2. INTRODUCTION
▸ This group of disorders is commonly associated with elevated serum IgE levels,
along with a characteristic cutaneous/airway hypersensitivity to a variety of
environmental and/or dietary allergens.
▸ AD is a chronic, relapsing eczematous skin condition, typically diagnosed based
on the presence of a recurring itchy flexural rash, with onset usually in infancy or
childhood.
3. EPIDEMIOLOGY
▸ Worldwide prevalence of atopic eczema was estimated at 7.9% and 7.3% in the
6- to 7-year and 13- to 14-year age groups, respectively.
▸ Prevalence of 3%–4.2% in the Indian subcontinent.
▸ Factors traditionally associated with the increased prevalence of AD include
higher socioeconomic status, higher level of education, the evolution of smaller
families, and increased urbanisation.
4. ETIOPATHOGENESIS
▸ Evidence suggests that AD may be a disease of primary barrier failure, including
defective stratum corneum permeability, and antimicrobial defense, which, in turn,
results in sustained and efficient epicutaneous allergen penetration, leading to
immune system activation, and the resultant inflammation and pruritus that are
typical of AD.
▸ The evidence to support this theory lies in the landmark finding of filaggrin gene
defects in patients with ichthyosis vulgaris and AD.
6. ETIOPATHOGENESIS - GENETICS OF AD
▸ AD and other atopic disorders have a strong tendency to run in families, with a
high concordance rate in twin studies, and increased susceptibility in the
presence of an affected parent(s).
7. ETIOPATHOGENESIS - GENETICS OF AD - SKIN
BARRIER DYSFUNCTION GENES
▸ Genes associated with skin barrier dysfunction, especially genes that reside in
the epidermal differentiation complex (EDC) locus on chromosome 1q21 are
associated with the risk of AD.
▸ The most important and widely studied gene at this locus is the filaggrin gene
(FLG).
▸ Others include the genes for loricrin, S100 proteins, proteases (stratum corneum
tryptic enzyme—SCTE, and stratum corneum chymotryptic enzyme—SCCE),
antiproteases, tight junctions, and so on.
8. FILAGGRIN MUTATIONS AND AD
▸ Profilaggrin is the major
component of the keratohyaline
granules of the stratum
corneum, which is degraded to
produce filaggrin, which
isfurther proteolysed into
various amino acids.
9. FLG MUTATIONS
▸ The presence of the mutation predicts early onset of AD, a worse prognosis, and
persistence of the disease into adulthood.13
▸ Patients with the mutation also have an increased tendency for eczema
herpeticum, early sensitization, multiple allergies (including peanut allergy) and
asthma.1
▸ FLG mutations are also implicated in the pathogenesis of ichthyosis vulgaris, a
disorder that is closely linked to, and often associated with AD.
10. ETIOPATHOGENESIS - GENETICS OF AD - ADAPTIVE AND
INNATE IMMUNE RESPONSE GENES
▸ Candidate genes in this category include those encoding CD14 (a pattern
recognition receptor for lipopolysaccharide— LPS—present on monocytes,
macrophages, and neutrophils), IL-4, IL-5, IL-13, toll-like receptors, pattern
recognition receptors, regulated on activation, normally T-expressed, and
presumably secreted (RANTES)—a chemotactic factor for eosinophils, and so on.
▸ These genes are involved in antigen presentation, cell-mediated and humoral
immune response, and cell signaling/movement in the skin.
11.
12. ETIOPATHOGENESIS - IMMUNE DYSREGULATION
IN AD
▸ Some of the defects in the systemic and cutaneous immune system6,17,18 that occur in
AD include the following:
1. Increased Th2-derived cytokine activity
2. Increased number of T-cells expressing cutaneous lymphocyte-associated
antigen (CLA)—the homing receptor for the skin.
3. Increased numbers of regulatory T-cells (Tregs) in the peripheral blood—these
cells normally inhibit antigen-specific Th2 responses.
4. Increased total and specific serum IgE levels and sensitization to various
environmental allergens.
5. Decreased expression of antimicrobial peptides.
6. Increased thymic stromal lymphopoietin (TSLP)
13. ETIOPATHOGENESIS - MICROBIAL COLONIZATION
IN AD
▸ Patients with AD have an increased susceptibility to a number of infections.
Infections in AD may be considered under the following headings:
1. Bacterial Infections
2. Viral Infections
3. Role of Malassezia
14. ETIOPATHOGENESIS - MICROBIAL COLONIZATION
IN AD - BACTERIAL INFECTIONS
▸ A number of factors such as epidermal barrier defects, reduction in antimicrobial
peptides, decreased recruitment of neutrophils to the skin, toll-like receptor
defects, and increased IgE levels contribute to increased bacterial colonization of
atopic skin.
