Methotrexate

1. Mechanism
   1. Antimetabolite Chemotherapy (Cell Cycle Specific)
      1. S-Phase toxin (DNA synthesis phase)
   2. Folic Acid structural analog
      1. Competitively inhibits at DHF Reductase
   3. Inhibits de novo Pyrimidine synthesis
2. Indications
   1. Ectopic Pregnancy
   2. Psoriasis
   3. Rheumatoid Arthritis (DMARD)
      1. Early Rheumatoid Arthritis
      2. Chronic Late Rheumatoid Arthritis
      3. Seronegative Rheumatoid Arthritis
   4. Cancer Chemotherapy
      1. Acute Myelocytic Anemia
      2. Head and Neck Cancer
      3. Cervical Cancer
      4. Breast Cancer
      5. Testicular Cancer
      6. Wilms Tumor
      7. Sarcoma
3. Dosing
   1. Co-administer Folic Acid 1 mg PO qd
      1. Reduces adverse effects
      2. Does not decrease efficacy
   2. Rheumatoid Arthritis
      1. Initial: 10 mg per week (5 mg PO bid every Monday)
      2. Lowest effective dose: 7.5 mg po qAM every Monday
      3. Average dose: 10 mg PO bid every Monday
      4. Maximum dose: 12.5 mg PO bid every Monday
      5. Methotrexate 7.5 - 20 mg/week PO, SQ, IM
   3. Cancer Chemotherapy
      1. Oral: 2.5 to 5 mg/day
      2. Intrathecal: 10 mg weekly to biweekly
4. Efficacy
   1. Rheumatoid Arthritis
      1. Very effective (>85% initially)
      2. Response in 4-6 weeks (faster than other DMARDs)
   2. Curative in Choriocarcinoma
5. Adverse Effects
   1. Oral and Gastrointestinal (most common)
      1. Nausea
      2. Oral Ulcers
      3. Stomatitis
      4. Diarrhea
   2. Hepatic
      1. Hepatic fibrosis
      2. Elevated transaminases
      3. Cirrhosis
   3. Pulmonary
      1. Pulmonary fibrosis or infiltrates
      2. Hypersensitivity Pneumonitis
         1. Presents with dry cough, fever, Dyspnea on exertion
         2. Stop Methotrexate and exclude infection
         3. Start high dose Corticosteroids
         4. Consider gallium lung scan
   4. Neuropsychiatric
      1. Dysphoria
   5. Hematologic
      1. Minimal Immunosuppression
         1. Contrast with Imuran, Cytoxan, Sandimmune
      2. Myelosuppression
      3. Thrombocytopenia
6. Cost
   1. Very expensive (>$1000 per year)
7. Monitoring
   1. Baseline screening
      1. Complete Blood Count with Platelet Count
      2. Recent Chest XRay
      3. Liver Function Tests
         1. Aspartate Aminotransferase (AST)
         2. Alanine Aminotransferase (ALT)
         3. Alkaline Phosphatase
         4. Albumin
         5. Consider Hepatitis B and Hepatitis C serologies
      4. Renal Function Tests
         1. Creatinine
   2. Follow-up Monitoring: (monthly x3, then every 8 weeks)
      1. Complete Blood Count with Platelet Count
      2. Liver Function Tests
         1. Aspartate Aminotransferase (AST)
         2. Alkaline Phosphatase
      3. Renal Function Tests
         1. Creatinine
   3. Liver Biopsy Indications
      1. Cumulative Methotrexate dose >8 gram
      2. Prior heavy Alcohol use
      3. Persistently elevated AST (SGOT) 2-3x normal
      4. Psoriatic Arthritis
8. Contraindications
   1. Renal Insufficiency (Serum Creatinine > 1.5)
   2. Pleural Effusion
   3. Ascites
   4. Active stomatitis
   5. Diarrhea
   6. Infection
9. Relative Contraindications (due to hepatotoxicity)
   1. Alcohol Use
   2. Pre-existing liver disease
   3. Diabetes Mellitus
   4. Obesity
   5. Age >70 years
10. Antidote in toxicity
    1. Effects reversed by Leucovorin (Citrovorum factor)
11. References
    1. Furst (1997) Br J Rheumatol 36:1196-204
    2. Jones (2000) Am Fam Physician 62(7):1607-14
    3. Matterson (2000) Mayo Clin Proc 75:669-74
    4. Pincus (1999) Clin Rheumatol 17(6 Suppl 18): S2-S124