Atopic dermatitis: a review of topical nonsteroid therapy.

BACKGROUND: Atopic dermatitis is a chronic inflammatory skin condition that affects up to 20% of children and 3% of adults globally. Although topical corticosteroids are considered to be the first-line agents, they can be associated with cutaneous and systemic adverse effects. Since the early 2000s, two new classes of nonsteroid topical therapies, topical calcineurin inhibitors and phosphodiesterase 4 (PDE4) inhibitors, have been introduced and provide a safe treatment alternative.
METHOD: We performed a search and review of clinical trials that examined the safety and efficacy of topical calcineurin inhibitors and PDE4 inhibitors. The search was conducted using the PubMed database as well as preselected keywords and filters. This review focuses on the safety and efficacy of each therapy.
RESULTS: Sixty-nine clinical trials identified in this study have demonstrated the efficacy and safety of topical calcineurin and a single novel PDE4 inhibitor in the treatment of atopic dermatitis. Topical calcineurin inhibitors have been shown to be effective in both achieving lesion clearance as well as reducing relapse when used long-term and proactively. Similarly, in clinical trials the PDE4 inhibitor showed success in lesion clearance and symptom management. All three therapies (pimecrolimus, tacrolimus, crisaborole) are associated with low systemic absorption. No clinical trials to date have shown an increased risk of systemic adverse events or malignancy such as lymphoma. The most commonly reported treatment-related adverse event across all three therapies was application-site discomfort, pain or pruritus. It is important to note that long-term studies are not yet available for the novel PDE4 inhibitor. DISCUSSION: Topical calcineurin inhibitors provide a safe and effective alternative to topical corticosteroid use in the treatment of atopic dermatitis. Although the US Food and Drug Administration (FDA) black box warning for topical calcineurin inhibitors remains, studies have not shown an increased risk of malignancy. These warnings have caused a decline in use in favor of topical steroids. A novel PDE4 inhibitor has shown efficacy and safety in studies up to one year. Further long-term safety data is needed.

Introduction

Atopic dermatitis (AD), an inflammatory skin condition, commonly follows a chronic course associated with periods of remission and relapse. AD is often associated with other atopic diagnoses such as asthma, allergic rhinitis and food allergies [1]. The incidence of AD is high, estimated to be approximately 15–20% of children and 1–3% of adults worldwide [1]. The effect of AD is far-reaching, negatively impacting quality of life as well as causing financial burden for both patients and their families. Pruritus, almost universally present in those suffering with AD, can be severe and has been associated with sleep disturbance. Economic impacts include additional annual doctor visits, medication costs and missed days of work or school [1].

There are currently three classes of US Food and Drug Administration (FDA) approved topical therapies for atopic dermatitis. These include topical steroids, two calcineurin inhibitors and one phosphodiesterase 4 inhibitor (PDE4 inhibitor). Due to the chronic nature of AD it is important that there is an effective and safe treatment that can be used for long-term management. While topical corticosteroids (TCS) have long been considered the first-line therapy, TCS are associated with serious adverse side effects that include skin atrophy, telangiectasia, striae and systemic absorption affecting the hypothalamic-pituitary-adrenal axis [2,3]. Studies have shown that many patients and caregivers have concerns about TCS use, which has led to a pattern of increased nonadherence [4]. Topical calcineurin inhibitors (TCI), which include pimecrolimus and tacrolimus, have been available since 2000. In 2006, the US FDA attached a black box warning to both drugs based on potential malignancy risk. Since this warning was established, clinical studies have not been able to establish a link between TCI use and increased risk of malignancy [5]. Most recently, a PDE4 inhibitor, crisaborole was FDA approved in 2016 and early studies show an excellent safety profile for the treatment and management of AD.

Method

Search strategy

A search was conducted on nonsteroid topical therapies for the treatment of AD, including tacrolimus, pimecrolimus and crisaborole. The search was performed using the PubMed database using the search ‘atopic dermatitis’ and ‘topical’ and (‘pimecrolimus’ or ‘tacrolimus’ or ‘crisaborole’). Additional literature was selected and reviewed to provide information on the chemical properties, current approved indications or to provide additional analysis on current treatment practices.

