Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 3913770 | Clinical pharmacology of very low dose methotrexate for use in rheumatoid arthritis. | 1985 Dec | The clinical pharmacokinetics of methotrexate, particularly when the drug is used at low doses for nonmalignant disease, are complicated and require extensive study. Bioavailability of the drug may be influenced--at least in part--by food intake. Biliary excretion can compensate for decreased renal excretion of methotrexate to some degree. However, further studies of the renal excretion of methotrexate are needed. | |
| 3913775 | Toxicity of low dose methotrexate in rheumatoid arthritis. | 1985 Dec | The efficacy and acceptability of low dose weekly methotrexate therapy in rheumatoid arthritis was reviewed in 587 patients in open and randomized trials. Gastrointestinal toxicity was reported most frequently. Bone marrow suppression, stomatitis, alopecia, headaches, and fever also occurred. A review of these adverse reactions, as well as of the effects of this drug on the reproductive, renal, and pulmonary systems, is discussed. | |
| 7108346 | Methotrexate: a perspective of its use in the treatment of rheumatic diseases. | 1982 Sep | MTX has been available for clinical use since 1951, and although it is widely accepted as a chemotherapeutic agent, its use in nonmalignant disorders has been sporadic and not well documented. Its mechanism of action is imprecisely understood but appears to involve both anti-inflammatory and immunosuppressive effects. The most extensive use of MTX in benign conditions has been in the treatment of psoriasis and more recently in psoriatic arthritis as well as polymyositis, sarcoid, and Reiter's syndrome. In addition, pilot studies have been carried out using MTX in patients with resistive RA. We have used MTX in 67 patients with severe RA. Maintained on oral pulse treatment schedule at 7.5 to 15.0 mg/week, approximately 75% had an improved global response with a significant decrease in active joints and ESR. Thirty-three patients have remained on therapy for periods of less than 1 year to more than 10 years. Thirty-four have discontinued treatment: 11 because of inefficacy, five with gastrointestinal complaints, three because of liver function abnormalities, and eight because of apprehension. Two patients died of neoplasm. Of the potential side effects of this agent, hepatotoxicity remains a serious consideration. We treat with attention to risk factors and rely on liver function tests to alert us to increased risk. There are data to suggest that a cumulative dose of MTX beyond 1.5 gm needs tissue surveillance. MTX appears to provide safe and effective treatment in resistive RA but requires further definitive trails. | |
| 6348949 | Low dose oral methotrexate in rheumatoid arthritis: an uncontrolled trial and review of th | 1983 May | New therapeutic alternatives are needed for patients with progressive RA unresponsive to gold or D-penicillamine. Azathioprine and cyclophosphamide can be effective but have been linked with the development of lymphoreticular malignancies. In an effort to exploit a less toxic agent, we have been impressed by the results and minimal toxicity of low dose oral MTX. Extensive application of this regimen in psoriasis and psoriatic arthritis indicates that low dose MTX does not have an unusual risk for developing cancer. In addition, prior experience with other rheumatic disorders and preliminary studies on the mechanism of action suggest a potential value in RA. We present our initial retrospective results in 28 patients with refractory RA given low dose oral MTX over the past 2.5 yr. An apparent positive response was noted in 19 of these patients (67%) and is similar to the experience of other clinicians. At the same time, the toxicity has been low and, with one exception, amenable to dose modification. Methotrexate in various regimens is being increasingly employed in refractory RA. Issues concerning the pharmacology and potential toxicity are, therefore, important. These topics are reviewed with emphasis on low dose therapy and hepatotoxicity. Despite the encouraging preliminary results it is unclear whether MTX can prevent erosions or improve long-term function and quality of life in RA. There are still no controlled perspective studies comparing MTX to placebo or other immunosuppressive agents in RA. Although short-term toxicity is low, long-term toxicity, especially hepatic, is uncertain. As a result, a controlled, long-term prospective study is necessary. | |
