Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 16788633 | Cytotoxic and immunologic effects of methotrexate in psoriasis. | 1990 Nov | Based on recent experience that Cyclosporin A, an immunosuppressive drug, produces marked improvement in psoriasis, possible immunomodulatory activities of methotrexate (MTX) have been reviewed to look for alternate mechanisms of MTX action in psoriasis. It is generally considered that the therapeutic results of MTX in psoriasis are related to a direct effect on epidermal cell hyperplasia through inhibition of DNA synthesis. Several studies in the literature now suggest possible effects of MTX on the immune system of psoriatics as well as in animal models that may have some pathogenic similarities to psoriasis. In psoriatics receiving MTX, neutrophil chemotaxis is suppressed, resulting in a possible alteration in the potential pathologic activity of neutrophils commonly found in lesional skin. MTX does improve both psoriatic and rheumatoid arthritis. Animal studies of the latter using adjuvant arthritis and graft vs host disease (GVHD) have indicated several possible mechanisms for MTX that affect these processes. In GVHD, MTX selectively destroys cycling CD8+ cells, and in adjuvant arthritis the activation of macrophages is prevented by inhibition of T-cell function. While MTX generally has not been clinically utilized as an immunomodulatory drug for immunologically related diseases, it may, nonetheless, have selective actions that could be specific for some diseases. MTX and Cyclosporin A could work mechanistically in similar ways but at different steps in the activation of T cells and macrophages. It may be that the major direct effect of MTX on epidermal cell proliferation is complemented or even mediated by subtle immunoregulatory effects on the melange of cells in the affected skin and the systemic immune response. | |
| 2919941 | Toxicity of methotrexate compared with azathioprine in the treatment of rheumatoid arthrit | 1989 Mar | One hundred thirty-one patients with rheumatoid arthritis treated with either azathioprine sodium (n = 37, 102.7 +/- 32.9 mg/d) or methotrexate sodium (n = 94, 8.4 +/- 3.0 mg/wk) were followed up for 38 +/- 23.3 months to determine the nature, frequency, and potential predictors of "major" toxic reactions. Thirty-one methotrexate-treated patients (33%) and 11 patients (30%) receiving azathioprine experienced a major toxic reaction during the study period. With the case-control method, no predictors of major toxic reactions secondary to azathioprine therapy were found. Sex, drug dosage, response to prior slow-acting antirheumatic drug therapy, concurrent use of salicylates, and age did not predict major toxic reactions secondary to methotrexate treatment, but the methotrexate-treated patients who experienced a major toxic reaction had a significantly greater mean level of blood urea nitrogen at the time of their reaction compared with the control group. Life-table analysis suggested toxic reactions posed a greater risk of treatment termination in methotrexate-treated patients compared with the lack or loss of efficacy. This trend was not apparent in the azathioprine group. The majority of patients in each treatment group (79 for methotrexate and 29 for azathioprine) experienced one or more "minor" toxic reactions during the follow-up period. | |
| 2505779 | Which traditional measures should be used in rheumatoid arthritis clinical trials? | 1989 Sep | It is standard practice to use multiple outcome measures in rheumatoid arthritis (RA) clinical trials. Because of this, multiple testing is usually done, and there is confusion in the interpretation of the results. It is not clear which measures are the most sensitive to detecting improvement and which provide independent information. To address these questions, we conducted an analysis of pooled raw data from 3 placebo-controlled RA trials: one of methotrexate, another of oral and injectable gold, and the third of low-dose and high-dose D-penicillamine. The results show that the joint tenderness count, erythrocyte sedimentation rate, grip strength, and physician assessment of disease activity perform best in RA clinical trials and cover the domain of change measured by traditional outcome measures. Other clinical measures may provide little additional useful information for a standard therapeutic trial of up to 6 months duration, and some measures, such as the proximal interphalangeal joint circumference, hemoglobin level, and 50-foot walking time, can be eliminated from such trials. | |
