Prevention is an active approach to fighting atopic dermatitis (AD). In fact, multiple studies provided a correlation between an impaired barrier and the risk of AD.1-3 By reviewing the trans-epidermal water loss (TEWL) as a functional state of the skin barrier in infants as early as 2 days old, Kelleher et al. was able to correlate a 7.1x greater increase in the development of AD at 12 months for those with TEWL in the upper quartile.1 Similarly, patients in the lower quartile had a protective outcome against the development of AD. It is of importance to mention that this early 2-day time point showed a correlation regardless of the filaggrin mutation status of the patient.1 These findings further suggest that there is a window of opportunity for the prevention of AD.
Randomized controlled trials in the first weeks of life in high risk infants demonstrated that emollient therapy from birth represents a feasible, safe and effective approach for AD prevention.2,3 One trial showed a relative risk reduction of 50% (95% CI, 0.28-0.9; P=0.017) over placebo at 6 months of age with the application of full-body emollient therapy.2 Another trial showed similar results with 32% fewer infants treated with emollients developing AD (P =0.012) at 32 weeks compared to placebo.3 Therefore, if confirmed in larger studies, emollient therapy from birth would be a simple and low-cost intervention that could reduce the global burden of allergic diseases.
In an effort to counteract the development of AD, research into skin deficiencies and its replacement in deficiencies has been studied. Eskai et al. performed a study quantifying the amount of filaggrin in AD adults and children, demonstrating that, despite the characteristic downregulation in adult patients with AD, filaggrin expression was similar in children with AD and healthy children.4 Therefore, filaggrin deficiency is not an issue in early pediatric AD (unless there is the presence of a mutation), while in the adult, it may reflect chronic exposure to cytokines and S. aureus.
A further review into the defectiveness in the barrier revealed that patients with AD had markedly reduced lipid levels in the stratum corneum in both lesional and non-lesional skin.5
Phosphodiesterase 4 (PDE4) inhibitors, such as crisaborole, prevent the degradation of cAMP to AMP.6 Increased intracellular cAMP levels activate protein kinase A and suppress transcription of pro-inflammatory cytokines.6 Two phase 3 trials (NCT02118766 and NCT02118792) have demonstrated effectiveness when using crisaborole in AD.7 More than >30% improvement was demonstrated at 4 weeks for the Investigator Static Global Assessment (ISGA) in both studies as well as improvements in pruritus when compared to placebo. Improvement for crisaborole was defined as ISGA of 0 (clear) or 1 (almost clear) at day 29 with 2-grade or greater improvement from baseline.7
Safety dosing information was also gathered when crisaborole was dosed topically to children and adolescents.8,9 Findings demonstrated minimal or no blood level elevations and no clinically important safety signals. Lastly, in the 48-week long open-label safety study, application site burning, and stinging were the most common treatment emergent adverse events (TEAEs) occurring in 2.3% of the crisaborole group.10
While crisaborole is the first PDE4 inhibitor that has been approved by the FDA, others are currently in development and include (Review https://clinicaltrials.gov/ for studies related to these PDE4 inhibitors):
JAK1 inhibitors, such as tofacitinib, showed an early effectiveness in the topical treatment of AD.
A 4-week, phase IIa, randomized, double-blind, vehicle-controlled trial (NCT02001181) in 69 adults with mild-to-moderate AD demonstrated significantly greater efficacy of tofacitinib ointment vs. vehicle, with early onset of effect and comparable safety/local tolerability to vehicle.11 There was limited detectable systemic absorption, infrequent TEAE, no serious adverse events, and no discontinuations because of TEAE. The mean percent change from baseline at week 4 in the Eczema Area and Severity Index (EASI) score was significantly greater (P<0.001) for tofacitinib (-81.7%) vs. vehicle (-29.9%).
Additional statistical significant and/or findings noted were:
JTE-052 ointment, a pan-JAK inhibitor, has been showing similar results for AD in a phase II, multicenter, randomized, vehicle-controlled clinical study (JapicCTI-152887).12 In a 4 week, twice a day dosing of 327 patients, 23% of patients in the highest dose (3%) achieved an ISGA of 0 or 1 with ≥2 improvement vs. 3% with vehicle (P=0.04). Ninety percent of these patients had moderate disease severity. The modified EASI (mEASI) was also statistically significant at all JTE-052 doses with mEASI reduction of -42 (0.25%) to -73 (3%) (all P<0.001) vs. vehicle (-12). Reductions in day and nighttime itch were also significant (P<0.001) at all concentrations. The pruritus numerical rating scale (NRS) score was reduced as early as day 1 night-time. JTE-052 ointment, at doses up to 3%, was safe and well tolerated.
Finally, tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and AD.13 The anti-inflammatory properties of this drug are mediated through activation of the aryl hydrocarbon receptor (AhR). Tapinarof, as an AhR agonist, increases barrier protein expression, and has similar qualities and effects of coal tar but without the limitations commonly found in its use. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels.13
Presenter disclosure: The presenter has reported that she is a consultant for Eli Lilly, Galderma, Genentech, GSK-Stiefel, Novartis, Pfizer, Sanofi-Regeneron, and Valeant and is a current investigator for Galderma, Incyte, Leo, Pfizer, Regeneron.
Written by: Debbie Anderson, PhD
Reviewed by: Victor Desmond Mandel, MD