ATOPIC DERMATITIS: SKIN BARRIER DYSFUNCTION, TH2-DOMINANT IMMUNOPATHOGENESIS, DIAGNOSTIC CRITERIA, AND TARGETED BIOLOGIC AND SMALL-MOLECULE THERAPY

Abstract

Background: Atopic dermatitis (AD) is the most prevalent chronic inflammatory skin disease, affecting 15–20% of children and 1–10% of adults worldwide—representing more than 230 million affected individuals globally. Characterized by intense pruritus, skin barrier dysfunction, and relapsing eczematous lesions, AD profoundly impairs quality of life and is the leading cause of years lived with disability (YLD) among skin diseases. Recent decades have established AD as a complex immunological disorder driven by type 2 helper T-cell (Th2) skewing, IL-4/IL-13 cytokine axis overactivation, and filaggrin-mediated skin barrier defects, fundamentally transforming therapeutic targeting.

Objective: To provide a concise, evidence-based review of the molecular pathogenesis of AD—encompassing skin barrier dysfunction, Th2/Th22/Th17 immunological axes, the itch-scratch cycle, and comorbid atopic march—and to evaluate the evidence base for conventional, biologic (dupilumab, tralokinumab), and JAK inhibitor (abrocitinib, upadacitinib) therapies.

Methods: A systematic review of eight primary sources—original mechanistic studies, pivotal randomized controlled trials, and authoritative clinical guidelines published between 2003 and 2024—was conducted.

Results: Filaggrin (FLG) loss-of-function mutations—present in 25–30% of European AD patients—reduce ceramide synthesis and raise transepidermal water loss (TEWL) by 3–5-fold, enabling allergen penetration and Staphylococcus aureus colonisation. Th2 cytokines IL-4 and IL-13 further suppress FLG and loricrin expression, forming a vicious cycle. Dupilumab (anti-IL-4Rα) achieves IGA 0/1 (clear/almost clear) in 38–40% of moderate-severe AD at 16 weeks (SOLO 1+2 trials) versus 10% for placebo. JAK1 inhibitors (upadacitinib, abrocitinib) achieve EASI-75 in 63–71% at 12–16 weeks. Ceramide-dominant emollients reduce TEWL and AD relapse rates by 30–50% in prevention programmes.

Conclusion: AD management has been transformed by IL-4/IL-13 pathway-targeted biologics and oral JAK inhibitors that achieve disease control previously impossible with conventional immunosuppressants. A severity-stratified treatment algorithm—from emollients and topical corticosteroids for mild disease to dupilumab and JAK inhibitors for moderate-severe disease—provides a evidence-based framework for individualized AD management.