What is the role of methotrexate (MTX) in treating a patient with moderate to severe chronic plaque psoriasis?

Methotrexate in Moderate to Severe Chronic Plaque Psoriasis

Methotrexate is recommended as an effective first-line systemic therapy for moderate to severe chronic plaque psoriasis in adults, with particularly strong evidence supporting subcutaneous administration at doses of 7.5-25 mg weekly combined with folic acid supplementation. 1

Primary Indications and Efficacy

Methotrexate is FDA-approved for severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy 2. The 2020 AAD-NPF guidelines provide a Grade A recommendation for methotrexate in moderate to severe psoriasis 1.

Clinical response timeline:

• Initial improvement typically occurs within 2 weeks 1
• PASI 75 response achieved in 38-41% of patients by week 16 with standard dosing 3, 4
• Subcutaneous administration at 17.5 mg weekly achieves 41% PASI 75 at 16 weeks, significantly superior to placebo (10%) 3

Optimal Dosing Strategy

Recommended dosing regimen:

• Starting dose: 7.5-10 mg weekly, not exceeding 0.2 mg/kg body weight for first dose 1
• Target maintenance range: 7.5-25 mg weekly 1
• Dose escalation: Increase gradually if inadequate response after 8 weeks 3
• Administration can be single weekly dose or divided into 3 doses over 24 hours 1

Route of administration matters significantly:

• Subcutaneous administration is superior to oral, with higher bioavailability, fewer gastrointestinal side effects, and improved efficacy through higher intracellular methotrexate polyglutamate levels 1, 5
• Consider test dose, especially in patients with impaired kidney function 1

Mandatory Folic Acid Supplementation

Folic acid 5 mg weekly or 1 mg daily (6 days/week) is required to reduce gastrointestinal and hepatic adverse effects 1, 3. However, avoid excessive doses as they may reduce methotrexate efficacy 1.

Special Clinical Scenarios

Methotrexate is particularly effective for:

• Acute generalized pustular psoriasis 1, 6
• Psoriatic erythroderma 1, 6
• Psoriatic arthritis (peripheral arthritis, though less effective than TNF inhibitors) 1
• Extensive chronic plaque psoriasis in elderly or infirm patients 1, 6

Important caveat: While methotrexate is less effective than adalimumab and infliximab for cutaneous psoriasis (Grade A evidence), it remains a valuable option due to cost, long-term safety data, and combination therapy potential 1.

Mandatory Monitoring Protocol

Baseline assessment required:

• Complete blood count with differential and platelets 1
• Liver function tests 1
• Serum creatinine and renal function 1
• Noninvasive liver fibrosis assessment (NOT liver biopsy) 1
• Hepatitis B and C screening if at risk 1

Ongoing monitoring schedule:

• CBC with differential 5-7 days after initiating therapy 1
• Liver function tests every 3-6 months (assuming no abnormalities) 1
• If liver enzymes elevate: repeat in 2-4 weeks; if persistent, refer to gastroenterology 1
• Annual noninvasive liver fibrosis assessment if risk factors present 1

Absolute Contraindications

Methotrexate is contraindicated in:

• Pregnancy and breastfeeding 1, 2
• Women of childbearing potential without reliable contraception 1, 2
• Men wishing to father children (causes spermal abnormalities) 1
• Significant hepatic damage 1, 2
• Severe anemia, leucopenia, or thrombocytopenia 1, 2
• Abnormal renal function 2

Contraception requirements: Both men and women must use contraception during treatment and for at least one menstrual cycle after stopping 1.

Critical Drug Interactions to Avoid

Never combine methotrexate with:

• Trimethoprim-sulfamethoxazole (interferes with folic acid metabolism) 7
• NSAIDs without careful monitoring (reduce renal clearance and can precipitate severe, sometimes fatal toxicity) 1, 2

Hepatotoxicity Risk Stratification

High-risk patients for methotrexate-induced hepatotoxicity:

• Greater than moderate alcohol use (>1 drink/day for women, >2 drinks/day for men) 1
• Obesity and nonalcoholic steatohepatitis (common psoriasis comorbidity) 1
• Chronic liver disease (hepatitis B or C) 1
• Prior exposure to hepatotoxic drugs 1
• Family history of inheritable liver disease 1

For high-risk patients: Consider alternative therapy; if methotrexate chosen, perform annual noninvasive hepatic serology regardless of cumulative dose 1.

Life-Threatening Toxicities Requiring Immediate Action

Discontinue methotrexate immediately if:

• Diarrhea and ulcerative stomatitis develop (can progress to hemorrhagic enteritis and intestinal perforation) 2
• Pulmonary symptoms occur, especially dry nonproductive cough (methotrexate-induced pneumonitis can be fatal) 2
• Unexpectedly severe bone marrow suppression (more likely in elderly, renal impairment, folate depletion) 2, 6

Combination Therapy Options

Evidence-based combinations:

• Methotrexate + narrowband UVB phototherapy enhances efficacy and lowers cumulative doses of both treatments (Grade B recommendation) 1
• Methotrexate can be combined with biologics, particularly to suppress antibodies against adalimumab and infliximab 1

Common Pitfalls to Avoid

1. Do not perform baseline liver biopsy regardless of risk factors; use noninvasive assessment instead 1
2. Do not use preserved formulations for high-dose therapy (contains benzyl alcohol) 2
3. Do not overlook renal impairment, ascites, or pleural effusions as these reduce methotrexate elimination and require dose reduction or discontinuation 2
4. Do not continue methotrexate if persistent liver enzyme elevations occur without gastroenterology referral 1
5. Weekly dosing is superior to daily dosing for both efficacy and gastrointestinal tolerability 8