A multicenter, double-blind, randomized, controlled phase III clinical trial of chicken type II collagen in rheumatoid arthritis.

INTRODUCTION: Chicken type II collagen (CCII) is a protein extracted from the cartilage of chicken breast and exhibits intriguing possibilities for the treatment of autoimmune diseases by inducing oral tolerance. A 24-week, double-blind, double-dummy, randomized, methotrexate (MTX)-controlled study was conducted to evaluate the efficacy and safety of CCII in the treatment of rheumatoid arthritis (RA). METHODS: Five hundred three RA patients were included in the study. Patients received either 0.1 mg daily of CCII (n = 326) or 10 mg once a week of MTX (n = 177) for 24 weeks. Each patient was evaluated for pain, morning stiffness, tender joint count, swollen joint count, health assessment questionnaire (HAQ), assessments by investigator and patient, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) by using the standard tools at baseline (week 0) and at weeks 12 and 24. Additionally, rheumatoid factor (RF) was evaluated at weeks 0 and 24. Measurement of a battery of biochemical parameters in serum, hematological parameters, and urine analysis was performed to evaluate the safety of CCII. RESULTS: Four hundred fifty-four patients (94.43%) completed the 24-week follow-up. In both groups, there were decreases in pain, morning stiffness, tender joint count, swollen joint count, HAQ, and assessments by investigator and patient, and all differences were statistically significant. In the MTX group, ESR and CRP decreased. RF did not change in either group. At 24 weeks, 41.55% of patients in the CCII group and 57.86% in the MTX group met the American College of Rheumatology 20% improvement criteria (ACR-20) and 16.89% and 30.82%, respectively, met the ACR 50% improvement criteria (ACR-50). Both response rates for ACR-20 and ACR-50 in the CCII group were lower than those of the MTX group, and this difference was statistically significant (P < 0.05). The DAS28 (disease activity score using 28 joint counts) values of the two treatment groups were calculated, and there was a statistically significant difference between the two treatment groups (P < 0.05). Gastrointestinal complaints were common in both groups, but there were fewer and milder side effects in the CCII group than in the MTX group. The incidence of adverse events between the two groups was statistically significant (P < 0.05). CONCLUSIONS: CCII is effective in the treatment of RA and is safe for human consumption. CCII exerts its beneficial effects by controlling inflammatory responses through inducing oral tolerance in RA patients. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-TRC-00000093.

A comparison study of a recombinant tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) and methotrexate in treatment of patients with active rheumatoid arthritis in China.

The objective of this study is to evaluate the efficacy and safety of rhTNFR:Fc: a recombinant tumor necrosis factor receptor:Fc fusion protein compared with methotrexate (MTX) in patients with rheumatoid arthritis in China. We treated 238 patients with active rheumatoid arthritis with either twice weekly subcutaneous injection rhTNFR:Fc (25 mg) or weekly oral MTX (mean 15 mg per week) for 24 weeks (registration number: 2003L01264). Clinical responses were defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology (ACR-N). As compared with MTX-treated patients, more patients who received rhTNFR:Fc had ACR20 improvement in disease activity during the first 2 weeks (P < 0.05). Similarly, more patients treated with rhTNFR:Fc having ACR20, ACR50, ACR70 improvement in disease activity during 8 weeks (P < 0.05). At the end of 12-week treatment, patients received rhTNFR:Fc also had significant improvement at ACR20 (P < 0.05). Compared with oral MTX, patients received rhTNFR:Fc also had significant improvement at ACR70 at the end of 24 weeks treatment (P < 0.05). In conclusion, compared with oral MTX subcutaneous injection, rhTNFR:Fc acted more rapidly to release symptoms and signs of active RA in Chinese patients, and well tolerated in patients with rheumatoid arthritis in China.

A randomized, double-blind, multicenter, controlled clinical trial of chicken type II collagen in patients with rheumatoid arthritis.

