Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs

Abstract

ObjectiveTo investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ).MethodsIn 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure.Results37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2−0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment.ConclusionsThe incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases

“…For every 1000 patients treated with TCZ per year, between one and two additional GIPs might be expected to occur for patients treated with TCZ compared with those treated with TNF inhibitors [69]. In particular, the risk for LIPs seems to be higher in patients with a history of diverticulitis [67,68], indicating that TCZ should be avoided in patients at risk for GIP. Furthermore, TCZ-treated patients with LIP often exhibit only mild or no symptoms and suppressed C-reactive protein (CRP) levels, which may delay diagnosis [67].…”

“…A higher incidence of GIPs and specifically lower intestinal perforations (LIPs) has been reported in patients treated with TCZ than in those treated with other biologics or csDMARDs (rates per 1000 patient-years: GIPs, 1.8-2.8 for TCZ vs. 0.6-0.9 for TNF inhibitors [difference: 1.2 -1.9/1000 patient-years]; LIPs, 1.26-2.7 for TCZ vs. 0.2-0.76 for TNF inhibitors) [67][68][69]. For every 1000 patients treated with TCZ per year, between one and two additional GIPs might be expected to occur for patients treated with TCZ compared with those treated with TNF inhibitors [69].…”

“…A [67][68][69]. For every 1000 patients treated with TCZ per year, between one and two additional GIPs might be expected to occur for patients treated with TCZ compared with those treated with TNF inhibitors [69].…”

“…In particular, the risk for LIPs seems to be higher in patients with a history of diverticulitis [67,68], indicating that TCZ should be avoided in patients at risk for GIP. Furthermore, TCZ-treated patients with LIP often exhibit only mild or no symptoms and suppressed C-reactive protein (CRP) levels, which may delay diagnosis [67]. These findings indicate a class effect for anti-IL-6 agents, highlighting the need for careful patient selection (i.e., exclusion of individuals with previous diverticulitis) in clinical trials evaluating TCZ and other anti-IL-6 agents in order to reduce the risk for LIP.…”

“…Other safety signals were not identified in a cumulative analysis of up to 4.6 years of TCZ exposure based on pooled data from the OPTION, TOWARD, RADIATE, AMBITION, and LITHE phase 3 trials (with 12,293 patient-years of exposure) compared with the placebo-controlled periods; infections were the most common AEs and SAEs [66]. As of 7 June 2017, the estimated cumulative TCZ exposure in the periodic benefit-risk evaluation report is [700,000 patient-years (F. Hoffmann-La Roche Ltd., data on file).A higher incidence of GIPs and specifically lower intestinal perforations (LIPs) has been reported in patients treated with TCZ than in those treated with other biologics or csDMARDs (rates per 1000 patient-years: GIPs, 1.8-2.8 for TCZ vs. 0.6-0.9 for TNF inhibitors [difference: 1.2 -1.9/1000 patient-years]; LIPs, 1.26-2.7 for TCZ vs. 0.2-0.76 for TNF inhibitors) [67][68][69]. For every 1000 patients treated with TCZ per year, between one and two additional GIPs might be expected to occur for patients treated with TCZ compared with those treated with TNF inhibitors [69].…”