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Methotrexate

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Rheumatoid Arthritis and Other Immunoregulatory Disorders

  • Drug Evaluation
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Summary

Synopsis

Methotrexate is a folic acid antagonist which appears to have immunosuppressive and/or anti-inflammatory effects.

Many well-designed studies have shown that methotrexate is at least as effective as more established slow-acting antirheumatic drugs (SAARDs) such as auranofin, intramuscular gold, penicillamine and azathioprine in patients with rheumatoid arthritis. Furthermore, a number of long term studies have demonstrated that discontinuation rates are much lower in patients with rheumatoid arthritis treated with methotrexate compared with other SAARDs. Methotrexate also appears to be the most effective treatment for patients with juvenile rheumatoid arthritis who have not responded to initial therapy with nonsteroidal antiinflammatory drugs (NSAIDs) although data are more limited here.

Results of studies evaluating the efficacy of methotrexate in patients with corticosteroid-dependent asthma have been conflicting, although some patients do benefit from this approach. While methotrexate has a well defined role in the treatment of psoriasis, its use in other immunoregulatory disorders remains to be fully evaluated.

Gastrointestinal symptoms are the most commonly reported adverse events during methotrexate therapy and occur in at least 10% of patients. Methotrexate-induced hepatotoxicity is well documented; however, the incidence of methotrexate-induced cirrhosis has so far been low in patients with rheumatoid arthritis treated with the drug. In addition, recent data suggest that the tolerability of methotrexate is comparable with that of other SAARDs. Methotrexate may interact with NSAIDs and cotrimoxazole resulting in increased serum methotrexate concentrations and haematological abnormalities, respectively. There is also potential for interactions with sulfasalazine, phenytoin and certain oral antibiotic drugs.

Thus, methotrexate should be seriously considered as the preferred SAARD in patients with rheumatoid arthritis or juvenile rheumatoid arthritis refractory to optimal treatment with NSAIDs and who have no risk factors for liver disease. Although the results from some studies have been favourable, the use of the drug in patients with corticosteroid-dependent asthma cannot be recommended until more conclusive data are available to clearly assess the risk: benefit ratio of such an approach.

Pharmacodynamic Properties

Methotrexate therapy produces significant reductions in the levels and/or activity of certain cytokines or circulating concentrations of their receptors, including interleukin-1, -1β, -2 and -6, and tumour necrosis factor, in patients with rheumatoid arthritis suggesting possible effects on the inflammatory cascade.

Dose-dependent inhibition of fibroblast proliferation and DNA synthesis in human endothelial cells following incubation with methotrexate has also been noted in vitro.

While the precise mechanism by which methotrexate exerts immunosuppressant activity is unknown, cytotoxic effects of intracellular polyglutamyl derivatives may be implicated.

Pharmacokinetic Properties

After oral administration, methotrexate’s bioavailability ranges between 0.4 and 1.0 (mean 0.67) with interpatient, and possibly intrapatient, variation.

Intravenously administered methotrexate is distributed within an initial volume of 18% of body weight, corresponding to extracellular space, then within a volume of 76% of body weight, corresponding to total body water.

The drug is approximately 50% bound to plasma albumin. At equilibrium, greatest concentrations of methotrexate are found in the kidneys, gallbladder, spleen, liver and skin.

Methotrexate undergoes intracellular conversion to polyglutamyl derivatives which are retained intracellularly in preference to the parent compound. The kidneys are the predominant elimination route for unchanged methotrexate and the drug also appears to undergo enterohepatic recycling.

Therapeutic Efficacy

The short term efficacy of methotrexate in patients with rheumatoid arthritis has been demonstrated in well designed comparative trials as well as in non-comparative studies. A comprehensive meta-analysis of second-line treatments involving almost 5000 patients with rheumatoid arthritis concluded that methotrexate, along with antimalarial drugs, had the best balance of efficacy and toxicity overall. Additional studies evaluating the duration of efficacy of methotrexate reported that patients continue to receive methotrexate for consistently longer periods of time than any other SAARD.

Although combination therapy with methotrexate and gold was no more effective than methotrexate monotherapy in 273 patients with rheumatoid arthritis, the addition of chloroquine 250 mg/day to methotrexate 7.5 mg/week significantly improved treatment efficacy compared with the addition of placebo.

Meta-analysis showed methotrexate and parenteral gold recipients had similar rates of disease progression, but slower rates than azathioprine or auranofin recipients. These findings were confirmed by several studies that did not meet the inclusion criteria for the meta-analysis. A further 4 trials suggest that treatment with methotrexate may retard radiological progression of rheumatoid arthritis. It appears that methotrexate may also be useful in rheumatoid arthritis associated with neutropenia and splenomegaly (Felty’s syndrome).

Several noncomparative studies have established the clinical efficacy of methotrexate as treatment for patients with juvenile rheumatoid arthritis. Intention-to-treat response rates to penicillamine 10 mg/kg/day (n = 54), hydroxychloroquine 6 mg/kg/day (n = 57), auranofin 0.15 to 0.2 mg/kg/day (n =119), methotrexate 5 mg/m2/week (n = 40) and methotrexate 10 mg/m2/week (n = 46) were compared by meta-analysis with only methotrexate 10mg/m2/week being significantly better than placebo (n = 51) after 6 to 12 months’ treatment.

Limited data are available regarding the effects of methotrexate on radiological progression in patients with juvenile rheumatoid arthritis; however, 1 study demonstrated radiological improvement in 11 of 17 children with juvenile rheumatoid arthritis receiving the drug.

Three double-blind placebo controlled studies have shown methotrexate to reduce steroid dependence in patients with severe asthma vs placebo, while a further 3 found no significant effect on steroid requirements. Results from 2 noncomparative studies suggest that methotrexate reduces steroid requirements in patients with steroid-dependent asthma over longer periods of time although a further trial did not show any benefit. Very limited data suggest that methotrexate may also be beneficial in children and adolescents with chronic steroid-dependent asthma.

Methotrexate has a well defined role in the treatment of psoriasis and limited results suggest possible activity in dermatomyositis, primary biliary cirrhosis, inflammatory bowel disease, sarcoidosis and systemic lupus erythematosus.

Tolerability

Gastrointestinal symptoms including anorexia, nausea, vomiting and diarrhoea are the most commonly reported adverse events during treatment with methotrexate, occurring in at least 10% of those who receive the drug. In a comprehensive meta-analysis of the toxicity of second-line treatments for rheumatoid arthritis, methotrexate and auranofin had the lowest toxicity-related withdrawal rates after antimalarial drugs. The incidence of severe toxicity was lower in methotrexate than that in gold recipients, but higher than that in patients treated with antimalarial drugs.

Studies conducted in patients with psoriasis indicate that methotrexate has hepatotoxic potential and can, albeit rarely, cause cirrhosis. Several trials involving a total of more than 900 patients with rheumatoid arthritis have evaluated findings from liver biopsy samples taken longitudinally during methotrexate therapy. All but 1 reported negligible histological deterioration; 3 of 134 patients in one study developed clinical and histological signs of severe liver disease. The latest guidelines from the American College of Rheumatology do not recommend liver biopsies in patients with rheumatoid arthritis about to commence treatment with methotrexate unless risk factors for liver disease are present at baseline. However, regular monitoring of AST, ALT and albumin during treatment is recommended, and a series of abnormal AST determinations or a decrease in serum albumin are indications that a biopsy should be performed.

Pulmonary adverse effects occurring in patients receiving low dose methotrexate include pneumonitis and insidious interstitial fibrosis. Studies have reported incidences of methotrexate-induced pneumonitis ranging between 0.3 and 11.6%.

Methotrexate recipients may be predisposed to opportunistic infection, notably with Pneumocystis carinii.

It has been suggested that the coadministration of small doses of folic or folinic acid during methotrexate therapy in patients with rheumatoid arthritis may reduce the incidence of methotrexate-associated toxicity without affecting its efficacy. Several studies have been conducted in this area but no clear consensus has yet emerged.

Drug Interactions

Interactions between methotrexate and several nonsteroidal anti-inflammatory drugs resulting in increased serum methotrexate concentrations, including some with fatal outcome, have been reported. In addition, several case reports have described an interaction between cotrimoxazole (trimethoprim/sulfamethoxazole) and methotrexate producing haematological abnormalities. Methotrexate may also interact with sulfasalazine, phenytoin and certain oral antibiotic drugs.

Dosage and Administration

In adult patients methotrexate can be given as a single oral 7.5mg dose or a course of three 2.5mg doses 12 hours apart, administered once weekly. These dosages may be gradually titrated to achieve optimal response but the total dosage should not exceed 20 mg/week.

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    Anthony Markham & Diana Faulds

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  1. Anthony Markham
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Various sections of the manuscript reviewed by: G.S. Alarcón, University of Alabama School of Medicine, Birmingham, Alabama, USA; P. Barrera, University Hospital Nijmegen, Nijmegen, The Netherlands; D.M. Geddes, Royal Brompton National Heart and Lung Hospital, London, England; E.H. Giannini, Children’s Hospital Medical Center, Cincinnati, Ohio, USA; T. Murayama, Kanazawa Rehabilitation Hospital, Kanazawa, Japan; R. Rau, Rheumaklinik Ratingen, Ratingen, Germany; P. Seideman, Karolinska Institutet at Danderyd Hospital, Danderyd, Sweden; R.D. Sturrock, Royal Infirmary, Glasgow, Scotland; R. Segal, Tel Aviv Souraski Medical Center, Ichilov Hospital, Sackler Faculty of Medicine, Tel Aviv, Israel; D.R. Taylor, University of Otago Medical School, Dunedin, New Zealand; M.E. Weinblatt, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

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Markham, A., Faulds, D. Methotrexate. Clin. Immunother. 1, 217–244 (1994). https://doi.org/10.1007/BF03258508

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