Methotrexate in rheumatoid arthritis

Fürst, Daniel E.; Kremer, Joel M.

doi:10.1002/art.1780310301

Cited by 157 publications

(49 citation statements)

References 61 publications

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“…adenosine under any condition, B lymphoblasts possess increased AMP-S'-nucleotidase activity (adenosine formation) and relatively little adenosine kinase or adenosine deaminase activity (adenosine utilization [ 1]). Thus, Barankiewicz et al postulated that, since AICARibonucleoside does not affect adenosine production or transport, intracellular accumulations of AICAR must inhibit adenosine kinase or adenosine deaminase activity in order to promote the increase in extracellular adenosine observed (11,19).…”

Section: Discussionmentioning

confidence: 99%

“…Methotrexate is a folate antagonist first developed for the treatment of malignancies and now widely used in the treatment of rheumatoid arthritis ( 1). Unlike its use in the treatment of malignancies (pulses of 20-250 mg/kg), methotrexate is administered weekly in low doses (0.1-0.3 mg/kg) to treat rheu- Receivedfor publication 6 July 1993 and in revisedform 26 July 1993.…”

Section: Introductionmentioning

confidence: 99%

“…matoid arthritis and other inflammatory diseases (1). Although the original rationale for the use of methotrexate in the treatment of rheumatoid arthritis was "immunosuppression," the molecular mechanism by which methotrexate suppresses inflammation is not well understood.…”

Section: Introductionmentioning

confidence: 99%

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The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation.

Cronstein¹,

Naime²,

Ostad³

1993

J. Clin. Invest.

615

393

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Methotrexate, a folate antagonist, is a potent antiinflammatory agent when used weekly in low concentrations. We examined the hypothesis that the antiphlogistic effects of methotrexate result from its capacity to promote intracellular accumulation of 5-aminoimidazole4-carboxamide ribonucleotide (AICAR) that, under conditions of cell injury, increases local adenosine release. We now present the first evidence to establish this mechanism of action in an in vivo model of inflammation, the murine air pouch model. Mice were injected intraperitoneally with either methotrexate or saline for 34 wk during induction of air pouches. Pharmacologically relevant doses of methotrexate increased splenocyte AICAR content, raised adenosine concentrations in exudates from carrageenan-inflamed air pouches, and markedly inhibited leukocyte accumulation in inflamed air pouches. The methotrexate-mediated reduction in leukocyte accumulation was partially reversed by injection of adenosine deaminase (ADA) into the air pouch, completely reversed by a specific adenosine A2 receptor antagonist, 3,7-dimethyl-l-propargylxanthine (DMPX), but not affected by an adenosine Al receptor antagonist, 8-cyclopentyl-dipropylxanthine. Neither ADA nor DMPX affected leukocyte accumulation in the inflamed pouches of animals treated with either saline or the potent antiinflammatory steroid dexamethasone. These results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites. (J. Clin. Invest. 1993Invest. . 92:2675Invest. -2682

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation.

Cronstein¹,

Naime²,

Ostad³

1993

J. Clin. Invest.

615

393

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“…Compared with other, more traditional disease-modifying antirheumatic drugs (DMARDs), methotrexate has a more rapid onset of action, superior long-term effectiveness, and fewer cumulative toxicities (3)(4)(5)(6). Studies show that 80% of patients discontinue other DMARDs after 2 years, while at least 50% continue to take methotrexate for Ͼ5 years (7)(8)(9).…”

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confidence: 99%

Etanercept added to background methotrexate therapy in patients with rheumatoid arthritis: Continued observations

