Atopic Dermatitis Therapeutic Challenges

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					  Atopic Dermatitis:
     Therapeutic
     Challenges
         PDA August 14, 2009
               Jon Hanifin
            OHSU, Portland




      Dominant Concepts in
        Atopic 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 Barrier
 Concept
  Outside-in
 Pathogenesis
                                                                      Ichthyosis
                                                                      vulgaris—F
                                                                      ilaggrin
                                                                      null
                                                                      mutations
                                                                      Palmer, Nature
                                                                      Genetics 2006




                  Hudson TJ: Nat Gen 38(4):399-400, 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.
    Treat the barrier--Early

• The clinical presence of ichthyosis can
 predict patients/families with:
    Allergic respiratory disease
    A more severe AD phenotype
    Early onset AD




          Allergy
    Atopic Dermatitis and
           Allergy
• 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 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 as
          Food 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:
A more balanced perspective is needed for
       parents… 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
• “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 Management
      Considerations 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 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 recalcitrant
eczema: A possible marker
 for lymphoma or leukemia


Callen, JP, et.al. JAAD 2000,
 43:207-10
     Hand Eczema & Eyelid
          Dermatitis
• 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 Adult
             Onset 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 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/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




                 Regimen

  • 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 Effective
       Management of AD
• Temerity (physician & patient) in
 using topical steroids
• Confusion and compliance issues
• Proper topical care diverted by
 allergy-seeking behavior
    Common Glitches in
Prescribing 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 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:
    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 Steroid
             Products
•   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 Therapies
            used in AD
•   Antihistamines
•   Cromolyn
•   Leukotriene inhibitors
•   “Allergy shots” (aka “immunotherapy”)
•   Probiotics
•   Borage/Evening Primrose oils
•   Herbals
•   Anti-IgE
      Systemic Therapy of AD
• Cyclosporin A      •   Systemic steroids
                     •   IVIg*
• Antibiotics        •   Leukotriene inhibitors**
• Gamma interferon   •   Antihistamines**
                     •   Anti-IgE (Xolair)**
• Methotrexate*      •   Thalidomide*
• Azathioprene
• Mycophenolate      * No Randomized Clinical Trials
                     ** RCT’S show no benefit
 mofetil*




       Biologic agents for AD

  !Will they be effective for AD?
  !Are they safe?
  !Which might show efficacy?
    !Interferon-gamma
    !Omalizumab and rituximab