Comparison of the impact of Tripterygium wilfordii Hook F and Methotrexate treatment on radiological progression in active rheumatoid arthritis: 2-year follow up of a randomized, non-blinded, controlled study.

BACKGROUND: Tripterygium wilfordii Hook F (TwHF) alone or in combination with methotrexate (MTX) has been shown to be more effective than MTX monotherapy in controlling the manifestations in subjects with disease-modifying antirheumatic drug (DMARD)-naïve active rheumatoid arthritis (RA) over a 6-month period. The long-term impact of these therapies on disease activity and radiographic progression in RA has not been examined. METHODS: Patients with DMARD-naïve RA enrolled in the "Comparison of Tripterygium wilfordii Hook F with methotrexate in the Treatment of Active Rheumatoid Arthritis" (TRIFRA) study were randomly allocated into three arms with TwHF or MTX or the two in combination. Clinical indexes and radiographic data at baseline and year 2 was collected and compared using an intent-to-treat (ITT) and a per-protocol (PP) analysis. Two radiologists blinded to the treatment scored the images independently. RESULTS: Of 207 subjects 109 completed the 2-year follow up. The number of subjects withdrawing from the study and the number adhering to the initial regimens were similar among the three groups (p > = 0.05). In the ITT analysis, proportions of patients reaching American College of Rheumatology 50% (ACR50) response criteria were 46.4%, 58.0% and 50.7% in the MTX, TwHF and MTX + TwHF groups (TwHF vs MTX monotherapy, p = 0.004). Similar patterns were found in ACR20, ACR70, Clinical Disease Activity Index good responses, European League Against Rheumatism good response, remission rate and low disease activity rate at year 2. The results of the PP analysis agreed with those in the ITT analysis. The changes in total Sharp scores and joint erosion and joint space narrowing during the 2 years were associated with changes in disease activity measured by the 28-joint count Disease Activity Score and were comparable among the three groups (p > 0.05). Adverse events were similar in the three treatment groups. CONCLUSIONS: During the 2-year therapy period, TwHF monotherapy was not inferior to MTX monotherapy in controlling disease activity and retarding radiological progression in patients with active RA. TRIAL REGISTRATION: This is a follow-up study. Original trial registration: ClinicalTrials.gov , NCT01613079 . Registered on 4 June 2012.

Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial.

OBJECTIVES: To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA). METHODS: Design: a multicentre, open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen. INTERVENTION: 207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5 mg once a week, or TwHF 20 mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was <30% in the monotherapy groups, the patient was switched to MTX+TwHF. The primary efficacy point was the proportion of patients achieving an American College of Rheumatology (ACR) 50 response at week 24. RESULTS: 174/207 (84.1%) patients completed 24 weeks of the trial. In an intention-to-treat analysis, the proportion of patients reaching the ACR50 response criteria was 46.4% (32/69), 55.1% (38/69) and 76.8% (53/69), respectively, in the MTX, TwHF and MTX+TwHF groups (TwHF vs MTX monotherapy, p=0.014; MTX+TwHF vs MTX monotherapy, p<0.001). Similar statistically significant patterns at week 24 were found for ACR20, ACR70, clinical Disease Activity Index good responses, EULAR good response, remission rate and low disease activity rate. Significant improvement in the Health Assessment Questionnaire and 36-item Short-Form Health Survey questionnaire scores from baseline to week 24 was seen in each treatment arm (p<0.05), though no significant difference was found among the treatment arms (p>0.05). The result of per-protocol analysis agreed with that seen in the intention-to-treat analysis. Seven, three and five women in the TwHF, MTX and combination groups, respectively, developed irregular menstruation (TwHF vs MTX monotherapy, p=0.216). CONCLUSIONS: TwHF monotherapy was not inferior to, and MTX+TwHF was better than, MTX monotherapy in controlling disease activity in patients with active RA. TRIAL REGISTRATION NUMBER: NCT01613079.

Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial.

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.

Effective therapy for nephritis in (NZB x NZW)F1 mice with triptolide and tripdiolide, the principal active components of the Chinese herbal remedy Tripterygium wilfordii Hook F.

