Hand Eczema

Introduction

Background

Hand eczema, also known as hand dermatitis, is a common inflammatory skin condition that primarily affects the hands. It is characterized by a range of symptoms including redness, itching, dryness, scaling, and sometimes blistering or cracking of the skin. The condition can manifest in various forms, such as irritant contact dermatitis, allergic contact dermatitis, or atopic hand eczema, and can be acute, chronic, or recurrent. Hand eczema significantly impacts an individual’s quality of life due to discomfort and functional limitations.

Biological Basis

The biological basis of hand eczema involves a complex interplay of genetic predisposition and environmental factors. A key component is a compromised skin barrier function, which allows irritants and allergens to penetrate the skin more easily, triggering immune responses. Genetic variations, particularly in genes responsible for skin barrier proteins like filaggrin (FLG), can predispose individuals to a weakened barrier. For example, mutations in FLGare strongly associated with atopic dermatitis, a condition often linked to hand eczema. The immune system also plays a crucial role, with specific immune cells and inflammatory mediators contributing to the characteristic skin inflammation. Genetic factors can influence the regulation of these immune responses, determining an individual’s susceptibility and the severity of their condition.

Clinical Relevance

Clinically, hand eczema poses a considerable challenge due to its chronic and often relapsing nature. Diagnosis typically relies on the clinical appearance and distribution of lesions, along with a thorough patient history to identify potential triggers. Treatment strategies often involve a multi-faceted approach, including avoidance of irritants and allergens, regular use of emollients to restore skin barrier function, topical corticosteroids to reduce inflammation, and in severe cases, systemic medications or phototherapy. Understanding the genetic underpinnings of hand eczema holds promise for more personalized medicine, allowing for the identification of individuals at higher risk or predicting their response to specific treatments based on their genetic profile.

Social Importance

The social importance of hand eczema is substantial, extending beyond physical symptoms. The constant itching, pain, and visible nature of the condition can lead to significant psychological distress, including feelings of embarrassment, self-consciousness, and social stigma. This can impact daily activities, sleep quality, personal relationships, and professional life. Certain occupations, such as healthcare workers, hairdressers, and cleaners, are at a higher risk due to frequent hand washing or exposure to various chemicals, making hand eczema a prominent occupational health concern. The chronic nature and potential for recurrence contribute to a significant burden on individuals, healthcare systems, and society through reduced productivity and increased healthcare costs.

Limitations

Methodological and Statistical Constraints

Genetic studies on hand eczema face several methodological challenges, often stemming from limitations in study design and statistical power. Many initial studies, particularly genome-wide association studies (GWAS), may be based on sample sizes that are insufficient to detect variants with small effect sizes or those that are rare in the population. This can lead to an underestimation of the true genetic architecture and potential effect-size inflation for initially reported associations, where the observed effect in the discovery cohort is larger than the true effect.

Furthermore, cohort selection can introduce biases, affecting the generalizability and robustness of findings. Differences in diagnostic criteria, participant recruitment strategies, and varying definitions of hand eczema severity across studies can complicate meta-analyses and replication efforts. The lack of consistent replication across diverse independent cohorts for all identified genetic associations highlights the need for larger, well-phenotyped populations to validate findings and provide more precise estimates of genetic effects.

Phenotypic Heterogeneity and Generalizability

A significant limitation in understanding the genetics of hand eczema is its inherent phenotypic heterogeneity. Hand eczema is not a single disease but rather a broad term encompassing various subtypes, such as irritant contact dermatitis, allergic contact dermatitis, and hyperkeratotic eczema, each potentially having distinct underlying genetic predispositions and environmental triggers. The challenge in consistently defining and measuring these subtypes across studies can obscure specific genetic signals relevant to particular forms of hand eczema, making it difficult to pinpoint precise genetic associations.

Moreover, many genetic studies have historically focused on populations of European ancestry, leading to limitations in the generalizability of findings. Genetic variants and their frequencies can differ significantly across diverse ancestral groups, meaning that associations identified in one population may not hold true or may have different effect sizes in another. This restricted ancestral diversity limits the comprehensive understanding of hand eczema genetics globally and may overlook important population-specific genetic factors contributing to the trait.

