Risk of GI Perforations on Biologics Save

Gastrointestinal perforation is a rare but serious complication that RA patients may be at particular risk for. With the advent of so many new biologics for the treatment of RA, tocilizumab has fallen under the spotlight for its association with lower GI perforations which was first noted during initial clinical trials.

There has also been concern for GI perforation with use of tofacitinib, a JAK inhibitor. To more closely examine this risk Curtis J, et al. examined patients from 2 large U.S. databases looking at risk factors for GI perforation, in particular for those involving the lower GI tract, in RA patients receiving biologics.

After excluding patients with a prior diagnosis of GI perforation, inflammatory bowel disease or malignancy other than non-melanoma skin cancer they had a cohort of 167,113 patients for analysis. The biologics studied included tofacitinib, tocilizumab, abatacept, and rituximab with TNF-inhibitors serving as the referent group. The primary outcome was GI perforation with hospitalization. They adjusted for diabetes, peptic ulcer disease, GERD, diverticulitis and other GI conditions, and concurrent medications including glucocorticoids.

They found the overall incidence rate of hospitalized GI perforation was highest with tocilizumab at 1.55 per 1,000 PYs (95% CI 0.95-2.54), based on 16 events. For tofacitinib the IR was 0.86 per 1,000 PYs (95% CI 0.10-3.60) based on only 2 events. For users of TNF inhibitors, the IR was 0.83 per 1,000 PYs. 62% of all perforations occurred in the lower GI tract, with a higher proportion occurring in the tocilizumab group (81%) compared to the referent group (55%).

After multivariate adjustment, there was a significantly increased risk of lower GI tract perforation with tocilizumab (HR 2.51 [95% CI 1.31-4.80]) and numerically increased with tofacitinib (HR 1.94 [95% CI 0.49-7.65]). Older age, diverticulitis and prednisone >7.5 mg/day were associated risk factors.

In conclusion, the authors found a greater than 2-fold increase in risk of lower GI tract perforation with use of tocilizumab compared to TNF inhibitors in RA patients, and a numerically elevated risk with tofacitinib. The overall mortality rate with perforation was 28. Although the number of events was low, this tells us to be cautious when administering these agents, in particular tocilizumab, to certain patients such as older patients with a history of diverticulitis.