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

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

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

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

Introduction

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

Pathogenesis

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

Clinical Features and Diagnosis

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

Associated Comorbidities

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

Treatment

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

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

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

Conclusion

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

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¹Beacon Dermatology, Calgary, AB, Canada
²Division of Dermatology, University of Calgary, Calgary, AB, Canada
³Dermatologie Clinic, Drummondville, QC, Canada
⁴Bausch Health Canada Inc, Laval, QC, Canada
⁵SKiN Centre for Dermatology, Peterborough, ON, Canada
⁶Queen’s University, Kingston, ON, Canada

Conflict of interest: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:
Isabelle Delorme has been a member of advisory boards for AbbVie, Bausch Health, Eli-Lilly, Janssen, Novartis, Sanofi-Genzyme. She has been a part of clinical trials for AbbVie, Amgen, Anaptys Bio, Arcutis, Bausch Health, BMS, Celgene, Dermira, Devonian, Eli-Lilly, Galderma, Glenmark Pharmaceutical, Innovaderm Research, Janssen, Leo Pharma, Novartis, Regeneron. She has recieved honoraria from AbbVie, Amgen, Avene, Celgene, Eli-Lilly, Janssen, Novartis, UCB Pharma. She has been part of speaker’s bureaus for AbbVie, Celgene, Bausch Health, Eli-Lilly, Janssen, Medexus Inc., Novartis, Sanofi Genzyme. Melinda Gooderham has been an investigator, speaker and/or advisor for – AbbVie, Amgen, Akros, Arcutis, Aslan, Bausch Health, BMS, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Andrei Metelitsa has been a consultant for Bausch Health, Galderma, Leo Pharma and Pfizer.
Daniel O’Sullivan, Rami Zeinab and Mark Legault are employees of Bausch Health Canada.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Dermatological diseases such as atopic dermatitis, acne, and psoriasis result in significant morbidity and decreased quality of life. The first line of treatment for such diseases is often topical medications. While topical delivery allows active drug to be delivered directly to the target site, the skin is a virtually impermeable barrier that impedes delivery of large molecules. Thus, the formulation and delivery system are integral elements of topical medications. Patients also have preferences for the properties of topical formulations and these preferences can positively or negatively impact adherence. Therefore, the choice of topical formulation is a key consideration. Recent developments in drug delivery systems have produced enhanced topical treatments that improve efficacy, safety, and patient acceptability. Awareness of the delivery system in which drugs are formulated is critical as this can have profound implications on treatment success. This paper provides an overview and clinical commentary on advances in topical delivery systems and their impact on dermatological practice.

Keywords: acne, corticosteroid, dermatitis, dermatology, halobetasol, psoriasis, retinoid, tazarotene, topical, vehicle, Duobrii, Arazlo, Bryhali

Introduction

Topical therapies are often the first line of treatment for common skin diseases such as atopic dermatitis (AD), acne vulgaris (AV), and psoriasis (PsO).¹ Prescribing effective therapy is crucial for optimal treatment outcomes.² However, the composition of topical treatments is complex and should be taken into consideration when choosing a topical treatment in terms of both “formulation” and “drug delivery system” wherein the formulation includes the active drug and vehicle while the delivery system refers to technologies affecting the therapeutic action of the drug (including potency, stability, dispersion, and penetration). Both formulation and delivery system should be considered for each patient on the basis of the potency of the active molecule, patient preference, skin type, skin condition, and affected site.³ Several recent reviews have discussed topical vehicles, ingredients, and their effects on the skin,^4-10 however, there is a gap in reviewing advanced delivery systems currently in clinical use. This paper provides an up-to-date review of advances in topical delivery systems with a focus on those in clinical use for the treatment of AD, AV, and PsO.

Atopic Dermatitis, Acne Vulgaris and Psoriasis

Skin conditions are a common cause of disease globally,¹¹ with AD, AV, and PsO amongst those with the highest disease burden on patients¹². These conditions disrupt the normal skin function,¹³ trigger abnormal inflammatory responses, alter skin microbiome, and increase susceptibility to irritants/allergens.^5-7 AD is a chronic, relapsing disease, presenting as inflamed skin with intense itching.^14,15 AV is due to inflammation of the sebaceous follicles, resulting in increased sebum production and a favorable environment for bacterial growth.¹⁶ PsO is a chronic disease that presents with characteristic scaling, redness, and thickening of the skin. All of these skin diseases can have important detrimental effects on short and long-term psychosocial and physical health, with substantial morbidity and reduced quality of life.^15,17,18 As such, early treatment with the most efficacious therapies available is critical.

Factors to Consider with Topical Drug Delivery Systems

Applying treatment topically provides several advantages for managing skin diseases. It enables delivery of drug directly to the target site, minimizing systemic exposure.¹⁹ The skin provides for a regulated, constant delivery rate and circumvents first-pass metabolism.²⁰ However, delivering drugs to targets beneath the epidermis can be challenging.²¹ The skin is a multi-layered defense barrier constructed to withstand the penetration of external compounds.²² The stratum corneum is very effective in performing this role and minimizes the ingress and egress of molecules/ chemicals.²³ As a result, the skin is impermeable to almost all compounds with a molecular weight greater than 500 Daltons.^22,23 As diffusion is the principal mechanism by which a drug penetrates the skin,²² formulations must be optimized to maintain solubility, stability, dispersion, and penetration of the active ingredient(s) while ensuring they are sustained at the target site for sufficient time, as well as limit systemic exposure³.

The effectiveness of a topical medication depends not only on pharmacodynamic factors but also on patient preferences, adherence, and the location of disease.^2,24 Patient preferences are related to the formulation and drug delivery system whose attributes include moisturization, absorption, greasiness, stickiness, as well as ease and frequency of use.²⁵ These attributes influence adherence to the therapeutic regimen which is a major determinant of treatment success.²⁵ Teixeira et al.²⁶ reported that adherence was impacted not only by patient preferences, but also the body area affected. For example, adherence was higher for patients using gel/cream vs. ointment formulations when the body area affected was large. However, this was reversed with smaller areas. As such, delivery systems are no longer only considered ‘carriers’ of active ingredients, but also integral to the formulation. Hence, drug delivery system research and development have been the main drivers of recent advancements in topical formulations.

Advanced Topical Drug Delivery Systems

Over the years, advanced drug delivery systems have been developed to enhance effectiveness, tolerability, safety, and patient acceptability of topical formulations. Some of these advanced delivery systems are integrated into approved products utilized in clinical practice in Canada (Figures 1 & 2). As such, it is important for healthcare providers to be aware of these systems and their profound implications on treatment outcomes. The following summary provides an overview of some recent advances in drug delivery systems and their clinical application (Table 1).

Table 1. Advanced topical drug delivery systems in clinical use

Microencapsulation

Description of Delivery System

Microencapsulation is a technique that involves entrapping active ingredient(s) in a microcapsule, creating a barrier between the ingredients and the skin.²⁷ Once applied, microcapsules allow controlled release of active ingredients over time.²⁸ This offers advantages for topical delivery of agents (Table 1) where active ingredients are protected against degradation and maintained at the target site for an extended time while limiting local adverse reactions.^28,29

Clinical Application Highlights

Encapsulation is the technology behind two topical treatments approved for treatment of moderate to severe AV in the US. The first formulation is a foam-based delivery system that optimizes the topical delivery of minocycline (minocycline topical foam 4%, Amzeeq®).³⁰ Minocycline was previously not available topically due to its instability and systemic side effects.³¹ Such limitations were mitigated with microencapsulation. In phase 2^32,33 and 3³⁴ clinical trials, microencapsulated minocycline significantly reduced AV lesions and severity compared to placebo; with minimal adverse effects. The second is a cream-based formulation combining tretinoin 0.1% and benzoyl peroxide (BPO) 3% (Twyneo®).³⁵ Tretinoin and BPO are individually entrapped within silica-based microcapsules preventing the degradation of tretinoin by BPO.²⁸ The active ingredients are released over time, providing a consistent drug concentration at the affected site.³⁶ Results from clinical trials show that patients who received this encapsulated combination therapy had improved treatment outcomes compared with patients who received vehicle only. The treatment was well tolerated.³⁶

Microsponges

Description of Delivery System

Microsponges are microscopic, uniform, spherical, porous delivery systems.³⁷ Some features of micropsonges are summarized in Table 1. Their large surface area allows a range of substances to be incorporated into gels, creams, liquids, or powders.³⁸ They can absorb skin secretions, therefore reducing the oiliness of the skin.^38,39 When applied, the release of drug is controlled through diffusion, rubbing, moisture, pH, friction, or ambient skin temperature, producing a controlled release and reducing side effects.⁴⁰ Microsponge polymers possess the ability to load a spectrum of active ingredients and provide the benefits of enhanced effectiveness, mildness, and tolerability to a wide range of skin therapies.⁴¹ The microsponge system is stable over a range of pH and temperatures, compatible with most vehicles and ingredients, self-sterilizing as average pore size prevents bacterial penetration, and has a higher payload⁴² (50-60%) vs. conventional topical drugs and microencapsulation. However, due to their size (5-300 μm), passage through the stratum corneum is limited.³⁹

Clinical Application Highlights

Early topical formulations of tretinoin had high concentrations of active ingredients in alcohol-based solutions leading to skin dryness and irritation.^43,44 The innovation of microsponges led to the first alcohol-free, topical retinoid delivery system (tretinoin gel, Retin-A Micro^®).⁴⁵ This microsponge gel contains tretinoin in concentrations of 0.04%, 0.06%, 0.08%, and 0.1%. Tretinoin is entrapped in patented methyl methacrylate/glycol dimethacrylate copolymer porous microspheres (Microsponges^® system), within a carbomer-based gel. In the vehicle-controlled clinical trials, tretinoin gel was significantly more effective than vehicle in reducing the severity of acne lesions; and significantly superior to vehicle in the investigator’s global evaluation of the clinical response.^46-48 Microsponge delivery of tretinoin has also been associated with decreased irritation compared to earlier alcoholbased cream (Retin-A® cream, 0.1%).⁴⁹

Polymeric Emulsion Technology

Description of Delivery System

In polymeric emulsion technology (PET), active ingredients are encapsulated within oil droplets, together with moisturizing/ hydrating ingredients (light mineral oil, diethyl sebacate).⁵⁰ The oil droplets are uniformly dispersed within an oil-in-water emulsion and separated by a three-dimensional mesh matrix.⁵¹ Recently, PET has been combined with optimized selection of excipients and emollients to produce a patented delivery system called Prismatrex™. This novel technology allows simultaneous and uniform dispersion of active ingredients onto the skin at lower doses than conventional formulations to achieve comparable therapeutic effect, while providing enhanced hydration and moisturization.⁵² Also, the technology allows many attributes of patient preferences to be met. By combining water-soluble moisturizing components within the matrix, a lotion can have a pleasant feel; the use of moisturizers over alcohol-based components creates a lowirritancy/ low-drying formulation; and the mesh network breaking down upon contact with the salts on the skin surface results in quick release and absorption, leaving behind minimal greasy or sticky residue.^50,51

Clinical Application Highlights

Prismatrex™ is used in recent formulations containing retinoids, corticosteroids, or combination of both. Topical corticosteroids are a mainstay in the treatment of AD and PsO. Due to the defective skin barrier in AD and PsO, formulations with moisturizing effects in a patient-preferred format offer additional therapeutic advantages over previous formulations.⁵³ Halobetasol propionate (HP) 0.01% lotion (Bryhali^®), formulated with Prismatrex™, provides several improvements compared to the older 0.05% cream formulation. For example, a reduced concentration of drug while maintaining comparable efficacy to the cream formulation, and a safety profile that allows extended use up to 8 weeks.⁵⁴ Furthermore, the formulation is non-greasy and aesthetically pleasing, providing a patient preferred treatment option.⁵⁵

Topical retinoids are a cornerstone in the treatment of AV. However, dryness, erythema, and peeling are important side effects that can impact treatment adherence.⁵⁶ Prismatrex™ has been used to formulate the third-generation retinoid, tazarotene (TAZ) 0.045% lotion (Arazlo®). The small particle size with this formulation allows better access to the pilosebaceous unit.⁵⁷ Also, this novel technology allows for uniform distribution of TAZ on the skin along with moisturizing ingredients and emollients, therefore, TAZ may be delivered at a lower and potentially less irritating concentration than the previous 0.1% cream formulation.⁵⁸ Two identical phase 3, vehicle-controlled studies demonstrated statistically superior efficacy for TAZ 0.045% lotion vs. placebo in once-daily treatment of moderate to severe AV.⁵⁹

A fixed-combination lotion containing both HP 0.01% and TAZ 0.045% (Duobrii®, HP/TAZ) is formulated using Prismatrex™ technology and indicated for PsO treatment. Higher tissue permeation efficiency of both HP (vs. HP 0.05% cream) and TAZ (vs. TAZ 0.1% cream, Tazorac®) has been achieved with the combination using Prismatrex™ technology.⁵⁰ The delivery of both active ingredients with anti-inflammatory and anti-proliferative properties into a lotion confers a synergistic effect.^50,52 Also, it has demonstrated improved efficacy, tolerability, and maintenance of therapeutic effect compared with monotherapy with either of the active ingredients.^50,52,60-62 HP/TAZ’s acute and long-term efficacy (including maintenance of efficacy after cessation of treatment), tolerability, and safety have been demonstrated in phase 2 and 3 vehicle-controlled trials and an open-label extension study.⁶³ Importantly, HP/TAZ is associated with low incidences of adverse events that may be of concern with corticosteroid and retinoid monotherapy.⁶⁴ Skin atrophy occurs in up to 5% of patients treated with topical corticosteroids.⁶⁴ In HP/TAZ clinical trials, incidences of skin atrophy were rare and generally resolved by the end of the study despite 8 weeks of daily application.^63-64 This may be because TAZ increases the number and activity of dermal fibroblasts and stimulates collagen and elastin production.⁶⁵ Irritation, pain, and retinoid dermatitis may be a challenge with retinoid monotherapy. Incidences of these AEs were lower with HP/TAZ, than with TAZ monotherapy, potentially due to the anti-inflammatory properties of HP.⁶⁴ Clinical trials have also shown that the majority of participants who achieve clear skin with HP/TAZ, experience prolonged maintenance of therapeutic effect after treatment cessation.⁶⁰ Taken together, HP/TAZ provides a treatment option for PsO that is efficacious, safe, combines the beneficial effects of corticosteroids and retinoids, delivers moisturizing and hydrating ingredients, yields longer remission, and is acceptable to patients.

Real World Clinical Commentary

A challenge frequently encountered by dermatologists when managing AD, AV, and PsO is balancing sustained disease suppression with the avoidance of local/systemic side effects. To address this concern, advanced drug delivery systems, such as Primsmatrex™, allow for more efficient delivery of lower doses of active ingredients without compromising efficacy. However, this must also be balanced with overall patient acceptance. Patients consistently cite the following preferences for treatment options: non-greasy applications, reduced skin irritation, spreadable and easily absorbed,³⁶ easily applied in certain body sites (e.g., scalp); easy to wash off with minimal residue, and fast skin responses.⁶⁶ Novel delivery systems often enhance utilization of existing ingredients making them more acceptable to patients, resulting in therapeutic advances. For example, in acne, the innovative drug delivery systems used in Retin-A Micro®, Arazlo® and Twyneo® have significantly improved tolerability of existing topical retinoid ingredients without sacrificing the overall efficacy of these molecules. While patients are advised to maintain a dosing schedule of every second day during the initial phases of treatment to avoid potential irritation, these agents are well tolerated given the nature of the formulations.

The microencapsulation of minocycline foam allows delivery in a topical formulation as opposed to an oral format, which significantly enhances the safety profile. In psoriasis, where availability of topical agents is quite limited, the Prismatrex™ technology in HP/TAZ provides an excellent new treatment option which combines two effective drugs and is a welcome addition to our therapeutic algorithm. In clinical practice, this formulation is effective, can be less irritating to the skin than TAZ alone and is less likely to induce steroid-induced atrophy as compared to HP alone. Another advantage to these advanced topicals is that they result in improved adherence and therefore better treatment outcomes in the long run. Overall, when choosing the optimal therapeutic agent for treatment of AD, AV, or PsO the dermatologist now has the option to select a formulation that uses an advanced drug delivery system to maximize the chances of achieving successful treatment outcomes. Research in advanced delivery systems is vast, with a wide range of technologies showing promise for future clinical use, such as nanoparticles⁶⁷, ethosomes⁶⁸, niosomes⁶⁹, and liposomes⁷⁰.

