Methotrexate and azathioprine in severe atopic dermatitis: A 5-year follow up study of a randomised controlled trial L.A.A. Gerbens, S.A.S Hamann, M.W.D. Brouwer, E. Roekevisch, M.M.G. Leeflang, and Ph.I. Spuls British Journal of Dermatology. DOI:10.1111/bjd.16240

Introduction What’s already known? Azathioprine (AZA) and methotrexate (MTX) seem to be effective and safe drugs on the short-term and up to 2 years for adults with severe atopic dermatitis (AD) based on a small body of evidence The paucity of evidence, especially on long-term effectiveness and safety, needs to be complemented to inform clinical management

Methods An open-label follow up phase of a single-blinded clinical trial, visits every 3 months for 5 years 43 patients randomized 35 patients in follow up study Treatment regimens MTX max. dose 22.5mg/week with folic acid 5mg/week AZA max. dose 2.5mg/kg/day Doses in- or decreased following daily clinical practice No restriction in concomitant treatment Switching and stopping possible

Methods – Outcomes Effectiveness Primary: SCORAD, 6-point IGA, SCORAD50, IGA <3 Secondary: Frequency of remissions, EASI, 6-point PGA, POEM, VAS pruritus, VAS sleeplessness, Skindex-17 Safety Type, frequency, severity, relatedness to treatment of AEs and SAEs (categorised according to MedDRA) Tolerability Frequency of use of rescue medication (i.e. prednisolone), antibiotics for skin infections and potent topical corticosteroids or calcineurin inhibitors Drug survival Five types of discontinuation Abbreviations: -SCORAD: SCORing Atopic Dermatitis -IGA: Investigator Global Assessment -EASI: Eczema Area and Severity Index -PGA: Patient Global Assessment -POEM: Patient-Oriented Eczema Measure -VAS: Visual analogue scale -AE: Adverse event -SAE: Serious adverse event -MedDRA: Medical Dictionary for Regulatory Activities

Methods – Statistical analyses Efficacy/Safety/Tolerability Descriptive Drug survival Kaplan-Meier

Results 27 patients completed follow up Effectiveness Safety At year 5 mean relative reduction in SCORAD index similar in MTX and AZA group: 52.8% and 53.8% Safety Twelve serious adverse events in 5 years For three a possible causal relationship Drug survival Longer drug survival for MTX, but survival in both groups was low after 5 years (MTX n=5, AZA n=1)

Discussion What does this study add? This is the first pragmatic study describing the 5 years effectiveness and safety of AZA and MTX in adults with moderate-to-severe AD MTX and AZA seem to be effective and safe on the long-term MTX seems to have a longer drug survival compared to AZA, but both groups have few survivals at year 5 although some discontinued due to controlled AD

Discussion - Limitations Small population Difficulties with performing statistical analyses Primary objective should have been safety and drug survival Set up as a randomized controlled trial, should have been a pragmatic trial

Conclusions No strong recommendations can be made More long-term and good sampled studies needed The relatively few patients in both groups surviving on their originally allocated drug after 5 years underline the need for effective treatments for these patients

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