Kremer¹,

Weinblatt²,

Bankhurst³

et al. 2003

Arthritis & Rheumatism

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Objective. To observe the long-term safety and efficacy of combination therapy with etanercept and methotrexate in patients with rheumatoid arthritis (RA), and to determine whether the addition of etanercept allowed reductions in methotrexate or corticosteroid dosages while maintaining a clinical response.Methods. Patients with RA who received methotrexate plus etanercept in a previous randomized, placebo-controlled trial were offered the opportunity to enroll in an open-label extension study for further evaluation of treatment with etanercept and methotrexate.Results. Seventy-nine of the 89 patients in the original blinded study enrolled in the extension study, and 65 of these patients continue in the study. Patients have received etanercept therapy for up to 47 months (median 44 months). The types and rate of adverse events noted during the extension trial were similar to those observed in the controlled trial. At the 3-year assessment, 77% of the 57 patients available for evaluation met American College of Rheumatology 20% (ACR20) criteria for improvement in RA, 47% met the ACR50 criteria, and 23% met the ACR70 criteria. Of the 36 patients assessed at 3 years in the extension study, 30 (83%) were able to decrease their dosages of corticosteroids, and 20 (56%) were able to discontinue corticosteroid therapy. At 3 years, the dosage of methotrexate was decreased in 41 of 66 patients (62%), and methotrexate therapy was discontinued in 19 patients (29%).Conclusion. In this observational continuation study, the addition of etanercept to background methotrexate provided sustained clinical benefit over a median period of 44 months. With etanercept therapy, there were trends toward dosage reduction or discontinuation of methotrexate and corticosteroids, without apparent worsening of ACR response rates. Compared with the controlled trial, no increases in the rate of adverse events were observed.Over the past several decades, methotrexate has become increasingly recognized among rheumatologists as the gold standard in treating patients with rheumatoid arthritis (RA) (1,2). Compared with other, more traditional disease-modifying antirheumatic drugs (DMARDs), methotrexate has a more rapid onset of action, superior long-term effectiveness, and fewer cumulative toxicities (3-6). Studies show that 80% of patients discontinue other DMARDs after 2 years, while at least 50% continue to take methotrexate for Ͼ5 years (7-9). However, despite its advantages over traditional agents, methotrexate is associated with toxicity, and Supported by Immunex Corporation, Seattle, Washington (study drug and grants to the investigational sites).

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“…Studies of the drug in psoriasis patients demonstrated that liver disease could not be predicted based on testing of liver enzyme levels (2-4). It was therefore understandable that recommendations emerged for regular liver biopsies after fixed intervals of MTX therapy in patients with RA (5). More recently, case reports have described significant liver disease in RA patients receiving MTX (6-9).…”

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confidence: 99%

Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long‐term methotrexate therapy followup over long treatment intervals and correlation with clinical and laboratory variables

Kremer

Kaye

et al. 1995

Arthritis & Rheumatism

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Objective. To describe liver histopathologic features and ultrastructural changes in a prospectively studied cohort of rheumatoid arthritis (RA) patients receiving long-term methotrexate (MTX) therapy, and to seek correlations between these changes and simultaneously measured laboratory indices of liver function.Methods. This was a long-term, prospective, open observational study. Twenty-seven outpatients with RA who began therapy with MTX and continued treatment for extended periods underwent baseline and followup liver biopsies. One hundred seventy liver biopsy specimens were analyzed by light microscopy (LM) and assessed according to a modified Roenigk score and a newly devised numerical grading system. Ninety-three biopsy specimens were also analyzed by electron microscopy (EM). Blood samples were obtained at 4-6-week intervals for determination of bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), and albumin levels, and the weekly dosage of MTX was adjusted if there were abnormalities in the AST or albumin level. A mean of 6.3 liver biopsies per patient were obtained over a mean followup period of 8.2 years (range 2-13 years).Results. cantly different from baseline at year 3, when it increased from a mean of 1.8 to 2.3 (P = 0.05) and at year 6, when it increased to 2.4 (P = 0.04), but this was not considered clinically meaningful. No other significant changes from baseline were observed by either LM grading system. No significant progression was observed by EM over the course of the investigation. Increases in serial measurements of AST correlated with both the modified Roenigk score (r = 0.21, P = 0.016) and the numerical rating score (r = 0.19, P = 0.027). Conclusion.Patients with RA who are receiving weekly single-dose oral MTX therapy exhibit little deterioration in hepatic architecture by LM or EM when the dosage of the drug is adjusted for abnormalities in AST and serum albumin, monitored at frequent intervals.

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Methotrexate in rheumatoid arthritis

Cited by 157 publications

References 61 publications

The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation.

The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation.

Etanercept added to background methotrexate therapy in patients with rheumatoid arthritis: Continued observations

Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long‐term methotrexate therapy followup over long treatment intervals and correlation with clinical and laboratory variables

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