¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
³Division of Dermatology, BC Children’s Hospital, Vancouver, BC, Canada

Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract:
Hidradenitis suppurativa (HS) is a chronic, recurring inflammatory skin disease that significantly impacts the quality of life of patients.¹ HS is more common in adults and adolescents, although true incidence rates may be underestimated due to a lack of earlier recognition of HS in children.² Pediatric HS is a challenging clinical entity to diagnose and manage. Although considered uncommon, treatment of pediatric HS can drastically improve psychosocial well-being and should be considered in children presenting with recurring painful skin nodules, abscesses, scarring and sinus tracts. Multiple comorbidities are associated with pediatric HS, including depression, anxiety, inflammatory bowel disease, metabolic syndrome, and obesity.³ Medical management of pediatric HS poses a unique challenge given the paucity of literature surrounding efficacy and long-term treatment outcomes in pediatric patients. The purpose of this article is to discuss the epidemiology, pathogenesis, comorbidities, and management of pediatric HS.

Keywords: childhood hidradenitis, early onset hidradenitis suppurativa, hidradenitis suppurativa in children, inflammatory disorders, pediatric dermatology

Introduction

Hidradenitis suppurativa (HS) is a chronic disease involving the follicular unit that typically presents with inflammatory intertriginous lesions.⁴ Depending on severity, cutaneous involvement can manifest as painful nodules, abscesses, sinus tracts, and/or hypertrophic scarring.⁵ HS usually presents in adolescents and adults, and is considered uncommon in children, with an estimated prevalence of less than 2% in prepubescent children.⁶ A recent cross-sectional analysis reported 96.8% of pediatric patients with HS were ≥10 years old, with the highest prevalence reported in patients aged 15-17 years old.⁷ Some have noted that delays in care for pediatric patients may reflect an under-recognition of pediatric HS.⁴ In the adult population, women are more commonly affected by HS in comparison to men. Similarly, pediatric HS is more commonly reported in girls, although the exact prevalence is unknown.⁸ Unfortunately, most literature on pediatric HS is limited to small case series, case studies, or extrapolation from adult studies.⁹ More pediatric focused research is needed to better understand disease burden, prevalence, and treatment.

Pathogenesis

The pathogenesis of HS specific to pediatric patients is not well understood and primarily relies on extrapolation from basic sciences and adults with HS. HS pathophysiology is complex and involves environmental, immunologic, and genetic factors. HS is considered a disorder of follicular occlusion, in which hair follicle dysregulation and inflammation play key roles.¹⁰ As affected hair follicles become occluded and eventually rupture, bacteria and keratin enter the surrounding dermis, promoting an inflammatory state and subsequent lesion formation. Many patients with HS have a positive family history, which has prompted genetic studies.¹¹ Gene mutations that alter antimicrobial peptides and cytokines have been demonstrated in patients with HS.¹² Heterozygous mutations in gamma‐secretase (γ‐S), a protease involved in follicular keratinization regulation have been identified in autosomal dominant forms, supporting a genetic link.^12,13 Gamma-secretase deficiencies have also been associated with impaired sebaceous gland formation and follicle disintegration in mice studies.¹⁴ Some research suggests that patients with early-onset HS appear more likely to have a positive family history.¹⁵ From an immunologic standpoint, both the innate and adaptive immune system play important roles. Decreased expression of antimicrobial peptides may facilitate superficial colonization by bacteria and promote ongoing inflammation through pro-inflammatory cytokines.¹⁶ Pro-inflammatory cytokines involved in HS include but are not limited to interleukin (IL)-1, IL-10, IL-17, IL-22, IL-23, and tumor necrosis factor (TNF)-alpha.^9,16 Other factors that can promote HS pathogenesis and impact disease severity include microbial dysbiosis, microbial colonization, mechanical friction, and hormones.¹⁷ In addition, sinus tracts develop a psoriasiform lining, which tries to recapitulate the epidermis, shedding keratin and causing further inflammation. Hence, persistent lesions still exist despite systemic therapy and deroofing is often curative and essential to include in full-spectrum care.

