Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 8164201 | Histologic changes in rheumatoid synovitis induced by naproxen and methotrexate. | 1993 Sep | OBJECTIVE: To study the changes in rheumatoid synovitis induced by the nonsteroidal antiinflammatory drug (NSAID), naproxen, and methotrexate (MTX). METHODS: Twelve patients were treated with naproxen, and 11 with MTX and a clinical activity index was measured before and after treatment. A synovial biopsy was taken, on entry into the study and after 73 +/- 43 days in the NSAID group and 145 +/- 35 in the MTX group. Synovial cells bearing CD3, CD4, CD8, CD19, LeuM5 (CD11c), HLA-DR, HLA-DP and CD25 antigens were measured by stereology. RESULTS: Patients treated with MTX showed a reduction in the number of CD3+ (p = 0.01), CD4+ (p = 0.007) and HLA-DR+ (p = 0.01) cells with an improvement in the activity index (p = 0.001). The patients treated with naproxen did not show changes in the activity index or in the synovial infiltrate. CONCLUSION: Our findings support the theory that clinical improvement in rheumatoid synovitis is associated with a significant decrease in the number of T cells infiltrating the synovial membrane. | |
| 8324961 | Methotrexate: anti-inflammatory or immunosuppressive? | 1993 Mar | Low dose methotrexate (MTX) is an effective drug for rheumatoid arthritis, suppressing joint inflammation and even radiographic progression of joint disease. Some disease-specific side effects suggest an immunomodulatory effect of the drug. However, most data currently available suggest a mechanism of action at the level of the non-specific efferent arc of the immuno-inflammatory process rather than on T cells. | |
| 8443257 | Dietary intake and circulating vitamin levels of rheumatoid arthritis patients treated wit | 1993 Mar | The nutrient intakes and circulating vitamin levels of 32 patients with rheumatoid arthritis who were treated with methotrexate were evaluated over a 6-month period. Dietary data were obtained and blood was drawn prior to the initiation of and following 12 and 24 weeks of methotrexate therapy. More than 50% of the patients had food intakes providing less than 67% of the recommended dietary allowance for zinc, vitamin E, folic acid, pyridoxine, and magnesium. Patients 51 years or older had better nutrient intakes than patients less than 51 years. Of the patients, 22% consumed vitamin supplements at the time they were recruited for the study. Mean circulating vitamin levels measured over the 6-month period were within normal limits. Our findings agree with previously published reports that patients with rheumatoid arthritis, particularly the subpopulation taking methotrexate, consume diets that are marginal in some nutrients. Additional research needs to be done to identify more sensitive nutrient assays and to establish more definitively the nutrient needs of patients with rheumatoid arthritis taking several therapeutic agents. | |
| 8826997 | Assessing the relative sensitivity to change of rheumatoid arthritis activity measures: is | 1996 Oct | Observational studies and meta-analyses of controlled clinical trials have been used to identify which measures of rheumatoid arthritis activity are most sensitive to change. These analyses often pool studies of different drugs, although it is not known if arthritis activity measures are differentially responsive to different drugs. In meta-analyses, estimates of the relative sensitivity to change of different measures may also be confounded by differences in drug efficacy, if studies of different drugs contribute different measures to the meta-analysis. To determine if the type of treatment acts as an important effect modifier or confounder in studies of the relative sensitivity to change of arthritis activity measures, we computed effect sizes for four measures (weighted tender joint count, grip strength, duration of morning stiffness, and erythrocyte sedimentation rate) used in each of 16 trials of five different disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, cyclosporin A, intramuscular gold, and D-penicillamine) in rheumatoid arthritis. In a complete factorial analysis of variance, effect sizes differed significantly among drugs (p = 0.0006), but differed only marginally among measures (p = 0.08). No interaction was detectable between drugs and measures. These results suggested that effect modification by drugs was not present, but that pooled estimates of the sensitivity to change of different measures may be confounded in meta-analyses, if trials of more efficacious drugs contribute different measures than trials of less efficacious drugs. In a similar analysis of 26 trials of nine nonsteroidal anti-inflammatory drugs, we found significant differences in effect sizes among measures (p < 0.0001), but no differences among drugs (p = 0.96), and no interaction between drugs and measures. This study suggests that pooled analyses of the relative sensitivity to change of arthritis activity measures based on trials of different disease-modifying drugs may be confounded by drug effects, but confounding by drug effects is unlikely if these meta-analyses are based on trials of different nonsteroidal anti-inflammatory drugs. Although the power of these analyses to detect small interaction effects was limited, effect modification by drugs was not observed, indicating that the measures we examined were not strongly differentially responsive to different drugs. | |
| 7986223 | Methotrexate concentrations in synovial membrane and trabecular and cortical bone in rheum | 1994 Dec | OBJECTIVE: To determine methotrexate (MTX) concentrations in the synovial membrane (SM) and cortical and trabecular bone of rheumatoid arthritis (RA) patients. METHODS: Ten RA patients (9 women, 1 man; mean +/- SD age 49.2 +/- 10.6, mean disease duration 13.2 +/- 9.9 years) undergoing surgical procedures for rheumatoid articular lesions participated in this study. Mean +/- SD MTX treatment duration was 26.4 +/- 21.3 months. The day preceding surgery, 10 mg of MTX was administered intramuscularly. During surgery, a mean +/- SD of 19.7 +/- 2.6 hours after MTX administration, SM, bone fragments, and blood were collected simultaneously. MTX was assayed by fluorescence polarization immunoassay in plasma and tissues. RESULTS: The mean +/- SD plasma concentration was 0.0252 +/- 0.01 nmoles/ml at the time of tissue sampling. The mean MTX concentration in SM was 0.285 +/- 0.159 nmoles/gm. The mean MTX concentrations in trabecular and cortical bone were 0.292 +/- 0.164 and 0.286 +/- 0.126 nmoles/gm, respectively. CONCLUSION: After intramuscular administration, high MTX concentrations are found in SM and cortical and trabecular bone of RA patients. | |
| 7510620 | Methotrexate in rheumatoid arthritis. An update. | 1994 Jan | Methotrexate has been approved for the treatment of refractory rheumatoid arthritis by several regulatory agencies, including the Food and Drug Administration. The tendency is now to prescribe it at earlier stages of the disease. Methotrexate is a well known antifolate. Its exact mechanism of action in rheumatoid arthritis remains uncertain. The polyglutamated derivatives of methotrexate are potent inhibitors of various enzymes, including dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Inhibitory effects on cytokines, particularly interleukin-1, and on arachidonic acid metabolism, as well as effects on proteolytic enzymes, have been reported. Some of them may be linked to the antifolate properties of methotrexate. Overall, the drug appears to act in rheumatoid arthritis as an anti-inflammatory agent with subtle immunomodulating properties. Direct inhibitory effects on rapidly proliferating cells in the synovium have also been suggested. Methotrexate is usually given orally. Marked interindividual variation in its bioavailability has been found. Food intake has no significant effect on the pharmacokinetics of oral methotrexate. Methotrexate undergoes significant metabolism. The functionally important metabolites are the polyglutamated derivatives of methotrexate, which are selectively retained in the cells. Less than 10% of a dose of methotrexate is oxidised to 7-hydroxy-methotrexate, irrespective of the route of administration. This metabolite is extensively (91 to 93%) bound to plasma proteins, in contrast to the parent drug (35 to 50% bound). Methotrexate is mainly excreted by the kidneys. It undergoes tubular secretion and may thereby compete with various organic acid compounds. Early placebo-controlled trials demonstrated that weekly low dosage methotrexate produced early symptomatic improvement in most rheumatoid arthritis patients. Two meta-analyses showed that methotrexate is among the most efficacious of slow-acting antirheumatic agents, together with parenteral