Our results indicate that patients with active rheumatoid arthritis can be effectively treated with a standardized extract of the roots of TwHF, a medicinal plant that has been widely used in Chinese traditional medicine (6
). During the 6-month study, treatment with TwHF extract resulted in rapid improvement in clinical signs and symptoms of rheumatoid arthritis, including joint pain, joint swelling, and measures of overall well-being, and in markers of inflammation, such as CRP, ESR, and the pro-inflammatory cytokine interleukin-6. Compared with sulfasalazine, 2 g/d (an approved standard therapy for rheumatoid arthritis), TwHF led to statistically significantly greater improvement in terms of patients achieving ACR 20, ACR 50, and ACR 70 responses and to moderate to good improvement in DAS 28. The improvement in clinical and laboratory markers translated into clinically and statistically significant improvement in patient function as measured by the HAQ disability score.
Because rates of noncompletion were relatively high, especially in the sulfasalazine group, we performed a sub-analysis on patients who completed the trial to assure that the effects of TwHF were not overestimated. We observed a significantly greater benefit of TwHF compared with sulfasalazine when we analyzed only patients who completed the study. Many other analyses, including a modified worst-case scenario analysis, also confirmed that the unequal withdrawal rate did not bias the study results in favor of TwHF. The sensitivity analyses, including patients who completed the study; as-treated patients; worst-case scenario; and a mixed-models repeated measures approach, which provides a sophisticated method of handling the problem of missing data explicitly, also yielded treatment results strongly in favor of TwHF, with estimated treatment effects often larger than those seen in these other approaches.
The oral administration of TwHF, 3 times per day, required a study design with another daily oral agent, such as sulfasalazine. Like TwHF, sulfasalazine is associated with gastrointestinal side effects at treatment initiation and, therefore, blinding was maintained during our study. Furthermore, because methotrexate is the most commonly used disease-modifying antirheumatic drug in the United States, using this drug as the active comparator would have made it likely that recruited participants in whom this therapy had failed might be randomly assigned to receive the same treatment again in the study. Sulfasalazine has been used as an active drug comparator in other studies (27
) and has been reported to be similar to other oral disease-modifying drugs.
The rapid improvement in HAQ disability measure in our trial may be because TwHF not only has potent anti-inflammatory and immunomodulatory effects but also inhibits the transcription of cyclooxygenase-2 (20
), which may result in the reduced production of prostaglandin E2
at inflammatory sites and therefore have a direct analgesic effect. This analgesic effect may have contributed to the early and significant improvement in pain and HAQ scores that we observed in patients who received TwHF.
Although our sample size was relatively small and the study was not powered to detect group differences in radiographic joint damage scores, the TwHF group trended to slower progression of radiographic joint damage than the sulfasalazine group. Because sulfasalazine has been shown to limit radiographic progression (30
), our result indicates that TwHF limits radiographic progression at least as well. Because our patient population was similar to patients in other recent studies in terms of joint damage and disease activity (31
), our results are encouraging but need to be verified in a larger cohort.
The withdrawal rates in our study were higher than the attrition rates of 19% to 28.5% in other rheumatoid arthritis efficacy trials that compared monotherapies, including sulfasalazine (36
). This difference may reflect a lower current threshold in the United States for rheumatoid arthritis study participants and physicians to exit an investigational study if a rapid clinical benefit is not observed or if adverse events occur. However, similar to our study, a review of placebo-controlled clinical trials in patients with rheumatoid arthritis (27
) reported overall attrition rates of 25% to 50% with sulfasalazine monotherapy. Furthermore, a second meta-analysis of 71 trials and 88 observational studies reported that with long-term use, only 22% of patients with rheumatoid arthritis continued sulfasalazine monotherapy compared with 36% receiving methotrexate (37
). Therefore, the withdrawal rate with sulfasalazine in our study may be as expected.
Gastrointestinal symptoms were the most frequently reported adverse events, occurring early in the course of treatment and leading to similar numbers of drug discontinuation in the TwHF and sulfasalazine groups. The gastrointestinal side effects subsided in more patients who continued receiving TwHF (59%) than in patients who continued receiving sulfasalazine (49%). However, a lower drug dose at initiation of therapy or a gradual dose increase to full levels may improve tolerability, and counseling patients on the improvement of the gastrointestinal symptoms with continuation of therapy may further improve drug adherence. Despite these limitations, the effect of TwHF in terms of HAQ improvement and the persistence of this benefit, even when we analyzed only patients who completed the study (data not shown), stress the magnitude of the benefit of this treatment.
Toxicities reported with the use of various nonstandardized preparations of TwHF are difficult to compare with the adverse events that occurred in our study, because peeling the roots and using a standardized extraction with ethanol followed by ethyl acetate partitioning (10
) seems to result in better tolerability and less toxicity. Adverse hematologic events included reversible neutropenia in 1 patient and thrombocytopenia in 2 patients who received TwHF. Reversible amenorrhea, which has also been reported in other studies (39
), occurred in 3 patients receiving TwHF; this effect may make this drug more attractive in the treatment of postmenopausal women.
Anti-inflammatory therapies with anti–tumor necrosis factor and anti–interleukin-6 activity have been associated with elevated serum levels of total cholesterol (31
). Further studies need to evaluate whether the increase in HDL and LDL cholesterol levels seen with administration of TwHF is mediated through the reduction in interleukin-6 levels or through unknown mechanisms and, more important, whether the effect on prostaglandins, the increase in HDL and LDL cholesterol levels, and the decrease in CRP and interleukin-6 levels will result in an increase or a decrease in atherosclerotic risk. Prolongation of the corrected QT interval on ECG may warrant monitoring when other drugs with similar effects are used in combination (42
Animal data (43
) suggested modification of the pituitary axis when TwHF is administered to rats, and initial in vitro results (13
) suggested that triptolide may exert some of its anti-inflammatory properties by binding to the glucocorticoid receptor. Nonetheless, we observed no weight gain, increase in glucose intolerance, or alterations in adrenocorticotropic hormone and cortisol in our patients, suggesting limited or no effect on the hypothalamic–pituitary–adrenal axis. Triptolide, the major mediator of the anti-inflammatory effect of the extract, has been reported (44
) to bind to the calcium channel, PC-2, mediating calcium release in kidney cells, which arrested the growth of kidney cysts (45
). Additional investigation is needed to determine whether all the clinical effects of this extract in the different tissues can be explained by these mechanisms. However, several diterpenoids have been described to have potent anti-inflammatory and analgesic properties and may serve as useful models of new drug development (13
In summary, our study demonstrates that treatment with a standardized extract from the peeled roots of the Chinese herbal remedy TwHF 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. The long-term effects and toxicities and the potential combination of TwHF with other antirheumatic therapies need to be addressed in further studies.