Clinical Features and Diagnosis

Pediatric HS is a clinical diagnosis based on its typical morphology of deep nodules, cysts, sinus tracts, and fibrotic scars in intertriginous areas. A cross-sectional study assessing the clinical features of children <18 years old (mean age of 15.3 years) with HS reported a similar presenting clinical spectrum to adult-onset disease.¹⁸ Typical sites include those abundant with apocrine glands, such as the axillae, inframammary area, groin, and perianal region. Drainage from involved sites is a commonly reported symptom.¹⁹ There are currently no guidelines regarding investigations for HS in pediatric patients or adults. Laboratory investigations or skin biopsy are unnecessary for diagnosis, but imaging may be considered for operative planning when assessing sinus tracts.¹⁸ Ultimately, given the lack of research and consensus, there are currently no screening guidelines for investigating potential comorbidities in pediatric patients with HS. The Hurley staging system is often used to categorize patients into three disease groups based on their level of severity.²⁰ Stage I includes abscess formation (single or multiple), without sinus tract(s) or scarring, Stage II includes those with recurrent abscesses with sinus tracts and scarring present, and Stage III encompasses diffuse involvement, with multiple abscesses and interconnected sinus tracts.²⁰ The Sartorius scoring system is typically reserved for clinical trials and is not commonly used in clinical practice.8 Another useful scoring system is the International Hidradenitis Suppurativa Severity Score System (IHS4) which is a validated, dynamic assessment of HS severity that encompasses counting nodules, abscesses, and draining sinus tracts/fistulas.²¹ The Hidradenitis Suppurativa Quality Of Life (HiSQOL) scoring system may also be useful for capturing impactful areas of HS such as pain, odor, and drainage, which are not measured by the Dermatology Life Quality Index (DLQI) and should be considered by treatment providers.

Associated Comorbidities

Multiple comorbidities have been associated with pediatric HS, including more hormonal imbalances in comparison to adult populations, with manifestations including acne, premature adrenarche, adrenal hyperplasia, metabolic syndrome, and obesity.⁶ Although the overall association between early-onset HS and premature adrenarche and hormonal imbalance remains unclear, assessing for precocious puberty in children presenting with HS may be an important consideration depending on the clinical presentation. From a database of 870 pediatric patients, an elevated body mass index (BMI) and obesity were higher in comparison to reference population standards, as was the prevalence of smoking.¹⁸ Aside from metabolic syndrome, inflammatory bowel disease (IBD) and spondyloarthropathy have also been shown to be associated with HS.⁹ Patients with Down syndrome have been shown in multiple studies to have an earlier onset of HS although the mechanism behind this remains unknown.⁹ A detailed history, including inquiring about a family history of HS and associated comorbid symptoms and a physical examination should be completed. From a psychosocial perspective, HS can drastically impact quality of life and is associated with significant psychological distress.⁸ Painful, inflammatory lesions can limit children’s ability to play, exercise, or attend school which can contribute to obesity and further worsening of disease.⁶ Furthermore, social stigma surrounding HS can negatively affect psychosocial well-being, especially during the adolescent period. Overall, higher rates of anxiety and depression have been reported in pediatric-aged HS patients compared to those without HS.⁹ A cross-sectional study recently examined the quality of life impacts of HS in 25 pediatric patients aged 12-17 years of age.²² They found that 32% of patients had positive screening results for depression on the Patient Health Questionnaire-2, a depression screening tool.²² The Skindex-Teen questionnaire, an adolescent quality of life questionnaire for skin disease was also used, which demonstrated a higher average score in patients with more moderate-severe HS.²² Overall, clinicians should have a high level of suspicion for psychological comorbidities when treating pediatric patients with HS.

Treatment

Management of HS in the pediatric population is limited given the lack of information surrounding long-term outcomes. Determining the appropriate treatment involves weighing the biopsychosocial impact on the child, disease severity, and side effects of medications or procedures. In general, treatment of HS includes topical or systemic medications and surgical modalities depending on the severity. Lifestyle modifications are typically encouraged for all patients and include smoking cessation, weight management, and avoidance of triggers. Patient and family education should emphasize that HS is a chronic disease without a cure, with treatment focusing on disease and symptom management.

