Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 11224479 | Current understanding of methotrexate pharmacology and efficacy in acute leukemias. Use of | 2001 Feb | BACKGROUND AND OBJECTIVES: Methotrexate (MTX) is a key drug in the curative regimen of children with acute lymphocytic leukemia. This drug is widely used not only in the treatment of neoplastic diseases such as leukemia, lymphoma, choriocarcinoma, head and neck cancer and osteogenic sarcoma, but also for various autoimmune diseases, e.g., rheumatoid arthritis and psoriasis, and for the prevention of graft-versus-host disease after transplantation. The development of drug resistance is the limiting factor in the use of MTX. This review will outline the mechanisms of acquired and natural resistance to MTX that have been studied in patients affected by acute lymphocytic leukemia and acute myelocytic leukemia and the cell cycle genes involved in MTX resistance. This information may improve the use of MTX or could lead to the development of better drugs. Moreover a short description of newer antifolates with their mechanisms of action is presented. EVIDENCE AND INFORMATION SOURCES: The authors of this review have a long-standing interest in the mechanism of action of and resistance to MTX and other antifolates. Information from journal articles covered by the Science Citation Index and Medline has been reviewed together with work performed by the authors. PERSPECTIVES: Antifolates continue to be an extremely important class of drugs for the treatment of non-neoplastic as well as neoplastic diseases. New inhibitors that target dihydrofolate reductase as well as other folate-dependent enzymes are being evaluated in the clinic, and show promise. | |
| 11587095 | Drug-induced pneumonitis: the role of methotrexate. | 2001 Oct | Methotrexate (MTX) is a folate antagonist used in several chronic inflammatory and neoplastic conditions. Pulmonary toxicity occurs in 0.5% to 14% of patients receiving low-dose MTX. Manifestations of pulmonary toxicity are protean and include parenchymal inflammation, pneumonia, airway hyperreactivity, air trapping and possibly neoplasm. We performed an exhaustive review of the English literature and identified 189 cases of methotrexate-induced pneumonitis (MIP). Rheumatoid arthritis (RA) was the most frequent underlying disease. In most patients, symptoms present subacutely with progression over several weeks. Most patients present with dyspnea, dry cough, fever, and bibasilar crackles. Peripheral eosinophilia has been cited in one third of cases. The chest radiograph may be normal, but more commonly reveals bilateral interstitial or mixed, interstitial and alveolar infiltrates with a predilection for the bases. Chest computed tomography (CT) scans demonstrate ground-glass opacities, interstitial infiltrates, septal lines or widespread consolidation. Pulmonary function studies reveal a restrictive ventilatory defect and/or impaired gas exchange. Bronchoalveolar lavage (BAL) may be helpful in ruling out an infectious etiology and in supporting the diagnosis of MIP. Cellular interstitial infiltrates, granulomas, fibrosis, atypical epithelial cells, and diffuse alveolar damage (DAD) are the main histologic features. Once MIP is suspected, the MTX should be withdrawn. Corticosteroids may accelerate resolution and are recommended in severe or fulminant cases. The prognosis of MIP is usually favorable, but occasionally the outcome may be fatal. | |
| 11577996 | Establishment of a consistent L929 bioassay system for TNF-alpha quantitation to evaluate | 2001 Aug | TUMOR necrosis factor-alpha (TNF-alpha) plays an important role in the pathogenesis of rheumatoid arthritis. The present study was to evaluate the effects of lipopolysaccharide (LPS), phytomitogens and cytodifferentiation agents on cytotoxicity of TNF-alpha secreted by adherent human mononuclear cells (AMC). TNF-alpha cytotoxicity in LPS-treated, phytomitogen-treated, and cytodifferentiation agent-treated AMC supernatants were analyzed by the L929 bioassay system. Our results showed that LPS could induce homogeneous TNF-alpha production by AMC whereas, in addition to TNF-alpha, phytomitogens could also induce other TNF-like factors. Neither methotrexate, retinoic acid nor sodium butyrate can inhibit TNF-alpha cytotoxicity, while hexamethylene bisacetamide could not only inhibit TNF-alpha cytotoxicity but also TNF-alpha inducing ability of LPS to AMC. | |
