Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 8371222 | Acute leukemia after low dose methotrexate therapy in a patient with rheumatoid arthritis. | 1993 Jul | An 83-year-old woman with seropositive rheumatoid arthritis (RA) developed acute myeloid leukemia after receiving weekly methotrexate (MTX) for 33 months (total dose 690 mg). Although cytogenetic abnormalities typical of damage by cytotoxic agents were not documented, our case may be the first report of acute myeloid leukemia in RA with MTX. We estimate that 6 similar cases should have been observed in France by chance alone. The absence of other reports suggests either that MTX possesses a paradoxical protective effect or that it is not considered a risk factor for malignancy by rheumatologists. Since the number of patients with RA taking MTX can be estimated with reasonable accuracy, the reporting of all suspected cases could help to assess the safety of the drug in rheumatology. | |
| 7917079 | A risk-benefit assessment of slow-acting antirheumatic drugs in rheumatoid arthritis. | 1994 Jul | There is no ideal slow-acting antirheumatic drug. Therapy of rheumatoid arthritis (RA) is currently being modified, with strong recommendations to abandon the traditional pyramidal approach. The call is for a more aggressive, earlier approach to suppress inflammation. Combination therapy rather than the use of a single agent is advocated by some. Improved methods for assessing disease activity as well as measurement of outcome have been developed. Markers of poor prognosis have helped to define patients for earlier treatment. Comparison of toxicity among such a diverse group of drugs is probably best achieved with a toxicity index measuring the number of episodes expressed in terms of patient-years of exposure. Toxicity remains the commonest reason for discontinuing an agent, while remission beyond 36 months on therapy is uncommon, except with methotrexate. The profile of toxicity is clearly defined for individual agents, but combination therapy may reveal an entirely different set of toxic manifestations. There is an urgent need to develop a set of risk factors to predict toxicity in an individual patient. Juvenile chronic arthritis behaves differently from adult RA. Drug toxicity profiles are similar, but less common. Outcome is more difficult to measure, with the major impact of disease and therapy being on growth retardation. | |
| 8474058 | Methotrexate inhibits proliferation but not interleukin 1 stimulated secretory activities | 1993 Feb | The effect of methotrexate (MTX) on proliferation and on interleukin 1 stimulated secretory activities of human synovial fibroblasts in culture was investigated. MTX caused a dose dependent inhibition of growth over the concentration range 0.07-2.2 microM with a half-maximal effect at 0.37 microM. INhibition was competitively relieved by coaddition of leucovorin. Cell growth was fully restored after MTX pretreatment of 24 h but not after 48 h, even on subsequent leucovorin addition. Cell viability was unaffected by MTX treatment. MTX had no effect on interleukin 1 stimulated production of prostaglandin E, hyaluronic acid and collagenase. Our results raise the possibility that one of the mechanisms contributing to the therapeutic effects of MTX in patients with rheumatoid arthritis may involve modulation of synovial fibroblast growth. | |
| 7566289 | Non-coeliac sprue possibly related to methotrexate in a rheumatoid arthritis patient. | 1995 Sep | We describe a case of non-coeliac sprue in a low-dose methotrexate treated patient suffering from rheumatoid arthritis. This is the first case report of this possibly reversible complication of methotrexate therapy. The diagnosis was confirmed by a duodenal mucosal biopsy revealing the characteristic intestinal histopathology of coeliac sprue. After discontinuation of the drug a repeat biopsy was almost normal, and completely normal after reintroduction of a normal diet. One could speculate about the methotrexate related mechanism of the villous atrophy: it might be either a direct toxic effect or a secondary effect of the immunosuppression. | |
