Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs.
OBJECTIVE
To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ).


METHODS
In 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.


RESULTS
37 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.


CONCLUSIONS
The 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.
['Strangfeld|A|A|', 'Richter|A|A|', 'Siegmund|B|B|', 'Herzer|P|P|', 'Rockwitz|K|K|', 'Demary|W|W|', 'Aringer|M|M|', 'Meißner|Y|Y|', 'Zink|A|A|', 'Listing|J|J|']
D000069594:Abatacept D000006:Abdomen, Acute D000328:Adult D000368:Aged D061067:Antibodies, Monoclonal, Humanized D018501:Antirheumatic Agents D001172:Arthritis, Rheumatoid D001688:Biological Products D002097:C-Reactive Protein D005858:Germany D006801:Humans D015994:Incidence D007416:Intestinal Perforation D008875:Middle Aged D011446:Prospective Studies D012042:Registries D018570:Risk Assessment D000069283:Rituximab D012810:Sigmoid Diseases D016037:Single-Blind Method D014409:Tumor Necrosis Factor-alpha
Corticosteroids DMARDs (biologic) NSAIDs Outcomes research