Optimal Use of Crisaborole in Atopic Dermatitis – An Expert Guidance Document

[Epub Ahead of Print] First published online: October 1, 2021

Charles W Lynde MD, FRCPC¹, James Bergman MD, FRCPC², Loretta Fiorillo MD³, Lyn Guenther MD, FRCPC⁴, Marissa Joseph MD, FRCPC, FAAD⁵, Jill Keddy-Grant MD⁶, Ian Landells MD, FRCPC⁷, Danielle Marcoux MD, FRCPC⁸, Catherine McCuaig MD, FRCPC⁹, Michele Ramien MD¹⁰, Wingfield Rehmus MD MPH FAAD¹¹

Introduction

Atopic dermatitis (AD) is a lifelong pruritic, inflammatory skin disease associated with altered immune function and epidermal barrier dysfunction.^1-3 The chronic and recurring cyclic waxing and waning nature of AD leads the patient to treatment fatigue and imposes a significant burden on both the patients’ and caregivers’ quality of life (QoL).¹ AD frequently appears early in childhood and affects over 20% of children and up to 3.5% of adults.^2,3 Measurements of the prevalence of AD can differ, and this variability can be impacted by geographic location, population studied, and definition of AD used. A Canadian study showed that the adult prevalence of AD is up to 3.5% and that AD may be more prevalent among First Nations populations.² This research further revealed that men were less affected than women and that AD decreases with age. Additionally, the study noted that the severity of AD varies per region.² In many countries, the prevalence of AD is on the rise, especially in young children from developing lower-income countries in South East Asia and Latin America.⁴ Although the role of race and ethnicity in the pathophysiology of AD remains unclear, a higher incidence of AD was observed in Black American children (17.3%) compared to White children (10.4%).⁴

The pathophysiology includes skin barrier defects, inflammatory cytokines, and immune abnormalities. ADs’ etiology is multifactorial and involves an incompletely understood interaction between genetic factors, immune system dysfunction, skin barrier disorders, genetic and environmental stressors.^5,6 Most of the patients with AD have mild disease; however, 10% – 20% of children with AD are categorized as severe, and these rates are slightly higher in adults.²

There is a need for a variety of therapeutics targeted to different levels of severity.^6,7 A treatment paradigm that recognizes that patients may oscillate between degrees of severity and integrates topical and systemic therapies may align more closely with clinical reality.^8,9 AD treatment is often challenging due to the disease itself, treatment fatigue, and patient/caregiver concerns. Patients and caregivers frequently have concerns about medication safety and adverse events (AEs) as well as the long-term use of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI).⁹ Crisaborole ointment is an effective and safe alternative to TCS and TCI.⁹ Sharing best clinical practice standards, addressing challenges in treatment application, and methods to improve patient adherence to therapy may improve treatment results.⁹

This paper aims to review best clinical practices in treating AD patients, explore optimal use of crisaborole in mild to moderate disease, and provide expert guidance for the real-world use of crisaborole ointment to improve patient outcomes. This papers’ target audience is general practitioners, pediatricians, pediatric dermatologists, and dermatologists who treat patients with AD.

Methods

The project used a modified Delphi communication technique for interactive decision-making for medical projects, adapted from face-to-face meetings to suit a virtual platform.^10-12 The meeting was virtually convened on May 8, 2021, and the expert panel consisted of eleven dermatologists, including nine pediatric dermatologists from diverse geographical regions within Canada, who commonly treat patients with AD. In preparation for the meeting, a literature review surrounding crisaborole for the treatment of mild-moderate AD was conducted, and the panel members were surveyed regarding the use of crisaborole ointment for the treatment of AD.

The literature review and the pre-meeting survey results were presented at the virtual meeting. During the meeting, the experts were divided into three breakout groups to discuss and adopt draft recommendations for the real-world use of crisaborole ointment that were prepared from the literature searches by CWL and AA. The three groups presented their adapted versions of the recommendations to the larger group following the breakout session. The adapted recommendations were then collated and edited if necessary. The panel then voted and adopted the recommendations using evidence coupled with expert opinion based on the clinical experience of the advisors. The meeting summary and subsequent review of the manuscript were performed online (Figure 1).

Literature Review

Searches for English-language literature [2015– 2020] took place on April 14, 2021, on PubMed and Google Scholar as a secondary source. The data gathered by the literature review prioritized clinical studies published on the use of crisaborole, articles describing the current best practice in AD, and the most recent clinical guidelines, consensus papers and, algorithms. Excluded were duplications, articles of insufficient quality [small sample size, flawed methodology], and the most recent reviews were used in the case of review articles.