| 7699679 | Examination of pharmacokinetic variables in a cohort of patients with rheumatoid arthritis | 1995 Jan | OBJECTIVE: To compare pharmacokinetic variables of a 7.5 mg dose of MTX in a cohort of patients with rheumatoid arthritis (RA) beginning therapy with the drug with a cohort of patients receiving the drug for a mean period of 81 months. METHODS: Standard pharmacokinetic measures were performed in 35 patients beginning MTX therapy and 15 patients who had received the drug for a mean of 81 months. RESULTS: No significant differences in area under the serum concentration versus time curve (AUC), maximal methotrexate concentration following dosing (Cmax), time to Cmax (Tmax), bioavailability (F), urinary MTX, renal clearance of MTX or creatinine clearance were observed between the 2 cohorts. CONCLUSION: We were unable to demonstrate significant differences in pharmacokinetic variables in these cohorts with a 7.5 mg standard dose of MTX. It is possible that a difference may exist when a standard higher dose of MTX is compared in these types of patients. | |
| 1626283 | A debate: should patients with rheumatoid arthritis on methotrexate undergo liver biopsies | 1992 Jun | The question of whether it is appropriate to perform liver biopsies in rheumatoid arthritis patients receiving long-term weekly methotrexate therapy is debated. This debate includes a detailed discussion of the literature to support the debaters' respective views. Points made in favor of biopsy include (1) the significant prevalence of hepatic abnormalities in psoriatic patients; (2) the need to continue administration of the drug to sustain a clinical response; (3) the high incidence of elevations in aspartate amino-transferase, which correlate significantly with hepatic histological outcome; and (4) the fact that the rheumatology community has had relatively short experience with the widespread use of the drug. Arguments against biopsy include (1) the poorly defined specific role of methotrexate in the development of hepatic histological abnormalities; (2) the nonquantitative histological grading system, which makes precise assessment of progression in hepatic disease difficult; (3) the poorly defined role of other factors in the progression of hepatic changes in patients taking methotrexate; and (4) the cost and potential morbidity of the procedure itself. The role of the hepatic Ito cell in the development of fibrosis is also discussed. The protagonists agree on the need to continue studies of liver biopsy tissue from rheumatoid arthritis patients receiving methotrexate to better define this key issue. | |
| 8187433 | Chronic interstitial cystitis occurring during the shift between rheumatoid arthritis and | 1994 Mar | This case reports documents the progressive development of chronic interstitial cystitis during the overlapping process from rheumatoid arthritis to lupus. Concomitantly high titer antinuclear antibody with an anti-68 KD RNP pattern and other biological markers of lupus were observed in the blood. The symptoms dramatically improved under methotrexate therapy. The pathogenic mechanism is discussed. | |
| 8054251 | Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and | 1994 May | The effects of three non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics of methotrexate were studied in 10 patients with rheumatoid arthritis. Ketoprofen (3 mg kg-1 day-1), flurbiprofen (3 mg kg-1 day-1), piroxicam (20 mg day-1), or a non-NSAID control (paracetamol/acetaminophen) were administered to patients for at least 6 days (13 days in the case of piroxicam to establish steady state) in a randomized crossover design prior to receiving a weekly oral dose of methotrexate. In the non-NSAID control portion of the study, MTX oral clearance (CLo) was 11.0 +/- 3.9 l h-1, renal clearance (CLR) was 7.9 +/- 2.8 l h-1, percent excreted unchanged was 72 +2- 19% and fraction unbound (fu) was 0.54 +/- 0.11. Values of oral clearance, renal clearance, fraction unbound and percentage excreted unchanged of methotrexate varied no more than 12.2% from non-NSAID control during concomitant administration of ketoprofen, flurbiprofen or piroxicam and were not statistically different from non-NSAID control. In contrast to other NSAIDs such as ibuprofen and salicylates, ketoprofen, flurbiprofen or piroxicam in clinically relevant doses do not appear to affect methotrexate disposition and may be used safely in combination with methotrexate. | |
