Insights into acne and the skin barrier: Optimizing treatment regimens with ceramide‐containing skincare

Acne is a common, complex, multifactorial inflammatory skin disease associated with epidermal barrier dysfunction. Beginning in childhood, acne affects many adolescents and adults. Acne is associated with lower self‐esteem, anxiety, and depression and may cause scars and pigmentary sequelae. The review explores the relationships between acne and the skin barrier function and discusses nuances in the prevention, treatment, and maintenance of acne and its impact on the skin barrier.

practical algorithm for treatment and maintenance, including skincare recommendations for pediatric acne patients and an algorithm for skin of color patients with acne.
Before the meeting, literature was culled on the relationship between the skin barrier and acne and current best practices in acne, addressing prescription and nonprescription acne products and skincare as monotherapy, adjunctive, and maintenance treatment.
Results: After discussing 13 draft statements, the advisors applied the selected literature and drew from their clinical knowledge and experience, and agreed on five statements.The follicular epithelial barrier is directly involved with changes that occur during both comedogenesis and in stages of inflammation, especially with follicular rupture compromising the barrier's integrity.In acne-affected skin, sebaceous glands are larger, sebum excretion and filaggrin expression higher, and stratum corneum lipids are reduced.
Educating patients and clinicians about inflammation's central role in acne and measures to reduce inflammation is essential.Skin irritation and xerosis from acne and treatments lead to poor treatment adherence.A skincare regimen should be included in the acne prevention, treatment, and maintenance care regimen and should be ongoing.Maintenance treatment with topical agents and skincare using gentle

| INTRODUC TI ON
[3] Globally acne caused 4.96 million (95% CL: 2.98-7.85)DALYs (Disability Adjusted Life Years) in 2019. 1 Beginning in childhood, acne affects many adolescents and young adults. 1 Acne may start at any stage of life and may continue into adulthood. 2,4Acne in adults is increasing, affecting up to 15% of women. 4,5More than 5.1 million people, primarily children, and young adults sought medical treatment for acne in 2013. 5ne may produce negative emotions such as embarrassment, humiliation, and self-consciousness and is associated with lower selfesteem, anxiety, and depression. 3,4ne may have a socioeconomic impact on the perceptions of others (e.g., increased unemployment rates in those with severe acne). 3Discoloration, such as post-inflammatory hyperpigmentation (PIH), and scar formation may occur in some patients making it necessary to initiate timely and effective treatment to help avoid these sequelae that can have an impact. 6,7e pathophysiology of acne is partly clarified, but further research is required.In acne-affected patients, sebaceous hypersecretion and follicular hyperkeratinization may be due to changes in the hormonal milieu, including androgens and insulin-like growth factors. 6,8These factors result in increased sebum formation and localization within sebaceous follicles with the resultant proliferation of Cutibacterium acnes (C.acnes), an intrafollicular bacterial commensal.C. acnes can lead to greater follicular occlusion and increase sebum secretion and inflammation.Triggered by a pattern of innate inflammation, acne may manifest underlying pathology such as an underlying endocrinologic disease, tumor, or other gonadal/ovarian pathology. 6ne is associated with inherent abnormalities in epidermal barrier functions. 8,9Moreover, some acne therapies can induce alterations within the epidermis that can lead to changes that disrupt some of the normal physiological functions of the epidermis, including the stratum corneum. 9The current review discusses epidermal barrier dysfunction in acne, and the role prescription treatment and skincare can play in promoting a healthy barrier function to support healthcare providers in achieving better outcomes for their acne patients.

| ME THODS
The panel of nine dermatologists (advisors) with extensive experience and knowledge in treating acne patients convened a meeting on February 11, 2023.First, they reviewed and discussed the literature on skin barrier dysfunction in acne, prescription and nonprescription acne treatments, and skincare including cleansers and moisturizers for acne patients.The advisors then developed five statements from 13 draft statements applying the selected literature and drawing from their clinical knowledge and experience.
During the meetings workshop, the three groups discussed and modified the statements.The advisors then presented the three versions to the group to fine-tune the final five statements and reach an agreement.An online process was then used to review the manuscript with the statements for publication.

