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