Topical Therapy

Introduction

Topical medications are the mainstay of treatment for Atopic Dermatitis (AD). They are often used as monotherapy in mild disease and in combination with systemic therapy in moderate-to-severe disease. Current topical therapies can be divided into five major categories:

• Moisturizers
• Corticosteroids
• Calcineurin inhibitors
• Phosphodiesterase-4 (PDE-4) inhibitors
• Janus kinase (JAK) inhibitors.

Other less common therapies will also be discussed.

Moisturizers

Moisturizers are used to restore the ability of intercellular lipid bilayers to absorb, retain and redistribute water, prevent trans-epidermal water loss and treat xerosis, a fundamental feature of AD. Traditional moisturizers come in a variety of formulations, including lotions, creams, ointments and gels. These formulations contain differing proportions of moisturizing substances, emollients, occlusive agents and humectants. Emollients sooth the skin via various mechanisms. Occlusive agents form a barrier layer to prevent water loss, whereas humectants attract and retain water within the stratum corneum. Formulations also contain different proportions of water: ointments contain relatively less water, but may be too greasy for certain patients; lotions have higher water content, but are less effective at treating patients with severe xerosis. Many studies demonstrated that moisturizers are effective at increasing hydration of the skin, lessening symptoms of AD and reducing the amount of prescription treatments necessary for disease control. In addition to being important components of primary treatment, they are also used for maintenance treatment and flare prevention.

In a Cochrane meta-analysis of the efficacy and safety of moisturizers in the treatment of AD, moisturizer use led to lower investigator-assessed disease severity scores, with no difference in adverse events compared to control. This analysis also showed that moisturizer use is an effective secondary AD prevention strategy, since it results in a lower rates of flares and prolonged time to flare. The safety and efficacy of combining prescription topical treatment with moisturizers was also assessed. Combination treatment was more effective at reducing investigator-assessed severity scores and flares than prescription treatment alone. There was no difference in frequency of adverse events. Patients also preferred combination therapy. As such, moisturizers are recommended in management plans for all patients, ranging from the mildest to most severe disease (Figure 7-1). No evidence was found to support the recommendation of one moisturizer over another. The American Academy of Dermatology (AAD) guidelines recommend that the choice of moisturizing agent be based on patient preference, but discourage the use of lotions. Data from two pilot randomized studies suggested that daily emollient use in neonates may be a feasible strategy to reduce AD incidence. These initially promising trials were followed up by two randomized studies in Scandinavia and the UK, which tested the use of emollients in the primary prevention of AD in a much larger population of newborns and infants. The Norwegian/Swedish study found no evidence that frequent (4 days per week or more) use of bath oil additives and face-emollient cream reduces the incidence of AD by age 12 months. Similarly, the UK study, which specifically examined children with a family history of AD, found no evidence that daily use of an emollient cream or gel prevents eczema by age 2 years. These results collectively indicate that emollient use is effective at improving AD severity and secondary prevention of AD flares, but may not be sufficient for primary prevention of AD onset in infants. Future studies are underway to determine whether there are specific subsets of patients and/or different moisturizing regimens that may be effective at primary prevention of AD.

Enlarge 

Recommendations for Nonpharmacologic Interventions

The AAD strongly recommends (strength level “A”) that the application of moisturizers should be an integral part of the treatment of patients with AD since there is strong evidence that their use can reduce disease verity and the need for pharmacologic intervention. AAD recommendations of strength level “B” and “C” are shown in Table 7-1. Other organizations have similar recommendations, including the American Academy of Allergy, Asthma and Immunology.

Enlarge 

Prescription Emollient Devices (PEDs)

PEDs are topical agents containing distinct ratios of lipids to mimic the natural composition of skin and are designed to target specific defects in skin barrier function observed in AD. They are applied two or three times daily, depending on the agent used. However, there are currently few controlled clinical trials that assessed their efficacy in reducing the symptoms and signs of AD. One head-to-head study randomized 39 patients with mild-to-moderate AD to receive either petroleum jelly or two different prescription emollient devices. Petroleum jelly was found to have comparable efficacy, while being ≥47 times more cost effective.

