¹Center for Clinical Studies, Webster, TX, USA
²Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there is no conflict of interest.
Funding sources: None.

Abstract:
Nanodermatology has been an emerging area of research and drug development in the last two decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has yielded potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery. Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been more frequently explored for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been increasingly investigated to improve efficacy of various drugs via enhanced delivery to the target site. Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but these formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to boost drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects. Enhanced drug delivery utilizing nanoparticles has been successfully trialed for treatment of psoriasis, vitiligo, acne vulgaris, and atopic dermatitis in many research studies, however more investigation is needed prior to utilization in humans.

Keywords:nanodermatology, nanoparticles, enhanced drug delivery, nanocarriers

Introduction

Nanodermatology has been an emerging area of research and drug development in the last decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has exhibited potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery.¹

Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been increasingly investigated for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been more frequently explored in order to improve the efficacy of various drugs via enhance delivery to the target site.

Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but topical formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to increase drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects.²

This article will discuss the promising application of nanotechnology as a route of increased transdermal drug delivery in order to treat various common dermatological conditions, including psoriasis, vitiligo, acne vulgaris and atopic dermatitis, as well as nanoparticle utilization in sun protection.

Psoriasis

Psoriasis is a common inflammatory skin disorder, affecting over 125 million people worldwide, that can range in presentation from erythematous plaques to pustules. Traditionally, mild psoriasis can be treated with topical medications, including corticosteroids, betamethasone/calcipotriol, calcineurin inhibitors, and retinoids.³ However, moderate to severe disease often requires systemic treatments such as methotrexate, cyclosporine, and biologic agents. These systemic treatments often come with the risk of significant adverse effects.

Multiple drug‐loaded nanoparticles and nanocarriers have been found to have promising potential in the treatment of psoriasis, while minimizing the risk for adverse effects and maximizing transdermal drug delivery.⁴ Tazarotene (TZ), a topical antipsoriatic retinoid with significant irritation potential, was loaded into fluidized spanlastic nanovesicles that measured about 260 nanometers. When compared to commercially available topical tazarotene, researchers found that the nanovesicles not only showed higher antipsoriatic activity in human subjects but also demonstrated deeper penetration during ex vivo testing.⁵ Tacrolimus, an immunosuppressive agent that has often been used topically to treat psoriasis, exhibits poor cutaneous bioavailability, particularly in hyperkeratotic plaques. Therefore, topical tacrolimus ointment was compared to a micelle nanocarrier tacrolimus formula. The micelle formula showed increased tacrolimus delivery into the stratum corneum and epidermis when compared to the traditional topical tacrolimus ointment.⁶

In addition to improved delivery of classic topical treatments, researchers have been utilizing nanotechnology to investigate the transdermal delivery potential of drugs traditionally used as systemic therapy, such as methotrexate and cyclosporine. Both methotrexate and cyclosporine are typically reserved for severe psoriasis due to the significant risks of toxicity and adverse effects. However, when combined with nanotechnology, these drugs can be applied topically, therefore greatly minimizing the risk for systemic adverse effects.⁴

Cyclosporine, a calcineurin inhibitor, is incredibly effective as a systemic therapy for psoriasis, but unfortunately, its use comes with risks of nephrotoxicity, neurotoxicity, metabolic disruptions, and immunosuppression.⁷ In an imiquimod induced psoriatic plaque on mice, cyclosporine‐loaded liposomes were more effective at reducing psoriatic features than cyclosporine gel.⁸

Like cyclosporine, systemic methotrexate has shown great utility in the treatment of psoriasis, however there is risk of significant side effects. In an in vivo skin deposition study, methotrexate niosomes, or non‐ionic surfactant vesicles, resulted in a greater percentage of drug deposition in the skin when compared to a simple methotrexate topical solution.⁹ Similarly, gold nanoparticles loaded with methotrexate led to improvement of scaling, erythema, epidermal thickness, and parakeratosis in mice models with imiquimod induced psoriasis. The methotrexate‐gold nanoparticles also showed deeper penetration when compared to topical methotrexate. Additionally, after treatment there was no significant difference in the blood count, AST, and ALT of the treatment group when compared to the control.¹⁰

Nanoparticles have not only allowed for greater skin penetration and drug delivery than classical topical treatments, but they have also allowed researchers to create topical formulations of systemic medications that come with risk of significant adverse effects. More research is needed to compare the efficacy of systemic therapy with nanoparticle formulations.

Vitiligo

Vitiligo, an acquired disorder characterized by the development of depigmented macules, is thought to be caused by autoimmune destruction of melanocytes. Treatment is typically focused on preventing progression and inducing some degree of repigmentation. Recent investigation into the utility of nanodermatology has led to exciting treatment potential.

Berberine, an isoquinoline alkaloid, despite exhibiting potential benefit as a topical vitiligo treatment, has limited utility due to its poor skin permeability. In order to improve delivery, berberine was loaded into hyalurosomes, which are modified nanovesicles that have enhanced skin penetration abilities and are non‐irritating. In human skin studies, berberine hyalurosomes showed greater permeability and greater drug retention when compared to a conventional berberine gel. In a vitiligo‐induced mouse model, the berberine loaded hyalurosomes showed a significant return of normal pigmentation that was greater than the conventional berberine gel.¹¹

Psoralen in combination with ultraviolet light (PUVA) is a common treatment for vitiligo. However, psoralen has weak percutaneous permeability. Resveratrol, a sirtuin activator, has the potential to manage vitiligo by reducing oxidative stress, therefore psoralen and resveratrol were loaded into ultra deformable liposomes and used as combination antioxidants in PUVA therapy for vitiligo. This combination not only demonstrated greater skin penetration but also showed significant melanin stimulation and tyrosinase activity. Administration of a nanocarrier loaded with resveratrol and psoralen in combination with UV light therapy stimulated pigment and reduced oxidative stress, making it a promising potential therapy for vitiligo.¹²

While the mechanism of vitiligo is not completely understood, oxidative stress is believed to play a significant role in the disease. Platinum and palladium have been investigated for their strong antioxidant properties as they are inducers of superoxide dismutase.¹³ PAPLAL, a topical cream consisting of platinum and palladium nanoparticles, has been shown to be an effective treatment for vitiligo that was refractory to first‐line therapies including narrow band UVB and topical corticosteroids.¹⁴

Acne Vulgaris

Acne vulgaris is one of the most common skin conditions, affecting up to 90 percent of adolescents with presentation ranging from mild to severe. The pathophysiology is multifactorial, making treatment complicated. Therapeutic options for mild to moderate acne typically consists of topical agents, including retinoids, antibiotics, benzoyl peroxide, and salicylic acid, whereas treatment for severe acne consists of oral therapy with isotretinoin, antibiotics, or hormonal agents.¹⁵

While topical tretinoin is an effective treatment, its use is limited by low water solubility and high instability in air and heat. Its use also comes with the risk of significant skin irritation and dryness. Therefore, nanocarriers have been investigated to achieve greater photostability and lower irritation potential. Tretinoin was encapsulated into solid lipid nanoparticles which improved its photostability and showed significantly less irritation when compared to the gel formula in an animal model.¹⁶

Similar to tretinoin, adapalene has been widely used in the treatment of acne vulgaris since gaining US FDA approval in 2016, however it has limited bioavailability in the hair follicle and its use also comes with the risk of irritation and dryness. Adapalene was successfully encapsulated into tyrosine derived nanospheres (TyroSphere™). In ex vivo follicular penetration studies, the tyrospheres significantly enhanced adapalene delivery to the pilosebaceous unit, when compared with commercially available adapalene. In vitro irritation studies also demonstrated decreased irritation potential of the tyrosphere formula.¹⁷

Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that presents with dry, eczematous, erythematous patches, and pruritus. AD is likely mediated by a combination of epidermal changes, increased immunoglobulin E levels, and T-helper 1 and 2 proliferation which leads to elevated levels of inflammatory cytokines. Traditionally, topical corticosteroids have been the treatment of choice for acute flares, however long-term use of topical corticosteroids can cause skin atrophy.

Liposomes, composed of phospholipids, have a strong affinity for the stratum corneum, allowing for increased skin permeability and uptake. Both betamethasone 17‐valerate (BMV), a moderate potency corticosteroid, and diflucortolone valerate (DFV), a high potency corticosteroid, were loaded into liposomes. The liposomes showed 2.68 to 3.22 times greater retention in the stratum corneum and epidermis when compared to the commercially available BMV and DFV creams. In pharmacodynamic evaluation, the liposome formula showed greater anti‐inflammatory activity when compared to the commercial creams, despite the liposome gel having 10 percent less active drug than the commercial cream. This result was thought to be due to enhanced delivery and decreased systemic absorption. Finally, in rat models, AD was induced by dinitrofluorobenzene, and the liposomes formulas not only showed lower erythema, edema, and scratching behaviors, but also to the commercial creams.¹⁸

In a similar study, chitosan nanoparticles were loaded with hydrocortisone (HC) and hydroxytyrosol (HT). These nanoparticles exhibited deeper penetration and a higher concentration of drug in the epidermal layer. This could reduce the dose and frequency of drug application needed for effective treatment, which could decrease the risk of adverse effects. Systemic adverse effects of glucocorticoids include hypocalcemia and hyperglycemia. When commercially available hydrocortisone was repeatedly applied to rat models, they showed a significant decrease in serum calcium concentration and an increase in serum glucose concentration, while the HC‐HT nanoparticle solution did not cause any biochemical derangements. This demonstrates that utilizing a nanoparticle drug delivery system could potentially reduce systemic adverse effects of glucocorticoids, while also increasing skin penetration.¹⁹

While corticosteroids have been considered the first‐line for AD, other topical calcineurin inhibitors, like tacrolimus and pimecrolimus, are being increasingly utilized in AD. Calcineurin inhibitors are often considered safer for long‐term use and use on sensitive areas like the face, but they often cause an uncomfortable burning sensation at the site of application. Tacrolimus has a high molecular weight and poor water solubility which limits its permeability. To reach therapeutic dosing, larger quantities of topical tacrolimus must be applied, which increases the risk of irritation. Chitosan nanoparticles were used as the carrier for tacrolimus. The nanoparticle solution led to greater drug retention in the stratum corneum, epidermis, and dermis than the commercially available cream. In AD induced rat models, AD was successfully managed with the nanoparticle solution containing one‐third the dose in the commercially available cream.²⁰

Sunscreen

Sunscreen commonly contains minerals like zinc oxide and titanium dioxide as the primary active sun protection agents. However, sunscreens with these ingredients are typically opaque and white, which lends cosmetic concerns to many users. Many cosmeceutical companies have begun incorporating nanoparticles into their sunscreens in an attempt to create a more desirable and better tolerated formula.

Sunscreens with zinc oxide and titanium dioxide nanoparticles have been shown, in an in vitro study, to provide enhanced sun protection. Additionally, sunscreen containing nanoparticles demonstrated improved texture with no residual white cast when compared to creams with zinc oxide and titanium dioxide particles.²¹

However, some studies have shown that zinc oxide and titanium dioxide nanoparticles lead to an alteration in the recommended UVA/UVB ratio. Currently, the FDA recommends that at least one‐third of the overall sun protection factor should be against UVA. Reducing the size of the zinc oxide and titanium dioxide particles confers an increased UVB protection at the expense of UVA protection. In order to mitigate this, some researchers have recommended that using various sizes of particles in one formulation, for example using micro and nano zinc oxide (20‐ 200 nanometers) particles and nano titanium dioxide (20‐35 nanometers) particles may remedy this discrepancy. However, more research is needed to determine the ideal size of particles to adhere to the recommended 3 to 1 UVB/UVA ratio.²²

Concerns

As nanoparticle use increases both in treatment of skin disease and in cosmetics, there are concerns regarding the long-term health effects and potential toxicities. The potential for nanoparticles to accumulate in the skin and contain harmful impurities are important considerations regarding toxicity.²³

Due to rising concerns that nanoparticles are depositing into deeper layers of the skin and causing cellular damage, multiple studies have sought to determine the long-term effects of utilizing nanoparticles in various formulations. One study found that both coated and uncoated zinc oxide nanoparticles localized primarily in the stratum corneum with limited penetration into viable epidermis. This study also found that the nanoparticles did not alter the skin barrier function or the redox state of the viable epidermis.²⁴ There are also concerns regarding the ability of titanium dioxide to induce DNA damage and potentially act as a carcinogen.²⁵ However, the carcinogenic effects of titanium dioxide are typically seen after subcutaneous injection or inhalation of nanoparticles.²⁶

There is conflicting data regarding the penetration of zinc and titanium nanoparticles, and thus the ability for these nanoparticles to cause damage. However, despite the conflicting data, the consensus appears to be that nanoparticles in sunscreens and skin care do not pose a health risk, however more research and collaboration is needed between the scientific and cosmetic communities as many cosmetic companies do not advertise their products as containing nanoparticles.^25,27

Conclusion

Nanoparticles, defined as a particle ranging from 1 to 1000 nanometers, have shown extremely encouraging potential in targeted drug delivery systems in the treatment of various dermatologic diseases and conditions. Not only do nanoparticles or nanocarriers exhibit increased penetration and retention of existing topical drugs, but they also have been employed to create topical formulations of drugs that are primarily given as systemic therapy. This allows drugs like methotrexate and cyclosporine to be used topically and without the risk of severe adverse effects. Overall, the utilization of nanoparticles as an enhanced drug delivery system is an incredibly promising area of research with exciting implications in the treatment of many common dermatologic conditions. Nanocarriers appear to be safe, however more research and development is needed as the majority of current research is being done in animal models. It is also important for cosmeceutical and scientific communities to collaborate on research, particularly when it comes to utilization of nanoparticles in sunscreens. Cosmetic companies should also be encouraged to publish or advertise the use of nanoparticles in their products.

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

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

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

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

Introduction

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

Pathogenesis

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

Clinical Features and Diagnosis

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

Associated Comorbidities

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

Treatment

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

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

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

Conclusion

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

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¹School of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
²Center for Clinical Studies, Webster, TX USA
³Dermatology Department, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest.
Funding sources: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
A biofilm is a diverse community of microorganisms enclosed in an extracellular matrix. Although this organization of cells exists naturally in healthy skin, it is also involved in the pathogenesis of multiple skin disorders, such as acne and atopic dermatitis. Because biofilms provide microorganisms with a survival advantage and increased resistance to traditional antibiotics, they can be very difficult to treat, particularly when the goal is to also preserve the natural skin microbiota. This review aims to provide an overview of the role of biofilms in various dermatological diseases, as well as the conventional and newly developed therapies that can be used in their treatment.