gold (sodium aurothiomalate), penicillamine and sulfasalazine. Furthermore, in the short term context of clinical trials, methotrexate has one of the best efficacy/toxicity ratios. There is little evidence that methotrexate, or any available slow-acting antirheumatic agent, is a true disease-modifying drug. However, the probability that a patient will continue methotrexate therapy over time appears quite favourable compared with any other slow-acting antirheumatic drug. Combination therapy with slow-acting drugs has been advised for the management of rheumatoid arthritis, but the evidence currently available does not support general use of combination therapy including methotrexate. Almost all investigations indicated that toxic effects, rather than lack of response, were the major reason for discontinuing methotrexate therapy.(ABSTRACT TRUNCATED AT 400 WORDS) | |
| 8211900 | [Pancytopenia during low-dosage methotrexate treatment in patients with rheumatoid arthrit | 1993 Sep 20 | Adverse effects are no more common during treatment with low doses of methotrexate than during treatment with conventional anti-rheumatic drugs. Serious events do occur, however, and among the most dangerous is pancytopenia. We describe five patients with this complication. Triggering factors for such adverse events are often interactions with other medication, especially drugs that reduce renal clearance of methotrexate, and also other anti-folate drugs, e.g. trimetoprim. Events that increase the rate of cell formation in the myelopoietic tissue, e.g. infection and haemorrhage, may also increase risk of complications. Use of leukovorin is recommended when bone marrow suppression is suspected. | |
| 7880186 | The cost-effectiveness of liver biopsy in rheumatoid arthritis patients treated with metho | 1995 Mar | OBJECTIVE: To assess the cost-effectiveness of liver biopsy in monitoring rheumatoid arthritis (RA) patients for methotrexate (MTX)-induced cirrhosis. METHODS: A decision analytic model was used to compare a strategy of no biopsy versus strategies of biopsy after 5 years or 10 years of MTX treatment. RESULTS: Biopsy after 5 years of MTX treatment had a cost-effectiveness ratio of $1,891,830 per year of life saved, while biopsy after 10 years of treatment had a cost-effectiveness ratio of $52,374 per year of life saved. Sensitivity analyses revealed that the cost-effectiveness of biopsy was most dependent on the probability of cirrhosis. CONCLUSION: Liver biopsy to monitor for MTX-induced cirrhosis in RA patients is not cost effective after 5 years of treatment, and even biopsy after 10 years has a high cost. | |
| 8187811 | Serum levels of interleukin-6 and tumour-necrosis-factor-alpha are not correlated to disea | 1994 Jan | Cytokines are major mediators of inflammatory responses in rheumatoid arthritis. Some of them have been shown to correlate with the disease activity and thus are proposed to be used for monitoring patients. Therefore the effects of a low-dose therapy with methotrexate on serum concentrations of interleukin-6 (IL-6) and tumour-necrosis-factor-alpha (TNF-alpha) were examined in eight patients with seropositive rheumatoid arthritis. Serum levels of IL-6 and TNF-alpha were significantly elevated in patients compared to healthy controls. Before the onset of MTX treatment IL-6 concentrations were correlated to the c-reactive protein (P < 0.05) but the correlation was abolished after treatment. For TNF-alpha no correlations neither before nor after treatment were observed. Both cytokines remained substantially elevated after MTX treatment despite a clear reduction in disease activity. Thus we suggest that one of the effects of MTX might be the inhibition of some of the actions of IL-6 and TNF-alpha. | |
| 1599518 | Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid | 1992 Jun | OBJECTIVE: To evaluate the influence of food on the bioavailability of an oral dose of methotrexate in patients with rheumatoid arthritis. METHODS: Methotrexate (15 mg) was given intravenously and orally, with or without a meal, to 10 patients. Blood samples were drawn at specific intervals to evaluate drug levels. RESULTS: Food reduced the peak concentration, from a mean of 0.71 mumoles/liter to 0.49 mumoles/liter (P less than 0.02), and slightly increased the time to peak concentration, from a mean of 1.3 hours to 2.0 hours. Bioavailability was highly variable (range 28-94%) but was not affected by food intake. CONCLUSION: Bioavailability of oral methotrexate shows marked interindividual variation but is not affected by the presence of food. | |
