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Systemic Treatments of Atopic Dermatitis

Presented by: Dr. Carsten Flohr
Unit for Population-Based Dermatology Research, St. John’s Institute of Dermatology
Guy’s & St. Thomas’ NHS Foundation Trust King’s College London, UK

Conventional systemic therapies commonly used for both children and adults for severe atopic dermatitis include azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil (Table 1).1

Regarding conventional systemic treatments, there is a lack of long-term safety data from atopic dermatitis cohorts.1 While there is an algorithm for when to start a patient on systemic therapy for atopic dermatitis, the algorithm fails to discuss which are the optimal drugs to use.2 There are many factors that should be considered each of which may influence clinical decision-making (Table 2). Weighting of these factors may differ between physicians and patients.

Based on a systemic literature search, there are currently 12 RCTs on conventional systemic therapies and 14 RCTs on novel therapeutics. Only 34% of these are head-to-head trials and they only exist for conventional systemic agents. Instead, 66% are placebo-controlled trials and they exist both for conventional and novel therapeutics.

RCTs have variable duration and primary endpoints including:

  • Change from baseline Six Area, Six Sign Atopic Dermatitis (SASSAD) severity score
  • Change in pruritus Visual Analogue Scale (VAS)
  • Change in Investigator’s Global Assessment (IGA) scores
  • Change from baseline Eczema Area and Severity Index (EASI)
  • EASI 50
  • EASI 75
  • Change from baseline SCORing Atopic Dermatitis (SCORAD)
  • SCORAD 50.

Unpublished data demonstrating the mean of various conventional therapies for EASI (16 and 64 weeks), SCORAD (16, 64, and 280 weeks) based on currently available public domain results are presented. The indirect comparisons suggest that methotrexate and azathioprine perform well or better than some novel agents for long-term control, but they appear inferior to dupilumab, baracitinib, and cyclosporine for short-term control. However, no study assessed the induction of disease remission when treatment was discontinued. In addition, no comparative cost-effectiveness analysis was performed. Based on this lack of data, there is no gold standard conventional treatment that serves as a benchmark at this point in time. To address this, a randomized controlled trial protocol regarding treatment naïve children aged 2 to 16 years old with severe atopic eczema is currently underway.3 Therapy consists of methotrexate (0.4 mg/kg per week) versus cyclosporine (4 mg/kg/day) for 9 months and then is discontinued for 6 months. The main aims of this trial are to assess whether there is a difference in the speed of onset, effectiveness, side-effect profile and reduction in flares post-treatment between methotrexate and cyclosporine. Cost-effectiveness of the drugs are also being assessed.3

While there are a significant amount of caveats to indirect comparisons, study populations, study designs, severity outcomes, follow-up, length of follow-up, and indirect comparisons allow for network meta-analysis to occur to review differences and similarities. Review the varied patient-reported symptoms used in the trials in the Table 3.

Unfortunately, there will likely always be a small number of head-to-head trials. RCTs also have very rigid inclusion and exclusion criteria, which may not represent the patients seen in daily dermatological practice. In addition, these trials only provide short-term data and are not necessarily real world nor do they provide long-evidence including effectiveness, safety, and cost. In an effort to harmonize data collected across clinical trials, an international taskforce has been developed to collect data for atopic eczema studies.4 This will permit a standardized approach across countries, enhance comparability, allow data pooling between countries, and identify rare important adverse events.

The initial appraisal consultation of dupilumab was not considered to be cost-effective for use by United Kingdom National Health Services. However, it is important to mention that the NICE has very strict requirements that cost effectiveness be <£30,000 per quality-adjusted life year (QALY). The final NICE decision recommended dupilumab in patients who have not responded to at least 1 conventional systemic therapy. The 2 main factors that influenced the updated analysis dealt with the inclusion of long-term data from an open-label study to inform the stopping rate of dupilumab beyond 52 weeks and to support the estimates of effect in patients receiving dupilumab beyond 2 years. Observational data, not just randomized controlled trial data, played a key role in NICE’s decision. Other HTA agencies in Europe have taken a similar approach.

Key messages

  • Conventional systemic therapies commonly used for both children and adults for severe atopic dermatitis include azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil.
  • There are many factors that need to be considered when determining the optimal drug to use.
  • Based on indirect comparisons of currently available trials, methotrexate and azathioprine appear inferior to dupilumab, baracitinib, and cyclosporine for short-term control. Methotrexate and azathioprine perform well or better than some novel agents for long-term control.
  • While there are a significant amount of caveats to indirect comparisons, they allow for network meta-analysis to occur to review differences and similarities.
  • There is a small amount of head-to-head trials and they usually have very rigid inclusion and exclusion criteria, which may not represent the patients seen in daily dermatological practice.
  • These trials only provide short-term data and are not necessarily real world nor do they provide long-evidence including effectiveness, safety, and cost.
  • Observational data played a key role in the NICE decision for the use of dupilumab.


REFERENCES

Present disclosure: The presenter was a chief investigator for the TREatment of severe atopic eczema Trial (TREAT) and UK-Irish Atopic eczema Systemic Therapy Register (A*STAR), and principal investigator for the International TREAT Registry Task Force. He received investigator-led funding from Sanofi and has consulted for Sanofi-Regeneron and Roche-Genentech.

Written by: Debbie Anderson, PhD

Reviewed by: Victor Desmond Mandel, MD



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