| 8535650 | Adverse events in methotrexate-treated rheumatoid arthritis patients. | 1995 Nov | Methotrexate (MTX) is an antifolate that has been in use for the treatment of rheumatoid arthritis (RA) since the early 1980s. Its efficacy has been clearly documented [1-4] and its administration early in the course of the disease is now generally accepted [5]. Side-effects from low weekly pulse MTX have been reported [1-6] and it was our initial experience that toxicity, rather than lack of efficacy, was the major factor limiting its clinical use [7]. However, when compared with other disease-modifying antirheumatic drugs, its toxicity appears to be comparable to that of antimalarials [8, 9]. The purpose of this paper is to discuss the possible mechanisms responsible for toxicity due to MTX used at low weekly pulse doses for the treatment of RA, as well as the different toxic manifestations reported in the literature. | |
| 7738959 | Leukoencephalopathy in a patient taking low dose oral methotrexate therapy for rheumatoid | 1995 Feb | We describe the case of a man who developed a dementing illness with leukoencephalopathy while receiving low dose weekly oral methotrexate (MTX) therapy for rheumatoid arthritis. The white matter changes seen on magnetic resonance imaging and computerized tomogram scan were the same as those seen in cases of leukoencephalopathy that have been reported in patients receiving intravenous or intrathecal methotrexate. Extensive investigation excluded other known causes of white matter disease. Although no improvement either subjectively or objectively occurred in his mental status after cessation of treatment with MTX, he has remained stable. We believe that this may represent a case of oral MTX induced leukoencephalopathy, which has not previously been reported. | |
| 7586985 | Serum soluble interleukin-2 receptor levels in rheumatoid arthritis: effect of methotrexat | 1995 Jul | The aim of this study was to assess the correlations of the serum soluble interleukin 2 receptor (sIL-2R) concentrations with disease activity parameters and response to treatment with second line drugs in patients with rheumatoid arthritis (RA). Sixty-seven patients with active disease completed a 24-week, open, randomized study of methotrexate (MTX) versus sulphasalazine (SSZ) or hydroxychloroquine (HCQ). Serum sIL-2R levels were evaluated before entry and after 24 weeks by ELISA. Serum sIL-2R were significantly higher in RA patients than in controls (P = 0.0001) and correlated significantly only with erythrocyte sedimentation rate (P = 0.03) and with Chronic Arthritis Systemic Index (P = 0.01) at study entry. No correlation was found between serum sIL-2R and other laboratory and clinical indices of disease activity. After 24 weeks of treatment no differences in serum sIL-2R in comparison with basal levels were found in either responding or in non-responding patients, although the mean reduction of sIL-2R was more marked in the MTX-treated cohort than in the HCQ and SSZ-treated groups. These data suggest that in RA the measurement of sIL-2R should be used with caution as an isolated index of disease activity and that it is not a useful marker of response to treatment with second line drugs. | |
| 8627446 | Accelerated nodulosis during methotrexate therapy for juvenile rheumatoid arthritis. | 1996 May | We describe two patients with rheumatoid factor-positive, polyarticular-onset juvenile rheumatoid arthritis in whom accelerated nodulosis developed during methotrexate therapy. Although they had only a few nodules at diagnosis, the nodules increased in number and size 3 to 4 months after the start of methotrexate therapy in both patients. The nodules regressed after withdrawal of methotrexate therapy in one patient and were arrested with the addition of hydroxychloroquine in the other. Physicians treating patients with methotrexate for juvenile rheumatoid arthritis must be aware of this extraarticular side effect. | |
