A long-term prospective study of the use of methotrexate in rheumatoid arthritis

Twenty-five patients have completed a mean of 53 months of treatment with methotrexate (MTX) as part of a prospective study of the long-term safety and efficacy of the drug. Since the times of the last report (at a mean of 29 months), the mean dosage of MTX has increased from 12.4 mg/week to 14.6 mg/week, whereas the mean prednisone dosage has decreased from a baseline of 7.1 mg/day to 1.9 mg/day. A significant improvement from baseline in all clinical parameters tested was maintained, and response to therapy did not vary significantly between the assessment at 29 months and that at 53 months. Toxic reactions were as common during months 30–53 as during the first 29 months of the study, with patterns of toxic reactions remaining consistent within each patient. Radiologic evidence of disease progression was not seen before 24 months of MTX treatment, but after this time, it was observed in some patients. We conclude that many clinical features of long-term MTX therapy are distinctly different from what might have been expected after the short-term trials.     

The use of methotrexate in rheumatoid arthritis

OBJECTIVE: To address the long-term efficacy and toxicity issues related to methotrexate (MTX) and compare it with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Review of the international literature on the clinical use of MTX in rheumatoid arthritis (RA) disease. RESULTS: MTX has emerged as a relatively safe and effective treatment for RA that compares favorably with other therapies, particularly because of its considerably longer median drug survival. The toxicity profile of MTX is well established and includes serious and sometimes fatal liver disease, pneumonitis, and cytopenias. Hence, regular and careful monitoring of patients taking MTX is essential, particularly when MTX is combined with other DMARDs. Folate supplementation can reduce some of the most common side effects of MTX, but it has not yet been established whether this translates into a reduced risk of serious disease. Another potential approach to reducing the toxicity of MTX is therapeutic drug monitoring and dose individualization. However, correlations between pharmacokinetics and clinical response have been addressed in only a few studies and with conflicting results. CONCLUSIONS: MTX is an effective DMARD with a relatively safe profile compared with other therapies. Folate supplementation can significantly reduce the risk of MTX toxicity. Finally, it is essential that patients be monitored carefully to reduce the potential serious toxicities of MTX.     

The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis

Twenty-nine patients participated in a prospective study of the safety and efficacy of oral methotrexate in the treatment of refractory rheumatoid arthritis. Patients received a mean dosage of 12.4 mg weekly over a mean duration of 29.1 months. All patients had liver biopsies at baseline, 2 years, and annually thereafter. Patients improved significantly by all clinical measures of efficacy after 1 month; maximum improvement tended to occur after approximately 6 months of therapy. Radiographs showed improvement of erosive disease in 7 of 11 patients measured. There was a significant reduction in mean prednisone dosage. Four patients required an increase in the dosage of methotrexate after prolonged therapy, because of declining clinical response. Toxicity was noted at some time in 26 of 29 patients (90%), but reactions universally became mild and tolerable after adjustment of the dosage. No significant hepatotoxicity was found in 60 sequential liver biopsies, although elevated transaminase levels were noted at some time in 20 of 29 patients (70%).     

Hepatic ultrastructure after methotrexate therapy for rheumatoid arthritis

Twenty-six patients receiving long-term oral methotrexate (MTX) therapy for rheumatoid arthritis (24 patients) or psoriasis (2 patients) were prospectively evaluated for alterations in liver morphology by light microscopy, electron microscopy, and immunofluorescence microscopy. Although only 4 MTX-treated patients had light microscopic evidence of mild fibrosis, all had evidence of collagen deposition in the space of Disse near Ito cells and changes in hepatocyte lysosomes on electron microscopy. These findings were absent from control livers. Fibrinogen, fibronectin, and type IV collagen were identified by immunofluorescence in both MTX-treated patients and controls. We conclude that long-term MTX therapy for rheumatoid arthritis is associated with alterations in hepatic ultrastructure, including collagen deposition in the space of Disse and changes in hepatocyte lysosomes.     

Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate therapy. Double-blind study

To determine if long-term methotrexate-induced improvement of rheumatoid arthritis is sustained after the drug is discontinued, 10 unselected patients with responses to weekly oral methotrexate given for at least 36 months (mean 40.1) were randomly assigned to receive methotrexate or identical-appearing placebo tablets for two months. After one month, all five patients receiving placebo had to have the study terminated due to a flare of their disease manifested by statistically significant deterioration in multiple clinical parameters. It is concluded that patients receiving long-term methotrexate must continue the drug to maintain clinical benefits.     

Development of calciphylaxis after long-term steroid and methotroxate use in a patient with rheumatoid arthritis

Calciphylaxis may be considered a small vessel vasculopathy which is generaly associated with end-stage renal disease and hyperparathyroidism. The precise pathogenesis of the disease is not known. It needs sensitizers and challengers to occur. Steroids and immunosuppressive drugs including methotrexate are among those challenger agents. Calciphylaxis in collagen vascular diseases is rare. Only one case in rheumatoid arthritis was recently reported. Here we describe a case of calciphylaxis associated with active rheumatoid arthritis. This patient had active disease despite treatment of steroids and methotrexate for a long time. She died shortly after the diagnosis of calciphylaxis due to sepsis.     

Hepatic fibrosis with the use of methotrexate for juvenile rheumatoid arthritis

Methotrexate (MTX) is currently under study for use in juvenile rheumatoid arthritis. One complication of MTX is hepatotoxicity. Although liver function tests may be abnormal with its use, in this setting they do not correlate well with the development of hepatic fibrosis. Periodic liver biopsy is required to monitor for the hepatotoxic changes secondary to MTX. We describe and discuss the case of a 17-year-old woman who developed evidence of hepatic fibrosis after 3 years of MTX therapy.     

Response to methotrexate predicts long-term patient-related outcomes in rheumatoid arthritis

This study was conducted to investigate the predictive value of the initial response to methotrexate (MTX) on long-term patient-related outcomes (PROs) in rheumatoid arthritis (RA). All RA patients starting MTX treatment between 1980 and 1987 in our department were enrolled in a prospective observational study. After an average of 18 years, patient-related outcomes were assessed in three dimensions according to the International Classification of Functioning, Disability and Health (ICF). Statistical analyses employed multivariable models with baseline values for age, gender, disease duration, rheumatoid factor positivity, disease activity, response to MTX after 1 year and continuous use of MTX as covariates. The 271 patients enrolled had a mean disease duration of 8.5 years, a mean number of swollen joints of 18 (out of 32), and a mean erythrocyte sedimentation rate of 55 mm/h. After 18 years, PRO was available in 89 patients (33 %). A clinical improvement of at least 20 % 1 year after the initiation of MTX was associated with a favourable outcome in all three dimensions of the ICF, independent of continuation of MTX (p?<?0.05). The initial response to MTX is an independent predictor of PRO in RA as assessed after an average of 18 years.     

Hepatotoxicity associated with low-dose, long-term methotrexate treatment of rheumatoid arthritis

Liver biopsies were performed in 17 patients with therapy-refractory rheumatoid arthritis who were treated successfully with 5-15 mg/week methotrexate (mtx). The average duration of exposure to mtx therapy for each patient was 2.8 years (range 1.5-5 years). Total cumulative mtx doses ranged between 633 and 1,655 mg (mean 1,060 mg). The biopsies revealed 16 cases of normal histology, of which 3 showed nuclear variability in the hepatocytes; 4 with mild fatty infiltration, 2 with mild fatty infiltration and portal round cell infiltration. Portal fibrosis was found in one patient who had psoriasis in addition to clinical RA.     

Concurrent use of folinic acid and methotrexate in rheumatoid arthritis

In a double blind placebo controlled crossover study, each arm of 4 weeks' duration, 20 mg of folinic acid/week or placebo were administered to 13 patients with rheumatoid arthritis. These individuals were receiving weekly intramuscular methotrexate (MTX) but were about to discontinue because of side effects. While there was considerable improvement in nausea during the study, the effect of folinic acid could not be differentiated from that of placebo. There was no adverse effect on control of disease activity. It therefore seems likely that polyglutamated tissue stores of MTX do not contribute to drug efficacy and in this format folinic acid could not be shown to be more useful than placebo in reducing drug induced nausea.     

