Practical Insights into Atopic Dermatitis

Contents
Part I: Introduction
	Introduction to Atopic Dermatitis
		History and Definition of Atopic Dermatitis Terms
		Terms of Eczema and Atopic Dermatitis
		Diagnosis of Atopic Dermatitis
		Treatment of Atopic Dermatitis
		References
Part II: Epidemiology
	Epidemiology of Atopic Dermatitis
		Epidemiology of Atopic Dermatitis in Korea
			Epidemiology of Atopic Dermatitis by Skin Examination
			Epidemiology of Atopic Dermatitis by Questionnaire
			Epidemiological Investigation of Atopic Dermatitis Based on Claims Data from the Health Insurance Review and Assessment Service
		Geographical Location According to Different Prevalence of Atopic Dermatitis
		Factors to Increase Atopic Dermatitis
			Hygiene Hypothesis
			Indoor Air Pollution
			Environmental Pollution
			Climate
			Diet
			Other Risk Factors
		Costs of Atopic Dermatitis
		Conclusion
		References
Part III: Clinical Manifestations
	Clinical Manifestations
		Clinical Features According to Age
			Early Infancy (<2 Years Old)
			Childhood (2~12 Years Old)
			Adolescent (>12 Years Old)
			Adulthood (>18 Years Old)
		Dermatologic Conditions that May Accompany AD
			Nummular Eczema
			Prurigo Nodularis
			Exfoliative Dermatitis
			Infections
				Viral Infection
				Fungal Infection
				Bacterial Infection
			Others
		Systemic Conditions that May Accompany AD
			Atopic March
			Ocular Symptoms
			Autoimmune Diseases
			Metabolic Syndrome
			Psychiatric Disorders
		Differential Diagnosis
			Seborrheic Dermatitis
			Contact Dermatitis
			Scabies
			Malignancy
		Prognosis
		References
	Pruritus
		Introduction
		Classification and Causes of Pruritus
		Pathophysiology of Pruritus (Fig. 1) [5]
			Mediator of Pruritus
			Mechanism of Pruritus: Signaling at Neuronal Terminals
			Neurotransmission Pathways in Pruritus
			The Difference Between Pruritus and Pain Transmission [16, 17]
		Treatment of Pruritus
			Systemic Therapy
				Antihistamines
				Neurological Drugs
				Antidepressants
				Opiate Agonists and Antagonists
				Immunomodulators [28]
				Biologics and Small Molecules (Fig. 3)
				UV Treatment
			Topical Drugs
				Topical Steroids
				Topical Calcineurin Inhibitors
				TRPV1 Activator
				TRPV 1 Inhibitor
				TRPM8 Activator
				Moisturizer
		Conclusions
		References
Part IV: Diagnosis
	Diagnosis and Severity Assessment of Atopic Dermatitis (Korean Guideline Included)
		Diagnosis of Atopic Dermatitis
			Diagnostic Criteria for AD
				Gold Standard Criteria for AD Diagnosis
				Diagnostic Criteria in Different Age Groups
					Diagnostic Criteria for Pediatric AD
					Diagnostic Features of Adult-Onset AD
					Diagnostic Features of AD in Elderly
			Differential Diagnosis
		Disease Severity Assessment of AD
			Physicians’ Measurement Tools
				SCORAD
				EASI
				Investigator’s Global Assessment
			Patient-Reported Outcome Measures
				Patient-Oriented Eczema Measure
				Patient Global Assessment
				Pruritus Scales
				Quality of Life Index
			Core Outcome Sets to Measure Disease Severity
			Definition of Moderate to Severe AD
				Other Objective Factors to Consider in Determining AD Severity
					Involved Area
					Comorbidities
