Guide to prescribing methotrexate to pediatric patients with inflammatory skin diseases

Key takeaways:

• The maximum methotrexate dose for inflammatory skin diseases is 1 mg/kg, not to exceed 25 mg per week.
• Onset of methotrexate efficacy may be 8 to 16 weeks.

In a panel-led project, 23 experts created a comprehensive guide for the long-term management of inflammatory skin diseases in pediatric patients treated with methotrexate.

In 2017, the first and only oral solution of methotrexate (MTX), Xatmep (Azurity), was FDA-approved for the treatment of pediatric patients with acute lymphoblastic leukemia and polyarticular juvenile idiopathic arthritis.

According to the authors in a study of the pediatric uses for MTX, this relatively recent approval presents an opportunity to utilize MTX in more pediatric indications, specifically dermatological ones.

“There is an opportunity to optimize the use of low-dose MTX in pediatric patients,” Elaine C. Siegfried, MD, of Saint Louis University School of Medicine, and colleagues wrote. “But given the lack of robust data, there remains a need for specific recommendations about the safest and most effective dosing and monitoring practices when prescribing MTX for pediatric patients with inflammatory skin diseases.”

In this study, the authors recruited clinicians with experience in clinical research and drug development in order to compile a comprehensive guide for the long-term management of inflammatory skin diseases in pediatric patients using MTX.

Two FDA representatives and 23 clinicians participated, including 15 pediatric dermatologists, four medical dermatologists and four pediatric rheumatologists. One industry representative, one patient advocate and a Pediatric Dermatology Research Alliance fellow also participated in the final review of the document.

Indications and contraindications

Although the FDA has not approved MTX for the treatment of inflammatory skin diseases in pediatric patients, participating panel clinicians said this does not impact their decision to prescribe MTX to patients aged 18 years and younger.

According to the panel, MTX has proven utility in many indications including morphea, psoriasis, dermatomyositis, atopic dermatitis, lupus, sarcoidosis and alopecia areata. However, the panel could not come to an agreement about the utility of MTX in more uncommon diseases such as lichen planus and eosinophilic fasciitis, among others, which was most likely due to a lack of data and clinical experience, according to the study.

Pregnancy and lactation were considered absolute contraindications, according to a consensus decision by the panel, when prescribing MTX for inflammatory skin diseases. Ultimately, patients and caregivers should make a decision jointly when discussing the possibility of off-label MTX prescription, according to the study.

Dosing

The panel recommends that weight-based dosing of MTX be utilized over body surface area-based dosing because weight-based dosing is easier to calculate and has been used in many studies.

For inflammatory skin diseases, the maximum dose should be 1 mg/kg and should not exceed 25 mg per week. The panel agreed that test doses were deemed unnecessary for pediatric patients starting at less than 1 mg/kg.

Parental administration of MTX increases the drug’s efficacy with onset of MTX effect being 8 to 12 weeks for atopic dermatitis, psoriasis and lichen planus, and 12 to 16 weeks for alopecia areata and morphea.

However, the effect of MTX is comparably slower to that of systemic corticosteroids or cyclosporine. Therefore, when rapid disease control is necessary, it is recommended that these other agents be used first.

MTX can be discontinued at any time with no adverse events other than a worsening of the disease, according to the study.

Interactions with immunizations, medications

The measles, mumps and rubella booster (MMR) and varicella-zoster virus booster were not contraindicated for patients taking MTX; however, there were insufficient data to make recommendations for or against primary immunization with the MMR vaccine in patients taking MTX.

The panel unanimously agreed that inactivated vaccines are safe for MTX patients, but again, there were not enough data to determine if MTX dose or duration affects vaccine responses.

Concomitant use of any MTX dose with trimethoprim/sulfamethoxazole is not contraindicated. However, the panel recommends that penicillin antibiotics, tetracycline, chloramphenicol and clindamycin only be used concurrently with low doses of MTX.

The same recommendation applied to most other medications with the panel stating that they can be used concomitantly with low-dose MTX except for herbal and dietary supplements that have been reported to cause hepatotoxicity.

Alcohol should always be avoided when taking MTX, according to the study.

Adverse effects

MTX may cause gastrointestinal effects, oral mucositis, fatigue and headaches. Thankfully, these can be mitigated with 1 mg a day of folic acid, according to the panel.

If other adverse events occur such as the total white blood cell count is less than 3,000 cells/L, the absolute neutrophil count is less than 1,000 cells/L or the platelet count is less than 100,000 cells/L, discontinue or lower the dose of MTX, according to the study.

Elevated liver enzymes are not uncommon in patients taking MTX; however, if these enzymes exceed three times the upper limit of normal for 2 consecutive months, the panel recommends temporarily discontinuing MTX. If patients present a fever, which may be a sign of infection, promptly investigate the source of infection before discontinuing MTX, according to the study.

Monitoring needs

Patients taking MTX should undergo baseline and ongoing laboratory monitoring after the first month and every 3 to 4 months. Physicians must monitor complete blood count, white blood cell differential, alanine aminotransferase, aspartate aminotransferase and serum creatinine. Anyone with elevated liver enzymes should undergo these labs sooner than usual.

Female patients of childbearing age that are not using contraceptives must be tested for pregnancy before taking MTX.

These monitoring guidelines should be performed regardless of MTX administration or dosage.