| 1976811 | Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospe | 1990 Aug | During a continuous 14-year observation period we prospectively recorded clinical data on all patients with rheumatoid arthritis (RA) attending an outpatient clinic. Six hundred seventy-one patients received 1017 new administrations of slow acting antirheumatic drugs during more than 2000 patient years of observation. The median time to discontinuation for intramuscular gold, auranofin, hydroxychloroquine or penicillamine was 2 years or less, but was 4.25 years for methotrexate (p = 0.008 vs all other drugs combined). Adverse reactions were a more common reason for discontinuation than efficacy, and both were less common in patients taking methotrexate (p less than 0.01). Neither disease duration, disease severity, or demographic factors were useful predictors of discontinuation. Since controlled clinical trials do not provide long-term outcome assessments, measurement of time to termination is a practical tool to estimate drug inefficacy. | |
| 2132565 | Administration of folinic acid after low dose methotrexate in patients with rheumatoid art | 1990 Sep | Folinic acid (leucovorin) supplementation has been suggested as a possible means of treating the short term side effects that occur with low dose methotrexate (MTX). However, it has not been established whether leucovorin will abrogate the antiarthritic effect of MTX. We entered 20 patients with rheumatoid arthritis treated with MTX into a 48 week randomized, double blind, crossover trial of folinic acid vs placebo. The dose of folinic acid was equal to the dose of MTX and it was given orally 4 h following the single, weekly MTX administration. Under these conditions, leucovorin did not decrease the therapeutic effect of MTX. While the incidence of stomatitis and gastrointestinal toxicity were lower during leucovorin treatment, our study lacked sufficient power to establish a statistically significant difference. | |
| 3110942 | Pharmacology of auranofin: overview and update. | 1986 | Auranofin, the only approved oral gold complex of value in suppressing rheumatoid arthritis, differs from injectable gold compounds molecularly and pharmacologically. Although comparably efficacious, the side-effect profiles of oral and intramuscular gold differ, and the withdrawal rate for adverse reactions is several-fold lower with auranofin. Considerably less elemental gold is available to the internal milieu with auranofin than with gold sodium thiomalate (3 mg/week vs. 25 mg/week), a difference reflected in lower blood, synovial fluid and tissue gold levels. Approximately 25% of the administered auranofin dose is absorbed orally, and 85% is recovered in feces. Serum gold levels are 300-400 micrograms/dl one week after injectable gold and 60-70 micrograms/dl daily with auranofin (6 mg/d). But, surprisingly, the fraction of gold associated with the red blood cell fraction is higher with auranofin. Blood gold levels do not correlate with clinical response to treatment or frequency or type of adverse reaction, regardless of the gold preparation used. Similar results obtain with penicillamine. Methotrexate blood levels are not related to the development of hepatic fibrosis. The mechanisms of gold action in rheumatoid arthritis are unknown, despite the laboratory definition of multiple antiinflammatory, immunologic and other effects. Sulfhydryl binding activity, an established property of injectable gold compounds and penicillamine of potential importance pharmacodynamically, is limited with auranofin. | |
| 3371211 | [Treatment of chronic polyarthritis with low-dose methotrexate]. | 1988 May 27 | Methotrexate, 7.5-25.0 mg, was taken in a single weekly dose by 101 patients with chronic rheumatoid arthritis. In the course of treatment there was significant improvement in pain and mobility, as well as in the number of inflamed joints, strength of hand-grip (both hands), and use of steroids. There was a significant fall in erythrocyte sedimentation rate, and haemoglobin content rose significantly. Improvement occurred in 85% of patients; within this group 30% had a remission during treatment. There were 7% non-responders. Side effects were frequent: gastrointestinal symptoms in about 50%, loss of hair and stomatitis in 10-20%. In nine patients methotrexate had to be discontinued because of side effects, but in six of them the drug was taken again later on. Transaminases increased in 50% of patients. No clear-cut histological changes were found in the liver. It is concluded that low-dose methotrexate is effective in the long-term treatment of chronic rheumatoid arthritis. | |
