Give RA Patients the 'Hook' - TwHF
Give RA Patients the 'Hook' - TwHF
Abstract & Commentary
By Russell H. Greenfield, MD, Editor
Synopsis: A standardized extract of Tripterygium wilfordii Hook F root was compared with sulfasalazine therapy in subjects with active rheumatoid arthritis. After a 24-week intervention, those taking the botanical remedy experienced significantly greater progress both clinically and in laboratory assessments when compared with the sulfasalazine group, with improvements occurring rapidly. The findings are hampered somewhat by a significant dropout rate in both study groups.
Source: Goldbach-Mansky R, et al. Comparison of Trip- terygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis. Ann Intern Med 2009;151: 229-240.
The authors devised this 24-week multicenter, double-blind, placebo-controlled, randomized active comparison trial to compare the effects of Tripterygium wilfordii Hook F (hereafter TwHF) extract with those of sulfasalazine for the treatment of active rheumatoid arthritis (RA). Adults (n = 121) with active RA for longer than 6 months and who had 6 or more painful and swollen joints were enrolled from two U.S. academic medical centers and 9 rheumatology subspecialty clinics. The subjects were evaluated clinically and by laboratory measures at baseline, 2 weeks, and every 4 weeks for a total of 24 weeks. Radiographs of hands and feet were obtained at baseline and 24 weeks, or at study discontinuation. Serum or plasma specimens were obtained at baseline, 4 weeks, and 24 weeks. Laboratory tests included hs-CRP, ESR, L-6 levels (measured at baseline, 4 weeks, and 24 weeks), RF, and cortisol and adrenocorticotrophic hormone levels, as well as lipids. Subjects were randomized to receive either TwHF extract 60 mg tid (180 mg/d, or 6 capsules) or sulfasalazine 1 g bid (2 g/d). They were permitted to continue stable doses (no change in previous 28 days) of oral prednisone up to 7.5 mg/d or NSAIDs, but had to stop disease-modifying anti-rheumatic drugs (DMARDs) at least 28 days before randomization.
Primary outcome of interest was the rate of achievement of 20% improvement in the American College of Rheumatology criteria (ACR 20) at 24 weeks. To achieve this level of response a subject had to have 20% or greater improvement in both tender and swollen joints and 20% or greater improvement in 3 or more of the following: physician's or subject's assessment of global health status, subject's assessment of pain on a VAS, subject's assessment of function (using a modified version of the Health Assessment Questionnaire [HAQ]), or serum CRP level. Secondary endpoints included safety; radiographic scores of joint damage; serum levels of interleukin-6, cholesterol, cortisol, and adrenocorticotrophic hormone; the efficacy of TwHF in achieving ACR 50 and ACR 70 responses at 24 weeks; the improvement in the European League Against Rheumatism Disease Activity Score 28 (DAS 28) measure; and a change in the Sharp-van der Heijde score of hand and foot radiographs.
Outcome data were available for only 62 subjects at 24 weeks (significantly more subjects in the sulfasalazine group discontinued treatment, reportedly due to either lack of efficacy or because of side effects). Individual objective and subjective measures of disease activity improved rapidly from baseline following TwHF administration, with differences compared to the sulfasalazine group apparent as early as 2 weeks post-initiation of therapy and persisting throughout the study for HAQ disability assessment, pain, the subject's and physician's global assessment of health, ESR, and hs-CRP level. Improvements in number of symptomatic joints were statistically significantly greater in the TwHF group starting from 8 weeks of therapy.
Using a mixed-model, intention-to-treat analysis to impute data for patients who dropped out, 65.0% of the TwHF group and 32.8% of the sulfasalazine group achieved ACR 20 criteria in 24 weeks. Using the same mixed-model analysis, subjects in the TwHF group also had significantly higher rates for achieving ACR 50 and ACR 70 (only 4% of those in the sulfasalazine group achieved ACR 50 or ACR 70 responses). Analyses of only those who completed the full trial revealed similar significant differences between the two groups (67.6% of those who received TwHF vs. 36.0% who received sulfasalazine achieved ACR 20 responses). Significant improvements were seen in all individual components of the ACR response, including the HAQ. Plasma IL-6 levels rapidly decreased within 6 weeks in the TwHF group, and no radiographic progression of joint space narrowing or erosion scores were identified in the TwHF group, albeit non-statistically, compared with noticeable progression in the sulfasalazine-treated subjects.
More than double the number of people who discontinued participation in the trial due to side effects were taking sulfasalazine as compared with TwHF (17 vs. 8); however, mild prolongation of the QTc interval on EKG was seen in those receiving TwHF without an increase in arrhythmias or an increase in QTc above normal range. In addition, cholesterol levels (both HDL-C and LDL-C) rose significantly in those on TwHF therapy, but the LDL/HDL ratio did not change.
The researchers summarized by stating that in patients who continued treatment for 24 weeks and who were also permitted to use stable doses of oral prednisone and NSAID drugs, attainment of the ACR 20 response criteria was significantly greater with TwHF extract than with sulfasalazine. They concluded that patients with active RA can be effectively treated with a standardized extract of TwHF root.
Commentary
Practitioners of traditional Chinese medicine have long used extracts of TwHF root ("thunder god vine") for a variety of maladies, and recent in vitro and in vivo studies suggest the extract offers impressive anti-inflammatory effects. Understanding of the inflammatory nature of the joint changes seen in active RA that create significant discomfort and functional disability led to the development of a number of promising therapies; however, as the authors of this trial are quick to point out, many patients discontinue these treatments due to side effects, perceived inadequacy of treatment, or dismay over the need for parenteral administration of the agents. The search for well-tolerated, effective interventions for the treatment of RA has thus gained even greater urgency.
The findings of the current study that employed an orally administered standardized extract of TwHF are thus compelling and timely; however, they are by no means definitive, as significant methodological concerns exist. The most glaring issue is the number of dropouts with such a relatively small sample size - only 62% of those receiving TwHF and 41% of those taking sulfasalazine completed the 24-week trial, higher dropout rates than are typically seen in RA intervention trials. Adherence to the study protocol was assessed by pill count and examination of the subjects' daily diaries, an accepted but flawed method. Questions about funding sources could also be appropriate, as Phytomedics formulated the study medication (under the auspices of National Institute of Arthritis and Musculoskeletal and Skin Disease investigators) and provided some funding toward completion of the study.
The study flaws slightly diminish initial enthusiasm for the findings, but they are not so great that the results should be dismissed entirely. Indeed, there appears to be great promise. The researchers were forthright in their assessment of weaknesses of their study, but also of the strengths. Consider that subjects receiving TwHF extract experienced rapid and significant clinical and laboratory improvements compared with those taking the widely accepted RA treatment sulfasalazine. Yes, further study is required to examine the long-term effects of TwHF in patients with RA, and to determine whether the extract can be used in conjunction with DMARDs, but there's reason for optimism when a low-cost botanical agent shows efficacy against a disease that severely impacts quality of life for those who have it and their caregivers. You can expect to see a great deal more research into the effects of TwHF. In the meantime, provided there is close observation of the patient, TwHF can be considered a useful adjunct in the treatment of mild-to-moderate RA.
A standardized extract of Tripterygium wilfordii Hook F root was compared with sulfasalazine therapy in subjects with active rheumatoid arthritis. After a 24-week intervention, those taking the botanical remedy experienced significantly greater progress both clinically and in laboratory assessments when compared with the sulfasalazine group, with improvements occurring rapidly. The findings are hampered somewhat by a significant dropout rate in both study groups.Subscribe Now for Access
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