Conclusion

Topical treatment is a cornerstone in managing AD, AV, and PsO;¹⁹ however, the delivery of active drugs through the dermal barrier remains a challenge. Furthermore, patient acceptability is a major contributing factor to the effectiveness and adherence to topical treatments. Advances in topical drug formulations and delivery systems address many limitations seen with older formulations. These advances allow for efficient and uniform delivery of active ingredients to target sites, greater patient acceptability, and enhanced treatment outcomes.

Acknowledgements

Medical writing assistance for this manuscript was provided by KTP (Knowledge Translation Partners), Montreal, Canada, funded by Bausch Health Canada.

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Abstract

Psoriasis vulgaris is a chronic, immune-mediated inflammatory skin disease affecting 2-4% of the Canadian population. Lifelong management is required. While most psoriasis vulgaris cases are mild-to-moderate (>80%) and do not require systemic treatment, these cases can still be particularly challenging to treat as topical therapies present limitations, including efficacy and administration, leading to poor long-term treatment compliance and unsatisfactory treatment responses. The intent of this paper is to provide physicians with a clinically relevant review of the currently available and newly developed topical therapies for psoriasis, the practice guidelines for topical management of mild-to-moderate psoriasis, and the common pitfalls and mitigation strategies to encourage long-term treatment compliance.

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Introduction

Psoriasis is a common immune-mediated skin disease affecting ~2-4% of the population in North America.¹ In nearly one-third of cases, disease begins during the first 2 decades of life and follows a chronic and persistent course, resulting in high cumulative lifetime disability.² Psoriasis is divided into 4 major clinical forms, including plaque psoriasis, guttate psoriasis, erythrodermic psoriasis and pustular psoriasis.³ Plaque psoriasis represents >90% of cases and will be the focus of this review. Classically, plaque psoriasis affects the trunk as well as the extensor surfaces of the elbows and knees; it can also affect other body sites, giving rise to regional variants such as scalp, face, intertriginous, palmoplantar, genital and nail psoriasis.³

Because psoriasis is often localized to visible and/or special body sites (knees, elbows, trunk and scalp) and is commonly associated with pain and itch, it often causes significant physical and psychological burdens.⁴ Stigmatization is common and contributes to poor health-related quality of life (HRQoL), elevated risk of multiple health comorbidities, and increased barrier to treatment.⁵ Indeed, a recent Global Burden of Disease (GBD) study ranked psoriasis as the second contributor to all skin-related Disability Adjusted Life Years (DALYs).⁶ The GBD study highlighted an increase in prevalence and morbidity of psoriasis globally, with North America and Europe being particularly affected, emphasizing the significant burden that psoriasis imposes on both individuals and society as a whole.⁶

Mild, moderate, and severe psoriasis are defined as plaques affecting <3%, between 3-10%, and >10% of body surface area (BSA), respectively.¹ Much progress has been realized in regards to managing severe disease with the approval of numerous advanced systemic therapies, including biologics and small molecules.⁷ Unfortunately, in contrast to severe disease, there has been very limited advancement in the management of mild-to-moderate disease, which affects >80% of the psoriatic patient population.^8,9 Mild psoriasis is typically managed with lifelong skin-directed topical therapies.¹⁰ Topical therapies are also often used to treat severe psoriasis vulgaris, either as monotherapy or as an adjunct to phototherapy and/or systemic therapy.¹⁰

The most commonly used topical therapies in psoriasis include corticosteroids, vitamin D3 analogues, retinoids, calcineurin inhibitors, keratolytics and tar. Multiple fixed-ingredient combination products have become commercially available in the last 20 years with the aim to overcome challenges related to lack of efficacy, compliance and adverse events.¹¹

Our objective is to review: 1) the currently available and newly developed topical therapies, both single and fixed-dose combination products; 2) clinical practice guidelines specific to the topical treatment of psoriasis; and 3) common pitfalls and mitigation strategies when managing psoriasis with topical therapies. While we recognize the importance of behavioural modification and skin care in the management of psoriasis vulgaris of all severities, we refer the reader to the review article by Ko et al. on the topic.¹²

Literature Search

This narrative literature review included studies that examined currently available therapies for psoriasis from 2010 to present. The review was conducted using the PubMed and Embase databases with the following search terms: (psoriasis) AND [(corticosteroids) OR (topical corticosteroids) OR (topical corticosteroids AND salicylic acid) OR (topical corticosteroids AND coal tar) OR (calcipotriol) OR (calcitriol) OR (tacalcitol) OR (pimecrolimus) OR (tacrolimus) OR (tazarotene) OR (retinoids) OR (corticosteroid* AND calcipotriol) OR (corticosteroid* AND calcitriol) OR (corticosteroids AND tazarotene) OR (roflumilast) OR (tapiranof) OR (topical treatment)] as either keywords or MeSH terms. Clinicaltrials.gov website was also searched for ongoing Phase II and III clinical trials. References of identified manuscripts were manually extracted to identify additional articles. Only articles published in English were considered. Articles were included if they reported on treatment of psoriasis in humans, regardless of study type. All publications were independently assessed by SG and EN first by screening titles, then abstract, followed by full-length manuscripts. Any discrepancies were discussed and resolved.

Topical Therapies for Psoriasis – Our Current Toolbox

Psoriasis is a chronic disease that requires a life-long treatment. Most patients are managed with topical treatments, therefore, it is important to recognize all presently available therapeutic options, taking into account their respective efficacy, safety profile, and usage considerations. Currently, available treatments that will be discussed include topical corticosteroids (TCS), vitamin D3 analogues, calcineurin inhibitors (TCI), tar-based preparations, retinoids, and combination therapies.¹³ These therapies can be used to induce skin clearance and to maintain disease control.¹⁴ Monotherapies with dithranol and salicylic acid will not be discussed, as their clinical use is limited. A clinical timeline of topical therapies for psoriasis is provided in Figure 1. This section will first discuss efficacy and safety considerations of monotherapies followed by combination treatments. Novel therapies, established or previously published guidelines for topical medications use and general recommendations to improve compliance are discussed in following sections.

Monotherapies

Topical Corticosteroids (TCS)

TCS have been used to treat psoriasis for over 60 years.¹⁵ TCS exert broad anti-inflammatory, immunosuppressive, and antimitotic effects.¹⁶ The most recent systematic review that we have identified focusing on TCS efficacy and safety in psoriasis dates back to 2012.¹⁵ It included 50 randomized controlled trials (RCTs), of which only 11 were placebo controlled. Potent and ultra-potent TCS were used in different formulations to induce and/or maintain disease control. Only 5 studies used the Psoriasis Area and Severity Index (PASI) assessment tool to measure efficacy outcomes. The mean percentage change in the PASI from baseline to 4-8 weeks ranged from 45-60%. However, the overall reported efficacy rating varied greatly depending on the study. An added benefit of occlusion was suggested (1 study), whereas no efficacy difference was established between different vehicles (2 studies). Three studies confirmed that weekend (or episodic) TCS treatment after achieving skin clearance was valuable to prevent plaque recurrence in 30-40% of patients at 6 months.

Since this publication, we identified 2 additional RCTs.^17,18 Desoximetasone 0.25% spray twice daily (BID) demonstrated statistically significant clinical success compared to the vehicle as measured by Physician Global Assessment (PGA) score 0/1 at 4 weeks (39% vs. 7%, respectively).¹⁷ Efficacy was better among compliant patients who received reminders compared to those that were not reminded, suggesting that compliance is an important barrier to treatment success.^18-20 Another RCT compared once daily (QD) halobetasol propionate 0.05% cream vs. halobetasol propionate 0.01% lotion suggesting similar efficacy at 2 weeks.²¹

Despite corticosteroid-sparing alternatives and combination therapies (discussed below) being commercially available, TCS remain widely used because of the low cost of some products as well as their versatility. They are available in a wide range of vehicles and potencies, ranging from I (ultra-high potency) to VII (low potency). Available vehicles include creams, lotions, foams, gels, ointments, shampoo, sprays, and solutions²² (Table 1). Typically, potent to ultra-potent TCS (class I-II) (e.g., clobetasol propionate) are used for thick plaques on the trunk/limbs or special sites, such as the scalp and palmoplantar regions; moderate potency TCS (class III-IV) (e.g., betamethasone valerate; triamcinolone acetonide) are suitable for thinner plaques on the trunk/limbs, whereas mild potency TCS (class VI-VII, e.g., desonide; hydrocortisone) are recommended for intertriginous areas, genitals and/or face.²² Milder potency preparations are also usually preferred to manage psoriasis in pediatric or pregnant patients.^23,24 The choice of the vehicle is made by the treating physician together with the patient. While some vehicles are preferred based on the anatomic site being treated and desired potency, patient preference is of utmost importance since this enhances treatment compliance. An RCT of vehicle preference among various TCS preparations assessed adherence to treatment and improvement of HRQoL among patients with psoriasis between spray, cream, ointment, gel, lotion, foam, and solution.²⁵ It was found that patient preference was highly variable, with less messy products favoured.²⁵ There was no overwhelming agreement on the effect of TCS vehicles in terms of efficacy, hence treatment should be individualized.

Table 1. Topical Corticosteroid Classes of Potency

Adverse events (AEs) with TCS use are generally rare, but may occur with prolonged and/or inappropriate use. These include local AEs such as skin atrophy, telangiectasia, striae, poor wound healing and infections. When used on the face or acne-prone skin, acne exacerbation or de novo periorificial dermatitis/folliculitis may occur.²⁶ Furthermore, even class VII TCS used on eyelids for prolonged periods can lead to cataracts and/or glaucoma.²⁷ Systemic AEs related to hypothalamic-pituitary axis (HPA) suppression are exceedingly rare.^28,29 Two systematic reviews/meta-analyses evaluated TCS safety in psoriasis. Literature identified was reassuring, with <5% risk of skin atrophy³⁰ and <5% rate of HPA suppression when TCS were used long-term.³¹ TCS withdrawal reactions, such as Red Skin Syndrome or topical steroid addiction, have also been reported with discontinuation of prolonged, frequent use of moderate to high potency TCS.³² These severe reactions are rare and are more likely to occur with use on special areas, such as the face and the genitals. A recent review article concluded that TCS are generally safe and effective when used correctly for short periods of time or with short breaks in longer treatments.³² Beside AEs, additional TCS related limitations include potential tachyphylaxis and corticophobia. Whether tachyphylaxis truly exists is debated among experts, as diminished efficacy over time may be related to low adherence to treatment among patients, especially when long-term treatment is required.³³ Corticophobia among patients and health care providers remains omnipresent and is a major barrier for treatment efficacy beyond inherent limitations associated with the drugs of this class.³⁴

Vitamin D3 Analogues

The introduction of Vitamin D3 analogues ~30 years ago was met with much enthusiasm due to their steroid-sparing effect.³⁵ Commercially available vitamin D3 analogues in Canada are calcipotriol and calcitriol ointments. Vitamin D3 analogues may be used as monotherapy, as an adjunct to TCS, or as fixed-dose combination therapy. They work by regulating gene transcription, modulating keratinocyte proliferation, and differentiation.³⁶ The mechanism of action also involves the inhibition of T cell proliferation and downstream inflammatory mediators.³⁶

There are several systematic reviews published assessing the efficacy of vitamin D3 analogues compared to vehicle or TCS.^37-41 As monotherapy, 1 review reported treatment success (defined as >90% reduction in the PASI score) with vitamin D3 analogues ranging from 4-40% after 6-12 weeks of therapy.³⁷ Another reported a decrease in the PASI ranging from 27.8-60.4% with calcipotriol monotherapy.³⁸ Further, BID use of vitamin D3 analogues was found to be at least as effective as TCS and more effective than placebo at 8 weeks.^38,39 A systematic review focused on efficacy of vitamin D3 analogues in pediatric psoriasis patients found 5 studies reporting improvement in PASI from baseline ranging from 17.3-94%, 1 study reporting improvement in Psoriasis Scalp Severity Index (PSSI) of 32.1%, and 1 study reporting 100% clearance of skin lesions.⁴⁰

In the last 10 years, only 2 new double-blind, vehicle-controlled phase III RCTs evaluated the efficacy and safety of calcipotriol 0.005% foam BID for mild-to-severe psoriasis (defined as plaque psoriasis involving 2-20% BSA) compared to vehicle.⁴² Both studies demonstrated significant treatment success, defined as the Investigator’s Static Global Assessment (ISGA) scores of 0/1 at 8 weeks. The primary outcome was achieved in 15% vs. 7% of calcipotriol vs. vehicle patients in the first study and 28% vs. 6% in the second study.⁴²

The use of vitamin D3 analogues in psoriasis has been shown to be safe and well-tolerated, with less AEs than TCS. AEs are generally comparable to the vehicle, with application site reactions occurring in less than 2% of subjects.⁴² Specifically, these include stinging, burning, and peeling of the skin.^37,43 Calcitriol may cause less irritation in sensitive areas compared to treatment with calcipotriol.⁴⁴ When used appropriately (maximum recommended dose of 100 g per week of calcipotriene or 200 g per week of calcitriol), the risk of hypercalcemia is very low.⁴³ Hypercalcemia risk was studied in 3 studies, occurring at a rate <1%.³⁷

Retinoids

Vitamin A and its naturally occurring and synthetic derivatives are referred to as retinoids.⁴⁵ They were introduced as a treatment for cutaneous disorders in the 1960s and, with the development of safer synthetic retinoids, have become widely used.⁴⁵ There are many topical retinoids used in dermatology, however, only tazarotene has been studied and indicated for psoriasis. While tazarotene lotion 0.045% is the only formulation commercially available in Canada, it is indicated for acne and used off-label for psoriasis. Tazarotene binds and modulates activity of retinoic acid receptors (RAR)-β and -γ, thereby decreasing inflammation and keratinocyte proliferation.⁴⁶

There were 2 systematic reviews assessing the efficacy of topical retinoids in psoriasis. The first contained 4 studies comparing tazarotene 0.05% or 0.1% gel or cream to placebo, finding tazarotene to be more effective in improving symptoms in the short-term (6-12 weeks).³⁹ However, the more recent systematic review comparing the same interventions found that symptom clearance as measured by Investigator’s Global Assessment (IGA) ranged from 5.5-6.2% with tazarotene 0.05% and 0.1% cream at 12 weeks, which was not better than placebo.⁴⁷ In the last 10 years, there have been no new published RCTs assessing the efficacy of topical retinoid monotherapy in psoriasis. Most clinical trials have focused on combination therapy of tazarotene and TCS.

The most common AEs associated with use of tazarotene are cutaneous local irritations such as peeling, erythema, itching, and burning at the site of application.⁴⁶ Cutaneous absorption of topical retinoids is limited, and there are no known systemic toxicities. However, as retinoids are teratogenic, women of childbearing age must use appropriate contraception.⁴⁶

Calcineurin Inhibitors (TCI)

Topical calcineurin inhibitors (TCI) have been approved since the early 2000s for the treatment of mild-to-moderate atopic dermatitis. While not indicated for psoriasis, TCI are often used off-label for facial and intertriginous psoriasis to avoid TCS-related AEs.⁴⁸ The available formulations are pimecrolimus 1% cream and tacrolimus 0.1% and 0.03% ointments. TCI bind to immunophilins, which lead to a decreased release of interleukin (IL)-2 and interferon (INF)-γ and thereby decreased T cell proliferation.⁴⁹

Systematic reviews assessing the efficacy of TCI for psoriasis confirmed tacrolimus superiority to placebo, TCS and calcitriol in treating facial and intertriginous psoriasis with treatment duration of 8 weeks.^50,51 However, pimecrolimus was inferior to standard psoriasis treatments.^50,52 One systematic review looked at the synergistic effect of TCI and TCS, which found that there was no additional benefit by combining these agents as opposed to TCS alone.⁵³

In the last 10 years, there have been 2 new RCTs published assessing the efficacy of TCI in psoriasis. The first studied the use of pimecrolimus 1% cream in the treatment of intertriginous psoriasis compared to placebo, finding that 71.4% in the treatment group reported an IGA of 0/1 at 8 weeks.⁵⁴ The second assessed tacrolimus 0.1% ointment in the treatment of nail psoriasis on 1 hand, using the other hand as a control. At 12 weeks, there was statistically significant improvement in the treated hand as evaluated by the Nail Psoriasis Severity Index (NAPSI) score.⁵⁵

AEs for topical TCI include skin irritation and discoloration to the site of application.⁵⁶ In 2006, a black box warning was issued for a potential link with skin cancer and lymphoma.⁵⁶ However, as a result of subsequent large-scale studies disproving this association,⁵⁷ Health Canada lifted the black box warning in 2021.⁵⁸ The systematic reviews and RCTs found similar rates of AEs between treatment and placebo groups,^51,54 however patients should be counselled regarding transient burning sensation when prescribed tacrolimus ointment to improve treatment adherence.

Tar

Historically, coal tar was considered a classic anti-psoriatic therapy and was used as a first-line agent for more than 2,000 years to treat psoriasis and other skin diseases.⁵⁹ Recent studies shed light into the mechanism of action of tar, suggesting modulation of epidermal differentiation and anti-inflammatory effects are likely achieved through activation of the aryl hydrocarbon receptor (AHR).⁵⁹ The efficacy of coal tar or its distillate, liquor carbonis detergens (LCD), in treating psoriasis was seldom formally evaluated. The limited available data suggests inferior efficacy to other commercially available agents. Specifically, a Cochrane Review (last updated in 2013), identified tar (including LCD) as generally less effective than TCS and vitamin D3 analogue monotherapies.⁴¹ Safety has been another important concern. As the “crude” word suggests, coal tar contains >10,000 organic compounds, including carcinogenic chemicals, such as benzene.⁵⁹ However, carcinogenic potential has not been proven.⁶⁰ Over-the-counter tar-containing products are available in different formats including lotions, creams, ointments, and shampoos, however, its application can be messy by staining hair, skin, nails, and clothing with a very unpleasant odour.⁶¹ While it can be compounded with TCS and other active ingredients to enhance effectiveness and penetration, currently it is primarily used in shampoos for the treatment of scalp psoriasis.⁶¹

Combination Therapies

Combination therapies were developed to improve treatment efficacy as it provides 2 mechanisms of action simultaneously and may have additive or synergistic effects.⁶² Further, they may decrease AEs related to each ingredient alone and are therefore better tolerated than monotherapy.⁶² Specifically, vitamin D3 analogues and retinoids decrease the risk of skin atrophy, whereas TCS decreases the irritation associated with vitamin D3 analogues and retinoids. Additionally, most fixed-dose combination topical therapies are prescribed to be applied QD as opposed to BID, thereby potentially improving long-term compliance. Commonly prescribed fixed-dose combination topical therapies include TCS and salicylic acid, TCS and vitamin D3 analogues (commercially available since 2001 as ointment, 2012 as gel, and 2016 as aerosol) as well as TCS and retinoids (commercially available as lotion since 2020).

Topical Corticosteroids and Keratolytics

Keratolytic agents, such as salicylic acid and urea, can improve the efficacy of TCS, especially for thicker plaques, by enhancing penetration and improving skin barrier. They are commercially available in combination as salicylic acid 3.0% and betamethasone dipropionate 0.05% ointment and salicylic acid 2.0% and betamethasone dipropionate 0.05% lotion. Additional alternatives can be compounded. There were several RCTs assessing combination therapy of salicylic acid and TCS showing superiority to monotherapy of either salicylic acid or the TCS alone.^53,63 However, 2 RCTs compared combination therapy of TCS and salicylic acid to calcipotriol monotherapy, with no clinical difference.⁶⁴ HRQoL was however improved with the combination therapy and was preferred by patients.⁶³ Only 1 RCT assessed urea in combination with TCS, which found a greater percentage of patients with an improved clinical score compared to monotherapy (47% vs. 33%).⁶³ Similarly, recent data showed that even simple moisturizers containing lipid-ceramides improve the efficacy of TCS.^65,66 In the last 10 years, there have been no newly published RCTs assessing the efficacy of topical salicylic acid and TCS combination therapy in psoriasis. Although rare, there is a risk of salicylic acid toxicity with topical application.⁶⁷

Calcipotriol and Betamethasone Dipropionate Fixed-Dose Combination

Calcipotriol 50 μg/g and betamethasone dipropionate 0.5 mg/g (Cal/BD), available in ointment, gel, and foam formulations in Canada, allows for both anti-inflammatory and anti-proliferative effects. A large Cochrane systematic review published in 2013 assessed the efficacy of combination therapies in psoriasis. Cal/BD was superior to placebo^41,68 and monotherapy (Cal or BD alone) in all but 1 RCT as early as after 2-8 weeks of treatment.⁴¹

In the last 10 years, there have been many new RCTs assessing the efficacy of Cal/BD for psoriasis focusing on the newer foam formulation, which when used QD for 4-12 weeks demonstrated a significant decrease in PASI from baseline of ~70%, superior to vehicle or either monotherapy.^69-72 Further, approximately half of participants achieved an IGA of 0/1.⁷³ Two studies compared Cal/BD to betamethasone valerate 0.1% dressing, showing in the first trial no significant efficacy difference at 4 weeks with Cal/BD ointment⁷⁴ and the second trial demonstrated superiority of the Cal/BD foam (at 4 weeks).⁷⁵ Several additional RCTs re-iterated the superiority of Cal/BD therapy vs. vitamin D3 analogue monotherapy.^76,70,77-80

Several RCTs focused on Cal/BD vehicle.^71,72,81 RCTs comparing different vehicles have shown better efficacy and superior HRQoL improvement with the use of Cal/BD foam compared to gel or ointment formulations^71,72,81 and cream compared to suspension.⁸² However, RCTs assessing vehicle preference as determined by patients did not find any significant preferences when comparing gel vs. foam, gel vs. ointment, and ointment vs. topical suspension, determining that individual patient preference should dictate treatment.^83-85 One real-world study found that patients using gel reported greater satisfaction compared to ointment due to ease of use.⁸⁶

One RCT focused on psoriasis relapse prevention following clinical clearance, defined as PGA score 0 or 1 (clear or almost clear).⁸⁷ In this study, both treatment arms received Cal/BD QD for 4 weeks initially to achieve skin clearance and were subsequently randomized into Cal/BD or vehicle biweekly as maintenance treatment. Patients that applied Cal/BD proactively experienced 3.1 relapses per year vs. 4.8 relapses (defined as PGA score 2 or higher) seen in the vehicle group. Median time to first relapse was also longer in the proactive management group (56 vs. 30 days) suggesting that proactive approach may be an interesting alternative to reactive approach for interested patients and could potentially be cost-effective.⁸⁷ As expected, both active treatment and proactive maintenance with Cal/BD were well-tolerated and no cases of skin atrophy were reported in either group.⁸⁷

Tazarotene and Halobetasol Fixed-Dose Combination

The only combination treatment of retinoid with TCS commercially available in Canada is halobetasol 0.01%/tazarotene 0.045% (HP/TAZ) lotion. A systematic review published in 2012 included 7 studies assessing the combination of retinoids (in general) with TCS, supporting superiority of combination as opposed to retinoid monotherapy at 4 weeks.⁸⁸ A recently published systematic review of 5 RCTs demonstrated treatment success, defined as at least 2-grade improvement from baseline in the IGA score and IGA score of 0 or 1 (clear or almost clear), of 32.8-52.5% for HP/TAZ compared to 33.3-34% for HP alone and 18.6% for TAZ alone with treatment duration of 2-8 weeks.⁸⁹

There have been several new RCTs published in the last 10 years assessing efficacy and safety of retinoids and TCS combination therapy. A combination tazarotene 0.05%/betamethasone diproprionate 0.05% (TAZ/BD) applied QD was superior to either agent used as monotherapy in 2 studies.^90,91 Treatment success of QD topical HP/TAZ lotion measured by the proportion of patients achieving IGA 0/1 ranged from 31.3-57.8% with treatment durations of 8-12 weeks,^92-99 which was significantly more effective than vehicle or either ingredient alone. The most frequent AEs reported were dermatitis, pruritus, pain, and irritation,^92,93,98 occurring in 6-20.8% of study participants.^91,97 A single RCT analyed the sensitization and irritation potential of HP/TAZ lotion with treatment duration of 4-6 weeks, finding that the topical did not induce contact sensitization and caused only minimal skin irritation, but significantly less than tazarotene alone.¹⁰⁰

Topical Therapies for Psoriasis – The Pipeline

As reviewed above, our current toolbox of topical therapy options is limited to TCS and a handful of other agents, such as vitamin D3 analogues, retinoids, tar or their combination. While the marketing of steroid-sparing monotherapies and fixed-dose combinations with TCS represents a major step forward in the management of psoriasis, these treatment options possess limitations in terms of efficacy, AEs, cost, patient satisfaction, and real-world adherence. Hence, there remains an unmet need for new topical therapies.¹⁰¹

There is an exciting topical therapy pipeline in psoriasis (Table 2), roflumilast and tapirnarof will be discussed in this section as phase III RCT data was recently published. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor that has been developed into 0.3% cream and foam formulations. Crisaborole, a topical PDE-4 inhibitor, was approved in 2016 for atopic dermatitis in adults and children.¹⁰² Its use has been investigated for psoriasis in phase II RCTs, however, despite demonstrating efficacy and safety, results were not published. Rather, focus has shifted to roflumilast, a more potent PDE-4 inhibitor by 25-300X based on in vitro studies.¹⁰² PDE-4 inhibition suppresses the breakdown of cyclic adenosine monophosphate (cAMP), decreasing the presence of proinflammatory cytokines involved in the pathogenesis of psoriasis, similar to apremilast used systemically or topical crisaborole.¹⁰³ Phase I and II RCT data have demonstrated that roflumilast cream QD was superior to the vehicle when used for 2-8 weeks.^104-106 Phase III RCT data regarding roflumilast 0.3% cream efficacy and safety has been recently published.¹⁰⁷ DERMIS-1 and DERMIS-2 were parallel double-blind RCTs including 439 and 442 patients, respectively. Patients aged ≥2 years with psoriasis affecting 2-20% BSA were recruited and randomized 2:1 into either roflumilast 0.3% cream or vehicle applied QD for 8 weeks. The primary outcome was IGA 0/1 response plus ≥2 grade improvement from baseline, which was achieved in 37.5-42.4% of roflumilast-treated patients vs. 6.1-6.9% vehicle-treated patients. Improvement of PASI ≥75% from baseline (PASI75) was achieved in 39.0-41.6% vs. 5.3-7.6% of roflumilast-treated vs. vehicle-treated patients, respectively. It was also shown to be effective for the treatment of intertriginous psoriasis (68.1-71.2% vs. 13.8-18.5%). The incidence of AEs was comparable to the vehicle, with the most commonly reported events being diarrhea and headache in the roflumilast group. Further, AE profiles were similar in individuals aged 12–17 years relative to adults.¹⁰⁷ Currently, roflumilast is approved by the US Food and Drug Administration (FDA) and Health Canada.

Table 2. Topical antipsoriatic agents undergoing clinical trials

Tapinarof is an AHR-modulating agent that acts as an anti-inflammatory compound. It has a similar mechanism of action to tar, which also activates AHRs, however it does not contain carcinogenic chemical compounds.¹⁰⁸ Tapinarof is able to regulate innate and adaptive immune responses, affecting Th17 and regulatory T cells. It also has an important role in the development and maintenance of the skin barrier and upregulating barrier genes, such as filaggrin. Lastly, tapinarof inhibits the migration of T cells, decreasing the presence of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, INF-γ, IL-2, IL-13 and IL-17A.¹⁰³ Phase III RCT data has been recently published. In 2 parallel double-blind RCTs including >600 patients each, adults with mild-to-severe psoriasis (PGA 2-4, BSA 3-20%) were recruited and randomized 2:1 into either tapiranof 1% cream or vehicle applied QD for 12 weeks. The primary endpoint was IGA 0/1 and 2-point reduction from baseline at 12 weeks, which was achieved in 35.4-40.2% of tapinarof-treated patients vs. 6.0-6.3% of vehicle-treated patients.¹⁰⁹ While it was generally well-tolerated, increased rates of pruritus, contact dermatitis and folliculitis were seen in the active treatment group. A second RCT found that significantly more participants achieved a 75% reduction in the PASI score from baseline (PASI75) with tapinarof (50.4%) compared to calcipotriol (38.5%) and placebo (13.9%) when used QD for 12 weeks.¹¹⁰ Tapinarof has been recently approved by the FDA.

Treatment Guidelines for Topical Antipsoriatic Agents

Treatment guidelines for severe psoriasis and psoriatic arthritis are beyond the scope of this manuscript. This section will focus on reviewing guidelines specific to the treatment of mild-to-moderate psoriasis or treatment focused on topical agents.

Current guidelines for the treatment of mild-to-moderate psoriasis recommend topical therapies which include monotherapy with TCS, vitamin D3 analogues, TCI, retinoids, anthralin, and tar as well as combination therapies as first-line options. In Canada specifically, treatment guidelines were initially published in 2011. At this point, Grade A recommendation for first-line topical therapies included TCS or vitamin D3 analogues (i.e. calcipotriol) monotherapy or Cal/BD fixed-dose combination therapy. The treatment guidelines noted that additional topical therapy options were superior to placebo (e.g., retinoids alone or in combination with TCS, 15% LCD) and may be used on a case-by-case basis.^10,111 An update of these treatment guidelines was published in 2016 adding topical calcitriol as an additional first-line topical therapy option for mild psoriasis.^10,111

The American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) have put forth the most recent guidelines in North America in 2020 focusing on topical therapies.¹⁴ The AAD-NPF guidelines do not mention specific recommendations for first-line topical therapy options, but rather provide guidance for use within each class. For TCS, Grade A recommendations include using class I to V agents for up to 4 weeks for body psoriasis (excluding intertriginous areas) and class I to VII agents for scalp psoriasis. The use of TCS for prolonged periods (>12 weeks) may be done under the supervision of a physician (Grade C). However, gradual reduction in frequency of TCS is suggested upon clinical improvement, but without defined tapering protocol. Following clinical improvement, maintenance of response can be achieved by using a steroid-sparing agent (e.g., vitamin D3 analogues or TCI) or by using TCS intermittently (e.g., biweekly, this is also known as proactive approach). Additional recommendations made in regards to TCS use were as follows: the use of emollient was suggested to reduce itching and desquamation and to prevent relapse after TCS discontinuation (Grade B). As well, topical salicylic acid alone or in combination with TCS was recommended as an alternative to TCS monotherapy to achieve clear skin (8-16 weeks of treatment, Grade B).

AAD/NPF guidelines recommended vitamin D3 analogue monotherapy and/or in combination with TCS (e.g., Cal/BD fixed-dose combinations) to induce clearance of scalp psoriasis (4-12 weeks treatment, Grade A), facial psoriasis (up to 8 weeks treatment, Grade B, caution to favour class VI-VII TCS agents) or body psoriasis (up to 52 weeks treatment, Grade A). Topical retinoids (e.g., tazarotene) were recommended either as monotherapy, fixed-dose combination (e.g., HP/Taz) or in combination with narrowband ultraviolet light phototherapy (NB-UVB) (Grade B) for plaque psoriasis and nail psoriasis. However, HP/Taz was preferred (Grade A) to induce clear skin (8-16 weeks treatment) due to better efficacy and tolerability.

The off-label use of TCI (e.g., tacrolimus and pimecrolimus) was recommended by AAD/NPF guidelines for facial and inverse psoriasis to achieve clinical improvement (Grade B recommendation) and to maintain response (Grade C recommendation). They also suggested a combination of tacrolimus/6% salicylic acid for body psoriasis (Grade B recommendation).

Grade B recommendation was also stated for short contact anthralin use (≤2 hours per day, up to 8-12 weeks treatment) and Goeckerman therapy (coal tar and NB-UVB) for mild-to-moderate plaque psoriasis.¹⁴ Coal tar preparations received Grade A recommendation as well.

Real-world Limitations with Topical Treatments and Strategies to Improve Compliance

As highlighted above, all current topical therapies come with limitations. Patient compliance is certainly among the most important barriers to success. Adherence rates with current topical therapies are low, estimated to range from 50-70% in general.¹⁰¹ The compliance rates for TCS are even more variable and in some instances are thought to be as low 8%, due to prevalent corticophobia among dermatology patients.^101,112 Adherence is an important concept that must be evaluated in patients as it is directly associated with better clinical outcomes. A recent RCT demonstrated that a decrease in adherence rate of 10% was associated with a 1-point increase in disease severity.¹¹³

Various interventions were studied to improve compliance. Three RCTs integrated reminders in the forms of BID telephone calls, text messages, or smartphone application to remind and motivate patients to use their topical therapy.^20,114,115 In all studies, adherence improved and almost doubled compared to non-interventional arms (65% vs. 38% adherence).¹¹⁵ This translated into significantly better clinical outcomes, such as reduction in PGA.^20,115 Another RCT developed a web-based application to educate patients with videos, graphics, and text.¹¹⁶ While knowledge was improved, this did not translate to increased treatment adherence.¹¹⁶ Four RCTs approached adherence by offering more clinical support, such as teaching from nursing staff or internet-based reporting.^117-120 Compared to standard of care, these clinical trials demonstrated that additional support resulted in greater clinical outcomes as early as 4 weeks, which were sustained at 3 months.^117-120

Vehicle selection is an important component of efficacy and adherence. Good vehicles can accelerate barrier restoration and enhance efficacy of active agents by promoting penetration and sustained drug release.¹²¹ As discussed above, RCTs assessing patient satisfaction have found that treatment preferences are heterogeneous and may even change over time.^83,122 Factors that may influence preferences included age, sex, comorbidities, disease duration, and prior treatments.¹²² Therefore, a vehicle should be selected to maximize efficacy and meet the diverse needs of the patient while considering bodily location of psoriasis, probability of improvement, and delivery method. An additional very important attribute for a topical therapy to improve patient adherence is convenience. While it may be patient-specific, an agent that does not need to be applied often (QD or less often), is universal (e.g., same product that can be applied anywhere on the skin), is cosmetically acceptable (texture, colour, and odour) and is affordable will likely promote higher patient adherence and thereby achieve better clinical success rates.

