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to an Exceptional Eczema Experience

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1 to an Exceptional Eczema Experience
The 5 E ’s to an Exceptional Eczema Experience Richard J. Antaya, MD, FAAP, FAAD Professor of Dermatology and Pediatrics Director, Pediatric Dermatology Yale University School of Medicine New Haven, CT

2 Potential Conflict of Interest Disclosure
Astellas Research local PI for APPLES registry for long term safety evaluation of Protopic 1

3 Impact of Atopic Dermatitis
prevalence % of all children* mild in 85% mod to severe -- profound effect on QOL intractable itching and sleep loss soreness, scarring, dyspigmentation messy topicals social stigma QOL impairment equivalent to CF costs more than childhood diabetes 4% of adults with persistent disease 40-60% continue to experience disease intermittent exacerbations prevalence between 10-15% of all children this is rapidly becoming a very significant problem. Moderate-to-severe atopic eczema can have a profound effect on the quality of life for both sufferers and their families. In addition to the effects of intractable itching, skin damage, soreness, sleep loss and the social stigma of a visible skin disease, other factors such as frequent visits to doctors, special clothing, need to constantly apply messy topical applications all add to the burden of disease. The cause of atopic dermatitis is unknown, though a genetic pre-disposition and a combination of allergic and non-allergic factors appear to be important in determining disease expression. Treatment of atopic dermatitis in the US is characterized by a profusion of treatments aimed at disease control. The evidential basis of these treatments is often unclear. Most people with atopic dermatitis are managed in primary care where the least research has been done. The costs are enormous and b/c of many factors, the yearly cost is more than diseases like diabetes in children. ****There is a tendency to wait and hope for the disease to remit, but studies show that over 60% of pts continue to experience disease. *adapted from Laughter D. J Am Acad Dermatol 2000; 43: 2

4 Diagnosis of Atopic Dermatitis Diagnostic Criteria
Pruritus Eczema (from Greek - to boil, to erupt) chronic & recurring acute chronic subacute Adapted from Hanifin, Rajka. Acta Dermato Venereol. 92(suppl):44-7;1980 and AAD Consensus Conference on Pediatric Atopic Dermatitis 3

5 Atopic Dermatitis Clinical Presentation
6 skin findings of eczema erythema papules/edema exudation - oozing and crusting scale excoriations linear erosions from scratching Lichenification thickened, hyperpigmented, leathery skin due to rubbing (accentuated skin markings) symmetric > asymmetric 4

6 5

7 Diagnosis of Atopic Dermatitis Diagnostic Criteria
Pruritus Eczema (from Greek - to boil, to erupt) chronic & recurring acute chronic subacute age-specific distribution Adapted from Hanifin, Rajka. Acta Dermato Venereol. 92(suppl):44-7;1980 and AAD Consensus Conference on Pediatric Atopic Dermatitis 6

8 ATOPIC DERMATITIS Infantile Distribution
face - cheeks and chin “head light” sign – mid-facial sparing extensor extremities, dorsal hands and feet very rarely on palms or soles can have widespread involvement diaper area often spared pruritus 7

9 8

10 ATOPIC DERMATITIS Childhood-Adult Distribution
antecubital and popliteal fossae posterior neck presacral back, buttocks, flanks eyelids scalp hands, feet  palms and soles may be severe and generalized “head light” sign head light sign is when the nose and surrounding skin is not involved. 9

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14 Diagnosis of Atopic Dermatitis Associated Features
early age at onset 80-90% by 5 years personal or family history of atopy xerosis associated with ichthyosis vulgaris (IV) worse prognosis in patients with IV 13

15 Deleted Old Secondary Criteria
keratosis pilaris infra-auricular fissures periorbital/ocular changes e.g. Dennie-Morgan folds prurigo lesions atypical vascular responses hyperlinear palms and ichthyosis 14

