What is the recommended dosage of folic acid when prescribing methotrexate (MTX) to an adult patient with moderate to severe psoriasis, particularly those with a history of liver disease or impaired renal function?

Folic Acid Supplementation with Methotrexate in Psoriasis

Prescribe folic acid at 1-5 mg daily on all days except the day(s) methotrexate is administered, with a minimum weekly dose of 5 mg, regardless of liver disease or renal impairment status. 1, 2

Standard Folic Acid Dosing

The Joint American Academy of Dermatology-National Psoriasis Foundation guidelines provide a Grade A recommendation that folic acid or folinic acid administration is essential to reduce gastrointestinal and hepatic adverse effects in all patients on methotrexate. 1 The evidence is unequivocal: folic acid supplementation reduces GI side effects by 58% (OR 0.42) and hepatotoxicity by 83% (OR 0.17) without compromising therapeutic efficacy. 2

Recommended dosing regimens include:

• 5 mg once weekly (taken the day after methotrexate administration) 3
• 1 mg daily (every day except methotrexate day) 2, 3
• Both approaches provide the minimum 5 mg weekly threshold 2, 3

Critical Timing Consideration

Never administer folic acid on the same day as methotrexate. 2, 3 Folic acid may theoretically compete with methotrexate for cellular uptake when given simultaneously, potentially reducing therapeutic efficacy. 2, 3 This timing restriction applies to all patients regardless of comorbidities.

Special Populations: Liver Disease and Renal Impairment

Patients with Liver Disease

For patients with chronic liver disease (hepatitis B/C, nonalcoholic steatohepatitis) or other hepatotoxicity risk factors, the folic acid dosing remains the same at 1-5 mg daily (excluding methotrexate day). 1 However, these patients require enhanced monitoring:

• Baseline noninvasive liver fibrosis assessment before starting methotrexate 1
• Annual GI/hepatology referral or vibration-controlled transient elastography if methotrexate is continued despite abnormal baseline results 1
• Liver function tests every 3-6 months (more frequently if abnormalities develop) 1
• Consider alternative therapy to methotrexate if significant risk factors exist 1

Patients with Renal Impairment

A test dose of methotrexate should be considered in patients with impaired kidney function (Grade B recommendation). 1 The folic acid supplementation dose itself does not change, but methotrexate dosing requires adjustment:

• GFR 20-50 mL/min: Reduce methotrexate dose by 50% 4
• GFR <20 mL/min: Avoid methotrexate entirely 4
• Folic acid supplementation at standard doses (1-5 mg daily, excluding methotrexate day) remains appropriate 2, 3

The critical issue in renal impairment is methotrexate accumulation and toxicity risk, not folic acid dosing. 5 Lack of folate supplementation is a major risk factor for methotrexate-induced hematologic toxicity, making folic acid even more essential in this vulnerable population. 2, 5

Folic Acid vs. Folinic Acid

Use folic acid, not folinic acid (leucovorin), for routine supplementation. 2, 3 Folic acid is preferred due to lower cost and similar effectiveness. 1, 2, 3 Meta-analysis demonstrates that folinic acid at doses >5 mg/week may actually reduce methotrexate efficacy (increased tender and swollen joints with OR 6.27 and 5.3 respectively). 2

Folinic acid is reserved exclusively for methotrexate overdose or severe toxicity as rescue therapy, not routine supplementation. 2

Dose Escalation Considerations

If patients experience intolerable side effects despite standard folic acid supplementation, increase folic acid to 5 mg daily (except methotrexate day) before reducing methotrexate dose. 3 For patients on methotrexate >15 mg/week, consider increasing to 7-10 mg folic acid weekly. 2

Common Pitfalls to Avoid

• Do not give folic acid on methotrexate day - this may compromise therapeutic effect 2, 3
• Do not use folinic acid for routine supplementation - it's more expensive and may reduce efficacy at higher doses 2, 3
• Do not omit folic acid in any patient on methotrexate - lack of supplementation is a major risk factor for hematologic toxicity 2, 5
• Do not assume folic acid eliminates need for monitoring - regular CBC, liver function tests, and creatinine monitoring remain essential every 3-6 months 1, 2

Fatal Toxicity Risk

A case report highlights the lethal potential of methotrexate without folic acid supplementation: a 67-year-old with end-stage renal disease on peritoneal dialysis taking methotrexate 10 mg weekly without folic acid developed fatal pancytopenia and multiorgan failure. 5 This underscores that folic acid supplementation is not optional—it is a mandatory safety measure, particularly in patients with renal impairment, advanced age, or other risk factors. 5