Shopping Cart

INTRODUCTION

Atopic dermatitis (AD) is a skin condition that affects both pediatric and adult patient populations. It is the most common form of eczema and one of the most common skin disorders in developed countries. AD is described as a chronic, pruritic, inflammatory skin disease; it is associated with a wide range of disease severity. There are several treatment modalities, both pharmacologic and nonpharmacologic, for AD. Additionally, novel agents have recently been approved in the United States (U.S.) by the Food and Drug Administration (FDA), which has allowed practitioners to expand treatment options that improve disease severity and provide patients with symptom relief. In 2014, the American Academy of Dermatology published guidelines for the care and management of AD.^1–3 The guidelines offer a multifaceted plan for the treatment of AD for patients of all ages. Many aspects of the guidelines are reviewed in this module.

EPIDEMIOLOGY OF AD

According to a study published in early 2017, the estimated prevalence of childhood AD in the U.S. ranges from 6% to 12.98%.⁴ The range is a consequence of the different study designs and approaches used to assess AD. Additionally, data from the last 15 years indicate that the prevalence of childhood AD is increasing over time.⁴ According to the National Eczema Association, approximately 9.6 million children under the age of 18 years currently suffer from AD.⁵ Most cases of AD present before the age of 5 years and some begin as early as 2 or 3 months of age.⁵ Within the pediatric population, 3.2 million (33%) patients have moderate–to–severe AD.⁶ A smaller portion of adults are affected by AD, with an estimated prevalence of only 2% to 3%, which equates to roughly 4.1 million adults who suffer from AD in the U.S.⁵

Clinical features of AD

There are several clinical features associated with AD, but the primary symptom is pruritus. Because many patients experience itching, scratching is used as relief. Unfortunately, this cycle, known as the itch–scratch cycle, can actually exacerbate AD. Another common clinical feature is xerosis, which can be seen in all stages of AD. Xerosis is defined as abnormal dryness of the skin, eyes, or mucous membranes.¹

It is important to recognize that clinical features of AD can differ among infants, children, and adults. In infants, the rash often appears on the scalp and face, especially on the cheeks, but it can also appear on other areas of the body. The skin may look dry and scaly and it will be itchy, as mentioned previously. In children, the rash most often presents in the creases of the elbows or knees in addition to the neck, wrists, ankles, and/or creases between the buttocks and legs. In addition to itchy skin, scaly patches may develop where the rash is present. Over time, bumps may develop and the skin may lighten or darken in the AD–affected areas. The skin may also thicken, a process known as lichenification, and take on a leathery appearance and knots may develop. Patients with thickened skin may experience itching even when the AD is not flaring.⁵

Even if a primary diagnosis of AD was present in infancy or childhood, a new diagnosis can occur in adulthood, since the clinical features are often different from pediatric AD and the rash can cover a larger portion of the body. It can appear in the creases of the elbows or knees and the nape of the neck, possibly extending to the neck and the face, and the rash may also develop around the eyes. Similar to infants and children with AD, adult patients experience itching and the skin can become very dry and scaly.⁵

Diagnosis of AD

The diagnosis of AD is based on several factors including historical features, morphology, distribution of skin lesions, and clinical signs.¹ In 2014, the American Academy of Dermatology published an updated approach to aid in the diagnosis of AD in infants, children, and adults.¹ This approach can easily be used in clinical settings by both general practitioners and specialists. Table 1 provides a complete summary of the diagnostic criteria.¹

Patients who are diagnosed with AD often have a family history of type I allergies, allergic rhinitis, and asthma.¹ Approximately 50% of children with moderate–to–severe AD eventually develop allergic asthma.⁶ Similarly, nearly 75% of children with moderate–to–severe AD develop allergic rhinitis or hay fever.⁶ Lastly, up to one–third of children diagnosed with AD also have food allergies. However, the guidelines do not recommend withholding possible allergenic foods, since the practice does not appear to alter the risk for AD.

Table 1. Diagnostic Criteria for Atopic Dermatitis1
Essential features	Important features	Associated features	Exclusionary conditions
Must be present	Seen in most cases, adding support to the diagnosis	Help to suggest diagnosis but are too nonspecific to be used for research	Accurate diagnosis depends on excluding these conditions
Pruritus Eczema (acute, subacute, chronic) Chronic or relapsing history	Early age of onset Atopy Personal and/or family history Immunoglobulin E reactivity Xerosis	Atypical vascular responses Keratosis pilaris/pityriasis alba/hyperlinear palms/ichthyosis Ocular/periorbital changes Other regional findings Perifollicular accentuation/lichenification/ prurigo lesions	Scabies Seborrheic dermatitis Contact dermatitis Ichthyoses Cutaneous T-cell lymphoma Psoriasis Photosensitivity dermatoses Immune deficiency diseases Erythroderma of other causes

NONPHARMACOLOGIC TREATMENT FOR AD

Patients can engage in many nonpharmacologic practices to help their AD symptoms. Many of them are simple self–care measures that can be initiated at home with over–the–counter products. If patients adhere to nonpharmacologic recommendations for AD, but the symptoms of AD worsen or interfere with daily activities, they should be directed to consult a primary care physician.

