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

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

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

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

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

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

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

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

Introduction

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

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

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

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

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

Methods

Aim of the Project

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

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

Steps in the Process

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

Role of the Panel

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

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

Topical Treatment for Mild-To-Moderate AD

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

Skincare Using Gentle Cleansers and Moisturizers

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

TCS and TCI

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

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

Systemic Therapy

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

Crisaborole Ointment

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

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

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

Data Gathering of Real-World Cases on Crisaborole Ointment Use

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

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

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

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

Selected Real-World Cases

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

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

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

Figure 1A – 1D

Figure 1E and 1F

Figure 1G and 1H

Figure 1I and 1G

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

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

Figure 2A and 2B

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

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

Figure 3A and 3B

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

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

Figure 4A and 4D

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

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

Figure 5A and 5D

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

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

Figure 6A and 6B

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

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

Figure 7A and 7B

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

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

Figure 8A and 8D

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

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

Figure 9A and 9B

Figure 9C and 9E

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

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

Figure 10A and 10G

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

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

Figure 11A and 11E

Discussion

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

Steroid Phobia

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

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

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

Irritation, Burning and Stinging

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

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

Antibiotic Resistance

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

Combination Treatment

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

Specific Body Locations

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

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

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

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

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

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

Maintenance Therapy

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

Conclusion

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

Acknowledgement

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

Limitations

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

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

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

Introduction

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

Epidemiology and Impact

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

Role of Androgens in Acne

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

Hormonal Therapy

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

Role of Spironolactone in Acne Treatment

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

Side Effects of Spironolactone

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

Role of Oral Contraceptives in Treatment of Acne

Oral Contraceptives (OGs)

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

Side Effects of Oral Contraceptives

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

Case-based Treatment Approaches

Rationale

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

Approach

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

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

Adherence

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

Conclusion

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

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Introduction

Atopic dermatitis (AD) is a chronic, relapsing, pruritic, inflammatory condition involving the skin which can have a significant impact on the quality of life (QoL).^1,2 Although many patients may be controlled with topical therapy, a subset of those affected will require systemic therapy to control their disease.³ There are currently no approved systemic therapies in North America for the long-term management of moderate-to-severe atopic dermatitis and many treatments are currently being used off-label. This article will guide the family practitioner on how to manage adults with moderate-to-severe AD and when to refer for specialist management.

Abbreviations: AD – atopic dermatitis; ADHD – attention deficit hyperactivity disorder; BSA – body surface area; HPA – hypothalamic-pituitary-adrenal, HTN – hypertension; IL – interleukin; PGA – Physician’s Global Assessment; QoL – quality of life; TCI – topical calcineurin inhibitors; TCS – topical corticosteroids; Th2 – T helper cell type 2; TPMT – thiopurine methyltransferase

Background

• Atopic dermatitis is a common chronic inflammatory disease in both children and adults.
• In developed countries, it is a common skin disorder, affecting up to 20% of children and 1% to 3% of adults.⁴
• Approximately 10% of adults are not controlled with topical therapy alone and require systemic therapy for disease control.³
• Many immunosuppressants are used off-label to control this disease. Cyclosporine is approved for use in AD only in Europe and Japan.^5,6
• The pathogenesis of AD is thought to be due to a defect in the skin barrier primarily through abnormal filaggrin and alterations of the innate and acquired immune system, with interleukin (IL) 4 and 13 as key players.⁷
• Increased knowledge of the immunopathogenesis of AD has allowed for the development of new, targeted therapies.⁸

The Burden of AD

• Up to two thirds of patients with AD also suffer from other atopic comorbidities including asthma, rhinitis and food allergies.^9-11
• A recent epidemiologic study from Germany showed that in addition to atopic comorbidities, patients with AD have a two-fold increased risk of developing ADHD.¹¹
• In one Phase 2b study, 86% of patients reported daily pruritus and 55% reported that itch disturbed their sleep 5-7 nights per week.¹²
• AD has a significant impact on patients and their families: itch, sleep disturbance, anxiety and depression can lead to a reduced QoL and stress on the family.¹³
• Risk factors for depression in patients with AD include an increasing severity of AD, female gender and increasing age. In addition to depression, there is also an increased risk of suicidality in this population and therefore, patients should be screened appropriately.¹³
• In a large US study, (2013 National Health and Wellness Survey:N=75,000), patients with AD reported overall lost work productivity of 30% compared to 16% in those workers without AD; an even greater loss of work productivity was noted when moderate-to-severe patients were compared to those with mild AD, 37% versus 23%, respectively.¹⁴

