What is the recommended initial dose, titration schedule, folic‑acid supplementation, renal dose adjustments, and monitoring plan for methotrexate in an adult with moderate‑to‑severe plaque psoriasis?

Methotrexate Dosing in Psoriasis

For adults with moderate-to-severe plaque psoriasis, start methotrexate at 10-15 mg subcutaneously once weekly, escalate gradually to 15-25 mg/week based on response, supplement with folic acid 5 mg weekly (or 1 mg daily except on methotrexate day), and monitor with complete blood count, liver function tests, and creatinine every 3-6 months after initial weekly monitoring. 1, 2, 3

Initial Dosing and Test Dose

• Start with 10-15 mg subcutaneously once weekly as the initial dose for most patients, though the FDA label allows 10-25 mg/week 1, 3, 4
• Consider a test dose of 5-10 mg in patients with impaired kidney function to assess for idiosyncratic bone marrow suppression before committing to regular dosing 1, 5
• The maximum first dose should not exceed 0.2 mg/kg body weight, particularly in patients over 70 years 1
• Subcutaneous administration is preferred over oral dosing due to superior bioavailability and efficacy, with 79.4% of patients in real-world practice using subcutaneous route 4, 6

Dose Escalation Schedule

• If inadequate response after 4-8 weeks, escalate by 2.5-5 mg increments to a maximum of 25 mg/week 1, 3
• Higher cumulative doses in the first month (>60 mg total in first 4 weeks) are associated with better PASI 75 response rates at week 12-16 7
• The METOP trial demonstrated that starting at 17.5 mg/week with escalation to 22.5 mg/week at 8 weeks if PASI 50 not achieved resulted in 41% PASI 75 response at week 16 4
• Do not exceed 25 mg/week, as doses above 20 mg/week significantly increase risk of myelosuppression and other serious adverse reactions 3

Folic Acid Supplementation (Critical)

• Prescribe folic acid 5 mg once weekly (taken the day after methotrexate) OR 1 mg daily on all days except methotrexate day 1, 2, 5
• Never administer folic acid on the same day as methotrexate, as it may compete for cellular uptake and reduce therapeutic efficacy 2, 5, 8
• Folic acid reduces gastrointestinal side effects by 58% and hepatotoxicity by 83% without compromising efficacy when dosed appropriately (≤5 mg/week) 1, 2
• Use folic acid, not folinic acid (leucovorin), for routine supplementation—folinic acid is reserved exclusively for methotrexate overdose or severe toxicity 2, 5
• If intolerable side effects persist despite standard supplementation, increase folic acid to 5 mg daily (except methotrexate day) before reducing methotrexate dose 2

Renal Dose Adjustments

• For GFR 20-50 mL/min: reduce methotrexate dose by 50% 1
• For GFR <20 mL/min: avoid methotrexate entirely 1
• Measure serum creatinine at baseline and monitor regularly, as methotrexate is primarily renally cleared and impaired clearance dramatically increases toxicity risk 1
• Consider a test dose in all patients with any degree of renal impairment before initiating regular dosing 1, 5

Monitoring Plan

Baseline (Before Starting Treatment)

• Complete blood count (CBC) with differential 1
• Comprehensive metabolic panel including liver function tests (AST, ALT, alkaline phosphatase, bilirubin) and serum creatinine 1
• Hepatitis B and C serologies 1
• Noninvasive liver fibrosis assessment (FIB-4 score or APRI score)—do NOT perform baseline liver biopsy 1
• Pregnancy test for women of reproductive potential 1, 3
• Chest X-ray to establish baseline pulmonary status 1

During Treatment

• Weeks 1-4: Monitor CBC, liver function tests, and creatinine weekly 1
• After stabilization: Monitor CBC, liver function tests, and creatinine every 3-6 months assuming no laboratory abnormalities 1, 2
• For persistent liver enzyme elevations (AST or ALT), repeat in 2-4 weeks; if still elevated, refer to gastroenterology/hepatology 1
• Annual noninvasive liver fibrosis assessment (vibration-controlled transient elastography or serology) for patients with risk factors for hepatotoxicity 1

High-Risk Populations Requiring Enhanced Monitoring

Patients with the following risk factors require annual GI/hepatology referral or vibration-controlled transient elastography 1:

• Body mass index ≥40 kg/m² 1
• Diabetes mellitus 1
• Hyperlipidemia 1
• Nonalcoholic fatty liver disease 1
• Chronic hepatitis B or C 1
• Alcohol use >1 drink/day for women or >2 drinks/day for men 1
• Family history of inheritable liver disease 1

Route of Administration

• Subcutaneous administration is strongly preferred over oral due to more predictable absorption and superior efficacy 4, 6
• The METOP trial showed subcutaneous route was an independent positive predictor of PASI 90 achievement 4, 6
• Oral administration may be considered if subcutaneous is not feasible, but expect potentially lower response rates 1
• Intramuscular administration is also FDA-approved but less commonly used in dermatology practice 3

Predictors of Treatment Success

Factors associated with better PASI 90 response 7, 6:

• No prior systemic treatment (methotrexate-naive patients respond better) 7, 6
• Subcutaneous rather than oral administration 6
• Concurrent folic acid supplementation 6
• Weekly dose ≤15 mg (paradoxically, moderate doses may be optimal) 6
• Higher cumulative dose in first month (>60 mg total) 7
• Absence of previous cyclosporine use 7

Common Pitfalls to Avoid

• Never give folic acid on the same day as methotrexate—this may reduce efficacy 2, 5, 8
• Never use folinic acid for routine supplementation—it is more expensive and may reduce efficacy at doses >5 mg/week; reserve it only for overdose/toxicity 2, 5
• Never skip folic acid supplementation—lack of folate is a major risk factor for hematologic toxicity 8
• Never continue methotrexate without regular monitoring—even with folic acid, CBC, liver function tests, and creatinine must be checked every 3-6 months 1, 2
• Never perform baseline liver biopsy—current guidelines recommend noninvasive assessment instead 1
• Never use oral route as first choice—subcutaneous is superior in efficacy and should be preferred 4, 6
• Never exceed 25 mg/week—higher doses dramatically increase serious adverse reaction risk without proportional efficacy gains 1, 3

Drug Interactions Requiring Caution

The following medications increase methotrexate activity and toxicity risk 1:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) 1
• Trimethoprim-sulfamethoxazole or trimethoprim alone 1
• Salicylates 1
• Probenecid 1
• Phenytoin 1
• Alcohol (advise patients to avoid or minimize) 1

Contraception Requirements

• Women of reproductive potential: use effective contraception during treatment and for 6 months after final dose 3
• Men with female partners of reproductive potential: use effective contraception during treatment and for 3 months after final dose 3
• Methotrexate is absolutely contraindicated in pregnancy for non-neoplastic diseases 3

Expected Response Timeline

• Majority of responses occur between 3-6 weeks from initiation, though responses may take up to 12 weeks 3
• At week 16, expect approximately 41% PASI 75 response with optimized subcutaneous dosing (17.5 mg/week) 4
• At week 24, expect approximately 37% PASI 90 response with continued treatment 6
• If no response by 12-16 weeks despite dose optimization, consider alternative therapy 1