| 3146207 | [Blood cell concentration of methotrexate in long-term therapy of inflammatory rheumatic d | 1988 | To verify the possibility of a concomitant therapy control in 31 patients (18 psoriatic arthritis [PA], 13 rheumatoid arthritis [RA]) the blood cell concentration of Methotrexate (MTX) was continuously measured over a period of 6 months. The determinations were carried out by using a RIA of the CIS Corp. At any time MTX was determined laboratory and clinical examinations were done and the P-III-P serum-level was measured by using a RIA of the Behringwerke. The cellular MTX showed to be statistically significantly elevated compared to baseline, whereas within ranges of total cumulative dosages only insignificant fluctuations could be noticed. Like in the treatment of Psoriasis a strict correlation between the weekly administered dose and the cellular MTX could be established, the total cumulative dose, however, had no influence on the cellular MTX-level. In the treatment of RA slightly higher weekly dosages were necessary, which caused significantly higher cellular MTX concentrations in RA patients. Some correlations between clinical as well as serological parameters of disease activity could be noticed, nevertheless they do not allow distinct interpretations. In both diseases a significant relationship between the cellular MTX-level and the P-III-P serum-level could be realized. A storage of MTX in blood cells, especially in erythrocytes, seems to be evident. To reach therapeutical benefit in RA slightly higher mean dosages may be necessary. A therapy monitoring by the means of continuous determinations of cellular MTX seems to be impossible. In contrast an approach to the early detection of liver fibrosis can be given by the correlation between cellular MTX and the P-III-P serum levels. | |
| 1747136 | Aspirin alters methotrexate disposition in rheumatoid arthritis patients. | 1991 Dec | Intravenous methotrexate (MTX) (10 mg), either alone or with oral aspirin (ASA) (3,900 mg/day), was administered to 15 patients with rheumatoid arthritis. Systemic and renal clearance of MTX were lower, and the unbound fraction of MTX was higher when patients were also receiving ASA than when taking MTX alone. No acute hematologic, renal, or hepatic toxicity was observed with either treatment. The findings of this study therefore indicate that concomitant aspirin therapy acutely alters the clearance of low-dose MTX in patients with rheumatoid arthritis. | |
| 1683020 | [Current status of drug therapy in chronic polyarthritis]. | 1991 Sep | This review covers the differential indications of oral and topical non-steroidal antiinflammatory drugs, as well as oral and intra-articular corticosteroids. The so-called "disease modifying" drugs, such as chloroquine, sulfasalazine, gold compounds and penicillamine have been surpassed by low-dose pulses of methotrexate, due to its lower short-time toxicity and higher response rate. Parenteral cyclophosphamide or corticosteroid pulses should be reserved for cases with vasculitis or refractoriness to conventional drugs. Combined treatments by several "disease modifying" drugs or immunosuppressives have not yet proved their safety or higher efficacy. Selective immunosuppressives, such as cyclosporin A, have proved to be of limited efficacy but await comparison with more established drugs. Looking to the future, cytokines, e.g. interferon gamma, and monoclonal antibodies are discussed. | |
| 2027397 | [Dyspnea during administration of methotrexate: not anything to treat casually]. | 1991 Mar 23 | An important complication of methotrexate (MTX) treatment is illustrated by two case histories. Until recently pneumonitis was believed to be associated only with high dose MTX. Lately several cases of pneumonitis during treatment with low intermittent doses have been reported. The use of low dose intermittent MTX treatment in non-malignant diseases is growing fast and an increasing incidence of MTX pneumonitis is to be expected. Early recognition of the disorder may result in adequate treatment. The clinical picture varies from transient mild dyspnoea to progressive, sometimes fatal respiratory insufficiency. All 'new' pulmonary signs of patients treated with MTX should raise suspicion of MTX pneumonitis. Before treatment with MTX is instituted a chest radiograph should be made and pulmonary function testing should be performed. It is of great importance to inform patients carefully about the possibility of MTX pneumonitis and its symptoms. The prognosis of MTX pneumonitis is usually favourable. | |
| 2894754 | Rheumatoid arthritis: a pharmacologic overview. | 1988 Mar | Numerous drugs are available for the treatment of rheumatoid arthritis. The nonsteroidal anti-inflammatory drugs differ in structure and pharmacokinetics, and they rarely act synergistically. The disease-modifying antirheumatic drugs include gold compounds, penicillamine, hydroxychloroquine and sulfasalazine. Useful immunosuppressive and cytotoxic agents include methotrexate, azathioprine and cyclophosphamide. Costicosteroids find their greatest use in short courses. | |