AD Management

• Non-prescription therapies are often used to help control the disease: moisturizers and emollients should be the cornerstone of any AD regimen.^15,16
• Controlling itch is also key for management as frequent scratching may put the patient at risk for infection.
• Dilute bleach baths can be helpful for patients who suffer from frequent bacterial infections due to their anti-staphylococcal activity, when used in conjunction with intranasal mupirocin. To prepare a bleach bath see Tip #1.^15,17
• Wet wrap therapy can also be an effective treatment to manage flares. This involves applying a wetted layer of gauze where TCS or TCI have been applied to the skin, and then cover with a second, outer dry layer of gauze. Wet wrap therapy provides more rapid improvement as it will increase medication penetration and provide a barrier to scratching.¹⁸

Tip #1: Dilute bleach baths at a concentration of 0.005% – 0.009% can help reduce colonization and recurrent infections in patients with AD.^15,17

How to prepare a bleach bath

• ¼ cup of bleach in a half tub of water to ½ cup bleach in a full bath tub of water
• Repeat 2 times per week

Topical Treatment and Phototherapy

• The gold standard of topical therapy is treatment with TCS and/or TCI.^15,16
• Both TCS and TCI can be used twice daily as needed for acute flares, or as maintenance therapy with a scheduled reduced frequency of application, such as 2-3 days per week.¹⁵
• Topical antihistamines and topical antimicrobials are not recommended for use in AD due to lack of efficacy and risk of contact dermatitis.¹⁵
• If available, phototherapy can be used in both the acute situation for management of flares, and as maintenance therapy for refractory or chronic disease; attention should be paid to any concomitant photosensitizing medications and underlying skin cancer risk.¹⁹

Tip #2: Topical or systemic antihistamines are NOT recommended for the routine care of patients with AD.

Candidates for systemic therapy have

• Moderate-to-severe atopic dermatitis
• Body surface area involvement ≥ 10%
• Areas with significant burden: involvement of face, hands or genitals
• Significant impact on QoL
• Ongoing pruritus
• Failed an adequate trial of TCS or TCI
• Failed phototherapy or cannot access it

Patient Selection for Systemic Therapy

• Patients with moderate-to-severe AD (PGA score ≥ 3) should be considered for systemic therapy when they have the following:
  • At least 10% body surface area (BSA) involvement
  • Ongoing significant impairment in QoL
  • Ongoing pruritus
  • Disease is not controlled with TCS or TCI or topical therapy is not appropriate
  • Treatment failure with phototherapy or phototherapy is not accessible
• Topical therapy is not appropriate if there is a history of adverse effects from TCS such as atrophy, telangiectasia and striae.¹⁵
• TCS are not appropriate if there is a need for application to large areas with a risk of absorption and hypothalamic-pituitary-adrenal (HPA) axis suppression.¹⁵
• TCI therapy can cause transient burning and stinging with application that may not be tolerated by some patients and, therefore, not considered an appropriate therapy.
• Special situations where systemic therapy may be considered appropriate include involvement of areas such as the face, hands or genitals, or when AD has a significant impact on a patient’s daily functioning due to lack of sleep, fatigue, intractable pruritus or significant psychological distress.^19,20

Systemic Therapy

• Antihistamines are not recommended; antihistamines used for the sedating effects have little to no impact on itch and may lead to disturbed sleep, so these are not typically recommended for regular use.^15,19
• Many immunosuppressants are used off label; the most commonly prescribed are cyclosporine, methotrexate, azathioprine and mycophenolate mofetil.³
• Evidence supporting use of these agents is lacking due to methodological limitations in most trials, small numbers and short duration of therapy.^3,21
• The best evidence available supports the use of cyclosporine as first-line therapy for short-term use (Table 1).³
• Systemic therapy is often limited by intolerance to common side effects (nausea, vomiting, headache) or by potential end-organ toxicity and sequelae of immunosuppression.²¹
• Routine monitoring of these agents for adverse events is required.¹⁹
• Oral corticosteroids should be considered as a rescue intervention for severe exacerbations and are not a suitable treatment option for the ongoing management of patients with AD.¹⁹

Tip #3: Avoid the use of systemic corticosteroids in the management of AD unless required as a rescue or salvage therapy of acute severe exacerbations of disease.

