Topical calcineurin inhibitors and the epidermal barrier in atopic dermatitis

BACKGROUND: The topical calcineurin inhibitors [TCIs] pimecrolimus and tacrolimus, offer an effective non-steroidal option for treating atopic dermatitis [AD], particularly in sensitive skin areas and for long-term use. There are several studies published on the effect of calcineurin inhibitors on the skin barrier but a comprehensive review on this topic is still missing. SUMMARY: This review summarizes current evidence on the impact of TCIs on epidermal barrier structure and function. Clinical studies in patients with AD show that TCIs improve transepidermal water loss [TEWL], enhance stratum corneum [SC] hydration, and promote normalization of structural proteins such as filaggrin and loricrin. Unlike topical corticosteroids [TCS], TCIs do not induce skin atrophy and may even reverse steroid-induced epidermal thinning. Additionally, TCIs partially preserve antimicrobial peptide [AMP] expression in lesional AD skin, which may help reduce Staphylococcus aureus colonization and support microbial diversity. Positive effects on lipid lamellar organization and natural moisturizing factor [NMF] levels further support barrier restoration. Animal data suggesting impaired lipid synthesis under TCI treatment contrast with consistent positive findings in clinical studies. Importantly, emerging evidence indicates that TCIs may improve the skin microbiome in AD. KEY MESSAGES: TCIs exert their beneficial effects on skin inflammation through selective T-cell modulation without disrupting keratinocyte differentiation or dermal matrix components. For this reason, the general indirect positive effects on skin barrier associated with reduction of skin inflammation is not counterbalanced by intrinsic barrier damaging mechanisms as observed with topical steroids. Further studies are needed to evaluate long-term effects on skin structure, microbiome stability, and their integration into biologic treatment algorithms.