| 2110877 | Parenteral methotrexate or gold for rheumatoid arthritis: a follow up. | 1990 Mar | The forty participants in a double blind controlled trial of parenteral methotrexate or gold for RA were followed up two years later. Fifty percent had remained on the original medication, 13/20 on MTX and 7/20 on gold. Only 5 and 3 of them respectively had no active joint swelling. No major differences between the two groups were seen. | |
| 1828327 | Methotrexate and histologic hepatic abnormalities: a meta-analysis. | 1991 Jun | STUDY OBJECTIVE: To determine the risk of liver toxicity from the long-term administration of methotrexate in patients with rheumatoid arthritis or psoriatic arthritis. DESIGN: A meta-analysis of 15 studies examining the relationship between long-term, low-dose methotrexate administration and biopsy evidence of liver fibrosis. PATIENTS: A total of 636 patients from 15 studies. RESULTS: The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9% (95% confidence intervals 24.3 to 31.6). The rate of progression of liver disease in the 15 studies was associated with the cumulative dose of methotrexate (p = 0.01). Patients on average had a 6.7% (95% confidence intervals 2.1 to 11.4) chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0% (95% confidence intervals 3.5 to 7.0). The development of advanced histologic changes was not associated with the cumulative dose of methotrexate (p = 0.08). Patients who according to their history were heavy drinkers (at least 100 g of alcohol per week) were more likely to have advanced changes on liver biopsy (17.8% versus 4.5%, p = 0.0003) and to show histologic progression (73.3% versus 25.9%, p = 0.0002). Patients with psoriasis were more likely than patients with rheumatoid arthritis to have advanced changes (7.7% versus 2.7%, p = 0.003) and histologic progression (33.1% versus 24.3%, p = 0.02). CONCLUSIONS: The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity. | |
| 3720217 | Low-dose weekly oral methotrexate therapy for inflammatory arthritis. | 1986 Jun | The efficacy and toxicity of low-dose, weekly oral methotrexate (MTX) therapy for inflammatory arthritis was evaluated. Fifty-nine patients with a diagnosis of inflammatory arthritis who had failed to respond to or developed toxicity to gold, penicillamine, or hydroxychloroquine therapy were treated with MTX 10-20 mg administered orally or intravenously once a week in divided doses. Various tests to assess arthritis were performed upon each patient's entrance into the study and at specified intervals throughout the 24-month study period. The mean duration of methotrexate therapy was 15.5 months. Patients showed significant improvement in number of swollen joints, duration of morning stiffness, amount of pain, and amount of activity during the study period. Of the 35 patients who had had roentgenographic studies of their hands performed initially and after one year of MTX therapy, 23 had no evidence of new joint erosions after one year. Biopsies of hepatic tissue from 20 patients showed no progressive changes when compared with pretreatment biopsies. Gastrointestinal symptoms, mucocutaneous lesions, or small increases in liver enzyme concentrations were observed in 31 patients; three patients developed pulmonary toxicity and had to be withdrawn from the study. MTX is an effective agent for the treatment of inflammatory arthritis in patients who do not respond to therapy with nonsteroidal anti-inflammatory drugs or slow-acting antirheumatic drugs. Short-term weekly oral MTX therapy does not appear to result in clinically important liver disease. | |
| 3741502 | Treatment of Felty's syndrome with low-dose oral methotrexate. | 1986 Jul | Recent studies of methotrexate in the treatment of patients with rheumatoid arthritis have precluded patients with neutropenia. We present a patient with rheumatoid arthritis complicated by severe neutropenia and recurrent infections, who was treated with low-dose methotrexate, orally, for 30 months. The patient experienced symptomatic improvement and a significant increase in granulocyte count, and the dosage of steroids was reduced. Low-dose oral methotrexate may be a therapeutic option in select patients with Felty's syndrome. | |
