Teaching an Old Drug New Tricks

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:

Protecting the most vulnerable

Although pediatric gastroenterologists are not on the front lines of the vaccine controversies, we should add our voices to support immunizations.  Some of our immunocompromised patients are among the most vulnerable and rely on herd immunity to lessen their chances of serious infection.  When healthy children and adults do not receive their immunizations, this does not only increase their risk of infections but the risk to others.

A perfect example of this is highlighted in NEJM 2012; 366: 391-92.  In 2010, California reported over 9000 cases of pertusis; of these cases, 89% occurred in infants less than 6 months.  This population is too young to be adequately immunized.  Ten of these infants died.

The author recommends trying to persuade those who are hesitant to proceed with immunizations.  Parents who are opposed based on personal beliefs will not be persuaded.

  • Remove socioeconomic barriers to vaccination
  • Enforce school entry requirements; it should not be easier to opt out of immunizations than to receive them
  • Aggressively address misinformation
  • Learn to use persuasion effectively: http://www.cdc.gov/vaccines/conversations

Additional references:

  • -NEJM 2011; 365: 1108. RV vaccine resulted in 64,000 less hospitalizations in US between 2007-2009.
  • -NEJM 2010; 362: 289, 299, & 358. Rotavirus vaccines lowering death rate in Africa & Mexico.
  • -NEJM 2011; 364: 2283. Rotavirus vaccine: risk of intussception ~1:50,000-1:70,000; thus could cause ~96 cases per year. Vaccine at same time prevented 80,000 hospitalizations & 1300 deaths in Brazil & Mexico.
  • -Gastroenterology 2007; 132: 1287. Two decades of HBV vaccination in Taiwan
  • -NEJM 2007; 16: 1275, 1278, 1281.  Medical evidence refuting Thimersol toxicity; yet many vaccine cases in litigation
  • -Liver Transplant 2008; 14: 1389.  Vaccine policies:  MMR/Varicella can be given as early as 6 months of age. Must give 3-4weeks before Tx. Can give inactivated ~6-12 mo p-OLT. Except for oral polio, good idea for contacts to get all their immunizations.
  • -Inflamm Bowel Dis 2009;15:1410–1416.  Vaccination Strategies for Patients with Inflammatory Bowel Disease on immunomodulators and biologics

Live Virus Vaccines, Generally Contraindicated in Patients Receiving Immune-Suppressive Therapy:

Anthrax vaccine
Intranasal influenza
Measles-mumps-rubella (MMR)
Polio live oral vaccine (OPV)
Rotavirus
Smallpox vaccine
Tuberculosis BCG vaccine
Typhoid live oral vaccine
Varicella
Yellow fever