Publication:

Systemic immunomodulatory therapies in severe atopic dermatitis: a comprehensive review of mechanisms, efficacy and long-term management stratagems

Severe atopic dermatitis (AD) represents a complex, chronic inflammatory dermatosis characterized by a profoundly debilitating course, significant comorbid burden and a substantial deterioration in quality of life. The pathophysiological paradigm has evolved beyond a purely T-helper 2 (Th2)-centric model to incorporate a broader spectrum of immune dysregulation, including roles for Th22, Th17 and IL-31-driven pathways, alongside crucial epithelial barrier dysfunction mediated by filaggrin and other structural protein deficiencies. This shift has catalyzed the development and clinical deployment of novel, targeted systemic agents that move beyond traditional immunosuppressants. This exhaustive review synthesizes contemporary evidence from recent clinical trials, real-world efficacy studies and international consensus guidelines to critically appraise the current therapeutic arsenal. We provide a detailed analysis of the pharmacodynamics, clinical trial data and safety profiles for biologic agents such as dupilumab, tralokinumab and lebrikizumab, which selectively inhibit key interleukins. Furthermore, we examine the emerging role of Janus kinase (JAK) inhibitors, including abrocitinib, upadacitinib and baricitinib, focusing on their rapid onset of action and the nuanced risk-benefit calculus mandated by their safety advisories. The review also contextualizes the enduring, though carefully circumscribed, role of conventional systemic immunosuppressants like cyclosporine, methotrexate and mycophenolate mofetil in the modern treatment algorithm. Particular emphasis is placed on therapeutic sequencing, combination approaches, management of secondary infections and strategies for long-term disease control while mitigating adverse effects. The concluding synthesis projects future directions, including combination biologic therapy and personalized medicine approaches guided by endotypic stratification, underscoring the transformative nature of current systemic treatments in altering the disease trajectory for patients with severe atopic dermatitis.