Bathing

Bathing is an important part of maintenance therapy for AD. The benefits of bathing with water include skin hydration and the removal of scale, crust, irritants, and allergens. While the goal frequency and duration of bathing are not well defined, the guidelines recommend up to once–a–day bathing with warm water for a short period of time (i.e., 5–10 minutes).¹ Longer periods of bathing (e.g., 20 minutes) or soaking in plain water may be useful for patients who have significant areas of inflamed skin.¹ If cleansers are used, patients should be directed to use hypoallergenic, fragrance–free, non–soap cleansers with a low to neutral pH. Following bathing, is important for patients to pat the skin dry instead of full towel drying to avoid irritation. A moisturizer should then be applied immediately after skin is dried.¹

Bleach baths may be considered as part of maintenance therapy for patients with moderate–to–severe AD with frequent bacterial infections.¹ The use of bleach baths does not increase the risk of bacterial resistance, which can occur with antibiotic therapy. To prepare a bleach bath, household bleach (6%) should be added to bath water. For infants and toddlers, 1 teaspoon of bleach per gallon of water is an appropriate dilution, and, for older children and adults, one–half cup of bleach for a full bathtub of water or one–quarter cup of bleach for a half–full bathtub of water is appropriate.⁵ The patient should soak for 5 to 10 minutes no more than 3 times weekly unless otherwise directed by a dermatologist.⁷

Moisturizing

Proper moisturizing is one of the most important components of AD treatment. For mild disease, moisturizing is the primary treatment and, for moderate–to–severe disease, it is part of the treatment regimen. Moisturizers help improve xerosis and decrease transepidermal water loss.¹ Additionally, their use can help reduce inflammation and severity of AD and can decrease the amount of prescription anti–inflammatory treatment needed to control AD.¹ All patients with AD should apply a moisturizer shortly following bathing to help maintain good skin hydration.¹

A plethora of moisturizing options is available. Products range from ointments to creams, contain varying amounts of preservatives, and are available at several price–points, from inexpensive to very expensive. There is some belief that greasy–feeling ointments may be better because they tend to have fewer preservatives and are associated with less stinging or burning upon application than lotions and creams; ointments also act as occlusive agents that immediately supplement barrier function. Lotions contain a higher amount of water than ointments, and the water can evaporate upon application; therefore, these are not the ideal choice for patients with severe xerosis. The American Academy of Dermatology guidelines do not recommend a specific moisturizing product but suggest that product selection be based on patient preference.¹

Additional skin care and maintenance

Another primary goal for the treatment of AD is avoidance of irritants and triggers. The use of fragrance–free cleansing and moisturizing products, as well as gentle soaps and detergents, is essential to avoid exacerbating the disease. While some triggers may be unavoidable, minimizing exposure to triggers, to the extent possible, can be helpful. Such triggers include aeroallergens, environmental allergens, infections (such as viral illnesses), rough or non–breathable clothing fabrics, sweat, excess saliva, and psychosocial stress.⁶

PHARMACOLOGIC TREATMENT FOR AD

Pharmacologic options for AD management range from periodic topical regimens to long–term systemic treatments. Options range from symptom relief to antimicrobial regimens to immune–modifying therapies. The choice of agent and route of administration depend on disease severity and patient–specific factors.

Topical treatments

Topical treatments for AD include corticosteroids, calcineurin inhibitors, antimicrobials and antiseptics, and antihistamines. Each class has varying efficacy and indications.

Corticosteroids

Topical corticosteroids (TCS) are a major component of AD treatment. The use of TCS is recommended for AD–affected patients who have failed to respond to good skin care and regular use of emollients alone.²

There are 7 classes of TCS ranging from very low potency (Group VII) to very high potency (Group I).⁸ Table 2 provides a summary of select TCS products available, including strengths and dosage forms.^2,9 When considering different dosage forms (i.e., ointment versus cream) it is important to remember that ointments allow for better percutaneous drug absorption and are, therefore, more potent than creams or lotions. When selecting a particular TCS, several factors should be considered such as patient age, where the product will be applied, degree of xerosis, patient preference, and cost of medication. For example, low potency steroids can be applied to the face, but higher potency steroids may be needed for the extremities and other parts of the body.²

Table 2. Select Topical Corticosteroid Products for the Treatment of Atopic Dermatitis2,9
Class	Drug	Strength (%)	Dosage form(s)
Group I: Very high potency	Augmented betamethasone diproprionate Clobetasol propionate Diflorasone diacetate Halobetasol propionate	0.05 0.05 0.05 0.05	Ointment Cream, foam, ointment Ointment Cream, ointment
Group II: High potency	Betamethasone dipropionate Diflorasone diacetate Fluocinonide Mometasone furoate Triamcinolone acetonide	0.05 0.05 0.05 0.1 0.5	Cream, foam, ointment, solution Cream Cream, gel, ointment, solution Ointment Cream, ointment
Group III-IV: Medium potency	Betamethasone valerate Fluocinolone acetonide Mometasone furoate Triamcinolone acetonide	0.1 0.025 0.1 0.1	Cream, foam, lotion, ointment Cream, ointment Cream Cream, ointment
Group V: Lower-medium potency	Hydrocortisone butyrate Hydrocortisone probutate Hydrocortisone valerate	0.1 0.1 0.2	Cream, ointment, solution Cream Cream, ointment
Group VI: Low potency	Desonide Fluocinolone acetonide	0.05 0.01	Cream, gel, foam, ointment Cream, solution
Group VII: Lowest potency	Hydrocortisone Hydrocortisone acetate	0.25, 0.5, 1 0.5, 1	Cream, lotion, ointment, solution Cream, ointment

Depending on the formulation, TCS may be applied 1 to 2 times daily. For acute AD flares, the TCS should be applied daily until the inflammatory lesions are significantly improved and less thick, which may take up to several weeks for each flare. For patients who experience frequent disease flares at the same body site, TCS can be applied 1 to 2 times weekly to the affected area(s). This may help reduce relapse rates and is more effective for treating AD than the use of emollients alone in these patients.² The use of TCS does not require specific monitoring for systemic side effects primarily due to low rates of absorption. However, there is potential for topical and systemic side effects to occur, especially in children. Topical side effects include allergic contact dermatitis, purpura, telangiectasia, striae, focal hypertrichosis, and skin atrophy. The primary systemic side effect is hypothalamic–pituitary–adrenal axis suppression, but the actual risk of this is low and most often associated with long–term use or concomitant use of other forms of steroids such as inhaled, oral, or intranasal. If hypothalamic–pituitary–adrenal axis suppression is suspected and/or there is concern for this, a cortisol stimulation test should be ordered and evaluated for appropriate adrenal response.²

Calcineurin inhibitors

Topical calcineurin inhibitors (TCIs) received approval in early 2000 and became an alternative to TCS in the treatment of AD. There are currently 2 products on the market: tacrolimus and pimecrolimus. Both are approved by the FDA for short–term and chronic intermittent treatment of AD in patients 2 years of age or older. TCIs are considered second–line treatment and reserved for patients who have contraindications to other therapies or for those in whom other therapies have been ineffective.¹⁰ Additionally, TCIs may be preferable to TCS for patients who have steroid–induced atrophy, are recalcitrant to steroids, or experienced long–term interrupted topical steroid use and when AD involves sensitive areas such as the face and skin folds.²

While pimecrolimus and tacrolimus are FDA approved for use in patients age 2 years and older, the age–based indications vary according to product strength: only the 0.03% tacrolimus is approved for use in patients aged 2 to 15 years and the 0.1% strength is approved for those aged 15 years or older.^11,12 There is data supporting the use of tacrolimus 0.03% and pimecrolimus 1% in patients younger than 2 years of age, but these formulations have not been approved for use in this age group. Additionally, tacrolimus 0.1% is used off–label in children and there is limited evidence that it is more effective than the 0.03% strength, though comparative studies have not been done.²

For children and adults, both TCIs are recommended for application twice daily. The guidelines suggest that proactive, intermittent application 2 to 3 times per week is effective in reducing relapses.² If signs and symptoms are present following 6 weeks of treatment with either pimecrolimus or tacrolimus, patients should be re–examined to determine if continuation of therapy or modification to the treatment plan is warranted. Table 3 summarizes the available TCIs, including dosing, contraindications and precautions, adverse drug reactions, and monitoring parameters related to each drug. Both agents contain a boxed warning stating that long–term safety of these agents has not been established and malignancies may be associated with the use of these immunomodulators .^9,11,12

Table 3. Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis9,11,12
Product	Strength	Dosing	Contraindications/precautions	Adverse drug reactions	Monitoring
Pimecrolimus cream	1%	Apply a thin layer to affected skin twice daily If signs and symptoms persist beyond 6 weeks, patients should be re-examined Continuous long-term use should be avoided	History of hypersensitivity to pimecrolimus or any component of the product Avoid use in immunocompromised patients, including those receiving systemic immunosuppressive medications Avoid use in patients with Netherton's Syndrome or skin diseases with potential for increased systemic absorption	Skin burning, headache, nasopharyngitis, cough, influenza, pyrexia, viral infection Boxed warning: Rare cases of malignancy (skin and lymphoma) have been reported (causal relationship not established)	Monitor for serious and common side effects
Tacrolimus ointment	Age 2 to 15 years: 0.03% only Adults: 0.03% and 0.1%	Apply a thin layer to affected skin twice daily If signs and symptoms persist beyond 6 weeks, patients should be re-examined Safety beyond 1 year of non-continuous use has not been established	History of hypersensitivity to tacrolimus or any component of the product Avoid use in immunocompromised patients	Pruritus, persistent erythema of skin, alopecia, diarrhea, nausea, vomiting, insomnia Boxed warning: Rare cases of skin malignancy and lymphoma have been reported (causal relationship not established)	Monitor for serious and common side effects