OBJECTIVE: Triptolide and tripdiolide are thought to be active components of the Chinese antirheumatic herbal remedy Tripterygium wilfordii Hook F, which has been shown to be effective in treating murine lupus nephritis. This study was undertaken to examine the therapeutic effect of triptolide and tripdiolide on established lupus nephritis in (NZB x NZW)F1 mice. METHODS: (NZB x NZW)F1 mice were treated with vehicle, triptolide, or tripdiolide for 15 weeks beginning at the age of 29 weeks (after the development of lupus nephritis). Body weight, proteinuria, and anti-double-stranded DNA (anti-dsDNA) antibodies were monitored, and the kidney and spleen were assessed histologically. Culture supernatants of spleen mononuclear cells were assayed for cytokines. RESULTS: By 28 weeks, most (NZB x NZW)F1 mice had developed lupus nephritis. Vehicle-treated mice exhibited progressive proteinuria, hypoalbuminemia, elevated blood urea nitrogen (BUN) levels, and evidence of severe nephritis. In contrast, proteinuria and BUN levels were significantly reduced in mice treated with either triptolide or tripdiolide as compared with those treated with vehicle. There was no hypoalbuminemia or apparent evidence of lupus nephritis in mice treated with either of the 2 diterpenoids. At 44 weeks of age, the survival rate in mice treated with vehicle (35.7%) was markedly lower than that in mice treated with either triptolide (87.5%) or tripdiolide (88.2%). The mean level of anti-dsDNA antibody in mice treated with tripdiolide was lower than that in the vehicle-treated mice upon completion of the treatment course. Production of tumor necrosis factor, interleukin-6, and monocyte chemoattractant protein 1 by spleen cells was also decreased after diterpenoid therapy. CONCLUSION: Therapy with triptolide or tripdiolide significantly ameliorated lupus nephritis in (NZB x NZW)F1 mice, reduced cytokine and chemokine production, and prolonged survival.

Revisiting the ancient concept of botanical therapeutics.

Mixtures of interacting compounds produced by plants may provide important combination therapies that simultaneously affect multiple pharmacological targets and provide clinical efficacy beyond the reach of single compound-based drugs. Developing innovative scientific methods for discovery, validation, characterization and standardization of these multicomponent botanical therapeutics is essential to their acceptance into mainstream medicine.

Anti-inflammatory and immunosuppressive compounds from Tripterygium wilfordii.

The extract of Tripterygium wilfordii Hook F. (TwHF), which showed anti-inflammatory and immunosuppressive activities in human clinical trials for rheumatoid arthritis, was subjected to the activity-guided fractionation and spectroscopic characterization of bioactives. A tetrahydrofuran lignan, tripterygiol (1), and eight known compounds, all capable of suppressing pro-inflammatory gene expression were identified. Most of the pharmacological activity of the extract can be attributed to triptolide, its most abundant and active component, with some contribution from tripdiolide.

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae).

Plants in the genus Tripterygium, such as Tripterygium wilfordii Hook.f., have a long history of use in traditional Chinese medicine. In recent years there has been considerable interest in the use of Tripterygium extracts and of the main bioactive constituent, the diterpene triepoxide triptolide (1), to treat a variety of autoimmune and inflammation-related conditions. The main mode of action of the Tripterygium extracts and triptolide (1) is the inhibition of expression of proinflammatory genes such as those for interleukin-2 (IL-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2) and interferon-gamma (IFN-gamma). The efficacy and safety of certain types of Tripterygium extracts were confirmed in human clinical trials in the US and abroad. Over 300 compounds have been identified in the genus Tripterygium, and many of these have been evaluated for biological activity. The overall activity of the extract is based on the interaction between its components. Therefore, the safety and efficacy of the extract cannot be fully mimicked by any individual constituent. This review discusses the biochemical composition and biological and pharmacological activities of Tripterygium extracts, and their main bioactive components.

Therapeutic impact of the ethyl acetate extract of Tripterygium wilfordii Hook F on nephritis in NZB/W F1 mice.

This study was designed to examine the potential use of the ethyl acetate (EA) extract of Tripterygium wilfordii Hook F (TwHF), a Chinese herbal medicine, in the treatment of systemic lupus erythematosus. A total of 48 28-week-old female NZB/W F1 mice were randomly divided into three groups and orally administered vehicle or the EA extract of TwHF at 18.25 mg/kg (EAlow) or 36.5 mg/kg (EAhigh) for 14 weeks. Proteinuria and serum anti-double-stranded (ds)DNA antibody titers were assayed before and after treatment. At the end of treatment, all animals were sacrificed and pathological changes in the kidneys were examined by observers blinded to the treatment regimens. Immunohistological studies were carried out on kidneys and spleens. At 28 weeks of age, proteinuria (>30 mg/dl) and anti-dsDNA antibodies were found in all mice in the three groups. Fourteen, sixteen and fifteen mice in the vehicle, EAlow and EAhigh groups, respectively, completed at least four weeks of treatment. At the end of treatment, the mean proteinuria of the EAlow and EAhigh groups was significantly less than that of the vehicle group and no different from proteinuria at the onset of treatment. Histological evidence of glomerulonephritis, glomerular deposition of IgG and complement 3 and cellular infiltration in the interstitium and perivascular regions were significantly less severe in the EA extract treated mice than in vehicle treated mice. Treatment with the EA extract significantly inhibited the progression of kidney disease in NZB/W F1 mice, though had no significant effect on the levels of anti-dsDNA antibody.

