Eczema: Pathophysiology, Mechanisms, and Evidence-Based Therapeutic Approaches

Eczema, also known as atopic dermatitis (AD), is a chronic inflammatory skin condition affecting approximately 200 million people worldwide with increasing incidence, particularly in high-income countries. This complex disorder typically manifests in early childhood but can emerge at any age, following a relapsing-remitting course that may persist throughout life. The condition is characterized by intense pruritus, skin barrier dysfunction, and immune dysregulation, which collectively contribute to significant impacts on quality of life. Though many children experience improvement or resolution by late childhood, a substantial proportion continue to be affected into adulthood, with flare-ups occurring even after extended periods of remission15. This report provides a comprehensive examination of eczema's pathophysiology, molecular mechanisms, and treatment approaches, distinguishing between well-established and emerging therapeutic options.

Epidemiology and Clinical Manifestations

Eczema presents a substantial global health burden, affecting up to 20% of children worldwide and persisting into adulthood for many patients. The condition manifests through various clinical subtypes, including atopic dermatitis, hand eczema, and dyshidrotic eczema, each with distinct presentation patterns. Hand eczema, for instance, represents a particularly challenging manifestation with significant impacts on occupational functioning and quality of life8. The condition follows diverse trajectories across the lifespan, with some individuals experiencing complete remission while others face persistent or intermittent symptoms throughout adulthood15. Clinical presentations vary by age and disease phase, with characteristic features including intense pruritus, erythema, vesiculation, scaling, and in chronic cases, lichenification. These manifestations often distribute differently based on age, with infantile eczema commonly affecting the face and extensor surfaces, while adult eczema frequently localizes to flexural areas and the hands1.

The burden of eczema extends beyond physical symptoms, encompassing psychological distress, sleep disturbance, and social stigmatization. The condition can also predispose patients to complications such as eczema herpeticum, a potentially life-threatening complication resulting from herpes simplex virus infection in individuals with atopic dermatitis. This serious complication primarily affects the pediatric population and requires prompt diagnosis and treatment to prevent systemic complications including keratoconjunctivitis, meningitis, encephalitis, and hepatitis13. The multifaceted nature of the disease and its substantial impact on patient well-being underscore the importance of understanding its underlying mechanisms to develop more effective therapeutic strategies.

Pathophysiology: The Interplay of Genetic, Immunological, and Environmental Factors

The pathophysiology of eczema involves a complex interplay between genetic predisposition, immune dysregulation, and environmental triggers. At the core of this condition lies a fundamental disruption of the skin barrier function coupled with aberrant immune responses, creating a self-perpetuating cycle of inflammation and barrier dysfunction. Recent research has significantly advanced our understanding of the molecular underpinnings of this condition, revealing multiple interconnected pathways that contribute to disease manifestation and progression.

Genetic factors play a crucial role in eczema pathogenesis, with filaggrin (FLG) gene mutations representing the most strongly implicated genetic risk factor. FLG encodes a protein essential for skin barrier integrity, and loss-of-function mutations lead to compromised barrier function, allowing greater penetration of allergens and irritants. Recent research has revealed that reduced filaggrin expression induces dysregulated intracellular signaling cascades, involving altered bone morphogenetic protein (BMP) signaling and downregulation of ERK1/2 and AKT1 pathways4. This dysregulation affects desmosomal expression and phosphorylation, further compromising skin barrier integrity. A SMAD1/Filaggrin/AKT axis has been identified as a potential therapeutic target, highlighting the downstream consequences of FLG deficiency beyond mere barrier dysfunction4. These genetic factors create the foundation upon which environmental triggers and immune dysregulation drive disease progression.

The skin barrier dysfunction characteristic of eczema involves multiple structural abnormalities beyond filaggrin deficiency, including alterations in lipid composition, tight junction proteins, and antimicrobial peptide expression. These defects collectively increase transepidermal water loss, enhance susceptibility to irritants and allergens, and diminish innate immune defense mechanisms. The compromised barrier allows greater penetration of environmental agents, triggering inflammatory cascades that further damage barrier function in a pathological feedback loop. In vesicular hand eczema specifically, comprehensive transcriptome analysis has revealed significant upregulation of genes involved in keratinocyte host defense and inflammation, alongside dysregulation of molecules critical for epidermal differentiation6. This illustrates the intertwined nature of barrier dysfunction and inflammatory responses in eczema pathophysiology.

