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

Abstract

ObjectivesTo compare incidence rates of gastrointestinal (GI) perforations between patients with RA and the general population, and between patients treated with tumour necrosis factor inhibitors (TNFi) and non-TNFi biologics.MethodsIn this nationwide cohort study, a total of 63 532 patients with RA, with 26 050 biological treatment episodes (TNFi, rituximab, abatacept or tocilizumab) and 76 304 general population controls, were followed between 2009 and 2017 until the first outcome event. The main outcome was hospitalisation or death due to lower GI perforations, identified according to a prespecified list of ICD-10 (International Classification of Diseases, 10th revision) codes. Inverse probability of treatment weighting was used for adjustment.ResultsThe sex-standardised and age-standardised incidence rates of lower GI perforations were 1.1 (95% CI 1.0 to 1.3) events per 1000 person-years among general population controls, 1.6 (1.5–1.7) among bionaïve patients and ranged from 1.8 (1.4–3.6) (TNFi) to 4.5 (2.7–10.4) (tocilizumab) among biologics-treated patients. After adjustment for glucocorticoid use, the risk in bionaïve, TNFi-treated, abatacept-treated or rituximab-treated patients with RA was no longer different from the general population, while for tocilizumab it remained significantly higher. Comparing tocilizumab to TNFi, the adjusted HR for lower GI perforations was 2.2 (1.3–3.8), corresponding to one additional GI perforation per 451 patient-years treated with tocilizumab instead of TNFi.ConclusionTocilizumab was associated with a higher risk of lower GI perforations compared with alternative biologics. In absolute numbers, the risk remained low on all biologics commonly used to treat RA, but the accumulated evidence across settings and outcome definitions supports that this risk should be considered in treatment guidelines for RA.

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

“…119 120 Overall incidence rates for lower GI perforations (LIP) under TCZ treatment were markedly increased compared with csDMARDs, TNF-inhibitors, RTX 121 or the general population. 122 Two of the included studies were further adjusted for concomitant treatment with GC and NSAIDs 120 121 and two for history of diverticulitis. 120 123 Diverticulitis itself was more often associated with perforation in TCZ exposed patients than in patients treated with other agents.…”

Rheumatologische Erkrankungen und der Gastrointestinaltrakt

“…Die intestinale Obstruktion ist eher eine Komplikation bei der onkologischen Therapie. Gastrointestinale Infektionen oder Perforationen unter Rituximab wurden bei rheumatologischen Erkrankungen insbesondere in der Kombination mit Steroiden gesehen [40,41]. Zudem kann es durch einen prolongierten Immunglobulin-Mangel zu persistierenden GI-Infektionen, z.…”

“…Tocilizumab ist ein humanisierter monoklonaler Antikörper gegen den Interleukin-6-Rezeptor zur Behandlung der RA, der systemischen juvenilen idiopathischen Arthritis und der Riesenzellarteriitis. Neben Bauchschmerzen und gastritischen Beschwerden kommt es unter Tocilizumab bei der Behandlung einer RA signifikant häufiger zu einer Perforation im Kolon als unter anti-TNFalpha-Therapie [41,42]. Risikofaktoren hierfür sind höheres Alter (HR 1,16 pro 5 Jahre; 95 % CI 1,10-1,22), Divertikulitis/andere GI-Erkrankungen (HR 3,25; 95 % CI 1,62-6,50) und begleitende Steroid-Einnahme > 7,5 mg/d (HR 2,29; 95 % CI 1,39-3,78) [42].…”

Comparison of the risk of gastrointestinal perforation between patients with and without rheumatoid arthritis: A nationwide cohort study in Asia

“…Rheumatoid arthritis (RA) is considered a risk factor for GIP because of RA medications, including non-steroidal antiinflammatory drugs (NSAIDs), steroids, and disease-modifying antirheumatic drugs (DMARDs) (4)(5)(6). The inflammation or other processes in RA may be also a risk factor for GIP (4,7). Many studies have reported the comparison of the risk of GIP using medications, including biologic agents, DMARDs, steroids, and NSAIDs (4,5,7).…”

“…Rheumatoid arthritis (RA) is considered a risk factor for GIP because of RA medications, including non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and disease-modifying antirheumatic drugs (DMARDs) ( 4 – 6 ). The inflammation or other processes in RA may be also a risk factor for GIP ( 4 , 7 ).…”