The searches yielded sixty-two papers deemed clinically relevant to current best practices of crisaborole use in AD. After removing duplicates and articles of insufficient quality, thirty publications remained: Four on epidemiology, ten reviews, three consensus papers and algorithms, four guidelines, five clinical studies, and four systematic reviews, meta-analyses, or posthoc analyses.

Results

The literature review indicated that the guidelines, algorithms, and consensus papers for topical AD treatment had not changed significantly over the past decade apart from adding crisaborole ointment and removing the black box for topical calcineurin inhibitor (TCI) treatment.^{7-9, 13-21}

A consensus paper and algorithm that explored the need for practical solutions to improve AD care was developed and published by the authors’ panel.⁸ The consensus statements and algorithm for topical treatment and maintenance of AD were integrated into the panels’ recommendations presented in this publication.

The DERMA (D: Diagnosis/Distribution; E: Education/Emollients; R: Red/Itchy; M: Medication/Maintenance; A: Assessment /Adherence) AD Algorithm targets a broad base of health care professionals treating patients with AD. The consensus statements and DERMA AD algorithm for topical treatment and maintenance of AD reflected current practice and were integrated into the panels’ recommendations (Figure 2).

Clinical Evidence of Crisaborole

Crisaborole is a small molecule, anti-inflammatory nonsteroidal PDE4-I inhibitor for the treatment of AD, which has demonstrated safety and efficacy in patients with mild-to-moderate AD.^22-30 Two percent crisaborole ointment was first approved by the American Food and Drug Administration (FDA) in December 2016 and then in 2018 by Health Canada for mild-to-moderate AD patients aged 2 years and over and in March 2020 (USA) and May 2021 (Canada) for patients aged 3 months and over.²⁵

The efficacy and safety studies on crisaborole used various clinical assessment scales such as Investigator Static Global Assessment (ISGA), Atopic Dermatitis Severity Index (ADSI), Eczema Area, and Severity Index (EASI) score, and Patient-Oriented Eczema Measure (POEM).

A randomized, double-blind, intra-patient controlled study (for the first 14 days) was continued as an open-label study applying crisaborole to all lesions. The study, including 40 patients of 18 years-old and older, demonstrated significant changes from baseline in crisaborole-treated lesions, ISGA, and pruritus NRS improvement from day fifteen assessment onwards.²³ The study also showed normalization of the genomic skin profile (approximated normal skin), inhibition of inflammatory genes known to be induced through degradation of cAMP by PDE4, and reduction in epidermal hyperplasia and TEWL.²³

The safety and efficacy of crisaborole treatment over 28 days were shown in two identical randomized, double-blind, vehicle-controlled studies including 1,522 patients with mild-to-moderate AD of 2 years and over.²² Significantly more patients treated with crisaborole than vehicle reached the primary endpoint (ISGA: clear, almost clear) than those treated with the vehicle at day 29 assessment.²² A long-term, open-label, single-arm 48 weeks safety study that included 517 patients of 2 years and over showed similar safety results as in a previous study that included adult AD patients.^22,24 In the long-term open-label study, nine patients (1.7%) withdrew due to AEs such as a stinging sensation after applying the ointment.²⁴ Another phase four open-label, single-arm study on 137 infants aged 3 months to less than 24 months of age demonstrated that crisaborole is safe and effective. ISGA of clear or almost clear was achieved at day 29 assessment by 30.2% of patients.²⁵ The study further indicated that improvements exceeded the minimal clinically significant difference in total POEM score at day eight and day twenty-nine.²⁵ The POEM subscale data further revealed improved sleep and pruritus, markedly improving patients’ and their caregivers’ quality of life.²⁵ Crisaborole yielded a rapid and statistically significant reduction in pruritus within four days.^26-28 Notably, in two vehicle-controlled studies, the vehicle effect on pruritus was considerable.^26,28

A pooled analysis of four studies of mild-to-moderate AD patients demonstrated efficacy and local tolerability of crisaborole treatment. After crisaborole use, most patients had mild to no pruritus from the first assessment through the remainder of treatment.²⁷

In a further study, treatment with crisaborole resulted in a marked improvement in QoL for patients and their parents, caregivers, and families.²⁸

A post hoc analysis of 2 phase 3 studies showed the effectiveness of crisaborole compared to the vehicle in significantly alleviating mild-to-moderate AD severity (per ADSI), and percentage of body surface area (%BSA) affected.²⁹

Finally, a systematic literature review and network meta-analysis comparing efficacy and safety profiles of crisaborole ointment, 2%, versus other topical treatments for mild-to-moderate AD showed crisaborole was superior to vehicle and pimecrolimus 1% cream, and comparable to tacrolimus, 0.1% or 0.03% ointments, concerning ISGA 0/1 at 28-42 days.³⁰ Additionally, the systematic review showed that the AEs rates for application site burning/stinging were much higher for TCIs than for crisaborole.³⁰ The studies included different patients, and endpoints varied, so comparative assessment of medications from this meta-analysis is difficult. Head to head comparative studies are needed to see objective scientifically-grounded efficacy comparison.

