¹Associate Professor, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Clinical Assistant Professor, Department of Dermatology, University of British Columbia, Vancouver, BC, Canada
³Clinical Professor, Director of Pediatric Dermatology, University of Alberta, Edmonton, AB, Canada
⁴Professor, Western University, London, ON, Canada
⁵Assistant Professor, Department of Medicine, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
⁶Assistant Professor, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
⁷Division of Dermatology, Sainte-Justine University Medical Center; Clinical Professor in Pediatrics, University of Montreal, Montreal, QC, Canada
⁸Division of Dermatology, Sainte-Justine University Medical Center; Clinical Professor in Pediatrics, University of Montreal, Montreal, QC, Canada
⁹Clinical Associate Professor, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Funding:
This Supplement was developed using the Authors’ Expert Opinion, supported by an unrestricted Educational Grant from Pfizer Canada.
Use crisaborole ointment in off-label settings is left up to the discretion of the treating health care professional after careful clinical evaluation.

Abstract:
Background: Atopic dermatitis (AD) is associated with epidermal barrier dysfunction. The chronic skin condition presents clinically with pruritus and recurrent skin lesions. The psychosocial impact of the condition is severe for most patients and their families.
Crisaborole, a topical PDE4 inhibitor, has demonstrated efficacy in patients with mild-to-moderate AD.

Objectives: A diversity of cases are presented that reflect real-world clinical use of topical crisaborole ointment, as a mechanism to help optimize patient care.

Methods: Evidence from the literature coupled with the panels’ expert opinion, experiences and, key insights reflect the panels’ clinical use of topical crisaborole ointment for AD and irritant dermatitis (off-label use) and how patients can benefit from its use, i.e., “what experienced specialists are doing across Canada.”

Results: The panel treated and presented cases that report on crisaborole ointment used as monotherapy, combination therapy, sequential therapy, and maintenance therapy. The presented cases aim to illustrate the diversity of crisaborole use concerning age range, skin type/ethnicity, and body location. Each case presents a summary of the learning points.

Conclusions: The presented cases reflect the panels’ real-world clinical experience with crisaborole for the treated patients. The panel suggested that crisaborole ointment provides a good safe alternative to TCS and TCI. Treatment with the ointment should be avoided on severely flaring skin and for those that experience irritation, burning, or stinging while testing it on unaffected skin areas.

Key Words:
Atopic dermatitis, Real-world cases, Topical PDE-4 inhibitor

Introduction

Atopic dermatitis (AD) is a lifelong inflammatory skin condition associated with epidermal barrier dysfunction and altered immune function, presents clinically with recurrent episodes of pruritic erythematous papules and plaques.¹ AD usually starts in infancy, where it affects up to 20% of children in North America, and is also highly prevalent in adults.² Two-thirds of AD patients are reported to have mild disease, 26% moderate, and 7% severe AD disease.³ The majority of patients are treated by primary care physicians who primarily use topical anti-inflammatory therapy for their mild-to-moderate AD cases.^4-13

The psychosocial burden of AD on patients and their families is enormous.¹⁵ The inflammatory skin disease increases the risk of other immune-mediated inflammatory atopic disorders, such as asthma, allergic rhinitis and food allergies, as well as mental health disorders in some.^15,16

Patients with AD should use gentle cleansers and moisturizers that are balanced to the skin pH in addition to behavioural measures such as avoidance of irritants and triggers.

AD is a chronic relapsing disorder with periods of quiescence punctuated by intermittent flares. When AD flares then treatments such as topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), and more recently, phosphodiesterase-4 (PDE4) inhibitors should be considered, while continuing skincare and measures to avoiding triggers of AD. TCS and TCI treatments are widely used as monotherapy in cases of mild-to-moderate AD or in combination with systemic treatments for more severe AD involvement. These treatment regimens are supported by clinical guidelines and clinical pathways worldwide and have an established safety record.^4-13 Crisaborole ointment (Eucrisa, Pfizer), a unique topical prescription option for AD, is a PDE4 inhibitor with demonstrated efficacy in patients aged two and older with mild to moderate AD.¹⁶

The presented real-world case-based approach explores the role topical crisaborole can play in the prevention, treatment and maintenance of AD and other inflammatory skin conditions, in clinical practice. The selected patient cases aim to outline a diversity of cases that reflect real-world use of topical crisaborole ointment for patients with AD and other skin conditions, either as monotherapy or in combination with other treatments. Any discussion concerning off-label use is considered an expert opinion only.

Methods

Aim of the Project

This current real-world case project was conceived as a mechanism to help optimize patient care by recognizing the role crisaborole ointment can play in the prevention, treatment and maintenance of AD. Additionally, the project explores where this therapeutic agent could be used in managing AD in patients who require a combination of therapies. The cases intend to illustrate the authors’ real-world clinical experience rather than reflect controlled clinical trial data. Evidence coupled with the expert opinion, experiences, key insights and recommendations is presented and discussed. Recommendations given by the panel reflect the use of topical crisaborole ointment for AD and how patients can potentially benefit from its use, i.e. “what experienced specialists are doing across Canada”. Any discussion concerning off-label use is considered an expert opinion only.

The target audience for this publication is physicians and other health-care professionals who treat patients with AD.

Steps in the Process

The five-step procedure included a) project definition and panel selection, b) collection of information and preparation of cases, c) meeting to select cases for the publication, d) literature review to support the cases, and e) creation, review, and finalization of the manuscript.¹⁷

Role of the Panel

An expert panel of eight dermatologists and pediatric dermatologists, selected to represent the diverse geographical regions within Canada, who commonly treat patients with AD, was convened on November 9, 2019, in Toronto, as part of the semiannual Dermatology Update conference. The panel members reported clinical cases of pediatric and adult patients who were suitable candidates for crisaborole ointment treatment.

The panel members discussed the cases in the light of the supporting literature, then decided which cases would be included in the publication. The publication was prepared and reviewed by the panel members.

Topical Treatment for Mild-To-Moderate AD

Avoidance of triggers of AD flares and education are the first steps in the prevention, treatment, and maintenance of AD.6

Skincare Using Gentle Cleansers and Moisturizers

Skincare using gentle cleansers and moisturizers remains the cornerstone of treatment for all severities of AD. Daily use of this skincare regimen is supported by established guidelines and clinical pathways.^4-13 Moisturizers play an important role in combating and controlling xerosis, decreasing epidermal water loss, and restoring epidermal barrier function.^6,10 Moisturizers should be liberally and frequently applied and can be used alone for mild disease or in combination with other therapies regardless of the severity of their AD. ^6,10

TCS and TCI

If avoidance of triggers and the use of a daily skincare regimen with gentle cleansers and moisturizers are not effective, topical anti-inflammatory agents, such as corticosteroids (TCSs) or calcineurin inhibitors (TCIs) are used twice a day until the lesions have cleared.^3-13 TCS is the first-line anti-inflammatory option, available in a variety of strengths from mild to potent and very potent.^6,11 Side effects such as skin atrophy, purpura, telangiectasia, striae, focal hypertrichosis, impaired wound healing, allergic contact dermatitis, and acneiform or rosacea-like eruptions on the face are very uncommon when TCS is used appropriately.⁶ Both patients’ and parents’ fear of TCS and steroid phobia should be discussed to improve adherence and avoid under-treatment.⁶

TCI’s are another safe and effective treatment option, however short-term side effects such as skin burning, and pruritus, especially when applied to acutely inflamed skin and cutaneous viral infections, may occur.⁶ Patients and parents should be informed about these potential side effects to avoid premature discontinuation of treatment.⁶ TCIs are therapeutic agents often used for mild AD on the face, neck, and folds, and used in prevention and TCS reduction elsewhere on the body.

Systemic Therapy

For patients affected by more severe AD, agents that target immune responses and inhibit T cells by targeting Th1, Th2, Th22, phosphodiesterase-4 (PDE4), IL-4, and IL-31 are available.¹⁸ Phototherapy and traditional systemic therapies, including methotrexate, cyclosporine, and mycophenolate mofetil, can also be used off-label in severe AD.

Crisaborole Ointment

Crisaborole (Eucrisa, Pfizer), a topical prescription option for AD, is a PDE4 inhibitor with demonstrated efficacy in patients aged two and older with mild to moderate AD.16 Two, multicenter phase III trials, demonstrated early sustained control of mild-to-moderate AD in patients aged over two years with crisaborole ointment use over twenty-eight days.¹⁶ When compared to the vehicle, treatment with the 2% crisaborole ointment showed reduced pruritus, AD severity, and other signs of AD (erythema, exudation, excoriation, induration/papulation, and lichenification), although clinicians have expressed concerns about stinging and burning on at application sites.^16,19

A multicenter extension study indicated that crisaborole ointment for up to fifty-two weeks is safe.¹⁷ The extension study reported an overall 10.2% rate of crisaborole treatment-related adverse events such as dermatitis (3.1%), application site pain, stinging, burning (2.3%), and application site infection (1.2%).³ These events were considered mild, and no one withdrew from the study due to these adverse events.

Less common potential side effects included skin irritation and hives or welts, which may be due to underlying atopy. Given the good tolerability and safety profile, crisaborole ointment makes for an alternative steroid-sparing topical option to TCS and TCI.¹⁶

Data Gathering of Real-World Cases on Crisaborole Ointment Use

The panel members used a template for their case studies, which asked the following questions:

• What are the cases and the impact of the condition?
• What are the treatment options, and what treatment(s) were previously used for this case
• Why might crisaborole ointment work in this case, where does it fit and what were the results of the treatment?
• Did any adverse events occur? If yes, describe.
• What (if any) are the special circumstances related to this particular case, and which lessons are learned?

Patient evaluations were at baseline (start) and at eight weeks (+/- 5 days) using physician reported skin condition (SCORing Atopic Dermatitis Clinical assessment [SCORAD] score.²¹ SCORAD recorded AD location and percentage area (A), Intensity (B): Redness, swelling, oozing/crusting, scratch marks, skin thickening, dryness [the intensity of each of the following signs is scored as none (0), mild (1), moderate (2) or severe (3)] and subjective symptoms (C) [Sleeplessness: 0 = no sleeplessness and 10 = the worst imaginable sleeplessness, Itch: 0 = no itch and 10 = the worst imaginable itch]). Total SCORAD is the sum of A, B, and C, minimum score = 0, maximum score = 103.21 The impact of the skin condition after treatment regime use and adverse events were recorded at baseline (start) and week 8 (+/- 5 days) (end).

Some of the physicians used quality of life for the participants 15 years or younger as assessed by Children’s Dermatology Life Quality Index (CDLQI). The minimum score is 0, and the maximum score is 30, the latter corresponds with the most severe impairment of quality of life. Other scores used were severity of itching as assessed by the Pruritus score determined using the Numerical Rating Scale (Minimum score is 0. The maximum score is 10, the latter corresponding to the most severe itching imaginable by the patient).

Selected Real-World Cases

The panel selected a total of eleven cases that reported on realworld use of crisaborole ointment as monotherapy, combination therapy, sequential therapy, maintenance therapy, preventive therapy, and its application in dermatitis beyond AD. (Table 1). The presented cases aim to illustrate the diversity of crisaborole use concerning age range, skin type/ethnicity, body location, the severity of AD, and reports of off-label use.

Case 1: A 4½-year old girl with AD since the first months of life, which had recently increased in severity. The moderate-tosevere condition involved multiple sites, including hands and feet. Previous treatment with various TCS formulations was unsuccessful. When crisaborole started, mometasone ointment was continued as needed on the lesions on her body. The rationale for starting topical 2% crisaborole ointment was the failure of previous treatments and a specific interest in improving the skin condition of her hands and feet. Her skin condition markedly improved over the eight week treatment period (Figure 1A-1J). No adverse events occurred, and the ointment was well tolerated even on the face.

Learning point: Crisaborole is a well-tolerated (even on the face) alternative for TCS and is effective on hands and feet.

Figure 1A – 1D

Figure 1E and 1F

Figure 1G and 1H

Figure 1I and 1G

Case 2: For four months, a 4-year-old boy had suffered from AD, primarily on the face, antecubital, and popliteal fossa. He had almost constant pruritus and open, erythematous skin. His interaction with other children was poor, and both the patient and parents had difficulty sleeping. Previous long-term TCS treatments lacked success. Moreover, his mother was concerned about prolonged steroid use and requested trying crisaborole ointment. After eight weeks of crisaborole ointment application, his skin condition had greatly improved (Figure 2A and 2B). Although at first, the ointment caused skin irritation, this was easily alleviated with the use of a moisturizer.

Learning point: Crisaborole seems to induce irritation, burning, and stinging more frequently in clinical practice than reported in clinical trials. The patient experienced irritation, burning, and stinging in the areas where crisaborole was used. Information and education on measures to prevent or to treat these side-effects were effective. The advice given included the use of a refrigerated moisturizer, frequently applied before and after application of the ointment to optimize crisaborole results and decrease irritation. The mother was encouraged to continue treatment after the physician discussed the expected outcomes of the therapy. The irritation was alleviated with the use of a moisturizer as instructed.

Figure 2A and 2B

Case 3: A 29-year-old neonatal intensive care unit (NICU) nurse developed hand dermatitis one year ago. During work, she frequently used a hand sanitizer causing pruritus and painful fissures. She had a negative history for AD, and other atopic disorders and Patch tests were negative. The eruptions cleared when she was on holiday. After consultation with the occupational health department for help and guidance, she received a special hand sanitizer. She refused TCS as she was concerned about developing skin thinning. Within eight weeks of starting crisaborole ointment, the condition had resolved. The ointment was well tolerated, and she resumed her work as a NICU nurse (Figure 3A and 3B).

Learning point: The patient with occupational irritant hand dermatitis did not want to use TCS. The alternative treatment with crisaborole ointment was successful for this patient. Use of crisaborole in the treatment of irritant contact hand dermatitis is off-label.

Figure 3A and 3B

Case 4: A 68-year-old woman with a history of rosacea also had recurrent facial eruptions. Patch testing was positive to Kathon CG, which was found in her laundry product which she had since avoided. Since TCS were unsuccessful, treatment with crisaborole ointment was started, used in combination with ceramides containing cream as needed. Her skin condition markedly improved within two weeks (Figure 4A – 4D).

Learning point: The ointment may be a useful alternative for TCS for facial areas in patients with concomitant facial inflammatory skin conditions. Although crisaborole may induce irritation, burning, and stinging, in this patient with underlying rosacea, the product was well tolerated. Topical steroids can induce a rosacealike eruption. Crisaborole did not aggravate this patient’s rosacea. Patch testing was useful in identifying the causative allergen. The use of crisaborole in allergic contact dermatitis is off-label.

Figure 4A and 4D

Case 5: An 11-month-old baby-boy had facial AD from the age of nine months. He had coincident acute myelogenous leukemia (AML) and was recovering from chemotherapy. His parents were concerned about TCS and TCI being immunosuppressive agents and due to his ongoing AML treatment refused them. Crisaborole ointment seemed a good alternative option. His skin condition improved within an eight week observation period, and no adverse events occurred (Figure 5A – 5D).

Learning point: In immunosuppressed or otherwise vulnerable patients, crisaborole ointment is an effective alternative to TCS to treat AD even on the face. Parental wishes to not use TCS or TCI were granted because crisaborole’s mechanism is not immunosuppressive. Although crisaborole is approved for use in individuals 2 years of age and older, it was safely and effectively used in this infant.

Figure 5A and 5D

Case 6: A 2-month-old baby boy presented with diffuse xerosis and AD present since three days of age. His condition impacted the entire family. His mother had applied Vaseline six times a day and TCS twice a day. He had not responded to treatment with several different types of TCS. The physician was concerned about absorption and possible adrenal axis suppression. After eight weeks of crisaborole ointment use, pruritus had subsided and both the baby and his family were able to sleep through the night (Figure 6A and 6B). Before starting treatment with crisaborole ointment, he had regularly had skin infections with MRSA, which did not reoccur since the start of the crisaborole ointment.

Learning point: Crisaborole proved to be a useful alternative for TCS where absorption and possible adrenal axis suppression were a major concern. Of interest is the resolved recurrent infection since the use of crisaborole, which may be attributed to the improved skin condition. Crisaborole is approved for use in individuals with AD two years of age and older.

Figure 6A and 6B

Case 7: A 15-year-old male had recurrent resistant atopic dermatitis and dyspigmentation from chronic TCS use. Treatment of the generalized flares and superinfection consisted of intravenous antibiotics and oral cyclosporine, to which he had a good initial response. To address his concern about TCS use and the desire for a simpler regimen, twice daily application with crisaborole ointment was started while continuing the cyclosporine. After eight weeks of use, he had an excellent response, with marked improvement in his quality of life. Whenever the patient stops topical crisaborole, some AD returns (Figure 7A and 7B).

Learning point: The use of crisaborole ointment in combination with systemic therapy was effective for this patient. The ointment is to be applied at the first sign of a flare before lesions develop and avoided the need to increase systemic therapy. As a result, he gained confidence in controlling his skin condition and improving his outlook on his situation.

Figure 7A and 7B

Case 8: A 5½-year-old boy had mild-to-moderate AD since the age of three and recently developed symptomatic hand and feet involvement. The rationale for crisaborole use on his hands and feet was the suboptimal response to previous TCS/TCI therapy. Concomitant use of TCS and TCI was continued together with crisaborole. His skin had almost cleared after eight weeks of crisaborole ointment use (Figure 8A – 8D).

Learning point: An incremental benefit of adding crisaborole as part of a combination regimen with TCS and TCI TCI introduces new possibilities for patients with AD on their hands and feet.

Figure 8A and 8D

Case 9: Since the first months of life, a 5-year-old male has had moderate-to-severe AD with symptomatic painful involvement of his hands, impacting daily activities. He had difficulty handling toys and interacting with other children and their parents. TCS and TCI treatments were not successful. With crisaborale, his hand palms and wrists’ involvement almost completely cleared. (Figure 9A – 9E).

Learning point: Effective penetration of crisaborole on thicker skin such as hand-palms and foot-soles may facilitate improvement in these special sites.

Figure 9A and 9B

Figure 9C and 9E

Case 10: A 4-year-old girl had AD. TCS therapy was started for her flaring disease. Her mother was concerned about vaccines and TCS use. Crisaborole ointment treatment was started to address the mother’s concerns. At eight weeks of ointment application, there was an 80% clinical improvement; however, some moderate AD persisted at some sites which required strong TCS.

Learning point: Although the crisaborole ointment did not completely resolve the disease, the mother preferred it to TCS for milder lesions and wished to reserve TCS for more resistant lesions.

Figure 10A and 10G

Case 11: A 12-year-old male with AD since infancy had involvement of the hands and limbs. His condition failed to show improvement from intermittent TCS. The rationale for starting crisaborole ointment was the family’s frustration with the lack of results and a possible penetration advantage of the ointment on the hands. A left/right assessment of clobetasol versus crisaborole ointment was conducted. His mothers’ perceptions were that his hands both improved, but the crisaborole ointment was more effective than clobetasol. On the arms and legs, both treatments were successful, but clobetasol outperformed crisaborole ointment. The therapy was continued after the eight weeks study period as the family was happy with the treatment response. No adverse events occurred. Subsequently, mom used crisaborole alone on his hands and had ongoing good maintenance and prevention of flares. (Figure 10A – 10G). Follow up results are shown in Figure 11A – 11E.

Learning point: The crisaborole ointment performed better on the hands than clobetasol, however when used on the arms and legs, the reverse was the case, indicating that the ointment may be particularly useful on thicker skin areas.

Figure 11A and 11E

Discussion

For each case, the age, skin type, underlying skin condition, rationale for using crisaborole, and in some cases, treatment duration were highlighted as well as its role as part of a maintenance/prevention and treatment regimen. The cases presented a spectrum of clinical responses to crisaborole, including instances of poor response, such as in case 10, where AD persisted, and TCS was further needed. The panel discussed challenges of recognizing and managing AD in darker skin which may be addressed using crisaborole ointment, although studies are needed to confirm possible benefits. Most of the cases were atopic dermatitis, the approved indication. Two other types of dermatitis (hand dermatitis, allergic contact dermatitis) were included although they have not approved indications since these conditions are often difficult to treat and do not always respond to topical steroids. In addition, on the face, topical steroids may be associated with a greater potential for adverse events.

Steroid Phobia

Steroid phobia refers to the negative feelings and beliefs related to TCSs experienced by patients and patients’ caregivers. The panel expressed concerns that this phenomenon may be a contributing factor in treatment failure in AD patients. A systematic review²² found that TCS phobia is present across all cultures and that adequate information for patients and parents is lacking. The authors of the systematic review propose that the sources from which patients are receiving information about TCS may be targetable for intervention to increase adherence to TCS treatment regimens.²²

Crisaborole can be an effective alternative for TCS and TCI, especially in patients with conditions requiring long-term TCS or TCI use.

In case of safety concerns (even when subjective) with TCS and TCI use in young patients or concerns about steroid absorption in all groups, patients can safely use crisaborole ointment. Moreover, preservatives in crisaborole pose no safety issues. The panel agreed that crisaborole ointment provides a good safe alternative to TCS and TCI in such cases, enhancing treatment adherence and thus outcomes.

Irritation, Burning and Stinging

Crisaborole seems to induce irritation, burning, and stinging more frequently in clinical practice than reported in clinical trials.^3,6,19 This side effect was also reported for two of the presented cases (case 2 and 4). The panel suggested that in their experience, irritation, burning, and stinging are more quickly resolved than in the case of TCI use, where similar side effects are also observed. If TCI related stinging occurs most clinicians will apply steroids temporarily and then subsequently TCIs are usually tolerated.

The panel recommended providing information on this issue and education on measures to prevent or to treat it before the start of the treatment with crisaborole. The panel recommended frequent use of a refrigerated moisturizer before and after application of the ointment, and the use of an anti-itch lotion as needed throughout the day. The panel further suggested that it may be helpful to have patients testing crisaborole on healthy skin. Modify or discontinue the treatment if the formulation triggers burning or stinging even on healthy skin with concomitant use of a refrigerated moisturizer. The panel discussed avoiding crisaborole ointment use on severely flaring skin and starting with TCS until the flare is controlled, followed by crisaborole ointment.

Antibiotic Resistance

Antibiotics are commonly used as part of the management of AD. However, only a minority of patients with AD have clinically significant S. aureus infection. Moreover, data is lacking for highly beneficial outcomes with exclusive use of antibiotics in the management of AD.²³ Case 6 shows an example of the possible use of crisaborole as a steroid-sparing and antibiotic-sparing agent. Because of antibiotic resistance, the use of the crisaborole ointment may be of interest and aligns with current emphasis on antibiotic stewardship in AD. Anti-inflammatory agents control eczema, which leads to less frequent infections and less antibiotic use.

Combination Treatment

Combining or alternating crisaborole with TCS or TCI may be successful for more severe disease. The ointment was safely used in time-intervals between the application of a moisturizer, TCS, or in combination with systemic therapy. Several cases showed a marked improvement in the skin condition of the treated patients and no adverse events.

Specific Body Locations

Case 4 shows an example of the safety and tolerability of crisaborole when used on specific sites (e.g., face and lips). An incremental benefit of crisaborole use as part of a combination regimen was shown in a patient (case 8) who recently had AD involvement of his feet, with hyperkeratosis and desquamation.

The rationale for crisaborole use, in this case, was good absorption of the ointment due to the relatively small size of the molecule allowing better penetration.

Case 11 showed beneficial crisaborole use on the hands, which did not improve with intermittent TCS application. This patient conducted a real-time comparative test using clobetasol on one side of the body and crisaborole on the other. Crisaborole worked better on the hands while clobetasol showed better results on his arms and legs.

The use of crisaborole for non-AD (case 3) was shown in a patient with occupational HD, which resulted in complete response. Advisors recommended further studies of crisaborole on the hands and feet (e.g., the study of occupational hand dermatitis and penetration study) to support the use of the ointment for these complex areas.

Table 1: Summary of the eleven cases studies
Case 1: TCS^a: Betametasone dipropionate 0.1% ointment, Mometasone ointment, TCI^b. Tacrolimus 0.1% ointment, Skincarec: Hydratation-Eucerin, Aquaphor, Aderma cleanser and hydrating agent.
Case 2: TCS^d: Desonide cream BID x 1 year, Hydrocortisone 17 valerate UNG BID x 1 year.
Case 3: TCS^e: Hydrocortisone cream
Case 4: TCS^f: 1% hydrocortisone cream
Case 6: TCS^g: Hydrocortisone 2.5%g then switched to desonide for body, Dermasmoothe FS for scalp and face. Then switched to hydroval 0.2% ointment to entire body.
Case 8: TCS^h: 0.1% betametasone valerate ointment (body), 0.1% protopic ointment (face).
Case 9: TCSⁱ and TCI: Betametasone dipropionate 0.1% ointment, Mometasone ointment, Tacrolimus 0.1% ointment.
Case 10: TCS^j: Begin with strong corticosteroids, Desonide ointment for the face, Betamethasone valerate 0,1% ointment for the hands and feet.
Case 11 : TCS^k : Clobetasol.

Atopic dermatitis (AD), Twice daily (BID), Crisaborole ointment (CO), Adverse events (AEs), Neonatal intensive care unit (NICU), Hand Dermatitis (HD), Medical history (Hx), Acute Myelogenous Leukemia (AML), Intravenous (IV) Oral (PO).

Maintenance Therapy

The panel discussed the spectrum of clinical response of crisaborole used in adjunction to a moisturizer as maintenance therapy and suggested that crisaborole ointment should start at the first sign of a new flare before the development of lesions. TCS should be added if it is not successful. Currently, data on the use of crisaborole ointment for long term maintenance therapy is lacking; however, the panel suggested further studies of crisaborole as maintenance therapy.

Conclusion

The discussed cases reflect the panels’ real-world clinical experience with crisaborole for the treatment of patients with AD and the off-label treatment of irritant dermatitis. The panel suggested that crisaborole ointment provides a good safe alternative to TCS and TCI. Use of crisaborole should be avoided on severely flaring skin and for those that experience irritation while testing it on unaffected skin areas.

Acknowledgement

The authors acknowledge and thank Anneke Andriessen, PhD, for her invaluable assistance with preparing this manuscript.

Limitations

The cases are intended to illustrate the real-world experience rather than reflect a controlled clinical trial data environment, nor do they presented cases mirror statistical outcomes. Use crisaborole ointment in off-label settings is left up to the discretion of the treating health care professional after careful clinical evaluation.

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¹Department of Dermatology, Baylor College of Medicine, Houston, TX, USA
²Department of Dermatology, University of Texas Medical School at Houston, Houston, TX, USA
³Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
None reported

ABSTRACT
Herpes labialis is a frequently occurring viral infection of the lips and oral mucosa. Recurring lesions are induced by viral reactivation and replication, but the symptoms leading to morbidity, such as pain and inflammation, are immune-mediated. The introduction of 5% acyclovir/1% hydrocortisone in a topical cream (Xerese™) represents a therapeutic strategy directed at both of these pathogenic processes. Applied at the onset of prodromal symptoms, this combination treatment has a good safety profile and is more effective in reducing healing time than antiviral or anti-inflammatory agents alone. Although it was US FDA-approved for herpes labialis in 2009, Xerese™ has only recently been approved for use in Canada in October 2013. Herein, we review the basic science and clinical studies that support the efficacy of this topical combination acyclovir-hydrocortisone product in treating herpes labialis and examine its safety profile, as well as touch upon other therapies that have been shown to be effective in treating this common viral condition.

Key Words:
cold sores, herpes labialis, Xerese, viral infection, Canada, drug approval

Introduction

Herpes labialis (colloquially known as “cold sores”) is a common viral infection characterized by vesicular lesions of the lips and oral mucosa. It is estimated to affect 1 in 5 Canadians annually and is associated with a negative stigma that can lead to depression, fear of rejection, and isolation for infected individuals during an outbreak.¹ Herpes labialis is mostly caused by the herpes simplex virus-1 (HSV-1), which enters the nerve during primary infection and remains latent in the ganglionic neuron for the rest of the individual’s life. Periodically, the virus travels back down the nerve to the skin and replicates, producing a clinical episode of reactivated HSV-1 infection. Intralesional viral replication is halted by the host immune response approximately 7 days after primary infection and 3 days after recurrent infection;² however, inflammation secondary to immune defense is also the cause of redness, swelling, and tenderness that is characteristic of herpes labialis lesions. As a result, although viral clearance happens rapidly following reactivation, the lesion often takes 7-10 days to heal completely.

Since the pathogenesis of herpes labialis is both viral- and immune-mediated, it is not surprising that administration of exclusively antiviral drugs has limited effects on the clinical parameters of the disease.³ Therefore, medications demonstrating dual mechanisms via inhibition of viral replication and modulation of the inflammatory response to facilitate healing, indicate a more successful therapeutic approach.⁴ Such an agent was introduced by Valeant Pharmaceuticals, consisting of 5% antiviral acyclovir plus 1% anti-inflammatory hydrocortisone (ACHC) in a topical cream formulation (Xerese™). Although it has been FDA-approved in the US for the treatment of recurrent herpes labials since 2009, authorization for Xerese™ in Canada was not officially granted until October 2013. In light of this recent Canadian approval, we review the data supporting the efficacy of this topical combination therapy and discuss the details regarding its clinical use, specifically incorporating our experience in prescribing ACHC for the past half-decade.

Drug Information

ACHC is intended for the early treatment of recurrent herpes simplex labialis (HSL) in adults and adolescents (12 years of age and older). It is designed for cutaneous use only and is applied to the lips and skin around the mouth. Usage should be avoided on the eyes, inside the mouth or nose, and on the genitals. The patient should be instructed to apply a thin layer across the affected area, including the outer margins of the cold sore. Treatment should be initiated at the first sign or symptom (prodromal stage), applying 5 times per day for a period of 5 consecutive days. If there is no noticeable improvement and/or the cold sore fails to heal within 2 weeks, patients are encouraged to seek further medical attention. At present, the efficacy of ACHC has not been established in the immunocompromised population.⁵

From Bench to Bedside: Duration and Efficacy

In order to obtain maximum clinical benefit from a topical antiviral medication, therapy should be initiated within 72 hours of onset of symptoms.⁶ Patients with recurrent herpes labialis experience a rapid onset of disease and a short viral shedding period, both of which make it difficult to measure responses to therapy.

In an early basic science study conducted in 2003, researchers used mice that had undergone adaptive transfer of immunity and infected the skin on the mice’s ear pinna with HSV-1.⁷ After the mice developed a zosteriform infection, treatment groups received topical ACHC, 5% acyclovir (Zovirax®), 1% hydrocortisone, or no treatment at all. Medication was applied 3 times daily for 4 days. The treatment groups were analyzed based on ear thickness increase and zoster score. The zoster scores were adapted from a scale previously described in another study, and the scores used were: 0 for unchanged ear, 1 for isolated zosteriform lesions, and 2-4 for describing the ulceration of confluent zosteriform lesions from mild to severe.⁸ ACHC outperformed both 5% acyclovir and 1% hydrocortisone creams, with an average increase in ear thickness of only 0.15 ± 0.03 mm compared to 0.48 ± 0.08 mm and 0.23 ± 0.03 mm, respectively. The average increase in ear thickness for ACHC was only 34% of that experienced by the mice in the control group, compared to 110% observed with acyclovir and 52% with hydrocortisone. The average zoster score for the ACHC group at day 9 was also the lowest of the four groups at 2.0 ± 0.2 (58% of control), compared to 2.4 ± 0.3 (70% of control) for acyclovir and 2.8 ± 0.2 (80% of control) for hydrocortisone.⁷

In a 2012 Phase 3 study, Strand et al instructed their human subjects to apply ACHC 5 times daily for 5 days at the onset of prodromal symptoms, preferably before the appearance of actual papules or vesicles. Of the 131 test subjects, 78 (59.5%) had nonulcerative recurrences, and 53 (40.5%) had ulcerative recurrences. At the follow-up visit, all 131 of the test subjects had returned to the stage of normal skin, 3 weeks after the last dose, with no signs or symptoms of herpes labialis recurrence. In the 40% of subjects who experienced ulcerative herpes lesions despite applying the ACHC cream, the mean maximum lesion area was 39 mm², which was a 48% decrease from the mean lesion area size of 75 mm² typically reported in immunocompetent adults.^9,10

A similar study published in 2011, also using a dosing regimen of applying cream 5 times daily for 5 days, studied a much larger patient population in a randomized, double-blind, placebocontrolled trial.¹¹ The 2,437 volunteers were randomized to receive either ACHC, acyclovir in the ACHC vehicle, or placebo in the form of the ACHC vehicle. Of the 1,443 subjects who experienced a recurrence of herpes labialis during the trial and initiated treatment, 42% used ACHC, 42% acyclovir, and 16% placebo. The authors reported that 58% of the patients on ACHC developed an ulcerative lesion, vs. 65% in the acyclovir group and 74% in the placebo group. In patients who experienced an ulcerative lesion, the healing times were reduced in those who received ACHC or acyclovir, compared with placebo. The patients using ACHC also had a smaller cumulative lesion area (~50% less) than the placebo group (Tables 1 and 2).

Finally, in a simulated 2002 trial, researchers tested the efficacy of ACHC in patients whose latent HSV-1 infection was intentionally reactivated using ultraviolet (UV) light.¹² Of the 380 subjects, 120 patients developed classical cold sores 2 days after UV light exposure, which was followed by initiation of treatment with either ACHC or placebo. Treatment with ACHC reduced lesion size, healing time, and lesion tenderness when compared with placebo. Healing time (defined as the time to restoration of normal skin) was reduced from 10.1 days in the placebo group to 9.0 days in the ACHC group (Table 2).