| 7697251 | Low-dose methotrexate may cause air trapping in patients with rheumatoid arthritis. | 1995 Apr | Both rheumatoid arthritis (RA) and methotrexate (MTX) are reported to be associated with the development of pulmonary disease. To determine whether MTX enhanced the risk of developing abnormalities in pulmonary function in patients with RA, we prospectively studied 31 subjects (12 male, 19 female) with the diagnosis of classic RA for an average period of 4.4 yr (range, 1 to 5 yr). Each subject was placed on low-dose weekly MTX (mean 17 mg, range 2.5 to 40) for control of RA symptoms. Other medications included non-steroidal anti-inflammatory agents and prednisone if required for control of arthritis symptoms. No other immunosuppressive therapy was used. Each subject was evaluated by pulmonary function tests (PFT) and chest X-ray initially, and at 1, 2, 3.5, and 5 yr. Chest X-rays obtained initially and at the end of the study period were found to be normal. The percent predicted values for initial PFTs in the study group were within the normal range. From the beginning to the end of the observation period, the following mean changes in lung function were observed: 1.9% increase in TLC, 5.1% increase in residual volume (RV), 1.8% increase in FVC, 0.71% decrease in FEV1, 14.7% improvement in alveolar-arterial oxygen (A-aO2) difference, and a 12.7% increase in single-breath diffusing capacity (DLCO). To determine whether MTX (average dose, weekly dose, or cumulative dose) was significantly related to changes in pulmonary function, we used multivariate techniques to control for the initial measure of lung function while assessing the relationship between MTX and the subsequent measures of lung function.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 8393676 | Circulating soluble tumor necrosis factor receptors, interleukin-2 receptors, tumor necros | 1993 Aug | OBJECTIVE: To assess whether circulating concentrations of soluble tumor necrosis factor receptors (sTNFR; p55 and p75), soluble interleukin-2 receptors (sIL-2R), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6) reflect clinical response and whether changes are dependent on the drug used in rheumatoid arthritis (RA) patients taking methotrexate (MTX) or azathioprine (AZA). METHODS: These cytokines and soluble receptors were assessed in 20 control subjects and serially for up to 48 weeks in 61 RA patients, by bioassay (IL-6) and immunoassays (sTNFR, sIL-2R, TNF alpha, and IL-6). RESULTS: Concentrations of p55 and p75, sIL-2R, and TNF alpha (but not IL-6) were significantly higher in RA patients than in controls. Significant decreases in sIL-2R and p55 concentrations were associated with clinical improvement and were observed in patients treated with MTX, but not AZA. Both treatments induced decreases in IL-6 concentrations, but circulating AZA (or its metabolites) appears to interfere with the measurement of IL-6 bioactivity. TNF alpha and p75 levels did not show significant changes. CONCLUSION: Measurement of circulating sIL-2R, p55, and IL-6 may be useful in the evaluation of RA disease activity and response to therapy. Interference by circulating levels of drugs must be ruled out when bioassays are used to evaluate cytokine levels. | |
| 8324945 | Early clinical studies of IL-2 fusion toxin in patients with severe rheumatoid arthritis a | 1993 Mar | DAB486IL-2 is the first of a new class of targeted biologicals called fusion toxins. This agent is an interleukin-2 receptor (IL-2R)-targeted cytotoxin which kills activated IL-2R-expressing lymphocytes at 10(-10) M concentrations. Since activated lymphocytes are thought to play a role in many autoimmune conditions, DAB486IL-2 has been evaluated in patients with severe rheumatoid arthritis and recent onset autoimmune insulin-dependent diabetes mellitus. Initial safety, pharmacokinetics and evidence of IL-2R specific cytotoxicity were obtained in patients with IL-2 receptor expressing malignancies; these studies served as a basis for the initiation of an open label phase I/II evaluation of DAB486IL-2 in patients with severe, methotrexate refractory rheumatoid arthritis. This pilot study provided preliminary evidence of acceptable safety at doses which induced meaningful (> 25%) or substantial (> 50%) improvement in 9 of 18 patients who received a mid (130 kU/kg/d) or a high (260 kU/kg/d) dose daily for 5 to 7 days. The most frequent adverse effects were transient hepatic transminase elevation and fever. Although some patients noted a transient increase in joint pain, onset of improvement occurred within 7 to 14 days of initiation of DAB486IL-2. Because of these results, a two-center, double-blind, placebo-controlled trial was conducted from December 1991 to December 1992. Forty-five patients with active severe RA unresponsive to at least 2 DMARDS were randomized to placebo or DAB486IL-2 following a 3 to 4 week washout/run-in period to establish a stable baseline (< 40% fluctuation in swollen and painful, tender joint counts).