A Chinese herb Tripterygium wilfordii Hook F in the treatment of rheumatoid arthritis: mechanism, efficacy, and safety

Tripterygium wilfordii Hook F (TwHF) is a Chinese herb with immunosuppressive effects and an established history of use in the treatment of rheumatoid arthritis (RA). Numerous preclinical studies have demonstrated that the extracts from the root of TwHF inhibit the expression of proinflammatory cytokines, proinflammatory mediators, adhesion molecules, and matrix metalloproteinases by macrophages, lymphocytes, synovial fibroblasts, and chondrocytes. TwHF also induces apoptosis in lymphocytes and synovial fibroblasts and inhibits their proliferation. Except numerous uncontrolled clinical trials, there are some prospective, double-blind, randomized, and placebo/sulfasalazine-controlled trials, also demonstrating greater improvement in RA disease activity by TwHF extract than placebo/sulfasalazine. Radiographic progression in RA may also be retarded by TwHF. Therefore, the immunosuppressive, cartilage protective, and anti-inflammatory effects of TwHF extracts are well demonstrated, and TwHF extract is an alternative disease modifying anti-rheumatic drug (DMARD) for the patients with RA refractory to conventional therapy.     

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.     

PG27, an extract of Tripterygium wilfordii hook f, induces antigen-specific tolerance in bone marrow transplantation in mice

PG27, an active fraction purified from an extract of a Chinese herb, Tripterygium wilfordii hook f, was used to prevent graft-versus-host disease (GVHD) in a murine model. Lethally irradiated BALB/c (H-2(d)) recipients of B10.D2 (H-2(d)) donor grafts were given daily intraperitoneal injections of PG27 (40 mg/kg per day) for the first 35 days after transplantation. Control mice were given daily injections of solvent vehicle (Ethanol and Cremophor EL). All the control recipients (15/15) died of GVHD within 90 days, but all the recipients given prophylactic treatment with PG27 (15/15) survived beyond 100 days without any signs of GVHD. Furthermore, the GVHD-free recipients were used as donors, and their bone marrow and spleen cells were transplanted into lethally irradiated normal BALB/c (same party) or lethally irradiated normal C3H (H-2(k), third party) mice. Although 10 of 10 same-party recipients survived more than 100 days without any signs of GVHD, 10 of 10 third-party C3H recipients died of GVHD within 40 days. Further studies of PG27 in the murine BCL1 leukemia/lymphoma model demonstrated that animals treated with PG27 partially retained the graft-versus-leukemia (GVL) effect of the graft without GVHD. These results suggest that treatment with PG27 induces host-specific tolerance and retains the GVL effect of allogeneic marrow grafts. (Blood. 2000;95:705-710)     

Inhibition of type II collagen induced arthritis in mice by an immunosuppressive extract of Tripterygium wilfordii Hook f.

The effects of Tripterygium wilfordii Hook f (TWHf), a Chinese herbal remedy, on type II collagen induced arthritis (CIA) in DBA/1LacJ mice were determined. Mice were divided into 4 groups receiving oral treatment for 63 days: Group A, sham feedings; Group B, TWHf (78 mg/day); Group C, TWHf (140 mg/day); Group D, TWHf (140 mg/day) starting 21 days after collagen immunization. Arthritis incidence was reduced and day of onset delayed in Groups B and C compared with A. Arthritic joint counts, arthritic severity scores, and anticollagen antibody titers were decreased in Groups B, C, and D compared with A. Histopathology revealed destructive arthritis only in Group A. Our results indicate that TWHf is a potent immunosuppressive inhibitor of CIA, even when treatment is begun 3 weeks after immunization.     

Termination of disease-modifying antirheumatic drugs in rheumatoid arthritis and in psoriatic arthritis. A comparative study of 270 cases

102 rheumatoid arthritis (RA) and 104 psoriatic arthritis (PsA) patients' records were analysed according to a standardised protocol. Using Cox regression, life-table analysis and log rank test, the effectiveness and toxicity of, and duration of disease modifying antirheumatic drug (DMARD) treatment were compared in RA and PsA. RA patients were treated with gold sodium thiomalate (GST), methotrexate (MTX) and sulphasalazine (SSZ) for a median duration of 35, 72 and 12 months respectively, whereas PsA patients were treated for 12, 12 and 17 months. The differences for GST and MTX were statistically significant (p=0.0043 and 0.0447). Drug toxicity was more frequently seen among patients with PsA (p=0.0023). No difference in efficacy could be proved. Results suggest that there is a significant difference between RA and PsA patients in terms of toxicity of these agents. Therefore, separate treatment strategies are needed, and earlier results with RA may not be directly applicable to PsA.     