16 ATOPIC DERMATITIS Differential Diagnosis
infancy seborrheic dermatitis scabies Wiskott-Aldrich Syndrome hyper-IgE syndrome (Job syndrome) Bruton’s agammaglobulinemia childhood contact dermatitis tinea corporis dermatophytid scabies pityriasis lichenoides CTCL (cutaneous T-cell lymphoma) 15

17 Complications of AD 16

18 Eczema Herpeticum 17

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21 Eczema Vaccinatum 20

22 Impetigo 21

23 S. aureus and Atopic Dermatitis Endogenous Antimicrobial Peptides
antimicrobial peptides in the skin cathelicidins human -defensin-2 (HBD-2) accumulate in response to skin inflammation normal levels in psoriasis lesions decreased levels in lesions AD, eczema herpeticum, eczema vaccinatum IL-4 and IL-13 inhibit HBD-2 production The innate immune system provides an immediate defensive response that includes phagocytosis by neutrophils and macrophages and their production of reactive oxygen intermediates that kill microbial agents. And it is now apparent that cutaneous antimicrobial peptides are part of the innate immune system defenses against infection in the skin. The innate immune system of human skin contains antimicrobial peptides known as cathelicidins and human beta defensin 2. Although the cathelicidins and beta defensins –the two major classes in mammalian skin-are normally negligibly present, they have been shown to accumulate in skin affected by such inflammatory conditions as psoriasis and wounds. Rich Gallo and Donald Leung noted that only 7% of psoriasis patients experience skin infections while 30% of atopic patients experience them. Donald Leung has discovered that S aureus accumulates primarily in the stratum corneum, apparently via binding with the increased fibronectin and fibrinogen found in the cornified layer of the atopic dermatitis can, and growing in colonies in the upper layers of the epidermis between keratinocytes, he observes. Because AD patients are prone to recurrent skin infections he suspects there could be a natural deficiency of the local immune response. In normal skin these peptides are negligible, but they accumulate in skin affected by inflammatory diseases such as psoriasis Ong and colleagues reported recently in the New England Journal of Medicine that the expression of these innate peptides were decreased in patients with atopic dermatitis, but not in those with psoriasis. Moreover, they showed in vitro (in HaCat cells) that the two IL’s associated with AD inhibit the production of defensins in the skin. The investigators assessed inflamed skin from AD patients and psoriasis patients, and skin from normal volunteers, for the presence of cathelicidins and defensin’s. They looked for evidence of the protein in the skin samples, for molecular presence and distribution, and for messenger RNA. And then they tested these two antimicrobial peptides in vitro-separately and together-for their activity against S aureus. For each of these antimicrobial peptides, they found a disparity in expression between psoriasis and AD lesions that went beyond their expectations. Both cathelicidins and defensens were absent in normal skin, confirming previous reports that these two antimicrobial peptides are not expressed when there is no definable threat. And in line with the 1997 data, cathelicidins were present in the psoriatic skin. Human beta defensin-2 was there is well, although cathelicidins was for more abundant. Yet both antimicrobials were virtually undetectable in the atopic lesions, especially in the granular layer and stratum corneum. Molecular, protein, and mRNA results all told the same story. When these antimicrobial peptides were tested in vitro against S. aureus cultured from AD lesions cathelicidins showed much stronger activity than human beta defensin-2, but the two peptides acting together have the most potent effect of all. Adapted from Ong P. N Engl J Med. 347(15), Oct 10, 22

24 Treatment of Atopic Dermatitis 23

25 What proof do we have regarding the efficacy of our treatments for AD?
What tangible proof do we really have regarding the efficacy our treatments for AD? Recently, as dermatologists we are turning back to evidence-based medicine to guide us through this quagmire of therapy and reports. To date the work of Howel Williams in Nottingham, England probably represents the most comprehensive analysis of the treatments of AD for all age groups. 24

