microbiome during both flares and remission.2,23,24,31-35 Table 1 depicts pathophysiologic mechanisms associated with AD. The complexity of AD pathophysiology underscores the need for a well-designed management plan. Optimal treatment of AD incorporates thorough patient/family education, identification and avoidance of potential triggers, proper integration of topical skin barrier products, and rational selection and use of specific medical therapies. The objectives of AD management are two-fold: (1) marked reduction of the symptoms and signs of the acute flare and (2) long term control of AD with prolonged maintenance of remission. Ultimately, individualized selection of therapies for AD warrants consideration of both objectives.Pharmacologic ManagementPharmacologic management of AD includes both topical and systemic agents, with selection based primarily on the severity of AD, patient age, and response to previous therapies. The following summarizes agents that are commonly used to treat AD.Topical AgentsTopical corticosteroids (TCs)TCs have been the mainstay of anti-inflammatory therapy for AD for >6 decades.27 They are primarily used to rapidly control AD flares. Prolonged TC application is limited by local adverse events (AEs), with systemic AEs a concern with widespread and prolonged use.26,27,36,37 Once the AD flare is stabilized, application of low-mid potency TCs twice weekly to sites of predilection (proactive therapy) can effectively reduce the frequency of subsequent flares.26,27 Adjunctive use of a well-formulated moisturizer is important with TC therapy, as even short term use of TCs applied to human skin has been shown to delay SC barrier recovery, with murine studies noting impairment of both lamellar body production and epidermal lipid synthesis.12,38Topical calcineurin inhibitors (TCIs)Pimecrolimus cream (1%) and tacrolimus ointment (0.03%, 0.1%) are TCIs approved in the US as second-line agents for short-term and non-continuous treatment of AD in patients ≥2 years of age.27,39,40 TCIs are not associated with the AEs seen with prolonged use of TCs.26,27 Judicious use of TCIs for AD as initial monotherapy or in combination approaches can reduce the need for TCs, and have also shown success in repigmentation of hypopigmented macules and patches.27 Proactive use of topical tacrolimus has been effective and safe in both children and adults with AD.26,27 Although multiple studies support the overall safety of TCIs, “black box” warnings regarding potential malignancy risks appear in the approved product labeling with both TCIs based on theoretical concerns from animal studies.26,27,39,40Topical phosphodiesterase-4 inhibitors (PDE4I)Crisaborole 2% oinment is the only available topical PDE4I, approved in the US for AD in patients ≥2 years of age.41 The approved labeling allows for application to any affected cutaneous sites, and does not restrict duration of use. Efficacy for signs and symptoms of AD and favorable safety were established in clinical trials, with the only relevant AEs being local tolerability reactions in 2-4% of subjects.41-44 As with TCIs, topical crisaborole is not associated with the AEs seen with prolonged TC use, and available data support the absence of systemic safety signals or drug accumulation.41-45Topical antimicrobialsUse of topical and/or systemic antibiotic therapy is recommended for treatment of cutaneous bacterial infections in AD, but not for chronic administration to suppress staphylococcal colonization and/or flares of AD.46 However, data are lacking on the use of non-antibiotic antimicrobial/antiseptic therapies in the long term management of AD. 26,27 Well-designed controlled studies are needed to evaluate clinical improvement and flare reduction with these agents.Systemic AgentsRefractory and/or severe cases of AD sometimes require use of systemic therapy. Short course corticosteroid therapy may be used very selectively for rapid control, although prolonged use is best avoided due to AEs.2,26 Dupilumab is a fully human anti-IL-4 receptor-alpha monoclonal antibody that inhibits IL-4 and IL-13 signaling, approved in the US for adults with inadequately controlled moderate to severe AD; the recommended dose is 300 mg injected subcutaneously every 2 weeks.47 Efficacy and overall favorable safety have been confirmed in both short term and long term studies, both as monotherapy and in combination with TC therapy.47-49 Conjunctivitis may be seen in some patients, and is usually manageable without discontinuation of therapy.47-50 Oral immunosuppressive agents, such as cyclosporin and azathioprine, are used as second and third line agents, respectively, in refractory/severe cases of AD.2,26 Careful monitoring is warranted with oral immunosuppressive therapy, with data on long term use relatively limited in AD, especially with azathioprine.26 Importantly, topical barrier repair therapies (ie, moisturizers) are recommended adjunctively in patients using systemic therapy for AD.12,26,27Adjunctive Topical Barrier Repair Approaches and Impact on PathophysiologyThe skin of AD patients is known to exhibit innate structural and functional abnormalities of epidermal/SC barrier functions.11-13,17,18 These include increased TEWL that is worsened during AD flares, abnormal SC lipid composition, inability to sustain SC hydration, augmented immunologic/ inflammatory responses to exogenous stimuli, and decrease in AMP levels and activity.11-22 The latter factor, combined with microfissuring associated with xerotic skin, leads to an altered cutaneous microbiome in non-lesional, xerotic, and eczematous atopic skin.12,20-23,51