Keywords: acne, atopic dermatitis, biofilms, dermal fillers, hidradenitis suppurativa, onychomycosis, chronic wounds

Introduction

Biofilms are a collection of microbial cells encased in a polymeric substance matrix.^1,2 Biofilms can range in population from tens of cells to hundreds of thousands, and can encompass multiple species of organisms.³ The first step in its formation involves the attachment of the microorganism to a living or abiotic surface.³ The cells can then begin secreting extracellular components of the matrix, including polysaccharides, DNA, proteins, and lipids.^3,4 This is followed by a maturation stage, with the formation of a stable, three-dimensional community that allows for the movement of nutrients and signaling particles within the biofilm.⁵

Biofilms provide cells with increased protection from desiccation, chemical perturbation, and invasion from other microorganisms.⁶ They can also reduce the susceptibility of bacteria to antibiotics by up to 1000 fold, due to reduced antibiotic penetration and the presence of metabolically dormant, antibiotic resistant persister cells, which can recolonize the biofilm following antibiotic administration.⁷ Biofilms can also alter the growth kinetics of bacteria, where cells deeper within the polymer are in a stationary phase of growth, which β‐lactam antibiotics are less effective against.⁷ These factors provide bacteria and certain species of fungi with a survival advantage compared to organisms in the planktonic state, which is the free floating state of microorganisms.³

Acne

The pathogenesis of acne is complex, involving inflammation of the pilosebaceous unit, as well as hyperkeratinization, androgen induced increase in sebum, and colonization of the follicle by Cutibacterium acnes (C. acnes).^8,9 The C. acnes genome was shown to encode genes for the synthesis of extracellular polysaccharides, an essential component of biofilms.³ In one study, over 50% of antibiotic treated patients were found to be colonized with erythromycin and clindamycin resistant strains, and over 20% of them had tetracycline resistant acne.⁸ Biofilms are one factor for this increased resistance to antibiotics observed in patients with severe acne.⁸ For example, in vitro studies showed that significantly higher concentrations of cefamandole, ciprofloxacin, and vancomycin were needed to inhibit C. acnes biofilms compared to free floating bacteria.⁸ In another study, C. acnes biofilms were less sensitive compared to planktonic bacteria to a range of antimicrobials, such as 0.5% minocycline, 1% clindamycin, 0.5% erythromycin, 0.3% doxycycline, 0.5% oxytetracycline and 2.5-5% benzoyl peroxide.⁸

One hypothesis for the pathogenesis of acne is the formation of the comedone, which is a collection of keratin and sebum in the pilosebaceous unit caused by the hyperproliferation of keratinocytes in the follicular lining.⁹ Biofilms are thought to increase the cohesiveness between keratinocytes, which promotes the formation of the comedone and enables C. acnes to strongly attach itself to the follicular epithelium.⁹ Following the hyperproliferation of keratinocytes, the comedone grows with debris and releases its immunogenic contents into the surrounding dermis.⁹ As a result, proinflammatory cytokines can infiltrate the pilosebaceous unit and promote the development of inflamed pustules and papules seen in acne.⁹

In addition to certain antibiotics and antimicrobial peptides, agents that can specifically target biofilms in acne include surfactants such as rhamnolipids, which are produced by Pseudomonas aeruginosa (P. aeruginosa) and can dysregulate biofilms by creating central hollow cavities.^9,10 Surfactants can also be used to weaken the adhesion of biofilms to surfaces and promote their dispersal.¹¹ Quorum sensing (QS) plays an important role in the formation and maintenance of biofilms.¹¹ By altering microbial gene expression, they can promote the transformation from the planktonic state into a sessile form.¹¹ The use of QS inhibitors such as azithromycin, bergamottin, usnic acid, quercetin, and ellagic acid may help inhibit C. acnes virulence factors and biofilm formation.^9,10 Moreover, dispersin B and deoxyribonuclease (DNase) can be employed to degrade biofilm proteins, while metal chelators can be used to bind to magnesium and calcium in the outer cell wall, which disrupts the stability of the biofilm.¹⁰ Nitric oxide generating agents can also be used to decrease intracellular cyclic dimeric guanosine monophosphate levels, which leads to a favoring of the planktonic state over the formation of biofilm.¹⁰ Finally, bacteriophage therapy specifically directed against C. acnes, has proved to be successful in the animal model and is an exciting new therapy that has been studied more extensively in other diseases such as meningitis, but not in the treatment of skin conditions.¹⁰

Atopic Dermatitis

Atopic dermatitis (AD) is present in 10% of children and 7% of adults in the United States. Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) are the two most commonly found bacteria in AD lesions, and are also known to form biofilms^12-14 In a study of 40 patients with AD, 93% of biopsied lesions contained staphylococci, with 85% being strong producers of biofilms.¹⁵ Bacteria naturally colonize the epidermis, forming biofilms between squamous epithelial cells even in healthy skin.¹² In AD however, S. aureus and other pathogens enhance inflammation and weaken the skin barrier.^12,13,16 Although staphylococci natrally colonize the skin, those associated with biofilms have only been found in AD lesions.¹² Moreover, S. aureus can cause keratinocytes to undergo apoptosis when present as biofilms but not in the planktonic state.¹² This is significant to the pathogenesis of AD, as damaged keratinocytes release double-stranded RNA (dsRNA), which initiates the toll-like receptor (TLR)-3-mediated secretion of thymic stromal lymphopoietin (TSLP), a cytokine that causes a strong itch response.¹² TSLP also activates dermal dendritic cells and recruits T helper 2 cells, which subsequently produce interleukin (IL)-4 and IL-13, leading to the inhibition of adenosine monophosphate (AMP) and further weakening immunity against pathogens.¹² Bacterial biofilms can also result in the blockage of eccrine sweat glands and ducts, causing further inflammation or potentially inducing the inflammation and pruritus observed in AD.^12,17

Traditional treatment of AD does not typically involve the use of antibiotics due to their insufficient specificity and risk of promoting antibiotic resistant bacteria.¹⁸ In terms of reducing inflammation in AD, a major goal of treatment is the improvement of dysbiosis, which involves reducing the population of S. aureus.¹⁸ Sodium hypochlorite bleach baths are helpful for improving clinical AD symptoms by limiting bacterial colonization and restoring skin surface microbiome. In vitro and in vivo investigations have provided evidence of efficacy, with one study demonstrating significant anti-staphylococcal and anti-biofilm activity when used at a concentration of 0.02% compared to the standard recommendation of 0.005%.^18,19 There is also evidence supporting the topical use of farnesol and xylitol in supressing the formation of biofilms.^14,20 Additionally, use of emollients can improve skin hydration and decrease pH, which may play a role in preventing S. aureus proliferation, with some studies suggesting a decreased incidence of AD in susceptible individuals after consistent emollient use.¹⁹ One of the novel treatments currently being developed to specifically target S. aureus in AD lesions is Staphefekt™, an engineered bacteriophage endolysin with bactericidal activity towards S. aureus.¹⁸ Other potential new therapies include synthetic antimicrobial peptides that target staphylococci as well as their biofilms, and omiganan, an indolicidin analog was found to improve microbial dysbiosis as well as clinical scores in phase II trials in the treatment of AD lesions.¹⁸ Finally, dupilumab and ultraviolet-B (UVB) therapy also exhibited efficacy in decreasing S. aureus colonization, while increasing the bacterial diversity in AD patients.¹⁸

Wounds

Wounds are particularly susceptible to the formation of biofilms due to the absence of the protective covering of the skin.²¹ S. aureus, P. aeruginosa, and the Clostridiales family are among the most common biofilm-forming bacteria found in wound infections.^4,22 In chronic wounds, the healing process is impaired due to multiple factors that result in a constant state of inflammation.^23,24 These wounds are characterized by the presence of proinflammatory cytokines such as tumor necrosis factor alpha and IL-1 alpha.²³ One element that contributes to this state of chronic inflammation and recruits inflammatory cells is biofilm formation in the initial wound.^23,25 These inflammatory cells then secrete proteases and reactive oxygen species that delay the healing process.²³ In some cases, extensive use of antimicrobials, particularly in doses under the minimum inhibitory concentrations required for the infectious agent, promotes biofilm formation.⁴

Debridement is essential in the initial management of chronic wounds, including the removal of necrotic tissue and biofilms.^23,26 This should be followed by the administration of antimicrobials such as polyhexamethylene biguanide, acetic acid, and iodine.²³ Silver and hypochlorous acid have also shown therapeutic potential against biofilms when tested in vitro, exhibiting bactericidal activity against multiple microorganisms, including Pseudomonas and Staphylococcus.²⁷ Low-frequency ultrasound, lasers, and photodynamic therapy are also potential options for biofilm breakdown.²⁰

Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by painful nodules, abscesses and pus-discharging sinus tracts or fistulas known as tunnels.^28,29 Microscopic analysis of HS lesions typically reveals inflammatory infiltrates that can partially be explained by the presence of biofilms in most cases of HS.²⁸ This is particularly evident in the late stages of HS pathogenesis.³⁰ Although HS is not an infectious disease itself, some studies have demonstrated the presence of slow-growing microbial agents.^28,31 One study of the microbiome of sinus tracts in patients with moderate to severe HS found that they were predominantly colonized by anaerobic species, such as Prevotella and Porphyromonas.³⁰ The deposition of intradermal corneocytes and hair fragments provides a suitable environment for the formation of biofilm by commensal bacteria.²⁸ This is supported by the consistent detection of anaerobic species in HS lesions, which can grow in the anoxic environment created by deep-seated HS nodules, dilated hair follicles, and sinus tracts.²⁸ In one study, 67% of sampled HS lesions contained biofilms.²⁸ Moreover, the difficulty in detecting these pathogens using traditional culturing techniques, which identify the planktonic state of bacteria, may be due to the presence of biofilms, especially in chronic lesions.²⁸

Conventional treatment of HS lesions continues to be tetracyclines, while second-line therapy involves a combination of clindamycin and rifampicin, which work synergistically and reduce risks of antibiotic resistance.³⁰ However, when administered as monotherapy, 65.7% and 69.3% of bacterial cultures from HS patients were found to be resistant to clindamycin and rifampicin, respectively.³⁰ Dapsone can also be used as a third-line treatment in mild to moderate HS, however, evidence supporting its use is weak.^30,32 Other therapeutic options include metronidazole or ertapenem in severe cases, with the latter exhibiting resistance rates of less than 1%.³⁰ Patients with HS often experience flare ups of the disease, which can also be partially attributed to biofilm formation.^28,33

Dermal Fillers

Injectable dermal fillers are the second most common nonsurgical cosmetic procedure performed in the United States.¹⁷ Adverse effects include erythema and nodules, which although heavily disputed, have recently been attributed to biofilm formation.^17,34 Conventional treatment of these side effects can involve the use of steroids, though when used at high doses can worsen the infection and symptoms.^17,34 In one study that investigated the role of dermal fillers in biofilm formation, the presence of as few as 40 bacteria was enough to cause infection.³⁵ Bacterial colonies in human skin contain up to 105 bacteria, which make them a potential source of needle contamination during skin penetration if proper precautions are not taken.³⁵

Treatment of dermal filler biofilms includes broad-spectrum antibiotics such as ciprofloxacin, amoxicillin or clarithromycin.³⁶ Dermal fillers composed of hyaluronic acid, one of the most common substances used in fillers, should also be treated with hyaluronidase.³⁶ This serves to lyse the gel and remove the mechanical support of the biofilm.³⁶ 5-fluorouracil, laser lyses, and surgical resection can also be employed in more severe, treatment-resistant cases.^17,36 Importantly, the conventional use of steroids, non-steroidal anti-inflammatory drugs, and antihistamines should be avoided.^17,36

Onychomycosis

Onychomycosis is a fungal infection of the nails that is associated with the formation of biofilms.^37-39 It is typically therapy resistant and relapses are common.³⁷ Trichophyton rubrum, Trichophyton mentagrophytes and the Candida family are all fungi that can cause onychomycosis, and are also potentially capable of producing biofilms.⁴ These biofilms are hypothesized to be responsible for the treatment resistance and infection recurrence observed in onychomycosis.³⁸ Multiple studies of patients with onychomycosis support the formation of fungal biofilms in vitro and ex vivo.³⁸ Amphotericin B and echinocandins are usually effective in clearing free existing fungi as well as biofilms, especially when combined with biofilm-targeted treatments such as cationic antimicrobial peptides and antibody-guided alpha radiation.³⁷ Antibody-mediated inhibition of matrix polysaccharides has been found to prevent biofilm formation in Cryptococcus neoformans.⁴⁰ Other biofilm-specific therapies being investigated aim to inhibit the extracellular matrix or matrix polysaccharides and increase antifungal penetration, including gentian violet, DNases, and quorum-sensing molecules.³⁷

Conclusion

The skin is colonized by a wide variety of microorganisms, which can aggregate and form biofilms.^3,41 In some conditions, these biofilms can play a significant role in the pathogenesis of multiple skin diseases such as acne, atopic dermatitis, and hidradenitis suppurativa.^8,12,28 With the growing concern of antibiotic resistance in dermatology, it is essential to consider the role of biofilms in the treatment of cutaneous disorders.^42,43 Recently developed treatments, such as bacteriophage therapy, that have been used extensively in other fields of medicine but not yet in dermatology, should also be investigated for their utility in the management of skin conditions.¹⁰

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Conflict of interest: Dr. Lipson has been a speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Bausch Health, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, L’Oréal, Galderma, Janssen, Leo, Lilly, Novartis, Pfizer, Sanofi, Sun Pharma and UCB.
Funding sources: None.

Abstract: Acne is a common inflammatory condition of the skin worldwide. The skin is an endocrine organ and hormones are a key pathogenic factor in all types of acne with a particularly important role in adult female acne pathogenesis and management. In females, we have the unique opportunity to manipulate hormones systemically to successfully manage acne and, more recently with the approval of clascoterone 1% cream, we can target the hormones topically in both genders. The intent of this paper is to provide physicians with an up-to-date clinically relevant review of the role of hormones in acne, the impact of currently available contraceptives and therapies available to target hormones in acne.