26 Atopic Dermatitis Treatments Randomized Controlled Trials (RCT)
RCT evidence supports topical corticosteroids oral cyclosporin ultraviolet light therapy psychological approaches (habit-reversal techniques) topical calcineurin inhibitors UVB is known to interfere with the antigen presentation of LC’s and alters the cytokine production from keratinocytes. There is evidence that UVA can both alter the function of LC and eosinophils in pts with AD. 6 RCT’s of UV tx were evaluated: There is some evidence to support UVB (broad and narrow band) in AD vs placebo. There is some evidence to support the use of high dose UVA vs UVA/UVB in AD. There is some evidence to support the use of nbUVB over standard UVA in AD. There is some evidence supporting slightly better efficacy of high dose UVA over topical steroids for acute flares in AD. There is lack of studies comparing the different forms of UV between each other or other systemic therapies or high dose UVA vs nbUVB. There were 3 RCT’s employing behavioral therapy such as habit-reversal techniques (instructing patients to rub, squeeze or pat pruritic areas instead of scratching. Even though they showed very impressive results both with and without topical steroid therapy, these were not blinded and have yet to be reproduced by other groups (Swedish researchers). Tacrolimus had 3 studies at time of the literature evaluation with 4-5 underway. Ascomycin had 2 studies at time of lit review. Hoare C, Li Wan Po A,Williams H. Health Technol Assess; 2000;4(37) 25

27 Atopic Dermatitis Treatments Randomized Controlled Trials (RCT)
Insufficient evidence to make recommendations on maternal allergen avoidance to avoid AD oral antihistamines Chinese herbs dietary restriction in established AD homeopathy topical coal tar massage therapy hypnotherapy evening primrose oil topical doxepin house dust mite reduction emollients Emollients- only 5 evaluable studies – Moisturel and Eucerin improved statistically and in addition to topical desonide Hoare C, Li Wan Po A,Williams H. Health Technol Assess; 2000;4(37) 26

28 Treatment Approach 27

29 ATOPIC DERMATITIS 5 E’s to an Exceptional Eczema Experience
Education - level of success is directly related to how much education patients and their families receive about AD* Expectations Endpoints Clearance vs Maintenance phases of therapy Encouragement Enough medication – campfire analogy Early return visit (2 weeks) Staab, D., Diepgen, T.L., Fartasch, M., Kupfer, J., Lob-Corzilius, T., Ring, J., Scheewe, S., Scheidt, R., Schmid-Ott, G., Schnopp, C., et al Age related, structured educational programmes for the management of atopic dermatitis in children and adolescents: multicentre, randomised controlled trial. BMJ 332: *Staab, D. BMJ 332: 28

30 Clinical Approach to Atopic Dermatitis My Spiel
Educate Explain what it is and what it is not No cure, not a single allergy, but can be controlled “The itch that rashes” Alloknesis (cutaneous hyperaesthesia)* perceive normally “nonitchy” stimuli as “itchy” Explain the provokers of itch in A.D. heat and perspiration 96% wool 91% emotional stress 81% certain foods (rarely) “common cold” 36% CF Wahlgren in his report of common provokers of itch in AD found the following: (Acta Derm venerol 71:488-94; 1991) *Hagermark O. in Bernhard JD. Pruritus in skin disease. McGraw-Hill, 1994 pp37-67 29

31 Clinical Approach to Atopic Dermatitis My Spiel
Expectations Endpoints Clearance with anti-inflammatory meds Maintenance with trigger avoidance and moisturization Explain rationale for proposed therapy Enough medicine -- Campfire analogy 30

32 ATOPIC DERMATITIS The Spiel on General Skin Care
soaps avoid “true soaps” Dial, Ivory, Irish Spring moisturizing cleansers Dove, Tone, Olay Complete soap free cleansers Cetaphil, Aquanil avoid entirely during flares 31

33 Nice & Smooth Not nice, Rough & Yucky 32

34 ATOPIC DERMATITIS The Spiel on General Skin Care
moisturizers immediately after bathing and prn (multiple times/day) avoid lotions; use creams and ointments Eucerin, Aquaphor, petrolatum, Cetaphil, Acid Mantle cream, Vanicream, Theraplex Emollient Ceremide-based – Epiceram, CeraVe, Cetaphil Restoraderm 33

35 ATOPIC DERMATITIS The Spiel on General Skin Care
laundry detergents hypoallergenic detergents Dreft, Ivory Snow avoid dryer sheets and fabric softeners wool and polyester fabrics extremes of temperature, humidity dust mites (mattress, box spring, pillow covers) Certain foods – milk, wheat, egg, soy 34

36 ATOPIC DERMATITIS Hanifin’s Truisms of Bathing
“Bathing dries the skin” A: True If skin allowed to air dry. “Bathing hydrates the skin” If moisturizer is applied immediately after. physicians and pts have long been stymied by 2 true but opposing factors about bathing: Bathing dries the skin. Wetting followed by evaporation causes stratum corneum contration and fissures, impairing epidermal barier. Bathing hydrates the skin TRUE if moisturizer is applied within 3 minutes to retain hydration, keeping the barrier soft and flexible. No conclusive data supported by studies 35

37 ATOPIC DERMATITIS Bathing Recommendations
showers - o.k. if not flaring bath - if more severe b.i.d. for 10 min, tepid do not rub, scrub or use washcloths pat dry partially with a towel - don’t rub within 3 minutes apply moisturizer and/or topical medication until fingers wrinkle wet compresses or what we call open wet dressings (cotton) also helpful for nighttime itch control 36

38 ATOPIC DERMATITIS For more severe flares
Open Wet Dressings cools and helps relieve pruritus regimen (q.d.- q.i.d.) soft cotton cloth (bed sheet, pillowcase) soak in tepid water, wring out apply one layer thick to affected area for min (don’t let dry out) remove and apply medication/moisturizer Wet Wraps apply low to medium potency topical steroid damp PJ’s or gauze covered by dry PJ’s or gauze night time usually, can continue during day also for very severe flares up to 2 weeks 37

39 ATOPIC DERMATITIS MEDICAL TREATMENT
weak topical corticosteroids non-fluorinated ointments or creams Hydrocortisone acetate 0.5, 1.0, or 2.5% Hydrocortisone valerate 0.2% Desonide, fluticasone lotion/cr (low), aclometasone medium to high potency steroids Triamcinolone (med) Fluticasone ointment (med) Mometasone cream (med)  mometasone ointment (high) 38

40 Topical Steroid Monotherapy Regimen
Standard regimen Twice daily for 2 weeks (esp. first treatment) Then p.r.n. based on need and response to Rx More severe regimen Pulse dose (once or twice) on weekends 3 consecutive days/week Most severe regimen Single application 3 days/week during maintenance phase Mon, Wed, and Fri Decreases frequency of flares 39

41 Enough Medication Frequency Duration Recommended amount per dose
adult hand = ~ 0.5 gm total BSA of 3-6 mo = gm total BSA of 6-10 yo = gm total BSA of an adult = gm Topical meds dispensed as 15, 30, 45, 60, 80 or 100 gram tubes 1 lb (454 gm) jars 40

42 Enough Medication ESTIMATES FOR QUICK MEMORIZATION
Recommended amount per dose total BSA of a 5 mo = 5 gm total BSA of a 5-10 yo = 10 gm total BSA of a 20 yo = 20 gm Do the math… 5 m.o. 100% BSA = 5gm x 2 = 10gm x 14 days = 140 gm 7 y.o. 100% BSA = 10gm x 2 = 20gm x 14 days = 280 gm 41

43 Enough Medication x 16 = Only topical steroids sold in 1 lb jars
triamcinolone acetonide hydrocortisone acetate 1 lb (454 gm) jar 30 gram tube x 16 = 42

44 Clinical Approach to Atopic Dermatitis Campfire Analogy
v v CF Wahlgren in his report of common provokers of itch in AD found the following: (Acta Derm venerol 71:488-94; 1991) 43

45 Dosing of Topical Medications
FTU (Finger tip unit) = ½ gm Distal finger of adult …DIP crease to tip 2 FTUs = 1 gram 1 FTU covers 2 adult hands and fingers Most topicals have a tube with orifice ~ 5 mm 1 FTU 44

46 “Soak and Smear” of Topical Steroids
Soak and Smear regimen Soak in a bath with plain water (no soap) for 10 min at night (or b.i.d.) Then smear on the topical steroid (usually triamcinolone 0.1% ointment) immediately without drying After skin is improved stop soaks but continue the topical steroid at night 28 adult pts with severe chronic recalcitrant dermatitis treated with Soak and Smear technique to apply topical steroid, 15 pts had AD Median duration of active disease was 3 years, Previous treatments – 17 pts – prednisone 2 pts - CyA 2 pts – UVB phototx Numerous topical therapies – all failed Results 17 pts showed complete response 9 pts showed % improvement 1 pt had 80% improvement 1 pt had 75% improvemement Most by several days to 2 weeks Gutman AB, Kligman AM, Sciacca J, James WD. Arch Dermatol Dec 2005;141: 45

47 Soak and Smear 28 adults severe chronic recalcitrant dermatitis (15 with AD) Duration - 3 years Previous treatments Numerous topical therapies – all failed 17 pts – prednisone 2 pts - CyA 2 pts – UVB phototx Results 17 pts showed complete response 9 pts showed % improvement Most by several days to 2 weeks 28 adult pts with severe chronic recalcitrant dermatitis treated with Soak and Smear technique to apply topical steroid, 15 pts had AD Median duration of active disease was 3 years, Previous treatments – 17 pts – prednisone 2 pts - CyA 2 pts – UVB phototx Numerous topical therapies – all failed Results 17 pts showed complete response 9 pts showed % improvement 1 pt had 80% improvement 1 pt had 75% improvemement Most by several days to 2 weeks Gutman AB, Kligman AM, Sciacca J, James WD. Arch Dermatol Dec 2005;141: 46

48 TAC 0.1% oint bid S&S for 5 day then qd for 2 weeks
4y.o. AD min response TCI’s, TS TAC 0.1% oint bid S&S for 5 day then qd for 2 weeks Vaseline Jensine Montreuil 4y.o. AD for life s/p TCI’s, moisturizers but min response.poor sleep TAC 0.1% oint bid S&S for 5 day then qd for a total of 2 weeks and Vaseline moisturizer. 47

49 BL 2wk 6wk BL 48

50 S&S HCO 2.5% qhs 10 min bath, and on dry skin in am x 2wk
5 mo with AD No response triamcinolone 0.1% cr mupirocin oint hypoallergenic formula S&S HCO 2.5% qhs 10 min bath, and on dry skin in am x 2wk Justin Gentallan 5 mo S&S HCO 2.5% qhs 10 min bath, and on dry skin in am x 2wk, no itch sleeping well S/P TAC 0.1% cream, Bactroban, Nutramigen-- all no help 49

51 STEROID-INDUCED ATROPHY
50

52 STRIAE DISTENSAE mometasone ointment x several months in a teen 51

53 Topical Calcineurin Inhibitors (TCI’s) Protopic Ointment (tacrolimus) Elidel Cream (pimecrolimus)
Proposed mechanism of action CD4+ lymphocytes inhibits calcineurin inhibits gene transcription IL-2, IL-3, IL-4, IL-5, GM-CSF, TNF-, IFN- Tac acts directly on T lymphocytes, especially CD4+ cells, binding to immunophilins, (FK-binding protein). This tac-immunophilin complex then binds to, and competively inhibits calcineurin, a phospotase that is active only when bound to calcium and calmodulin. This binding phenomenon inhibits the ability of calcineurin to activate the promotor region of the gene for IL-2, 3,4,5, GM-CSF, TNF-A, IFN-Gamma. It also may bind to cell surface steroid receptors, it inhibits the release of mast cell preformed mediators, downregulates IL-8 receptor expression, drecreases ICAM-1 and E-selectin lesional blood vessel expression and downregulates FcERI on Langerhans cells. 52

54 Tacrolimus 0.1% Open label Phase III b Study: Baseline
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55 Tacrolimus 0.1% Open label Phase III b Study: Month 9
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56 Pimecrolimus Treatment of Atopic Dermatitis
Baseline 3 weeks 55

57 When do I use the TCI’s? Concerns about steroid use
Can’t get off topical steroid Using steroids too frequently or continuously Location too risky Intertriginous areas Eyelids Steroids ineffective Discuss FDA boxed warning 56

58 ATOPIC DERMATITIS ADJUNCTIVE ANTIBIOTICS/ANTIBACTERIALS
Treat impetigo/ superinfection oral antibiotics Reduce S aureus topically N3 (Nose, Nails, Navel) mupirocin b.i.d. 5 days/mo Bleach baths* 4 oz/ ~25 gal (tubful) water or ~2 tsp/gal H2O 3 times weekly - daily Clinically proven to improve eczema scores in patients who previously had AD-associated impetigo Chlortopic coined by me and Lenny Krystal a peds derm on Long Island Huang JT et al, Pediatrics. 123(5):e808-14, 2009 May Huang JT, Rademaker A, Paller AS. Arch Dermatol. 147(2):246-7, 2011 Feb. 57

59 ATOPIC DERMATITIS ANTIHISTAMINES
especially hs hydroxyzine (Atarax) diphenhydramine (Benadryl) cyproheptadine (Periactin) doxepin (Sinequan) – cardiotoxic ! randomized trials have not demonstrated improvement with sedating or non-sedating antihistamines It may be that the trials to date have not been powered well enough to detect a positive effect for antihistamines. 58

60 AD Habit-Reversal Techniques (HRT) Breaking the itch-scratch cycle
 pruritus Scratching Epidermal Damage Increased Adhesin Exposure collagen, fibronectin, fibrinogen Its been postulated that much of the scratching in AD may ultimately becomes habitual and the habit is detrimental, as scratching damages the skin and leads to further eczema forming in the so-called itch-scratch cycle. Habit reversal is a modified behavioral technique which teaches patients to recognize the habit, identify situations that provoke the habit and then progressively train them to develop a “competing response practice” such as simply touching, squeezing or tapping the itchy area. The technique has been described in 2 RCTs conducted by ther same group in Sweden and compared to topical steroids. Scratching may become habitual Habit is detrimental  itch-scratch cycle 2 Randomized controlled trials Increased S. aureus binding/ inflammation 59

61 AD Habit-Reversal Techniques (HRT)
Effective for tics and nervous habits Scratching is maintained by operant reinforcement HRT teaches recognize the habit identify situations that provoke it train to develop a “competing response practice” Striking, patting, or grasping the area Requires a motivated patient and physician Predicated on proven methods that assist patients in extinguishing tics and nervous habits (nail biting, jerking…) Conditions – LSC That scratching in people with certain disorders was much more reinforced than in normals, either because of a stronger itch itch reducing effect or because of a long history of scratching. Operant conditioning- in conditioning any behavior or specific response chosen by the experimenter; its frequency is intended to increase or decrease by the judicious pairing with it of a reinforcer when it occurs (target behavior) 60

62 Atopic Dermatitis Therapeutic Pyramid
Prayer and/or divine intervention Systemic Immunomodulators UV Phototherapy Allergy Testing/Avoidance Habit Reversal Antihistamines Anti-Staph Antibiotics Topical Calcineurin Inhibitors Topical Steroids Protective Skin Care & Trigger Avoidance 61

63 ATOPIC DERMATITIS 5 E’s to an Exceptional Eczema Experience
Education Expectations Endpoints Clearance vs Maintenance Encouragement Enough medication – campfire analogy Early return visit (2 weeks) 62

64 Thanks for your attention!
63

65 Cure sometimes Relieve often Comfort always 64


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