Efficacy of methotrexate in ankylosing spondylitis: a randomized, double blind, placebo controlled trial. Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: a randomized trial. [A short-term randomized controlled study with methotrexate in rheumatoid arthritis]. Cyclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study. Risk factors associated with the cumulative survival of low-dose methotrexate in 273 Japanese patients with rheumatoid arthritis. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood.
To evaluate the efficacy and safety of methotrexate (MTX) compared with placebo in patients with active ankylosing spondylitis (AS).
                This 24 week, double bind, randomized, placebo controlled trial compared the response between MTX 7.5 mg/week or placebo in patients with active AS. The primary outcome measure was a composite index of improvement in 5 of the following scales: severity of morning stiffness, physical well being, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S), and physician and patient global assessment of disease activity.
                Seventeen patients received MTX and 18 placebo. In the intention-to-treat analysis at 24 weeks, 53% of patients in the MTX group had a treatment response, compared with 17% in the placebo group (p = 0.03). We observed significant improvements with MTX in physical well being (p = 0.009), BASDAI (p = 0.02), BASFI (p = 0.02), physician global assessment (p < 0.001), patient global assessment (p = 0.03), and HAQ-S (p = 0.02). In the adjusted analysis only MTX determined the improvement in the primary outcome. At the end of the trial, one patient with MTX withdrew due to a lack of compliance, and one with placebo due to a lack of efficacy. We did not observe significant differences in rates of side effects between the 2 groups.
                MTX is safe and effective for patients with AS. Longterm studies are needed to evaluate the permanence of its benefit. The superiority of the combination therapy of methotrexate (MTX) and anti-tumor necrosis factor (TNF) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis (RA) has been demonstrated. We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept (ETN) in patients with active RA despite MTX therapy. In total, 151 patients with active RA despite treatment with MTX were randomized to either ETN 25 mg twice a week and MTX 6-8 mg/week (the E + M group) or ETN alone (the E group). Co-primary endpoints included the European League Against Rheumatism (EULAR) good response rate and the American College of Rheumatology (ACR) 50 response rate at week 24. Demographic and clinical features between groups at baseline were similar. The EULAR good response rates were significantly higher in the E + M group (52%) than in the E group (33%) at week 24 (p = 0.0001). Although the ACR50 response rate, one of the co-primary endpoints, and the ACR70 response rate at week 24 were not significantly greater in the E + M group (64 and 38%, respectively) than in the E group (48 and 26%, respectively), the ACR20 response rate was significantly greater in the E + M group (90%) than in the E group (64%; p = 0.0002). Safety profiles were similar for the groups. Thus, MTX should be continued at the commencement of ETN therapy, even in RA patients who show an inappropriate response to MTX. Randomized, controlled and double-blind study of 36 patients aimed at the evaluation of the efficacy and toxicity of MTX in the treatment of rheumatoid arthritis. Twenty-eight patients completed the study period: 14 in the MTX group and 14 in the placebo group. The patients treated with MTX presented a statistically significant improvement (p < 0.05) in pain, grip strength and functional ability when compared to placebo treated patients. Mild adverse effects were observed in 4 patients treated with MTX and in 2 patients treated with placebo. These findings support other studies and give to methotrexate a relevant position in the treatment of rheumatoid arthritis, owing to its convenient posology, beneficial effectivity and favourable toxicity. To determine the effectiveness and tolerance of treatment with cyclosporine A (CyA) or methotrexate (MTX) added to corticosteroids in patients with severe, active polymyositis (PM) and dermatomyositis (DM).
                Thirty-six patients (20 with DM, 16 with PM) were enrolled into the study and randomized in MTX (n = 17) and CyA (n = 19) groups. Muscle endurance and functional test (MEFT), clinical assessment (CA), global patient's assessment (GPA), muscle MRI, serum CK, myoglobin, IL-1Ra, and autoantibody status were used to assess the response to therapy after 1, 3, and 6 months.
                Significant improvement in MEFT, CA, GPA, and muscle MRI was found in both groups. Patients treated with MTX showed insignificantly better response than patients with CyA. CK levels in the MTX group decreased significantly after 1, 3, and 6 months, whereas a significant reduction in the CyA group was first observed after 6 months. IL-1Ra serum levels significantly dropped in the CyA group after two weeks, whereas in the MTX group the significant decrease was first seen after 3 months of treatment. Good correlation was found between each of the clinical parameters (MEFT, CA, and GPA), none of them showed any correlation with CK or IL-1Ra levels.
                Administration of MTX or CyA added to corticosteroids was associated with clinical and laboratory improvement. Changes in CK and IL-1Ra levels were not associated with parameters of clinical disease severity measured in this study. Juvenile idiopathic arthritis (JIA) can persist through adolescence and adulthood, resulting in significant disability. The use of low-dose oral methotrexate (MTX) for persistent polyarthritis has been shown to be effective by the USA/USSR collaborative study group. However, 2 of the most disabling subgroups of JIA, systemic and extended oligoarthritis, were underrepresented in that study. The present study was therefore conducted to investigate the efficacy of MTX in these 2 subgroups.
                Patients under the age of 16 years who fulfilled the International League of Associations for Rheumatology criteria for systemic or extended oligoarticular arthritis were eligible for this multicenter, double-blind, placebo-controlled crossover trial. Forty-five patients with systemic and 43 with extended oligoarticular arthritis were enrolled. The dosage of MTX or placebo was 15 mg/m2, which could be increased to 20 mg/m2 after 2 months. Core outcome variables were considered as primary measures, giving a final score of "improved" or "not improved." Secondary measures included scores of systemic features and biochemical laboratory measures. Assessment of function was not included since there were no validated functional measures at the start of this trial in 1991.
