What is the use of methotrexate in an adult patient with a history of cancer, autoimmune diseases such as rheumatoid arthritis, or psoriasis?

What Methotrexate Does

Methotrexate is an antimetabolite drug that works by inhibiting folate metabolism, thereby suppressing DNA synthesis and cell proliferation, making it effective for treating cancer, severe psoriasis, rheumatoid arthritis, and psoriatic arthritis. 1

Mechanism of Action

Methotrexate functions as a folate antagonist that interferes with cellular metabolism and immune function 2, 3:

• Blocks dihydrofolate reductase, preventing conversion of dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis 3
• Forms active polyglutamylated metabolites intracellularly that enhance drug retention and increase affinity for target enzymes 2
• Suppresses T-cell activation in autoimmune conditions, providing immunosuppressive effects 4
• Inhibits rapidly dividing cells, making it effective against malignancies and hyperproliferative skin conditions 1

FDA-Approved Clinical Uses

Cancer Treatment 1

• Gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole
• Acute lymphocytic leukemia (prophylaxis and treatment of meningeal leukemia, maintenance therapy)
• Breast cancer (alone or in combination with other agents)
• Head and neck epidermoid cancers
• Advanced mycosis fungoides (cutaneous T-cell lymphoma)
• Lung cancer (particularly squamous cell and small cell types)
• Advanced stage non-Hodgkin's lymphomas (in combination regimens)
• Non-metastatic osteosarcoma (high-dose with leucovorin rescue after surgical resection)

Dermatologic Conditions 1

• Severe, recalcitrant, disabling psoriasis that has not responded adequately to other therapies 4
• Particularly effective for acute generalized pustular psoriasis, psoriatic erythroderma, and extensive chronic plaque psoriasis in elderly or infirm patients 4
• Achieves approximately 60% PASI 75 response at 16 weeks 5

Rheumatologic Conditions 1

• Severe, active rheumatoid arthritis in adults who have failed or are intolerant to first-line therapy including NSAIDs 4
• Active polyarticular-course juvenile rheumatoid arthritis 1
• Psoriatic arthritis, though evidence from controlled trials is limited 4
• Considered the "anchor-drug" among disease-modifying antirheumatic drugs (DMARDs) 6, 7

Clinical Effectiveness Profile

Response Timeline 4

• Psoriasis: Clinical improvement typically seen within 2 weeks of initiation
• Rheumatoid arthritis: Response may take several weeks to months
• Can be used for short-term control of unstable disease or as long-term maintenance therapy 4

Combination Therapy Benefits 4

• Reduces immunogenicity when combined with biologic therapies (anti-TNF agents, ustekinumab) 4
• Prolongs efficacy of monoclonal antibody-based biologics by decreasing anti-drug antibody formation 4
• May be continued with low-dose corticosteroids, NSAIDs, or aspirin in rheumatoid arthritis, though increased toxicity risk exists 1

Critical Safety Considerations

Absolute Contraindications 4, 1

• Pregnancy (Category X - causes fetal death and congenital anomalies) 1
• Breastfeeding 4
• Cirrhosis or significant hepatic damage 4
• Severe anemia, leucopenia, or thrombocytopenia 4

Major Toxicities Requiring Monitoring 1

• Hepatotoxicity: Fibrosis and cirrhosis can develop after prolonged use; liver biopsies traditionally recommended after 1.5-3.5g cumulative dose in psoriasis patients 4
• Bone marrow suppression: Can be acute and severe, particularly with concomitant NSAID use 1
• Pulmonary toxicity: Methotrexate-induced pneumonitis can occur at any time, even at low doses; dry nonproductive cough requires immediate evaluation 1
• Renal impairment: Reduced elimination increases toxicity risk 1
• Opportunistic infections: Risk highest in first 12 weeks but persists throughout treatment; methotrexate must be discontinued if opportunistic infections develop 4, 8

Monitoring Requirements 4

• Baseline: Complete blood count, liver function tests, serum creatinine, hepatitis B/C screening, tuberculosis testing 4
• Ongoing: CBC and liver function tests every 1-3 months depending on dose and risk factors 4
• Renal function (BUN, creatinine) every 2-3 months 4

Important Clinical Pitfalls

Dosing Errors 4, 7

• Methotrexate is dosed ONCE WEEKLY, not daily - accidental daily dosing can be fatal 7
• Prescribe only the 25mg tablet strength and write dose in full uppercase letters to avoid decimal point errors 4

Drug Interactions 1

• NSAIDs (including aspirin) can cause unexpectedly severe bone marrow suppression and GI toxicity when combined with methotrexate 1
• Numerous other drug interactions exist that can impair methotrexate elimination 4

Fertility and Conception 4

• Women: Must avoid conception during treatment and for at least one menstrual cycle after stopping 4
• Men: Causes spermal abnormalities; should discontinue 3 months before attempting to father children 4

Infection Management 4, 8

• Temporarily discontinue during severe infections or infections not responding to standard treatment 4
• Permanently discontinue if opportunistic infections develop 4, 8
• Consider prophylactic antivirals for herpes and pneumocystis prophylaxis when CD4 counts are low or with concurrent high-dose corticosteroids 8