Reviewed: Lv Q-W, Zhang W, Shi Q, et al. Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial [published online April 14, 2014]. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-204807.

Rheumatoid arthritis (RA) is a painful and debilitating chronic autoimmune/inflammatory disease, which typically is treated with disease-modifying antirheumatic drugs (DMARDs). The root extract of the traditional Chinese medicine tripterygium (Tripterygium wilfordii, Celastraceae; sometimes referred to as thunder god vine) that is used to treat RA has anti-inflammatory and immunosuppressive activities, and has shown efficacy in three small RA clinical trials. Methotrexate is one of the most commonly used DMARD treatments in Western countries. The authors of this study have been using tripterygium plus methotrexate at the Peking Union Medical College Hospital in Beijing, China, to treat approximately 20,000 patients with RA per year. The purpose of this randomized, controlled, multicenter trial was to compare the efficacy of tripterygium (T), methotrexate (M), and the combination of tripterygium and methotrexate (C) in the treatment of RA.

Patients (n=207, aged 18-65 years) diagnosed with RA according to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria participated in this study conducted at nine general hospitals in China. Included patients had at least three swollen joints, five tender joints, RA for six weeks or longer, erythrocyte sedimentation rates (ESR) greater than 28 mm/hour, and C-reactive protein (CRP) concentrations greater than 20 mg/L. Patients were excluded from the study if they had an infection, cancer, received DMARDs within three months of study commencement, or were pregnant or lactating. All patients were informed of the risk of infertility associated with tripterygium, and patients who wanted to have children were excluded. Patients were permitted to take non-steroidal anti-inflammatory drugs (NSAIDs) and stable dosages of oral corticosteroids (no more than 10 mg prednisone or equivalent/day) during the study.

Patients were randomly assigned into one of three groups for 24 weeks of oral medication as follows: (T) 20 mg tripterygium (Zhejiang DND Pharmaceutical Company; Shanghai, China) extract three times per day; (M) 7.5 mg methotrexate one time per week (which was increased once per week to 12.5 mg over four weeks) with 10 mg folic acid supplementation the day after each administration; or (C) tripterygium plus methotrexate. At week 12, patients with a reduction in the 28-joint Disease Activity Score (DAS28) of 30% or more were maintained on their current therapy; T and M patients with less than a 30% reduction in scores were changed to the combination therapy. Patients in the C group who had a DAS28 reduction of less than 30% left the trial and were considered treatment failures.

The primary endpoint was the proportion of patients at week 24 who met the ACR efficacy criteria (ACR50), which include at least 50% improvement in DAS28 and at least 50% improvement in three or more of the following: the evaluator’s or patient’s assessment of global health status, the patient’s assessment of pain on a visual analog scale, the patient’s assessment of function using the Health Assessment Questionnaire (HAQ), and ESR or serum CRP levels. Outcome measures were assessed by a blinded investigator; patients and physicians were not blinded. There were no significant differences among the three groups at baseline.

Altogether, 269 patients were screened, 207 eligible patients were enrolled (intent to treat; ITT), and 174 completed the study per protocol (PP). At week 24, the ITT analysis indicated that ACR50 efficacy criteria were met by 46.4% of the methotrexate group, 55.1% of the tripterygium group, and 76.8% of the combination group. There were significantly more patients reaching 50% improvement in the C group compared with the M group (P<0.001) and the T group compared with the M group (P=0.014). Significantly more patients reached remission (DAS28 scores less than 2.6; P=0.002), had at least a 50% improvement in clinical Disease Activity Index (P=0.003), had a good or moderate EULAR response (P<0.001), and had low disease activity (P<0.001) in both the C/M group and T/M group comparisons. There was no significant difference between the T and M groups in DAS28 improvement from baseline to week 24; however, the C group showed significant improvement compared with the M group (P=0.032). Patients receiving tripterygium also had a much more rapid reduction in ESR compared with the M group.

Similar results were observed in the PP analysis of the 49 patients each in the tripterygium and methotrexate groups (86%) and the 56 patients in the combination group (81%) that completed the trial. Ten patients each in the tripterygium and methotrexate groups were switched to the combination therapy at 12 weeks. Four patients each in the T and M groups and three in the C group withdrew due to lack of efficacy. Ten patients were withdrawn from the study due to protocol violations: one in the M group, three in the T group, and five in the C group. Seven patients discontinued the study due to severe adverse effects (AEs): one in the T group, two in the M group, and three in the C group. A total of 52.7% patients reported AEs; the frequency of AEs was not significantly different among groups. Fifteen (8.8%) of the female patients had irregular menstruation, which is a known AE of tripterygium; however, there were no significant differences among groups.

The authors conclude that tripterygium extract was not inferior to methotrexate, and the tripterygium-methotrexate combination therapy was better than methotrexate alone for treating patients with RA who were naïve to DMARDs. The combination therapy was safe and effective. The acknowledged limitations of this study were that only evaluators assessing the clinical outcomes were blinded, disease progression was not documented radiologically, and while the dose of methotrexate evaluated (12.5 mg/week) is standard in Asia, higher doses commonly are used in Western countries. The authors point out that higher doses are unlikely to produce better results since the response to the combination therapy was higher than those reported with methotrexate monotherapy.

—Heather S. Oliff, PhD