		Treatment Responses
			Treatment Refractoriness of AD
			Persistent or Recurrent AD
		Conclusion
		References
Part V: Pathophysiology
	Genetics of Atopic Dermatitis
		Introduction
		Atopic Dermatitis Is a Heritable Disease and a Complex Trait
		Methods for Identifying Atopic Dermatitis Risk Genes
			Genome-Wide Studies
			Candidate Gene Association Studies
		Skin Barrier–Related Genetic Mutations
			FLG Mutations
			SPINK5 and KLK7 Mutations
			Other Genes Related to the Skin Barrier
		Inflammatory and Immune Response–Related Gene Polymorphisms
			Pattern-Recognition Receptors and Antimicrobial Peptides
			IL-1 Family Cytokines
			Thymic Stromal Lymphopoietin
			TH2 Cytokines
				IL-4 and IL-4 Receptor-α
				IL-13
			TH1 Cytokines and Other Cytokines
				IL-10
				IL-9
				IL-12B
			High-Affinity IgE Receptor Mutations
		References
	Skin Barrier-Related Pathogenesis of Atopic Dermatitis
		Introduction
		Lipid Barrier Impairment: Abnormal SC Intercellular Lipids
		Protein Barrier Impairment
			Deficiency of Filaggrin and Its Metabolites
			Serine Protease Inhibitor Deficiency
		Tight Junction Abnormality
		Correlation Between the Immune Response and Skin Barrier Function
			Skin Barrier Damage Due to the Immune Response
			Activation of the Immune Response Due to Skin Barrier Dysfunction
		Conclusion
		References
	Immune-Meidated Pathogenesis of Atopic Dermatitis
		Innate Immune Response
			Innate Immune Cell
				Eosinophil
				Mast Cell
				Basophil
				Innate T Cell
				Innate Lymphoid Cell (ILC)
			Pattern Recognition Receptor (PRR)
				Toll-like Receptor (TLR)
				NOD-Like Receptor (NLR)
				Retinoic Acid-Inducible Gene-Like Receptor (RLR)
				C-Type Lectin Receptor (CLR)
			Antimicrobial Peptide (AMP)
				Defensin
				Cathelicidin (LL-37)
				RNase7
				Dermcidin
				S100A7 (Psoriasin), S100A8, S100A9
		Adaptive Immune Response
			T Cell
				Th1/Th2 Cell Imbalance
				Cytokines
					IL-4 and IL-13
					IL-5
					IL-18
					IL-31
					IL-33
				Treg Cell
				Th17 Cell
				Th22 Cell
			Dendritic Cell
			B Cell
			Chemokines
		References
	Evironmental Factors Related To Atopic Dermatitis
		Introduction
		Characteristics of AD Pathogenesis
		Hygiene Hypothesis
		Immaturity of Skin Barrier
			“Outside–Inside” Hypothesis
			Mutation of Filaggrin Gene
			Atopic March
		Correlation Between Atopic Dermatitis and Environmental Factors
			Air Pollution
			Sick Building Syndrome, Sick House Syndrome
			Heavy Metal and Water Pollution
			Climate Change
			Clothing
			Psychosomatic Aspect
		References
	Food, Inhalant, and Microbial Allergens
		Food Allergens
		Inhalant Allergens
		Microbial Allergens
		References
	Role of Infection and Microbial Factors
		Changes in Cutaneous Microbiome in Atopic Dermatitis
			Cutaneous Microbiome in Healthy Skin
			Dysbiosis in Atopic Dermatitis Skin
		The Role of Staphylococcus aureus in the AD Pathogenesis
			Virulent Factors from Staphylococcus aureus
			Regulation of Staphylococcus aureus Virulence
		The Protective Role of Skin Commensal Bacteria Against Atopic Dermatitis and the Important Role of Early-Life Skin Microbiome in the Development of Atopic Dermatitis
		Fungal Infection in AD