Inclusion criteria for studies included (1) English language; (2) available full text; (3) study design of ‘clinical study’, ‘clinical trial’, ‘clinical trial, Phase I’, ‘clinical trial, Phase II’, ‘clinical trial, Phase III’, ‘clinical trial, Phase IV’, ‘controlled clinical trial’ and ‘randomized controlled trial’ on PubMed; (4) study size; and (5) drugs studied in relation to AD.

Study selection and data collection

The first search in PubMed using just the keywords given above yielded 656 articles for review. After applying the inclusion criteria and filters listed above, 128 studies were then selected for further review of relevance. Of these articles reviewed, 69 were selected for inclusion. An additional 8 resources were selected during the writing process for a total of 77 resources.

Calcineurin inhibitors

Overview

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, were FDA approved for the treatment of AD in 2000 and 2001, respectively [6]. TCIs are anti-inflammatory drugs with a lipophilic structure that act by inhibiting the calcineurin phosphatase. This disrupts the activation of T cells and mast cells as well as the transcription and release of inflammatory cytokines [7-9]. Tacrolimus has been shown to impact Langerhans cells while pimecrolimus does not [2,10,11].

In addition to their anti-inflammatory effects, both TCIs have been shown to have additional positive effects on epidermal integrity [12-16]. Tacrolimus use results in improved skin barrier function, skin hydration, and skin thickness in patients with AD [12-15]. Kyllönen and colleagues reported that treatment with 0.1% tacrolimus resulted in a significant increase in collagen synthesis leading to improved skin thickness and reversal of skin atrophy from prior TCS use [12]. Murrell and colleagues reported that in addition to significant clearance of AD lesions, patients treated with pimecrolimus saw a reversal of skin thinning of the neck and head, including the eyelids [16]. These treatments provide a safe alternative to TCS, particularly for treatment of sensitive skin sites such as the head and neck [8,16-19].

Current FDA black box warning

In March 2006, the FDA announced a blanket black box warning for both pimecrolimus and tacrolimus. This notice recommended the use of TCIs only after the failure of other treatments due to a potential increase in risk of malignancies including lymphoma [6]. Additionally, the FDA’s Public Health Advisory also released treatment advice that includes using the minimum amount for short-term or intermittent use, in children older than 2 years of age and only in those without a weakened or compromised immune system [6].

This boxed warning was based on a theoretical increase in risk of malignancy including lymphoma [5]. Prior to its topical use in AD, oral and intravenous tacrolimus had been used to suppress the systemic immune system in transplant patients. Malignancies have been associated with oral tacrolimus when used systemically at high concentrations. An animal study with pimecrolimus using a 30× greater exposure than seen with topical use also showed associated malignancy development [5]. These findings were used to support the addition of the black box warning. New malignancies have been reported in patients using topical pimecrolimus or tacrolimus as well. These have been reported by the FDA and by the parent drug manufacturer. Independent experts reviewing these cases found no causal association between topical use of CNI and malignancy. The rate of reported lymphoma in patients exposed to topical tacrolimus is lower than the expected incidence in age-matched controls [20]. No increased risk of malignancy has been seen in recent meta-analyses or the 10-year Pediatric Eczema Elective Registry as of May 2014 [8,21].

Pimecrolimus

Pimecrolimus is a 33-epi-chloro-derivative of the ascomycin macrolactam, which binds to the macrophilin-12 receptor, blocking calcium-dependent activation cascade normally mediated by calcineurin [22]. Pimecrolimus is currently indicated as a second-line therapy for short-term and noncontinuous use in the treatment of mild-to-moderate AD in patients older than 2 years of age [23]. Despite these FDA-approved indications, clinical trials have shown drug safety in patients as young as 3 months and in long-term use in patients of all ages [8,24-29].