▸ Methicillin resistant Staphyllococcus aureus infections are becoming more
common in AD, especially since these children are often treated with extended
courses of antistaphylococcal antibiotics.
15. ETIOPATHOGENESIS - MICROBIAL COLONIZATION
IN AD - VIRAL INFECTIONS
▸ A subset of patients with AD are particularly susceptible to herpes simplex virus
infections, with eczema herpeticum occurring in 10%–20% of atopics.
▸ Patients with AD are also at increased risk for molluscum contagiosum infections,
which can be severe and disfiguring at times.
16. ETIOPATHOGENESIS - MICROBIAL COLONIZATION
IN AD - ROLE OF MALASSEZIA
▸ Malassezia spp. are capable of activating mast cells, and inducing the production
of Malassezia specific IgEs, thereby contributing to inflammation in AD.
▸ Patient with AD lesions on the head, neck and upper trunk tend to respond well to
anti-Malassezia measures
17. ETIOPATHOGENESIS - HYGIENE HYPOTHESIS
▸ This hypothesis indicates that lack of microbial stimulation in the newborns’
immune system due to hygienic environment in modern societies has resulted in
lack of signals diverting Th2 responses to regulatory and Th1 responses.
▸ A systematic review on this subject24 has shown that, among the infections
encountered in childhood, helminths, in particular, hookworm and
schistosomiasis, can protect against the development of AD, especially if such
exposures occur during pregnancy, while bacterial and viral infections confer no
protection.
18. ETIOPATHOGENESIS - ROLE OF ALLERGENS
▸ A number of environmental and other factors are known to worsen AD. These
are listed below:
a. Changes in temperature
b. Sweating
c. Decrease in humidity
d. Contact with irritants (wool, chemicals, cosmetics, soaps, cigarette smoke)
e. Aeroallergens (house dust mite, pollen, molds, pet dander, human dander)
f. Food allergens (eggs, peanuts, milk, fish, soy, wheat)
g. Emotional stress and
h. Hormones (menstrual cycle and pregnancy).
19. ETIOPATHOGENESIS - ROLE OF ALLERGENS -
FOOD ALLERGENS
▸ Food allergies are broadly divided into those that are mediated by IgE antibodies and
those that are not.
▸ The IgE-mediated allergies usually manifest as acute phenomena such as urticaria,
angioedema, anaphylaxis, immediate gastrointestinal hypersensitivity, and oral allergy
syndrome.
▸ 90% of food allergies in AD occur after exposure to the following six foods—milk, eggs,
fish, wheat, soy, and peanut.
▸ AD have a higher prevalence of IgE-mediated food allergy, estimated at around 35%.
20. ETIOPATHOGENESIS - ROLE OF ALLERGENS -
AERO ALLERGENS
▸ Certain aeroallergens such as house dust mite, pollen, molds, and animal dander
can cause exacerbations of eczema.
▸ Especially in older children (>5 years) with severe AD, a house dust mite (HDM)
allergy is frequently detected by skin prick testing or the presence of specific IgE
in serum.
▸ The severity of AD has been correlated with the degree of sensitisation to
aeroallergens.
22. INFANTILE PHASE (BIRTH TO 2 YEARS)
▸ Infants often present with acute
lesions.
▸ Poorly defined erythema with
edema, vesicles, excoriations, and
serous exudate.
▸ Typically involves the face and
extensor surfaces of the limbs.
▸ The trunk might be affected but the
nappy area is typically spared.
23. CHILDHOOD PHASE (2–12 YEARS)
▸ Eczema becomes more localised and
chronic than in infancy.
▸ Paler erythema, dry skin (xerosis),
poorly defined lesions.
▸ Commonly affecting flexor surfaces
with thickening (lichenification) of
chronic areas.
24. ADULT PHASE (12 YEARS TO ADULT)
▸ Adolescents and adults usually have
diffuse eczema.
▸ They can also have localised lesions
typically affecting hands, eyelids and
flexures.
▸ Adults can have chronic hand eczema
only or head- neck dermatitis as well,
involving the upper trunk, shoulders and
scalp.
25. DIAGNOSIS OF AD
▸ In 1980, major and minor criteria for a diagnosis of AD were proposed by Hanifin
and Rajka which is considered to be the “gold standard” for the clinical diagnosis
of AD.
▸ Three of 4 major criteria and three of 23 minor criteria are required for a diagnosis
of AD.
32. INVESTIGATIONS
▸ The classical tests for IgE-mediated hypersensitivity are the skin prick test and RAST
(radio allergosorbent test for specific IgEs in the blood).
▸ For food allergies, the double-blind placebo-controlled food challenge (DBPCFC) is
considered to be the gold standard, while the APT(atopy patch test) is preferred for
aeroallergens such as house dust mite, pet dander and pollen.