For Hurley Stage I disease, conservative management with topical treatment, such as clindamycin 1% solution, azelaic acid 15%, resorcinol 15%, or combination treatment with clindamycin/ benzoyl peroxide is recommended.⁶ Of note, resorcinol is the only topical treatment with studies completed for HS in adults and is a medication that must be compounded. Topical antiseptics and clindamycin are considered safe for use but may be ineffective for more moderate or severe HS.²³ For non-prescription treatments, laser hair removal has been effective via the Hidradenitis Suppurativa Clinical Response (HiSCR) response in patients with mild-to-moderate disease.²⁴ Supplementation with 100 mg of oral zinc has also been shown to improve HS.²⁵ Concurrent supplementation with 4 mg of copper should be considered to prevent copper deficiency.²⁵ For those where topical treatments fail or children with Hurley Stage II disease, systemic medications can be explored. Systemic antibiotics such as doxycycline, clindamycin with rifampicin, metronidazole, and erythromycin are appropriate for use in children with more severe disease.⁶ Counselling regarding potential tooth discoloration and enamel hypoplasia should be done for patients under 8 years old receiving tetracycline antibiotics.²³ However, antibiotics are not a feasible long-term solution. If there is recurrence after treatment, adalimumab or secukinumab should be considered. Oral finasteride demonstrated improvement in resistant cases from a small pediatric case series, however potential side effects include transient sexual dysfunction in males, and pediatric safety data is lacking, particularly for prepubertal males.²⁶ Systemic retinoids used for the treatment of HS include acitretin and isotretinoin, although these have considerable risks and isotretinoin tends to be more effective in milder, folliculocentric subtypes. The long-lasting teratogenic effects of acitretin make it unsuitable for patients with childbearing potential and isotretinoin in children under 12 years of age has been reported to cause premature epiphyseal closure.²⁷ Importantly, all patients of childbearing potential should be counselled surrounding teratogenic effects where applicable.

In terms of biologics, adalimumab is currently the only approved choice in North America for pediatric patients older than 12 years of age who weigh at least 30 kg.²⁸ Safety data surrounding the use of adalimumab in pediatric patients for HS is limited, although adalimumab has been used effectively in pediatric patients for other inflammatory diseases including Crohn’s disease, psoriasis, and juvenile idiopathic arthritis.²⁹ Secukinumab, an IL-17 inhibitor, is both Health Canada and US FDA approved for treatment of adults with moderate-to-severe HS. Based on clinical studies in adults, it may be a therapeutic option for first- or second-line off-label treatment of pediatric HS patients.^30,31 Overall, dermatologists should have a low threshold to treat systemically and preventatively, as HS is typically a progressive disease that can become less responsive to biologic therapy as time passes and severity increases. Surgical modalities may be another option for older children. Depending on the extent of disease, wide excision and/or minimally invasive deroofing can be considered. A recent cross-sectional study found that surgical excision and deroofing were reported as useful for all 23 pediatric patients assessed, while those treated with simple excision had zero responders in 7 cases treated with simple excision.³² However, a surgical approach is more invasive and carries the risk of infection, scarring, and recurrence.⁹ A retrospective review of 11 patients under 18 years old with a total of 23 operative sites reported an overall complication rate of 87% and a 7% reoperation rate.³³ Remission after a single procedure was reported in 57% of included sites.³³ However, it is crucial to combine both medical preventative treatments with surgical therapy, as success rates are much higher with a combination approach.

Conclusion

Pediatric HS is an understudied and underrecognized disease with significant biopsychosocial impacts. Unfortunately, diagnosis is often delayed given the wide variety of presentations in early disease. Clinicians should consider associated comorbidities such as metabolic syndrome, inflammatory bowel disease, and anxiety and depression. Early recognition, diagnosis, and management are essential in improving quality of life and managing symptoms for children and adolescents with HS. Further research focused on long-term outcomes, associated comorbidities, and medical management is needed to improve our understanding and treatment of pediatric hidradenitis suppurativa.

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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.