Key Molecular Mechanisms and Immunological Pathways

The immunological dysregulation in eczema is characterized by a predominance of T-helper 2 (Th2) responses, particularly in the acute phase of the disease. Th2 cells produce key cytokines including interleukin-4 (IL-4), IL-5, IL-9, and IL-13, which drive many of the hallmark features of eczema. These cytokines promote immunoglobulin E (IgE) production, tissue eosinophilia, and mast cell activation, collectively contributing to the allergic inflammation characteristic of the disease18. The balance between Th1 and Th2 responses is critically important, as Th1 cells (which produce interferon-γ and tumor necrosis factor-β) are associated with cell-mediated immunity against intracellular pathogens, while dysregulated Th2 responses underlie atopic conditions including eczema18. Recent research also highlights the role of additional T cell subsets, including Th17 and Th22 cells, in the complex immunopathology of eczema.

The IL-4/IL-13 axis represents a central pathway in eczema pathophysiology. Both cytokines signal through receptors containing the IL-4 receptor alpha chain (IL-4Rα), activating signal transducer and activator of transcription 6 (STAT6), which is essential for their biological activities16. This signaling cascade promotes Th2 cell differentiation, IgE synthesis, and suppression of antimicrobial peptide production. Genetic studies have identified polymorphisms in the IL-4Rα gene, particularly the Ile50Val variant, that correlate with atopy through both genetic and functional mechanisms16. IL-4 has been shown to inhibit Th1 and Th17 differentiation while influencing keratinocytes by diminishing fibronectin expression, thereby impairing wound healing2. These findings explain the efficacy of therapies targeting this pathway in managing eczema.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway represents another crucial mechanism in eczema pathophysiology. This pathway transduces signals from multiple cytokine receptors, including those for IL-4 and IL-13, and is involved in regulating immune cell activation, differentiation, and function5. JAK inhibitors block the enzymatic activity of JAK proteins, thereby interrupting cytokine signaling and modulating immune responses5. This pathway's importance in eczema has been highlighted by the efficacy of JAK inhibitors in clinical studies, suggesting that targeting specific immune pathways enables more precise disease management519.

Recent research has also identified the role of hyaluronan production and E-cadherin expression in spongiosis formation, a characteristic histopathological feature of eczema. Cytokine-stimulated keratinocytes show increased hyaluronan production and decreased E-cadherin expression, which contribute to the intercellular edema observed in spongiotic lesions14. Additionally, the role of BMP signaling following filaggrin knockdown has been validated in vivo, with phosphoproteomic analysis identifying significant alterations in protein phosphorylation patterns4. These molecular insights provide potential targets for therapeutic intervention and highlight the complex interplay between structural proteins, signaling pathways, and immune mediators in eczema pathophysiology.

Established Treatment Approaches: Evidence-Based Interventions

The management of eczema encompasses a spectrum of therapeutic options, ranging from topical treatments for mild disease to systemic agents for severe, recalcitrant cases. Conventional approaches focus on symptomatic relief, inflammation control, and skin barrier repair, with treatment selection guided by disease severity, chronicity, and impact on quality of life. For chronic hand eczema specifically, treatment presents particular challenges requiring not only therapeutic expertise but also excellent patient communication skills8.

Topical therapies form the foundation of eczema management, with corticosteroids representing a mainstay of treatment due to their anti-inflammatory properties. However, concerns regarding long-term safety, particularly skin atrophy and hypothalamic-pituitary-adrenal axis suppression, have motivated the development of alternative options. Topical calcineurin inhibitors provide an effective steroid-sparing alternative, though they may be associated with application site reactions and carry a boxed warning regarding theoretical malignancy risk8. More recently, topical Janus kinase (JAK) inhibitors have emerged as promising options for hand eczema, demonstrating good bioavailability and patient tolerability5. These agents specifically target JAK enzymatic activity, providing precise immunomodulation with potentially fewer systemic effects than oral alternatives.

For moderate-to-severe or recalcitrant eczema, systemic treatments may be necessary. Conventional immunosuppressants, including cyclosporine, methotrexate, and azathioprine, have demonstrated efficacy but are limited by extensive side effect profiles requiring close monitoring7. The advent of targeted biologic therapies has revolutionized the management of severe eczema, with dupilumab, an IL-4/IL-13 inhibitor, representing a breakthrough in treatment. Clinical evidence demonstrates significant efficacy of dupilumab in improving eczema severity, reducing pruritus, and enhancing quality of life with a favorable safety profile27. Notably, a case report of dupilumab in STAT3 hyper IgE syndrome demonstrated not only resolution of eczema but also clearance of diffuse skin infections, suggesting that IL-4/IL-13 blockade may have additional benefits in preventing skin infections by affecting Th1 responses involved in controlling Staphylococcal infections2.

