Atopic Dermatitis: Pediatric Use of Crisaborole

Ian T.Y. Wong, BSc(Pharm), MD¹ and James N. Bergman MD, FRCPC²;

¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Clinical Assistant Professor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Introduction

Atopic dermatitis (AD), often referred to as eczema, is a chronic, inflammatory skin disorder that causes a significant physical, psychosocial and economic burden on affected patients and their families.¹ Crisaborole, a phosphodiesterase 4 inhibitor (PDE4I), is the first new class of topical agents in over 15 years approved by Health Canada and available for use in mild-to-moderate AD in adults and children 2 years of age and older. Herein we provide an overview to atopic dermatitis care and focus our review to topical agents used in AD including topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) and discuss the newest topical agent accessible in the physician’s armamentarium, crisaborole.

Background

• AD has a prevalence of approximately 20% in children and 10% in adults.^2,3
• AD commonly presents as pruritic, ill-defined, erythematous scaly papules and plaques that can be associated with xerosis, excoriation, lichenification, and oozing.⁴
• AD typically follows a variable waxing-and-waning pattern with periods of minimal disease activity interrupted by episodes of active disease (flares).⁵
• AD typically affects different areas at different stages in life.
  • • In early childhood, these areas include the forehead, face, and extensor extremities.⁴
    • In adulthood, these areas include the periocular, neck, hands, and flexor extremities.⁴
• AD can present with different patterns depending on the severity, age of the patient, presence or absence of secondary infection, disease chronicity and severity.⁴
• AD patients often present with other forms of atopy (allergic rhinitis, asthma, food allergies).⁴
• There are a variety of diagnostic criteria but in clinical practice the diagnosis of AD is clinical and is based upon the presenting skin lesion’s morphology, distribution and accompanying history.⁴
• The pathophysiology of AD is not well-defined as its manifestation is multifaceted.1 At the present time, it is understood that AD pathogenesis centres primarily around dysfunction of the skin barrier, and also includes immune dysregulation and environmental susceptibility each playing a part in the manifestation of AD.¹ Skin barrier dysfunction can be the result of genetic mutations in filaggrin or even due to environmental irritants and inflammation.⁶ A poor skin barrier enables irritants and allergens to penetrate the skin and allows the skin to dry out more readily.⁶

Treatment Approach to Atopic Dermatitis

• AD is a chronic disease for which there is no cure.
  • Educating the family about the disease and treatment is of utmost importance and improves adherence and outcomes.⁸
  • AD has significant effects on quality of life (QOL). QOL surveys score the impact of eczema similar to diabetes and cystic fibrosis.
• The principle approach to AD management focuses on the prevention of AD flares through maintenance of the skin barrier and treatment of inflammation during AD flare ups.⁷
• In the physician’s tool kit, currently available therapies for AD include emollients, topical therapies, phototherapy, systemic agents, and biologics.^7-9
• Improving the barrier with moisturizers/emollients is the cornerstone of therapy and is required on an ongoing basis whether or not the disease is active.^4,7,8
• Topical therapies (TC/TCI/PDE4I) are used in a variety of cases of AD from mild AD to severe localized AD.^7,8
• Phototherapy, systemic agents and biologics are typically reserved for moderate-to-severe or refractory AD.⁹
• Each patient’s adherence behaviour and tolerance to various therapies is different. Their respective AD can also present uniquely in terms of severity, distribution and chronicity. Therefore, each therapy plan should be tailored to consider both the patientand disease-related factors. The goal is to achieve optimal therapy effectiveness, while balancing patient preference and medication safety.¹
• Regular, daily basic skin care with liberal use of emollients and irritant avoidance are key aspects to maintaining the skin barrier and preventing AD flares.⁷ Regular emollient use has shown to decrease AD flare ups and also decrease the need for TCS.^10-12
• Bathing practices in which one uses non-irritating nonsoap cleansers with a short warm water shower or bath is recommended.⁸
  • The general rule is to use as little cleanser as possible so as not to remove the natural lipids within the surface of the skin.
  • Cleansers should have a pH that is similar to the skins pH ~5.5.⁸
• Irritants to avoid are unique to each patient but can generally be categorized as physical (e.g. dust), chemical (e.g. perfumes) or environmental irritants (e.g. cold, dry air).¹³
• Irritants to avoid are unique to each patient but can generally be categorized as physical (e.g. dust), chemical (e.g. perfumes) or environmental irritants (e.g. cold, dry air).¹³
• Irritants to avoid are unique to each patient but can generally be categorized as physical (e.g. dust), chemical (e.g. perfumes) or environmental irritants (e.g. cold, dry air).¹³
• The fingertip unit (FTU) is a system which aims to help guide patients quantify how much topical product to apply to their AD. A single FTU is defined as the amount of topical product extruded from a 5mm diameter nozzle applied from the distal interphalangeal joint skin crease to the tip of the digit.¹⁴ As a general guide, 1 FTU can cover approximately 2 hand prints of body surface area.
• Other techniques to consider in the care of AD patients include dilute bleach baths (1 teaspoon bleach per gallon of water) and wet wraps (bathe, apply emollient over body, dress in warm damp stretchy pajamas, cover in second layer of dry pajamas over night for up to a week). Both dilute bleach baths and wet wraps have shown to improve AD severity.^15,16 Although some recent research questions the mechanism and true effectiveness of bleach baths the utilization of bleach baths continues and is based on clinician’s judgement.

Treatment Options for Mild-to-Moderate Atopic Dermatitis

Topical Corticosteroids

• TCS when used appropriately for active AD has a low risk of adverse effects.⁸
• Undertreatment of AD, due to variety of factors like “steroid phobia”, is associated with greater harm than the potential for adverse effects from TCS.⁸
• Generally, low-potency TCS are used for areas with thin skin like the face, axilla and groin.8 Mid-potency TCS are used on thicker skin like the torso.8 High-potency TCS is usually used for refractory, thick AD lesions or the palms and soles that are characteristically thicker skin.⁸
• TCS adverse effects, although rare when used appropriately, include skin atrophy, striae, perioral dermatitis and hypothalamicpituitary- axis suppression, if there is systemic absorption.¹⁷
• Skin atrophy is at increased risk with the use of higher potency TCS, TCS with occlusive dressing, or with prolonged TCS use.¹⁸

Topical Calcineurin Inhibitors

• TCI black-box warning
  • There has been no substantial evidence suggesting a link between TCI and malignancy or systemic immunosuppression.^19-22
• Like TCS, TCI are effective in the management of AD. TCI are nonsteroidal immunomodulators.⁸
• TCI do not lead to skin atrophy.¹⁴
• TCI adverse effects are primarily a burning sensation and transient itching.¹⁴

Topical Phosphodiesterase 4 Inhibitor (PDE4I): Crisaborole

• Phosphodiesterase E4 (PDE4) plays a major role in inflammation control as it functions to regulate the production of inflammatory cytokines. PDE4 works by degrading cyclic adenosine monophosphate (cAMP) which in turn leads to signaling of proinflammatory cytokine production.
• Crisaborole is a novel boron-based, non-steroidal, antiinflammatory topical PDE4 inhibitor that works to inhibit overactive PDE4 in AD.
• Crisaborole is indicated by Health Canada for use in adults and children 2 years of age and older with mild-to-moderate AD.
• Crisaborole, marketed as Eucrisa, is available as a 2% ointment formulation to be applied to affected areas twice daily.
• Crisaborole is contraindicated in patients with known hypersensitivity to crisaborole or any component of the formulation.
• With respect to access, the cost of crisaborole is comparable to TCI.
• Crisaborole is quickly metabolized into its inactive metabolites Thus any systemic adverse effects from topical use would be very unlikely. To date there have been no clinical or trial-based reports of systemic effects.
• To date, 2 key studies (AD-301, AD-302) have been conducted to investigate the efficacy and safety of crisaborole.
  • AD-301 (ncrisaborole group=503, nvehicle group=256) and AD- 302 (ncrisaborole group=513, nvehicle group=250) were identically designed, phase III, vehicle-controlled, double blind studies where participants ages 2 years or older with mild-to-moderate AD were randomly assigned to either crisaborole or vehicle group (2:1, respectively). The study treatment dosing was twice daily use for 28 days.²³
  • The studies’ primary end point was Investigator’s Static Global Assessment (ISGA) at day 29 reporting an outcome of clear (0)/almost clear (1) accompanied with a two grade or better improvement from baseline ISGA assessment.23 Additional outcomes evaluated include time to achieve target ISGA score, proportion of patients achieving target ISGA score, time needed for pruritus improvement, and improvement in AD severity.²³
  • AD-301 and AD-302 found that more crisaborole-treated participants achieved the primary endpoint (crisaborole-treated 32.8% vs. vehicle-treated 25.4%, p=0.038; crisaboroletreated 31.4% vs. vehicle-treated 18.0%, p<0.001 in respective studies).²³
  • Moreover, AD-301 and AD-302 showed that crisaborole-treated participants achieved the primary endpoint and faster time to pruritus improvement when compared to vehicle-treated participants (in both cases, p≤0.001).²³
  • Adverse events associated with crisaborole use was minimal in frequency and severity and showed a favourable safety profile.²³
    • Main side effect was stinging to application area ~4%
  • A notable “vehicle effect” was seen in AD-301 and AD-302. However, this is not a novel or unexpected occurrence in AD studies that compare therapeutic agents with emollients.²³ This is because emollients provide physiologic benefit in the management of AD, through maintenance of the skin barrier, and provide concomitant benefit for active therapeutic agents compounded in emollient bases.²³
  • A general principle is that improved eczema typically leads to improved Qol.
    • Crisaborole improves quality of life as perceived by the patients and caregivers.²⁴
• To assess the long-term safety profile of crisaborole, 1 multi-center, open-label, 48-week study (AD-303, n=517, ages 2 years and older and continued crisaborole therapy) was conducted recruiting participants who completed the 28-day studies AD-301 and AD-302.²⁵
  • AD-303 found the most commonly reported long-term adverse events by participants included atopic dermatitis (3.1%), application-site pain (2.3%) and application-site infection (1.2%).²⁵
  • Overall, crisaborole was found to have a low frequency of reported crisaborole-related adverse events.²⁵

Conclusion

Crisaborole has emerged onto the Canadian market as the first PDE4 inhibitor, nonsteroidal topical agent for the management of AD. The arrival of crisaborole addresses a longstanding need for additional alternative topical therapies that are safe and efficacious, to help tailor and individualize AD management according to patient preferences, unique disease factors, and prescriber experience. At the present time, crisaborole is indicated in mild-to-moderate AD for patients ages 2 years or older. In order to determine Crisaborole’s exact role in eczema management, further clinical experience will be needed. The relative effectiveness of crisaborole may be partially answered by a study listed on clinicaltrials.gov that will directly compare crisaborale 2%, pimecrolimus 1%, and hydrocortisone butyrate 0.1% (NCT03539601). Until then, crisaborole is an available treatment that is both a safe and efficacious for mild-to-moderate AD in patients 2 years and older.