Targeting Variability: A New Look at Systemic Therapies in Pediatric Severe Atopic Dermatitis

A secondary analysis from the TREAT trial advances the conversation on therapeutic drug monitoring (TDM) in children and young people (CYP) with severe atopic dermatitis (AD).

While both ciclosporin and methotrexate proved effective in reducing disease severity, only one of the two drugs showed a potential dose–response correlation based on blood concentration levels. Let’s dive into the study and its findings.

Targeting the Exposure-Response Gap in AD

Despite the widespread use of ciclosporin and methotrexate as systemic therapies for pediatric AD, data linking blood concentration levels to clinical outcomes remain sparse. But the TREAT trial offers a rigorous dataset: 103 CYP were randomized to either ciclosporin or methotrexate for 36 weeks, with drug levels and disease severity scores (EASI and o-SCORAD) tracked longitudinally.

What further sets this analysis apart is its focus on actual drug exposure over time, which is an often underutilized metric in dermatologic practice. Trough ciclosporin concentrations and steady-state erythrocyte methotrexate polyglutamate (MTX-PG) levels were measured and tested for association with clinical response.

The study found a statistically significant association between higher trough ciclosporin levels and lower EASI scores (β = –0.586; P = 0.027), along with a borderline association with o-SCORAD improvement (β = –4.495; P = 0.062).

Importantly, the benefit of higher drug concentrations appeared to increase over time—a signal reinforced by significant interaction terms in mixed-model analysis.

These findings support the utility of TDM for ciclosporin in CYP with AD, a population where pharmacokinetic variability can be high due to differences in metabolism, body composition, and organ function. Despite decades of TDM use in transplant medicine, this is the first known longitudinal RCT to correlate ciclosporin trough levels with treatment response in pediatric AD.

In contrast, erythrocyte MTX-PG levels, which is a proposed biomarker for methotrexate exposure, showed no significant association with treatment response (EASI or o-SCORAD) at either week 12 or 36. This result diverges from earlier findings, including a cross-sectional study by Rahman et al., which reported higher MTX-PG concentrations among clinical responders.

Interestingly, TREAT participants had much higher MTX-PG concentrations (mean ~130 nmol/L) than those reported in previous studies, despite comparable dosing. This discrepancy likely reflects the wide interindividual pharmacokinetic variability highlighted in the analysis—a variability that complicates the biomarker's reliability.

Both medications were well tolerated, with a low incidence of serious adverse events. Notably, drug concentration levels did not differ between patients with and without adverse events, reinforcing that higher trough levels, particularly for ciclosporin, do not inherently increase toxicity risk within studied parameters.

Clinical Implications: Toward Personalized Systemic Therapy

The data suggest a practical path forward: clinicians treating severe pediatric AD may benefit from incorporating trough ciclosporin monitoring to optimize therapy, especially when response is suboptimal. However, reliance on erythrocyte MTX-PG as a biomarker for methotrexate efficacy remains unsupported in this context.

Given the cost and accessibility limitations of newer biologics, fine-tuning conventional systemic agents using pharmacokinetic insights may serve as a clinically valuable—and scalable—approach.

Reference

Wan M, Jones AP, Maskrey D, et al. Exposure–response of ciclosporin and methotrexate in children and young people with severe atopic dermatitis: A secondary analysis of the TREatment of severe Atopic dermatitis Trial (TREAT). Clin Exp Dermatol. 2025;50(8):1623–1627. doi:10.1093/ced/llaf147