Raphaela Goldbach-Mansky, MD, MHS; Mildred Wilson, RN; Roy Fleischmann, MD; Nancy Olsen, MD; Joel Silverfield, MD; Phillip Kempf, MD; Alan Kivitz, MD; Yvonne Sherrer, MD; Frank Pucino, PharmD; Gyorgy Csako, MD; Rene Costello, BS; Tuyet Hang Pham, MT; Christopher Snyder, BS; Désirée van der Heijde, MD; Xuelian Tao, MD; Robert Wesley, PhD; Peter E. Lipsky, MD
Extracts of the medicinal plant Tripterygium wilfordii Hook F (TwHF) have been used in China for centuries to treat a spectrum of inflammatory diseases.
To compare the benefits and side effects of TwHF extract with those of sulfasalazine for the treatment of active rheumatoid arthritis.
Randomized, controlled trial. A computer-generated code with random, permuted blocks was used to assign treatment.
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).
121 patients with active rheumatoid arthritis and 6 or more painful and swollen joints.
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.
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.
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 (PÂ = 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.
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.
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.
National Institute of Arthritis and Musculoskeletal and Skin Diseases.
In Chinese medicine, extracts of Tripterygium wilfordii Hook F (TwHF, known as “lei gong teng” or “thunder god vine”) are used to treat autoimmune and inflammatory conditions. Small clinical trials suggest that TwHF may benefit patients with rheumatoid arthritis.
This trial compared TwHF extract with sulfasalazine in 121 patients with active rheumatoid arthritis who could continue oral prednisone and nonsteroidal anti-inflammatory drugs but not disease-modifying antirheumatic drugs. Among patients who continued treatment for 24 weeks, achievement of 20% improvement in American College of Rheumatology criteria was greater with TwHF than with sulfasalazine. Adverse event rates were similar.
Only 62% and 41% of patients continued TwHF and sulfasalazine treatment, respectively, and provided 24 weeks of data.
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.
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.
Appendix Table 1.
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.
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.
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 Table 2.
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.
Appendix Table 3.
Appendix Table 4.
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Nelson M Leite
August 22, 2009
Is there a statistic bias?
I read with interest the article and it points to efficacy of an old Chinese drug, but the results will need new clinical experiences in volunteers: first with a necessary placebo group and second inside any treatment group only one drug will be used.
Other aspect to correct in the study design is the concomitant use of other anti-inflammatory drug only as rescue drug. I'm concerned that the high number of patient discontinuation of treatment in both groups in this published article could be a negative influence in the results.
Finally I want say that it appears that a new window was opened using ancient Chinese herbal medicine, but it will be necessary other studies to confirm the efficacy.
Pablo Villasenor Ovies
Instituto Nacional de Nutricion de Mexico
November 11, 2009
Missing data management.
Patients involved in this clinical trial had rheumatoid arthritis lasting longer than 6 months. It is not stated, however, the actual disease duration of patients in both groups. Although a fair argument is offered for the use of Sulfasalazine as a comparator in this trial; it is noticeable that only 13% and 16% of patients were receiving methotrexate by the time they were screened; it is even more noticeable that only about a quarter of patients were taking any DMARD at this time point (this is assuming that no patient was taking two or more DMARDs). What about the rest of this group of patients with active, established, rheumatoid arthritis? Were they without any disease modifying treatment? Since such a high desertion rate could have been, at least partially anticipated for sulfasalazine I wonder if the authors contemplated the possibility of a different trial design. It seems that modeling missing data is not the best a priori established strategy to manage attrition; personally I think this would have only been acceptable should this had been a post hoc analysis. But it was not. Right?
Goldbach-Mansky R, Wilson M, Fleischmann R, Olsen N, Silverfield J, Kempf P, et al. Comparison of Tripterygium wilfordii Hook F Versus Sulfasalazine in the Treatment of Rheumatoid Arthritis: A Randomized Trial. Ann Intern Med. 2009;151:229-240. doi: 10.7326/0003-4819-151-4-200908180-00005
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Published: Ann Intern Med. 2009;151(4):229-240.
Prevention/Screening, Rheumatoid Arthritis, Rheumatology.
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