Inhibitory effect of enzyme therapy and combination therapy with cyclosporin A on collagen-induced arthritis.

OBJECTIVE: There is increasing interest in the use of combination therapy for rheumatoid arthritis and in the possibility of combining the conventional drug approach with newer antirheumatic therapy. The present study investigates the efficacy of long-term prophylactic enzyme therapy and combination therapy with cyclosporin A in rats with collagen-induced arthritis. METHODS: Rats with collagen-induced arthritis were administered the following drugs: cyclosporin A (5 mg/kg/day and 10 mg/kg/day orally); a mixture of enzymes containing pure substances (bromelain, trypsin, rutin) in the same ratio as in Phlogenzym (PHL, 150 mg/kg, twice daily intrarectally); and a combination of 5 mg/kg/day cyclosporin A plus 300 mg/kg/day PHL for a period of 50 days from the immunization. Levels of serum albumin, serum nitrite/nitrate concentrations, changes in hind paw swelling and bone erosions were measured in the rats as variables of inflammation and destructive arthritis-associated changes. RESULTS: Treatment with 10 mg/kg cyclosporin A, as well as combination therapy with half dosages of cyclosporin A (5 mg/kg) plus PHL significantly inhibited both inflammation and destructive arthritis-associated changes. Significant differences in favor of combination therapy with 5 mg/kg CsA + 300 mg/kg PHL as compared to 5 mg/kg CsA alone were seen in hind paw swelling. Also, reduction of the radiographic scores was more significant in the combination therapy group. Five mg cyclosporin A or PHL alone reduced the disease markers studied to a lesser extent, and in the case of enzyme therapy this occurred at a later stage of arthritis development. CONCLUSION: Our results show the inhibitory effect of enzyme therapy on collagen-induced arthritis in rats, as well as the efficacy of cyclosporin A given in low doses in combination with enzyme therapy, which may be useful in the treatment of rheumatoid arthritis.     

Suppression of type II collagen-induced arthritis by monoclonal antibodies.

Some mouse monoclonal antibodies raised against chicken type II collagen suppressed or delayed the onset of chicken type II collagen-induced arthritis in DBA/1 mice. This was correlated with the suppression of anti-mouse type II collagen antibody responses following immunization with chicken type II collagen. The epitopes recognized by the suppressive antibodies were found to be present on cyanogen bromide (CB)-digested collagen peptides CB-11 and CB-12. This was also confirmed by the finding that administration of the CB-11 or CB-12 peptide suppressed the induction of arthritis.     

羟基喜树碱与甲氨蝶呤治疗胶原诱导性关节炎模型大鼠的比较研究

目的 探讨羟基喜树碱(HCPT)在胶原诱导性关节炎(CIA)大鼠的治疗作用及临床治疗类风湿关节炎(RA)的潜在价值.方法 ①建立CIA大鼠模型:随机分为健康对照组、模型组、甲氨蝶呤(MTX)治疗组、低剂量HCPT治疗组、高剂量HCPT治疗组;②观察不同时间点大鼠一般情况、关节肿胀度;③测量造模15周后大鼠关节滑膜病理改变及原位末端标记技术(TUNEL)染色滑膜细胞凋亡率;④测定血清肿瘤坏死因子(TNF)-α和白细胞介素(IL)-1β浓度.结果 HCPT、MTX治疗组与模型组比较,各治疗组均可改善模型鼠一般情况、缓解关节炎指数及足肿胀度、减少炎性细胞浸润、滑膜细胞增生及减轻关节内软骨和骨破坏、提高滑膜细胞凋亡率、降低血清TNF-α、IL-1β浓度,差异有统计学意义(P<0.05),各治疗组间无统计学意义(P>0.05).结论 HCPT在临床治疗RA方面具有潜在价值.     

Step-down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis

OBJECTIVE: To evaluate the feasibility and outcome of the step-down approach using either cyclosporin A (CSA) or methotrexate (MTX) as maintenance therapy following 6 months treatment with these 2 agents in combination in early, nonerosive rheumatoid arthritis (RA). METHODS: Fifty-seven patients younger than 65 years with early, nonerosive RA were first treated with CSA and MTX in combination for 6 months. They were then randomly stepped down to single-agent maintenance treatment for another 18 months. Safety, clinical efficacy, survival on treatment, and radiographic progression were evaluated. RESULTS: When being treated with combination therapy, 7 of the 57 patients (12.3%) withdrew because of adverse events. Of the remaining 50 patients, 42 (84.0%) were American College of Rheumatology (ACR) 20% responders, 30 (60.0%) were ACR 50% responders, and 23 (46.0%) were ACR 70% responders. At month 6, 22 patients were randomized to CSA and 27 to MTX. During this trial period, the treatment was discontinued by 16 patients taking CSA (mainly because of loss of efficacy) and by 4 taking MTX. At month 24, the probability (+/- SEM) of survival on treatment was 0.273 +/- 0.09 for CSA and 0.852 +/- 0.07 for MTX. Of the 6 CSA patients who completed the trial, 4 (66.7%) were ACR 20% responders, and 3 (50%) were both ACR 50% and ACR 70% responders. Of the 23 completers in the MTX arm, 21 (91.3%) were ACR 20% responders, 18 (78.3%) were ACR 50%, and 10 (43.5%) were ACR 70% responders. The treatment was not responsible for severe adverse events. Radiography showed a slow progression in the damage score and number of eroded joints in both treatment groups. CONCLUSION: Stepping down to single agent maintenance therapy following 6 months of combination treatment with CSA and MTX in early RA was only successful with MTX. Because this treatment did not prevent some radiographic progression, other approaches (e.g., step-up approach) may be more appropriate in early RA.     

Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial

OBJECTIVE: To compare the efficacy and toxicity of cyclosporin A (CsA) monotherapy with CsA plus methotrexate (MTX) combination therapy in patients with early rheumatoid arthritis (RA). PATIENTS AND METHODS: 120 patients with active RA, rheumatoid factor positive and/or erosive, were randomly allocated to receive CsA with MTX (n=60) or CsA with placebo (n=60). Treatment with CsA was started in all patients at 2.5 mg/kg/day and increased to a maximum of 5 mg/kg/day in 16 weeks. MTX was started at 7.5 mg/week and increased to a maximal dose of 15 mg/week at week 16. Primary outcomes were clinical remission (Pinals criteria) and radiological damage (Larsen score), at week 48. RESULTS: Treatment was discontinued prematurely in 27 patients in the monotherapy group (21 because of inefficacy, and six because of toxicity) and in 26 patients in the combination therapy group (14 and 12, respectively). At week 48, clinical remission was achieved in four patients in the monotherapy group and in six patients in the combination therapy group (p=0.5). The median Larsen score increased to 10 (25th, 75th centiles: 3.5; 13.3) points in the monotherapy group and to 4 (1.0; 10.5) points in the combination therapy group (p=0.004). 28/60 (47%) of patients in the monotherapy group v 34/60 (57%) of patients in the combination therapy group had reached an American college of Rheumatology 20% (ACR20) response (p=0.36) at week 48; 15/60 (25%) v 29/60 (48%) of patients had reached an ACR50 response (p=0.013); and 7 (12%) v 12 (20%) of patients had reached an ACR70 response (p=0.11).Their was a tendency towards more toxicity in the combination therapy group. CONCLUSIONS: In patients with early RA, neither CsA plus MTX combination therapy nor CsA monotherapy is very effective in inducing clinical remission. Combination therapy is probably better at improving clinical disease activity, and definitely better at slowing radiological progression. Combination therapy should still be compared with methotrexate monotherapy.     

Suppression of collagen-induced arthritis with histone H1

Besides roles in nucleus mediating the condensation of DNA into chromatin, the involvement of histones in autoimmune diseases, hormone regulation, and killing leukemia cells has been reported. In order to investigate the functions of histones on an autoimmune disease, histone H1 was injected into collagen-induced arthritis (CIA) mice. A dramatic suppression of CIA by histone H1 was observed at a dose of 1 mg/kg bodyweight of mouse. In addition, the increased level of anti-inflammatory cytokine IL-10 was detected in cultured splenocytes from the mouse treated with histone H1. These findings suggest that histone H1 suppresses the collagen-induced arthritis, possibly by increasing the level of IL-10 production.     

Combined oral cyclosporin and methotrexate therapy in patients with rheumatoid arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate levels when compared with methotrexate alone

OBJECTIVE: To study the pharmacokinetics of methotrexate (MTX) plus cyclosporin A (CSA) in patients with rheumatoid arthritis (RA). METHODS: On day 1 of the study, patients with RA receiving stable doses of MTX had blood and urine levels of MTX and its metabolite 7-hydroxymethotrexate (7-OH-MTX) measured post oral dosing of the drug. MTX was then discontinued and CSA therapy was started on day 8. On day 20, blood levels of CSA and CSA metabolites were measured post drug dosing. On day 23, MTX therapy was restarted and levels of MTX, CSA and their metabolites were again measured as described above. RESULTS: In the 30 patients, coadministration of CSA and MTX led to a 26% increase in mean peak plasma MTX concentration (P < 0.01), an 18% increase in the mean plasma MTX concentration area under the curve (AUC, P=0.01) and an 80% decrease in plasma 7-OH-MTX AUC (P < 0.01). In 13 patients receiving a 10 mg MTX dose, CSA reduced urinary 7-OH-MTX excretion by 87% (P < 0.01) without altering MTX excretion. MTX did not alter the pharmacokinetics of CSA or its metabolites. CONCLUSION: CSA may block oxidation of MTX to its relatively inactive metabolite, 7-OH-MTX, thereby potentiating MTX efficacy.     

Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone

OBJECTIVE: To determine whether patients with early rheumatoid arthritis (RA) treated with cyclosporin A (CsA) and methotrexate (MTX) in combination for 12 months show a lower rate of radiographic deterioration than those treated with MTX alone. METHODS: In this controlled and randomized single-blind trial, 61 consecutive patients with untreated RA of less than 2 yr duration were treated with either CsA + MTX combination therapy (n = 30) or MTX alone (n = 31). The primary end-point was radiographic progression after 12 months, measured using the damage score (DS) of the Sharp and van der Heijde method. RESULTS: Although there was a significant difference between the mean baseline and 12-month DS in both treatment groups (MTX/CsA, 1.93 +/- 0.90; MTX, 7.47 +/- 2.03), it was significantly less in the combination arm (P = 0.018). Of the 30 evaluable CsA + MTX patients, 16 (53%) were ACR20 responders, 15 (50%) ACR50 and 14 (47%) ACR70; the corresponding figures in the MTX arm were 19 (61%), 13 (44%) and 6 (19%). Toxicity was acceptable in both groups. CONCLUSIONS: In patients with early RA, CsA + MTX combination therapy led to a significantly lower rate of 12-month radiographic progression, was effective on inflammatory articular symptoms, and was well tolerated.     

Step‐down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis

Objective

To evaluate the feasibility and outcome of the step‐down approach using either cyclosporin A (CSA) or methotrexate (MTX) as maintenance therapy following 6 months treatment with these 2 agents in combination in early, nonerosive rheumatoid arthritis (RA).

Methods

Fifty‐seven patients younger than 65 years with early, nonerosive RA were first treated with CSA and MTX in combination for 6 months. They were then randomly stepped down to single‐agent maintenance treatment for another 18 months. Safety, clinical efficacy, survival on treatment, and radiographic progression were evaluated.

Results

When being treated with combination therapy, 7 of the 57 patients (12.3%) withdrew because of adverse events. Of the remaining 50 patients, 42 (84.0%) were American College of Rheumatology (ACR) 20% responders, 30 (60.0%) were ACR 50% responders, and 23 (46.0%) were ACR 70% responders. At month 6, 22 patients were randomized to CSA and 27 to MTX. During this trial period, the treatment was discontinued by 16 patients taking CSA (mainly because of loss of efficacy) and by 4 taking MTX. At month 24, the probability (± SEM) of survival on treatment was 0.273 ± 0.09 for CSA and 0.852 ± 0.07 for MTX. Of the 6 CSA patients who completed the trial, 4 (66.7%) were ACR 20% responders, and 3 (50%) were both ACR 50% and ACR 70% responders. Of the 23 completers in the MTX arm, 21 (91.3%) were ACR 20% responders, 18 (78.3%) were ACR 50%, and 10 (43.5%) were ACR 70% responders. The treatment was not responsible for severe adverse events. Radiography showed a slow progression in the damage score and number of eroded joints in both treatment groups.