Adverse Effects

The combination cream of 5% acyclovir and 1% hydrocortisone has been shown to induce only minimal side effects when used to treat herpes labialis infections. In Strand et al’s 2012 Phase 3, open-label, multicenter study, 131 of 134 subjects were categorized with recurrence at the post-treatment visit.¹⁰ Of these 131 subjects, only 5 reported any adverse events. The events were classified as mild to moderate in intensity and consisted of secondary herpes labialis recurrences (n=2), infectious rhinitis (n=1), application site inflammation (n=1), and bronchial asthma (n=1). Additional studies have corroborated the safety of ACHC, observing only minor side effects.^11,12 The most common adverse reactions reported in clinical trials were drying or flaking of the skin, burning or tingling at the application sight, erythema, and pigmentation changes; these infrequent adverse effects occurred in less than 1% of patients studied.⁵

Other Therapies for Herpes Labialis

Prior to the authorization of Xerese™ by Health Canada, the mainstays of treatment for recurrent HSL included over-thecounter docosanol cream, and prescription-only members of the acyclovir family (oral and topical). If ACHC is contraindicated for use in a particular patient due to adverse effects, docosanol or acyclovir may provide therapeutic benefit.

Docosanol 10% cream (Abreva®) is an approved treatment for recurrent herpes labialis, with efficacy demonstrated in two identical double-blind, placebo-controlled studies conducted at 21 sites.¹³ Therapy was initiated at the onset of prodromal symptoms or the erythema stage in subjects who were otherwise healthy adults with documented histories of herpes labialis. Treatment was administered 5 times daily until healing occurred, with twice-daily visits to the investigative clinic for the first 7 days. For the 370 patients who were treated with docosanol, the median time to heal was 4.1 days, which was 18 hours shorter than the healing time for the 367 patients treated with placebo (Table 2). The patients treated with docosanol also reported earlier cessation of pain and exhibited complete healing, as well as experienced reduced lesion progression to the ulcer or soft crust stage.

A well-established mainstay in the treatment of recurrent herpes labialis is valacyclovir. This prodrug of acyclovir has proven to be a safe and effective therapy for long-term HSV suppression.¹⁴ It has been studied in children, pregnancy, and immunocompromised patients. The most common adverse events associated with oral valacyclovir are headache, rhinitis, infection, nausea, and pharyngitis, with all of these occurring infrequently. Despite many years of use by clinicians, HSV resistance remains low at approximately 0.1-0.4% in the UK and the US.¹⁴

A new form of acyclovir was recently approved by the US FDA in April 2013. This medication consists of acyclovir in the form of a mucoadhesive buccal tablet (ABT) (Sitavig®), which is applied to the upper gum region within the first hour of prodromal symptoms. A Phase 3 double-blind trial found that acyclovir, utilizing the proprietary Lauriad® technology, decreased the median duration time and development of primary vesicular lesions when compared to placebo (Tables 1 and 2).¹⁵

Lastly, a non-pharmacologic treatment for recurrent HSL involves low-level light therapy. A paper published in 2013 demonstrated that 1072 nm light-emitting diode therapy applied 3 times a day for 2 days was able to shorten healing time in patients with HSL to a median of 129 hours vs. 177 hours for the control group (Table 2).¹⁶

Clinical Observations

When taken daily (along with topical sunscreens), oral acyclovir, famciclovir, or valacyclovir are better at preventing herpes labialis than topical therapies are at treating outbreaks; however, it is the authors’ experience over the past 5 years that when used appropriately, ACHC is the superior topical therapy. Because the signs and symptoms of herpes labialis are attributable to both viral and inflammatory mechanisms, prescription topicals exerting only antiviral or anti-inflammatory activities have limited efficacy. Most over-the-counter therapies fail to target underlying pathogenic mechanisms (i.e., viral and inflammatory) and, thus, have little to no efficacy. While the optimal strategy is to prevent herpes labialis outbreaks via reduction of sun exposure, as well as through the use of sunscreen and oral anti-viral agents (especially in individuals experiencing frequent outbreaks), we recommend to our patients that they fill their prescriptions for ACHC as soon as possible and keep the cream at home, at work, and/or carry it with them while on vacation. At the onset of prodromal symptoms, therapy should be initiated immediately and no later than the appearance of the first sign of a recurrence.

Conclusion

Herpes labialis still lacks a cure, but several options are now available to limit inflammation and decrease healing time. The introduction of 5% acyclovir/1% hydrocortisone topical cream represents a forward step in understanding disease pathogenesis and targeting both the viral and immunogenic components of recurrent HSL.

References

1. Kuehl B. Cold sores – how to prevent and treat them
2. Spruance SL, Rea TL, Thoming C, et al. Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebocontrolled trial. Topical Penciclovir Collaborative Study Group. JAMA. 1997 May 7;277(17):1374-9.
3. Corey L, Nahmias AJ, Guinan ME, et al. A trial of topical acyclovir in genital herpes simplex virus infections. N Engl J Med. 1982 Jun 3;306(22):1313-9.
4. Hull CM, Levin MJ, Tyring SK, et al. Novel composite efficacy measure to demonstrate the rationale and efficacy of combination antiviral-antiinflammatory treatment for recurrent herpes simplex labialis. Antimicrob Agents Chemother. 2014 Mar;58(3):1273-8.
5. Xerese® prescribing information. Date of revision: January 2012. Coria Laboratories, a division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ.
6. Vestey JP, Norval M. Mucocutaneous infections with herpes simplex virus and their management. Clin Exp Dermatol. 1992 Jul;17(4):221-37.
7. Harmenberg JG, Awan AR, Alenius S, et al. ME-609: a treatment for recurrent herpes simplex virus infections. Antivir Chem Chemother. 2003 Jul;14(4): 205-15.
8. Nagafuchi S, Oda H, Mori R, et al. Mechanism of acquired resistance to herpes simplex virus infection as studied in nude mice. J Gen Virol. 1979 Sep;44(3):715-23.
9. Spruance SL. Herpes simplex labialis. In: Sacks SL, Straus SE, Whitley RJ, et al. editors. Clinical management of herpes viruses. Amsterdam, Washington DC: IOS Press. 1995;p3-42.
10. Strand A, Bottiger D, Gever LN, Wheeler W. Safety and tolerability of combination acyclovir 5% and hydrocortisone 1% cream in adolescents with recurrent herpes simplex labialis. Pediatr Dermatol. 2012 Jan-Feb;29(1): 105-10.
11. Hull CM, Harmenberg J, Arlander E, et al. Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial. J Am Acad Dermatol. 2011 Apr;64(4):696 e1-11.
12. Evans TG, Bernstein DI, Raborn GW, et al. Double-blind, randomized, placebocontrolled study of topical 5% acyclovir-1% hydrocortisone cream (ME-609) for treatment of UV radiation-induced herpes labialis. Antimicrob Agents Chemother. 2002 Jun;46(6):1870-4.
13. Sacks SL, Thisted RA, Jones TM, et al. Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebocontrolled trial. J Am Acad Dermatol. 2001 Aug;45(2):222-30.
14. Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir. J Infect Dis. 2002 Oct 15;186 Suppl 1:S40-6.
15. Downing C, Moayyad J, Tamirisa A, et al. Acyclovir Lauriad((R)): a mucoadhesive buccal tablet for the treatment of recurrent herpes labialis. Expert Rev Anti Infect Ther. 2014 Mar;12(3):283-7.
16. Dougal G, Lee SY. Evaluation of the efficacy of low-level light therapy using 1072 nm infrared light for the treatment of herpes simplex labialis. Clin Exp Dermatol. 2013 Oct;38(7):713-8.
17. Raborn GW, Martel AY, Lassonde M, et al. Effective treatment of herpes simplex labialis with penciclovir cream: combined results of two trials. J Am Dent Assoc. 2002 Mar;133(3):303-9.
18. Spruance SL, Jones TM, Blatter MM, et al. High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies. Antimicrob Agents Chemother. 2003 Mar;47(3):1072-80.
19. Morrel EM, Spruance SL, Goldberg DI. Topical iontophoretic administration of acyclovir for the episodic treatment of herpes labialis: a randomized, double-blind, placebo-controlled, clinic-initiated trial. Clin Infect Dis. 2006 Aug 15;43(4):460-7.
20. Spruance SL, Bodsworth N, Resnick H, et al. Single-dose, patient-initiated famciclovir: a randomized, double-blind, placebo-controlled trial for episodic treatment of herpes labialis. J Am Acad Dermatol. 2006 Jul;55(1):47-53.

Faculty of Medicine and Faculty of Public Health, University of Toronto, Toronto, ON

Introduction

Herpes simplex virus (HSV) is responsible for an infection around the lips (herpes labialis) that often occurs with a longer primary infection and then may result in shorter recurrences (cold sores, fever blisters).¹ Herpes simplex infection is ubiquitous in the adult population with various studies documenting between 60-90% of tested individuals having previous infections.² Currently available treatments include prescription and non-prescription drugs in topical and oral formulations, with antiviral medications representing a mainstay of treatment. They are reviewed below, as are data from a clinical trial of a new formulation of topical 5% acyclovir with 1% hydrocortisone cream (Xerese®).

Background

• Most herpes labialis lesions are caused by herpes simplex type 1 (HSV-1). Genital herpes simplex is predominantly herpes simplex type 2 virus (HSV-2).²
• With an increase in oral sex, there are more cases (although still a minority) of herpes labialis associated with type 2 infections.²
• Primary HSV infection in children or young adults may cause severe stomatitis and pharyngitis with an erosive, painful infection of the buccal mucosa and gums.²
• Primary infections may be associated with pain on swallowing and lymphadenopathy.
• In adults, the primary infection may be limited to a pharyngitis without involvement of the mouth (gingival- stomatitis).²
• Some primary infections are completely asymptomatic.
• Viral shedding and potential spread of infection is most common with an open lesion.
• After the primary infection, the virus remains latent in the sensory nerve (Trigeminal) ganglion of the facial nerve for life.³ It may re-activate at a later date, in a non-primary episode, with a clinical course that is often less severe than a primary episode but more severe than a typical recurrence.⁴
• Asymptomatic viral shedding can occur sporadically between acute episodes and result in spread of the infection.
• Recurrent infections follow a shorter time period and have a number of identifiable stages, specifically:³
  1. Prodrome: tingling, itching, burning or local pain may occur for a few hours up to a couple of days prior to the development of local erythema.
  2. Day 1 of the eruption is often associated with virus replication at the end of the nerve and in the epithelial cells resulting in local erythema and swelling.
  3. Days 2-3 (or sooner) results in the appearance of tender papules and subsequent vesicles usually around the lips but the lesions may appear on the nose, chin or cheeks.
  4. Day 4 or sooner, a painful ulcer may develop from ruptured vesicles that may coalesce into a larger single ulcer with the characteristic herpetiform edges that have a semi-circular peripheral appearance similar to the outline of a cluster of grapes. The serous or serosanginous discharge is loaded with viral particles and represents the most contagious stage of the cold sore. Submental lymphadenopathy may be present but is less severe than signs associated with a primary infection. Secondary bacterial infection with staphylococcus or streptococcus may result in a pustular element to the discharging fluid.
  5. Days 5-8 is the crusting stage (serosanginous, occasionally pustular) which forms from the dried exudate.
  6. The healing stage can take from day 9 to day 14 but is variable. It may be shorter with aborted recurrent episodes or with early treatment at the prodrome or early lesion stage.

Diagnosis

• The diagnosis of herpes labialis is often recognized by the clinical appearance alone.
• If a lesion is atypical, laboratory investigations can be ordered that will identify HSV-1, HSV-2, or return a negative result (more common from late lesion samples).⁵

Patient Impact

A recent survey of 231 patients (age >18 years) with recurrent herpes labialis (outbreaks at least once a year) revealed that cold sores had a severe negative influence on social life/self-image in 55.5% of survey respondents.⁶ Additional findings include:

• The most troublesome aspects of the cold sores are the blister/ulcer and the subsequent crust formation.
• The duration of the cold sores can be prolonged and more significant than acknowledged by many clinicians.
• The majority of infected individuals (65.9%) preferred topical treatment, either over-the-counter or prescription treatment for cold sore recurrences.
• 77.2% preferred a topical preparation for the first sign of an outbreak (46.2% prescription, 31% non-prescription) and 9.6% would prefer not to prevent or treat outbreaks. Oral prophylaxis was preferred by 19.8% with a topical agent for a breakthrough.

Treatment of Recurrent Herpes Simplex Labialis

Topical Prescription Drugs

• A recent, multicenter, randomized, double-blind study identified the combination of 5% acyclovir with 1% hydrocortisone cream (Xerese®) as effective and well tolerated in the control of herpes simplex labialis recurrences in adults.²
• Topical acyclovir (Zovirax®) is a nucleoside antiviral agent that targets the viral replication stage.² The 1% hydrocortisone component is anti-inflammatory, designed to decrease the host response time post viral replication.²
• The study compared a new base of 5% acyclovir with 1% hydrocortisone cream to 5% acyclovir base and the Xerese® vehicle base cream. The study included 1,443 treated subjects with 601 receiving combination 5% acyclovir / 1% hydrocortisone cream, 610 receiving topical acyclovir cream, and 232 placebo cream for a randomization ratio of 2.7/ 2.7 to 1.
• The number of patients not progressing to the ulcerative stage compared to non-ulcerative recurrences was 42% for the acyclovir combined with 1% hydrocortisone (Fig. 1) compared to 35% for acyclovir cream alone (p=0.14) and 20% for Xerese® vehicle alone (p=0.001). This is the first study to demonstrate effectiveness of topical acyclovir cream compared to the vehicle alone.
• The enhanced effect was likely due to the reformulation with the partial replacement of propylene glycol with isopropyl myristate that enhances stratum corneum penetration of the topical acyclovir.
• The addition of the anti-inflammatory effect of topical 1% hydrocortisone further enhanced the effectiveness of the topical acyclovir in the new cream formulation.
• The cumulative lesion area in the study was calculated from the area of the ulcerative lesions that were added from daily measurements. The combination of 5% acyclovir with 1% hydrocortisone had a cumulative lesion area that was 50% smaller than the placebo cream cumulative area (p<0.0001), and the 5% acyclovir area was 25% smaller than the placebo cream cumulative area.
• Healing of lesions with the combination cream occurred in 3 vs. 4 days for acyclovir cream and 5 days for the placebo cream.
• The average lesion tenderness duration with the combination cream was 5 days, similar to acyclovir cream but less than the 6 day average for placebo cream (p=0.019). Positive cultures for herpes simplex were no higher with the combination cream (22%) compared to acyclovir cream alone (24%) and less than the placebo cream (40%).
• Overall adverse event rates were similar in all 3 groups.
• The combination cream is applied 5 times per day for 5 days.
• These results can be compared favourably to a previous study by Shaw et al, using an original vehicle formulation of topical acyclovir.⁷ This older formulation of topical acyclovir in the relatively small number of subjects failed to demonstrate benefit in 45 patients with 72 recurrences.
• Spruance et al, combined the results of two randomized clinical trials (RCTs) comparing the original topical 5% acyclovir cream with placebo cream in 1,385 subjects, and found a reduced time to healing with the 5% acyclovir preparation, from 5 to 4.4 days.⁸

Significantly reduced cold sore ulceration and duration of ulcerative lesions£,Δ

ΔHull CM, Brunion S. The Role of topical 5% Acyclovir and 1% hydrocortisone Cream (Xerese) in the Treatment of Recurrent Herpes Simplex Labilias: Postgraduate Medicine. Vol 122. June 5, Sept 2010. ISSN = 0032-5481.

£ Adapted from Spruance et al. High-Dose, Short Duration Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results from Two Randomized, Placebocontrolled, multicenter studies.