Folate status of rheumatoid arthritis patients receiving long-term, low-dose methotrexate therapy

The folate status of 29 healthy control subjects, 16 rheumatoid arthritis (RA) patients taking methotrexate (MTX), and 20 RA patients who were not being treated with MTX was estimated by an assay of the folate-dependent enzymatic synthesis of serine from formate and glycine, which is termed the C1 index. Analysis of variance demonstrated that the specific activity of the enzyme system in lymphocytes was significantly lower in the MTX-treated group, with an activity approximately one-half that of the control and the non-MTX-treated groups. Since the C1 index is one of the first biochemical parameters found to be different between MTX-treated and non-MTX-treated groups, alterations in folate-mediated amino acid metabolism may be involved in the mechanism of response to MTX therapy. Use of the C1 index may assist in the development of protocols which preserve the efficacy of MTX therapy while minimizing toxicity.     

The effect of long-term methotrexate therapy on hepatic fibrosis in rheumatoid arthritis

Objective. To evaluate the progression of hepatic fibrosis in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). Methods. Fifteen patients receiving MTX for RA were prospectively studied by electron microscopic analysis of biopsy specimens. Results. Five of the 15 patients had evidence of increased hepatic collagen after 2 years of MTX therapy. Conclusion. Hepatic fibrosis may progress in a subgroup of RA patients treated with MTX.     

Prevalence of liver fibrosis by Fibroscan in patients on long-term methotrexate therapy for rheumatoid arthritis

Clinical Rheumatology - Data on the long-term use of methotrexate (MTX) causing liver fibrosis in patients with rheumatoid arthritis (RA) is sparse. Liver biopsy is the gold standard to assess...     

Toxicity of methotrexate in rheumatoid arthritis

Seventy-two patients with rheumatoid arthritis had been treated with pulse weekly oral methotrexate with a mean followup of one year. Minor side effects (oral ulcers, transient elevation of liver enzymes, nausea, vomiting) were present in 46 patients (63.8%), whereas major side effects (severe infection, cytopenia, respiratory failure, seizures, gastrointestinal bleeding) were present in 7 (9.7%), 2 of whom died. Patients with major side effects had shorter disease duration and increased frequency of extraarticular manifestations as compared to those with no side effects. No association between a particular clinical or genetic variable and occurrence of side effects to methotrexate was found.     

Sustained cough in methotrexate therapy for rheumatoid arthritis

Summary Sustained cough is a frequent complaint in methotrexate (MTX) treatment for rheumatoid arthritis and can be a symptom of incipient MTX-induced pneumonitis. This study was performed to characterize MTX-associated cough clinically and to clarify by which means this condition can be distinguished from incipient MTX pneumonitis.Three patients with MTX-induced pneumonitis and 10 patients with sustained cough unassociated with pneumonitis were examined clinically, by pulmonary function testing, and bronchoalveolar lavage (BAL). In MTX pneumonitis, cough was associated with progressive dyspnoea, constitutional symptoms, impaired pulmonary function, and interstitial infiltration of variable degree by chest X-ray. BAL cytology invariably showed lymphocytic alveolitis while transbronchial biopsy revealed active interstitial inflammation in only one patient. Ten patients had sustained, nonprogressive cough in the absence of constitutional symptoms, progressive dyspnoea and impaired pulmonary function. Neither X-ray nor BAL nor transbronchial biopsy revealed any evidence of interstitial lung disease. In the majority of these patients, cough abated with symptomatic treatment with or without temporary discontinuation of MTX.It is concluded that MTX-associated cough can be a reflection of isolated airway disease. Clinically, absence of constitutional symptoms, impaired pulmonary function, and interstitial infiltration on X-ray distinguished this condition from incipient MTX pneumonitis. Cough without pulmonary parenchymal involvement appears to result from an irritant effect of MTX on the airways.     

Systematic review of recommendations on the use of methotrexate in rheumatoid arthritis

Clinical Rheumatology - Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries. It is unknown whether they are relevant globally. We...