Chinese Herb Equals Methotrexate in Rheumatoid Arthritis Study

Janis C. Kelly

April 16, 2014

A preparation of "thunder god vine" (Tripterygium wilfordii Hook f [TwHF], also known as lei gong teng) tested in an open-label randomized clinical trial was noninferior to methotrexate (MTX) in treatment of active rheumatoid arthritis (RA), but "homebrew" versions should be discouraged because most parts of the plant are extremely toxic, researchers report in an article published online April 14 in the Annals of the Rheumatic Diseases. The researchers also found that combining TwHF, which is widely used in China for treating joint pain, fever, and local inflammation, with MTX was more effective than treatment with MTX monotherapy.

"TwHF is used in traditional Chinese medicine for the treatment of joint pain and local inflammation. In Peking Union Medical College Hospital, the tertiary referral centre in China, we treat over 30,000 patients with RA each year, and more than half of them are treated with TwHF, in most cases in combination with MTX, because of the low cost of TwHF (about US$10 a month). Importantly, in 'real-world' clinical practice, we have observed the considerable effectiveness of the MTX+TwHF combination, but the efficacy of this combination had not been studied in randomized clinical trials," senior author Xuan Zhang, MD, professor of medicine in the Department of Rheumatology at Peking Union Medical College Hospital, Beijing, China, told Medscape Medical News.

"This prompted us to conduct the comparison of [TwHF] with [MTX] in the treatment of active rheumatoid arthritis study to determine whether TwHF was noninferior to MTX, and also whether the combination might be superior to MTX," Dr. Zhang added.

Study Used TwHF Extract Approved for RA in China

The researchers randomly allocated 207 patients with active RA (1:1:1) to treatment with MTX 12.5 mg once a week, TwHF 20 mg 3 times a day, or the 2 in combination. The researchers recruited patients from rheumatology clinics at 9 general hospitals in China. All met the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for having had RA for at least 6 weeks, had at least 3 swollen joints and 5 tender joints, and had an erythrocyte sedimentation rate higher than 28 mm/hour or a C-reactive protein level higher than 20 μg/L.

The authors note that the 12.5 mg/week MTX dose is standard in Asia but is lower than MTX doses often used in the West.

All patients were treated with TwHF from the same batch, produced by Zhejiang DND pharmaceutical Company, which contained triptolide (C20H24O5), at 1.2 μg/10 mg, and wilforlide (C30H46O3

The primary endpoint was the proportion of patients achieving ACR50 criteria at week 24. This included 50% or more reduction in both tender and swollen joint counts and 50% or more improvement in 3 or more of the following: evaluator's or patient's assessment of global health, patient's visual analogue scale pain assessment, patient's Health Assessment Questionnaire function assessment, and erythrocyte sedimentation rate or serum C-reactive protein level.

Adding TwHF Increased MTX Response

At week 24, the ACR50 response rates were 46.4% with MTX monotherapy, 55.1% with TwHF monotherapy, and 76.8% with MTX+TwHF. Response to TwHF monotherapy was significantly greater than to MTX monotherapy (P = .014), and response to combined MTX+TwHF was significantly greater than to MTX alone (P < .001).

Coauthor Peter E. Lipsky, MD, who previously reported promising results from a randomized, placebo-controlled comparison of TxHF with sulfasalazine, told Medscape Medical News that the new study provides proof of concept for TwHF efficacy in RA. "The key findings were that TwHF monotherapy was not inferior to MTX monotherapy and that TwHF+MTX treatment was superior to MTX monotherapy," Dr. Lipsky said.

Dr. Lipsky, formerly from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Rockville, Maryland, added, "A postdoctoral fellow from China (Xuelian Tao, PhD) joined my lab in Dallas more than 20 years ago, had experience with the product, and wanted to study it. The more we studied it, the more interesting it became, especially with regard to mechanism of action."

The current study is ongoing, and Dr. Lipsky said that radiographic progression will be examined after 2 years.

"7 Steps and Die" Vine: Don't Try This at Home

The toxicity risk associated with the leaves, flowers, and outer layers of the root of Tripterygium wilfordi is illustrated by another Chinese name for it: "Walk 7 Steps and Die." Total adverse events and serious adverse events were not significantly higher in any of the 3 treatment groups in Dr. Zhang's study, using the standardized TwFH preparation, but that might not be true for other extracts.

Thunder god vine extracts have been associated with nephrotoxicity, hepatotoxicity, reversible ovarian failure, fatal cardiogenic shock caused by myocardial damage, fatal renal failure resulting from toxic nephrosis, fatal hypovolemic shock, and hepatotoxicity. The herb is so potentially dangerous that it is not included in the Chinese herbal medicines discussed at most American schools of acupuncture, and in 2011, it was the subject of a consumer warning by British medical authorities.

Medscape Medical News found numerous "thunder god vine" preparations available from traditional Chinese pharmacies in the United States and via the Internet, as well as instances of patients with arthritis asking on Internet bulletin boards for advice on how to prepare and use thunder god vine.

David Pyatt, PharmD, whose group reported TwHF hematotoxicity, worked with dried thunder god vine root obtained in just this way.

"The results from the Zhang study are strong enough to support larger, placebo-controlled, randomized clinical trials of [TwHF] for treatment of RA, but clinicians and patients should wait for the results of such studies before trying to use this Chinese herbal remedy," Dr. Pyatt told Medscape Medical News. "Our lab obtained dried TwHF root from China and made extracts for in vitro toxicity tests. We found that the extracts were toxic to bone-marrow cells in a dose-dependent manner. Patients should definitely not be trying to 'homebrew' TwHF extracts for self-treatment. Patients should not use TwHF without clinical supervision."

He added, "In addition, clinical trial designs should include regular blood monitoring, and any clinician faced with a patient who intends to use imported TwHF formulations should order baseline blood work and repeat it regularly." Dr. Pyatt is assistant clinical professor at the Colorado School of Public Health, Denver, and founder of Summit Toxicology, Denver.

He noted that aplastic anemia caused by TwHF is likely the result of the compound's functional suppression of hematopoiesis by rendering progenitor hematopoietic progenitor cells unable to respond to growth factors.

Dr. Zhang said, "The effects of TwHF on reproductive hormones and the results of safety evaluation of our study suggest the application of TwHF treatment [only] in postmenopausal female patients and in patients who no longer are interested in having children."

Dr. Lipsky added, "Our long-range goal is to have a properly prepared and uniform extract available to patients. However, that is not currently available, and therefore we would recommend caution."

This work was supported by the grants from the National Natural Science Foundation of China, Beijing Municipal Natural Science Foundation, the Research Special Fund for Public Welfare Industry of Health, the Capital Health Research and Development of Special Fund, and the National laboratory Special Fund. The authors and Dr. Pyatt have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online April 14, 2014. Abstract

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