| 7858592 | [Comparison of azathioprine and methotrexate in rheumatoid arthritis: an open-randomized c | 1994 Oct | Thirty-eight patients with active rheumatoid arthritis (RA) were entered in an open randomized 24-week study comparing azathioprine (AZA; initial daily dose 1 mg/kg) with methotrexate (MTX; initial weekly dose 7.5 mg). The patients had previously been treated with antimalarials, gold salts and/or D-penicillamine. The groups were well balanced in baseline characteristics. There were three premature withdrawals in each group, all of which were due to toxicity. The present study did not show any significant differences between AZA and MTX in ability to reduce activity in RA after 24 weeks of treatment. | |
| 8353979 | Lack of immunosuppressive effect of low-dose oral methotrexate on lymphocytes in rheumatoi | 1993 May | Whether methotrexate (MTX) is effective in rheumatoid arthritis (RA) because of immunosuppressive and/or anti-inflammatory mechanisms of action is controversial. Many lines of investigation point to the latter. We evaluated DNA synthesis in peripheral blood lymphocytes (PBL) from 33 RA patients on oral MTX (7.5-15 mg/wk) and in 30 healthy controls by flow cytometric cell cycle analysis (CCA). DNA synthesis was also evaluated with a thymidilate synthetase activity assay (TSA) (3H-deoxyuridine incorporation) in 12 patients and 21 controls (12 on MTX and NSAID, and 9 healthy subjects). The patients had taken MTX for at least 3 months and were in different stages of clinical activity. There were no significant differences in TSA or in the cell cycle phase distributions (especially the S phase) between treated RA patients and controls. These data suggest that low-dose oral MTX does not inhibit DNA synthesis and therefore does not have an immunosuppressive effect on lymphocytes from patients with RA. | |
| 7562775 | Pancytopenia related eosinophilia in rheumatoid arthritis: a specific methotrexate phenome | 1995 Jul | Methotrexate (MTX) induced pancytopenia has been reported in about 3% of patients with rheumatoid arthritis (RA) receiving low dose MTX. We describe 4 additional patients with RA (2M, 2F; mean age 65 yrs; mean duration of RA 9 yrs) who developed pancytopenia while receiving low dose MTX. Risk factors identified for the development of pancytopenia in our patients included impaired renal function, hypoalbuminemia, advanced age, low folate level, concurrent use of multiple comedication, nonsteroidal antiinflammatory drugs, and cotrimoxazole). Remarkably, pancytopenia related eosinophilia was observed in blood and bone marrow after restoring the intracellular folate level by folinic acid. The range of eosinophils was 22-56% of the number of peripheral white blood cells (mean nadir 33%). The peak level of eosinophilic granulocytes was reached after a mean of 6 days in hospital (range 4-8), whereas the peak of neutrophils was reached after a mean of 11 days (range 9-13 days). The duration of the eosinophilic response was 11 days. As eosinophilia has not been observed in other drug induced pancytopenias in patients with RA this could be a specific MTX induced phenomenon. | |
| 8835576 | Temporal association between the use of methotrexate and development of leukemia in 2 pati | 1995 Dec | To date only a single case of leukemia coincident with the use of methotrexate (MTX) in rheumatoid arthritis (RA) has been reported. We report 2 additional patients with RA, each of whom developed leukemia after receiving short term low dose MTX. Whether these cases represent an adverse effect of MTX treatment has yet to be determined. | |
