(Ch12) Atopic Dermatitis Flashcards
what is the epidemiology of AD ?
10–30% kids & 2–10% adults.
↓rural areas than urban/high- income areas
What are the subtypes of AD?
- Early Onset: (MC) AD in < 2 Yrs.
- Late Onset: AD after puberty.
- Senile Onset: Unusual
what percentage of children will have AD by age of 6 months?
Starts < 6 mo in 45%
1st year in 60%
< 5 years in 85%
what percentage of children will have allergen specific IgE by age of 2?
1/2 children develop allergen-specific IgE by 2 Yrs of age.
what percentage of children will develop remission by age of 12y?
60% go into remission at 12 years.
Strongest risk factor for AD?
Parental Hx of AD
stronger risk factor than asthma or allergic rhinitis
what are the major components in the pathogenesis of AD?
- Epidermal Barrier Dysfunction (↑TEWL, pH and permeability+altered lipids)
- ** Immune dysregulation**
- ** Altered microbiome**
What correlates with severity of AD ?
Level of TEWL in nonlesional skin
what can predict increased risk of AD in the 1st year of life ?
↑ level of transepidermal water loss (TEWL), on day 2 of life predicts ↑ risk of AD at 1 year of age.
what could reduce filaggrin level?
↑ local pH
protease activity
Th2 cytokine levels
what is filaggrin?
Keratin filament-aggregating protein.
Major structural component of SC
Strongest genetic risk factor for AD ?
Loss-of-function FLG Mx
(Both AD & ichthyosis vulgars)
Ass/w early-onset AD, ↑ severity, persistence into adulthood
Factors that contribute to impaired barrier function?
- abnormal Filaggrin and other structural proteins.
2.Alteration in SC lipids.
3.Imbalance between Proteases and protease inhibitors.
Mention few epidermal barrier proteins other than Filaggrin involved in barrier dysfunction?
loricrin, corneodesmosin, involucrin, SPRR3/4, claudin-1, and late cornified envelope protein 2B
Filaggrin and its breakdown products (e.g. histidine) contribute to?
1- epidermal hydration
2-acid mantle formation
3-lipid processing
4-barrier function
Epidermal barrier dysfunction can result in ?
↑TEWL, pH and permeability+altered lipids
also
1-Entry for irritants, allergens and microbes → ↑ immune responses → ↑ proinflammatory cytokines.
2- Epicutaneous sensitization to aeroallergens ➤ asthma + allergic rhinoconjunctivitis
How do SC lipids altered in AD?
1.Filaggrin-deficient cytoskeletal ➤ ✗ loading / secretion of lamellar bodies ➤ ✗ post-secretory lipid organization and processing.
2.Disruption of acidic mantle → ↓lipid-processing enzymes such as β-glucoscerebrosidase + acid sphingomyelinase.
3.Th2 cytokines also ↓ SC lipid
4.components.
Satph A colonization
mention 2 enzymes involved in lipid processing in AD ?
β-glucoscerebrosidase
acid sphingomyelinase
Which SPINK5 mutation associated with AD ?
SPINK5 polymorphisms ➤ ↑ risk of AD
Biallelic loss-of-function SPINK5 Mx ➤ Netherton syndrome.
Which endogenous serine proteases has ↑levels in AD skin?
Endogenous serine proteases e.g. kallikrein 5/7.
Imbalance in serine proteases enzymes and protease inhibitors such as lymphoepithelial Kazal-type trypsin inhibitor (LEKTI) encoded by SPINK5 lead to ↑levels of endogenous serine proteases e.g. kallikrein 5/7.
Which protease inhibitors encoded by SPINK5?
lymphoepithelial Kazal-type trypsin inhibitor (LEKTI)
How does LEKTI deficiency affect epidermal barrier function?
LEKTI deficiency ➤ ↓ Dsg1 → ✗ SC detachment → Disrupted epidermal barrier
S. aureus extracellular V8 protease (similar to S. aureus exfoliative toxins) also degrade Dsg1.
what is unique about adult onset AD
30% patients esp F have non-IgE- associated AD
what is the consistent feature of AD?
Epidermal barrier dysfunction
which cytokine present in both acute and chronic AD
Th17 cytokines
Acute AD is mediated by Th?
Th2
Chronic AD mediated by Th?
Th1 & Th22
Master switch of allergic inflammation?
thymic stromal lymphopoietin (TSLP)
What Cytokines induce Th2 response in AD?
IL-1, IL-25 (17E), IL-33 & thymic stromal lymphopoietin (TSLP)
all known as Keratinocyte-derived cytokines
Th2 response produce in AD?
IL-4, IL-5, and IL-13
Eosinophils and mast cells
↑ allergen-specific Ig
results in:
1. ↓ terminal differentiation proteins: loricrin, filaggrin, and involucrin.