| Literature review
Prior to the meeting, literature was culled on acne, exploring relationships between acne and epidermal barrier dysfunction and current best practices in acne, addressing prescription and nonprescription acne products and skincare as monotherapy, adjunctive, and maintenance treatment.A structured literature search used keywords related to this topic, and searches were performed on PubMed and Google Scholar on January 31, 2023, by a dermatologist and a physician/scientist.Selected articles included guidelines, consensus papers, reviews describing current best practices in acne treatment using acne products and skincare, and clinical research studies Although acne is associated with inherent abnormalities in epidermal barrier functions, there has been limited research on the epidermal permeability barrier in untreated skin and after acne therapies. 8,9,11In acne-affected skin, inflammation can be mediated via the activation of toll-like receptors (TLR) on inflammatory cell membranes and by the pro-inflammatory effects of free fatty acids from lipid oxidization due to C. acnes. 8,9,11tibacterium acnes, a commensal organism, can initiate and propagate the inflammatory cascade in acne. 11,12C. acnes proliferation and decreased diversity of the C. acnes phylotype is involved in skin dysbiosis attributing to acne pathogenesis. 11rmonal initiators in acne include elevated insulin growth factor (IGF)-1 and androgen levels which may lead to increased local pilosebaceous androgenesis, lipogenesis, and increased squalene, fatty acid production, and desaturation. 8,9,11,12Increased sebum production stimulates the proliferation of C. acnes. 11Together with interleukin (IL)-1 β, upregulation and subsequent adaptive immune response activation leads to the development of inflammatory papules, pustules, and nodules. 11,12Comedo formation results from the direct effect of squalene monohydroperoxide and oleic acid from lipogenesis and ultraviolet A (UVA) photooxidation or from the degradative effect of C. acnes lipases on triglycerides (Figure 1). 11,12e follicular epithelial barrier is directly involved with changes that occur during both comedogenesis and in stages of inflammation, especially with follicular rupture. 8,9,11,12In acne patients, skin barrier integrity may be compromised, demonstrated by a higher sebum excretion, larger sebaceous glands, and subclinical inflammation. 8,9,13Further changes in the skin barrier comprise elevated filaggrin expression, decreased free fatty acids, linoleic acid, sphingosine, and total ceramide levels. 8,9,13,14[15][16] F I G U R E 1 Pathways to inflammation in acne pathogenesis.Modified from Melnik BC.Clin Cosmetic Invest Dermatol 2015:8371-388.10.2.2147/CCID.S69135. 12C. acnes, Cutibacterium acnes; IGF 1, Fox01, forkhead box protein 01; insulin-like growth factor 1; IL, interleukin; mTORC1, mammalian target of rapamycin complex 1. [±2.9 years]). 13The researchers showed elevated transepidermal water loss (TEWL) and lower conductance in the mild-moderate acne patients compared to the healthy males (Figure 2A,B). 13paired water barrier function is related to decreased skin ceramides that may play a role in comedone formation since skin barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium. 13ppas and colleagues examined the correlation between altered ceramide levels and increased TEWL in acne patients. 14The study showed that all subclasses of ceramide were negatively correlated with increased TEWL but not with acne symptoms. 14They examined the ceramide composition of subjects with healthy skin and acne-affected skin according to season and showed that decreased ceramide levels aggravated the symptoms, especially in winter months. 14[16] Subclinical inflammation is present early in the emergence of acne lesion development, even in the absence of follicular hyperkeratinization. 6,8,9,16 Sebum production is higher, and the size of sebaceous glands is larger in people with acne-affected facial skin and those with acne lesions than in healthy subjects' facial skin. 16herent structural or functional epidermal barrier issues in acne must be addressed therapeutically, especially as certain acne medications can alter some epidermal properties (Table 1). 6,8,9,11,13,14atement 3. Common ingredients in topical acne products (e.g., BPO and retinoids) may irritate the skin.