(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 7981988 | Circulating concentrations and production of cytokines and soluble receptors in rheumatoid | 1994 Nov | Methotrexate (MTX) is an effective treatment for RA and its effects may be partly due to cytokine modulation. Herein, we assessed the effects of a single MTX dose on the production and circulating concentrations of several cytokines and soluble receptors in 42 RA patients on three consecutive days. Three patient groups were studied: (a) 16 patients taking the first MTX dose, (b) 11 patients on chronic MTX treatment and (c) a control group of 15 patients not treated with MTX. Cytokine production was studied in peripheral blood mononuclear cells (PBMNC) and in a whole-blood culture system (WBCS). Group (a) had a more active disease according to laboratory parameters as well as higher circulating IL-6 levels (P = 0.002). The secretion of IL-1 beta by stimulated PBMNC (P = 0.008) was higher in this group and decreased significantly (P = 0.03) after a single MTX dose. No significant change in any parameter was observed after MTX in group (b). In the total patient group, circulating concentrations of IL-1 beta and TNF-alpha were low but blood cells showed a high capacity of production for these cytokines. In contrast for sTNFRs, high circulating levels but a limited in vitro production were observed. In conclusion, a single MTX dose may result in decreased production of IL-1 beta by PBMNC in patients with active RA. Furthermore, we observed an imbalance in the production of TNF-alpha and sTNFRs by peripheral blood cells of RA patients and propose that the WBCS is convenient for studying cytokine production in RA. | |
| 8978962 | High dose intravenous immunoglobulin (IVIg) in severe refractory rheumatoid arthritis: no | 1996 Nov | OBJECTIVE: A number of reports have recently suggested that high doses of intravenous immunoglobulins may exert beneficial effects in rheumatoid arthritis. One proposed mechanism for this effect is suppression of the generation of pro-inflammatory cytokines, particularly tumor necrosis factor alpha (TNF alpha). We have undertaken a prospective open study of IVIg in patients with severe refractory RA who have failed at least four second line drugs, including methotrexate, and who were receiving NSAIDs and prednisone only. METHODS: Four patients, 3 males and 1 female, with an average age of 58.25 years (range 41-69 years) and a mean disease duration of 13 years (range 9-14 years), were given IVIg at a dose of 1 g per day for 2 days once a month for 3 months. All patients had active disease at baseline as indicated by an average tender joint count of 15 and an average swollen joint count of 15.25. Clinical assessments were performed according to the WHO/ILAR recommendations at baseline and at monthly intervals up to 4 months after the initiation of IVIg therapy. Patients were classified as responders or non-responders according to the Paulus criteria. Laboratory assessment included a CBC, ESR, and whole blood cytokine ELISA for TNF alpha, TNF R1, and TNF R2 at baseline, 1 day, 7 days and 3 months after the initiation of therapy. RESULTS: None of the patients met the Paulus criteria for either improvement or worsening. Furthermore, increased TNF alpha production in lipopolysaccharide (LPS) stimulated whole blood assays was consistently noted in 3 out of the 4 patients during the course of therapy which, together with the lack of clinical efficacy, prompted us to curtail further evaluation of this therapy. CONCLUSION: We were unable to discern any beneficial effects of IVIg therapy, and suggestions that it may enhance TNF alpha generation as well as its substantial cost mandate caution in the future use of this agent in RA. | |