Keywords: adult female acne, etiopathogenesis, hormones, oral contraceptives, prevalence, systemic therapy, topical therapy

Introduction

Acne is an incredibly common condition affecting almost 10% of the global population and recognized as the 8th most common condition worldwide.¹ There is a misconception among the public that acne is only a disease of adolescence. Acne is prevalent through adulthood, especially in women. The results from the ALL PROJECT research initiative presented at the European Academy of Dermatology and Venereology (EADV) Congress in October 2023 reported the prevalence of acne in 50,552 patients aged 16 years and older (69.5% older than 34 years of age) from 20 countries across 5 continents. This study found the frequency of acne in this broad population to be 18.99%, 16.3% in men and 21.95% in woman.² The prevalence of adult female acne (AFA) has been shown to peak in the 20s (50.9%) and decreases with each decade to 15.3% in patients aged 50 years and older.³ In keeping with adolescent acne, acne in adult woman has sequelae of scarring and dyspigmentation, as well as mental health impacts. A 2014 survey of American women with AFA elucidated that the majority feel less confident, more self-conscious, frustrated and embarrassed when they see or think about their acne. The isolating nature of this condition was also identified in this survey; the majority of women reported feeling like ‘no one understands what it’s like to have adult female acne’.⁴

Acne Pathophysiology

Management of acne focuses on targeting the four main pathogenic factors: sebum, Cutibacterium acnes (C. acnes), inflammation and abnormal follicular keratinization. The relationship between these factors is complex. Acne begins with adrenarche, when sex hormone production begins. Sebocytes have androgen receptors and are exquisitely androgen responsive. Sebocytes begin to produce increased sebum upon androgen stimulation and sebum production rates have been shown to correlate with acne severity.^5,6 The sebum in patients with acne has altered composition contributing to development of acne.^6,7 Androgens also directly stimulate sebocytes to produce inflammatory cytokines in the skin, another important pathophysiologic factor in acne.^6,8 Studies have shown that in the sebocytes of patients with acne there are increased number and/or activity of enzymes converting weak androgens to potent androgens, such as 5-alpha reductase, which converts testosterone to dihydrotestosterone (DHT). Patients with acne may also have increased numbers of androgen receptors and/or polymorphisms of androgen receptors making them more sensitive.⁶ Other hormones can stimulate the sebaceous gland, but to a lesser extent, such as insulin-like growth factor-1 (IGF-1), growth hormone and pro-opiomelanocortin. Within the pilosebaceous unit, the sebum rich environment creates a microenvironment ideal for C. acnes proliferation and activity.⁵ Loss of diversity of C. acnes with increased proportion of acnegenic phylotypes, such as phylotype IA1, stimulate inflammation and the break down of triglycerides in sebum to free fatty acids. Pro-inflammatory free fatty acids from the sebum and C. acnes biofilm stimulate keratinocytes and result in hyperkeratinization and comedogenesis.^5,6

The Skin is an Endocrine Organ

AFA is notoriously challenging to treat with standard acne therapies that do not address the hormones. It frequently does not respond to monotherapy with topicals and is recurrent after courses of antibiotics and isotretinoin.⁹ Women experience acne lesions on the lower face and jawline often flaring prior to menses. As lesions resolve, post-acne dyspigmentation, erythema and even scarring are common. AFA responds well to systemic anti-androgen treatment. This is possibly a contributing factor to the common misconception that women with AFA have abnormal hormone levels and the condition being referred to as ‘hormonal acne’. Hormones play an integral role in all acne. While it is known that women with polycystic ovarian syndrome (PCOS) and several other hormonal conditions have greater incidence of acne, the majority of women with AFA have normal systemic hormone levels.⁶ The skin is an endocrine organ and, as reviewed in the pathophysiology, the increased androgen and androgen effect implicated in acne is at the level of the skin. Women with adult female acne do not require assessment of systemic hormone levels unless there are other signs or symptoms indicating hormonal abnormalities.¹⁰

Managing the Hormones

Targeting the hormones in the treatment of patients with AFA is highly effective. In female patients we have the unique opportunity to manipulate the hormones systemically to manage acne. Traditionally this has been achieved with combined oral contraceptives and/or spironolactone. The combined oral contraceptives (COCs), which contain both estrogen and a progestin, have varying degrees of anti-androgenic effects. Estrogen is anti-androgenic through the increase of sex hormone globulin, which results in lower levels of circulating free testosterone.⁹ The progestins vary in their androgenic and anti-androgenic effect, resulting in distinct differences in efficacy of the various COCs.^11,12 First generation progestins, such as norethindrone, have a marked intrinsic androgenic effect. COCs containing first generation progestin can cause or exacerbate acne and should be avoided in acne prone women or stopped in women who develop acne (Table 1).^2,11 Second generation progestins have variable androgenic effect. COCs containing second generation progestins such as levonorgestrel and norgestrel are commonly prescribed and may improve acne in some patients and exacerbate in others. While there are levonorgestrel-containing COCs approved for both contraception and treatment of acne, they are not as effective at treating acne as COCs containing more anti-androgenic progestins.¹³ Third generation progestins, such as desogestrel, norgestimate and etonogestrel, are the least androgenic. COCs containing third generation progestin are effective for treating acne.^11,14 The fourth generation synthetic progesterone analogues, drospirenone and cyproterone acetate, are anti-androgenic and highly effective in the treatment of acne.¹⁴ In Canada, there are only five COCs approved for the treatment of acne (Table 2).^15-19 Based on pathophysiology of the hormones, all COCs containing third or fourth generation synthetic progesterone should work effectively to treat acne. COCs can take at least 4-6 months to show effect when treating acne.

Forms of contraception other than COCs also impact acne (Table 3). Depo-Provera® and the older progesterone-only pills Micronor® and Movisse™ contain first generation progestins, medroxyprogesterone acetate and norethindrone, respectively. These can cause or exacerbate acne. The new and highly effective progesterone-only birth control pill Slynd® is a fourth generation synthetic progesterone, drospirenone, at a dose equivalent to 25 mg of spironolactone.²⁰ While there are no studies investigating the effect of Slynd® on acne, based on the pathophysiology of drospirenone, this contraceptive option has promise as a treatment option for acne-prone women, in particular for those who require contraception without estrogen or are breastfeeding. Hormonal intrauterine devices (IUDs) contain the second generation progestin levonorgestrel without estrogen, and may cause or exacerbate acne.^21,22 The contraceptive vaginal ring and patch containing third generation progestins may reduce acne. The newer contraceptive device, Nexplanon®, contains a third generation progestin etonogestrel without estrogen. The effect of Nexplanon® implant on acne has yet to be determined. There is a promising retrospective claims-based analysis that looked at new incident acne encounters among women starting COC compared with various other forms of contraception. This showed increased risk of clinical encounters for acne with both copper and levonorgestrel IUDs and decreased risk of incident clinical encounters for acne with the etonogestrel implant.²³ More data is required on this topic. Interestingly, there are hormonal treatments prescribed for menopausal symptoms which contain first generation progestin and may cause acne; this should be considered in post-menopausal women presenting with acne (Table 1).

Spironolactone, an antagonist of the androgen receptor and aldosterone, is effectively used off-label for treatment of acne in females at doses typically between 50-200 mg daily.²⁴ Like COCs, spironolactone is very slow to show effect. Spironolactone is contraindicated in pregnancy but safe during lactation.

Another off-label therapy that has been used to target hormones in the treatment of acne is metformin. Metformin enhances peripheral tissue sensitivity to insulin, thereby reducing IGF-1. IGF-1 stimulates androgen production from the gonads and adrenals and decreases sex hormone binding globulin leading to increased free testosterone.^25,26 Metformin has long been considered a treatment option for patients with PCOS associated acne, with mixed efficacy results in the literature.²⁵ There are now studies showing promising results for treatment of acne with metformin in males and females as monotherapy (500 mg BID) or adjunct therapy (875 mg OD).^25,26

Most recently, clascoterone 1% cream (Winlevi®) has entered the acne treatment landscape; this first-in-class topical anti-androgen is approved for the treatment of mild to severe acne in males and females aged 12 years and older.²⁷ Clascoterone is believed to work by competitive inhibition of the androgen receptor resulting in decreased sebum and inflammatory cytokine production locally in treated skin.⁸ This will be a great addition to the repertoire of treatment options for all acne, including AFA. Clascoterone 1% cream is currently the only treatment available to target the hormonal factor in males with acne.

Conclusion

AFA is a common and devastating condition. It is frequently recurrent after standard acne treatments (topicals, antibiotics and isotretinoin) and responds very well to anti-androgen treatment. The majority of females with AFA have normal circulating hormone levels; the increased androgen level and effect is locally at the level of the skin. Understanding the androgenic effect of the various progestins in currently available hormonal treatments is helpful in managing AFA. Third and fourth generation COCs and spironolactone play important roles in treating this common condition. The drospirenone containing progesterone only birth control pill is a new option for females with acne who cannot take COC. Often simply an adjustment of contraceptive can result in acne resolution. Clascoterone cream is a topical anti-androgen with local effect in the skin and has a promising future in treatment of acne, including AFA.

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¹University of Central Florida/HCA Consortium, Tallahassee, FL, USA
²Dermatology Associates of Tallahassee, Tallahassee, FL, USA
³Florida State University College of Medicine, Tallahassee, FL, USA

Conflict of interest: The authors have no conflicts of interest to declare. Funding sources: None.

Abstract:
Hidradenitis suppurativa (HS) is a severe, debilitating, chronic inflammatory skin disease characterized by recurrent painful nodules, abscesses and draining sinus tracts in intertriginous areas. While this condition appears to stem from follicular unit dysfunction, its cause is multifactorial and the exact pathogenesis has yet to be fully elucidated. These factors make treatment selection challenging and contribute to variable therapeutic response among affected patients. Typical regimens consist of a combination of medical and surgical modalities, tailored to individual responses. However, HS is often refractory to traditional treatments, prompting the need for newer and more effective therapies. Herein, we review current and emerging HS therapies.

Keywords: hidradenitis suppurativa, treatment, secukinumab, bimekizumab, izokibep, upadacitinib, povorcitinib, eltrekibart

Introduction

Hidradenitis suppurativa (HS) is a severe, debilitating, chronic inflammatory skin disease characterized by recurrent painful nodules, abscesses and draining sinus tracts.¹ The condition primarily affects intertriginous areas, often leading to permanent scarring and disfigurement. There is a strong psychosocial impact of the condition, with HS patients reporting high rates of depression, anxiety, social stigmatization, and shame leading to significant reductions in quality of life. While an estimated 1% prevalence rate is often described in literature, HS is thought to be widely underdiagnosed. The onset of HS typically occurs between ages 20-40 years with a 3:1 predilection for women over men and higher rates among those of African descent.¹ HS has been linked to genetic predisposition, skin microbiota, chronic inflammatory conditions, and hormonal factors, as well as environmental factors like obesity and smoking.²

Although the pathophysiology of HS has not been fully elucidated and is multifactorial, current evidence supports an inflammatory etiology with follicular unit dysfunction.³ The current driving theory suggests disease initiation is associated with a chronic subclinical inflammatory state and/or excess keratinocyte proliferation, which results in follicular occlusion and rupture with subsequent abnormal and diffuse inflammatory response. Recurrent events lead to the eventual loss of follicular structures and replacement with dense inflammatory infiltrates and scarring. Elevated levels of many pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-10, IL-17, and IL-23 have been observed in blood and skin biopsy samples of HS patients, further implicating immune dysregulation. There is welldocumented evidence regarding positive feedback loops where IL-17 interactions with other cytokines (namely IL-1, IL-6 and TNF-α) lead to further auto-production of these cytokines as well as downstream activation of acute phase reactants, neutrophilic and complement mediated inflammatory responses.³ It should be noted that while the primary driver of HS is not infectious, bacterial colonization of lesions can complicate acute flares and worsen symptoms.

Current Management in HS

The management of HS involves a multimodal approach including lifestyle modifications, such as weight loss and smoking cessation, various medical/surgical therapies and psychological support. The efficacy of medical therapies depends largely on disease severity and, thus, clinical grading using the Hurley staging system can guide medical decision making. This system is universally accepted and classifies stage 1 (mild) as abscess formation without scarring, stage 2 (moderate) as recurrent abscesses with limited scarring and/or sinus tracts and stage 3 (severe) as diffuse involvement with extensive scarring and/or interconnected sinus tracts.¹ The mainstay of medical management in mild-to-moderate disease is oral antibiotics and topical therapies, with consideration of hormonal treatments and systemic retinoids as adjunctive therapy.⁴ Intralesional or systemic steroids are often used for acute flares. For more severe, extensive disease, however, these regimens are rarely sufficient and immunomodulatory agents should be introduced. Currently, there are two biologics approved in the US for HS treatment: adalimumab, a monoclonal antibody (MAb) that targets TNF-α, and secukinumab, an IL-17A inhibitor.

Topicals

For mild disease, topical clindamycin is considered a first-line treatment option that can reduce bacterial colonization and inflammation within HS lesions.⁴ Based on low-level evidence involving 30 patients, topical clindamycin use decreased pustules by approximately 95% after 3 months of treatment, but had no significant effect on deeper abscesses or nodules.⁵ Resorcinol is a topical keratolytic and anti-inflammatory that has shown some benefit for pain and lesion reduction in small studies, though data is limited. Of note, resorcinol is only available in the US through compounding pharmacies, further limiting its practicality. Overthe- counter cleansers containing chlorhexidine, benzoyl peroxide or zinc pyrithione, while not evidence-based, are commonly used in clinical practice as adjunct maintenance therapy across all disease stages.⁵

Systemic Antibiotics

Based on North American clinical guidelines published in 2022, oral tetracyclines or clindamycin plus rifampin are two antibiotic regimens that are generally recommended as first- or secondline options in HS management.⁴ While quality evidence is lacking across the board, previous case series have demonstrated meaningful clinical improvement with these antibiotics. A recent prospective cohort study involving 283 patients (majority with moderate or severe HS) is the first and only to compare the two antibiotic regimens head-to-head over 12 weeks.⁶ Investigators found that while a large proportion of both groups achieved 50% or greater reduction from baseline in the total abscess and inflammatory nodule count and remission, there was no significant difference between the oral tetracyclines group (40.1%) and clindamycin plus rifampin group (48.2%, P=0.26). Another recent study in 28 Hurley stage 1 HS patients reported the efficacy of combination rifampin-moxifloxacin-metronidazole therapy.⁷ They observed that 75% of patients achieved clinical remission of all lesions at 12 weeks of treatment. After the initial 12-week study period, those who achieved remission were switched to a low dose maintenance regimen of cotrimoxazole and at 1-year follow up experienced significantly less flares (average of 1/year vs. 21/ year before treatment). Substantial gastrointestinal side effects and remission rates, as well as concern for bacterial resistance, may limit long-term antibiotic use.

Adjunctive Oral Agents

While hormones are thought to play a role in HS, there have not been many studies on the efficacy of hormonal therapies in this setting. Current guidelines state that estrogen-containing contraceptives and anti-androgens therapies like spironolactone, metformin and finasteride can be considered in women, namely those with comorbid polycystic ovary syndrome and/or reported HS flares around menses.⁴ Similarly, oral retinoids can be considered if adequate control is not achieved with other therapies, as an adjunct, or in patients with concomitant nodulocystic acne. Results from small studies have been mixed and show modest improvement in milder disease.⁴ Finally, those with HS have high risk of certain vitamin and mineral deficiencies, such as vitamin D and zinc. Two case series have shown modest clinical improvements with zinc supplementation.⁸ While zinc supplementation can be considered in patients, there is insufficient evidence to recommend vitamin D supplementation based on North American guidelines.⁸

Surgery

Surgical intervention is often necessary with advanced disease refractory to medical management to address tunnels and chronic scarring. The options are beyond the scope of this review, but include laser therapies, deroofing and surgical excision. These procedures come with their own set of risks and even after radical excision, it is reported that nearly a third of patients still experienced disease recurrence.⁹

Biologics

Biologic therapies are recommended for patients with mildmoderate disease that previously failed first-line therapies or as first-line therapy in individuals with moderate-severe disease.⁴

Adalimumab (Selective TNF-α Inhibitor)

Until very recently, adalimumab was the only approved treatment of HS. In two phase 3 trials, Pioneer I and II (n=633), 316 patients were randomized to receive 40 mg adalimumab once weekly.¹⁰ Pooled data of the trials demonstrated a modest but significant clinical improvement at week 12 with 50.6% of patients in the treatment group achieving Hidradenitis Suppurativa Clinical Response score of 50 (HiSCR50, reduction of at least 50% in the total abscess and inflammatory nodule count, with no increase in abscess or draining tunnel count) compared to 26.8% receiving placebo. Additional surveillance as part of an open-label trial extension demonstrated sustained results on weekly adalimumab with HiSCR50 of 52.3% at week 168.¹¹ During this period, about 15% of patients experienced adverse events leading to discontinuation of the drug. While efficacious, this leaves about half of patients without adequate response. Other TNF-α inhibitors used in HS face the same challenges, including infliximab and etanercept.