Figure 1: Similar efficacy between Xerese® and Valtrex® in preventing ulcerative lesions

Topical Non-Prescription Formulations

• Topical docosanol (Abreva®) is a saturated fatty alcohol proposed to be effective in preventing the HSV envelope from attaching to the host cell.
• Sacks et al, published results of an RCT with 737 patients comparing the 10% docosanol cream to a placebo (polyethylene glycol) in the prodromal stage.⁹
• Treatment with docosanol cream significantly (p=0.002) shortened the duration of pain, itching, tingling or burning and reduced the time to complete healing (p=0.002).⁹
• Docosanol cream has a low risk of drug resistance.
• Symptomatic relief may be obtained by preparations with local anesthetic effects including Blistex® with menthol, phenol and camphor and zilactin with benzoyl alcohol.¹⁰
• Propolis extract from honey is the active component in ColdSore-FX® with in vitro anti-inflammatory and antimicrobial properties.¹⁰

Oral Prescription and Non-Prescription Drugs

• Effective oral antiviral medications that can speed the healing of labial herpes simplex recurrences include acyclovir and penciclovir.
• Spruance et al, conducted an RCT of 114 subjects with recurrent herpes labialis treated with oral acyclovir 400 mg 5 times a day for 5 days compared to 60 patients given a similar course of placebo treatment. The lesions treated with acyclovir were less painful and healed faster compared to placebo.¹¹
• Valacyclovir (Valtrex®) is the prodrug of acyclovir. It increases gastrointestinal absorption of the antiviral agent. Spruance et al, conducted a high-dose, short duration, early valacyclovir treatment RCT for recurrent episodes of labial cold sores vs. placebo. The dose of valacyclovir was either 2 grams twice daily for 1 day or with the addition of 1 gm twice daily on day 2.¹² There were more aborted episodes with both of these treatment regimens compared with placebo, but the episode duration was reduced by a half to one day.
• Famciclovir, (Famvir®) the prodrug of penciclovir, increases the gastrointestinal absorption of this antiviral agent. An RCT conducted with high dose famciclovir (750 mg twice daily or 1500 mg in a single dose) vs. placebo showed that recurrences healed in both active groups in 4 vs. 6 days with placebo. ¹³
• The newer, high dose, short treatment duration studies have shown better therapeutic efficacy compared to the traditional treatment of lower doses over 5-7 days.
• One non-prescription drug, oral lysine, is available in most health food stores. This medication has been popular with patients for the treatment or prevention of herpes labialis based on in vitro studies but the evidence supporting this treatment in humans is inconclusive.

Prevention

• A study by Rooney et al, utilizing an experimental system of ultraviolet light to induce reactivation of herpes labialis lesions did not produce any lesions in 35 patients using sunscreen but reactivated a herpes lesion in 27 of 38 patients (71%) utilizing the placebo sunscreen.¹⁴
• Continuous prophylaxis is often considered for individuals with 6 or more herpes lesions per year. Twenty patients completed a randomized, 4-month crossover trial with oral acyclovir 400 mg twice daily or placebo.¹⁵ Placebo treatment was associated with 1.8 reactivation episodes per subject while the continuous prophylaxis had 0.85 reactivation episodes.¹⁵
• Similar continuous prophylaxis has also been proposed for valacyclovir at a dose of 500 mg or 100 mg p/day or famciclovir 250 mg or 500 mg daily.¹²

Conclusion

Because oral antivirals have a narrow therapeutic window, they should be initiated at the prodromal stage. However, if the antiviral medication is taken after the prodromal stage, efficacy is decreased significantly. The oral medication has no effect on the inflammatory component of a cold sore. A way to optimize treatment is to offer patients two options, i.e. oral therapy and the topical treatment that contains acyclovir 5% and hydrocortisone 1% (Xerese®). The combination would address not only the viral replication but the inflammatory response. This strategy could potentially optimize patient outcomes.

References

1. Lee C, et al. Cochrane Database of Systematic Reviews. Published Online: 5 OCT 2011. DOI: 10.1002/14651858.CD009375
2. Hull CM, et al. ME-609 Study Group. J Am Acad Dermatol. 2011;(64):696.
3. Bruce AJ, et al. Clin. Dermatol. 2004;(22):520–527.
4. Opstelten W, et al. J Canadian Fam Physician. 2008;(54):1683–1687.
5. Sterling JC. Herpes labialis. In:Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I. Treatment of skin disease; comprehensive therapeutic strategies. 3rd ed. Saunders Elsevier. 2010;303-305.
6. Sibbald RG. Evaluation of patient concerns and quality of life aspects of early cold sores treatment in 231 subjects. Poster presentation: Derm Update. 2013. Montreal, Canada.
7. Shaw M, et al. Br Med J (Clin Res Ed). 1985;(291):7-9.
8. Spruance SL, et al. Antimicrob Agents Chemother. 2002;(46):2238-2243.
9. Sacks SL, et al. J Am Acad Dermatol. 2001;(45):222-230.
10. Harmenberg J, et al. Acta Dermato Venereologica. 2010;(90):122–130.
11. Spruance SL, et al. J Infect Dis. 1990;(161):185-190.
12. Spruance SL, et al. Antimicrob Agents Chemother. 2003;(47):1072-1080.
13. Spruance SL, et al. J Am Acad Dermatol. 2006;(1):47-53.
14. Rooney JF, et al. Lancet.1991;(338):1419-1422.
15. Rooney et al. Ann Intern Med. 1993;(118):268-272

The Mount Sinai School of Medicine, Department of Dermatology, New York, NY, US A

Conflict of interest: No conflicts of interest
ABSTRACT

Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs) are very effective treatments in inflammatory dermatoses, but carry risks with long-term use. TCS are associated with cutaneous atrophy and tachyphylaxis and TCIs can be irritating and contain a black box warning of an increased risk of cancers including lymphoma and non-melanomatous skin cancers. Nevertheless, they are appropriate treatments for inflammatory conditions such as psoriasis and atopic dermatitis (AD) and should be used more often with disease flares and less as maintenance therapy. Given the associated risks of long-term continuous use with these pharmacologic agents, alternatives are needed with similar anti-inflammatory and barrier repair properties that can be used indefinitely without risk. Some over-the-counter (OTC) ingredients such as colloidal oatmeal and petrolatum, as well as anti-inflammatory prescription moisturizers (medical device creams), have demonstrated efficacy with little complications in skin barrier repair and symptom relief in steroid-responsive conditions. With regimented application, these non-drug options are safe and effective and can limit the long-term continuous use of TCS or TCIs.

Key Words:
atopic dermatitis, emollients, eczema, skin barrier repair, moisturizers, topical corticosteroids, topical calcineurin inhibitors

Introduction

Topical corticosteroids (TCS) are the cornerstone of treatment for inflammatory dermatoses, particularly for the swift resolution of acute flares, as TCS can calm inflamed and irritated skin due to rapid absorption and action.¹ A wide range of potencies and vehicles enables tailoring of therapy to be site-specific and considerate of patient preference. Long-term continuous therapy with TCS can lead to localized side effects such as cutaneous atrophy, telangiectasias, acne and rosacea exacerbation, and tachyphylaxis, as well as systemic absorption if used on large surface areas causing hypothalamic-pituitary-adrenal (HPA) axis suppression, growth retardation in children, and cataract and glaucoma formation in adults.^2-6 Thus, intermittent therapy should be supplemented with alternative treatments that can help limit localized side effects and provide epidermal barrier dysfunction improvement.⁷

Topical calcineurin inhibitors (TCIs; tacrolimus ointment/ Protopic®; pimecrolimus cream/Elidel®) represent secondline therapies for the short-term and non-continuous chronic treatment of moderate-to-severe atopic dermatitis (AD) in non-immunocompromised adults and children who have failed to respond adequately to or are not suitable for other topical prescription AD treatments.^8,9 TCIs inhibit calcineurin in T-cells, reducing the production of interleukin (IL)-2 and related proinflammatory cytokines. Clinical studies have demonstrated longterm efficacy, minimal systemic absorption, and few transient side effects, such as localized irritation, with the use of these agents.^10-12 TCIs do not induce skin atrophy or inhibit collagen synthesis, enabling their use on the face, neck and intertriginous areas.¹³ In 2006 the United States Food and Drug Administration (USFDA) placed a black box warning on TCIs based on safety concerns over the possible risk of systemic absorption and on data from transplantation research reporting systemic immune suppression with oral calcineurin inhibitors (tacrolimus and cyclosporine) is associated with an increased cancer risk.¹⁴ To date, this risk remains theoretical and is based mainly on the drug’s mechanism of action, data from animal studies and a few single case reports of lymphoma and skin cancer in patients treated with TCIs.

Recently, medical device creams (Table 1), which are nonsteroidal agents with emollient, anti-inflammatory and antipruritic properties, have entered the marketplace for the treatment of inflammatory dermatoses to help treat epidermal barrier dysfunction as well as limit potential long-term use of TCS and TCIs. Atopiclair® is a hydrolipidic cream containing Butyrospermum parkii (shea tree), glycyrrhetinic acid (licorice), Vitis vinifera (grapevine) extract, bisabolol (German chamomile), hyaluronic acid and tocopheryl acetate (vitamin E), and is thought to have moisturizing, anti-inflammatory and antioxidant properties.¹⁵ It also contains telmesteine, which inhibits elastase, collagenase and matrix metalloproteinases, helping to prevent epidermal breakdown. MimyX™ contains lipid components that mimic the normal skin barrier (triglycerides, phospholipids, and squalene) along with the anti-inflammatory cannabinoid N-palmitoylethanolamine (N-PEA), an endogenous fatty acid amide thought to target the peroxisome proliferator-activated receptor-alpha (PPAR-α).¹⁶ Other added ingredients such as purified water, olive oil, glycerin, pentylene glycol, vegetable oil, and hydrogenated lecithin have humectant and emollient effects. EpiCeram® is a microencapsulation system emulsion of ceramide, conjugated linoleic acid, cholesterol and palmitic acid formulated with Euphorbia cerifera (candelilla) wax, corn syrup solids, squalene, glycerin, petrolatum, and dimethicone.^17,18 Eletone® has a high lipid content dispersed in an outer aqueous phase (Hydrolipid Technology™) in petrolatum, purified water, and mineral oil.¹⁹ Hylatopic Plus® is an emollient cream and foam containing Theobroma grandiflorum seed butter (a skin conditioning butter made from the fruit of a the Cupuaçu tree that is native to Brazil), hyaluronic acid, glycerin, dimethicone, petrolatum, and tocopheryl acetate (vitamin E).²⁰ All of the medical device creams are indicated for the treatment of various dermatoses such as AD, allergic contact dermatitis, and radiation dermatitis, which are associated with symptoms of itching, burning, and pain.

Epidermal Barrier Dysfunction

Defects in skin barrier function and stratum corneum hydration have been identified in a variety of inflammatory dermatoses.²¹ A functioning stratum corneum consists of corneocytes surrounded by ceramides, cholesterol, and free fatty acids – the so-called “bricks and mortar” model.²² Topical balms containing lipids and lipid-like substances have been shown to restore the barrier function of an impaired stratum corneum by replacing the deficient lipids, thereby improving skin hydration through decreasing transepidermal water loss (TEWL).²³ Further, epidermal barrier disruption results in greater density of epidermal Langerhans cells (antigen-presenting immune cells), enhanced inflammatory responses by increased foreign antigen presentation, and decreased anti-microbial proteins (AMPs), which play a role in innate skin defense (first-line skin protection).²⁴

In AD, the disturbed epidermal barrier is explained by nonsense mutations in the gene encoding filaggrin (FLG) and subsequent affect on the pro-inflammatory cascade, such as abnormal elevation in IL-1 cytokine profile in the stratum corneum.^25,26 FLG is a structural protein essential in the cornified envelope and is expressed as pro-FLG, which functions to secure keratinocytes together in the stratum corneum. Dysfunction or loss of FLG heavily influences keratinocyte adhesion, enhances TEWL, and causes dysregulation of skin pH, resulting in increased skin permeability.²⁷ Overall, this can induce persistent, recalcitrant and/or severe disease, increase the risk of cutaneous infections caused by microbes such as herpesvirus (eczema herpeticum) and Staphylococcus aureus, as well as increase the risk of sensitization to allergens and asthma.²⁸ Thus, the importance of an uncompromised skin barrier in improving inflammatory conditions cannot be over-emphasized and should be a major consideration in the treatment of acute flares as well as in longterm disease management.

It is important to note that despite the acknowledged contributions of a defective epidermal permeability barrier [i.e., FLG mutations, decreased AMPs such as human tissue kallikreins and cathelicidins (LL-37)] and dryness of eczematous skin, immunologic abnormalities such as T-helper type 2 (Th2) cytokines [i.e., IL-4 and IL-13 that influence immunoglobulin E (IgE) synthesis and adhesion molecule expression] also contribute to the pathogenesis of AD.²⁹ This suggests the development of inflammatory disorders is likely due to underlying immune dysregulation as the primary cause and epidermal dysfunction may be a secondary consequence.

Over-The-Counter Options and Clinical Studies

Petrolatum

Petrolatum – a mixture of long-chain hydrocarbons that is pale yellow in color, translucent, odorless, and hydrophobic – has been used for over 100 years as a healing ointment. Originally thought to be an occlusive moisturizer that forms a hydrophobic layer on the skin surface, petrolatum can penetrate and restore the stratum corneum by filling the spaces between desquamating corneocytes. This can reduce the appearance of fine lines and impart a soft, silky feel to the skin. Increased skin hydration is a consequence of epidermal lipogenesis and production of free sterols, sphingolipids, and free fatty acids.^30-32 Occlusives are generally not appealing to patients, due to their greasy feel, but can be very beneficial directly as a moisturizer and indirectly by reducing TEWL. A recently published study demonstrated the clinical efficacy and cost-effectiveness of a petrolatum-based moisturizer (Aquaphor® Healing) in treating mild-to-moderate AD as compared to two commonly prescribed medical device creams; one glycyrrhetinic acid-containing barrier repair cream (Atopiclair™) and another a ceramide-dominant barrier repair cream (EpiCeram®).³³ Some barrier repair creams contain petrolatum as their primary ingredient (Eletone®) and one study demonstrated comparable efficacy to a TCI (i.e., Elidel®) in the treatment of AD.³⁴

Dimethicone

Dimethicone – a mixture of polydimethylsiloxanes and silicon dioxide sometimes called simethicone – is another occlusive (insoluble in water) used in many OTC moisturizers and found to be safe and effective at skin moisturizing, though it is not as effective as petrolatum at reducing TEWL.^35,36 Dimethicone is the first ingredient in a foam formulated for the relief of irritation from inflammatory dermatoses such as AD and allergic contact dermatitis (Neosalus™). A combination of cyclomethicone (a cyclic higher-viscosity silicone) and dimethicone are used in barrier creams designed to prevent skin sensitization to allergens and can be useful in patients with itching and burning associated with contact dermatitis (Tetrix™).^37,38 Additionally, a recent study showed significant reduction in the incidence of incontinenceassociated dermatitis in patients using dimethicone-impregnated clothes.³⁹

Colloidal Oatmeal

Colloidal oatmeal has a long-standing history of benefit in dermatologic conditions associated with itch and irritation because of the ability to soothe and protect inflamed skin.⁴⁰ It contains a variety of active components including polysaccharides, proteins, lipids, saponins, enzymes, flavonoids, vitamins and avenanthramides (polyphenol).⁴¹ In 2003, colloidal oatmeal became an approved OTC monograph ingredient.⁴⁰ Current, ready-to-use oatmeal preparations are the concentrated starch-protein fraction of the oat grain mixed with emollient. Fine particles disperse on the skin and form a protective, occlusive barrier that retards water loss and moisturizes to improve the epidermal barrier. Further, oatmeal saponins help to solubilize dirt, oil and sebaceous secretions, which may normalize the skin pH.⁴² Oats have important antioxidant, ultraviolet (UV) absorbent and anti-inflammatory properties attributed to the ferulic, caffeic and coumaric acids, as well as flavonoids and α-tocopherol (vitamin E) components.^43,44 Recent research has identified avenanthramides (phenolic compounds) as a minor component of oat grains and in vitro work has demonstrated anti-inflammatory and anti-pruritic properties by decreased production of Nuclear Factor-kappaB (NF-κB) in keratinocytes and reduced pro-inflammatory cytokine (such as IL-8) production.⁴⁵ Avenanthramides have also been reported to inhibit prostaglandin synthesis.⁴⁶ As a result, many studies have substantiated the anti-inflammatory, hydrating and anti-pruritic properties of colloidal oatmeal and their use in the management of common inflammatory dermatoses.

Ceramides

As discussed previously the ceramides – which are a family of lipid molecules composed of sphingosine and a fatty acid, and found in high concentrations within the membrane of cells in the stratum corneum – are an essential component of the normal stratum corneum and function to help maintain the integrity of the skin barrier.⁴⁷ They serve as important water-holding molecules in the extracellular space, linking corneocytes and creating a waterproof barrier. In ceraminde-deficient skin there is enhanced TEWL, dryness, and increased permeability to environmental irritants and allergens. A recent study found that the mechanisms of ceramide changes in atopic skin are due to both Th1 (accentuate) and Th2 (attenuate) cytokines, as both IL-4 and IL-6, as well as interferon (IFN)-γ and tumor necrosis factor (TNF)-α influenced ceramide content in the stratum corneum.⁴⁸ This further solidifies that immune dysregulation in AD has a multitude of pathophysiological effects on the skin.