¹Hospital for Sick Children, Toronto, ON, Canada
²University of Calgary, Calgary, AB, Canada
³University of British Columbia, Vancouver, BC, Canada
⁴Toronto Western Hospital, University Health Network, Toronto, ON, Canada and Department of Dermatology, Brown University, Providence, RI, USA
⁵University Health Network, Toronto, ON, Canada
⁶Centre hospitalier universitaire Sainte-Justine, Montreal, QC, Canada
⁷British Columbia Children’s Hospital, Vancouver, BC, Canada
⁸Eczema Society of Canada / Société canadienne de l’eczéma, Keswick, ON, Canada

This manuscript was previously disseminated by Eczema Society of Canada Copyright© by the Eczema Society of Canada / Société canadienne de l’eczéma July 2016; revised 2017. All rights reserved. Third Edition

About Atopic Dermatitis

Eczema (atopic dermatitis), is a chronic, pruritic inflammatory skin condition that follows a relapsing course affecting people of all ages, although it is more frequent in children. Eczema is most often diagnosed and managed by primary care providers. This article aims to provide practical guidance to primary healthcare practitioners who care for patients with eczema. The Eczema Society of Canada/Société canadienne de l’eczéma convened a group of Canadian dermatologists with extensive experience in managing paediatric and adult patients with atopic dermatitis, to develop practical recommendations for the management of atopic dermatitis. They developed clinical recommendations based on expert consensus opinion and the best available medical evidence. The experts developed recommendations that focus on three key areas of managing patients with eczema: (1) patient/caregiver education, (2) addressing skin barrier dysfunction and (3) inflammation control. Therapeutic education directed to the patient or main caregiver(s) has been demonstrated to improve QoL.¹ While complete guidelines on AD are available,^2-5 these guidelines may not be practical for everyday clinical practice in primary care, nor are they specific to the Canadian healthcare system.

Abbreviations: AD – Atopic Dermatitis, QoL – Quality of Life, SOA – Sedating Oral Antihistamine, TCI – Topical Calcineurin Inhibitors, TCS – Topical Corticosteroids

Background

• Atopic dermatitis (AD)-also commonly referred to as eczema or atopic eczema-is a chronic, pruritic, relapsing inflammatory skin condition that impacts quality of life (QoL) and places a significant burden on patients and families.
• It can affect people of all ages but it is more frequent in children.
• Eczema is characterized by periods of acute worsening symptoms, known as flares, alternating with periods of symptom remission, but some patients do not have any remission.
• Patients often have associated atopic disorders, such as allergic rhinoconjuncitivitis, food allergies and/or asthma.
• The onset of eczema is typically between 2 and 6 months of age, although it can begin at any age. It was previously thought that eczema resolved or improved by adulthood in most cases, but evidence suggests that it is a chronic condition that may persist into adulthood.^6-8
• Eczema is caused by a dysfunctional skin barrier and dysregulation of the immune system, due to genetic, immunologic, and environmental factors. Pruritus is the most notable feature of eczema, which is at the centre of much of the disease burden for patients and their families.

Diagnosis & Assessment

• Eczema is most often diagnosed and managed by primary care providers.⁹
• Eczema is diagnosed based on the morphology and distribution of the patient’s skin lesions, associated clinical signs, and family history (Table 1).¹⁰ Eczema can range from mild to severe, based on body surface area involvement, extent of eczematous lesions, and the impact on a patient’s QoL.
• At this time, eczema remains a clinical diagnosis. In select cases additional testing may be performed, such as a biopsy or patch testing, to rule out other conditions, but this is usually unnecessary. If the diagnosis is unclear, referral to a dermatologist should be considered.

Quality of Life in Eczema Assessment

• Eczema has a significant impact on QoL for patients and their families. Physicians should consider addressing this impact on QoL with their patients and patients’ families, in addition to assessing the signs and symptoms of the disease.
• Sleep is disturbed, often for the whole family. Healthcare providers should address itch, sleep loss, and disease impact on mood, activities, behaviour and self-esteem, when diagnosing eczema and formulating a management plan.
• The impact of AD on QoL for the patient and his or her family is often very significant. The level of impact has been found to be similar and at times can surpass the effect that diabetes has on the family.¹¹

