Novel Therapies in Atopic Dermatitis

INTRODUCTION

Atopic dermatitis (AD) is among the most common chronic inflammatory skin disorders in the Western world, with studies suggesting that 10.7% of the US population is affected.¹ Although more common in infancy and early childhood, AD can occur at any age. Given its topical nature and common incidence, patients with this condition are frequently encountered by pharmacists. Like many dermatologic conditions, AD is considered an autoimmune disorder, occurring due to multiple factors including a compromised skin barrier, genetic factors that predispose to this condition, and a dysfunctional cutaneous immune system.² Clinical symptoms of AD can be diverse, and this heterogeneity may be due to this multifactorial pathogenesis. Common symptoms include extreme pruritus with red, rough, flaky, and often fissured regions of the skin that become chronically thickened, rough, and discolored (figure 1). Most patients have generalized eczematous lesions, with lesions on the head and neck and upper extremities occurring in about onethird of patients; they are slightly less common on the lower extremities and trunk.³ AD is associated with a number of other conditions, particularly systemic allergies, and exposure to the culprit allergen can often trigger a flare of AD. Additionally, due to the breakdown of skin barrier, infections of affected skin by Staphylococcus aureus, group A streptococcus, and, rarely, Candida, can occur and also cause symptom flares.^3,4 AD can have a profound impact on the quality of life experienced by patients and their families, because of its potential effects on sleep, behavior, mood, and absences from school and work.⁵

AD may be classified into extrinsic and intrinsic forms, also known as allergic and non-allergic types. Patients with the intrinsic form usually do not demonstrate atopy, have normal immunoglobulin E (IgE) levels, and do not have systemic allergies.^6,7 Extrinsic AD patients often have elevated IgE levels with sensitization to specific allergens, including foods such as eggs, milk, peanuts, soybeans, fish, and wheat.⁸ Temperature and humidity can affect AD severity. For many patients, symptoms often improve in summer and worsen in winter. AD of the hands is often aggravated by wetting and washing with detergents and harsh soaps. Clothing can also act as a trigger, with skin exposure to wool often causing a flare of symptoms. Pet fur can also trigger symptoms in some patients. Although the pathogenesis is not well understood, it is thought that emotional stress may also trigger flares in some patients.⁸

MANAGEMENT OF AD

According to the American Academy of Dermatology's AD guidelines published in 2014, topical corticosteroids (TCS) are the first-line pharmacologic treatment for AD and are used when moisturizers alone aren’t providing adequate relief of symptoms.⁹ TCS are available in 7 different potencies ranging from very low to very high.³ Two main strategies exist for using TCS in the treatment of AD. The first uses a high-potency agent initially, followed by a quick taper to a lower potency option. The second starts with a lower potency agent and increases potency, as needed, based on patient response.^8,9 Due to the adverse effects (AEs) associated with corticosteroid use, the goal for long-term management is to use the lowest possible potency that is still effective. Selection of a specific product (table^{9,12,13,16,19,20}) can be based on cost, availability, and patient preference as there are no data to support one agent over another.⁹ Although systemic AEs are rare with the use of TCS, children are more susceptible to systemic AEs; use of higher potency agents should be avoided, if possible, in areas such as the face, neck, and skin folds due to increased risk of systemic absorption in these areas.^3,9

Topical calcineurin inhibitors (TCIs) are approved as second- line treatment for AD. The 2 available medications in this class are tacrolimus ointment and pimecrolimus cream. Clinical trials have shown that 0.1% topical tacrolimus is as efficacious as a mid-potency TCS.⁹ Although considered a second-line option, the guidelines suggest certain situations when a TCI may be preferable over a topical corticosteroid. These are: recalcitrance to steroids, sensitive area involvement such as face or anogenital areas, steroid-induced atrophy, and long-term uninterrupted TCS use.^9,10 TCS agents are still recommended to be used initially for acute flares, but a TCI can replace the TCS after the initial use or can be used concomitantly with TCS. Essentially, the major role of a TCI is to reduce the exposure to TCS.⁹ TCIs are generally well tolerated with minimal risk for systemic AEs. The most common AE is local irritation, and the guidelines recommend the patient be counseled that the irritation will most likely decrease with each use and can also be lessened by using a TCS prior to the TCI. Finally, tacrolimus ointment is available in 2 strengths (0.03% and 0.1%). The 2 strengths have been found to be equally efficacious in children, but the 0.1% has been shown to be superior in adults. The 0.03% strength is approved for children aged 2 and older, but the guidelines state that tacrolimus 0.03% ointment and pimecrolimus 1% cream can both be used off-label in patients aged <2 years.⁹

Systemic immunomodulatory agents are not recommended for patients unless the symptoms of AD have a significant impact on their daily life, and they have failed to experience adequate relief with TCS, TCI, and phototherapy.¹¹ Cyclosporine, azathioprine, and methotrexate (with folate supplementation) have the best evidence and are recommended over other immunomodulatory medications.¹² When used, the minimal effective dose should be utilized to reduce the risk of AEs. The guidelines recommend choosing a systemic immunomodulatory agent based on specific patient factors and preferences, and state that there are not enough data to recommend specific doses, durations, and monitoring plans for these medications. Phototherapy has also been shown to be effective and can be used in moderate-to-severe AD.¹²

NOVEL AGENTS FOR AD

Crisaborole

Inflammation plays an important role in the manifestation of AD symptoms. A critical mediator of inflammation in AD is phosphodiesterase 4 (PDE4), and increased PDE4 levels lead to increased production of inflammatory cytokines and, consequently, symptoms.^11,13 Crisaborole is a small-molecule PDE4 inhibitor that can be delivered topically to affected areas of the skin, thereby reducing systemic AEs.¹³ A 2% topical crisaborole ointment was recently approved by the FDA.¹⁴ In clinical studies compared with an inert topical vehicle control, crisaborole resulted in significant improvement of AD symptoms (defined as an Investigator’s Static Global Assessment [ISGA] score of 0 [complete clearing of lesions] or 1 [nearly complete clearing] on a scale of 1-4 with higher scores indicating more severe symptoms).¹³ In a recent paper describing 2 such studies in children 2 years or older and adults with mild-to-moderate AD, crisaborole achieved improvement after 29 days of treatment in roughly 33% of patients compared with about 20% to 25% of vehicle patients. Importantly, systemic AEs were not seen more commonly in the crisaborole arm, with temporary burning on application seen most commonly. Crisaborole would not be expected to cause the dermatologic AEs sometimes seen with topical steroids including striae and local cutaneous atrophy.¹³ Although its acquisition price is higher compared with topical steroids, crisaborole may be appropriate for patients in whom the former drugs are not effective or tolerated.

Dupilumab

The development of biologic therapies that has shaped treatments in gastroenterology and rheumatology is now impacting dermatology as well. Dupilumab is a fully human monoclonal antibody that binds to interleukin 4Ra, which inhibits the signaling of interleukin-4 and interleukin-13 receptors and downregulates inflammatory responses.¹⁵ It was approved by the FDA in March 2017 for patients with moderate-to-severe AD.¹⁶ The 1-year LIBERTY AD CHRONOS trial was a randomized, placebo-controlled, double-blind, international phase 2 study on adults with moderate-to-severe AD. Patients whose symptoms persisted despite topical steroids were randomized to dupilumab or placebo, with the primary outcome being an ISGA score of 0 or 1 and at least 75% improvement in AD symptoms.¹⁷

Dupilumab given weekly by subcutaneous injection with TCS versus placebo plus TCS was effective in achieving the co-primary outcome in roughly 40% of patients at 1 year compared with 13% of the placebo arm. To date, dupilumab has been relatively safe, especially compared with other biologic drugs.¹⁸ However, like most other biologics, live vaccines should not be given while receiving dupilumab. In addition, conjunctivitis has been reported as an AE, and the product information notes that AD patients with asthma should not adjust their medications for asthma without consulting their provider.¹⁶

CONCLUSIONS

AD is a common and often serious condition that pharmacists will encounter frequently. Pharmacists can play an important role in the care of patients with AD, by educating them about avoiding triggers, monitoring for the development of skin infections and AEs, and selecting pharmacotherapies. Figure 2^9,12,13,17 contains a suggested algorithm for treatment of AD. With newer therapies approved recently in the United States, those AD patients with even severe disease now have new, effective, and safe options to help treat this disorder. Future studies examining cost effectiveness and long-term safety will allow health care professionals to appropriately place these drugs in the AD armamentarium.

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Geoffrey C. Wall, PharmD, FCCP, BCPS, is professor of clinical sciences at Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa.Catherine E. Defino, is a student pharmacist at Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa.