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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¹School of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, 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. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Prurigo nodularis and atopic dermatitis are chronic, inflammatory skin conditions characterized by significant pruritus that disrupts daily life. They also involve dysfunction of the T-helper 2 immune response, leading to the over secretion of interleukin-31 (IL-13) in the dermis and serum. Nemolizumab is a new IL-31 receptor antagonist that has shown high efficacy in the treatment of prurigo nodularis (PN) and atopic dermatitis (AD) in multiple phase 3 trials, with a good safety profile. A brief overview of PN and AD including highlights of the findings from three trials of nemolizumab in treating these disorders will be presented herein.

Keywords: atopic dermatitis, interleukin-31, nemolizumab-ilto, prurigo nodularis, pruritus

Introduction

Prurigo nodularis (PN) is a chronic, inflammatory skin condition characterized mainly by pruritus, leading to a disruption of sleep and daily activities.^1,2 The pruritus is often intense, lasting over 6 weeks, and may also present with a burning or stinging sensation.^3,4 Diagnosis is primarily made by clinical examination of the lesions and through the patient’s history, revealing clusters of nodules commonly located on the extremities or trunk.³ Biopsy can also help to confirm the diagnosis in unusual cases, which typically reveals hyperkeratosis, hypergranulosis and increased fibroblasts.³

PN disproportionally impacts individuals of African ancestry and the elderly, although it can affect patients of any age.⁴ Men and women are equally susceptible.⁵ A significant number of patients also suffer from anxiety, depression, and suicidal ideation due to the severity of the condition.^2,4,5 In 2022, dupilumab became the first US Food and Drug Administration approved treatment for PN.⁶ Other conventional treatments have typically been less effective, involve off-label uses of medications and mainly aim to reduce itching by targeting the neural and immunologic aspects of the condition.³

Similarly, atopic dermatitis (AD) is also an inflammatory cutaneous disease commonly manifesting with erythema, papules, edema, and crusting.^7,8 AD most commonly affects the pediatric population, with 90% of cases first presenting with symptoms under the age of 5 years, persisting with episodical outbreaks in adulthood.⁸ AD is highly variable in presentation and current management of the condition depends on its severity.^7,9 First-line therapy involves the use of topical corticosteroids, along with emollients and regular bathing.⁹ Systemic therapies are also commonly used, including ciclosporin, methotrexate, azathioprine, and mycophenolate mofetil.¹⁰ Other treatments include calcineurin inhibitors, crisaborole, rofumilast, ruxolitinib, ultraviolet B phototherapy, and, more recently, dupilumab, tralokinumab, abrocitinib, and upadacitinib, which may be used in more severe or treatmentresistant AD.⁹

IL-31 Pathway and Mechanism of Nemolizumab

T-helper 2 (Th2) cells are primarily responsible for the release of interleukin-31 (IL-31), with CD4+, CD8+, and mast cells also producing IL-31 in the presence of allergens of pathogens.^4,11-13 This leads to the stimulation of eosinophils and contributes to the itching in AD, as well as other inflammatory skin disorders.¹¹ There are multiple proposed mechanisms as to how IL-31 leads to the pruritus in AD and PN, such as the abundance of IL-31 receptors in the dorsal root ganglia (DRG) of cutaneous sensory nerves.¹¹ IL-31 may also activate receptors present in keratinocytes, which subsequently activate unmyelinated C fibers, leading to pruritus.¹¹ Transient receptor potential cation channels in the DRG and chemokine release by keratinocytes due to IL-31 are possible additional mechanisms.¹¹

Both PN and AD are inflammatory cutaneous conditions that involve impaired IL-31 signaling.⁴ PN skin lesions form as a result of the chronic scratching induced by immunologic and neural dysfunction.⁴ Skin biopsy reveals the presence of T lymphocytes, mast cells, and eosinophils that release IL-31, tryptase, and histamine.⁴ There is also increased nerve fiber density, along with neuropeptides such as substance P and calcitonin gene-related peptide in the dermis, which contribute to the pathogenesis of pruritus in PN.^3,4 Similarly, IL-31 serum levels increase with higher severity of AD, and gene polymorphisms have been linked with the development of the disease.^4,11-13 Nemolizumab is an IL-31 receptor alpha antagonist that has shown potential in treating both PN and AD in multiple phase 3 clinical trials.⁴ These investigations demonstrated that treatment with nemolizumab reduced itch intensity, improved lesion healing and inhibited Th2 (IL-13) and Th17 (IL-17) cells.⁴

Phase 3 Clinical Trials for Prurigo Nodularis

A phase 3 clinical trial of nemolizumab in PN enrolled 274 patients, aged 18 years and older, from 68 sites and 9 different countries, for a 16-week treatment period and subsequent 8-week follow-up.⁵ Patients were selected based on a history of PN for ≥6 months and pruritus classified as severe by the Peak Pruritus Numerical Rating Scale (PP-NRS).⁵ This scale ranges from a score of 0 (no itch) to 10 (worst itch), where a score of 7 or greater is severe and qualified patients for enrollment in the trial.⁵ Patients were also selected for the presence of 20 or more nodules, and a score of 3 or 4 on the Investigator’s Global Assessment (IGA), which assesses the severity of the disease on a scale of 0-4 by the type, size and quantity of lesions.^5,14 Patients with active AD, neuropathic or psychogenic pruritus, or pruritus due to causes other than PN were excluded from the study.⁵

183 patients were randomly chosen to receive nemolizumab and another 91 patients were given a placebo.⁵ Participants were administered an initial dose of 60 mg of nemolizumab, followed by 30 mg or 60 mg based on their starting weight, every 4 weeks over a period of 16 weeks.⁵ Overall, both groups were similar and balanced prior to treatment; only 4.4% of participants were Black.⁵

19.7% and 35% of the nemolizumab group achieved almost complete itch relief at 4 weeks and 16 weeks, respectively.⁵ In the placebo group, 2.2% and 7.7% reported similar itch relief after 4 weeks and 16 weeks, respectively.⁵ 37.2% and 51.9% of patients receiving nemolizumab achieved a decrease in sleep disturbance by 4 and 16 weeks, respectively.⁵ In contrast, only 9.9% and 20.9% of the placebo group reported a clinically significant decrease in sleep disturbance.⁵ 16 week after treatment, 56.3% of the nemolizumab group and 20.9% of the control group achieved a significant decrease in itch intensity, defined as a 4 or greater point decrease on the PP-NRS.⁵ Patients who received nemolizumab demonstrated significant improvements in skin lesions, pruritus, sleep disturbance, pain, global disease assessment, quality of life, and anxiety and depression symptoms compared to the control group.⁵ Improvements in itch, skin lesions, sleep disturbance, and quality of life continued through week 52, with more than two-thirds of patients becoming itch-free or nearly itch-free and 90% reporting clinically meaningful improvement in quality of life.¹⁵ Quality of life was assessed using the Dermatology Life Quality Index (DLQI), which is composed of 10 questions designed to evaluate how patients perceive the impact of their skin condition on different areas of their life, including symptoms/feelings, daily activities, leisure, work/school, personal relationships, and treatment.⁵

61.2% of participants that received nemolizumab and 52.7% of placebo experienced at least one adverse event (AE) (Table 1).⁵ In the treatment group, most AEs were common side effects and included mild AD and headache.⁵ Peripheral or facial edema and asthma were more common in patients receiving nemolizumab, while infections were more prevalent in the control group.⁵ One case of bullous pemphigoid was reported in the nemolizumab group, and a case of generalized exfoliative dermatitis was recorded in the placebo group.⁵ In addition, a higher number of placebo patients required rescue therapy (15.4%) compared to those receiving nemolizumab (4.9%).⁵ 2.2% of patients in each group withdrew from the trial due to adverse reactions.⁵ Long-term data over a 52- week extended study remained consistent with the safety profiles in phase 3 trials.¹⁵

In patients with no history of asthma, 6 of 156 in the nemolizumab group and 2 of 77 in the placebo group had decreased expiratory flow below 80% during the treatment period.⁵ In those with a history of asthma, 5 of 22 patients receiving nemolizumab showed peak expiratory flow under 80% of the predicted value during the treatment period, however, only 2 of these were confirmed as worsening asthma.⁵ In comparison, 1 of 13 patients with a history of asthma in the placebo group experienced a peak expiratory flow under 80% of the expected value during the treatment period.⁵ An increased eosinophil count was reported in 7.7% of the nemolizumab group and 4.4% of the placebo group.⁵ Moreover, 5.8% of nemolizumab patients developed antidrug antibodies.⁵

Table 1.

Phase 3 Clinical Trials for Atopic Dermatitis

In two identical phase 3 trials of nemolizumab for the management of AD, ARCADIA 1 and ARCADIA 2, 1142 patients over the age of 12 years received 30 mg of nemolizumab (after a loading dose of 60 mg), while 586 participants were given a placebo every 4 weeks over a period of 16 weeks.¹⁶ The Eczema Area and Severity Index (EASI), which assesses the surface area of the skin affected by AD and the severity of lesions, as well as the IGA, were used to characterize the severity of AD.^16,17 Primary endpoints were defined as an IGA score of 0 or 1 with a ≥2-point improvement from baseline and at least 75% improvement in EASI.¹⁶ Patients in the nemolizumab group who successfully achieved these endpoints were then randomly reassigned in a 1:1:1 ratio.¹⁶ They were to receive either 30 mg of nemolizumab every 4 weeks, 30 mg of nemolizumab every 8 weeks, or a placebo every 4 weeks in a maintenance period.¹⁶

In the nemolizumab group, 36% of patients in ARCADIA 1 and 38% in ARCADIA 2 achieved IGA success, compared to 25% (ARCADIA 1) and 26% (ARCADIA 2) of patients in the control group.¹⁶ 75% improvement in EASI was observed in 44% (ARCADIA 1) and 42% (ARCADIA 2) of patients in the nemolizumab group, compared to 29% (ARCADIA 1) and 30% (ARCADIA 2) of those receiving placebo.¹⁶ Improvements in pruritus were observed from week 1 in the nemolizumab group, with additional improvements reported in quality of life, sleep, and a decrease in pain by 16 weeks.¹⁶ Additionally, clinically meaningful improvements in itch, skin lesions, and sleep disturbance persisted through week 56 of an extended study.¹⁸ Overall, the study showed that a statistically significant proportion of patients with moderate to severe AD achieved clinically meaningful improvements in symptoms of pruritus and inflammation with nemolizumab (Table 2).¹⁶

Table 2.

In terms of safety, 50% of patients in ARCADIA 1 and 41% in ARCADIA 2 receiving nemolizumab reported an AE, with serious effects occurring in 1% and 3% of patients in each respective trial.¹⁶ Worsening of AD was the most commonly reported adverse effect, occurring in a total of 112 patients receiving nemolizumab from both trials, compared to 49 patients in the control group. Worsening of asthma was reported in 1% of patients in ARCADIA 1 and 5% of patients in ARCADIA 2 in the nemolizumab group; however, there was no significant difference compared to those receiving placebo.¹⁶ Serious drug-related AEs were rare, reported in 5 patients in ARCADIA 2, and included infection, peripheral edema, eosinophilic colitis, and small intestinal obstruction.¹⁶ Additionally, AEs resulting in treatment discontinuation occurred in a total of 24 patients in the nemolizumab group, compared to 6 patients in the control group across both trials.¹⁶ Safety results of nemolizumab after 56 weeks aligned with previous findings, supporting its use in adolescents and adults with moderate-to-severe AD.¹⁸

Conclusion

Nemolizumab demonstrated high efficacy in the treatment of PN and AD in phase 3 trials, yielding marked improvements in symptom control with an overall favorable safety profile.^5,16 In the PN trial, a significant number of patients receiving nemolizumab exhibited improvements in pruritus, sleep disturbances, and quality of life based on the DLQI compared to the control group.⁵ The most common side effects were nasopharyngitis, AD, and headaches.⁵ In the AD trials, similar improvements in pruritus, sleep quality, and a decrease in pain levels were observed with the most common side effect being worsening of AD.¹⁶ Overall, nemolizumab has shown promising results in reducing pruritus and is particularly useful in treating severe or therapy-resistant PN and AD.^4,5,16

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¹John P. and Kathrine G. McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, The University of Texas Health Science Center at Houston, Houston, TX, USA

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

Abstract: Psoriatic arthritis (PsA) is a chronic, inflammatory disease with heterogeneous clinical features. The pathogenesis of PsA involves a complex interplay of genetic, immunologic, and environmental factors, leading to the activation of the immune system and subsequent inflammation. Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23/T helper 17 pathway in the disease process. Guselkumab, a novel IL-23 inhibitor, has emerged as a promising therapeutic option for PsA, offering an alternative to conventional therapies and other biologics. This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Keywords: psoriatic arthritis, guselkumab, treatment, efficacy, psoriasis, arthritis

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory disease that will develop in about 30% of individuals with psoriasis. The condition is characterized by a wide range of clinical features, making it complex and diverse in its presentation. The pathogenesis of PsA involves a multifaceted interaction between genetic, immunologic, and environmental factors, which leads to immune system activation and subsequent inflammation.¹

Currently, there are no specific diagnostic criteria or tests for PsA. Diagnosis is typically based on the presence of inflammatory musculoskeletal symptoms in joints, entheses, or the spine, alongside skin and/or nail psoriasis, and the usual absence of rheumatoid factor and anti-cyclic citrullinated peptide. The progression from psoriasis to PsA may occur in stages, although the underlying mechanisms remain unclear. Interestingly, the severity of musculoskeletal inflammation does not always correlate with the severity of skin or nail psoriasis, a phenomenon likely influenced by genetic variability, particularly in the human leukocyte antigen (HLA) region.¹

Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23 (IL-23)/T helper 17 (Th17) pathway in the disease process. Guselkumab is a human monoclonal antibody that selectively binds to the p19 subunit of IL-23, thereby inhibiting its interaction with the IL-23 receptor. By blocking IL-23 signaling, guselkumab prevents the activation and proliferation of Th17 cells, which are pivotal in the pathogenesis of PsA. Th17 cells produce several pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22, which contribute to the inflammation and joint damage observed in PsA. By targeting IL-23, guselkumab effectively reduces the levels of these downstream cytokines, thereby attenuating the inflammatory response and improving clinical outcomes in patients with PsA.²

Guselkumab has been approved by the United States Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA) for the treatment of adult patients with active psoriatic arthritis and moderate-to-severe psoriasis (PSO) who are candidates for systemic therapy. Additionally, the EMA has approved guselkumab for the treatment of active psoriatic arthritis in adults who have had an inadequate response to, or are intolerant of, previous disease-modifying antirheumatic drug (DMARD) therapy.²

This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Methods

Our search focused on English-language literature concerning clinical trials of guselkumab in adults with psoriatic arthritis. We conducted a search in the Medline database via PubMed up until September 1, 2024, using the MeSH terms “guselkumab” AND “psoriatic arthritis.” This search yielded 177 results. We excluded books, meta-analyses, reviews, and systematic reviews, narrowing our focus to clinical trials and randomized controlled trials, resulting in 30 trials. Out of these, we included 9 trials and excluded 10 due to integrated analysis of multiple trials, 7 due to duplication, and 4 due to a focus on topics other than PsA.

Results

The included studies primarily consisted of double-blind, randomized, placebo-controlled Phase 3 trials that evaluated the efficacy of guselkumab in patients with PsA (Table 1). Across these trials, guselkumab demonstrated significant efficacy in achieving American College of Rheumatology (ACR) response criteria at various time points:

Table 1

ACR20 Response

Guselkumab consistently showed superior results compared to placebo. For instance, Deodhar et al. reported that 59% of patients treated with guselkumab every 4 weeks and 52% treated every 8 weeks achieved ACR20, compared to 22% in the placebo group.³ Similar trends were observed in other studies, with response rates ranging from 44% to 76% for guselkumab, significantly higher than the placebo groups, which ranged from 20% to 33%.^4-7

ACR50 and ACR70 Responses

Some trials also assessed higher response thresholds. McInnes et al. observed ACR50 and ACR70 responses in 48-56% and 30-36% of patients, respectively, in the guselkumab-treated groups.⁸ Ritchlin et al. noted that 33% and 31% of patients achieved ACR50 at week 24 in the every-4-weeks and every-8-weeks groups, respectively, compared to 14% in the placebo group. ACR70 responses were achieved by 13-19% of guselkumab-treated patients, compared to 4% in the placebo group.⁹

Additional Outcomes

Beyond ACR responses, trials such as Curtis et al. and Orbai et al. assessed work productivity and patient-reported outcomes, showing significant improvements in these domains among patients treated with guselkumab. Improvements in presenteeism, work productivity, non-work activity, and Patient-Reported Outcomes Measurement Information System® (PROMIS)-29 scores were all more substantial in guselkumab groups compared to placebo, with improvements continuing through week 52 after placebo patients were switched to guselkumab.^10,11

These results highlight the efficacy of guselkumab in improving clinical outcomes in PsA patients, particularly in achieving ACR response criteria and enhancing patient-reported outcomes.

Discussion

In the management of PsA, the primary objective of pharmacological treatment is to enhance patients’ health-related quality of life. This is achieved by alleviating symptoms, preventing structural joint damage, and restoring normal function and daily activities. A significant reduction in inflammation is crucial to reaching these goals. Within this therapeutic landscape, guselkumab offers several distinct advantages over other biologics, particularly tumor necrosis factor (TNF) inhibitors and IL-17 inhibitors.

TNF inhibitors are commonly used in PsA treatment, but their efficacy in managing skin symptoms can be variable, and they are associated with a higher risk of certain adverse events (AEs), such as infections and demyelinating diseases. IL-17 inhibitors, including secukinumab and ixekizumab, are effective for both skin and joint manifestations but may increase the risk of inflammatory bowel disease. In contrast, guselkumab specifically targets the IL-23 pathway, offering a more focused modulation of the immune response in PsA. This targeted inhibition may lead to fewer offtarget effects and a more favorable safety profile, particularly concerning infections and autoimmune-related AEs. Additionally, guselkumab has shown efficacy in patients who have not responded adequately to TNF inhibitors, making it an invaluable option for this challenging subset of patients.¹²

The safety profile of guselkumab has been thoroughly evaluated in both clinical trials and post-marketing surveillance. Across these studies, the incidence of AEs was comparable between guselkumab and placebo groups, with the most common being nasopharyngitis, upper respiratory tract infections, and headaches. Serious adverse events were infrequent and occurred at similar rates across treatment groups. Importantly, guselkumab did not increase the risk of serious infections, malignancies, or major cardiovascular events, which supports its suitability for long-term use.

Overall, guselkumab emerges as a promising therapeutic option for PsA, particularly for patients who require an alternative to TNF inhibitors or those concerned with the safety profiles of currently available biologics. Its focused mechanism of action, combined with a robust safety profile, positions guselkumab as an effective and well-tolerated treatment in the ongoing effort to improve patient outcomes in PsA.

Conclusion

Guselkumab represents a significant advancement in the treatment of PsA, providing a novel mechanism of action with robust clinical efficacy and a favorable safety profile. The evidence from RCTs and real-world studies supports its use in a broad range of patients, including those who are biologic-naïve and those with previous biologic exposure. As the understanding of the IL-23/Th17 pathway continues to evolve, guselkumab and other IL-23 inhibitors are likely to play an increasingly important role in the management of PsA, offering patients new hope for improved disease control and quality of life. Future research should focus on long-term outcomes, comparative effectiveness with other biologics, and the identification of biomarkers to personalize treatment strategies for patients with PsA.

References

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¹University of Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA

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

Abstract:
Cutaneous leishmaniasis (CL) is an infection caused by the Leishmania protozoa, which are primarily transmitted through bites of infected female sandflies. This article provides a comprehensive overview of the clinical management of CL, including an in-depth analysis of its epidemiology, prevention and control measures, diagnostic modalities – particularly molecular and serological, differential diagnosis with other lesions, and treatment options. Also discussed are recent concerns regarding the endemicity of CL, with a focus on the significant rise in travel-related cases as well as locally acquired cases, providing insight into the changing epidemiological landscape.

Keywords: cutaneous leishmaniasis, neglected tropical diseases, zoonotic diseases, clinical management, differential diagnosis

Introduction

Cutaneous leishmaniasis (CL) is a form of leishmaniasis, a protozoal infection that affects the skin or internal organs. Other forms of leishmanisis are more severe but rarer. CL remains a significant public health challenge due to its widespread prevalence and potential to cause severe disfigurement and morbidity.^1,2 The prevention, diagnosis, and treatment of CL require a multifaceted approach. According to the World Health Organization (WHO), there were over 200,000 reported cases of CL in 2022, and the number of cases continues to rise, making CL one of the most common skin diseases globally.³ The WHO has classified CL and its other forms as neglected tropical diseases (NTDs), reflecting their significant impact in endemic regions.³ The impact of CL is also increasing in non-endemic areas due to factors such as international travel, migration, and the influence of climate change.^4,5 Therefore, managing CL and other NTDs has become a critical issue.

Epidemiology

The global distribution of CL encompasses tropical and subtropical regions, with endemic areas in the Central and South Americas, Mediterranean basin, Middle East, and parts of Asia and Africa.³ According to the WHO, CL affects approximately 0.7 to 1.2 million people annually.^1,3 The disease burden is particularly high in countries like Brazil, Iran, Afghanistan, and Syria.^6,7

In North America, CL is not commonly found, but there have been cases reported among travelers and military personnel returning from regions where the disease is prevalent.⁸ It is important to note that there have been cases of CL originating in Texas and Oklahoma, indicating the potential for local transmission.^2,8,9 In 2023 alone, the Texas Department of State Health Services has reported at least 9 new cases of CL (also the average number of new cases in the past decade), and new cases are recommended to be reported within a week.^10,11 These locally acquired cases are believed to be a result of climate change, which has expanded the habitable range of sandfly vectors.¹² The increasing number of reported cases in non-endemic regions emphasizes the need for heightened surveillance and awareness among healthcare providers in these areas.¹³

Prevention and Control

It is essential to implement effective prevention and control strategies to reduce the incidence of CL. One of the primary methods of prevention is vector control, which involves measures such as the use of insecticide-treated bed nets and indoor residual spraying.⁴ Personal protective measures, including wearing long-sleeved clothing and using insect repellents, are also recommended.¹⁴ It is also advisable to avoid outdoor activities during dusk and dawn when sandflies are most active.¹⁵ These comprehensive strategies collectively contribute to reducing the risk of contracting CL.

Environmental management strategies focus on reducing sandfly breeding sites by improving sanitation and housing conditions.^1,3,12 Such approaches include the removal of organic waste and rubble, which serve as breeding sites for sandflies, and improving housing structures to prevent sandfly entry.^7,16 Public health education campaigns are also essential in raising awareness about preventive measures and encouraging community participation.^17-19 These campaigns target both endemic regions and non-endemic areas at risk of CL introduction, emphasizing the importance of early diagnosis and treatment.^20,21 Additionally, the development and distribution of a vaccine for CL is an area of active research, though no effective vaccine is currently available.^8,22

Diagnosis

An accurate diagnosis of CL is crucial for effective treatment, as most species present a unique manifestation (Table 1). Clinically, CL is characterized by ulcerative skin lesions, often located on exposed areas such as the face, arms, and legs.^2,14,17-19 The lesions may vary in appearance and can be single or multiple, with a chronic course if left untreated.^4,23

Laboratory confirmation of CL is achieved through several methods:

Microscopy

A direct visualization of Leishmania amastigotes in stained tissue smears is a common diagnostic method. However, its sensitivity varies depending on the parasite load and the skill of the technician.^1,15 Giemsa-stained smears of lesion material can be examined under a microscope; this method remains widely used due to its simplicity and low cost.²⁴

Culture

Culturing Leishmania parasites from lesion aspirates or biopsies in specialized media can provide a definitive diagnosis, but it is time-consuming and requires laboratory facilities.⁴ Media such as Novy-MacNeal-Nicolle (NNN) or Schneider’s Drosophila medium are commonly used for parasite cultures.^25,26

Molecular Techniques

Polymerase chain reaction (PCR) has become increasingly popular due to its high sensitivity and specificity. It can detect and identify Leishmania species, which is essential for guiding treatment decisions.^2,4 Real-time and loop-mediated isothermal amplification (LAMP) are advanced molecular techniques that can also provide rapid and accurate diagnosis.^27,28

Serological Tests

These are generally less useful for CL due to variable antibody responses but may have a role in epidemiological studies.²⁹ However, specific serological tests such as enzyme-linked immunosorbent assay (ELISA) and immunofluorescent antibody test (IFAT) can aid in diagnosis under certain conditions.^8,30,31

Other recent advancements include the development of rapid diagnostic tests (RDTs) that offer point-of-care diagnosis with minimal laboratory infrastructure.^1,30 These tests are particularly useful in resource-limited settings and for large-scale epidemiological surveys.³⁰ The combination of RDTs and clinical presentations, along with anecdotal histories, provides the best diagnosis of CL and can improve the subsequent quality of care.

Differential Diagnosis

Differentiating CL from other skin conditions is critical to avoid misdiagnosis and inappropriate treatment (Figure 1).^17-20,32 The differential diagnosis includes:

Fungal Infections

Sporotrichosis and chromoblastomycosis present with chronic skin lesions resembling CL. Sporotrichosis, caused by Sporothrix schenckii, typically presents with nodular lesions that can ulcerate, resembling CL.³⁴

Parasitic Infections

Cutaneous larva migrans (CLM) and myiasis should be considered, particularly in endemic regions. CLM, caused by hookworm larvae, presents with serpiginous tracks on the skin, which can be distinguished from CL lesions.³⁵

Non-Infectious Conditions

Skin cancers, eczema, psoriasis, and autoimmune diseases such as lupus erythematosus can present with lesions that resemble CL.² Basal cell carcinoma and squamous cell carcinoma may present as ulcerative lesions similar to CL but typically have different clinical and histopathological features.⁹

Therefore, a combination of thorough clinical evaluations and appropriate laboratory tests is necessary to establish the correct diagnosis.¹⁵ Biopsy and histopathological examination can aid in differentiating CL from other conditions, especially when combined with molecular techniques.¹⁸

Pharmaceutical Treatments

One of the difficulties in the management of CL is that its treatment varies based on the species of Leishmania, geographical region, and patient factors.^17,19 The mainstay of treatment includes antimonial compounds, amphotericin B, pentamidine, and miltefosine.^{4,7,14,15,20,24} Most of these pharmacologic agents can be effective against multiple species, but the conditions presented by each case should guide the treatment decision and may limit the choice of therapy (Table 2). Recent studies have even considered the use of multiple treatments to synergize therapeutic effects.^1,3

Pentavalent Antimonial Compounds

Meglumine antimoniate and sodium stibogluconate (SSG) have been the first-line treatments for decades. They are effective but associated with significant side effects such as cardiotoxicity and hepatotoxicity.¹⁵ These drugs require intramuscular or intravenous administration, and treatment courses typically last 20 to 28 days.²⁴

Amphotericin B

This antifungal agent is effective against various Leishmania species. Liposomal formulations have improved the safety profile but remain expensive.² Liposomal amphotericin B (AmBisome®) is administered intravenously and is preferred for its lower toxicity and shorter treatment duration compared to conventional formulations.³⁶

Pentamidine

Used primarily for L. guyanensis infections, pentamidine is an alternative when antimonies are contraindicated or ineffective.³⁷ It is administered intramuscularly or intravenously, and common side effects include nephrotoxicity, hypotension, and hyperglycemia.²⁰

Miltefosine

As the first oral drug approved for CL, miltefosine is effective against several species and has a more favorable safety profile, though it is teratogenic and requires monitoring for gastrointestinal side effects.³⁸ Treatment with miltefosine typically lasts 28 days and is even effective against visceral leishmaniasis.^24,39

Recent research has focused on combination therapies to improve efficacy and reduce the duration of treatment.⁴ Combination therapy using miltefosine with other drugs such as paromomycin or liposomal amphotericin B has shown promise in clinical trials.²⁴

Drug Resistance

The emergence of drug resistance in CL is influenced by various factors, including parasite genetics, host immune responses, and treatment regimens.⁴⁰ Studies have highlighted the role of genetic mutations in mediating resistance to antimonies, amphotericin B, and miltefosine.^39,41 For instance, mutations in genes encoding proteins involved in drug transport and metabolism, such as aquaglyceroporin 1 (AQP1) and multidrug resistance protein 1 (MRP1), have been associated with decreased drug susceptibility in Leishmania parasites.^42,43

AQP1 is a transmembrane channel protein that facilitates the passage of water, glycerol, and certain small solutes across the cell membrane of Leishmania parasites.^42,44 Importantly, the channel also serves as a conduit for the uptake of antimonial drugs like SSG. Therefore, mutations in the AQP1 gene can lead to structural alterations in the protein, resulting in reduced drug uptake and diminished susceptibility to antimonials.⁴⁵ Similarly, MRP1 belongs to the ATP-binding cassette (ABC) transporter family and is involved in the efflux of a broad range of substrates, including chemotherapeutic agents.⁴¹ Overexpression or mutations of MRP1 can confer resistance to multiple antileishmanial drugs by actively reducing their intracellular concentrations and, consequently, their therapeutic efficacy.⁴³ Therefore, an understanding of the molecular basis of drug resistance is essential for the development of effective therapeutic strategies and the identification of novel drug targets to combat CL.

Moreover, environmental factors, including drug pressure and host immune status, play a crucial role in shaping the dynamics of drug resistance in CL. Prolonged exposure to suboptimal drug concentrations can select for resistant parasite strains.^40,42 Additionally, immunocompromised individuals, such as those co-infected with human immunodeficiency virus (HIV), are more susceptible to treatment failure and the development of drug resistance due to impaired immune responses.³³

Non-Pharmaceutical Treatments

Non-pharmaceutical treatments are often used in conjunction with pharmaceutical therapies or when drug treatment is contraindicated.^2,46 These methods provide alternative patient options and can be tailored to individual needs and preferences. Current treatments include cryotherapy, photodynamic therapy, and surgical excision.^19,20,46

Cryotherapy

Cryotherarpy involves the application of liquid nitrogen to freeze and destroy the lesion. It is effective for localized lesions but may require multiple sessions.⁴⁷ Cryotherapy is a simple, low-cost option that can be performed in outpatient settings and is particularly useful for lesions in accessible areas.⁴⁸

Photodynamic Therapy

Photodynamic therapy utilizes light-activated compounds to selectively target and destroy Leishmania parasites. The application of a photosensitizing agent followed by exposure to a specific wavelength of light, leads to the generation of reactive oxygen species that kill the parasites.⁴⁹ For patients who cannot tolerate systemic treatments, photodynamic therapy is a promising solution.⁵⁰

Surgical Excision

Surgical excision can be considered for single, well-defined lesions that are resistant to other treatments.^23,51 It carries the risk of scarring and should be performed by experienced clinicians.^2,52

Conclusion

Managing CL involves a comprehensive approach that includes prevention, accurate diagnosis, and effective treatment. Recent advancements in diagnostic tools and treatment options have improved the management of CL. However, challenges remain, particularly in non-endemic regions like North America, where awareness and expertise may be limited.^4,8 Increased travel and climate change could lead to a rise in cases, highlighting the need for continued research and international collaboration to address these challenges and reduce the burden of CL globally.³

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

Conflict of interest:
Susuana Adjei, Austinn Miller and Laurie Temiz have no conflicts of interest to disclose. Stephen Tyring was a principal investigator for the Almirall PROSES clinical trial.

Abstract:
Tetracycline-class drugs have been used for first-line treatment of moderate-to-severe acne and rosacea for decades. Recently, a new third generation tetracycline, sarecycline, was US FDA-approved for the treatment of moderate-to-severe acne. This narrow-spectrum tetracycline-derived antibiotic has been shown to be effective with an improved safety profile.

Key Words:
sarecycline, tetracyclines, moderate-to-severe acne, antimicrobial resistance, adverse effects

Introduction

To date, one of the first-line classes of oral antibiotic treatments for moderate-to-severe acne has been tetracycline-class antibiotics due to their anti-inflammatory effects, antimicrobial activity, bioavailability, and lipophilicity.¹ The pathogenesis of acne vulgaris is multifaceted with key factors being abnormal follicular keratinization, Cutibacterium acnes (C. acnes) proliferation/ colonization, and increased sebum production.² Inflammation also ensues with the expression and upregulation of inflammatory factors/cells such as CD3+, CD4+ T cells, interleukin-1, integrins, toll-like receptors, and macrophages.²

Various methods for grading acne severity have been debated. Consensus remains elusive, as acne assessment must account for a spectrum of factors such as the number, location, type of lesions, associated scarring, and psychosocial influences.^1,3 In fact, the established scoring tools Global Acne Grading System (GAGS) and Investigator Global Assessment (IGA), which are widely used in clinical trials, FDA efficacy endpoints, and patient care, do not account for all the associated factors in acne assessment.³

Moderate-to-severe acne classically presents with inflamed papules, pustules, and occasional nodules with lesions commonly affecting the face, chest, and back.^4,5 Oral antibiotics are a mainstay of treatment (Table 1).¹ Tetracyclines, specifically doxycycline and minocycline, are broad-spectrum antibiotics widely used for acne treatment as they limit inflammation by inhibition of protein synthesis and proliferation of C. acnes.⁶ However, because of their broad-spectrum activity, tetracyclines not only contribute to the emergence of bacterial resistance, but also disrupt the gut and skin normal microflora, resulting in dysbiosis.^7,8 Dysbiosis of the gut has been linked to inflammatory bowel disease. Doxycycline has shown to be associated with 2.25-fold increase in the risk of developing Crohn’s disease.⁹

Table 1

Discussion

Efficacy of Sarecycline

Leyden et al. compared dose ranges of sarecycline versus placebo in a 12-week phase 2 clinical trial with 285 patients. The subjects ranged from ages 12-45 years old with moderate-to-severe acne and were randomized to receive sarecycline dosed at 0.75 mg/kg, 1.5 mg/kg or 3.0 mg/kg, or placebo.¹⁰ Reductions of 52.7% and 51.8% in inflammatory lesions were reported in the 1.5mg/kg and 3.0mg/kg treatment groups, respectively, as compared to 38.3% for placebo. These results suggest no difference in efficacy for doses of 1.5 mg/kg and 3.0 mg/kg.¹⁰

In two identical 12-week phase 3 trials (SC1401 and SC1402), a total of 2002 subjects aged 9-45 years with moderate-to-severe acne were randomized 1:1 to receive sarecycline or placebo. As early as 3 weeks, there was a mean percentage reduction in inflammatory lesions of -49.9% to -51.8% in the sarecycline group versus -35.1% to -35.4% in the placebo group.^11,12 In addition, there was significant improvement in truncal and chest acne by 12 weeks, which was observed as early as 3 weeks.^11,12 In non-inflammatory facial acne, Moore et al. revealed a larger mean change from baseline in subjects using sarecycline versus placebo at week 12.¹² IGA also improved in truncal acne by 2 points (and clear or almost clear) at week 12 in subjects on sarecycline that had an IGA of more than 2 at baseline.^12,13

In a pilot study of 100 patients, sarecycline demonstrated significant efficacy in papulopustular rosacea, reducing not only lesion counts, but also erythema.¹⁴ Additionally, one case report showed the effectiveness of sarecycline in periorificial dermatitis.¹⁵

Mechanism of Action

Tetracyclines share a common four ring naphthacene core but differ by a variety of structures attached to the carbon groups.¹⁶ Sarecycline has a 7-[[methoxy(methyl)amino]methyl] group attached to the C7 position. It binds to the A site codon of tRNA, blocking protein synthesis and inhibiting bacterial growth (Figure 1).^16,17 Unlike other tetracyclines, sarecycline extends to mRNA due to its long C7 moiety and allows for direct interaction with the mRNA channel.¹⁶ This increases its stabilization, leading to better inhibitory activity by blocking tRNA accommodation and mRNA translation.^17,18

Antibacterial Resistance

Antimicrobial resistance complicates the prolonged use of antibiotics, in general. Due to its narrow-spectrum coverage, sarecycline is less likely to induce resistance.⁶ C. acnes displayed low propensity for the development of resistance to sarecycline with spontaneous mutation frequency of 10^-10 at 4-8 times the MIC.⁶ Bacteria confer resistance to tetracyclines by forming efflux pumps and acquiring Tet proteins that bind to the A site codon of the tRNA, releasing the bacteria from the antibiotics.^16,19 The acquisition of combined Tet(K) and Tet(M) genes among S. aureus strains confers resistance against tetracyclines.⁶ Compared to the other agents in its drug class, sarecycline has shown superiority in its activity against these tetracyclineresistant S. aureus strains against Tet(K) at MIC ranging from 0.12-0.5 g/mL as compared to 16-65 g/mL with the other tetracyclines.⁶ Due to its narrow-spectrum activity, sarecycline is expected to yield lower rates of antimicrobial resistance; however, it has not been found to be statistically significant when compared to other tetracyclines.⁶ Zhanel et al. noted that sarecycline’s propensity to lead to C. acnes mutations was not found to be significantly different from minocycline.⁶

Safety Profile

The broad-spectrum activity of minocycline and doxycycline elicits common adverse effects such as gastrointestinal symptoms, photosensitivity, dizziness, microbial resistance, and tinnitus.^1,19-21 Data has shown that, thus far, the most common adverse effect associated with sarecycline is nausea at an incidence of ≥1%.¹⁰ Moore et al. reported that treatment-emergent adverse events were similar in both the sarecycline and placebo groups, the most common being nausea.¹² A phase 1 randomized, double-blinded, placebo-controlled study was conducted to assess phototoxicity in 18 healthy adult males with Fitzpatrick skin types I, II, and III on 240 mg sarecycline.²² There was no significant dermal response to ultraviolet light exposure. Photosensitivity reactions were uncommon and limited to mild erythema.²² Dizziness was experienced by <1% of patients receiving sarecycline, and no vertigo or tinnitus was reported.²³ Sarecycline is less likely to penetrate the blood-brain barrier, which may explain the very low rates of vestibular adverse events observed in the clinical trials.²³

Conclusion

Sarecycline is a novel antibiotic that has shown significant promise in acne treatment due to its narrow-spectrum activity and weight-based dosing. The advantages of this new systemic therapy include improved tolerability, reduced drug resistance and potentially longer-lasting efficacy. There remain more avenues to explore including sarecycline’s utility in treating other cutaneous infections and inflammatory dermatoses.

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¹Texas A&M College of Medicine, Dallas, TX, USA
²University of Texas Medical Branch, Galveston, TX, USA
³University of Texas Health Science Center McGovern Medical School, Houston, TX, USA
⁴Center for Clinical Studies, Webster, TX, USA
⁵Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
None.

Funding resource:
None.

*Co-first authors

Abstract:
Janus kinase inhibitors, also commonly referred to as JAK inhibitors, are a novel drug class that target and block cytokine signaling mediated by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, thereby regulating immune response and cell growth. Although JAK inhibitors are mainly used for rheumatological conditions such as rheumatoid arthritis, their application in the field of dermatology is actively being investigated. Tofacitinib is US FDA-approved for psoriatic arthritis and showing promise for treating psoriasis. Most recently, regulatory approvals for the US were gained by ruxolitinib as a first-in-class, selective, topical therapy for atopic dermatitis and oral upadacitinib for active psoriatic psoriasis. Additionally, abrocitinib and upadacitinib have demonstrated efficacy in atopic dermatitis and are pending FDA approval for this indication. The therapeutic potential of JAK inhibitors in dermatological conditions such as alopecia areata, psoriasis, atopic dermatitis, vitiligo, and dermatomyositis are showing promising results in clinical trials. Adverse events for JAK inhibitors seem to be similar to that of biologic drugs. Common adverse effects include increased risk of infections and thromboembolic events. Further investigation is needed to not only better understand the safety profile of JAK inhibitors, but also their full utility within the field of dermatology.

Key Words:
Janus kinase inhibitors, JAK inhibitors, JAK-STAT, tyrosine kinase inhibitors, TYK2 inhibitors, dermatology, ruxolitinib, abrocitinib, upadacitinib, tofacitinib, baricitinib

Introduction

Autoimmune and inflammatory diseases are common and on the rise, affecting 3% to 5% of the Western population.^1-4 These disorders are thought to evolve from a complex, incompletely understood interplay of host genetics, microbiota, and environmental factors that contribute to dysregulated T-cell and B-cell activity against the host, leading to tissue damage.¹ In the realm of dermatology, there have been considerable advances enabling examination of deep molecular processes and immunological pattern analyses that allow us to better understand the pathophysiological mechanisms of autoimmune and inflammatory skin diseases.^5-8 Furthermore, skin biopsy analysis has facilitated our ability to characterize the influencing factors such as cytokines, receptors, and signaling molecules in order to develop targeted therapeutic agents.⁵

Various therapeutics can be used to attenuate the immune response either through direct suppression of T-cell activity or by directly or indirectly blocking cytokines. Glucocorticoids have long been used to suppress an aberrant immune response; however, they have the drawback of eliciting nonspecific immunosuppressive effects. Many cells express steroid receptors and adverse effects of glucocorticoids are common, thus their use in the management of chronic autoimmune or inflammatory diseases should be cautioned given their side effect profile.¹ Cytokine activity can likewise be inhibited by biologic therapy. Most recently, inhibitors of signaling proteins have been introduced for the treatment of psoriatic arthritis and rheumatoid arthritis.¹ These inhibitors target the Janus kinases (JAKs) family of proteins by modulating the inflammatory process through activation of intracytoplasmic transcription factors called signal transducer and activator of transcription (STAT).⁵ STATs get activated, dimerize, and translocate into the nucleus where they modulate the expression of various genes.

Inflammation of the skin relies on this interaction between cytokines, as well as immune and tissue cells, to propagate the different distinct inflammatory cascades. Because of these unique mechanisms, JAK-STAT inhibitors are gaining traction in clinical development as new potential therapeutics for various inflammatory dermatological conditions.

Aims and Objectives

The aim of this literature review is to provide updates on the mechanism of JAK inhibitors and assess their efficacy in the treatment of alopecia areata, psoriasis, psoriatic arthritis, atopic dermatitis, dermatomyositis, and vitiligo. A class-wide safety review and future considerations will also be discussed.

Methods

A review of the literature regarding the mechanism of action and efficacy of JAK inhibitors in skin diseases was done by searching the PubMed, Scopus, and EBSCO databases. The following keywords were used to find articles: ‘Janus kinase-inhibitors’, ‘JAK-inhibitors’, ‘JAK-inhibitors pathway’ combined with ‘dermatology’, ‘atopic dermatitis’, ‘alopecia areata’, ‘psoriasis’, ‘dermatomyositis’, ‘vitiligo’, ‘side effects’, and ‘safety’.

JAK-STAT Signaling Pathway

The JAK-STAT pathway is activated by numerous different cytokines, which bind directly to the Janus kinase receptor and initiate transphosphorylation. This ligand-mediated receptor binding brings two JAKs in close proximity, allowing for its autophosphorylation and activation. The activated JAKs subsequently lead to the phosphorylation of the tyrosine residues on the receptor. The phosphorylation of the tyrosine residues on the receptor recruits STATs, inactive latent transcription factors in the cytoplasm. Using their SH2 domain, the STATs bind to the phosphorylated tyrosine residue on the receptor and are phosphorylated by JAKs. This causes the STATs to dissociate from the receptor, dimerize, and travel from the cytosol into the nucleus where they are able to modify gene transcription.⁹ There are four members within the JAK family of kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]), and the STAT family has six proteins (STAT1, STAT2, STAT3, STAT5A/B and STAT6).¹⁰

One or more members of the JAK and STAT families may be recruited by any specific receptor influencing different aspects of immune cell development and function.¹¹ Various combinations of different types of JAK proteins can be associated with several receptors that have variable effects on specific signaling pathways of the immune system, such as the combination of JAK1 and JAK3 related to cytokine receptors fundamental for the function of lymphocytes or the TYK2/JAK2 combination that is essential for the signaling of interferon (IFN)-a, interleukin (IL)-12, and IL-23 receptors.¹¹ The varied distribution amongst different JAK/STAT proteins across distinct cell types shows how a genetic defect of JAKs or STATs might determine various clinical conditions, such as JAK3 deficiency in severe combined immunodeficiency syndrome.¹¹ Additionally, the modulation or inhibition of the activity of these intracellular pathways represents a potential target in immune mediated diseases such as psoriasis and atopic dermatitis.^11,12

The mechanism of action of JAK inhibitors targets the kinase component of JAKs. This prevents the JAK protein from phosphorylating, thus halting the intracellular signaling transduction.¹ First generation JAK inhibitors, such as baricitinib, ruxolitinib, and tofacitinib, inhibit many JAKs. For example, tofacitinib, which is FDA-approved for psoriatic arthritis, inhibits JAK1 and JAK3 mainly, with some selectivity towards the JAK2 isoform.¹³ The rationale behind the nonselective, multi-JAK inhibition is the notion that blocking multiple JAKs may enhance therapeutic efficacy.¹⁴ On the other hand, the second generation JAK inhibitors are more selective to particular JAK isoforms to limit adverse effects and possibly maintain treatment efficacy. Deucravacitinib is a second generation JAK inhibitor that specifically targets TYK2.^13-15 This drug has shown efficacy in the treatment of systemic lupus erythematosus and is currently in a phase III trial for psoriasis.¹ Research into the efficacy of JAK inhibitors continues at a rapid pace as a host of new drug candidates are under development, thus shedding light on their mechanisms in treating rheumatological and dermatological diseases.

Applications in Dermatology

JAK inhibitors have shown significant clinical efficacy in patients with psoriasis and psoriatic arthritis.¹ Currently, the FDA-approved JAK inhibitors in dermatology are oral tofacitinib and upadacitinib for the treatment of psoriatic arthritis^1,2 and topical ruxolitinib for mild to moderate atopic dermatitis. However, the use of first and second generation JAK inhibitors in other dermatological diseases such as alopecia areata, atopic dermatitis, dermatomyositis, vitiligo, and systemic lupus erythematosus is being heavily investigated in numerous clinical trials (Table 1).¹³

Alopecia Areata (AA)

AA is a chronic, autoimmune non-scarring hair loss disorder that involves the destruction of hair follicles by autoreactive CD8 T cells.³ It classically presents as smooth, circular hair loss patches with no erythema, pain, pruritus, or inflammation. JAK-STAT dependent cytokines IFN-γ and IL-15 contribute to signaling cascades through JAK1 and JAK3.³ They lead to the proliferation of autoreactive T cells that are active in AA.

Systemic and topical administration of JAK inhibitors have shown to be beneficial in patients with AA. In 2014, a case report was published featuring a patient with diagnosed alopecia universalis and psoriasis. While using tofacitinib to treat psoriasis, the patient experienced complete regrowth of body and scalp hair, as well as eyelashes and eyebrows.⁴ Since then, several other case reports and studies have been published illustrating the successful treatment of AA using JAK inhibitors (primarily tofacitinib, ruxolitinib, and baricitinib).^5-8,10 However, relapse of hair loss has been reported in the literature after drug discontinuation.⁹ In a recent phase II trial, ritlecitinib and brepocitinib were found to be well tolerated and led to clinically meaningful improvements in hair growth. Approximately 25% and 34% of patients treated with ritlecitinib and brepocitinib, respectively, saw near-complete regrowth.¹⁶ Topical JAK inhibitors for the treatment of localized AA could be proven useful, but more studies are needed for validation. In the case of topical tofacitinib, one pilot study of patients treated with 2% tofacitinib twice daily revealed a poor response with only 3 responders.17Another study describes almost complete regrowth of hair with topical 2% tofacitinib every 12 hours for 7 months.¹⁷ Topical ruxolitinib has also shown various responses in AA, with one study showcasing regrowth at 28 weeks in 5 patients in the area treated. In adolescent patients, topical ruxolitinib 0.6% applied twice daily showed complete growth of the eyebrows observed at 3 months, while there was only 10% regrowth of the scalp.¹⁷ Currently, positive results from numerous early phase clinical trials have increased interest in this area. Further investigation is needed to determine optimal dosing of JAK inhibitors in AA and whether maintenance therapy is required.

Psoriasis and Psoriatic Arthritis

Psoriasis has been the most studied dermatological disease in relation to JAK inhibitors. JAK-STAT dependent cytokines are implicated in the pathogenesis of psoriasis, with IL-12 and IL-23 being fundamental mediators.¹¹ Several phase III randomized controlled clinical trials have shown significant reduction, up to 75%, in the Psoriasis Area and Severity Index (PASI 75) when patients were treated with tofacitinib at both 5 mg and 10 mg twice daily doses, with improvement seen in a dose dependent manner.¹² Improvements from the treatment were sustained up to 52 weeks and side effects appeared to be similar in both dosing regimens. Furthermore, a phase III non-inferiority trial determined that tofacitinib at 10 mg twice daily was non-inferior to etanercept 50 mg twice weekly.¹⁴ Nevertheless, the FDA did not approve tofacitinib for psoriasis, likely attributable to the need for more safety data on the 10 mg dose.

Several other JAK inhibitors have demonstrated promising results. A phase IIb clinical trial of baricitinib showed more patients achieved PASI 75 when compared to placebo in the treatment of moderate-to-severe plaque psoriasis.18 Deucravacitinib, a novel, selective TYK2 inhibitor has demonstrated to be more advantageous in the treatment of moderate-to-severe plaque psoriasis when compared to placebo and apremilast in a phase III clinical trial.¹⁹ Patients achieved PASI 75 after 16 weeks of treatment, with the overall safety of the drug being consistent with previous results.¹⁹

As opposed to systemic therapy, medications administered topically generally have more favorable safety profiles given less systemic absorption. Topical formulations of ruxolitinib and tofacitinib have been tested in phase II clinical trials for psoriasis.²⁰ Side effects in both these trials were mild and there were no signs of systemic symptoms in any of the patients. Treatment with topical ruxolitinib twice daily showed improvement in psoriasis lesion size compared with placebo.²¹ Improvement in psoriasis was also noted in patients treated with topical tofacitinib. Discontinuation of the topical drugs led to worsening of psoriasis.²⁰

Tofacitinib was FDA-approved in December 2017 for the treatment of patients with psoriatic arthritis who have had little to no improvement in their symptoms using methotrexate or other disease-modifying antirheumatic drugs.¹³ The decision was based on the results of two phase III clinical trials that showed statistically significant improvements in American College of Rheumatology 20 (ACR 20) response at 3 months when patients were treated with tofacitinib 5 mg and 10 mg twice daily.¹³ In a recent 24-week, phase III trial, oral upadacitinib was assigned to patients with psoriatic arthritis at a dose of 30 mg or 15 mg once daily, while other patients received either placebo or subcutaneous adalimumab 40 mg every other week. Results showed that the ACR 20 response rate was significantly higher for patients receiving the two doses of upadacitinib versus placebo. Furthermore, only the 30 mg dose of upadacitinib was shown to be superior to adalimumab.²²

Atopic Dermatitis

Atopic dermatitis (AD) is one of the most common, chronic and pruritic inflammatory skin diseases. The pathogenesis of this disease is fueled by functional impairment of the epidermal barrier and abnormal immune activation. IL-4 is one of the main culprits in AD known to play a pivotal role in signaling through the JAK-STAT pathway.^1,14

Oral tofacitinib was reported to be efficacious in 6 patients with moderate-to-severe refractory AD. Tofacitinib 5 mg twice daily or daily for 14 weeks led to a decrease in the average Severity Scoring of Atopic Dermatitis (SCORAD) index by approximately 55%.²³ Moreover, the study reported significant reduction in pruritus scores as well. A recently published, randomized, double-blinded, placebo-controlled phase III clinical trial showed that the treatment of moderate-to-severe AD with oral abrocitinib resulted in greater reductions in signs and symptoms of the disease, as well as greater itch response when compared to dupilumab and placebo.²⁴ Abrocitinib’s pending FDA approval has been delayed for an unspecified amount of time as data analysis continues.²⁵ In multiple phase III clinical trials, upadacitinib has been shown to improve skin and itch symptoms in adolescent and adult patients with moderate-tosevere AD.^26,27

Topical JAK-STAT treatments such as tofacitinib, ruxolitinib and delgocitinib have also shown promise in the treatment of AD, with topical delgocitinib being approved in Japan under the trade name Corectim^® and topical ruxolitinib (Opzelura™) receiving FDA approval for mild to moderate AD.²⁸ Topical tofacitinib 2% every 12 hours in 69 patients with mild to moderate AD for 4 weeks led to an 81.7% reduction in Eczema Area and Severity Index score after 4 weeks.²⁸ Topical ruxolitinib was also found to have a therapeutic benefit for patients by week 4 with each variant of ruxolitinib regimen; the drug rapidly improved pruritus and was well tolerated.²⁸ Phase I and phase II studies of delgocitinib proved the therapeutic efficiency of the medication with respect to severity and pruritus, with pruritus improving 1 day after initiating treatment.²⁸

Evidence for clinical efficacy of JAK inhibitors in the treatment of AD has been shown in several other phase II and III clinical trials, forging a possible future when these drugs may become mainstay therapy for the disease.^29-32

Dermatomyositis

Dermatomyositis is an autoimmune myopathy that is characterized by symmetric proximal muscle weakness and rash. Pathogenesis of the disease is mediated by CD4 lymphocytes and complement activation. There have been several reported cases demonstrating the efficacy of JAK inhibitors in treatmentrefractory dermatomyositis.^33-36 A case series of three patients treated with tofacitinib reported that they had improved significantly in their Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score.³⁵

Additionally, one case reported a patient with myelofibrosis and concomitant refractory dermatomyositis who improved significantly while on ruxolitinib.³³ Nonetheless, it is unknown whether the improvement of the patient’s dermatomyositis was an indirect effect of treating myelofibrosis or a direct effect of ruxolitinib-mediated JAK inhibition. Furthermore, another case report of a patient with dermatomyositis experienced significant improvement in her cutaneous disease, arthritis, and muscle strength while being treated with tofacitinib.³⁶

Vitiligo

Vitiligo is an autoimmune condition characterized by absence of pigmentation due to loss of melanocytes. While the exact etiology of the disease is unknown, evidence from literature has shown that the destruction of melanocytes is mediated by CD8 T cells.^1,37 As with AA, IFN-γ plays a vital role in the pathogenesis of vitiligo, thus making this disease susceptible to treatment with JAK inhibitors.¹ For example, a patient with generalized vitiligo showed near complete repigmentation of areas in the hands, forearms, and face over 5 months while on tofacitinib.³⁸ However, discontinuation of the drug led to depigmentation in affected areas.³⁸

An additional case report of a patient with both AA and vitiligo experienced hair regrowth and repigmentation while being treated with ruxolitinib.³⁹ As is the case with the previous patient mentioned, depigmentation occurred with discontinuation of the drug. Currently, topical ruxolitinib is in a phase 3 clinical trial to evaluate its efficacy and safety in treatment of vitiligo.⁴⁰ Clinical trials are vital for clarifying the role of JAK inhibitors in
the treatment of vitiligo.

Other Dermatologic Conditions

There is evidence from the literature suggesting that JAK inhibitors are efficacious in the treatment of refractory dermatologic cases or rare diseases with no effective therapies – chronic mucocutaneous candidiasis, cutaneous sarcoidosis, mastocytosis, polyarteritis nodosa, hypereosinophilic syndrome, and chronic actinic dermatitis. Data from case reports and case series hints at potential broader use for JAK inhibitors in the field of dermatology.^1-2,41

Adverse Effects and Safety Profile

The JAK inhibitors that are approved for autoimmune disease have an associated black box warning for the potential increased incidence of malignancy, serious infections, and thrombosis based on data from oral use in rheumatoid arthritis.¹ Tofacitinib and baricitinib have the most data on their safety and side effect profiles. However, the long-term safety of JAK inhibitors is still not completely understood. Current data suggests the safety of JAK inhibitors may be comparable to other biologics, and as investigations of this promising drug class continue, the safety profile should become more clear.¹ According to the literature, JAK inhibitors may potentially increase the risk of malignancies, as they could impair the immune system’s surveillance mechanism to vet inconspicuous cells that could eventually become cancers.¹ The rate of serious infections in patients treated with JAK inhibitors is comparable to that of other biologic agents such as TNF-a,^1,20 though there is an increased risk of herpes zoster with JAK inhibitor usage.^1,21 Baricitinib, tofacitinib, ruxolitinib and upadacitinib all include warnings for potential deep vein thrombosis, pulmonary embolism, and arterial thrombosis.^1,18 Though these risks appear to be low and dose dependent, additional studies are needed to determine the exact mechanism behind it’s pro-thrombotic effects.^1,37 Additional adverse effects include gastrointestinal perforations, hyperlipidemia, as well as impaired drug metabolism due to interaction with the CYP3A4 system.^1,42

Discussion

There is an increasing body of evidence that suggests JAK inhibitors may be an effective treatment for various inflammatory skin conditions. However, numerous cytokines and immunomodulating molecules act via the JAK-STAT pathway and blunting its activity may have unintended consequences. Long-term follow up studies are needed to establish treatment guidelines and evaluate the risk-benefit profile of JAK inhibitors. As mentioned before, tofacitinib was found to be non-inferior to etanercept for plaque psoriasis, but more studies are needed to compare the efficacy of JAK inhibitors to biologics currently approved for dermatologic use.⁴³ Lastly, future studies should assess the utility and safety of JAK inhibitors in pregnancy and for the pediatric population.

Conclusion

Many inflammatory cytokines involved in the pathogenesis of skin disorders signal via the JAK-STAT pathway. Thus, this drug class has the potential for broad therapeutic utility within dermatology. Currently, JAK inhibitors are only FDA approved for dermatologic, rheumatologic, and hematologic conditions. Recent studies show the utility of JAK inhibitors in treating atopic dermatitis, psoriasis, psoriatic arthritis, vitiligo, and alopecia areata. However, more robust studies are needed to assess long-term safety and establish treatment guidelines. JAK inhibitors are poised to become important additions to the therapeutic arsenal for a wide range of inflammatory skin conditions.

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¹Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX, USA
²Texas A&M University College of Medicine, Dallas, TX, USA
³Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Abstract:
Small-vessel vasculitides (SVV) are a group of disorders that occur due to primarily systemic inflammation or as sequelae of an infection, malignancy, or other rheumatic disease. Arising in any organ including the skin, the clinical features of SVV encompass a variety of manifestations. A comprehensive diagnostic assessment should be performed as management protocols widely differ. Although rare, physicians should be familiar with the common types of SVV to ensure prompt management and prevention of severe, life-threatening end-organ damage. Given the variable manifestations and associated etiologies of SVV, the following review aims to discuss the pathogenesis of more prevalent SVVs, highlight distinguishing features to aid in patient evaluation and diagnosis, and examine evidence-based management options for treatment and care.

Key Words:
cryoglobulinemic vasculitis, diagnostic workup, eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, immunoglobulin A vasculitis, management, microscopic polyangiitis, primary vasculitis, small-vessel vasculitis, SVV, treatment, vasculitides

Introduction

Vasculitis is defined as inflammation of blood vessel walls.¹ Such inflammation manifests as thickening, weakening, narrowing, or scarring of the vessels, leading to restricted blood flow and tissue damage. Vasculitides can occur in any organ, including the skin, and can present with a variety of clinical symptoms.² This broad spectrum of disease is most often classified by the size of the blood vessel involved.^1,2 Small-vessel vasculitis, the focus of our review, is a disease subtype that targets arterioles, venules, and capillaries.² Given this disease’s variable manifestations and associated etiologies, the following review aims to discuss the pathogenesis of common primary small-vessel vasculitides (SVV), highlight distinguishing features to aid in patient evaluation and diagnosis, and define evidence-based management options for patient treatment and care.

Pathogenesis/Distinguishing Clinical Features

Vasculitides are primarily defined by the size of blood vessels affected, typically small, medium, large, or variable, but are more recently defined using the Chapel Hill nomenclature system, which is based on clinical and histopathological features.^3,4 Small vessels include arterioles, capillaries, and venules; medium vessels include main visceral arteries and veins; and large vessels include the aorta and its major branches.³ Using the Chapel Hill system, the systemic vasculitides are categorized into two groups – large-vessel vasculitis and necrotizing vasculitis.

Primary Vasculitis

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) is a rare, anti-neutrophil cytoplasmic antibody (ANCA)-associated subtype of the necrotizing vasculitides, affecting small- to medium-sized vessels. Patients afflicted with this condition can be ANCA-positive or -negative, which reflects the disease’s inherent heterogeneity.⁵ The mechanism underlying ANCA-negative disease involves T helper cell type 2 (TH-2)-mediated immune response in which cytokines released by the TH-2 lymphocytes, most notably interleukin (IL)-5, activate epithelial and endothelial cells. Not only is IL-5 key in the regulation of eosinophil maturation and release, but its role in EGPA is important, as serum levels of IL-5 correlate with disease activity and have been seen to decrease with immunosuppressive therapy.^5,6 Once activated, epithelial and endothelial cells release eosinophil-specific chemokines, which facilitate recruitment of eosinophils and effector TH-2 cells via C-C chemokine receptor type 4 (CCR4) interaction. Eosinophils then secrete peroxidases, neurotoxins, and eosinophil granule major basic protein, leading to tissue damage.⁶ Distinguishing features from other necrotizing vasculitides include the presence of asthma, rhinosinusitis, and peripheral eosinophilia.^5,6 Skin findings are seen in half to two-thirds of EGPA patients and include granulomas, nonthrombocytopenic palpable purpura, urticarial rashes, skin infarcts, and livedo reticularis.⁶

Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) is another ANCA-associated, small-vessel, necrotizing vasculitis. Patients with GPA have a high frequency of self-reactive B lymphocytes, which mature into plasma cells that secrete ANCA. ANCA is able to target cytoplasmic (c)-ANCA and p-ANCA on neutrophils and monocytes, which then generates reactive oxygen species, cytokines, proteases, and neutrophil extracellular trap (NET-derived) products. The subsequent inflammatory response involving complement activation and formation of membrane attack complexes (MACs) leads to necrotizing systemic vasculitis, necrotizing glomerulonephritis, and granulomatous inflammation of the airways.⁷ GPA can be characterized, much like EGPA, by a combination of vague generalized symptoms (malaise, myalgia, arthralgia, weight loss, and fevers) and multi-organ damage. Cutaneous manifestations of GPA range from leukocytoclastic vasculitis to purpura to skin infarcts, ulcers, and gangrene.⁷ Ear, nose, respiratory tract, cardiovascular, gastrointestinal, renal, and central nervous system findings have been noted in GPA patients.⁷

Microscopic polyangiitis (MPA) is yet another small-vessel, ANCA-associated vasculitis (AAV). However, its underlying mechanism is poorly understood beyond the evidence suggesting an autoimmune etiology. The presence of p-ANCA in patients with MPA is most common, but c-ANCA can be present as well. Interestingly, it has been found that titers of p-ANCA do not correlate well with disease activity in MPA, suggesting a multifactorial pathophysiology.⁸ MPA does not typically present until the fifth or sixth decade of life, with renal involvement being its most prominent feature. Pulmonary hemorrhage or findings mirroring idiopathic pulmonary fibrosis; myalgias, arthralgias, and arthritis; ocular, ear, nose, and throat symptoms; gastrointestinal pain or bleeding; and neuropathy are also common. Dermatologic manifestations include purpura and splinter hemorrhages.⁹

Immunoglobulin A vasculitis (IgAV, formerly Henoch- Schönlein purpura) is a small-vessel, immune-complex vasculitis. Antigen exposure via bacteria, viruses, and parasites in genetically predisposed individuals can lead to increased IgA type 1 (IgA1) production. Abnormal glycosylation of IgA1 results in decreased clearance and subsequent increased serum levels of the immunoglobulin (Ig). Additionally, identification of human leukocyte antigen DR beta 4 (HLA-DRB4) supports the role of a genetic component to this disease’s pathogenesis.¹⁰ It is characterized clinically by purpura or petechiae greatest in the lower extremities, abdominal pain (classically secondary to intussusception), arthritis or arthralgia, and renal symptoms.^11,12

Cryoglobulinemic vasculitis (CV) is a small-vessel vasculitis that involves the skin, joints, peripheral nervous system (PNS), and kidneys. Mainly produced as a consequence of chronic hepatitis C (HCV) infection, cryoglobulins are immune complexes that deposit in small vessels, leading to systemic vasculitis in affected patients. It often presents with a triad of purpura, arthralgia, and asthenia in hepatitis C-positive patients. Other skin findings include acrocyanosis, livedo reticularis, nonhealing ulcers, and Raynaud’s phenomenon. Renal, neurologic, and hyperviscosity symptoms are also common in CV, with respiratory and gastrointestinal manifestations more rare. Thyroid disease, type-2 diabetes mellitus, and B-cell non- Hodgkin lymphoma have also been reported in CV patients.¹³ CV can be detected by precipitation of proteins in patients’ serum and is then categorized by immunochemical analysis into types I, II, and III. Type I involves the presence of single monoclonal Igs due to an underlying B-cell lymphoproliferative disorder. Type II is categorized as a mixed cryoglobulinemia and involves polyclonal IgG and monoclonal IgM with rheumatoid factor activity. Type III is also a mixed cryoglobulinemia with polyclonal IgG, polyclonal IgM, and rheumatoid factor activity.¹⁴ In patients with chronic HCV infection, intrahepatic and circulating B-cells are persistently stimulated, resulting in an expanded B-cell population. This population includes VH1-69 clones that can produce Igs with rheumatoid factor activity, eventually leading to the formation of cryoglobulins. Lesion development in CV is dependent on physical and chemical properties of the Igs involved, such as heavy-chain glycosylation and differences in solubility and rigidity. These properties influence the Igs’ ability to form immune complexes and induce inflammation.¹⁵

Secondary Vasculitis

The general pathogenesis driving these blood vessel disorders involves cell-mediated inflammation, immune complex (IC)- mediated inflammation, and ANCA-mediated inflammation. These pathways of inflammation can result in vessel occlusion and tissue destruction due to endothelial cell activation, leading to long-standing disease.⁴ Common secondary causes include autoimmune diseases, infection, drugs and malignancy. It is important to note these common causes for a thorough differential diagnostic evaluation. In this manuscript, the common secondary causes of small-vessel vasculitis will not be further discussed. We aim to focus solely on the clinical approaches to primary small-vessel vasculitis.

Diagnostic Workup

The diagnosis of SVV is based on compatible clinical, histological and laboratory findings. It is recommended to perform an initial screen to exclude infection, as infection can commonly mimic vasculitis. This includes obtaining blood cultures, echocardiogram, hepatitis screen (B and C), HIV test, anti-glomerular basement membrane antibody, antiphospholipid antibodies and antinuclear antibodies. To assess for the extent of vasculitis involvement, examine for internal organ involvement, even in individuals with isolated cutaneous vasculitis. This can be performed with a thorough history, physical examination, urine dipstick, chest radiograph, and nerve conduction studies. To confirm diagnosis, a biopsy is done, with the biopsy site choice dependent on its likelihood of affecting treatment decisions. To identify the specific type of small-vessel vasculitis, it is particularly important to check serum levels of ANCA, cryoglobulin, complement, and eosinophils/IgE. In addition, specific findings on biopsies such as the presence or absence of necrotizing granulomatous inflammation, IgA deposits, and immune complex formation can aid in specific diagnostic identification.¹⁶ Figure 1 provides a summarized workup in diagnosing small-vessel vasculitis.

Current Management

Management of SVV is based on the severity of systemic involvement, skin lesions, and treatment of any underlying comorbidities. A multidisciplinary approach involving rheumatology, pulmonology, nephrology, and others is often beneficial in severe cases. The most common and effective therapies for SVV can be found in Table 1.

Of note, while the majority of IgAV cases require symptomatic treatment only (i.e., managing arthropathy and abdominal pain with rest and analgesia), preventative measures are attempted to manage associated renal disease.¹⁸ Although there are multiple therapeutic agents used for renal disease intervention, their treatment efficacy is still being debated. A meta-analysis of 13 randomized controlled trials was conducted to analyze the benefits and harms of these agents compared to placebo in the prevention and treatment of kidney disease in adults and children. Results revealed no evidence of benefit in the use of prednisone or antiplatelet agents in preventing kidney disease in children with IgAV, and no evidence of benefit has been found for cyclophosphamide treatment in adults or children with severe kidney disease.²³

Management of cutaneous lesions consists of providing supportive care, avoiding triggers, assessing skin lesion severity, and treating the underlying systemic disease. For mild and non-ulcerative skin lesions, supportive measures including leg elevation, gradient support hose, and avoidance of tight clothing, sun exposure, and cold temperatures are recommended. Medications such as antihistamines, topical steroids and topical calcineurin inhibitors can be helpful to alleviate skin symptoms. Antibiotics should also be employed when there is an associated infection. High-dose steroids can be used to treat patients with symptoms of ulcerative cutaneous lesions and signs of minimal systemic disease. It is recommended that high-dose prednisone of up to 1 mg/kg/day be given along with a slow 4-6 week taper to limit some of the severe side effects of long-term systemic corticosteroid use. If recurrent vasculitis occurs during tapering, the addition of a steroid-sparing agent may reduce a patient’s exposure to high-dose steroid therapy. Helpful agents include methotrexate (MTX) at <25 mg weekly after proper evaluation of the patient’s creatinine clearance or azathioprine at 2 mg/kg/day. For patients displaying a more severe cutaneous/ systemic presentation, pulse doses of prednisone can be given intermittently instead of a long taper.²

Lastly, since comorbid conditions such as hypertension, diabetes, hypercholesterolemia, and smoking can accelerate vascular damage, appropriate management of these diseases and cessation of smoking should be highly recommended.¹

Future Aims in Management

In the setting of small-vessel vasculitis, future management through a biological approach would potentially be the most beneficial, since pathology of the systemic vasculitides, especially ANCA-associated, is better understood.²⁴ The success of nonselective B-cell depletion using rituximab has paved the way for the next generation of targeted therapies focusing on innate and adaptive immunity. Researchers have noted that B-cellactivating factor (BAFF) is highly involved in stimulating B-cell proliferation and promoting immature B-cell survival. Increased BAFF levels lead to increased production of autoantibodies and is seen in patients with GPA. The ANCA-stimulated neutrophils observed in this disease release BAFF to promote B-cell survival, and because studies have shown increased BAFF after B-cell depletion with rituximab in ANCA-associated vasculitis models, it has been proposed that BAFF may have a key role in promoting autoreactive B-cell survival, facilitating relapse and chronicity of disease. Belimumab, a monoclonal antibody against BAFF in the treatment of systemic lupus erythematosus, has been investigated in a phase III trial to evaluate its efficacy and safety in combination with azathioprine for GPA and MPA maintenance of remission.²⁵

In addition, abnormal T-cell activation may also have a role in the pathogenicity of AAV. A study evaluating abatacept, a fusion protein that blocks the T-cell activation co-stimulatory signal, demonstrated disease improvement in 90% of the study population. A phase III trial (NCT02108860) evaluating abatacept in the setting of relapsing, non-severe AAV is ongoing. Component C5a of the complement system has also been implicated in the pathogenesis of AAV. C5a serves as a priming agent for neutrophils, resulting in an increased surface expression of PR3 and MPO. Their interaction with ANCA leads to an amplification loop of ANCA-mediated neutrophil activation, further propagating disease. CCX168 (avacopan) is an orally administered inhibitor of the C5a receptor with phase II data reporting complete remission in a majority of patients receiving a combination of cyclophosphamide or rituximab and CCX168 versus placebo. Although the data is promising, further research is needed.²⁵

Finally, it has been shown that inflammatory cytokines may also play an important role in AAV pathogenicity. In patients with active AAV, serum and histopathologic sample levels of IL-6 are increased and appear to be associated with patients who frequently relapse and suffer more severe organ damage. A few case reports have shown that an IL-6 blockade with tocilizumab is successful but requires further evaluation. Along with IL-6, IL-17 and IL-23 may also be involved in more active disease. For this reason, additional research regarding targeted antiinflammatory cytokine therapies is key.^25,26

Conclusion

The SVV are a heterogenous group of diseases that include eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, microscopic polyangiitis, IgA vasculitis, and cryoglobulinemic vasculitis. These disorders can arise without obvious cause or in the setting of autoimmune disease or infection. Clinical manifestations are broad, but often involve cutaneous findings such as purpura and petechiae that can distress affected patients. Effective therapy is founded upon adequate management of the vasculitis primarily via immunomodulation as well as identification and control of modifiable risk factors such as diabetes, hypercholesterolemia, and tobacco use. SVV have the potential to be impacted by emerging immunotherapeutic interventions, especially biologic agents targeting B- and T-cells; however, additional research is needed in this area.

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