American College Of Surgeons - Inspiring Quality: Highest Standards, Better Outcomes

Featured Commentary

The online formats of SRGS include access to What You Should Know (WYSK): commentaries on articles published recently in top medical journals. These commentaries, written by practicing surgeons and other medical experts, focus on the strengths and weaknesses of the research, as well as on the articles' contributions in advancing the field of surgery.

Below is a sample of one of the commentaries published in the current edition of WYSK.

Fenglong Xie, Huifeng Yun, Sasha Bernatsky, and Jeffrey R Curtis. Risk of Gastrointestinal Perforation among Rheumatoid Arthritis Patients Receiving Tofacitinib, Tocilizumab or Other Biologic Treatments. Arthritis Rheum. 2016; 68 (11): 2612-2617.

Commentary by: Heather Yeo, MD, FACS, MHS

Patients with Rheumatoid Arthritis (RA) are at higher risk of gastrointestinal (GI) perforation than the general population, often related to the medication that they need for disease management. Traditionally, these patients have been considered to have a high risk of upper GI perforation due to chronic NSAID use.1 More recently, in part due to initial RCT data, there has been concern that some patients treated with tocilizumab and tofacitinib have a higher risk of lower GI perforation. However, due to limitations of previous clinical trials as well as a lack of comparative evidence, there is no clear sense of comparative risk of lower GI perforation for patients receiving different RA agents.

Xie and coauthors used data from two large administrative databases to compare rates of lower GI perforation over time in several cohorts of rheumatoid arthritis patients receiving biologic agents or tumor necrosis factor inhibitors (TNFi). Using Medicare data from 2006 to 2013 and MarketScan® data from 2010 to 2014, the authors identified 167,109 patients with rheumatoid arthritis who started receiving treatment with tofacitinib or another biologic agent or any TNFi who did not have a prior history of GI perforation.

Overall, they found that ccompared with TNFi recipients, the risk of GI perforation was significantly higher for tofacitinib recipients (adjusted hazard ratio [HR] 3.24; 95% CI 1.05, 10.04) and tocilizumab recipients (HR 2.55; 1.16, 3.73). Lower tract GI perforation was also predicted by other known risk factors such as older age (HR 1.16 per 5 years; 1.10, 1.22), the presence of diverticulitis or other gastrointestinal conditions (HR 3.25; 1.62, 6.51), and receipt of prednisone at >7.5 mg/day (HR 2.24; 1.36, 3.70).

Limitations of this study are significant. Due to the nature of administrative databases, it is unclear why these patients were selected for different treatments; thus, there may be an underlying selection bias that cannot be identified by using administrative data. In addition, it is unclear what the total exposures were to the medication. As a result, the direct causality is also unclear. Correlation does not necessarily mean causation. One thing that readers should be careful of is making clinical judgments from a large administrative database, where it is easy to see statistical differences, but little clinical significance exists. Despite these differences in relative risk, the absolute rate differences between treatments were small (as the authors themselves noted): 1.55 cases per 1,000 patient years in the tocilizumab group compared to 0.83 cases per 1,000 patient years overall in the TNFi group.

Despite these limitations, event rates in this study are comparable to those in the previous tocilizumab trials and also those from the German RABBIT Registry (which had 11 patients), thus adding to the face validity of the data.1 In addition, a recent study reported even higher rates of perforation over a three-year post-marketing study, with an incidence of 2.4% per 1,000 patient years.2 While there is likely an association between the use of biologics such as tofacitinib and tocilizumab, the underlying mechanism or reason for this association is less clear.

Overall the data are still limited and should be read with caution. Further work comparing these different modalities could be strengthened by increasing registry data for new medications and post-market surveillance.3


  1. Strangfeld A, Richter A, Siegmund B, et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis. 2017 Mar;76(3):504-510. Free Full Text
  2. Yamamoto K, Goto H, Hirao K, et al. Longterm Safety of Tocilizumab: Results from 3 Years of Followup Postmarketing Surveillance of 5573 Patients with Rheumatoid Arthritis in Japan. J Rheumatol. 2015 Aug;42(8):1368-75. Free Full Text
  3. Monemi S, Berber E, Sarsour K, et al. Incidence of Gastrointestinal Perforations in Patients with Rheumatoid Arthritis Treated with Tocilizumab from Clinical Trial, Postmarketing, and Real-World Data Sources. Rheumatol Ther. 2016 Dec;3(2):337-352. Free Full Text