| 9031380 | Immunosuppressive drug use during pregnancy. | 1997 Feb | Women with rheumatic diseases frequently need treatment throughout pregnancy and lactation. Physicians must confront the dual challenge of monitoring the possible effects of the underlying maternal disease and the medications on both mother and child. It is essential that the maternal disease be well controlled before, during, and after pregnancy to ensure the best possible outcome for the mother and child. Corticosteroids have been used extensively and safely in pregnant patients with systemic lupus erythematosus and rheumatoid arthritis; there have been no reports of congenital malformations in the exposed infants. There is considerable experience using azathioprine during pregnancy if the maternal condition requires use of a cytotoxic drug; there has been no increased risk of congenital malformations in the exposed infants. There is limited information on the safety of other medications, including 6-mercaptopurine, cyclophosphamide, and cyclosporine. Methotrexate is contraindicated during pregnancy, and chlorambucil should be avoided because there are other effective immunosuppressive agents available for use. Corticosteroids (prednisone and methylprednisolone) can be used safely during lactation. All other immunosuppressive medications, azathioprine and 6-mercaptopurine, chlorambucil, cyclophosphamide, cyclosporine, and methotrexate, are contraindicated during lactation. | |
| 10922951 | [Drug-induced oral ulcerations]. | 2000 Jun | Different side effects of drugs have been described in the oral cavity, including oral ulcerations. Direct contact between drugs and oral mucosa may induce chemical burn or local hypersensitivity. Less frequently, these drug-induced oral ulcerations are part of a complex reaction with cutaneous or systemic manifestations. Sometimes, one or more oral ulcerations appear as the main side-effect of a drug, or exceptionally as solitary lesions. Solitary oral ulcerations usually appear after few weeks of treatment. In most of cases, these lesions resist to conventional treatments, with a rapid healing following the suppression of the responsible drug. This diagnosis is usually difficult, particularly with patients receiving multiple drug therapy. Besides, special attention must be paid to new drugs. Oral ulcerations following symptoms of burning mouth, metallic taste, dysgueusia or agueusia are strongly suggestive of a pharmacological origin. Most of the molecules able to induce solitary oral ulcerations are commonly prescribed in a) rheumatology: NSAI (diclofenac, flurbiprofen, indomethacin, naproxen), long-term rheumatoid arthritis therapy (azathioprine, methotrexate, penicillamine, gold compounds, tiopronin); b) cardiology: angiotensin-converting-enzyme inhibitors (captopril, enalapril), angiotensin 2-receptor antagonist (losartan), anti-angorous (nicorandil), c) psychiatry: antidepressants (fluoxetine, lithium), d) AIDS therapy (foscarnet, zalcitabine). | |
| 10063803 | Light activates reduction of methotrexate by NADPH in the ternary complex with Escherichia | 1999 Jan | Methotrexate (MTX), a strong inhibitor of dihydrofolate reductase (DHFR), has been widely used for chemotherapy for many types of cancer as well as for juvenile rheumatoid arthritis. It mimics folate substrates and binds tightly to the active site of DHFR, perhaps in a conformation close to the transition state of the folate catalyzed reaction. Absorption, fluorescence and ultrasensitive Raman difference spectroscopies show that light-activated MTX reacts with NADPH in the enzyme active site, producing 5,8-dihydromethotrexate (5,8-dihydro-MTX) and NADP+. The reaction, which proceeds with a hydride transfer between C4 (pro-R side) of the nicotinamide ring and N5 of the pteridine ring, is similar to that between folate and NADPH except that the hydride is transferred to C6 in this case. Hence, MTX is catalytically competent in its excited state. Most experiments were performed on the Escherichia coli enzyme, but preliminary studies show that the reaction also occurs with human DHFR. | |
| 9133925 | Effect of methotrexate and sulphasalazine on UMR 106 rat osteosarcoma cells. | 1997 Feb | Methotrexate is commonly used in the treatment of rheumatoid arthritis. An osteopathy has been described in children treated with methotrexate for leukaemia, consisting of bone pain, osteoporosis and fractures. Animals given short-term high-dose and long-term low-dose methotrexate have both reduced bone formation and increased resorption on histomorphometry. As patients with rheumatic diseases have numerous risk factors for osteoporosis, possible additional risk from low-dose methotrexate is of relevance to the rheumatologist. To investigate further the mechanism of osteoporosis in animals and man, in vitro studies were carried out on an osteoblast cell line, using concentrations found in patients with rheumatic disease. UMR 106 rat osteoblast-like osteosarcoma cells were incubated with methotrexate, and also with sulphasalazine, an anti-rheumatic drug with no known effect on bone, for comparison. A dose-dependent toxic effect of methotrexate on the cell line was observed using concentrations found in patients with rheumatic disease. This was not observed with sulphasalazine. The reduced bone formation observed in animals and man may be due to a direct effect of methotrexate on the osteoblast. | |
| 9972972 | Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease. | 1999 Feb | OBJECTIVE: Adult Still's disease (ASD) is a rare chronic polyarthritis, usually treated with corticosteroid therapy. Because some patients become dependent on high dose prednisone or are refractory to that treatment, and because adverse events are frequent with corticosteroid, we evaluated the efficacy of low dose methotrexate (MTX) as a second-line drug. METHODS: We retrospectively studied 26 patients with ASD treated with low dose MTX because their disease was either resistant to or dependent on corticosteroids. RESULTS: The group included 13 women and 13 men, with a mean age of 32.6 years at onset of ASD. Mean disease duration at the beginning of MTX treatment was 59.9 mo (range 7 to 444). Evaluation took place at the maximum followup, which averaged 48.9 mo (range 8 to 136). The mean dose of MTX was 11.5+/-3.6 mg/week (range 7.5 to 17.5). Twenty-three patients responded to MTX; 18 had complete remission. No difference was seen between patients with or without extraarticular manifestations. Leukocyte and neutrophil counts and erythrocyte sedimentation rate were significantly reduced (p = 0.0001). Daily prednisone intake decreased by 69% (21.5 mg) (p = 0.0001). Eleven patients were able to stop taking corticosteroids. One patient with AA amyloidosis renal failure died of neutropenia: this was the only serious adverse event. CONCLUSION: MTX is an effective second-line treatment of ASD that does not respond to prednisone. It allows significant reduction of corticosteroid doses, which is beneficial to these patients, who have frequent and numerous corticosteroid related adverse events. | |
| 9361162 | The remarkable spectrum of methotrexate toxicities. | 1997 Nov | This article outlines a general scheme for categorizing medication-related adverse events. This is followed by a review of the less well-recognized adverse events attributed to low-dose methotrexate therapy. Known and suspected risk factors are described and causative mechanisms are suggested. Ultimately, this article aims at increasing the readers awareness of uncommon or underreported methotrexate-associated adverse events so that prescribing and monitoring practices can be tailored to enhance the safe use of this valuable antirheumatic agent. | |
| 10807299 | Improving rheumatologists' screening for alcohol use and sexual activity. | 2000 May | OBJECTIVES: To design, implement, and assess the impact of an office-based intervention designed to improve rheumatologists' identification of risk behaviors, especially alcohol use and sexual activity, among adolescents and young adults with chronic rheumatologic conditions. DESIGNS: Prospective intervention study. SETTING: Midwestern academic pediatric rheumatology practice. PARTICIPANTS: Ten attending rheumatologists and fellows and 178 patients (mean age, 18.1 years; 67% female; 88% white; 69% with juvenile rheumatoid arthritis) seen in the practice during the baseline and intervention years. MAIN OUTCOME MEASURES: Change in the rate of screening for alcohol use and sexual activity from the baseline to the intervention year, and physician perceptions of the intervention. RESULTS: Screening for alcohol use increased from 4.2% (9/208) at baseline to 31.6% (56/177) after the intervention (P<.001). Of those patients undergoing screening at follow-up, 20 (36%) of 56 patients reported any alcohol use and 11 (20%) reported current alcohol use. Of those reporting current use, 7 (64%) were counseled or referred. Methotrexate use increased the likelihood of alcohol screening (43% [33/76] vs 26% 123/871; P = .02). Screening for sexual activity increased from 12.4% (27/ 218) to 36.2% (64/177) (P<.001) from