Atopic Dermatitis:Atopic Dermatitis:

TherapeuticTherapeutic

ChallengesChallenges

PDA August 14, 2009

Jon Hanifin

OHSU, Portland

Dominant Concepts inDominant Concepts in

Atopic DermatitisAtopic Dermatitis

• Allergy / Immunology Era: 1915-2006

• The Epidermal Era: 2006----

� Barrier dysfunction

� KC / immunocyte interactions

� Innate immunity

1/5/82: It’s a

barrier problem!

Hydration protects!

The BarrierThe Barrier

ConceptConcept

Outside-in

Pathogenesis

IchthyosisIchthyosis

vulgarisvulgaris——FF

ilaggrinilaggrin

nullnull

mutationsmutationsPalmer, NaturePalmer, Nature

Genetics 2006Genetics 2006

Figure 1 Skin barrier function and allergic risk. An intact epithelial barrier (a) prevents

allergens from reaching antigen-presenting cells (APCs) in subepithelial tissues. Damage to

this barrier (b) allows allergens to penetrate into the subepidermal layer and interact with

APCs, leading to allergic sensitization and, secondarily, to allergic manifestations in the host.

Hudson TJ: Nat Gen 38(4):399-400, 2006

Treat the barrier--Treat the barrier--EarlyEarly

• The clinical presence of ichthyosis can

predict patients/families with:

� Allergic respiratory disease

� A more severe AD phenotype

� Early onset AD

AllergyAllergy

Atopic Dermatitis andAtopic Dermatitis and

AllergyAllergy

•AD is not an IgE-mediated

disease

•AD is not an allergic skin disease

•AD is a skin disease which

predisposes to allergies

Define Food AllergyDefine Food Allergy

• An adverse health effect that results from

stimulation of a specific immune response

• No immediate clinical reaction? Not

allergy!

• Eczema ups & downs diagnosed as

allergy are almost always wrong

Misdiagnosing Eczema asMisdiagnosing Eczema as

Food AllergyFood Allergy

• Positive allergy test— only a test!!!

• Allergy is an immediate clinical

reaction--by history or challenge

• Diet restriction--no challenge, no proof

• Skin care diverted to allergy search--

eczema continues

Allergy and AD:Allergy and AD:A more balanced perspective is needed forA more balanced perspective is needed for

parentsparents…… and pediatricians and pediatricians

• AD and ichthyosis promote IgE

production.

• Allergic reactivity is secondary

to barrier dysfunction.

•We now recognize the potential

to modulate / prevent allergic

diseases with barrier care.

AD in Teenagers AD in Teenagers

• “Rebelling out” is a way of life

• Non-compliance is assumed

• Magical thinking must be replaced

by reality

• Systematic care

� The teen’s lowest priority

� Negotiate to find room on a full

schedule

AD ManagementAD Management

Considerations in TeenagersConsiderations in Teenagers

• Sideline parents to consulting role

� Calls and appts initiate with teen

� Parent in room only at start and end

� Offer counseling

• Lower the threshold for considering

systemic therapy (e.g. CsA, MTX)

Adult Onset ADAdult Onset AD

• Rare in temperate climates

• Can follow move from tropics

• Might signal

� Allergic contact dermatitis

� Lymphoma

• Always consider biopsy

(JAAD 2005, 52: 579-82

BJD 2006, 155:557-60)

Adult-onset recalcitrantAdult-onset recalcitrant

eczema: A possible markereczema: A possible marker

for lymphoma or leukemiafor lymphoma or leukemia

Callen, JP, et.al. JAAD 2000,

43:207-10

Hand Eczema & EyelidHand Eczema & Eyelid

DermatitisDermatitis

• ACD or AD?—AD much more

frequent cause

• Treat first; patch tests if

recalcitrant

• Calcineurin inhibitors crucial for

control of AD eyelid problems

Case Finding for AdultCase Finding for Adult

Onset ADOnset AD

• Sensitive skin?

• Infant or early childhood eczema?

� Adult can’t recall mild/mod disease

� Maybe only manifest in winter

� Parents needed for history

� ?Food allergy

• Mime the itch—scratch antecubitals/popliteals

NACDG Patch Test tray negative

30 yo Asian/American man30 yo Asian/American man

• Flaring of chronic AD with lichenification,

pigmentation and itch—using only Cetaphil cr

• Similar presentation 3 yrs ago; responded

well to topicals steroids and CI’s

• Stopped all medications because of warnings

� Hesitant to restart

� Especially concerned about steroid near eyes

� Hates ointments

Discussion/NegotiationDiscussion/Negotiation

• Why flaring? Winter?, out of meds?

?depressed

• Options

� Topicals safer than systemics

� Potent steroids needed for lichenified lesions

• No danger from short-term, aggressive use

• Evaluate each week—phone or clinic

RegimenRegimen

• Betamethasone ung (1#) b.i.d after

20 minute tub bath for 1 week

• Only 3-4 days on face, then TCI

• Call 1 wk—plan taper to qd x 1 wk,

then qod, then goal: twice weekly

Obstacles to EffectiveObstacles to Effective

Management of ADManagement of AD

• Temerity (physician & patient) in

using topical steroids

•Confusion and compliance issues

•Proper topical care diverted by

allergy-seeking behavior

Common Glitches inCommon Glitches in

Prescribing Topical SteroidsPrescribing Topical Steroids

• Confusing when more than one steroid prescribed

initially (triamcinolone 0.1% safe on face bid x 3d;

then biw)

• Failing to hydrate before topical medication

• Dilution (mixing steroid + emollient or TCI) reduces

drug effect

• Vehicle—creams can’t compete

• Size matters!!! Small tubes cause recurrent flares

Impact of Topical Calcineurin InhibitorsImpact of Topical Calcineurin Inhibitors

• Effective anti-inflammatory to follow

corticosteroids

• Safe (hopefully long-term) maintenance

for prolonged therapy

• More efficient management of AD

patients:

� Increased optimism with good control

� Reduced concern about allergy

� Potential to reduce later allergy

Barrier Maintenance Devices:Barrier Maintenance Devices:

Atopiclair, Epiceram, MimyX Atopiclair, Epiceram, MimyX

• For maintenance over co-existing

skin cancer areas

• For steroid over-indulgers

•Recurrent infection sites

• For steroidophobics

• For the well-insured

Newer Topical SteroidNewer Topical Steroid

ProductsProducts

• Desonate—0.05% desonide in hydrocolloid gel *

• Verdeso--0.05% desonide foam *

• Olux-E—0.05%clobetasol in emollient foam

• Cutivate—0.05% fluticasone lotion

• Vanos--0.1% cream

*These and fluticasone cream approved for infants

as young as 3 months

Unsupported TherapiesUnsupported Therapies

used in ADused in AD

• Antihistamines

• Cromolyn

• Leukotriene inhibitors

• “Allergy shots” (aka “immunotherapy”)

• Probiotics

• Borage/Evening Primrose oils

• Herbals

• Anti-IgE

Systemic Therapy of ADSystemic Therapy of AD

• Cyclosporin A

• Antibiotics

• Gamma interferon

• Methotrexate*

• Azathioprene

• Mycophenolate

mofetil*

• Systemic steroids

• IVIg*

• Leukotriene inhibitors**

• Antihistamines**

• Anti-IgE (Xolair)**

• Thalidomide*

* No Randomized Clinical Trials

** RCT’S show no benefit

Biologic agents for ADBiologic agents for AD

!Will they be effective for AD?

!Are they safe?

!Which might show efficacy?

!Interferon-gamma

!Omalizumab and rituximab