Complex Etiology and Unexplained Variation

Hand eczema is a complex condition influenced by a multifaceted interplay of genetic factors and environmental exposures. Current research often struggles to fully capture and model these gene-environment interactions, where genetic predispositions may only manifest under specific environmental conditions (e.g., exposure to irritants, allergens, or certain occupations). The inability to precisely account for these environmental confounders and interactions can lead to an incomplete picture of etiology and may mask the true genetic contributions.

The concept of “missing heritability” also remains a significant challenge for hand eczema, similar to many other complex traits. While some genetic loci have been identified, they explain only a fraction of the estimated heritability, suggesting that a substantial portion of the genetic influences remains undiscovered. This unexplained variation could be attributed to numerous factors, including rare genetic variants, structural variations, epigenetic modifications, or complex epistatic interactions between genes that are not easily detected by current study designs, representing significant knowledge gaps.

Variants

Genetic variations play a crucial role in an individual’s susceptibility to and the manifestation of inflammatory skin conditions like hand eczema, influencing immune responses, cellular integrity, and metabolic pathways. TheRTEL1-TNFRSF6B locus, encompassing the RTEL1 gene and the TNFRSF6B gene, is implicated in both genomic stability and immune modulation. RTEL1 (Regulator of Telomere Elongation Helicase 1) is vital for DNA repair and maintaining telomere length, processes essential for the health and regeneration of skin cells. ^[1] A variant such as rs8114049 in RTEL1 could potentially alter these functions, contributing to cellular stress or impaired repair responses in the skin, which can exacerbate inflammatory conditions. Nearby, TNFRSF6B (TNF Receptor Superfamily Member 6b) acts as a decoy receptor for tumor necrosis factor (TNF) ligands, thereby dampening inflammatory signaling; dysregulation here could lead to an overactive immune response characteristic of chronic eczema. ^[1] Furthermore, IL5(Interleukin 5) is a cytokine centrally involved in allergic inflammation and the activation of eosinophils, which are often elevated in atopic conditions. TheIL5 variant rs2078392 may influence the production or activity of this cytokine, thus modulating the allergic component frequently associated with or underlying hand eczema, particularly its atopic subtype.^[1]

Maintaining a robust skin barrier is fundamental to preventing the onset and progression of hand eczema, and genes involved in cellular adhesion are key to this function. TheCHL1 gene, which encodes the Cell Adhesion Molecule L1 Like, is crucial for cell-cell interactions and the structural integrity of tissues, including the epidermis. ^[1] A compromised epidermal barrier allows irritants, allergens, and microbes to penetrate more easily, triggering inflammatory responses. The variant rs149453851 in CHL1could potentially affect the protein’s function or expression, thereby weakening the skin’s protective barrier and increasing susceptibility to the environmental triggers that commonly provoke hand eczema.^[1] This genetic influence on barrier function underscores its critical role in the pathogenesis of various forms of eczema.

Other genetic variations can influence the skin’s ability to respond to environmental stressors and regulate cellular processes. The CYP2G1P gene is a pseudogene from the Cytochrome P450 family, which typically includes enzymes vital for metabolizing drugs and detoxifying environmental compounds. ^[1] Although CYP2G1P itself does not produce a functional protein, the presence of the rs146691976 variant within its locus may influence the expression or regulation of nearby functional genes involved in xenobiotic metabolism or inflammatory responses within the skin. Such an indirect effect could alter the skin’s resilience to irritants and allergens, contributing to the development or persistence of hand eczema.^[1] Additionally, ZGPAT (Zinc Finger CCCH-Type And G-Rich Sequence DNA-Binding Protein) encodes a zinc finger protein, a class of proteins known to regulate gene expression by binding to DNA. The variant rs6011058 in ZGPATmight affect the transcription of genes involved in cellular stress responses, inflammatory pathways, or epidermal cell differentiation, thereby influencing an individual’s predisposition to inflammatory skin conditions like hand eczema.

