Atopic Dermatitis and Ichthyosis

Amy S. Paller, M.D.Walter J. Hamlin Professor and

Chair of Dermatology Professor of Pediatrics

Northwestern University Feinberg School of Medicine

Chicago, Illinois

Atopic Dermatitis = Eczema • Very itchy inflammatory skin disorder that

affects 17% of US children

• Onset in 1st year in 60%; by 5 years in 90%

• Increased prevalence, esp. in industrialized countries; parallels increase in asthma

…and AD can be miserable!

AD persists in >80% of US children to 2nd decade

1-year prevalence of AD in US adults is 7-10%

‐ Not too different from 10.7% prevalence found in US children

Silverberg and Hanifin. JACI 2013;132:1132

Margolis et al. JAMA Dermatol. 2014 Apr 2

Shaw et al. JID 2011;131:57

Percentage of children with mod severe AD

Silverberg, Simpson. Pedi Allergy Immunol. 2013;24:476

with mod-severe AD increases with age, esp. after 3 years (p<.0002)

Silverberg, Simpson. Dermatitis. 2014;25:107

Comorbidities of AD• Asthma• Hay fever/respiratory allergies• Food and digestive allergy

• Itch• Poor sleep efficiency

i

• Keratoconus• Cataracts/ Glaucoma• Dental health problems

• Impetigo/cellulitis/furuncles• Viral warts

i• Insomnia

• Depression• Anxiety• ADD / ADHD• Epilepsy/seizures

• Accidental/traumatic injury

• Eczema herpeticum

• Urinary tract infections• Upper respiratory infections• Pneumonia• Influenza• Recurrent ear infections

What causes AD?

• Genetics: Runs in families with eczema, dry skin, allergic disorders

Proksch E. J Derm Sci 2006; 43:159

• Immune issues in the skin: abnormal reactivity to triggers

• Poor skin barrier: Impairedwater retention; easier ingress of bacteria/certain viruses and allergy triggers

• Formation of tightly stacked outer skin cells

Role of filaggrin in barrier integrity

Precursor to natural moisturizing factor (NMF): breakdown products urocanicacid and pyrrolidonecarboxylic acid – retain water, lower pH, reduce bacteria

Miajlovic et al. JACI 2010;126:1184

• Semi-dominant• Fine scaling• Mild-moderate PPK

with hyperlinear

Filaggrin deficiency: Ichthyosis vulgaris

with hyperlinear palms and soles

Smith et al. Nat Genet. 2006;38:337

Ichthyosis vulgaris• Most prominent and

larger scales on lower extremities: worst in cold, dry weatherFl l• Flexural areas characteristically spared

• Generally improves with age, in summer, and in warm moist environments

F.I.R.S.T. (www.firstskinfoundation.org)

• 1:10 persons (N. European) carry mutation in FLG (profilaggrin): different mutations in different ethnic/racial populations

• Leads to dry skin (water loss) and easier ingress or triggering of immune reactivity by external agents ( i i i i b )

Ichthyosis vulgaris and risk of eczema

(antigens, irritants, microbes)

Ichthyosis vulgaris: Polygonal scaling on legs and hyperlinear palms

Meta-analyses: Strong genetic association between eczema and ichthyosis vulgaris/ FLG mutations

Greatest known risk factor

Ichthyosis vulgaris• 20-30% with FLG mutation have AD• 14-56% with AD have FLG mutation

• Fewer filaggrin repeats correlates with dry skinSandilands et al. J Cell Sci 2009;122:1285

Ginger et al. Arch Derm Res 2005;297:235

Ichthyosis vulgaris and eczema• Higher risk of asthma, hay fever, food and

other allergies if filaggrin mutations and eczema (“atopic march”)

Osawa et al. Allergol Int 2011;60:1

How do we manage atopic dermatitis?

• Section 1. Diagnosis and assessment of atopic dermatitis.

• Section 2. Management and treatment of atopic dermatitis with topical therapies.

• Section 3. Management and treatment with phototherapy d t i t

Guidelines of Care for the Management of Atopic Dermatitis

and systemic agents.

• Section 4. Prevention of disease flares and use of adjunctive therapies and approaches.

JAAD 4-part series, 2014

Standard Therapies for Pediatric Atopic Dermatitis

• Irritant and allergen avoidance• Moisturization a few times daily/ barrier repair• Bathe at least once daily

W d f l t h d t ki– Wonderful way to hydrate skin– Important for parent-baby bonding– Clears dead skin cells– Decreases bacteria– Water softeners make no difference

• Moisturize immediately after bath with good emollient

Standard Therapies for Pediatric Atopic Dermatitis

• Anti-inflammatories as main therapy

• Managing infection

• Sedating antihistamines to help with sleep (child• Sedating antihistamines to help with sleep (child and parents)

• *Education: Chronicity, flare factors hard to find

– Patient understanding is critical for compliance

Improve the barrier

- Avoid irritants and potential allergic triggers

- Bathing to hydrate

Moisturizing several times daily- Moisturizing several times daily, esp. after bath

- Opportunity to deliver: alter pH, ceramides, natural moisturizing factors/ missing proteins

Can prophylactic barrier repair prevent AD and sensitization

Simpson et al. JACI 2014;134:818

Barrier therapy to decrease AD risk• Randomized controlled trial (US and UK) in

infants at high risk for AD (1o family with atopy)• Intervention arm: Full-body emollient therapy at

least once per day starting within 3 weeks of birth; Control arm: No emollients

• Cream formulation (67%)>sunflower oil (23%)>ointment ; 85% used at least 5x/wk

• Reduced AD incidence of AD by 50% (relative risk, 0.50; 95% CI, 0.28-0.9; p=0.017)

Simpson et al. JACI 2014;134:818

Horimukai et al. JACI 2014;134:824

• 32% fewer infants with AD in active treatment group (p = 0.012); had better skin hydration

Anti-inflammatory Therapy• Anti-inflammatory medications are key for

suppressing inflammation and pruritus• Topical steroids have been mainstay

• In general, ointments are more potent, better emollients, and with fewer additives than creams

• Patient and parental preference should be heeded

Anti-inflammatory Therapy

• Various successful techniques of steroid use– Discontinuation leads to flare– Burst therapy vs. maintenance– Dial down to lower strength steroid or

calcineurin inhibitors- Proactive therapy

• Be familiar with strengths of topical steroids– Superpotent steroids are inappropriate – Potent steroids for older children at

recalcitrant sites, intermittent as needed– Do not use halogenated steroids on face, groin,

intertriginous areas

• Salicylic acid (2-6%) with topical steroid (e.g., triamcinolone) and can put in emollient base (Aquaphor); sometimes add tar as anti-inflammatory

Recalcitrant lichenified dermatitis: Compounded steroids

- Compounding adds expense; 1 lb.- Monitor carefully – more side effects

and systemic absorption- Taper dosing and substitute as patient

improves

Limitations of Topical Corticosteroid Therapy

• Side effects– Unusual unless inappropriate use– Atrophy/ striae– Potential for systemic absorption

• Efficacy– Tachyphylaxis: Resistance and

requirement for stronger steroids– Limited by steroid phobia: 36% are non-

adherent to treatment because of phobia– Latest issue: Phobia about “steroid addiction”

“Steroid Addiction”?

• Growing media attention and public concern

• Uncommon side effect: occurs after TCS withdrawal (esp 2-3 wks after), usually after use for AD

• Particularly rare in children (7% <18 y/o; 0.3% <3 y/o)

• Follows prolonged, inappropriate and frequent use

Systematic review of ~300 articles: Hajar et al. JAAD 2015;72:541

What is “steroid addiction”?- 81% are women; 97% use on face (can affect

genitalia); 86% use mid to high-potency steroids - 92% showed persistent erythema, often

with sharp demarcation; may spare nose and ears (“headlight sign”); sometimes papules/nodules

Hajar et al. JAAD 2015;72:541

p p

- Frequent burning/stinging (65%), itch

- Recognize, provide supportive therapy

- Should not discourage from appropriate use of TCS for AD

Compliance is a major issue Microprocessor in cap for stealth monitoring32% compliance to AD regimen during 8 weeks; most compliant before visits

Krejci-Manwaring et al. JAAD 2007;56:211

Explore reasons for noncompliance and address them creatively (steroid phobia; timing; vehicle)Heed patient and parental preferenceConsider shorter duration before 1st followup

Written action plans

Shah et al. Cutis 2013;91:105

• Calcineurin inhibitors and “medical devices” as “steroid-sparing agents”

• Topical calcineurin inhibitors (tacrolimus ointment and pimecrolimus cream) do not lead to

Other anti-inflammatories?

ointment and pimecrolimus cream) do not lead to skin thinning or eye risks: safe for face

– Off-label use for 0.1% tacrolimus ointment

– Off-label use for <2 years of age

• Topical calcineurin inhibitors may allow repair of steroid-induced side effects/ barrier issues

Proactive maintenance therapy

173 9

200

• Regular use to clear/almost clear areas– Decreased potential risk, increased compliance

• Intermittent fluticasone cream to maintain

• Intermittent tacrolimus ointment Hanifin. BJD 2002;147:528; Schmitt t al. BJD 2011;164:415

• 3x/wk once clear-almost clearBreneman JAAD 2008;58:990173.9

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TCL (n=67) Vehicle (n=36)

• 2x/wk: indication in Europe

• 1x/wk as good as 3x/wk

• Fluticasone slightly more effective

Breneman. JAAD 2008;58:990 Paller. Pediatrics 2008;122:e1210

Reitamo and Allsopp. J Derm Treat 2010;21:34 Thaci et al. JEADV 2010;24:1040

Schmitt al. BJD 2011;164:415

Chung. BJD 2013;168:908

• Risk of non-melanoma skin cancer decreased with TCI use and potency

No signal to date in adults or children

What about the Black Box warning?

• Increased lymphoma risk with AD, esp. severe – No correlation with use of TCIs

Margolis. JAMA Derm 2015 Feb 18; Arellano. JACI 2009;127:808; Arellano. JID 2007;127:808; Siegfried. Am J Clin Derm 2013;14:163

• 10-year study of tacrolimus in 8000 children worldwide, 6 year U.S. study in ~7500 infants and toddlers and PEER study of pimecrolimus (6000) as well as FDA’s adverse event reporting system

– No increased risk of skin cancer, lymphoma through 2014 data

Consider contact allergic reactionsEspecially with face or hand dermatitis

• Up to 22% with AD react to non-nickel allergens – Emollient ingredient 50% (esp. avena extract, wheat

protein, calendula, lanolin)– Topical antiseptic (chlorhexidine), cleanser– Topical steroid

• Extensive dermatitis may reflect airborne allergens (exposed areas) or systematized reactions

Reaction to baby wipes (broponol preservative, fragrance))

• 19% react to balsam of Peru, 20% to fragrance mix

Courtesy, Dr. S. Jacobs

• 80-90% of patients with AD harbor S. aureus• Decreased innate immune responses

- Poor barrier (filaggrin down, proteases up)- Decreased antimicrobial peptides

• Microbiome studies: reduction in normal flora with flares and increased S. aureus

What about Infection? Staph worsens AD

- What is role of normal flora?- Factors secreted by S. epi kill S. aureus;

nonpathogenic bacteria reduce inflammation in NC/NgA mice

• MRSA is a growing concern

Volz et al. JID 2014;134:96

Bacterial swabs from rims, nozzles, container content; preserved and unpreserved ointments - 53% of containers were contaminated‐ 25% with S. aureus

‐ Nasal carriage of same S. aureus strain in 65% of parents

‐ Pets can carry same microbiota incl MRSA

Carr and Cork, ISAD 2008

Chiu et al. Arch Derm 2010;146:748; Bonness et al. J Clin Microbiol 2008;46:456

Reducing environmental S. aureus

‐ Pets can carry same microbiota, incl MRSA

Recommendations:– Keep open moisturizers in refrigerator– Pumps or pour bottles rather than jars– Avoid direct contact with hands; decant– Avoid sharing personal hygiene items– Consider decolonizing household members, incl pets

Misic et al. Presented at SID, 2014

• Bleach baths (sodium hypochlorite) .005% at least 2x weekly (1/2 cup per full tub; 4cc tsp/gallon; 1 cc/L)

• Moderate to severe AD with history of infection

How can we decrease S. aureus levels?Can we decrease the severity of AD?

Huang et al. Pediatrics 2009;123:e808; Huang et al. Arch Derm 2011;147:246

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p=0.004 p=0.004

Eczema severity Body surface area

“Exposed” sites: Head and NeckMean change: Baseline to 1 month: p=.32Mean change: Baseline to 3 months: p= 62

Baths or the mupirocin combo?“Bath Submerged” sites: Limbs, Trunk

Mean change: Baseline to 1 month: p=.03Mean change: Baseline to 3 months: p=.0005

Mean change: Baseline to 3 months: p=.62

• Did not fully clear S. aureus– Maintenance use up to daily (if severe) now

standard of care; don’t need for mild, <3 mos.– Marketing of new bleach-based antiseptics

Huang et al. Pediatrics 2009;123:e808; Huang et al. Arch Derm 2011;147:246

Na hypochlorite 0.006% cleanser for showers

• 12 wk open-label trial of 18 children with moderate to severe AD

• Positive lesional cultures for S. aureus• At least 3x/wk with shower; no other changes• Significant reduction in IGA by 2 wks (p=.01) and

SA 1 ( 0 00 )BSA by 1 month (p=0.005)

Ryan et al. Pediatr Derm 2013;30:308

Day 0 Day 11

Week 8Week 10

• Is there more than anti-bacterial action?• Reversibly inhibits NF-κB signaling in cultured KCs

Sodium hypochlorite may be anti-inflammatory

• Reduces disease severity d l i i ith

Leung et al. JCI 2013;123:5361

and ulcers in mice with acute radiation dermatitis

• In aged mice, enhanced epidermal thickness and proliferation

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Not improving on topicals?

Some pearls to consider

Have you tried? Wet wraps• Traditional: wrap with wet gauze after bathing

and topical medication or moisturizer

• Modified: Damp PJ’s (cotton long underwear-Dabade et al. JAAD 10/4/11 Epub

like) and socks; top with dry PJ’s or sweat suit and socks to avoid chilling

• Modify for hand dermatitis by wet cotton gloves topped with vinyl glove

Wet wrap management

• Decreases pruritus and discomfort

• Best applied for severely affected infants and toddlers (compliance)and toddlers (compliance)

• May increase absorption of topically applied medication

Have you considered Allergy?

• Dietary manipulation controversial

• Consider allergy testing, challenge testing and dietary avoidance in infants or toddlers with ysevere, resistant AD

– Referral to an allergist with experience

– Maintain good nutrition (risk kwashiorkor, rickets)

• Rarely necessary• Virtually all children improve in a few days…

maintenance is tricky

O t it t t h ti t d t b t

Hospitalization to “cool down”

• Opportunity to teach patient and parents about proper use of medication

• Opportunity for consultation (beyond derm)• Gives family a “break”

• Balance with risk of exposure/ acquisition of resistant microorganisms

Narrow band UVB• Retrospective review of 50 children with severe

AD with > 10 exposures– Complete clearance in 40%; good

improvement in 23%; moderate in 26%– Median length of remission 3 months

Clayton et al. Clin Exp Derm 2007;32:28

• Problems:– Requires cooperation– Can’t start when too inflamed– Potential risk of skin cancer and premature

aging– Busy schedules if school-aged (Home nUVB)

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• Is the quality of life for the patient and family impacted enough to justify?

• Weighing risks and benefits with family

Systemic Immunosuppressants

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• Families need to be advised about risks (infections, neoplasia)

• No comparative trials or detailed treatment guidelines, esp for use in children

• Cyclosporine (short-term)• Methotrexate• Mycophenolate mofetil• Azathioprine

– 1-2 years max on immunosuppressant

Systemic Immunosuppressants

y pp– Side effects are unusual

• Corticosteroids– Typically avoided because of effects of

continued use– Rebound is major problem: slow taper

• Continue “rotational” topicals

What’s on the horizon?

– AN2728: Unique boron-based anti-inflammatory• Increases cAMP

Topical Therapy in Trials:Phosphodiesterase 4 inhibition

Reduces inflammatory cytokines, incl. IL-31

Well tolerated across 16 completed clinical studies

No clinically important safety signals; most AEs mild (esp. application site reactions) and considered unlikely to be related to study drug

cytokines, incl. IL 31

Atopic ExperienceThree phase 2 studies completed in mild-moderate AD: 2 in adolescents

- Double-blind, randomized, dose-ranging ().5% vs 2%) in 86 adolescents with 35% BSA: twice daily for 28 d

Confidential

daily for 28 d- Open label pK study at 2% dosing in 23

adolescents (10-35% BSA): twice daily for 4 wks

Safety and pK study in children as young as 2 years: No safety signals; most AE’s mild (application site); no blood levels

>70% Clear or Almost Clear (IGA) after 4 >70% Clear or Almost Clear (IGA) after 4 Wks of twice daily therapyWks of twice daily therapy

ISGA Scale:0  Clear1  Almost Clear2 Mild

Proportion of Subjects Achieving Clear or Almost Clear on ISGA

2  Mild3  Moderate4  Severe

Confidential AN2728-AD-203

Common IL-4Rα subunit for dual IL-4/IL-13 cytokine antagonism

• Dupilumab: fully human IL-4Rα mAb

Type I ReceptorB cells, T cells, Monocytes, Eosinophils, Fibroblasts

Type II ReceptorKeratinocytes, Smooth muscle cells, Fibroblasts, Monocytes, Activated B cells

• Potent inhibition of Th2 pathway

• 12 weeks of weekly s.c. dupilumab in adults with moderate to severe AD

Beck et al; NEJM 2014; 371:130

• Improves AD transcriptome

Beck et al; NEJM 2014; 371:130

• Decreases elevation in IL-22 expression as well as Th2 cytokines

Thank you for your attention