Conclusion

Stepping down to single agent maintenance therapy following 6 months of combination treatment with CSA and MTX in early RA was only successful with MTX. Because this treatment did not prevent some radiographic progression, other approaches (e.g., step‐up approach) may be more appropriate in early RA.

     

Suppression of type II collagen-induced arthritis by the endogenous estrogen metabolite 2-methoxyestradiol

Objective. To evaluate the antiarthritic properties of 2-methoxyestradiol, an endogenous metabolite of estradiol, on type II collagen-induced arthritis (CIA) in DBA/1 mice. Methods. The effects of treatment with 2-methoxyestradiol on the development of CIA were evaluated clinically and histologically. The in vitro effects of 2-methoxyestradiol on lymphocyte and endothelial cell proliferation and differentiation were analyzed by standard methods. Results. The development of CIA was significantly suppressed by 2-methoxyestradiol. Incubation with 2-methoxyestradiol suppressed the in vitro proliferation of endothelial cells, indicating that this compound down-regulates angiogenesis. Endothelial cell production of nitric oxide (NO) was also down-regulated by 2-methoxyestradiol. In contrast to estradiol, 2-methoxyestradiol exerted neither detectable feminizing effects on the sex organs nor inhibition of leukocyte development in hematopoietic organs. Conclusion. The development of CIA is suppressed by 2-methoxyestradiol, possibly via inhibition of angiogenesis. Diminished NO production could be of importance in vivo because it is a potent proinflammatory mediator. Since 2-methoxyestradiol exerts only mild side effects compared with estradiol, it is an interesting candidate for therapeutic use in inflammatory diseases.     

Safety and efficacy of leflunomide and infliximab versus methotrexate and infliximab combination therapy in rheumatoid arthritis

SIR, There is little experience about the safety and efficacyof the combination of leflunomide with infliximab (LEF-INF)in rheumatoid arthritis (RA), and published data have shownsome controversy [1–4]. We have read with interest thepaper of Flendrie et al. [5], where they compare previous andconcomitant LEF therapy plus INF with treatment with INF plusother DMARDs [5]. In order to provide further information inthis field we present our results on the safety     

来氟米特与甲氨蝶呤治疗银屑病关节炎关节病变的临床研究

目的 评价来氟米特、甲氨蝶呤及甲氨蝶呤与来氟米特联用治疗银屑病关节炎(PsA)关节病变的疗效与安全性.方法 2个中心的开放性临床对照研究.选确诊的PsA患者,接受甲氨蝶呤(甲氨蝶呤组)、来氟米特(来氟米特组)、甲氨蝶呤+来氟米特(联合治疗组)中的任意一种治疗方案,治疗24周.以PsA疗效标准(PsARC)为主要疗效指标,修改的美国风湿病学会疗效标准提高20%(ACR20)为次要疗效指标,对关节病变进行评估,并分析具体评价指标[包括压痛关节数、肿胀关节数、疼痛视觉模拟评分、患者总体评价(PGA)、医生总体评价、健康评估问卷(HAQ)]的变化.结果 治疗24周时甲氨蝶呤组、来氟米特组、联合治疗组达到PsARC的比例分别为75.0%、68.8%、83.3%,达到ACR20的比例分别为66.7%、50.0%、83.3%.24周后3组患者压痛关节数、肿胀关节数、疼痛视觉模拟评分、PGA、医生总体评价、HAQ均显著低于基线水平(P<0.05).联合治疗组在疼痛视觉模拟评分、HAQ、ESR的改善程度显著高于来氟米特组,甲氨蝶呤组在疼痛视觉模拟评分、PGA、HAQ、ESR的改善程度亦显著高于来氟米特组.甲氨蝶呤、来氟米特、联合治疗组不良反应发生率分别为38.5%、38.9%、35.0%,无严重不良事件发生.结论 甲氨蝶呤与来氟米特联合治疗与单用药物治疗对PsA的关节病变均具有良好的疗效和安全性.