INNOVATION BLOSSOMS IN
From pathophysiology to treatment in 2022
Insights in pathophysiology
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. It is an excellent example of how an increase in the understanding of the pathophysiology of the disease has directly resulted in the development of novel treatment options. It is important to have an overview on how the understanding of the nature of the disease has developed, and give some immunological context to current and future targeted treatments, which are not only safe and efficacious therapeutics, but also help us to better understand skin inflammation altogether.
Topical treatment in 2022
Although most new therapeutics are systemic, several new topical therapies are already in use or in development. The previously available topical corticosteroids and calcineurin inhibitors posed considerable adherence problems due to their side effects and black box warning. Therefore new effective topical agents are needed, especially for those who have mild and moderate disease without the need for systemic therapies.
Inhibition of the JAK/STAT signaling pathway has proven to be effective in moderate to severe atopic dermatitis when systemically administered. Several systemic JAK inhibitors are already approved and used in AD worldwide, and studies are ongoing for topical JAK inhibitors. In addition to JAK inhibitors, several topical phosphodiesterase 4 inhibitor (PDE4) are also in development, and among them crisaborole was approved both by the FDA and the EMA, even though it has not been launched in Europe. Other targets for promising topical agents are SYK, aryl hydrocarbon receptor (AHR) and antimicrobial agents.
All these new, promising therapies will not eliminate the need for emollients or moisturizers as basic therapy to improve the barrier function of AD skin by decreasing dryness and water loss, they still have to complement other therapies.
Systemic treatment in 2022
New treatments for atopic dermatitis also confirmed its pathogenesis with barrier function and type-2 immune inflammation being inversely correlated. Consequently, interventions targeting type-2 inflammation allow reconstitution of the cutaneous barrier function. In addition, the dysbiosis in AD characterized by dominant S. aureus can also be corrected by these therapies. Biologics shown to be effective in the treatment of AD target primarily Interleukins (IL-) 4 and IL-13 (dupilumab, tralokinunab, lebrikizumab). A downstream target mediating inflammation and pruritus, IL-31, is targeted by nemolizumab, an antibody blocking the receptor of IL-31 (in development).
The signaling cascade downstream of type 1 and 2 cytokine receptors involves the association of so-called Janus kinases. The inhibition of JAKs is highly promising to block cytokine activity and JAK inhibitors are developed for a variety of immune-mediated diseases. Among them there is AD, and three JAK inhibitors were approved in Europe for the treatment of moderate to severe AD patients. These are baricitinib (JAK1 and JAK2), upadacitinib (mostly JAK1), and abrocitinib (mostly JAK1).
All show efficacy in AD, with the first one approved being baricitinib. Therefore, real-world experience with baricitinib is available, confirming findings from clinical trials: rapid reduction of pruritis, clinical effects in most patients, and a very good safety profile. However, monitoring of possible side effects is a prerequisite when choosing JAK inhibitors, including clarification of thrombosis risk. In addition, a slightly increased risk for infections has to be taken into account.
Finally, what is the best individual therapy? A personalised choice may be based on comorbidities. Atopic comorbidities are probably best targeted by direct type 2 immune cytokine blockage. However, further investigations will define the exact placement of these treatments in AD and dermatology.
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