Systemic Agents on the Horizon

• Due to an increased understanding of the pathogenesis of AD, several targeted therapies are being developed.²¹ Monoclonal antibodies are among them, as they can provide reduced toxicity and improved efficacy compared to oral systemic agents that may have unintended effects and end organ toxicity.⁸
• A number of small molecule targets and monoclonal antibodies which target Th2 cytokines such as IL-4, IL-5, IL-13 and IL-31, or their receptors, are in development.⁸
• Dupilumab, a human monoclonal antibody against the receptor for IL-4 and IL-13 is the first agent to have demonstrated safety and efficacy in phase 3 trials.^21,22
• Dupilumab is furthest along in development and poised to be the first commercially available biologic for AD.
• Tralokinumab and lebrikizumab, which target IL-13, mepolizumab which targets IL-5, and nemolizumab which targets the IL-31 receptor, are also in earlier stages of development.⁷

Next Steps

• When your patient presents with ongoing difficulties managing AD, it is important to review their current treatment regimen and rule out other diagnoses, such as contact dermatitis.²³
• Encourage regular and generous use of emollients.
• Discuss adherence to the application of topical medications; TCS and TCI should be applied twice daily when there is an acute flare, and when controlled, applied on a schedule of 2-3 times weekly for maintenance, to prolong the flare-free period.^15,16
• During flares, consider wet wrap therapy to improve the efficacy of the applied topical agents, TCS and TCI, and reduce scratching.¹⁸
• If available and convenient, consider phototherapy for widespread acute or chronic disease.¹⁹
• For patients experiencing frequent skin infections, consider dilute bleach baths with intranasal mupirocin to reduce Staphylococcal colonization and infection.¹⁷
• Assess the patient for sleep loss, pruritus, and the impact on QoL and consider screening for depression, anxiety and suicidality.¹³
• If the disease cannot be controlled by these measures, the patient should be managed with systemic medication such as cyclosporine, azathioprine or methotrexate.^3,21
• For physicians not familiar with prescribing immunosuppressive medications, a referral to a dermatologist should be made for the systemic management of AD.

Conclusion

HD can have a significant burden on the patient with an impact on QoL. Early diagnosis of acute or chronic HD is important for optimal management. Other conditions such as tinea manuum and psoriasis need to be ruled out and managed appropriately. Once a diagnosis of HD is confirmed, treatment depends on the severity of the disease. A treatment algorithm has been developed to assist the general practitioner to make a diagnosis and either refer or treat accordingly. Whichever treatment option is prescribed, all patients should be educated on emollient therapy, hand protection and avoidance of irritants or allergens, which may be contributing to their disease.

References

1. Silverberg JI, Hanifin JM. J Allergy Clin Immunol. 2013 Nov;132(5):1132-8.
2. Lundberg L, Johannesson M, Silverdahl M, et al. Acta Derm Venerol. 2000 Nov;80(6):430-4.
3. Roekevisch E, Spuls PI, Kuester D, et al. J Allergy Clin Immunol. 2014 Feb;133(2):429-38.
4. Williams H, Robertson C, Stewart A, et al. J Allergy Clin Immunol. 1999 Jan;103(1):125-38.
5. Bieber T, Straeter B. Allergy. 2015 Jan;70(1):6-11.
6. Saeki H, Nakahara T, Tanaka A, et al. J Dermatol. 2016 Oct;43(10):1117-45.
7. Gandhi NA, Bennett BL, Graham NMH, et al. Nat Rev Drug Discov. 2016 Jan;15(1):35-50.
8. Harskamp C, Armstrong A. Semin Cutan Med Surg. 2013 Sep;32(3):132-9.
9. Zeppa L, Bellini V, Lisi P. Dermatitis. 2011;22(1):40-6.
10. Langenbruch A, Radtke M, Franzke N, et al. J Eur Acad Dermatol Venereol. 2014 Jun;28(6):719-26.
11. Radtke MA, Schäfer I, Glaeske G, et al. J Eur Acad Dermatol Venereol. 2017 Jan;31(1):151-7.
12. Simpson EL, Bieber T, Eckert L, et al. J Am Acad Dermatol. 2016 Mar;74(3):491-8.
13. Nicholas MN, Gooderham MJ. Atopic Dermatitis, depression, and Suicidality. J of Cutaneous Med Surg. 2017 Jan 9:1203475416685078.
14. Whiteley J, Emir B, Seitzman R, et al. Curr Med Res Opin. 2016 Jun;32(10):1645-51.
15. Eichenfield LF, Tom WL, Berger TG, et al. J Am Acad Dermatol. 2014;71(6):116-32.
16. Lynde C, Barber K, Claveau J, et al. J Cutan Med Surg. 2005;8(suppl 5):1-9.
17. Ryan C, Shaw RE, Cockerell CJ, et al. Pediatr Dermatol. 2013;30(3):308-15.
18. Devillers ACA, Oranje AP. Br J Dermatol. 2006;154(4):579-85.
19. Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(6):327-49.
20. Evers AW, Lu Y, Duller P, et al. Br J Dermatol. 2005 Jun;152(6):1275-81.
21. Gooderham M, Lynde CW, Papp K, et al. J Cutan Med Surg. 2016;21(1):31-9.
22. Simpson EL, Bieber T, Guttman-Yassky E, et al. N Engl J Med. 2016; 375(24):2335-48.
23. Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70:338-51.

