Update on Atopic DermatitisLucretia Adina Frasin & Carlo Gelmetti

AD: an overview

Ch i i fl t di ith

AD: an overview

• Chronic inflammatory disease with no known cure1,2

• Both genetic and environmental causes1

• Intensely pruritic1

Relapsing/remitting co rse often diffic lt• Relapsing/remitting course, often difficult to treat1

1. Darsow U, et al. J Eur Acad Dermatol Venereol 2010; 24:317–328;2. Alomar A, et al. Br J Dermatol 2004; 151 (Suppl. 70):3–27.

AD: a definition of termsAtopic

• = atopy /at·o·py/ (at´ah-pe) a genetic predisposition toward the development of immediate hypersensitivity reactions against common environmental antigens (atopic allergy), most commonly manifested as allergic rhinitis but also as bronchial asthma atopic dermatitis or food allergybronchial asthma, atopic dermatitis, or food allergy. (Dorland’s 2007)

• A state of ↑ sensitivity to common antigens - eg, house dust, animal dander, pollen, with ↑ production of allergen-specificanimal dander, pollen, with ↑ production of allergen specific IgE; …(McGraw-Hill Concise Dictionary of Modern Medicine. 2002)

AD: a definition of termsAD: a definition of terms

• Dermatitis = inflammation of the skin (= eczema)( eczema)

AD Classification - 1980 (Brunello Wuthrich)

Atopic Dermatitis

ExtrinsicExtrinsicADAD

IntrinsicIntrinsicADAD

==Raised IgERaised IgE

==Normal IgENormal IgE

More frequently More frequently linked with otherlinked with otherlinked with otherlinked with otherallergic diseasesallergic diseases

Classification EAACI, 2001The Atopic Eczema/Dermatitis Syndrome = AEDS

AEDS

The Atopic Eczema/Dermatitis Syndrome AEDS

AEDS

All i AEDS N ll i AEDSAllergic AEDS Nonallergic AEDS

IgE-associated AEDS Non-IgE-associated AEDS

Johansson SG. A revised nomenclature for allergy. Allergy 2001;56:813-24.

2004

Intrinsic ADExtrinsic AD

J Allergy Clin Immunol 2004;113:832-836

How atopic is AD?

• A systematic review was undertaken of

o atop c s

A systematic review was undertaken of studies in children with AD in hospital and community populations measuring specificcommunity populations, measuring specific and non-specific IgE1

1• Atopy is clearly associated with AD1

• However, up to 2/3 of people with AD may , p p p ynot be immunologically atopic2

1. Flohr C, et al. J Allergy Clin Immunol 2004; 114:150–158;2. Cork MJ, et al. J Allergy Clin Immunol 2006; 118:3–21.

AD in evolution: an hypothetic path

2008

E l i f

Intrinsic ADEarly infancy

IgE sensitization

Extrinsic ADg

Autoallergic ADAutoantigens sensitizationsg

Bierber T. N Engl J Med 2008 358;14: 1483-94

Prevalence of AD has steadily increasedy• Prevalence of AD has risen progressively since 1940s1-4

3027 3

30.8 Australia4

35

Denmark3

(%)

20

25

27.3 Australia

15

Chi

ldre

n (

12.2 11.9New Zealand1

20 17.3

Denmark316.7

5

105.1

7.3British birth cohort studies1

4.45.6

8.3

3.1USA1

Western1

Sweden1

UK1

19450

1975Year of birth (median1/mean3,4)

UK1 USA1 Australia1

1965 199519851955

1. Taylor B, et al. Lancet 1984; 2:1255–1257; 2. Diepgen TL. Is the prevalence of atopic dermatitis increasing?In: Atopic Dermatitis, 2000. Ed: Williams HC. Cambridge: Cambridge University Press;

3. Stensen L, et al. Allergy Asthma Proc 2008; 29:392–396; 4. Foley P, et al. Arch Dermatol 2001; 137:293–300.

( )

Reasons for increasing prevalence of ADReasons for increasing prevalence of AD

• Geographical location• Western lifestyle factors: socio-economic

status, family size, y• Diminished exposure to infection/infestations• Environmental triggers

Diepgen TL. Is the prevalence of atopic dermatitis increasing? In: Atopic Dermatitis, 2000. Ed: Williams HC. Cambridge: Cambridge University Press.