As discussed in the guideline review section above, the first aim of psoriasis treatment is to achieve clear/almost clear skin with a topical agent of choice (combined physician/patient decision for agent selection). Prior to fixed-dose combination topical therapies, in order to increase efficacy while mitigating AEs, different strategies were used. These included rotational treatment where patients alternated between 2 agents, usually a TCS and a corticosteroid-sparing molecule;¹²³ or a sequential treatment approach where a superpotent agent (usually TCS class I-II) was used initially with subsequent step down to either a milder TCS, steroid-sparing molecule or a rotational treatment. However, nowadays fixed-dose combination topical therapies are more popular for their additive efficacy, simplicity, and convenience.¹²³ Once acceptable control is achieved, discussion of relapse prevention is important.

Because psoriasis is chronic and likely to recur upon discontinuation of the topical therapy, it is important to educate the patient about the chronicity of the disease and its treatment at the initial and subsequent visits. Two approaches following initial improvement of psoriasis are commonly used in clinical practice to maintain response over longer-term: the proactive and reactive approaches. Combined physician-patient decision-making may opt for either a proactive approach which consists of using the same agent to achieve clear skin (or another topical) intermittently (e.g., biweekly) to psoriasis-prone areas in order to prevent recurrence, or a reactive approach where all treatments are discontinued upon clinical resolution and restarted promptly with first signs of disease recurrence.

Conclusion

The vast majority of our psoriasis patients have a mild-to-moderate disease requiring topical therapies life-long. Consequently, the availability of safe, effective, and convenient products is essential to achieve and maintain clear/almost clear skin and promote long term treatment adherence. In this review, we provided clinicians an up to date safety and efficacy data of commercially available topical products as well as imminent pipeline topicals. North American guidelines for topical treatment of mild-to-moderate psoriasis are summarized as well as clinical tips are provided.

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Abstract

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

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

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

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

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Background

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

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

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

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

Methods

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

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

Literature Review

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

The Nomenclature Used for the Searches

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

Search Terms

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

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

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

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

Role of the Panel

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

Results

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 1: Cleanser and moisturizer use

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

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

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

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

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

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

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

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

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

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

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

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

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

Limitations

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

Conclusions

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

¹Diplomate of the American Board of Dermatology, Fellow of the Royal College of Physicians of Canada, Associate Professor, Department of Medicine University of Toronto, Onco-dermatologist, Princess Margaret Cancer Centre, Director, Toronto, ON, Canada.
²Fellow of the Royal College of Physicians of Canada, Diplomate of the American Board of Dermatology, Associate Professor, Department of Medicine, Division of Dermatology, Laval University, Director Melanoma and Skin Clinic, Le Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, Quebec City, QC, Canada.
³Medical Oncologist, Medical Oncology Disease Site Lead for Melanoma/Skin Oncology, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre. Assistant Professor, Department of Medicine, University of Toronto, Associate Member, Department of Immunology, University of Toronto, Toronto, ON, Canada
⁴Radboud UMC, Nijmegen and Andriessen Consultants, Malden, The Netherlands.
⁵Fellow of the Royal College of Physicians of Canada, Associate Professor, Department of Oncology, McGill University; Director, Division of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada.
⁶Fellow of the Royal College of Physicians of Canada, Diplomate of the American Board of Dermatology, Associate Professor, Department of Medicine University of Toronto, Toronto, ON, Canada, Lynderm Research, Markham, ON, Canada.

Abstract
The Canadian skin management in oncology (CaSMO) project was developed to improve cancer patients’ (both active and survivors) quality of life by offering tools to healthcare professionals for preventing, reducing and/or managing cutaneous adverse events (cAEs).
Immunotherapy, specifically immune checkpoint inhibitors (ICIs), for cancer patients is both increasing in indications and use. Similarly, the incidence and onset of cutaneous immunotherapy-related adverse events (cirAEs) vary based on the class and dose of immunotherapy administered, the type of cancer, and factors related to the patients. Dermatologists will increasingly see side effects from immunotherapy.

The CaSMO advisors developed a practical primer on prevention, identification, and treatment, including skincare for cirAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.
A modified Delphi approach was used for the cirAEs practical primer’s development. Recommendations given by the CaSMO advisers are based on information from the guidelines, algorithms, consensus papers, and systematic reviews coupled with their clinical experience and resulting from discussions.

According to the CaSMO group, the management of cirAEs starts with physician awareness and patient education on the occurrence of toxicities, preventive measures, and skincare using gentle cleansers, moisturizers, and sunscreen started before immunotherapy begins and ongoing thereafter as part of the lifestyle.

Keywords: Immunotherapy, cutaneous adverse events, immune checkpoint inhibitor, skin toxicity, psoriasis, pruritus, morbilliform, eczema, bullous pemphigoid

Disclosures
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the manuscript, reviewed it and agree with its content and publication.

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Introduction

In 2021 an estimated 229,200 Canadians were diagnosed with cancer.¹ In Canada, of the four most commonly diagnosed types of cancer (lung, breast, colorectal, and prostate), excluding non-melanoma skin cancer, lung cancer is the most lethal and expected to cause more deaths than the other types combined.^2,3

Immunotherapy activates the body’s immune system to fight cancer. Immune checkpoint inhibitors (ICIs) prevent the deactivating signal by blocking the T-cell shut-off receptors and ligands from binding to each other, thereby disrupting signaling so that T cells remain active and can then recognize and attack cancer cells.^4,5 ICIs are approved for treatment across almost every type of solid-organ tumors, many hematologic malignancies, and in many instances, first-line therapy.^4,5 In 2019, in the United States, approximately 40% of oncology patients were eligible for treatment with immunotherapy.⁶ ICIs may be administered as a single agent (anti-CTLA-4 (ipilimumab), anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab, durvalumab, and avelumab)) or as combination immunotherapy (ipilimumab and nivolumab) and even as a combination with other agents.^4-6

Oncology patients treated with immunotherapy may experience cutaneous immunotherapy-related adverse events (cirAEs) at any time during and after the cancer treatment, severely impacting the quality of life (QoL) and potentially cancer treatment outcomes.^7-24 The incidence and onset of cirAEs vary depending on the drug class, the type of cancer, and factors related to the patient.²⁵ Adverse skin reactions occur in 14%–47% of patients treated with ICIs, ranging from mild and localized to debilitating and widespread in 1%–3% of patients and even potentially causing death.^15,16,26-30 Nivolumab-related cirAEs, including isolated pruritus, occurred in approximately 13–20% of patients, of which 0.7% of patients reported grade three or higher cAEs.^29-33 Pembrolizumab-induced cirAEs occurred in 9%–27% of patients, of which 1%−4% of patients reported grade three or higher cirAEs.^34,35

Frequently occurring cirAEs include pruritus without primary dermatologic findings (isolated pruritus), lichen planus or lichenoid drug eruptions, psoriasiform reactions, eczematoid eruptions, morbilliform eruptions, and bullous diseases, primarily bullous pemphigoid.^7-24  

The cirAEs may indicate a therapeutic response. A multicenter retrospective study on patients with non-small-cell lung carcinoma (NSCLC) receiving nivolumab showed that AEs and cirAEs were a strong predictor of survival outcomes, and those presenting with more than 2 AEs showed more benefit than patients with fewer AEs.¹⁴  Vitiligo occurs in some patients with melanoma receiving ICIs (Figure 1), and this is significantly associated with both progression-free-survival (PFS) and overall survival (OS) which indicated a two to four times lower risk of disease progression and death.^32,36

Major guidelines^10-12 recommend the use of systemic steroids for grade 2 or higher “rash” contrary to evidence showing the use of systemic steroids reduces the anticancer effect of ICIs.³³  A secondary analysis of a randomized trial on stage III melanoma patients with cirAEs showed that patients who received treatment with systemic steroids for 30 days or longer had lower OS than those without steroid treatment.³³  Another multicenter retrospective analysis of patients treated with anti-PD-1 therapy showed that high-dose glucocorticoids used to treat AEs were associated with poorer PFS and OS.³⁵

Scope of the Canadian Skin Management in Oncology Project

The Canadian skin management in oncology (CaSMO) project was developed to improve cancer patients’ (both active and survivors) QoL by offering tools for preventing and managing cAEs.^37-39 A general management algorithm to reduce the incidence of all cutaneous toxicities and maintain healthy skin using general measures and over-the-counter agents³⁸ and an algorithm to reduce and treat acute radiation dermatitis³⁹ were previously published. These algorithms aim to support all healthcare providers treating oncology patients, including physicians, nurses, pharmacists, and other medical providers.^38,39 The next step in the project was to develop a practical primer on prevention, identification, and treatment for cirAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.

Table 1: Immunotherapy classes, molecules, and indications

CTLA-4 impinges on many features of T-cell biology.^43,44  The CTLA-4 signaling pathway and the PD-1/PD-L1/PD-L2 signaling pathway are critical checkpoints that are used to down-regulate the body’s immune system that tumors often exploit and activate, thereby evading the body’s immune system.^43,44 CTLA-4 dampens T-cell responses via cell-intrinsic and extrinsic pathways. Intrinsic events include, among others, inhibition of protein translation, recruitment of phosphatases, activation of ubiquitin ligases, inhibition of cytokine receptor signaling, and inhibition of lipid microdomain formation on the surface of T-cells. Cell extrinsic events include the competition for CD28 in binding to its ligands CD80/86, the removal of CD80/86, the release of suppressive indoleamine-dioxygenase, and the modulation of Treg function. Antibodies to CTLA-4 may facilitate T-cell tumor entry and alter the movement in tumors and rates of egress.^43,44

cirAEs can present as almost any dermatologic condition, but most are inflammatory dermatoses.^7-11,26 The median time to onset of cirAEs is four weeks but has a broad range from 2 to 150 weeks, including beyond treatment discontinuation.^15,17,45

cirAEs of any grade have been reported at 30-40% of patients receiving PD-1/PD-L1 and approximately 50% of patients treated with ipilimumab.³¹  Maculopapular rash and pruritus are common cirAEs related to these treatments.³¹

A systematic literature review on cancer treatment with pembrolizumab and nivolumab observed that the most frequently occurring cirAEs were inflammatory dermatitis, pruritus, and vitiligo.⁴⁶ The rate of any-grade cirAEs with pembrolizumab and nivolumab was reported at 16.7% (RR=2.6) and 14.3% (RR=2.5), respectively.⁴⁶ The cirAEs may be associated with pruritus and comprised of erythematous macules, papules, and plaques, predominantly low-grade and localized to the trunk and extremities.⁴⁶ Challenges with reports of cirAEs are accurate descriptions and diagnoses of the specific dermatoses as many are simply reported as “rash”. Additional cirAEs comprised pruritus [incidence pembrolizumab and nivolumab was 20.2% (RR=49.9) and 13.2% (RR=34.5) respectively] and vitiligo [incidence, 8.3% (RR=17.5) and 7.5% (RR=14.6) respectively].⁴⁵ The researchers noted that knowledge of cirAEs is critical in delivering optimal cancer treatment, maintaining therapeutic agent dose, and health-related QoL.⁴⁶

The advisors agreed that cirAEs are likely an indicator of ICIs treatment efficacy and should be managed with topical treatment and judicious, ideally steroid-sparing systemic treatment where possible.^33,35-38

Approaches to the most common immunotherapy-related cAEs

The advisors discussed and selected the most common cirAEs: isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, morbilliform (maculopapular) eruptions, and bullous pemphigoid eruptions.^7-25,27-30

According to the advisors, the management of cirAEs starts with patient education on the occurrence of cirAEs, preventive measures, and skincare using gentle cleansers, moisturizers, and sunscreen started before ICIs treatment begins and ongoing during survival as part of the lifestyle.^9-25

Diagnosis of cirAEs

When diagnosing the cirAEs, other etiologies such as an infection, an effect of other agents, or other skin conditions should be ruled out.^8-11 

Biopsies play a role in accurately diagnosing the cirAEs when morphology is not clear. Histopathologically, cirAEs can be categorized into four broad groups, group 1: Inflammatory skin disorders, which reflect acute, subacute, or chronic inflammation of various patterns associated with variable epidermal changes, including psoriasiform or lichenoid interface chronic dermatitis.^16,50-53 Group 2: ICIs-related bullous skin lesions such as bullous pemphigoid or dermatitis herpetiformis, group 3: Keratinocyte alteration—Grover’s disease⁵⁴/acantholytic dyskeratosis, and group 4: Immune-reaction mediated by alteration of melanocytes such as regression of nevi, tumoural melanosis, and vitiligo.^29,36,48-52 For this review, we will only be focusing on the selected cirAEs.

When assessing the severity of cirAEs, grading systems’ trial limitations need to be considered.⁹ The Common Terminology Criteria for Adverse Events (CTCAE) classification is typically used; however, in the case of clinical trials, clinicians should be cognisant of the version the trial is using as different versions of CTCAE have different definitions and categorizations.²⁶

A general approach to prevention or reduction of cirAEs as well as initial management of the previously published CaSMO algorithm is displayed (Figure 2) for reference.³⁸  

Isolated Pruritus

Immunotherapy-related isolated pruritus occurs frequently and has a significant impact on QoL (Figure 3).^{7-25,31,46,55-57}  Diagnostic criteria for pruritus have been described as core symptoms, including duration of pruritus (more than six weeks) and a history of signs of scratching.^63,64 Associated criteria comprise a range of clinical manifestations, symptoms, functions, and emotions. The function includes the extent of impaired QoL, sleep loss, and days of absence from work. Emotions include possible psychological reactions such as, depression, anxiety, anger, and helplessness.⁶⁴

Isolated pruritus should be a diagnosis of exclusion once other causes such as pre-bullous pemphigoid, bites, or other drug reactions are ruled out.

A stepwise approach includes starting with over-the-counter topical agents, topical prescription agents, systemic drugs, and phototherapy.^63,64 General principles before starting topical and/or systemic treatment comprise skincare using gentle cleansers and moisturizers, especially in the presence of xerosis.^63,48

The CaSMO algorithm educates on general measures such as avoiding skin irritants, scented products, temperature extremes, sun, and the use of sun-protective clothing (e.g., brim hats and sunglasses). The information should be provided before immunotherapy starts, and this is especially important for isolated pruritus.³⁸ The daily skincare regimen should be reinforced with emphasis on gentle cleansers, skin moisturization, and sun protection – similar counseling to a patient with atopic dermatitis.^37,38,47  

A prurigo nodularis 4-tier treatment ladder⁶⁴ addresses neutral and immunologic mechanisms that may be applicable to ICIs-induced pruritus.⁶⁴ Immunologic mechanisms are more likely to be the underlying mechanism in ICIs-induced pruritus. Patients can enter the treatment ladder at any tier and move up or down the ladder based on their clinical presentation.⁶⁴  Immunologic tier 1 is more likely mechanisms can be treated with TCS, TCI, or topical calcipotriol.⁶⁴  Moisturizers, including antipruritics such as pramoxine 1% or formulations with menthol or camphor, may be used as an adjunct therapy.⁶⁴ 

For tier 2 neural mechanisms of pruritus medications include selective nor­epinephrine reuptake inhibitors (SNRIs) (i.e., mirtazapine) and gabapentinoids (gabapentin and pregabalin), which have antipru­ritic properties.^63,64  Second-generation histamine H1 receptor antagonists were shown to be effective and safe for patients receiving ICIs.⁶⁴ 

Additional second-line systemic therapies such as neurokinin 1 inhibitors (i.e., aprepitant) and inhibi­tors of interleukins (ILs) 4, 13 may be considered for the tier 3 immunologic mechanisms approach.⁶⁴ When evaluating the need for systemic or topical treatment, possible interactions with cancer therapy are assessed together with concomitant conditions and cirAEs.^{9-11,15,16,23,24 37,38,47}

Clinicians should take caution using systemic steroids and immunomodulators for patients receiving cancer treatment with ICIs (Table 2).^9-11

Table 2: Isolated pruritus

Psoriasiform Eruptions

T helper (Th) cells producing interleukin (IL)-17, IL-22, and tumor necrosis factor (TNF) drive the pathogenesis of psoriasis by orchestrating inflammation in the skin triggering proliferation of keratinocytes and endothelial cells.⁶⁵ Besides Th17 cells, other immune cells that are capable of producing IL-17-associated cytokines participate in psoriatic inflammation.^66-70  ICIs are thought to be driven through the TH17 pathway, and this may have implications on the development of psoriasis but also on the use of systemic psoriasis medications.^64,65,71,72

Immunotherapy with anti-PD1 and anti-PDL1 can exacerbate psoriasis, although more severe flares were noted in patients treated with durvalumab.^65-68,70,71

A personal or family history of psoriasis is a significant risk factor that should be identified before starting immunotherapy.^65,66,68 These patients require regular skin monitoring enabling early diagnosis and treatment of psoriatic exacerbations.^65,66,68 Prompt diagnosis can prevent a severe impact on QoL of this cirAE that may compromise therapeutic protocols and final cancer prognosis (Figure 4).^53,65,66 A skin biopsy to confirm the diagnosis, although not required, includes parakeratosis, hypogranulosis, regular acanthosis, suprapapillary plate thinning, and neutrophils at various layers of the epidermis.^68,70

Psoriasiform cirAEs can affect skin, nails, and joints and significantly impact QOL.^65-71 Psoriasis can be associated with arthritis as patients have a greater-than-expected incidence of psoriatic arthritis when it occurs as a cirAE of cancer treatment.^33,65,66 The choice of therapy takes many factors into account, including the extent and area of involvement, lifestyle, other health issues, and medications. First-line treatments include topical treatment with TCS, TCI, calcitriol, or a combina­tion of a super potent TCS with calcipotriol or tazarotene can be given.^65-71  For recalcitrant cases, consider adjuvant narrowband ultraviolet B therapy or oral treatment such as systemic retinoids [acitretin] or apremilast.^72-75  Although there is no direct evidence in ICIs treated cancer patients, methotrexate is immunosuppressive and may reduce the therapeutic effect of ICIs, similar to systemic steroids that have been shown to reduce RFS and OS.^32,33,35

Acitretin or apremilast is preferred over methotrexate; however, there is an absence of data for apremilast on the effect it may have on the anticancer treatment.^68-75  If the lesions persist, treatment with biologics may be required to treat psoriasiform cirAEs. IL-23 agents (gulselkumab, risankizumab, tildrakizumab) are considered most targeted and have the least direct evidence of immunosuppression (e.g. infection and TB reactivation). However, the risk/benefit needs to be considered before starting treatment with biologics (Table 3).^76-86

Lichen Planus

Immunotherapy-induced lichen planus is a pruritic, papulosquamous disease that can affect skin, hair, and nails (Figure 5). Treatment is required, especially if pruritic when it can severely impact QoL.^{7-19,27,33,46,63,77,78} When examining the patient exclude guttate psoriasis, mucositis, and bullous disease. Specific investigations include a detailed medical history and medication use, liver function tests including hepatitis C status, and, if required, a skin biopsy.⁷⁹

Pruritus may be treated with second-generation histamine H1 receptor antagonists (e.g., blistane, rupatadine, cetirizine and fexofendadine).^63,64,79 A retrospective analysis of clinical data investigating if commonly used medications might influence responses to checkpoint inhibitors. The researchers found that concurrent use of second-generation histamine H1 receptor antagonists correlated with significantly improved survival outcomes in those with melanoma or lung cancer. In addition, the antihistamine was effective for treating pruritus in cirAEs.^63,64,79 The choice of therapy takes many factors into account, including the extent and area of involvement, other health issues, and medications.^{8-11,67-69,78,80} First-line treatment includes moisturization and sun avoidance, antihistamines, TCS, and TCI.^80,81 Other second-line treatments include oral retinoids (acitretin), apremilast, sulfasalazine, metronidazole, hydroxychloroquine (especially for scalp or presentation with arthritis).⁸⁰ Additionally, narrowband or broadband UVB or PUVA may be used. Treatment with cyclosporine should be avoided as it may exert effects on the immune system (Table 4).^25,31,78

Table 4: Lichen planus

Eczematous Eruptions

Eczematous eruptions (EE) are associated with altered immune function, epidermal barrier dysfunction, genetic and environmental factors, and poorly understood interaction between these factors.^82-85 EE presents clinically as relapsing erythematous and pruritic patches of skin with varying severity (Figure 6).^9-11,82-85  Skin biopsies may be taken if the condition is extensive or not responding to therapy or if the diagnosis is in doubt.^9-11 Canadian and US guidelines for topical treatment of atopic dermatitis include education and avoiding triggers, routine skincare with gentle cleansers and moisturizers, and EE management foundation regardless of disease severity and prescription treatment.^82,83 Conventional moisturizers contain occlusives, humectants, and emulsions. Newer moisturizers designed to restore skin barrier defects include distinct ratios of lipids that resemble physiological compositions.^{36,38,47,82,83} If EE is not controlled with a moisturizer alone, TCS, TCI, or crisaborole ointment, an anti-inflammatory inhibitor of PDE4, is recommended while continuing skincare.^9-11,82-86   Treatment with crisaborole ointment achieved early sustained control of atopic dermatitis flares (reduced pruritus, erythema, exudation, excoriation, induration/papulation, and lichenification).^84,85  The topical PDE4 inhibitor offered a safe alternative to TCS and TCI.^84,85

For those not adequately controlled with topical treatment, nbUVB may be considered.^82,83 Dupilumab is a humanized monoclonal antibody against the shared alpha subunit of IL-4 and IL-13 receptors, blocking these cytokines commonly found in atopic dermatitis-affected skin. The use of dupilumab may be considered for extensive, moderate-to-severe EE. Two large, long-term RCTs demonstrated its efficacy and safety.^{9-11,82,83,86}  

Another option is tralokinumab (IL-13 inhibitor) which was shown to be effective and safe for the treatment of severe atopic dermatitis.⁸⁷

Treatment with the biologic is preferred to methotrexate which is an immunosuppressive and may reduce the anticancer effect.^9-11 TCS, TCI, and crisaborole can be used with any systemic treatment to address an EE flare (Table 5).^82-85,93

Morbilliform (maculopapular) Eruptions

These cirAEs may present as pruritic, nontender, erythematous papular, and macular eruptions on various body locations.^37,38,46,47 Physical examination focusing on the morphology and the distribution, starting on the trunk and then spreading to limbs, of the presented morbilliform eruptions is required to distinguish between the various cirAEs (Figure 7).^37,38,46,47 Laboratory tests may be needed and include a complete blood count, electrolytes, renal and liver function, and inflammatory markers.^37,38,46,47 Peripheral blood eosinophilia (≥500 eosinophils/microL) may be caused by numerous conditions, including allergic, infectious, inflammatory, and neoplastic disorders (Table 6).^37,38,46,47  Mild to moderate conditions may be treated with general skin care measures, TCS, TCI, and oral histamine H1 receptor antagonists to reduce pruritus.^63,64,94 Generally, this condition can be managed with aggressive topical treatment; however, for very severe and symptomatic cases, ICIs-treatment may be held, and a short course of systemic corticosteroids may be indicated.⁹⁴ 

Table 6: Morbilliform eruptions

cirAE BP can occur at any time, including after discontinuation of ICI. The onset to developing BP is within days or weeks of ICI exposure or may be delayed several months after starting ICI.³¹ Upon diagnosis ICIs is to be held and may require permanent discontinuation.^3,15,46 In milder cases, aggressive topical treatments with class I TCS may be as effective as systemic steroids.⁹²  cirAE BP may require systemic treatment and temporary, if not permanent, cessation of immunotherapy.^3,15,46 Systemic corticosteroids may be used the achieve control quickly while waiting for steroid-sparing treatments to take effect.^88,90-92 Non-immunosuppressive systemic treatment includes oral tetracycline-class antibiotics combined with oral niacinamide 500 mg twice a day, omalizumab, IVIg, and dupilumab.^31,88,90-92 However, steroid-sparing agents that are immunosuppressive may be required in order to control BP ongoing, including methotrexate, mycophenolate mofetil or rituximab.⁹¹ While rituximab may be immunosuppressive, it works on B-cells and may not hinder the T-cell activation from ICIs. In patients with cirAE BP, obtaining disease control as quickly as possible is ideal not only for improved QoL, and decreased morbidity but also if treatment is to be reinitiated (Table 7).^93,95

Table 7: Bullous eruptions

Limitations

The details provided on the mode of action of ICIs were limited to what is clinically relevant for this primer on cirAEs. Clinical studies on prescription medications and skin care for cirAEs frequently are case reports, case series, or have small sample sizes. For this reason, grading the evidence resulting from the literature searches was irrelevant. Therefore, recommendations given by the CaSMO project advisers are based on information from the guidelines, algorithms, consensus papers, and systematic reviews coupled with their clinical experience and resulting from discussions. More work is required to identify the best practice evidence-based management of cirAEs.

Summary and Conclusions

Immunotherapy for cancer patients is fast-developing into the standard of care for many malignancies. Although many publications are available on cirAEs, publications on the treatment using prescription medications and skincare are scarce.

The CaSMO practical primer focuses on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid. The practical primer addresses the need for physician awareness, patient education on the occurrence of cirAEs, prompt diagnosis, prevention, treatment, and ongoing skincare started before ICI.

