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Rheumatoid arthritis
Review
Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor–methotrexate combination therapy versus triple therapy in rheumatoid arthritis
  1. Roy Fleischmann1,
  2. Vanita Tongbram2,
  3. Ronald van Vollenhoven3,
  4. Derek H Tang4,5,
  5. James Chung4,
  6. David Collier4,
  7. Shilpa Urs2,6,
  8. Kerigo Ndirangu2,
  9. George Wells7 and
  10. Janet Pope8
  1. 1Department of Internal Medicine, University of Texas Southwestern Medical Center and Metroplex Clinical Research Center, Dallas, Texas, USA
  2. 2Oxford Outcomes, ICON plc, Morristown, New Jersey, USA
  3. 3Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  4. 4Amgen Inc., Thousand Oaks, California, USA
  5. 5Novartis Pharmaceuticals, East Hanover, New Jersey, USA
  6. 6Doctors’ Hospital of Michigan, Pontiac, Michigan, USA
  7. 7Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
  8. 8Department of Rheumatology, St. Joseph's Health Care, London, Ontario, Canada
  1. Correspondence to Dr Roy Fleischmann; RFleischmann{at}arthdocs.com

Abstract

Objective Clinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi–methotrexate versus triple therapy in patients with RA.

Methods A systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi–methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi–methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models.

Results We analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi–methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi−methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate.

Conclusions In this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi–methotrexate, no clear differences were observed. The odds of infection were greater with TNFi–methotrexate. No differences were observed for patients naive to methotrexate. These results may help inform care of patients who fail methotrexate first-line therapy.

  • Rheumatoid Arthritis
  • DMARDs (synthetic)
  • DMARDs (biologic)
  • Methotrexate
  • TNF-alpha

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/rmdopen-2016-000371

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    Footnotes

    • Contributors All authors meet the criteria for authorship, participated in the writing and/or critical revision of the manuscript, and have seen and approved the submitted version. JC, DC, RF, KN, JP, DHT, VT, RvV and GW contributed to the conception, design or planning of the study. KN, VT, SU and RvV were involved in data acquisition. JC, DC, RF, KN, JP, VT, SU and RvV analysed the data. JC, DC, RF and JP drafted the manuscript. All authors interpreted the results and critically revised the manuscript.

    • Funding Amgen Inc.

    • Competing interests RF has received grants and non-financial support from Amgen. VT, SU and KN are employees of ICON plc, which received grants and consulting fees from Amgen. RvV has received grants from Abbvie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche and Union Chimique Belge, and personal fees from Abbvie, Amgen, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Roche, Union Chimique Belge and Vertex. DHT, JC and DC are employees and stockholders of Amgen. JP received grants from Amgen and received consulting fees from Abbvie, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche and Union Chimique Belge. GW had nothing to disclose.

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

    • Data sharing statement No additional data are available.