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Atopic Dermatitis: New Research on Disease Course and Treatment.

Recent observational findings have upended the conception of atopic dermatitis (AD) as a disease of early childhood onset and late childhood/adolescent resolution marked mostly by cutaneous symptoms and comorbidities. Childhood AD may persist into adulthood, and adult onset is now well established. Novel treatments are also becoming available after years with no new therapies. Crisaborole and dupilumab are now among AD treatment options. Many systemic and topical therapies are in development.

Variable Course of AD

Longitudinal follow-up of 2 large birth cohorts has revealed multiple patterns of AD development. The stereotypical course of early onset-early resolving disease was the most common, but sizable proportions of children who developed the disease followed other patterns (Figure). (1) Although many children outgrow AD by or during adolescence, the disease sometimes persists into later adolescence and adulthood. A 25-study meta-analysis reported that roughly 26% cases of AD began in adulthood ([greater than or equal to]16 years old).

Pediatric and Adult Prevalence

Two recent US-based surveys yielded almost identical prevalence figures of AD in adults--7.2% and 7.3%--for a total of about 16.5 million adults with AD. (3,4) In the United States, the 12-month AD prevalence is 10.7% in children age 17 years and younger. (5) Diagnosing AD in adults is more difficult than diagnosing AD in children. Identifying AD in adults requires not only awareness of the disorder but evaluation of a larger differential diagnosis than in children, including psoriasis, contact dermatitis, and T-cell lymphoma.

How Often Is AD Moderate or Severe?

About one-third of children with AD have moderate or severe disease. (6) Rates of moderate-to-severe disease were higher in adults with AD, at 47%. (4)

Defining Moderate-to-Severe AD in Clinical Practice

A recent consensus report established criteria for defining moderate-to-severe disease in clinical practice (Table 1). (7) Patients with more than 10% of their body surface area affected who have been untreated or undertreated and who respond well to topical therapies may have mild disease.

Treatment

Older Agents

Many commonly used agents, including antimicrobials, antiseptics, and antihistamines, are not approved by the US Food and Drug Administration (FDA) for AD, and no evidence supports their use. Efficacious older therapies include cyclosporine, corticosteroids, and methotrexate. The newest agents are the topical treatment crisaborole and the systemic biologic dupilumab. The most recent American Academy of Dermatology guidelines predate the newest therapies for AD, (8,9) but the Atopic Dermatitis Yardstick attempts to fill the gap by incorporating current treatments into the algorithm. (10)

Crisaborole

Crisaborole, a topical phosphodiesterase-4 inhibitor, was FDA-approved in 2016 for use in AD. Recently it was shown to improve quality of life (QOL) for both patients and their families after 29 days of therapy. The vehicle also improved QOL from baseline, meeting the threshold for a minimal clinically important difference. But improvements with crisaborole significantly exceeded those observed with the vehicle, a petrolatum-based moisturizer. (11)

Dupilumab

Dupilumab, an anti-interleukin (IL)-4, anti-IL-13 injectable biologic agent, has received FDA approval to treat AD in adolescents (age [greater than or equal to]12 years) as well as adults. (12) Phase 3 data showing efficacy in an adolescent population with moderate-to-severe AD were presented recently. (13) Interestingly, roughly half of the patients in this trial had asthma at baseline, and dupilumab is FDA-approved as add-on therapy in asthma for adolescents with an eosinophilic phenotype or dependent on oral corticosteroids. (12) This agent may have multiple benefits in this subset of patients.

New Systemic Therapies

At least 5 compounds are in phase 3 development (Table 2) and 15 compounds are in phase 2 development for systemic treatment of AD.

New Topical Therapies

Several new agents are in phase 3 development for use as topical therapies in AD (Table 3). (14-16)

Vitamin D Supplementation

Vitamin D deficiency was correlated with AD severity in children, but vitamin D supplementation did not significantly improve disease severity. (17)

Summary

For many patients, AD extends beyond childhood or starts after childhood. Topical crisaborole and the biologic agent dupilumab offer additional treatment options to alleviate the substantial disease burden associated with AD. Additional new topicals and systemic therapies for treating AD are in clinical development.

References

(1.) Paternoster L, Savenije OEM. Heron J, et al. Identification of atopic dermatitis subgroups in children from 2 longitudinal birth cohorts. J Allergy Clin Immunol. 201S; 141(3):964-971.

(2.) Lee HH, Patel KR, Singam V, Rastogi S, Silverberg JI. A systematic review and meta-analysis of the prevalence and phenotype of adult-onset atopic dermatitis. J Am Acad Dermatol. 2019; 80(6): 1526-1532.e7.

(3.) Hua T, Silverberg J I. Atopic dermatitis in US adults: epidemiology, association with marital status, and atopy. Aim Allergy Asthma Immunol. 2018;121(5):622-624.

(4.) Silverberg JI, Gelfand JM, Margolis DJ, et al. Patient burden and quality of life in atopic dermatitis in US adults: a population-based cross-sectional study. Ann Allergy Asthma Immunol. 2018; 121 (3):340-347.

(5.) 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;131(1):67-73.

(6.) Silverberg JI, Simpson EL. Associations of childhood eczema severity: a US population-based study. Dermatitis. 2014;25(3):107-114.

(7.) Boguniewicz M, Alexis AF, Beck LA. et al. Expert perspectives on management of moderate-to-severe atopic dermatitis: a multidisciplinary consensus addressing current and emerging therapies. J Allergy Clin Immunol Pract. 20172(6): 1519-1331.

(8.) Sidbury R, Davis DM, Cohen DE. et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014:71(2):327-349.

(9.) Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am A cad Dermatol. 2014;71 (1): 116-132.

(10.) Boguniewicz M, Fonacier L, Guttman-Yassky E, Ong PY, Silverberg J, Farrar JR. Atopic dermatitis yardstick: practical recommendations for an evolving therapeutic landscape. Ann Allergy Asthma Immunol. 2018;120(1):10-22.e12.

(11.) Simpson EL, Palier AS, Boguniewicz M. et al. Crisaborole ointment improves quality of life of patients with mild to moderate atopic dermatitis and their families. Dermatol Ther (Heidelb). 2018;8(4):605-619.

(12.) Dupixent [prescribing information], Tarrytown, NY: Regeneran Pharmaceuticals; March 2019.

(13.) Simpson EL, Palier AS, Siegfried EC, et al. Dupilumab efficacy and safety in adolescents with moderate-to-severe atopic dermatitis: results from a multicenter, randomized, placebo-controlled, double-blind, parallel-group, phase 3 study. Presented at: 27th European Academy of Dermatology and Venereology Congress; September 15, 2018; Paris, France. Presentation #4640.

(14.) Peppers J, Palier AS. Maeda-Chubachi T, et al. A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis. J Am Acad Dermatol. 2019;80(1):89-98.e83.

(15.) Hanifin JM. Ellis CN, Frieden IJ, et al. OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): a phase-II randomized, double-blind, placebo-controlled study. J Am Acad Dermatol. 2016;75(2):297-305.

(16.) Lee YW, Won CH. Jung K, et al. Efficacy and safety of PAC-14028 cream-a novel, topical, non-steroidal selective TRPV1 antagonist in patients with mild-to-moderate atopic dermatitis: a phase lib randomized trial. Br J Dermatol. 2019; 180(5): 1030-1038.

(17.) Lara-Corrales I, Huang CM, Parkin PC, et al. Vitamin D level and supplementation in pediatric atopic dermatitis: a randomized controlled trial. J Cutan Med Surg. 2019;23(l):44-49.
TABLE 1. Clinical Criteria for Moderate-to-Severe AD (7)

* Involvement of [greater than or equal to]10% BSA

* Regardless of degree of BSA involvement:

** Individual lesions with moderate-to-severe features

** Involvement of highly visible areas or areas important
for function (eg, neck, face, genitals, palms, and/or soles)

** Significantly impaired QOL

Clinicians should actively assess the impact of disease on QOL
during clinic visits (ie, sleep, pruritus, activities of daily living,
and work).

AD, atopic dermatitis; BSA, body surface area; QOL, quality of life.

TABLE 2. Targeted Systemic Treatments for AD in Phase 3 Development

Drug               Treatment Type      Target         Trial
                                                   Identifier

Tralokinumab          Biologic         IL-13       NCT03363854
Baricitinib        Small molecule    JAK1/JAK2     NCT03435081
Abrocitinib        Small molecule       JAK1       NCT03796676
  (PF-04965842)
Upadacitinib       Small molecule       JAK1       NCT03569293
Tradipitant        Small molecule   NK1 receptor   NCT03568331

AD, atopic dermatitis; IL-13, Interleukin 13; JAK, Janus kinase;
NK1, neurokininl. Trial identifier; www.clinicaltrials.gou.

TABLE 3. Topical Treatments for AD in or Near Phase 3 Development

Drug                   Target        Trial Identifier

Delgocitinib          All JAK          NCT03725722

Ruxolitinib          JAK1/JAK2         NCT03745638
                                       NCT03745651

Tapinarof (14)    Aryl hydrocarbon          --
                      receptor

OPA-15406 (15)         PDE-4           NCT03911401

IDP-124             Not reported       NCT03058783

PAC-14028 (16)         TRPV1           NCT02965118

AD, atopic dermatitis; JAK, Janus kinase; PDE4, phosphodiesterase
4; TRPV1, transient receptor potential vanilloid subfamily, member
1. Trial identifier: www.clinicaltrials.gov.

FIGURE. Diverse Patterns of Atopic Dermatitis Onset
and Resolution

Birth Cohort 1: ALSPAC

Unaffected/transient           58.0%
Early onset--early resolving   12.9%
Early onset-persistent          7.3%
Early onset-late resolving      7.0%
Mid-onset-resolving             7.0%
Late onset-resolving            7.9%

Birth Cohort 2: PIAMA

Unaffected/transient           62.9%
Early onset--early resolving   15.4%
Early onset-persistent          4.9%
Early onset-late resolving      3.8%
Mid-onset-resolving             6.5%
Late onset-resolving            6.5%

ALSPAC, Avon Longitudinal Study of Parents and
Children; PIAMA, Prevention and Incidence of
Asthma and Mite Allergy.

Source; Paternoster L, et al. J Allergy Clin
Immunol. 2018;141:964-971. (1)

Note: Table made from pie chart.
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Author:Silverberg, Jonathan I.
Publication:Dermatology News
Date:Aug 1, 2019
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