Topical Corticosteroids

Topical corticosteroids were used in the treatment of AD for more than 60 years, and were demonstrated to improve both acute and chronic signs of AD. In addition to being used in the treatment of active inflammatory disease, they can also be used to prevent relapses. Topical corticosteroids exert their effect by acting on multiple types of immune cells, including B cells, helper and cytotoxic T cells, dendritic cells, macrophages, eosinophils and neutrophils. As such, they are effective at treating many overlapping inflammatory skin conditions, such as seborrheic dermatitis and allergic and irritant contact dermatitis.

There are seven classes of topical corticosteroids, which are categorized by potency based on vasoconstriction assays, from very low/lowest potency to very high potency. Representative members from each class are shown in Table 7-2. Mid-potency topical corticosteroids are used in the management of most AD lesions on the body, whereas low-potency agents are typically used on sensitive skin areas, such as the face and groin. Higher potency corticosteroids are typically reserved for refractory lesions, as well as certain tougher-to-treat body sites such as the palms and soles. There are limited or no data to support a single or few select agents as being more efficacious than others within a particular class of steroids. However, there are several important considerations.

Absorption (and ultimately potency) of the active steroid ingredients is greatest with ointments, followed by creams, then lotions, gels and sprays. For example, triamcinolone 0.1% ointment is more potent than the respective cream or lotion. However, patients may prefer to not use ointments, as they are greasy and can stain clothing. On the other hand, less-occlusive creams and lotions require the addition of preservatives and ingredients to enhance the absorption of the active ingredients. These additional chemicals are a potential source for allergen exposure and have the potential to initiate or flare allergic contact dermatitis in patients with AD. As such, patient preference, cost and availability should be balanced in determining selection.

In general, a twice-daily application schedule for topical corticosteroids is recommended, as this is the dosing schedule used in most efficacy studies. However, some potent corticosteroids and newer formulations can be applied once daily. During significant flares, mid- or higher-potency topical corticosteroids can be used to rapidly control symptoms. Potency should be reduced when treating thin skin sites, where there is a higher risk for systemic absorption. When applying topical corticosteroids, there is no universal standard for the quantity to apply. One simple method proposes spreading an adult fingertip unit (an amount fitting between the tip of an adult finger and the distal skin crease [~0.5 g]) over an area equal to approximately two adult palms.

“Soak and smear” (also known as “soak and seal” or prehydration) is a technique whereby a shower or bath precedes moisturizer and/or topical corticosteroid application to prehydrate the skin. This technique was reported to improve the benefits of topical corticosteroid treatment, and is currently recommended by the AAD in patients with areas of significantly inflamed skin.

In patients with both intermittent and chronic persistent AD, corticosteroids should be applied daily for several weeks during a flare, until inflammatory lesions improve. In patients with intermittent disease and infrequent flares, corticosteroid application can be discontinued once the signs and symptoms of disease are well-controlled. However, in patients with chronic persistent disease or numerous flares, emphasis should be put on preventing flares and prolonging the period until the next flare. The proactive application of mid-potency topical steroids to areas prone to recurrence one to two times weekly was shown to be effective in reducing relapses compared to moisturizers alone, and was used for up to 40 weeks without significant cutaneous adverse events.

Topical corticosteroids are associated with several AEs, namely skin atrophy, which may manifest with dyspigmentation, fragility, poor wound healing, cutaneous immunosuppression and striae. These AEs tend to occur with long-term application of topical steroids on a daily or almost daily basis and many resolve following discontinuation of treatment, but this may take months to occur. Systemic absorption can also be clinically significant if applied to large body areas, especially in infants and elderly patients, but this is generally regarded to be a rare occurrence. Thus, while topical corticosteroids are generally well tolerated by patients, they are not ideal for the long-term daily or almost daily treatment of AD.

Enlarge 

American Academy of Dermatology Recommendations for Topical Corticosteroids

The AAD strongly recommends (strength level “A”) topical corticosteroids for AD-affected individuals who failed to respond to good skin care and regular use of emollients alone. AAD recommendations of strength level “B” and “C” are shown in Table 7-3.