Irritants and allergens are key environmental triggersenvironmental triggers

Irritants AllergensSoaps/detergents1 Foods, e.g. milk, eggs, p gHeat and sweatingAbrasive clothing2

g ggpeanuts, wheat, soy, fish2

House dust mites1gPerspiration1

Chemicals1

Weeds1

Animal dander1

Smoke1

Chlorine1

Mould1

Pollen3Chlorine

1. Leung DY & Bieber T. Lancet 2003; 361:151–160; 2. Boguniewicz M, et al. J Allergy Clin Immunol 2003;

112 (6 Suppl.):S140–150; 3. Fleischer AB. Postgrad Med 1999; 106:49–55.

Determinants of AD: population-based cross-sectional study in Germanyy y

Methods: Data from a nationwide cross-sectional representative survey conducted between 2003 and 2006 including 17 641survey conducted between 2003 and 2006 including 17,641 children aged 0-17Results: The weighted prevalence of ever physician-diagnosedResults: The weighted prevalence of ever physician-diagnosed AD was 13.2%. Significant positive associations of parental allergies, parent-reported infection after birth and parent-g , p p preported jaundice after birth were revealed. Being a migrant and keeping a dog showed significant inverse associations with AD. Other lifestyle (alcohol consumption during pregnancy) and

f ( fenvironmental factors (mould on the walls, pets, origin from East/West Germany) were not significantly related to AD.

Apfelbacher CJ et al. Allergy. 2011;66:206-13

Meta-analyses of epidemiological studies demonstrate a correlation between specific ambient exposures and a p preduction in allergic risk during childhood

Tse K. Horner A. Allergen tolerance versus the allergic march: The hygiene hypothesis revisited. Curr Allergy Asthma Rep. 2008 ;8:475–483

The hygiene hypothesisThe hygiene hypothesis

Children raised on farms are less likely to develop allergic diseases than children raised in cities

AD has both genetic and environmental origins• AD has a complex, multifactorial aetiology arising from

gene-gene and gene-environment interactionsg g g• Changes in genes related to skin barrier function,

combined with exposure to environmental triggers, b t ti ll i i k f ADsubstantially increase risk of AD

Dermatitis

gger

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etc

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Healthy skin

Genetic disposition to a defective skin barrier

Cork MJ, et al. J Allergy Clin Immunol 2006; 118:3–21.

AD has a strong genetic componentAD has a strong genetic component

• Two major groups of genes implicatedg p– Genes encoding major

elements of immuneelements of immune systemGenes encoding– Genes encoding epidermal or other epithelialepithelial structural proteins

Bieber T. N Engl J Med 2008; 558:1483–1494

AD: causality

• Long-standing debate regarding causality of AD

Outside-inside hypothesis?Skin barrier dysfunction enables allergen penetration leading toSkin barrier dysfunction enables allergen penetration, leading to

cytokine production, inflammation and disease flares1

ORInside-outside hypothesis?

Inflammatory response to irritants/allergens drives

OR

More recently the pathophysiology has been found to involve

Inflammatory response to irritants/allergens drives skin barrier dysfunction1

• More recently, the pathophysiology has been found to involve genes encoding BOTH skin barrier proteins such as filaggrinAND components of the immune system2

1. Elias PM, et al. Am J Contact Dermat 1999; 10:119–126; 2. Bieber T. N Engl J Med. 2008; 358:1483–1494.

A defective epidermal barrier is a poor permeability barrier, which permits the entry of allergens and the , p y gloss of moisture.

H2O

Defective id lepidermal

barrierSubclinicalSubclinical inflammation

Cork MJ, et al. J Invest Dermatol 2009; 129:1892–1908.