Crisaborole works better for mild than moderate disease, where it provides a faster reduction of pruritus and other AD symptoms relieve.^9,25-30 Crisaborole is not typically used with TCI due to potential irritation, but the combination may be suitable for steroid-phobic patients and those at high risk of sequelae.⁹

It is advisable to avoid crisaborole application on significantly flared skin due to possible irritation. Crisaborole ointment can be beneficial for dermatitis of the hands and feet due to the potential for deeper penetration into inflamed, thicker lichenified skin as a result of the smaller molecular size of crisaborole. There appears to be less irritation of the hands and feet, and the good safety profile of crisaborole justifies application in infants and children.^9,25-30

Statements and Recommendations

Statement 1: Atopic dermatitis (AD) is a lifelong inflammatory skin condition associated with epidermal barrier dysfunction and altered immune function. When AD is not controlled by behavioral measures such as skincare and avoidance of triggers, treatments such as TCS, TCI, and more recently, PDE4-I should be considered. It is important to use topical agents in conjunction with moisturizers and gentle cleansers.

The complex multifactorial pathogenesis of AD includes genetic and environmental factors.⁵ The skin barrier in AD is dysfunctional, and this defective skin barrier leads to water loss from the skin and the ingress of irritants, pathogens and allergens resulting in further inflammation.⁷ As the dysfunctional barrier at baseline is further disrupted, an inflammatory immune response is upregulated, which further disrupts the barrier leading to a feedback loop.^6,31,5,6

AD presents clinically as recurrent scaly erythematous and pruritic papules and plaques of skin with varying severity. This morphology, in addition to pruritus and family history of atopy, are important diagnostic criteria.^7,32 Specific signs of AD include oozing, scaling, crusting, erythema, edema, and lichenification, which, together with the body surface area involved and the impairment of daily activities, help determine AD severity (Figure 3-5).
Most patients with AD present with mild disease and can be adequately treated with frequent moisturization and topical therapy such as TCS, TCI, or crisaborole.^{3,5,7,8,12-21}

Educating patients and caregivers about the condition, avoiding triggers, and daily skincare regime, including gentle cleansers and moisturizers, is a vital part of the approach.^{7-9, 13-21}

AD is a chronic disease, and as a result, adherence to therapy is a major obstacle. Education and patient support and can improve adherence and, in turn, outcomes. It is important to remember that AD education is not a one-and-done phenomenon. Ongoing reinforcement of the treatment plan and goals is needed. Clinicians need to explain the condition, the rationale for treatment, optimal treatment use, and demonstrate the application process in their office.^8,9 During the detailed conversation, solicit the patients’ or caregivers’ input and questions to enable their active role in the process.⁹ This will help manage expectations, adherence to treatment, and maintenance of the lifelong chronic disease.⁹ Actions to improve patient adherence with treatment include detailed but easy to follow information and options to revisit the information by reading materials or trusted websites (Box 1).^8,9,15,19

Box 1: Patient and caregivers information and education about crisaborole

Statement 2: Crisaborole, 1% ointment, is a nonsteroidal anti-inflammatory PDE4-I with demonstrated efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any body site. It may be especially beneficial for:

• Sensitive areas prone to thinning from TCS such as the face, intertriginous areas, and genitals
• Hand, feet, palms, and soles, where the small molecular size may allow potential deeper penetration

A previous publication by the panel reviewed various cases that reflect real-world clinical use of crisaborole aimed to clarify its optimal use as monotherapy, combination therapy, sequential therapy, and maintenance therapy.⁹ Crisaborole can provide a good and safe alternative to TCS and TCI, such as in cases of steroid or TCI avoidance, and can be used in mild-to-moderate AD patients from 3 months of age upwards.²⁵

The case studies discussed in the article suggested that crisaborole treatment was effective and well-tolerated for pediatric AD of the face, hands, and feet of infants, toddlers, young children, and adults where therapy with TCS or TCI had failed.⁹ One of the cases was a 5-year-old boy with moderate-to-severe AD of his hands that was painful and severely impacting daily activities, such as playing and interacting with other children. After eight weeks of crisaborole use, his hand palms and wrists involvement had almost entirely cleared.⁹

The advisors recommend that the smaller molecular size of crisaborole may allow better penetration into the skin to the site of inflammation.⁹ The advisors also indicated that there might be a cumulative effect of adding crisaborole for hands and feet that can benefit from its optimal penetration as part of a combination regimen with TCS and TCI in moderate-to-severe AD cases.⁹

Statement 3: Crisaborole may be used as a first-line topical agent and is also a good choice when previous treatment has yielded suboptimal results when TCS side effects constitute a significant concern, and in the case of TCS/TCI phobia.