Enlarge 

Topical Calcineurin Inhibitors (TCIs)

TCIs are nonsteroidal immunomodulators that inhibit calcineurin, in turn inhibiting the production of cytokines, such as IL-2, by activated T cells. Currently, there are two FDA-approved TCIs for the treatment of AD: pimecrolimus cream (1% strength) and topical tacrolimus ointment (0.03% and 0.1% strength). Pimecrolimus is indicated for mild-to-moderate AD, whereas tacrolimus is approved for moderate-to-severe AD. Their exact indications follow.

• Elidel (pimecrolimus) cream, 1% is indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild-to-moderate AD in non-immunocompromised adults and children 2 years of age and older, who failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.
• Protopic (tacrolimus) ointment, both 0.03% and 0.1% for adults and only 0.03% for children aged 2 to 15 years, is indicated as second-line therapy for the short-term and non-continuous chronic treatment of moderate-to-severe atopic dermatitis in non-immunocompromised adults and children who failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable.

Although tacrolimus 0.03% ointment and pimecrolimus cream are not indicated for use in children less than 2 years of age, numerous studies demonstrated both good efficacy and safety in this age group. The AAD supports the off-label use of these medicinal products in patients with AD less than 2 years of age.

Efficacy

Both pimecrolimus and tacrolimus were shown to be more effective than vehicle in short- and long-term studies in adult and pediatric patients with active disease, as assessed by physician global evaluation scores, percent body surface involvement and patient-evaluated symptoms and signs of disease. Studies comparing efficacies of pimecrolimus and tacrolimus showed greater efficacy for tacrolimus over 6 weeks for all AD severities. Tacrolimus 0.1% ointment is more effective than tacrolimus 0.03% ointment, which is more effective than pimecrolimus 1% cream. A meta-analysis of 25 RCTs found tacrolimus 0.1% to be as effective as or slightly less effective than the mid-potency topical corticosteroid hydrocortisone butyrate 0.1%, whereas tacrolimus 0.03% is more effective than the low-potency topical corticosteroid acetate 1%, but less effective than hydrocortisone butyrate 0.1%. Pimecrolimus is less effective than mid- and high-potency topical corticosteroids, but was not directly compared with low-potency topical corticosteroids.

Safety

The most common AEs seen are local application-site reactions, such as stinging and burning. Such reactions often lessen after several applications or when preceded by a short period of topical corticosteroid use. However, some patients may experience these reactions after every application. To avoid premature discontinuation, patients should be advised of these AEs. Strategies to prevent or reduce application site pain, which is common with other steroid-sparing agents as well as TCIs, are discussed in the Topical PDE-4 Inhibitors section below. In three randomized pediatric clinical trials and a single active-controlled adult trial, treatment with pimecrolimus or vehicle resulted in similar proportion of patients discontinuing therapy due to adverse events (4% vs 3%, respectively). Discontinuations were primarily due to application site reactions and cutaneous infections.

Both pimecrolimus and tacrolimus have black box warnings for rare cases of malignancy (e.g., skin cancer and lymphoma), although a causal relationship was not established. This warning was added based on theoretical risk from the use of TCIs in patients post-transplantation and in animal studies with exposures 25 to 50 times the maximum recommended human dose. Published results from 10-year surveillance studies in adult and pediatric patients treated with topical pimecrolimus and tacrolimus showed no evidence to-date of increased malignancy rates relative to the general population. One large European pharmacovigilance study did uncover evidence of slightly increased lymphoma (but not skin cancer) risk in adults using tacrolimus or pimecrolimus and children using tacrolimus. However, it is not clear whether this represents a causal relationship (and if so, what the direction of causality is) or a residual confounding effect of AD severity, as severe patients are more closely monitored.

Dosage and Administration

Pimecrolimus and tacrolimus should be applied in a thin layer to the areas of skin affected by active inflamed lesions once to twice daily. Treatment should be discontinued once signs and symptoms of AD (e.g., itch, rash and redness) resolve. If signs and symptoms persist beyond 6 weeks despite adherence to appropriate treatment, patients should be re-examined by their healthcare provider to confirm the diagnosis of AD. Given the abovementioned potential safety concerns related to malignancy, continuous long-term daily use is generally avoided. Avoid the use of TCIs with occlusive dressings. Before commencing treatment, cutaneous bacterial or viral infections at treatment sites should be resolved.

TCIs can be prescribed in combination with topical corticosteroids. Topical corticosteroids are often given short-term first to control a flare and reduce occurrence of some local symptoms associated with TCIs, such as stinging and burning. Some authorities recommend “cooling off” the skin with 5 or 7 consecutive days of once- or twice-daily application of topical corticosteroids either prior to initiation of or concomitantly with TCIs. TCIs can then be used to spare topical steroids, both once or twice daily for several weeks on actively inflamed lesions and two to three times a week for the long-term prevention of flares. However, combination treatment can carry addition risks. In a 1-year safety study in pediatric patients involving the sequential use of pimecrolimus and corticosteroids, an increased incidence of impetigo, skin infection, superinfection (infected atopic dermatitis), rhinitis and urticaria were found in patients that had used pimecrolimus and topical corticosteroid sequentially as compared to pimecrolimus alone. Once acute disease is controlled, the proactive application of TCIs to areas prone to recurrence two to three times weekly was shown to be effective in reducing relapses, and was used for up to 1 year without significant adverse events.

American Academy of Dermatology Recommendations for TCIs

Strength level “A” AAD recommendations for the use of topical calcineurin inhibitors are as follows:

• TCI are recommended and effective for acute and chronic treatment, along with maintenance, in both adults and children with AD, and may be preferred to topical steroids in select clinical situations, including steroid-refractory AD, the treatment of areas more vulnerable to AEs from topical corticosteroids (e.g., eyelids, face, groin and axillae), or in situations of steroid-induced atrophy or long-term uninterrupted topical steroid use.
• TCI are recommended for use on actively affected areas as a steroid-sparing agent for the treatment of AD.
• For patient with AD <2 years of age with mild-to-severe disease, off-label use of 0.03% tacrolimus or 1% pimecrolimus ointment can be recommended.
• Proactive, intermittent use of TCI as maintenance therapy (two to three times per week) on areas that commonly flare is recommended to help prevent relapses while reducing the need for topical corticosteroids, and is more effective than the use of emollients alone.
• Routine blood monitoring of tacrolimus and pimecrolimus levels in patients with AD who are applying these agents is not recommended at this time.

AAD recommendations of strength level “B” and “C” are shown in Table 7-4.

Enlarge 

Topical Phosphodiesterase-4 (PDE-4) Inhibitors

The hallmark symptom of AD is chronic, localized or general pruritus, with disease severity typically being correlated with the intensity of pruritus. Inflammation associated with elevated PDE activity is an important aspect of AD and allergic disease. Increased PDE-4 and other PDE activity was demonstrated in patients with AD and allergic disease since the 1990s. Increased PDE-4 activity leads to decreased intracellular levels of cyclic adenosine monophosphate (cAMP), which impacts the production of inflammatory cytokines, such as IL-4, IL-5, IL-10, IL-13 and prostaglandin E2. PDE-4 inhibitors therefore increase intracellular cAMP and disrupt the inflammatory process characteristic of AD.

A single topical PDE-4 inhibitor is currently approved by the FDA for the treatment of AD: crisaborole. Several other topical PDE-4 inhibitors are in early phases of development, including OPA-15406 and cerdulatinib.

Eucrisa (Crisaborole)

Crisaborole was approved by the FDA in 2016 and inhibits the PDE-4 enzyme in the skin. Crisaborole is indicated for topical treatment of mild to moderate AD in patients 3 months of age and older.

Efficacy

The efficacy of crisaborole was assessed in two Phase 3, multicenter, randomized, double-blind, parallel-group, vehicle-controlled trials (AD-301 and AD-302), as well as a multicenter, open-label, single-arm, Phase 4 trial in infants (CrisADe CARE 1). The AD-301 and AD-302 trials collectively enrolled 1522 patients 2 to 79 years of age with a 5% to 95% treatable body surface area. The majority (86.3%) of patients were 2 to 17 years of age. At baseline, 38.5% of the patients had an Investigator’s Static Global Assessment (ISGA) score of 2 (mild) and 61.5% had a score of 3 (moderate). Patients were randomized 2:1 to receive either crisaborole 2% or vehicle applied topically twice daily for 28 days. The primary endpoint of AD-301 and AD-302 was the proportion of patients who achieved success at Day 29, defined as an ISGA score of 0 (clear) or 1 (almost clear) with a 2-grade or more improvement from baseline. At Day 29, a greater proportion of crisaborole-treated patients achieved success in ISGA score than those treated with vehicle (AD-301: 32.8% vs 25.4%, P=0.038; AD-302: 31.4% vs 18.0%, P <0.001; Figure 7-2).

