¹Schulich School of Medicine and Dentistry, Western University, Windsor, ON, Canada
²Department of Health Sciences, Brock University, St. Catharines, ON, Canada
³Windsor Clinical Research Inc, Windsor, ON, Canada

Conflict of interest: Karen Michael, Jaefer Mohaad and Nuha Nasir have no conflicts. Jerry Tan is an advisor, consultant, speaker and/or trialist for Bausch, Cipher, Cutera, Galderma and Sun Pharma.

Funding sources: None.

Abstract: Clindamycin phosphate 1.2%/benzoyl peroxide 3.1%/adapalene 0.15% (IDP-126) is a novel fixed-dose triad gel combination approved by the US FDA October 2023 and by Health Canada August 2024 for the treatment of acne vulgaris in patients aged 12 years and older. IDP-126 was efficacious in moderate to severe acne compared to vehicle and component topical dyads in phase 2 and to vehicle in phase 3 randomized controlled studies. Efficacy outcomes were inflammatory and noninflammatory lesion counts and Evaluator’s Global Severity Score. IDP-126 also had a favorable tolerability and safety profile.

Keywords: acne, topical, triple combination, fixed-dose, clindamycin, adapalene, benzoyl peroxide, treatment, Cabtreo™

Introduction

The pathogenesis of acne involves different mechanisms including follicular proliferation of Cutibacterium acnes (C. acnes), follicular hyperkeratinization, inflammation, and increased sebum production.¹ Current topical medications include retinoids, benzoyl peroxide, antibiotics, azelaic acid, and dapsone – either as monads or dyads. Recently, a novel topical fixed-dose triad, combining clindamycin phosphate 1.2%/benzoyl peroxide (BPO) 3.1%/adapalene 0.15% (IDP-126) has been developed. Herein, we summarize pivotal trials leading to regulatory approval in the US and Canada.

Phase 2 Studies

The phase 2 study, conducted in the US and Canada, was randomized, controlled and double-blinded involving participants 9 years or older with moderate [Evaluator’s Global Severity Score (EGSS) of 3] to severe (EGSS 4) facial acne.² Participants were randomized to one of five different treatment groups for 12 weeks: vehicle, IDP-126 (triple combination), and the following dyad formulations: benzoyl peroxide 3.1%/adapalene 0.15% gel (BPO/ ADAP), clindamycin phosphate 1.2%/benzoyl peroxide 3.1% (CLIN/BPO), or clindamycin phosphate 1.2%/adapalene 0.15% gel (CLIN/ADAP).

Treatment success, defined by achievement of ≥2-grade reduction in EGSS and clear/almost clear (EGSS 0 or 1), was achieved by 52.5% of participants at week 12 with IDP-126. This was significantly greater than the three dyad gels (range 27.8-30.5%; P ≤ 0.001, all) and vehicle (8.1%; P < 0.001). IDP-126 resulted in significant mean reductions in inflammatory (29.9) and noninflammatory lesions (35.5) from baseline to week 12 (P < 0.05, all) compared to all dyad treatments and vehicle (Figure 1). Overall, IDP-126 demonstrated over 70% reductions in both inflammatory and noninflammatory lesions.

Phase 3 Studies

Two identical randomized, double-blind, vehicle-controlled 12-week trials were conducted in subjects aged 9 years and older in moderate to severe acne.³ Participants were randomized to IDP-126 or vehicle gel, at a 2:1 ratio. Co-primary outcomes were ≥2-grade reduction from baseline and achievement of clear/almost clear on EGSS, and changes in inflammatory and noninflammatory lesion counts.

All coprimary efficacy endpoints were achieved in both trials with IDP-126 gel outperforming vehicle at week 12. Significantly greater percentages of participants achieved a 2-grade reduction in EGSS and clear/almost clear at week 12 with IDP-126 vs. vehicle (Study 1: 49.6% vs. 24.9%, P ≤ 0.01; Study 2: 50.5% vs. 20.5%; P ≤ 0.001).

When comparing IDP-126 vs. vehicle at week 12, greater reductions were also observed in inflammatory (Study 1: 27.7% vs. 21.7%, P ≤ 0.01; Study 2: 30.1% vs. 20.8%; P ≤ 0.001) and noninflammatory (Study 1: 35.4% vs. 23.5%, P ≤ 0.01; Study 2: 35.2% vs. 22.0%; P ≤ 0.001) lesion counts (Figure 2). Significant differences in inflammatory and noninflammatory lesion counts with IDP-126 vs. vehicle were noted by week 4 (P < 0.05).

Treatment-emergent adverse events (TEAEs) were observed with greater frequency in the IDP-126 group (Study 1: 24.6% vs. 8.2%; Study 2: 30.0% vs. 8.3%) and considered related in a smaller proportion (Study 1: 18.0% vs. 0%; Study 2: 21.7% vs. 3.3%). These were primarily mild-moderate in severity and attributed to application site pain (Study 1: 10%; Study 2: 15.0%), erythema (Study 1: 4.9%; Study 2: 2.5%), dryness (Study 1: 1.6%; Study 2: 4.2%), irritation (Study 1: 0.8%; Study 2: 3.3%), exfoliation (Study 1: 3.3%; Study 2: 0%) and xerosis (Study 1: 0%; Study 2: 2.5%). Three severe adverse events were reported, all in the IDP-126 cohorts (Study 1: application site burn, n = 1, led to study withdrawal; Study 2: application site pain and dryness, n =1; application site pain, n = 1; related). No serious adverse events were reported.

Network Meta-Analysis

A network meta-analysis compared the relative efficacy of commercially available acne treatments for moderate to severe acne.⁴ Inclusion criteria were randomized controlled trials (RCTs) with minimum duration of 4 weeks involving subjects aged 9 years and older. Notably, isotretinoin studies were excluded from this analysis due to either absence of global assessments in current use for regulatory approval, or non-randomized designs. Primary outcomes evaluated were percentage of patients achieving a ≥2-grade reduction in acne severity, almost clear/clear for global severity score, and changes in inflammatory lesion (IL) counts, and noninflammatory (NIL) counts. Treatments were ranked using surface under cumulative ranking (SUCRA) values. SUCRA scores rank treatments based on their effectiveness across studies, simplifying comparison by assigning higher scores to more consistently effective treatments. The top treatments across these outcomes were: (1) IDP-126, a combination of topical antibiotics/ BPO/retinoids (SUCRA 0.96 for Global Assessment, 0.90 for inflammatory lesions, and 0.91 for noninflammatory lesions), (2) fixed-dose dyad topical treatments with oral antibiotics (SUCRA 0.88, 0.98, and 0.99, respectively), and (3) topical retinoid/ BPO combinations (SUCRA 0.74, 0.79, and 0.79, respectively). These rankings highlight the strong overall performance of these treatment combinations across different acne efficacy outcome measures. In addition to efficacy, IDP-126 showed a favorable safety and tolerability profile with lower discontinuation rates (2.8%). It also had fewer patients with TEAEs than dyads.

Conclusion

The topical fixed-dose triad of clindamycin phosphate 1.2%/BPO 3.1%/adapalene 0.15% gel (IDP-126) represents an effective and well-tolerated novel topical treatment option for moderate to severe acne. In comparison to currently available topical and systemic treatments (except for oral isotretinoin), it ranks within the top three of the most effective treatments for moderate to severe acne.

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Abstract

Background: Skin barrier differences and variations in the presentation of common dermatoses such as xerosis and atopic dermatitis (AD) have been reported in racial/ethnic Canadian patients. This review discusses skin barrier differences and explores the role of ceramide-containing skin care in promoting a healthy skin barrier and mitigating AD.
Methodology: A literature review and panel discussions followed by an online review were used to adopt five statements and recommendations to promote a healthy skin barrier in various racial/ethnic Canadian AD populations.
Results: The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations. Studies comparing ethnic groups have reported variations in transepidermal water loss, skin lipid levels, and stratum corneum pH. However, these studies frequently have flaws. The panel agreed that essential skincare principles apply to all AD-affected patients regardless of racial/ethnic background.
Conclusion: Robust comparative studies are needed to help clinicians to tailor patient education and recommend routine skincare with gentle cleansers and moisturizers containing lipids for AD management regardless of disease severity and prescription treatment.

Acknowledgments: All authors participated in all the steps of the project, selection of the literature, and the review of the manuscript. All authors read and approved the final version of the manuscript.

Disclosures:
The authors disclosed receipt of an unrestricted educational grant from CeraVe Canada for support with the research of this work. The authors also received consultancy fees for their work on this project.

Keywords: Racial/ethnic skin barrier variations, skincare, atopic dermatitis

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Background

Genetic and environmental factors influence the structure and function of the stratum corneum (SC) barrier.¹ Approximately 30% of Canadians are estimated to be part of a fast-growing racial/ethnic population by 2031.² However, morphology and descriptions of dermatoses are based on White patients and the historic assumption that most residents of Canada and the United States are of Northern European descent.²

Differences in the skin barrier properties and function and the presentation of common dermatoses such as xerosis and atopic dermatitis (AD) have been observed in subjects with richly pigmented skin compared to White subjects.^1-6 Several studies have investigated SC differences between racial/ethnic skin, comparing SC properties of self-identified Black, White, and Asian skin.¹ In one such study, White subjects had an intermediate barrier strength as evidenced by tape strippings, and Asians have been demonstrated to require the least number of tape strippings to disrupt the SC barrier.¹ This finding indicates a weaker barrier strength and slower recovery from barrier damage in the Asian population, supporting the observation of sensitive skin seen in Asians.¹

There are significant disparities in the prevalence and treatment of skin conditions across Canadian populations.^2-6 The burden of AD is higher in racial/ethnic populations, and numerous barriers to treatment exist, including systemic and institutional racism, poverty, crowded housing conditions on reserves, access and cost of basic skincare regimens, and clean water access.^2-4 Promoting a healthy skin barrier remains a particular challenge for Indigenous groups, who lack access to appropriate treatments and skincare.^2-6

This review discusses skin barrier differences in various racial/ethnic Canadian populations and explores the role of ceramide-containing skin care in promoting a healthy skin barrier and mitigating AD.

Methods

A group of dermatologists assembled during the Dermatology Update conference on November 13, 2021, in Montreal, Quebec. The panel (advisors) [four Canadian dermatologists and one dermatologist from the US] reviewed skin barrier differences in various racial/ethnic Canadian groups exploring dermatology issues related to skin barrier integrity. Additionally, the advisors determined the relevance of skincare-containing ceramides comprising cleansers and moisturizers for these populations to promote a healthy skin barrier and mitigate AD. Finally, the advisors looked into patient and clinician education tools to promote a healthy skin barrier in various racial/ethnic Canadian populations.

The project used a modified Delphi process comprising face-to-face discussions followed by an online follow-up.^7-9

Literature Review

Structured literature searches on PubMed and Google Scholar as secondary source of the English-language literature (2010 – September 2021) were conducted before the meeting on September 21 and 22, 2021. We searched for guidelines, consensus papers, clinical studies, and reviews describing skin barrier properties in various racial/ethnic Canadian populations and current best-practice in promoting a healthy skin barrier and mitigation of AD using ceramides containing non-prescription skincare cleansers and moisturizers. Excluded were papers with no original data (unless a review article was deemed relevant), or not dealing with racial/ethnic Canadian or skincare, and publication language other than English.

The Nomenclature Used for the Searches

Searches were performed for the main ethnic Canadian groups [Black, White, Asian and Indigenous populations] and ethnic regions in Canada.^2-6 Indigenous is a preferred term within Canadian communities. It is an umbrella term that covers Aboriginal, Metis, and Inuit populations. The publications collected a range of demographic data, including ethnic origin. Demographic factors referred to the quantitative data relating to the study population and its composition, which allowed portions of the population to be broken down into subgroups for closer examination.^2-6 Further searches included associations between these demographic factors and the biophysical nature of racial/ethnic skin, skin care practices, and AD treatment product use.

Search Terms

The searches explored present clinical guidelines, treatment options, and therapeutic approaches addressing racial/ethnic Canadian populations using the following terms:
Racial/ethnic Canadian populations AND AD prone skin, OR Black, White, Asian and Indigenous populations in Canada AND AD, OR racial/ethnic Canadians AND skin barrier physiology OR skin barrier function/dysfunction OR racial/ethnic Canadians AND depletion of stratum corneum lipids, OR racial/ethnic Canadians AND AD prevention, OR racial/ethnic Canadians AND AD treatment, OR Black, White, Asian and Indigenous populations in Canada AND mitigation of AD, OR racial/ethnic Canadian populations with AD/AD prone skin AND skincare, OR Black, White, Asian and Indigenous people in Canada AND cleansers OR moisturizers OR emollients OR ceramides OR ce¬ramide containing skincare OR racial/ethnic Canadian AD populations AND skincare efficacy OR safety OR tolerability OR skin irritation

The searches were performed by a dermatologist and a physician/scientist (reviewers). After selection, the publicatiodns were manually reviewed for additional resources.

Priority was given to studies on SC barrier function and the benefits of skincare using cleansers and moisturizers in racial/ethnic Canadian populations with AD or AD-prone skin.

The searches yielded 248 papers, and after excluding 173 articles [duplicates, poor quality, not about Canadian racial/ethnic AD populations or skincare], 75 remained, comprising 4 epidemiology, 4 quality of life (QoL) studies, 20 guidelines, consensus papers and systematic reviews, 19 reviews, 24 clinical studies, and 4 others.

Role of the Panel

The advisors used the literature review results, clinical experience, and expertise to adopt statements and recommendations. The results were integrated into the summary statements presented and discussed during the face-to-face meeting. For example, in a workshop, advisors divided into three groups to create a final set of summary statements about Canadians’ racial/ethnic differences in SC barrier structure and function and skincare for this population, working with 12 draft messages. The final five statements integrate the combined output from the workshop groups and post-meeting online reviews from individual advisors.

Results

Statement 1: The properties and conditions of the skin vary with body site and can be influenced by factors such as skin type, ethnicity, gender, or lifestyle.
Epidemiological data indicate a higher prevalence and severity of AD in racial/ethnic Canadian populations.^6,10-13

A three months population survey of all children aged 2-12 years in the community in the First Nations reserve of Natuashish, Labrador, Canada, showed that of 182 examined children, 30 (16.5%) mainly (20/30) had moderate to severe AD.⁶ IgE levels in children with and without AD had average values at least ten-fold higher than other populations.⁶

A systematic review and meta-analysis extracted 21 studies [1990 to 2020] from three medical databases [Pubmed, Embase, and Web of Science] to examine the prevalence of AD, clinical manifestation, and risk factors among children and adolescents in the Arctic.¹⁰ The cumulative AD incidence was 23%, and the 1-year prevalence was 19%, with the highest incidence in Arctic Scandinavia, lower Greenland, and Russia.¹⁰ The review indicated that the risk for AD in indigenous children living in rural Arctic areas seems slightly lower.¹⁰ Although the systematic review looked at the Arctic regions and included indigenous peoples, it did not mention Canadians.