Key Variants

RS ID	Gene	Related Traits
rs8114049	RTEL1-TNFRSF6B, RTEL1	chromosome, telomeric region length hand eczema
rs6011058	ZGPAT	hand eczema body height neutrophil measurement, lymphocyte amount
rs2078392	IL5	hand eczema
rs146691976	CYP2G1P, CYP2G1P	hand eczema
rs149453851	CHL1	hand eczema

Classification, Definition, and Terminology

Defining Hand Eczema and its Core Characteristics

Hand eczema, also frequently referred to as hand dermatitis, is a common inflammatory skin condition characterized by erythema, scaling, pruritus, vesicles, and fissures primarily affecting the hands.^[2] This chronic or recurrent dermatosis significantly impacts quality of life due to its visible nature, discomfort, and potential for occupational impairment. ^[3] Operationally, it is defined by the presence of eczematous lesions on the hands for at least three months, or by two or more recurrences within a 12-month period. ^[4]Conceptual frameworks often categorize hand eczema as a multifactorial condition influenced by endogenous factors, such as atopy and genetics, and exogenous factors, including irritant exposures and allergic contact sensitization.

Classification Systems and Subtypes

The classification of hand eczema is crucial for guiding diagnosis and treatment, typically employing both morphological and etiological approaches. Morphologically, subtypes include hyperkeratotic, vesicular (dyshidrotic), irritant, and allergic contact hand eczema, reflecting distinct clinical presentations.^[5]Etiologically, hand eczema is broadly categorized into exogenous forms, such as irritant contact dermatitis and allergic contact dermatitis, and endogenous forms, which often link to atopic dermatitis or specific genetic predispositions.^[6]Severity is commonly graded using tools like the Hand Eczema Severity Index (HECSI), which provides a dimensional assessment of erythema, infiltration, papulation, vesicles, fissures, and scaling across different hand areas, or the Physician Global Assessment (PGA), offering a categorical score from clear to severe.^[2]

Diagnostic Criteria and Measurement Approaches

Diagnosis of hand eczema primarily relies on clinical criteria, including a detailed history of onset, duration, exacerbating factors, and a thorough physical examination of the hands.^[5]Differentiating subtypes often requires specific measurement approaches; for instance, patch testing is the gold standard for identifying allergic contact dermatitis by detecting specific delayed-type hypersensitivity reactions to allergens.^[3]While specific biomarkers for hand eczema are an area of ongoing research, elevated serum immunoglobulin E (IgE) levels or genetic variants in theFLG gene, encoding filaggrin, may indicate an underlying atopic predisposition, especially in chronic cases. ^[2] Clinical research criteria may also incorporate objective measures like transepidermal water loss (TEWL) to assess skin barrier function or scoring systems to quantify lesion extent and intensity more precisely.

Signs and Symptoms

Clinical Manifestations and Phenotypes

Hand eczema presents with a diverse range of clinical signs and symptoms, reflecting its heterogeneous nature. Common signs include erythema (redness), scaling, lichenification (skin thickening), and fissures, which are often accompanied by symptoms such as intense pruritus (itching), pain, and a burning sensation. Acute presentations may feature vesicles (small blisters) or bullae (larger blisters) and edema, whereas chronic forms are typically characterized by dryness, cracking, and hyperkeratosis. Clinical phenotypes vary, encompassing hyperkeratotic hand eczema, vesicular hand eczema (pompholyx), fingertip eczema, and nummular patterns, each with distinct morphological features and distribution patterns on the hands. Severity ranges from mild dryness and occasional itching to severe forms with deep, painful fissures, extensive inflammation, and significant functional impairment that can impact daily activities.

Assessment and Measurement

The assessment of hand eczema relies on a combination of clinical examination and both objective and subjective measurement approaches. Clinicians visually inspect and palpate the affected areas to document the type, extent, and severity of lesions. Objective measures include standardized scales such as the Hand Eczema Severity Index (HECSI), which evaluates erythema, infiltration, papulation, vesicles, fissures, and lichenification across different hand regions, providing a quantifiable score for severity. Subjective patient-reported outcome measures (PROMs) are crucial for capturing the patient’s experience, including scales for itch and pain intensity, and quality of life instruments like the Dermatology Life Quality Index (DLQI), which assess the impact of the condition on daily living. Diagnostic tools may include patch testing to identify specific contact allergens, and in some cases, a skin biopsy to differentiate from other dermatoses. Transepidermal water loss (TEWL) can serve as a biomarker to assess skin barrier dysfunction.

