Comparison of Tripterygium wilfordii Hook F Versus Sulfasalazine in the Treatment of Rheumatoid Arthritis

A Randomized Trial

  1. Raphaela Goldbach-Mansky, MD, MHS;
  2. Mildred Wilson, RN;
  3. Roy Fleischmann, MD;
  4. Nancy Olsen, MD;
  5. Joel Silverfield, MD;
  6. Phillip Kempf, MD;
  7. Alan Kivitz, MD;
  8. Yvonne Sherrer, MD;
  9. Frank Pucino, PharmD;
  10. Gyorgy Csako, MD;
  11. Rene Costello, BS;
  12. Tuyet Hang Pham, MT;
  13. Christopher Snyder, BS;
  14. Désirée van der Heijde, MD;
  15. Xuelian Tao, MD;
  16. Robert Wesley, PhD; and
  17. Peter E. Lipsky, MD
  1. From the National Institute of Arthritis and Musculoskeletal and Skin Diseases and Clinical Center, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland; Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, Texas; Tampa Medical Group, Tampa, and Arthritis Center, Fort Lauderdale, Florida; Arthritis Clinic of Northern Virginia, Arlington, Virginia, Altoona Center for Clinical Research, Duncanville, Pennsylvania; and Leiden University Medical Center, Leiden, the Netherlands.

    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.

    Primary Funding Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases.

    Article and Author Information

    • Acknowledgment: The authors thank Dr. Richard Trout for help with the statistical analysis; Albert Nitche of Phytomedics, for his help with the logistical assistance with this study; Dr. Douglas Rosing for his help with the ECG analysis; Dr. Sack, Dr. Alan K. Matsumoto, Dr. Justus Fiechtner, and Dr. Lourie for contributing patients; and Elizabeth Joyal and Cedric McClinton for their help with the organization of patient material.

    • Grant Support: By the Intramural Research Program of the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and Phytomedics.

    • 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).

    • Reproducible Research Statement: Study protocol: Available from Dr. Goldbach-Mansky (e-mail, goldbacr{at}mail.nih.gov). Statistical code: Available from Dr. Wesley (e-mail, bwesley{at}cc.nih.gov). Data set: Available to qualified investigators by contacting Dr. Goldbach-Mansky (e-mail, goldbacr{at}mail.nih.gov).

    • Requests for Single Reprints: Raphaela Goldbach-Mansky, MD, MHS, National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Building 10, Room 6D-47B, 10 Center Drive, Bethesda, MD 20892-0001; e-mail, goldbacr{at}mail.nih.gov.

    • Current Author Addresses: Dr. Goldbach-Mansky: National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Building 10, Room 6D-47B, 10 Center Drive, Bethesda, MD 20892.

    • Ms. Wilson: National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Building 10, Room 6N226, 10 Center Drive, Bethesda, MD 20892.

    • Dr. Fleischmann: Metroplex Clinical Research Center, 5939 Harry Hines Boulevard, Suite 400, Dallas, TX 75235.

    • Dr. Olsen: UT Southwestern, 5323 Harry Hines Boulevards, Dallas, TX 75390.

    • Dr. Silverfield: Tampa Medical Group, PA, 4700 North Habana Avenue #303, Tampa, FL 33614.

    • Dr. Kempf: Arthritis Clinic of Northern Virginia, 1653 North George Mason Drive #220, Arlington, VA 22205.

    • Dr. Kivitz: 1125 Old Route 220 North, Duncanville, PA 16635.

    • Dr. Sherrer: 5333 North Dixie Highway, Suite 110, Oakland Park, FL 33334.

    • Dr. Pucino: National Institutes of Health Clinical Center, 10 Center Drive, Building 10, Room 1N257, Bethesda, MD 20892.

    • Dr. Csako and Mr. Costello: National Institutes of Health Clinical Center, 10 Center Drive, Building 10, Room 2C407, Bethesda, MD 20892.

    • Ms. Pham: National Institutes of Health Clinical Center, 10 Center Drive, Building 10, Room 6D-52, Bethesda, MD 20892.

    • Mr. Snyder: National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Building 10, CRC/4-1350, Bethesda, MD 20892.

    • Dr. van der Heijde: Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.

    • Dr. Tao: National Institute of Arthritis and Musculoskeletal and Skin Diseases, 8000 Rockville Pike, Bethesda, MD 20878.

    • Dr. Wesley: National Institutes of Health Clinical Center, 10 Center Drive, Building 10, Room 2N228B, Bethesda, MD 20892.

    • Dr. Lipsky: 10301 Grosvenor Place, Rockville, MD 20852.

    • Author Contributions: Conception and design: R. Goldbach-Mansky, F. Pucino, X. Tao, R. Wesley, P.E. Lipsky.

    • Analysis and interpretation of the data: R. Goldbach-Mansky, G. Csako, R. Costello, T.H. Pham, D. van der Heijde, P.E. Lipsky.

    • Drafting of the article: R. Goldbach-Mansky, P.E. Lipsky.

    • Critical revision of the article for important intellectual content: R. Goldbach-Mansky, R. Fleischmann, N. Olsen, J. Silverfield, P. Kempf, A. Kivitz, Y. Sherrer, F. Pucino, G. Csako, R. Costello, D. van der Heijde, R. Wesley, P.E. Lipsky.

    • Final approval of the article: R. Goldbach-Mansky, R. Fleischmann, N. Olsen, J. Silverfield, P. Kempf, A. Kivitz, Y. Sherrer, F. Pucino, G. Csako, D. van der Heijde, R. Wesley, P.E. Lipsky.

    • Provision of study materials or patients: R. Goldbach-Mansky, M. Wilson, R. Fleischmann, N. Olsen, J. Silverfield, P. Kempf, A. Kivitz, Y. Sherrer, D. van der Heijde, X. Tao.

    • Statistical expertise: R. Wesley.

    • Administrative, technical, or logistic support: R. Goldbach-Mansky, M. Wilson, T.H. Pham, C. Snyder.

    • Collection and assembly of data: R. Goldbach-Mansky, M. Wilson, F. Pucino, G. Csako, R. Costello, T.H. Pham, C. Snyder, D. van der Heijde.

    • ClinicalTrials.gov registration number: NCT00062465.

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    Summary for Patients

    • Summaries for Patients:The Chinese Herbal Remedy Tripterygium wilfordii Hook F in the Treatment of Rheumatoid Arthritis Ann Intern Med August 18, 2009 151:I-36; doi:10.1059/0003-4819-151-4-200908180-00002
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