A further study [2018] showed an AD prevalence of 20.5%, with the highest prevalence recorded among grade-1 Inuit children at 25%, compared to 15.4% among mixed ethnicity and 14.3% among non-Inuit children.¹¹ The variations in prevalence and risk factors of asthma, allergic rhinitis, and AD among the different ethnicities living in the same subarctic environment may be related to genetic, gene-environment interaction, or lifestyle factors.¹¹

An international study of asthma and allergies using written questionnaires included 8334 adolescents aged 13 to 14 in Vancouver, Saskatoon, Winnipeg, Hamilton, and Halifax, Canada.¹² Although AD was significantly more prevalent in Winnipeg (1.31; 1.01-1.69) and Vancouver (1.28; 1.04-1.58), the highest prevalence rates of allergic rhinoconjunctivitis or AD were not observed in the same regions as the highest prevalence rates of wheezing, suggesting dissimilar risk factors.¹²

A cross-sectional study in Europe and Canada on AD patient-reported burden of disease showed a substantial impact (pruritus, pain, loss of sleep, higher levels of anxiety and depression) which was highest in those with severe AD.¹³

A similar high burden of AD has been shown in studies from other countries.^14-18

Statement 2: The literature suggests racial/ethnic variations in ceramide content, SC structure, and filaggrin mutations. Racial/ethnic differences in barrier structure and function have been observed between Black, White, Asian, and Indigenous populations. Differences in TEWL have also been reported, but data are conflicting, and further research is needed.

The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations.¹⁹ Genetic and immunophenotypic differences between racial/ ethnic AD populations, such as lower rates of filaggrin gene mutations, have been described among Black populations.^20-33 Studies involving small groups of East Asian and African American patients have identified differences in cytokine expression compared to European-American patients.^20-33 A literature review on clinical and molecular features of AD found differences in filaggrin (FLG) loss-of-function mutations across various ethnic groups with AD.²⁹ The authors noted that studies in European American compared to Asian American AD populations have consistently shown a higher prevalence of FLG loss-of-function mutations in up to 50% of European and 27% of Asian American patients, respectively.^29,30 However, the association between FLG loss-of-function mutations and AD development in populations of African descent is unclear, and other genes may be involved in skin barrier dysfunction.³⁰

A higher prevalence and persistence of AD has been noted in African American children and racial/ethnic disparities in health care utilization and access to therapies.^22-30

However, most of the information on racial/ethnic and geographic AD population variations originates from the US and may only be partially applicable to Canadians.

Statement 3: Data on racial/ethnic differences in skin barrier structure and function are limited but suggest variations in some characteristics relevant to skincare.

A healthy skin barrier function depends on the complex interplay among SC pH, desquamation rate, and the appropriate ratio of intrinsic lipids.^37-40 The lipids comprise approximately twenty percent of the volume of the healthy stratum corneum (SC) and are composed of CERs (40–50%), cholesterols (20-33%), and free fatty acids (7–13%).^37-39 Further lipids include cholesterol-3-sulfate (0-7 %) and cholesteryl esters (0-20 %).^37-40

The slightly acidic surface of healthy skin is required to mature and maintain the SC barrier, inhibiting the growth of pathogenic microorganisms.³⁹ Skin acidification plays an important role in SC barrier maturation and the activation of enzymes involved in the extracellular processing of SC lipids.³⁹ The SC pH influences barrier homeostasis, integrity and cohesion, and antimicrobial defense mechanisms.³⁹

It is unclear why specific changes in CER composition do not seem to affect a healthy SC and why deficiency of specific CER species and alterations in fatty acid composition occur in certain skin diseases such as AD.^41-45

There is some evidence that the skin barrier in Black skin contains fewer CERs and that the skin barrier in Asian skin is most vulnerable to disruption.^1,19 A less cohesive skin barrier in Asian skin might help explain differences in trans-epidermal water loss in this population.^1,19 The advisors suggested that studies correlating skin barrier structure to dysfunction in Asian skin (perhaps involving tape stripping) could provide insights. Skin barrier differences (lipids, less cohesive skin barrier) may contribute to ethnic differences in the prevalence of xerosis, pruritus, and AD.

Some individuals with AD may produce inadequate amounts of certain CERs.^31,41-45 Many with AD or AD-prone skin exhibit baseline increases in TEWL even within their unaffected, normal-appearing skin.^31,41-45 Racial and ethnic differences have been reported in the SC barrier function, including CERs content and TEWL.⁴⁵

Conventional moisturizers contain occlusives, humectants, and emulsions.³⁹ Newer classes of moisturizers designed to restore skin barrier defects include distinct ratios of lipids that resemble physiological compositions, such as CERs, cholesterol, and essential fatty acids.^37-40

CER-containing moisturizers were found to benefit AD patients when used as mono, adjunctive, and maintenance treatment.^{19,37-39,46-52} Guidelines, algorithms, and consensus papers agreed that the use of moisturizers that contain lipids, such as CERs (or their precursors) reduces pruritus, helps control xerosis, and improve the dysfunctional skin barrier in AD patients.^34-39,53

Other ingredients in moisturizers (i.e., virgin coconut oil, glycyrrhetinic acid, V. vinifera, shea butter, mineral water and hyaluronic acid) have also been recommended.^54-59

A Canadian study including 47 patients with inflammatory dermatosis, applied thermal water and hyaluronic acid-containing moisturizer for 4 weeks as an adjunct to treatment and found a markedly improved skin condition.⁵⁹

A systematic review of 92 randomized controlled trials on the efficacy and safety of moisturizers for AD showed that those containing a mixture of substances (urea, glycerin or glycyrrhetinic acid, ceramides) seem to have greater effectiveness than basic emollients.⁶²

Additionally, regular moisturizer use improves pruritus frequently caused by AD.⁶³
As the mainstay of treatment, moisturizers should be liberally applied both in AD-prone skin and AD.^{34-39, 53, 60-62} The moisturizer should be used at least twice daily directly after bathing and more frequently during acute flare-ups.^{34-39, 53} Further moisturizers must be suitable for the patient’s skin type, climate, humidity, and environmental conditions.^36-39,53-55

The advisors agreed that focusing too much on minor ethnic variations in the skin barrier of AD-affected patients could interfere with essential skincare principles that apply to all skin types. Instead, concentrating on similarities while acknowledging the differences may be more helpful.

A Canadian algorithm for topical treatment of mild-to-moderate AD for adults and pediatric patients and US guidelines for topical treatment of AD include education and avoiding triggers.^34,35 Routine skincare with gentle cleansers and moisturizers is considered an integral part of AD management regardless of disease severity and prescription treatment (Table 1).^34-38

Table 1: Cleanser and moisturizer use

Statement 4: Skin barrier differences between racial/ethnic populations may contribute to variations in the prevalence and severity of atopic dermatitis, xerosis, and, pruritus. Environmental issues and disparities in access to care may also play a role.

Although some authors reported a direct relationship between the severity of AD and the degree of SC lipid depletion^41-45, the evidence demonstrating an association between CER depletion and AD is inconclusive.¹⁹ Other factors may play a role in SC lipid depletion, and the reduced CER could be an epiphenomenon of AD.¹⁹

Epidemiological data indicate a higher prevalence and severity of AD in racial/ethnic Canadian populations; while studies do not support the assumption that skin barrier differences are a factor.^26-31 It is presumed that the impact of the cold, dry climate throughout parts of Canada may play a role in skin barrier dysfunction amongst these populations at large.

Delays in diagnosis or underestimation of severity may occur in patients with richly pigmented skin due to knowledge gaps in recognizing morphologic features of AD across the spectrum of skin complexions and racial/ethnic populations.^19,64-66 Patients with richly pigmented skin may present with variations in the appearance of erythema (Figure 1). AD lesions may appear reddish-brown, violaceous, gray, or hyperchromic rather than bright red (Figure 2). Perifollicular accentuation, papules, scaling, lichenification, and pigmentary changes may be more prominent (Figure 3 and Figure 4). As a consequence, patients with SOC may present with a more advanced stage of AD severely impacting their QoL.¹⁹

Canadian Indigenous children and young adults continue to face higher rates of health disparities than their non-Indigenous counterparts.² In dermatology, this includes a high burden of AD and secondary skin infections.^2,3 Environmental factors and disparities in access to care could be a particular challenge for Indigenous groups, who frequently lack access to appropriate treatments.^2,3 A systematic review of the pediatric dermatology literature reported on systemic [finances, wait times, geography], sociocultural [culture beliefs and communication], and individual barriers [patient beliefs and health knowledge] to diagnosis, treatment, and maintenance approaches of AD and other skin conditions.⁶⁷ The identified barriers are interesting to explore further in Canadian AD populations. However, further research is needed to obtain insight into any interventions’ impact on overcoming these barriers.

Awareness amongst AD patients and caretakers, specifically Indigenous groups, on the cause of AD, general treatment principles, available treatments and the role of moisturizers, and adherence to moisturizer regimens are inconsistent.⁶⁸

Statement 5: Cultural perceptions of healthy skin impact the choice of skincare.

First Nations people have been using medicinal plants for AD treatment. Natural Indigenous medicinal discoveries [safrole, salicylic acid, and ascorbic acid derived from Sassafras albidum, genus Salix trees, and Sassafras officinale] by the Iroquoian and Algonquian-speaking Peoples of North America for AD and other dermatologic conditions are mentioned in the European literature.⁷¹ Further examples are Western red cedar’s known principal active compound, β-thujaplicin, has shown efficacy in AD.⁷⁰ Another active principal compound (7-hydroxymatairesinol) of White spruce may offer benefits due to its anti-inflammatory activity.⁷⁰ Plants and algae such as hazel may also have benefits; however, studies need to confirm this.⁷¹

The effect of traditional treatments and natural remedies for AD may be of interest in managing racial/ethnic Canadian AD populations.^70,71 However, such AD treatments may result in adverse effects such as postinflammatory hyperpigmentation or keloid scarring at a higher rate than evidence-based treatment.¹⁹

Optimal management of AD is multipronged and includes patient education, prescription treatment, and skincare promoting a healthy skin barrier.^68,72-74

Nurse practitioner or physician assistant interventions may significantly increase correct and frequent moisturizer use, reducing AD.⁷⁶

The choice of skincare should be supported by evidence but is mainly a personal and individual choice.^{34,36-38,61,75}

It is important to note that there are variations in skincare norms across diverse populations; therefore, these cultural variations when providing skincare recommendations need to be considered.¹⁹ Integrating evidence-based recommendations for skin care in a culturally competent manner that aligns with the patient’s norms/preferences is key to successful outcomes across diverse populations.^2,19 More research is needed to guide culturally appropriate recommendations better.

Limitations

A detailed discussion on genetic factors of racial/ethnic Canadian AD populations is outside the scope of the review. There is an overall lack of robust studies focusing on the prevention, treatment, and maintenance of AD in racial/ethnic Canadian AD populations.

Conclusions

The multifactorial pathogenesis of AD includes genetic and environmental factors that may vary among racial/ethnic and geographic populations. Available data suggest that skincare strategies to improve AD patients’ outcomes should consider racial/ethnic differences, integrating recommendations for skin care in a culturally competent manner that aligns with the patient’s norms and preferences. Future robust comparative studies will help clinicians to tailor patient education and recommend routine skincare with gentle cleansers and moisturizers as an integral part of AD management.

¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Windsor Clinical Research, Windsor, ON, Canada
³Western University, Schulich School of Medicine, Windsor, ON, Canada

Conflict of interest:
Cindy Kang and Monica Shah have no conflicts of interest to disclose. Jerry Tan has been a consultant, investigator and/or speaker for Almirall, Bausch, Boots/Walgreens, Cipher, Galderma, L’Oréal, Promius, Sun and Vichy. Disclaimers: This manuscript is an original submission. Views expressed in the submitted article are our own and not official positions of our institutions.

Abstract:
The diagnosis and classification of rosacea has been modified to reflect presenting features. On exclusion of differentials, the diagnosis of rosacea is based on the presence of either (1) phymatous changes, or (2) centrofacial persistent erythema. In their absence, diagnosis can be established by presence of any two of: flushing/transient erythema, papules and pustules, telangiectases, or ocular manifestations. Management of rosacea depends on presenting feature(s), their severity, and impact. General management includes gentle skin care, sun protection, and trigger avoidance. Evidence-based treatment recommendations include topical brimonidine and oxymetazoline for persistent erythema; topical azelaic acid, ivermectin, metronidazole, minocycline and oral doxycycline, tetracycline and isotretinoin for papules and pustules; vascular lasers and light devices for telangiectases; and omega-3 fatty acids and cyclosporine ophthalmic emulsion for ocular rosacea. While surgical or laser therapy can be considered for clinically noninflamed phyma, there are no trials on their utility. Combination therapies include topical brimonidine with topical ivermectin, or topical metronidazole with oral doxycycline. Topical metronidazole, topical ivermectin, and topical azelaic acid are appropriate for maintenance therapy. In conclusion, the updated phenotype approach, based on presenting clinical features, is the foundation for current diagnosis, classification, and treatment of rosacea.

