Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 8396846 | Methotrexate: new mechanisms and old toxicities. | 1993 | Over the last several years, information on methotrexate's mechanism(s) of action (which affects its efficacy) and toxicities continue to evolve. This popular second line agent (DMARD) is a potent anti-inflammatory drug, with effects on LTB4 and adenosine release (EC-50: 1-13 nM). As such, it may be a sufficiently potent anti-inflammatory drug to affect rheumatoid arthritis's basic course, as shown by a recent meta-analysis where methotrexate equalled gold and was better than azathioprine, when examining radiographic erosions. Its toxicities continue to be documented, with cirrhosis occurring between 2:100 and 1:1000 cases. Pneumonitis continues to be found. NSAID-MTX interactions, too, have been documented, although their kinetic mechanisms remain controversial. | |
| 8913793 | In vitro and in vivo biological activities of a novel nonpolyglutamable anti-folate, MX-68 | 1996 Oct | MX-68 is a newly synthesized anti-folate, chemically designed not to undergo intracellular polyglutamation and to have increased affinity to dihydrofolate reductase (DHFR). In the present study, we examined the in vitro and in vivo biological activities of MX-68 compared with methotrexate (MTX) which forms several polyglutamates intracellularly. MX-68 dose-dependently inhibited the proliferation of PHA-, anti-CD3-, or PMA plus ionomycin-stimulated peripheral blood mononuclear cells (PBMC) and endothelial cells (EC) from normal subjects as well as IL-1 beta- or TNF alpha-stimulated synovial fibroblastic cells (SC) from rheumatoid arthritis (RA) patients. Coaddition of folinic acid completely reversed the anti-proliferative effects of both MX-68 and MTX. Although the anti-proliferative activities of MX-68 were almost comparable to those of MTX, the washout study clearly showed the characteristic nature of MX-68. When drugs were removed during culture, the suppressive effect of MX-68 completely disappeared, whereas suppression by MTX was merely weakened. MX-68 dramatically suppressed the onset of collagen-induced arthritis (CIA) in mice when the drug was orally administered three times a week. starting from the day of first immunization. In this model, 2 mg/kg of MX-68 was sufficient to completely suppress arthritis, whereas suppression by the same dose of MTX was partial. These lines of evidence suggest that polyglutamation is not always a prerequisite in the anti-rheumatic effects of anti-folate. In addition, since intracellular accumulation of polyglutamates is thought to have adverse effects, MX-68 may become a more potent and less toxic anti-rheumatic drug than MTX. | |
| 8805017 | The glucocorticoid insensitivity syndrome. | 1996 | Recent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively 'hypersensitive' to glucocorticoids, while 2.3% are relatively 'resistant'. These abnormalities might explain the well-known phenomenon that some individuals develop severe adverse effects during therapy with a low dose of glucocorticosteroids, while others do not develop side effects even during long-term therapy with a much higher dose. This heterogeneity in glucocorticoid sensitivity in the normal population might eventually allow the prediction of a 'safe' dose of glucocorticosteroids in individual patients. 'Resistance' to the beneficial clinical effects of glucocorticosteroid therapy in some patients with severe rheumatoid arthritis and asthma is probably seldom related to generalized primary (hereditary) glucocorticoid resistance. In most patients this 'resistance' seems to be acquired and localized to the inflammation sites, where it is caused by high local cytokine production which interferes with glucocorticoid action. Recognition of localized, acquired glucocorticoid resistance is of great importance, as alternative drug therapy with other immune-modulating drugs, such as cyclosporin and methotrexate, should be considered. Chronic high-dose glucocorticosteroid treatment in such patients insufficiently reduces symptomatology, while generalized side effects occur, as the rest of the body of the patient has a normal sensitivity to these drugs. | |
| 7523242 | Immunosuppressive agents in chronic severe asthma. | 1994 May | Previous immunosuppressive agents utilized as therapies for immune system mediated diseases such as chronic allergic asthma, and rheumatoid arthritis include purine antagonists, methotrexate, and gold salts. These treatment modalities have been shown to elicit either limited treatment efficacy or to produce undesirable side effects in many individuals. Cyclosporin A is a potent immunosuppressive agent which appears to arrest division of T lymphocytes and inhibit mediator release from mast cells. However, like other immunosuppressive agents, cyclosporin A may also produce many potentially serious side effects; among these is the possibility of irreversible renal damage. Nephrotoxicity can be attenuated, because renal pathological changes seem to be high cumulative dose-related. If whole blood levels of cyclosporin A are maintained between 200 and 500 ng/mL, serious renal toxicity is unusual. Investigation of cyclosporin A in individuals who have severe long-term corticosteroid-dependent chronic asthma has demonstrated the efficacy of this agent, resulting in clinically significant improvement in pulmonary function. Therefore, it can be hypothesized that T lymphocytes may act as effector cells in cell-mediated hypersensitivity reactions in atopic allergic inflammation. | |
| 1615302 | [Vasculitic skin lesions caused by nonsteroidal anti-inflammatory agents]. | 1992 Jun 13 | Today, non-steroidal anti-inflammatory drugs are very frequently prescribed agents. These drugs are responsible for side effects which are rarely recognized and poorly understood. One of these side effects is leukocytoclastic vasculitis with or without skin ulcerations. Rheumatoid arthritis and other mixed connective tissue diseases may also lead to vasculitis ulcerations, which explains the difficulty of correct diagnosis in each case. In addition, disease-modifying drugs such as methotrexate, frequently used in the above-mentioned syndromes, further complicate the situation because these agents may also produce vasculitis. In the present case study we analyze and discuss the diagnosis and follow-up in three of our patients with vasculitis skin ulcerations. In two of them, the vasculitis was attributed to the use of naproxen. Despite thorough examination and documentation of all three cases, etiologic evaluation was difficult and complex. | |
| 8763101 | [Fatal infectious complications in 2 patients with adult onset Still disease]. | 1996 | If adult Still's disease (ASD) can sometimes lead to severe destructive joint lesions and to various systemic manifestations, life-threatening complications are very rare. However, a long-term and high-dose corticosteroid therapy is often required to control the disease, with frequent corticodependence. Some authors have proposed methotrexate as a second line drug for ASD, that could permit a corticosteroid sparing effect. We report two cases of acute fatal infectious complications--legionella pneumonitis and multiple brain abscess caused by Nocardia asteroides--in two patients treated for ASD with both corticosteroids and methotrexate. These two cases raise the problem of the immunodepression induced by this combination therapy and point out the difficulties in aggressive forms of ASD. | |
| 7473485 | Influence of food on the bioavailability of oral methotrexate in children. | 1995 Aug | OBJECTIVE: To determine the bioavailability of oral methotrexate (MTX) in patients with juvenile rheumatoid arthritis in the fasting and fed states. METHODS: Each patient randomly received their usual weekly MTX dose either orally (po) after an overnight fast, po immediately after a breakfast of their choice, or intravenously (iv) on 3 consecutive weeks. Blood samples were taken at 0, 0.5, 1, 1.5, 2, 3, 4, and 6 h after po and 0, 0.08, 0.25, 0.5, 1, 1.5, 2, 3, 4, and 6 h after iv administration. RESULTS: Fourteen patients (10 female) aged 2.8 to 15.1 yrs completed the study; the results of 13 patients were evaluable. The mean elimination rate constant was 0.27 +/- 0.065, 0.26 +/- 0.067, and 0.25 +/- 0.11 h-1 after po fasting, po fed, and iv administration, respectively. The total area under the serum concentration vs time curve was 1.87 +/- 0.83, 1.50 +/- 0.51, and 1.85 +/- 0.80 mumol/l.h after po fasting, po fed, and iv administration, respectively. The maximum serum MTX concentration (Cmax) was 0.65 +/- 0.33 and 0.39 +/- 0.18 mumol/l after po fasting and po fed administration, respectively (p = 0.0022). The time to Cmax was 0.94 +/- 0.40 and 1.32 +/- 0.68 h after po fasting and po fed administration, respectively (p = 0.1464). The bioavailability of oral MTX while fasting was 1.1 +/- 0.51, while that after a meal was 0.88 +/- 0.35 (p = 0.0211). CONCLUSION: These data indicate greater oral bioavailability of MTX in the fasting state. We recommend that children receive MTX on an empty stomach. | |
| 11082754 | Low-dose methotrexate as a risk factor for Pneumocystis carinii pneumonia. | 1996 Jan | Low-dose methotrexate is a commonly prescribed medication for the treatment of rheumatoid arthritis and other rheumatic diseases. Its effectiveness in ameliorating the clinical symptoms and findings has been well established, and adverse effects have been relatively infrequent, particularly compared to other immunosuppressive agents. Pneumocystis carinii pneumonia is most often seen in severely immunosuppressed patients related to the acquired immunodeficiency syndrome or treatment of malignancies with potent cytotoxic agents. However, P. carinii pneumonia can occur in patients receiving low-dose methotrexate concurrent with corticosteroids, nonsteroidal anti-inflammatory drugs, renal impairment, or a combination of factors. We report 1 patient and review 10 additional cases that support this relationship. | |
| 8630630 | A review of the clinical pharmacokinetics of meloxicam. | 1996 Apr | Meloxicam is a new preferential cyclooxygenase-2 (COX-2) inhibitor currently for the treatment of osteoarthritis and rheumatoid arthritis. Its pharmacokinetic profile is characterized by a prolonged and almost complete absorption and the drug is > 99.5% bound to plasma proteins. Meloxicam is metabolized to four biologically inactive main metabolites, which are excreted in both urine and faeces. The elimination half-life (t1/2) of meloxicam is approximately 20 h. This is reflected in a total plasma clearance (CL) of 0.42-0.48 1/h. Steady-state plasma concentrations are achieved within 3-5 days. The pharmacokinetic parameters of meloxicam are linear over the dose range 7.5-30 mg and bioequivalence has been shown for a number of different formulations. No interactions were observed following the concomitant administration of food, cimetidine, antacid, aspirin, beta-acetyldigoxin, methotrexate, warfarin or furosemide. Neither hepatic insufficiency nor moderate renal dysfunction have any relevant effects on the pharmacokinetics of meloxicam and dosage adjustments in the elderly are not required. | |
| 7718423 | Musculoskeletal syndromes associated with malignancies. | 1995 Jan | Literature on the association of malignancies with various rheumatic disorders published over the past year is summarized in this review. The possible roles of methotrexate treatment in predisposing to the development of lung cancer and Felty's syndrome in predisposing to non-Hodgkin's lymphoma in rheumatoid arthritis patients are discussed. The increased occurrence of monoclonal gammopathies and non-Hodgkin's lymphoma in patients with Sjögren's syndrome is reported. The possible increased frequency of malignancies among patients with systemic lupus erythematosus (SLE), scleroderma, and polymositis-dermatomyositis is revisited; of interest, the overlapping clinical features of non-Hodgkin's lymphoma and SLE are presented, as well as the increased occurrence of ovarian cancer in patients (especially older women) with dermatomyositis. The proceedings of the first International Workshop on Hypertrophic Osteoarthropathy, as well as the association of this syndrome with nasopharyngeal carcinoma in the childhood years, are presented. Finally, postchemotherapy and post-bacille Calmette-Guérin rheumatism are described. | |
| 8913659 | Methotrexate in primary Sjögren's syndrome. | 1996 Sep | OBJECTIVE: To determine the safety and efficacy of methotrexate (MTX) in the treatment of primary Sjögren's syndrome (SS). METHODS: An open, one-year pilot study of MTX (0.2 mg/kg body weight taken weekly) for the treatment of SS was performed. Seventeen patients with primary SS according to EEC criteria were enrolled in the study. Outcome was determined on the basis of clinical and laboratory parameters. RESULTS: Weekly administration of MTX resulted in improvement of the main subjective symptoms (dry mouth and eyes) as well as in the frequency of parotid gland enlargement, dry cough and purpura. However, no improvement in the objective parameters of dry eyes and dry mouth were observed. Persistent asymptomatic elevation of the hepatic transaminase levels led to a dosage reduction in 7 patients (41%). CONCLUSIONS: Weekly MTX may be an acceptable form of therapy for SS patients. Double-blind trials are needed to substantiate the efficacy of this therapeutic modality. | |
| 8052076 | Methotrexate therapy for autoimmune hearing loss: a preliminary report. | 1994 Aug | The management of autoimmune sensorineural hearing loss (SNHL) continues to challenge the otologist. Steroids and cyclophosphamide, the two traditional medications for this malady, are often associated with serious adverse reactions. In an effort to use a less toxic medication, the authors treated five autoimmune SNHL patients with low-dose oral methotrexate. Methotrexate has been found to be very effective in rheumatoid arthritis patients with acceptable adverse reactions. Preliminary results from this study indicate that methotrexate has the potential of being effective for autoimmune SNHL and associated otologic symptoms. Tolerance has been very good and side effects have been minimal. | |
| 8615853 | Auranofin inhibits the induction of interleukin 1 beta and tumor necrosis factor alpha mRN | 1995 Nov 27 | Gold compounds are widely used in the treatment of rheumatoid arthritis, but their mechanisms of action remain unclear. We demonstrate here that auranofin (AF) (0.1-3 microM), but neither the hydrophilic gold compounds aurothiomalate (ATM) and aurothioglucose nor methotrexate or D-penicillamine, inhibits the induction of interleukin 1 beta and tumor necrosis factor (TNF) alpha mRNA and protein by either zymosan, lipopolysaccharide (LPS), or various bacteria in mouse macrophages. The auranofin-mediated inhibition of the induction of TNF-alpha mRNA was stronger than that of interleukin (IL) 1 beta mRNA. AF, but not the other drugs, also inhibited zymosan-induced mobilization of arachidonate. The fact that AF inhibited the induction of mRNA for both these proinflammatory cytokines, irrespective of which stimulus was used, may indicate that it affects some common signal transduction step vital to their induction. | |
| 8732992 | Clinical aspects of glucocorticoid sensitivity. | 1996 Apr | Recent studies demonstrate that primary (hereditary) abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively "hypersensitive" to glucocorticoids, while 2.3% are relatively "resistant." These abnormalities might explain why some individuals develop severe adverse effects during low dose glucocorticoid therapy, while others do not develop side effects even during long-term therapy with a much higher dose. Awareness of this heterogeneity in glucocorticoid sensitivity in the normal population might eventually allow the prediction of a "safe" dose of glucocorticoid in individual patients. "Resistance" to the beneficial clinical effects of glucocorticoid therapy in part of the patients with severe rheumatoid arthritis and asthma is probably rarely related to generalized primary (hereditary) glucocorticoid resistance. In the majority of patients this "resistance" seems to be acquired and localized to the sites of inflammation, where it reflects high local cytokine production, which interferes with glucocorticoid action. Recognition of localized, acquired glucocorticoid resistance is of great importance indicating as alternative drug therapy with other immune-modulating drugs like cyclosporin and methotrexate. Chronic high dose glucocorticoid treatment in such patients is ineffective in alleviating symptomatology, while generalized side effects occur, reflecting the patient's normal systemic sensitivity to these drugs. | |
| 8729419 | [Still disease in adults revealed by a digestive manifestation]. | 1995 Dec | Adult Still's disease is characterized by typical spiking fever, oligopolyarthritis, neutrophilic leukocytosis and involvement of various organs. We report a case which illustrated typical digestive features of Still's disease as dysphagia, peritonitis and manifests the hitherto unreported complication of gastric ulcerations. Treatment with prednisone was started in order to control arthritis, resulting in improvement of both gastric ulcerations (partially resistant to omeprazole treatment) and arthralgia. After seven years of follow-up, the patient remains clinically and biochemically stable with steroid and methotrexate treatment. | |
| 8602122 | Methotrexate and misoprostol for abortion. | 1996 Apr 26 | ||
| 1285866 | Treatment with immunosuppressive and disease modifying drugs during pregnancy and lactatio | 1992 Oct | Active rheumatic disease may necessitate the treatment of pregnant and lactating patients with disease modifying (DMARD) or immunosuppressive drugs. This review summarizes data from the literature, and attempts to give some recommendations. Possible teratogenic effects of gold, penicillamine, and chloroquine are still disputed. As long as the issue is not settled, it seems prudent to stop using these agents as soon as pregnancy is diagnosed. Hydroxychloroquine has been used by some rheumatologists for treating pregnant patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) without malformations detected in the neonates. Sulphasalazine does not increase the rate of congenital abnormalities. Selected case reports have not shown any teratogenicity of cyclosporine A so far. However, the drug may cause fetal retardation. The use of standard doses of azathioprine does not increase the risk of congenital anomalies. By contrast, the antitumor agents cyclophosphamide, chlorambucil, and methotrexate are possibly teratogenic when given during early pregnancy, but may be less harmful in late pregnancy. Data on the excretion of DMARD and the cytostatic drugs are sparse. Because of insufficient data, breast feeding is not recommended in patients on antimalarials, penicillamine, cyclosporine A, and cytostatic drugs. Intramuscular gold and sulphasalazine seem to impose no major risk on the nursing infant. | |
| 1450620 | Three cases of malignant neoplasm, pneumonitis, and pancytopenia during treatment with low | 1992 Oct | A 77-year-old man with chronic obstructive pulmonary disease was treated with low-dose methotrexate (7.5-15 mg per week). After 15 months a diagnosis of urothelial carcinoma of the bladder was made; after a further 6 months pneumonitis and pancytopenia developed. The patient died due to massive pulmonary hemorrhage. A malignant teratoma was diagnosed in a 65-year-old asthmatic man 16 months after initiation of methotrexate therapy (15 mg per week). The patient died 4 months later due to fulminant progression of the neoplasm. A third malignant neoplasm (dermal squamous cell carcinoma) was seen in a 64-year-old woman with rheumatoid arthritis after 13 months treatment with 7.5 mg methotrexate per week. These three cases, while obviously not proving a causal relationship between long-term treatment with low-dose methotrexate and development of malignant neoplasm, do call for stringent treatment criteria, close surveillance, and prospective studies. | |
| 8060760 | Immunosuppressive drug therapy. | 1994 May | Interstitial lung disease frequently complicates rheumatic disorders, especially polymyositis-dermatomyositis, rheumatoid arthritis, systemic sclerosis, and mixed connective tissue disease. In this article, we review the current data supporting the use of azathioprine, cyclophosphamide, chlorambucil, cyclosporine, and methotrexate in the management of chronic interstitial pneumonitis-fibrosis. The literature addressing the utility of these immunosuppressive-cytotoxic agents, however, consists almost entirely of anecdotal successes and small, uncontrolled series. Although no convincing data have proven that the use of any of these agents with or without corticosteroids is superior to therapy with corticosteroids alone, the literature may suggest a slight long-term survival advantage when either azathioprine or cyclophosphamide is added to prednisone therapy. Studies in which cyclosporine was used, however, have been less encouraging. Data regarding the use of chlorambucil and methotrexate are too sparse to permit any conclusions. Further controlled studies are required to clarify the role of these immunosuppressive agents in the treatment of interstitial lung disease. | |
| 1312060 | Colchicine and methotrexate reduce leukocyte adherence and emigration in rat mesenteric ve | 1992 Feb | Colchicine and methotrexate are commonly used in the treatment of gout and rheumatoid arthritis, respectively; however the mechanism(s) of action of these drugs remain(s) unknown. The objective of this study was to determine whether colchicine and methotrexate can modify the adhesion and emigration of leukocytes in postcapillary venules that are exposed to inflammatory mediators such as platelet-activating factor (PAF) and leukotriene B4 (LTB4). The rat mesentery was prepared for in vivo microscopic observation. Venules with internal diameters ranging between 25 and 35 microns were selected for study. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for greater than or equal to 30 sec) and emigrated leukocytes were measured during superfusion of the mesentery with bicarbonate-buffered saline (BBS). Repeat measurements of adhesive and hemodynamic parameters were obtained between 50 and 60 min of superfusion with either 100 nM PAF or 20 nM LTB4 added to the superfusate. In some experiments, 1 microM of either colchicine or methotrexate was added to the superfusate containing either PAF or LTB4. Both PAF and LTB4 caused increases in leukocyte adherence and emigration and reductions in leukocyte rolling velocity and venular shear rate. Colchicine effectively prevented all of the adhesive and hemodynamic alterations induced by both inflammatory mediators, while methotrexate was largely effective in preventing the responses elicited by PAF, but not LTB4. These results indicate that the therapeutic actions of colchicine and methotrexate may result from the ability of these agents to interfere with the adhesion and emigration of leukocytes from postcapillary venules. |