AD: immune dysfunction underlies the pathobiology and etiologypathobiology and etiology

Distorted adaptive immunity

Impairedinnate immunity adaptive immunityinnate immunity

Viral skin infection

Protein allergen sensitisationT cell responseIgE productionAutoimmunity

Bacterial colonisationAutoimmunity

Hereditary skin barrier defect Dry and scaly skin

Facilitated penetration

Wollenberg A. Clin Rev Allergy Immunol. 2007;33:35-44

Facilitated penetrationof water and protein

Inflammatory cascade of AD: explaining the itch scratch cycleexplaining the itch-scratch cycle

1. Scratching triggers 4. Chronic itching ensues and the

Patientscratches

Chronicitching

keratinocytes to release an array of cytokines and

chemokines

cycle begins again

scratchesitching

Cytokines released from Increased

i fl ti keratinocytesinflammation

2. Cytokines/chemokines activate antigen-presenting cells and cause the

differentiation of Th0 cells, which in turn causes additional cytokines to be produced

3. These cytokines lead to skin inflammation in a similar manner to allergen induced flares

Kang K & Stevens SR. Clin Dermatol 2003; 21:116–121;Leung DY & Bieber T. Lancet 2003; 361:151–160.

additional cytokines to be producedto allergen-induced flares

AD in evolution: an hypothetic path

2008

E l i f

Intrinsic AD Sensitization toself proteinsEarly infancy self proteins

IgE sensitization

Extrinsic ADg

Sensitization Autoallergic AD

Autoantigens sensitizations

Se s t at oto allergens

g

Bierber T. N Engl J Med 2008 358;14: 1483-94

Diagnosing AD

There is no gold t d d f d fi itstandard for a definite

diagnosis!!

Chronic itching is

g

Chronic itching is key to diagnosing AD

Common differential diagnoses of AD

AdultsChildrenInfants

Nummular dermatitis2

Scabies1,2

Seborrheic dermatitis1,2

Contact dermatitis (allergic)2

P i i 2

Contact dermatitis (irritant)2

Molluscum dermatitis2

Perioral dermatitis2

Psoriasis2

Tinea corporis2

Immunodeficiencies1,2

Ichthyoses2

Immunodeficiencies1,2

Malignancies e.g. cutaneous T cell l h (CTCL)1 3

Metabolic disorders e.g. zinc deficiency2

1. Eigenmann PA. Pediatr Allergy Immunol 2001; 12 (Suppl. 14):69–74;2. Krol A & Krafchik B. Dermatologic Therapy 2006; 19:73–82;

3. Leung DYM & Bieber T. Lancet 2003; 361:151–60.

lymphoma (CTCL)1,3

European Task Force on Atopic Dermatitis/EADV Eczema Task Force

Darsow U Wollenberg A Simon D Taïeb A Werfel T Oranje A Gelmetti CDarsow U, Wollenberg A, Simon D, Taïeb A, Werfel T, Oranje A, Gelmetti C, Svensson A, Deleuran M, Calza AM, Giusti F, Lübbe J, Seidenari S, Ring J

ETFAD/EADV eczema task force 2009 iti di i2009 position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol. 2010;24:317-28.;

Goals of management of AD

Sh t t t l f t t

Goals of management of AD

–Short-term control of acute symptoms–Long-term stabilisation flareLong-term stabilisation, flare

prevention and avoidance of side effects

“Atopic dermatitis is a chronic condition. The treatment has to be planned with a long-term perspective.”

Darsow U, et al. J Eur Acad Dermatol Venereol 2010; 24:317–328.

AD: a multifactorial disease requires a multifactorial approachmultifactorial approach

Basic skincare regimen to cleanse and hydrate the skin

and aid barrier repair1Appropriate anti-inflammatory

treatment1

Skin barrier f Patient/

Immune system

dysfunction Atopicdermatitis

Atopicdermatitis

Patient/parent/carer

education1

Emotional support1

dysfunction

Identification of triggers and their subsequent avoidance1

Behavioural modification2 or physical barriers3 to break the

1. Darsow U, et al. J Eur Acad Dermatol Venereol 2005; 19:286–295;2. Hoare C & Williams H. Health Technol Assess 2000; 4:1–191;

3. Leung DY & Bieber T. Lancet 2003; 361:151–160.

qitch-scratch cycle

Traditional stepwise flare treatment of AD1

Systemic therapy (e.g. Step 4: Recalcitrant, severe AD

y py ( gciclosporin A) or UV therapy

Mid–high potency TCS or TCI*

Step 3: Moderate to severe ADg p y

(TCI if AD not adequately responsive or intolerant to TCS)

Step 2: Mild to moderate ADLow–mid potency TCS or TCI*

(TCI if moderate AD not adequately responsive or intolerant to TCS)

Step 1: Dry skin onlyBasic treatment: skin hydration, emollients,

avoidance of irritants, identification and addressing of specific trigger factorsaddressing of specific trigger factors

1. Akdis C, et al. Allergy 2006; 61:969–987;2. Wollenberg A, et al. J Dtsch Dermatol Ges 2009; 7:117–121.

Over the age of 2 years. TCS = topical corticosteroid TCI = topical calcineurin inhibitor

*

Old paradigm: three steps of AD management

Step 3: Treatment of flares with TCS/TCI+ Education

Step 2: Identification and avoidance of allergens/triggers+ Education

Step 1: Complete emollient therapyStep 1: Complete emollient therapy+ Education

New paradigm: four steps of AD management

Step 4: Prevention of flares with TCS/TCI twice weekly+ Education

Step 3: Treatment of flares with TCS/TCI+ Education

Step 2: Identification and avoidance of allergens/triggers

+ Education

St 1

Step 2: Identification and avoidance of allergens/triggers+ Education

Step 1: Complete emollient therapy+ Education

Rationale for ongoing active management: non-lesional skin is not ‘normal’non-lesional skin is not normal

• Lesional skin is characterised by clinical inflammation (flare)• Non-lesional skin shows signs of sub-clinical inflammation betweenNon lesional skin shows signs of sub clinical inflammation between

flares, which progresses to clinical inflammation and recurrence of flares at irregular intervals

Inflammation (flare)

nn

Inflammation (flare)

amm

atio

nam

mat

ion

Lesional skin

ee o

f inf

laee

of i

nfla

Non-lesional

Deg

reD

egre Non-lesional

skin, sub-clinical inflammation

Non lesional

Sub-clinical inflammation

Wollenberg A & Bieber T. Allergy 2009; 64:276–278.Time

No inflammation

Time

No inflammation Non-lesional skin, no

inflammation

No inflammation

The final goal is to control subclinical inflammationinflammation

• Aim of active maintenance treatment is to prevent flares by p ycontinuously controlling sub-clinical inflammation, even after resolution of clinical signs of flare

Inflammation (flare)

nn

Inflammation (flare)Short-term induction therapy with intensive topical anti-inflammatory

+

amm

atio

amm

atio

Active maintenance treatment of previously affected areas in combination

with emollient therapy of entire skin

Lesional skin

+

ree

of in

flre

e of

infl with emollient therapy of entire skin

surface

Non-lesional

Deg

r

No inflammation

Deg

r

N i fl ti

skin, sub-clinical inflammation

Non-lesional No inflammation

Sub-clinical inflammation

Wollenberg A & Bieber T. Allergy 2009; 64:276–278.Time

No inflammation

Time

No inflammation skin, no inflammation

No inflammation

AD: EBM THERAPYAD: EBM THERAPY

1. Topical Corticosteroids2. Topical Calcineurin Inhibitors3 UV therapy3. UV-therapy4. Cyclosporine A4. Cyclosporine A5. Psychotherapy

Fukuie T, Nomura I, Horimukai K et al. Proactive treatment appears to decrease serum immunoglobulin-E levels in patients with severe atopic dermatitis.patients with severe atopic dermatitis. Br J Dermatol. 2010 Nov;163(5):1127-9.

• There were no serious AE in any of the pts during tx; 8 pts y p g ; p(32%) in the proactive tx group experienced fungal infection (2 pts in reactive group). Skin thinning and striae formation were not seen in any patients Hypertrichosis was suspected innot seen in any patients. Hypertrichosis was suspected in some pts before titration of frequency of topical CTS, but normalized when the frequency of topical CTS was decreased to twice a week or less.

• We used proactive tx for the management of severe AD and the serum IgE level appeared to decrease Continuous closethe serum IgE level appeared to decrease. Continuous close adherence to the proactive tx may suppress inflammatory cells and lower the serum IgE. Decrease of egg white- and milk-specific IgE was also seen, and may play an important role in alleviating food allergies.

• This is the first report to evaluate the effectiveness of proactive• This is the first report to evaluate the effectiveness of proactive therapy in reducing the serum IgE level.