Key Words:
alpha-adrenergic agonist, anti-parasitic, antibiotic, diagnosis, dicarboxylic acid, erythema, laser therapy, management, phenotype approach, phyma, retinoids, rosacea, telangiectasia

Table of Content:

1. Introduction
2. Quality of Evidence
3. Diagnosis
4. Evaluation and Differential Diagnosis
5. Associated Comorbidities
6. Management
7. Conclusion

Introduction

Rosacea is a chronic inflammatory dermatosis affecting the centrofacial region (cheeks, chin, nose, and central forehead), with a prevalence of 5.5% of the adult population.¹ While rosacea has been considered to primarily affect fair-skinned individuals, this may be due to difficulty in detecting facial redness in darker skin types. Nevertheless, rosacea patients of Asian, Hispanic, or African ancestry have been described in literature.² Women are more likely to develop rosacea, however, when present in men, the disease tends to be more severe.³ The typical age of onset is after 30 years old;^4,5 however, ocular rosacea can occur as early as 22 months of age.⁶ Pediatric rosacea is rare and is usually associated with a family history of the condition.^6,7 Ocular manifestations of rosacea occur in more than 50% of rosacea patients.⁸

There are several flare triggers in patients with rosacea including temperature changes, heat, cold, exercise, ultraviolet radiation, spicy food, and alcoholic beverages.⁹ Microbes have also been implicated in the pathophysiology of rosacea, including Demodex species, Bacillus oleronius, Staphylococcus epidermidis, Helicobacter pylori, and Bartonella quintana.¹⁰ The immune system, neurogenic inflammation, and vascular hyperreactivity are central to the pathophysiology of rosacea. Specifically, innate immune system activation via toll-like receptor 2 (TLR2), transient receptor potential (TRP) ion channels, and proinflammatory cytokines contribute to clinical manifestations of rosacea.¹¹

Rosacea has a significant impact on the emotional, social, and occupational wellbeing of affected individuals. Due to the altered facial features characterising this disease, patients with rosacea frequently experience stigmatization. Consequently, they can suffer from depression and anxiety and tend to avoid social situations.¹²

The phenotype approach establishes diagnosis and management based on the presenting features of the individual.¹³ While previously classified according to subtypes, each potentially comprising multiple signs and symptoms, this nomenclature should be abandoned as it limits the ability to study, evaluate, and treat individual features.¹³ The phenotype approach more accurately addresses patient features and can facilitate focused treatment on those of greatest severity and impact.¹³ Thus, this review provides an overview of the updated phenotype approach in the diagnosis and management of rosacea.

Quality of Evidence

The PubMed database was searched for systematic reviews, meta-analyses, and guidelines on the diagnosis, classification, and management of rosacea, with a focus on phenotypes. Key words included “rosacea” and “diagnosis” or “classification” or “management” or “guidelines” or “treatment”. There were no limits on age, sex, or nationality or year of publication. Only studies published in English on human subjects were included.

Diagnosis

The diagnosis of rosacea is clinical and based on specific features according to the ROSacea COnsensus expert panel (ROSCO)¹³ and the National Rosacea Society (NRS).¹⁴ On clinical exclusion of other conditions with similar presenting features, the diagnosis of rosacea is established with either: (1) phymatous changes, or (2) centrofacial persistent erythema (Table 1).^13,15 In their absence, diagnosis can be established by the presence of any two of the following major features: flushing/transient erythema, papules and pustules, telangiectases (Table 1), or ocular rosacea (Table 2).^13,15 Minor features, such as burning, stinging, dry sensation of the skin, or edema are not diagnostic of rosacea (Table 1).¹⁵ The diagnosis of rosacea in darker skin types (Fitzpatrick phototypes V and VI) is difficult as erythema and telangiectasia may not be readily visible, and a high level of suspicion based on minor features is required. A less common variant of rosacea is granulomatous rosacea, with multiple brown, yellow, or red cutaneous papules of uniform size. Occasionally, skin biopsy may be useful for diagnostic support.¹³

Table 1: Descriptions of cutaneous rosacea features by consensus

Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1273.¹⁵

Table 2: Descriptions of ocular rosacea features

Note that these are recommendations rather than consensus due to n = 2. Both ophthalmologists voted ‘Agree’ or ‘Strongly agree’ to the descriptions.
Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1274.¹⁵

Evaluation and Differential Diagnosis

Differential diagnoses of rosacea depend on the clinical feature(s) present (Table 3). Examples include contact dermatitis, photodermatitis, seborrheic dermatitis, and systemic lupus erythromatous for facial erythema; perimenopausal flushing, emotional flushing, carcinoid syndrome, and mastocytosis for flushing; and acne vulgaris and folliculitis for papules and pustules.¹⁶ Exclusion of mimics can be established by taking an adequate history, performing a directed physical evaluation for distinguishing features, and further testing as required.

Table 3: Differential diagnoses of rosacea

Information from Asai et al., 2016,¹⁶ Ogé et al., 2015,¹⁹ Scheinfeld et al., 2010,⁵⁵ and Izikson et al., 2006.⁵⁶

Associated Comorbidities

Associations between rosacea and metabolic, cardiovascular, gastrointestinal (GI), neurologic, and psychiatric diseases have been established (Table 4).¹⁷ Some of these share common innate inflammatory elements with rosacea, such as macrophage and macrophage-derived mediators, reactive oxygen species, matrix metalloproteinases, interleukin-1b (IL-1b), and tumor-necrosis-factor (TNF).¹⁸

Table 4: Rosacea and associated comorbidities

CI = confidence interval, N/A = not available, OR = odds ratio, P = probability

Management

The goals of rosacea treatment are to reduce the severity of features and the frequency and intensity of flares.¹³ General management includes routine skin care: gentle cleansers, moisturizers, sun protection, and avoidance of triggers.^16,19 Specific treatments should be targeted at clinical features (Table 5 on pages 7-8). If multiple features are present, combination treatment should be considered.¹⁶ The phenotype approach allows for such feature-based treatment according to the severity and impact of the presentation.²⁰ An updated systematic review of rosacea treatment based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, is outlined below (Table 5).²¹

Table 5: Treatment recommendations and certainty of evidence

CI = confidence interval, Er:YAG = erbium-doped yttrium aluminium garnet, I2 = heterogeneity, IPL = intense pulsed light, MD = mean difference, MR = modified release, N/A = not available, Nd:YAG = neodymium-doped yttrium aluminum garnet, NNTB = number needed to benefit, NNTH = number needed to harm, PDL = pulsed dye laser, P = probability, RCT = randomized controlled trial, RR = relative risk
Information from van Zuuren et al., 2019.²¹

Flushing/Transient Erythema

No randomized controlled trials available.

Persistent Erythema

Evidence to support the efficacy and safety in transient reduction of persistent erythema was derived from two randomized vehicle-controlled trials for topical brimonidine 0.33% gel²² and topical oxymetazoline 1% cream.^23,24 Quality of evidence for efficacy was reported as high-certainty for brimonidine 0.33% gel and moderate-certainty for oxymetazoline 1% cream.²¹ Adverse event frequency was similar to vehicle for both brimonidine²² (moderate-certainty evidence)²¹ and for oxymetazoline^23,24 (moderate-certainty evidence).²¹ In both, there is ongoing concern about the potential risk of worsening erythema with repeated use.^25,26

Papules and Pustules

Dicarboxylic Acids

Topical azelaic acid 15% foam twice daily is a safe and effective treatment for papules and pustules^27,28 (high-certainty evidence)²¹ with an adverse event frequency similar to vehicle^27,28 (moderate-certainty evidence)²¹ according to two randomized vehicle-controlled trials.^27,28

Another randomized controlled trial showed that azelaic acid 15% gel may be more effective in reducing mean nominal lesion count than metronidazole 0.75% gel²⁹ (moderate-certainty evidence).²¹ These differences, however, were not reproducible and were considered to be unimportant.^30,31

Antiparasitics

Topical ivermectin 1% cream once daily is more effective in the treatment of papules and pustules compared to vehicle³² (high-certainty evidence),²¹ and compared to metronidazole 0.75% cream twice daily³³ (moderate-certainty evidence).²¹ Adverse event rates for topical ivermectin were similar compared to vehicle³² (moderate-certainty evidence)²¹ and topical metronidazole.³³

Retinoids

In two randomized controlled trials, low-dose oral isotretinoin 0.25 mg/kg and low-dose oral isotretinoin 0.30 mg/kg were more effective than placebo³⁴ (high-certainty evidence)²¹ and oral doxycycline (100 mg for 14 days, then tapered to 50 mg)³⁵ (moderate-certainty evidence),²¹ respectively. The frequency of adverse events was higher for isotretinoin compared to placebo³⁴ (moderate-certainty evidence),²¹ but similar to oral doxycycline³⁵ (moderate-certainty evidence).²¹

Antibiotics

Several randomized vehicle- or placebo-controlled trials demonstrated the efficacy of topical metronidazole 1% cream,^36-38 topical minocycline 1.5% and 3% foam,³⁹ oral doxycycline 40 mg modified-release (MR),⁴⁰ and oral tetracycline 250 mg twice daily^41,42 in the treatment of papules and pustules. The quality of evidence for efficacy was moderate-certainty for the first three treatments, but low-certainty for oral tetracycline.²¹ Adverse event frequency was similar to vehicle/placebo for topical metronidazole^36-38 (moderate-certainty evidence),²¹ oral doxycycline,⁴⁰ and oral tetracycline,^41,42 but higher than vehicle for topical minocycline39 (moderate-certainty evidence).²¹ Topical clindamycin 1% cream or gel was found to be no more effective than vehicle for any outcome⁴³ (low-to-moderate certainty evidence).²¹ Compared to oral doxycycline 40 mg MR, oral minocycline 100 mg is similarly effective⁴⁴ (moderate-certainty evidence)²¹ with no differences in the rate of adverse events⁴⁴ (low-certainty evidence).²¹ Compared to oral doxycycline 100 mg, oral azithromycin 500 mg three times a week then tapered is similarly effective in reducing lesion counts⁴⁵ (very low-certainty evidence).²¹ Finally, 40 mg MR doxycycline is as effective as 100 mg with fewer side effects.⁴⁶

Telangiectases

There is low-to-moderate certainty evidence that long pulsed dye laser (PDL), neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and intense pulsed light (IPL) therapy reduce telangiectasia.²¹

Clinically Non-inflamed Phyma

Physical modalities, such as ablative laser surgery using carbon dioxide or erbium-doped yttrium aluminium garnet (Er:YAG) modalities, electrosurgery, or cryosurgery, may improve clinically noninflamed phyma.¹⁶ However, it is difficult to determine their effectiveness due to the lack of evaluation by randomized controlled trials.^16,21

Clinically Inflamed Phyma

While there are no randomized controlled trials evaluating the efficacy of treatments for clinically inflamed phyma, oral doxycycline or oral isotretinoin are still recommended.^16,21

Ocular Rosacea

One randomized placebo-controlled trial supported omega-3 fatty acids (180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid) one capsule twice daily⁴⁷ (moderate-certainty evidence)²¹ in the treatment of ocular rosacea. Another randomized controlled trial supported cyclosporine ophthalmic emulsion 0.05% twice daily versus artificial tears⁴⁸ (low-certainty evidence)²¹ and versus oral doxycycline 100 mg twice daily for the first month followed by 2 months once daily⁴⁹ (low-certainty evidence).²¹ For the cyclosporine ophthalmic emulsion, there were no differences in the rate of adverse events compared to artificial tears (low-certainty evidence).²¹ For severe ocular rosacea or when there is diagnostic uncertainty, referral to an ophthalmologist should be arranged.²¹

Combination Therapies

Treatment combinations may address several different clinical features of rosacea. For example, compared to vehicle, topical brimonidine 0.33% gel with topical ivermectin 1% cream can effectively reduce both erythema and papules and pustules.⁵⁰ Compared to metronidazole 1% gel alone, metronidazole 1% gel with oral doxycycline 40 mg MR can reduce lesion counts to a greater extent.⁵¹

Finally, randomized controlled trials reported no difference in efficacy between oral minocycline 45 mg with or without topical azelaic acid 15% gel⁵² (moderate-certainty evidence)²¹ or between topical clindamycin phosphate 1.2% with tretinoin 0.025% gel compared to placebo⁵³ (moderate-certainty evidence).²¹ However, in the latter, there was a higher rate of adverse events in the topical clindamycin/tretinoin group compared to placebo (moderate-certainty evidence).²¹

Maintenance Therapies

Topical metronidazole 0.75% gel, ivermectin 1% cream, and azelaic acid 15% gel are reported as effective and safe for maintenance therapy of papules and pustules.^21,54

Conclusion

The diagnosis and classification of rosacea has evolved to a phenotype approach to accurately address the clinical features presenting in an individual and to advance epidemiological and clinical trials research.¹³ This review details the rosacea phenotype approach to diagnosis and classification, and summarizes current evidence-based treatment recommendations for individual features. There is no singularly effective treatment for all features of rosacea. There is an unmet need for high quality investigations for treatment of inflamed phyma, flushing/transient erythema, and ocular rosacea.

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¹Windsor Clinical Research Inc., Windsor, ON, Canada
²Schulich School of Medicine and Dentistry, Western University, Windsor Campus, ON, Canada

Conflict of interest:
Jerry Tan has served as an advisor, consultant, investigator and speaker for Galderma. Maegan Miklas has no conflicts to declare.

Abstract:
Trifarotene 50 μg/g cream is a fourth generation topical retinoid with retinoic acid receptor gamma selectivity. It was recently approved by the US FDA and Health Canada for the topical treatment of facial and truncal acne for those aged 9 and older based on two identically designed phase 3 trials demonstrating superiority in lesion count reduction and global acne improvement compared to vehicle. These studies and a 1 year study also demonstrated safety and tolerability with cutaneous adverse events developing in an anticipated timeframe (1 week) for the face. These were of lesser degree and tended to develop later at the trunk. Future studies will be required to evaluate the comparative efficacy of trifarotene 50 μg/g cream against other treatments for acne.

Key Words:
acne, facial, retinoid, topical, trifarotene, truncal

Background

Topical retinoids serve as cornerstone therapy for acne with efficacy demonstrated across the spectrum of acne severity. Retinoids are classified by their common biological pathway, where the molecules themselves or their metabolites bind to a retinoid receptor: either retinoic acid receptors (RARs) or retinoid X receptors (RXRs), both of which have three subtypes: alpha, beta, and gamma.¹ Since tretinoin, subsequent generations of topical retinoids, determined by structural modifications, have sought to either increase efficacy, improve tolerability, or both.² Trifarotene (chemical name 4-[3-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-4-(2-hydroxyethoxy)phenyl]benzoic acid; C29H33NO4) is a fourth generation retinoid with higher selectivity and agonist activity for RAR gamma (RARγ), the most abundant subtype in skin.^3,4 The selectivity of trifarotene for RARγ differentiates it from the existing first- and third-generation topical retinoids, which target both RARβ and RARγ.⁴ Trifarotene is pharmacokinetically stable in keratinocytes but quickly metabolized in hepatic microsomes, indicating a favorable safety profile. In addition, it has comedolytic, anti-inflammatory, and antipigmenting properties.^4,5 In this paper, we review the efficacy, safety, and tolerability of trifarotene 50 μg/g cream, a novel topical retinoid recently approved by the US FDA and Health Canada for the topical treatment of facial and truncal acne.⁶

Clinical Trials in Acne

The efficacy, safety, and tolerability of Trifarotene 50 μg/g cream was assessed in two large identically designed randomized, double-blind, vehicle-controlled trials of 12-week duration (PERFECT 1 and PERFECT 2 ClinicalTrials.gov: NCT02566369 and NCT02556788).⁵ Subjects aged 9 years and older with moderate acne vulgaris of the face and trunk were enrolled. Evaluation of acne at the trunk was a unique feature of these trials and required appropriate delineation of truncal sites that could be amenable to self application, repeatable evaluation, and modesty as recruitment would involve males and females. A special T-shirt, with cutouts at the décolletage and upper back, was developed to outline the appropriate regions to fulfill the prior enrollment criteria.