OBJECTIVE: To assess the efficacy and safety of chicken type II collagen (CCII) in rheumatoid arthritis (RA) compared with methotrexate (MTX). METHODS: We conducted a prospective, 24-week, followup, multicenter, double-blind, controlled study of CCII (0.1 mg/day) versus MTX (10 mg/week) in patients with active RA. Clinical assessments were performed at screening and at 12, 18, and 24 weeks of treatment. RESULTS: A total of 236 RA patients were included; 211 patients (89.4%) completed the 24-week followup. In both groups there was a decrease in pain, morning stiffness, tender joint count, swollen joint count, Health Assessment Questionnaire score, and investigator and patient assessment of function; all differences were statistically significant. In the MTX group, erythrocyte sedimentation rate and C-reactive protein level decreased. Rheumatoid factor did not change in either group. At 24 weeks, 68.57% of patients in the CCII group and 83.02% in the MTX group met the American College of Rheumatology 20% improvement criteria (ACR20), and 40.95% and 57.54%, respectively, met the ACR50 criteria. The ACR20 and ACR50 response rates in the CCII group were lower than those in the MTX group, and this difference was statistically significant (P < 0.05). Gastrointestinal symptoms were common in both groups. There were fewer and milder side effects in the CCII group than the MTX group. The difference in incidence of adverse events between the 2 groups was statistically significant (P < 0.05). CONCLUSION: CCII is effective in the treatment of RA. CCII is well tolerated, and the incidence of adverse events of CCII is lower than that of MTX.

Vaccination with selected synovial T cells in rheumatoid arthritis.

OBJECTIVE: This pilot clinical study was undertaken to investigate the role of T cell vaccination in the induction of regulatory immune responses in patients with rheumatoid arthritis (RA). METHODS: Autologous synovial T cells were selected for pathologic relevance, rendered inactive by irradiation, and used for vaccination. Fifteen patients received T cell vaccination via 6 subcutaneous inoculations over a period of 12 months. RESULTS: T cell vaccination led to induction of CD4+ Tregs and CD8+ cytotoxic T cells specific for T cell vaccine. There was selective expansion of CD4+,V(beta)2+ Tregs that produced interleukin-10 (IL-10) and expressed a high level of transcription factor Foxp3, which coincided with depletion of overexpressed BV14+ T cells in treated patients. CD4+ IL-10-secreting Tregs induced by T cell vaccination were found to react specifically with peptides derived from IL-2 receptor alpha-chain. The expression level of Foxp3 in CD4+ T cells and increased inhibitory activity of CD4+,CD25+ Tregs were significantly elevated following T cell vaccination. The observed regulatory immune responses collectively correlated with clinical improvement in treated patients. In an intent-to-treat analysis, a substantial response, defined as meeting the American College of Rheumatology 50% improvement criteria, was shown in 10 of the 15 patients (66.7%) and was accompanied by a marked improvement in RA-related laboratory parameters. CONCLUSION: These findings suggest that T cell vaccination induces regulatory immune responses that are associated with improved clinical and laboratory variables in RA patients.

Role of osteopontin in amplification and perpetuation of rheumatoid synovitis.

Osteopontin (OPN) is an extracellular matrix protein of pleiotropic properties and has been recently recognized as a potential inflammatory cytokine. In this study, we demonstrate, for the first time to our knowledge, that overexpression of OPN in synovial T cells is associated with local inflammatory milieu and that OPN acts as an important mediator in amplification and perpetuation of rheumatoid synovitis. The study revealed that mRNA expression of OPN was highly elevated in CD4(+) synovial T cells derived from patients with RA, which correlated with increased OPN concentrations in synovial fluid (SF). The pattern of OPN overexpression was confined to rheumatoid synovium and correlated with coexpression of selected OPN receptors in synovial T cells, including integrins alphav and beta1 and CD44. RA-derived SF stimulated the expression of OPN in T cells, which was attributable to IL-10 present in SF and abrogated by anti-IL-10 antibody. Among the more than 300 autoimmune and inflammatory response genes examined, OPN selectively induced the expression of proinflammatory cytokines and chemokines known to promote migration and recruitment of inflammatory cells. Furthermore, it was evident that OPN activated transcription factor NF-kappaB in mononuclear cells. The study has important implications for understanding the role of OPN in rheumatoid synovitis and other inflammatory conditions.

Overexpression of osteopontin in rheumatoid synovial mononuclear cells is associated with joint inflammation, not with genetic polymorphism.