The targets involved in acne are the sebaceous glands, infundibular keratinocytes, hair follicles, and organs such as the adrenal gland, ovary, and brain. 8[8] Oral isotretinoin is effective for moderate-to-severe acne and can inhibit hyperkeratosis, and sebum production and reduce the size of the sebaceous glands. 6,8,17,22en recommending treatments, physicians should consider the psychosocial aspects of acne (e.g., depression, mood effects of drugs such as oral contraceptives and isotretinoin) and physical aspects such as xerosis. 6,8,17,18,19,20,22ompt diagnosis and initiation of treatment may prevent emotional stress and possible sequelae such as post-inflammatory hyperpigmentation (PIH) and scarring. 6,7,8,17,25e clinician should inform the patient about acne-related sequelae such as PIH and scarring to avoid risk factors and promote treatment and maintenance therapy adherence.Educating patients about the central role of inflammation in acne and measures to reduce inflammation is essential. 6,7,8,9,15,17,18ompt and effective reduction in inflammation may reduce the number of acne flares and prolong the time between flares and may reduce sequelae such as PIH and scaring. 6,7,8,9,15,17,18e physician should explain that decreasing washing, avoiding topical alcohol, an abrasive scrub, and rubbing the skin may prevent irritation and, thus, inflammation (Table 2). 6,7,8,17incare products should suit acne patients with all skin types, from irritation-prone to oily skin. 6,7,9,14,15,17,18,19Cleansers and moisturizers should be non-comedogenic and complement acne treatments offering benefits such as gentle cleansing, hydration, and promoting a healthy skin barrier (Table 3). 6,7,9,14,15,17,18,19Daily use of fragrance-free, non-irritating, and non-comedogenic cleansers, moisturizers, and sunscreen may reduce inflammation, xerosis, erythema, and photosensitivity resulting from topical or oral acne treatments. 6,7,17,18,26Over-vigorous washing may irritate the skin, enhancing inflammation and exacerbating acne. 7,19,26Cleansers and moisturizers, such as those containing ceramides, promote a healthy skin barrier, reducing inflammation and irritation that may result from topical or systemic treatments (Figure 3). 6,7,9,14,15,17,18,19I G U R E 2 (A) Differences in stratum corneum ceramide level comparing acneaffected skin with no acne.Ceramides AP, NP, EOP.Reproduced with permission. 13B) Differences in TEWL comparing acneaffected skin with no acne.Reproduced with permission. 13Transepidermal water loss (TEWL).The skincare regimen should be included in the acne prevention, treatment, and maintenance care regimen and should be ongoing even after treatment prescription and other nonprescription products are discontinued. 6,7,17successful clinical outcome requires adherence to acne treatment.Factors in poor acne therapy adherence include an incomplete or slow response to therapy, adverse effects such as skin irritation or dryness, burning, and peeling, and regimens that are too complicated and/or inconvenient. 19Cleansers and moisturizers, such as those containing ceramides, promote a healthy skin barrier and have been successfully used to reduce adverse events resulting from topical or systemic treatments enhancing treatment adherence and improving patient outcomes.

