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Extended report
Comparative effectiveness of tumour necrosis factor α inhibitors in combination with either methotrexate or leflunomide
  1. A Strangfeld1,
  2. F Hierse1,
  3. J Kekow2,
  4. U von Hinueber3,
  5. H-P Tony4,
  6. R Dockhorn5,
  7. J Listing1,
  8. A Zink1,6
  1. 1
    German Rheumatism Research Centre, Epidemiology Unit, Berlin, Germany
  2. 2
    University of Magdeburg, Magdeburg, Germany
  3. 3
    Hildesheim, Germany
  4. 4
    University of Wuerzburg, Wuerzburg, Germany
  5. 5
    Weener, Germany
  6. 6
    Charité University Medicine, Department of Rheumatology, Berlin, Germany
  1. Correspondence to Dr A Strangfeld, German Rheumatism Research Centre, Epidemiology Unit, Chariteplatz 1, 10117 Berlin, Germany; Strangfeld{at}


Objective: The objective of this study was to compare the effectiveness of a combination of tumour necrosis factor α (TNFα) inhibitors with either methotrexate or leflunomide in the treatment of patients with rheumatoid arthritis in a real-world setting.

Methods: Data from 1769 outpatients enrolled in the German biologics register RABBIT who were treated with one of the TNFα inhibitors adalimumab, etanercept, or infliximab in combination with either methotrexate (n  =  1375) or leflunomide (n  =  394) were included in the analysis. Clinical status including disease activity as well as treatment data were documented by the treating rheumatologist at baseline and at 3, 6, 12, 18, 24, 30 and 36 months of follow-up.

Results: Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide.

Conclusion: The current clinical practice is to use methotrexate as a first choice for the combination with TNFα antagonists. In a number of patients methotrexate has to be replaced by another disease-modifying antirheumatic drug. Our data support the view that leflunomide is a useful alternative if methotrexate is contraindicated.

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  • Funding RABBIT has been supported by an unconditional, joint grant from Essex Pharma (since 2001), Wyeth Pharma (since 2001), Amgen (since 1/2003), Abbott (since 9/2003), Roche Pharma (since 1/2007) and Bristol-Myers Squibb (since 7/2007).

  • Competing interests None.

  • Ethics approval Ethics approval was obtained from the Ethics Committee of the Charite Medical School, Berlin.

  • Patient consent Obtained.

  • Role of the sponsors: All six sponsoring companies received the manuscript 30 days before submission for the purposes of information. Under the terms of the RABBIT contract the investigators are free to publish all findings; in case the companies do not agree they can comment on this in a footnote. They do not have any influence on the design and conduct of the study, data collection, development of the analysis plan, or preparation and conducting the analysis. The interpretation of the data, and the drafting, critical revision and approval of the final manuscript was done solely by the authors.