Biologic disease-modifying antirheumatic drugs (DMARDs) alone or with methotrexate (MTX) and tofacitinib plus MTX improved disease activity and remission rates in patients with rheumatoid arthritis (RA) who have not responded to previous biologic therapy. The study results were published in the Cochrane Database of Systematic Reviews.1
In patients with RA who have been unsuccessfully treated with a biologic, the 2015 American College of Rheumatology (ACR) Guidelines for RA treatment recommend using a second biologic or tofacitinib, and either agent may be used with or without MTX.2 However, the optimal choice of subsequent treatment in this population is unclear. No head-to-head comparisons or meta-analyses of the available biologic agents have been performed in this population.1
Jasvinder Singh, MD, MPH, from the University of Alabama at Birmingham, and colleagues conducted a systematic review to investigate the risks and benefits of biologics and tofacitinib as monotherapy or in combination with MTX compared with placebo or other DMARDs in patients with RA who have not responded to previous biologic treatment.
A total of 12 randomized controlled trials (RCTs; n=3364) were included for analysis, and agents evaluated in these trials included abatacept, etanercept, certolizumab pegol, infliximab, golimumab, tocilizumab, rituximab, and tofacitinib.1
High-Yield Data Summary
- In patients with RA who underwent prior unsuccessful treatment with biologics, the use of subsequent biologic monotherapy, a biologic in combination with MTX, or tofacitinib in combination with MTX led to more clinical improvement compared with placebo or an active comparator. However, the conclusions for tofacitinib were based on one trial only, limiting confidence in this finding.
Biologic monotherapy was more effective than placebo in achieving ACR50 (≥50% improvement in the ACR response criteria; risk ratio [RR], 4.10; number needed to treat for additional benefit outcome [NNTB], 8) and remission (RR, 13.51; NNTB, 11). However, the benefit of biologic monotherapy on remission was based on only 1 RCT.1
Combination biologic plus MTX also demonstrated greater benefit than MTX or other DMARDs in improving clinical outcomes as measured by ACR50 (RR, 4.07; NNTB, 7) and Health Assessment Questionnaire (HAQ) scores (improvement in mean difference [MD], 0.29; NNTB, 5). Patients receiving a biologic plus methotrexate were more likely to attain remission than patients receiving a comparator (RR, 20.73; NNTB, 17).
Only 1 study compared tofacitinib plus MTX with another DMARD (MTX). Compared with MTX alone, tofacitinib plus MTX reduced disease activity (ACR50; RR, 3.24; NNTB, 6) and improved function (HAQ; improvement in MD, 0.27; NNTB, 5). Although not statistically significant, the likelihood of remission was higher in patients treated with tofacitinib than in patients treated with MTX alone (RR, 15.44).
No RCTs that compared tofacitinib monotherapy with placebo or evaluated the outcome of radiographic progression were available.
“Events were too few for harms — such as serious adverse events, cancer, or withdrawals due to adverse events — to draw any firm conclusions, indicating the need for more data. Most evidence for benefits was moderate-high quality, and was of low quality for harms,” Dr Singh told Rheumatology Advisor.
Summary and Clinical Applicability
In patients with RA who have not responded to at least 1 biologic agent, the ACR recommends subsequent treatment with another biologic or with tofacitinib. Until recently, no direct comparisons or meta-analyses of subsequent treatment with these agents have been conducted in this population. Dr Singh and colleagues performed a systematic review of the RCTs comparing biologics and tofacitinib with placebo or another DMARD.
“We found that in RA patients with prior unsuccessful treatment with biologics, use of biologic monotherapy, biologic in combination with MTX, or tofacitinib in combination with MTX led to more clinical improvement compared to placebo or an active comparator (MTX/other traditional DMARDs), in [the] presence of inconclusive evidence of more harm,” Dr Singh said.
“This makes a second biologic a reasonable option in RA patients who have had prior unsuccessful treatment with a biologic; data for tofacitinib was based on one trial only, limiting our confidence in this finding,” he added.
- The overall quality of evidence for adverse events and harms was low
- The analysis of the risks and benefits of tofacitinib plus MTX vs MTX alone was based on only 1 RCT
Dr Singh reports financial relationships with Takeda, Savient, Regeneron, Merz, Iroko, Bioiberica, Crealta, Allergan Pharmaceuticals, WebMD, UBM LLC, Horizon Pharmaceuticals, and the American College of Rheumatology.
- Singh JA, Hossain A, Tanjong Ghogomu E, et al. Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2017;3:CD012591. doi:10.1002/14651858.CD012591.
- Singh JA, Saag KG, Bridges SL Jr, et al; American College of Rheumatology. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25. doi:10.1002/acr.22783