Newer moisturizers/topical skin care products (Table 2) targeted to improve epidermal barrier dysfunction by replenishing the amount of ceramides in the skin – with ceramide and pseudoceramide products mimicking the natural physiological skin barrier – are a mainstay of adjunctive therapy for patients with AD. Although evidence on their efficacy compared to older, less expensive traditional therapies, such as occlusives and humectants, remains to be validated.⁴⁹ It is known that proper moisture therapy can reduce the frequency of flares and limit the need for TCS or TCIs, likely a result of barrier recovery, including restoration of proper permeability function and increased levels of AMPs. In one study, a ceramide-hyaluronic acid emollient foam (Hylatopic Plus®) and pimecrolimus both showed equivalent improvement in the signs and symptoms of AD.⁵⁰ In another study, a ceramide-dominant, physiologic lipid-based, barrier repair emollient (TriCeram®) showed improvement when substituted for other OTC moisturizers in 24 children also receiving standard therapy (TCS or TCIs) for recalcitrant AD, thereby demonstrating the use of a ceramide-dominant moisturizer as compared to traditional agents can elicit significant improvement in symptoms of AD.⁵¹ TriCeram® has been discontinued by the manufacturer and is no longer available on the market.

EpiCeram® (a prescription device) consists of a specific combination of ceramides, cholesterol and fatty acids (in the ratio of 3:1:1) that mimics those naturally found in the skin and is reported to have similar efficacy to a mid-potency topical corticosteroid.^1,52,53 It contains capric acid, cholesterol, conjugated linolenic acid, candelilla and petrolatum. In a fivecenter, investigator-blinded, randomized trial, EpiCeram® was compared to fluticasone (Cutivate®) cream in 121 patients with moderate-to-severe AD and showed reduced clinical disease severity, decreased pruritus and improved sleep habits at both 14 and 28 days after initiation of therapy. The fluticasone group improved faster – greater improvement by day 14 – but by day 28, both interventions showed equal efficacy.¹⁷ A more recent study established improvement in clinical dryness scores and skin hydration and reduction in TEWL with the use of a new moisturizer (Cetaphil® Restoraderm® Body Moisturzier; CRM) containing FLG breakdown products [natural moisturizing factor (NMF)], a ceramide precursor pseudoceramide 5 or N-(2-hydroxyhexadecanoyl) sphinganine and niacinamide (vitamin B3), at week 4 as compared to the untreated areas.⁵⁴ A significantly higher level of ceramide and a trend toward increased water content were observed in the stratum corneum of CRM-treated skin when compared to the control.

Additional Ingredients

Additional ingredients such as glycerin or glycerol, urea, hydroxy acids and propylene glycol are common humectants added to OTC ingredients to help increase the ability of the skin to absorb water; although they are typically combined with an occlusive to prevent upward migration of water from the dermis and inadvertent increased TEWL. Glycerol or glycerin are the most effective as they have the ability to activate transglutaminase activity in the stratum corneum, accelerating the maturation of corneocytes as well as increasing water channels called aquaporins (particularly aquaporin-3) in diseased skin, which ultimately increases cutaneous hydration and reduces TEWL.^55,56

Clinical Studies

Several studies have directly examined the steroid-sparing potential of OTC emollients in patients with AD. Daily hydrocortisone 2.5% cream in the morning combined with a once daily water-in-oil emollient cream in the evening (Eucerin® Creme) was equally efficacious as twice daily hydrocortisone 2.5% cream in children.⁵⁷ Similarly, once daily betamethasone diproprionate cream with Eucerin® Creme was equally efficacious as twice daily betamethasone diproprionate cream in patients with plaque psoriasis.⁵⁸ As well, in infants under 12 months of age with AD, the addition of an emollient containing water, petrolatum, shea butter, evening primrose oil, glycerin, paraffin oil, niacinamide, butylene glycol, benzoic acid, carbomer and also specific active Rhealba® oat extracts (flavonoids and saponins) (Exomega® Emolient Lotion) significantly reduced the use of topical corticosteroids (desonide 0.1% cream).⁵⁹

Prescription Alternatives: Medical Device Creams

Prescription medical device creams are not classified as drugs, but rather as medical devices that have received 510(k) FDA clearance based on a demonstrated reduction in TEWL, which is a less extensive regulatory process that focuses on safety and less on efficacy. Each device cream has ingredients with proposed moisturizing, anti-inflammatory and anti-pruritic properties that may be useful as adjunctive or maintenance therapy in inflammatory dermatoses and, thereby, may help to limit the use of TCS or TCIs. Whether these device creams are equivalent in efficacy and long-term maintenance as compared to their OTC counterparts remains to be seen. Financial burden and supply limitation (insurance approval required in the US) may create difficulty in initiating and continuing therapy, especially in cases of severe disease.

Conclusion

Epidermal barrier dysfunction is a consequence of a combination of genetic factors influenced by immune dysregulation and abnormal structural proteins. Inflammatory dermatoses require treatment with TCS and/or TCIs to control acute flares, but also necessate appropriate and adequate moisturization to mitigate structural dysfunction and insufficient skin hydration. High predisposition to recurrent and recalcitrant disease, as well as infections and sensitization to allergens, makes long-term management with the goal to prolong periods of remission and reduce the severity of flares of utmost importance. As TCS can induce long-term complications and some patients are concerned with the black box warning of TCIs, non-drug options such as OTC and/or prescription medical device creams containing active ingredients known to have moisturizing, anti-inflammatory and anti-pruritic properties, are important therapeutic adjuncts that can be used daily without the risks associated with pharmacologics. Further studies are needed to determine the long-term efficacy of these products in treating chronic inflammatory dermatoses and validate their role through the development of management guidelines.

References

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2. Haeck IM, Rouwen TJ, Timmer-de Mik L, et al. Topical corticosteroids in atopic dermatitis and the risk of glaucoma and cataracts. J Am Acad Dermatol. 2010 Feb;64(2):275-81.
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25. Pellerin L, Henry J, Hsu CY, et al. Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin. J Allergy Clin Immunol. 2013 Apr;131(4):1094-102.
26. Kezic S, O’Regan GM, Lutter R, et al. Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency. J Allergy Clin Immunol. 2012 Apr;129(4):1031-9.e1
27. Eichenfield LF, Ellis CN, Mancini AJ, et al. Atopic dermatitis: epidemiology and pathogenesis update. Semin Cutan Med Surg. 2012 Sep;31(3 Suppl):S3-5.
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29. Kuo IH, Yoshida T, De Benedetto A, et al. The cutaneous innate immune response in patients with atopic dermatitis. J Allergy Clin Immunol. 2013 Feb;131(2):266-78.
30. Ghadially R, Halkier-Sorensen L, Elias PM. Effects of petrolatum on stratum corneum structure and function. J Am Acad Dermatol. 1992 Mar;26(3 Pt 2):387-96.
31. Nolan K, Marmur E. Moisturizers: reality and the skin benefits. Dermatol Ther. 2012 May-Jun;25(3):229-33.
32. Grubauer G, Feingold KR, Elias PM. Relationship of epidermal lipogenesis to cutaneous barrier function. J Lipid Res. 1987 Jun;28(6):746-52.
33. Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial. J Drugs Dermatol. 2011 May;10(5):531-7.
34. Emer JJ, Frankel A, Sohn A, et al. A bilateral comparison study of pimecrolimus cream 1% and a topical medical device cream in the treatment of patients with atopic dermatitis. J Drugs Dermatol. 2011 Jul;10(7):735-43.
35. Draelos ZD. New treatments for restoring impaired epidermal barrier permeability: skin barrier repair creams. Clin Dermatol. 2012 May-Jun;30(3):345-8.
36. Nair B; Cosmetic Ingredients Review Expert Panel. Final report on the safety assessment of stearoxy dimethicone, dimethicone, methicone, amino bispropyl dimethicone, aminopropyl dimethicone, amodimethicone, amodimethicone hydroxystearate, behenoxy dimethicone, C24-28 alkyl methicone, C30-45 alkyl methicone, C30-45 alkyl dimethicone, cetearyl methicone, cetyl dimethicone, dimethoxysilyl ethylenediaminopropyl dimethicone, hexyl methicone, hydroxypropyldimethicone, stearamidopropyl dimethicone, stearyl dimethicone, stearyl methicone, and vinyldimethicone. Int J Toxicol. 2003;22(Suppl 2):11-35.
37. Slade HB, Fowler J, Draelos ZD, et al. Clinical efficacy evaluation of a novel barrier protection cream. Cutis. 2008 Oct;82(4 Suppl):21-8.
38. Slade HB, Fowler J, Reece BT, et al. Clinical safety evaluation of a novel barrier protection cream. Cutis. 2008 Oct;82(4 Suppl):16-20.
39. Beeckman D, Verhaeghe S, Defloor T, et al. A 3-in-1 perineal care washclothimpregnated with dimethicone 3% versus water and pH neutral soap to prevent and treat incontinence-associated dermatitis: a randomized, controlled clinical trial. J Wound Ostomy Continence Nurs. 2011 Nov-Dec;38(6):627-34.
40. Cerio R, Dohil M, Jeanine D, et al. Mechanism of action and clinical benefits of colloidal oatmeal for dermatologic practice. J Drugs Dermatol. 2010 Sep;9(9):1116-20.
41. Kurtz ES, Wallo W. Colloidal oatmeal: history, chemistry and clinical properties. J Drugs Dermatol. 2007 Feb;6(2):167-70.
42. Baumann L, Woolery-Lloyd H, Friedman A. “Natural” ingredients in cosmetic dermatology. J Drugs Dermatol. 2009 Jun;8(6 Suppl):s5-9.
43. Graf E. Antioxidant potential of ferulic acid. Free Radic Biol Med. 1992 Oct;13(4):435-48.
44. Kikuzaki H, Hisamoto M, Hirose K, et al. Antioxidant properties of ferulic acid and its related compounds. J Agric Food Chem. 2002 Mar 27;50(7):2161-8.
45. Sur R, Nigam A, Grote D, et al. Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and anti-itch activity. Arch Dermatol Res. 2008 Nov;300(10):569-74.
46. Guo W, Nie L, Wu D, et al. Avenanthramides inhibit proliferation of human colon cancer cell lines in vitro. Nutr Cancer. 2010;62(8):1007-16.
47. Hon KL, Leung AK. Use of ceramides and related products for childhood-onset eczema. Recent Pat Inflamm Allergy Drug Discov. 2013 Jan 1;7(1):12-9.
48. Sawada E, Yoshida N, Sugiura A, et al. Th1 cytokines accentuate but Th2 cytokines attenuate ceramide production in the stratum corneum of human epidermal equivalents: an implication for the disrupted barrier mechanism in atopic dermatitis. J Dermatol Sci. 2012 Oct;68(1):25-35.
49. Madison KC. Barrier function of the skin: “la raison d’être” of the epidermis. J Invest Dermatol. 2003 Aug;121(2):231-41.
50. Frankel A, Sohn A, Patel RV, et al. Bilateral comparison study of pimecrolimus cream 1% and a ceramide-hyaluronic acid emollient foam in the treatment of patients with atopic dermatitis. J Drugs Dermatol. 2011 Jun;10(6):666-72.
51. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J Am Acad Dermatol. 2002 Aug;47(2):198-208.
52. Madaan A. Epiceram for the treatment of atopic dermatitis. Drugs Today (Barc). 2008 Oct;44(10):751-5.
53. Bikowski J. Case studies assessing a new skin barrier repair cream for the treatment of atopic dermatitis. J Drugs Dermatol. 2009 Nov;8(11):1037-41.
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Division of Dermatology, University of Calgary, Calgary, AB, Canada
Reprinted from Skin Therapy Letter FP 6(3):1-4 (December 2010) due to content update

Introduction

Psoriasis and eczema, especially atopic eczema, are two of the most common cutaneous conditions seen by family physicians and dermatologists. Although the etiology of both conditions is unknown, immunologic abnormalities with an increase in immune mediators are thought to play major roles. These skin disorders are not curable, but can be controlled with proper topical therapy. However, psoriasis and eczema can at times be recalcitrant to conservative topical treatment. As such, it may be helpful for family physicians to be aware of more aggressive or innovative topical options for recalcitrant cases. Patients unresponsive to aggressive topical therapy may require systemic treatment or phototherapy, which carry a greater potential for adverse effects. Such cases are best managed by dermatologists with more experience in using these therapies.

Overview of Topical Corticosteroids

Due to their anti-inflammatory, immunosuppressive, and antiproliferative properties, corticosteroids are effective for treating a variety of inflammatory dermatoses, including psoriasis and atopic eczema.

Potency

• • • • The potency rating of a topical corticosteroid describes the intensity of the agent’s clinical effect

¹

• • • .

Seven groups of topical steroid potencies have been developed, these are ranked from superpotent (Group 1) to low potency (Group 7). Table 1 lists the topical corticosteroid potencies and gives available examples in Canada.

Vehicle Considerations

• Ointments are water-in-oil emulsions and are more hydrating to the stratum corneum. They provide an occlusive barrier, and because of an increased depot effect, drug penetration is enhanced, leading to greater potency.
  • For example, Table 1 shows the same chemical compound, triamcinolone acetonide 0.1%, can be Class 4 potency as an ointment, but only Class 5 as a cream. Therefore, an ointment can be useful in treating refractory dermatoses, especially for thick, fissured, and lichenified skin lesions.

Administration and Dosing

• Localized recalcitrant conditions may benefit from using a corticosteroid ointment under occlusion (e.g., plastic wraps and hydrocolloid dressings), which can increase the drug permeability up to 10 times.²
• Topical corticosteroids are usually applied once or twice daily. The duration of daily use of ultra-potent formulations should not exceed 3 weeks.³ Medium and high strength topical corticosteroids can be used up to 3 months.³ It can be difficult to adhere to these guidelines, as psoriasis and atopic eczema are chronic, requiring long-term therapy.
• In general, it is best to treat active disease more aggressively and then taper to the lowest strength that can maintain disease control.
• Use of superpotent topical corticosteroids should not exceed 50 grams per week in order to avoid excessive absorption and adrenal suppression.

Adverse Effects from Overuse or Prolonged Use

• Risks from long-term topical corticosteroid use include tachyphylaxis – a diminished pharmacologic response after repeated drug administration.¹
• There is a potential for rebound – a severe exacerbation of the dermatosis after abrupt discontinuation.4
• Systemic complications include suppression of the hypothalamic-pituitary axis, hyperglycemia, Cushing’s syndrome, and avascular necrosis.⁴
• Local adverse effects associated with prolonged use of potent topical corticosteroids include skin atrophy, striae, purpura, telangiectasia, acneiform eruptions (steroid-induced acne, perioral dermatitis, and rosacea), hypopigmentation, and hypertrichosis.⁴

Topical Treatments for Psoriasis

Psoriasis vulgaris is a common, chronic, inflammatory skin disease affecting 2% of the population.⁵ Most psoriatic patients have limited disease (>5% body surface area) and can be successfully treated with topical agents.⁵ Plaque psoriasis (PPs) and psoriasis involving the scalp, palms or soles can be particularly refractory to topical therapy.

Topical agents used to treat psoriasis include corticosteroids, vitamin D analogue (calcipotriol), retinoids (tazarotene), tar, anthralin,⁶ salicylic acid, and topical calcineurin inhibitors (TCIs). Also, combination therapies are available and may be useful because of their increased potency, decreased side-effects, and increased adherence due to less frequent dosing. A systematic review of topical treatments for chronic PPs included 131 randomized controlled trials with 21,448 participants concluded:⁷

• Vitamin D analogue (calcipotriol) was significantly more effective than placebo.
• Potent (betamethasone dipropionate) and very potent (clobetasol propionate) topical corticosteroids were better than placebo, with very potent preparations working better than weaker ones.
• Dithranol (anthralin) and tazarotene worked better than placebo.
• Combination therapies with a vitamin D analogue (calcipotriol) and a potent corticosteroid were more effective than either product alone.
• Potent topical corticosteroids were less likely than calcipotriol to cause local adverse events.

Recalcitrant Plaque Psoriasis

For recalcitrant PPs, a well-tolerated first-line regime would normally be a combination of a vitamin D analogue (calcipotriol) and potent steroid (betamethasone dipropionate 0.05%) applied daily at bedtime.