References

1. https://cdn.cancer.ca/-/media/files/cancer-information/resources/publications/2021-canadian-cancer-statistics-special-report/0835-2976-2021-canadian-cancer-statistics-en.pdf?rev=8e016fe8c5ea4c23b05ea08bf1018ca6&hash=C5BAEC543E496EDD8460CBBF6D44A010&_ga=2.47880293.391373246.1644172159-1100777747.1644172159
2. Canadian Cancer Society; 2021. Available at: https://www.cancer.ca/en/cancer-information/cancer-101/cancer-statistics-at-a-glance/
3. Mittmann N, Liu N, Cheng SY, Seung SJ. Health system costs for cancer medications and radiation treatment in Ontario for the most 4 most common cancers: a retrospective cohort study. Can Med Association J Open 2020;8:E191-8. Epub 2020 March 16 doi: https://doi.org/10.9778/cmajo.20190114
4. Dine J, Gordon R, Shames Y, et al: Immune checkpoint inhibitors: An innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs 2017; 4:127-135.
5. American Society of Clinical Oncology (ASCO). Understanding immunotherapy therapy. Accessed at https://www.cancer.net/ navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/understanding-immunotherapy on January 16, 2022.
6. Haslam A, Gill J, Prasad V: Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw Open 2020;3:e200423.
7. Malviya N, Tattersall IW, Leventhal J, et al. Cutaneous immune-related adverse events to checkpoint inhibitors. Clin Dermatol 2020;38:660-678.
8. Lacouture ME, Sibaud V. Toxic side effects of targeted therapies and immunotherapies affecting the skin, oral mucosa, hair, and nails. Am J Clin Dermatol. 2018 Nov;19(Suppl 1):31-39.
9. Haanen J, Carbonnel F, Robert C, et al. management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(7) (suppl_4):119-142.
10. Schneider BJ, Naidoo J, Santomasso BD, et al. management of immunotherapy-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology (ASCO) guideline update. J Clin Oncol 2021;39(12):4073-4126. PIMD: 34724392.
11. Thompson JA, Schneider BJ, Brahmer J et al. NCCN Guidelines insights: Management of immunotherapy-related toxicities, Version 1.2020. J Natl Compr Cancer Netw. 2020;18(3):230-241.DOI: 10.6004/jnccn.2020.0012
12. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010 March 10;28(8):1351-7.
13. Qin Q, Patel VG, Wang B, et al. Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors. J Clin Oncol 2020;38:e15160.
14. Ricciuti B, Genova C, de Giglio A, et al. Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab. J Cancer Res Clin Oncol. 2019 Feb;145(2):479-48
15. Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol. 2018 Jun;19(3):345-361.
16. Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017;44(2):158-76.
17. Tang SQ, Tang LL, Mao YP, et al: The pattern of time to onset and resolution of immune-related adverse events caused by immune checkpoint inhibitors in cancer: A pooled analysis of 23 clinical trials and 8,436 patients. Cancer Res Treat 2021;53:339-354.
18. Druyts E, Boye M, Agg H, et al. Immune-related adverse events and efficacy outcomes in patients treated with immunotherapy: A systematic review and meta-analysis. J Clin Oncol 2020;38.
19. Patel AB, Pacha O: Skin reactions to immune checkpoint inhibitors. Adv Exp Med Biol 2018;995:117-129.
20. Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol 2020; 83:1255-1268.
21. Kaul S, Kaffenberger BH, Choi JN, et al. Cutaneous adverse reactions of anticancer agents. Dermatol Clin 2019;37:555-568.
22. Wang LL, Patel G, Chiesa-Fuxench ZC, et al. Timing of onset of adverse cutaneous reactions associated with programmed cell death protein 1 inhibitor therapy. JAMA Dermatol 2018;154:1057-1061.
23. Simonsen AB, Kaae J, Ellebaek E, et al. Cutaneous adverse reactions to anti-PD-1 treatment—A systematic review. J Am Acad Dermatol 2020;83:1415-1424.
24. Hussaini S, Chehade R, Boldt RG, et al. Association between immune-related side effects and efficacy and benefit of immune checkpoint inhibitors—A systematic review and meta-analysis. Cancer Treat Rev 2021;92:102134.
25. Raschi E, Gatti M, Gelsomino F, et al. Lessons to be learned from real-world studies on immune-related adverse events with checkpoint inhibitors: A clinical perspective from pharmacovigilance. Target Oncol 2020;15:449-466.
26. National Cancer Institute: Common Terminology Criteria for Adverse Events Version 5.0. NIH Publication, Bethesda, MD, 2018
27. Schaberg KB, Novoa RA, Wakelee HA, et al. Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. J Cutan Pathol. 2016 Apr;43(4):339-46.
28. Voudouri D, Nikolaou V, Laschos K, et al.Anti-PD1/PDL1 induced psoriasis. Curr Probl Cancer. Nov-Dec 2017;41(6):407-12
29. Rofe O, Bar-Sela G, Keidar Z, et al. Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression. Clin Exp Dermatol. 2017 Apr;42(3):309-12.
30. Vivar KL, Deschaine M, Messina J, et al. Epidermal programmed cell death-ligand 1 expression in TEN associated with nivolumab therapy. J Cutan Pathol. 2017 Apr;44(4):381-84.
31. Puzanov I, Diab A, Abdallah K et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations for the Society for immunotherapy of Cancer (SITC) Toxicity Management Working group. J Immuno Therapy Cancer 2017;5:95 DOI 10.1186/s40425-017-0300-z
32. Teulings HE, Limpens J, Jansen SN et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015 March 1;33(7):773-81.
33. Eggermont AMM, Kicinski M, Blank CU et al. Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo. A secondary analysis of a randomized clinical trial. JAMA Oncol. 2020;6(4):519-527. Doi: 10.1001/jamaoncol.2019.5570 PMID: 31895407
34. Herbst RS, Baas P, Kim DW et al. Pembrolizumab versus docetaxel for previously treated, PD‐L1‐positive, advanced non‐small‐cell lung cancer (KEYNOTE‐010). Lancet 2016;387:1540–1550.
35. Bai X, Hu J, Betof Warner A et al. Early Use of High-Dose Glucocorticoid for the management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy. Clin Cancer Res. 2021 Nov 1;27(21):5993-6000. doi: 10.1158/1078-0432.CCR-21-1283. Epub 2021 August 10. PMID: 34376536.
36. Hua C, Boussemart L, Mateus C et al. Association of virtiligo with tumor response in patients with metastatic melanoma treated with pemobrolizumab. JAMA Dermatol. 2016;15(1)45-51. Doi: 10.1001/jamadermatol.2015.2707
37. Sauder MB, Addona M, Andriessen A, et al. The role of skin care in oncology patients. Skin Ther Letter; 2020 S Oct(10):1-12.
38. Sauder MB, Andriessen A, Claveau J, et al. Canadian skin management in oncology (CaSMO) algorithm for patients with oncology treatment-related skin toxicities. Skin Ther Letter; 2021 S March 21:1-10.
39. Hijal T, Sauder MB, Andriessen A, Claveau J, Lynde CW. Canadian Skin Management in Oncology Group (CaSMO) algorithm for the prevention and management of acute radiation dermatitis. Skin Ther Letter; 2021 S.
40. Brouwers M, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in healthcare. Can Med Association J 2010,182:E839-42
41. Trevelyan EG, Robinson N. Delphi methodology in health research: how to do it? Eur J Integrative Med 2015;7(4):423-428.
42. Smith Begolka W, Elston DM, Beutner KR. American Academy of Dermatology evidence-based guideline development process: responding to new challenges and establishing transparency. J Am Acad Dermatol.2011 Jun;64(6):e105-12. doi: 10.1016/j.jaad.2010.10.029.
43. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.
44. Digklia A, Duran R, Homicsko K et al. Cancer Immunotherapy: A Simple Guide for Interventional Radiologists of New Therapeutic Approaches. Cardiovasc Intervent Radiol. 2019 Sep;42(9):1221-1229. doi: 10.1007/s00270-018-2074-1.
45. Qin Q, Patel VG, Wang B, et al. Type, timing, and patient characteristics associated with immune-related adverse event development in patients with advanced solid tumors treated with immune checkpoint inhibitors. J Clin Oncol 2020;38:e15160.
46. Belum VR, Benhuri B, Pastow MA et al. Characterization and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60(6) 12–25. doi:10.1016/j.ejca.2016.02.010.
47. Lacouture ME, Choi J, Ho A et al. US cutaneous oncodermatology management (USCOM) a practical algorithm. J Drugs Dermatol 2021; 20(9)(Suppl):s3-19.
48. Larkin J et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.
49. Anforth RM, Blumetti TCMP, Kefford RF, et al. Cutaneous manifestations of dabrafenib in patients with metastatic melanoma. Br J Dermatol. 2012 Nov;167(5):1153-60.
50. Shi VJ, Rodic N, Gettinger S et al. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti-programmed cell dealth 1 and anti-programmed cell death ligand 1 immunotherapy. J Am Med Assoc Dermatol 2016; 152: 1128–1136.
51. Tetzlaff MT, Nelson KC, Diab A et al. Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients Am J Dermatopathol 2017; 39: 121–129.
52. Koelzer VH, Buser T, Willi N et al. Grover’s-like drug eruption in a patient with metastatic melanoma under ipilimumab therapy. J Immunother Cancer 2016;4(8): 47. DOI: 1186/s40425-016-0151-z
53. Boada A, Carrera C, Segura S, et al. Cutaneous toxicities of new treatments for melanoma. Clin Transl Oncol. 2018;20:1373-1384.
54. Bayer V, Amaya B, Baniewicz D, et al. Cancer immunotherapy: An evidence-based overview and implications for practice. Clin J Oncol Nurs 2017;21:13-21.
55. Keiser MF, Patel AB, Altan M: Cutaneous toxicities in lung cancer patients on immune checkpoint inhibitor therapy. Clin Lung Cancer 2021;22:195-e1.
56. Ala-Leppilampi K, Baker NA, McKillop C, et al. Cancer patients’ experiences with immune checkpoint modulators: A qualitative study. Cancer Med 2020;9:3015-3022.
57. Kumar V, Chaudhary N, Garg M, et al. Current diagnosis and management of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017; 8:49.
58. Prior LM et al. Toxicities in immunotherapy: Can they predict response? J Clin Oncol. 2016;34(15 suppl):e14534-e14534.
59. Muntyanu A, Netchiporouk E, Gerstein W, et al. Cutaneous immune-related adverse events (irAEs) to immune checkpoint inhibitors: A dermatology perspective on management. J Cutan Med Surg 2021;25:59-76.
60. Ai L, Gao J, Zhao S et al. Nivolumab-associated DRESS in a genetic susceptible individual. J Immunother Cancer 2021;9:e002879. doi:10.1136/jitc-2021-002879
61. Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 2019;7:306
62. Matsubara T, Uchi H, Takamori S et al. Acute Generalized Exanthematous Pustulosis Caused by the Combination of Pembrolizumab Plus Chemotherapy in a Patient With Squamous-Cell Carcinoma. Clin Lung Cancer 2020;21(2):e54-e56.
63. Ständer S, Pereira MP, Yosipovitch G et al. IFSI-guideline on chronic prurigo including prurigo nodularis. Itch 2020;5:e42 http://dx.doi.org/10.1097/itx.0000000000000042
64. Elmariah S, Kim BS, Yosipovitch G, et al. Practical approaches for diagnosis and management of prurigo nodularis: United States expert panel consensus. J Am Acad Dermatol 2021;(3):747-760. doi.org/10.1016/j.jaad.2020.07.025
65. Guven DC, Kilickap S, Guner G, et al. Development of de novo psoriasis during nivolumab therapy in a patient with small-cell lung cancer. J Oncol Pharm Pract 2020;26:256-258.
66. Voudouri D, Nikolaou V, Laschos K, et al. Anti-PD1/PDL1 induced psoriasis. Curr Probl Cancer 2017;41:407-412.
67. Choi Y, Jang D, Byun HJ et al. Psoriasiform dermatitis related with T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains inhibitor in a patient with non-small-cell lung cancer. Ann Dermatol 2020;32(2):172-174. PMID: 33911733 | PMCID: PMC7992544
68. Amaris N, Geisler BS, Lacouture ME et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Acad Dermatol 2020;83(5):1255-1268.
69. Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol. 2019;37:2746–2758.
70. Kato Y, Otsuka A, Miyachi Y, Kabashima K. Exacerbation of psoriasis vulgaris during nivolumab for oral mucosal melanoma. J Eur Acad Dermatol Venereol. 2016;30:e89–e91.
71. Totonchy MB, Ezaldein HH, Ko CJ, Choi JN. Inverse psoriasiform eruption during pembrolizumab therapy for metastatic melanoma. JAMA Dermatol. 2016;152:590–592.
72. Brahmer JR, Lacchetti C, Schneider BJ, et al. management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline. J Clin Oncol 2018;36:1714–68.doi:10.1200/JCO.2017.77.6385
73. Elmets CA, Leonardi CL, Davis DMR, et al. Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019; 80: 1073–113. x
74. Siciliano MA, Dastoli S, d’Apolito M et al. Pembrolizumab-Induced Psoriasis in Metastatic Melanoma: Activity and Safety of Apremilast, a Case Report. Front. Oncol. 2020;10:579445. doi: 10.3389/fonc.2020.579445
75. Fattore D, Annunziata MC, Panariello L, Marasca C, Fabbrocini G. Successful treatment of psoriasis induced by immune checkpoint inhibitors with apremilast. Eur J Cancer 2019;110:107–9. doi: 10.1016/j.ejca.2019.01.010
76. Frieder J, Kivelevitch D, Menter A: Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis. 2018;9:5-21. 1177/2040622317738910
77. De Bock M, Hulstaert E, Kruse V, Brochez L: Psoriasis vulgaris exacerbation during treatment with a PD-1 checkpoint inhibitor: case report and literature review. Case Rep Dermatol. 2018;10:190-197. 10.1159/000491572
78. Martinez-Domenech A, Garcia-Legaz Martinez M, Magdaleno-Tapial J, et al. Digital ulcerative lichenoid dermatitis in a patient receiving anti-PD-1 therapy. Dermatol Online J 2019;25.
79. De la Paz Sarasola M, Taquez Delgado MA, Medina VA et al. Histamine in cancer immunology and immunotherapy. Current status and new perspectives. Pharmacol Res Perspect. 2021;9(5):e00778.
80. Tziotzios C, Lee JYW, Brier T, et al. Lichen planus and lichenoid dermatoses. J Am Acad Dermatol 2018; 79: 789–818.
81. Tattersall IW, Leventhal JS: Cutaneous toxicities of immune checkpoint inhibitors: The role of the dermatologist. Yale J Biol Med 2020;93:123-132.
82. Lynde CW, Bergman J, Fiorillo L, et al. Clinical insights about topical treatment of mild-to-moderate pediatric and adult atopic dermatitis. J Cutan Med Surg. 2019 May/Jun;23(3_suppl):3S-13S.
83. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71:116–132.
84. Yosipovitch G, Simpson EL, Tan H et al. Effect of crisaborole topical ointment, 2%, on atopic dermatitis–associated pruritus: an extended analysis of 2 phase 3 clinical trials. Itch 2019;4(1)p e12.
85. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 Sep;75(3):494-503.e6
86. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of Dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–2348
87. Wollenberg A, Blauvelt A, Guttman-Yassky E et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021;184(3):437-449.
88. Fontecilla NM, Khanna T, Bayan CY, et al. Bullous pemphigoid associated with a new combination checkpoint inhibitor immunotherapy. J Drugs Dermatol 2019;18:103-104.
89. Kubicki SL, Welborn ME, Garg N, et al. Granulomatous dermatitis associated with ipilimumab therapy (ipilimumab associated granulomatous dermatitis). J Cutan Pathol 2018;45:636-638.
90. Siegel J, Totonchy M, Damsky W, et al: Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol 2018;79:1081-1088.
91. Lopez AT, Khanna T, Antonov N, et al. A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol 2018;57:664-669.
92. Joly P, Roujeau JC, Benichou J et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002; 346:321-327
    DOI: 10.1056/NEJMoa011592
93. EsfahaniK, Elkrief A, Calabrese C, et al. Moving towards personalized treatments of immune-related adverse events. Nat Rev Clin Oncol 2020;17:504–15. doi:10.1038/s41571-020-0352-8
94. Fatima S, Veenstra J, Antonyan AS et al. Severe recalcitrant morbilliform eruption from dual immune checkpoint blockade. JAAD Case Rep 2018;4(6):593-595. PMID: 29955646
95. Aizman L, Nelson K, Sparks AD, et al. The influence of supportive oncodermatology interventions on patient quality of life: A Cross-Sectional survey. J Drugs Dermatol. 2020May 1;19(5):477-82.

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

Conflict of interest:
Stephen Tyring received grant support, paid to the Center for Clinical Studies, from Athenex. The other authors have no conflicts of interest.

Abstract:
Actinic keratosis (AK) is a common precancerous condition found on chronically sun-damaged skin, particularly on the face, scalp, arms, and legs. Early and effective treatment of AKs is important to prevent progression to squamous cell carcinoma. Many topical treatments for AKs are often limited because of poor tolerability, prolonged treatment duration, and reduced adherence. Tirbanibulin 1% ointment, a new topical field therapy for AKs, reduces these issues. It requires a consecutive 5-day application period and is effective, demonstrating complete (100%) clearance of AK lesions in 49% of patients, partial (>75%) clearance in 72%, and a median reduction in lesion count of 87.5% while exhibiting a favorable safety profile, mild adverse events, improved tolerability, and long-term results.

Key Words:
tirbanibulin; actinic keratosis, field therapy, 5-fluorouracil, diclofenac, imiquimod, face, scalp

Introduction

Actinic keratosis (AK) is a common, recurrent precancerous condition found on chronically sun-damaged skin, particularly on the face, scalp, arms, and legs.¹ Clinically AKs appear as macules, papules, or hyperkeratotic plaques with an erythematous background.² Its prevalence steadily increases with age and prolonged sun-exposure. The American Academy of Dermatology (AAD) notes that approximately 60% of predisposed individuals over the age of 40 are diagnosed with at least one AK.³ Other risk factors include male gender, fair skin (Fitzpatrick type I-II), ultraviolet (UV) exposure, immunosuppression, previous history of AKs or skin cancer, human papillomavirus (HPV) infection, and genetic diseases.³

Cumulative UV exposure is considered a major risk factor for AK development because of the resultant modification of cellular repair mechanisms in keratinocytes.⁴ UVB irradiation causes the formation of thymidine dimers in DNA and mutations of the telomerase gene, whereas UVA indirectly induces DNA mutation through photo-oxidative stress.³ The clinical significance of AKs is secondary to the associated discomfort, cosmetic burden, and the possibility of progression to invasive squamous cell carcinoma (SCC).⁵ Rates of malignant transformation vary from 0.025% to 16%, and the risk of progression increases in patients with multiple AKs (more than five).³ While AKs are a risk factor for the development of SCC, it is impossible to predict which lesions will transform, therefore treatment of all AKs is recommended.³

Many treatments exist for AKs. Single or few discrete AKs are typically treated with cryosurgery.¹ Treatment of multiple lesions and surrounding photo-damaged skin (field cancerization) includes topical agents and photodynamic therapy (Table 1).¹ These treatments may be associated with local skin reactions of pain, irritation, redness, flaking, erosions, ulcerations, and irreversible skin changes of pigmentation and scarring.¹ Furthermore, some treatments have to be administered over periods of weeks or months, which may reduce adherence and undermine treatment success.¹

Table 1

More recently, the role of the Src kinase in carcinogenesis has shed light on an alternative therapeutic option. In UV damaged skin, a cascade of events activates peroxisome proliferator activated receptor (PPAR) beta/delta which stimulates the Src oncogene expression, increases Src kinase activity and enhances the EGFR/Erk1/2 signaling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression.⁶ Elevated levels of Src have been linked to AKs and SCCs, and play a role in both primary tumor growth and metastases.⁷ Therefore, Src inhibitors were viewed as a plausible therapeutic option and many have since been developed. Tirbanibulin is a novel compound that inhibits Src kinase signaling and tubulin polymerization in rapidly dividing cells. It has shown promise as a new therapeutic agent for the treatment of AKs on the face or scalp.

Background

Mechanism of Action

The chemical name of tirbanibulin is N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridine-2-yal) acetamide (Figure 1).⁴ It is a synthetic, first-in-class, anti-proliferative agent that disrupts Src kinase signaling and inhibits tubulin polymerization (Figure 2).⁸ Through these mechanisms, it also promotes the induction of p53, G2/M arrest of proliferating cell populations, and subsequent apoptosis.⁸

Clinical Trials

Phase I⁸

The Phase I trial was an open-label, single-center study in subjects aged ≥18 years with clinically typical AKs on the forearm. Thirty participants were enrolled into 4 sequential cohorts (n=4, 10, 8, and 8 in each cohort, respectively): Cohort 1 received tirbanibulin ointment 1% 50 mg/day once daily for 3 days over 25 cm² treatment area with 4-8 AK lesions; Cohort 2 received 200 mg/day once daily for 3 days over 100 cm² treatment area with 8-16 AK lesions; Cohort 3 and Cohort 4 were similar to Cohort 1 and Cohort 2, respectively, but treatment was for 5 days. The follow-up period was through day 45.

To assess tirbanibulin activity, AK lesion numbers at baseline (day 1), days 10, 17, 31, and 45 were collected. Complete (100%) and partial (≥75%) AK clearance rates (defined by the reduction in AK lesions in the treatment area at day 45 compared with baseline) were evaluated for each cohort.

Twenty-nine participants completed the study with one participant withdrawing consent on day 2. Reductions in lesion counts from day 1 to 45 were observed in all cohorts. On day 45, Cohorts 1-4 demonstrated 25%, 0%, 50%, and 12.5% of complete AK clearance in the treatment area, respectively.

Dermal safety clinical studies in healthy subjects demonstrated that tirbanibulin 1% ointment did not cause contact sensitization, phototoxic skin reactions, or photoallergic skin reactions.⁴

Phase II⁸

The Phase II trial was an open-label, uncontrolled, dose-regimen- finding, multicenter study in subjects aged ≥18 years with clinically typical AKs on the face or scalp. One hundred and sixty-eight participants were enrolled into 2 sequential cohorts (n=84 in each cohort): Cohort 1 received 50 mg/day tirbanibulin ointment 1% once daily for 3 days over 25 cm² treatment area with 4–8 AK lesions; Cohort 2 received the same treatment for 5 days.

AK lesion counts at baseline (day 1), 8, 15, 29, and 57 were collected, with a 12-month follow-up period for participants that achieved complete AK clearance to monitor for recurrence. All 168 participants completed the trial. Extensive overall AK clearance on the face or scalp was demonstrated in both cohorts. More participants had 100% clearance at day 57 in the 5-day (43% [95% Confidence Interval (CI) = 32, 54]) vs. the 3-day cohort (32% [95% CI = 22, 43]). Partial clearance rates were also slightly higher in the 5-day (56% [95% CI = 45, 67]) vs. the 3-day cohort (52% [95% CI = 41, 63]). There was a consistent decrease in lesion counts across all visits from baseline to day 57 for both cohorts.

All 63 participants who had 100% clearance at day 57 in the Phase 2 study were included in the Recurrence Follow-up Set. At 12 months post-day 57, recurrence rates for the 5-day cohort (57% [95% CI = 41, 73]) were lower than the 3-day cohort (70% [95% CI = 51, 87]). Most recurrence occurred within 6 months post-day 57.