¹University of Toronto Department of Medicine, Toronto, ON, Canada
²Mediprobe Research Inc., London, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada

Conflicts of Interest:
AKG has been a clinical trials investigator for Valeant Canada, Nuvolase, Bristol Meyers Squibb, Eli Lilly, Merck, Novartis, Janssen and Allergan. AKG has served as a speaker or consultant for Valeant Canada, Almirall, Janssen, Novartis, Sandoz, Moberg Pharma, and Bayer. CWL has been an investigator in clinical trials sponsored by Abbvie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Dermira, Galderma, Innovaderm, Janssen, Eli Lilly, Leo Pharma, Merck, MSD, Medimmune, Novartis, Pfizer, Regeneron and Xoma. CWL has acted as an advisor or speaker, or received travel support, from Abbvie, Amgen, Boehringer, Celgene, Eli Lilly, Janssen, Leo-Pharma, Merck-Serono, MSD, Novartis, Pfizer, Sandoz, and Valeant. MC is a former employee of Mediprobe Research Inc. which conducts clinical trials under the supervision of AKG.

ABSTRACT
Tofacitinib is an oral immunosuppressant approved for the treatment of rheumatoid arthritis (RA) and is currently undergoing investigation (Phase III trials) for treating chronic plaque psoriasis. Tofacitinib inhibits Janus kinases (JAKs), which are essential for the signaling of multiple inflammatory pathways and have been implicated in the pathogenesis of RA and psoriasis. The efficacy and safety of tofacitinib in the treatment of RA and psoriasis have been demonstrated in Phase III trials. Across all studies, the efficacy of tofacitinib in alleviating symptoms of RA and psoriasis were superior to placebo. Moreover, treatment was generally well-tolerated, with the most frequently reported adverse events, for both RA and psoriasis, being nasopharyngitis and upper respiratory tract infection. As such, tofacitinib proves to be an effective therapeutic option for RA and a promising new therapy for psoriasis.

Key Words:
IL-17, interleukin-17, interleukin-17A, monoclonal antibody, chronic plaque psoriasis

Introduction

Tofacitinib (CP-690,550; trade name: Xeljanz®) is an oral immunosuppressant developed by Pfizer¹ that is currently approved for the treatment of rheumatoid arthritis (RA)^2,3 and is undergoing Phase III trials for the treatment of chronic plaque psoriasis.^4-6 Tofacitinib is a pan-Janus-activated kinase (JAK) inhibitor, which works by inhibiting JAK3, JAK1, and, to a lesser extent, JAK2.⁷ Members of the JAK family play a key role in the signaling pathways of multiple cytokines (e.g., tumour necrosis factor [TNF]), growth factors, and hormones.² Activation of these immune pathways involving JAKs have been implicated in the pathogenesis of RA^2,8 and psoriasis.⁹

Since its FDA approval in 2012, tofacitinib has demonstrated promising results in Phase III clinical trials by significantly reducing RA associated symptoms such as synovial inflammation and structural joint damage.¹⁰ Moreover, ongoing Phase III studies are demonstrating that tofacitinib could emerge as a valuable therapy for psoriasis.¹¹ The focus of this paper is to evaluate the efficacy and safety of tofacitinib in the treatment of RA and psoriasis by reviewing recent clinical trials.

