What does methotrexate (MTX) treatment necessitate to mitigate its potential side effects?

Methotrexate Treatment Requirements

All patients on methotrexate must receive folic acid supplementation (1-5 mg daily, except on the day of methotrexate administration) and undergo regular laboratory monitoring to prevent life-threatening toxicities including myelosuppression, hepatotoxicity, and pulmonary fibrosis. 1

Essential Supplementation

Folic Acid Requirement

• Administer folic acid 1-5 mg daily on all days except the day methotrexate is taken 1
• The American Academy of Dermatology and British Association of Dermatologists both strongly recommend universal folate supplementation for all patients on methotrexate 1
• Folic acid reduces gastrointestinal toxicity (nausea, stomatitis), hepatotoxicity, and hematologic toxicity without compromising efficacy 1
• Alternative dosing: 5 mg once weekly is acceptable, though daily dosing may provide better protection 2
• Do not give folic acid on the same day as methotrexate to avoid interfering with therapeutic effect 1

Mandatory Baseline Testing

Before initiating methotrexate, obtain: 1, 3

• Complete blood count with differential and platelet count
• Comprehensive metabolic panel including liver function tests (AST, ALT, albumin) and renal function (creatinine, eGFR)
• Chest X-ray (to establish baseline for pulmonary monitoring)
• Hepatitis B and C screening (based on risk factors)
• Tuberculosis testing (PPD, QuantiFERON, or T-Spot) if risk factors present
• Pregnancy test for women of childbearing potential

Regular Monitoring Schedule

During Rheumatoid Arthritis/Psoriasis Treatment

• Complete blood count: monthly 1, 3
• Liver and renal function tests: every 1-2 months initially, then every 3 months once stable 1, 3
• More frequent monitoring required during dose escalation or if risk factors present (renal impairment, advanced age, drug interactions) 1, 2

High-Risk Situations Requiring Increased Monitoring

Monitor more frequently (every 2-4 weeks) when: 1, 2

• Increasing methotrexate dose (toxicity may occur 4-6 weeks after dose increase)
• Dehydration or volume depletion present
• Concurrent use of NSAIDs, sulfonamides, or other interacting medications
• Renal insufficiency (eGFR 30-59 mL/min)
• Advanced age (>65 years)

Critical Safety Measures

Hydration and Alkalinization (High-Dose Methotrexate >500 mg/m²)

• Administer 1,000 mL/m² IV fluid over 6 hours before methotrexate infusion 3
• Continue hydration at 125 mL/m²/hr (3 liters/m²/day) during infusion and for 2 days after completion 3
• Alkalinize urine with sodium bicarbonate to maintain pH >7.0 throughout infusion and leucovorin therapy 3, 4
• This prevents methotrexate crystallization in renal tubules, the primary cause of acute kidney injury 4

Leucovorin Rescue (High-Dose Regimens)

• Begin leucovorin 24 hours after methotrexate administration 3
• Continue until methotrexate level falls below 0.05 micromolar 3
• Dose and duration adjusted based on serum methotrexate levels and renal function 3

Contraindications and Dose Adjustments

Renal Function

• Contraindicated if eGFR <30 mL/min 5
• Reduce dose by 50% if eGFR 20-50 mL/min 6
• Use test dose (2.5-5 mg) with CBC check 5-6 days later in patients with decreased GFR before full dosing 1

Hepatic Risk Factors Requiring Enhanced Monitoring

Patients with the following require non-invasive liver assessment (FibroScan/FIB-4) at baseline: 1

• BMI >28 kg/m²
• Alcohol intake >14 drinks per week
• History of liver disease
• Diabetes mellitus
• Hyperlipidemia
• Chronic hepatitis B or C

Management of Common Toxicities

Gastrointestinal Side Effects (Nausea, Stomatitis)

If these occur despite folic acid supplementation: 1

• Switch from oral to subcutaneous or intramuscular administration
• Split weekly dose into 3 divided doses given 12 hours apart
• Take medication with food or at bedtime
• Increase folic acid dose to 5 mg daily

Hematologic Toxicity

Hold methotrexate if: 2

• White blood cell count <3.5 × 10⁹/L
• Neutrophils <2 × 10⁹/L
• Platelets significantly decreased

Resume only after counts recover, with consideration of dose reduction 2

Hepatotoxicity

• Stop methotrexate if transaminases exceed 2× upper limit of normal 2
• Recheck in 2-4 weeks; if persistently elevated or albumin declining, obtain GI consultation 1
• Consider liver biopsy or transient elastography if stage 3 fibrosis suspected 1

Pulmonary Symptoms

Any new cough, dyspnea, or fever requires immediate evaluation to rule out methotrexate-induced pneumonitis, though this is rare in psoriasis patients compared to rheumatoid arthritis 1

Common Pitfalls to Avoid

• Never prescribe methotrexate on a PRN basis - weekly dosing errors have caused fatalities 3
• Do not combine with NSAIDs before or during high-dose methotrexate (>500 mg/m²) 3
• Avoid sulfonamide antibiotics - major risk factor for pancytopenia 1
• Check all medications for interactions - weak organic acids, salicylates, and proton pump inhibitors can increase toxicity 3
• Ensure adequate contraception - methotrexate is teratogenic 1, 3