Suppression of renal disease and arthritis,and prolongation of survival in MRL-lpr mice treated with an extract of tripterygium wilfordii hook F

Objective. Treatment of MRL-lpr/lpr mice with Tripterygium wilfordii Hook f (TWHf) to evaluate its effects on mortality, renal disease, and arthritis. Methods. Mice were fed water (group A, control), TWHf (group B), or first water and then TWHf (group C) from age 7 weeks until age 21 weeks. Results. Arthritis and glomerulonephritis were decreased in groups B and C mice, and survival was increased in group B mice. Conclusion. TWHf decreases the mortality rate, and severity of glomerulonephritis and arthritis in MRL-Ipr/lpr mice.     

Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness

Tripterygium wilfordii Hook F (TWH) is a vine-like plant that grows in a wide area of south China. An alcohol extract of this plant known as T2 has been suggested to be effective in the treatment of rheumatoid arthritis (RA). To examine the mechanism by which this herbal remedy might be effective in RA, the capacity of T2 to alter human immune responsiveness in vitro was investigated. Human peripheral blood mononuclear cells were obtained from normal adults and separated into purified populations of monocytes, T cells, and B cells. T2 at 0.1-1 micrograms/ml inhibited antigen- and mitogen-stimulated proliferation of T cells and B cells, interleukin-2 (IL-2) production by T cells, and immunoglobulin production by B cells. T2 did not affect IL-2 receptor expression by T cells, IL-1 production by monocytes, or the capacity of monocytes to present antigen. Inhibition could not be accounted for by nonspecific toxicity. These results support the conclusion that T2 exerts a powerful suppressive effect on human immune responses. This action might account for its therapeutic effectiveness in RA.     

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.

     

A randomized double blind,placebo controlled trial of topical Tripterygium wilfordii in rheumatoid arthritis: reanalysis using logistic regression analysis

OBJECTIVE: To assess the efficacy of topical Tripterygium wilfordii (TW), a Chinese herbal therapy, in rheumatoid arthritis (RA). METHODS: A 6 week randomized double blind placebo controlled study of 61 patients with RA meeting American College of Rheumatology (ACR) criteria was conducted in China. The primary outcome was a modified ACR-20 response rate, analyzed by logistic regression analysis. RESULTS: The modified ACR-20 response rate differed significantly (topical TW 58% vs placebo 20%; p = 0.002). There was an 8.1-fold (95% CI 1.9-35.4) increase in the modified ACR-20 response for the TW compared to the placebo group, adjusted for age and erythrocyte sedimentation rate. CONCLUSION: Topical TW appears efficacious for the treatment of RA, but larger studies are needed.     

The Chinese herb Tripterygium wilfordii Hook F for the treatment of systemic sclerosis-associated interstitial lung disease: data from a Chinese EUSTAR Center

Clinical Rheumatology - To assess the efficacy and safety of the Chinese herb Tripterygium wilfordii Hook F (TwHF) for the treatment of systemic sclerosis-associated interstitial lung disease...     

Survival analysis of disease modifying antirheumatic drugs in Spanish rheumatoid arthritis patients.

OBJECTIVES--To evaluate the duration of treatment and the reasons for discontinuing therapy with disease modifying antirheumatic drugs in Spanish rheumatoid arthritis patients. METHODS--An observational study was made of 629 patients with rheumatoid arthritis treated with disease modifying antirheumatic drugs between 1979 and 1991. The outcomes (treatment termination because of toxicity and lack of response) of 991 treatment starts with intramuscular gold salts, D-penicillamine, azathioprine, and methotrexate were subjected to survival analysis. Cumulative probability of continuation of each drug (drug survival) was calculated by the Kaplan-Meier method and comparison between the survival curve of each was made by log rank testing. RESULTS--Median drug survival (95% confidence interval) was 51 (25-76.9) months for methotrexate, 39.9 (19.9-48.2) months for azathioprine, 34.9 (29.4-41.4) months for gold salts, and 16.4 (13.9-21) months for D-penicillamine. The highest cumulative probability of drug survival at five years was for methotrexate (45%); that at 10 years was for gold salts (15%). Up to 60% of the patients discontinued D-penicillamine in the first two years. Lack of response was the major limiting factor for all drugs except D-penicillamine, for which it was toxicity. D-Penicillamine was associated with a greater rate of discontinuations because of toxicity in women and patients older than 65. Previous disease modifying antirheumatic drug administration did not influence current drug survival. CONCLUSION--Overall, gold salts remain useful for the treatment of rheumatoid arthritis over long periods of time in the population studied. Because of the high rate of continuation of treatment (survival) and the optimal efficacy and toxicity profiles observed with methotrexate after five years of treatment, it should be the drug of first choice for second line treatment of these RA patients.     

