In a 45-year-old man with psoriasis and markedly elevated aspartate aminotransferase (~250 U/L) and alanine aminotransferase (~320 U/L), should oral methotrexate be avoided and what is the preferred alternative therapy?

Methotrexate is Contraindicated in This Patient

Oral methotrexate should NOT be given to this 45-year-old man with markedly elevated liver transaminases (SGOT 250, SGPT 320), as methotrexate is absolutely contraindicated in patients with significant hepatic damage. 1

Why Methotrexate is Contraindicated

• Methotrexate causes direct hepatotoxicity, fibrosis, and cirrhosis with prolonged use, making it absolutely contraindicated when significant hepatic damage already exists. 1

• The British Association of Dermatologists guidelines require baseline liver function tests and clinical liver examination before initiating methotrexate, and this patient's transaminases are approximately 6-8 times the upper limit of normal. 2

• Guidelines specify that persistent elevations ≥2-fold but <3-fold upper limit of normal require close monitoring and dose reduction, while elevations ≥3-fold require holding the medication. 2 This patient's values far exceed these thresholds.

• Even in patients without pre-existing liver disease, methotrexate monitoring protocols call for holding the drug when liver enzymes exceed 2× normal and discontinuing when they exceed 3× normal. 2 Starting methotrexate with baseline values 6-8× normal would be dangerous.

Preferred Alternative: Biologics (Ustekinumab or IL-17 Inhibitors)

The optimal alternative for this patient is a biologic agent, specifically ustekinumab, secukinumab, or ixekizumab, as these have demonstrated safety even in patients with pre-existing liver disease. 3, 4

Evidence Supporting Biologics in Hepatic Impairment:

• Ustekinumab has been shown to be safe in patients with pre-existing liver disease, with only mild Grade 1 transaminase elevations in 6 of 44 patients and no cases of severe hypertransaminasemia. 3

• A 2025 real-world study of 278 psoriasis patients demonstrated that secukinumab, ixekizumab, adalimumab, and apremilast are safe in patients with elevated baseline liver function tests. 4

• Critically, patients with initially elevated liver enzymes showed significant decreases in all liver function tests during treatment with these biologics, suggesting therapeutic benefit rather than harm. 4

• These biologics achieved comparable PASI-75 response rates and drug survival regardless of baseline liver function status. 4

Why Other Traditional Systemics Are Also Problematic

Cyclosporine:

• While not absolutely contraindicated for liver disease like methotrexate, cyclosporine requires careful baseline assessment including liver function tests. 5
• Cyclosporine is absolutely contraindicated in renal disease and increases risk of malignancies. 1
• Given this patient's significant hepatic dysfunction, cyclosporine would require intensive monitoring and carries unnecessary risk when safer alternatives exist.

Acitretin (Retinoids):

• Retinoids can cause hepatotoxicity and require baseline liver function testing. 2
• In a patient with already markedly elevated transaminases, adding another potentially hepatotoxic agent is inadvisable.
• Retinoids also have severe teratogenic effects requiring 2-3 years of contraception after discontinuation in women. 2

Critical Next Steps Before Any Systemic Therapy

Before initiating any systemic therapy, this patient requires urgent evaluation of the cause of his hepatic dysfunction: 5, 6

• Complete hepatitis B and C serologies 5, 6
• Assessment for nonalcoholic fatty liver disease (NAFLD), which is highly prevalent in psoriasis patients 6, 7
• Evaluation for alcohol use, as this significantly increases risk of liver fibrosis 7
• Assessment for metabolic syndrome components (diabetes, obesity, hyperlipidemia), which are independent risk factors for liver disease in psoriasis 2, 7
• Liver imaging (ultrasound) to assess for steatosis or cirrhosis 3

Treatment Algorithm for This Patient

1. Immediately refer to hepatology or gastroenterology for evaluation of the elevated transaminases before initiating any systemic psoriasis therapy. 6

2. Once hepatic workup is complete and the patient is stable, initiate biologic therapy with ustekinumab, secukinumab, or ixekizumab as first-line systemic treatment. 3, 4

3. Monitor liver function tests at baseline, 3 months, and 6 months during biologic therapy, though significant worsening is unlikely. 4

4. Avoid methotrexate, acitretin, and potentially cyclosporine given the pre-existing hepatic dysfunction. 1, 6

Common Pitfalls to Avoid

• Never assume elevated liver enzymes will "normalize" with methotrexate treatment - methotrexate causes hepatotoxicity and will worsen pre-existing liver disease. 1, 6

• Do not delay systemic therapy indefinitely waiting for perfect liver function tests - modern biologics are safe even with elevated baseline values and may actually improve liver parameters. 4

• Avoid systemic corticosteroids, as these are contraindicated in psoriasis and can precipitate erythrodermic or pustular psoriasis upon withdrawal. 1

• Document all current medications to assess for drug-induced liver injury or interactions before starting systemic therapy. 5