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
Authors: Flohr Carsten , Rosala-Hallas Anna , Jones Ashley P , Beattie Paula , Baron Susannah , Browne Fiona , Brown Sara J , Gach Joanna E , Greenblatt Danielle , Hearn Ross , Hilger Eva , Esdaile Ben , Cork Michael J , Howard Emma , Lovgren Marie-Louise , August Suzannah , Ashoor Farhiya , Williamson Paula R , McPherson Tess , O’Kane Donal , Ravenscroft Jane , Shaw Lindsay , Sinha Manish D , Spowart Catherine , Taams Leonie S , Thomas Bjorn R , Wan Mandy , Sach Tracey H , Irvine Alan D ,   the TREAT Trial Investigators, Layton Alison , Burton Tim , Grainge Michael , Arden-Jones Michael , King Saskia , Perkin Michael , Taieb Alain , Ormerod Anthony , Chalmers Robert , Liu Xinxue , Ahmed Amina , Ashoor Farhiya , Flohr Carsten , Rosala-Hallas Anna , Holton Amy , Mason Hannah , Irvine Alan , Jones Ashley , Sach Tracey , Spowart Catherine , Wan Mandy , Walker Charlotte , August Suzannah , Beattie Paula , Brown Sara , Cork Mike , Esdaile Ben , Flohr Carsten , Gach Joanna , Howard Emma , Irvine Alan , McPherson Tess , O'Kane Donal , Ravenscroft Jane , Shaw Lindsay , Allen Caroline , Baron Susannah , Greenblatt Danielle , Hearn Robert , Hoey Susannah , Jarret Rachael , Jury Catherine , Mitchell Charlie , Murphy Ruth , Ogg Graham , Plant Alice , Newell Louise , Srinivasan Jothsana , Wedgeworth Emma , Browne Fiona 
Published: September 2023

Abstract

Background
Conventional systemic drugs are used to treat children and young people (CYP) with severe atopic dermatitis (AD) worldwide, but no robust randomized controlled trial (RCT) evidence exists regarding their efficacy and safety in this population. While novel therapies have expanded therapeutic options, their high cost means traditional agents remain important, especially in lower-resource settings.

Objectives
To compare the safety and efficacy of ciclosporin (CyA) with methotrexate (MTX) in CYP with severe AD in the TREatment of severe Atopic Eczema Trial (TREAT) trial.

Methods
We conducted a parallel group assessor-blinded RCT in 13 UK and Irish centres. Eligible participants aged 2–16 years and unresponsive to potent topical treatment were randomized to either oral CyA (4 mg kg–1 daily) or MTX (0.4 mg kg–1 weekly) for 36 weeks and followed-up for 24 weeks. Co-primary outcomes were change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare (relapse) after treatment cessation. Secondary outcomes included change in quality of life (QoL) from baseline to 60 weeks; number of participant-reported flares following treatment cessation; proportion of participants achieving ≥ 50% improvement in Eczema Area and Severity Index (EASI 50) and ≥ 75% improvement in EASI (EASI 75); and stratification of outcomes by filaggrin status.

Results
In total, 103 participants were randomized (May 2016–February 2019): 52 to CyA and 51 to MTX. CyA showed greater improvement in disease severity by 12 weeks [mean difference in o-SCORAD –5.69, 97.5% confidence interval (CI) –10.81 to –0.57 (P = 0.01)]. More participants achieved ≥ 50% improvement in o-SCORAD (o-SCORAD 50) at 12 weeks in the CyA arm vs. the MTX arm [odds ratio (OR) 2.60, 95% CI 1.23–5.49; P = 0.01]. By 60 weeks MTX was superior (OR 0.33, 95% CI 0.13–0.85; P = 0.02), a trend also seen for ≥ 75% improvement in o-SCORAD (o-SCORAD 75), EASI 50 and EASI 75. Participant-reported flares post-treatment were higher in the CyA arm (OR 3.22, 95% CI 0.42–6.01; P = 0.02). QoL improved with both treatments and was sustained after treatment cessation. Filaggrin status did not affect outcomes. The frequency of adverse events (AEs) was comparable between both treatments. Five (10%) participants on CyA and seven (14%) on MTX experienced a serious AE.

Conclusions
Both CyA and MTX proved effective in CYP with severe AD over 36 weeks. Participants who received CyA showed a more rapid response to treatment, while MTX induced more sustained disease control after discontinuation.