clinical topic updates

Triple Therapy vs Targeted Combination Therapy in Rheumatoid Arthritis

by Jonathan Kay, MD


Options for patients with rheumatoid arthritis who inadequately respond to initial methotrexate (MTX) therapy include triple therapy (ie, MTX, sulfasalazine, and hydroxychloroquine) and combinations of targeted biologic agents with MTX. Although triple therapy is less expensive than targeted combination therapy, drug cost is but one of several treatment considerations.

Expert Commentary

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

“An advantage of triple therapy is that it is less costly than the addition of a targeted biologic agent to MTX; however, the number of pills that a patient must take on a daily basis for triple therapy presents a substantial inconvenience compared with the combination of weekly MTX and weekly to monthly TNFi dosing.”

Jonathan Kay, MD

For patients with an inadequate response to MTX, both triple therapy with MTX, sulfasalazine, and hydroxychloroquine and the addition of a targeted biologic agent to MTX are effective treatment options. The RACAT study, a 48-week, randomized, double-blind, noninferiority trial, compared triple therapy with treatment with etanercept and MTX in patients who were inadequately responsive to MTX monotherapy. Both treatment groups experienced significant improvement in clinical outcomes. Switching to the alternative treatment regimen was required in 27% of patients in each group at 24 weeks, and both groups achieved improvement in disease activity with the alternative therapy.

An advantage of triple therapy is that it is less costly than the addition of a targeted biologic agent to MTX; however, the number of pills that a patient must take on a daily basis for triple therapy presents a substantial inconvenience compared with the combination of weekly MTX and weekly to monthly tumor necrosis factor inhibitor (TNFi) dosing. This results in a higher rate of treatment discontinuation among those receiving triple therapy compared with those receiving a TNFi and MTX. In a retrospective analysis of patients with rheumatoid arthritis enrolled in the Corrona registry, 97% of patients were treated with the combination of a TNFi and MTX, whereas only 3% were taking triple therapy. Additionally, patients receiving triple therapy were significantly more likely to discontinue treatment compared with those receiving a TNFi and MTX. Thus, although the cost of treatment with triple therapy may be lower than that of the combination of a targeted biologic agent and MTX, the long-term benefits of triple therapy may be less. I believe that the most important consideration when choosing a treatment regimen should be its potential benefit to the patient. 


Curtis JR, Palmer JL, Reed GW, et al. Real-world outcomes associated with triple therapy versus TNFi/MTX therapy. Arthritis Care Res (Hoboken). 2020 May 6. doi:10.1002/acr.24253

Fleischmann R, Tongbram V, van Vollenhoven R, et al. 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. RMD Open. 2017;3(1):e000371. doi:10.1136/rmdopen-2016-000371

O’Dell JR, Mikuls TR, Taylor TH, et al; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med. 2013;369(4):307-318. doi:10.1056/NEJMoa1303006

Peper SM, Lew R, Mikuls T, et al. Rheumatoid arthritis treatment after methotrexate: the durability of triple therapy versus etanercept. Arthritis Care Res (Hoboken). 2017;69(10):1467-1472. doi:10.1002/acr.23255

Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26. doi:10.1002/art.39480

Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79:685-699. doi:10.1136/annrheumdis-2019-216655

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