Gastrointestinal Perforations with Biologics in Patients with Rheumatoid Arthritis: Implications for Clinicians

Abstract

Gastrointestinal (GI) perforations are rare events in rheumatoid arthritis (RA) patients, but cause significant morbidity and mortality. Several studies indicate that RA patients may be at higher risk of GI perforation. Traditional RA treatments such as glucocorticoids and non-steroidal anti-inflammatory drugs increase the risk of perforation. In the past two decades, a new class of therapeutic agents called biologics has been added to the RA treatment armamentarium. Biologics are effective in controlling disease activity and are generally well tolerated; however, reports of GI perforations in association with biologics have arisen. In particular, drugs that inhibit the interleukin (IL)-6 cytokine receptor have demonstrated a higher risk of perforation compared with other therapies. Recent reports also suggest that janus kinase inhibitors may increase the risk of perforation, perhaps via downstream effects on IL-6 signaling. In this review, we discuss current data on the risk of GI perforations among RA patients receiving targeted therapies and its clinical relevance.

A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Sirukumab in the Treatment of Giant Cell Arteritis

“…Unlike previous sirukumab trials in RA [31,32,37], no gastrointestinal perforations, a known consequence of anti-IL-6 therapies [39], were reported in the current study; and there were no reported deaths or tuberculosis re-activations. Two patients receiving sirukumab had visual disturbances considered potentially GCA related.…”

Gastrointestinal perforations in patients with rheumatoid arthritis treated with biological disease-modifying antirheumatic drugs in Sweden: a nationwide cohort study

“…Data on other non-TNFi bDMARDs and comparisons between bDMARDs is limited, 12 but available data suggests a possibly increased risk of lower GI perforations associated with tocilizumab. A safety signal was first triggered by several cases reported in preapproval clinical trials and postmarketing surveillance for tocilizumab.…”

“…[8][9][10] However, one large analysis of data from the British Society for Rheumatology Biologics Register found no difference in risk, comparing tumour necrosis factor inhibitor (TNFi) versus csDMARDs, after adjusting for GC use and other risk factors. 11 Data on other non-TNFi bDMARDs and comparisons between bDMARDs is limited, 12 but available data suggests a possibly increased risk of lower GI perforations associated with tocilizumab. A safety signal was first triggered by several cases reported in preapproval clinical trials and postmarketing surveillance for tocilizumab.…”

Is Tocilizumab A Risk Factor for Lower Gastrointestinal Perforations? Isolated Cecal Necrosis: A Rare Case Report

“…9,10 As the effect of TCZ, although the exact mechanism of GI perforations due to IL-6 receptor blockade is not yet understood, it is thought they may be associated with the effects of IL-6 inhibition on vascular endothelial growth factor (VEGF). 11 VEGF plays an important role in maintaining the integrity of the intestinal mucosa in intestinal damage caused by acute or chronic processes, and it is a targeted cytokines in many cancer treatments as it is highly effective during angiogenesis. 12 Similar to TCZ, clinical studies have shown that drugs with active substance of bevacizumab, another VEGF inhibitor, are also associated with GI perforations.…”

“…13 Therefore, a decrease in VEGF levels may increase the risk of GI perforation. 11 Especially in the treatment of elderly RA patients with a history of diverticulitis, the use of these drugs should be paid attention; likewise, the use of TCZ alone in patients with a history of diverticulitis increases the risk of lower GI perforation. 10,14 In ancient times, GI complications were among the most common causes of death in patients diagnosed with RA.…”