• Resistant patients can also be treated with a potent corticosteroid, such as clobetasol propionate 0.05% cream or ointment, twice daily for 2-3 weeks.
  • Use of a potent corticosteroid as “intermittent pulse dosing” may be helpful as a maintenance regimen.⁸
  • In this regimen, after clearing the patient with the potent steroid, remission is maintained with continued use of the potent steroid, using it for 3 consecutive doses at 12-hour intervals once weekly.
  • A study using betamethasone dipropionate glycol 0.05% with this regimen extended remission to 6 months in 60% of patients.⁹ No serious local or systemic side-effects were observed.
• A new treatment that may be effective for recalcitrant PPs of the body is clobetasol propionate 0.05% spray.
  • In a randomized double-blinded vehicle-controlled study of moderate to severe psoriasis, 75% of patients were reported to be clear or almost clear at 4 weeks following twice daily use of the spray.¹⁰
  • There were no reports of hypothalamic-pituitary-adrenal suppression and patients showed reductions in scaling, erythema, and plaque elevation.
• Calcipotriol + betamethasone dipropionate ointment, clobetasol propionate ointment, followed by pulsed therapy, or clobetasol propionate 0.05% spray could be tried for recalcitrant psoriasis on the palms and soles.
  • Very potent steroids can be used on the palms with little risk of atrophy. Superpotent steroids have been used under occlusion on palms and soles with good results.¹¹
• Tazarotene cream or gel can be used as monotherapy, but this retinoid is often used in combination with a topical steroid, such as mometasone furoate 0.1% cream, to reduce skin irritation, which is the major side-effect of tazarotene.
  • Tazarotene 0.1% gel once daily in combination with mometasone furoate 0.1% cream once daily has been shown to be more effective than calcipotriol ointment twice daily or mometasone furoate 0.1% cream twice daily.¹²

Scalp Psoriasis

For recalcitrant scalp psoriasis, the following treatments could be considered:

• Salicylic acid 3% + betamethasone dipropionate 0.05% lotion may be helpful as the salicylic acid has been shown to increase penetration of the topical steroid.¹³
• A new gel formulation containing calcipotriol + betamethasone dipropionate 0.05 % can be very helpful for moderate to severe scalp psoriasis.¹⁴
• A clobetasol propionate 0.05% shampoo applied to the scalp for 15 minutes and then lathered and shampooed out can be effective for difficult scalp psoriasis.¹⁵
• Another option is fluocinolone 0.01% in a peanut oil base that is applied to the scalp under a shower cap at bedtime and washed out the next morning.

Topical Treatment Suggestions for Recalcitrant Psoriasis

Plaque Psoriasis (excluding face and body folds)

• Calcipotriol + betamethasone dipropionate ointment (e.g., Dovobet™)
• Pulsed superpotent topical corticosteroids, such as clobetasol propionate or halobetasol propionate 0.05% (e.g., Ultravate®) ointment/cream used twice daily Saturday and Sunday
• Clobetasol propionate spray (e.g., Clobex™)

Palms and Soles

• All treatments suggested for plaque psoriasis (above) can be tried
• Superpotent topical corticosteroid with saran wrap or hydrocolloid occlusion overnight
• Topical tazarotene 0.1% cream/gel once daily +/– topical mometasone furoate 0.1% cream once daily

Scalp Psoriasis

• Betamethasone dipropionate + salicylic acid lotion (e.g., Diprosalic™)
• Calcipotriol + betamethasone dipropionate (e.g., Xamiol™ gel)
• Clobetasol propionate shampoo (e.g., Clobex™)
• Fluocinolone acetonide topical oil 0.01% (e.g., Derma- Smoothe/FS®)

Dosing Strategies for Protracted Remission

• Typically, Class 1 topical steroids are prescribed for rapid clearing in acute flares. Following initial control of psoriasis with a superpotent topical steroid, weekend-only therapy has been demonstrated to be extremely beneficial in maintaining long-term remission.^16-19
• With the aim of prolonging the initial therapeutic response while limiting the risks associated with extended corticosteroid use, a recent randomized, double-blind, placebo-controlled study of mild to moderate psoriasis assessed the safety and efficacy of a combination regimen of initial short course superpotent corticosteroid (halobetasol ointment 0.05%) followed by long-term weekend-only use to previously affected sites of psoriasis.¹⁶ Twice daily adjunctive therapy with a moisturizer (ammonium lactate lotion 12%) was added to enhance the steroidal component of treatment and minimize potential localized skin reactions.
  • Findings showed that the combination of twice daily halobetasol with the moisturizer for 2 weeks had excellent clinical efficacy with an absence of adverse effects.
  • Subsequent reduction in the dosing frequency of halobetasol ointment to weekend-only use (known as weekend or pulse therapy) while continuing twice daily emollient therapy maintained initial clinical efficacy for a longer duration when assessed at 12 weeks.
• The use of a second agent, such as calcipotriol ointment, applied on weekdays in combination with a weekend-only regimen of halobetasol ointment has also been shown to increase the duration of remission versus weekend-only halobetasol alone when assessed at 6 months.¹⁹

Topical Treatment of Eczema

Atopic Eczema (AE)

AE is a chronic, pruritic, relapsing inflammatory skin disease.²⁰ The lifetime prevalence is estimated to be between 10-20% in children and 1-3% in adults.²¹

• The topical treatment approach includes reducing inflammation with topical corticosteroids or TCIs (i.e., tacrolimus or pimecrolimus).
• AE patients have a skin barrier abnormality,²² as such, regular daily use of moisturizers to decrease transepidermal water loss is important. Recently, barrier repair creams²³ have become available for improving the skin barrier function. In an investigator-blinded, randomized trial of moderate to severe AE, a barrier cream reduced clinical disease and pruritus at 28 days of treatment comparably to fluticasone propionate 0.05% cream, a Class 5 corticosteroid.
• Avoidance of external irritants (e.g., harsh soaps, strong laundry detergents, and wool clothing) is beneficial.

Topical corticosteroids are the treatment of choice for AE; selection depends on disease severity and treatment site.

• For milder AE of the face and body folds, mild to moderate steroids (Class 6 or 7) are commonly used.
• For more severe AE and eczema on the trunk and extremities, more potent corticosteroids may be necessary (Class 4 or 5), but are best used only for a few weeks, then tapered to a milder preparation for maintenance. Generally, ointments work better than creams.
• Once the pruritus and thickness are controlled, switching to a TCI, such as tacrolimus ointment (0.03% for ages 2-15, 0.1% for >15 years), is very useful and helps to minimize side-effects from corticosteroids.
• If potent topical steroids are needed for long duration, consider pulse application at 1-2 times weekly dosing.

Chronic Hand Eczema (CHE)

CHE is a common condition and irritant dermatitis is more prevalent than allergic dermatitis. Early-onset hand eczema may be associated with atopy.

• A recent consensus statement on the management of CHE²⁴ suggested that topical therapy should include corticosteroids and TCIs.
• There is evidence of efficacy for long-term intermittent monotherapy with mometasone furoate cream.²⁵
• For very refractory hand eczema, especially on the palms, superpotent topical corticosteroids can be helpful and sideeffects, such as atrophy, are unusual when used on thick palmar skin.
• Möller²⁶ found the risk of recurrence of CHE was reduced by the very potent corticosteroid, clobetasol propionate, when used on an intermittent schedule of 2 applications a week, compared with a moderately potent corticosteroid cream.

Lichen Simplex Chronicus (LSC)

LSC is characterized by lichenification of the skin as a result of primary excessive scratching or rubbing.²⁷

• When treated topically, often potent corticosteroid creams or ointments, such as betamethasone dipropionate, are necessary to control the pruritus and inflammation and to break the “itch-scratch” cycle.
• The use of potent topical corticosteroids under occlusion may be needed for successful treatment.
• Topical tacrolimus has been reported to be effective.²⁸

Topical Treatment Suggestions for Recalcitrant Eczema

Atopic Eczema (excluding face and body folds)

• Potent topical corticosteroids for 2-3 weeks followed by tapering to a milder topical corticosteroid or TCI (i.e., Protopic™ ointment or Elidel® cream)
• Pulsed potent topical corticosteroid (i.e., fluocinonide 0.05% ointment/cream used twice daily Saturday and Sunday (use with caution in young children and if treating for longer than 2-3 weeks)
• Barrier repair creams (e.g., CeraVe®, EpiCeram®) can be tried in conjunction with topical corticosteroids or TCIs

Chronic Hand Eczema

• Superpotent topical corticosteroid for 2-3 weeks followed by tapering to a milder corticosteroid or TCI
• Superpotent topical corticosteroid with saran wrap or hydrocolloid occlusion overnight

Lichen Simplex Chronicus

• Superpotent topical corticosteroid for 2-3 weeks followed by tapering to a milder corticosteroid or TCI
• Superpotent topical corticosteroid with saran wrap or hydrocolloid occlusion overnight

References

1. Warner MR, Camisa C. Topical corticosteroids. In: Wolverton SE (ed). Comprehensive dermatologic drug therapy. 2nd ed. Philadelphia: Elsevier- Saunders, p595-624 (2007).
2. Feldmann RJ, et al. Penetration of 14c hydrocortisone through normal skin: the effect of stripping and occlusion. Arch Dermatol 91:661-6 (1965 Jun).
3. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for the use of topical glucocorticosteroids. American Academy of Dermatology. J Am Acad Dermatol 35(4):615-9 (1996 Oct).
4. Lee NP, Arriola ER. Topical corticosteroids: back to basics. West J Med 171 (5-6):351-3 (1999 Nov-Dec).
5. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 60(4):643-59 (2009 Apr).
6. Lebwohl M, Ting PT, Koo JY. Psoriasis treatment: traditional therapy. Ann Rheum Dis 64(Suppl 2):ii83-6 (2005 Mar).
7. Mason AR, Mason J, Cork M, et al. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev (2):CD005028 (2009).
8. Mikhail M, Scheinfeld. Evidence-based review of topical treatment for psoriasis. Adv Stud Med 4(8):420-29 (2004).
9. Katz HI, Prawer SE, Medansky RS, et al. Intermittent corticosteroid maintenance treatment of psoriasis: a double-blind multicenter trial of augmented betamethasone dipropionate ointment in a pulse dose treatment regimen. Dermatologica 183(4):269-74 (1991).
10. Jarratt MT, Clark SD, Savin RC, et al. Evaluation of the efficacy and safety of clobetasol propionate spray in the treatment of plaque-type psoriasis. Cutis 78(5):348-54 (2006 Nov).
11. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol 72(1):69-71 (1992).
12. Guenther LC. Topical tazarotene therapy for psoriasis, acne vulgaris, and photoaging. Skin Therapy Lett 7(3):1-4 (2002 Mar).
13. Lebwohl M. The role of salicylic acid in the treatment of psoriasis. Int J Dermatol 38(1):16-24 (1999 Jan).
14. van de Kerkhof PC, Hoffmann V, Anstey A, et al. A new scalp formulation of calcipotriol plus betamethasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. Br J Dermatol 160(1):170-6 (2009 Jan).
15. Andres P, Poncet M, Farzaneh S, et al. Short-term safety assessment of clobetasol propionate 0.05% shampoo: hypothalamic-pituitary-adrenal axis suppression, atrophogenicity, and ocular safety in subjects with scalp psoriasis. J Drugs Dermatol 5(4):328-32 (2006 Apr).
16. Emer JJ, Frankel A, Sohn A, et al. A randomized, double-blind, placebocontrolled study to evaluate the safety and efficacy of ammonium lactate lotion 12% and halobetasol propionate ointment 0.05% in the treatment and maintenance of psoriasis. J Clin Aesthet Dermatol 4(2):28-39 (2011 Feb).
17. Katz HI, Hien NT, Prawer SE, et al. Betamethasone dipropionate in optimized vehicle. Intermittent pulse dosing for extended maintenance treatment of psoriasis. Arch Dermatol 123(10):1308-11 (1987 Oct).
18. Katz HI, Prawer SE, Medansky RS, et al. Intermittent corticosteroid maintenance treatment of psoriasis: a double-blind multicenter trial of augmented betamethasone dipropionate ointment in a pulse dose treatment regimen. Dermatologica 183(4):269-74 (1991).
19. Lebwohl M, Yoles A, Lombardi K, et al. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 39(3):447-50 (1998 Sep).
20. Simpson EL. Atopic dermatitis: a review of topical treatment options. Curr Med Res Opin 26(3):633-40 (Mar 2010).
21. Leung DY, Bieber T. Atopic dermatitis. Lancet 361(9352):151-60 (2003 Jan 11).
22. McGrath JA. Filaggrin and the great epidermal barrier grief. Australas J Dermatol 49(2):67-73 (2008 May).
23. Sugarman JL, Parish LC. Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol 8(12):1106-11 (2009 Dec).
24. English J, Aldridge R, Gawkrodger DJ, et al. Consensus statement on the management of chronic hand eczema. Clin Exp Dermatol 34(7):761-9 (2009 Oct).
25. Veien NK, Olholm Larsen P, Thestrup-Pedersen K, et al. Long-term, intermittent treatment of chronic hand eczema with mometasone furoate. Br J Dermatol 140(5):882-6 (1999 May).
26. Moller H, Svartholm H, Dahl G. Intermittent maintenance therapy in chronic hand eczema with clobetasol propionate and flupredniden acetate. Curr Med Res Opin 8(9):640-4 (1983).
27. Lotti T, Buggiani G, Prignano F. Prurigo nodularis and lichen simplex chronicus. Dermatol Ther 21(1):42-6 (2008 Jan-Feb).
28. Aschoff R, Wozel G. Topical tacrolimus for the treatment of lichen simplex chronicus. J Dermatolog Treat 18(2):115-7 (2007).

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC,Canada

ABSTRACT

Propylene glycol (PG) is considered to be a ubiquitous formulary ingredient used in many personal care products and pharmaceutical preparations. It is an organic compound commonly found in topical corticosteroids (CS). Cutaneous reactions to PG are mostly irritant, but allergic contact dermatitis to PG is well-documented. Cosensitization to PG and topical CS can occur, making it challenging to choose the appropriate topical CS in a PG-allergic patient. This review is aimed at guiding clinicians in the selection of a suitable topical corticosteroid when presented with patients allergic to PG.

Key Words:
allergic contact dermatitis, corticosteroids, propylene glycol, topical

Propylene glycol (PG) is a colorless, viscous, nearly odorless liquid that is used as an intermediate for the synthesis of other chemicals.^1,2 It is a multifunctional excipient that is used in many products as a solvent, vehicle, humectant, or emulsifier.³ The annual PG production and global demand are rapidly increasing.³ Vehicles for topical corticosteroid preparations commonly include PG for enhancing stratum corneum penetration. In addition to topical steroids, PG can also be found in other topical pharmacologic preparations, including antibacterials, antifungals, benzoyl peroxide, and emollients,¹ Cutaneous reactions to PG have been recognized since 1952.¹

Sources of PG

Approximately half of the PG produced is used in the synthesis of other chemicals.² The other half is utilized in the manufacturing of many industrial and personal care products. PG is used as a plasticizer, solvent (in lacquers and varnishes), and as a component in antifreeze products, lubricants, cutting-fluids, and inks. It is found in many cosmetic and pharmaceutical preparations, food (for coloring, thickening, and flavoring), and household cleansers. In a recent study by the North American Contact Dermatitis Group (NACDG), personal care products were found to be the most common sources of exposure to PG (53.8%), followed by topical steroids, and other topical medicaments.³

Allergic Contact Dermatitis to PG

Cutaneous reactions to PG are classified into four groups: irritant contact dermatitis, allergic contact dermatitis (ACD), non-immunologic contact urticaria, and subjective or sensory irritation.⁴ The incidence of true ACD to PG is unknown. This is primarily attributed to the difficulty in determining the ideal concentration for patch testing that would be nonirritating, but high enough to elicit an allergic response. The majority of skin reactions to PG are irritant in nature, however, true allergic sensitization does occur. The most convincing evidence of allergic sensitization to PG is the development of systemic contact dermatitis after giving PG orally to PG-allergic patients.⁵ The overall prevalence of allergic reactions to PG was found to be relatively low (3.5%) by the NACDG.³ The NACDG currently recommends using a 30% aqueous PG solution for patch testing.³ In our experience at the University of British Columbia Contact Dermatitis Clinic, the prevalence of positive patch test reactions to PG over a 2 year period was 1.57% (13/828 patients). It was presumed that an increased individual susceptibility to irritation may also be associated with allergic reactivity through reduction of the skin’s barrier function and the release of cytokines.2 To confirm an allergy to PG, it has been recommended that positive patch test reactions should be followed by serial dilution patch tests, repeat open application tests or oral challenge tests, or all three of these assessments.⁴

PG and ACD to Topical Corticosteroids

The prevalence of ACD from topical corticosteroids (CS) is unknown. ACD to topical CS should be suspected if the
dermatitis worsens or does not improve during treatment. ACD can result from an allergy to the steroid molecule or to a component of the vehicle. CS are divided into four classes on the basis of structure and cross-reactivity pattern: classes A (hydrocortisone type), B (triamcinolone acetonide type), C (betamethasone type), and D.⁶ Class D is further divided into D1 (betamethasone dipropionate type) and D2 (methylprednisolone aceponate type). There are different screening markers that are used for patch testing to the corticosteroid classes. The screening markers used on the NACGD screening series are as follows: tixocortol-21-pivalate (class A), budesonide and triamcinolone acetonide (class B), clobetasol-17-propionate (class D1), and hydrocortisone-17-butyrate (class D2).6 Patch test reactions to class A steroids are the most common.⁷ Reactions to classes B and D steroids are less common, whereas reactions to class C steroids are extremely rare.⁷ The most common cross-reactions are between steroids in classes A and D2, followed by classes B and D2, and classes A and B.⁸

An investigation by the NACDG demonstrated that topical CS were responsible for 18.3% of the positive patch test reactions to PG.³ In a recent study, PG was found to be the most common allergen in topical CS, being present in 64% of the steroidal products.⁷ It was especially common in branded ointments and gels. Moreover, studies have reported a significant number of patients have a concomitant reaction to both topical CS and PG, which suggests the possibility of cosensitization.^3,8

Case Report

A 55-year-old female presented to our clinic with a history of severe recurrent eyelid dermatitis resulting in multiple visits to the emergency room and treatment with systemic steroids. Her left leg dermatitis also recently worsened. The patient’s past medical history was significant for a previously treated venous ulcer of the left leg and chronic venous insufficiency dermatitis. There was a positive family history of atopy, but she denied any personal history of atopy. She had been applying amcinonide 0.1% (Cyclocort®) and fusidic acid 2% (Fucidin®) ointments on the leg dermatitis for many years with only intermittent improvement. Patch testing was done with the 2010 NACDG screening series (Table 1). She was found to be allergic to PG, budesonide, lanolin alcohol, balsam of Peru, and glyceryl thioglycolate. We could not identify the source of PG (amcinonide 0.1% and fusidic acid 2% ointments are both PG-free), but this patient could have been sensitized to PG from her personal care products. She was most likely sensitized to budesonide from prolonged application of amcinonide 1% ointment (a class B corticosteroid). Fusidic acid 2% ointment contains lanolin, which was an additional factor for the persistence of her dermatitis. Given that she was allergic to both PG and budesonide, it would have been helpful to know which topical CS were PG-free. Ideally, we would have prescribed her a PG-free class C or D1 topical CS. Consequently, we switched her to tacrolimus 0.1% ointment (PG- and corticosteroid-free) for treating both the eyelid and leg dermatitis. Subsequently, the eyelid dermatitis cleared. Her leg dermatitis occasionally recurs secondary to underlying venous insufficiency, for which she continues compression stocking therapy.