Secukinumab (Selective IL-17A Monoclonal Antibody)

In October 2023, the FDA approved the expanded label of secukinumab to cover moderate-to-severe HS in adults. This decision was based on results from two major phase 3 randomized controlled trials (RCT)12 showing promise of subcutaneous secukinumab in patients with moderate-to-severe HS. SUNSHINE (n=541) and SUNRISE (n=543) included a placebo-controlled study period of 16 weeks, followed by long-term treatment without placebo to 52 weeks. In both trials, significantly more patients receiving secukinumab biweekly achieved HiSCR50 at 16 weeks when compared to placebo (42-45% vs. 31-34%). Response rates were sustained and even increased throughout the study period, with 56% of patients in SUNSHINE and 65% in SUNRISE achieving meaningful clinical response as well as significant pain reduction at 52 weeks. Roughly 84% of participants experienced an adverse event, though the great majority were minor with the most common being headache (10%) followed by nasopharyngitis and worsening of HS.

Emerging Biologic Therapies in HS

While the aforementioned therapies have been efficacious, there are many treatment gaps that highlight the need for better options. For one, HS is biologically complex and driven by multiple mechanisms that differ from individual to individual, as evidenced by significant variations in disease severity and lack of response to treatment in many. This warrants a shift away from a ‘one size fits all’ or random trial-and-error treatment algorithm, but rather a personalized approach that caters to the specific markers expressed in each patient. Even for those who achieve excellent results on medication, there is high probability of eventual recurrence, likely related to the fact that current treatment options do not address the underlying causes of HS.

Given the need for further therapeutic options in HS, a plethora of targets are currently being explored, including other inflammatory cytokines (IL-1, IL-17, IL-23), neutrophils, the complement pathway, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The remainder of this paper will focus on the efficacy and safety of these drugs from recent phase 2 and 3 clinical trial results. Unless otherwise stated, the primary trial endpoint was HiSCR50. Additional endpoints could also include HiSCR of 75%, 90% and/or 100%. Participants included those with moderate-to-severe HS, defined as Hurley stages 2 or 3. The main points of these clinical trials and next steps are summarized in Table 1.

IL-17 Inhibitors

Bimekizumab (Dual IL-17A and IL-17F MAb)

Bimekizumab is a MAb that selectively targets IL-17F, in addition to IL-17A. Since both subunits independently cooperate with other inflammatory mediators like IL-1 and TNF-α to drive the chronic inflammatory cascade and tissue destruction seen in HS, bimekizumab’s efficacy profile has been hypothesized to be more favorable than IL-17A inhibitors alone.

In recently released data from BE HEARD I (n=505) and BE HEARD II (n=509) phase 3 trials,¹³ those receiving bimekizumab biweekly achieved statistically significant improvements over placebo in HS severity (HiSCR50 48-52% vs. 29-32%, placebo) and self-reported quality of life at week 16, which was sustained out to 48 weeks without any unexpected safety concerns. According to a March 2023 late-breaking presentation at the annual American Academy of Dermatology (AAD) conference, in an observed case analysis of the two trials combined, over 55% of patients on continuous bimekizumab achieved the higher benchmark of HiSCR75 at week 48.¹⁴

Izokibep (Non-MAb IL-17A Inhibitor)

Izokibep is a novel fusion protein that may address several shortcomings of some other MAbs. The molecule is about oneeighth the size of a traditional MAb, which is thought to allow for high drug exposure levels and deeper tissue penetration. Additionally, izokibep is produced in an inexpensive Escherichia coli (E. coli) system versus the costly mammalian expression systems that MAbs are routinely manufactured in, which could translate into a more affordable treatment option.¹⁵

Data from a small open-label part A of phase 2b/3 trial (n=30) presented at the AAD conference in March 2023 observed 65% of participants achieved HiSCR50 at 12 weeks.¹⁶ Further, about 1 in 3 patients had complete clearance of abscesses and inflammatory nodules (HiSCR100) by week 12. The drug was generally welltolerated, with localized injection site reaction as the most common adverse event. The double-blind, placebo-controlled part B of this phase 2b/3 trial is currently ongoing with plans for an additional phase 3 trial. These results will be much more telling.

Janus Kinase Inhibitors

Expression of genes in the JAK-STAT pathway transduce proinflammatory cytokine signals like IL-6, IL-23, and interferons which have been shown to be upregulated in sites affected by HS,¹⁷ making for a potential therapeutic target. Currently, JAK inhibitors are mainly used in rheumatological conditions, but are increasingly being used and studied across a broad spectrum of dermatological disorders including atopic dermatitis, psoriasis, alopecia areata and vitiligo.¹⁸ Still, there is very limited published clinical data in the use of these drugs for HS specifically. A literature review published in April 2023 included 25 articles using JAK inhibitors in HS patients, mainly small case series and reports, and concluded encouraging findings of their efficacy and safety in this setting thus far.¹⁷ Several clinical trials are currently ongoing and upcoming to further investigate.

Upadacitinib

Results from a phase 2 RCT¹⁹ presented at AAD in March 2023 showed that 38.3% of 41 patients treated with daily oral upadacitinib achieved HiSCR50 at week 12, compared to 23.8% of the placebo group. Response rates were sustained through week 40 with no new safety concerns. They also reported similar efficacy rates in those who had previously failed anti-TNF biologics (HiSCR50 41.7%) and TNF-naïve patients (HiSCR50 37.1%). It should be noted that results were only statistically significant when compared to historic placebo levels from previous trials, but not when compared to the placebo arm within the same study.

Povorcitinib

In 2022, a phase 2 RCT²⁰ that spanned 16 weeks and enrolled 209 patients with HS of any Hurley stage met its primary endpoint of statistically significant decreases from baseline abscess and inflammatory nodule count at all three tested dose levels (povorcitinib 15 mg, 45 mg, 75 mg) compared to placebo with no new safety concerns. Early 2023, new 52-week results²¹ were presented at the European Academy of Dermatology and Venereology Congress as part of the open-label extension period in which all 174 qualifying patients received povorcitinib 75 mg daily. Nearly 30% of patients had 100% clearance of abscesses and inflammatory nodules (HiSCR100) by week 52. Additional 52-week efficacy results include HiSCR50 and HiSCR75 values of roughly 60% and 50%, respectively. Stop-HS1 and Stop-HS2 are two phase 3 RCTs currently recruiting 600 patients each with results expected in 2025 and would be the largest HS drug trial to date.

Chemokine Receptor (CXCR) Inhibitors

Eltrekibart (LY3041658) is a MAb that selectively binds to the ligands that signal CXCR1 and CXCR2. These chemokine receptors are known to play a role in neutrophil migration to areas of inflammation, which is a key aspect in the pathogenesis of HS.²² Phase 2 RCT trial (n=72) data was presented at the AAD in March 2023 where 66% of patients receiving eltrekibart biweekly achieved HiSCR50 at 16 weeks compared to 41% in the placebo arm.²³ These improvements were sustained in the treatment group to week 36. While these results are quite favorable, further quantification of safety and efficacy will need to be determined in a subsequent phase 3 trial which has not yet been announced.

Upcoming Notable Clinical Trial Results

An additional IL-17 inhibitor worth mentioning is sonelokimab, which incorporates specific desirable features of both bimekizumab and izokibep. Similar to izokibep, sonelokimab uses newer nanobody biotechnology for better drug delivery and enhanced tissue penetration while also having dual targets of IL-17A and IL-17F, like bimekizumab.²⁴ A phase 2 RCT, the MIRA trial, comprising 210 patients is currently underway testing two doses of sonelokimab compared to placebo and adalimumab.²⁴ Notably, this is the first time that a HS trial has the higher benchmark of HiSCR75 as the primary endpoint; 57% of patients achieved HiSCR75 at 24 weeks.

The same company developing secukinumab for HS, has testing underway for several other targets in HS. A phase 2 RCT is recruiting 200 individuals to determine the safety and efficacy of five different drugs for moderate-to-severe HS: Bruton’s tyrosine kinase (BTK) inhibitor, leukotriene A4 hydrolase (LTA4H) inhibitor, CD40 MAb, T-cell immunoglobulin and mucin domain 3 (TIM-3)/ IL-1β/IL-18 MAb, and anti-B-cell activating factor (BAFF) receptor MAb.²⁵ LTA4H, BTK and TIM-3 all play a role in inflammation, though have not been tested previously as targets for HS therapy.

Additional clinical drug trials with results expected in the near future are summarized in Table 2.

Conclusion

The management of HS is a challenge, in part due to its chronic and variable nature with a poorly understood pathophysiology. Further, delays in diagnosis can lead to disease progression and extensive scarring which creates another layer of complexity in treatment. In addition to its painful dermatologic implications, HS is associated with many comorbidities including inflammatory bowel disease, psoriasis, and metabolic syndromes, as well as significant mental health burden with increased depression, anxiety and suicide rates observed.²⁶ While the existing standard management with antibiotics and topicals with steroids for flares can be sufficient for mild disease, more intensive measures involving surgery and/or biologic drugs are frequently required in more severe cases.

An improved understanding of the disease mechanisms and wider range of biologic therapies aimed at these underlying inflammatory pathways and specific pathophysiology of HS is poised to create a major shift in this management conundrum. Currently, only two biologics are approved for HS. Adalimumab has demonstrated its effectiveness and sustained response in over half of individuals with moderate-severe HS across several studies. However, even in responders, complete remission is uncommon, and an even larger treatment gap exists when adalimumab fails or is contraindicated. Notwithstanding, the recent approval of secukinumab has the potential to change clinical practice by offering meaningful and durable improvement of symptoms.

Furthermore, a number of alternative biologics are being studied in HS with different targets including inhibitors of IL-17, IL-1, chemokine receptors and the JAK pathway, to name a few. The drugs discussed within this paper are furthest along in the pipeline and recent favorable phase 2/3 trial data indicate support for positive regulatory decisions in the coming future. While these therapeutics will undoubtedly bring value to patients, there remains a need for personalized medicine through enhanced insight into the etiology and progression of HS, along with identifying optimal targets. The further development of new therapies for the treatment of HS is crucial in continuing to improve outcomes and quality of life for patients with this debilitating disease.

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Abstract

Introduction: Advances in cancer treatment have contributed to a reduction in mortality but survivors and healthcare providers should be aware of the potential adverse effects of these advanced treatments.

Objectives: The Canadian skin management in oncology (CaSMO) practical recommendation was developed to improve the quality of life for cancer patients and survivors who experience targeted therapy-related cutaneous adverse events.

Methods: The CaSMO advisory board (advisors) identified four common cutaneous adverse events related to targeted therapy and gave practical recommendations for managing these cutaneous adverse effects based on the results of a literature search and clinical expertise.

Results: Papulopustular eruption, xerosis, paronychia, and hand-foot skin reaction were identified as common cutaneous adverse events related to targeted therapy. The advisors provide practical steps for preventing and treating these cutaneous conditions.

Conclusions: The CaSMO practical guidance is for all healthcare providers who treat oncology patients receiving targeted therapy and can be used to help prevent and manage common cutaneous adverse events, thereby improving treatment adherence, quality of life, and outcomes.

Acknowledgments and Disclosure:  This educational supplement to the Journal of Drugs in Dermatology was funded by La Roche Posay Canada.

Keywords: targeted cancer therapy, management of cutaneous adverse events

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Introduction

Improved understanding of the molecular basis of numerous cancers has led to the development of targeted therapies. Epidermal growth factor receptor (EGFR) inhibitors, multikinase inhibitors, vascular endothelial growth factor (VEGF) inhibitors, mammalian target of Rapamycin (mTOR) inhibitors, BRAF inhibitors, and MEK inhibitors (Table 1) are all molecular targeted agents that have emerged as effective cancer treatments. As opposed to conventional chemotherapies which usually target rapidly dividing cells and are not specific to cancer cells, targeted therapies more selectively attack cancer cells by inhibiting specific molecules involved in tumor pathogenesis.

Table 1: Targeted therapy categories and specific agents

The increased specificity of these therapies leads to an improved safety profile compared with conventional chemotherapy, with fewer systemic side effects. However, the most prevalent side effect of targeted therapies are skin and appendage toxicities. The targeted therapy cutaneous adverse events (ttCAEs) profile is broad and differs for each specific agent. In general, most common ttCAEs include papulopustular eruption, xerosis, pruritus, hand-foot skin reaction (HFSR), paronychia, and mucositis. Targeted therapies can also lead to uncommon but serious toxicities such as morbilliform exanthema, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

ttCAEs can lead to severe symptoms with profound effects on cosmesis, quality of life, and compliance with cancer medication. Common ttCAEs are not life-threatening toxicities by themselves but can lead to targeted therapy dose reduction, therapeutic holidays, or even permanent discontinuation, which may compromise cancer outcomes.

Targeted therapy toxicities generally are a positive prognostic sign to therapeutic response. CAEs incidence as well as severity are associated with a longer time to progression of cancer (TTP) and increased overall survival (OS).¹ Most data show a positive relation between papulopustular eruption incidence and severity and TTP and OS in patients receiving EGFR inhibitors.^2-5 The goal for dermatologists and oncologists should be to treat the dermatological toxicities prior to considering dose reduction, interruption, or discontinuation, whenever possible.

While ttCAEs are common, treatments and guidelines are mostly based on reviews, expert consensus, and case series. Very few controlled studies are published on specific treatments to prevent or manage these CAEs. Even more, in most published clinical trials studying targeted therapies, cutaneous side effects are reported as “rash” without details about the clinical appearance and management of specific cutaneous toxicities.

Mechanisms underlying these ttCAEs are poorly understood. Most explanations come from literature on EGFR inhibitors. EGFR is overexpressed in some cancer cells, but is also expressed in normal basal keratinocytes, the outer layers of hair follicles, sebaceous epithelium, and periungual tissues. It plays an essential role in skin physiology and differentiation and proliferation of these tissues. EGFR blockage induces upregulation of IL-1 and TNF-alpha and increases synthesis of other inflammatory chemokines and cytokines, leading to an inflammatory response.⁶ Apoptosis of normal keratinocytes, abnormal keratinization, and the subsequent inflammatory response could explain the occurrence of papulopustular eruption. EGFR inhibitor-induced xerosis results from abnormal keratinocyte proliferation and differentiation, leading to a deteriorated stratum corneum and a decrease in moisture retention.^{7, 8} Paronychia pathogenesis is unclear. It could be secondary to skin fragility, leading to onychocryptosis and subsequent paronychial inflammation.⁹ EGFR inhibitors induce an inflammatory response which could result in paronychia.¹⁰ EGFR inhibition-induced abnormal keratinocyte differentiation and proliferation lead to periungual stratum corneum thinning and fragility, resulting in piercing of paronychium and granulation tissue formation.¹¹ EGFR is also involved in the normal healing process, so EGFR blockage leads to abnormal healing which could contribute to excessive periungual granulation tissue.¹¹ Infection does not appear to play a consistent role in the pathogenesis of paronychia.⁹ HFSR pathophysiology is even less understood. In contrast to hand-foot syndrome induced by chemotherapy agents excreted in sweat, a study on sorafenib showed that this targeted therapy is not excreted through eccrine glands.¹²

In an era in which there is a growing number of targeted therapy indications and use, it is essential that dermatologists, oncologists, and other physicians know how to manage these common CAEs to enable patients to continue receiving these survival-prolonging therapies and improve their outcomes.

This review article discusses the management of four common CAEs induced by targeted therapy: papulopustular eruption, xerosis, paronychia, and HFSR.

Scope

The CaSMO project aims to improve the quality of life for cancer patients and survivors by offering tools to prevent and manage CAEs.^13-16 A general management algorithm to reduce the incidence of all CAEs and maintain healthy skin using general measures and skin care,¹⁴ an algorithm to reduce and treat acute radiation dermatitis,¹⁵ and an algorithm for the management of hormonal therapy-related CAEs¹⁶ were previously published. These algorithms aim to support all health care providers (HCPs) treating oncology patients, including physicians, nurses, pharmacists, and advanced providers. A practical primer followed on prevention, identification, and treatment, including skin care for immune-related CAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.¹⁷ The next step in the project was to develop practical guidance for the management of four common CAEs (papulopustular eruption, xerosis, paronychia, and HFSR) in oncology patients receiving targeted therapies.

Methods

The CaSMO advisors convened for a meeting to develop practical guidance for targeted therapy-related CAEs. The advisors used a modified Delphi approach following the AGREE II instrument.^18-20

Literature Review

Searches included literature describing current best-practice in improving comfort during targeted therapy, reducing/treating CAEs, and promoting healing of affected skin. Selected literature is clinically relevant to the practical guidance and included guidelines, consensus papers, reviews, and publications describing current best-practice in CAEs-related targeted therapy in the English language from January 2010 to May 2022. Excluded were articles with no original data (unless a review was deemed relevant), articles not dealing with prescription treatment, skincare for cAEs-related to targeted therapy, and publication language other than English.

A dermatologist and physician/scientist conducted searches on PubMed and Google Scholar for English-language literature on May 20 and 21, 2022, using the following AND OR search terms:

Group 1: TKIs OR MKIs OR tyrosine kinase inhibitors OR multikinase inhibitors OR EGFR inhibitor OR VEGF inhibitor OR FGFR inhibitor OR MEK inhibitor OR BRAF inhibitor OR PanRAF inhibitor OR BCR-abl inhibitor OR osimertinib OR afatinib OR dacomitinib OR erlotinib OR gefitinib OR lapatinib OR cetuximab OR panitumumab OR sunitinib OR bevacizumab OR Lenvatinib OR vandetanib OR regorafenib OR sorafenib OR axitinib OR pazopanib OR erdafitinib OR pemigatinib OR trametinib OR cobimetinib OR dabrafenib OR vemurafenib OR belvarafenib OR KIT OR PDGFR OR imatinib OR dasatinib OR nilotinib AND cutaneous adverse event

Group 2: paronychia OR hand-foot skin reaction OR papulopustular rash OR acneiform rash OR xerosis OR pruritus OR rash OR skin toxicities AND targeted therapy

Group 3: prescription medication OR skincare OR topical OR prevention OR treatment OR maintenance OR QOL OR quality of life OR adjunctive OR education OR communication OR communication strategies OR adherence OR concordance OR efficacy OR safety OR tolerability OR skin irritation AND cutaneous adverse event AND targeted therapy

Two reviewers independently evaluated the results of the literature search. The abstracts of 422 articles were reviewed after which 116 were excluded for duplication or poor quality. After a review of the articles in full, 297 remained (Figure 1).

General Management Principles for Skin Toxicities of Anti-cancer Treatment (Stats), Including Caes Induced by Targeted Therapy

A recently published article by the CaSMO working group reviewed in details general skincare measures to prevent STATs, including CAEs induced by targeted therapies.¹⁴ Their preventive algorithm is mainly based on three major behaviors: cleanse, moisturize, and protect. (Tables from the previous publication).

Papulopustular Eruption

EGFR inhibitors and mTOR inhibitors can induce a papulopustular eruption. MEK inhibitor monotherapy is also a common cause whereas BRAF inhibitors rarely induce this toxicity. Combining a BRAF inhibitor to MEK inhibitors significantly decreases the incidence and severity of MEK inhibitor induced papulopustular eruption.²¹ Papulopustular eruption is the most common toxicity of EGFR inhibitors, affecting 50-100% of patients, depending on the agent.²² Cancer response and survival have a positive correlation with the incidence and severity of the papulopustular eruption in patients receiving EGFR inhibitors.⁴

Papulopustular eruption, also sometimes referred as acneiform eruption or folliculitis, classically occurs early after the initiation of targeted therapy, in the first 7 to 10 days of treatment. It peaks after two to four weeks, then stabilizes and decreases in intensity after six to eight weeks. A mild papulopustular eruption often persists over months or the eruption may sometimes self-relieve despite continuing targeted therapy. It affects seborrheic and UV-exposed areas, mainly the scalp, face, neck, upper chest, and back. The eruption is characterized by monomorphous inflammatory papules and pustules. Pruritus is a common associated symptom. As opposed to classic acne, it lacks typical comedones and cysts. Papulopustular eruption is dose dependent.

Atypical acneiform eruption warrants bacterial culture and viral swab to exclude bacterial and herpetic infection. It can either be a primary cutaneous infection or a superinfection developing on a pre-existing papulopustular eruption. Infection should be considered when papulopustular eruption is widespread and involves non-seborrheic areas such as upper extremities, lower extremities, abdomen, and buttocks, does not involve the face, lasts longer than eight weeks, appears late after more than 12 weeks of targeted therapy, or is recalcitrant to appropriate treatment.^{23, 24} Other signs of infection include the presence of vesicles, yellow crusts, discharge, or painful lesions.^{23, 24}

Some trials have studied preventive tools to decrease the incidence and severity of papulopustular eruption (Table 2). A phase II randomized controlled trial (STEPP trial) evaluated a pre-emptive regimen in patients receiving panitumumab, an EGFR inhibitor, for metastatic adenocarcinoma of the colon or rectum.²⁵ Patients were randomized into two groups. One group received a pre-emptive treatment beginning day -1 of panitumumab and continued through weeks 1 to 6 and it consisted of a combination of skin moisturizer daily in the morning, sunscreen before going outdoors, hydrocortisone 1% cream at night, and oral doxycycline 100 mg twice a day. The other group received only reactive treatment deemed necessary by the investigator to manage emergent skin toxicity. The incidence of protocol-specified grade 2 or higher skin toxicities during the 6-week skin treatment period was 29% and 62% for the pre-emptive and reactive groups, respectively. These protocol-specified skin toxicities included pruritus, acneiform dermatitis, skin desquamation, exfoliative dermatitis, paronychia, nail disorder, skin fissures, skin laceration, pruritus, rash, pustular rash, skin infection, skin ulceration, and local infections. Papulopustular eruption was reported less frequently with pre-emptive treatment (77%) comparing to reactive treatment (85%). This preventive regimen should be initiated in patient receiving EGFR inhibitors and MEK inhibitors which are targeted therapies with a higher risk of papulopustular eruption. Another randomized controlled trial evaluated the preventive use of doxycycline to prevent erlotinib-induced acneiform eruption.²⁶ Incidence was comparable between patients receiving doxycycline and the ones receiving the placebo, but doxycycline decreased the eruption severity.

Photoprotection is likely an important preventive tool even though some studies did not show any benefits.²⁷ Patients must avoid using tanning bed. A physical/inorganic sunscreen should be favored instead of chemical/organic sunscreen that can irritate the skin²⁸.

Treatment lines are detailed in Table 2. Typical over the counter and prescribed topical acne treatments such as benzoyl peroxide, retinoid, azelaic acid, and alpha-hydroxy acid should be avoided. These therapies are typically drying and irritating, which may worsen the papulopustular eruption. Topical tazarotene was studied in a cohort of patients on cetuximab.²⁹ Patients applied it on one side of the face and the other side was used as control. Most patients did not experience any improvement with the use of topical tazarotene. Furthermore, the rash was assessed as more severe on the tazarotene side for some patients.

Phototoxicity induced by tetracycline class antibiotics must be taken into consideration in patients receiving targeted therapy. Doxycycline has an overall better tolerance and safety profile than minocycline but comes with a risk of phototoxicity which could potentially worsen the papulopustular eruption. Photoprotection must be reinforced in this setting. Minocycline is another option that does not lead to phototoxicity but has potential serious side effects including autoimmune hepatitis and drug-induced systemic lupus. In patients who cannot commit to strong photoprotective measures or who are living in areas with high ultraviolet index, minocycline may be a better option, but should be given for less than a year to decrease the risk of autoimmune side effects. For all other patients, doxycycline is a better option because of its safety profile. Especially for patients with renal insufficiency, doxycycline is the drug of choice.

Topical dapsone has been studied in patients receiving cetuximab.³⁰ They were randomized to apply dapsone 5% gel to one side of the face and chest twice daily, and a moisturizer to the contralateral side, used as control. All patients were also receiving oral minocycline. A statistically significant reduction in lesion count was observed on the dapsone-treated sides. Dapsone has anti-inflammatory and anti-bacterial properties without the risk of skin atrophy or microbial resistance potentially induced by the prolonged application of topical steroids and antibiotics, respectively.³⁰

Isotretinoin is an effective treatment if tetracyclines or topical treatments fail. A low dose of 0.15-0.35 mg/kg is recommended.³¹ Tetracyclines should be stopped before starting isotretinoin. Concomitant use of isotretinoin and tetracycline increases the risk of pseudotumor cerebri (idiopathic intracranial hypertension). Isotretinoin has overlapping side effects with targeted therapy such as xerosis and excessive granulation tissue. Isotretinoin-induced xerosis may exacerbate the papulopustular eruption, so the regular application of an emollient should be reinforced. Isotretinoin can also induce photosensitivity, which can worsen the acneiform eruption. Photoprotective measures must be reinforced in patients receiving isotretinoin.

Targeted therapy dosage sometimes needs to be reduced or the medication even needs to be temporarily stopped. If targeted therapy is stopped, it should be restarted when papulopustular eruption is back to a CTCAE severity grades 0 or 1 (papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness).³² Some recommend restarting targeted therapy at 50% of the initial dosage.³³

Table 2: Prevention and treatment recommendations for targeted therapy-induced papulopustular eruption

Xerosis

All targeted therapies can induce xerosis. This ttCAE is progressive and appears usually one to three months after the initiation of cancer treatment. Xerosis can potentially worsen papulopustular eruptions. It can also lead to pruritus, asteatotic eczema, and painful fissures, especially on the hands and feet.

Emollient containing humectant such as urea and lactic acid can be effective to manage xerosis. Fissures are challenging to treat. They can be symptomatic with a burning sensation and significant pain. Emollient and barrier cream are essential. Cyanoacrylate glue, more commonly known as liquid skin glue or liquid bandage, can be applied directly in the fissures to decrease the healing time. Hydrocolloid dressing is another treatment option.

Pruritus induced by targeted therapy is challenging to manage and can be multifactorial. A detailed discussion about pruritus is beyond the scope of this article.

Table 3: Prevention and treatment recommendations for targeted therapy-induced xerosis

Paronychia

Paronychia is a late CAE that can be induced by EGFR inhibitors, MEK inhibitors, mTOR inhibitors, multikinase inhibitors, and VEGF inhibitors. It usually appears after one to two months of targeted therapy with painful periungual inflammation characterized by erythema and swelling. The first digit and first toe are most affected. Paronychia is highly morbid with severe pain and functional limitation. It can lead to the formation of excessive friable granulation tissue, onychocryptosis/ingrown nail, and periungual abscess. It is a common cause of targeted therapy dose reduction or discontinuation. Bacterial and fungal superinfections represent a common complication. If a superinfection is suspected, a bacterial and fungal culture must be done, and the infection treated accordingly.

A few trials have evaluated paronychia treatment. In a retrospective cohort study evaluating the topical use of timolol 0.5% gel twice daily under occlusion to treat targeted therapy-induced paronychia and/or periungueal pyogenic granuloma, 15% of patients were considered in complete response (2/13 patients), 46% in partial response (6/13) and 39% in failure (5/13).³⁵

Surgical interventions may be needed for severe or refractory cases. In a retrospective case series, partial matricectomy, nail avulsion, debridement/clipping, and incision and drainage were performed with resolution rates of 100% (11/11), 38.5% (5/13), 12.5% (1/8), and 0% (0/4), respectively.³⁶

Table 4: Prevention and treatment recommendations for targeted therapy-induced paronychia and periungual hypergranulation

Hand Foot Skin Reaction

HFSR can be induced by multikinase inhibitors, VEGF inhibitors, BRAF inhibitors, and one specific EGFR inhibitor (lapatinib). It usually appears after one-to-six weeks of treatment and has three overlapping clinical phases. It first presents with an inflammatory phase described as symmetrical well-defined erythema over palms and soles with occasional painful tense blisters. Then, it evolves to painful yellowish plaques with surrounding erythema. This is followed by hyperkeratotic plaques more pronounced over pressure points and friction-prone areas on both hands and feet. Soles are more commonly involved than palms. HFSR is most severe with first cycles of treatment and tends to decrease in severity and incidence with subsequent cycles.³⁷ HFSR is another highly morbid toxicity with significant tenderness and functional impairment. It may lead to dose reduction, temporary interruption, or even permanent discontinuation of targeted therapy, compromising cancer outcomes.

HFSR, also referred as acquired palmoplantar keratoderma in few articles, must be differentiated from hand foot syndrome and periarticular thenar erythema with onycholysis (PATEO) that are also STATs involving hands and feet, but with different clinical presentations and causal medications (Table 5).

Table 5: Description of hand foot skin reaction (HFSR), hand foot syndrome, and periarticular thenar erythema with onycholysis (PATEO)

HFSR preventive and management tools are described in Table 6. One multicenter randomized controlled trial evaluated the preventive application of 10% urea three times a day on hands and feet in patients receiving sorafenib for advanced hepatocellular carcinoma.⁴⁰ Incidence of any grade HFSR within twelve weeks of starting sorafenib was significantly lower in the urea group compared to the group with best supportive care alone excluding the use of any cream. Incidence of grades 2 and 3 HFSR was also lower in the urea group. Pre-emptive visits to a podiatrist should be considered, especially for patients starting a targeted therapy associated with a high risk of HFSR (vemurafenib for example).

HFSR has two main components, hyperkeratosis and inflammation, and they guide treatments. Hyperkeratosis is treated with topical keratolytics or retinoids. Inflammation is treated with high potency topical steroids. Oral acitretin has been described in a retrospective study for the treatment of refractory HFSR induced by multikinase inhibitors.⁴¹ It was effective in seven out of eight patients.