baseline to follow-up. Of 52 females undergoing screening at follow-up, 31 (60%) were sexually active. Eleven (41%) of 27 sexually active females were not using contraception other than condoms (4 were not asked about contraception); 7 (82%) of these were referred for contraceptive counseling. Seven rheumatologists completed in-depth semistructured interviews after the intervention. All reported time as a main barrier to screening. Other barriers included logistical problems, discomfort with the subject area, ambivalence about whether risk behavior screening is the province of pediatric rheumatologists, and perceived lack of applicability to their patients. CONCLUSIONS: Despite knowledge and concern about the interaction of immunosuppressive therapy and risk behaviors, few rheumatologists adequately screen the behavior of their adolescent and young adult patients. Time constraints, organizational issues, and physician beliefs remain barriers to widespread screening. | |
| 10027640 | Improved high-performance liquid chromatography determination of methotrexate and its majo | 1999 Jan 8 | A sensitive high-performance liquid chromatographic assay has been developed for measuring plasma concentrations of methotrexate and its major metabolite, 7-hydroxymethotrexate. Methotrexate and metabolite were extracted from plasma using solid-phase extraction. An internal standard, aminopterin was used. Chromatographic separation was achieved using a 15-cm poly(styrene-divinylbenzene) (PRP-1) column. This column is more robust than a silica-based stationary phase. Post column, the eluent was irradiated with UV light, producing fluorescent photolytic degradation products of methotrexate and the metabolite. The excitation and emission wavelengths of fluorescence detection were at 350 and 435 nm, respectively. The mobile phase consisted of 0.1 M phosphate buffer (pH 6.5), with 6% N,N-dimethylformamide and 0.2% of 30% hydrogen peroxide. The absolute recoveries for methotrexate and 7-hydroxymethotrexate were greater than 86%. Precision, expressed as a coefficient of variation (n=6), was <10% at each of five methotrexate concentrations in the range 2.5-50 ng/ml. The limits of quantitation of methotrexate were 1 and 2.5 ng/ml for methotrexate and 7-hydroxymethotrexate, respectively (using 1 ml plasma). A robust HPLC method has been developed for the reproducible quantitation of methotrexate in plasma of patients taking a weekly dose of methotrexate for rheumatoid arthritis. | |
| 9797568 | Effects of methotrexate on normal articular cartilage in vitro and in vivo. | 1998 Jul | OBJECTIVE: Methotrexate (MTX) has become the disease modifying drug of choice for the treatment of rheumatoid arthritis (RA). Direct effects of MTX on articular cartilage in vivo and in vitro were studied to determine possible adverse effects of the drug. METHODS: For in vitro experiments, adult bovine articular cartilage explants were cultured in the presence of MTX (0 to 100 microM), and effects on DNA and matrix metabolism were studied. For in vivo studies, 48 adult female rabbits were treated with MTX (30 mg/kg/week intramuscularly) or placebo, respectively, for up to 12 weeks, and effects on the cartilage of the femoral condyles were assessed. RESULTS: In vitro, MTX dose dependently increased the uptake of [3H]-thymidine, and decreased incorporation of [3H]-d-uridine into chondrocytes with a half maximal effect at 0.03 microM, suggesting inhibition of thymidylate-synthetase activity by the drug. MTX also dose dependently reduced the proportion of chondrocytes in S-phase, as determined by flow cytometry. MTX did not affect LDH release from chondrocytes or the proportion of viable cells, nor did it change the rate of protein synthesis, proteoglycan synthesis, proteoglycan breakdown, or the hydrodynamic size of newly synthesised proteoglycans. In vivo, MTX did not appreciably affect proteoglycan synthesis of the chondrocytes, proteoglycan content of the cartilage matrix, density of the chondrocyte population, or histological integrity of the cartilage. CONCLUSIONS: The data suggest the absence of major adverse effects by MTX on articular cartilage proteoglycan metabolism. Chondrocyte DNA metabolism seems to be changed by MTX only in concentrations and exposition periods clearly exceeding those found in synovial fluid of RA patients receiving the commonly prescribed doses of the drug. | |
| 11138330 | The effects of low-dose methotrexate on thymidylate synthetase activity in human periphera | 2000 Nov | OBJECTIVE: Methotrexate (MTX) in low doses is widely used in the treatment of rheumatoid arthritis (RA) and it is not known whether its effects are due to immunosuppressive and/or anti-inflammatory actions. High concentrations of MTX inhibit the activity of thymidylate synthetase (TS) and dihydrofolate reductase essential for DNA synthesis. This study investigated the effects of low-dose MTX on TS activity and proliferation in human peripheral blood mononuclear cells (PBMC). METHODS: The MTX concentrations in our experiments were chosen according to the plasma concentrations measured in 8 RA patients treated with MTX. The effect of MTX on TS activity and DNA synthesis were measured in stimulated normal PBMC and in PBMC obtained from 6 RA patients treated with oral MTX before and 2 hours after intake of their weekly MTX dose. The effect of MTX on the TS mRNA concentration was also investigated in order to elucidate its effect on TS production. RESULTS: Low-dose MTX significantly inhibited TS activity and the proliferation of stimulated PBMC independent of the mode of activation. Interestingly, the concentration of TS mRNA in normal PBMC was upregulated by the presence of MTX. Finally, there was no difference between TS activity measured before and after MTX intake in 6 RA patients on long-term MTX treatment. CONCLUSION: We show that low concentrations of MTX inhibit TS activity in vitro. An in vivo effect cannot, however, be proven given our study design. The role of these in vitro findings is discussed, particularly in relation to the in vivo effects of MTX. | |
| 9811059 | Effects of methotrexate on differentiation of monocytes and production of cytokine inhibit | 1998 Nov | OBJECTIVE: To examine the potential of methotrexate (MTX) to act as a differentiation-stimulating factor for monocytes, which could explain the antiinflammatory properties of this agent in the treatment of rheumatoid arthritis (RA). METHODS: Fluorescence-activated cell sorter analysis was used to measure the changes in antigen expression (CD11b/c, CD16, CD64, CD14, CD68, and CD95) in response to MTX, 1,25-OH-cholecalciferol (1,25-OH-CCF), and granulocyte-macrophage colony-stimulating factor in the human monoblastic leukemia cell line U937, bone marrow mononuclear cells (BMMC), and peripheral blood mononuclear cells (PBMC). Release of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), tumor necrosis factor a, and soluble tumor necrosis factor receptors (sTNFR) p55 and p75 during the differentiation in vitro was assessed by immunoassay in the culture supernatants. RESULTS: MTX alone and in combination with 1,25-OH-CCF markedly stimulated the differentiation of the monocytic U937 cells and simultaneously increased Fas-antigen expression. Differentiation was associated with enhanced IL-1Ra and sTNFR p75 release from U937 cells. MTX had fewer effects on phenotypic differentiation of human BMMC and PBMC, but did stimulate IL-1Ra release and inhibit IL-1beta synthesis in BMMC. CONCLUSION: MTX acts as a strong differentiation factor for immature and undifferentiated monocytic cells. Differentiation in vitro is associated with an increase in natural cytokine inhibitor release and a simultaneous down-regulation of IL-1beta. These findings may explain the marked clinical antiinflammatory effects of MTX when used in the treatment of RA. | |
| 11357886 | Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation me | 2001 Apr | The objective of this study was to investigate the therapeutic potential of FK506 and other immunosuppressive agents for the treatment of rheumatoid arthritis (RA), focusing on the effects on in vitro IL-6 production and IL-6-mediated immune response. We employed an in vitro model producing IL-6 via T cell activation in human PBMC, based on the hypothesis that T cells play a central role in the pathogenesis of RA. FK506 potently inhibited IL-6 production from PBMC stimulated with anti-CD3 and anti-CD28 monoclonal antibody (anti-CD3/CD28). Cyclosporin A (CsA) also inhibited the anti-CD3/CD28 induced IL-6 production but was about 100 times less potent than FK506. Dexamethasone (DEX) inhibited both anti-CD3/CD28 and LPS induced IL-6 production at almost the same concentration. Methotrexate (MTX) did not affect cytokine production. Anti-CD3/CD28 stimulated PBMC culture supernatants were found to enhance IgM production in SKW6.4 cells. The effects of anti-CD3/CD28 stimulated culture supernatants in the presence of agents on IgM production in SKW6.4 cells were investigated. FK506 and CsA led to suppression of IgM production induced by culture supernatants probably via inhibition of IgM inducible cytokine production from PBMC. DEX profoundly enhanced IgM production, although IL-6 production from PBMC was strongly inhibited by the agent. MTX decreased IgM production although it has no inhibitory effect on IL-6 production. The present study suggests that FK506 is the most effective among the four agents for the suppression of IL-6 production and IL-6-mediated autoantibody production in T cell activation related autoimmune diseases such as RA. | |