Phase III¹

The Phase III trial was a randomized, double-blind, parallel-group, vehicle-controlled, multicenter (62 US centers) trial in subjects aged >18 years with 4-8 clinically typical AKs on the face or scalp within a contiguous area measuring 25 cm². A total of 702 participants, divided among two identical trials (n=351 at each site), were randomly assigned in a 1:1 ratio to receive either tirbanibulin 1% ointment for 5 days self-administered to a 25 cm² contiguous area or vehicle ointment (placebo). Enrollment across patients was controlled to achieve a 2:1 ratio of facial: scalp treatment areas. The primary outcome was the percentage of patients with a complete reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year.

Tirbanibulin demonstrated higher complete clearance levels in trial 1 (44% [95% CI = 32, 47]; P<0.001) and trial 2 (54% [95% CI = 33, 51]; P<0.001) compared to the vehicle groups (5% and 13% in trials 1 and 2, respectively). Pooled data from both trials demonstrated complete clearance in 49% ([95% CI = 35, 47]; P<0.001) of patients in the tirbanibulin groups and in 9% of the vehicle groups.

Partial clearance was significantly higher in both tirbanibulin groups at 68% (trial 1) and 76% (trial 2) than in the vehicle groups. Pooled data revealed partial clearance in 72% ([95% CI = 48, 60]; P<0.001) of patients in the tirbanibulin groups and in 18% of the vehicle groups. At 1 year, 47% of patients with complete clearance experienced recurrence of AKs.

Median reduction in AK lesion count in patients received tirbanibulin was 87.5% vs. 20% for vehicle (P<0.0001).¹

Safety and Tolerability

Throughout all phases, no serious adverse events (AEs) were reported secondary to tirbanibulin.^1,8 Local skin reactions (LSRs) consisted mostly of mild-moderate erythema, flaking or scaling, application-site pruritus, and application-site pain.¹ Erythema (93%) and flaking (82%) were most common.¹ Severe LSRs (all types) were observed in <10% of patients, with severe erythema in 6% of patients.¹ Other LSRs included crusting, swelling, scaling, vesiculation or pustulation, and ulcerations or erosions.⁴ LSRs typically appeared on treatment day 2 and peaked on treatment day 8, before spontaneously resolving in ~2 weeks-1 month.^1,8 No participants were withdrawn from the clinical trials due to AEs or LSRs.

Laboratory evaluation of blood chemistry, hematology, urine analysis, vital signs, electrocardiograms, and physical examinations in association with the phase III trials were not indicative of any systemic side effects.¹ Tirbanibulin produces adverse ophthalmic reactions, and therefore, patients must be careful not to transfer the drug into the periocular area or eyes.

There has been no data on possible birth defects and/or adverse fetal/maternal outcomes during pregnancy with the use of tirbanibulin.⁴ However, extremely high doses were noted to cause birth defects in rats and rabbits (more than 70 and 159 times the recommended human dose, respectively).⁴

Regulatory Approval

The topical 1% ointment formulation of tirbanibulin was approved by the US FDA in December 2020 for the treatment of AKs on the face and scalp.⁷ One packet of ointment (250 mg) contains 2.5 mg (1%) of tirabanibulin.⁴ The medication is applied on the affected area of the face or scalp once a day for 5 consecutive days.⁴ Each packet will cover up to 25 cm² on the face or scalp and is disposed of after its one-time use.⁴

There are no contraindications listed in the FDA-approved prescribing information.⁴

Discussion

Compared to other older topical treatments for AKs, tirbanibulin demonstrates several advantages. Tirbanibulin effectively and completely cleared AK lesions with a 5-day application while demonstrating a favorable safety profile and long-term results. The most common AEs for tirbanibulin were mild and included erythema, flaking, pruritus and pain at the application site. Unlike most other topical treatments for AKs, severe local
reactions, including vesiculation or pustulation and erosion or ulceration, were infrequent.¹ The favorable tolerability is attributed to tirbanibulin mechanism of action in which it induces apoptosis rather than necrosis. Apoptosis is associated with little or no inflammation.¹⁰

Treatment adherence and patient satisfaction has shown to be significantly better with shorter duration topical treatments for AK.¹¹ Current first-line topical field therapies for AKs include 5-fluorouracil (5-FU), imiquimod, and diclofenac gel, all of which have unfavorable aspects undermining compliance and thus successful treatment (Table 1).¹² These therapies more frequently result in AEs, severe LSRs, and prolonged patient discomfort, at times necessitating a pause in treatment until the healthy skin has healed.¹² In addition, each requires an extended period of application ranging from 3-4 weeks to 8-12 weeks with more than one application daily and/or a second cycle.¹² Ingenol mebutate, a promising short duration (3-day) AK treatment, recently lost its first-line status after being discontinued in 2020 secondary to increased risk of skin malignancy.

A combination of 5% 5-FU cream plus 0.005% calcipotriol ointment has been used off-label to treat AKs with variable results.¹³ The evidence was based on a single center study using the combination topical treatment twice daily for 4 days applied to 25 cm² area.¹³ Twenty-seven percent of patients achieved complete clearance of AK lesions on the face, and <20% on the scalp at week 8.¹³ Severe erythema on the face was observed in 80% of patients.¹³

The incidence of recurrence with conventional treatments has ranged from 20% to 96%.¹ However, owing to the chronic nature of AKs, recurrence of lesions in sun-damaged areas is expected.¹ With tirbanibulin, 47% of patients with complete clearance experienced a recurrence at 1 year in the phase III trials. Despite the apparent benefits of tirbanibulin, no direct comparisons have been made with other AK treatments.¹ Ultimately, head-to-head studies will be needed to determine true superiority/inferiority.

Other uses of tirbanibulin are being explored. Phase I trials are underway in Taiwan to investigate its potential as a treatment for psoriasis.⁷ Tirbanibulin was noted to successfully eradicate periungual SCC in a patient that failed to clear with imiquimod 5% in combination with monthly cryotherapy, suggesting its potential as a nonsurgical therapeutic option for SCC.¹⁴

Conclusion

Early and effective treatment of AKs is important to prevent progression to SCC.⁴ Many topical treatments for AKs are often limited because of patient tolerability, treatment duration, and adherence. Tirbanibulin effectively and completely cleared AK lesions with a 5-day application period while demonstrating a favorable safety profile, mild AEs, improved tolerability, and long-term results, making it a promising field therapy for AKs.

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¹Division of Dermatology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Baywood Dermatology and CCA Medical Research, Ajax, ON, Canada
³Probity Medical Research, Waterloo, ON, Canada
⁴Dermatology on Bloor, Toronto ON, Canada
⁵Skin Centre for Dermatology, Peterborough, ON, Canada
⁶imc North America, Toronto, ON, Canada
⁷LEO Pharma Inc. Canada, Thornhill, ON, Canada

Conflict of interest:
D. Adam has been an investigator, speaker, or advisory board member for LEO Pharma, AbbVie, Amgen, Arcutis, Bausch Health, Boehringer Ingelheim, BMS, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, Incyte, Janssen, Merck, Novatrtis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB. S. Abdulla has been a speaker or advisory board member for LEO Pharma, AbbVie, Celgene, Eli Lilly, Galderma, Janssen, Novartis, Pfizer, Sanofi Genzyme, UCB, and Bausch/Valeant. P. Fleming has received honorarium and/or consulting and/or advisory boards and/or speaking fees for AbbVie, Altius, Aralez, Bausch Health, Cipher, Galderma, Eli Lilly, UCB, Janssen, Novartis, Pfizer, and Sanofi-Genzyme. M. Gooderham has been an investigator, speaker, or advisory board member for LEO Pharma, AbbVie, Amgen, Akros, Arcutis, Boehringer Ingelheim, BMS, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Janssen, Kyowa Kirin, Medimmune, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, UCB, and Bausch/Valeant. J. Ashkenas received support via imc North America (Toronto, ON) from LEO Pharma Inc. Canada for participating in the development of the practice reflective and for analyzing the findings. He has no other financial interest to declare. C. McCracken is employed by LEO Pharma Inc. Canada.

Abstract:
Patient preferences for psoriasis treatment may affect treatment adherence and disease control; changing topical formulation may improve adherence and patient acceptance of treatment. This study explored dermatologists’ reasons for transitioning psoriasis patients from an ointment or gel (Dovobet^®) formulation to an aerosol foam (Enstilar^®) formulation of calcipotriol and betamethasone dipropionate (Cal/BD), and to assess the success of this transition. Medical records of 81 Canadian patients from 9 dermatologists were retrospectively reviewed for symptoms affecting quality of life, reasons for transitioning treatment, and whether transition was successful. Reasons for transition included efficacy, quality of life, and patient adherence. At follow-up, median psoriasis severity and body surface area affected had decreased from baseline, and patients experienced improved quality of life. Itch and itch-related sleep loss, which were identified as burdensome in 63% of patients at baseline, had resolved in 33% and improved in 54% of patients at follow-up. Dermatologists deemed the transition successful in 85% of patients, with the most common reasons being patient-reported success, clearance of signs/symptoms, and continued prescription refills. Transition from Cal/BD ointment or gel to aerosol foam was generally deemed successful by patients and dermatologists, and was associated with improved quality of life and improved itch control.

Key Words:
psoriasis; topical treatment; foam; formulation; fixed combination

Introduction

Psoriasis is a chronic condition that commonly requires topical treatment, either as monotherapy or in combination with phototherapy or systemic treatment. Given the challenge of consistent long-term adherence to treatment for psoriasis,^1-3 patient acceptance of topical treatment is an important consideration.^4,5 Formulations with more appealing cosmetic features could affect patient acceptance, and therefore adherence and ultimately disease control.^6-9

Calcipotriol and betamethasone dipropionate (Cal/BD) are the active ingredients in Dovobet^® ointment or gel (Cal/BD ointment or gel) and Enstilar^® aerosol foam (Cal/BD foam). Cal/BD aerosol foam has improved skin penetration and is reported to be better accepted by patients, relative to Cal/BD ointment or gel.¹⁰ Switching to Cal/BD foam can improve disease control. Significantly more patients using Cal/BD foam achieved a 2-grade improvement according to the physician’s global assessment of disease severity, with their psoriasis being clear or almost clear, by week 4 compared with patients using Cal/BD gel by week 8 (38.3% vs. 22.5%, respectively; P < 0.001).^11,12 Given that the active ingredients are the same, comparisons between the products relate purely to formulation.

In this study, medical records of Canadian psoriasis patients who transitioned from Cal/BD ointment or gel to Cal/BD foam were examined retrospectively. The objective was to explore Canadian dermatologists’ reasons for changing topical treatment formulation in these patients and to assess reasons the transition was judged successful or unsuccessful. As patients on topical monotherapy may have different motivations for and success with treatment transition, compared with those receiving concomitant topical and non-topical therapies (i.e., systemic treatment or phototherapy), the study included patients from both populations.

Patients and Methods

In this retrospective chart review, 9 Canadian dermatologists reviewed the medical records of their patients with plaque psoriasis who were previously treated with Cal/BD ointment or gel and were switched to treatment with Cal/BD foam. The study protocol was approved by RRB (Research Review Board Inc., Waterloo, ON, Canada; approval # 2019.538). The need for informed consent was waived due to the retrospective design of the study.

The dermatologists reviewed the medical records from their 10 most recent patients meeting all inclusion criteria: ≥18 years of age, with active psoriasis, and transitioned from Cal/BD ointment or gel to Cal/BD foam at the baseline visit (defined as the visit where the change in treatment occurred). Patients could not have made any change in prescribed systemic treatment or phototherapy from 3 months before to 1 month after the switch to Cal/BD foam. Baseline findings were from the visit during which the dermatologist first prescribed Cal/BD aerosol foam. Follow-up data were from the first subsequent visit, no less than 4 weeks and no more than 32 weeks after the baseline visit.

Using the data collected from the medical records, the dermatologists completed an online questionnaire developed from a pilot study carried out by 3 authors of the current study. The pilot study sought to identify classes of data that could be reliably found in medical records for psoriasis patients seen in normal Canadian dermatology practice. Pilot study data were not included in the current report.

Demographic and clinical characteristics extracted from the baseline visit records included age, gender, symptoms affecting quality of life, the dermatologist’s reasons for transitioning the patient to Cal/BD foam, the number of clinic visits in the 12 months prior to baseline, and history of psoriasis therapies in the 24 months prior to baseline. Patients were considered to be on topical monotherapy if they were using Cal/BD ointment or gel with or without other prescription or non-prescription topical agents, but without systemic treatment or phototherapy. Conversely, patients were considered as on combination therapy if they were using Cal/BD ointment or gel concomitant with phototherapy or systemic therapy. Physicians submitted their findings for each patient electronically until they had completed 10 reports. After the seventh report of patients in one class of treatment (topical monotherapy or combination therapy), the physician received an automatic reminder that both classes should be represented among their 10 reports.

The dermatologist’s assessments of psoriasis severity, as noted in the medical records, for the patient’s lifetime worst severity, severity at baseline, and severity at follow-up, were reported in the questionnaire using a 5-point scale (0 = absent; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe). Estimated percent body surface area (BSA) affected by psoriasis was extracted from the baseline and follow-up visits. The dermatologist’s assessments of improvement in quality of life, the impact of Cal/BD foam on overall psoriasis disease and itch or itch-related sleep loss, and whether the transition to Cal/BD was successful, were extracted from the records of the follow-up visit. Improvement in quality of life was rated on a 4-point scale (0 = no improvement; 4 = significant improvement). The level of impact on overall psoriasis disease and itch or itch-related sleep loss was rated as ‘Worsened’, ‘Same’, ‘Improved’, or ‘Resolved’. Dermatologists were asked to identify one or more specific signs or symptoms with the greatest impact on quality of life. If the patient’s record did not include the relevant information, dermatologists indicated ‘Unknown/Not documented’.

Descriptive statistics were analyzed using Microsoft^® Excel for Mac version 16.40 and reported as mean ± standard deviation (SD), median (range), and proportions. Missing data were not imputed, and the results for each variable were reported based on the number of patients for whom data were available.

Results

Nine dermatologists completed questionnaires for 10 patients each. Of those 90 questionnaires, 9 were excluded, leaving 81 patient records for analysis. Reasons for exclusion were that insufficient data were included (n = 1), Cal/BD foam was not used between baseline and follow-up (n = 4), and the follow-up visit was not within the 4 to 32-week timeframe (n = 4).

Baseline demographic and clinical characteristics are shown in Table 1. More patients were on monotherapy than on combination therapy. Psoriasis at lifetime worst was less severe in patients on topical monotherapy vs. combination therapy. The most commonly affected body areas were the legs, arms, trunk, and scalp.

Complete data for psoriasis severity (at worst, at baseline, and at follow-up) were available for 72 patients (Figure 1); with the remainder missing data from at least one of those time points. In those patients with complete data, severity at worst was mild or moderate in 36 (50%) patients. At baseline and at follow-up, 53 (74%) patients and 62 (86%) patients, respectively, experienced mild or moderate disease.

Patients who had experienced severe, or very severe psoriasis at its worst, were more likely to be on combination therapy and had greater baseline psoriasis severity and BSA affected, relative to those with mild or moderate psoriasis at worst (Table 2). For patients with severe or very severe disease, scaling, itch or itch-related sleep loss, and redness were identified as the signs and symptoms with the greatest impact on the quality of life. Among patients with mild or moderate psoriasis at worst, itch or itch-related sleep loss had the greatest impact on the quality of life. Similarly, redness had the greatest impact on quality of life for 8 of 14 (57%) patients on combination therapy but 3 of 14 (21%) patients on monotherapy, whereas itch or itch-related sleep loss had the greatest impact in 10 of 14 (71%) patients on monotherapy but 7 of 14 (50%) patients on combination therapy.

The most common reasons cited for transitioning to Cal/BD foam were to improve clinical efficacy (74/81; 91%), quality of life (49/81; 61%), and treatment adherence (41/81; 51%). These reasons were ranked similarly for patients on monotherapy and on combination therapy (data not shown).

In patients for whom data were available at both baseline and follow-up, median psoriasis severity score (range) was 2.0 (1.0-4.0) at baseline and 1.0 (0.0-4.0) at follow-up. Median BSA was 4.0 (1.0-45.0) at baseline and 1.5 (0.0-25.0) at follow-up. The median and overall ranges for psoriasis severity and BSA were similar for patients on mono- and combination therapy. These findings were comparable across all 9 dermatologists’ patient sets.