Combining a BRAF inhibitor with a MEK inhibitor decreases the incidence and severity HFSR induced by BRAF inhibitor.⁴² Approved combinations of BRAF inhibitors and MEK inhibitors are dabrafenib with trametinib, vemurafenib with cobimetinib, and encorafenib and binimetinib. These combinations are used in the adjuvant or active settings for stage III and stage IV melanoma harboring a BRAF V600 mutation.

Table 6: Prevention and treatment recommendations for targeted therapy-induced hand foot skin reaction

Conclusion

Cancer treatments are constantly evolving, and targeted molecular therapy indications are increasing. Targeted therapies are safer than conventional chemotherapies, but they come with a high risk of CAEs that can lead to poor quality-of-life and cancer treatment dose reduction or even discontinuation, compromising cancer outcomes. This article aims to provide physicians information on frequent skin toxicities associated with targeted cancer therapies, including preventing and treating these CAEs. With this knowledge, dermatologists, medical oncologists, and other physicians can manage ttCAEs with confidence, thereby improving quality of life, treatment adherence, and cancer outcomes.

Disclosures: The authors disclosed receipt of the following financial support for the research, authorship, and publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the study and the manuscript, reviewed it, and agreed with its content. LG: AbbVie, Amgen, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, La Roche Posay, LEO Pharma, Merck Frosst, Novartis, Pfizer, Sun Pharmaceuticals, and UCB – consultant, investigator, and speaker; BMS Consultant and investigator.

Abstract

Introduction: Over the years, the number of surgical excisions, cryosurgery, electrodesiccation, curettage, and facial laser treatment has increased. Presently pre- and post-procedural care and minor wound management remain highly variable, and standards are lacking. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods: A panel of eight Canadian dermatologists (panel) who perform dermato-surgery convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment. The information from the literature searches, together with the panels’ expert opinions and experience, was applied in this review.

Results: Peri-procedural measures depend on individual patient factors and the type of treatment. Post-procedure moisturizer application may be beneficial for promoting wound healing. Studies have shown no differences in infection rates between post-procedural sites treated with topical antibiotics and petrolatum-based products. Moreover, topical antibiotics are among the top ten allergic contact dermatitis-causing agents.

Conclusions: Cutaneous healing should occur with minimal discomfort and an esthetic scar. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Standards for peri-procedural care and minor wound management may support healthcare providers in improving patient outcomes.

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Introduction

Over the years, the number of skin surgery procedures (surgical shave and elliptical excision, Mohs surgery, cryosurgery, electrodesiccation, curettage, electrodesiccation and curettage (ED&C), laser, and other facial rejuvenation treatments) has increased. The American Society for Dermatologic Surgery reported over 15.6 million cosmetic treatments performed in 2020 in the United States (U.S.) alone.¹ About 13.3 million of these were minimally invasive cosmetic procedures, including neuromodulator injections, soft tissue filler injections, microdermabrasion and chemical peels).¹ The top minimally invasive cosmetic procedures comprised neurotoxins 3.65 million (33%), dermal fillers 1.85 million (32%), skin treatment (chemical peels, hydro-facials) 1.39 million (6%), hair removal 0.45 million (2%), skin treatment (combination Lasers) 0.43 million (4%) and skin tightening 0.39 million (7%).²

While many guidance and consensus documents exist that describe best practices for performing skin surgery procedures, few discuss specific pre- and post-procedure measures. Surveys of aesthetic medicine providers confirmed a lack of consistency in the types and duration of peri-procedural measures for dermatosurgery, laser, and minimally invasive cosmetic procedures.^3,4 Presently, skin surgery pre and post clinical care and minor wound management remain highly variable and there are no standards,^3,4 however, cutaneous healing should occur with minimal discomfort and an esthetic scar. This review addresses peri-procedural treatment requirements to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing.

Methods

The project aims to provide insights into skin conditions and lesions created when performing dermatosurgery, minimally invasive cosmetic procedures, and facial laser treatment, followed by developing standards for these measures.

A panel of eight Canadian dermatologists (panel) who perform skin surgery was convened to discuss the findings of a structured literature search on peri-procedural measures for surgical excision, cryosurgery, electrodesiccation, curettage, and facial laser treatment.

We searched PubMed and Google Scholar (secondary source) databases for studies published from 2010 until September 2022. We divided the search terms into four groups to allow optimal results and avoid duplications.

Group 1: Pre-/post-procedure measures AND surgical excision OR curettage OR ED & C) OR cryotherapy OR facial laser treatment; AND Guidelines OR Algorithms OR consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure; AND antimicrobial stewardship OR topical antimicrobials OR systemic antimicrobials

Group 2: Surgical excision, curettage, ED & C, cryotherapy AND healing by primary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 3: Surgical excision healing by secondary intent; AND post-procedure measures OR skincare OR topical wound treatment OR wound dressings

Group 4: Peri-procedure measures for laser treatment; AND Guidelines OR Algorithms OR Consensus papers; AND Adverse events OR Complications OR Pain OR Bruising OR Swelling OR Discoloration OR Infection OR Reactivation of herpes simplex virus OR Antiviral medication OR Scarring OR Comfort OR Sun exposure OR Skincare OR wound healing regimen

Exclusion criteria were no original data, information not specific to peri-procedure measures for skin surgery, minimally invasive procedures, and facial laser treatment, and publication in a language other than English. The results of the searches were evaluated independently by two reviewers (AA, TE) and yielded 98 papers. After reviewing abstracts and removing duplicates and papers that did not contribute to this review (n = 43), fifty-five remained. Guidance and consensus documents are available on dermatosurgery, minimally invasive procedures, and facial laser treatment; however, few discussed peri-procedural measures and wound treatment which did not allow for grading.

Results

Procedures Included in the Review

The review addresses the following procedures: surgical excision, cryotherapy, electrodesiccation, curettage, ED&C, and facial laser treatment.

Surgical Excision

A Canadian national survey amongst dermatologists showed that epileptiform excisions, shave excisions, punch biopsies, curettage, and ED&C was most frequently performed, whereas Mohs micrographic surgery (MMS) was the least frequent procedure.⁵ These procedures are used to remove benign and malignant lesions.⁵

Adverse events are usually minor and include bleeding, hematoma, wound dehiscence, infection, discoloration (post-inflammatory hyper (PIH) or hypopigmentation), and atrophic, hypertrophic, or keloid scar formation.⁵

Curettage and Electrodesiccation

Curettage or electrodesiccation can be used to remove benign (e.g. condyloma acuminatum, seborrheic keratosis, pyogenic granuloma, excess granulation tissue) and malignant lesions. With malignant lesions, curettage is often combined with electrodesiccation (ED&C) or cryotherapy. For many indications, ED&C has been replaced by curettage alone, as it yields similar cure rates and a better cosmetic outcome.^12-16 Dermatologists routinely perform these procedures in their offices.

The disadvantage of curettage with or without electrodesiccation or cryotherapy is the absence of histopathologic margin evaluation.^13-15 Studies on low-risk non-melanoma skin cancers show 5-year ED&C cure rates from 91 to 97%.^15,16

Cryosurgery

Cryosurgery has several indications for both benign and malignant lesions. Benign lesions that can be treated with cryosurgery include seborrheic keratosis, verruca, skin tags, molluscum contagiosum, solar or senile lentigo, and actinic keratosis.^16-20 In the case of exophytic lesions, curettage should be considered prior to cryotherapy. This procedure can be delivered quickly and cost-effectively in an outpatient setting.^16-20

Recurrence rates of actinic keratoses treated with cryotherapy vary significantly (1–39%) in prospective studies likely due to a lack of homogeneity in patient and tumor selection, follow-up period, and inter-operator performance approach.^19,20 Malignant lesions can be treated with this modality, but the depth and extent of freezing may not be known without the use of a cryoprobe. Light cryotherapy often leaves no mark but may not remove the desired lesions. A deeper freeze may be associated with permanent white marks due to the destruction of melanocytes, postinflammatory hyperpigmentation, pseudoepitheliomatous hyperplasia, and depressed scars, which may resolve spontaneously, alopecia which may be permanent due to the destruction of hair bulge cells, and tissue distortion (e.g. nail dystrophy or notching of cartilage) due to damage to the nail matrix/cartilage.¹⁶ Cryosurgery should not be used for conditions that can be exacerbated by cold exposure (cryoglobulinemia, multiple myeloma, Raynaud disease, cold urticaria) and a previous history of cold-induced injury or poor circulation at the site or in that body part.¹⁷ Vasoconstriction induced by cryosurgery in poorly perfused areas may lead to tissue necrosis.¹⁷

Facial Laser treatment

Many different types of lasers are available, and laser treatment has many indications.³ Pulsed dye lasers (PDL) may be used for the treatment of port wine stains in adults and children. A further indication for PDL may be the treatment of telangiectatic rosacea.³ Other indications include radiodermatitis, ulcerated hemangioma, and erythrose of the neck.

For hair removal, various types of lasers, such as pulsed diode lasers, Nd: YAG lasers, or intense pulsed light (IPL) lasers, can be used.³ With the proper preparation and an experienced provider, patients with richly pigmented skin can also safely undergo laser and light-based treatments for hair removal, pigment abnormalities, skin resurfacing, and skin tightening.²¹ Facial rejuvenation aims to correct rhytides, telangiectasias, lentigines, and skin texture.³ Laser and energy devices may be used for facial resurfacing, depending on clinical indication, individual subject characteristics, and the operator’s expertise.^3,4 Lasers, such as CO2 or erbium laser, can be used to remove tattoos, Ota’s nevus, and, to a lesser degree, liver spots and Becker’s nevus.^3,21-24 These lasers permit dermabrasion in treating verrucous hematoma, extensive benign superficial dermo-epidermal lesions, and the esthetic treatment of non-muscular wrinkles, i.e., excepting wrinkles of the forehead and nasal sulcus.^21-24 Laser-assisted administration of photodynamic therapy (PDT) photosensitizers has demonstrated efficacy for superficial BCC.^25-27 The recurrence rates of BCC were markedly reduced in two randomized controlled trials using aminolaevulinic acid PDT with erbium compared to PDT and erbium.^25-27

Cutaneous adverse events with all types of laser treatment, such as reactive hyperemia, edema, scarring, and discomfort, may occur.^3,21-24

Pre-procedural Measures

All Discussed Procedures

Skin conditions and infections can exacerbate and cause complications following skin surgery.^3,4,28,29 For all patients considering having a procedure done, medical history including current and previous treatments, including procedures for the lesion under question, what the patient and treating physician hope to accomplish with the proposed procedure, current medications, and allergies, history of systemic disease, history of abnormal wound healing such as post-inflammatory dyspigmentations, abnormal scarring.^3,4,28,29 In patients that have had previous surgical treatments anywhere on their body, it is often good to assess the resultant scars prior to agreeing to perform a procedure on the individual.

Before the procedure, patients should attend the clinic with clean skin without makeup or cosmetics in the area to be treated.^30-34 Hair should be secured away from the treatment area. Patients should not shave since shaving can cause micro-wounds and increase the risk of infection.

Curettage, Electrodesiccation, ED&C, and Cryotherapy

Typically, additional pre-procedural measures are not required.

Laser Treatment

Laser devices are frequently used for facial rejuvenation. Device and treatment choice depends on individual patient characteristics, expectations, and physician expertise.^22-24 For optimal treatment outcomes, patients should be appropriately selected and screened, followed by a physical exam before treatment, depending on the type of procedure.^23,24 Outcomes of previous skin or surgical treatments are obtained, especially dermabrasion (if previously performed) responses.^28,29 People with hypertrophic scars, keloids, or changes in pigmentation will need peri-procedural cosmetic practices to reduce the risk of these complications or should be advised against the procedure.^28,29 Previously published surveys and algorithms confirmed more than 90% of clinicians recommended sun avoidance before, during, and after facial cosmetic treatments.^3,28,29

Peri-procedural measures are based on individual patient factors and the type of laser procedure.^21-24 For patients receiving ablative laser therapy, pre-treatment of underlying conditions, such as rosacea, dermatitis, and prevention of recurrences in patients with recurrent Herpes simplex, may reduce complications and enable adequate healing time to restore the skin’s barrier function.^3,28 Check patients for remote infections. Caution should be applied when considering extensive laser procedures in patients with compromised immune systems, such as HIV, cancer treatment, immunotherapy, or poorly controlled diabetes.^3-28

Measures During the Procedure

Surgical Excision

Prior to the procedure, the surgical site may be prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Povidone iodine is less commonly used since it is messy and permanently stains clothing. Chlorhexidine is an effective cleanser but may induce allergic contact dermatitis and can be toxic to the eyes and ears, whereas isopropyl alcohol is flammable and can irritate the skin.^31,32 Stabilized HOCL is highly active against bacteria, viruses, and fungal organisms without chlorhexidine’s oto or ocular toxicity; it has been proposed as a future gold standard for wound care.³³ HOCL has been shown to have dose-dependent favorable effects on fibroblast and keratinocyte migration compared to povidone-iodine and media alone.^33,34 It also increases skin oxygenation at treatment sites which may aid healing. There is evidence that HOCL may reduce the risk of hypertrophic scars and keloids as it reduces inflammation and the risk of infection. ^33,34

Local anesthesia and pain management can be customized depending need based on the procedure and patient factors and added at the treating physician’s discretion.

Cryosurgery, Electrodesiccation, Curettage, ED&C

Minimal skin preparation is needed for cryosurgery, ED or curettage if the procedure does not result in bleeding. Therefore, antiseptics are not typically indicated in the majority of procedures.¹⁶ However, topical antiseptics should be applied to lesions that are to be curetted or treated with ED&C.¹⁶

Pain management can be customized depending on the procedure and added at the treating physician’s discretion. Pre-procedure anesthesia should be considered for lesions to be curetted or treated with ED&C and large or extensive lesions. Topical anesthetics applied several hours before the procedure or intralesional anesthesia can help reduce surgical pain. For small lesions, injection of local anesthetic may be more painful than the procedure itself and is therefore not indicated.

Laser Treatment

Before the procedure, makeup removal and skin cleansing using a gentle cleanser is required.^30-34 The treatment site is prepared with chlorhexidine (2%), isopropyl alcohol (70%), or hypochlorous acid (HOCL).^30-34 Local anesthesia and pain management can be customized depending on the procedure and added at the discretion of the treating physician.^28,29

Post-procedural and Wound Healing Measures

Surgical Excision Healing by Primary Intent

A local anesthetic given before the procedure takes about 1-2 hours to wear off. For further pain management post-surgery, oral acetaminophen is preferred over aspirin, naproxen, or ibuprofen, as the latter encourages bleeding.

Topical postoperative wound care involves maintaining a protected wound and a clean, moisturized surface.^35,36 Wound care includes cleansing with either a gentle cleanser or water, applying a topical, and covering the wound with a dressing.^35,36 While previous investigators have evaluated methods for reducing risks of adverse events due to the treatment procedure, robust studies on post-procedural wound management for primarily closed wounds are lacking.^35-38

Physicians typically cover sutured wounds using either a dressing, adhesive tape strips, or both.^35-38 Wound dressings can be classified according to their function, material, and physical form of the dressing (Table 1).³⁵ Wound dressings for sutured wounds are typically left in place for 24-48 hours after surgery.^35-37 If there is a lot of tension on the wound or bleeding during the procedure, the dressing is typically left on for 2 or more days. The dressing can act as a physical barrier to protect the wound until skin continuity is restored and to absorb exudate from the wound, and prevent bacterial contamination from the external environment.^35-37 Some studies have found that the moist environment created by some dressings accelerates wound healing, although excessive exudate can cause maceration of the suture line and peri-wound skin.^35-37 A dressing should absorb wound exudate, minimize maceration and prevent bacterial contamination.³⁶

Table 1: Types of wound dressings and moisturizers

The utility of dressing surgical wounds beyond 48 hours of surgery is controversial, although^35-37 in addition to the above, dressings can prevent irritation from rubbing from clothing.

A systematic review on early versus delayed dressing removal after primary closure of clean superficial wounds found no detrimental effect on the patient when removing the dressing after 24 hours.³⁵ However, the point estimate supporting the conclusion is based on very low-quality evidence.³⁵

Cleansing the suture line after dressing removal post-procedure using an antimicrobial solution or applying an antimicrobial ointment is equally controversial.^35,36

The incidence of surgical site infections (SSI) varies between 1% and 80% depending upon the types of surgery, the hospital setting (community hospital, tertiary‐care hospital, etc.), the classification of surgical wounds, and the method of skin closure.³⁵ In addition, many skin surgeries are performed in the community in physician offices where infection rates range from 0.2% to 2.5%.⁴¹ Antimicrobial resistance is a growing concern, especially when antimicrobial products are used routinely and inappropriately.^39-44 Moisturizers are frequently used to keep the wound moist; however, evidence for beneficial effects on sutured wounds is inconclusive and mainly from small studies.^45-50

After suture removal, the topical application of a moisturizer containing madecassoside, panthenol, and copper-zinc-manganese has been shown to be beneficial.^45-48 The product is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48 Petrolatum jelly and water-free petrolatum-containing ointments or products containing HOCL may also be used postoperatively to keep the wound moist, however, since they are occlusive, they may induce maceration.^49,50

In a study on postoperative wound care after MMS procedures (N = 76) patients were randomized to wound care with an ointment containing petrolatum, humectants, and natural barrier lipids (group 1: n = 27), white petrolatum (group 2: n = 32) or no ointment (group 3: n = 17).⁵⁰ Group 1 demonstrated an incidence of swelling and erythema of 52% (14/27); in group 2 erythema occurred in 12% (4/32) and swelling and erythema in 9% (3/27); and in group 3 erythema was noted in 12% (2/17) and swelling and erythema in 6% (1/17) patients.⁵⁰ The use of antibiotic-containing ointments is best avoided as they may cause allergic reactions and contribute to antimicrobial resistance.^39-44 Moreover, the rate of surgical site infections in minor surgical wounds is low and preventive use of topical antibiotics is not indicated.^35,44-52

If a hypertrophic scar develops, treatment with a silicone gel sheet or gel may improve the scar appearance and pain. Another option is self-adhesive propylene glycol and hydroxyethyl cellulose sheeting; however, evidence of the efficacy of these products in improving scar appearance and reduction of pain is inconclusive.⁵³

Surgical Excision, Curettage, ED&C, and Cryosurgery Healing by Secondary Intent

In a simplified model, wound healing processes occur in four phases 1) vascular response, 2) coagulation, 3) inflammation, and 4) new tissue formation.^54-57 During the initial inflammatory phase, the adaptive immune system is activated to prevent infection at the wound site.^54-57 Macrophages remove neutrophils, bacteria, and debris from the wound site. They then change phenotype to M2 macrophages, starting the proliferative and epithelialization phase, producing anti-inflammatory mediators and extracellular matrices.^54-57 If this phase is hindered, wound healing may be disturbed. The proliferative or epithelialization phase overlaps with the inflammatory phase and usually takes two to three weeks post-procedure.⁵⁴ During this phase, the dermal matrix matures, and inflammatory processes continue in the reticular dermis. The reticular dermis is sensitive to wound stress and infection and is affected by patient-related conditions such as age, sun exposure, or genetic profile.^54-57 Persistent inflammation plays a role in the development of hypertrophic or keloid scars, although it may not be the entire cause.^54-57 During the remodeling phase the wound contracts, and collagen remodeling occurs, which can last for up to a year post-procedure.

Pain management is similar to that previously discussed for primary healing wounds. Patients should be instructed to avoid sun exposure to the treated area, along with sun protection measures such as sunscreen with SPF 50 plus UVA block to prevent discoloration.^3,4,28,29

When a dressing is used post-procedure, the patient should be instructed to keep it dry and leave it in place for 24-48 hours. After dressing removal, a gentle, non-irritating cleanser can be used twice daily to cleanse the treated area.^3,4,28,29 The wound site must be handled with care, particularly during the initial healing phase of 7-10 days when newly formed epithelium can be early inadvertly removed.^3,4,28,29

Moisturizers or products containing HOCL may be applied to keep the wound moist and to promote wound healing (Table 2).^49,50 Similar to what was discussed for sutured wounds, moisturizers containing antibiotics should not be used on wounds not showing signs of infection to avoid allergic reactions and antimicrobial resistance.^39-44,49-52

Table 2: Complications from laser treatment

A moisturizer containing madecassoside, panthenol, and copper-zinc-manganese may be beneficial.^45-48 It is available as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in a concentration of 2-5%.^45-48,59 In an unpublished international observation study, 11,464 adults, children, and infants with a mean age of 31 years (1 week to 97 years) with superficial wounds applied the ointment for 14 days. Clinical (desquamation, cracks, erosion, erythema) and subjective symptoms (tightness, pain, burning sensation, pruritus) showed a significant improvement at 14 days, while tolerance and esthetic aspects of the ointment were rated good.

Wound Healing After Laser Procedures

For patients undergoing ablative procedures, prophylactic oral antivirals such as acyclovir (400 mg orally three times daily) or valacyclovir (500 mg orally two times daily), starting typically one day before resurfacing and continuing for 6–10 days post-procedure may be indicated.^3,28 Patients undergoing ablative laser treatment with baseline melasma or post-inflammatory hyperpigmentation may require pre-procedure lightening agents such as hydroquinone 2-4% cream twice per day in the morning and evening.^3,28

Gold and colleagues developed an algorithm for pre-/post-procedure measures for facial laser and energy device treatment and listed complications from laser treatment and actions that can be taken (Table 2).²⁸

Post-laser management is similar to that discussed for secondary healing wounds.

Limitation

Although few studies on peri-procedural measures for dermato-surgery care and minor wound management are available, the advisors recommend applying a moisturizer without antibiotics for antimicrobial stewardship and contact allergy avoidance.

Conclusion

Peri-procedural measures depend on individual patient factors and the type of dermato-surgery. Standards are required to support healthcare providers to optimize outcomes, prevent infection, enhance comfort, and reduce downtime while reducing inflammation and time to healing. Applying a moisturizer without an antibiotic was shown to be beneficial in promoting cutaneous healing. Studies are required to evaluate purpose-designed moisturizers for dermato-surgery post-procedural application improving patient outcomes.

¹Center for Clinical Studies Webster, TX, USA
²Meharry Medical College, Nashville, TN, USA
³Texas A&M University College of Medicine, Temple, TX, USA
⁴University of Texas Health Science Center, Department of Dermatology, Houston, TX, USA

Conflict of interest: All authors have no conflicts of interest.

Abstract:
Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand how dermatologists can combat this issue.

Keywords: antibiotic resistance, dermatology, antibiotic, antimicrobial, infection, acne, rosacea, hidradenitis suppurativa, folliculitis decalvans, bullous pemphigoid, CARP

Introduction

There are many reasons for the development of antibiotic resistant bacteria. Aside from rampant use in agriculture settings, poor antibiotic stewardship among physicians is a major contributor. Dermatologists play an essential role in this process given the significant incidence of inflammatory dermatoses, as well as skin and soft tissue infections (SSTIs) treated with antibiotics. Furthermore, dermatologists have a higher rate of prescribing antibiotics compared to other specialists.¹ Therefore, it is crucial for dermatologists to understand strategies to combat bacterial resistance and reduce its global burden.

Combating Antibiotic Resistance in Dermatology

Molecular resistance is perpetuated through poor antibiotic stewardship. Commonly, this stems from unclear instructions on self-administration of antibiotics, use of sub-antimicrobial dosing, prescription of antibiotics for minor bacterial infections, use of antibacterial drugs for non-bacterial infections, and use of broad-spectrum antibiotics for narrow-spectrum indications.²

General methods for diminishing risk of antibiotic resistance include detailed history and physical, diagnostic laboratory and culture studies, close monitoring of clinical response, appropriate directed-therapy when the causative organism is identified, relevant empiric treatment based on local antimicrobial susceptibilities within the community, and continuing therapy for the appropriate duration.³ All of these general precautions, as well as discontinuing of antibiotics when deemed unnecessary, will aid to reduce the rate of antibiotic resistance.³

In the United States, individuals with acne vulgaris and rosacea account for 20% of the patients prescribed antimicrobials in dermatology.⁴ SSTIs account for a significant amount of the remaining portion. Specific strategies can be utilized to combat emerging resistance in the treatment of acne vulgaris, rosacea, hidradenitis suppurativa (HS), folliculitis decalvans (FD), bullous pemphigoid (BP), and confluent and reticulated papillomatosis (CARP) and SSTIs.

Acne Vulgaris

Antibiotic monotherapy is not recommended for acne vulgaris treatment. Both topical and systemic monotherapy may induce resistance among Cutibacterium acnes (C. acnes) and other organisms that comprise the commensal and transient flora.⁵ The American Academy of Dermatology (AAD) guidelines recommend coadministration of benzoyl peroxide, a topical bactericidal agent not reported to cause resistance, together with both topical and oral antibiotics.^6,7 Added to topical antibiotics, benzoyl peroxide may prevent the formation of resistance and increase treatment efficacy.⁶ Only indirect evidence supports the ability of benzoyl peroxide to limit resistance when used with oral antibiotics.^6,8 Additionally, the AAD recommends using the shortest possible courses, limiting antibiotic use to 3-4 months.⁷

Low-dose or “sub-antimicrobial” doses of doxycycline have been used in rosacea and acne vulgaris, with the intention to only derive benefits from the anti-inflammatory properties of the antibiotic.^2,9,10 However, contrary to the common belief, recent studies demonstrated that low-dose antibiotic exposure leads to the development of high-level resistance.^2,9,11

A unique method being utilized to bypass bacterial resistance in acne is the development of narrow spectrum drugs such as the new tetracycline, sarecycline. Sarecycline is a US FDA approved therapy specifically designed to treat moderate-severe acne and is the only antibiotic with a low resistance claim in its label.² It is narrow spectrum with coverage limited to clinically relevant gram-positive organisms, including C. acnes. Its structural design involves an elongated C7 moiety that extends into the 30S ribosome and directly interferes with mRNA unlike typical tetracyclines.² This newer design allows for stronger binding and increased inhibitory effects.

Rosacea

The large body of evidence supporting an inflammatory pathogenesis of rosacea not triggered by a bacterial etiology has led to rosacea management guidelines that support avoidance of antibiotics whenever possible.⁵ This includes the papulopustular subtype. Antibiotics should only be used after failure of topical and oral anti-inflammatory therapy.¹² Like acne, if antibiotics are used, the course should be as short as possible with treatment for no longer than 2 months.¹²

Hidradenitis Suppurativa (HS)

Given that topical clindamycin and oral tetracycline are firstline therapies for HS, it is not surprising that a high percentage of HS patients harbor lincosamide and tetracycline resistant bacteria.¹³ Therefore, it is recommended that antibiotics be used as adjunctive therapy with other management options, including chlorhexidine or benzoyl peroxide wash, adalimumab, smoking cessation, weight loss, and other non-antimicrobial treatments.^13,14

Folliculitis Decalvans (FD)

A small study of patients with FD who received one or more courses of antibiotic therapy demonstrated a third of patients harbored antibiotic resistant Staphylococcus aureus (S. aureus).¹⁵ The resistance rates in FD patients were significantly higher than the community reference values.¹⁵

Given FD is thought to stem from S. aureus, antibiotic therapy will likely remain the gold standard for exacerbations.¹⁵ However, treatments should be based on bacterial culture/sensitivities, with the aim to transition to nonantibiotic medical therapies (isotretinoin/dapsone/photodynamic therapy) or destructive therapies (laser hair removal/surgery) to suppress inflammation and address hair follicle structural abnormalities and biofilm formation to induce long-term remission.^15,16

Bullous Pemphigoid (BP)

Although topical and systemic steroids are considered the first-line treatment for BP, the substantial morbidity and mortality associated with these regimens presents a therapeutic challenge. Inasmuch, other treatment options are being sought. Among the plethora of agents trialed have been antibiotics, most notably tetracyclines given their anti-inflammatory properties. While some trials have concluded that systemic tetracyclines are effective in BP treatment, they are inferior in recovery rate when compared to systemic steroids.¹⁷ Moreover, those with milder BP and shorter courses of tetracyclines tend to achieve a lower proportion of remission than those with severe disease, indicating that disease severity and the potential need for prolonged treatment should to be taken into account before initiation.¹⁸ Therefore, judicious consideration is needed before placing patients on antibiotics for BP treatment. In general, tetracyclines may be appropriate in older patients with comorbidities that contraindicate systemic steroid use.¹⁸

Confluent and Reticulated Papillomatosis (CARP)

Oral tetracyclines are the most commonly cited monotherapy for CARP; minocycline is utilized most frequently, but other antibiotics used include amoxicillin and azithromycin.¹⁹ Evidence suggests dysfunctional keratinization as a cause of CARP, and this is supported by successful treatment with both topical and oral retinoids.²¹ Efficacy of this treatment is attributed to the anti-inflammatory and immunomodulating properties of retinoids and normalization of keratinization.²⁰ Advantages of retinoid therapy include higher patient compliance and decreased side effects.²⁰ Other treatment options that have demonstrated clinical effects include topical vitamin D derivatives.¹⁹

Skin and Soft Tissue Infections (SSTIs)

Resistance has emerged against many commonly used topical and oral antibiotics for SSTIs. This is likely a result of overuse and misuse.

Topical

Prophylactic use of topical antibiotics after surgical procedures is often unnecessary. A meta-analysis based on data pooled from four studies failed to demonstrate a statistically significant difference between application of topical antibiotics versus topical petrolatum/paraffin in preventing post-surgical infections after low risk office-based dermatologic procedures.^5,22 Low risk procedures include those with clean and clean-contaminated wounds, and following procedures in patients that are immunocompetent and not at high risk of infection, surgeries performed in regions above the knee, and surgeries not involving the groin, ears, or mucosal region of the nose or mouth.⁵ In cases where risk of post-operative infection is high, it is a better choice to utilize oral antibiotic prophylaxis, as topical therapy alone is not as likely to provide adequate prevention of infection.^5,23

Other prophylactic uses of topical antibiotics, such as with atopic dermatitis (AD), have not demonstrated efficacy either. When a cutaneous infection is present, antibiotic therapy is therapeutically beneficial in AD.¹⁸ However, chronic topical or oral antibiotic therapy is not advised to manage or suppress AD in the absence of a true skin infection, and it serves only to promote antibiotic resistance.¹⁸

Another factor to keep in mind is that topical antibiotic therapy is capable of inducing antibiotic resistance beyond areas of application.⁵ Topical erythromycin used on the face induced resistant C. acnes and staphylococci on the back and anterior nares where it was not applied.²⁴ Similar results have been demonstrated with other bacteria such as streptococci.⁵

Mupirocin resistance has reached up to 80% among bacterial strains such as S. aureus in certain communities with heavy usage.^13,25 Low resistance alternatives are fusidic acid and topical pleuromutilins.¹³ Moreover, regular local antiseptic treatment including octenidine or polyhexanide is broadly efficacious and confers a significantly lower risk of resistance relative to topical antibiotics.²⁶

Systemic

Prophylactic oral antibiotics are rarely appropriate for routine dermatologic surgery and are not indicated for patients who have prosthetic joints or vascular grafts.²³ It is recommended only for a small group of patients that have abnormal cardiac valves, and then only with surgery involving clearly infected skin or soft-tissue.²³

Controlled trials indicate that antimicrobial agents are unhelpful in treating cutaneous abscesses, inflamed epidermal cysts, uninfected atopic eczema, and cutaneous ulcers caused by venous insufficiency or diabetes in the absence of significant contiguous soft-tissue inflammation.²³

Between 5-10% of the North American population is classified as beta-lactam allergic.²⁷ However, only 10% of these can be confirmed by allergy diagnostics.²⁷ A false beta-lactam allergy diagnosis may lead to inappropriate use of broad spectrum antibiotics. Common reasons for a false beta-lactam allergy include misinterpretation of known predictable side effects, misinterpretation of infection-induced urticaria or viral exanthema as an immediate type drug reaction or drug exanthema; interpreting non-specific symptoms as an allergy, and considering known reactions in the family as signs of personal allergy.²⁷ To verify a true beta-lactam allergy, risk stratification of all patients should be performed. Patients with a questionable allergy may be excluded based on history alone.²⁷ Patients with an incomplete history or mild reaction may be tested on a case-by-case basis.²⁷ Patients with a medical history strongly suggesting a true allergy should undergo formal testing through a skin test (skin prick, intradermal/patch), lab test (specific immunoglobulin E, basophil activation test), and/or oral provocation test with fractionated administration of beta-lactam.²⁷

Future Directions

To confront the challenge of resistance, modification of existing antibiotics to improve potency and efficacy is underway.¹³ Additionally, development of new narrow spectrum agents with novel mechanisms of action is being pursued.¹³ Given that drug development is a slow process, it cannot keep up with the spread of resistant bacteria. Therefore, alternative methods are under investigation.

One promising avenue is modulation of the skin microbiome.¹³ Abnormalities in the skin microbiome have been observed in patients with acne.^13,28 Treatment with isotretinoin in these patients restored microbiomes to normal.²⁸ Thus, infectious and inflammatory dermatoses may respond to direct manipulation of the skin microbiome via live biotherapeutic products or transplantation of human skin microbiota.¹³ Recent trials have already demonstrated success in treating AD with skin microbiota transplantation.²⁹

Another alternative gaining traction is phage therapy, which uses bacteriophages to infect and lyse bacteria.^13,30 Recent studies have reported successful use of personalized bacteriophage therapy in patients with multidrug-resistant infections.³¹

Further strategies include implementation of electroporation, antimicrobial peptides, photodynamic therapy (PDT), photothermal therapy, nitrous oxide-releasing nanoparticles, cannabidiol, or combinations of these options.³² PDT is a therapeutic option for cutaneous infections immune to antibiotics. PDT use in acne results in reduced follicular obstruction and lower sebum excretion.³² At higher doses, it can destroy sebaceous glands.³² For cutaneous leishmaniasis and warts, PDT has demonstrated clearance rates of up to 100%.³² PDT has also been initiated as a treatment option for onychomycosis.³² Transdermal iontophoresis has been coupled with PDT to increase its effectiveness.³² It uses small electrical currents to permit controlled drug delivery and use of smaller drug concentrations.³² Its use has demonstrated broad spectrum antimicrobial efficacy against bacteria, fungi, and viruses.

Conclusion

Correct and appropriate use of antibiotics will help to preserve their utility in the face of increasing antibiotic resistance; however, greater awareness of the etiologies of resistance and how to combat each is required among prescribing providers.

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¹Center for Clinical Studies, Webster, TX, USA
²Meharry Medical College, Nashville, TN, USA
³Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
All authors have no conflicts of interest.

Abstract:
Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand the mechanisms at play that contribute to resistance.

Key Words:
antibiotic resistance, dermatology, mechanisms of resistance, antibiotic, antimicrobial, infection

Introduction

The advent of antibiotics is arguably one of the greatest achievements in history, permitting survival among many with infections who would have previously died without intervention. Amid the fields in which the use of antibiotics is particularly widespread lies dermatology. A spectrum of inflammatory and infectious dermatologic conditions have been treated with antibiotics since their inception. The continued success of any therapeutic agent is compromised by the potential development of tolerance or resistance to that compound over time.¹ In the case of antibiotics, resistance among bacteria has become a serious issue and has been named one of the greatest threats to human health.² The number of infections caused by multidrug-resistant bacteria is increasing, and the specter of untreatable infections is now a reality.² As this number increases, new antibiotic developments cannot match the pace.²

While many factors contribute to the development of resistance, its basis stems from bacterial alterations at the molecular level. Therefore, it is important for dermatologists to understand the mechanisms at play.

Brief Review of Antibiotics in Dermatology and Mechanism of Action

Many antibiotics are utilized in dermatology. Countless isolates of bacteria may cause skin and soft tissue infections (SSTIs) resulting in a wide variety of clinical presentations. Most commonly, superficial cutaneous infections and pyodermas are caused by Staphylococcus aureus (S. aureus) resulting in impetigo, ecthyma, folliculitis, intertrigo, and paronychia. However, other bacterial organisms may also be responsible. Deeper infections like cellulitis, erysipelas, and necrotizing fasciitis are also classically caused by S. aureus or Streptococcus pyogenes, but are also commonly caused by a variety of other gram-positive and negative organisms. Antibiotics may also be used for anti-inflammatory effects, such as with the treatment of acne vulgaris, rosacea, folliculitis decalvans, and hidradenitis suppurativa.

Given the wide variety of conditions treated with antibiotics, nearly the entire gamut may be utilized by dermatologists at some point in time. Understanding the antibiotic mechanism of action is key to understanding mechanisms of resistance (Figure 1, Table 1).

Mechanisms of Resistance

Mechanisms by which bacteria evade antibiotic destruction vary in complexity. The most basic method involves mutations in the bacterial target gene, creating a mutant target protein that prevents interaction with the antibiotic, rendering it ineffective.² Given the intrinsic error prone process of DNA replication/ repair, this type of resistance is inevitable as mutations are bound to occur.³ Resistance may also occur through acquisition of genes encoding proteins that reduce antibiotic binding to molecular targets.² Bacteria can produce enzymes capable of manipulating molecular targets and blocking antibiotics from binding.² In addition to modifying the molecular target, bacteria can also reduce the concentration of antibiotics through chemical or enzymatic modification.² Finally, if an antibiotic target comprises an entity other than a single gene product, resistance to these drugs is attained via retrieval of pre-existing diversity in cell structures and altering their biosynthesis through global cell adaptations.^2,3

Modification of Antibacterial Target

Bacteria are capable of modifying any protein that an antibiotic might target.⁴ Among the most popular antibiotic protein targets is the bacterial ribosome, a complex protein producing machine.⁵ Bacterial ribosomes consist of dozens of proteins that are arranged into large (50S) and small (30S) subunits.⁶ Each subunit is associated with specialized ribosomal RNA (50S – 23S, 5S; 30S – 16S). Ribosomes produce proteins through translation – a three-step process: initiation, elongation, and termination.

By targeting ribosomal proteins, antibiotics block protein synthesis in bacteria thus halting proliferation. To survive, bacteria have evolved mechanisms to elude antibiotic protein targeting.

Target Protection

Target protection is a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition.⁵ Target protection is an important mode of bacterial resistance to many antibiotics used in dermatology, especially against tetracyclines.⁷

To disrupt tetracycline action, bacteria deploy ribosomal protection proteins (RPPs) Tet(O) and Tet(M).⁵ Both of the RPPs are hydrolases that become active in a tetracycline dependent manner. When tetracycline interacts with its ribosomal target, it induces changes in the cellular environment that results in increased affinity of the RPPs to the antibiotic-30S structure.⁵ The RPPs then hydrolyze antibiotic-30S bonds, dislodging the tetracycline, which permits normal protein synthesis to resume.⁵

Target Site Modification

By design, antibiotics are selective of target structures. When target structures are modified, chemical properties are altered which change antibiotic target affinity.² For organisms to survive with resistance, these modifications must result in a loss of target affinity while still maintaining adequate function of normal activities. Most often, this is accomplished by point mutations in genes encoding target sites, enzymatic alterations of binding sites, and replacement or bypass of target sites.²

Mutations of Target Site

Mutations of the 16S portion of the 30S ribosomal subunit target site are the most common form of resistance to aminoglycosides.⁸ Macrolides are also resisted via target site mutations. The 23S portions of the 50S ribosomal subunit targeted by macrolides can undergo multiple viable mutations.³ Quinolone resistance can occur through target mutation.⁹ Quinolone resistance determining regions (QRDR) are target gene sequences susceptible to viable mutations that decrease quinolone target affinity.¹⁰ Specifically, substitutions in the gyrA and gyrB sequences affect DNA gyrase, while substitutions in parC and parE affect topoisomerase IV.¹⁰

Enzymatic Alteration of Target Site

Many different enzymes play a role in antibiotic resistance. One method by which enzymes contribute is through modification of the target site, which results in decreased antibiotic affinity similar to target site mutations. Methylation of strategic nucleotides in the antibiotic binding site weakens antibiotic binding via steric clashes with the modified nucleotide.¹¹ Since some antibiotics share partially overlapping binding sites, methylation of a single nucleotide can result in resistance to multiple antibiotic classes.¹¹

Enzymatic methylation of the ribosome confers resistance to many antibiotics that target the 23S portion of the 50S subunit. Moreover, a specific family of genes encoding for enzymatic methylation may confer resistance against multiple antibiotics that share the same ribosomal binding region.¹² For example, the erythromycin ribosomal methylation (erm) gene confers cross resistance to macrolides, lincosamides, and streptogramin B which all bind the same ribosomal site.² This gene is commonly found in gram-positive cocci and is shared among bacteria via plasmids and transposons. The cfr gene functions similarly to erm, producing a methylation enzyme that provides resistance among gram-positive and gram-negative organisms to oxazolidinones, pleuromutilins, and streptogramin A.^2,12

Bypass or Replacement of Target Site

Bypassing of target sites occurs when the target site is changed so that the antibiotic is rendered useless. It may occur through several mechanisms.² A popular example of resistance to beta (β)-lactams is seen with the mecA gene in Staphylococcus aureus.^2,13 This gene results in replacement of normal penicillin-binding proteins (PBPs) with PBP2a that has a low affinity for β-lactams. Its induction occurs in the presence of β-lactams.^2,13

Antibiotic Alteration

One method of resistance that bacteria can employ is antibiotic alteration. This is done through enzymatic modification or degradation.^2,14 Inactivating modifications interfere with antibiotic-target site binding and include acetylation, phosphorylation, glycosylation, and hydroxylation.^2,14 Enzymatic degradation results in the destruction of antibiotics.²

Aminoglycosides are subject to modification through aminoglycoside modifying enzymes (AMEs).^2,14 AMEs consists of acetyltransferases, adenyl transferases, and phosphotransferases.² β-lactams are subject to degradation via β-lactamases.¹⁵ In gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, rendering β-lactams useless.¹⁵ β-lactamases can be encoded intrinsically (chromosomal) or disseminating on mobile genetic elements like plasmids across opportunistic pathogens.¹⁵ In the more recent past, β-lactamases have extended beyond penicillins and cephalosporins to carbapenems.¹⁵ Macrolide resistant bacteria have developed enzymes, such as erythromycin esterases, that cleave essential ester bonds and thus disrupt macrolide structure.¹⁶ The genes encoding these enzymes are found on mobile genetic elements, establishing the potential for widespread resistance.¹⁶

Membrane Permeability Variation

Antibiotic resistance can be mediated by changes to the cell membrane permeability.¹⁷ This can be done through alteration in lipid, porin, and transporter structures such as efflux pumps.²

To gain entry into the bacterial cells, antibiotics like β-lactams cross the lipid bilayer of the cell membrane via porins, whereas other lipophilic antibiotics such as macrolides traverse the bilayer via diffusion.³ Alterations to porins or lipid structure result in permeability changes that potentiate resistance. Some gram-negative bacteria intrinsically express full length lipopolysaccharide that prevent diffusion of lipophilic antibiotics.¹⁸

Porin mediated resistance is achieved through decreasing the rate of antibiotic entry.² Loss of porin function can be acquired via changes in OmpF porin protein resulting in replacement/loss of major porins and reduced permeability.¹⁹

Efflux pumps extrude toxic compounds out of bacterial cells, including antibiotics.² A variety of efflux pumps exist and are seen in both gram-positive and gram-negative organisms.¹⁷ In clinically important bacteria, such as multidrug-resistant (<MDR) Mycobacterium tuberculosis, methicillin-resistant S. aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa, efflux pumps have critical roles in ensuring bacterial survival and evolution into resistant strains.¹⁷

Global Cell Adaptations

Instead of a specific change in one cellular process, some bacteria have developed resistance to antibiotics via global cell adaptations. Through years of evolution, bacteria have developed sophisticated mechanisms to cope with environmental stressors and pressures in order to survive hostile environments.² This involves very complex mechanisms to avoid the disruption of vital cellular processes such as cell wall synthesis and membrane homeostasis.² The two main examples of global cell adaptation resistance occur with lipopeptides and glycopeptides.²

Lipopeptides have a multifaceted mechanism of action that results in disruption of cell membrane homeostasis.²⁰ Activity correlates with the levels of calcium and phosphatidylglycerol in the membrane.²⁰ Resistance can be accomplished in some organisms via alteration in cell membrane charge and downregulation of phosphatidylglycerol.²⁰

Glycopeptides are susceptible to resistance via multiple adaptations observed with S. aureus including increased fructose utilization, increased fatty acid metabolism, decreased glutamate availability, and increased expression of cell wall synthesis genes.² These global adaptations result in reduced autolytic activity, a thickened cell wall, and an increased amount of free D-Ala-D-Ala, all of which reduce effective activity of glycopeptides.²

Conclusion

Awareness of the molecular mechanisms of antibiotic resistance among bacteria is necessary to understand the etiology of antibiotic resistance in dermatology at the most basic level.

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