Antimicrobials and antiseptics

Staphylococcus aureus is a gram–positive bacterium that is commonly found in the nose and on the skin. Patients with AD have defective skin barrier function, which is one of the reasons for increased S. aureus colonization and proliferation in this patient population.¹³ Topical antimicrobials to eradicate the bacteria have been considered as part of AD treatment plans, but there is a lack of data supporting the use of topical antimicrobials, so this is not routinely recommended in the treatment of AD. However, the current guidelines do present a single exception—the use of bleach baths plus intranasal topical mupirocin.²

Antihistamines

Topical antihistamines, such as doxepin and diphenhydramine, have been used in the treatment of AD, though limited data have evaluated their roles in AD. One study did demonstrate a reduction in pruritus after 7 days of treatment with topical doxepin, but the long–term benefits were not evaluated. The most common adverse events reported were localized stinging or burning and drowsiness.¹⁴ The use of topical diphenhydramine in AD has not been evaluated in controlled studies. Additionally, when used in conjunction with oral diphenhydramine or in the case of significant topical application and/or application to areas of broken skin, topical diphenhydramine poses an increased risk of systemic toxicities. Owing to the lack of evidence, the risk of contact dermatitis, and the risk of increased absorption leading to systemic effects, the guidelines do not recommend the use of topical antihistamines in the treatment of AD.³

Proper application of topical agents

While there is currently no universal standard for the quantity of topical therapies that should be applied in AD, a suggested method is the use of the adult fingertip unit (FTU). One FTU is the amount of ointment or cream that fits from the distal interphalangeal joint to the fingertip, or approximately 0.5 grams: this amount should be applied in a thin, even layer over an area equal to 2 adult palms.²

Another approach to considering the application quantity is the "Rule of 9s." This method measures the percentage of body area affected by AD lesions and then uses charts to determine the amount of TCS to be applied based on the patient age and body site.²

Systemic treatments

The use of systemic agents in the treatment of AD is recommended when nonpharmacologic and topical pharmacologic therapies do not achieve disease improvement, primarily in patients with moderate–to–severe disease. The long–term use of systemic agents may be limited due to the risk of adverse drug reactions.

Cyclosporines

Cyclosporine A is a commonly prescribed immunosuppressant used to help prevent graft rejection in patients receiving organ transplants. It has also been studied in refractory AD and, when compared to placebo, is considered moderately beneficial.³ Therefore, cyclosporine A is recommended as a treatment option for patients, both pediatric and adult, with AD refractory to conventional topical treatments.³ It is important to note that the use of cyclosporine A in the treatment of AD is considered off–label.

The dosing strategy for cyclosporine A varies, ranging from 3 to 6 mg/kg/day in both pediatric and adult patients. In adults, this equates to 150 to 300 mg/day of cyclosporine A.³ Guidelines suggest using the lowest effective dose able to achieve the desired results.³ The drug should be administered in divided doses twice daily. All formulations of cyclosporine A can be used and are effective in AD. One study suggested that the microemulsion formulation has greater initial efficacy, measured after 2 weeks of therapy, perhaps related to the faster onset of action compared to other formulations. However, after 8 weeks of treatment, the microemulsion and non–microemulsion formulations yielded similar disease improvements.¹⁵ There is no data to support the long–term effectiveness of cyclosporine A, and, once the AD symptoms have cleared or nearly cleared, cyclosporine A should be tapered or discontinued.³

Cyclosporine has an extensive list of adverse effects and all patients should be counseled prior to therapy initiation, as well as monitored closely throughout treatment. The possible adverse effects include infection, nephrotoxicity, hypertension, tremor, hypertrichosis, headache, gingival hyperplasia, and increased risk of skin cancer and lymphoma. Cyclosporine is extensively metabolized in the liver by the cytochrome P450 3A4 enzyme, which offers the potential for several drug interactions and should be considered prior to and during treatment.¹⁶

Azathioprine

Azathioprine is commonly prescribed for the treatment of rheumatoid arthritis and prevention of renal transplant rejection, but there is also evidence supporting the use of azathioprine in moderate–to–severe AD. One study compared azathioprine to placebo: the azathioprine group showed improvement in mean disease activity, as well as significant improvements in patient–reported itch, areas of involvement, global assessment, and quality of life.¹⁷ The guidelines recommend azathioprine for the treatment of refractory AD in adult patients. In the pediatric population, the use of azathioprine is recommended in cases of recalcitrant AD or when there are significant psychosocial impacts for the patient and family.³ As with cyclosporine A, the use of azathioprine in the treatment of AD is considered off–label.

The optimal dosing of azathioprine in AD has not been established, but regimens usually range from 1 to 3 mg/kg/day in adults and from 1 to 4 mg/kg/day in pediatric patients. Azathioprine can be dosed once daily. As with other systemic agents, the lowest effective dose is recommended to decrease the risk of toxicity associated with higher doses. Regardless of the dose, it may take 12 weeks or longer to achieve full clinical benefit. When the symptoms of AD have cleared, azathioprine should be tapered or discontinued.³

Common side effects of azathioprine include nausea, vomiting, bloating, anorexia, and cramping. Less common side effects include: headache, hypersensitivity reactions, elevated liver enzymes, and leukopenia. Rare but serious risks include infection, lymphoma, and nonmelanoma skin cancer. Azathioprine is metabolized in the liver to 6–mercaptopurine, which then undergoes further metabolism by 3 different pathways.⁹ Due to the extensive liver metabolism of azathioprine, there are many drug interactions associated with its use. A review of a patient's current medications for the presence of interactions prior to treatment and continuing review of medication changes during therapy with azathioprine are warranted.

Methotrexate

Methotrexate is a folate antimetabolite that is approved for the treatment of acute lymphoid leukemia, juvenile idiopathic arthritis, psoriasis (severe), and rheumatoid arthritis (severe). Published studies evaluating methotrexate in the treatment of moderate–to–severe AD show positive results, but inconsistencies among the studies exist. One open–label, dose–ranging study used incremental methotrexate dosing during a 24–week treatment period; patients were allowed unrestricted use of standard topical therapies throughout the study. The results showed improvement in disease activity and significant improvements in quality of life, body surface area affected, sleep loss, and itch scores. The median dose achieved was 15 mg weekly and no serious adverse drug reactions were noted.¹⁸ The guidelines suggest that, although studies have demonstrated positive outcomes, further investigation with randomized, controlled trials are necessary to determine methotrexate dosing and disease response. Despite the need for additional studies, methotrexate is recommended for the treatment of refractory AD, but its use in the treatment of AD is considered off–label.³

The dosing recommendations for methotrexate in refractory AD are unclear and based on dosing used to treat psoriasis. The dose range is 7.5 to 25 mg weekly for adults and 0.2 to 0.7 mg/kg/week in pediatric patients. While methotrexate is commonly given as a single weekly dose, it can be divided and dosed every 12 hours for a total of 3 doses. Unlike the other systemic agents discussed, methotrexate can be administered as an intramuscular or subcutaneous injection, in addition to an oral formulation. While patients may prefer the oral route, the bioavailability of the oral formulation is approximately 60% in adult patients and decreases as the dose increases. In pediatric patients, the bioavailability of the oral formulation is highly variable.¹⁹ As with other systemic agents, the lowest effective dose should be used to decrease the risk of toxicity at higher doses, and the drug should be tapered or discontinued once clearance or near–clearance is achieved. If disease improvement is not seen after 12 to 16 weeks of therapy, methotrexate should be discontinued.³

There are several side effects associated with methotrexate that have been identified through its use in treating disease states other than AD. These include nausea, vomiting, diarrhea, stomatitis, alopecia, photosensitivity rash, and headache. More serious adverse events include hepatic fibrosis, leukopenia, and pulmonary fibrosis.¹⁹ In addition to adverse events, monitoring for drug interactions is necessary prior to and during treatment. It is recommended that all patients taking methotrexate receive folic acid supplementation to decrease the risk of toxicities (gastrointestinal and hematologic). Folic acid should be dosed at 1 mg/day but may be increased to 5 mg/day if needed.³

Mycophenolate mofetil

Mycophenolate mofetil is an FDA–approved immunosuppressant for the prevention of solid organ transplant rejection. Data supporting the use of mycophenolate mofetil in AD is not consistent. However, an observer–blinded, randomized, controlled trial compared mycophenolate mofetil to cyclosporine A in patients with severe AD. Patients received cyclosporine during a 6–week run–in period followed by either continuation of cyclosporine or enteric–coated mycophenolate sodium for a maintenance phase of 30 weeks. Patients in the cyclosporine arm achieved better results at 10 weeks, but disease activity was comparable in both study arms during the maintenance phase. It is worth noting that 7 of 24 patients in the mycophenolate arm required a short course of oral corticosteroids during the study period. Following discontinuation of the study medication, patients in the cyclosporine arm experienced significantly increased disease activity compared to the mycophenolate group.²⁰ The guidelines recommend mycophenolate for the treatment of refractory AD, but, like other systemic therapies, it is considered an off–label use.³

The appropriate dose and duration of mycophenolate mofetil for the treatment of AD are not well–established. The dose range recommended in the guidelines is 0.5 to 3 grams/day for adult patients. The pediatric dose range is 600 to 1200 mg/m²; it is based on body surface area due to increased hepatic metabolism in this population. The relapse rate after drug discontinuation is unknown.³Mycophenolate mofetil has less severe adverse effects than other systemic therapies. The most common adverse effects include nausea, vomiting, and abdominal cramping. Additional effects include headache and fatigue; hematologic and genitourinary symptoms have been reported infrequently.³

Table 4 provides a summary of all the systemic agents used to treat AD, including dosing, contraindications for use, common and serious adverse drug reactions, and monitoring parameters.^3,9,16,19

Table 4. Systemic Agents Used to Treat Atopic Dermatitis3,9,16,19
Product	Dosing	Contraindications/precautions	Adverse drug reactions	Monitoring
Cyclosporine A	Adult: 150-300 mg/day Pediatric: 3-6 mg/kg/day	Contraindications: Avoid use if hypersensitivity to cyclosporine Precautions: Concomitant use with agents that decrease cyclosporine absorption, such as aliskerin, dabigatran, bosentan, potassium sparing agents, grapefruit/grapefruit juice Avoid use of live vaccines with cyclosporine Black box warning: Immunosuppression increases risks for infection and lymphoma	Common: Hypertension, tremor, hypertrichosis, headache, gingival hyperplasia Serious: Infection, nephrotoxicity, increased risks of skin cancer and lymphoma	Monitor for serious and common side effects Drug interactions (CYP3A4 enzyme)
Azathioprine	Adult: 1-3 mg/kg/day Pediatric: 1-4 mg/kg/day; most common dose is 2.5 mg/kg/day	Contraindications: Avoid use if hypersensitivity to azathioprine Avoid use if TMPT activity is very low or absent Avoid use if pregnant Precautions: Hematologic toxicities, gastrointestinal hypersensitivity reaction, infection	Common: Nausea, vomiting, bloating, anorexia, cramping Other: Headache, hypersensitivity reactions, elevated liver enzymes, leukopenia Serious: Increased risks of infection, lymphoma, nonmelanoma skin cancer	Monitor for serious and common side effects Baseline TPMT level CBC, liver enzymes
Methotrexate	Adult: 7.5-25 mg/week Pediatric: 1-4 mg/kg/day	Contraindications: Known hypersensitivity to methotrexate Breastfeeding, pregnancy, chronic liver disease, alcoholism, immunodeficiency syndromes, preexisting blood dyscrasias Precautions: Acute renal failure, bone marrow suppression, CNS effects, GI toxicity, impaired fertility, hepatotoxicity, secondary malignancy, tumor lysis syndrome	Common: Nausea, vomiting, diarrhea, headache Other: Stomatitis, alopecia, hypersensitivity rash Serious: Hepatic fibrosis, leukopenia, pulmonary fibrosis	Monitor for serious and common side effects Pulmonary function testing prior to drug initiation Liver enzymes
Mycophenolate mofetil	Adult: 1-1.5 g orally twice daily Pediatric: 1200 mg/m2 daily; young children, 40-50 mg/kg/day; adolescents, 30-40 mg/kg/day	Contraindications: Known hypersensitivity to mycophenolate mofetil Precautions: Concomitant use with azathioprine Avoid use of live vaccines with mycophenolate Black box warning: May cause fetal harm (first trimester) Black box warning: Immunosuppression increases risks for infection and lymphoma or malignancies	Common: Nausea, vomiting, abdominal cramping Rare: Urinary urgency/frequency, dysuria Serious: Increased risks of infection, anemia, leukopenia, thrombocytopenia, cutaneous malignancy, and lymphoma	Monitor for serious and common side effects Pregnancy test CBC, ANC
Abbreviations: ANC, absolute neutrophil count; CBC, complete blood count; CNS, central nervous system; CYP3A4, cytochrome P450 3A4 isoenzyme; GI, gastrointestinal; TMPT, thiopurine methyltransferase.

NOVEL TREATMENTS FOR AD

Recently, novel therapies for the treatment of AD have been approved and introduced to the market. Table 5 summarizes 2 of the newest agents.^9,21–24 The first, dupilumab, is a monoclonal antibody that blocks interleukin–4 and interleukin–13. It was approved in March 2017 and is the first biologic agent approved for adults with moderate–to–severe AD who are not adequately controlled by topical therapies or for whom topical therapies are not advisable. Dupilumab can be given with or without TCS.

In 2016, the results of 2 pivotal trials leading to the approval of dupilumab were published. The randomized, double–blind, placebo–controlled, parallel–group phase 3 trials (SOLO 1 and SOLO 2) had identical designs; they compared dupilumab weekly, placebo weekly, and dupilumab every other week alternating with placebo for a total of 16 weeks.^21,22 The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment (IGA) and a reduction of 2 points or more in the IGA score from baseline at week 16.^21,22

A total of 671 patients with moderate–to–severe AD were enrolled in SOLO 1 and 708 in SOLO 2. The results of SOLO 1 showed that 38% of patients achieved the primary outcome in the dupilumab every other week group, 37% in the dupilumab weekly group, and 10% in the placebo group (P<0.001 for both comparisons with placebo). The SOLO 2 trial demonstrated similar results, with 36% of patients achieving the primary outcome in the dupilumab every other week group, 36% in the dupilumab weekly group, and 8% in the placebo group (P<0.001 for both comparisons with placebo). In addition to improvements on the IGA, improvements in pruritis and symptoms of anxiety or depression and quality of life were demonstrated. The most common adverse events seen in both trials were exacerbations of AD, injection–site reactions, and nasopharyngitis. Injection–site reactions were more common in the dupilumab groups, exacerbations of AD were more common in the placebo group, and nasopharyngitis was seen in both treatment and placebo groups. The authors noted that rates of conjunctivitis (unspecified cause and allergic) were higher in the dupilumab groups compared to placebo.^21,22

Dupilumab is available as a 300 mg/2 mL solution in a single–dose, pre–filled syringe (with needle shield) intended for subcutaneous injection only. The recommended dose is 600 mg (2 injections of the 300–mg solution in different injection sites), followed by 300 mg every other week.²³ If a dose is missed, the patient should be instructed to administer the injection within 7 days of the missed dose and then resume the original schedule. If a missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.²³ Dupilumab prescriptions can only be filled through certain retail pharmacies or a specialty pharmacy.

In December 2016, the FDA approved crisaborole for the treatment of mild–to–moderate AD in patients 2 years of age or older. Crisaborole is a phosphodiesterase–4 inhibitor and the exact mechanism of action in AD is unknown. The data supporting crisaborale's efficacy include 2 identically designed multicenter, randomized, double–blind, vehicle–controlled phase II studies conducted in the U.S.²⁵ Patients with mild or moderate AD were randomized in a 2:1 ratio to receive crisaborole or vehicle treatment. Exclusion criteria included previous use of biologic therapy or systemic corticosteroids within 28 days or TCS or TCIs within 14 days, as well as active skin infections. The primary efficacy endpoint was an Investigator's Static Global Assessment (ISGA) score at day 29 of clear/almost clear lesions with 2–grade or greater improvement from baseline. The results showed that a higher number of crisaborole–treated patients achieved ISGA score success compared to vehicle–treated patients. Also, crisaborole–treated patients showed improvement in pruritis earlier than the vehicle–treated group. The authors noted that the short study duration was a limitation.²⁵ Crisaborole is available as a 2% ointment, which is petrolatum–based and should be stored at room temperature. The recommended dose is application of a thin later twice daily to affected areas.

Table 5. Novel Therapies for the Treatment of Atopic Dermatitis9,21–24
Product	Strength	Dosing	Contraindications/precautions	Adverse drug reactions	Monitoring
Dupilumab	300 mg/ 2 mL solution	600 mg once followed by 300 mg every other week	Contraindications: Known hypersensitivity to dupilumab or any product excipients Precautions: Conjunctivitis, keratitis Comorbid asthma Avoid use of live vaccines Additional monitoring required with concomitant use of drugs that are CYP substrates (e.g., warfarin)	Injection-site reaction, nasopharyngitis, conjunctivitis oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye	Monitor for serious and common side effects
Crisaborole	2% ointment	Apply a thin layer twice daily to affected areas	Contraindications: Known hypersensitivity to crisaborole or any component of formulation Precautions: Hypersensitivity reactions	Application site pain (burning, stinging)	Monitor for serious and common side effects
Abbreviations: CYP, cytochrome P450 enzymes.

ROLE OF THE PHARMACIST IN AD TREATMENT

Pharmacists serve a vital role in caring for patients with AD. Given the wide variety of treatment options for AD, it is likely that patients and caregivers will want to discuss treatment options, including over–the–counter and nonpharmacologic recommendations, with a pharmacist. Pharmacists must understand the different treatment modalities available, including both nonpharmacologic and pharmacologic, in order to serve as the medication expert on the health care team. In addition to patients and caregivers, providers may also depend on pharmacists for assistance with drug selection, dosing, drug–drug interactions, contraindications and precautions, and monitoring.

Prior to making any recommendation, it is important for pharmacists to obtain a full patient history, including past medical history, current medications, allergies, family history, and any prior diagnosis and treatment (if applicable) of AD or other skin disorders. Depending on the practice setting, the pharmacist should assess for possible etiologies of the symptoms. It is important to rule out other causes of presenting symptoms including adverse drug reactions, plant or chemical exposure, and contagious skin conditions such as scabies. If any of these etiologies are possible causes of the presenting symptoms, the patient should be referred for further evaluation by their primary care provider or other available practitioner. If AD is suspected, a review of symptoms is necessary to assess the disease severity, which will help determine if nonpharmacologic therapy is appropriate. The primary symptoms that should be assessed are dry skin, pruritus, patches of redness, scaling, weeping, crusting vesicles, and location. Once a diagnosis of AD has been confirmed, and if the patient is experiencing only mild symptoms, the pharmacist can make recommendations regarding nonpharmacologic and over–the–counter pharmacologic treatment options.

For all patients receiving treatment for AD, pharmacists should provide proper medication education to both patients and caregivers. It is important for patients and caregivers to understand key drug information including administration, side effects, monitoring, and storage requirements. Pharmacists should reinforce the identification of irritants and the importance of avoiding anything that can exacerbate AD symptoms. Furthermore, pharmacists may be in a position to provide disease state education, so understanding the basic management of AD including nonpharmacologic interventions, such as bathing and moisturizing, is imperative. Pharmacists must remain up–to–date on treatment options for disease states for which patients seek care, especially those such as AD, in which over–the–counter products are integral to the treatment plans. Table 6 summarizes the roles of pharmacists in the treatment of AD when working with patients and other health care providers. Pharmacists' knowledge and expertise improve patient engagement and ensure that they are receiving proper therapy that is both safe and effective.

Table 6. Roles of Pharmacists in the Management of Atopic Dermatitis (AD)
When working with patients and caregivers	Obtain patient history Assess for possible etiologies Identify possible irritants Review symptoms Evaluate previous treatments Recommend appropriate therapy after diagnosis is confirmed Refer to primary care physician if moderate-to-severe AD, large areas of skin involved, or symptoms not consistent with AD Help patients fill prescriptions through specialty pharmacy, when applicable Provide counseling, stress adherence, and offer follow-up in 7-14 days Provide medication and disease state education
When consulting with providers	Recommend over-the-counter options (moisturizers, non-soap cleaners) Assist with drug selection, dosing, and availability, including recently approved agents Review potential drug-drug interactions Note contraindications and precautions Endorse and assist with routine monitoring

REFERENCES

1. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338–351.
2. 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 Acad Dermatol. 2014;71(1):116–132.
3. Sidbury R, Davis DM, Cohen DE, et al; American Academy of Dermatology. 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.
4. Silverberg JI. Public health burden and epidemiology of atopic dermatitis. Dermatol Clin. 2017;35(3):283–289.
5. American Academy of Dermatology. Atopic dermatitis. https://www.aad.org/public/diseases/eczema/atopic–dermatitis. Accessed September 1, 2017.
6. National Eczema Association. Atopic dermatitis. https://nationaleczema.org/eczema/types–of–eczema/atopic–dermatitis/. Accessed August 17, 2017.
7. Gittler JK, Wang JF, Orlow SJ. Bathing and associated treatments in atopic dermatitis. Am J Clin Dermatol. 2017;18(1):45–57.
8. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135–140.
9. Lexicomp Online. Lexi–Comp, Inc. www.EXAMPLE.com. Published DATE, YEAR. Accessed September 5, 2017.
10. Carr WW. Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations. Paediatr Drugs. 2013;15(4):303–310.
11. Elidel [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC;2017.
12. Protopic [package insert]. Seven Giralda Farms, Madison, NJ: LEO Pharma Inc.;2016.
13. Leung, DYM. The role of Staphylococcus aureus in atopic eczema. Acta Derm Venereol. 2008;Suppl 216:21–27.
14. Drake LA, Fallon JD, Sober A. Relief of pruritis in patients with atopic dermatitis after treatment with topical doxepin cream. J Am Acad Dermatol. 1994;31(4):613–616.
15. Zurbriggen B, Wuthrich B, Cachelin AB, et al. Comparison of two formulations of cyclosporin A in the treatment of atopic dermatitis. A double–blind, single–centre, cross–over pilot study. Dermatology. 1999;198(1):56–60.
16. DRUGDEX System. Cyclosporine. http://micromedexsolutions.com. Published 2017. Accessed August 30, 2017.
17. Meggitt SJ, Gray JC, Reynolds NJ. Azathioprine dosed by thiopurine methyltransferase activity for moderate–to–severe atopic eczema; a double–blind, randomised controlled trial. Lancet. 2006;367(9513):839–846.
18. Weatherhead SC, Wahie S, Reynolds NJ, Meggitt SJ. An open–label, dose–ranging study of methotrexate for moderate–to–severe adult atopic eczema. Br J Dermatol. 2007;156(2):346–351.
19. DRUGDEX System. Methotrexate. http://micromedexsolutions.com. Published 2017. Accessed August 30, 2017.
20. Haeck IM, Knol MJ, Ten Berge O, et al. Enteric–coated mycophenolate sodium versus cyclosporin A as long–term treatment in adult patients with severe atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol. 2011;64(6):1074–1084.
21. Simpson EL, Bieber T, Guttman–Yassky E, et al; SOLO 1 and SOLO 2 Investigators. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–2348.
22. Blauvelt A, de Bruin–Weller M, Gooderham M, et al. Long–term management of moderate–to–severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1–year, randomised, double–blinded, placebo–controlled, phase 3 trial. Lancet. 2017;389(10086):2287–2303.
23. Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.;2017.
24. Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.;2016.
25. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phophodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494–503.

Back to Top