Therapies for atopic dermatitis: still moving forward

The armamentarium of topical and systemic treatments for atopic dermatitis (AD) is constantly growing. In the future, this will not only allow for higher therapeutic goals in the cutaneous domain but may also broaden the choice of targets in features like comorbidities.

“Over the last couple of years, we have seen new treatments, and there are still new ones coming – is this really the revolution for AD?” Prof. Christian Vestergaard (Aarhus University Hospital, Denmark) asked, laying the land for his talk [1].

The incidence of AD has risen by 2–3 times over the last 3 decades, making it the most prevalent skin disease. Although the proportion of children with AD (15–20%) is higher than the percentage of adults (2–10%), numerically, adults are more common as patients. At the beginning of AD, genetic and environmental factors impair the skin barrier. As part of the type-2 inflammation cascade, the skin generates upstream molecules such as TARC, TSLP, IL-25, and IL-33 that induce various cytokines, e.g. IL-4, IL-5, IL-31. “These will increase the itch and thereby the vicious circle,” Prof. Vestergaard stressed. Subsequent scratching further impairs the skin barrier and entails a downregulation of structural proteins. “This leads to a lower differentiation of keratinocytes and lipids, which, in turn, induces inflammation and is in itself also induced by inflammation,” he further explained the pathophysiology of AD. Thus, various cytokines are potential targets for therapies. Furthermore, there are currently ongoing clinical trials exploring drugs aiming at Janus kinases (JAK), phosphodiesterase (PDE)4, as well as the H4-receptor that is found in a variety of cells, including lymphocytes and keratinocytes.

In the SOLO 1 and 2 trials (NCT02277743 and NCT02277769), up to 51% of participants on dupilumab reached an Eczema Area and Severity Index (EASI)75 score as a key secondary outcome [2]. “We saw it within 1–2 months, and I dare say that this revolutionised the way that we started to treat AD,” Prof. Vestergaard commented. Also, the IL-13 inhibitor tralokinumab demonstrated significant superiority over placebo in EASI75 responses and Investigator‘s Global Assessment (IGA) 0/1 [3]. Nemolizumab, an IL-31 inhibitor, showed itch reduction and improved sleep quality [4]. As examples of small molecule agents with proven efficacy, Prof. Vestergaard mentioned baricitinib, abrocitinib, and upadacitinib [1]. In the BREEZE trial program, baricitinib significantly improved EASI75 responses, which were further increased when adding topical steroids in BREEZE-AD7 (NCT03733301): 48% on 4 mg versus 23% on placebo (P<0.01) [5]. Abrocitinib was tested against placebo and in comparison with dupilumab (NCT03720470), also outperforming the latter in terms of EASI75 (abrocitinib 200 mg 70% vs dupilumab 300 mg 58%) and EASI90 (abrocitinib 200 mg 46% vs dupilumab 300 mg 35%) responses [6]. Moreover, very convincing results were observed for upadacitinib. In the Measure Up 1 trial (NCT03569293), EASI75 and EASI90 were achieved by 80% and 66% on 30 mg of the study drug, compared with 16% and 8% on placebo, respectively [7]. “Now we are talking about EASI90 among the AD patients, so the next step will be to talk about EASI100. I don’t know when that will happen, but if we look at the development of psoriasis, I think we should be there in a couple of years,” Prof. Vestergaard added. Progress has also been made in topical treatments for AD, e.g. with the JAK1 inhibitor delgocitinib and the PDE4 inhibitor crisaborol, both demonstrating significant efficacy in the treatment of AD.

The concept of treatable traits in AD

Looking at the so-called treatable traits of AD besides the skin domain, comorbidities, psychological and occupational domains should also be considered. “One thing is an EASI90, but we also need to look at whether the patients are sleeping well, whether the depression disappeared, or whether they are going to work again,” Prof. Vestergaard stressed. Data about important patient’s goals for their AD treatment identified “being itch-free”, “getting better skin quickly”, and “healing of all skin defects” as the top 3 and, according to Prof. Vestergaard, these areas are currently already covered. “But we also have to look at regaining control of the skin disease, maybe inducing remission, having confidence in the therapy, being free of pain, and having no fear that the disease will become worse,” Prof. Vestergaard mentioned as an outlook.

1. Vestergaard C. Targeted therapies for atopic dermatitis- Have we hit the head of the nail? OS, SPIN 2022 Congress, 06–08 July, Paris, France.
2. Simpson EL, et al. N Engl J Med. 2016;375:2335-48.
3. Wollenberg A, et al. Br J Dermatol. 2021;184:437-49.
4. Kabashima K, et al. N Engl J Med. 2020;383:141-50.
5. Reich K, et al. JAMA Dermatol. 2020;156:1333-143.
6. Bieber T, et al. N Engl J Med. 2021;384:1101-12.
7. Guttman-Yassky E, et al. 2021;397:2151-68.

 

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Posted on 26 August, 202227 March, 2024