Primary efficacy endpoints for facial acne were based on a composite of global success and absolute change in inflammatory and noninflammatory lesion counts. Secondary efficacy endpoints were for truncal acne and based on corresponding measures. Global success required achievement of clear or almost clear, and at least a 2-grade improvement from baseline of moderate or severe over the course of the 12-week studies (global grading was on a 5 category scale of none, almost clear, mild, moderate, and severe). Standard safety and tolerability assessments were undertaken.

A total of 2420 subjects were randomized 1:1 (1214 to trifarotene 50 μg/g versus 1206 to vehicle) in the two studies with a mean age of 20 years, slight predominance of females, and mainly phototypes II-III. Almost 90% of subjects were white with lesser proportions of black/African-Americans, Asians and others.

Onset of effect, such as reduction in inflammatory and noninflammatory lesions, were seen as early as week 1 for the face and week 2 for the trunk.⁵ The proportion of subjects achieving facial global success was significantly in favor of trifarotene for both studies, with a treatment difference at week 12 of 9.9% for study 1 and 16.6% for study 2 (p<0.001 for both). Reduction of facial acne lesion count was also in favor of trifarotene in inflammatory and noninflammatory lesion counts in both studies. For inflammatory counts, the difference from baseline to end of study between arms was -3.6 in study 1 and -5.5 in study 2 (p < 0.001 for both). For noninflammatory counts, the corresponding results were -7.1 and -8.5 (p < 0.001 for both).

The proportion of subjects achieving truncal global success was also significantly in favor of trifarotene for both studies with a treatment difference at week 12 of 10.7% for study 1 and 12.7% for study 2 (p<0.001 for both). Truncal acne lesion count reduction was also in favor of trifarotene in inflammatory and noninflammatory lesion counts in both studies. For inflammatory counts, the difference from baseline to end of study between arms was -2.6 in study 1 and -5.7 in study 2 (p<0.001 for both). For noninflammatory counts, the corresponding results were -4.1 and -5.1 (p<0.001 for both).

Cutaneous tolerability assessments showed greater levels of erythema, scaling, dryness, and stinging/burning compared to vehicle, which tended to peak at week 1 for the face and week 2 for the trunk. Mean levels for these parameters were mild or less for the face and trunk.

Overall, truncal mean scores for intolerability were less compared with the face. The proportion discontinuing treatment due to adverse events in the trifarotene arms was 1.5%.

In a 52-week open-label study involving 453 patients with moderate acne on the face and trunk, 13% experienced cutaneous adverse events related to trifarotene 50 μg/g cream.⁷ The majority of these adverse effects developed in the first 3 months of treatment, were mainly of mild severity and reported as itching (4.6%), irritation (4.2%), and sunburn (1.8%). Severe related adverse events occurred in three different patients and were reported as irritation, pruritus, and erythema. Local intolerability scores (related to erythema, dryness, scaling, stinging/burning) trended higher for facial compared to truncal sites of application. Maximum scores for facial involvement tended to be within the first week compared to trunk, which occurred more frequently in weeks 2-4. Overall, 2.9% of subjects discontinued due to related emergent adverse events. Global success at end of study was 65% for facial and 67% for truncal acne.

Conclusion

In two large randomized vehicle-controlled 12-week trials and in a 52-week open label study of moderate-to-severe acne at the face and trunk in subjects aged 9 years and older, trifarotene 50 μg/g cream demonstrated efficacy, safety, and cutaneous tolerability. As expected with topical retinoids, cutaneous adverse events developed with trifarotene use in an anticipated time for the face. At the trunk, these adverse reactions were of a lesser degree and tended to develop later. Future studies will be required to evaluate the comparative efficacy of this novel agent against current topical incumbents in the treatment of acne.

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Faculty of Medicine, Western University, London, ON, Canada

Introduction

Interventions to reduce atrophic acne scarring can be conceived in 3 dimensions: prevention of acne, early/aggressive treatment of acne, and correction of existing acne scars. Newly developed atrophic acne scars from primary acne lesions are not always permanent. Up to ⅓ can spontaneously resolve within 6 months. The evolution to persistence or resolution is due to a balance between matrix degradation and repair mechanisms. A recent study with a fixed dose combination adapalene 0.3%/BPO 2.5% (Tactupump ForteTM; Galderma) provides evidence for efficacy in both acne as well as mitigation of ongoing scar formation and enhancement of scar resolution. The mechanism of the latter effect may be due to enhanced collagen deposition due to the topical retinoid component, adapalene. The added benefit of this option in preparation for scar repair procedures is worthy of future research.

Acne and Acne Scarring

• Acne scarring is a direct consequence of acne and can lead to adverse physical, social and psychological impact. These include embarrassment, negative self-perception, anxiety and depression.¹
• Acne scarring can also lead to stigmatization as those with scars are perceived to be shyer and more stressed; less healthy, physically skilled; and more likely to make others feel uncomfortable.²
• Acne scars are changes in skin texture and volume resulting from primary acne lesions. Initiating lesions are primarily inflammatory papules/pustules and nodules. Scars do not refer to changes solely in skin color such as redness or brown discoloration in the absence of volume changes.
• Acne scarring is observed across the spectrum of severity, even in those with milder grades of acne. Those at higher risk of developing atrophic acne scars include severe and very severe acne presentations, with a prolonged duration of acne, family history of scarring and history of squeezing and manipulation of acne lesions.³

Natural Evolution

• Atrophic acne scars develop directly from inflammatory papules or from a transitional state of macular discoloration from inflammatory papules.
• In a non-interventional observational study, of scars developing within a 6-month observation period, ⅓ spontaneously resolved.⁴
• Those at higher risk of acne scarring have a more intense early innate immune response and a prolonged adaptive response leading to greater inflammatory intensity and duration.^5,6
• Acne scar resolution or persistence is likely due to relative contributions by matrix degradation (matrix metalloprotease activation versus tissue inhibitors of matrix metalloproteases) and repair (platelet derived growth factor, transforming growth factor beta) mechanisms.

Types

• Acne scars can be due to volume loss or gain:
  • Volume loss can occur at the epidermis (sometimes termed macular atrophy) or dermis (atrophic scars);
  • Volume gain can be within the perimeter of the initiating injury (hypertrophic scar) or beyond (keloidal).
• Most acne scars are atrophic (Figure 1).⁷

Severity Grading

• Scales in frequent use include global grading measures for severity determination and for guidance in scar repair options.
• A morphological scale for acne scars with relevance to repair methods is based on presumed cross-sectional features of atrophic acne scars. These are categorized as ice-pick, boxcar and rolling.⁸
• A global assessment measure based on involved extent of atrophic acne scars termed SCAR-S, can be applied to each of the face, chest and back.

  • Grades and descriptive text range from clear (no visible scars), almost clear (hardly visible scars from 2.5 m), mild (easily recognizable with less than half the affected area involved), moderate (more than half the affected area involved), severe (entire area involved) and very severe (entire area with prominent atrophic or hypertrophic scars).⁹

Prevalence

• In acne patients, readily discernible acne scars are observed on the face, back and chest in 55%, 24% and 14% respectively.⁹
• Atrophic acne scars are observed across the spectrum of acne severity at time of presentation. Scar prevalence increased with acne severity whereby scarring was observed in 28% with minimal/mild acne, 51% in moderate and 77% in severe acne.¹⁰
• The prevalence and severity of scarring increases with duration of acne such that acne scar severity scores peak at approximately 3 years.^11,12

Management

Atrophic acne scar management can be divided into prevention, mitigation and correction.

1. Prevention of acne will negate acne scar development

   • Genetic and environmental factors are important in acne development.
     • Ongoing topics of debate include avoidance of high glycemic index diets and dairy products.

• • However, there are no studies evaluating prevention of acne.

1. Timely and effective therapy of acne can mitigate increased acne scarring risk

   • Acne clinical practice guidelines can provide guidance on appropriate therapy based on severity.
   • Topical retinoids and BPO are important options in all acne severities except for those with nodulocystic presentations.
   • The fixed dose combination of adapalene and benzoyl peroxide is a rational combination for treatment of mild – moderate acne (adapalene 0.1%/BPO 2.5%,

     TactuPump) and moderate-severe acne (adapalene 0.3%/BPO 2.5%, TactuPump FORTE).

     • Adapalene is a retinoid with anti-inflammatory, anti-comedogenic, and comedolytic activity.
     • BPO is an antimicrobial with anti-inflammatory and comedolytic properties but no risk of inducing antibiotic resistance.
   • In a 12 week RCT of moderate and severe acne, adapalene 0.3%/BPO 2.5% was threefold more effective than vehicle in acne lesion reduction and achieving overall grade of clear/almost clear (34% vs 11%).¹³
     • Tolerability profile of adapalene 0.3%/BPO 2.5% was comparable to adapalene 0.1%/BPO 2.5% with mean scores of less than mild at all study visits and with reports of skin irritation in 4%.
   • In a 24 week split face RCT of moderate acne, adapalene 0.3%/BPO 2.5% (TactuPump FORTE) was more effective than vehicle in reducing acne (threefold greater proportions achieving clear/almost clear on a 5 category global grading scale of clear, almost clear, mild, moderate and severe) and in reducing risk of acne scars with approximately 30% difference in numbers of scars (from baseline, percentage of scars increased with vehicle by 14% but decreased with adapalene 0.3%/BPO 2.5% by 15%).¹⁴
   • In a 24 week open label study of adapalene 0.3% twice daily in moderate to severe facial atrophic acne scars improvement in acne scars was observed in at least 50% of patients. Immunohistochemistry studies of treated skin demonstrated increased procollagen-1 and collagen-3 levels.¹⁵

1. With extant acne scars, corrective procedures are available

• Scar correction procedures depend on the type and extent of acne scars. Ice-pick scars are primarily addressed by TCA cross technique, punch excision/elevation; boxcars scars by resurfacing with mechanical, chemical, laser (including fractionated ablative and non-ablative) means, microneedling techniques with or without radiofrequency; and rolling scars by filler elevation and possible subcision.
• As most patients present with multiple atrophic acne scar types, combination therapy is typically required.
• These procedures are often costly, discomforting and incompletely effective.  Furthermore, there is little high-quality evidence to help direct patients and providers to best corrective options. More evidence-based research is an unmet need in this context.

For keloidal and hypertrophic acne scars

• Consider conservative monitoring or silicone gel applications as some will resolve with time.
• Alternate options include intralesional steroid injections, topical imiquimod, pulse dye laser, and cryotherapy.¹⁶

Conclusion

There have been important advances in our understanding of acne scarring. Specifically, acne scars affect a large proportion of people with acne. Acne scars can resolve, and their evolution is determined by a balance between matrix repair and degradation. Timely, effective management of acne can minimize risk of subsequent acne scarring. The use of a combined topical retinoid and BPO product has been shown to be efficacious in mild – moderate acne (adapalene 0.1%/BPO 2.5%, TactuPump) and moderate-severe acne (adapalene 0.3%/BPO 2.5%, TactuPump FORTE). The latter has also been shown to mitigate further development of acne scars and may enhance scar repair. This is likely due to the effect of adapalene enhancing dermal deposition of collagen. Further advances in understanding the mechanisms underlying acne scarring will lead to further therapeutic options for this prevalent and consequential sequela of acne.

¹Associate Professor, University of Toronto, Toronto, ON, Canada
²University of Western Ontario, Windsor, ON, Canada
³Clinical Instructor, University of British Columbia, Vancouver, BC, Canada
⁴Dermatologist, Calgary, AB, Canada
⁵Dermatologist, Montreal, QC, Canada
⁶Dermatologist, Quebec City, QC, Canada
⁷Dermatologist, West Vancouver, BC, Canada
⁸Clinical Associate Professor, University of Calgary, Calgary, AB, Canada
⁹UMC St Radboud, Nijmegen, The Netherlands

Conflicts of interest: The consensus meeting was supported by an educational grant from Aspri Canada. All authors of this article participated in the meeting.

Introduction

Acne is the most common disorder encountered in dermatologic practice¹, and can have a highly significant negative impact on quality of life. Our evolving understanding of the role of hormones in acne, along with a growing body of data from clinical trials, calls for a reappraisal of the role of hormonal therapy for acne.