Clinical trials have demonstrated that pimecrolimus is effective in achieving clearance of AD lesions and associated symptoms as well as for long-term management. Pimecrolimus has a significant steroid-sparing effect, by significantly increasing the time between flares and producing a reduction in days requiring TCS [8,19,24,30-38]. Meurer and colleagues reported a median 144 days before first flare compared with 26 days in the vehicle control in adults with moderate-to-severe AD [37]. In a study with children and adolescents, the difference in AD-free days was also significant averaging 160.2 compared with 137.7 days with 50% fewer relapses overall [30]. Pruritus was shown to be significantly reduced in as early as 48 hours after initiation of treatment [37,39].

A 5-year study of children beginning in infancy supports the efficacy and safety of long-term management of AD with pimecrolimus. Sigurgeirsson and colleagues reported that global successful treatment outcomes were observed in 88.7% of children and in 96.6% of children for facial AD [8]. The association of pimecrolimus treatment with an increased number of disease-free days and reduced need for TCS use (median 7 days) is consistent with a previous trial in infants [24].

Treatment with pimecrolimus is associated with low systemic absorption [2,25,26,29,40-42]. These findings are in line with expectations based on its highly lipophilic structure. In adults with moderate-to-severe AD, Van Leent and colleagues reported that 98% of patients showed systemic levels below the limit of quantification and a maximum measured blood concentration of only 0.8 g/mL after twice daily application [40]. Similarly, trials involving children and infants have demonstrated similar results, with no significant drug accumulation [25,27,29]. Drug absorption remained low even with short-term use four times daily for up to 3 weeks [41]. Pimecrolimus has shown lower systemic absorption compared with tacrolimus [2,42]. Although, it is important to note that generally patients treated with pimecrolimus have milder disease and therefore potentially have less drug exposure [42].

The most frequently reported treatment-related adverse event (TRAE) was application-site pain or burning that was transient [16,18,19,28,30,31,33,36-38,40,43]. In a long-term safety study of adults with moderate-to-severe atopic dermatitis 25.9% of patients reported mild-to-moderate application-site burning [36].

Review of clinical trials and literature shows no significant systemic TRAEs, impairment of systemic immunity or treatment-associated malignancies [8,24–27,29,30,33,36–38, 40,41]. Sigurgeirsson and colleagues reported that normal antibody titers were reported in children treated with pimecrolimus following vaccination (Table 1) [8].

Table 1

Summary of pimecrolimus activity and safety.

Pimecrolimus efficacy compared to control vehicle	Pimecrolimus safety
Significant increase in time between flares	Most common adverse event is application-site pain/burning, mild-to-moderate intensity
Significant reduction in TCS use	Low systemic absorption
Significant increase in number of AD free days	FDA issued black box warning on risk of malignancy
Significant reduction in pruritus

Tacrolimus

Tacrolimus is a macrolide molecule that binds to the FKBP-12 protein and inhibits normal activation of calcineurin phosphatase activity. This results in a decrease in cytokine production and downstream decrease in T-lymphocyte activation. Tacrolimus has been isolated from Streptomyces tsukubaensis bacterial strain [25]. Tacrolimus is available in both 0.03 and 0.1% ointment formulations for the short-term and intermittent treatment of moderate-to-severe AD in adults and children >2 years of age [44].

Similar to pimecrolimus, tacrolimus has been shown to be safe and effective over longer treatment periods and in children less than 2 years of age. Clinical trials have shown both concentrations of tacrolimus are safe and effective in treating AD for short and long-term use, including in sensitive skin areas such as the head and neck [45-57]. Tacrolimus 0.1% has shown superior efficacy in treating children and adults with more severe AD versus 0.03% tacrolimus as well as pimecrolimus [43,53,58]. While tacrolimus is effective in treating AD, there are conflicting findings in comparing tacrolimus to traditional TCS. In a Phase III trial, Reitamo and colleagues reported that by month 3, significantly more patients in the 0.1% tacrolimus arm had seen a response to treatment (72.6%) compared with those treated with 0.1% hydrocortisone butyrate (52.3%). Patients treated with tacrolimus continued to see superior results in terms of skin healing and AD symptoms at every point over the 6-month study [59]. Similar findings were seen by Reitamo and colleagues comparing tacrolimus 0.03% and 0.1–1% hydrocortisone acetate in the pediatric population as well as Doss and colleagues comparing tacrolimus 0.1% to fluticasone 0.005% for facial AD [17,51,58]. However, in a trial completed by Bieber and colleagues methylprednisolone aceponate 0.1% showed superior efficacy compared to tacrolimus 0.03% in children [47]. Additional studies have shown that while both treatments are effective, there are no statistical differences overall [46,51,60]. It is important to note that findings in comparative studies are limited by low potency steroids and varying degrees of disease severity [51,61].

As with pimecrolimus, long-term trials have shown the potential of tacrolimus to be used proactively to sustain disease improvement and reduce recurrences while maintaining a high safety profile [59,62-65]. Wollenberg and colleagues reported that twice-weekly proactive treatment (0.1%) in adults was significant in reducing the severity and time until exacerbation with a mean 142 days before first exacerbation compared to 15 days in those treated reactively [62]. In the pediatric population, tacrolimus 0.03% applied to healthy-appearing but affected skin reduced the number and severity of relapses [64]. Paller and colleagues reported consistent findings, but that significantly more patients treated with TCS (first 4 days) prior to tacrolimus had results of ‘clear’ or ‘almost clear’ at study end than with tacrolimus alone [66].

Across all clinical trials reviewed, the most commonly reported TRAE was application-site irritation including pain, burning, stinging and pruritus [15-18,21,43,47-49,51,54,55,57-71]. Application-site reactions were commonly described as mild-to-moderate and transient. Burning with application may be due to the vehicle contents of TCIs. Transient nature of application-site discomfort is attributed to lesion healing and increased skin thickness [59,72].

Pharmacokinetic studies show low systemic absorption, consistent with expectations of a topical lipophilic drug. In a Phase I trial of patients >5 years of age, Alaiti and colleagues reported that topical tacrolimus 0.3% was associated with low systemic absorption and no significant accumulation [67]. Follow-up studies of tacrolimus 0.03 and 0.1% report consistent findings in both adults and children, with low systemic absorption that decreases over time as lesions improve [45,50,52,55-57,67,73].

No clinical trials reviewed reported treatment-related malignant neoplasms or significant treatment-related laboratory changes over time [17,45,49,51,52,54-59,61,64,65,67-70,72]. Hofman and colleagues cite normal antibody titers following vaccination in children treated with tacrolimus, helping to reduce systemic immunity concerns [68]. Additionally, Kang and colleagues reported that there was no growth restriction in children 2–15 years treated with tacrolimus over 12 months [54].

Although not yet FDA approved for use in children <2 years of age, long-term studies of tacrolimus 0.03% have been completed and report similar findings to studies conducted in older children [71,72]. A Phase II trial completed over 2 years concluded that tacrolimus 0.03% was effective with 63.3% of patients evaluated as ‘clear’ or ‘excellent response’ at study conclusion [71]. In a pharmacokinetic study, Reitamo and colleagues reported low systemic exposure and skin concentrations that decreased with increased skin thickness [72]. TRAEs in both trials included minor infections and application-site irritation, consistent with studies of older children and adults (Table 2).

Table 2

Summary of tacrolimus efficacy and safety.

Tacrolimus efficacy	Tacrolimus safety
Superior efficacy at 0.1% concentration over tacrolimus 0.03% and pimecrolimus 1%	Most common adverse event is application-site pain/burning, mild-to-moderate intensity
Conflicting studies on efficacy compared to topical corticosteroid (CS) use	Low systemic absorption
Significant improvement in time between flares compared to vehicle control	FDA issued black box warning on risk of malignancy
Significant reduction in number of disease flares compared to vehicle control

PDE4 Inhibitor

Crisaborole 2%

Crisaborole is a benzoxaborole compound whose central boron atom has the ability to bind to the bimetal center of the PDE4 enzyme, thereby inhibiting normal PDE4 activity. PDE4 inhibitors suppress cytokine production and inhibit reactive oxygen species production [74,75]. It is the latest topical anti-inflammatory treatment to be FDA approved for the treatment of atopic dermatitis in both children and adults. Crisaborole 2% topical ointment is indicated in adults and children over 2 years of age with mild-to-moderate atopic dermatitis [76].

