Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial

Abstract

Background: Extracts of the medicinal plant Tripterygium wilfordii Hook F (TwHF) have been used in China for centuries to treat a spectrum of inflammatory diseases.

Objective: To compare the benefits and side effects of TwHF extract with those of sulfasalazine for the treatment of active rheumatoid arthritis.

Design: Randomized, controlled trial. A computer-generated code with random, permuted blocks was used to assign treatment.

Setting: 2 U.S. academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan).

Patients: 121 patients with active rheumatoid arthritis and 6 or more painful and swollen joints.

Intervention: TwHF extract, 60 mg 3 times daily, or sulfasalazine, 1 g twice daily. Patients could continue stable doses of oral prednisone or nonsteroidal anti-inflammatory drugs but had to stop taking disease-modifying antirheumatic drugs at least 28 days before randomization.

Measurements: The primary outcome was the rate of achievement of 20% improvement in the American College of Rheumatology criteria (ACR 20) at 24 weeks. Secondary end points were safety; radiographic scores of joint damage; and serum levels of interleukin-6, cholesterol, cortisol, and adrenocorticotropic hormone.

Results: Outcome data were available for only 62 patients at 24 weeks. In a mixed-model analysis that imputed data for patients who dropped out, 65.0% (95% CI, 51.6% to 76.9%) of the TwHF group and 32.8% (CI, 21.3% to 46.0%) of the sulfasalazine group met the ACR 20 response criteria (P=0.001). Patients receiving TwHF also had significantly higher response rates for ACR 50 and ACR 70 in mixed-model analyses. Analyses of only completers showed similar significant differences between the treatment groups. Significant improvement was demonstrated in all individual components of the ACR response, including the Health Assessment Questionnaire disability score. Interleukin-6 levels rapidly and significantly decreased in the TwHF group. Although not statistically significant, radiographic progression was lower in the TwHF group. The frequency of adverse events was similar in both groups.

Limitations: Only 62% and 41% of patients continued receiving TwHF extract and sulfasalazine, respectively, during the 24 weeks of the study. Long-term outcome data were not collected on participants who discontinued treatment.

Conclusion: In patients who continued treatment for 24 weeks and could also use stable oral prednisone and nonsteroidal anti-inflammatory drugs, attainment of the ACR 20 response criteria was significantly greater with TwHF extract than with sulfasalazine.

Conflict of interest statement

Potential Financial Conflicts of Interest: Consultancies: P.E. Lipsky (Phytomedics). Honoraria: Y. Sherrer (Abbott, Amgen, Bristol-Myers Squibb, Genentech, Wyeth). Grants received: N.J. Olsen (Phytomedics). Patents received: N.J. Olsen (2 patents related to the use of TwHF). Other: Y. Sherrer (Abbott, Amgen, Biogen Idec, Genentech, Genmab, Medarex, Roche).

Figures

Figure 1. Study flow diagram

TwHF = Tripterygium wilfordii Hook F. * 62 patients were not included because disease activity was too low and 6 patients because of health issues. † Significant difference (P = 0.039) between the sulfasalazine group and the TwHF group.

Figure 2. Time trajectory of withdrawals

Values below the trajectory are the numbers of patients in the TwHF and sulfasalazine groups who discontinued treatment because of AEs, LOE, or other reasons. AE = adverse event; LOE = lack of effect; TwHF = Tripterygium wilfordii Hook F.

Figure 3. Clinical outcomes at 2 to 24 weeks

Group comparisons were made at each visit. Data are shown only for patients who had the actual visit. Another analysis included all participants who were present at the respective visit. The number of participants in each group at a given visit is stated at the bottom of Figure 4. This analysis confirms the rapid onset of the clinical and laboratory response. A significant group difference between treatment groups is already seen early in the study, at a time when the withdrawal rate was much lower. ACR = American College of Rheumatology; TwHF = Tripterygium wilfordii Hook F.

Figure 4. Comparisons of clinical responses by American College of Rheumatology criteria

CRP = C-reative protein; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire; TwHF = Tripterygium wilfordii Hook F. Outcomes from all patients who were evaluated on the respective visit are depicted. The actual number of patients evaluated at the respective visit is listed at the bottom. The HAQ score; patient assessment of global disease activity and pain and physician assessment of disease activity, both measured on a visual analogue scale from 0 to 10 mm (with higher numbers indicating greater severity); the number of painful and swollen joints on physical examination out of a total of 68 tender joints and 66 swollen joints (hips excluded); ESR; and CRP were assessed at each study visit. * P < 0.05. † P < 0.01. ‡ P < 0.001.

Appendix Figure 1. ACR responses based on last-observation-carried-forward analysis

Green bars represent the sulfasalazine group, and white bars represent the TwHF group. ACR = American College of Rheumatology; TwHF = Tripterygium wilfordii Hook F. Top. Percentages of patients achieving responses defined by the ACR 20, ACR 50, and ACR 70 criteria at 24 weeks. Bottom. Percentages of patients with moderate or good European League Against Rheumatism responses at 24 weeks. A moderate European League Against Rheumatism response is a decrease (improvement) of >0.6 and ≤1.2, and a good response is a decrease of >1.2.

Appendix Figure 2. Probability plot of change in radiographic score from baseline to end of study

The probability plot shows changes in total radiographic score from baseline to follow-up ranked for magnitude of change and organized by treatment group of all participants with available data. The graph shows that more patients in the sulfasalazine group than in the TwHF group have an increase in radiographic scores and that the magnitude of the increase is also larger in the sulfasalazine group than in the TwHF group. The graph also shows that most patients in both treatment groups have no radiographic progression. All of these patients are graphed at or around zero. TwHF = Tripterygium wilfordii Hook F.