▸ Negative IgE tests (skin prick and RAST) help to rule out rather than diagnose
allergies, while positive IgE tests may not always be relevant. The results of the IgE
tests are interpreted in conjunction with APT and oral food challenges.
▸ Test results should be interpreted in conjunction with the history and clinical
relevance in an individual patient.
33. INVESTIGATIONS - ATOPY PATCH TEST
▸ The APT essentially helps to identify delayed type hypersensitivity reactions to allergens, most
commonly aeroallergens, and sometimes food allergens (delayed reactions) as well.
▸ The mechanism involved is allergen-specific IgE-mediated activation of Langerhans cells (carrying
IgE receptors) in the skin by aeroallergens, which in turn cause stimulation of allergen-specific T-
cells, leading to the development of eczematous skin lesions at sites of contact.
▸ The test involves epicutaneous application of allergens (e.g., house dust mite, cat dander, pollen)
in a petrolatum base on the back, using Finn chambers. Readings are taken at 48 and 72 hours,
and positive results are graded from + to ++++, based on the presence of erythema, papules, and
vesicles.
▸ Patients who give a clear history of worsening of skin lesions after encountering aeroallergens tend
to have a higher positivity rate with APT.
34. FOOD ALLERGY
▸ Food allergies relating to AD is commonly found in children < 5 years of age.
▸ The Food allergy test may be considered in children with moderate to severe AD
who do not respond well after proper treatment.
▸ 1/3rd of children with AD who tests positive for food allergies do not have clinical
symptoms after sensitisation.
36. MANAGEMENT OF AD
▸ The Aims of AD treatment are. -
a. Reduce symptoms (pruritus and dermatitis)
b. Prevent exacerbations
c. Optimise treatment to prevent therapeutic risks
37. TREATMENT OF AD
▸ Treatment plans need to be
individualized and adherence to
treatment regimens need to be
stressed in order to achieve
optimal outcomes.
40. TREATMENT OF AD - EMOLLIENTS
▸ It hydrate the stratum corneum, reduce transepidermal water loss, and even
reduce pruritus and inflammation, thereby decreasing the requirement for topical
steroids/immunomodulators.
▸ Most traditional emollients contain nonphysiologic lipids, such as petrolatum,
lanolin mineral oil, and silicone.
▸ Urea-based creams are also effective for xerosis, but may cause stinging.
41. TREATMENT OF AD - ANTIHISTAMINES
▸ The itch of AD is notoriously resistant to the action of antihistamines, but these
agents may still need to be used, particularly those belonging to the sedating
class (promethazine, hydroxyzine, etc.), in order to produce sedation and thereby
break the vicious “itch-scratch” cycle.
▸ It should be kept in mind that antihistamines can cause paradoxical stimulation
rather than sedation in infants.
42. TREATMENT OF AD - TOPICAL ANTI-
INFLAMMATORY AGENTS - TOPICAL STEROIDS
▸ Topical corticosteroids are widely endorsed as the first line anti inflammatory
treatment.
▸ Twice daily application on affected areas is recommended.
▸ Local side effects -
> Skin Atrophy. > Telanglectasias
> Purpura > Dyspigmentation
> Striae > Facial acneiform changes
▸ Systemic Side effects -
> Hypothalamic-pituitary-adrenal suppression
> Growth retardation
45. TREATMENT OF AD - TOPICAL ANTI-INFLAMMATORY
AGENTS - TOPICAL CALCINEURIN INHIBITORS
▸ TCIs are immunomodulatory agents, which suppress antigen-specific T-cell activation and
reduce the production of pro-inflammatory cytokines.
▸ Topical calcineurin inhibitors
> Tacrolimus 0.03% and 0.1% ointment
> Pimecrolimus 1% cream
▸ Tacrolimus 0.03% ointment and pimecrolimus 1% cream are approved for use in children
older than 2 years. Tacrolimus 0.1% is indicated in children older than 15 years and adults.
▸ Equal to or less effective than moderately potent topical corticosteroids
▸ Advantages -
> No skin atrophy > Useful at susceptible sites ( face, intertriginous areas )
▸ Disadvantage
> Side effects are burning and pruritus > High cost
46. TREATMENT OF AD - TREATMENT OF BACTERIAL
INFECTIONS
▸ The high rate of S. aureus colonization in AD often tempts clinicians to attempt
protracted decolonization procedures using topical and systemic antibiotics.
▸ Clinical signs of bacterial impetiginization (oozing, crusting, pustules, and fissures)
warrant the use of systemic antimicrobials such as first generation cephalosporins
(cephalexin, cefadroxil), amoxicillin/clavulanate, or dicloxacillin for 7–10 days.
▸ Second line agents include macrolides (erythromycin, azithromycin) and clindamycin.
