Methotrexate for Psoriasis and Rheumatoid Arthritis
Dosing and Administration
For both psoriasis and rheumatoid arthritis, start methotrexate at 10-15 mg once weekly as a single oral dose, escalating by 5 mg every 2-4 weeks until optimal response is achieved, typically not exceeding 25-30 mg/week. 1, 2
Starting Dose Recommendations
- Rheumatoid Arthritis: Begin at 10-15 mg/week orally, with dose escalation of 5 mg every 2-4 weeks up to 20-30 mg/week based on clinical response 1
- Psoriasis: Start at 10-25 mg per week as a single dose, with a test dose of 2.5-5 mg recommended before initiating regular dosing 1
- Juvenile Rheumatoid Arthritis: 10 mg/m² once weekly 2
Route of Administration
Consider switching to subcutaneous or intramuscular administration if oral methotrexate shows inadequate response or causes gastrointestinal intolerance. 1 Parenteral methotrexate has higher bioavailability due to saturable intestinal absorption with oral dosing, resulting in more predictable drug levels and potentially better efficacy 3.
Test Dose Protocol
Administer a test dose of 2.5-5 mg with CBC monitoring 5-6 days later, particularly mandatory in patients with decreased renal function, elderly patients, or those with risk factors for hematologic toxicity. 1
Folic Acid Supplementation
Prescribe at least 5 mg of folic acid per week for all patients on methotrexate, given daily EXCEPT on the day(s) methotrexate is administered. 1, 4, 5
Specific Folic Acid Regimens
- Preferred regimen: 1 mg daily for 5-6 days per week, skipping the methotrexate day 4, 5
- Alternative regimen: 5 mg once weekly, taken the day after methotrexate 4
- For persistent side effects: Increase to 5 mg daily (except methotrexate day) 4
Critical Timing Consideration
Never give folic acid on the same day as methotrexate, as it may compete for cellular uptake and reduce therapeutic efficacy. 4, 5 Use folic acid rather than folinic acid (leucovorin) for routine supplementation—folinic acid is more expensive with no proven advantage and may reduce efficacy at doses >5 mg/week 4, 5.
Baseline Monitoring Requirements
Before initiating methotrexate, obtain: 1
- Complete blood count with differential and platelet count
- Liver function tests: AST, ALT, alkaline phosphatase, albumin
- Renal function: Serum creatinine, BUN, calculated GFR (especially in elderly or those with decreased muscle mass)
- Hepatitis B and C serology
- Pregnancy test in women of childbearing age
- Chest X-ray (if underlying pulmonary disease or obtained within previous year)
- Consider PPD for tuberculosis screening
- Noninvasive liver fibrosis assessment (vibration-controlled transient elastography preferred over baseline liver biopsy) 1
Ongoing Monitoring Schedule
Patients WITHOUT Hepatotoxicity Risk Factors
- CBC and platelets: Every 2-4 weeks for first few months, then every 1-3 months 1
- Liver function tests: Every 3-6 months (monthly for first 6 months per older guidelines) 1
- Renal function (BUN, creatinine): Every 2-3 months 1
Patients WITH Hepatotoxicity Risk Factors
Risk factors include: diabetes, obesity, chronic liver disease, hepatitis B/C, greater than moderate alcohol use (>1 drink/day for women, >2 drinks/day for men), family history of inheritable liver disease 1
- Same monitoring as low-risk patients
- Annual GI/hepatology referral or transient elastography 1
- Consider alternative therapy to methotrexate if multiple risk factors present 1
Liver Function Test Abnormalities
If ALT/AST elevation exceeds 2× normal, check more frequently; if exceeds 3× normal, consider dose reduction; if exceeds 5× normal, discontinue methotrexate. 1 For persistent elevations, repeat in 2-4 weeks and refer to GI/hepatology if abnormalities persist 1.
Liver Biopsy Considerations (Updated Guidelines)
Baseline liver biopsy is NOT recommended regardless of risk factors. 1 For patients without risk factors, consider first liver biopsy only after cumulative dose of 3.5-4 g (not the older 1.5 g threshold), with subsequent biopsies after each additional 1.5 g 1. This represents a significant liberalization from older guidelines based on evidence that hepatic fibrosis is less common than initially reported 1.
