Current Treatment Agents: Revolutionizing Atopic

Dermatitis ManagementFaculty: Sarah Ofori, PharmD, MBA, BSc

Post-doctoral FellowRutgers University/Pfizer

DISCLAIMER

● The presenter for this activity has been required to disclose all relationships with any proprietary entity producing health care goods or services, with the exemption of non-government organizations and non-healthcare related companies

● No significant financial relationships with commercial entities were disclosed by the speaker

(Please note any possible conflicts of interests or bias is to be disclosed early on and appropriate resolution taken or appropriately disclosed)

LEARNING OBJECTIVES

1. Describe the pathophysiology of atopic dermatitis2. Evaluate the atopic dermatitis diagnostic scales and classification3. Identify the signs, symptoms, and risk factors related to atopic

dermatitis4. Define the mechanism of action of treatment agents

PRE-TEST ACTIVITY

QUESTION #1

Atopic dermatitis is the most common, chronic, allergic inflammatory skin condition worldwideA. TrueB. False

QUESTION #5

Most cases of atopic dermatitis are seen in adults?A. TrueB. False

QUESTION #2

Mutation in the filaggrin gene is a contributor to all of the following EXCEPT?A. Severe eczemaB. Delayed onset of atopic dermatitisC. Increased risk of asthma D. Development of food allergies

QUESTION #3

Skin fibrosis is commonly associated with which interleukin ?A. IL-4B. IL-10C. IL-5D. IL-31

QUESTION #4

Which of the following is a major criteria in the diagnosis of atopic dermatitis?A. XerosisB. LichenificationC. Elevated serum IgED. Pruritus

ATOPICDERMATITIS

EPIDEMIOLOGY

ATOPIC DERMATITIS

● Atopic dermatitis (AD) also known as atopic eczema is the most common, chronic, allergic, inflammatory skin condition.1,2

● In the United States, there are an estimated 17.8 million currently affected by AD.3

○ In industrialized countries, there has been an increase in AD, affecting approximately 15% to 20% of children and 1% to 3% of adults worldwide.4

1. Nutten, S. (2015). Atopic dermatitis: global epidemiology and risk factors. Annals of Nutrition and Metabolism, 66(Suppl. 1), 8-16. 2. Peng, W., & Novak, N. (2015). Pathogenesis of atopic dermatitis. Clinical & Experimental Allergy, 45(3), 566-574.3.Spergel, J. M. (2010). Epidemiology of atopic dermatitis and atopic march in children. Immunology and Allergy Clinics, 30(3), 269-280. 4. Avena-Woods, C. (2017). Overview of atopic dermatitis. The American journal of managed care, 23(8 Suppl), S115-S123.

● Analyzed a nationwide health register on prescription data to determine incidence rate (IR) of AD in an entire pediatric population○ Disease-specific prescriptions analyzed = 295,286

● All children residents in Norway < 6 years● January 1, 2009 to December 31, 2015

Mohn, C. H., Blix, H. S., Halvorsen, J. A., Nafstad, P., Valberg, M., & Lagerløv, P. (2018). Incidence trends of atopic dermatitis in infancy and early childhood in a nationwide prescription registry study in Norway. JAMA network open, 1(7), e184145-e184145.

● Overall incidence rate increased from 0.028 per PY (95% CI 0.028 -0.029 per PY) in 2009 to 0.034 per PY ( 95% CI 0.050 - 0.053 PY) in 2014

Mohn, C. H., Blix, H. S., Halvorsen, J. A., Nafstad, P., Valberg, M., & Lagerløv, P. (2018). Incidence trends of atopic dermatitis in infancy and early childhood in a nationwide prescription registry study in Norway. JAMA network open, 1(7), e184145-e184145.

PATHOPHYSIOLOGY

DISEASE COMPONENTS

Environment

Genetics

Skin Barrier Dysfunction

Immunology

SKIN BARRIER DYSFUNCTIONEpidermal barrier Abnormalities Functional effects

Transepidermal epithelial differentiation products

↓ filaggrin, loricrin, involucrin, corneodesmosin, keratin 1 and 10

↓ skin water content, enhanced allergen, microbial penetration and ↑ skin pH

Tight junctions ↓ claudin-1, 8 and 23 ↑ transepidermal water loss (TEWL), enhanced allergen & microbial penetration↓ cohesion

Microbial barriers Cutaneous dysbiosis Skin inflammation, microbial skin infections, keratinocytes death and exacerbation of AD

1.Kim, B. E., & Leung, D. Y. (2018). Significance of skin barrier dysfunction in atopic dermatitis. Allergy, asthma & immunology research, 10(3), 207-215. 2.Kim, J., Kim, B. E., & Leung, D. Y. (2019, March). Pathophysiology of atopic dermatitis: Clinical implications. In Allergy and asthma proceedings (Vol. 40, No. 2, p. 84). OceanSide Publications. 3.Cork, M. J., Danby, S., Vasilopoulos, Y., Moustafa, M., MacGowan, A., Varghese, J., ... & Ward, S. J. (2008). Epidermal barrier dysfunction in atopic dermatitis. In Textbook of Atopic Dermatitis (pp. 47-70). CRC Press.

SKIN BARRIER DYSFUNCTION

Epidermal barrier Abnormalities Functional effects

Lipids Altered composition of epidermal lipids and ↓ ceramide

Staphylococcal infection, dry skin ↑ TEWL

Immune barrier ↓ cathelicidin, HBD-2, & HBD-3

Recurrent microbial infections, skin dysbiosis and exacerbation of AD

1.Kim, B. E., & Leung, D. Y. (2018). Significance of skin barrier dysfunction in atopic dermatitis. Allergy, asthma & immunology research, 10(3), 207-215. 2.Kim, J., Kim, B. E., & Leung, D. Y. (2019, March). Pathophysiology of atopic dermatitis: Clinical implications. In Allergy and asthma proceedings (Vol. 40, No. 2, p. 84). OceanSide Publications. 3.Cork, M. J., Danby, S., Vasilopoulos, Y., Moustafa, M., MacGowan, A., Varghese, J., ... & Ward, S. J. (2008). Epidermal barrier dysfunction in atopic dermatitis. In Textbook of Atopic Dermatitis (pp. 47-70). CRC Press.

GENETICS● Familial link

○ Genetic risk of a child with a family history of allergies developing other allergic conditions related to the atopic march

○ Dold et al● Questionnaire filled out by 6665 families ● Data collected in population based cross sectional survey of 9-11 year old

children in Munich and southern Bavaria ● Results support the hypothesis that asthma, allergic rhinitis, and atopic

dermatitis are multifactorial diseases brought about by various familial and environmental influences

Dold, S., Wjst, M., Von Mutius, E., Reitmeir, P., & Stiepel, E. (1992). Genetic risk for asthma, allergic rhinitis, and atopic dermatitis. Archives of disease in childhood, 67(8), 1018-1022.

Genetic Risk Of Asthma, Allergic Rhinitis, And Atopic Dermatitis

Family history Boys (%) Girls (%) Total (%)

No allergic family history 14 16 15

One parent with AD 38 37 38

OR (95% CI) 3.8 (2.7 to 5.5) 3.2 (2.2 to 4.5) 3.4 (2.6 to 4.4)

One parent with allergic rhinitis

18 23 20

OR (95% CI) 1.3 (0.9 to 1.8) 1.5 (1.2 to 2.1) 1.4 (1.1 to 1.8)

One parent with asthma 14 27 21

OR (95% CI) 1.0 (0.5 to 1.9) 2.0 (1.2 to 3.3) 1.5 (1.0 to 2.2)

Child’s Atopic Dermatitis (Ad) In Relation To One Of The Parent With AD

Dold, S., Wjst, M., Von Mutius, E., Reitmeir, P., & Stiepel, E. (1992). Genetic risk for asthma, allergic rhinitis, and atopic dermatitis. Archives of disease in childhood, 67(8), 1018-1022.

FILAGGRIN (FLG)● Crucial protein in skin barrier● Most frequent mutation involving variation in genes● Observed in 10% - 50% of patients with AD worldwide

● Margolis et al.

● Contributor to the atopic march

○ Associated with severe eczema, early onset AD, ↑ risk of asthma

Margolis, D. J., Apter, A. J., Gupta, J., Hoffstad, O., Papadopoulos, M., Campbell, L. E., ... & Mitra, N. (2012). The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. Journal of Allergy and Clinical Immunology, 130(4), 912-917.

● Evaluated the effect of individual FLG null mutation on the persistence of AD

● Multiyear, prospective cohort study● Children with respect the FLG null mutations

○ n=857 subjects Individuals with a FLG null mutation were less likely to report that their skin was symptom-free at any time as compared to those without a FLG null mutation [OR: 0.54 (95% CI 0.41 - 0.71)]

ATOPIC MARCH● Also referred to as the “allergic march”● Early development of atopic dermatitis during infancy, followed by the

progression of IgE-mediated allergic rhinitis, food allergies and asthma later in childhood.

1.Bantz, S. K., Zhu, Z., & Zheng, T. (2014). The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma. Journal of clinical & cellular immunology, 5(2). 2.Hill, D. A., & Spergel, J. M. (2018). The atopic march: critical evidence and clinical relevance. Annals of Allergy, Asthma & Immunology, 120(2), 131-137.

IMMUNE RESPONSE ● Key cells involved in the innate immunity for the the skin: keratinocytes

& dendritic cells (DCs)● Defects in the innate immunity associated with increased bacterial &

viral infections in AD● Epidermal DCs carry a high-affinity receptor (FcεRI) for IgE

○ IgE plays a role in allergen presentation to T-helper type (Th2) cells via Langerhans cells

○ LCs cells with FcεRI that bear IgE are necessary to provoke eczematous skin lesions in unprovoked AD of skin

● Keratinocytes produce antimicrobial peptides (AMPs)○ ↓ AMP = ↑ Staphylococcus aureus infections

1.Kumar, S., Jeong, Y., Ashraf, M. U., & Bae, Y. S. (2019). Dendritic Cell-Mediated Th2 Immunity and Immune Disorders. International journal of molecular sciences, 20(9), 2159. 2.Leung, D. Y. (1993). Role of IgE in atopic dermatitis. Current opinion in immunology, 5(6), 956-962.

TH2 CYTOKINES INVOLVED IN ATOPIC DERMATITIS DERMATITIS

Brandt, E. B., & Sivaprasad, U. (2011). Th2 cytokines and atopic dermatitis. Journal of clinical & cellular immunology, 2(3).

SELECTED CYTOKINES AND THEIR ABNORMALITIES IN ATOPIC DERMATITIS

Cytokine Abnormality in AD

IL-4 ↑ IL-4 = pruritus, ↑ inflammatory cells in skin, ↑ bacterial infection, ↑ IgE

IL-13 ↑ IL-13 = pruritic dermatitis, ↑ IgG1 and IgE levels, inflammatory cell infiltration into the skin, skin fibrosis

IL-5 ↑ IL-5 = ↑ eosinophilia

IL-31 ↑ IL-31 = severe pruritus, skin lesions

IL-10 Potentially modulates disease severity ?

Brandt, E. B., & Sivaprasad, U. (2011). Th2 cytokines and atopic dermatitis. Journal of clinical & cellular immunology, 2(3).

ENVIRONMENT & LIFESTYLE FACTORS

CLIMATE • Worldwide data collected from 146 centers of the International Study of

Asthma and Allergies in Childhood (ISAAC)

• 155 study centers in 56 countries on six countries

• Involved 463 801 children in this age group and had a participation of more than 85% in most study centers

• Prevalence of eczema symptoms correlated with latitude (positively) and mean annual outdoor temperature (negatively)

Weiland, S. K., Hüsing, A., Strachan, D. P., Rzehak, P., & Pearce, N. (2004). Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. Occupational and environmental medicine, 61(7), 609-615.

FOOD ALLERGIES • Certain foods can trigger IgE-mediated hypersensitivity reactions as

well as eczematous lesions either immediately

• Food allergies are seen in roughly, 1/3 of children with moderate to severe AD

• Most common food allergens observed in ≥ 90% of individuals with AD: cow’s milk, nuts, wheat, hen’s eggs and fish

• Once a potential allergen is identified, it is recommended to avoid the agent in an effort to minimize AD exacerbation

1. Katta, R., & Schlichte, M. (2014). Diet and dermatitis: food triggers. The Journal of clinical and aesthetic dermatology, 7(3), 30. 2.Bergmann, M. M., Caubet, J. C., Boguniewicz, M., & Eigenmann, P. A. (2013). Evaluation of food allergy in patients with atopic dermatitis. The journal of allergy and clinical immunology: In Practice, 1(1), 22-28.

BODY MASS INDEX (BMI)

• Investigated the association between AD, body weight and serum lipid levels

• 239 children under the age of 14

• Mean body mass index (BMI) was slightly higher in AD patients compared to healthy controls

• Additionally, slightly higher in AD patients aged 0-2 years and 12-14 years

• BMI was significantly higher in those with severe atopic dermatitis in the 9-12 age group (P=0.03) and 12 -14 age group (P=0.01)

BODY MASS INDEX (BMI) Age Group Mild AD Moderate

ADSevere AD P-value

0-2 15.0 17.3 15.8 NS2-5 18.7 15.9 15.2 NS5-9 17.7 17.6 16.3 NS9-12 18.8 19.3 24.4 0.0312-14 - 21.9 27.8 0.01NS = Not significant

BMI was significantly higher in those with severe atopic dermatitis in the 9-12 age group (P=0.03) and 12 -14 age group (P=0.01)

Agón‐Banzo, P. J., Sanmartin, R., García‐Malinis, A. J., Hernández‐Martín, Á., Puzo, J., Doste, D., ... & Gilaberte, Y. (2019). Body mass index and serum lipid profile: Association with atopic dermatitis in a paediatric population. Australasian Journal of Dermatology.

MULTIFACTORIAL DISEASE

Image adapted from: American Academy of Allergy, Asthma & Immunology (n.d.). Amplification cycle and mediators involved in atopic dermatitis.. [image] Available at: https://www.aaaai.org/about-aaaai/newsroom/photo-gallery/photos-graphics-atopic-dermatitis [Accessed 9 Jan. 2020].

SIGNS, SYMPTOMS & RISK FACTORS

SIGNS & SYMPTOMS● Usually presents within the first 5 years of life in 90% of patients

● In infants and children, the face, scalp and extensor regions of the body is affected

● Older children and adults are affected in mainly in the flexural areas

● Most common symptom related to AD is pruritus

○ Another important symptom is xerosis reported across both children and adults

Lyons, J. J., Milner, J. D., & Stone, K. D. (2015). Atopic dermatitis in children: clinical features, pathophysiology, and treatment. Immunology and Allergy Clinics, 35(1), 161-183.

MAJOR CRITERIA MINOR CRITERIA Pruritus

Characteristic morphology and distribution:● Facial and extensor involvement in

infants and children; flexural involvement with lichenification in adults

Chronic or chronic, relapsing coursePersonal or family history of atopy, including asthma, allergic rhinitis, atopic dermatitis

Early age of onset

Xerosis

Palmar hyperlinearity, ichthyosis, keratosis pilaris

Elevated serum IgE

Cutaneous infection

Cheilitis/Pityriasis alba

Facial erythema or pallor

SELECTED DIAGNOSTIC CRITERIA

Eichenfield, L. F., Tom, W. L., Chamlin, S. L., Feldman, S. R., Hanifin, J. M., Simpson, E. L., ... & Cordoro, K. M. (2014). Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. Journal of the American Academy of Dermatology, 70(2), 338-351.

Images adapted from: American Academy of Allergy, Asthma & Immunology (n.d.).[image] Available at: https://www.aaaai.org/about-aaaai/newsroom/photo-gallery/photos-graphics-atopic-dermatitis [Accessed 9 Jan. 2020].

RISK FACTORS OF ATOPIC DERMATITIS

Two major risk factor associated with the development of AD:1. A family history of atopy2. Loss of function mutations in the filaggrin (FLG) gene

Eichenfield, L. F., Tom, W. L., Chamlin, S. L., Feldman, S. R., Hanifin, J. M., Simpson, E. L., ... & Cordoro, K. M. (2014). Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. Journal of the American Academy of Dermatology, 70(2), 338-351.

DIAGNOSTIC TOOLS

SCORING SYSTEM DESCRIPTION SEVERITY RATING

SCORing Atopic Dermatitis (SCORAD)

3 components:(A) Extent—sites affected(B) Intensity score for redness, swelling, crusting or oozing, skin thickening (lichenification), dryness, scratch marks(C) Subjective score for sleeplessness and itch

SCORAD total score = A/5 + 7B/2 + C (maximum 103)

Mild <25, moderate >25 to <50, severe >50

Eczema Area and Severity Index (EASI)

2 components: (A) Area score recorded for 4 regions (B) Severity score for each region calculated based on intensity of redness, thickness or swelling, scratching, lichenification

Maximum score of 12 for each region

Mild 1.1–7, moderate 7.1–21, severe 21.1–50, very severe 50.1–72

Investigator Global Assessment (IGA)

Utilized by the FDA to categorize AD severity based on investigator's subjective assessment of a lesion according to erythema, induration or papulation, and/or oozing or crusting.

0 = clear to 4 = severe

Dermatology Life and Quality Index (DLQI)

10-question validated questionnaire providing patient's perception of the impact of AD on quality of life in past week

Each question is answered according to ratings: 0 = not at all, 1 = a little, 2 = a lot, 3 = very much; maximum 30

SELECTED DIAGNOSTIC TOOLS USED IN ATOPIC DERMATITIS CLINICAL RESEARCH

Joji, T. A. D. A. (2002). Diagnostic standard for atopic dermatitis. JMA Policies, 45(11), 460-5.

NON-PHARMACOLOGIC AGENTS

EMOLLIENTS & MOISTURIZERS

● Mainstay of therapy● Form a thin hydrophobic surface on the skin that ↓

transepidermal water loss (TEWL) and ↑ skin hydration● Mimic components found on the skin:

○ ceramides, cholesterol and free fatty acids ● Loden et al

1.Hon, K. L., Pong, N. H., Wang, S. S., Lee, V. W., Luk, N. M., & Leung, T. F. (2013). Acceptability and efficacy of an emollient containing ceramide-precursor lipids and moisturizing factors for atopic dermatitis in pediatric patients. Drugs in R&D, 13(1), 37-42. 2.Hon, K. L., Kung, J. S. C., Ng, W. G. G., & Leung, T. F. (2018). Emollient treatment of atopic dermatitis: latest evidence and clinical considerations. Drugs in context, 7.

• The use of urea-containing moisturizers on the barrier properties of atopic skin

• N= 15 patients• AD patients treated one of their forearms BID with a moisturizing cream for

20 days• Measured skin capacitance and TEWL at baseline, Day 10 and Day 20

○ Irritant exposure – sodium lauryl sulfate: Day 21

TEWL Skin Capacitance

RESULTS IN THE TREATED ARM

The moisturizer had no meaningful effect on TEWL. However, there was significant improvement in skin

capacitance. Loden, M., Andersson, A. C., & Lindberg, M. (1999). Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm). The British journal of dermatology, 140(2), 264-267.

Irritative response: measured by TEWL and superficial skin blood

flow

RESULTS IN THE TREATED ARM

Prophylactic treatment with a urea‐containing moisturizer showed improvement in barrier properties of atopic skin

Loden, M., Andersson, A. C., & Lindberg, M. (1999). Improvement in skin barrier function in patients with atopic dermatitis after treatment with a moisturizing cream (Canoderm). The British journal of dermatology, 140(2), 264-267.

EMOLLIENTS & MOISTURIZERSAgents Ingredients Function

Emollients Glycol and glyceryl stearate, soy sterols)

Lubricate and soften the skin

Occlusive Agents Petrolatum, dimethicone, mineral oil, lanolin, liquid paraffin

Form a layer to retard evaporation of water

Humectants Glycerol, lactic acid, urea, propylene glycol

Attract and hold water

1.Eichenfield, L. F., Tom, W. L., Berger, T. G., Krol, A., Paller, A. S., Schwarzenberger, K., ... & Cordoro, K. M. (2014). Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topicaltherapies. Journal of the American Academy of Dermatology, 71(1), 116-132. 2.Gelmetti, C., & Wollenberg, A. (2014). Atopic dermatitis–all you can do from the outside. British Journal of Dermatology, 170, 19-24. 3.Buys, L. M. (2007). Treatment options for atopic dermatitis. American family physician, 75(4)

● The efficacy of moisturizing is greater following twice daily application (morning and evening) compared to once daily. It is recommended to apply emollients immediately after bathing.35-36 For patients with mild AD moisturizers can be the main primary therapy; and should be added as part of the regimen for patients with moderate to severe AD.37 Currently, there are a variety of emollients and moisturizers on the market that can be used in the management of AD. They are available in multiple formulations ranging from creams to ointments

PHARMACOLOGIC AGENTS

TOPICAL CORTICOSTEROIDS (TCS)

● Approved for both children and adults with AD● Primarily used in the management of AD flares and in the prevention

of relapses● Mainstay of anti-inflammatory therapy

○ Acts on multiple immune cells: T-lymphocytes, macrophages and DCs

○ Suppress the release of pro-inflammatory cytokines ○ Interferes with antigen processing

● Available in low to high potency range1.Ring, J., Alomar, A., Bieber, T., Deleuran, M., Fink‐Wagner, A., Gelmetti, C., ... & Schäfer, T. (2012). Guidelines for treatment of atopic eczema (atopic dermatitis) part I. Journal of the European Academy of Dermatology and Venereology, 26(8), 1045-1060. 2.Eichenfield, L. F., Boguniewicz, M., Simpson, E. L., Russell, J. J., Block, J. K., Feldman, S. R., ... & Paller, A. S. (2015). Translating atopic dermatitis management guidelines into practice for primary care providers. Pediatrics, 136(3), 554-565.

• Multicenter, double-masked, placebo-controlled, randomized study

• Evaluated the efficacy, safety, tolerability and cosmetic acceptability of hydrocortisone buteprate 0.1% cream

○ N=194 adults

• Hydrocortisone buteprate 0.1% cream or placebo (cream base of the medication) applied topically once daily for 14 days

• Investigators assessed the severity of dermatitis signs on a 4-point scale at baseline and on Days 3, 7 and 14

• Most commonly reported adverse event was burning sensation

RESULTS

Sears, H. W., Bailer, J. W., & Yeadon, A. (1997). Efficacy and safety of hydrocortisone buteprate 0.1% cream in patients with atopic dermatitis. Clinical therapeutics, 19(4), 710-719.

Hydrocortisone buteprate 0.1% was rated as having greater overall improvement at each efficacy level versus placebo

Potency Drug Formulation(s) Strength (%)

I. Very High Augmented betamethasone dipropionate Ointment 0.05

Clobetasol propionate Cream, foam, ointment 0.05

II. High Augmented betamethasone dipropionate Cream 0.05

Triamcinolone acetonide Cream, ointment 0.5

III-IV. Medium Betamethasone valerate Cream, foam, lotion, ointment

0.1

Mometasone furoate Cream 0.1

Triamcinolone acetonide Cream, ointment 0.1

V. Lower-medium

Hydrocortisone butyrate Cream, ointment, solution 0.1

Hydrocortisone probutate Cream 0.1

Hydrocortisone valerate Cream, ointment 0.2

VI. Low Alclometasone dipropionate Cream, ointment 0.05

SELECTED TOPICAL CORTICOSTEROIDS USED IN ATOPIC DERMATITIS

.Eichenfield, L. F., Boguniewicz, M., Simpson, E. L., Russell, J. J., Block, J. K., Feldman, S. R., ... & Paller, A. S. (2015). Translating atopic dermatitis management guidelines into practice for primary care providers. Pediatrics, 136(3), 554-565.

ADMINISTRATION

American College of Allergy, Asthma and Immunology. (2019) Proper Use and Monitoring of Topical Corticosteroids Side Effects. Retrieved from https://education.acaai.org/content/proper-use-and-monitoring-topical-corticosteroids-side-effects

TOPICAL CALCINEURIN INHIBITORS (TCIs)● Tacrolimus and pimecrolimus are approved for short-term or chronic

intermittent AD in patients ≥ 2 years of age who have failed other treatment agents

● Macrolactams that suppress the immune system by inhibiting the action of T-lymphocytes thus decreasing the release of pro-inflammatory cytokines.

● Both agents inhibit mast cell and neutrophil activation and release of inflammatory mediators.

● Tacrolimus has additional effects on basophils and eosinophils function● Black Box warning on TCIs for the lack of long-term safety data and the

potential risk of the development of malignancies

1.Carr, W. W. (2013). Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations. Pediatric Drugs, 15(4), 303-310. 2.Gutfreund, K., Bienias, W., Szewczyk, A., & Kaszuba, A. (2013). Topical calcineurin inhibitors in dermatology. Part I: Properties, method and effectiveness of drug use. Advances in Dermatology and Allergology/Postȩpy Dermatologii I Alergologii, 30(3), 165.

TOPICAL CALCINEURIN INHIBITORS (TCIs)

● Pimecrolimus is approved for mild-to-moderate AD when TCS are not well tolerated or contraindicated

● Tacrolimus is approved for patients with moderate-to-severe AD when there is minimal response to other treatment options including TCS

● Additional usages:○ To prevent relapses and prevent flares in patients experiencing ≥

four exacerbations per year, who previously responded to treatment with tacrolimus ointment 2 times a day for maximum 6 weeks

1.Carr, W. W. (2013). Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations. Pediatric Drugs, 15(4), 303-310. 2.Gutfreund, K., Bienias, W., Szewczyk, A., & Kaszuba, A. (2013). Topical calcineurin inhibitors in dermatology. Part I: Properties, method and effectiveness of drug use. Advances in Dermatology and Allergology/Postȩpy Dermatologii I Alergologii, 30(3), 165.

SELECTED TOPICAL CALCINEURIN INHIBITORS USED IN ATOPIC DERMATITIS

Drug Formulation(s)

Strength(s) Administration

Tacrolimus Ointment 0.1%, 0.03% ● Ages 2 to 16 years, first 0.03% ointment twice daily for 3 weeks, then once daily until disappearance of lesions

● From the age of 16 years, 0.1% ointment until disappearance of lesions

Pimecrolimus

Cream 1% ● Adults and children older than 2 years, twice daily until lesions disappear, not longer than 6 weeks

.Gutfreund, K., Bienias, W., Szewczyk, A., & Kaszuba, A. (2013). Topical calcineurin inhibitors in dermatology. Part I: Properties, method and effectiveness of drug use. Advances in Dermatology and Allergology/Postȩpy Dermatologii I Alergologii, 30(3), 165.

CRISABOROLE 2% TOPICAL OINTMENT

● Crisaborole is a nonsteroidal, phosphodiesterase 4 (PDE-4) inhibitor● Inhibition of PDE-4 results in increased intracellular cyclic adenosine

monophosphate (cAMP) levels○ The overall mechanism of action of crisaborole on AD lesions is not

well understood● Crisaborole is indicated for mild-to-moderate AD in patients aged 2 years

and older. ● Most common adverse event note is application site pain

1.Eucrisa [package insert]. New York, NY: Pfizer Laboratories Div Pfizer Inc; 2017 2.Paller, A. S., Tom, W. L., Lebwohl, M. G., Blumenthal, R. L., Boguniewicz, M., Call, R. S., ... & Spellman, M. C. (2016). Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Journal of the American Academy of Dermatology, 75(3), 494-503.

CRISABOROLE● Approved December 14th 2016

● PDE4 is a key regulator of inflammatory cytokine production in AD through the breakdown of cAMP

● The inhibition of PDE4 in monocytes in vitro has demonstrated reduction in the release of proinflammatory cytokines.

● Crisaborole is indicated for mild-to-moderate AD in patients aged 2 years and older. A thin layer is applied twice daily to affected areas on the skin.

● Most common adverse event note is application site pain

.Eucrisa [package insert]. New York, NY: Pfizer Laboratories Div Pfizer Inc; 2017 2.Paller, A. S., Tom, W. L., Lebwohl, M. G., Blumenthal, R. L., Boguniewicz, M., Call, R. S., ... & Spellman, M. C. (2016). Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Journal of the American Academy of Dermatology, 75(3), 494-503.

Efficacy And Safety Of Crisaborole Ointment, A Novel, Nonsteroidal Phosphodiesterase 4 (PDE-4) Inhibitor For The Topical Treatment Of

Atopic Dermatitis (AD) In Children And Adults.

Paller, A. S., Tom, W. L., Lebwohl, M. G., Blumenthal, R. L., Boguniewicz, M., Call, R. S., ... & Spellman, M. C. (2016). Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Journal of the American Academy of Dermatology, 75(3), 494-503

• Two identically designed multicenter, randomized, double-blind, vehicle-controlled phase III clinical studies

• Assessed the efficacy and safety of crisaborole in patients with mild to moderate AD

• Patients were instructed to apply a layer of study drug to cover each lesion twice daily for 28 days

• The primary efficacy end point of success in ISGA score at day 29 was defined as clear (0) or almost clear (1) with a 2-grade or more improvement from baseline

RESULTS• Patients in the crisaborole treatment arm

achieved a higher ISGA score success and improvement in pruritus (clear/almost clear with ≥2-grade improvement)

• AD-301: 32.8% vs 25.4%, P = 0.038

• AD-302: 31.4% vs 18.0%, P < 0.001

Paller, A. S., Tom, W. L., Lebwohl, M. G., Blumenthal, R. L., Boguniewicz, M., Call, R. S., ... & Spellman, M. C. (2016). Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Journal of the American Academy of Dermatology, 75(3), 494-503

DUPILUMAB● Approved March 28th, 2017

● First biologic agent approved for the treatment of AD● Subcutaneous administration for the treatment of patients aged 12 years

or older with moderate-to-severe AD● 400-mg loading dose followed by 200 mg every 2 weeks with baseline

body weight <60 kg or a 600-mg loading dose followed by 300 mg every 2 weeks in patients weighing ≥60 kg or more with moderate to severe AD inadequately controlled with topical prescription therapies or when those therapies are not advisable

● Most common adverse reaction associated with dupilumab is injection site reaction and conjunctivitis

1.Simpson, E. L., Bieber, T., Guttman-Yassky, E., Beck, L. A., Blauvelt, A., Cork, M. J., ... & Kingo, K. (2016). Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. New England Journal of Medicine, 375(24), 2335-2348. 2.Simpson, E. L., Paller, A. S., Siegfried, E. C., Boguniewicz, M., Sher, L., Gooderham, M. J., ... & Weisman, J. (2019). Efficacy and safety of dupilumab in adolescents with uncontrolled moderate to severe atopic dermatitis: a phase 3 randomized clinical trial. JAMA dermatology.

A Fully Human Monoclonal Antibody That Binds Specifically To The Shared Alpha Chain Subunit Of The Interleukin-4 (Il-4) And

Interleukin-13 (Il-13) Receptors, Thereby Inhibiting The Signaling Of Both Interleukin

Bao, K., & Reinhardt, R. L. (2015). The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine, 75(1), 25-37.

Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis

Simpson, E. L., Bieber, T., Guttman-Yassky, E., Beck, L. A., Blauvelt, A., Cork, M. J., ... & Kingo, K. (2016). Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. New England Journal of Medicine, 375(24), 2335-2348.

• Two identical, randomized, placebo-controlled, phase 3 trials of dupilumab versus placebo in atopic dermatitis (SOLO 1 and SOLO 2)

• Adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment were enrolled into the study

• Subjects received subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo based on 1:1:1 randomization for 16 weeks

• The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the IGA and a reduction of 2 points or more in that score from baseline at week 16.

Simpson, E. L., Bieber, T., Guttman-Yassky, E., Beck, L. A., Blauvelt, A., Cork, M. J., ... & Kingo, K. (2016). Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. New England Journal of Medicine, 375(24), 2335-2348.

RESULTS• Similar results were observed between

both SOLO 1 and SOLO 2• Dupilumab showed significant

improvement in AD signs and symptoms • The most frequently reported adverse

event related to dupilumab was conjunctivitis and injection-site pain

CONCLUSION

● Atopic dermatitis is a chronic, allergic, inflammatory skin condition that has increased incidence rates in industrialized countries.

● AD is multifactorial ● Emollients and moisturizers as a mainstay of therapy with the addition of

other agents to manage symptoms, reduce relapses and decrease flares. ● Topical corticosteroids and calcineurin are among the agents utilized in

the treatment paradigm● Novel agents such as crisaborole and dupilumab have recently been

approved to provide additional treatment options to patients.

Have you seen Atopic Dermatitis at your

Practice?

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