| 770131 | Clinical use of immunosuppressive drugs: part I. | 1976 | While immunosuppressive drugs are principally used in the treatment of malignant disease, their use in non-malignant disease and transplantation has become commonplace. The mechanisms of action of immunosuppressive agents differ. Alkylating agents react with nucleophilic centres of D, and rna. Folic acid antagonists prevnt the conversion of dihydrofolic acid to tetrahydrofolic acid. Antibiotics act in a variety of different ways; the alkaloids cause metaphase arrest. Cytarabine (cytosine arabinoside), methotrexate, hydroxyurea and thioguanine act during mitosis and the latter also acts during replication is not known... | |
| 3877983 | Pancytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid ar | 1985 Nov | Low dose pulse MTX was associated with the development of pancytopenia in six patients with RA. Two patients died. Factors implicated in the occurrence of this complication were renal impairment in five patients, medication errors by two patients, preexisting marrow injury from occult alcoholism in one patient, and an apparent idiosyncratic reaction to the drug in another. Medication errors were associated with the use of five or more medications, and the unusual schedule of administration of low dose MTX may also have been contributory. From a consideration of the clinical pharmacokinetics of MTX, we suggest other factors that may predispose to the occurrence of marrow toxicity: the presence of hypoalbuminemia, interactions between MTX and other protein bound or weakly acidic drugs, and the repetitive dosing schedule of low dose MTX. Based on our experience, patients with impaired renal function (creatinine greater than or equal to 2.0 mg/dL) should not receive MTX. Renal function should be monitored regularly during treatment with MTX, and blood counts should be observed carefully if a new drug is added or substituted. A 5 mg test dose of MTX before initiating weekly therapy may identify patients with severe hypersensitivity to the drug. The potential risks of using MTX in a patient unwilling to accept blood products should be acknowledged and discussed with the patient. Furthermore, we recommend the use of leucovorin if pancytopenia occurs, even if low or undetectable serum levels of MTX are present. | |
| 6398173 | Methotrexate: its use in the rheumatic diseases. | 1984 Apr | Methotrexate in a low dose intermittent regimen has become popular as a therapeutic choice for refractory psoriatic arthritis, polymyositis, Reiter's disease and more recently rheumatoid arthritis. As a folate analogue, it inhibits the formation of reduced folate cofactors which participate in a host of important reactions including DNA synthesis. It has been shown to have both immunosuppressive and anti-inflammatory properties although its precise mechanism of action in these diseases is not known. It may be variably absorbed especially in psoriatics and its action may be antagonized by folate supplements. Its major route of metabolism appears to be via the enterohepatic circulation. Numerous drugs, including salicylates, may increase serum levels by displacing the drug from protein binding sites and by competing for renal excretion. It has fewer short term side effects than the other immunosuppressives used in rheumatic disease. Its major long term toxicity is liver fibrosis or cirrhosis which appears to increase with greater cumulative dosage and treatment duration. Several recent reports of hypersensitivity pneumonitis reinforce the previous literature on this topic. Pulmonary toxicity may be more common than suggested as more patients are treated with methotrexate for rheumatic diseases. Clinical studies in general have been uncontrolled and lacking in scope and size. Nevertheless, the literature to date appears to show this to be an excellent drug for use in the diseases mentioned. Prospective double blind controlled studies on psoriatic arthritis and rheumatoid arthritis should help establish this drug as the immunosuppressive of choice in these diseases. | |
| 3967557 | Low incidence of hepatotoxicity associated with long-term, low-dose oral methotrexate in t | 1985 Feb | Thirty patients with psoriasis or other nonmalignant diseases had liver biopsies done before treatment with low-dose methotrexate, 15 mg/week, and then at one- to two-year intervals as long as they continued the methotrexate. All patients were symptomatically improved on this regimen. The 15 patients who had normal liver biopsies at the start of the study had normal biopsies after methotrexate. Fifteen others had minor hepatic histologic abnormalities before treatment. Eleven patients had fatty infiltration. Ten showed no significant change after treatment while one had increased fat and portal fibrosis on a fourth liver biopsy done seven years after MTX was begun. This last patient, a former alcohol abuser, continued methotrexate and showed no further worsening at 8 years. The remaining four had portal fibrosis before treatment. One patient had less fibrosis after methotrexate, two patients slightly more fibrosis, and one a marked increase in portal fibrosis. No patient developed cirrhosis or clinical liver disease. Our results suggest that in the absence of alcohol consumption, low-dose weekly methotrexate treatment rarely causes clinically significant liver damage. | |
| 3831362 | Methotrexate and the liver. | 1985 Dec | The findings of liver studies in 29 patients who were treated with low dose pulse methotrexate for rheumatoid arthritis (RA) are described. The biopsy specimens of 22 patients (76%) showed liver abnormalities, but cirrhosis did not develop in any patient. There were no statistically significant differences in age, duration of treatment, or cumulative dose between patients in whom abnormal liver histology developed and those in whom it did not. Our findings showed that isolated elevations of the aminotransferase enzymes or alkaline phosphatase levels did not predict liver disease, nor did the absence of elevation of these enzymes assure the absence of liver disease. Serial elevations of the aminotransferase and/or alkaline phosphatase enzyme levels and the development of hypoalbuminemia during treatment were specific indicators of the development of liver disease. In the patients studied, significant liver disease did not develop before 2 years of therapy or with a cumulative dose of methotrexate of less than 1500 mg. | |
| 3913771 | Drug interactions with methotrexate. | 1985 Dec | General mechanisms of drug interactions are reviewed, as well as the effects of various drugs on the absorption, distribution, protein binding, eliminations and cellular transport of methotrexate. Published studies demonstrate that prior or concomitant administration of other drugs can alter the efficacy and toxicity of methotrexate. Nonabsorbable antibiotics can decrease methotrexate absorption. Nephrotoxic drugs can decrease methotrexate renal clearance. Salicylates and probenecid may decrease the plasma protein binding and renal tubular secretion of methotrexate. However, the clinical significance of many of these drug interactions is not known or has not been substantiated by extensive clinical observations. | |
| 4087270 | Studies on the effect of low dose methotrexate on rat adjuvant arthritis. | 1985 Oct | Adjuvant arthritis in rats was induced by the intradermal administration of Freund's complete adjuvant. When these immunized rats were treated orally with low doses of methotrexate (150-600 micrograms/kg/week) a statistically significant suppression of paw inflammation was observed. This low dose of methotrexate was comparable to that used in the treatment of human rheumatoid arthritis (RA). Our results are the first demonstration of the efficacy of low dose methotrexate in an animal model of human RA. | |
| 6356904 | Reappraisal of the use of methotrexate in rheumatic disease. | 1983 Oct 31 | Methotrexate has been available for clinical use since 1951. Initially, it was utilized as a chemotherapeutic agent, but it has since been widely used in the treatment of such nonmalignant disorders as psoriasis and, more recently, experimentally in psoriatic arthritis and polymyositis. Its mechanism of action is imprecisely understood but it appears to involve both anti-inflammatory and immunosuppressive effects. Controlled pilot studies are underway using methotrexate in patients with severe rheumatoid arthritis. | |
| 340129 | Comparison of intra-articular methotrexate with intra-articular triamcinolone hexacetonide | 1977 | A comparison of intra-articular methotrexate and intra-articular triamcinolone hexacetonide was made in 42 arthritic patients with persistent bilateral knee effusions. One knee was injected with either 5 mg methotrexate (two injections of 2.5 mg a week apart) or a single injection of 20 mg triamcinolone. An objective assessment of both knees was made by quantitative thermography at 0,3,7,14 and 21 days. Joints injected with triamcinolone showed a greater fall in thermographic index (T.I) than the joints injected with methotrexate, which showed similar change to the non-injected knee joints in both groups. Four patients received larger doses of methotrexate, up to 20 mg, though the fall in T.I. was still less than the mean fall for triamcinolone injected joints. Peak venous blood levels of methotrexate were reached 1 hour after intra-articular injection, and a sphygmomanometer cuff inflated around the leg above the injected knee for periods of up to 1 hour did not appreciably delay this. Methotrexate had no immediate anti-inflammatory effect, even in psoriatic arthropathy, and did not give the relief of intra-articular steroid. | |
| 342086 | The clinical pharmacology of methotrexate: new applications of an old drug. | 1978 Jan | Methotrexate is now used widely for the treatment of acute leukemia, non-Hodgkin's lymphoma, osteogenic sarcoma, choriocarcinoma, breast carcinoma, pulmonary and epidermoid carcinoma, and intrathecal chemotherapy. It is also useful in bone marrow transplantation, severe psoriasis, rheumatoid arthritis, dermatomyositis, Wegener's granulomatosis and sarcoidosis. The recent dramatic intensification of methotrexate therapy can be attributed in part to advances in our understanding of the clinical pharmacology of the folate antagonists, as well as to the combination of positive results and their effective dissemination to medical oncologists. The review summarizes the pharmacologic findings and illustrates how they are currently being applied to the treatment of malignant disease. | |
| 932231 | Biopterin derivatives in human body fluids and tissues. | 1976 May | Levels of biopterin derivatives in urine, serum, milk, cerebrospinal fluid, brain, and liver have been measured with the Crithidia fasciculata assay. Normal levels in serum and urine have been given and compared with those in a number of benign and malignant proliferative disorders, phenylketonuria, kidney disease, Parkinson's disease, schizophrenia, controlled epilepsy, rheumatoid arthritis, and pernicious anaemia. The active component of Crithidia factor in serum was 7,8-dihydrobiopterin. Tissue, urine, and some serum samples contained two active materials, the principal one being 7,8-dihydrobiopterin; a minor constituent was probably tetrahydrobiopterin. Serum biopterin levels following methotrexate administration were raised and subsequent administration of folic acid and 5-formyltetrahydrofolic acid further increased serum levels of biopterin derivatives; this was in contrast to the total absence of response to oral folates without prior methotrexate and to 5-methyltetrahydrofolic acid either with or without methotrexate being given. | |
| 2410122 | Analysis of "early" thymidine/inosine protection as an adjunct to methotrexate therapy. | 1985 Jul | The feasibility of "early" thymidine and inosine protection of methotrexate (MTX) toxicity is evaluated in this paper. This approach is based on the proposition that the most vulnerable period for susceptible host cells to MTX toxicity is an interval following a pulse of MTX when the MTX monoglutamate level is high. In contrast, tumor cells that accumulate active MTX polyglutamyl derivatives are exposed to the cytotoxic effects of MTX, not only when the monoglutamate levels are high, but also over the much longer interval during which polyglutamyl derivatives are retained within these cells. The protecting agents employed, thymidine and inosine, circumvent the antipurine and antipyrimidine effects of MTX, but neither agent inhibits the transport or the polyglutamylation of MTX. Nucleoside protection given over 6 hours after MTX markedly decreased toxicity to normal BDF1 mice at MTX doses up to 150 mg/kg/day for 3 consecutive days. The LD10 for unprotected mice was 14 mg/kg/day, while the LD10 for the protected mice was 114 mg/kg/day, a greater than eightfold increase in the drug dose delivered. MTX with early nucleoside protection produced a 50% increase in median life span in tumor-bearing mice at doses of drug that were toxic to unprotected mice. Flow cytometric analyses indicated that consecutive daily pulses of MTX with early nucleoside protection alter the cell cycle distribution. By 24 hours after the last of three daily pulses of MTX, the G1 component was maximal (80% of the cell population), with less than 2% of the cells in G2M and 17% of the cells in S phase. This distribution persisted for 24 hours, after which a normal pattern emerged, a process that was accelerated by neither thymidine/inosine nor leucovorin. These studies support the concept that toxicity to the host is initiated largely in the interval shortly after MTX administration. The data indicate that early nucleoside protection permits the repetitive administration of much higher doses of MTX than can be given with MTX alone. This approach may be useful not only in the treatment of human neoplasms but in the treatment of other disorders, such as rheumatoid arthritis, psoriatic arthritis, or psoriasis. Finally, this paper considers the potential advantages of early thymidine/inosine protection in comparison to leucovorin rescue with the administration of low or moderate doses of MTX. | |
| 1844376 | [Methotrexate in rheumatoid arthritis]. | 1991 Jun | Methotrexate may be effective in patients with rheumatoid arthritis refractory to other treatments (gold salts, d-penicillamine and antimalarial drugs). Success rates from 39 to 88% have been reported. The mechanism of action is unknown, but is supposedly related to anti-inflammatory and immunosuppressive effects. Frequent side effects are observed on prolonged treatment. Most of these are mild and disappear with dose reduction. An exception is pneumonitis, a hypersensitivity reaction that may appear early and at low doses. Hepatotoxic effects are milder than those observed in patients with psoriasis. Intraarticular administration is not effective. No carcinogenic effects have been observed in humans. The drug should be administered with caution in fertile males and females due to possible teratogenic effects. New studies involving larger number of patients may help establish a significant role for methotrexate in the treatment of rheumatoid arthritis. | |