Tofacitinib for Rheumatoid Arthritis

Phase III Trials

Six Phase III trials (belonging to the Oral Rheumatoid Arthritis triaLs [ORAL] series) have been conducted to assess the efficacy of tofacitinib in the treatment of RA in various patient groups.^12-17 A summary of the details from each Phase III trial and two long-term open extension trials¹⁸ can be found in Table 1. Three primary efficacy outcomes were similar between the five Phase III trials: 1) American College of Rheumatology (ACR) 20 ( ≥20% reduction in the number of both tender and swollen joints and ≥20% improvement in three of five other criteria: the patient’s assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician) response criteria; 2) changes from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI; range of score 0-3, “no difficulty” to “unable to do”); and 3) percentage of patients with Disease Activity Score for 28 joint counts based on erythrocyte sedimentation rate (DAS28-4 [ESR]) of less than 2.6 (range 0-9.4). The sixth trial (ORAL Start) used the primary efficacy outcome of ARC 70 response and the modified total Sharp score (mTSS) from baseline. In the groups receiving tofacitinib treatment, ARC 20 or 70 (for the ORAL Start trial) response rates and the HAQ-DI scores were significantly higher compared to the placebo groups. Most studies also showed significant changes from baseline in the DAS28-4 (ESR) score in the tofacitinib group(s) compared to placebo and the ORAL Start trials showed that the change in mTSS from baseline was significantly smaller in the tofacitinib groups. The most common adverse event (AE) throughout the studies was upper respiratory tract infection. During the first 3 months of tofacitinib therapy, significant decreases in neutrophil counts and increases in low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol counts were observed compared to placebo groups. Safety and tolerability data for these studies are summarized in Table 2.

Data from Phase II and Phase III Trials

A study using pooled data from tofacitinib Phase II, Phase III and long-term extension studies was conducted to determine the rate of infection and all-cause mortality across studies in patients receiving tofacitinib monotherapy or tofacitinib in conjunction with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARDs).¹⁹ The overall rate of serious infection in 4,789 patients was 3.09 events per 100 patientyears, with the overall rates of mortality and infection being similar in the tofacitinib groups and groups being treated with biological agents. A recent Phase II randomized control study was conducted to test the efficacy of tofacitinib monotherapy vs. placebo for the treatment of RA in Japanese patients.²⁰ Similar to the Phase III ORAL studies, dose-dependent decreases were observed in neutrophil and platelet counts, with a significant increase in low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and total cholesterol levels compare to placebo groups.²⁰ The significant decrease in neutrophil counts led to moderate-severe neutropenia in seven patients that was not life threatening.²⁰ Furthermore, 23.3% of patients across all groups had a decrease in absolute lymphocyte counts, however, this did not lead to an increase in severe infections.²⁰ Of note, RA patients from Asia may be at increased risk for herpes zoster when undergoing tofacitinib treatment. An open-label, longterm extension study of tofacitinib in Japanese patients reported herpes zoster in 19.3% of patients,²¹ while analysis of tofacitinib patients from the worldwide clinical program identified Asia as an enrollment center to be an independent risk factor for developing herpes zoster.²²

Another study conducted using data from the Phase III trial ORAL Step assessed patient-reported outcomes for tofacitinib.²³ Patients reported improvements in patient global assessment of disease activity (p<0.0001) and the physical and mental component of the Short Form 36 Health Survey version 2 scores (p<0.05) for both tofacitinib doses compared with placebo. Furthermore, improvements were more frequently reported by tofacitinib treated patients vs. placebo for pain (p<0.0001). The results are consistent with recently published data from the ORAL Solo trial, demonstrating statistically significant improvements in pain, Medical Outcome Survey (MOS) for Physical and Mental health, and Functional Assessment of Chronic Illness Therapy-Fatigue in patients receiving tofacitinib (5 mg or 10 mg) vs. placebo (p<0.0001 for all).²⁴

A systematic review of randomized Phase II and III controlled trials concluded that tofacitinib, at dosages of 5 mg and 10 mg twice daily, is effective in patients with active RA who show an inadequate response to methotrexate or DMARDs.²⁵ The ACR 20 response rates were significantly higher in the tofacitinib 5 mg and 10 mg groups than in the placebo groups in all studies. Moreover, the safety outcomes did not differ between the tofacitinib groups and placebo groups, with the exception of infection in the tofacitinib 10 mg group.