Epidemiology and Impact

• 85% of 15 to 17-year-olds have acne¹
• 45% of women aged 21-30 years²
• 26% of women aged 31-40 years²
• 12% of women aged 41-50 years²
• Acne is associated with mood symptoms.
  • Suicidal ideation is two times more common with substantial acne versus little to no acne in girls, and three times in boys.³
  • Degree of distress and psychologic harm caused by acne does not always correlate with clinical severity.⁴

Role of Androgens in Acne

• Adrenarche
  • ~Age 8 or 9 years adrenal gland starts to produce large quantities of dehydroepiandrosterone (DHEA) sulfate⁵ ➝ increased sebum, abnormal keratinization of the follicular epithelium.¹
• Androgens
  • Produced by: adrenal glands, gonads, and sebaceous glands in the skin.⁶
  • Sebocytes, sweat glands and dermal papilla cells convert circulating DHEA and androstenedione to more potent steroids
  • DHEA ➝ testosterone ➝ dihydrotestosterone (DHT) by 5α reductase.⁶
  • Sebum production ➝ comedone formation & provides a growth medium for P. acnes.⁶
  • Women with excessive levels of androgens, as in polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia, are more likely to develop acne.^1,2
  • Most people with acne have androgen levels within normal limits. In these patients, increased sensitivity of sebaceous glands to androgens may account for the development of acne.⁶

Hormonal Therapy

• Aim is to reduce androgen action on cutaneous pilosebaceous units in women with elevated and normal androgen levels.⁷
• First-line option in women with hyperandrogenism.⁸
• Among women with normal androgen levels, hormonal therapy is usually reserved for those who are not trying to conceive and cannot be effectively managed with topical therapy
• May be particularly effective in adult women with inflammatory acne that involves the lower face and neck.⁷
• Can also be considered in women whose acne appears linked to their menstrual cycle (e.g., premenstrual flares).^7,8

Role of Spironolactone in Acne Treatment

• Despite lack of high grade evidence for efficacy, spironolactone is a frequently recommended option in the management of acne in women.
• Competitive androgen receptor blocker.⁷
• May also inhibit 5-alpha-reductase and increase steroid hormone binding globulin.⁷
• 50 to 200 mg taken with meals ➝ decrease sebum excretion by 30 to 50%.⁹
• Can be used as monotherapy in adult women with cyclic or late onset acne or in combination with other topical and oral agents.¹⁰
• Has been prescribed in doses of up to 200 mg/day, but clinical improvement may occur with doses as low as 25 mg/day, and most physicians do not recommend above 100mg/day.¹¹
• Therapy may be started with a lower dose with subsequent upward titration.¹⁰
• Although a 2009 Cochrane review found insufficient evidence to establish the efficacy of spironolactone¹², several low quality studies have reported a clinically significant benefit, with reductions in lesions from 50 to 100%.⁹
• Data for truncal acne as well as facial acne.¹⁰
• Spironolactone and Diane-35 have both shown similar efficacy in improving acne in women with PCOS.¹³

Side Effects of Spironolactone

• Generally, well tolerated and the side effects are dose-related with lesser frequency at doses ≤100 mg/day.^12,14
• Side effects include: menstrual irregularities, breast tenderness, minor gastrointestinal symptoms, orthostatic hypotension, headaches, dizziness, and fatigue.
• Potassium-sparing diuretic thus hyperkalemia is a potentially serious adverse effect. But most likely to occur at high doses and in patients with renal insufficiency or severe heart failure.¹⁵
• Educate about avoiding foods that are high in dietary potassium (ex. low-sodium processed foods and coconut water). However, testing for potassium in young and healthy women taking spironolactone for acne is unnecessary.¹⁵
• Concern over induction of estrogen-dependent malignancies raised over the years.
  • No definitive evidence linking human breast or other estrogen-dependent tumors to the use of spironolactone exists.^10,16
  • Unclear whether there is increased risk for women with a personal or family history of breast or other estrogen-dependent malignancies.¹⁶
• Co-administration of spironolactone with an oral contraceptive is advised because of serious fetal effect (feminization of the male fetus), along with the menstrual irregularities that may occur during treatment.¹⁷

Role of Oral Contraceptives in Treatment of Acne

Oral Contraceptives (OGs)

• Reduce acne lesions by increasing estrogen levels and decreasing free testosterone and androgen levels.⁷
• Estrogens in OCs inhibits androgen production by the ovaries and possibly the sebaceous glands.¹¹
• Progestins in OCs may have androgenic properties (which are counteracted by the anti-androgenic properties of the estrogen component) or anti-androgenic properties.¹⁷
• OCs indicated for acne are effective across the spectrum of disease severity.¹⁸
• In Canada, 4 OCs (Alesse/Alysena, Diane 35/Cleo 35, Yaz/Yasmine and Tri-cyclen) are indicated for the treatment of acne. These agents all contain estrogen, and progestins with either minimal androgenicity or with anti-androgenic potential.¹⁸
• OCs^18,19 may play a role:
  • Mild acne – adjunct to topical therapy for female patients desiring contraception.
  • Moderate acne – form of systemic therapy.
  • Severe acne – primary form of therapy or form of contraception in women treated with systemic isotretinoin.
• Clinical trials have consistently supported the efficacy of OCs for acne.
• Cochrane review of 31 trials of combined oral contraceptives (COCs) for acne with a total of 12,579 participants.
  • 9 placebo-controlled trials with suitable data for analysis, COCs reduced acne severity and lesion counts in all trials vs. placebo.²⁰
  • Some differences²⁰ in the comparative effectiveness of COCs containing varying progestin types and dosages were observed, but they were not pronounced and data for each comparison were limited:
  • OCs that contained cyproterone acetate (examples – Diane 35/ Cleo 35) improved acne to a greater degree than levonorgestrel (example – Alesse/Alysena), although this apparent advantage was based on limited data.²⁰
  • Levonorgestrel (example Alesse/Alysena) showed a slight improvement over desogestrel (example Marvelon) in acne outcomes, but results were not consistent.²⁰
  • A drospirenone (example Yaz/Yasmine) COC appeared to be more effective than norgestimate (example Tri-cyclen) or nomegestrol acetate plus 17β-estradiol, but less effective than cyproterone acetate (examples Diane 35/Cleo 35).
• Oral contraceptive versus other treatments
  • Review of 32 randomized controlled trials of OCs and antibiotics
    • Antibiotics superior after 3 months of treatment,
    • OCs and antibiotics had equivalent efficacy at 6 months.²¹
    • At 6-month oral antibiotics and OCs reduced acne lesions by an average of 52.8% and 55% respectively.²¹
  • If considering long-term therapy (over 6 months) it may be more reasonable use OC rather than antibiotics due to emergence of antibiotic resistance.

Side Effects of Oral Contraceptives

• Main adverse events to consider when selecting hormonal treatments: cardiovascular disease, stroke, breast cancer, pulmonary emboli, deep vein thrombosis, arterial thrombosis and abnormal vaginal bleeding.²¹
• Decreased risk of ovarian cancer after five years of use, but there has been concern about the possible association between oral contraceptive use and the risk of breast cancer.²² The net effect of COC use may well be positive (i.e., slight increase in life expectancy).²³
• A safety review of drospirenone-containing oral contraceptives (example Yaz/Yasmin) in 2011 determined they may be associated with a 1.5-to-3 per 10 000 patients per year risk of blood clots versus 1 per 10 000 patients per year in Levonorgestrel containing pills (example Alesse).²⁴
• Similar review of cyproterone acetate/ethinyl estradiol-containing OCs (Diane 35/Cleo 35) was completed in 2014. The review, concluded that the risk of blood clots from these COCs in people without additional risk factors (e.g., obesity, smoking, decreased mobility) is very low and that these agents have a favourable benefit/risk profile when used as prescribed.²⁵

Case-based Treatment Approaches

Rationale

• A case-based approach may facilitate a treatment selection process that reflects real-world scenarios and patient-specific challenges.

Approach

• A panel of 8 dermatologists was convened for a meeting on May 2, 2015 in Toronto, to discuss, refine and select patient profiles compatible with hormonal therapy for acne. Draft cases were developed by the group prior to the meeting.
• The panel developed 5 case in which hormonal therapy can be considered. The cases were selected to cover a spectrum of real-world acne presentations compatible with the use of hormonal therapy.

Case 1: 34-year-old female with facial acne that varies with menstrual cycle
	Her acne is present since adolescence, is mainly inflammatory and often located along the jawline, chin and periorally. She is otherwise healthy and has normal menses. She reports that her acne significantly interferes with her quality of life. Previous topical acne therapy caused dryness, peeling, and irritation. She failed a trial of oral antibiotics. To the best of her recollection, past use of OCs (for contraception) did not significantly improve her acne.
Discussion Negative experience with topical therapy consider systemic therapy. Her acne appears to have a hormonal component. Has used OCs in the past for contraception rather than acne, the lack of observed improvement in her acne argues against OC monotherapy as a first choice. Thus, spironolactone10-12 seems a reasonable option to consider, either alone or in combination with OCs.13
Case 2: 17-year-old female presents with sensitive skin, moderate-to-severe acne and potential sexual activity
	She first developed acne at the beginning of puberty, and it has since progressively worsened. She has tried many topical treatments, which yielded generally poor results and caused dryness and irritation on her face. A light smoker for the past 2 years, she reports that she is not yet sexually active but has a steady boyfriend. She has no signs of elevated androgen levels, but has bothersome skin oiliness. She and her parents are opposed to using antibiotics, and her mother is concerned that using OCs could promote sexual activity.
	Discussion Adolescent acne tending toward the severe end of the spectrum – had not responded to topical treatment and scarring is a concern thus systemic therapy seems appropriate in this case.19 Options include OCs18,20, spironolactone10,18, isotretinoin26 and antibiotics.19 OCs could be considered as a first-line option18,20, with the addition of isotretinoin if response is suboptimal.13
Case 3: 30-year-old sexually active female with severe truncal-predominant acne located mainly on the upper back
	She has no signs of hyperandrogenism. Certain fabrics irritate her back, and application of topical treatments on this area has proven challenging. For this reason, she finds topical products inconvenient. She has tried oral antibiotics in the past, and they only worked while she was taking the medication. She had a similar experience with isotretinoin, which she does not want to try again. She quit smoking 2 years ago after smoking for 11 years. She lives alone and is occasionally sexually active.
Discussion All systemic therapies (OCs, spironolactone, isotretinoin, antibiotics) can be considered.19,26,27 Because of the patient’s time-limited response to prior oral antibiotic therapy, this option should be kept in reserve in case the other options prove unsatisfactory.19 OCs are effective in truncal acne and provide added benefit of birth control.18 PCOS should be addressed by appropriate evaluations. BPO wash can be considered concomitantly.19
Case 4: 34-year-old female with multisite acne of variable severity and features consistent with PCOS
	She was diagnosed with type 2 diabetes a year ago and is currently taking metformin. She has Class I obesity (BMI 30.9). Upon questioning, she states that her periods have always been irregular and also has excessive facial hair that requires her to shave every few days. She also has a lot of hair on her abdomen and arms. She mentions that her mother is similarly hirsute. Her voice is lower than average, but within the normal female range. Upon testing, the patient’s follicle-stimulating-hormone (FSH) levels are normal, but her luteinizing hormone (LH) levels are elevated. Her fasting insulin levels were also high. Other lab results are normal, and pelvic ultrasound results are equivocal, with “possible” signs of polycystic ovaries. Overall, these results are consistent with PCOS.
Discussion Would benefit from OCs26, 27 or spironolactone.10 Target the hormonal abnormalities underlying acne and provide other benefits such as diminution of hirsutism and regularization of menses.16
Case 5: 32-year-old female with skin of colour and moderate-to-severe acne including some painful lesions, scarring and PIH
	She has some scarring and post-inflammatory hyperpigmentation (PIH). Previous acne therapy has resulted in dryness, peeling and irritation. She in a long-term relationship, has two children, and is not currently trying to conceive.
Discussion Would benefit from OCs26, 27 or spironolactone.10 Target the hormonal abnormalities underlying acne and provide other benefits such as diminution of hirsutism and regularization of menses.16

Adherence

• Adherence to topical agents is related to duration of treatment, complexity of the treatment regimen, as well as therapy cost, patient self-image and QoL.^8,35
• Demands associated with disease management can create a significant treatment burden for patients with chronic diseases. This burden combined with general life demands (e.g., job, family) comprises the overall patient workload.
• Treatment fatigue is common, with disengagement from recommended health behaviors when a person’s workload exceeds their capacity, a primary contributing factor to non-adherence.³⁶
• When considering cost of therapy, it is important to remember both direct (e.g., prescription drug costs, physician visits, treatment in day clinics) and indirect costs (e.g., loss of time from work, loss of income, non-prescription drug costs). These costs are likely exacerbated by non-adherence to medication. In psoriasis particularly, QoL is adversely affected with people coping by avoiding social situations and covering their lesions.⁸
• With topical dermatologic products, studies suggest that patients prefer, and are more adherent to, certain topical vehicles based on convenience and cosmetic acceptability.³⁷

Conclusion

• In appropriately selected patients, hormonal therapy provides an effective alternative to topical and oral antibiotics.²⁹
• While relatively few OCs are approved for the use in acne, clinical trials suggest that many other OCs are also effective.³⁰
• The benefits of hormonal therapy may extend beyond improvement of acne in some patient subgroups, such as those with PCOS or those with menstrual irregularities.
• More research into the subtypes of acne most responsive to hormonal treatment, as well as the comparative efficacy of available hormonal treatments, will help tailor treatment to different acne patient presentations.

¹Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
²Faculty of Medicine, Western University, London, ON, Canada

Conflicts of Interest Disclosures:
Mr. Liu has nothing to disclose. Dr. Tan has served on an advisory board for Novartis, Cipher, Galderma, Valeant, and Roche; and has served as an investigator for Abbvie, BoehringerIngelheim, Pfizer, Novartis, Dermira, Galderma, and Xenon; and has received grants in compensation.

Introduction

Acne vulgaris (AV) is one of the most common skin diseases. Characterized by lesions resulting from inflammation of pilosebaceous units,¹ predominant sites of involvement include the face, chest, and back – areas with the highest density of these units.¹ Truncal acne refers to AV affecting the chest and/or back, a common presentation in acne patients.² This article offers guidance in clinical differentiation of truncal acne from other acneiform diseases and provides management recommendations.

Background

• Prevalence of truncal AV in those with facial acne is approximately 50%⁴, with 61% having lesions on the back and 45% on the chest.⁵
• Current instruments measuring quality of life have only been validated for facial acne, however an instrument intended for both truncal and facial acne is now in development.⁶
• Pathogenesis of acne has been described to be a complex process with four major pathogenic mechanisms: increased sebum production, colonization by Propionibacterium acnes, blockage of pilosebaceous ducts due to hyperkeratinisation, and inflammation.¹

Clinical Presentation & Assessment

• Acne lesions begin as microcomedones that become clinically apparent as open (blackheads) or closed (whiteheads) comedones.¹
• Erythematous papules and pustules develop when comedones become increasingly inflamed. If it becomes severe, deep pustules and nodules and/or cysts may develop.¹
• During the physical exam, individual assessment of the face, chest and back should be performed to evaluate severity and extent of disease.
• Lesion types, size, distribution, and the presence of scars or dyspigmentation are important details to capture.⁷
• Although several acne grading scales have been developed, few incorporate evaluations of truncal acne, and none are recommended for universal use.⁸
• Practitioners should use a validated scale for facial and truncal acne for treatment selection and monitoring outcomes.⁸
• The Comprehensive Acne Severity Scale (CASS) is one example of a grading scale validated for facial and truncal acne (Table 1) and can be applied separately to each of the face, chest and back.⁷

Differential Diagnoses

• Several diseases affecting the trunk may mimic truncal acne.
  • Folliculitis is an inflammatory process caused by infection of hair follicles. The source of the infection may be fungal (Malassezia), bacterial (Staphylococcus, Pseudomonas) or viral (herpetic). Differentiating features include the absence of comedones and the presence of monomorphic lesions that may be pruritic.^9,10
  • Pseudofolliculitis presents with inflammatory papulopustules due to ingrown hairs. This can be differentiated from truncal acne by the absence of comedones.¹¹
  • Steatocystoma multiplex is a rare, autosomal-dominant disorder of the pilosebaceous unit that causes asymptomatic, yellow and/or skin-coloured cysts. Differentiating features include the monomorphic appearance and absence of inflammatory lesions.¹²

Management of Truncal Acne

Treatment Rationale & General Principles

• Although truncal acne may not be the primary concern for facial acne patients, more than ¾ with incidental truncal acne desire treatment.¹³
• Atrophic and/or hypertrophic scarring may result from truncal acne, therefore early diagnosis and effective management are important for prevention.²
• Therapies should target the four processes that contribute to acne development: sebum production, bacterial colonization, ductal blockage due to hyperkeratinisation and inflammation.²
• A combination approach targeting different mechanisms in pathogenesis should be considered.⁸
• Selection of therapies should incorporate the practitioner’s clinical judgment, AV severity, prior history and patient preferences.
• The following treatment recommendations are based on current acne guidelines and feature practical tips to facilitate management.