Minimizing and Controlling Flares

• Eczema is a relapsing-remitting, chronic disease with cyclical periods of relative quiescence and periods of flares.
• Currently, there is no cure for eczema. As such, the main goal of eczema management is to improve baseline inflammation and xerosis and to reduce the frequency and severity of flares. For some patients, treating baseline disease activity will involve emollient use only. For others it will involve the use of emollients and topical anti-inflammatory medications to any inflamed areas. In periods of flare, treatment needs to be increased beyond this baseline.
• For those mild disease and mild flares, adding a topical anti-inflammatory medication to their emollient regimen may be necessary.
• For others with more severe eczema, a temporary increase in the potency of topical anti-inflammatory medications may be required.
• For patients with frequent flares and flares that require high-potency topical corticosteroids, referral to a dermatologist is recommended.

Patient Education

• Suboptimal treatment and poor adherence to therapy are common in patients with eczema, much like in patients with other chronic diseases that require regular intervention. Therefore, therapeutic education is particularly important in the face of many sources of potentially misleading or inaccurate information, or patient misconceptions and fears present in the community.¹²
• Patient and caregiver education is a key aspect of successful eczema management.¹³ Studies have demonstrated that therapeutic patient education increases adherence to therapy, increases the use of moisturizers, and decreases fear of medications.^14-16

Patient counselling should focus on the following key points:

• Eczema is a chronic disease. There is no cure, but control of the disease can be achieved. Eczema typically goes through periods of flares and remissions. Moisturizing is the mainstay of therapy during remission, and prescription treatments are needed for any areas of inflammation.
• Eczema flares can be managed by hydrating the skin (bathing and moisturizing appropriately) and reducing inflammation with topical medication.
• Undertreating, starting treatment too late, or stopping treatment too soon, should be avoided. Treatment of eczema flares should begin at the first sign of inflammation. Patients and caregivers often stop treatment before the skin is fully clear of lesions, mistakenly believing that the vast improvement they have seen means the skin is “clear enough.”
• Clinicians should encourage patients and caregivers to make sure the skin is completely clear of lesions before stopping treatment, since even though eczema flares may seem to be much less severe, the patient still has chronic active inflammation, and often the skin rapidly becomes worse.
• Patients need to be counselled on how to apply the medication, as applying the treatment sparingly may contribute to under treatment.
• Adherence to therapy is essential for the optimal management of eczema. Poor adherence may be the most significant barrier to optimal care in eczema. In a survey of 200 eczema outpatients, 24% admitted that they did not adhere to treatment, and experts estimate this percentage could be significantly higher.⁵ Healthcare providers should counsel patients and caregivers about the importance of adhering to treatment.
• Trigger avoidance:
  • Patients should be counselled to attempt to identify and avoid their triggers, and to understand that some eczema flares occur despite strict trigger avoidance and diligent skin care. This is often a source of frustration for patients.
  • Many eczema flares do result from some environmental trigger. Common triggers include harsh or fragranced soaps and self-care products, rough fabrics, overheating and sweating, and winter weather. Often these triggers can be identified but not avoided, such as weather changes.
  • Lifestyle can impact eczema as well, such as sweating for a young athlete. Instead of advising the patient to avoid pleasurable activities, help the patient learn about ways to manage the eczema flare that may follow an activity or exposure to an eczema trigger.
  • Additional actions can be taken to help the condition, such as keeping nails trimmed short and filed smooth to help reduce damage done by scratching.
  • Distraction can also be helpful during episodes of acute itch, particularly activities that keep the hands busy.
• Patients and caregivers often seek causes or cures for eczema, which diverts attention away from the treatment plan. Patients should be counselled on the chronicity of atopic dermatitis, and reminded that broad panel allergy testing and restrictive diets are not recommended in the absence of signs and symptoms consistent with an IgE-mediated allergy.
• For additional patient support, information and education, recommend reliable sources, such as the Eczema Society of Canada/ Société canadienne de l’eczéma, Canadian Dermatology Association, American Academy of Dermatology, National Eczema Association (USA), or National Eczema Society (UK)

Written Eczema Care Plans

• A written eczema care plan is a recommended tool to improve therapeutic outcomes.^{17, 18} Patients and caregivers may benefit from having a written plan in order to carry out the multi-step plan of caring for eczema, which often includes specific bathing and moisturizing recommendations and instructions for using prescription medications (type and dosage). For a sample written eczema care plan, see Figure 1.

Skin Care

Moisturizers

• Frequent application of moisturizers is the cornerstone of eczema management,¹⁹ helping to decrease itch, preventing and reducing flares, and decreasing the need for prescription medications.
• Xerosis results from skin barrier dysfunction and is present to some degree in most patients with eczema. Moisturizers are used to reduce xerosis, which reduces itching, and they also reduce transepidermal water loss.²⁰
• For patients with mild eczema, frequent and consistent use of moisturizers may sufficiently manage the disease. In moderate to severe disease, moisturizing is still a fundamental part of treatment. Patients may need to be explicitly counselled on how to use moisturizers in conjunction with other topical prescription treatments.
• Patients should select moisturizers that are soothing and do not irritate the skin. Ideal moisturizers contain varying amounts of emollient, occlusive and humectant ingredients. While thicker products that both moisturize and provide a barrier are recommended, there are many moisturizers to choose from and patient preference is important.
• The consistent use of a moisturizer that is well-tolerated by a patient is more important than the specific product selected.
• There is insufficient evidence to recommend a specific optimal regimen for use of moisturizers. However, this consensus group suggests that generous application, one to several times a day, is necessary to help minimize skin dryness. It is highly recommended to apply moisturizers immediately after bathing or any water exposure to improve skin hydration.^{21, 22}

Barrier Repair & Barrier Repair Products

• Patients with atopic dermatitis have impaired skin barrier function, partly due to deficiencies in ceramides (lipids) and filaggrin (a protein), components of the outer skin barrier. These deficiencies contribute to a degraded skin barrier that allows bacteria, irritants, and allergens to enter the skin, and also allows moisture to escape.²³ To address this, ceramides are increasingly available in over-the-counter moisturizers, as well as one prescription barrier repair treatment.

Bathing & Showering

• Daily bathing is often recommended for patients with eczema; however, there is no evidence to support a standard recommendation for the frequency, duration or the method of bathing. Moisturizing after bathing is strongly recommended.^{21, 22}
• Clinicians can recommend that patients bathe or shower (5-10 minutes) in warm, plain water once daily, or every other day, based on patient preference (e.g., baths may sting open eczema lesions making daily bathing challenging).
• Gentle cleansers may be used only on areas that need cleaning, and should be used at the end of the bath or shower. Bathing using this method should not aggravate eczema.
• Moisturizing should immediately follow bathing or showering, since exposure to water can exacerbate eczema if the skin is not moisturized soon after exiting the water.
• Evidence is lacking to support the use of bath additives such as oils, emollients, bath salts, and most other products.

Inflammation Control

Topical Corticosteroids

• Appropriate use of topical corticosteroids (TCS) is a safe and effective first-line therapy in the treatment of the inflammatory component of eczema.²⁴
• Consider factors such as the age of the patient, areas of the body to be treated, xerosis, and patient preference when prescribing appropriate topical corticosteroids.
• Selecting the appropriate agent, including the appropriate strength, can be challenging. In general, low potency TCS (classes VI and VII) are recommended for the face, neck, skin folds, and groin, for both paediatric and adult patients.
• Moderately potent medications (classes III, IV, and V) are recommended for the trunk and extremities. Higher potency TCS may be required for refractory eczema or lichenified areas.
• Consider referral to a dermatologist in these cases.
• Once to twice daily application of TCS are the generally recommended treatment during an acute eczema flare.
• Treatment should be stopped once the affected areas are smooth to the touch and no longer itchy or red.
• If no response to treatment is seen after 1 to 2 weeks, re-evaluate to consider other diagnoses or treatment plans. With appropriate use, the incidence of adverse events is minimal.²⁵
• When prescribing combination treatments, TCS strength should be taken into consideration, as the TCS could be of higher potency than is appropriate.
• Patients and caregivers may fear the side effects of pharmacological treatments. Fear of topical corticosteroids is common and should be recognized and addressed. This may be particularly important for paediatric patients.
• Addressing fears and concerns may help improve adherence and avoid under-treatment or non-treatment.
• Patients who are using corticosteroids over the long term should be monitored, and should have regular physical examinations to watch for cutaneous side effects. Monitoring of eczema patients for systemic side effects from topical corticosteroids is not routinely recommended.^{26, 27}
• In patients who have good adherence to their treatment plan and experience periods of remission, but flare frequently in predictable areas, maintenance treatment with topical corticosteroids may be suitable. Intermittent application (one application 1 to 2 times a week) of a moderately potent topical corticosteroid is recommended for proactive treatment on areas that are commonly at risk of flare.²⁸

