title: 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: 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 registerRheumatoidArthritis: Observation ofBiologicTherapy, 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.
authors.affiliation: Department of Epidemiology, German Rheumatism Research Centre, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Strangfeld
authors.affiliation: Department of Epidemiology, German Rheumatism Research Centre, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.affiliation: Centrum Innere Medizin mit Gastroenterologie und Nephrologie CC 13, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Siegmund
authors.affiliation: Scientific Advisory Board, Munich, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Herzer
authors.affiliation: Goslar, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Rockwitz
authors.affiliation: Hildesheim, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Demary
authors.affiliation: Department of Internal Medicine III, Division of Rheumatology, University Medicine Dresden, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Aringer
authors.affiliation: Department of Epidemiology, German Rheumatism Research Centre, Berlin, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Meißner
authors.affiliation: Department of Epidemiology, German Rheumatism Research Centre, Berlin, Germany.|Centrum Innere Medizin mit Gastroenterologie und Nephrologie CC 13, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Zink
authors.affiliation: Department of Epidemiology, German Rheumatism Research Centre, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Listing
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use; D000006:Abdomen, Acute / Q000453:epidemiology; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D001688:Biological Products / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000378:metabolism; D005858:Germany / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D007416:Intestinal Perforation / Q000097:blood / Q000453:epidemiology* / Q000401:mortality; D008875:Middle Aged; D011446:Prospective Studies; D012042:Registries; D018570:Risk Assessment; D000069283:Rituximab / Q000627:therapeutic use; D012810:Sigmoid Diseases / Q000097:blood / Q000453:epidemiology* / Q000401:mortality; D016037:Single-Blind Method; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha; D000069283:Rituximab; D000069594:Abatacept; D002097:C-Reactive Protein; C502936:tocilizumab
keywords: Corticosteroids; DMARDs (biologic); NSAIDs; Outcomes research