Lebrikizumab, another monoclonal antibody specifically targeting IL-13, has shown promise in phase II randomized controlled trials involving 289 patients with moderate-severe AD and inadequate response to topical corticosteroids. Patients receiving lebrikizumab experienced significantly greater improvement in eczema compared to placebo, as measured by Eczema Area and Severity Index (EASI) scores, pruritus scores, and reduction in affected body surface area7. The clinical efficacy appears dose-dependent, with a favorable side effect profile and good tolerability, suggesting lebrikizumab as a valuable addition to the therapeutic armamentarium for eczema7.

Systemic JAK inhibitors represent another class of emerging therapies with substantial evidence supporting their use in eczema. These small molecule inhibitors target specific immune pathways, providing precise management options that extend the range of potential therapeutic interventions519. Clinical trials have introduced JAK inhibitors as alternatives to other topical and systemic therapies for hand eczema patients, though future studies need to further evaluate their safety, potential risks and benefits, and impact on quality of life5.

Emerging Therapies and Investigational Approaches

While established treatments provide relief for many patients with eczema, ongoing research continues to explore novel therapeutic targets and approaches. The broader understanding of eczema pathophysiology has led to the development of new drugs, both topical and systemic, targeting specific pathways implicated in disease pathogenesis. These emerging therapies offer potential alternatives for patients with inadequate response to conventional treatments or those unable to tolerate existing options.

The JAK-STAT cascade, IL-4/IL-13 axis, phosphodiesterase 4 enzyme, and chemo-attractant cytokines represent the most relevant pathways targeted by emerging therapies19. The burgeoning array of therapeutic alternatives necessitates that physicians be well-trained not only in the use of individual treatments but also in combining these interventions to address ongoing challenges related to efficacy, tolerability, and safety19. For hand eczema specifically, recent developments in both topical and systemic JAK inhibitors show promising results, though further evaluation of their long-term safety profile and efficacy is needed5.

The growing interest in herbal therapies as adjunctive or alternative treatments for eczema management represents another area of active investigation. Comprehensive reviews have explored the development and evaluation of topical herbal formulations targeted at managing infectious eczema, encompassing the selection of herbal ingredients, optimization of base formulations, and rigorous stability testing17. Safety evaluation strategies, including toxicological assessments, skin irritation potential, and allergenicity testing, help ensure the safety and tolerability of these herbal formulations17. However, while preclinical and early clinical data show promise, more robust evidence from well-designed clinical trials is needed to establish the efficacy and safety of herbal interventions for eczema.

Research into the SMAD1/Filaggrin/AKT axis identified in recent studies offers another potential avenue for therapeutic development. By targeting the downstream effects of filaggrin deficiency, interventions addressing this pathway might help restore normal cellular signaling and improve skin barrier function4. Similarly, the identification of specific transcriptome profiles in vesicular hand eczema provides insights that could guide the development of targeted therapies addressing the particular pathophysiological features of this eczema subtype6.

Conclusion: Current Understanding and Future Directions

The current understanding of eczema has evolved significantly in recent years, with advances in molecular biology and immunology illuminating the complex interplay between genetic factors, immune dysregulation, and environmental triggers that drive disease pathogenesis. From the central role of filaggrin mutations and subsequent signaling disruptions to the importance of Th2-mediated inflammation and the IL-4/IL-13 axis, these insights have transformed our conceptualization of eczema from a purely inflammatory condition to a multifaceted disorder involving fundamental abnormalities in skin barrier function and immune regulation.

These pathophysiological insights have directly informed therapeutic developments, with targeted interventions such as dupilumab and JAK inhibitors demonstrating significant efficacy by addressing specific molecular pathways implicated in disease progression. The success of these approaches validates the importance of understanding disease mechanisms to develop effective treatments. However, despite these advances, significant challenges remain in eczema management, particularly for severe, recalcitrant cases and special populations such as children and the elderly.

Looking forward, the field continues to evolve with investigation of novel targets and therapeutic approaches. The identification of specific molecular signatures in different eczema subtypes may enable more personalized treatment strategies tailored to individual pathophysiological profiles. Integration of genetic, immunological, and clinical data could further refine our ability to predict disease course and treatment response, ultimately improving outcomes for patients with this challenging condition. As our understanding of eczema pathophysiology continues to deepen, the future holds promise for increasingly effective and targeted therapeutic interventions that address the underlying mechanisms of this complex disorder.