| LI M ITATI O N S
Our literature searches found no specific clinical studies comparing various skincare products with others.The skincare recommendations are therefore based on clinical experience and the panels' opinions.Abbreviation: BPO, benzoyl peroxide.

TA B L E 3
The role of skincare for patients with acne.

Skincare Reason for skincare use References
Daily use ongoing of fragrance-free, non-irritating, and non-comedogenic cleansers, moisturizers, and sunscreen May reduce adverse events such as xerosis, erythema, photosensitivity, and PIH resulting from prescription oral and topical drugs.Monotherapy is mostly for mild acne for its antiinflammatory action, reduction in acne flares, oil control, and minimization of scars.
CERs-containing skincare may offer acne patients benefits to help restore skin barrier function.Maintenance treatment depends on the type of acne.CER-containing cleansers or lotions and sunscreen can be used as a mono treatment or as adjunctive to medical treatment.CER-containing cleansers may reduce follicular occlusion, and control oily skin.CER-containing skincare helps to promote a healthy skin barrier, reducing inflammation and acne flares.7,14,15,19,26   Abbreviations: BPO, benzoyl peroxide; CER-containing, ceramide-containing; PIH, post-inflammatory hyperpigmentation.
cleansers and moisturizers is a recommended strategy after successfully controlling the disease.Conclusions: Epidermal barrier dysfunction contributes to acne exacerbation.Using the appropriate treatment and skincare helps to minimize irritation and inflammation, enhance treatment adherence, and improve patient outcomes.K E Y W O R D S acne skin barrier, cleansers, moisturizers, skincare Take home messages Inflammation plays an important role in acne development and exacerbation.Educating patients and clinicians about inflammation's central role in acne and measures to reduce inflammation may improve patient outcomes.The approach to acne should include a daily and ongoing skincare regimen to prevent or reduce skin irritation and xerosis from acne and treatments leading to poor treatment adherence.published in English from 2010 to January 31, 2023.Search terms used: Acne vulgaris AND pathogenesis OR skin barrier dysfunction OR inflammation OR hyperkeratinization OR skin microbiome OR dysbiosis OR acne guidelines OR algorithms OR consensus recommendations OR prescription treatment OR nonprescription treatment OR skincare OR retinoids OR benzoyl peroxide OR isotretinoin OR hormonal treatment OR adherence to treatment OR bacterial resistance OR efficacy, safety, tolerability, skin irritation, handling, comfort.The results of the searches were evaluated independently by two reviewers.Based on reviewer consensus, each treatment within the publications was assigned an alphanumeric level of evidence (1 to 4 and A to C), using pre-established criteria by the American Academy of Dermatology. 10Initially, the searches yielded 78 articles, and after excluding 52 duplications and poor-quality papers, 26 articles remained.Notably, no clinical studies were specifically on the skin barrier, acne, or skincare, making rating irrelevant.3 | ACNE AND EPIDERMAL BARRIER DYS FUN C TION Statement 1.The pathophysiology of acne (including comedogenesis, inflammation, and follicular rupture) is associated with skin barrier dysfunction.

Statement 2 .
Studies have found an impaired water barrier function (higher transepidermal water loss and conductance value) in acne-affected skin.Altered ceramide levels have been observed in inflammatory skin disorders such as acne although the mechanisms involved have not yet been elucidated. 13,14The ceramidase metabolism pathways require further studies in acne-affected skin to provide insights into mechanisms involved in reducing ceramides.In xerotic skin, ceramide I, II, III, IV, V, and VI may be reduced; however, the acne-related factors contributing to the total ceramide reduction are yet to be clarified.Reduced ceramide levels in acne lesions compared to healthy skin have been observed, which may lead to impaired skin barrier function. 13A study compared skin barrier function in 65 males comprising 36 males with mild (n = 25) or moderate (n = 11) facial acne (age range: 14-26 years, mean age 21.1 [±3.4 years]) and 29 healthy males without acne (age range: 16-24 years, mean age 21.8

Statement 5 .
Ceramidecontaining cleansers and moisturizers, used as an adjunct to acne treatment, have improved the skin barrier function and reduced irritation.

7, 14 ,
15,19,26 6kin irritation and xerosis associated with acne treatment.Modified with permission from Schachner et al.6 Acne is associated with inherent abnormalities in epidermal barrier functions.Studies have shown that acne-affected skin may be prone to irritation, frequently resulting from acne treatment.Systemic andTA B L E 2 Adjunctive skincare to acne treatment.Common ingredients in acne treatment products (eg, BPO and retinoids) are effective but may cause skin irritation and impair the skin barrier function.CER-containing cleansers, creams, or serums are frequently used on the face for moderate-to-severe acne in combination with prescription acne products to reduce inflammation, irritation, and xerosis that may result from acne treatment.