Topical Therapies

• Topical therapies, available through prescription or over-the-counter, are effective agents that provide targeted therapy with minimal to no risk of systemic side effects.¹⁰
• Evidence is lacking for topical management of truncal acne as studies are limited to facial acne. We infer that mechanisms and efficacy may also apply to truncal acne.

1. Benzoyl peroxide (BPO) acts to decrease inflammation and hyperkeratinisation, and has antimicrobial properties.⁸ However, this may result in bleaching of clothing and bedding – of concern with truncal application.
2. Retinoids (such as tretinoin, adapalene and tazarotene) decrease inflammation and follicular hyperkeratinisation, and are thus comedolytic and anticomedogenic.⁸
3. Topical antibiotics, such as erythromycin and clindamycin, act to limit proliferation of P. acnes. However, they are not recommended as monotherapy due to the risk of bacterial resistance.⁸ In addition to joint use with BPO or topical tretinoin, fixed dose combinations of clindamycin with tretinoin and with BPO are available.
4. Dapsone is anti-inflammatory and is effective in addressing inflammatory papules/pustules.⁸
5. Azelaic acid is effective in reducing acne and postinflammatory hyperpigmentation.⁸

Systemic Therapies

Oral Antibiotics

• Limit proliferation of P. acnes. Useful in moderate to severe acne, especially presentations that are resistant to topical therapies.^8,14
• Should not be used as monotherapy: a combination approach with BPO is recommended to enhance efficacy and reduce risk of bacterial resistance.^8,14
• Treatment should be kept as short as possible, ideally no more than 3-4 months, to reduce risk of bacterial resistance.⁸
• Tetracyclines are considered first-line,^8,14 however minocycline is not recommended when other options are available (e.g. tetracycline, doxycycline) as it has been associated with drug-induced hepatitis and lupus.¹⁴
• Tetracyclines are contraindicated in those who are pregnant, allergic, or under the age of 8 years.⁸
• Macrolides, such as erythromycin and azithromycin, are second-line agents used for patients with contraindications against tetracyclines.⁸ Erythromycin should be avoided due to increased risk of bacterial resistance.⁸
• Use of other antibiotics is not recommended due to limited data on their efficacy and risk of bacterial resistance when they may be required for community acquired infections.⁸

Hormonal Therapies

• Combined oral contraceptives (COCs) contain both estrogen and progestin, and act together to exert anti-androgenic effects through negative feedback mechanisms.⁸ Reduced circulating androgens has been linked to decreased sebum production.¹⁵
• Most progestins are testosterone derivatives that are androgenic, especially those from earlier generations.8 Therefore, it is ideal to select COCs featuring newer progestins, such as norgestimate and drospirenone, that have minimal to no androgenic potential.^8,14
• COCs are effective in inflammatory acne in females, and may be particularly suitable for those with menstrual irregularities or who desire contraception.⁸
• COCs are not recommended in patients who are pregnant, heavy smokers, aged greater than 35 years, have hypertension, diabetes, migraine headaches or history of DVT/PE.⁸
• Spironolactone, despite its antiandrogenic effects and widespread use,¹⁶ has limited high quality evidence.^8,14

Oral Isotretinoin

• Isotretinoin is an oral retinoid that decreases sebum production, bacterial proliferation, hyperkeratinisation, and inflammation. Recommended for treating severe acne, and those resistant to other therapies.^8,14
• It is teratogenic,¹⁷ thus prescribers and female patients of child bearing potential must adhere to policies outlined by pregnancy prevention programs.⁸
• Isotretinoin should be avoided in breastfeeding females as it may be transferred to infants through breast milk.⁸
• Lab and clinical monitoring should include testing for liver function, serum cholesterol, TGs, and psychiatric disturbances.⁸
• Prescription should be limited to physicians who are trained and experienced in its use.¹⁴

Conclusions

• Truncal acne is common in patients presenting with acne, and may be underdiagnosed and undertreated.²
• Other skin disorders may result in lesions that resemble truncal acne, thus careful examination for differentiating features can assist in accurate diagnosis.
• Treatments for truncal AV are derived from recommendations for facial AV.² Evaluate for response at 2-3 months and consider escalation if inadequate improvement.
  • For mild and moderate severity – consider topical retinoids (with or without topical antibiotics or BPO); azelaic acid; dapsone.
  • For moderate and moderate/severe presentations, consider a combination of topical therapies with systemic antibiotics or COCs in females.
  • For severe truncal acne – oral isotretinoin is the treatment of choice.
    • Oral antibiotics and topicals (retinoids + BPO or topical antibiotics) and ethinyl estradiol/cyproterone acetate are alternatives if patients are intolerant, unable or unwilling to consider oral isotretinoin.

References

1. Degitz K, Ochsendorf F. J Dtsch Dermatol Ges. 2017 Jul;15(7):709-722.
2. Bikowski J. J Clin Aesthet Dermatol. 2010 Nov;3(11):26-9.
3. White GM. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3): S34-7.
4. Del Rosso JQ. Cutis. 2006 May;77(5):285-9.
5. Tan JK, et al. J Drugs Dermatol. Jun;7(6):551-6.
6. McLellan C, et al. Development of a Comprehensive Quality of Life Measure for Facial and Torso Acne. [Under Review].
7. Tan JK, et al. J Cutan Med Surg. 2007 Nov-Dec;11(6):211-6.
8. Zaenglein AL, et al. J Am Acad Dermatol. 2016 May;74(5):945-73.e33.
9. Rubenstein RM, Malerich SA. J Clin Aesthet Dermatol. 2014 Mar;7(3):37-41.
10. Gjede J, Graber E. Infectious diseases mimicking acne vulgaris: Bacterial folliculitis In: Zeichner, J, ed. Acneiform Eruptions in Dermatology: A Differential Diagnosis. 1st ed. New York, NY: Springer; 2014:43-47.
11. Coley MK, et al. Pseudofolliculitis barbae and acne keloidalis nuchae. In: Alexis AF, Barbosa VH, eds. Skin of Color. 1st ed. New York, NY: Springer; 2013:123-137.
12. Varshney M, et al. BMJ Case Red. 2011 Sep;2011. pii: bcr0420114165. doi: 10.1136/bcr.04.2011.4165.
13. Del Rosso JQ, et al. Prevalence of truncal acne vulgaris: a population study based on private practice experience. Poster presented at: 65th Annual Meeting of the AA; Feb 2-6, 2007;Washington, DC.
14. Asai Y, et al. CMAJ. 2016 Feb;188(2):118-26.
15. O’Connell K, Westhoff C. Cutis. 2008 Jan;81(S1):8-12.
16. Brown J, et al. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD000194.
17. Lammer EJ, et al. N Engl J Med. 1985 Oct;313(14):837-41.

¹Department of Medicine, University of Western Ontario, London, ON, Canada
²Windsor Clinical Research Inc., Windsor, ON, Canada

Introduction

Acne vulgaris is a multifactorial disease characterized by different types of lesions at various stages of development. Treatment options must address a spectrum of disease from mild to severe; and encompasses topical to systemic agents, respectively. For all acne therapy however, adherence remains an issue. Advances in delivery mechanisms have been developed to improve patient compliance with both topical and systemic modalities. Most recently, the novel lipid technology (Lidose®) has been utilized in the administration of oral isotretinoin. CIP-Isotretinoin (Epuris™), approved by Health Canada in November 2012 and released commercially in June 2013, enhances drug absorption during fasted states and lessens the need for administration with a high-fat meal, thereby potentially improving bioavailability and patient adherence.

UVA and UVB Light-Induced Skin Reactions

• Acne treatment selection is generally based on the severity and type of lesions, with the goal of treatment being to reduce sebum production, infundibular occlusion, inflammation and Propionibacterium acnes proliferation.
• Conventional topical therapies were originally composed of single agent preparations.
• Improved knowledge of acne pathogenesis and topical formulation chemistry led to development and clinical application of combination products (Table 1).
• Recent studies have demonstrated greater efficacy and tolerability with combination therapy compared to monotherapy.
• As a result, current consensus guidelines recommend the use of combination treatment as first-line therapy for most patients with mild to moderate acne.
• Notwithstanding efficacy, issues such as irritation and the emergence of bacterial resistance to both topical and oral antibiotics remain significant barriers to improved treatment outcomes.
• It is estimated that 30-40% of patients using topical formulations do not adhere to their prescribed regimen.¹

Improving Patient Adherence to Topical Therapy

• Treatment efficacy, local tolerance and adherence have all been improved through recent advances in vehicle technology.²
• Additionally, delivery mechanisms such as pumps which provide convenience, are preferred by patients and may improve adherence.³
• In a Patient Preferences in Acne: A Point-of-Care Educational Initiative, a national survey of 1709 Canadian patients showed that pump delivery systems are the preferred format (42% of patients).³
• However, patient preferences have been shown to extend beyond treatment side-effects: variables such as vehicle composition, messiness, texture, aroma, difficulty of use, lack of early improvement, and staining, can all decrease compliance.⁴
• Many new topical acne formulations have aqueous-based gel vehicle delivery systems that do not contain alcohol and are suitable for use in all skin types as they are less drying.
• Topical acne agents can cause cutaneous irritation related in part to impaired epidermal barrier function.⁵ Therefore:
  • the use of gentle cleansers and moisturizers has been shown to reduce this cutaneous irritation;⁶
  • moisturizers containing ceramides can improve skin barrier function.
• Additionally, vehicle advances, such as microsphere technology and solubilized crystalline formulations, reduce the potential of irritation from tretinoin.
• Photodegradation is not increased with microsphere tretinoin, tazarotene and adapalene, allowing for morning application.
• Clindamycin/BPO formulations with humectants and emollients may reduce the dry skin associated with BPO use.
• Clindamycin/BPO formulations without preservatives may reduce the irritation associated with these agents.⁷
• The addition of BPO to topical antibiotic agents and the use of BPO with long-term oral antibiotics can reduce the risk of cutaneous bacterial resistance.

Systemic Treatment for Severe Acne

Oral Isotretinoin

• Since US FDA approval of the oral isotretinoin agent Accutane™ in 1982, and its subsequent approval by Health Canada in 1983, it has remained the standard of treatment for severe nodular acne in Canada.
• Oral isotretinoin is a synthetic derivative of vitamin A, and is similar to the parent compound in being highly fat-soluble.
• As a result, ingestion of oral isotretinoin with food increases its bioavailability.⁸
  • In the fasted state, ingestion of standard oral isotretinoin formulations leads to plasma levels that are approximately 60% lower compared to the fed state.⁸
  • Accordingly, standard practice recommendations promote ingestion with food, particularly a high-fat meal, to enhance absorption.
• However, patient adherence and reliability in taking isotretinoin with high-fat meals may be inconsistent.^9-11
• Irregular eating habits may result in irregular dosing and therefore variable drug absorption.

CIP-Isotretinoin (Epuris™)

• CIP-Isotretinoin (Epuris™) was approved by Health Canada in November 2012 and launched in June of 2013.
  • It utilizes Lidose® technology to imbed isotretinoin in a lipid matrix, thereby increasing drug absorption during fasted state.¹²
  • CIP-Isotretinoin may lead to more consistent plasma levels of isotretinoin during variable dietary conditions, providing the potential for enhanced patient outcomes.
• Particularly for those with irregular eating times, treatment adherence may be improved as the absorption of the drug is better than the standard formulation in the absence of a high fat meal.
• This technology has already been successfully combined with a fenofibrate formulation (Lipofen™) to create a novel capsule used for treatment of hyperlipidemia.
• An application of this delivery platform encompassing oral CIP-Isotretinoin was approved by the US FDA in May 2012 (Absorica™) with indications for treatment of severe nodular and or inflammatory acne, acne conglobate, and recalcitrant acne.

Efficacy & Safety

• An open label, single dose randomized crossover study demonstrated pharmacokinetic bioequivalence of CIPIsotretinoin to standard isotretinoin formulations during high fat fed states, with significantly greater absorption during fasting.¹³
  • In the fasted state, the absorption of CIP-Isotretinoin, was approximately 83% greater than that of conventional isotretinoin.
  • The products were bioequivalent when taken with a high fat meal.¹³
• In a double-blind, randomized, controlled trial comparing CIP-Isotretinoin under high fat fed conditions to a currently marketed formulation of oral isotretinoin (Accutane™), 925 subjects with severe recalcitrant nodular acne aged 12-54 years were recruited.⁸ Subjects had to have at least 10 acne nodules on the face and/or trunk.
  • The number of responders, defined as those with ≥90% reduction in nodules at end of study compared to baseline, was similar in both treatment groups with overlapping 95% confidence intervals in per protocol (79% CIPIsotretinoin versus 81% Accutane™) and intent-to-treat (70% versus 75%) analyses.
  • Furthermore, the mean reduction in nodules in both groups was similar for both analyses (-17 versus -16, -16 versus -16, respectively), demonstrating clinical noninferiority.
  • Almost all patients experienced at least one adverse event in both groups at a similar rate (92% with CIP-Isotretinoin to 90% with Accutane™).¹⁴
  • Reported adverse events were typical for oral isotretinoin use, with the majority related to dry skin and cheilitis.¹⁴
  • Rates of serious adverse events occurring with the use of both CIP-Isotretinoin and standard oral isotretinoin were low (5/464 or 1.1% and 7/464 or 1.5%, respectively).¹⁴
  • Adverse events leading to discontinuation of participation occurred in 4.1% (19/464) of patients with CIPIsotretinoin, compared to 3.3% (15/460) of patients with standard oral isotretinoin.

Dosage & Administration

• Capsules of CIP-Isotretinoin are available in 10 mg (yellow), 20 mg (red), 30 mg (brown), and 40 mg (brown and red) doses in packages of 30 capsules (3 x 10 blister cards), which provides for flexible, individualized dosing according to the patient’s weight and disease severity.
• Inactive ingredients in this formulation include: stearoyl macrogolglycerides, soybean oil, sorbitan monooleate, and propyl gallate.
• Accutane™ is currently available in Canada in 10 mg (pink), and 40 mg (orange) doses in blister packages of 30 capsules. Ingredients include beeswax, black iron oxide, gelatin, glycerol, soybean and peanut oils, parabens, shellac, and titanium dioxide.
• To prevent potential allergic reactions, Accutane™ should particularly be avoided in patients with sensitivities to peanut oil and parabens, in addition to the aforementioned contents.
• As with standard isotretinoin formulations, the starting dose of CIP-Isotretinoin should be administered according to the patient’s weight and severity of the disease.
• In general, patients should initially receive CIP-Isotretinoin 0.5 mg/kg body weight daily for 2-4 weeks while monitoring their responsiveness to the drug.¹⁴
• Maintenance dose should be adjusted between 0.1 mg and 1 mg/kg body weight daily, depending on response and tolerance.
• A complete course of therapy consists of 12-16 weeks of CIP-Isotretinoin administration.¹⁴
• In view of differences in bioavailability, CIP-Isotretinoin is not interchangeable with standard oral isotretinoin formulations.
• As with any oral retinoid treatment, the need for ongoing pregnancy prevention and safety monitoring is of paramount concern.
• Generally, the side effects of oral isotretinoin have been well characterized, with the most common ones being mucocutaneous and mild.
• It is recommended to initiate CIP-Isotretinoin treatment at a low dose of 0.5 mg/kg/day for 2-4 weeks to assess drug tolerance.

Conclusion

Advances in delivery technologies for mild, moderate and severe acne are improving treatment adherence. Additionally, in mild to moderate acne, a greater understanding of acne pathogenesis has led to the development of effective combination treatments. In severe nodular acne, the novel CIPIsotretinoin formulation has been designed to reduce variation in bioavailability during fed and fasted states. In the context of clinical use, where patients may be unable to consistently take oral isotretinoin with a high-fat meal, this product enhances bioavailability and has the potential of improving clinical outcomes.

References

1. Finlay AY. J Eur Acad Dermatol Venereol. 1999;12(Suppl 2):S77.
2. Koo J. Skinmed. 2003;2(4):229-33.
3. Vender R, et al. Patient preferences in acne: a point-of-care educational initiative. Poster presentation.
4. Kircik LH, et al. Practical Dermatol. 2010;7(6 Suppl):1-16.
5. Del Rosso JQ, et al. J Drugs Dermatol. 2006;5(2):160-4.
6. Gollnick H, et al. J Am Acad Dermatol. 2003;49(1 Suppl):S1-37.
7. Zeichner JA. J Drugs Dermatol. 2012;11(3):313-7.
8. Colburn WA, et al. J Clin Pharmacol. 1983;23(11-12):534-9.
9. Hogan DJ, et al. CMAJ. 1988;138(1):47-50.
10. Cohen B, et al. Can J Public Health. 2003;94(1):41-4.
11. Rampersaud GC, et al. J Am Diet Assoc. 2005;105(5):743-60.
12. Laboratories S.M.B., Brussels, Belgium. Web site. Lidose. Accessed July 29, 2013.
13. Webster GF, et al. J Am Acad Dermatol. 2013 Aug 13. [Epub ahead of print]
14. Epuris™ [Product monograph]. March 14, 2013. Cipher Pharmaceuticals Inc., Mississauga, ON.

¹Department of Medicine, University of Western Ontario, London, ON, Canada
²Windsor Clinical Research Inc., Windsor, ON, Canada

ABSTRACT

Current practice guidelines recommend administration of oral isotretinoin with high-fat meals, which may pose issues with patient compliance. Isotretinoin-Lidose (Epuris™), approved by Health Canada in November 2012 and scheduled for commercial release June 2013, is based on novel lipid encapsulation technology (Lidose®) to enclose isotretinoin, thereby increasing drug absorption during fasted states. An open label, single dose randomized crossover study demonstrated pharmacokinetic bioequivalence of isotretinoin-Lidose to standard isotretinoin formulations during fed states, with significantly greater absorption during fasting. Isotretinoin-Lidose, may lead to more consistent plasma levels of isotretinoin during variable dietary conditions, providing the potential for enhanced patient outcomes.

Key Words:
acne vulgaris, bioavailability, drug delivery, isotretinoin

Introduction

Since US FDA approval of the oral isotretinoin agent Accutane™ in 1982, and its subsequent approval by Health Canada in 1983, it has been and continues to be the standard of treatment for severe nodular acne in the US and Canada. As this agent is a synthetic derivative of vitamin A, it is similar to the parent compound in being fat-soluble. As a result, ingestion of oral isotretinoin with food increases bioavailability.¹ In the fasted state, ingestion of standard oral isotretinoin formulations leads to plasma levels that are approximately 60% lower compared to the fed state.¹ Accordingly, standard practice recommendations promote ingestion with food, particularly a high-fat meal, to enhance absorption.

However, patient adherence and reliability in taking isotretinoin with high-fat meals may be problematic.^2-4 Inconsistent eating habits during drug administration may result in irregular dosing and considerable variation in plasma levels of isotretinoin, within and between patients. Thus, a previous unmet need with oral isotretinoin has been a formulation less dependent on the fed state to reduce this potential for suboptimal absorption and subtherapeutic plasma levels. Hoffman-La Roche Pharmaceuticals Inc., the manufacturer of Accutane™ the incumbent branded oral isotretinoin formulation, addressed this issue through the development of Accutane-NF (new formulation). This microionized version of Accutane™ was developed to reduce particle size, thereby increasing bioavailability.⁵ Accutane-NF was projected to result in therapeutic levels of isotretinoin with once-daily dosing and without the need for administration with food.⁵ A randomized, double-blind clinical trial comparing these two formulations in 600 patients with severe recalcitrant nodular acne showed that the overall efficacy of Accutane-NF was statistically similar to standard Accutane™. However, the new formulation trended towards lower efficacy as demonstrated in the proportion of subjects achieving >90% reduction in nodule counts, including percentage changes with respect to nodule counts, papules/pustules, and total inflammatory lesion counts, as well as global evaluations of excellent response/clearance. At the dosages tested, a lower risk of mucocutaneous adverse event and hypertriglyceridemia were noted.⁵ However, in the absence of clear advantages of the new formulation compared to standard Accutane™, when considering the balance of efficacy to adverse events (benefit:risk), there was no apparent public health benefit to marketing both formulations.⁵

Recently, this ongoing inadequacy was addressed with an innovative technology that encapsulates lipophilic drugs, such as isotretinoin, with lipid agents – thereby providing a more optimal environment for absorption within the formulation. Originally developed by SMB Laboratories, the Lidose® drug delivery system consists of a hard gelatin capsule containing liquid or semi-liquid contents composed of an active drug melted together with lipid excipients, then cooled under specific conditions.⁶ This technology has already been successfully combined with a fenofibrate formulation (Lipofen™, Cipher Pharmaceuticals Inc.) to create a novel capsule used for treatment of hyperlipidemia.

Potential advantages of Lidose® over conventional capsule technology include greater tolerability with less gastric irritation, rapid absorption, and protection of drug against oxidation.⁶ An application of this delivery platform encompassing oral isotretinoin-Lidose was approved by the US FDA in May 2012 (Absorica™, Cipher Pharmaceuticals Inc.) with indications for treatment of severe nodular and or inflammatory acne, acne conglobate, and recalcitrant acne. Health Canada approved isotretinoin-Lidose for the same indication in November 2012 (Epuris™, Cipher Pharmaceuticals Inc.).

Pharmacokinetic Studies

In an open label, single dose, randomized, crossover study involving 60 healthy subjects comparing isotretinoin-Lidose against standard oral isotretinoin, these preparations were shown to be pharmacokinetically bioequivalent under fed conditions (modified high-fat, high-calorie breakfast with reduced vitamin A content). However, administration of isotretinoin- Lidose resulted in significantly better absorption of isotretinoin and its metabolites under fasted conditions than did the standard isotretinoin formulation (Accutane™). Plasma levels of isotretinoin using the Lidose® formulation attained 67% of that achieved with a fatty meal compared to 40% using standard Accutane™.⁷ Furthermore, while more than 75% of subjects absorbed less than 50% isotretinoin with Accutane™ during the fasting state compared to fed state, 75% of patients prescribed isotretinoin-Lidose formulation absorbed at least 60%.⁷ A total of 55 adverse effects were reported, with the most common being headache. No significant difference in adverse event frequency between treatments was observed and no serious adverse events were reported.⁷

Clinical Trials

In a double-blind, randomized, controlled trial comparing isotretinoin-Lidose to a currently marketed formulation of oral isotretinoin (Accutane™), 925 subjects with severe recalcitrant nodular acne aged 12-54 years were recruited. Subjects had to have at least 10 acne nodules on the face and/or trunk. Active treatment under fed conditions with isotretinoin-Lidose or the reference marketed formulation was initiated at a dose of 0.5 mg/kg/day for the first 4 weeks, followed thereafter by 1 mg/kg/day for the subsequent 16 weeks. All participants were instructed to take the assigned isotretinoin formulation twicedaily with meals at breakfast and dinner for the full 20 weeks of treatment.⁸ The number of responders, defined as those with ≥90% reduction in nodules at end of study compared to baseline, was similar in both treatment groups with overlapping 95% confidence intervals in per protocol (79% isotretinoin- Lidose versus 81% Accutane™) and intent to treat (70% versus 75%) analyses. Furthermore, the mean reduction in nodules in both groups was similar for both analyses (-17 versus -16, -16 versus -16, respectively), demonstrating clinical noninferiority. Almost all patients experienced at least one adverse event in both groups at a similar rate (92% with isotretinoin- Lidose to 90% with Accutane™). Reported adverse events were typical for oral isotretinoin use, with the majority related to dry skin and cheilitis. No significant differences were observed in frequency of adverse events between treatment groups for psychiatric, ocular, auditory, musculoskeletal, cardiovascular, or gastrointestinal systems.⁸ Rates of serious adverse events occurring with the use of both isotretinoin-Lidose and standard oral isotretinoin were low (5/464 or 1.1% and 7/464 or 1.5%, respectively). Three serious side effects possibly related to isotretinoin-Lidose were severe abdominal pain, severe upper abdominal pain, and moderate migraine, all of which resolved completely. Serious adverse events related to standard oral isotretinoin were not included in this publication. Adverse events leading to discontinuation of participation were reported in 4.1% (19/464) of patients with isotretinoin-Lidose, compared to 3.3% (15/460) of patients with standard oral isotretinoin. These were classified as psychiatric and gastrointestinal events in the isotretinoin-Lidose group, and as psychiatric and musculoskeletal/connective tissue events in the reference group.

Dosage Forms and Administration

Capsules of isotretinoin-Lidose are available in 10 mg (yellow), 20 mg (red), 30 mg (brown), and 40 mg (brown and red) doses in packages of 30 capsules (3 x 10 blister cards). Inactive ingredients in this formulation include: stearoyl macrogolglycerides, soybean oil, sorbitan monooleate, and propyl gallate. Accutane™ is currently available in 10 mg (pink), 20 mg (red; not available in Canada) and 40 mg (orange) doses in blister packages of 30 capsules, and ingredients include beeswax, black iron oxide, gelatin, glycerol, soybean and peanut oils, parabens, shellac, and titanium dioxide. To prevent potential allergic reactions, Accutane™ should particularly be avoided in patients with sensitivities to peanut oil and parabens, in addition to the aforementioned contents. Isotretinoin-Lidose dye systems vary with the dose forms: 10 mg – iron oxide (yellow) and titanium dioxide; 20 mg – iron oxide (red) and titanium dioxide; 30 mg – iron oxide (yellow, red, and black) and titanium dioxide; and 40 mg – iron oxide (yellow, red, and black) and titanium dioxide.

As with standard isotretinoin formulations, the starting dose of isotretinoin-Lidose should be administered according to the patient’s weight and severity of the disease. In general, patients should initially receive isotretinoin-Lidose 0.5 mg/kg body weight daily for 2-4 weeks while monitoring their responsiveness to the drug.⁸ Maintenance dose should be adjusted between 0.1 mg and 1 mg/kg body weight daily, depending on the response and tolerance. A complete course of therapy consists of 12-16 weeks of isotretinoin-Lidose administration.⁸ In view of differences in bioavailability, the use of isotretinoin-Lidose is not considered interchangeable with standard oral isotretinoin formulations.

As with any oral retinoid treatment, the need for on-going pregnancy prevention and safety monitoring is of paramount concern. Generally, the side effects of oral isotretinoin have been well characterized, with the most common ones being mucocutaneous and mild. As isotretinoin-Lidose is formulated to be a more bioavailable form of oral isotretinoin under fasted conditions, rates of adverse events should not be appreciably different between the two therapies – as demonstrated by the clinical trial.⁸ However, due to the specific parameters and controlled conditions of the study, this data may not directly generalize to overall rates observed in clinical practice. Therefore, it is recommended to initiate isotretinoin-Lidose treatment at a low dose of 0.5 mg/kg/day for 2-4 weeks to assess drug tolerance.

Discussion: Epuris™ and Other Recent Isotretinoin Advancements

Several current guidelines for the treatment of severe nodulocystic and conglobate acne indicate the use of isotretinoin as a monotherapy in doses ranging from 0.5-2.0 mg/kg/day over 4-6 months^9-11 to achieve a final cumulative dose of 120-150 mg/kg.^9,11 This cumulative dose has been considered to be optimal to minimize relapse requiring retreatment. Preventing the need for retreatment is a desirable prospect, as it would reduce the likelihood of fetal exposure to teratogens in women of child-bearing age with additional treatment courses, decrease the overall occurrence of adverse events, and lessen the development of permanent acne scarring resulting from incomplete resolution of acne lesions. As the isotretinoin-Lidose formulation increases isotretinoin bioavailability during fasted states, it may mitigate the obstacle of variable patient compliance, thereby increasing the probability of efficiently attaining the recommended cumulative dose. However, the evidence basis for current cumulative dose thresholds is tenuous. Recent evidence suggests that there may be less of a role for cumulative dose in the treatment of acne than previously thought, and prevention of relapse may be more directly attributable to prolonged sebosuppresion.¹² In particular, it is unclear whether prolonged remission is best achieved through prolonged sebosuppression achievable by long-term, low-dose administration, or through apoptosis and sebaceous gland atrophy requiring higher doses. Nevertheless, though it currently serves as an acceptable approximation of appropriate treatment duration, further investigation is required to provide high-level evidence for remissions with varying dosing regimens.