▸ Recently, silver-impregnated textiles and antimicrobial silk fabrics have been shown to
reduce staphylococcal colonization in AD.6
47. SYSTEMIC TREATMENT
▸ Systemic agents include immunomodulatory agents (systemic steroids, cyclosporine,
azathioprine, mycophenolate mofetil, methotrexate) and phototherapy.
▸ Cyclosporine is one of the most commonly used systemic agents for AD, in a dose of
3–5 mg/kg/day, with total duration of treatment being ideally limited to 1 year.
▸ In the United Kingdom, azathioprine is the steroid-sparing agent of choice in the
treatment of AD.52 It is used in a dose of 2.5–3.5 mg/kg/day.
▸ Mycophenolate mofetil has also shown good results in AD, with a better side effect
profile than most other immunosuppressive agents. Methotrexate is used in some
centers as maintenance treatment for severe AD in adults, once the acute flare has
subsided.
48. PHOTOTHERAPY
▸ All forms of phototherapy, including broadband UVB, narrow band UVB, PUVA,
and UVA1 have been tried and found to be effective in AD, for long-term
maintenance treatment, in conjunction with topicals.
▸ UV light has potent inhibitory effects on antigen presentation by Langerhans
cells, T-cell activation, and cytokine production by keratinocytes.
▸ NBUVB is better tolerated than PUVA, and is preferable, especially in children.
49. OMALIZUMAB
▸ Omalizumab is an anti-IgE recombinant humanized monoclonal antibody that
blocks the Cε3 receptor of IgE. It thereby prevents serum IgE from attaching to
high affinity FcεR1 receptors on mast cells and other immune cells and the
subsequent IgE mediated inflammatory changes.
▸ used in several countries for the treatment of moderate to- severe asthma in
patients older than 6 years, who are not adequately controlled with regular
antiasthma medications.
50. PROBIOTICS
▸ Lactobacilli and Bifidobacteria are gut microorganisms hypothesised to educate
the neonatal immune system by converting the Th2-biased prenatal responses
into balanced immune responses.
▸ The symbiotic flora in the gut (e.g., Lactobacillus) also function as probiotics, by
modulating the immune response in the gut-associated lymphoid tissue (GALT).
51. IMMUNOTHERAPY
▸ Specific allergen immunotherapy (SIT) is effective in certain disorders such as
allergic rhinitis/conjunctivitis, asthma, and insect sting hypersensitivity.
▸ Allergens are administered either subcutaneously or sublingually, in several
sittings, with gradually escalating doses over a period of months to years,
followed by maintenance therapy.
54. ▸ Dupilimab - It is a monoclonal antibody that targets IL-4 receptor alpha subunit,
eventually blocking the signaling of IL-4 and IL-13, the two cytokines which a play a
key role in AD .
A recent meta analysis concluded that dupilumab is more efficacious in the initial 4
months of therapy in controlling adult AD than methotrexate or azathioprine and is
comparable to cyclosporine given at a higher dose of more than 3 mg/kg/ day.
However, an improvement in EASI (eczema area and severity index) score of over
90% was observed in <40% of AD patients treated with dupilumab.
INTERLEUKIN (IL)-4 AND IL-13 INHIBITORS
55. ▸ Tralokinumab - It targets IL-13, a cytokine which is preferentially expressed in
keratinocytes . Upregulation of IL-13 has been consistently documented in the
lesional skin of AD patients.
▸ Lebrikizumab - It is a more selective inhibitor of IL-13
56. JAK INHIBITORS
▸ Tofacitnob - Oral tofacitinib was tested in patients older than 18 years with AD. An
improvement was noticed from week 4 onward. SCORAD (SCORing atopic
dermatitis) index was reduced by 58% at week 14. This was accompanied by a
significant decrease in pruritus score by 69.9%.
▸ Baricitinib - The broad ranging activity of baricitinib was effective in relieving
pruritus, which was noticeable within 2 days of use in adult AD patients.
▸ Ruxolitinib - Itch relief was obtained within 36 hours of twice daily application of
ruxolitinib 1.5% as a cream in adults older than 18 years and the effect remained
till the end of the study period of 12 weeks.
57. PHOSPHODIESTERASE INHIBITORS
▸ Crisaborole - It is an inhibitor of phosphodiesterase (PDE) 4, a cyclic AMP degrading
enzyme expressed in monocytes, lymphocytes, endothelial cells, and smooth muscle
cells. Improvement in disease severity was seen as early as day 8 of therapy with
crisaborole. However, application site pain developed in 5 out of 10 adults who applied
crisaborole over face
▸ Apremilast - It is an oral PDE inhibitor which failed to show a clinically meaningful
response in a recently conducted phase 2 trial in AD patients, when used at a dose of 30
mg twice a day
