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Chinese Herb Tripterygium Shown Effective Compared to Sulfasalazine in Treatment of Rheumatoid Arthritis
ISSUE:
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24-25

Chinese Herb Tripterygium Shown Effective Compared to Sulfasalazine in Treatment of Rheumatoid Arthritis

Reviewed: Goldbach-Mansky R, Wilson M, Fleischmann R, et al. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis. Ann Intern Med. 2009;151(4):229-240.

Rheumatoid arthritis (RA) is an inflammatory disease of the joint lining, which causes pain and swelling of the diarthrodial joint. Uncontrolled RA results in progressive joint damage and subsequent disability and increased mortality. A better understanding of the immune mechanisms that perpetuate inflammation has led to the development of various therapies to treat this condition. Although these therapies have been shown to be clinically efficacious, many patients do not achieve clinically meaningful responses, or they experience adverse effects and discontinue treatment.

In Traditional Chinese Medicine, extracts of the roots from tripterygium (Tripterygium wilfordii, Celastraceae) have shown therapeutic benefit in the treatment of autoimmune and inflammatory disorders and some forms of cancer. The potent inhibition of pro-inflammatory genes by tripterygium in an earlier small placebo-controlled study1 prompted the present multicenter, double-blind, randomized trial, which compared the efficacy of sulfasalazine (a drug with analgesic and anti-inflammatory properties used to treat RA) with that of a standardized extract of tripterygium in patients with RA.

This trial was conducted between March 2004 and October 2005 at 11 US centers in 121 patients with established (at least 6 months) active RA. Any patient taking a disease-modifying anti-rheumatic drug was required to discontinue use for 28 days before beginning the study, though nonsteroidal anti-inflammatory drugs (or oral prednisone taken by 17 patients in each treatment group) were allowed to continue at stable doses.

Eligible patients were randomly assigned to receive either 60 mg of tripterygium extract 3 times daily for a total daily dose of 180 mg (Phytomedics; Jamesburg, NJ) (n = 60; age: 54 ± 11 years) or 1 g sulfasalazine twice daily for a total daily dose of 2 g (n = 61; age: 52 ± 12 years) for 24 weeks. Tripterygium roots were purchased in Fujian and Hunan provinces, China, and the tripterygium root extract was analyzed for diterpenoids content and biological activity.

Blood samples were collected at baseline and at frequent intervals throughout the 24 weeks for the measurement of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP, a marker of inflammation), interleukin-6 (IL-6), cholesterol panel, cortisol, adrenocorticotropic hormone, and rheumatoid factor concentrations. Radiographs of the hands and feet were obtained at baseline and at 24 weeks, and body weight and blood pressure were also measured.

The primary outcome measure was a 20% or greater improvement (ACR 20 response) in tender and swollen joints and in 3 or more of the following: physician’s or patient’s assessment of global health status, patient’s assessment of pain on a visual analogue scale, patient’s assessment of function, and CRP concentration. Secondary outcome measures included the efficacy of tripterygium in achieving 50% (ACR 50 response) and 70% (ACR 70 response) improvements in the above-mentioned outcomes at 24 weeks, improvement in the European League Against Rheumatism Disease Activity Score 28 (DAS 28), and radiographic scores of the hands and feet. The subjects were instructed to record any adverse events experienced, which were graded by severity.

There was a high drop-out rate in this trial; only 62 subjects (37 tripterygium, 25 sulfasalazine) completed the 24-week study. Significantly more of the sulfasalazine subjects withdrew due to lack of efficacy or adverse effects (P < 0.001). Approximately 68% of the tripterygium group and 36% of the sulfasalazine group who completed the study achieved an ACR 20 response (P = 0.02). Similarly, approximately 54% of the tripterygium group and 4% of the sulfasalazine group achieved an ACR 50 response, and approximately 38% of the tripterygium group and 4% of the sulfasalazine group achieved an ACR 70 response at 24 weeks (P < 0.001 and P = 0.002, respectively). The mean improvement in the DAS 28 score was 2.4 points in the tripterygium group and 1.5 points in the sulfasalazine group (P < 0.001). Significantly greater improvements in disability, pain, patient’s and physician’s global assessments of health, ESR, and CRP concentrations were observed in the tripterygium group than in the sulfasalazine group, beginning at 2 weeks. A significantly greater improvement in the number of swollen and tender joints was observed in the tripterygium group than in the sulfasalazine group, beginning at 8 weeks.

Radiographic scores indicated no progression in mean joint space narrowing or erosion in the tripterygium group. Compared with the sulfasalazine group, significantly greater decreases in IL-6 were observed at 24 weeks (P = 0.037) and in rheumatoid factor at 4 weeks in the tripterygium group (P < 0.001). Blood pressure, body weight, and cortisol and adrenocorticotropic hormone concentrations did not change significantly with treatment. Of note, total cholesterol concentrations increased significantly in the tripterygium group (P < 0.001); high-density-lipoprotein cholesterol increased by 53% and low-density-lipoprotein concentrations by 48%, but the ratio remained unchanged. The frequency of adverse events reported related to the treatments was not significantly different between groups (57% in the tripterygium group and 61% in the sulfasalazine group). Gastrointestinal events were the most frequent adverse event (AE) in both groups. While these events resolved in most cases, 6 patients discontinued the study. Other AEs in the tripterygium group that led to study discontinuation were thrombocytopenia (1) and 1 serious event: a femoral fracture. Four patients discontinued the study in the sulfasalazine group due to serious AEs: cholecystitis with cholecystectomy, an incarcerated inguinal hernia, and gastroparesis and partial small-bowel obstruction (1), atrial fibrillation and pancreatitis (1), viral infection (1), and exacerbation of asthma and hypertension (1). Other AEs included nausea, allergic drug reaction, headache, rash, and fatigue.

The authors conclude that “treatment with a standardized extract from the peeled roots of the Chinese herbal remedy [tripterygium] administered over 24 weeks may be both effective and safe in treating patients with active rheumatoid arthritis. The rapid improvement in function and pain and the profound effect on inflammation may make this extract an attractive and affordable alternative to currently available agents.” Further studies need to evaluate the impact on cholesterol levels, long-term effects and potential toxicities, and combination with other anti-rheumatic therapies.

Editor’s note: Regarding the relative safety of tripterygium, previous experience suggests a likelihood of potentially serious toxicity associated for this herb in some subjects. This includes renal failure and bone marrow suppression. Such effects apparently did not occur in this study. Several publications have referred to this safety issue, including a systematic review of clinical trials on tripterygium for RA,2 and a trial where licorice (Glycyrrhiza uralensis, Fabaceae) was included to attenuate the adverse effects of tripterygium.3

—Brenda Milot, ELS
References
  1. Tao X, Younger J, Fan FZ, Wang B, Lipsky PE. Benefit of an extract of Tripterygium wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. Arthritis Rheum. 2002;46:1735-1743.

  2. Canter PH, Lee HS, Ernst E. A systematic review of randomised clinical trials of Tripterygium wilfordii for rheumatoid arthritis. Phytomedicine. 2006;13(5):371-377.

  3. Li YS, Tong PJ, Ma HZ. Toxicity attenuation and efficacy potentiation effect of liqourice on treatment of rheumatoid arthritis with Tripterygium wilfordii. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006;26(12):1117-1119. [Article in Chinese]