| 9113437 | Clinical pharmacokinetics of naproxen. | 1997 Apr | Naproxen is a stereochemically pure nonsteroidal anti-inflammatory drug of the 2-arylpropionic acid class. The absorption of naproxen is rapid and complete when given orally. Naproxen binds extensively, in a concentration-dependent manner, to plasma albumin. The area under the plasma concentration-time curve (AUC) of naproxen is linearly proportional to the dose for oral doses up to a total dose of 500 mg. At doses greater than 500 mg there is an increase in the unbound fraction of drug, leading to an increased renal clearance of total naproxen while unbound renal clearance remains unchanged. Substantial concentrations of the drug are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Relationships between the total and unbound plasma concentration, unbound synovial fluid concentration and therapeutic effect have been established. Naproxen is eliminated following biotransformation to glucuroconjugated and sulphate metabolites which are excreted in urine, with only a small amount of the drug being eliminated unchanged. The excretion of the 6-O-desmethylnaproxen metabolite conjugate may be tied to renal function, as accumulation occurs in end-stage renal disease but does not appear to be influenced by age. Hepatic disease and rheumatoid arthritis can also significantly alter the disposition kinetics of naproxen. Although naproxen is excreted into breast milk the amount of drug transferred comprises only a small fraction of the maternal exposure. Significant drug interactions have been demonstrated for probenecid, lithium and methotrexate. | |
| 9152796 | Malignant lymphoma in patients with rheumatic diseases other than Sjögren's syndrome: a c | 1997 Apr | We conducted clinicopathologic and immunohistochemical analysis of five patients with malignant lymphoma complicating rheumatic diseases other than Sjögren's syndrome, and reviewed 26 cases of similar lesions reported in the Japanese literature over a 17-year period. All five patients were women ranging in age from 31 to 74 years (mean 55 years). Two of them fulfilled the diagnostic criteria for systemic lupus erythematosus, two for dermatomyositis and one for progressive systemic sclerosis. The use of immunosuppressive drugs before the onset of malignant lymphoma was recorded in four patients. All the biopsied or resected specimens showed non-Hodgkin's lymphoma of B-cell phenotype. Three were nodal in origin (one diffuse mixed, one diffuse large cell and one immunoblastic) and two were extranodal (one low-grade B-cell lymphoma of mucosa-associated lymphoid tissue and one diffuse large cell). In three of four cases examined, Epstein-Barr virus-encoded small RNAs were identified in a small to large number of the lymphoma cells by in situ hybridization. Our study showed that the clinicopathological features of malignant lymphomas complicating rheumatic disease in Japan were similar to those in England and the USA. Furthermore, our findings suggested no evidence for a causative association between iatrogenic immunosuppression due to methotrexate therapy and the development of EBV-related lymphoid neoplasms. | |
| 9256610 | [Effective treatment with low-dose methotrexate pulses of a child of mixed connective tiss | 1997 Jun | A 13-year-old girl with mixed connective tissue disease (MCTD) was described. She visited our hospital with recurrent parotid gland swelling, arthritis, and myositis. Sclerodactyly and Raynaud's phenomenon were also defined, and the laboratory findings of high titers of antinuclear antibody (speckled type), positive anti-RNP antibody, positive rheumatoid factor, and hypergammaglobulinemia suggested the diagnosis of MCTD associated with Sjögren syndrome. The muscle weakness and the increased levels of CK prompted us to examine the muscle biopsy and to perform the electromyography, both of which suggested severe muscle inflammation. The siarography and lip biopsy indicated definitively the association of Sjögren syndrome. Corticosteroid therapy including methyl-prednisolone pulses was started, but the effects were limited. The addition of low-dose methotrexate effectively lowered the levels of CK, and gradually improved the muscle strength. Thus, low-dose methotrexate therapy is recommended to the patients with MCTD who have severe myositis refractory to corticosteroid. | |