Clinical trials have shown that crisaborole is effective in improving both AD lesions and associated symptoms. Paller and colleagues reported that crisaborole 2% ointment was efficacious with 51.7 and 48.5% of patients achieving scores of ‘clear’ or ‘almost clear’ during dual Phase III trials [77]. Trials have also shown significant improvement in AD symptoms including erythema, excoriation, exudation, lichenification and pruritus [74,77]. The earlier Phase Ib trial showed tolerability in sensitive skin areas including the genitalia, intertriginous areas, face and hairline, where treatment with topical corticosteroids is often avoided [78].

Crisaborole has been found to be well-tolerated with limited reported adverse events. Across all clinical trials, the most common TRAE was application-site pain, burning or stinging. In dual Phase III trials, Paller and colleagues reported that 94.3% of TRAEs were considered mild to moderate, with most application-site discomfort resolving within 1 day of application [77]. Findings were consistent with previous studies [75,78-80]. Eichenfield and colleagues demonstrated through a 48-week extension that crisaborole has a favorable long-term safety profile without increasing risk for TRAEs [76]. Researchers expressed confidence in the application of these results as a significant amount of ointment (~133 g/patient/month) was used by each patient throughout each treatment period over the 48-week trial [76].

No serious TRAEs, deaths or significant measured changes in laboratory values or vital signs have been reported [75-80]. Systemic exposure of both crisaborole and its metabolite (AN7603) were found to be limited during its maximal use study [75]. Eichenfield and colleagues found no increasing incidence of neoplasms or infections associated with the long-term use of treatment [76].

Ciaravino and colleagues investigated the long-term carcinogenicity of high-dose oral and topical crisaborole in rats and mice respectively. Topical application to animals was not associated with adverse effects. Crisaborole was found to be nontumorigenic in mice and male rats. While large doses of 300 mg/kg/day of oral therapy was shown to increase the incidence of benign granular cell tumors in the reproductive tract of female rat, it was nontumorigenic at 100 mg/kg/day or 1× human safety levels. Researchers considered human-relevance of these benign granular tumors to be low (Table 3) [81].

Table 3

Summary of crisaborole efficacy and safety.

Crisaborole efficacy compared to vehicle control	Crisaborole safety
Significant improvement in investigator global assessment	Most common adverse event is application-site pain/burning, mild-to-moderate intensity
Significant improvement in pruritus	Low systemic absorption
Well-tolerated in intertriginous skin and facial skin	No black box warning regarding malignancy

Discussion

Atopic dermatitis is a chronic inflammatory cutaneous disease that affects a large portion of the population both here in the United States as well as globally. Due to the chronic and recurring nature of the disease, effective and safe drugs are needed that can be used for long-term disease management.

The mainstay of treatment in the management of AD is TCS. However, long-term use of TCS may be associated with severe systemic and cutaneous adverse reactions, especially if used improperly. Knowledge of these risks has been shown to increase patient nonadherence. Pimecrolimus and tacrolimus are currently considered second-line options for AD due the FDA black box warning that is based on a theoretical increased risk of malignancy [5,7]. Although many studies have shown that long-term use of tacrolimus and pimecrolimus is effective with a favorable safety profile and low systemic absorption, the black box warning has remained in place. In comparing TCIs, tacrolimus has been shown to be more effective than pimecrolimus with similar safety profile [43]. However, these warnings have led to a decline in their use in adults and children and their off-label use in infants. A recent systematic review by Siegfried and colleagues of clinical trials and meta-analyses have not shown a significant increased risk of malignancy with TCI use [21].

The approval of crisaborole in 2016 has provided an additional alternative to TCS in the treatment of AD. Completed safety trials have demonstrated that crisaborole can be used safely with minimal side effects for over a year, however longer safety data is not yet available due to the novelty of this topical agent [76].