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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
106.7
0
50
100
150 p = 0.0008
Flar
e-fr
ee d
ays
(Mea
n)
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
-25
-20
-15
-10
-5
00 1 2 3
Time
Cha
nge
in %
BSA
(-)
Placebo Treatment
-18-16-14-12-10-8-6-4-20
0 1 2 3
Time
Cha
nge
in E
ASI
scor
e
PlaceboTreatment
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
H2O
HOCl
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)
y p ;
• Is the quality of life for the patient and family impacted enough to justify?
• Weighing risks and benefits with family
Systemic Immunosuppressants
g g y
• 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