At follow-up, quality of life as assessed by the investigator had improved for 79% and worsened for 4% of the 80 patients for whom quality of life data were reported (Figure 2A). Improvement was also experienced by 5/10 (50%) patients for whom stigma was reported as having a major impact on quality of life. Itch or itch-related sleep loss resolved in 33% and improved in 54% of patients overall (Figure 2B). Of note, very similar improvements were observed for both quality of life and itch/itch-related sleep loss measures in subsets of patients who cited those specific respective factors as the reason for seeking to transition. Overall, disease resolved in 16%, improved in 66%, and stayed the same in 15% but worsened in 3% of patients (n = 79) at the follow-up visit.

In each category of psoriasis severity at baseline, at least half of patients experienced improved quality of life, improved or resolved overall disease, and improved or resolved itch or itch-related sleep loss (Table 3). When grouped by baseline severity, the proportions of patients showing improved quality of life (mild: 15/17, 88%; moderate: 33/40, 83%; severe/very severe: 12/20, 60%) and improved itch or itch-related sleep loss (mild: 11/17, 65%; moderate: 20/40, 50%; severe: 11/20, 60%) were highest for the mild severity patients but roughly similar across groups; the study was not powered to draw any conclusions with respect to improvement according to baseline severity.

Transition was considered successful in 69 of 81 (85%) patients. Of the 12 patients for whom transition was deemed unsuccessful, 7 needed systemic treatment, including biologics (3 and 4 patients on monotherapy and combination therapy, respectively), and no improvement was seen in 2 (1 on monotherapy; 1 on combination therapy). In addition, 1 patient disliked the cosmetic features of the aerosol foam; for 2 patients, no reason was cited. The most common reasons cited for considering transition successful were that the patient reported success (40/69; 58%), signs and symptoms of psoriasis had cleared at follow-up (32/69; 46%), and the patient continued to fill prescriptions (22/69; 32%).

Discussion

In this retrospective chart review, the transition from a Cal/ BD ointment or gel formulation (Dovobet^®) to a Cal/BD foam formulation (Enstilar^®) was rated successful in most cases. The most common reason cited was patient-reported success, and most patients experienced improvement in the specific measure (e.g., itch or itch-related sleep loss) cited as a reason for wanting to transition. These findings are supported by results of a previous survey in which Canadian respondents generally rated Cal/BD foam as more pleasant cosmetically, relative to previously used topical products,^8,9 consistent with other data that foam products are well accepted relative to other formulations.⁶

Transition success in the current study did not appear related to whether the patient was on mono- vs. combination therapy, as similar benefits were found in both groups. These benefits included improvements in overall disease, quality of life, and itch and itch-related sleep loss.

Itch is a pervasive challenge for psoriasis management, and itch severity is broadly associated with clinical severity.¹³ In this population, itch or itch-related sleep loss was reported in all severity groups. Following transition to Cal/BD foam, most patients with mild disease at baseline, as well as approximately half of others, experienced improvement or resolution of itch or itch-related sleep loss. Resolution was reported at a similar rate in the overall population and in patients for whom itch control was identified as a reason for treatment change. Given the clear disease burden associated with itch, dermatologists should ask their patients about their experience of itch and itch-related sleep loss, regardless of overall disease severity, and they should consider a change of topical treatment regimen in those who are dissatisfied with their current level of itch control.

Strengths and Limitations

This was a retrospective chart review of individuals transitioning between topical formulations, namely Cal/BD ointment or gel, to Cal/BD foam. The population may not be fully representative of Canadian psoriasis patients under a dermatologist’s care, since it would be expected to disproportionately include patients who are unsatisfied with Cal/BD gel or ointment. Due to the absence of a control group, no firm conclusions can be drawn regarding changes in symptoms of psoriasis related to the use of Cal/BD foam. For similar reasons, the findings here may not be generalized to other topical formulation transitions, including other transitions to foam formulations.

Conversely, strengths of this study include the real-world setting of treatment and the fact that the questionnaire used was developed through a pilot study that helped ensure that sufficient data could be captured for most variables of interest. It is also reassuring to note that the 9 physicians reported similar levels of treatment success among their individual patient sets, suggesting that the questionnaire was reliable and transparent to the respondents.

Conclusion

The benefits of transitioning from Cal/BD ointment or gel to aerosol foam formulation in this Canadian patient population were similar to those reported in clinical studies and were seen consistently among patients with a range of treatment priorities and with differing history of psoriasis severity and treatment history. Changing the topical treatment formulation, even without a change in active ingredients, should be considered for patients who are dissatisfied with their current topical treatment, independent of their psoriasis severity.

Acknowledgements

The authors thank the dermatologists who participated in the survey, Alice Kowalczyk, PharmD (LEO Pharma Inc. Canada) and Kristel Bermejo, PhD (imc North America, integrated medhealth communication) for contributing to the study design, and Celeste Lavallee, MSc (imc North America, integrated medhealth communication) for contributing to the data analysis and writing the article.

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Acknowledgments and Disclosure: The authors disclosed receipt of the following financial support for the research, authorship, and publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada.

All authors contributed to the development of this work and its review and agreed with its content.

Introduction

Up to one out of two Canadians will develop cancer in their lifetime.¹ It has been estimated that 225,800 Canadians were diagnosed with cancer in 2021.¹

Approximately 30-40% of cancer patients receive radiotherapy.² A study in Ontario on breast, colorectal, lung, and prostate cancer showed that in the year following the cancer diagnosis, 96,003 patients received radiation therapy.²

Radiotherapy damages cancerous cells’ by directly or indirectly damaging their DNA via ionization and free-radical formation.^3-5 Radiation-induced cutaneous AEs occur in up to 95% of cancer patients who will develop some form of radiodermatitis (RD).^3-5 Of those with breast cancer, 87% develop RD, and concurrent anti-cancer therapies may aggravate RD in 90% of head and neck patients.^4,5

RD affects the area that received irradiation, and the severity depends on the area treated, beam energy, total dose, dose per fraction, treatment schedule, and use of concomitant systemic agents. RD varies considerably in severity, course, and prognosis and can have severe sequelae that impact the quality of life (QoL) and potentially alter cancer treatment course and outcomes.^3-7

Radiation treatment’s impact on QoL may be profound. A prospective study conducted from July 2017 to June 2018 using the Skindex-16 pre-and post-treatment included eighty-three cancer patients [breast cancer (49%), head and neck cancer (45%), and anal canal cancer (6%)] receiving radiation treatment.⁷ All patients developed RD [Grade 1 – 59%, Grade 2 – 33%, and Grade 3 – 8%].⁷ The median composite Skindex-16 pre-treatment was 0, and post-treatment 34, demonstrating a marked negative impact on QoL.⁷

RD is categorized as acute, occurring within 1 to 4 weeks of treatment, or chronic, manifesting beyond four weeks to years after treatment.⁴

Strategies to prevent or mitigate RD are aimed at ensuring an optimal skin condition starting before the treatment. Skincare aims to improve comfort during radiotherapy, reducing inflammation and promoting healing of skin areas affected by RD.^8-12 Patients should be educated on a daily skincare regime focusing on: hygiene, moisturization, and sun avoidance and protection measures.^8-13

The Canadian Skin Management in Oncology Group (CaSMO) developed an algorithm for the reduction of severity and management of acute RD, which follows previous publications from this group that addressed general oncology-treatment related cutaneous adverse events [AEs], prevention, and skin management.^8,13

Scope

The CaSMO project initiated by La-Roche Posay Canada aims to improve cancer patients’ and survivors’ quality of life by offering tools for preventing and managing cancer-treatment-related cutaneous AEs.

The CaSMO panel of clinicians who treat cancer patients with radiation treatment-related cutaneous AEs developed, discussed, and reached a consensus on an evidence-based algorithm supporting prevention, treatment, and maintenance using OTC skin care measures for acute RD. The algorithm focuses on skincare measures to prevent and treat RD using prevention measures and a skincare regime involving hygiene, moisturization, and sun protection measures and products. The algorithm aims to improve patient outcomes and determine the best approach for oncology skin care programs for all stakeholders in the Canadian health care setting. These include oncologists, family practice/internal medicine physicians, dermatologists, oncology nurses, advanced practice providers (APPs), nurse practitioners (NP), physician assistants and pharmacists.

Methods

In the algorithm’s development, the panel used a modified Delphi approach following the AGREE II instrument.^14,15 The modified Delphi method is a communication technique for interactive decision-making for medical projects.¹⁵ The used process was adapted from face-to-face meetings to a virtual meeting to discuss the outcome of literature searches and reach a consensus on the algorithm based on the selected literature.^15,16 The virtual discussion was followed by online follow-up replacing the use of a questionnaire.¹⁵ The process entailed preparing the project, selecting the panel, and conducting systematic literature searches followed by summarizing the literature search results, grading the literature, and drafting the algorithm. On January 23, 2021, a virtual panel meeting reviewed the systematic literature review results, discussed and adopted the algorithm using evidence coupled with the expert opinion and experience of the panel. The online process was to fine-tune the algorithm and to prepare and review the publication. (Figure 1)

The CaSMO working group’s consensus on the algorithm was established as a hundred percent agreement was obtained.

Literature Review

A literature review included guidelines, consensus papers, and publications describing current best-practice in radiation-treatment related to cutaneous AEs that benefit from topical treatment using OTC skincare, clinical, and other research studies in the English language from January 2010 to December 2020. Excluded were articles with no original data (unless a review was deemed relevant), articles not dealing with skincare for prevention and treatment of RD, and publication language other than English. A dermatologist and a physician/scientist conducted the searches on January 3 and 4, 2021, on PubMed and Google Scholar as a secondary source of the English-language literature, using the terms:

RD; skincare and topical regimes for prevention, treatment, and maintenance of RD; QoL of patients with RD; adjunctive skincare use; education of staff and patients; communication strategies; adherence; concordance; efficacy; safety; tolerability; skin irritation.

The results of the searches were evaluated independently by two reviewers, resolving discrepancies by discussion. The searches yielded one hundred and twenty-two publications. After excluding duplicates and articles deemed not relevant for the algorithm ([n = 52] other subjects, low quality, a small number, case studies), seventy papers remained. Twenty-five review articles (including one guideline, one algorithm and, eighteen systemic literature reviews), and forty-five were clinical studies (including eighteen randomized controlled trials, eighteen clinical evaluations, and cohort studies, four randomized trials, and five other).

Radiation Dermatitis, Prevention, and Treatment

The goal of radiation therapy is either curative or palliative.^3,4 It can be delivered in the neoadjuvant or adjuvant setting, or can be the main treatment, with or without combined systemic treatment.^3,4 The multidisciplinary team guiding the patient through the radiation treatment process comprises the radiation oncologist, the radiation oncology nurse, the radiation therapist, medical physicist, and dosimetrist.^3,4

Radiation therapy can be external [i.e. 3-D conformal radiation therapy, intensity-modulated radiation treatment, image-guided, Thomotherapy, and stereotactic radiosurgery] or internal, such as brachytherapy, radioisotope therapy, radioimmunotherapy, and radioembolization (Table 1).¹⁷ RD is defined as a cutaneous inflammatory reaction induced by exposure to biologically effective levels of ionizing radiation.¹⁷ The mechanisms associated with a radiation induced AE include an inflammatory response and oxidative stress, which interact and promote each other.¹⁸ Inflammatory markers involved in acute inflammation secondary to ionizing radiation including IL-1, IL-6, TNF-alpha and TGF-Beta, can be expressed within hours after receiving the first radiation treatment.¹⁸ Radiation treatment exhibits biological effects within hours to weeks of exposure, through irreversible breaks of the nuclear DNA strands that cause extensive genetic damage and inhibit cells’ ability to divide and replicate.^3,18 Further damage comprises structural tissue destruction, generation of reactive oxygen species, a decrease in functional stem cells, initiation of epidermal and dermal inflammation, and skin cell necrosis.^3,18 Radiation damage is complex, and a variety of factors influence its severity.

Table 1: External beam radiation therapy

RD is generally limited to the irradiated area and depends on several factors, including the target area, dose and fractionation schedule, patient’s condition, and the use of other concomitant cancer treatments (e.g. platinum-based regimens, cetuximab, 5-fluorouracil).^3,4-6,18-22

Intrinsic factors that influence the occurrence and severity of RD include demographic or patient-related characteristics.⁶ These include age, ethnic origin, skin type, smoking, obesity, breast size, hormonal status, presence of infection, and co-existing diseases, such as diabetes or cardiovascular disease.^6,17-22

Extrinsic factors include treatment-related characteristics such as technique, dose, volume, fractionation, beam energy, use of bolus, immobilization devices, and the use of combined systemic anti-cancer therapies. Further factors comprise the clinical site of treatment, e.g., areas with skin folds [head and neck, breast and axilla].^17-22

Certain drugs (e.g. platinum-based regimens, cetuximab, 5-fluorouracil) increase sensitivity to radiation treatment, causing increased cellular damage and delayed tissue repair.²² Conventional chemotherapy agents and cancer treatment with EGFR inhibitors increase the risk for severe RD (Box 1).^22,23

RD is categorized as acute, occurring within 1 to 4 weeks of radiation treatment, or chronic, manifesting beyond four weeks to years after treatment (Table 2).^3,4,6,18-23

Box 1: Contributing factors to radiodermatitis (RD)

Table 2: Acute and chronic radiation dermatitis²⁰

*Grades of Acute Dermatitis (CTCAE V5– common terminology criteria for adverse events (National Cancer Institute)¹⁹

Cutaneous effects of radiotherapy vary considerably in severity, course, and prognosis and can have severe sequelae that impact the quality of life and disrupt cancer treatment.^7,8 The two most prevalent grading systems of RD are the RTOG (Radiation Therapy Oncology Group) and CTCAE v5 (Common Terminology Criteria for Adverse Events) systems. The RTOG assessment tool classifies RD from 0 [no visible signs of RD] to 4 [ulceration, bleeding, necrosis].^20,21 For the present algorithm, the CTCAE v5 grading system for acute RD from the National Cancer Institute (NCI) is used. This tool has five classes from 1 [faint erythema and dry desquamation] to 5 [death] (Table 3).^19,22

Table 3: CTCAE and RTOG grading for acute RD

Division of Cancer Treatment & Diagnosis Dermatitis Radiation Grading (DCTD); Radiation Therapy Oncology Group (RTOG)
Grades of Acute Dermatitis (CTCAE – common terminology criteria for adverse events (National Cancer Institute)¹⁹
A-B – Grade 1 – faint erythema and dry desquamation
C-D – Grade 2 – moderate erythema and/or edema; patchy desquamation confined to folds
E-F – Grade 3 – moist desquamation in areas other than folds and bleeding from minor trauma
Grade 4 – Life-threatening consequences; full-thickness necrosis, spontaneous bleeding; skin graft indicated

Algorithm for the Prevention and Management of Acute Rd

The CaSMO algorithm for acute RD used the mnemonic RECUR (Reliable, Efficient, Clear instructions, Understandable, Remember easily).²⁴

A clinical algorithm’s function is to standardize and support medical decision-making, such as regulating the selection and use of treatment regimens, thereby improving adherence to evidence-based guidelines.¹⁴ The algorithms have inputs and outputs, precisely defined specific steps, and uniquely defined results that depend on the preceding steps.²⁴ The current algorithm for the prevention and management of acute RD focused on preventing or reducing and managing RD using OTC skincare and topical treatment (Figure 2). Detailed information on the various grades of RD is given in Figure 3.

The algorithm details measures to be taken before radiation treatment which include education, avoidance of skin irritants, preventative skincare, and sun avoidance and sunscreen use; it also describes prophylactic measures to be taken when radiation starts. Finally, it describes how treatment assessment of skin condition and grading of RD should take place during treatment while the preventative measures continue.

Each section is discussed in the order as they appear in the algorithm.

Grading	Prevention, skincare and treatment
Grade 1: Faint erythema or dry desquamation, possible pain	Check adherence to treatment. Cleanse the skin and use a moisturizer. Avoid sun exposure and use sunscreen. For dry desquamation start or continue with low to mid potency TCS to decrease progression and severity of itching, burning and irritation.3
Grade 2: Moderate to brisk erythema; Patchy moist desquamation mostly confined to skin folds and creases; Moderate edema, pain	Check adherence to treatment. Cleanse the skin and use a moisturizer. Avoid sun exposure and use sunscreen. Use saline compresses for cooling. Continue TCS in the surrounding area of moist desquamation
Grade 3: Moist desquamation in areas other than skin folds and creases; Bleeding induced by minor trauma or abrasion, severe pain	Check adherence to treatment. Cleanse the skin and use a moisturizer. