Future treatments of atopic dermatitis

Except for the recent approval of dupilumab, current treatments for atopic dermatitis do not focus on the individual pathogenesis of the condition. Several novel targeted, phenotype-specific therapies are on the horizon that may start an era of personalised therapy in atopic dermatitis (Cabanillas et al., 2017). This is of particular interest given the theory that early aggressive treatment of atopic dermatitis may help prevent the development of chronic disease and the atopic march (Bieber et al., 2012; McPherson, 2016).

Phosphodiesterase 4 inhibitors (PDE4)

Normally, cyclic AMP (cAMP) is present at high levels within cells with PDE4 regulating its breakdown. Patients with atopic dermatitis have been shown to have elevated levels of PDE4 in circulating inflammatory cells resulting in a reduction in cAMP and an increase in proinflammatory cytokine production (Cabanillas et al., 2017). 

A number of PDE4 inhibitors are under investigation for their ability to reduce the production of proinflammatory cytokines in patients with atopic dermatitis. The first to reach the market is crisaborole, a small lipophilic, boron-based molecule added to a topical vehicle that has been approved for the treatment of mild-to-moderate atopic dermatitis by the FDA in the USA. However, it has not yet received approval in Europe (Cabanillas et al., 2017). Other PDE4 inhibitors under development include other topical therapies such as OPA-15406 and RVT-501 (both in Phase II); and oral therapies apremilast and roflumilast, which are both indicated for other conditions (Ahluwalia et al., 2017).

PDE4 inhibitor-mediated downregulation of proinflammatory cytokines.

Figure 22: PDE4 inhibitor-mediated downregulation of proinflammatory cytokines. Adapted from Ahluwalia et al., 2017.
AC adenylyl cyclase; CREB cAMP response element-binding protein; IL interleukin; NFAT nuclear factor of activated T-cells; NFjB nuclear factor kappa-light-chain-enhancer of activated B cells; PKA protein kinase A.

Anti-IL-5

The Th2 cytokine IL-5, acts within inflamed tissue to attract eosinophils and has been identified as playing a key role in eosinophilic asthma. Mepolizumab is an anti-IL-5 monoclonal antibody that has been approved for the treatment of severe eosinophilic asthma. While initial studies in patients with atopic dermatitis were underwhelming (Oldhoff et al., 2005), studies are ongoing looking at the benefits of anti-IL-5 therapy in patients with an increased eosinophil count (Paller et al., 2017).

Action of IL-5 on eosinophil and inhibition via mepolizumab.

Figure 23: Action of IL-5 on eosinophil and inhibition via mepolizumab.

Anti-IL-13

While the anti-IL-4 Receptor A monoclonal antibody dupilumab blocks IL-4 and IL-13 signalling, the opportunity to block IL-13 only is also being investigated. Tralokinumab and lebrikizumab are anti-IL-13 monoclonal antibodies that are both currently being investigated in Phase III trials for moderate-to-severe atopic dermatitis (Paller et al., 2017). 

Anti-IL-31

T helper 2 cells are the predominant producers of IL-31 which has been linked to intense pruritus in atopic dermatitis. The IL-31 receptor A is expressed on keratinocytes and a subset of dorsal root ganglions where the binding of IL-31 induces itch through the stimulation of sensory neurons.

An anti-IL-31 receptor A monoclonal antibody, nemolizumab, binds the receptor preventing IL-31 signalling and induction of pruritus. Phase II data was recently reported in 216 patients with moderate-to-severe atopic dermatitis (Ruzicka et al., 2017).

Inhibition of IL-31-mediated activation of gene transcription.

Figure 24: Inhibition of IL-31-mediated activation of gene transcription. Adapted from Paller et al., 2017.

Janus kinases (JAK) inhibitors

Janus kinases (JAK) are a family of intracellular tyrosine kinases that signal via the Signal Transducer and Activator of Transcription (STAT) transcription factors to elicit he physiological effects of a variety of proinflammatory cytokines including IL-4, IL-5, IL-13 and IL-31. Inhibition of inflammation has already been demonstrated in rheumatoid arthritis with JAK inhibitors and so several trials are currently investigating both topical and oral formulations in atopic dermatitis (Paller et al., 2017).