Atopic Dermatitis.Jonathan I. Silverberg, M.D., Ph.D., M.P.H.

Assistant Professor, Departments of Dermatology, Preventive Medicine and Medical Social Sciences

Director, Northwestern Multidisciplinary Eczema Center

Northwestern University, Feinberg School of MedicineChicago, IL USA

No relevant financial disclosures or conflicts of interest

At times, I will use the term eczema and atopic dermatitis. These are not actually the same thing.

We will touch upon a number of important topics in eczema, but there is so much more that we wont have time to address.

What does eczema look like?

How common is eczema?

What are some common risk factors for eczema?

What are some common treatment approaches for eczema?

What health problems occur in patients with eczema?

Ill-definedHard to delineate where the

lesions start and stop

ErythematousRanges from light pink to flaming

red

Patches or PlaquesRanges from flat to very thick

plaques

asdsad SpongiosisFluid between

cells

Perivascular infiltrate

Inflammation around the blood vessels

EosinophilsEarly or acute eczema

asdsadParakeratosis

Scale

Acanthosis Thickening of the

epidermis

Chronic eczema

asdsadEczema is a morphological pattern either visually or microscopically.

There are several types of eczema: Atopic dermatitis (AD) Contact dermatitis

▪ Irritant contact dermatitis (ICD)▪ Allergic contact dermatitis (ACD)

Drug-induced dermatitis

Age related changes of distribution:

Infancy: Facial and scalp dermatitisToddler: Extensor dermatitisOlder children and adults: Flexural distributionAdults: More head & neck and hand lesions.

Head and neck distribution

More common in adults

EyelidsUsually accompanied by other

signs and symptoms of AD.

Case reports of AD presenting exclusively on the eyelids.

HandsOften only finding in adults with

AD.

Katsarou A, Armenaka M. Atopic dermatitis in older patients: particular points. Journal of the European Academy of Dermatology and Venereology : JEADV. 2011;25(1):12-18.

1-year prevalence of eczema in US adults is 10.2%Silverberg JI, Hanifin J. Adult eczema prevalence and associations with asthma and other variables: A US population-based study. Journal of Allergy and Clinical Immunology. 2013 Nov;132(5):1132-8.

Remarkably similar to the 10.7% prevalence of eczema found in US children.

Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema prevalence in the United States:

data from the 2003 National Survey of Children's Health. J Invest Dermatol. 2011

Jan;131(1):67-73.

Most common inflammatory skin disease.

Statewide prevalence of eczema was divided into tertiles. Data are presented as the percent (95% CI) of subjects who endorsed having eczema in the past 12 months.

Silverberg JI. Unpublished data.

2012 National Health Interview SurveyChildren: 12.0% (11.3-12.7%)Adults: 7.2% (6.9-7.6%)

Silverberg JI. Unpublished data.

Silverberg JI and Simpson EL. Pediatric Allergy and Immunology. 2013.

VariableNo

eczemaEczema

P-value

Race/ethnicity – no. (%)

< 0.0001

African-American

6495 (80.3)

1618 (19.7)

Hispanic8582 (89.7)

1215 (10.3)

White46777 (87.9)

6326 (12.1)

Other/mixed6186 (86.1)

1079 (13.9)

* Rao-Scott Chi square test

Higher prevalence in African American children and adolescents.

Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated with childhood eczema prevalence in US. Journal of Investigative Dermatology. July 2013.

Similar results observed in: Shaw T, Currie GP, Koudelka CW, Simpson EL: Eczema prevalence in the United States: Data from the 2003 National Survey of Children’s Health. J Invest Dermatol 131:67-73, 2011.

Inside US Outside USChild’s birthplace

FreqPercent(95% CI)

FreqPercent(95% CI)

OR(95% CI)

P-valueaOR

(95% CI)P-value

1013313.3

(12.7 – 13.8)174

6.1(4.1 – 8.1)

0.43(0.30 – 0.61)

<0.00010.45

(0.30 – 0.69)0.0003

Mother’s birthplace

FreqPercent(95% CI)

FreqPercent(95% CI)

OR(95% CI)

P-valueaOR

(95% CI)P-value

873113.2

(13.5 – 14.8)1076

9.2(8.0 – 10.5)

0.62(0.53 – 0.72)

<0.00010.58

(0.48 – 0.71)<0.0001

Father’s birthplace

FreqPercent(95% CI)

FreqPercent(95% CI)

OR(95% CI)

P-valueaOR

(95% CI)P-value

700413.0

(12.3 – 13.7)894

9.5(8.2 – 10.8)

0.70(0.59 – 0.82)

<0.00010.68

(0.54 – 0.85)0.0009

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Silverberg JI, Simpson EL, Durkin HG, Joks R. Prevalence of allergic disease is lower in foreign-born American children, but increases with prolonged US residence. JAMA Pediatrics. 2013.

Duration of residence in the US (yr)

0 – 2 3 – 10 > 10

FreqPercent(95% CI)

FreqPercent(95% CI)

aOR(95% CI)

P-value FreqPercent(95% CI)

aOR(95% CI)

P-value

445.1

(2.7 – 7.5)94

6.5(3.4 – 9.7)

1.96(0.79 – 4.85)

0.1535 6.8

(1.9 – 11.7)4.93

(1.18 – 20.62)0.029

Children born outside the US have significantly lower prevalence of eczema (and other allergic disorders).

Duration of residence in the US is a previously unrecognized factor in the epidemiology of AD.

Silverberg JI, Simpson EL, Durkin HG, Joks R. Prevalence of allergic disease is lower in foreign-born American children, but increases with prolonged US residence. JAMA Pediatrics. 2013.

Silverberg JI, Hanifin J, Simpson EL. Journal of Investigative Dermatology. 2013.

Recent meta-analysis of 30 studies from across the medical literature. Obesity was associated with higher rates of eczema in children and

adults in North America and Asia.

Zhang A and Silverberg JI. Journal of the American Academy of Dermatology. In Press.

Topical agents Corticosteroids, e.g. hydrocortisone Calcineurin inhibitors, e.g. tacrolimus.

Systemic agents Corticosteroids Cyclosporine Mycophenolate mofetil Tacrolimus Methotrexate Azathioprine

Light therapy and lasers NBUVB, Excimer, PUVA

Oral: prednisone, methylprednisolone, etc.

IV: methylprednisolone Intralesional and intramuscular:

Triamcinolone

Rapid onset, dramatic improvement of disease.

Horrific adverse effect profile: Weight gain, Cushingoid habitus, diabetes, hypertension,

gastroesophageal reflux, osteoporosis with prolonged use, osteonecrosis even with a single dose, adrenal insufficiency, increased risk of mild and serious infections and malignancy, neurocognitive events including depression and psychosis, fluid overload secondary to mineralcorticoid activity, etc.

More appropriate for contact dermatitis with brief or limited exposures, e.g. poison ivy.

Should be avoided for chronic persistent atopic dermatitis.

Best evidence for shutting down active disease and preventing flares

Typically works as fast as prednisone, but has longer lasting benefit.

Adverse effect profile not perfect, but better than prednisone:

Hypertension, kidney injury/disease, hyperkalemia, hypomagnesemia, gingival hypertrophy, hypertrichosis, dizziness, GI upset, increased risk of infection, increased risk of solid organ and hematological malignancy especially with prolonged use.

Can only use for limited period of time (6-24 months).

Must monitor blood pressure regularly and check bloodwork periodically.

Efficacy also established in well-designed trials Easier dosing: once weekly Slower onset of action than CsA. Can be used for

extended periods. May not be as effective as CsA at standard doses

Adverse effects: Anemia/pancytopenia, elevated transaminases and liver

fibrosis/failure, GI upset, heavy menstrual bleeding, increased risk of infection and malignancy

Must monitor bloodwork periodically. Should be given with folic acid 1mg daily

Efficacy demonstrated in well-designed trials; however, allowed the most breakthrough flares requiring add-on tx with prednisone

My personal experience: not as effective as CsA or MTX

Generally, better tolerated than other systemics. Adverse effects:

Anemia, pancytopenia, gastrointestinal discomfort and diarrhea, genitourinary complaints, swelling, increased risk of infection and malignancy, case-report of PMLE.

Multiple RCT demonstrated efficacy in AD. Used commonly in Europe. Not as much in US. Check bloodwork at baseline and periodically. Can monitor therapeutic levels with blood test.

Adverse effects: Hypersensitivity with rash, GI upset, increased risk of

infections and malignancy, bone marrow suppression.

Fully human anti- interleukin 4 receptor alpha antibody

Blocking antibody downregulation of IL4 and IL13 pathways, i.e. Th2 immune responses.

Th2 responses are found in acute and chronic AD skin lesions, asthma, hay fever and food allergies.

Represents first “targeted therapy” for AD Initial benefit demonstrated in asthma with

eosinophilia (NEJM, 2013). Currently in phase 2B recruitment.

The toxicity of the abovementioned systemic agents lies in their blanket immunosuppression.

More targeted therapy may: Improve efficacy Eliminate toxicity beyond the immune system Minimize immunological sequelae with decreased

risk of infection and malignancy. In turn, these open the door for ongoing

maintenance therapy for months or even years.

Phase 2 study of a monoclonal anti-IL31 antibody for AD (Chugai).

Phase 1 study of a monoclonal anti-IL31 antibody for AD (Bristol-Myers Squibb).

Both with promising results as treatments for itch in AD and well tolerated.

Intravenous immunoglobulin, omalizumab – evidence does not support efficacy in AD. AD is a Th2 mediated, but not an IgE

mediated disease.

Anti-interleukin 5 antibodies – only modest effects.

Higher out of pocket (OOP) costs overall.

$32,875,382,250 annual OOP costs in eczema patients.

$502/ year additional OOP cost per patient.

Silverberg JI. JAMA Dermatology. In Press.

5,898,289 lost workdays for eczema per se

221,607,545 days in bed for adults with eczema

More doctor visits and ER visits for adults with eczema.

1 in 4 adults with eczema did not see a doctor for their eczema.

Silverberg JI. JAMA Dermatology. In Press.

One third of adults with eczema reported having regular fatigue, daytime sleepiness and insomnia.

Sleep disturbance and fatigue are major players in the poor quality of life, number of sick days and doctor visits in patients with eczema.

Silverberg JI, et al. Journal of Investigative Dermatology. 2014.

Silverberg JI and Simpson EL. Pediatric Allergy and Immunology. 2014.

Silverberg JI and Simpson EL. Pediatric Allergy and Immunology. 2014.

Children with eczema have lower bone mineral density.

Silverberg JI. Pediatric Allergy and Immunology. In Press.

Adults with eczema have: Lower bone mineral density overall. Higher rates of osteoporosis. Higher rates of fractures.

Garg NK and Silverberg JI. Journal of Allergy and Clinical Immunology. In Press.

Children with eczema have higher rates of serious injuries requiring medical attention.

Garg NK and Silverberg JI. Annals of Allergy, Asthma and Immunology. 2014.

Garg NK and Silverberg JI. JAMA Dermatology. 2014.

Not an allergy per se. Infrequent exposure to strong irritants or

frequent exposure to milder irritants. Often occurs in atopic dermatitis due to

impaired barrier and lower irritant threshold.Nassif A, Chan SC, Storrs FJ, Hanifin JM. Abnormal skin irritancy in atopic dermatitis and in atopy without dermatitis. Archives of dermatology. 1994;130(11):1402-1407.

Common exposures include: Frequent hand washing Hand sanitizers Harsh soaps, e.g. antibacterial. Heavily fragrant skin care products.

Skin allergy. May become allergic after infrequent

exposure to strong allergens or frequent exposure to milder allergens.

Once an allergy develops, even minimal exposures can be provocative.

Delayed reactions that take takes, sometimes weeks, to develop.

Thursday: Final reading.

Sometimes: Monday, Thursday, Monday sequence

Monday: Patches applied to back with adhesive tape.

Wednesday: Patches removed and placemarker grid is drawn with marker.

Rationale 15.7% of adults with eczema have active hay fever 21.1% of adults with eczema have a history of

asthma, of which 40.8% had an asthma attack in past year.Silverberg JI, Hanifin J. Adult eczema prevalence and associations with asthma and other variables: A US population-based study. Journal of Allergy and Clinical Immunology. 2013 Nov;132(5):1132-8.

One third of adults with eczema have sleep disturbances that cause poor quality of life.Silverberg JI, Garg NK, Paller AS, Fishbein A, Zee PC. Sleep disturbances in adults with eczema are associated with impaired overall health: A US population-based study. Journal of Investigative Dermatology. 31 July 2014; doi: 10.1038/jid.2014.325.

Eczema is associated with significant psychological comorbidities and behavioral problems, including depression, anxiety and attention deficit (hyperactivity) disorder.Gark NK, Silverberg JI. Association between childhood allergic disease, psychological comorbidity and injury requiring medical attention. Annals of Allergy, Asthma and Immunology. 2014 Jun. 112(6): 525-32.

Monthly clinic Providers from Dermatology (Silverberg),

Allergy-Immunology (Peters and Grammer) and Neurology-Sleep Medicine (Attarian).

Psychiatry will be joining soon (Franks).

Services provided include: Consultation and treatment. Patch testing for allergic contact dermatitis. Skin prick testing for seasonal and food allergies. Spirometry for asthma assessment. Actigraphy for assessment of sleep disturbances.

History First session in May, 2014 Seen >70 patients from 6 states to-date. Provided unique insight into the

comorbidities of atopic dermatitis, resulting in two research grant submissions.

Thank you.

Questions??