Effectiveness, safety and cost-effectiveness of methotrexate versus ciclosporin for severe childhood atopic dermatitis: a synopsis of the TREAT RCT

Parts of this abstract have been reproduced from Flohr C, Rosala-Hallas A, Jones AP, Beattie P, Baron S, Browne F, et al .; TREAT Trial Investigators. Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel-group assessor-blinded clinical trial. Br J Dermatol 2023; 189 :674–84. https://doi.org/10.1093/bjd/ljad281. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. Background Atopic dermatitis is a chronic, inflammatory skin disease characterised by intensely itchy skin. Atopic dermatitis has the highest disease burden among cutaneous diseases as measured by disability-adjusted life-years and approximately 20% of United Kingdom children experience atopic dermatitis, of whom 16% have moderate or severe forms. Treatment options for severe childhood atopic dermatitis are limited, and this is compounded by the lack of widely available information regarding short- and long-term side effects and cost-effectiveness of different treatments. Ciclosporin is the most commonly used systemic treatment for severe paediatric atopic dermatitis, but methotrexate is being increasingly used as an alternative first-line systemic treatment. Although these medications are regularly used off-licence in children with severe atopic dermatitis, there had been no firm evidence about the effectiveness, safety, cost-effectiveness, or impact on quality of life from an adequately powered randomised controlled trial using systemic medication in children. Design and methods The TREatment of severe Atopic dermatitis Trial addressed this gap, assessing potential differences in the speed of onset, effectiveness, side-effect profiles and reduction in flares post treatment between ciclosporin and methotrexate, and the cost-effectiveness of the drugs. Treatment impact on quality of life was also examined in addition to whether filaggrin genotype influences treatment response. Furthermore, the trial studied the immunological effects of ciclosporin and methotrexate. TREatment of severe Atopic dermatitis Trial was a multicentre, parallel-group, assessor-blind randomised controlled trial of 15 months duration (9-month treatment phase, 6-month follow-up period). In total, 103 children aged 2–16 years with moderate to severe atopic dermatitis, unresponsive to topical treatment were randomised (1 : 1) to receive methotrexate (0.4 mg/kg/week) or ciclosporin (4 mg/kg/day). Objectives The trial had two primary outcomes: change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis and time to first significant flare following treatment cessation. Results The TREatment of severe Atopic dermatitis Trial found that ciclosporin had a faster onset of results compared to methotrexate up until approximately 20 weeks on treatment, with a mean difference in change between baseline and 12 weeks of −5.69 (97.5% CI −10.81 to −0.57, p = 0.013). Following this time point, methotrexate became more effective up to the end of treatment and showed better longer-term disease control; however, there was no statistically significant difference between treatment groups in the time to first significant flare after treatment cessation (log-rank test p = 0.15; HR = 1.55; 97.5% CI 0.77 to 3.10, p = 0.16). These results were supported by the immunological readouts measured during the study, suggesting the methotrexate-driven strengthening of the skin barrier. The data also suggest no significant benefit for increased kidney monitoring to detect renal dysfunction. A reduced need for renal monitoring would reduce both financial and carbon costs of care for patients moving forward. Limitations The primary limitations for this project include missing data from patient diaries, a small sample size for a randomised controlled trial comparing two active treatments, and a lack of hepatotoxicity marker collection. Conclusions The results of the TREatment of severe Atopic dermatitis Trial have changed the treatment paradigm for the use of conventional systemic medication, favouring methotrexate, especially because the health economics analysis found that methotrexate is more cost-effective than ciclosporin. The findings of the TREatment of severe Atopic dermatitis Trial have been incorporated into updates of international treatment guidelines for atopic dermatitis. Future work Looking forward, it would be clinically useful to conduct longer-term, real-world studies to determine the optimal duration of methotrexate treatment for atopic dermatitis. It will also be useful to take advantage of atopic dermatitis registers for future research – these provide a wealth of real-world data that can be harnessed for clinical knowledge.