1. 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: /bjd.16240

2. 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

3. 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

4. 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

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

6. 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)

7. 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

8. 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

9. 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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