Absolute Contraindications
Methotrexate is absolutely contraindicated in: 1
- Pregnancy (Category X)
- Nursing mothers
- Alcoholism or alcoholic liver disease
- Chronic liver disease or cirrhosis
- Immunodeficiency syndromes
- Bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia
- Hypersensitivity to methotrexate
Relative Contraindications
Exercise caution with: 1
- Abnormalities in renal or liver function
- Active infection
- Obesity
- Diabetes mellitus
- Unreliable patients who cannot adhere to monitoring
Pregnancy and Contraception
Women of childbearing age MUST use contraception during methotrexate therapy. 1 Both men and women should wait at least 3 months after discontinuing methotrexate before attempting conception, as the drug persists in liver and other tissues and may affect spermatogenesis 1. Fetal abnormalities occur at all gestational ages, with the critical teratogenic period being weeks 6-8 of pregnancy 1.
Major Toxicities and Management
Hematologic Toxicity
Risk factors include: advanced age, renal impairment, lack of folic acid supplementation, drug interactions, hypoalbuminemia, and dosing errors 1, 6. Pancytopenia is the most common manifestation of low-dose methotrexate toxicity (78.5% of hospitalized cases) and can be life-threatening, with 25% mortality in one series due to sepsis 6.
If significant reduction in leukocyte or platelet counts occurs, reduce dose or temporarily discontinue methotrexate. 1 For suspected overdose or worrisome blood count decrements, administer folinic acid (leucovorin) 10 mg/m² immediately, then every 6 hours until recovery 1.
Hepatotoxicity
Hepatotoxicity risk is significantly higher in psoriasis patients compared to rheumatoid arthritis patients 1. Monitor for persistent LFT abnormalities and decreased serum albumin as indicators of serious liver toxicity 2. Recent evidence shows hepatic fibrosis and cirrhosis are considerably less common than initially reported 1.
Pulmonary Toxicity
Interstitial pneumonitis can occur at any time during therapy 1. Consider pulmonary function tests if methotrexate-induced lung disease is suspected, especially with baseline measurements available 2.
Gastrointestinal Effects
Common side effects include nausea (up to 25% of patients), vomiting, diarrhea, ulcerative stomatitis, and GI ulceration 1, 5. Folic acid supplementation significantly reduces these effects (OR 0.42 for GI side effects) 5.
Critical Drug Interactions
Avoid or use extreme caution with: 1, 2
- NSAIDs and salicylates: Reduce tubular secretion of methotrexate, potentially enhancing toxicity; particularly dangerous with high-dose methotrexate
- Trimethoprim/sulfamethoxazole: Folic acid antagonist effect increases toxicity risk
- Probenecid: Decreases renal tubular transport
- Hepatotoxic drugs: Barbiturates, acitretin (can be used together with appropriate monitoring), alcohol
- Penicillins, sulfonamides: Decrease methotrexate binding to albumin, increasing free drug levels
Efficacy Data
Psoriasis
In the only placebo-controlled trial, 36% of patients achieved PASI 75 after 16 weeks with methotrexate 7.5 mg/week escalated to 25 mg/week as needed 1. Therapeutic response typically begins within 3-6 weeks, with continued improvement for another 12 weeks or more 2.
Rheumatoid Arthritis
Methotrexate is the DMARD of first choice for RA, with efficacy almost similar to biologic monotherapy when both are combined with glucocorticoids 7. However, biologics inhibit structural damage to a significantly greater degree 7. The combination of methotrexate with biologics is superior to either agent alone 1, 7.
Psoriatic Arthritis
Methotrexate is efficacious for peripheral arthritis but NOT for axial involvement, with lower efficacy than TNF-inhibitors. 1 Despite limited controlled trial data, methotrexate is often used as the primary agent for psoriatic arthritis 1.
Common Pitfalls to Avoid
Daily dosing error: The most dangerous mistake is patients taking the weekly dose daily—this has led to fatal toxicity 1, 2. Prescriptions should clearly state "ONCE WEEKLY" and should not be written PRN 2.
Inadequate folic acid supplementation: Lack of folate is a major risk factor for hematologic toxicity 1, 5.
Ignoring drug interactions: Particularly dangerous are NSAIDs with high-dose methotrexate, sulfa drugs, and other medications affecting renal clearance 1, 2.
Insufficient monitoring in high-risk patients: Elderly patients, those with renal impairment, or multiple hepatotoxicity risk factors require more frequent monitoring 1.
Continuing therapy during acute illness: Patients with dehydration, acute renal failure, or active infection are at markedly increased risk for toxicity 1, 6.
Inadequate patient education: Patients must understand weekly dosing, the need for contraception, alcohol avoidance, and when to report symptoms 1, 2.