A systematic review of randomized Phase II and III controlled trials concluded that tofacitinib, at dosages of 5 mg and 10 mg twice daily, is effective in patients with active RA who show an inadequate response to methotrexate or DMARDs.²⁵ The ACR 20 response rates were significantly higher in the tofacitinib 5 mg and 10 mg groups than in the placebo groups in all studies. Moreover, the safety outcomes did not differ between the tofacitinib groups and placebo groups, with the exception of infection in the tofacitinib 10 mg group.

A meta-analysis of 10 randomized controlled studies evaluating the efficacy and safety of tofacitinib in patients with active RA showed that tofacitinib, at dosages of 5 mg and 10 mg twice daily, in combination with methotrexate, was the most effective therapy for active RA and was not associated with a significant risk for withdrawal due to AEs.²⁶

From an economic/societal perspective, studies conducted in Korea²⁷ and Brazil²⁸ showed that incorporating tofacitinib into the treatment regime or as a first-line therapy for patients with moderate to severe RA is a cost-effective alternative to the current standard of care.

Tofacitinib for Psoriasis

Phase II Trials (NCT00678210)

A 12 week, Phase IIb multicenter, randomized, double-blind, parallel-group, placebo-controlled trial was conducted to evaluate the efficacy and safety of various doses of oral tofacitinib (2 mg, 5 mg, or 15 mg twice daily) in 197 patients with moderate-tosevere psoriasis.²⁹ At week 12, Psoriasis Area and Severity Index 75 (PASI 75; the percentage of patients who have achieved a 75% or more reduction in their PASI score from baseline) responses were observed in 25% (2 mg; p<0.001), 40.8% (5 mg; p<0.0001), and 66.7% (15 mg; p<0.0001) of the patients in the tofacitinib groups compared with 2% in the placebo group. The most common AEs were upper respiratory tract infections, nasopharyngitis, and headache. Moreover, mild dose-dependent decreases in hemoglobin and neutrophil counts, and increased total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol occurred over the duration of treatment compared to placebo.²⁹ In this same study cohort, outcome questionnaires were completed by the patient³⁰ and showed that treatment with tofacitinib resulted in significant, dose-dependent improvements in several patient-reported outcomes compared with placebo. In the same study cohort, the efficacy of tofacitinib was evaluated in four body regions (head and neck, upper limbs, trunk, and lower limbs).³¹ Mean improvements in PASI 75 and body surface area (BSA) values were significantly improved with tofacitinib vs. placebo across all four body regions.

Data from the Phase IIb trial was also used to elucidate the correlation between pruritus (a severe and bothersome symptom of psoriasis which is not assessed by the PASI or Physician’s Global Assessment [PGA] rating of ‘clear’ or ‘almost clear’ using a 5-point scale: 0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe)³² and the clinical signs of psoriasis (erythema, induration and scaling).³³ This study showed that tofacitinib acts directly to improve patient-reported pruritus and this effect is independent from improvements in clinician-reported psoriasis severity signs.

Phase III Trials

A summary of the details for the Phase III psoriasis trials can be found in Table 3. The most common AEs were nasopharyngitis and upper respiratory tract infection. Safety and tolerability data for these studies are summarized in Table 4. Laboratory findings were similar to those reported for tofacitinib for the treatment of RA. Two additional Phase III trials are undergoing clinical investigation: NCT01163253 (OPT Extend) is in the process of recruiting participants and is a long-term open label extension study available to patients enrolled in a qualifying clinical study, while NCT01815424 has been concluded and investigated the efficacy of tofacitinib 5 mg and 10 mg in Asian patients; results have not yet been published.