In a post-hoc analysis of data from the Phase 3 AD-301 and AD-302 trials, the efficacy of crisaborole treatment was evaluated using the Atopic Dermatitis Severity Index (ADSI) and percentage of treatable BSA. At day 29, patients in the crisaborole group had a significantly greater decrease in the mean ADSI score (-3.5 vs -2.4; P < 0.0001) and mean %BSA change (–7.43 vs –4.44; P < 0.0001) than those in the vehicle group. Another post-hoc analysis of pooled data from AD-301 and AD-302 assessed the efficacy of crisaborole by patient race (white or nonwhite) and ethnicity (Hispanic and not Hispanic). At day 29, patients of all racial and ethnic groups exhibited a significant improvement in ISGA. Notably, crisaborole treatment improved specific signs of AD, which are more common in patients with skin of color, including lichenification in nonwhite and Hispanic patients and induration/papulation in nonwhite patients.

The use of crisaborole in infants younger than 2 years of age is supported by data from CrisADe CARE 1. This trial enrolled 137 infants age 3 to <24 months with mild-to-moderate AD and ≥5% treatable BSA (with the scalp excluded). At baseline, the median age was 13 months, the median ISGA was 3.0, and the mean BSA was 28.1%. Patients received open-label crisaborole 2% twice daily on all affected body areas (except scalp) for 28 days, regardless of whether the AD lesions resolved. The efficacy endpoints in CrisADe CARE 1 were exploratory and included ISGA, Eczema Area and Severity Index (EASI), percentage of treatable BSA and Patient-Oriented Eczema Measure (POEM). ISGA success (score of 0 or 1) was achieved by 20.0% and 30.2% of patients by day 8 and 29, respectively. At day 29, the mean EASI score decreased from 11.8 at baseline to 5.0, and the mean %BSA decreased from 28.1% at baseline to 12.4%. The mean POEM total score also improved from baseline.

A network meta-analysis compared the efficacy of crisaborole with that of other topical agents for the treatment of mild-to-moderate AD in patients of at least 2 years of age. Using an ISGA score of 0 or 1 as a measure of efficacy, this analysis showed that crisaborole 2% ointment may have comparable efficacy to tacrolimus ointment and is superior to pimecrolimus cream. However, these results must be interpreted with caution, as there are still no head-to-head studies comparing the efficacy, safety and tolerability of topical non-steroidal agents.

The efficacy and safety of crisaborole as a long-term maintenance treatment in adults with mild-to-moderate AD is currently under investigation in an ongoing double-blind, randomized Phase 3 trial.

Safety

In AD-301 and AD-302, 1012 patients were treated with crisaborole twice daily for 4 weeks. Crisaborole demonstrated a favorable safety profile, with a similar proportion of treatment-emergent adverse events (TEAEs) occurring between treatment groups (2.7% crisaborole vs 2.4% vehicle). Of the TEAEs reported, the majority in both treatment groups were mild or moderate in severity (94.3% of crisaborole TEAEs vs 96.9% of vehicle TEAEs), with most considered unrelated or unlikely to be related to the treatment. Application site pain, referring to skin sensations such as burning or stinging, was the only treatment-related AE that occurred in 1% or more of patients (4% crisaborole vs 1% vehicle). Rates of study discontinuation due to AEs were the same in both treatment groups, at 1.2%.

Patients who completed AD-301 and AD-302 without experiencing a crisaborole treatment-related AE or a serious AE that prevented further treatment were eligible for enrollment in a 48-week safety extension study (AD-303). In the extension, the ISGA score was evaluated at baseline and every 4 weeks. If the patient’s ISGA score was ≥2, then they were assigned to an on-treatment period with crisaborole ointment. If the patient’s ISGA score was 0 (clear) or 1 (almost clear), then they began an off-treatment period and received no treatment. Patients in the on-treatment group applied crisaborole twice daily for 28 days. If no improvement was observed after three consecutive on-treatment periods, then treatment with crisaborole was discontinued. The primary endpoints of the study were AEs, serious AEs (SAEs) and rescue therapy use. In total, 517 patients were included in the safety population, with 59.6% being children.

The most commonly reported TEAEs over the full 52-week period (AD-301/302 and AD-303) were upper respiratory tract infection (10.3%) and dermatitis atopic (worsening, exacerbation, flare, or flare-up of an existing condition; 11.2%). Most TEAEs were mild (51.2%) or moderate (44.6%), and unrelated to crisaborole treatment (93.1%). TEAEs did not differ in severity over time. Seven treatment-emergent SAEs occurred in AD-303, but none were considered related to treatment. Treatment-related AEs occurred in 10.3% of patients, with 85.9% being mild or moderate in severity; the most frequently reported were dermatitis atopic (3.1%), application-site pain (2.3%) and application-site infection (1.2%). Treatment-related AEs did not increase over time.

In AD-303, 77.8% of patients did not require rescue therapy, and of those who did, most (79.1%) resumed crisaborole treatment at a later point. In conclusion, the extension study demonstrated that crisaborole had a favorable safety profile with few safety concerns, indicating that it has the potential to treat AD safely over an extended period.

Dyspigmentation is an AE of general concern in patients with skin of color. In AD-301/302, no dyspigmentation was reported in patients of color, with only one white, not Hispanic patient experiencing application-site hyperpigmentation. The overall safety profile was consistent across racial and ethnic groups.

In CrisADe CARE 1, safety endpoints, including TEAE incidence, clinically significant vital sign changes, and physical and laboratory assessments, were the primary endpoints. All-cause TEAEs and treatment-related AEs were reported in 64.2% and 16.1% of patients, respectively. The most frequent all-cause TEAEs included pyrexia (9.5%), upper respiratory tract infection (7.3%), diarrhea (7.3%), atopic dermatitis (6.6%), diaper dermatitis (6.6%) and cough (5.1%), while the most frequent treatment-related AEs were application site pain (3.6%), application site discomfort (2.9%) and erythema (2.9%). No safety signals were observed in vital signs, laboratory assessments, or other safety outcomes and no new safety signals overall were identified compared to prior studies of crisaborole.

Dosage and Administration

Crisaborole is supplied as a 2% ointment (20 mg of crisaborole per gram of ointment) and is for topical use only. A thin layer of crisaborole should be applied twice daily to affected areas. Crisaborole should be discontinued immediately in patients who exhibit signs and symptoms of hypersensitivity. Suspect hypersensitivity in the event of severe pruritus, swelling and erythema at the application site or at a distant site. Crisaborole ointment contains propylene glycol and should therefore be avoided in patients with allergic contact dermatitis to propylene glycol.

Enlarge 

Management of Steroid-Sparing Agent-Associated Pain

As discussed above, application site pain is a common AE associated with crisaborole as well as other steroid-sparing agents (SSAs), such as TCIs. Pain may result via mechanisms that involve the active agent and/or the vehicle. Practical strategies to limit SSA-associated pain and therefore increase treatment adherence include: avoiding excessive SSA use, testing the SSA on a smaller area before a wider application, applying it on dry instead of damp skin, priming the application site with corticosteroids or moisturizers before applying the SSA, refrigerating the SSA so that it is cool when applied, and, for adult patients, taking aspirin before applying the SSA.

Topical Janus Kinase (JAK) Inhibitors

Janus kinases (JAKs) and activators of transcription (STATs) are intracellular components of the JAK-STAT cell signaling pathways that regulate several important physiological processes, including hematopoiesis and immune function. JAK-STAT signaling is involved in the modulation of T_h2, T_h22, T_h1 and T_h17 pathways and plays a role in the pathogenesis of AD. Several JAK inhibitors are in various stages of development for the treatment of AD. A single JAK inhibitor (ruxolitinib) has received FDA approval for topical use in AD, while others (delgocitinib, brepocitinib) are currently under investigation.

Opzelura (Ruxolitinib)

Ruxolitinib, a JAK1 and JAK2 inhibitor, received FDA approval in 2021 for the topical short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

Efficacy

Efficacy of ruxolitinib was investigated in two identically designed, Phase 3, randomized, double-blind, vehicle-controlled trials - TRuE-AD1 and TRuE-AD2. Eligible patients were 12 years old or older, with diagnosed AD lasting at least 2 years, an Investigator’s Global Assessment (IGA) score of 2 or 3, and a BSA involvement of 3%-20% (excluding the scalp). Overall, 631 patients (median age 32 years, 19.5% age 12-17 years) and 618 patients (median age 33 years, 19.7% age 12-17 years) were randomized in TRuE-AD1 and TRuE-AD2, respectively. In both trials, the mean baseline itch NRS score was 5.1. Patients were randomized (2:2:1) to receive a twice-daily dose of 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or vehicle (control) cream over an 8-week period. The primary efficacy endpoint was the proportion of patients achieving IGA treatment success (IGA-TS), which was defined as an IGA score of 0 or 1 with at least a 2-grade improvement from baseline at Week 8.

A significantly higher proportion of patients treated with ruxolitinib achieved IGA-TS at Week 8 compared to those treated with the vehicle in both TRuE-AD1 (50.0% with 0.75% ruxolitinib, 53.8% with 1.5% ruxolitinib, and 15.1% with vehicle; P<0.0001; Figure 7-3) and TRuE-AD2 (39.0% with 0.75% ruxolitinib, 51.3% with 1.5% ruxolitinib, and 7.6% with vehicle; P<0.0001 Figure 7-3). Significantly more patients in both trials achieved EASI-75 and EASI-90 with both doses of ruxolitinib compared to vehicle (P<0.0001 for both). Patients treated with ruxolitinib also showed significantly greater reduction from baseline itch NRS (P<0.0001) compared to those in the vehicle group. A significant reduction in itch NRS (P<0.05) was observed within 12 hours of applying ruxolitinib 1.5% cream.

Safety

In TRuE-AD1 and TRuE-AD2, both doses of ruxolitinib cream demonstrated a favorable safety profile during the 8-week treatment period. The proportion of patients with TEAEs was similar across the treatment groups (29.0% for ruxolitinib 0.75%, 26.5% for ruxolitinib 1.5%, and 33.2% for vehicle). The most common TEAE was a burning sensation at the application site, which was more common in the vehicle group (4.4%) than in the ruxolitinib 0.75% (0.6%) or ruxolitinib 1.5% (0.8%) groups. Serious TEAEs were rare (0.8% for ruxolitinib 0.75%, 0.6% for ruxolitinib 1.5% and 0.8% for vehicle) and were not deemed related to ruxolitinib treatment. Long-term safety is currently under investigation in a 44-week extension in eligible patients from the ruxolitinib 0.75% and 1.5% groups.

The prescribing information for ruxolitinib cream includes boxed warnings about higher rates of serious infections, all-cause mortality, and major adverse cardiovascular events (including cardiovascular death, myocardial infarction and stroke) observed in patients treated with oral JAK inhibitors for inflammatory conditions, as well as reported malignancies (including lymphoma) and increased incidence of thrombosis observed in patients treated with JAK inhibitors for inflammatory conditions.

Enlarge 

Bath Treatments

Bathing is an important component of the basic management of AD, as it can hydrate the skin and remove scales, crust, irritants and allergens. However, bathing can also dry out the skin if the water is left to evaporate from the skin, so the post-bath application of moisturizer is essential in maintaining good epidermal hydration. Currently, there are no comparative studies that demonstrate bathing is superior to showering. It is generally recommended that bathing or showering be performed up to once daily in warm water for 5 to 10 minutes, followed by moisturization. Results from a randomized, cross-over-controlled trial in pediatric patients indicate that a “soak and seal” bath performed twice daily is superior to the same method applied twice-weekly in improving AD severity according to SCORAD. If there are areas of significantly inflamed skin, longer (up to 20 minutes without towel drying) baths or showers followed by the application of anti-inflammatory therapies to the affected sites can be performed.