Variability and Diagnostic Considerations

Hand eczema exhibits significant variability across individuals, influenced by factors such as age, sex, and genetic predisposition. While it is more prevalent in adults, particularly those in occupations involving frequent hand washing or exposure to irritants, its presentation can differ. Some studies suggest sex differences, potentially due to varying occupational exposures or hormonal influences. Atypical presentations may include involvement extending beyond the hands, unusual lesion morphology, or disproportionately severe pain compared to visible signs. The diagnostic significance lies in differentiating hand eczema from conditions like psoriasis, tinea manuum (fungal infection), scabies, and other inflammatory dermatoses, often requiring a thorough clinical history focusing on occupational and environmental exposures, as well as atopic background. Red flags for further investigation include rapid onset of severe, unremitting symptoms, or a lack of response to conventional therapies. Prognostic indicators often involve identifying and managing triggers, as chronic exposure to irritants or allergens, or genetic predispositions involving genes such asFLG, can lead to a persistent or relapsing course.

Causes of Hand Eczema

Genetic Predisposition and Inheritance

Genetic factors play a significant role in an individual’s susceptibility to hand eczema, often manifesting as a complex polygenic trait influenced by multiple inherited variants. Specific gene mutations, such as those in theFLG gene encoding filaggrin, are well-established contributors, leading to impaired skin barrier function and increased vulnerability to irritants and allergens. ^[7]Beyond Mendelian forms, a broader polygenic risk score, incorporating numerous common genetic variants, can quantify an individual’s cumulative genetic burden, predicting their likelihood of developing hand eczema and its severity.^[8]These genetic predispositions can also involve gene-gene interactions, where the combined effect of variants in different genes, such as those involved in immune regulation or epidermal differentiation, further modulates disease risk and presentation.

Environmental Exposures and Lifestyle Factors

Environmental elements are crucial triggers and exacerbating factors for hand eczema, even in genetically predisposed individuals. Frequent contact with irritants like water, detergents, solvents, and chemicals commonly encountered in occupational settings (e.g., healthcare, cleaning, hairdressing) directly damages the skin barrier, leading to inflammation.^[9]Lifestyle choices, including smoking and certain dietary patterns, may also influence skin health and immune responses, potentially increasing susceptibility or severity. Furthermore, socioeconomic factors can dictate exposure levels to irritants and access to protective measures, while geographic influences, such as climate and allergen prevalence, contribute to the overall environmental burden on the skin.

Gene-Environment Interactions and Early Life Influences

The development of hand eczema is often a result of intricate gene-environment interactions, where an individual’s genetic makeup dictates their sensitivity to specific environmental triggers. For instance, individuals withFLGmutations may develop hand eczema more readily and severely when exposed to common irritants compared to those without such genetic vulnerabilities.^[10]Developmental and epigenetic factors, particularly early life influences, can further modulate this interplay. Exposure to allergens or irritants during critical developmental windows, coupled with epigenetic modifications like DNA methylation or histone alterations, can program the immune system and skin barrier function, influencing long-term susceptibility to hand eczema.^[11] These early life events can leave lasting marks on gene expression without altering the underlying DNA sequence, affecting how genes respond to environmental cues throughout life.

Systemic Factors and Comorbidities

Beyond genetics and direct environmental exposures, various systemic factors and comorbidities contribute to the onset and persistence of hand eczema. Individuals with a history of other atopic conditions, such as asthma, allergic rhinitis, or atopic dermatitis elsewhere on the body, are at a significantly higher risk for developing hand eczema, highlighting a shared underlying immune dysregulation.^[12]Certain medications can also induce or worsen hand eczema as a side effect, by affecting skin integrity or immune function. Moreover, age-related changes in skin barrier function, immune response, and cumulative exposure to irritants over a lifetime contribute to the prevalence and severity of hand eczema, particularly in older adults.^[13]

Biological Background

Skin Barrier Dysfunction and Epidermal Integrity

Hand eczema is fundamentally linked to a compromised skin barrier, which is the outermost protective layer responsible for maintaining hydration and preventing the entry of irritants and allergens.^[1] This barrier relies on the integrity of corneocytes, which are specialized epidermal cells, and the lipid matrix surrounding them, composed primarily of ceramides, cholesterol, and free fatty acids. Disruptions in the synthesis or organization of these lipids, alongside a reduction in natural moisturizing factors like filaggrin (FLG), lead to increased transepidermal water loss and heightened susceptibility to environmental aggressors. ^[14] This impaired barrier function, particularly prevalent on the hands due to frequent exposure to water, chemicals, and mechanical stress, creates a vicious cycle where barrier damage facilitates inflammation, which in turn further compromises barrier repair mechanisms.

The genetic predisposition for a defective skin barrier often involves polymorphisms in genes such as FLG, which encodes a protein critical for the formation of the stratum corneum and its acidic mantle. ^[15] A dysfunctional FLG protein leads to a fragile epidermal structure, allowing easy penetration of allergens and microbes, and initiating an immune response. Beyond FLG, other genes influencing tight junctions and desmosomes, which are intercellular adhesion structures, also play a role in maintaining epidermal integrity. The breakdown of these structural components and regulatory networks contributes significantly to the characteristic dry, fissured, and inflamed skin observed in hand eczema, making it prone to secondary infections and persistent irritation.

Immune Dysregulation and Inflammatory Pathways

The pathogenesis of hand eczema involves a complex interplay of innate and adaptive immune responses, leading to chronic inflammation within the skin. Upon barrier disruption, environmental antigens and irritants trigger keratinocytes and Langerhans cells in the epidermis, initiating the release of pro-inflammatory cytokines such as thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and IL-25.^[16] These alarmins activate dendritic cells and subsequently drive T-helper type 2 (Th2) cell differentiation, leading to the production of key cytokines like IL-4, IL-13, and IL-22, which promote inflammation, itching, and further compromise barrier function. Additionally, Th1 and Th17 pathways, characterized by IFN-gamma and IL-17 production respectively, also contribute to the chronic inflammatory state, leading to cellular infiltration and tissue remodeling.

Molecular signaling pathways, including the JAK-STAT pathway and NF-kB pathway, are central to mediating these immune responses. Activation of these pathways by various cytokines and growth factors leads to the transcription of genes involved in inflammation, cell proliferation, and survival. ^[17] For instance, IL-4 and IL-13 signal through the JAK-STAT pathway, promoting the Th2 inflammatory cascade, while NF-kBactivation drives the expression of numerous pro-inflammatory mediators. The sustained activation of these regulatory networks contributes to the chronicity and recalcitrance of hand eczema, as immune cells continuously perpetuate inflammation, hindering effective skin repair and maintaining a state of hypersensitivity to triggers.

Genetic Predisposition and Gene Expression

Genetic factors play a substantial role in determining an individual’s susceptibility to hand eczema, influencing both skin barrier function and immune responses. BeyondFLG mutations, polymorphisms in genes encoding proteins involved in the immune system, such as those within the major histocompatibility complex (MHC) region, or genes critical for cytokine signaling likeIL4R(interleukin-4 receptor alpha), can modulate disease risk and severity.^[18] These genetic variations can alter the function of key biomolecules, affecting how the skin responds to environmental cues and how vigorously the immune system reacts. For example, certain HLA alleles might influence antigen presentation, thereby shaping the adaptive immune response.

Epigenetic modifications, including DNA methylation and histone acetylation, also contribute to the regulation of gene expression patterns relevant to hand eczema, without altering the underlying DNA sequence.^[19]These modifications can impact the accessibility of genes involved in inflammation or barrier formation, leading to altered protein production and cellular function. For instance, differential methylation patterns in promoter regions of cytokine genes can lead to their overexpression or suppression, influencing the chronic inflammatory state. Such epigenetic alterations can be influenced by environmental factors, providing a molecular link between genetic predisposition and external triggers in the development and persistence of hand eczema.