                In the extended oligoarticular arthritis group, MTX treatment produced significant improvement in 3 of 5 core variables (erythrocyte sedimentation rate, physician's global assessment of disease activity, and parent's global assessment of disease activity). By the primary improvement criteria, there was significant overall improvement during MTX treatment. In the systemic arthritis group, only 2 of 5 core variables were significantly improved (physician's and parent's global assessment of disease activity). Systemic features were not part of the core variables, but the systemic feature score was not significantly different between MTX and placebo treatment. There was no significant overall improvement in this group during MTX treatment. However, no significant interaction between disease subgroup and treatment effect was demonstrated. When the data from both disease subgroups were combined, there was significant clinical improvement during MTX treatment (P = 0.006).
                MTX 15-20 mg/m2 given orally once a week was found to be an effective treatment for both extended oligoarticular and systemic JIA in this shortterm trial. Long-term efficacy needs to be addressed in future studies. Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 +/- 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 +/- 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies. Methotrexate (MTX) has become the most commonly prescribed disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). In the Western countries, the MTX dosage is safely increased to a maximum of 25 mg/wk until a significant response is observed. On the contrary, in Japan, MTX has been approved only as a second-line agent, and the approved maximum MTX dosage is only 8 mg/wk. This suboptimal dosage may affect MTX survival in Japanese RA patients.
                To study risk factors associated with the cumulative survival of MTX in Japanese RA patients.
                Data on 273 patients (male 44, female 229) with RA treated with MTX between January 1, 2000 and September 30, 2004 in our center were studied.
                Two hundred seventy-three patients were followed for 437 person-years of MTX exposure. Mean MTX dosage was 5.5 +/- 1.9 mg/wk. The cumulative MTX survival probability after 5 years was 61.9%. Univariate Cox regression analysis showed a significant correlation between MTX survival probability and use of fewer previous DMARDs, higher dose of MTX, inclusion of folate supplementation, and shorter disease duration. In the multivariate Cox regression model, use of fewer previous DMARDs remained significantly related to MTX survival. Reasons for discontinuation included adverse effects in 34 patients (12.5%) and inefficacy in 6 patients (2.2%).
                Cumulative survival was the same or slightly better than those in reports from Western countries, with less withdrawals reported due to adverse events or inefficacy. Whether these results are due to different MTX needs in Japanese or to acceptance of less clinical efficacy will require further studies. The use of fewer previous DMARDs was associated with longer MTX survival. Thirty-two patients with rheumatoid arthritis completed a 24-week, placebo-controlled, double-blind trial of folic acid (FA) supplementation during low-dose methotrexate (MTX) therapy. Administration of the daily FA supplement significantly lowered toxicity scores without affecting efficacy, as measured by joint counts, joint indices, and patient and physician evaluation of disease activity. Fifteen patients experienced some sort of toxicity; 67% were in the placebo group, and 33% were in the FA supplement group. Four patients in the placebo group had toxicity levels serious enough to require discontinuation of the MTX, while no patients in the FA supplement group discontinued MTX because of toxicity. Low-normal initial plasma and red blood cell folate levels were predictive of future toxicity with MTX therapy. We conclude that a daily supplement of 1 mg of FA during low-dose MTX therapy (median dose 7.5 mg/week [16.4 mumoles]) is usefull in lessening toxicity without altering efficacy during the first 6 months of treatment. Serial liver-enzyme determinations were performed on 36 children with acute lymphoblastic leukemia who were randomized to receive either conventional intrathecal methotrexate (MTX) therapy with cranial irradiation, or an investigational high-dose MTX regimen consisting of 10 courses of 33,600 mg/m2 over 24 hours, with high-dose leucovorin rescue. Both groups of patients received intermittent low-dose oral MTX during maintenance therapy. Serum transaminase elevations in the group of conventionally treated patients were infrequent and moderate in severity (less than 300 IU/liter). In the investigational group, however, the majority of patients had severe, acute increases in SGPT (greater than 300 IU/liter), with peaks up to 1000 to 2000 IU/liter. The incidence and severity of acute transaminasemia were directly proportional to the number of high-dose MTX courses received: courses 1, 2, 3, 4, 5, and 6 caused transaminase elevations in 31%, 50%, 50%, 73%, 100%, and 100% of courses, respectively, and 0%, 14%, 20%, 44%, 55%, and 92%, respectively, were over 300 IU/liter. Patients in both treatment groups developed a pattern of increasing serum alkaline phosphatase concentrations after initiation of low-dose oral MTX therapy; isoenzyme analysis indicated that this effect was osseous rather than hepatic. Serum bilirubin was rarely elevated. Transaminases returned to normal within 1 to 2 weeks after each high-dose MTX treatment, and with follow-up for as long as 7 years, no patient has developed clinical evidence of residual liver disease, after 3 years of high-dose MTX therapy and multiple other antileukemia drugs. The acute hypertransaminasemia frequently observed after high-dose MTX therapy is transient and reversible, and, in children, does not appear to result in chronic liver disease.
There is not enough evidence to support any benefit of MTX in the treatment of AS. High-quality RCTs of larger sample sizes are needed to clarify the effect(s) of MTX on AS.