Topical Corticosteroid Side Effects

• As with all medications, TCS can have side effects (Table 2). However, when they are used appropriately, the incidence of side effects is low, and patients should be counselled accordingly.²⁹
• The burden of under- and untreated eczema usually outweighs the risks associated with TCS.³⁰

Topical Calcineurin Inhibitors

• Topical calcineurin inhibitors (TCI) (i.e. tacrolimus and pimecrolimus) are a class of anti-inflammatory medications that are a recommended safe and effective second-line therapy option for treatment of acute flares of eczema.³¹
• Whereas TCS are generally considered first-line topical treatment for eczema, TCI can also be used off-label as first-line therapy in select cases, particularly for areas that are sensitive to the adverse effects of TCS, such as the eyelids.
• TCI are also appropriate second-line therapy for eczema that does not respond to TCS or in patients intolerant of TCS.
• TCI can also be used as a preventive therapy, 2 to 3 times a week in areas of predictable flares similar to the preventative strategy described for TCS above.³²
• Proactive, intermittent use of TCI has been shown to be more effective than the use of emollients alone.^{33, 34}

Topical Calcineurin Inhibitor Side Effects

• Mild to moderate burning or stinging sensation of the skin can occur with TCI use, and patients and caregivers should be counselled about this possible reaction.
• Patients who use tacrolimus may have flushing of the face when they consume alcohol.
• Based on concerns about an increased risk of cancer with the use of TCI use, the US Food and Drug Administration (FDA) issued a black-box warning shortly after the class of medications came on to the market. Shortly after the FDA warning was issued, Health Canada issued a similar warning. However, TCI have been available for over 15 years and recently published data does not support those concerns.^35-39 Healthcare providers should be aware of the black-box warning and discuss it with patients.

Adjunctive Therapies

Antimicrobials

• Skin infections can worsen eczema and should be addressed when present.
• Clinical signs of infected eczema include crusting, oozing, and pus.
• Gram-positive bacteria, in particular Staphylococcus aureus, is frequently found on the skin in eczema.⁴⁰
• Mild infection may be treated with a topical antibiotic adjunctively with a topical anti-inflammatory agent.
• The routine use of topical antistaphylococcal antibiotic treatment in the absence of clinical signs of infection is not recommended.⁴¹
• When clinical signs of bacterial infection are seen, swabs for culture and sensitivity should be considered, partly because of the increased prevalence of resistant organisms, and empiric oral antibiotics targeting streptococcal and staphylococcal infections can be started.
• In patients who frequently show clinical signs of secondary bacterial infection, consider bleach baths as prophylactic therapy.⁴²

Bleach Baths

• In patients where infections are common, bleach baths can be done once to twice per week, and consist of bathing in a dilute solution of bleach and clear warm water.⁴³
• Patients and/or caregivers can create a dilute bleach bath at home by adding 120 mL (1/2 a cup) of regular strength household bleach (6% sodium hypochlorite) to a full standard-size bathtub of warm water (which is usually about 150 litres). This concentration of bleach is quite low (0.005%).
• For smaller bathtubs, patients may use 1 teaspoon (5 mL) of regular bleach for every 5 litres of water.⁴²
• The bleach and clear water should be mixed well, and the patient should bathe in the solution for 5 to 10 minutes, thoroughly rinsing the skin after with warm clear water.
• Rinsing should be immediately followed by application of prescription treatments, if needed, and moisturizers.
• Patients and caregivers should be explicitly counselled on how to perform the bleach bath, including how to select the correct concentration of bleach and safe dilution practices.