The Choice of a Topical CS in a PG-allergic Patient

Given that PG is the most common allergen in topical CS, it is important to know which topical corticosteroid to prescribe to a PG-allergic patient. We have conducted a search of all topical CS available in Canada. We have excluded topical CS that contain other active ingredients (e.g., salicylic acid). We then searched carefully for preparations that are PG-free. Ingredients of the different topical CS were checked using the Compendium of Pharmaceuticals and Specialties (CPS) 2010 drug reference guide in addition to pharmaceutical company website searches. We have created a chart containing all PG-free topical CS available in Canada sorted on the basis of potency and structural class
(Table 2 on page 7).

Conclusion

PG is found in many products. The sensitizing potential of PG is well documented, but the true incidence of its role in ACD is unknown. PG is the most common allergen in topical CS. Cosensitization to PG and topical CS is possible. If patch testing is unavailable and the physician is highly suspecting PG allergy, we recommend prescribing any PG-free topical corticosteroid. Another option is to consider tacrolimus ointment, which is a PG-free steroid-sparing agent (pimecrolimus 1% cream contains PG). Empirically, one can prescribe a PG-free class C topical corticosteroid given the rarity of ACD to class C topical CS. Ideally, patch testing should be done if the clinical picture is suggestive of allergy to PG and/or topical CS. It is important to note that the steroid formulations discussed in this paper pertain only to topical CS products available in Canada, as products from other countries may contain different compositions of non-medicinal ingredients. We hope that this review will be of benefit in guiding physicians when choosing the appropriate topical corticosteroid in patients allergic to PG.

References

1. Catanzaro JM, Smith JG, Jr. Propylene glycol dermatitis. J Am Acad Dermatol 24(1):90-5 (1991 Jan).
2. Lessmann H, Schnuch A, Geier J, et al. Skin-sensitizing and irritant properties of propylene glycol. Contact Dermatitis 53(5):247-59 (2005 Nov).
3. Warshaw EM, Botto NC, Maibach HI, et al. Positive patch-test reactions to propylene glycol: a retrospective cross-sectional analysis from the North American Contact Dermatitis Group, 1996 to 2006. Dermatitis 20(1):14-20 (2009 Jan-Feb).
4. Funk JO, Maibach HI. Propylene glycol dermatitis: re-evaluation of an old problem. Contact Dermatitis 31(4):236-41 (1994 Oct).
5. Hannuksela M, Forstrom L. Reactions to peroral propylene glycol. Contact Dermatitis 4(1):41-5 (1978 Feb).
6. Jacob SE, Steele T. Corticosteroid classes: a quick reference guide including patch test substances and cross-reactivity. J Am Acad Dermatol 54(4):723-7 (2006 Apr).
7. Coloe J, Zirwas MJ. Allergens in corticosteroid vehicles. Dermatitis 19(1):38-42 (2008 Jan-Feb).
8. Mimesh S, Pratt M. Allergic contact dermatitis from corticosteroids: reproducibility of patch testing and correlation with intradermal testing. Dermatitis 17(3):137-42 (2006 Sep).

¹ McMaster University, Hamilton, ON, Canada
² Toronto Dermatology Centre, Toronto, ON, Canada

Introduction

Eczema is a chronic relapsing dermatitis and, as such, it is imperative to maintain the hydration and barrier function of the skin in these patients with daily moisturizer use. Emollients have long been used to maintain the skin barrier function in patients with eczema (atopic dermatitis). Ceramide and urea-based moisturizers have been shown to be beneficial in reducing transepidermal water loss (TEWL), improving barrier function, and maintaining hydration of the stratum corneum layer of the epidermis; thus, they should be considered a mainstay of treatment in patients with xerosis (dry skin) and eczema.

Overview of Eczema

Eczema is a chronic, pruritic, inflammatory skin disease with wide ranging severity; it is usually the first manifestation of atopic disease. Eczema is a major public health problem worldwide that commonly presents during early infancy and childhood, but can persist or start in adulthood (prevalence in children is 10-20% and 1-3% in adults).¹ Prevalence has increased by two to threefold during the past 30 years in urban areas and industrialized countries, but it remains much lower in rural and less industrialized regions.²

• The causes of eczema are not completely understood, but dysfunction of the skin barrier, likely the result of both genetic and environmental factors, and immune dysregulation are important in its pathophysiology.³
• Acute eczema presents as erythematous patches, papules, plaques, and excoriations secondary to scratching; there may also be weeping of serous exudate. Chronic lesions have the same characteristics, with the addition of lichenification, fissures, and occasional alopecia.⁴
• Partly due to the ease of accessibility for scratching, infantile eczema predominantly involves extensor surfaces of the arms and legs, face, and trunk. Scaling, exudate, and fissures are also common findings in infants.
• In adults, flexural areas, face and neck, wrists, and the dorsal areas of the hands and feet are the most commonly affected regions.

Treatment Rationale

The major goal of disease management is to reduce the frequency and severity of flares, and prolong periods of remission. Comprehensive long-term management addresses both skin barrier dysfunction and immune dysregulation, but also includes patient and caregiver education, flare prevention through trigger avoidance and hydration, as well as pharmacologic and non-pharmacologic therapies.³

• Non-pharmacologic patient-specific strategies include removal of allergens (e.g., foods, pet dander, pollen), identification of trigger factors (e.g., stress, low humidity), and a balanced intake of dietary nutrients.⁵
• Short (5-10 minutes) tepid baths or showers can help to hydrate the skin. A soft towel should be used to pat dry without rubbing, a moisturizer is applied within 3 minutes.
• Particularly during infancy, a higher intake of vitamin A may reduce the incidence of eczema seen in children with a positive family history of atopy. The use of Lactobacillus during pregnancy and while nursing may postpone the onset of eczema in infants and children.⁵
• Pharmacologic therapy includes the use of emollients, topical corticosteroids, and topical calcineurin inhibitors.
• For mild eczema, over-the-counter (OTC) emollients and topical corticosteroids, e.g., hydrocortisone 0.5% (low potency) and clobetasone 0.05% (mid potency) are available for self-treatment.
• Physicians can emphasize to patients that the goals of selftreatment are to stop the itch-scratch cycle, maintain skin hydration, and avoid or minimize factors that can trigger or aggravate eczema.
• An ideal moisturizer is one that performs four functions:⁶
  1. repair the skin barrier,
  2. maintain skin integrity and appearance,
  3. reduce transepidermal water loss (TEWL),
  4. restore the lipid barrier’s ability to attract, hold, and redistribute water.
• It is appropriate for patients or caregivers to consult a physician if OTC treatments are not providing adequate relief, eczematous lesions appear to be infected, or the patient’s sleep is frequently disturbed by pruritus.⁵

Available Therapeutic Moisturizers

Ceramide-based Moisturizers

• Recent biochemical findings indicate that disturbances of epidermal lipid compartment structures (particularly of ceramides) account for the defects in barrier function of atopic dry skin.⁷
• Optimal barrier function requires the presence of sufficient extracellular lipids to form a competent lamellar bilayer system of the stratum corneum.⁷
• Ceramides, which consist of different sub-fractions of lipids, represent one of the major lipid constituents of the extracellular lipids and are functionally important for the stability of the multilamellar bilayer system.
• Studies have revealed that ceramides are reduced in the whole atopic population, but particularly in those individuals in an active phase of the disease.⁸
• A reduction of ceramides has been inversely correlated with TEWL, which can result in chronically dry skin.
• Topical ceramide supplementation controls ceramide deficiency and improves the overall skin condition.⁶
• Their benefits are derived from prophylactic and regular use, which may reduce the need for topical corticosteroids and calcineurin inhibitors, and possibly mitigate the side-effects from these medications.
• OTC ceramide-based moisturizers include Impruv® cream and Cetaphil Restoraderm™ lotion. CeraVe® and TriCeram® are currently available in the U.S. only, however, CeraVe® is due to be launched in Canada soon.

Prescription Ceramide-based Moisturizers

• These consist of a higher percentage (compared to OTC brands) combination of ceramides, cholesterol, and fatty acids that mimic those naturally found in the skin.9
• EpiCeram® was approved by Health Canada in September 2009 as a Class 2 medical device for use as a non-steroidal lipid barrier emulsion to manage burning and itching symptoms associated with dry skin conditions, such as eczema.
  • In a study involving 113 children with moderate to severe atopic dermatitis, similar efficacy to a mid-strength topical corticosteroid was demonstrated.⁹
  • This multi-lipid emulsion has a favourable safety profile and does not appear to have substantial restrictions for use, such as treatment duration or patient age.
• Prescription ceramide-dominant formulations include EpiCeram® cream (available in Canada and the U.S.) as well as Atopiclair® and MimyX® (available in the U.S. only).

Urea-based Moisturizers without Hydrocortisone

• Urea-based moisturizers are OTC formulations that are indicated for xerotic skin with or without pruritus.
• Urea works by enhancing the water-binding capacity of the stratum corneum and long-term treatment with urea has been demonstrated to decrease TEWL.¹⁰
• Application of these moisturizers is recommended shortly after bathing, while the skin is still wet.
• The short-term therapeutic effects of urea-based moisturizers are apparent in patients even after 1 week of daily application in those with dry skin and eczema.¹¹
• It has also been shown that long-term urea application reduces the susceptibility to skin irritation from sodium lauryl sulfate, a surfactant commonly used in many soaps, shampoos, detergents, and toothpastes.
• The protective effect (after prolonged application) of urea-containing moisturizers has promising clinical ramifications, such as reduction of contact dermatitis from irritating stimuli.¹⁰
• Higher concentration urea-based formulations induce more prominent keratolytic (softening/shedding) activity that can increase skin irritation. A lower concentration is generally used on the face and body, whereas a higher concentration may be applied to thickened skin areas (e.g., feet).
• OTC urea-based moisturizers include various strengths of urea: 5% (e.g., Eucerin® cream); 10% (e.g., Uremol® 10 cream or lotion, Eucerin® lotion or cream, Urisecâ„¢ cream); 12% (e.g., Uresecâ„¢ lotion); 20% (e.g., Uremol® 20 cream); 22% and 40% urea creams.
• Urea 40% cream is a potent keratolytic that is not suitable for use as a regular moisturizer.

Urea-based Moisturizers with Hydrocortisone

• Urea-based moisturizers with hydrocortisone are prescription strength formulations and are effective for xerotic skin with inflammation and mild eczema.⁴
• Topical corticosteroids are effectively used for controlling active skin inflammation in eczema. The lowest effective potency of topical corticosteroids is always preferred for the local treatment of lesions.
• Combining an emollient with a corticosteroid has been shown to be effective. A cohort study found that the addition of 10% urea to a commercially prepared steroid cream gave better results in treating subacute atopic eczema than the steroid cream alone.¹²
• Side-effects from topical steroids are directly related to the potency of the compound and the length of use.
• Potential risks from long-term topical steroid use include fungal infections, impetigo, viral warts, and herpes simplex. As well, discontinuation of topical corticosteroids may lead to a flare of symptoms.
• Low-potency hydrocortisone 1% cream has been found to be quite safe for cutaneous use.
• Prescription-based urea moisturizers containing 10% urea with 1% hydrocortisone are available in lotion or cream preparations (e.g., Uremol® HC).

Diabetic Skin Care Management

Xerosis of the feet is a common skin condition; incidence increases with age, exposure to dry winter conditions, and physiological changes that alter circulatory supply to the lower extremities (e.g., diabetes).
People with diabetes have a high incidence of xerosis of the feet, especially on the heels.
While assessing for predictors of foot lesions in diabetic patients, one study found that 82.1% of this cohort had skin with dryness, cracks, or fissures.¹¹ An unpublished survey of 105 consecutive patients with diabetes conducted by one of the authors revealed that 75% had clinical manifestations of dry skin.

Dry skin often leads to cracks and fissures that can act as portals of entry for bacteria. These cracks and fissures are associated with an increased risk of cellulitis and foot ulceration that, if left unchecked, can eventually lead to amputation. Xerosis of the feet in diabetic individuals can be controlled with the regimented use of moisturizers.¹¹ Healthcare providers should routinely inspect the feet of diabetic patients and encourage daily moisturization. Urea has been found to be a potent skin humidifier (by decreasing TEWL) and descaling agent.

Studies of diabetic patients revealed that urea is safe and effective in controlling xerosis of the feet and showed longerlasting effect than other emollient creams.¹¹

Urea cream works as a keratinolytic and helps in the treatment of corns and calluses of the feet.¹³ This can be functionally important as these hyperkeratotic papules can be uncomfortable, and even painful, thereby restricting physical activity in affected individuals.

Conclusion

Eczema is a chronic relapsing dermatitis and, as such, it is imperative to maintain the hydration and barrier function of the skin in these patients with daily moisturizer use. Ceramide and urea-based moisturizers have been shown to be beneficial in reducing TEWL, improving barrier function, and maintaining hydration of the stratum corneum layer of the epidermis, and thus, should be a mainstay of treatment in patients with dry skin and eczema.

Failure to adequately moisturize the skin can lead to a flare of symptoms or an increased incidence of infections. However, adherence to a schedule of regular moisturizer use is associated with improved patient quality of life outcomes (e.g., reduced pruritus, improved sleep patterns, less depression) and a reduction in the severity and frequency of eczematous flares.¹⁴

References

1. Simpson EL. Curr Med Res Opin 26(3):633-40 (2010 Mar).
2. Leung DYM, et al. Lancet 361(9352):151-60 (2003 Jan).
3. Levy ML. Curr Med Res Opin 23(12):3091-103 (2007 Dec).
4. Ahuja A. South Med J 96(11):1068-72 (2003 Nov).
5. Carbone A, et al. Ann Pharmacother 44(9):1448-58 (2010 Sep).
6. Anderson PC, et al. Curr Opin Pediatr 21(4):486-90 (2009 Aug).
7. Chamlin SL, et al. J Am Acad Dermatol 47(2):198-208 (2002 Aug).
8. Di Nardo A. Acta Derm Venereol 78(1):27-30 (1998 Jan).
9. Madaan A. Drugs Today 44(10):751-5 (2008 Oct).
10. Flynn TC, et al. Clin Dermatol 19(4):387-92 (2001 Jul).
11. Trung H, et al. Ostomy Wound Manage 48(5):30-6 (2002 May).
12. Hindson TC. Arch Dermatol 104(3):284-5 (1971 Sep).
13. Hogan DJ, et al. Corns: treatment and medication. Available at: http://emedicine.medscape.com/article/1089807-treatment. Accessed: September 30, 2010.
14. Loden M. J Eur Acad Dermatol Venereol 19(6):672-88 (2005 Nov).

Division of Dermatology, University of Calgary, Calgary, AB, Canada

Introduction

Psoriasis and eczema, especially atopic eczema, are two of the most common cutaneous conditions seen by family physicians and dermatologists. Although the etiology of both conditions is unknown, immunologic abnormalities with an increase in immune mediators are thought to play major roles. These skin disorders are not curable, but can be controlled with proper topical therapy. However, psoriasis and eczema can at times be recalcitrant to conservative topical treatment. As such, it may be helpful for family physicians to be aware of more aggressive or innovative topical options for recalcitrant cases. Patients unresponsive to aggressive topical therapy may require systemic treatment or phototherapy, which carry a greater potential for adverse effects. Such cases are best managed by dermatologists with more experience in using these therapies.