		Viral Infection in AD
		References
	Psychological Stress
		Introduction
		Clinical Evidence of the Psychological Stress-Induced Aggravation in Atopic Dermatitis
		Hypothalamic–Pituitary–Adrenal Axis in Stress Response
		Autonomic Nervous System in Stress Response
		Immune Response in Stress
			T Cells
			Dendritic Cells and Langerhans Cells
			Other Cells
		Neurogenic Mediators and Mast Cells
			Mast Cell Mediators
		Psychological Stress and Barrier
		Psychological Intervention
		Conclusion
		References
	Endophenotype and Biomarker
		Introduction
		Endophenotypes and Biomarkers: Implement to Achieve Personalized Medicine in AD
		Clinical Heterogeneity of AD
		Classic Clinical Phenotypes of AD
			Acute AD Versus Chronic AD
			AD Associated with Ichthyosis (Filaggrin Mutation)
			Intrinsic AD Versus Extrinsic AD
			Phenotypes According to Age of Onset
			Phenotypes According to the Typical Clinical Features by Age
			Phenotypes According to the Severity of AD
			Phenotypes According to Ethnicity
		Definition of Biomarkers and Their Clinical Application
		The Need for Biomarkers in Atopic Dermatitis
			Biomarkers for the Classification of Phenotypes and Figuring Out the Disease Heterogeneity
			Biomarkers for Prediction of Treatment Response
			Biomarkers for Objective Measurement of AD Severity
		Current Candidate Biomarkers of AD
			Screening Biomarkers
			Diagnostic Biomarkers
			Severity Biomarkers
			Predictive and Prognostic Biomarkers
			Pharmacodynamic Biomarkers
			Monitoring Biomarkers
		Conclusions and Future Perspectives
		References
Part VI: Management
	Topical Treatment
		Topical Corticosteroids
			Introduction
			Action Mechanism
				Anti-inflammation
				Immunosuppression
				Vasoconstriction
				Anti-proliferation
			Classification and Formulation
			Efficacy of TCS in Atopic Dermatitis
			How to Choose TCS According to the Potency and Place of Treatment on the Body?
				The Considerations of Drug Choice
				Choice According to Drug Potency and Application Site
			How to Apply TCS for Atopic Dermatitis?
			Amount, Frequency, and Duration of Application
				Amount Unit of Application
				Frequency and Duration of Application
			Special Application Method of TCS
				Simple Occlusive Dressing
				Wet Wrap Therapy
				Proactive Treatment
			Use of TCS in Children
			Use of TCS in Pregnant Women and the Elderly
			Adverse Reactions
				Local Adverse Reactions
				Systemic Adverse Reactions
			Concerns Surrounding TCS Adverse Effects
		Topical Calcineurin Inhibitors
			Introduction
				Types and Origins of TCI
			Mechanism of Action [32, 33]
			Application in Atopic Dermatitis
				Tacrolimus
				Pimecrolimus
				Efficacy Comparison Among TCIs and TCSs
				Proactive Treatment with TCIs
			Pharmacokinetics
				Tacrolimus
				Pimecrolimus
			Adverse Reactions
				Tacrolimus
				Pimecrolimus
				Risk of Malignancy
		Topical Phosphodiesterase 4 Inhibitors (Topical Crisaborole and Others)
		Novel Topical Therapy
		Moisturizers
			Physiologic Lipid Mixture (Barrier Cream)
			Functional Moisturizer with Anti-inflammatory and Anti-bacterial Properties
			Recommendation of Moisturizer Application
			What Is the Best Moisturizer?
