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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


Donahue KE1,2, Schulman ER3, Gartlehner G4,5, Jonas BL6, Coker-Schwimmer E7, Patel SV4, Weber RP7, Bann CM4, Viswanathan M4. J Gen Intern Med. 2019 Aug 6. doi: 10.1007/s11606-019-05230-0. [Epub ahead of print]

Author Information

1 University of North Carolina Department of Family Medicine, Chapel Hill, NC, USA. kdonahue@med.unc.edu.

2 Cecil G Sheps Center for Health Services Research, Chapel Hill, NC, USA. kdonahue@med.unc.edu.

3 Hospital for Special Surgery, New York, NY, USA.

4 RTI International, Research Triangle Park, NC, USA.

5 Department for Evidence-based Medicine and Clinical Epidemiology, Danube University, Krems, Austria.

6 Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina, Chapel Hill, NC, USA. 

7 Cecil G Sheps Center for Health Services Research, Chapel Hill, NC, USA.



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.


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.


Two persons independently selected studies based on predefined inclusion criteria.


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


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.


PROSPERO (available at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017079260 ).