MethotrexateRx

Trade Names: Rheumatrex, Trexall

Synonyms: MTX

Drug Class: Antimetabolite and cytotoxic (at high doses); DMARD, anti-inflammatory (at low doses)

Preparations: Tablet: generic and Rheumatrex 2.5 mg;  Trexall 5-, 7.5-, 10-, 15 mg ; Injection: 25 mg/mL (2 mL vial)

Dose: MTX is typically initiated in a dose of 7.5 mg  or 10 mg once weekly (all tablets taken on the same day). Start elderly patients with 5 mg/wk. Most patients start on oral tablets. Dose may be increased after 4 weeks if clinical benefit is not achieved. If necessary, increase dose by 2.5–5 mg (one to two tablets) every 4–8 weeks to 15 mg/wk. Higher doses are occasionally used in RA (to as much as 20 or 25 mg/wk). Absorption of oral doses above 15 mg plateaus; consider subcutaneous injection for doses above 15 mg. Doses of 20–25 mg/wk may be necessary to control cutaneous psoriasis or inflammatory muscle disease.

If nausea, diarrhea, or mucositis occurs, the clinician has several options: (a) lower the dose or temporarily suspend therapy (for 1–2 weeks); (b) divide the total weekly dose and administer two doses at 12-hour intervals; (c) premedicate with antiemetics (e.g., promethazine); or (d) switch to weekly intramuscular or subcutaneous injections for an improved side effect profile and more reliable absorption (patients can be taught to self-administer weekly subcutaneous injections); (e) increase dose of folate to 2 mg/day.

The injectable form is 80%–90% cheaper than the tablets and is the preferred alternative for those of limited financial resources. The injectable (parenteral) form may be administered intramuscularly, subcutaneously, or orally (diluted in water or fruit juice). Patients must be taught how to draw up the proper amount of parenteral MTX accurately. All patients should receive concomitant folate (1 mg/day) to lessen the incidence of serious toxicities, especially hepatic, pulmonary, and marrow toxicity.

Indications: RA, psoriasis, psoriatic arthritis, juvenile RA, inflammatory myositis, maintenance in vasculitis (after control achieved with cyclophosphamide or rituximab), SLE

Mechanism of Action: The cytotoxic action is based on inhibition of dihydrofolate reductase by MTX, but this does not appear to be the mechanism of action with the doses typically used in rheumatic diseases. Thus, concomitant folate administration will not negate the clinical effects of MTX. Postulated mechanisms underlying its anti-inflammatory effects include inhibition of methylation reactions and increased adenosine release.

Contraindications: Hypersensitivity to MTX, liver disease, alcoholism, pregnancy, renal impairment, hepatitis B or C. Most rheumatologists avoid its use in patients with marked leukopenia or HIV infection.

Precautions: The patient must understand the risks and benefits of treatment and the requirement for monitoring. Pregnant women must not receive MTX. Contraceptive methods should be reviewed and ensured (in both men and women) before starting MTX therapy, during MTX therapy, and for at least 3 months after discontinuing MTX. Patients should wait at least 3 months after discontinuing MTX before becoming pregnant. MTX toxicity is more common in those with renal impairment, Down syndrome, or folate deficiency and those receiving high-dose aspirin (4–6 g/day). Elimination reduced if ascites or pleural effusions.

Monitoring
Baseline: CBC, platelets, LFTs, creatinine, chest x-ray (within the past year). Check for hepatitis B and C infection and tuberculosis; if at risk, exclude human immunodeficiency virus infection.
Maintenance: CBC and creatinine 2 weeks after initiating treatment; then CBC, LFTs (including albumin, AST, ALT), and creatinine every 4 weeks until efficacy and stable dose are achieved. Patients on a stable dose with no previous WBC or LFT abnormalities may have the laboratory testing interval gradually increased to every 4–8 weeks. Dose reduction is indicated for minor increases in liver enzymes. Check whether the patient is receiving other hepatotoxic agents (e.g., alcohol, NSAIDs). If minor elevations persist, a liver biopsy or discontinuation of MTX should be considered. Detailed guidelines on monitoring MTX use in RA have been established and are outlined in Table 2.

Pregnancy Risk: X (teratogen). Ensure that women are not pregnant before starting treatment, ensure reliable contraception during treatment, and avoid conception for at least 3 months after discontinuing MTX.

Adverse Effects
Common: Oral ulcers, post-dose (1–2 days) nausea or diarrhea
Less common: Worsening of rheumatoid nodules (MTX nodulosis), fatigue, somnolence, photosensitivity, reversible hair loss, vomiting, increased LFTs
Uncommon: Pneumonitis (MTX lung), impotence, bone marrow suppression (primarily leukopenia or pancytopenia), increased risk of infection, irreversible hepatic fibrosis, lymphoma (sometimes reversible on stopping MTX), Stevens-Johnson syndrome

Drug Interactions
Trimethoprim/sulfamethoxazole: Increased marrow toxicity of MTX
Immunosuppressants: Additive toxicities
NSAIDs: Minor increases in MTX levels (seldom of clinical significance with RA doses of MTX)
Probenecid: Increased risk of MTX toxicity
Penicillins: Increased MTX concentrations
Hepatotoxic drugs: Increased hepatotoxicity

Patient Instructions: Take MTX only once weekly. Never increase the dose by yourself. Do not become pregnant. Do not drink alcohol. Avoid prolonged exposure to direct sunlight.

Comments: MTX is the most widely used first-line drug for the treatment of RA in the United States, primarily because of its ease of use, relatively rapid onset of action (4–8 weeks), and durable responses. Approximately 40% to 50% of patients are still taking it after 5 years. Folic acid supplementation (1 mg/day) decreases side effects and is used routinely by many rheumatologists. Impaired renal function and patients mistakenly taking the drug every day are the two most important cause of serious MTX toxicity.Studies of MTX used in combination with cyclosporine, sulfasalazine, hydroxychloroquine, TNF antagonists, anakinra, tocilizumab and tofacitinib suggest increased benefit in patients not controlled with MTX alone. MTX is not a first-line drug in the treatment of vasculitis but has been used after control is achieved with cyclophosphamide or rituximab in conditions such as granulomatosis with polyangiitis. Similarly, in SLE and inflammatory myositis, MTX has been used as a steroid-sparing agent.

Clinical Pharmacology: Most MTX is eliminated unchanged in urine. Some is metabolized in the liver to 7-hydroxymethotrexate. Plasma half-life is approximately 3-10 hours. Intracellular MTX forms polyglutamates which increase the biologic effect and toxicity of MTX beyond that expected from the plasma half-life. Cellular toxicity is related to concentration but more importantly to duration of exposure. Accumulates in pleural effusions and ascites and can cause toxicity.

Cost: Parenteral form, $; oral tablets, $$$

BIBLIOGRAPHY

American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for
monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:723–731.PMID: 8639168

Bykerk VP, Akhavan P, Hazlewood GS, et al. Canadian Rheumatology Association recommendations for pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs. J Rheumatol 2012;39:1559-82. PMID: 21921096.

Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2009 Jul;68(7):1086-93. PMID:19033291