Background/Purpose: Several studies have reported an increased risk of gastro-intestinal perforation (GIP) in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ) compared to conventional synthetic disease modifying anti rheumatic drugs (csDMARDs) or TNF inhibitors (TNFis) (1–3). However, a recent study did not find an increased risk of GIP with TCZ compared to TNFis and even compared to others biologic-DMARDs (bDMARDs), namely rituximab (RTX) and abatacept (ABA) (4). The aim of our study was to compare the risk of diverticulitis and GIP in RA patients treated with TCZ compared to RTX and ABA using a propensity-matched analysis.

Methods: We conducted a study of patients with TNFis refractory RA, prospectively followed in 3 observational French registries evaluating the effectiveness and safety of RTX (Autoimmunity and Rituximab (AIR)), ABA (Orencia and Rheumatoid Arthritis (ORA)), and TCZ (REGistry–RoAcTEmra (REGATE)). Adult patients with RA according to the 1987 ACR criteria, initiating intravenous treatment with RTX, ABA, or TCZ were enrolled from 107 clinical centers between September 2005 and August 2013 (5). Using a propensity score approach, we compared the risk of diverticulitis or GIP during treatment with TCZ vs RTX and ABA. Pearson Chi-squared analysis and multivariable logistic regression were used to evaluate correlation between different risk factors and the onset of diverticulitis or GIP among TCZ, RTX or ABA (the latter 2 pooled). We also retrospectively collected the outcome of these specific adverse events and compared the clinical presentation by treatment.

Results: Forty-one diverticulitis and 19 GIP occurred in 4501 RA patients (patient’s characteristics are shown in table 1) (corresponding incidences of 0.027 and 0.012 per 1000 person-years). Based on inverse probability weighting, there was an increased risk of GIP due to diverticulitis (5.66 [2.63-12.18], p< 0.0001) in the TCZ group vs RTX and ABA. There was also an increased risk of diverticulitis and GIP but not GIP due to another etiology. In multivariate analysis, age was associated with an increased risk of diverticulitis (1.03/year [1.01-1.06], p=0.03) in all patients, and history of neoplasia was associated with an increased risk of GIP in patients treated with TCZ (5.04 [1.03-24.65], p=0.04). Compared to RTX and ABA, diverticulitis and GIP during TCZ occurred earlier after the last perfusion (24.5+/-18.4 vs 58.6+/-49.2 days, p=0.01), with usually atypical clinical presentation (slow transit in 30% vs 0, p=0.04) and milder biological inflammatory markers  at the time of the event (hemoglobin: 13.9+/-1.8 vs 10.6+/-2.8 g/dL, p=0.01; platelets: 251583+/-85976 vs 371500+/-68066/mm3, p=0.04; and C-reactive protein: 31.2+/- 58.4 vs 88.2+/-89.6 mg/L, p=0.005).

Conclusion: TCZ was associated with an increased risk of diverticulitis, GIP and GIP due to diverticulitis, but not those caused by another etiology, compared to RTX and ABA. Our study confirms an increased risk of GIP in RA patients treated with TCZ and could be explained by an increased risk of diverticulitis with misleading clinical presentation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/risk-of-diverticulitis-and-gastro-intestinal-perforation-in-rheumatoid-arthritis-treated-with-tocilizumab-compared-to-rituximab-and-abatacept-a-prospective-propensity-matched-cohort-study/