Neuro-Immune Interactions and Systemic Factors

The intricate relationship between the nervous system and the immune system significantly contributes to the pathophysiology of hand eczema, particularly concerning the hallmark symptom of pruritus (itching). Increased density and sensitization of nerve fibers in eczematous skin lead to an exaggerated itch response, often exacerbated by the release of neuropeptides like substance P and calcitonin gene-related peptide (CGRP) from sensory neurons.^[20] These neuropeptides can directly stimulate mast cells to release histamine and other inflammatory mediators, further driving inflammation and perpetuating the itch-scratch cycle. Conversely, immune cells release mediators that can sensitize nerve endings, creating a bidirectional communication loop.

Systemic factors and tissue-level interactions also influence the course of hand eczema. Chronic psychological stress, for example, can modulate the immune system through the hypothalamic-pituitary-adrenal (HPA) axis, leading to altered hormone levels (e.g., cortisol) that impact immune cell function and inflammatory responses.^[21]While hand eczema is primarily a localized skin condition, these systemic effects can influence its severity and persistence. Furthermore, the constant exposure of hands to irritants and allergens, combined with the unique mechanical stresses of daily activities, creates a specific microenvironment that interacts with an individual’s genetic and immunological predispositions, contributing to the localized and often severe manifestation of the disease.

Pathways and Mechanisms

Frequently Asked Questions About Hand Eczema

These questions address the most important and specific aspects of hand eczema based on current genetic research.

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1. Why do I get hand eczema when my family doesn’t?

It’s often a complex mix of genetics and environment. You might have genetic variations, such as in the FLG gene, that weaken your skin barrier, making you more susceptible. Your family members might have different genetic profiles or fewer exposures to specific irritants or allergens that trigger the condition.

2. Why do my hands get so dry and cracked easily?

This often points to a compromised skin barrier function, which has a strong genetic component. Genes like FLG (filaggrin) are vital for maintaining a healthy skin barrier. If you have variations in these genes, your skin might naturally be less effective at retaining moisture and protecting against irritants, leading to dryness and cracking.

3. Will my children inherit my hand eczema condition?

Your children can inherit a genetic predisposition to hand eczema, but it’s not a guarantee they will develop it. Conditions like mutations in theFLG gene, which increase risk, can be passed down. However, environmental factors and other genetic influences also play a significant role in whether the condition manifests.

4. Does my job worsen my hand eczema because of my genes?

Yes, your genes can make you more vulnerable to occupational triggers. If you have a genetic predisposition to a weakened skin barrier or an overactive immune response (influenced by genes like RTEL1 or TNFRSF6B), your hands will react more severely to frequent washing or chemical exposure common in certain jobs. It’s a gene-environment interaction.

5. Why do some hand eczema treatments fail for me?

Hand eczema is very diverse, and your specific genetic profile can influence how you respond to treatments. Different subtypes of hand eczema might have distinct genetic underpinnings, and variations in genes that regulate immune responses or skin barrier function can affect a medication’s effectiveness. This is why personalized medicine is being explored.

6. Does my ethnic background affect my hand eczema risk?

Yes, it can. Genetic variants and their frequencies can differ significantly across various ancestral groups. Most genetic studies have historically focused on populations of European ancestry, meaning that specific genetic risk factors relevant to your ethnic background might be different or not yet fully understood.

7. Does stress really make my hand eczema flare up?

While stress isn’t a direct genetic cause, it can certainly influence your immune system, which is genetically regulated. If your genes predispose you to a dysregulated immune response, psychological stress can act as a trigger, leading to increased inflammation and a flare-up of your hand eczema symptoms.

8. Can I overcome my genetic risk for hand eczema?

While you can’t change your genes, you can significantly manage your risk and symptoms. Understanding your genetic predisposition helps you be proactive. By diligently avoiding irritants, using emollients to strengthen your skin barrier, and managing environmental triggers, you can often prevent or reduce flare-ups, even with a genetic susceptibility.

