MILWAUKEE – In children with severe atopic dermatitis or psoriasis, the methotrexate polyglutamate assay appears useful in guiding dose modification in those failing to respond to methotrexate at 12 weeks, a retrospective study has shown.
The methotrexate polyglutamate 3 assay (MTX PG3) measures concentrations of methotrexate polyglutamates, the active metabolites of methotrexate, Syed Rahman said at the annual meeting of the Society for Pediatric Dermatology.
Methotrexate, a prodrug, requires enzymatic conversion via sequential addition of glutamic acid residues. Those residues form a glutamate "tail" that enhances intracellular methotrexate retention. The 3-tail metabolite, MTX PG3, is the predominant species in most patients, explained Mr. Rahman of St. Louis University.
"This study supports the usefulness of a commercially available tool for customizing optimal methotrexate dosing, coauthor Dr. Elaine Siegfried, professor of pediatrics and dermatology at the university, said in an interview.
The MTX PG3 assay has been validated in adults with rheumatoid arthritis where patients with a therapeutic methotrexate polyglutamate level of more than 60 nmol/L were fivefold more likely to have a good response to methotrexate than those with levels below this threshold, according to poster results presented at the 2008 American College of Rheumatology annual meeting (cited on the company website). However, the test was not predictive of response in 36% of patients whose arthritis improved with treatment despite subtherapeutic levels.
For the current analysis, the investigators reviewed the charts of 46 children with severe atopic dermatitis, psoriasis, or atopic dermatitis–psoriasis overlap, who were treated with a starting dose of oral methotrexate 0.5 mg/kg per week (maximum, 15 mg) and assessed by MTX PG3 assay at week 12. In a subset of children who failed to respond, the dose was modified and the level rechecked at 8 weeks. Disease severity was rated using a 5-point physician global assessment scale, with a good to excellent response defined by a 2-point improvement.
In all, 83% of children achieved a good to excellent response, with 27 patients doing so within 12 weeks and 11 responding after dose adjustment involving either a higher oral dose or switching to subcutaneous administration, Mr. Rahman reported.
Response rates to methotrexate were slightly higher in children with psoriasis or overlap (the two groups were combined) than those with atopic dermatitis (94% vs. 77%; no P value given). Overall, 8 children failed to respond.
The mean MTX PG3 level significantly correlated with efficacy in patients with atopic dermatitis (responders, 34.8 nmol/L, vs. 17.8 nmol/L, nonresponders; P = .018), but not in those with psoriasis–atopic dermatitis overlap (responders, 26.5 nmol/L, vs. 20.7, nonresponders; P = .724), Mr. Rahman reported.
The data suggest that compared with the therapeutic level of 60 nmol/L identified in adults, "pediatric patients have a lower therapeutic value," he said.
A subset analysis of MTX PG3 levels based on response identified a significantly higher mean maximum MTX PG3 level for responders than nonresponders (31.5 vs. 18.1 nmol/L; P = .035).
More importantly, late responders had the highest methotrexate levels. All late responders achieved levels greater than 30 nmol/L, and mean levels were significantly higher than for early responders (41.9 vs. 27.3 nmol/L; P = .024), suggesting that the test is most valuable for the subset of children requiring dose adjustment, Mr. Rahman said.
"Patients who respond won’t even need the test, but for those at the 12-week juncture who do not respond and their levels are less than 30 nmol/L, this [study] suggests that if we increase the PO [dose] or change to subcutaneous [administration], we will eventually have a response," he said.
During a discussion of the results, an audience member questioned whether the test, with its added expense, really enhances clinical judgment because most clinicians would already adjust the dose in their patients failing to respond at 12 weeks.
Mr. Rahman replied that not all patients will respond to continued treatment with methotrexate, and that the test could differentiate between responders and nonresponders, thereby directing the patient to alternative therapy earlier.
Session moderator Dr. Amy Paller, chair of dermatology and professor of pediatrics and dermatology at Northwestern University in Chicago, agreed that the test is most valuable for the subset of children who are nonresponders at 12 weeks.
"In these children, this test can guide dose modification," she said in an interview. "Pharmacogenetic variation can require relatively higher oral doses or subcutaneous administration."
In contrast to a therapeutic level of more than 60 nmol/L established for adults, a level of 30 nmol/L may be sufficient in children, Dr. Paller said.
"A MTX PG3 less than 30 nmol/L in a child who has failed to respond within 12 weeks suggests that an increase in oral dose, or even a change to subcutaneous [administration], will boost efficacy," she commented.