| 3275843 | Rheumatoid arthritis: can the long-term outcome be altered? | 1988 Jan | Although several agents (for example, intramuscularly administered gold, auranofin, D-penicillamine, hydroxychloroquine, and methotrexate) are of clinical benefit in the management of rheumatoid arthritis (RA), their effect on the long-term outcome of the disease is controversial. Assessment of the influence of therapeutic interventions in RA is difficult because the natural history of the disease remains poorly defined and unpredictable, and neither the traditional clinical and laboratory measurements of inflammation nor radiographic analyses of progression of joint destruction provide an accurate estimate of the long-term outcome of RA. Furthermore, there is little evidence that second-line agents yield benefits beyond 3 years. Therefore, adequately tested comprehensive measures should be used in large, long-term, multicenter controlled clinical trials to determine whether the long-term outcome of RA can be altered. | |
| 3052055 | Role of disease-modifying antirheumatic drugs versus cytotoxic agents in the therapy of rh | 1988 Oct 14 | Disease-modifying antirheumatic drugs are used to modify or alter the rheumatoid arthritis disease process. Disease-modifying antirheumatic drugs do not demonstrate the characteristic analgesic, antipyretic, and anti-inflammatory actions of the nonsteroidal anti-inflammatory drugs, since weeks or months of treatment are required before clinical benefit is observed. Although they have not been proved to delay, prevent, or reverse articular damage, therapy with disease-modifying antirheumatic drugs, when successful, is associated with decreased pain and joint swelling and improved function. Disease-modifying antirheumatic drugs and cytotoxic agents should not be considered as routine treatment for patients with rheumatoid arthritis. Before disease-modifying antirheumatic drug therapy is implemented, an optimal basic program of physical therapy, rest, and nonsteroidal anti-inflammatory drugs should be implemented, and it must be documented that the patient still has sufficient disease to justify the costs, risks, and benefits of these treatments. Drugs that are approved by the Food and Drug Administration (FDA) are preferred over nonapproved drugs. Hydroxychloroquine, parenteral gold salts, oral gold, D-penicillamine, and the cytotoxic drug azathioprine are the FDA-approved disease-modifying antirheumatic drugs for use in rheumatoid arthritis. Many, not all, rheumatologists would employ hydroxychloroquine as the first-choice disease-modifying antirheumatic drug in patients who have early, mild, and nonerosive disease; treatment should be continued for six months before being abandoned for lack of efficacy, and appropriate ophthalmologic examination every four to six months is indicated. An alternative would be auranofin, whose efficacy approaches that of parenteral gold, yet may be safer. For patients who have severe active rheumatoid arthritis, especially with erosive changes, parenteral gold salts are usually a first choice. D-penicillamine is also effective in controlling the signs and symptoms of rheumatoid arthritis, but serious toxicity may occur. Azathioprine might be considered a competitor to D-penicillamine, although the FDA approval restricts its use to patients who have failed gold therapy. Two cytotoxic drugs that are not FDA approved are methotrexate and cyclophosphamide. Methotrexate can be very effective, but its side effects, particularly pulmonary and hepatic, must be carefully monitored. Cyclophosphamide is generally considered too toxic for use in patients with rheumatoid arthritis, although it may be helpful in patients with systemic rheumatoid vasculitis or patients who have failed all other therapies.(ABSTRACT TRUNCATED AT 400 WORDS) | |
| 2251508 | Resolve: methotrexate is the drug of choice after NSAIDs in rheumatoid arthritis. | 1990 Oct | This article, in favor of the resolution that methotrexate (MTX) is the drug of choice after nonsteroidal antiinflammatory treatment, develops the following four points. MTX is an effective treatment of rheumatoid arthritis. MTX is easy to administer and to monitor for effectiveness and safety. MTX has demonstrated a therapeutic to toxic ratio that exceeds that of other second-line antirheumatic drugs. MTX has the potential to impair disease progression. |