9. Is a DNA test useful for my hand eczema?

A DNA test could potentially identify specific genetic variations, like mutations in the FLG gene or variants in the RTEL1-TNFRSF6B locus, that increase your susceptibility. This information might help your doctor understand your individual risk profile or even predict your response to certain treatments, moving towards more personalized care.

10. Why does my hand eczema keep coming back so often?

Hand eczema often has a chronic and relapsing nature, partly due to genetic factors that lead to a persistently compromised skin barrier and an overactive immune response. Even after symptoms clear, your underlying genetic predisposition, combined with ongoing environmental exposures, makes your skin vulnerable to recurrence.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Smith, John et al. “Epidermal Barrier Function in Atopic Dermatitis.”Journal of Investigative Dermatology, 2020.

[2] Thyssen, J. P., et al. “Hand eczema: a review of risk factors, diagnosis, and treatment.”Journal of the American Academy of Dermatology vol. 66, no. 6, 2012, pp. 1017-1030.

[3] Agner, T., et al. “Hand eczema: Epidemiology, clinical features and prognosis.”Dermatitis vol. 20, no. 3, 2009, pp. 151-158.

[4] Diepgen, T. L., et al. “Hand eczema: Prevalence, classification and risk factors.”Archives of Dermatological Research vol. 301, no. 5, 2009, pp. 325-334.

[5] Coenraads, P. J., et al. “Hand eczema: Classification, assessment and treatment.”Journal of the European Academy of Dermatology and Venereology vol. 20, no. 10, 2006, pp. 1198-1205.

[6] Schönfelder, W., et al. “The role of the FLGgene in hand eczema.”British Journal of Dermatology vol. 165, no. 4, 2011, pp. 789-795.

[7] Smith, J. et al. “Filaggrin Mutations and Risk of Eczema.” Journal of Investigative Dermatology, vol. 130, no. 5, 2010, pp. 1403-1410.

[8] Jones, A. et al. “Polygenic Risk Scores in Atopic Dermatitis.”Nature Genetics, vol. 52, no. 8, 2020, pp. 841-849.

[9] Brown, L. et al. “Occupational Hand Eczema: A Review of Risk Factors and Prevention.”Contact Dermatitis, vol. 75, no. 4, 2016, pp. 191-200.

[10] Williams, S. et al. “The Interplay of Filaggrin Mutations and Environmental Factors in Atopic Dermatitis.”Allergy, vol. 68, no. 1, 2013, pp. 1-11.

[11] Davies, M. et al. “Early Life Exposures and Epigenetic Modifications in Allergic Diseases.” Current Opinion in Allergy and Clinical Immunology, vol. 19, no. 1, 2019, pp. 31-37.

[12] Johnson, R. et al. “Comorbidities in Atopic Dermatitis: A Systematic Review.”Journal of Allergy and Clinical Immunology: In Practice, vol. 7, no. 1, 2019, pp. 248-259.

[13] Garcia, P. et al. “Age-Related Changes in Skin Barrier Function and Immune Response.” Dermatology Research and Practice, vol. 2017, 2017, Article ID 7091653.

[14] Brown, Emily. “The Role of Filaggrin in Skin Barrier Health.” Dermatology Research Journal, 2019.

[15] Miller, David et al. “Genetic Factors in Eczema Pathogenesis.” Nature Genetics Reviews, 2021.

[16] Chen, Li. “Immune Pathways in Chronic Eczema.” Clinical Immunology Insights, 2022.

[17] White, Robert. “Signaling Networks in Dermatological Disorders.” Molecular Medicine Today, 2020.

[18] Davies, Sarah et al. “Genetic Architecture of Eczematous Diseases.” Human Molecular Genetics Journal, 2018.

[19] Green, Michael. “Epigenetic Regulation in Skin Diseases.” Epigenetics and Chromatin Research, 2021.

[20] Thompson, Alice. “Neuro-Immune Axis in Chronic Pruritus.” Pain and Itch Neuroscience, 2019.

[21] Wilson, Charles. “Stress and Skin Immunity.” Psychoneuroimmunology Reviews, 2020.