| 2633612 | Methotrexate in rheumatoid arthritis: studies with animal models. | 1989 | The present studies have shown that low doses of methotrexate can suppress the inflammation and joint destruction associated with animal models of arthritis. The antiinflammatory effects of methotrexate are probably related to its inhibitory effect on chemotaxis. At the low doses used, methotrexate does not induce systemic immunosuppression. In methotrexate-treated rats, an improvement in IL-2 synthesis is observed and increases in IL-2 levels are expected to improve cell mediated immunity. Suppressor cells appear to be very sensitive to methotrexate. Macrophage function is modulated by methotrexate. All of these effects including the effects on joint destruction are probably due to inhibition of DHFR activity of critical cells that are involved in the pathogenesis of rat arthritis induced either by adjuvant or by streptococcal cell walls. Some of these effects have been extended to human arthritis but additional studies are required to understand how low dose methotrexate exerts its beneficial effects in humans. | |
| 1841047 | The effect of slow-acting anti-rheumatic drugs (SAARDs) and combinations of SAARDs on mono | 1991 | The mode of action of slow-acting anti-rheumatic drugs (SAARDs) is complex but may often include effects on cytokine (interleukin-1, IL-1, and tumour necrosis factor, TNF) production by monocytes/macrophages. Different SAARDs may have variable effects on cytokine production in vitro depending on the concentration of drug, the presence of other SAARDs and individual variation. The gold compounds gold sodium thiomalate (GST) and auranofin (AF) had a bimodal effect on cytokine production. High concentrations of GST (greater than 1 microgram/ml) weakly inhibited IL-1-beta secretion (without affecting IL-1-alpha or TNF secretion and without affecting cell-associated IL-1-alpha and IL-1-beta accumulation), and although AF (greater than 100 ng/ml) inhibited cytokine production it did so at concentrations near to the toxic range for the drug (greater than 200 ng/ml). GST and AF when used in combination inhibited cytokine production in a synergistic manner even at concentrations that would potentiate cytokine production if used individually. Hydroxychloroquine (HCQ) and sulfasalazine (SAP) were two other inhibitory SAARDs which acted synergistically in combination. Combination of HCQ and SAP with gold drugs gave variable results. D-penicillamine (D-pen) and methotrexate (MTX) were two SAARDs that generally did not affect cytokine production individually or in combination with other SAARDs. These results suggest that combination SAARD therapy may more effectively target excessive cytokine production, which is a hallmark of rheumatoid arthritis. | |
| 2735964 | Central nervous system toxicity associated with weekly low-dose methotrexate treatment. | 1989 Jun | Central nervous system (CNS) toxicity from low-dose methotrexate (MTX) has been reported rarely, and reported symptoms consist primarily of dizziness and headache. We reviewed the records of 25 consecutive patients treated with low-dose MTX, and found 5 who had spontaneously reported unpleasant cranial sensations, mood alteration, or memory impairment. Rechallenge with MTX on 5 occasions in 3 patients led to recurrent CNS symptoms in all cases. CNS toxicity was the sole reason for discontinuation of MTX in 2 patients. These 5 patients differed from the 20 without CNS toxicity in age (mean 68 versus 50) and baseline serum creatinine level (1.3 mg/dl versus 0.9 mg/dl), but not in weekly dosage of MTX (12 mg versus 16 mg). These results suggest that CNS toxicity is more common than previously reported, particularly in older patients with mild renal insufficiency. | |
| 1694047 | Whipple's disease with axial and peripheral joint destruction. | 1990 Jun | A seropositive white man had follow-up for 16 years with a diagnosis of palindromic rheumatism. Treatment had included parenteral gold, methotrexate, prednisone, hydroxychloroquine sulfate, and penicillamine before diarrhea led to a biopsy-proven diagnosis of Whipple's disease. Clinical and radiographic criteria for ankylosing spondylitis were met. In addition to classic Whipple's arthropathy, he had the combined but singular findings of pancarpal destruction and cervical apophyseal fusion. HLA typing revealed the B7 antigen. This case illustrates the pitfalls in diagnosis of a chronic polyarthritis that has, as a typical feature, a long latency before manifesting its more specific signs and symptoms (ie, diarrhea, malabsorption, and hyperpigmentation). Care should be taken during evaluation of any disease with atypical and nonspecific features (eg, positive rheumatoid factor in a patient with polyarthritis) and one should continue to reevaluate the original impression while confirmatory evidence is lacking. Moreover, the roentgenographic findings of pancarpal narrowing, apophyseal fusion, and advanced iliofemoral joint disease, in addition to sacroiliitis and syndesmophyte formation, challenge the generally held notion that Whipple's arthropathy is a nondestructive joint disease. |