Fig 1. Percentage changes of total IgE levels during the treatment. Baseline (just before the start of inpatient treatment) total IgE of each patient was determined as 100% I th ti th t t l I E l l d d b100%. In the proactive group, the total IgE level was reduced by our comprehensive treatment and IgE levels at 2 years after treatment commencement were significantly lower than in the reactive group. *Significant differences b t th t ft 2 (P < 0Æ01 M Whit U t t)between the two groups after 2 years (P < 0Æ01, Mann–Whitney U-test).

Fig 2. Changes in egg white- and milkspecific IgE levels after the start of treatment. Food-specific IgE levels in the patients in the proactive treatment group (bl li ) d d i ifi tl d i f ll N i ifi t d(blue line) decreased significantly during follow-up. No significant decreases were seen in the reactive treatment group patients (red lines). *Significant difference in Wilcoxon signed rank test.

Meurer M, Eichenfield LF, Ho V, Potter PC, Werfel T, Hultsch T. Addition of pimecrolimus cream 1% to a topical corticosteroid tx regimen in paediatric patients with severe atopic dermatitis: a randomized double-blind trialpaediatric patients with severe atopic dermatitis: a randomized, double-blind trial. J Dermatolog Treat. 2010 May;21(3):157-66.

• Pimecrolimus and topical corticosteroids combination tx may• Pimecrolimus and topical corticosteroids combination tx may provide an alternative tx for pts with severe AD.

• To assess the safety profile of pimecrolimus cream 1% (PIM) bi d i h fl i (F U) F U l i di icombined with fluticasone (FLU) versus FLU alone in paediatric pts

with severe AD. • Pts (n = 376) were randomized to a combination of PIM with FLU or ( )

vehicle plus FLU for 4 weeks. The primary outcome was the frequency of clinically relevant pre-defined adverse events (AEs).

• Erythematous rash was the only AE occurring more frequently in• Erythematous rash was the only AE, occurring more frequently in the combination group, while there were no noticeable differences in the frequency of other AEs. Efficacy variables were comparable b t th 2 A t d f t ti t lbetween the 2 groups. A trend for greater time to relapse was observed for the combination of PIM with FLU in pts who were clear at the end of tx, with a marked improvement in facial AD.

• In paediatric pts with severe AD the overall safety profile of PIM combined with FLU was similar to that of FLU alone.

Mandelin J, Remitz A, Virtanen H, Reitamo S. One-year treatment with 0.1% tacrolimus ointment versus a corticosteroid regimen in adults with moderate to severe atopic dermatitis: A randomized, g p ,double-blind, comparative trial. Acta Derm Venereol. 2010 Mar;90(2):170-4.

• A one-year, randomized, double-blind study was conducted in 80 pts with AD treated with tacrolimus (TAC) ointment or a corticosteroid (CTS) (hydrocortisone acetate 1% ointment for head ( ) ( yand neck, hydrocortisone butyrate 0.1% ointment for trunk and limbs) to compare efficacy and safety, and effects on Th2-reactivity.

• The study was completed by 36/40 pts in the TAC group and 31/40• The study was completed by 36/40 pts in the TAC group, and 31/40 pts in the CTS group. In both groups affected BSA, eczema area and severity index, and TEWL decreased at months 6 and 12. TAC was

i f ll ffi t th 6 d i th h d d ksuperior for all efficacy scores at month 6, and in the head and neck area at month 12. Recall antigen reactivity increased at month 12 in both groups. Adverse events were reported by 40/40 pts in the TAC, and by 34/40 pts in the CTS group.

• Long-term tx with topical TAC or a CTS regimen improves AD and recall antigen reactivity, suggesting an improvement in the Th1/Th2-recall antigen reactivity, suggesting an improvement in the Th1/Th2balance.

Chen SL, Yan J, Wang FS. Two topical calcineurin inhibitors for the treatment of atopic dermatitis in pediatric patients: a meta-analysis of randomized clinical trials.p p yJ Dermatolog Treat. 2010;21:144-56.

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus ointment and pimecrolimus cream for the treatment of AD inointment and pimecrolimus cream for the treatment of AD in pediatric patients.

METHODS: MEDLINE, Embase, the CNKI and Cochrane Library databases were searched up to December 2008databases were searched up to December 2008.

RESULTS: Twenty trials involving 6288 infants and children with AD met the inclusion criteria. More patients using tacrolimus had a good response than those in control groups including vehicle 1%good response than those in control groups including vehicle, 1% hydrocortisone acetate and 1% pimecrolimus.

• The effect difference between 0.03% tacrolimus and 0.1% tacrolimus ointments was not statistically significanttacrolimus ointments was not statistically significant

• The incidence of adverse events of tacrolimus ointment or pimecrolimus cream was similar to the vehicle. The major adverse

t b i d itevents were burning and pruritus. CONCLUSIONS: Both tacrolimus ointment and pimecrolimus cream

are safe and effective in the treatment of AD in pediatric patients. T li i t t i t i liTacrolimus ointments were superior to pimecrolimus cream.

Anti-pruritic therapy (Darsow/ Ständer/ Gieler)

• Itch is the most important clinical symptom• Itch is the most important clinical symptom in AD, with peculiar impact on emotional dimensions of perception as compared todimensions of perception as compared to other pruritic dermatoses like urticaria. C i it i AD l• Concerning pruritus accompanying AD, only few studies investigate the antipruritic effect

l I t t di it i t f thonly. In most studies, pruritus is part of the total symptom score using the EASI and SCORADSCORAD.

Specific antipruritic therapiesSpecific antipruritic therapies

1. Topical anesthetics2 Cannabinoid receptor agonist2. Cannabinoid receptor agonist3. Capsaicin4. Topical doxepin5 Topical mast cell stabilizers5. Topical mast cell stabilizers6. Opioid receptor antagonists 7. Selective serotonin reuptake inhibitors

Searing DA, Leung DY.Vitamin D in atopic dermatitis, asthma and allergic diseases. I l All Cli N th A 2010 30(3) 397 409Immunol Allergy Clin North Am. 2010;30(3):397-409

• This review examines the scientific evidence behind theThis review examines the scientific evidence behind the hypothesis that vitamin D plays a role in the pathogenesis of allergic diseases, along with a focus on emerging data regarding vitamin D and ADemerging data regarding vitamin D and AD.

• Elucidated molecular interactions of vitamin D with components of the immune system and clinical data regarding vitamin D deficiency and atopic diseases areregarding vitamin D deficiency and atopic diseases are discussed.

• The rationale behind the sunshine hypothesis, laboratory yp , yevidence supporting links between vitamin D deficiency and allergic diseases, the clinical evidence for and against vitamin D playing a role in allergic diseases, and g p y g g ,the emerging evidence regarding the potential use of vitamin D to augment the innate immune response in atopic dermatitis are reviewed. p

New therapeutic perspectives in ADNew therapeutic perspectives in AD

• PPAR (Peroxisome Proliferative-Activated Receptors) Activatorsp )

• Skin Protease InhibitorsS l ti Gl ti id R t• Selective Glucocorticoid Receptor Agonists (SEGRA)

• Chemokine Inhibitors

Complications of AD

Increased risk of manifestation

Other atopic conditions including asthma and allergic

rhinitis manifestationof autoimmune

states later in life8

rhinitis (atopic march)1

Increased susceptibility to skin infections Ocular complications:skin infections

• Bacterial infections, e.g. Staphylococcus aureus2

• Viral infections, e g herpes simplex virus3

Ocular complications: blepharitis,

keratoconjunctivitis, keratoconus, uveitis, subcapsular cataract, e.g. herpes simplex virus3

• Fungal infections, e.g. Malassezia furfur4

retinal detachment, ocular herpes simplex6,7

1. Weinberg EG. Curr Allergy Clin Immunol2005; 18:4–5; 2. du Vivier A. Dermatology In

Practice, 1990. London: Gower Medical Publishing; 3. Wollenberg A, et al. J Am Acad Dermatol 2003; 49:198–205;

4 Leung DY & Bieber T Lancet 2003; 361:151 160;

Reduced quality of life, e.g. sleep disturbance

ff i 4. Leung DY & Bieber T. Lancet 2003; 361:151–160; 5. Lewis-Jones S. Int J Clin Pract 2006; 60:984–992;

6. Garrity JA & Liesegang TJ. Can J Ophthalmol 1984; 19:21–24; 7. Carmi E, et al. Acta Derm Venereol 2006; 86:515–517;

8. Kokkonen J & Niinimäki A. J Autoimmun 2004; 22:341–344.

common, affecting physical/mental states,

behaviour, children’s growth5