Triple Therapy Retention Slightly Outperforms Double Therapy in RA


The median survival for triple therapy was longer compared with double therapy (15.1 months vs 9.6 months).

Triple Therapy Retention Slightly Outperforms Double Therapy in RA

Mohammad Movahedi, MD, PhD

Credit: University of Toronto

Among a cohort of patients with rheumatoid arthritis (RA), those on triple therapy remained on treatment longer compared with those on double therapy, although the difference was not statistically significant, according to a study published in Joint Bone Spine.1

A “treat-to-target” strategy to achieve disease control often utilizes multiple disease-modifying antirheumatic drugs (DMARDs), including targeted synthetic, conventional synthetic, and biologic DMARDs (tsDMARDs, csDMARDs, and bDMARDs, respectively). Although monotherapy with methotrexate is considered first-line DMARD in RA, a proportion of patients may need a combination of DMARD treatments to achieve remission or low-disease activity. Previous data have shown combinations of csDMARDs are superior to monotherapy, with combination strategies including triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine, and double therapy using concomitant methotrexate and leflunomide.2

“Retention of DMARD therapy in RA is a valuable outcome that encompasses efficacy, durability, and safety of a specific therapy,” wrote a team of investigators including Mohammad Movahedi, MD, PhD, a clinical epidemiologist with the Ontario Best Practices Research Initiative (OBRI). “Comparison of retention rates between therapies provides insight into potentially preferable treatment paradigms.”

Eligible adult patients with clinically diagnosed RA who were treated with triple or double therapy during or after enrollment in OBRI, a multicenter registry in Ontario, Canada, were recruited into the analysis to compare real-world retention rates between these treatment combinations. In addition, investigators focused on which medication within the combination therapy was discontinued as well as the reason for treatment discontinuation. Disease activity was evaluated at baseline, 6 months, and 12 months after initiation of treatment as well as the time of discontinuation. Discontinuation risk factors were also determined.

A total of 692 patients were enrolled in the study, with 434 patients receiving double therapy and 258 receiving triple therapy. Most patients were female (76%) with a mean age of 57.4 years.

During the trial, 67.8% (n = 175) discontinued treatment in the triple therapy cohort compared with 66.1% (n = 287) discontinuations in the double therapy cohort. The proportion of patients discontinuing methotrexate was similar among cohorts (double: n = 67/434; triple: n = 46/258), with the most common reason for discontinuation reported as adverse events.

Overall, approximately 20% of patients were at low disease activity or remission at initiation of therapy in both cohorts according to the Clinical Disease Activity Index (CDAI) measurements. These proportions were comparable between groups.

The median survival for triple therapy was longer (15.1 months; 95% confidence interval [CI]: 11.2 - 21.2) compared with double therapy (9.6 months; 95% CI: 7.03 - 12.2). However, investigators did not deem this statistically significant.

Using the 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity at the 6 and 12 months were lower in patients receiving triple therapy compared with double therapy (mean DAS28 at 6 months 3.4 vs 3.9, P <.0001; 12 months: 3.2 vs 3.5, P = .0005).

Investigators noted the observational nature of the study as a limitation due to the potential for inherent bias, including selection bias and the inability to control for unknown confounding factors. Further, discontinuation reasons and adverse events are also subject to bias from both patients and clinicians. Lastly, it was impossible to determine the preferences of physicians regarding combination strategies and thresholds for discontinuation or escalation.

“To the best of our knowledge, this is the first study to conduct a head-to-head comparison of these 2 combination csDMARD strategies,” investigators concluded. “This study provides practical evidence that can be used in routine patient care. These findings should be further investigated through other registry studies and ideally through well-designed randomized control trials.”


  1. Bhavsar SV, Movahedi M, Cesta A, Pope JE, Bombardier C; other OBRI investigators. Retention of triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine compared to combination methotrexate and leflunomide in rheumatoid arthritis. Joint Bone Spine. Published online April 5, 2024. doi:10.1016/j.jbspin.2024.105732
  2. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Annals of internal medicine. 2006;144(12):865-76
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