TCS and TCI hesitancy exists among all cultures and likely contribute to AD treatment failure.³³ Widely available biased unreliable, and inaccurate sources of information about eczema and topical therapies such as TCS and TCI are not helpful for AD patients and hinder physicians ability to educate and treat appropriately.³³ Clinicians must inquire about and if present must thoroughly discuss the patients and caregivers’ concerns about TCS and TCI and emphasize that these treatments are vital and, if used appropriately, safe and effective.^{5,7,8,9,12-21} Providing the patient with trusted websites can give balanced information, thus addressing the issues that are adding to patients concerns, especially in those with TCS and TCI phobia.^15,19

If patients or caregivers continue to have safety concerns surrounding TCS/TCI treatment, then crisaborole can offer a safe alternative even in infants as young as three months of age.²⁵ In this situation, offering a safe and effective alternative to TCS or TCI may improve treatment adherence and patient outcomes.⁹

Statement 4: When starting topical therapies such as crisaborole, consider the following:

• Test the patients’ tolerability with a sample before a prescription to determine the degree of stinging
• Avoid its initial use on severely inflamed or open areas of skin
• Limit its use to areas less likely to sting/burn
• Use the product in combination with a refrigerated moisturizer

The recommendations are supported by the advisors’ clinical experience⁹, a post hoc analysis of 2 phase 3 studies²⁹, and a systematic literature review comparing efficacy and safety profiles of crisaborole and other topical treatments in mild-to-moderate AD.³⁰ Crisaborole is used in mild-to-moderate AD, but it is best to avoid application on severely inflamed and open areas if possible to minimize stinging.^29,30

Testing the patients’ tolerability in-office before prescribing crisaborole provides an opportunity to teach the patient about the appropriate application of the medication and identifies the uncommon patient who has more prominent stinging and thus may not tolerate the medication. The application also helps to identify the patient who has mild discomfort. Proper education and guidance can minimize the symptoms and allow then to get past the short-term symptom. Application in the office and identifying these subgroups will instill greater confidence in the medication and make it more likely that the prescription will be filled and utilized rather than abandoned after one application.

Improved knowledge about the central roles a defective skin barrier and dry skin may play in AD increasingly recognizes the benefits of daily and ongoing use of mild cleansers and moisturizers.³⁴ The use of a gentle cleanser that employs advanced vehicles with a near-physiologic pH (4.0–6.0) may help maintain skin barrier function by optimizing skin surface pH levels.³⁴ Utilizing moisturizers to optimize the barrier decreases water loss, decreases inflammation, and improves the skin’s barrier and natural moisturizing factors. Moisturizers that contain skin lipids such as ceramides have shown benefits over standard emollients when used for AD patients.³⁵

In an algorithm for South and East Asian AD patients, moisturizers were included as a standard measure when using topical treatments for AD, such as pimecrolimus.³⁶ A refrigerated moisturizer used in combination with crisaborole ointment may prevent irritation, burning, or stinging.⁹

Statement 5: TCS, TCIs, and PDE4-I may induce application site pain such as burning and stinging. Information and education on measures to prevent or treat these side-effects, such as testing/limiting application sites and concomitant use of a refrigerated moisturizer, can help optimize results and decrease skin irritation.

Few AEs such as irritation, burning, and stinging were reported in clinical studies using crisaborole but seem to be occurring more frequently in clinical practice.^16,9

Clinical trials report stinging or burning occurring in up to 8%, but the symptoms are usually transient, and 1.7% of patients withdrew due to these symptoms. In practice, clinicians have anecdotally noted that the rate of stinging seems to be greater than that reported in clinical trials, but generally, the stinging is mild and transient.^16,9 Topical medications can sting due to the stabilizers and preservatives in the vehicle cream or due to the medication itself. TCIs can sting, and this stinging is often correlated to the degree of inflammation in the area. Clinicians often apply TCS initially to calm down the AD, after which the TCI is better tolerated. Whether this technique applies to crisaborole is not clear but should be answered by future reports/ studies.^8,9

Before starting crisaborole therapy, inform and educate the patient and caregiver on measures that may prevent or quickly resolve irritation, burning, or stinging if it occurs.⁹ Best practice tips of the panel include the use of crisaborole with daily skincare, such as a gentle cleanser and a refrigerated moisturizer.⁹ Apply a patient age-appropriate regimen and patient education.⁹ Identifying patients prone to skin irritation may benefit from an in-office trial with a sample before prescribing the ointment.

