Comparative Effectiveness of Combining MTX with Biologic Drug Therapy Versus Either MTX or Biologics Alone for Early Rheumatoid Arthritis in Adults: a Systematic Review and Network Meta-analysis

  • Katrina E. DonahueEmail author
  • Elizabeth R. Schulman
  • Gerald Gartlehner
  • Beth L. Jonas
  • Emmanuel Coker-Schwimmer
  • Sheila V. Patel
  • Rachel Palmieri Weber
  • Carla M. Bann
  • Meera Viswanathan
Review Paper



Comparative effectiveness of early rheumatoid arthritis (RA) treatments remains uncertain.


Compare benefits and harms of biologic drug therapies for adults with early RA within 1 year of diagnosis.

Data Sources

English language articles from the 2012 review to October 2017 identified through MEDLINE, Cochrane Library and International Pharmaceutical Abstracts, gray literature, expert recommendations, reference lists of published literature, and supplemental evidence data requests.

Study Selection

Two persons independently selected studies based on predefined inclusion criteria.

Data Extraction

One reviewer extracted data; a second reviewer checked accuracy. Two independent reviewers assigned risk of bias ratings.

Data Synthesis

We identified 22 eligible studies with 9934 participants. Combination therapy with tumor necrosis factor (TNF) or non-TNF biologics plus methotrexate (MTX) improved disease control, remission, and functional capacity compared with monotherapy of either MTX or a biologic. Network meta-analyses found higher ACR50 response (50% improvement) for combination therapy of biologic plus MTX than for MTX monotherapy (relative risk range 1.20 [95% confidence interval (CI), 1.04 to 1.38] to 1.57 [95% CI, 1.30 to 1.88]). No significant differences emerged between treatment discontinuation rates because of adverse events or serious adverse events. Subgroup data (disease activity, prior therapy, demographics, serious conditions) were limited.


Trials enrolled almost exclusively selected populations with high disease activity. Network meta-analyses were derived from indirect comparisons relative to MTX due to the dearth of head-to-head studies comparing interventions. No eligible data on biosimilars were found.


Qualitative and network meta-analyses suggest that the combination of MTX with TNF or non-TNF biologics reduces disease activity and improves remission when compared with MTX monotherapy. Overall adverse event and discontinuation rates were similar between treatment groups.



The authors thank Laurie Leadbetter, M.S.L.S., and Christiane Voisin, M.S.L.S., who provided library services; Loraine Monroe for editorial assistance; Charli Randolph, B.A., who assisted with data abstraction, data accuracy checking, and full-text article retrieval; Claire Baker, who assisted with data accuracy checking and full-text article retrieval; Cassandra J. Barnhart, M.P.H., who assisted with full-text article retrieval; Ursula Griebler, Ph.D., M.P.H., who helped assign risk of bias ratings to our included studies; Christina Kien, M.A., who helped assign risk of bias ratings to our included studies; Gernot Wagner, M.D., who provided instruction to Mr. Coker-Schwimmer on using data visualization software to read figure-only study data and reviewed data retrieved this way; and Carol Woodell, B.S.P.H., for project management.

Financial Support

This project was funded under contract HHSA290201500011I_HHSA29032010T from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, Rockville, MD (AHRQ Publication No. 18-EHC015-EF).

The Patient-Centered Outcomes Research Institute (PCORI) funded the report (PCORI Publication No. 2018-SR-02). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ or PCORI. Therefore, no statement in this report should be construed as an official position of PCORI, AHRQ, or of the U.S. Department of Health and Human Services.

Compliance with ethical standards

Conflict of interest

The authors declare that they do not have a conflict of interest.


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Copyright information

© Society of General Internal Medicine 2019

Authors and Affiliations

  • Katrina E. Donahue
    • 1
    • 2
    Email author
  • Elizabeth R. Schulman
    • 3
  • Gerald Gartlehner
    • 5
    • 6
  • Beth L. Jonas
    • 4
  • Emmanuel Coker-Schwimmer
    • 2
  • Sheila V. Patel
    • 5
  • Rachel Palmieri Weber
    • 2
  • Carla M. Bann
    • 5
  • Meera Viswanathan
    • 5
  1. 1.University of North Carolina Department of Family MedicineChapel HillUSA
  2. 2.Cecil G Sheps Center for Health Services ResearchChapel HillUSA
  3. 3.Hospital for Special SurgeryNew YorkUSA
  4. 4.Department of Medicine, Division of Rheumatology, Allergy, and ImmunologyUniversity of North CarolinaChapel HillUSA
  5. 5.RTI InternationalResearch Triangle ParkUSA
  6. 6.Department for Evidence-based Medicine and Clinical EpidemiologyDanube UniversityKremsAustria

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