OBJECTIVE: Osteopontin (OPN) is thought to play an important role in rheumatoid synovitis. We investigated the expression of OPN in rheumatoid synovial fluid mononuclear cells (SFMC) and its potential association with genetic polymorphism of the OPN gene and joint inflammation in rheumatoid arthritis (RA). METHODS: 1. The expression of OPN mRNA in peripheral blood mononuclear cells (PBMC) and SFMC of patients with RA was analyzed quantitatively by real-time polymerase chain reaction (PCR). Results were analyzed in paired PBMC and SFMC and control PBMC. 2. Six single nuclear acid polymorphisms of the OPN gene were genotyped in a cohort of 192 Chinese patients with RA and controls (n = 288) by restriction fragment length polymorphism PCR or direct DNA sequencing. 3. SF derived from RA patients was examined for the stimulating effect on mRNA expression of the OPN gene in PBMC. RESULTS: The expression of OPN gene was significantly increased in SFMC and, to a lesser degree, in PBMC of patients with RA compared to control PBMC (p < 0.01). However, the prevalence of OPN genotype and allele frequencies at the selected positions did not differ significantly between RA patients and the control group (p > 0.05). Further characterization indicated that SF known to contain a variety of proinflammatory factors significantly stimulated mRNA expression of OPN in PBMC obtained from RA patients or healthy controls. CONCLUSION: Overexpression of OPN mRNA in SFMC is associated with proinflammatory factors produced in inflamed joints, but not with OPN genetic polymorphisms. OPN gene polymorphisms do not correlate with susceptibility to RA.

Leflunomide, a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase II clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of leflunomide in comparison with methotrexate (MTX) on patients with rheumatoid arthritis (RA) in China. METHODS: Five hundred and sixty-six patients with active rheumatoid arthritis were randomly assigned to receive leflunomide at 20 mg once daily or MTX at 15 mg once weekly in a controlled trial. Five hundred and four patients completed the 12-week treatment and some patients continued the treatment for 24 weeks. RESULTS: Both leflunomide and MTX could improve the symptoms, signs, and joint function, but there were no changes in X-ray observations of patients with rheumatoid arthritis. In the leflunomide group, the overall rates of effectiveness at 12 weeks and 24 weeks were 86.94% and 92.31% respectively; the rates of remarkable improvement were 64.95% and 79.81% respectively. In the MTX group, the overall rates of effectiveness at 12 weeks and 24 weeks were 84.04% and 83.15% respectively; the rates of remarkable improvement were 56.81% and 75.28% respectively. According to intent-to-treat analysis, the ACR 20% response rates at 12 weeks and 24 weeks in the leflunomide group were 62.54% and 67.18% respectively, compared with 60.08% and 61.32% respectively in MTX group. No statistical differences were shown in the efficacy between the two groups (P > 0.05). The adverse events in the leflunomide group were gastrointestinal symptoms, skin rash, alopecia, nervous system symptoms, decreased leukocyte count, and elevation of alanine aminotransferase (ALT). Most of these side effects were mild and transient. The incidence of adverse events in the leflunomide group was 16.84%, significantly lower than that in MTX group (28.17%, P = 0.002). CONCLUSIONS: Leflunomide is effective in the treatment of RA with less adverse events than MTX. Its efficacy is similar to MTX, but the incidence of adverse events and the rate of withdrawal due to adverse events were lower in the leflunomide group than in MTX group.

[Retrospective study of adverse events in patients with rheumatoid arthritis treated with second-line drugs].

OBJECTIVE: To evaluate rates on the adverse side effect and discontinuation of second-line drugs frequently used in the treatment of rheumatoid arthritis (RA). METHOD: Eight hundred and sixty-four RA patients were studied in a retrospective program. RESULTS: Upper abdominal discomfort was most commonly seen when using second-line drugs. Rash was often associated with D-penicillamine (20.6%) and Sinomenium therapy (13.7%). Methotrexate (MTX) was uniquely characterized by substantial upper GI toxicity (32.2%) and Tripterygium wilfordii Hook. f. (TWH) (14.4%) by menstrual abnormality. Sulfasalazine users reported adverse events including upper abdominal trouble (39.0%), nausea (7.3%) and anorexia (7.3%) while the risk of GI malaise was greater. Patients taking hydroxychloroquine complained of blurred vision (19.6%) but no one went blind. Toxic side effects seemed to be the most common reasons for stoppages, and the patients taking MTX had the lowest discontinuation rate. Combination of D-penicillamine and Methotrexate did not increase the incidence of adverse events. CONCLUSIONS: Knowledge on these different patterns of toxicity provided choices in the selection of second line agents for particular RA patients. However, long-term monitor are required when drugs are being used.