| 11095334 | Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disea | 2000 Nov | OBJECTIVE: Methotrexate is currently used as a treatment for refractory inflammatory bowel disease. This study sought to evaluate the hepatic effects of long-term methotrexate therapy in patients with inflammatory bowel disease and to determine whether the established guidelines for monitoring methotrexate-related hepatotoxicity with surveillance liver biopsy in patients with psoriasis or rheumatoid arthritis are applicable to these patients. METHODS: Thirty-two patients with inflammatory bowel disease receiving cumulative methotrexate doses of > or = 1500 mg were studied. Liver chemistry tests were obtained before and during therapy. Twenty patients underwent liver biopsies as recommended for methotrexate-treated patients with psoriasis; the biopsies were reviewed and graded according to Roenigk's criteria for methotrexate-induced hepatotoxicity (a grading system for methotrexate hepatotoxicity in psoriasis patients) by a liver pathologist blinded to the methotrexate dose. RESULTS: In patients who had liver biopsies, the mean cumulative methotrexate dose was 2633 mg (range, 1500-5410 mg), given for a mean of 131.7 wk (range, 66-281 wk). Nineteen of 20 patients (95%) had mild histological abnormalities (Roenigk's grade I and II), and one patient had hepatic fibrosis (Roenigk's grade IIIB). Abnormal liver chemistry tests, present in 6 of 20 (30%) patients, did not identify the patient with Roenigk's grade IIIB hepatotoxicity. CONCLUSIONS: Cumulative methotrexate doses up to 5410 mg given up to 281 wk in patients with inflammatory bowel disease are associated with little hepatotoxicity. Surveillance liver biopsies based on cumulative methotrexate doses are not warranted in these patients. | |
| 11426028 | Hyperhomocysteinaemia in Behçet's disease. | 2001 Jun | OBJECTIVE: Arterial and venous thrombosis are among the clinical features of Behçet's disease (BD), the pathogenesis of which is not completely understood. In this study, we investigated whether hyperhomocysteinaemia, being a well known risk factor for thrombosis, is also a contributive risk factor for the arterial and venous thrombosis of BD. METHODS: Eighty-four patients fulfilling the criteria of the International Study Group for Behçet's Disease (54 males, 30 females, mean age 36+/-9 yr) were enrolled. All the patients were carefully screened for a history of venous thrombosis and were separated into two groups with respect to thrombosis history. Thirty-six healthy individuals (23 males, 13 females), matched for age and sex with the BD group, were included as a negative control group. Patients were excluded if they had any condition that might affect plasma homocysteine concentration. As methotrexate (MTX) causes hyperhomocysteinaemia, we also included 29 rheumatoid arthritis patients (five males, 24 females) receiving MTX weekly. Fasting plasma homocysteine concentrations were measured by high-performance liquid chromatography. The data were analysed with the chi(2) test and Student's t-test. RESULTS: The highest homocysteine concentrations were found in the MTX group (17.5+/-5.3 micromol/l). Mean plasma homocysteine concentrations in BD patients were significantly higher than in the healthy controls (11.5+/-5.3 vs. 8.8+/-3.1 micromol/l, P<0.001). Among BD patients with a history of thrombosis, 20 of 31 (64%) had hyperhomocysteinaemia, and this was significantly higher than in those without thrombosis (9%). On the other hand, there was no significant difference between patients with non-thrombotic BD and healthy controls (P>0.05). In patients with thrombosis, we found no correlation between the duration of the post-thrombotic period and homocysteine concentration. Among all the variables investigated, only hyperhomocysteinaemia was found to be related to thrombosis. CONCLUSION: Hyperhomocysteinaemia may be assumed to be an independent risk factor for venous thrombosis in BD. Unlike the factor V Leiden mutation, hyperhomocysteinaemia is a correctable risk factor. This finding might lead to new avenues in the prophylaxis of thrombosis in BD. |