| 8685225 | Epstein-Barr virus and lymphoproliferation in methotrexate-treated rheumatoid arthritis. | 1996 Mar | Generalized lymphadenopathy developed in a 60-year-old female receiving methotrexate and prednisone for treatment of rheumatoid arthritis. Histologic examination of an enlarged right axillary lymph node revealed effacement of normal architecture by a polymorphic population of lymphocytes. The recognition that the patient was medically immunosuppressed and the similarity of lymph node histology to that of a polymorphic post-transplantation lymphoid proliferation led to suspicion that the adenopathy might represent an immunosuppression-related lymphoid proliferation. This possibility was supported by regression of the adenopathy on discontinuation of methotrexate, despite continued corticosteroid therapy, which is an outcome reminiscent of the remissions observed with reduction of immunosuppressive therapy in post-transplantation lymphoproliferative disorders. Subsequent ancillary laboratory studies of lymph node tissue included genetic probe analysis, which revealed a monoclonal population of B-lymphocytes containing clonal Epstein-Barr virus DNA. In situ hybridization studies performed on lymph node tissue revealed expression of Epstein-Barr virus-encoded RNA 1 transcripts, and immunohistochemical studies revealed expression of Epstein-Barr virus latent membrane protein 1. These ancillary studies confirmed the similarity to post-transplantation lymphoproliferative disorder. Although immunosuppression-related lymphoproliferative disorders share features with malignant lymphoma, the possibility of resolution in situations in which immunosuppression can be reversed provides a distinction from true malignancy and is of profound importance in therapeutic decision making. | |
| 1491385 | The effects of methotrexate on interleukin 1 in patients with rheumatoid arthritis. | 1992 Nov | The effect of methotrexate (MTX) treatment on patients with rheumatoid arthritis on interleukin 1 (IL-1) was evaluated. Eight patients received a weekly MTX dose of 7.5 mg for 6 weeks; none received concomitant corticosteroids. Peripheral blood was obtained 1 day before and 1 day after their weekly MTX dose at Week 1 and 6, isolated monocytes stimulated ex vivo with 1 mg/ml zymosan for 18 h and IL-1 measured by bioassay. Serum and plasma IL-1 levels were measured by immunoassay. Four patients manifested a sharp decrease in IL-1 production 6 weeks after MTX administration associated with a decrease in the number of painful but not swollen joints. No effect on blood levels was observed. Our results suggest that MTX may affect IL-1 production and IL-1 mediated events in some patients. | |
| 8846651 | The use of Sandimmun (cyclosporin A) in severe refractory rheumatoid arthritis: the Belgia | 1995 Sep | OBJECTIVE: To investigate practicability, efficacy and tolerability of low starting doses of Sandimmun (cyclosporin A) (2.5 mg/kg daily) in patients with severe refractory rheumatoid arthritis in the short (6 months) and middle (12 months) term. METHODS: Fifty-nine patients, presenting with active and severe rheumatoid arthritis unresponding to conventional DMRADs were allowed to start Sandimmun at the dose of 2.5 mg/kg daily. This dose was progressively increased by steps of 25 mg daily up to a maximum of 5 mg/kg daily according to the renal function and blood pressure. RESULTS: A mean maintenance dose of 3.9 mg/kg daily was reached after 5 months and maintained throughout the study. Twenty-one patients (36%) completed the one year study. The reasons for discontinuation were: inefficacy (13), adverse events (17), both inefficacy and adverse events (5) and non-compliance (3). For those patients who completed the trial, clinical relevant improvements were observed within 3 months of treatment and were maintained until the end of the study for the Lee functional and the Ritchie articular index, as well as for the number of tender and swollen joints. No changes for the grip strength, the biological and immunological parameters were observed. Mean serum creatinine values rose from 0.81 mg/dl at start to 1.1 mg/dl after 5 months of therapy and remained at that level throughout the study. In patients who discontinued, the serum creatinine level nearly normalized after one month of Sandimmun withdrawal. One hundred and sixty-two side effects were reported of which most were minor and known to occur with Sandimmun. Twenty-two cases (37% of patients) dropped out for adverse events before 1 year treatment. The criteria to withdraw the patients from the study differed greatly from centre to centre. CONCLUSIONS: Managing RA patients presenting with very long and severe disease remains difficult. Therefore low dose Sandimmun (2.5-5 mg/kg daily) appears to be a valuable therapeutic opportunity in RA patients refractory to various other conventional drugs, including methotrexate. | |
| 8782146 | Non-Hodgkin's lymphoma in patients with rheumatoid arthritis treated with low dose methotr | 1996 Jun | We describe 2 patients who developed non-Hodgkin's lymphoma during treatment with low dose methotrexate (MTX) for rheumatoid arthritis (RA). A review of the literature identified 16 more cases published in English. Among these 18 patients, the mean RA duration was 16 yrs and lymphoma developed after a mean of 2.8 yrs of treatment with MTX. The mean total dose of MTX was 1224 mg. Although 3 patients had spontaneous regression of lymphoma, 5 of the 18 patients died. It is not known whether there is cause-effect relationship between MTX and lymphoma among patients with RA. Special awareness of this possible complication of MTX is important. | |
| 8261056 | Accelerated nodulosis and systemic manifestations during methotrexate therapy for rheumato | 1993 Mar | OBJECTIVES: Methotrexate is successfully used in the treatment of arthritis but little is known about its effects on extra-articular manifestations of rheumatoid arthritis. We focused this work on the incidence and clinical course of extra-articular manifestations during long-term treatment with methotrexate. METHODS: The effect of methotrexate on extra-articular manifestations was investigated in 176 patients with rheumatoid arthritis who had obtained, in a prospective study, a good clinical response to methotrexate (10 mg/week) taken for 33 months (range 4-68). RESULTS: Before taking methotrexate, 44 patients (25.1%) had extra-articular manifestations: nodules (n = 40) and vasculitis (n = 9). With methotrexate, nodulosis and vasculitis were stable in 31 cases, improved in 3 and worsened in 10 (23%). Among the 132 patients without extra-articular manifestations before methotrexate therapy, 15 (11%) developed accelerated nodulosis preferentially located on the fingers, 7 had a vasculitis and 3 a pericarditis during methotrexate therapy. Extra-articular manifestations occurred between 1 and 24 months of initiating methotrexate therapy. Rheumatoid factor was positive in 88% of the patients with extra-articular manifestations. No relationship was noted between extra-articular manifestations and HLA type or antinuclear antibodies. In 3 out of 4 patients who developed accelerated nodulosis while taking methotrexate, the addition of hydroxychloroquine (400 mg/day) resulted in a significant reduction in the number and size of the nodules within 3 to 10 months after starting combined therapy. CONCLUSION: These data suggest that methotrexate is not effective in the treatment of extra-articular manifestations in rheumatoid arthritis and that nodulosis may occur in about 11% of patients taking methotrexate therapy for rheumatoid arthritis. The combination of hydroxychloroquine and methotrexate may have a beneficial effect on nodulosis that needs to be evaluated. | |
| 8308769 | Adverse effects of low dose methotrexate therapy in rheumatoid arthritis. | 1993 Nov | OBJECTIVE: To determine (1) the risk of treatment termination for low dose, weekly methotrexate (MTX) therapy in patients with rheumatoid arthritis (RA), and (2) the prevalence, nature and predictors of adverse effects due to longterm low dose MTX therapy. METHODS: A 13-year, retrospective survey of all patients with RA receiving low dose MTX therapy was conducted using life table, logistic regression and case control methods of analyses. Major and minor adverse effects were defined. RESULTS: Consecutive patients with RA (144) starting MTX (mean dose 8.2 mg/week) were observed to have a 75% risk of treatment termination at 60 months. Reasons for 81 patients stopping MTX were adverse effects (43), loss/lack of effect (18), other medical and nonmedical reasons (13), and lost to followup (7). Sixty-two patients experienced 83 major adverse events, including gastrointestinal symptoms (29), hepatic enzyme test abnormalities (23), pneumonitis (5) and severe leukopenia (8). Aging was the only predictor of treatment discontinuation associated with a major toxicity. Five patients developed a malignancy during the observation period. CONCLUSIONS: In our survey the risk of treatment termination was 75% in patients with RA taking MTX after 60 months. An adverse drug effect is a more common reason for treatment termination (53%), compared to loss/lack of beneficial effect (22%) or other reasons (16%) or lost to followup (9%). Increasing age is associated with an increased risk of treatment termination associated with a major toxicity. |