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Extended report
Serious adverse events and the risk of stroke in patients with rheumatoid arthritis: results from the German RABBIT cohort
  1. Y Meissner1,
  2. A Richter1,
  3. B Manger2,
  4. HP Tony3,
  5. E Wilden4,
  6. J Listing1,
  7. A Zink1,5,
  8. A Strangfeld1
  1. 1 Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany
  2. 2 Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
  3. 3 Medizinische Klinik und Poliklinik II, University Medicine Würzburg, Würzburg, Germany
  4. 4 Rheumatologist, Köln, Germany
  5. 5 Charité University Medicine Berlin, Berlin, Germany
  1. Correspondence to Y Meissner, Deutsches Rheuma-Forschungszentrum Berlin, Ein Leibniz Institut, Programmbereich Epidemiologie, Charitéplatz 1, 10117 Berlin, Germany; y.meissner{at}


Objective In the general population, the incidence of stroke is increased following other serious events and hospitalisation. We investigated the impact of serious adverse events on the risk of stroke in patients with rheumatoid arthritis (RA), taking risk factors and treatment into account.

Methods Using data of the German biologics register RABBIT (Rheumatoid Arthritis: Observation of Biologic Therapy) with 12354 patients with RA, incidence rates (IRs) and risk factors for stroke were investigated using multi-state and Cox proportional hazard models. In addition, in a nested case–control study, all patients with stroke were matched 1:2 to patients with identical baseline risk profile and analysed using a shared frailty model.

Results During follow-up, 166 strokes were reported. The overall IR was 3.2/1000 patient-years (PY) (95% CI 2.7 to 3.7). It was higher after a serious adverse event (IR: 9.0 (7.3 to 11.0)), particularly within 30 days after the event (IR: 94.9 (72.6 to 121.9)). The adjusted Cox model showed increased risks of age per 5 years (HR: 1.4 (1.3 to 1.5)), hyperlipoproteinaemia (HR: 1.6 (1.0 to 2.5)) and smoking (HR: 1.9 (1.3 to 2.6)). The risk decreased with better physical function (HR: 0.9 (0.8 to 0.96)). In the case–control study, 163 patients were matched to 326 controls. Major risk factors for stroke were untreated cardiovascular disease (HR: 3.3 (1.5 to 7.2)) and serious infections (HR:4.4 (1.6 to 12.5)) or other serious adverse events (HR: 2.6 (1.4 to 4.8)).

Conclusions Incident adverse events, in particular serious infections, and insufficient treatment of cardiovascular diseases are independent drivers of the risk of stroke. Physicians should be aware that patients who experience a serious event are at increased risk of subsequent stroke.

  • rheumatoid arthritis – stroke – cerebrovascular events - serious adverse events – multi state models

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  • Contributors YM, AR, JL, AZ and AS: had full access to all data of this study and take responsibility for data integrity and accuracy of the analysis. YM, AR, JL, AZ and AS: study concept and design. BM, HPT and EW: acquisition of the data. YM, AR, and AS: analysis and interpretation of the data. YM: drafting the manuscript. YM, AR, BM, HPT, EW, JL, AZ and AS: critical revision of the manuscript for important intellectual content. AZ and AS: obtaining funding. All authors read and approved the manuscript.

  • Funding RABBIT is supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, Celltrion, MSD Sharp & Dohme, Pfizer, Roche, Samsung Bioepis and UCB. The principal investigators and their team had full academic freedom in study design and conduct, data analysis and publication of results. These stipulations were delineated in their contract with the sponsors. For the purpose of information, all eight funding companies received the manuscript 30 days prior to submission. Publication of this article was not contingent on their approval.

  • Competing interests YM: no competing interests. AR: honoraria from Pfizer. BM: honoraria for lectures and consulting fees from Abbvie, BMS, MSD, Pfizer, Roche and UCB outside the submitted work. HPT: personal fees from Abbvie, Astra-Zeneca, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and Sanofi outside the submitted work. EW: personal fees from Pfizer outside the submitted work. JL: personal fees from Sandoz and Pfizer outside the submitted work. AZ: grants and personal fees from AbbVie, BMS, MSD, Pfizer, Roche and UCB outside the submitted work. AS: personal fees from BMS, MSD, Pfizer, Roche and Sanofi-Aventis outside the submitted work.

  • Patient consent Obtained.

  • Ethics approval The study protocol was approved by the ethics committee of the Charité-Universitätsmedizin Berlin.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data sharing of RABBIT data is not approved.