		Bathing
		Conclusion
		References
	Systemic Treatment
		Systemic Steroids
			Action Mechanisms
				Structure and Metabolism of Steroids
				Absorption and Distribution of Systemic Steroids
				The Hypothalamic–Pituitary–Adrenal (HPA) Axis
				Molecular Genetic Action Mechanisms of Systemic Steroids
			Types of Steroids (by Potency, for Injection, for Oral)
			Indications and Efficacy of Systemic Steroids for the Treatment of Atopic Dermatitis
			Adverse Events of Systemic Steroids
				Osteoporosis
				Avascular Necrosis
				Myopathy
				Cataract
				Gastrointestinal Adverse Reactions
				Metabolic Effects
				Atherosclerosis
				Gynecological Effects
				Nervous System Effects
				Skin
				Adrenal Suppression
				Mental Effects
				Drug Interaction
				Immunological Adverse Events
				Special Consideration When Used in Pediatric Patients
		Other Systemic Immunomodulatory Therapies
			Cyclosporine
			Azathioprine
			Methotrexate (MTX)
			Mycophenolate Mofetil (MMF)
		Other Alternative Therapies
			Antihistamines
				Mechanisms and Types of Antihistamine Agents
				Atopic Dermatitis and Antihistamines
			Control of Skin Infections
				Staphylococcus aureus
				Eczema Herpeticum
				Molluscum Contagiosum
				Fungal Infection
		References
	Emerging Treatment of AD: Biologics and Small Molecules
		Biologics
			Th2 Cell Inhibition
				IL-4, 13 Inhibition
					Dupilumab
				IL-13 Inhibition
					Tralokinumab
					Lebrikizumab
				IL-33 Inhibjition
					Etokimab
				IL-31 Inhibition
					Nemolizumab
					BMS-981164
				TSLP Inhibition
					Tezepelumab
				OX40 Inhibition
					GBR830
				IL-5 Inhibition
					Mepolizumab
			Th1/Th17/Th22 Cell Inhibition
				IL12/23 Inhibition
					Ustekinumab
				IL-17 Inhibition
					Secukinumab
					MOR106
				IL-22 Inhibition
					Fezakinumab
		Small Molecules
			JAK Inhibitor
				JAK1 Inhibition
					Upadacitinib
					Abracitinib
				JAK 1/2 Inhibition
					Baricitinib
					Ruxolitinib
				JAK 1/3 Inhibition
					Tofacitinib
				Pan JAK Inhibition
					ASN002
					Delgocitinib
				Phosphodiesterase Enzyme 4 Inhibition
					Apremilast
					Roflumilast
					Crisaborole
					OPA15406
					DRM-02, LEO29102
		Conclusion
		References
	Phototherapy
		Introduction
		Biological Mechanism of Phototherapy in AD
		Various Light Sources and Practical Consideration of Phototherapy for the Treatment of AD
			Light Sources in AD
				Heliotherapy
				BB-UVB, Full-Spectrum UVA, UVA+UVB, Full-Spectrum Light, and Blue Light
				Photochemotherapy
				NB-UVB
				UVA1
				308 nm Monochromatic Excimer Light or Laser
			Practical Consideration of Phototherapy for the Treatment of AD
		Summary and Recommendation of Phototherapy in AD
		References
	Allergen Immunotherapy for Atopic Dermatitis
		Introduction
		History of AIT for AD
		Scientific Rationale of AIT for AD: Importance of Allergic Mechanism in the Pathogenesis of AD
		Method of AIT
			Subcutaneous Allergen Immunotherapy and Sublingual Allergen Immunotherapy
			The Schedules of AIT
			Total Duration of AIT
		Selection of Allergen for AIT
			Method to Select a Clinically Relevant Allergen for AIT
			Type of Commercial Allergen Preparations for AIT
		Patient Selection
			Clinical Indication of AIT in Patients with AD
			Contraindication of AIT in Patients with AD
		Mechanism of AIT
		Clinical Efficacy of AIT
			Evaluation of Clinical Efficacy of AIT in Patients with AD
			Clinical Efficacy of AIT in Patients with AD
			Characteristics of Patients with AD Who Experienced a Favorable Clinical Response After AIT
			Long-Term Clinical Efficacy of AIT in Patients with AD
		Safety of AIT
		Limitations of Current form of AIT
		Comparison of AIT and Monoclonal Antibody Therapy for the Treatment of AD
		Recent Trials and Future Directions for the Development of AIT
		Conclusion
		References
	Treatment Algorithms
		Introduction
		I. Basic Treatment
		II. Topical Treatment
			1. Topical Corticosteroids
			2. Topical Calcineurin Inhibitors
			3. Small Molecules
		III. Phototherapy
		IV. Systemic Treatment
			1. Systemic Corticosteroid
			2. Systemic Immunomodulators
				1) Cyclosporine
				2) Methotrexate
				3) Azathioprine
				4) Mycophenolate Mofetil
				5) Biologics
			3. Allergen-Specific Immunotherapy
		Discussion
		References
Part VII: Prevention
	Prevention of Atopic Dermatitis
		Introduction
		Moisturizers
		Probiotics
		Diet
		Other Factors
		Conclusions
		References