The therapeutic landscape of atopic dermatitis changed tremendously in the previous decade. Novel insights into the pathogenesis enabled researchers to find important targets for therapy. With regard to topical therapy, novel hyperselective phosphodiesterase-4 blockers show promising results.
Increased cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) activity in peripheral blood leukocytes is associated with the immune and inflammatory hyperreactivity that characterises atopic dermatitis (AD). PDE inhibitors exert an anti-inflammatory action by increasing the intracellular cAMP concentration, inhibiting the production of inflammatory cytokines (interferon-gamma, TNF-alpha, IL-4, IL-12, IL-17a, and IL-23) and other inflammatory mediators. “Difamilast is a novel hyperselective PDE-4B Blocker that looks really promising,” said Prof. David Cohen (New York University School of Medicine, USA) . In animal models, PDE-4B turned out to be a key regulatory and therapeutic target to reduce inflammation . In a poster presented during the AAD meeting, a 1% ointment containing difamilast demonstrated rapid itch relief with a median time to pruritus improvement of only 5.76 hours (see Figure), which was sustained at 29 days in patients with moderate-to-severe AD . In addition, there was both a marked improvement in EASI score and sleep disturbance in patients treated twice daily with the ointment . Another novel anti-inflammatory inhibitor of PDE-4 is crisaborole ointment (2%). Phase 3 studies in children and adults with mild-to-moderate AD have shown that crisaborole leads to clear or almost clear skin in about a third of patients [4,5]. “As in all studies with topical agents, there was also a sizeable effect of the vehicle, because AD patients have a benefit of the regular use of emollients,” said Prof. Cohen.
Figure: Median time to improvement of pruritus after treatment with difamilast. Success defined as Verbal Rating Scale (VRS) of 0 (No Itch) or 1 (Low) with ≥1-Point Reduction from Baseline 
Subjects who achieved a success more than 8 hours after first treatment are not displayed in figure. ITT population; subject responses. Kaplan-Meier plot.
The IL-4/IL-13 blocker dupilumab is at present approved for adult AD patients with moderate-to-severe disease. “I tend to warn my patients of conjunctivitis, which is the most frequent adverse event that is seen in 10-15% of patients. However, this side effect is easily manageable,” said Prof. Cohen. The responses seen with dupilumab are also durable, as demonstrated in the LIBERTY AD CHRONOS trial . In this trial, dupilumab added to standard topical corticosteroid treatment for 1 year improved AD signs and symptoms, with acceptable safety.
There are also promising study results with dupilumab in adolescents, with a third obtaining almost clear skin . In adolescents with severe disease, a high medical need exists for an effective treatment. “Hopefully, this study will lead to the approval of dupilumab in adolescents,” said Prof. Cohen.
Tralokinumab is an interesting new agent that blocks IL-13 only. In a phase 2 study, therapy with tralokinumab in combination with topical steroids led to significant reductions in S. aureus colonisation compared with topical steroids with placebo . “This is an interesting study, because now we have documented that if you get greater control of the disease, you also induce a change in the microbiome,” said Prof. Cohen. This effect might potentially lead to fewer skin infections and AD flares, in addition to improving disease severity scores.
JAK inhibitors are also an interesting addition to the AD armamentarium. Baricitinib is already approved for the therapy of rheumatoid arthritis, and a phase 2 study showed that this JAK inhibitor is also efficacious in AD . The agent showed rapid improvements in EASI, itch, sleep disturbance, and quality of life, with significant improvements seen as early as week 1. A big advantage of the JAK inhibitors is that they can be administered orally. In rheumatology, there have been recent concerns about potential thromboembolic risks with the two JAK inhibitors, baricitinib and tofacitinib . “Right now, the adverse event profile looks good, but we will see how things develop. Thromboembolic events will be the caveat of these drugs,” concluded Prof. Cohen.
Another novel topical option is tapinarof cream. This agent demonstrated efficacy for patients with either psoriasis or AD. Its anti-inflammatory properties are mediated through activation of the aryl hydrocarbon receptor in multiple cell types. In addition, tapinarof impacts barrier gene expression in primary human keratinocytes. “In a dose-finding study it was tested in various doses and there is certainly some efficacy here,” said Prof. Cohen. All newer therapies offer the opportunity for a more targeted approach with fewer potential adverse events.
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