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Teaching an Old Drug New Tricks

February 10, 2014 7:00 am

A couple recent articles focused on the new uses of methotrexate (MTX) and how to handle potential hepatotoxicity:

1. J Pediatr 2014; 164: 231-36
2. Inflamm Bowel Dis 2014; 20: 47-59

In the first medical review article, the authors note the efficacy of MTX for the following:

• Juvenile idiopathic arthritis
• Uveitis
• Psoriasis
• Crohn disease
• Juvenile dermatomyositis
• Localized scleroderma
• Vasculitis

This review article discusses mechanism of action which is poorly understood along with pharmacogenomics and practical issues in usage.  The latter includes the need for supplemental folic acid.  Other points:

• “The long-term safety of MTX is remarkable”
• “The issue of nausea and vomiting…can be especially disturbing.”  They note that one study demonstrated that ondansetron 1 hour prior to MTX from the first injection prevented nausea, which was often difficult to treat once developed.
• “Liver enzyme abnormalities occur frequently (up to 30% of patients) but are usually of minimal clinical significance.”  Best to draw blood tests 1-2 days before MTX dosing.
• “In children, unlike adults, MTX-related pulmonary adverse events are very rare.”
• “In recent years it was shown that live vaccine boosters are effective and safe during MTX use (caution may be needed if MTX is used with other immunosuppression medications)” Ref: JAMA 2013; 309: 2449–56.
• “Use during pregnancy or within 3 months of planning pregnancy is contraindicated”

The second article was a systemic review which identified 12 high-quality studies which focused on MTX hepatotoxicity in children.  Key findings:

• 57 of 457 developed some degree of abnormal liver biochemistries.
• Due to hepatotoxicity, dose reductions were undertaken in 6.4% and 4.5% discontinued MTX.

The authors note that studies of MTX in adults with IBD have not demonstrated cumulative liver toxicity from MTX.  In addition, many of the patients with hepatotoxicity may have had  other reasons for abnormal liver biochemistries including other medications (eg. glucocorticoids).  “Confirmation of MTX hepatotoxicity with a liver biopsy is seldom performed in children;” as a consequence, the exact rate of MTX hepatotoxicity is unknown.

The authors propose that liver biochemistry monitoring occur at baseline, biweekly x 2, then every 2-3 months.  Also, the authors recommend:

• If ALT < 2 times upper limit of normal (ULN), check liver biochemistries every 2 weeks
• If persistent abnormalities, the authors recommend an ultrasound
• If ALT ≥ 2 times ULN, repeat testing should be obtained and consider consultation with a hepatologist

Bottomline: Methotrexate is an important medication for Crohn disease –there are not very many available.  If there are persistent liver enzyme elevations, dose reduction of MTX (or cessation) may be necessary.  As a practical matter, it is advisable to obtain blood draws 1-2 days prior to MTX rather than afterwards. Nausea can be minimized with ondansetron and weekend dosing.

Related blog posts:

• Liver toxicity -where to look online | gutsandgrowth
• Advice on drug-induced liver injury (DILI) | gutsandgrowth
• Liver Injury from Anti-TNF Agents | gutsandgrowth
• Switching from Thiopurines to Methotrexate | gutsandgrowth
• Methotrexate and liver toxicity | gutsandgrowth
• Adding Methotrexate to anti-TNF therapy | gutsandgrowth

Posted by gutsandgrowth

Categories: Pediatric Gastroenterology Intestinal Disorder, Pediatric Gastroenterology Liver Disease

Tags: Crohn's disease, hepatotoxicity, juvenile idiopathic arthritis, live virus vaccines, Methotrexate, nausea

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One Response to “Teaching an Old Drug New Tricks”

1. I also find that dividing the dose into am, pm, am minimizes nausea and sometimes the flu like syndrome some patients get.

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   By Stan Cohen on February 10, 2014 at 8:55 am

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