Lower gastrointestinal perforation in rheumatoid arthritis patients treated with conventional DMARDs or tocilizumab: a systematic literature review

Abstract

Tocilizumab, a monoclonal antibody targeting the IL-6 receptor, has recently been added to the therapeutic armamentarium against rheumatoid arthritis (RA). Despite its overall safety, concerns have been raised regarding diverticular perforation in patients receiving the drug. The aim of our research was to document the incidence of diverticular disease in RA patients treated in the pre-disease-modifying anti-rheumatic drug (DMARD) era, following treatment with conventional DMARDs, and subsequent to tocilizumab therapy. We performed a systematic literature review in MEDLINE, EMBASE, Conference Proceedings Citation Index-Science, Cochrane Central Register of Controlled Trials and Current Controlled Trials up to Nov. 2010. The publication titles and abstracts were independently assessed by two reviewers for relevance and quality, and the review was conducted following guidelines from the Centre for Reviews and Dissemination. In the pre-DMARD period of RA management, where patients were largely treated with NSAIDs and corticosteroids, gastrointestinal (GI) complications were a substantial cause of mortality with diverticulitis and colonic ulcers accounting for almost a third of GI-related deaths. In contrast, our search did not reveal any evidence of diverticular perforation in patients treated with conventional DMARDs. Eighteen cases of lower GI perforation (16 of whom had diverticulitis) have been documented in recent conference proceedings following tocilizumab treatment in clinical trials, with a lower GI perforation rate of 1.9 per 1,000 patient years (PY). This lies between the reported rate of GI perforations for corticosteroids and anti-TNF-α agents in the United Health Care database, with rates of 3.9 per 1,000 PY (95% CI 3.1-4.8) and 1.3 per 1,000 PY (95% CI 0.8-1.9), respectively. The majority of these patients were concurrently prescribed NSAIDs and/or long-term corticosteroids. Traditional DMARD therapy for RA appears not only to have modified the risk of lower GI perforation but prevented it. The risk of diverticular perforation may be slightly higher in patients treated with tocilizumab compared with conventional DMARDs or anti-TNF agents, but lower than that for corticosteroids. The mechanism of action of IL-6 antagonism in the pathophysiology of diverticular perforation has yet to be elucidated.

Longterm Safety of Tocilizumab: Results from 3 Years of Followup Postmarketing Surveillance of 5573 Patients with Rheumatoid Arthritis in Japan

“…Lower GI perforations are rare, but serious complications of TCZ treatment appear to occur more frequently in patients receiving glucocorticoids 15 . The overall incidence of GI perforation in our study was comparable with reports from longterm extensions of TCZ randomized trials and did not increase over time 8 .…”

Rheumatoid arthritis and the era of biologic therapy

“…IL-6 is a key driver of the features of inflammation and reports suggest that the use of tocilizumab is associated with suppression of temperature and acute phase response (Hirao et al 2009). In addition, there has been a concern regarding gastro-intestinal perforation, and review by us (Gout et al 2011) has revealed that the risk is similar to that of anti-TNF agents but way below that for corticosteroids. IL-6 inhibition is also associated with reversible neutropenia, abnormalities of the lipid profile and transient elevation of liver enzymes, therefore, studies are looking at the medium and long-term implications of these findings.…”

Biological treatments

“…Bu ilac› alan bir hastada yeni ortaya ç›kan kar›n a¤r›s› varl›¤›nda bu olas›l›k akla gelmelidir. [6,48] • Maligniteler: Malignite görülme s›kl›¤› 100 hasta y›-l› için, tüm maligniteler aç›s›ndan 1.1, sadece nonmelanom deri kanseri için 0.3, solid organ kanserleri için 0.7 ve lenfoma gibi hematolojik maligniteler için 0.1 olarak bildirilmifltir. TCZ kullan›m süresi uzad›k-ça, malignite görülme s›kl›¤› artmamaktad›r.…”