What is methotrexate and how is it used?

Methotrexate: A Comprehensive Overview

Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, affecting DNA, RNA, and protein synthesis, and is used to treat various conditions including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and certain cancers. 1

Indications

• FDA-approved for treatment of:

  • Severe, recalcitrant, disabling psoriasis 1
  • Rheumatoid arthritis including polyarticular-course juvenile rheumatoid arthritis 1
  • Various neoplastic diseases (gestational choriocarcinoma, acute lymphocytic leukemia, breast cancer, lung cancer, advanced mycosis fungoides) 1

• Off-label uses include:

  • Atopic dermatitis 2
  • Inflammatory bowel disease 2
  • Giant-cell arteritis and polymyalgia rheumatica 2
  • Systemic lupus erythematosus and dermatomyositis 2

Dosing and Administration

• Psoriasis and rheumatoid arthritis:

  • Starting dose: 10-15 mg/week orally 2
  • Dose escalation: 5 mg every 2-4 weeks up to 20-30 mg/week based on clinical response and tolerability 2
  • Parenteral administration (subcutaneous or intramuscular) should be considered if oral route shows inadequate response or intolerance 2

• Atopic dermatitis (off-label):

  • 10-25 mg/week 2

• Inflammatory bowel disease (off-label):

  • 25 mg/week intramuscularly for induction 2
  • 15 mg/week for maintenance 2

• Pediatric dosing:

  • 15 mg/m² (body surface area) once weekly to a maximum of 25 mg 2

Mechanism of Action

• Inhibits dihydrofolate reductase, preventing conversion of dihydrofolate to tetrahydrofolate 1, 3
• Blocks synthesis of DNA, RNA, and proteins 3
• Suppresses T-cell function and inflammatory pathways 2, 4

Monitoring Requirements

Before Starting Treatment:

• Complete history and physical examination 2
• Laboratory tests:
  • Complete blood count (CBC) with differential 2
  • Liver function tests (AST, ALT, albumin, bilirubin) 2
  • Renal function (creatinine, eGFR) 2
  • Hepatitis B and C screening 2
  • Pregnancy test when applicable 2
  • Consider chest X-ray if pulmonary disease is suspected 2

Ongoing Monitoring:

• CBC and platelet counts:

  • Every 2-4 weeks for first few months
  • Then every 1-3 months depending on dose adjustments and previous results 2

• Liver function tests:

  • Monthly initially
  • Then every 2-3 months based on dose adjustments and previous results 2

• Renal function:

  • Every 2-3 months 2

Side Effects and Toxicity

Common Side Effects:

• Gastrointestinal symptoms (nausea, vomiting, diarrhea, stomatitis) - occurs in up to 25% of patients 2, 5
• Fatigue and malaise 5
• Headache 5

Serious Adverse Effects:

• Bone marrow suppression (leukopenia, thrombocytopenia, anemia) 3
• Hepatotoxicity - may lead to fibrosis and cirrhosis with long-term use 2
• Pulmonary toxicity (pneumonitis, fibrosis) - rare but serious 2, 3
• Nephrotoxicity - especially with high doses or in renal impairment 3, 6
• Increased risk of infections 3

Risk Mitigation Strategies

• Folic acid supplementation:

  • At least 5 mg folic acid per week is strongly recommended 2
  • Reduces gastrointestinal and liver toxicity without reducing efficacy 2
  • Should be taken daily except on the day methotrexate is administered 7

• Dose adjustments for renal impairment:

  • eGFR >90 mL/min: normal dose
  • eGFR 20-50 mL/min: half dose
  • eGFR <20 mL/min: avoid methotrexate 2, 6

• Alcohol limitation:

  • Avoid alcohol consumption due to increased risk of hepatotoxicity 2

Drug Interactions

Medications that may increase methotrexate toxicity:

• NSAIDs including salicylates, naproxen, ibuprofen 2, 7
• Antibiotics: trimethoprim/sulfamethoxazole, sulfonamides, penicillins, minocycline, ciprofloxacin 2
• Diuretics: furosemide, thiazides 2
• Others: barbiturates, colchicine, dipyridamole, ethanol, phenytoin 2, 7

Contraindications

Absolute Contraindications:

• Pregnancy and breastfeeding 2
• Significant hepatic damage or cirrhosis 2
• Severe renal impairment (eGFR <20 mL/min) 2, 6
• Bone marrow suppression (anemia, leukopenia, thrombocytopenia) 2

Pregnancy Considerations:

• Women should wait at least 3 months after discontinuing methotrexate before attempting to conceive 2
• Men should also wait 3 months after discontinuation before attempting to father children 2

Efficacy

• In rheumatoid arthritis:

  • Significantly more effective than placebo 8
  • Improves physical function and quality of life 8
  • Reduces radiographic progression 8

• In psoriasis:

  • Effective for extensive chronic plaque psoriasis, pustular psoriasis, and psoriatic erythroderma 2
  • Can be used short-term to gain control of unstable psoriasis or as long-term maintenance 2

• In inflammatory bowel disease:

  • Effective for inducing remission and preventing relapse in Crohn's disease 2
  • 39% of steroid-dependent patients able to withdraw steroids and enter remission (vs. 19% with placebo) 2

By understanding methotrexate's mechanism of action, appropriate dosing, monitoring requirements, and potential side effects, clinicians can optimize its use while minimizing risks, making it a valuable treatment option for multiple inflammatory and autoimmune conditions.