Treatment Withdrawal & Retreatment Study (NCT01186744)

A Phase III, randomized, double-blind, parallel-group study was conducted to evaluate the efficacy of tofacitinib in three phases of treatment (OPT Retreatment).⁵ At the end of the initial treatment, patients were classified as treatment responders if they achieved both PASI 75 response and a PGA rating of ‘clear’ or ‘almost clear’. Responders entered the treatment-withdrawal period, and were re-randomized to placebo or their previous dose of tofacitinib. Patients who relapsed (defined as >50% reduction in the PASI improvement from baseline to week 24) entered the retreatment period. All remaining patients continued in the treatmentwithdrawal period before entering the retreatment period. In the retreatment period, patients who received placebo during treatment withdrawal were retreated with the same dose of tofacitinib that they received during the initial treatment period. After initial treatment, 33.5% and 55.2% of patients achieved both PASI 75 and PGA responses with tofacitinib 5 mg and 10 mg, respectively, and were eligible to enter the treatment withdrawal phase. At the end of the withdrawal period, a greater number of patients receiving tofacitinib 5 mg (56.2%) and 10 mg (62.3%) maintained a PASI 75 response compared to patients who were switched to placebo (23.3%, p=0.008 and 26.1% p<0.0001). Moreover, 92.3% and 93.0% of patients receiving tofacitinib 5 mg and 10 mg, respectively, did not relapse compared with 32.8% and 42.9% of those who were switched to placebo. At the end of the retreatment period, 63.0% and 73.8% of patients who continued to receive tofacitinib 5 mg and 10 mg during the treatmentwithdrawal period regained or maintained a PASI 75 response and 66.7% and 64.3% regained or maintained a PGA response. Moreover, 48.0% and 72.5% of the patients treated with placebo during the treatment-withdrawal period regained or maintained a PASI 75 response, and 52.0% and 64.2% regained or maintained a PGA response after 16 weeks of retreatment with tofacitinib 5 mg or 10 mg, respectively.

Pivotal Trials (NCT01276639 & NCT01309737)

Two similarly designed Phase III studies (OPT Pivotal 1, n=901 and OPT Pivotal 2, n=960) were conducted to evaluate the efficacy and safety of tofacitinib 5 mg and 10 mg twice daily.⁴ At Week 16, higher PASI 75 rates were observed in both tofacitinib groups vs. placebo (OPT Pivotal 1: 39.9%, 59.2% and 6.2% for tofacitinib 5 mg and 10 mg, and placebo; OPT Pivotal 2: 46.0%, 59.6% and 11.4%; all p<0.0001). Moreover, higher PGA ratings were seen in patients receiving tofacitinib 5 mg and 10 mg vs. placebo (OPT Pivotal 1: 41.9% and 59.2% vs 9.0%; OPT Pivotal 2: 46.0% and 59.1% vs. 10.9%; all p<0.0001).

Tofacitinib vs. Etanercept (NCT01241591)

A Phase III, randomized, multicenter, double-dummy, placebocontrolled trial compared the non-inferiority of tofacitinib with etanercept (50 mg) subcutaneously twice weekly or placebo (OPT Compare).⁶ At week 12, a greater number of patients receiving active treatment (39.5% for tofacitinib 5 mg, 63.6% for tofacitinib 10 mg, and 58.8% for etanercept) achieved PASI 75 responses compared to placebo (5.6%, p<0.0001 for all treatments vs. placebo). Moreover, a PGA response was achieved by 47.1%, 68.2%, 66.3%, and 15.0% of the patients in the tofacitinib 5 mg, 10 mg, etanercept and placebo groups (p<0.0001 for all treatments vs. placebo).

Conclusion

Numerous Phase II and Phase III trials have shown that tofacitinib is safe and effective in alleviating RA symptoms, relieving pain, and improving physical and mental health, either when used as monotherapy in patients who show inadequate responses to TNF inhibitors, methotrexate or DMARDs, or as combination therapy with methotrexate or DMARDs. In addition, tofacitinib has been shown to be effective in the treatment of chronic plaque psoriasis in Phase II and III clinical trials, with continuous therapy resulting in better treatment prognosis than intermittent therapy. Efficacy of tofacitinib was comparable to etanercept and superior to placebo in improving the clinical symptoms of psoriasis. Moreover, tofacitinib was also shown to improve pruritus, a common and troublesome symptom of psoriasis not typically assessed in clinical studies. These studies provide support for tofacitinib as an innovative and valuable oral systemic therapy for the treatment of RA and psoriasis.

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