When bathing, limited use of hypoallergenic non-soap cleansers with a neutral to low pH is recommended. Soaps are not recommended since they contain harsh surfactants that can damage, dry and irritate the stratum corneum. It is uncertain if the addition of oils, emollients and other additives to bath water is beneficial in the treatment of AD. Since it is likely that direct application to the skin is more beneficial, the AAD does not recommend the routine use of bath additives.

A dilute bleach bath (sodium hypochlorite; ~0.5 cups per full bath [40 gallons of water]) may be recommended as part of maintenance therapy in certain patients, especially those with recurrent skin infections, as they were shown to reduce the severity of AD. These baths should be done twice weekly, or more frequently in more severely affected patients. Despite being recommended in clinical practice guidelines, there is conflicting evidence regarding their efficacy. A systematic review assessed whether bleach baths are consistently effective in improving the severity of AD. The study found that water baths were as effective as bleach baths in a pooled analysis of three studies at Week 4, with no differences in Staphylococcus aureus density between treatment groups.

In concordance with these findings, an in vitro assessment of the bactericidal efficacy of bleach solutions found that the concentration commonly recommended for bleach baths did not significantly impair S aureus growth compared to water alone. A retrospective study of pediatric patients found that while recommendations for bathing with bleach and other topical anti-infectives, including dilute acetic acid, increased in the past two decades, these interventions were not associated with a decreased exposure to systemic antibiotics. Acetic acid in the form of apple cider vinegar (ACV) is an increasingly popular anti-infective bath additive. However, evidence of its efficacy in controlling AD is lacking, with a pilot trial finding no long-term improvement in skin barrier integrity with soaking in dilute ACV compared to water.Collectively, these results indicate that much of the efficacy of bleach and other anti-infective baths in reducing AD severity is attributable to bathing itself rather than the addition of an anti-infective agent. Given the lack of evidence for efficacy and the potential risk of allergic contact dermatitis, which is associated with the use of topical AD agents, the use of anti-infective agents in bath treatments should be approached with caution.

Wet Wrap Therapy

Wet-wrap therapy is the use of a topical agent that is covered with a wetted layer of bandage, gauze, or cotton, which is covered by a second, dry outer layer. It is commonly used to quickly reduce AD severity in the setting of significant flares or persistent disease. Wet-wrap therapy works by occluding the topical agent, thus increasing penetration, decreasing water loss and protecting skin from physical insult. It is generally used for several days, depending on patient tolerance, with some studies using wet-wrap therapy for up to 2 weeks. Some patients may require skilled nursing or even inpatient admission to perform wet-wrap therapy.

Other Topical Approaches

Topical Antihistamines

Topical antihistamines are not recommended for AD, as they failed to demonstrate adequate efficacy in clinical studies. In some cases, doxepin was shown to improve pruritus in the short term, but without reduction in AD severity. In addition, doxepin is associated with local side effects and can cause sedation. No controlled studies exist for topical diphenhydramine in AD; regardless, it is not considered an ideal treatment of AD, due to the risk of systemic toxicities (e.g., toxic psychosis) when combined with oral diphenhydramine, used on broken skin, or with widespread application.

Topical Antimicrobials and Antiseptics

Topical antimicrobials are generally not recommended for the treatment of AD. A Cochrane review failed to find clear benefits for the use of topical antibiotics/antiseptics, antibacterial soaps, or antibacterial bath additives for infected or uninfected AD. In addition, their use is associated with contact dermatitis and may contribute to the spread of antibiotic drug resistance.

Topical Coal Tar Derivatives

Coal tar was used in a variety of formulations for years in the treatment of inflammatory skin diseases. However, few clinical trials assessed the efficacy of topical coal tar derivatives in the treatment of AD. As such, there is currently inadequate data to support their use.

Common adverse reactions include local irritation, phototoxicity, burning, contact dermatitis and folliculitis. Patients may also complain about its odor and propensity to stain. Although polycyclic aromatic hydrocarbons were linked to an increased risk of cancer, a large 25-year follow-up study found no increased risk of skin or non-skin cancers in patients using dermatologic coal tar products.