| 8849387 | Methotrexate-associated lymphoma in patients with rheumatoid arthritis: report of two case | 1996 Feb | This report describes 2 patients with longstanding seropositive rheumatoid arthritis (RA) treated with oral methotrexate (MTX) who developed large cell lymphoma of B cell phenotype. In situ hybridization studies showed nuclear staining for Epstein-Barr virus (EBV) within the malignant lymphoid cells. In both cases, the lymphoma was undetectable several weeks after diagnostic biopsy followed by discontinuation of MTX. These observations suggest that, in patients with RA who develop an EBV-associated lymphoproliferative disorder, a trial of discontinuation of immunosuppressive agents may be warranted before chemotherapy is considered. In addition, there is a need for a heightened awareness of the development of lymphoma in this patient population. | |
| 8877917 | Interleukin 1 (IL-1) receptor antagonist, soluble tumor necrosis factor receptors, IL-1 be | 1996 Sep | OBJECTIVE: To examine circulating levels of cytokines and cytokine inhibitors and their production by blood mononuclear cells (MNC) in patients with active rheumatoid arthritis (RA) before treatment with methotrexate (MTX) and inactive disease upon treatment as well as healthy control individuals. METHODS: Interleukin-1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptors p55 and p75 (sTNFr; p55 and p75), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8), and monocyte chemoattractant protein 1 (MCP-1) were assessed by immunoassays in sera and MNC culture supernatants of 27 patients with RA with active disease before and 14 patients with inactive disease during MTX treatment, and 10 healthy controls. RESULTS: Levels of circulating IL-1ra, sTNFr p55 and p75 were higher in patients with active RA compared to those with inactive disease or controls. At the cellular level, resting MNC of patients with active RA released more IL-1 beta and IL-8, but less IL-1ra, and showed a lower ratio of IL-1ra:IL-1 beta than MNC of patients without inflammatory symptoms or healthy controls. In addition, unstimulated and in vitro lipopolysaccharide stimulated MNC cultures of patients with inactive RA released higher amounts of sTNFr p75 than MNC of patients with active RA. CONCLUSION: Circulating levels of IL-1ra and sTNFr as well as IL-1 beta, IL-8, and sTNFr p75 release from MNC and the ratio of IL-1ra:IL-1 beta production by these cells serve as markers to assess complete disease remission in patients with RA during MTX treatment. | |
| 8871839 | Association of methotrexate and corticosteroids in the treatment of patients with rheumato | 1996 Jul | OBJECTIVE: To investigate whether the association of methotrexate (MTX) and corticosteroids introduced concomitantly is more effective than MTX alone in patients with rheumatoid arthritis (RA). METHODS: Twenty-eight RA patients (group 1) were treated with MTX (mean dose: 10 +/- 1.4 mg/week) and corticosteroids (mean dose: 14.9 +/- 5.6 mg/day, range: 5-25) introduced concomitantly, and were compared to 251 RA patients (group 2) treated with MTX alone (mean dose: 9.8 +/-1.5 mg/week). Variations in the clinical (number of swollen and painful joints, morning stiffness, Ritchie's articular index), biological (ESR, CRP), and radiological parameters were studied. Remission was defined according to Pinals' criteria. At baseline, there were no significant differences between the two groups, except for a greater number of swollen and painful joints in group 1 (p = 0.03 and p = 0.01, respectively). The total MTX dose and the duration of treatment (26 +/- 21.8 months in group 1 versus 33.5 +/- 27.2) months in group 2) did not differ between the two groups. RESULTS: We noted a more marked reduction in the number of swollen and the number of painful joints in group 1 (p = 0.03). No differences were noted for the other clinical and biological parameters. The proportion of patients fulfilling Pinals' remission criteria was higher in group 1 (25% versus 10.1% in group 2, p = 0.04). The steroid dosage could be significantly reduced in group 1 (-3.4 +/- 6.1 mg/day, p = 0.05) and corticosteroids were stopped in 11 patients. The frequency and type of side effects, as well as the frequency and reasons leading to MTX withdrawal, did not significantly differ between the two groups. CONCLUSION: The association of MTX and corticosteroids seems to bring about a greater improvement in the different clinical activity parameters of RA than MTX alone, without any significant increase in the frequency of side effects. These results need to be confirmed in larger scale prospective studies. |