Overview of Topical Corticosteroids

Due to their anti-inflammatory, immunosuppressive, and anti-proliferative properties, corticosteroids are effective for treating a variety of inflammatory dermatoses, including psoriasis and atopic eczema.

Potency

• The potency rating of a topical corticosteroid describes the intensity of the agent’s clinical effect.¹ Seven groups of topical steroid potencies have been developed, these are ranked from superpotent (Group 1) to low potency (Group 7). Table 1 lists the topical corticosteroid potencies and gives available examples in Canada.

Vehicle Considerations

• Ointments are water-in-oil emulsions and are more hydrating to the stratum corneum. They provide an occlusive barrier, and because of an increased depot effect, drug penetration is enhanced, leading to greater potency.
  • For example, Table 1 shows the same chemical compound, triamcinolone acetonide 0.1%, can be Class 4 potency as an ointment, but only Class 5 as a cream. Therefore, an ointment can be useful in treating refractory dermatoses, especially for thick, fissured, and lichenified skin lesions.

Administration and Dosing

• Localized recalcitrant conditions may benefit from using a corticosteroid ointment under occlusion (e.g., plastic wraps and hydrocolloid dressings), which can increase the drug permeability up to 10 times.²
• Topical corticosteroids are usually applied once or twice daily. The duration of daily use of ultra-potent formulations should not exceed 3 weeks.³ Medium and high strength topical corticosteroids can be used up to 3 months.³ It can be difficult to adhere to these guidelines, as psoriasis and atopic eczema are chronic, requiring long-term therapy for management.

Topical Treatment Suggestions for Recalcitrant Eczema

Atopic Eczema (excluding face and body folds)

• Potent topical corticosteroids for 2-3 weeks followed by tapering to a milder topical corticosteroid or TCI (i.e., Protopic™ ointment or Elidel® cream)
• Pulsed potent topical corticosteroid (i.e., fluocinonide 0.05% ointment/cream used twice daily Saturday and Sunday (use with caution in young children and if treating for longer than 2-3 weeks)
• Barrier repair creams (e.g., EpiCeram™) can be tried in conjunction with topical corticosteroids or TCIs

Chronic Hand Eczema

• Superpotent topical corticosteroid for 2-3 weeks followed by tapering to a milder corticosteroid or TCI
• Superpotent topical corticosteroid with saran wrap or hydrocolloid occlusion overnight

Lichen Simplex Chronicus

• Superpotent topical corticosteroid for 2-3 weeks followed by tapering to a milder corticosteroid or TCI
• Superpotent topical corticosteroid with saran wrap or hydrocolloid occlusion overnight

Disclaimer: I have tried to give evidence-based suggestions for treating these cutaneous diseases that can be chronic and recalcitrant to treatment. However, these are suggestions only and it must be remembered that potent topical corticosteroids can have significant side-effects as discussed. The guidelines of care for the use of topical glucocorticosteroids from the American Academy of Dermatology (reference 3) should be kept in mind, including the duration of use of superpotent and potent topical corticosteroids and maximal daily use. Extra caution needs to be given when using these agents in children. Close supervision by the prescribing physician is recommended.

References

1. Warner MR, et al. Topical corticosteroids. In: Wolverton SE (ed). Comprehensive dermatologic drug therapy. 2nd ed. Philadelphia: Elsevier-Saunders, p595-624 (2007).
2. Feldmann RJ, et al. Arch Dermatol 91:661-6 (1965).
3. Drake LA, et al. J Am Acad Dermatol 35(4):615-9 (1996).
4. Lee NP, et al. West J Med 171(5-6):351-3 (1999).
5. Menter A, et al. J Am Acad Dermatol 60(4):643-59 (2009).
6. Lebwohl M, et al. Ann Rheum Dis 64(Suppl 2):ii83-6 (2005).
7. Mason AR, et al. Cochrane Database Syst Rev (2):CD005028 (2009).
8. Mikhail M, et al. Adv Stud Med 4(8):420-429 (2004).
9. Katz HI, et al. Dermatologica 183(4):269-74 (1991).
10. Jarratt MT, et al. Cutis 78(5):348-54 (2006).
11. Volden G. Acta Derm Venereol 72(1):69-71 (1992).
12. Guenther LC. Skin Therapy Lett 7(3):1-4 (2002).
13. Lebwohl M. Int J Dermatol 38(1):16-24 (1999).
14. van de Kerkhof PC, et al. Br J Dermatol 160(1):170-6 (2009).
15. Andres P, et al. J Drugs Dermatol 5(4):328-32 (2006).
16. Simpson EL. Curr Med Res Opin 26(3):633-40 (2010).
17. Leung DY, et al. Lancet 361(9352):151-60 (2003).
18. McGrath JA. Australas J Dermatol 49(2):67-73 (2008).
19. Sugarman JL, et al. J Drugs Dermatol 8(12):1106-11 (2009).
20. English J, et al. Clin Exp Dermatol 34(7):761-9 (2009).
21. Veien NK, et al. Br J Dermatol 140(5):882-6 (1999).
22. Moller H, et al. Curr Med Res Opin 8(9):640-4 (1983).
23. Lotti T, et al. Dermatol Ther 21(1):42-6 (2008).
24. Aschoff R, et al. J Dermatolog Treat 18(2):115-7 (2007).

¹ McMaster University, Hamilton, ON, Canada
² Toronto Dermatology Centre, Toronto, ON, Canada

Introduction

Eczema is a chronic relapsing dermatitis and, as such, it is imperative to maintain the hydration and barrier function of the skin in these patients with daily moisturizer use. Emollients have long been used to maintain the skin barrier function in patients with eczema (atopic dermatitis). Ceramide and urea-based moisturizers have been shown to be beneficial in reducing transepidermal water loss (TEWL), improving barrier function, and maintaining hydration of the stratum corneum layer of the epidermis; thus, they should be considered a mainstay of treatment in patients with xerosis (dry skin) and eczema.

Overview of Eczema

Eczema is a chronic, pruritic, inflammatory skin disease with wide ranging severity; it is usually the first manifestation of atopic disease. Eczema is a major public health problem worldwide that commonly presents during early infancy and childhood, but can persist or start in adulthood (prevalence in children is 10-20% and 1-3% in adults).¹ Prevalence has increased by two to threefold during the past 30 years in urban areas and industrialized countries, but it remains much lower in rural and less industrialized regions.²

• The causes of eczema are not completely understood, but dysfunction of the skin barrier, likely the result of both genetic and environmental factors, and immune dysregulation are important in its pathophysiology.³
• Acute eczema presents as erythematous patches, papules, plaques, and excoriations secondary to scratching; there may also be weeping of serous exudate. Chronic lesions have the same characteristics, with the addition of lichenification, fissures, and occasional alopecia.⁴
• Partly due to the ease of accessibility for scratching, infantile eczema predominantly involves extensor surfaces of the arms and legs, face, and trunk. Scaling, exudate, and fissures are also common findings in infants.
• In adults, flexural areas, face and neck, wrists, and the dorsal areas of the hands and feet are the most commonly affected regions.

Top

Treatment Rationale

The major goal of disease management is to reduce the frequency and severity of flares, and prolong periods of remission. Comprehensive long-term management addresses both skin barrier dysfunction and immune dysregulation, but also includes patient and caregiver education, flare prevention through trigger avoidance and hydration, as well as pharmacologic and non-pharmacologic therapies.³

• Non-pharmacologic patient-specific strategies include removal of allergens (e.g., foods, pet dander, pollen), identification of trigger factors (e.g., stress, low humidity), and a balanced intake of dietary nutrients.⁵
• Short (5-10 minutes) tepid baths or showers can help to hydrate the skin. A soft towel should be used to pat dry without rubbing, a moisturizer is applied within 3 minutes.
• Particularly during infancy, a higher intake of vitamin A may reduce the incidence of eczema seen in children with a positive family history of atopy. The use of Lactobacillus during pregnancy and while nursing may postpone the onset of eczema in infants and children.⁵
• Pharmacologic therapy includes the use of emollients, topical corticosteroids, and topical calcineurin inhibitors.
• For mild eczema, over-the-counter (OTC) emollients and topical corticosteroids, e.g., hydrocortisone 0.5% (low potency) and clobetasone 0.05% (mid potency) are available for self-treatment.
• Physicians can emphasize to patients that the goals of selftreatment are to stop the itch-scratch cycle, maintain skin hydration, and avoid or minimize factors that can trigger or aggravate eczema.
• An ideal moisturizer is one that performs four functions:⁶
  1. repair the skin barrier,
  2. maintain skin integrity and appearance,
  3. reduce transepidermal water loss (TEWL),
  4. restore the lipid barrier’s ability to attract, hold, and redistribute water.
• It is appropriate for patients or caregivers to consult a physician if OTC treatments are not providing adequate relief, eczematous lesions appear to be infected, or the patient’s sleep is frequently disturbed by pruritus.⁵

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Available Therapeutic Moisturizers

Ceramide-based Moisturizers

• Recent biochemical findings indicate that disturbances of epidermal lipid compartment structures (particularly of ceramides) account for the defects in barrier function of atopic dry skin.⁷
• Optimal barrier function requires the presence of sufficient extracellular lipids to form a competent lamellar bilayer system of the stratum corneum.⁷
• Ceramides, which consist of different sub-fractions of lipids, represent one of the major lipid constituents of the extracellular lipids and are functionally important for the stability of the multilamellar bilayer system.
• Studies have revealed that ceramides are reduced in the whole atopic population, but particularly in those individuals in an active phase of the disease.⁸
• A reduction of ceramides has been inversely correlated with TEWL, which can result in chronically dry skin.
• Topical ceramide supplementation controls ceramide deficiency and improves the overall skin condition.⁶
• Their benefits are derived from prophylactic and regular use, which may reduce the need for topical corticosteroids and calcineurin inhibitors, and possibly mitigate the side-effects from these medications.
• OTC ceramide-based moisturizers include Impruv® cream and Cetaphil Restoraderm™ lotion. CeraVe® and TriCeram® are currently available in the U.S. only, however, CeraVe® is due to be launched in Canada soon.

Prescription Ceramide-based Moisturizers

• These consist of a higher percentage (compared to OTC brands) combination of ceramides, cholesterol, and fatty acids that mimic those naturally found in the skin.9
• EpiCeram® was approved by Health Canada in September 2009 as a Class 2 medical device for use as a non-steroidal lipid barrier emulsion to manage burning and itching symptoms associated with dry skin conditions, such as eczema.
  • In a study involving 113 children with moderate to severe atopic dermatitis, similar efficacy to a mid-strength topical corticosteroid was demonstrated.⁹
  • This multi-lipid emulsion has a favourable safety profile and does not appear to have substantial restrictions for use, such as treatment duration or patient age.
• Prescription ceramide-dominant formulations include EpiCeram® cream (available in Canada and the U.S.) as well as Atopiclair® and MimyX® (available in the U.S. only).

Urea-based Moisturizers without Hydrocortisone

• Urea-based moisturizers are OTC formulations that are indicated for xerotic skin with or without pruritus.
• Urea works by enhancing the water-binding capacity of the stratum corneum and long-term treatment with urea has been demonstrated to decrease TEWL.¹⁰
• Application of these moisturizers is recommended shortly after bathing, while the skin is still wet.
• The short-term therapeutic effects of urea-based moisturizers are apparent in patients even after 1 week of daily application in those with dry skin and eczema.¹¹
• It has also been shown that long-term urea application reduces the susceptibility to skin irritation from sodium lauryl sulfate, a surfactant commonly used in many soaps, shampoos, detergents, and toothpastes.
• The protective effect (after prolonged application) of urea-containing moisturizers has promising clinical ramifications, such as reduction of contact dermatitis from irritating stimuli.¹⁰
• Higher concentration urea-based formulations induce more prominent keratolytic (softening/shedding) activity that can increase skin irritation. A lower concentration is generally used on the face and body, whereas a higher concentration may be applied to thickened skin areas (e.g., feet).
• OTC urea-based moisturizers include various strengths of urea: 5% (e.g., Eucerin® cream); 10% (e.g., Uremol® 10 cream or lotion, Eucerin® lotion or cream, Urisecâ„¢ cream); 12% (e.g., Uresecâ„¢ lotion); 20% (e.g., Uremol® 20 cream); 22% and 40% urea creams.
• Urea 40% cream is a potent keratolytic that is not suitable for use as a regular moisturizer.

Urea-based Moisturizers with Hydrocortisone

• Urea-based moisturizers with hydrocortisone are prescription strength formulations and are effective for xerotic skin with inflammation and mild eczema.⁴
• Topical corticosteroids are effectively used for controlling active skin inflammation in eczema. The lowest effective potency of topical corticosteroids is always preferred for the local treatment of lesions.
• Combining an emollient with a corticosteroid has been shown to be effective. A cohort study found that the addition of 10% urea to a commercially prepared steroid cream gave better results in treating subacute atopic eczema than the steroid cream alone.¹²
• Side-effects from topical steroids are directly related to the potency of the compound and the length of use.
• Potential risks from long-term topical steroid use include fungal infections, impetigo, viral warts, and herpes simplex. As well, discontinuation of topical corticosteroids may lead to a flare of symptoms.
• Low-potency hydrocortisone 1% cream has been found to be quite safe for cutaneous use.
• Prescription-based urea moisturizers containing 10% urea with 1% hydrocortisone are available in lotion or cream preparations (e.g., Uremol® HC).

Top

Diabetic Skin Care Management

Xerosis of the feet is a common skin condition; incidence increases with age, exposure to dry winter conditions, and physiological changes that alter circulatory supply to the lower extremities (e.g., diabetes).
People with diabetes have a high incidence of xerosis of the feet, especially on the heels.

While assessing for predictors of foot lesions in diabetic patients, one study found that 82.1% of this cohort had skin with dryness, cracks, or fissures.¹¹ An unpublished survey of 105 consecutive patients with diabetes conducted by one of the authors revealed that 75% had clinical manifestations of dry skin.

Dry skin often leads to cracks and fissures that can act as portals of entry for bacteria. These cracks and fissures are associated with an increased risk of cellulitis and foot ulceration that, if left unchecked, can eventually lead to amputation.
Xerosis of the feet in diabetic individuals can be controlled with the regimented use of moisturizers.¹¹
Healthcare providers should routinely inspect the feet of diabetic patients and encourage daily moisturization.
Urea has been found to be a potent skin humidifier (by decreasing TEWL) and descaling agent.

Studies of diabetic patients revealed that urea is safe and effective in controlling xerosis of the feet and showed longerlasting effect than other emollient creams.¹¹

Urea cream works as a keratinolytic and helps in the treatment of corns and calluses of the feet.¹³ This can be functionally important as these hyperkeratotic papules can be uncomfortable, and even painful, thereby restricting physical activity in affected individuals.

Top

Conclusion

Eczema is a chronic relapsing dermatitis and, as such, it is
imperative to maintain the hydration and barrier function of the
skin in these patients with daily moisturizer use. Ceramide and
urea-based moisturizers have been shown to be beneficial in
reducing TEWL, improving barrier function, and maintaining
hydration of the stratum corneum layer of the epidermis, and
thus, should be a mainstay of treatment in patients with dry
skin and eczema.

Failure to adequately moisturize the skin
can lead to a flare of symptoms or an increased incidence
of infections. However, adherence to a schedule of regular
moisturizer use is associated with improved patient quality of
life outcomes (e.g., reduced pruritus, improved sleep patterns,
less depression) and a reduction in the severity and frequency
of eczematous flares.¹⁴

References

1. Simpson EL. Curr Med Res Opin 26(3):633-40 (2010 Mar).
2. Leung DYM, et al. Lancet 361(9352):151-60 (2003 Jan).
3. Levy ML. Curr Med Res Opin 23(12):3091-103 (2007 Dec).
4. Ahuja A. South Med J 96(11):1068-72 (2003 Nov).
5. Carbone A, et al. Ann Pharmacother 44(9):1448-58 (2010 Sep).
6. Anderson PC, et al. Curr Opin Pediatr 21(4):486-90 (2009 Aug).
7. Chamlin SL, et al. J Am Acad Dermatol 47(2):198-208 (2002 Aug).
8. Di Nardo A. Acta Derm Venereol 78(1):27-30 (1998 Jan).
9. Madaan A. Drugs Today 44(10):751-5 (2008 Oct).
10. Flynn TC, et al. Clin Dermatol 19(4):387-92 (2001 Jul).
11. Trung H, et al. Ostomy Wound Manage 48(5):30-6 (2002 May).
12. Hindson TC. Arch Dermatol 104(3):284-5 (1971 Sep).
13. Hogan DJ, et al. Corns: treatment and medication. Available at: http://emedicine.medscape.com/article/1089807-treatment. Accessed: September 30, 2010.
14. Loden M. J Eur Acad Dermatol Venereol 19(6):672-88 (2005 Nov).