Survey Results

A pre-meeting survey was conducted among the panel to share best practice standards and clinical pearls they use in prescribing crisaborole to mild-to-moderate AD patients. All eleven advisors completed the survey. Demographics, number of visits of AD patients, the severity of AD, and treatment are shown in Table 1. When asked: If Crisaborole is not your first choice, indicate why not? stinging (63% [7]), burning (40% [4]) and costs (91% [10]) were frequently mentioned. Six physicians also answered crisaborole was not used for other reasons, which included: Lack of payer coverage, Need to be off-flare to initiate the treatment to get a good response, It is not as effective and does not work as quickly as TCS or TCI, Other medications are effective and more readily available and with which there is more clinical experience. The advisors noted to specifically use crisaborole for various body locations such as the face (72% [8]), hands (91% [10]), eyelids (55% [6]), intertriginous areas (63% [7]), genitals (63% [7]), and feet (81% [9]). According to the advisors, they hypothesize that the small molecular size of crisaborole appears to allow better penetration on areas with thicker skin.

Table 1: Pre-meeting survey results
N=11
Topical corticosteroid (TCS), atopic dermatitis (AD)

When asked the main reasons to prescribe crisaborole, all (100% [11]) answered that there is a need for a nonsteroidal alternative. Other answers included TCS phobia (91% [10]) and TCI phobia (63% [7]) and suboptimal results with previous therapy (63% [7]).

When stinging or burning occurred with crisaborole use, the advisors discontinued the treatment more frequently in children than adults. For preventing and managing AEs, the advisors provided education before starting crisaborole treatment. Some tested patients’ tolerability to the treatment in the office prior to a prescription to determine the degree of stinging. Further, they recommended measures to reduce stinging, such as concomitant use of a gentle cleanser and refrigerated moisturizer, cooling the ointment in the fridge, and concomitant TCS or TCI use (Figure 6). Finally, the advisors agreed to avoid the application of crisaborole on severely flaring skin.

When asked about the patients’ response to crisaborole treatment within four weeks, forty percent of responders noted that on average, 20-50% of patients had improved, and 50% of the panel noted an improvement in over 50% of their patients (Figure 7 and 8).

Limitations

Measures to reduce burning and stinging that may occur when using crisaborole were developed using the authors’ expert opinion and clinical experience, and further studies are needed to support the possible benefits of these measures.

Conclusions

The review explored best clinical practices of crisaborole for mild to moderate AD patients and provided expert guidance for the real-world use of crisaborole ointment.

Atopic dermatitis is a common chronic inflammatory disorder in which patients experience a waxing and waning disease state that is punctuated by episodes of flares. If their disease is quiescent, then the patient continues good skincare by utilizing moisturizers and avoiding irritants. Patients will escalate and add topical medications at the first sign of a flare. Since every patient has a distinct disease course, some patients may never be fully clear while others clear between episodes. Recognition that patients with AD have a disease that often varies in severity and location on their body allows physicians to choose the appropriate treatments based on their clinical experience. The physician needs to educate their patient to escalate therapy accordingly at the first sign of disease in order to prevent severe flares. An eczema treatment plan is a necessity to ensure a smooth transition of therapy from baseline to flare. For mild to moderate AD patients, three topical options can be prescribed to control inflammation. Traditionally these medications have been divided into first and second-line therapy. However, the expert panel believes that the choice of a specific agent should be decided by the clinician based on factors such as disease severity, location, physician experience with the product, cost, and patient preference.

Crisaborole is a nonsteroidal PDE4-I with demonstrated safety and efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any cutaneous non-mucosal body site. It may be especially beneficial for areas with thicker skin, such as hands and feet, possibly due to improved penetration to the site of inflammation as a result of its small molecular size. There are no concerning serious safety signals associated with crisaborole. Crisaborole does cause a burning sensation in 8% of patients, but this is usually transient and may be minimized by the concomitant application of cool moisturizers. Consideration of in-clinic test site application of crisaborole to high-risk individuals may help identify those at risk and allow patient education, which may decrease the side effect and in turn improve adherence and outcome.