Managing Viral Infections

• Viral infection with herpes simplex virus can cause eczema herpeticum, a potentially life-threatening condition.
• Swabs for viral detection (such as viral culture, or polymerase chain reaction) should be performed in suspected cases of eczema herpeticum, in addition to initiation of treatment with an appropriate antiviral agent.⁴⁴
• Eczema coxsackium is a form of hand-foot-and-mouth disease in patients with eczema that is more extensive than routine hand-foot-and-mouth disease, and can look similar to eczema herpeticum.
• Molluscum contagiosum occurs more commonly in eczema patients and the presence of the virus can lead to eczema surrounding the mollusca, potentially exacerbating an eczema flare.

Antihistamines

• Due to a lack of evidence of their efficacy in patients with eczema, non-sedating oral antihistamines are not recommended for use.⁴⁵
• Sedating oral antihistamines (SOA), such as hydroxyzine and diphenhydramine, can be used in patients whose disease significantly interferes with sleep.
• It should be noted that long-term use of SOA may lead to a reduction in the efficacy and sedative effects of the treatment.⁴⁶
• Control of inflammation and itch, through the use of previously discussed prescription anti-inflammatory medications and appropriate bathing and moisturizing may mitigate the need for sedating antihistamines in many patients.
• Patient reliance upon regular antihistamine use should be an indication that the treatment plan is not optimally managing the condition.⁴⁷

Allergy Testing & Restrictive Diets

• The relationship between eczema and allergy is complex. While children with eczema have a significantly higher incidence of food allergies, food does not cause eczema flares for most patients.
• In an AD patient who has confirmed food allergies, exposure to the allergenic foods can induce urticaria, which can indirectly worsen the eczema.
• If a patient shows true allergic signs and symptoms such as urticaria or anaphylaxis to a food, that food should be avoided and an epinephrine auto injector should be prescribed, until an allergist/immunologist can be consulted.
• Routine allergy testing with eczema as the only symptom is not currently recommended.
• Broad spectrum panel testing for a variety of foods is not recommended, as it often leads to a number of false positive results.⁴⁸
• Food elimination diets or restrictive diets are not recommended as an eczema intervention.
• Excessive, prolonged food elimination diets, especially in children, may lead to weight loss, poor growth, and nutritional deficiency.⁴⁹

Supplements & Alternative Therapies

• There is limited evidence to support the routine use of dietary supplements and alternative medicines for the treatment of eczema. However, some patients may find dietary supplements or alternative interventions to be helpful.
• If the dietary supplements or interventions are not harmful, the patient should be counselled and supported accordingly. However, if these interventions could be harmful, patients should be counselled and cautioned.
• Extra caution should be taken in the case of infants and children.

Refractory and Severe Eczema

• Phototherapy⁵⁰ and/or systemic immunomodulatory agents may be necessary for refractory and severe eczema, and they should be used by health care providers versed in their use.⁵¹
• Phototherapy, specifically broad- and narrow-band UVB, can be used for pediatric and adult patients with AD. It is a safe and effective treatment for most patients, but a major barrier to its use is accessibility as it requires visits to a physician’s office multiple times per week. Furthermore, long term side effects, such as skin cancer, have not been well-established in the paediatric population.
• Cyclosporine, methotrexate, azathioprine and mycophenolate mofetil are the systemic agents commonly used for atopic dermatitis. All of these agents may cause significant adverse events and require regular monitoring, so they should be used with caution and after appropriate discussion of their risks and benefits with patients and their families. Specific guidelines for their use, including dosing schedules and adverse effects, are beyond the scope of this review.
• Referral to a dermatologist should be considered in patients with refractory eczema in whom systemic therapy is being contemplated.

Systemic Corticosteroids

• Systemic corticosteroids, such as prednisone, are not recommended for the routine management of atopic dermatitis.
• While systemic corticosteroids can rapidly ameliorate the signs and symptoms of an acute eczema flare, patients often have a disease flare upon withdrawal of the corticosteroid.
• Given the long-term consequences of chronic systemic corticosteroid use, they should be avoided whenever possible in patients with atopic dermatitis.⁵²