSAIDs). As we discussed [1], infection represented a possible cause of ulcers because of the immunocompromised nature of the patient. Celecoxib, which is a cyclooxygenase-2-selective inhibitor with a lower risk of gastrointestinal mucosal damage than classical NSAIDs, was given to relieve arthralgia. However, Chang et al. reported that even celecoxib could increase the risk of lower gastrointestinal adverse events [3]. It is therefore likely that erosions or small ulcers initially developed as a result of infection or celecoxib treatment, and that tocilizumab subsequently suppressed mucosal healing, allowing their deterioration into intestinal ulcers. This suggests that attention should be paid to pre-existing gastrointestinal injuries before administering tocilizumab therapy, to reduce the risk of adverse gastrointestinal events. We therefore recommend the use of esophagogastroduodenoscopy, colonoscopy, or capsule endoscopy before starting tocilizumab therapy.

References

• 1 Iwasa T, Nakamura K, Ogino H et al. Multiple ulcers in the small and large intestines occurred during tocilizumab therapy for rheumatoid arthritis.  Endoscopy. 2011;  43 70-72
• 2 Nishimoto N, Ito K, Takagi N et al. 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
• 3 Chang C H, Lin J W, Chen H C et al. Non-steroidal anti-inflammatory drugs and risk of lower gastrointestinal adverse events: a nationwide study in Taiwan.  Gut. DOI: 10.11361gut.2010.229906