The reassessment of isotretinoin dosing regimens has increased in recent years, with the aim of determining the most efficient and scientifically credible means of oral isotretinoin administration. Recognition of the efficacious role of low-dose isotretinoin therapy in severe acne is compelling and emerging evidence suggests that current practice guidelines may be recommending unnecessary high doses of isotretinoin, resulting in preventable side effects. Several studies have suggested that continuous, low-dose regimens may be as effective for treatment of acne and prevention of relapse as those using higher, classic doses.^13-16 A recent randomized, double-blind, placebo-controlled trial demonstrated that doses as low as 5 mg/day isotretinoin independent of body weight, significantly reduced acne lesion count and improved Dermatology Life Quality Index (DQLI) scores after 16 weeks of treatment.¹⁴ Patients continued to improve 10 weeks after treatment discontinuation and relapses were not observed during this post-treatment follow-up. Furthermore, in one of the largest studies evaluating low-dose isotretinoin treatment, 638 patients were successfully treated with 0.3-0.4 mg/kg/day over 6 months, with none relapsing at the 24-week follow-up.¹⁶ Although these studies may not have had adequate follow-up durations to sufficiently assess relapse, their findings present considerable potential in improving patient satisfaction, as lower-dose regimens have been associated with fewer overall adverse events and increased cost effectiveness.¹⁷ A prospective, randomized, controlled study investigating the clinical efficacy and tolerance of low-dose regimens reported that patient satisfaction was significantly higher in the low-dose treatment group (0.25-0.4 mg/kg/day) compared to higher dose group (0.5-0.7 mg/kg/day).¹³ A major limitation of evidence for low-dose regimens is that they have not been directly compared to full-dosing (1.0 mg/kg/day). The combination of low-dose strategies with increased bioavailability formulations such as isotretinoin-Lidose could optimize the benefits of treatment with less medication.

Conclusion

The novel isotretinoin-Lidose formulation was designed to reduce variation in bioavailability during fed and fasted states compared to standard isotretinoin. In the context of clinical use, where patients may be unable to consistently take oral isotretinoin with a high-fat meal, this product enhances bioavailability and has the potential of improving clinical outcomes.

References

1. Colburn WA, Gibson DM, Wiens RE, et al. Food increases the bioavailability of isotretinoin. J Clin Pharmacol. 1983 Nov-Dec;23(11-12):534-9.
2. Hogan DJ, Strand LM, Lane PR. Isotretinoin therapy for acne: a populationbased study. CMAJ. 1988 Jan 1;138(1):47-50.
3. Cohen B, Evers S, Manske S, et al. Smoking, physical activity and breakfast consumption among secondary school students in a southwestern Ontario community. Can J Public Health. 2003 Jan-Feb;94(1):41-4.
4. Rampersaud GC, Pereira MA, Girard BL, et al. Breakfast habits, nutritional status, body weight, and academic performance in children and adolescents. J Am Diet Assoc. 2005 May;105(5):743-60.
5. HLR Technology Corporation (Hoffman-La Roche), Nutley, NJ. NDA 21-177: New formulation isotretinoin [Executive Summary]. Summary date: August 9, 2000. Available at: www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1d_01. doc. Accessed July 29, 2013.
6. Laboratories S.M.B., Brussels, Belgium. Web site. Lidose.
7. Webster GF, Leyden JJ, Gross JA. Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-Lidose) and the innovator isotretinoin formulation: a randomized, 4-treatment, crossover study. J Am Acad Dermatol. 2013 Aug 13. [Epub ahead of print]
8. Epuris™ [Product monograph]. March 14, 2013. Cipher Pharmaceuticals Inc., Mississauga, ON.
9. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007 Apr;56(4):651-63.
10. Nast A, Dreno B, Bettoli V, et al. European evidence-based (S3) guidelines for the treatment of acne. J Eur Acad Dermatol Venereol. 2012 Feb;26 Suppl 1:1-29.
11. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003 Jul;49(1 Suppl):S1-37.
12. Rademaker M. Isotretinoin: dose, duration and relapse. What does 30 years of usage tell us? Australas J Dermatol. 2012 Sep 26.
13. Lee JW, Yoo KH, Park KY, et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin in the treatment of acne: a randomized, controlled comparative study. Br J Dermatol. 2011 Jun;164(6):1369-75.
14. Rademaker M, Wishart JM, Birchall NM. Isotretinoin 5 mg daily for low-grade adult acne vulgaris – a placebo-controlled, randomized double-blind study. J Eur Acad Dermatol Venereol. 2013 Apr 27. [Epub ahead of print]
15. Boyraz N, Mustak PK. Comparison of the efficacies of intermittent and continuous low-dose isotretinoin regimens in the treatment of moderate acne vulgaris. Int J Dermatol. 2013 May 17. [Epub ahead of print]
16. Agarwal US, Besarwal RK, Bhola K. Oral isotretinoin in different dose regimens for acne vulgaris: a randomized comparative trial. Indian J Dermatol Venereol Leprol. 2011 Nov-Dec;77(6):688-94.
17. Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the treatment of acne vulgaris. J Am Acad Dermatol. 2006 Apr;54(4):644-6.

Department of Medicine, University of Western Ontario, London, ON, Canada

ABSTRACT

Dapsone 5% gel for the topical treatment for acne vulgaris was recently introduced in Canada. It represents the first new anti-acne agent to gain North American regulatory approval in the past decade. Dapsone’s utility is attributable to its anti-inflammatory and antimicrobial properties that improve both inflammatory and non-inflammatory acne, with more prominent effects occurring in inflammatory lesions. Short- and long-term safety and efficacy have been demonstrated. Especially for patients exhibiting sensitivities or intolerance to conventional anti-acne agents, topical dapsone is a novel addition to the treatment armamentarium.

Key Words:
acne vulgaris, dapsone, sulfone

What Is It?

Dapsone, a synthetic sulfone with an amino moiety linking two sulfone rings (4,4′-diaminodiphenyl sulfone; molecular weight 248.30), has had medical applications for more than 7 decades for treating various medical conditions including dermatitis herpetiformis, leprosy, and malaria. It has been used in the past for severe recalcitrant acne in doses ranging from 25-50 mg/day.

The primary metabolites of dapsone are N-acetyl dapsone and dapsone hydroxylamine. The most important adverse events of dapsone result from the hydroxylamine metabolite. This compound increases oxidative stress on erythrocytes with resultant potential for dose-dependent hemolysis and methemoglobinemia. Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are more susceptible, as the absence of functional G6PD increases the risk of hemolysis and denaturation of hemoglobin.

It was hypothesized that a topical formulation of dapsone may be appropriate for treating acne vulgaris while minimizing systemic exposure and hematologic risk. Accordingly, a topical gel formulation of dapsone 5% was developed by Atrix Laboratories almost a decade ago for the treatment of acne vulgaris. While this product was approved by Health Canada in 2006, it has only recently been marketed in Canada.

Mechanism of Action

Dapsone has both anti-inflammatory and antimicrobial properties.¹ A combination of these activities may account for its efficacy in acne. Anti-inflammatory effects include inhibition of neutrophil myeloperoxidase and eosinophil peroxidase activity, suppression of hypochlorous acid production, scavenging of reactive oxygen species, suppression of neutrophil activity, and inhibition of chemoattractant-induced signal transduction. Antimicrobial activity, similar to that of sulfones and sulfonamides, is by inhibition of bacterial dihydropterase synthase in the folic acid metabolic pathway. This mechanism is effective against microorganisms synthesizing their own folic acid. In vitro susceptibility testing has demonstrated some activity for dapsone against Propionibacterium species, including Propionibacterium acnes (P. acnes). In vivo, a 10 week randomized single-blind vehicle-controlled microbiological study demonstrated reduction in Propionibacterium counts for vehicle between 54-78%, and for topical 5% dapsone gel of 63-70% (not significant).¹

Evidence for Efficacy

Two identically designed 12 week phase 3 double-blind randomized vehicle-controlled trials in acne (total N=3010) have been performed.² The objective of these studies was to evaluate the efficacy and safety of twice daily topical dapsone 5% gel in acne vulgaris. Subjects were aged 12 years or older with facial acne, including 20-50 inflammatory lesions and 20-100 noninflammatory lesions at baseline. The primary efficacy endpoints were global success (achievement of clear or minimal on global assessment) and mean percent reduction from baseline in lesion counts. Baseline characteristics for the vehicle and active treatment groups were similar, with the majority of patients having moderate acne (58%) and a third (33%) having mild acne. At end of the study, 41% of the dapsone gel cohort achieved global success, compared with 33% of patients treated with vehicle (P>0.001). Significant reduction in non-inflammatory, inflammatory, and total lesion counts were noted in dapsone gel versus vehicle groups (32% versus 24%, 39% versus 32%, 48% versus 42%, all P>0.001, respectively).²

The efficacy of dapsone gel 5% in combination with adapalene gel 0.1%, benzoyl peroxide gel 4%, or moisturizer was evaluated in a 12 week double-blind randomized study involving 301 acne subjects.³ Dapsone gel was applied twice daily and 1 of the 3 additional treatments was applied once daily. Subjects treated with dapsone gel and adapalene showed a significantly greater improvement in non-inflammatory and total lesion count reduction compared to dapsone gel and moisturizer. The dapsoneadapalene treatment group showed a slightly higher incidence of application site burning. Overall, local adverse reactions were minimal and generally mild in severity and improved during treatment. Seven patients in the dapsone gel and benzoyl peroxide group reported temporary tan/brown residue at application sites. However, this discolored residue could be wiped away if observed. The authors suggest that, when used together, the first product should be completely absorbed prior to application of the second, without a visible layer of either product on the skin after application. Alternatively, application of these agents at different times of the day can obviate this discoloration.

Evidence for Safety

In the phase 3 studies, few patients withdrew due to side effects (6 dapsone gel, 9 vehicle). The overall incidence of adverse events was similar in both groups. The most common local intolerance events were dryness (20%), erythema (16%), and other reactions (including facial stinging, peeling, sensitivity, flaking, greasiness, photosensitivity, acne breakouts, tingling, and skin tightness). Serious adverse events were observed in 9 subjects, but they were not considered to be related to the treatment (4 dapsone gel, 5 vehicle). No significant changes in hemoglobin or other laboratory values were noted, despite 44 subjects recruited with glucose-6-phosphate dehydrogenase (G6PD) deficiency (19 dapsone gel, 25 vehicle). For all patients, the most frequently reported laboratory abnormality was elevated creatine kinase (12 dapsone gel, 11 vehicle), the majority of which were attributed to physical activity.²

A long-term safety study was performed with 486 acne patients applying dapsone gel twice daily for 12 months. Application site reactions were reported in 8.2% and were mostly mild to moderate in severity – the most common being dryness in 3%, rash 3%, sunburn 2%, burning 2%, erythema 2%, pruritus 1%, aggravation of acne 1%, and peeling 1%.⁴

The pharmacokinetic profile of topical dapsone gel was evaluated by reviewing data from three prospective open label studies, two phase 1 pharmacokinetic studies, and a phase 3 long-term safety study. Blood samples were drawn at various times in each trial for assessment of drug and metabolite concentrations. In various settings ranging from 2 weeks to 12 months application of dapsone gel, systemic levels (area under the curve) of dapsone and metabolites were approximately 100-fold less than those after a single dose of oral dapsone. Furthermore, the concentrations of dapsone and its metabolites achieved steady state and did not increase with prolonged treatment with dapsone gel.⁵

Further evaluation of hemolysis risk in subjects during dapsone gel use was performed in 64 patients with G6PD deficiency. Subjects were randomized to 12 week treatment periods of either vehicle followed by dapsone gel or dapsone gel followed by vehicle. Chemical and hematological analyses were performed, as well as levels of dapsone and metabolites, along with spontaneous reports of adverse events. Reduction in mean hemoglobin concentration of 0.32 g/dL was observed from baseline to 2 weeks during dapsone gel treatment, unaccompanied by laboratory features of hemolysis. This change was no longer apparent at 12 weeks of treatment. Proportion of subjects with 1 g/dL reduction in hemoglobin was similar between treatment groups at both week 2 and week 12 and no clinical signs or symptoms of hemolytic anemia were observed. Thus, no clinical or laboratory evidence of drug-induced hemolytic anemia in patients with G6PD deficiency was observed during treatment with dapsone 5% gel.⁶ The results of this study led to Health Canada and the US FDA removing the G6PD screening and monitoring requirements from the official label for this product.

Although sulfones, such as dapsone, have structural similarities to sulfonamides, the two compounds have distinct chemical properties, e.g., sulfones have both anti-inflammatory and antibacterial properties, whereas sulfonamides are antimicrobial agents. Additionally, sulphonamides have been implicated in sulfa sensitivites, but dapsone may be used in sulfonamide-allergic patients.^5,7

Conclusion

Dapsone 5% gel is a novel option in Canada for treating acne vulgaris that may be operating via anti-inflammatory mechanisms. Efficacy in acne has been demonstrated in phase 3 and long-term studies. It has undergone rigorous evaluation for safety with no evidence of increased hemolytic risk even in G6PD-deficient patients.

References

1. Center for Drug Evaluation and Research. Application number 21-794, Aczone (dapsone) gel 5%. Microbiology Review, pp 6-7.
2. Draelos ZD, Carter E, Maloney JM, et al. Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. J Am Acad Dermatol. 2007 Mar;56(3):439 e1-10.
3. Fleischer AB, Jr., Shalita A, Eichenfield LF, et al. Dapsone gel 5% in combination with adapalene gel 0.1%, benzoyl peroxide gel 4% or moisturizer for the treatment of acne vulgaris: a 12-week, randomized, double-blind study. J Drugs Dermatol. 2010 Jan;9(1):33-40.
4. Lucky AW, Maloney JM, Roberts J, et al. Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long-term (1 year) treatment. J Drugs Dermatol. 2007 Oct;6(10):981-7.
5. Thiboutot DM, Willmer J, Sharata H, et al. Pharmacokinetics of dapsone gel, 5% for the treatment of acne vulgaris. Clin Pharmacokinet. 2007;46(8):697- 712.
6. Piette WW, Taylor S, Pariser D, et al. Hematologic safety of dapsone gel, 5%, for topical treatment of acne vulgaris. Arch Dermatol. 2008 Dec;144(12):1564-70.
7. Webster GF. Is topical dapsone safe in glucose-6-phosphate dehydrogenasedeficient and sulfonamide-allergic patients? J Drugs Dermatol. 2010 May; 9(5):532-6.