2.↓ β-defensin-2/3
3 main cell types involved in AD immune dysregulation?
Keratinocytes
T cells
Antigen presenting cells(ILC) e.g. NK
IL involved in pruritis and receptors can be found in C nerve fibres as well as keratinocytes?
IL-31
Nemolizumab, anti-IL-31 receptor A subunit.
Induced by Staphylococcal superantigen
Thymic stromal lymphopoietin (TSLP)
Expressed in acute and chronic AD (only in lesions skin)
Stimulated by: allergens, viruses, trauma, and other cytokines (e.g. IL-1β, TNF)
Produced by: keratinocytes, fibroblasts, and mast cells
Cytokines Characteristic of new-onset pediatric AD?
L-17 and IL-19
Produced by Th17
percentage of patient with AD colonized by Staph A
> 90% of AD colonized with S. aureus,
During flare ↑Staphylococcus spp. from ~35% to ~90%
mention antimicrobial peptides reduced in AD?
cathelicidins, defensins2/3
How does Staph A affects AD?
- Superantigenic exotoxins by S. aureus →↑ Th2
- S. aureus δ-toxin →↑ mast cell degranulation and Th2.
- ↓Filaggrin increases susceptibility of KC to S. aureus α-toxin-induced cytotoxicity
IL-4 and IL-13
IL-4 Function→ IMP for ↑Th2 cell differentiation, ↑IgE and ↑eosinophil
IL-4 and IL-13 heterodimeric receptors contain IL- 4Rα subunit and STAT6 → naive T cells into Th2
what is the age-dependent sequence, referred to as Atopic March?
- Atopic dermatitis – in first 2 years of life (infants and young children)
2.Food allergies – in first 2 years of life (infants and young children)
- Asthma – around 2-5 years (older children)
4.Allergic rhinitis – 10 years + (predominates in adolescents)
5.Eosinophilic esophagitis (rare
Predictors of persistence of AD into adulthood?
1.Young age at onset
2.Concurrent asthma and/or allergic rhinoconjunctivitis
3.Low socioeconomic status
4.non-White ethnicity
- filaggrin mutations
Essential features of AD?
Must be present and sufficient for dx
- Pruritus
2.Typical eczematous morphology or Age-specific distribution
- Chronic or relapsing course
Important Features of AD?
- Onset during infancy or early childhood
- Personal or fam hx of Atopy
- Xerosis
Triggers of AD
- Climate extremes or low humidity
- Irritants
- infections
- Environemental Allergies
- Food Allergies
Mention 5 mutations As/w AD
Encodes Epidermal protein:
1. FLG
2. FLG2
3. SPINK5
Encodes immunologic proteins
4. IL4&R, IL13&R, IL31&R
5- TSLP
AD subtypes based on Age
- Infantile
- childhood
- Adolescent/ adult
4.Senile
which anatomical locations not affected by AD ?
Axilla and groins
which eczema variant common in skin of colour?
papular eczema
SOC eczema associated with Th17
Regional Variants of AD?
- Cheilitis sicca
- Ear eczema
- Eyelid eczema
- Head and neck dermatitis
- Juvenile plantar dermatosis
- Atopic hand eczema
- Prurigo AD
- Nummular / Discoid AD
- Frictional lichenoid eruption
- Nipple eczema
Hallmark of eczema
Pruritus
Pathophysiology of Pityriasis alba
low-grade eczematous dermatitis disrupts transfer of melanosomes to K
itch that rashes
Rubbing & scratching initiate flares or exacerbate existing dermatitis
infantile AD vs diaper rash or Seboderm
Sparing of diaper area in AD
Atopic Stigmata (associated features)
- Xerosis
- Icthyosis Vulgaris
- Palmoplanter hyper linearity
- Keratosis pilaris
- Dennie Morgan lines
- Allergic Shiners
- Ant neck folds
- Hertoghe
- White dermatographism
- Follicular prominence
Complications of AD
- Bacterial and viral infections (strep P, HSV, Molluscum)
- risk of ↑ cardiovascular complications
- Anterior Subcapsular cataracts
- Psychological/emotional impact
Ophthalmological complication As/w AD?
Anterior Subcapsular cataracts
AD pruritus worst timing?
in the evening
Mention few scoring systems to assess severity of AD?
- EASI (Eczema Area Scoring Index)
- SCORAD (SCORing Atopic Dermatitis
- Diepgen score
- POEM (Patient-Oriented Eczema Measure.
“Soak and smear” technique
TCS or anti-inflammatory Rx immediately after bathing, prior to moisturizer
6 + 3 rule
6 minutes in bath
3min after bath window for occlusion
Name 2 risk factors for hand eczema development in AD patients?