Suppression of renal disease and arthritis, and prolongation of survival in MRL-lpr mice treated with an extract of Tripterygium wilfordii Hook f.

OBJECTIVE. Treatment of MRL-lpr/lpr mice with Tripterygium wilfordii Hook f (TWHf) to evaluate its effects on mortality, renal disease, and arthritis. METHODS. Mice were fed water (group A, control), TWHf (group B), or first water and then TWHf (group C) from age 7 weeks until age 21 weeks. RESULTS. Arthritis and glomerulonephritis were decreased in groups B and C mice, and survival was increased in group B mice. CONCLUSION. TWHf decreases the mortality rate, and severity of glomerulonephritis and arthritis in MRL-lpr/lpr mice.     

High response rate in the phase I/II study of meloxicam in juvenile rheumatoid arthritis

OBJECTIVE: Use of meloxicam as a selective COX-2 inhibitor for treatment of adult rheumatic diseases decreases the frequency of gastrointestinal (GI) side effects in comparison with nonselective COX inhibitors. Up to 50% of children with juvenile rheumatoid arthritis (JRA) also develop GI side effects through nonselective COX inhibitors. In this 12 week Phase I/II study, with an additional open extension lasting up to 52 weeks, the safety, efficacy, and pharmacokinetics of meloxicam in JRA were investigated. METHODS: Meloxicam suspension 0.25 mg/kg once daily was given to 36 patients with JRA who required a nonsteroidal antiinflammatory drug. Safety evaluation and periodic measurement of efficacy were carried out using the Pediatric Rheumatology International Trials Organisation (PRINTO) criteria. Eighteen patients underwent pharmacokinetic (PK) evaluation. RESULTS: Thirty-one patients completed the study. Four were dropped due to administrative reasons. One patient, who found the drug ineffective, discontinued participation. A response was seen according to PRINTO outcome criteria in 44% of the patients at Week 4, 62% at Week 12, and 74% at Week 52. Drug related adverse events were observed in 5 patients. PK evaluation showed that the maximum plasma concentration Cmax of -34% and AUC(0-infinity) of -28% tended to be lower in younger children (2-6 years) versus older children. Plasma elimination half-life (13 h) was similar in all patients. CONCLUSION: Meloxicam suspension 0.25 mg/kg once daily seems to be effective and safe for treating active JRA over a period of 52 weeks.     

A tissue culture model of cartilage breakdown in rheumatoid arthritis. III. Effects of antirheumatic drugs.

The effects of hydrocortisone, indomethacin, and gold thiomalate on proteoglycan release were assessed in bovine nasal cartilage-rheumatoid synovium cocultures. Of the three agents, only hydrocortisone consistently inhibited both basal and synovium-stimulated cartilage breakdown. Hydrocortisone responsivity was a direct function of the degradative capacity of synovial specimens, and this was equally well demonstrated both in patients receiving long-term therapy and those given perioperative glucocorticoid therapy. The data are consistent with significant hydrocortisone inhibition of lysosomal enzyme-mediated degradation of cartilage.     

Intranasal administration of recombinant human cartilage glycoprotein-39. A phase I escalating cohort study in patients with rheumatoid arthritis

OBJECTIVE: To investigate safety and tolerability and pilot efficacy of repeated single doses of Org39141 in patients with active rheumatoid arthritis (RA). Org 39141 is recombinant human cartilage glycoprotein-39, intended to induce mucosal tolerance upon intranasal administration. METHODS: RA patients with moderate disease activity were treated for 4 weeks and followed for another 8 weeks. The trial had a sequential cohort design: RA patients in the first cohort received 4 intranasal doses (one per week) of either 25 microg Org 39141 or placebo; in subsequent cohorts, treatment with 125microg, 625 microg, or 3125 microg Org39141 was compared to placebo. Safety was evaluated by means of reporting adverse events, standard laboratory testing, and nose examination. The primary efficacy endpoint was RA disease activity as measured by the Disease Activity Score 28 (DAS28). RESULTS: A total of 36 patients were randomized. Org39141 was well tolerated, and no severe or serious adverse events (AE) were reported. In the pooled placebo group, a decrease in DAS28 was observed, but to a lesser extent than in the Org 39141 treatment groups. After 4 weeks of treatment, the mean decrease in DAS in the 625 microg Org 39141 treatment group (-24%) was statistically (p = 0.02) and clinically (EULAR criteria) significantly larger than in the pooled placebo group (-3%). Once-weekly intranasal treatment with Org39141 was well tolerated, and no serious or severe AE were reported. A trend towards efficacy was observed. Our results are encouraging for further clinical development of Org39141.