Integrating biologic therapy into the comprehensive care of patients with rheumatoid arthritis.

The advent of biologic therapy has not only provided the opportunity for better care of patients with rheumatoid arthritis (RA), but also has permitted a better understanding of the pathogenesis of this autoimmune/inflammatory disease. The capacity of these agents to suppress signs and symptoms as well as radiographic progression of RA strongly indicates that they can alter the course of the disease. Appropriate analysis of the effect of biologics should provide new insight into the role of the specific targeted molecules in rheumatoid inflammation, and provide information about means to optimize therapy with these highly potent therapeutics.

TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-{kappa}B activation.

FRET experiments utilizing confocal microscopy or flow cytometry assessed homo- and heterotrimeric association of human tumor necrosis factor receptor-associated factors (TRAF) in living cells. Following transfection of HeLa cells with plasmids expressing CFP- or YFP-TRAF fusion proteins, constitutive homotypic association of TRAF2, -3, and -5 was observed, as well as heterotypic association of TRAF1-TRAF2 and TRAF3-TRAF5. A novel heterotypic association between TRAF2 and -3 was detected and confirmed by immunoprecipitation in Ramos B cells that constitutively express both TRAF2 and -3. Experiments employing deletion mutants of TRAF2 and TRAF3 revealed that this heterotypic interaction minimally involved the TRAF-C domain of TRAF3 as well as the TRAF-N domain and zinc fingers 4 and 5 of TRAF2. A novel flow cytometric FRET analysis utilizing a two-step approach to achieve linked FRET from CFP to YFP to HcRed established that TRAF2 and -3 constitutively form homo- and heterotrimers. The functional importance of TRAF2-TRAF3 heterotrimerization was demonstrated by the finding that TRAF3 inhibited spontaneous NF-kappaB, but not AP-1, activation induced by TRAF2. Ligation of CD40 on Ramos B cells by recombinant CD154 caused TRAF2 and TRAF3 to dissociate, whereas overexpression of TRAF3 in Ramos B cells inhibited CD154-induced TRAF2-mediated activation of NF-kappaB. Together, these results reveal a novel association between TRAF2 and TRAF3 that is mediated by unique portions of each protein and that specifically regulates activation of NF-kappaB, but not AP-1.

Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study.

OBJECTIVE: To examine the safety and efficacy of an extract of Tripterygium wilfordii Hook F (TWHF) in the treatment of patients with rheumatoid arthritis (RA). METHODS: An ethanol/ethyl acetate extract from the roots of TWHF was prepared and used in a prospective, double-blind, placebo-controlled study in patients with longstanding RA in whom conventional therapy had failed. Patients were randomly assigned to receive either placebo or low-dose (180 mg/day) or high-dose (360 mg/day) extract for 20 weeks, followed by an open-label extension period. Clinical responses were defined as 20% improvement in disease activity according to the American College of Rheumatology criteria. Side effects were actively queried and recorded at each visit. RESULTS: A total of 35 patients were enrolled in the trial; 21 patients completed the 20-week study. One patient from each group withdrew because of side effects. Twelve, 10, and 10 patients in the placebo, low-dose, and high-dose groups, respectively, completed at least 4 weeks of treatment. Of these patients, 8 and 4 in the high-dose and low-dose groups, but none in the placebo group, met criteria for clinical response. Four, 4, and 7 patients in the placebo, low-dose, and high-dose groups, respectively, were enrolled in the open-label extension; of these, 2, 4, and 5 patients, respectively, met criteria for clinical response. The most common side effect was diarrhea, which caused 1 patient in the high-dose group to withdraw from the trial. No patients withdrew because of adverse events during the open-label extension. CONCLUSION: The ethanol/ethyl acetate extract of TWHF shows therapeutic benefit in patients with treatment-refractory RA. At therapeutic dosages, the TWHF extract was well tolerated by most patients in this study.