-FLG mutation
-Frequent exposure to water and other irritants
What is the Ddx of pityriasis alba?
-PIH from other inflammatory skin conditions (e.g. seb derm, PLC)
-Pityriasis versicolor: more sharply demarcated, scale
-Vitiligo: sharply demarcated,
depigmented not hypopigmented
-Hypopigmented MF: extrafacial involvement
What is the treatment of pityriasis alba?
Sunscreen, photoprotection, emollients
What clinical features help to distinguish infantile AD vs. seb derm?
AD: mainly in extensors + cheeks
Seb derm: mainly in folds; earlier onset (1 wk post-birth); a/w yellow-white greasy adherent scales; surrounded by satellite lesions; absence of pruritus, irritability and sleeplessness
Ddx of AD
Seborrheic dermatitis
Contact dermatitis (ACD or ICD)
Psoriasis
Asteatotic eczema
LSC
Scabies
Dermatophytosis
Name 5 immunodeficiencies that are part of the AD Ddx?
Wiskott-Aldrich
Hyper IgE syndromes
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
Omenn syndrome
DiGeorge syndrome
Ig deficiencies (X-linked hypogammaglobulinemia, IgA deficiency)
Ataxia telangiectasia
What should you think of if a patient with AD is not improving, or worsening despite, regular use of TCS?
Allergic contact dermatitis
What are the 3 objectives of maintenance therapy in AD?
- Prevent triggers
- Control subclinical inflammation
- Restore barrier
What is the minimum age approved for the use of TCIs for AD?
≥ 2 yo
What is the therapeutic ladder of treatment for AD?
General
Educational interventions: disease mechanisms and course, triggers, appropriate use of therapies, goals of management, support groups and organizations, psychological interventions
Gentle skin care: bath/shower guidelines, avoidance of fragrance, soap cleansers and hot water, moisturizer after bath
Moisturizer: immediately after bath/shower, apply liberally and frequently daily
Topical
TCS
TCI
Crisaborole
Topical tofacitinib
Phototherapy
NBUVB
UVA1
PUVA
Systemic
First line
Dupilumab
CsA
AZA
MTX
MMF
SCS
Second line
Omalizumab: anti IgE monoclonal Ab
Nemolizumab
Tofacitinib
Rituximab
IFN-gamma
IVIg
Other: crude coal tar, HCQ, ECP
Adjunctive
Wet wraps
Bleach baths
Antimicrobials and antiseptics – if superinfection
Antihistamines – sedating effects for pruritus control
Leukotriene antagonists
Sodium cromoglycate
Probiotics
Vit. D supplementation and other dietary supplements
Systemic allergen-specific immunotherapy
Management of co-existing allergic diseases (food, aeroallergens, ACD)
Explain how to do a wet wrap?
- Application of TCS
- Inner wet layer
- Outer dry layer of cotton gauze or garments
- Leave in place for 8-24 hours per day
- Treatment duration should not exceed 2 weeks
What are the 5 MC food allergies associated with AD?
- Eggs *most often a/w AD exacerbations
- Milk
- Peanuts
- Soy
- Wheat
Is there an association between food allergies and AD?
percentage of children with AD who has food allergy
In 10-30% of infants and young children with AD, exposure to food allergens may exacerbate their eczema (especially in those with severe, recalcitrant dz)
Name 5 side effects of TCS?
1.Atrophy
2. Telangiectasias
3. Steroidal acne
4. Poor wound healing
5. Perioral dermatitis
6. Cataracts
7. Iatrogenic Cushing’s
7. Hypopigmentation
8. Hypertrichosis
9. Milia, folliculitis.
Name 2 primary preventive strategies for AD development?
- For infants with +famhx of atopy: exclusive breastfeeding during first 3-4mos of life may decrease risk (longer exclusive feeding does not confer additional benefit/protection against developing AD)
- Maternal vitamin D supplementation
MOA of Crisaborole, Roflumilast
PDE4 inhibitors
(PDE4 degrades cAMP which increases cytokines like IL-10 and IL-4 so Crisaborole decreases the pro-inflammatory cytokines)
MOA of Tralokinumab
targets IL-13R alpha1 and IL13R a2 🡪 decreases IL-23
MOA of AZA and MMF
AZA: inhibitor of purine synthesis that reduces leukocyte proliferation
MMF: inhibits the de novo pathway of purine synthesis, resulting in suppression of lymphocyte function
MOA of CSA
CsA: potent inhibitor of T-cell-dependent immune responses and IL-2 production
Role of Phototherapy in AD
Phototherapy: immunomodulatory effects occur via induction of T-cell apoptosis, reduction of dendritic cells, and decreased expression of Th2 cytokines such as IL-5, IL-13, and IL-31
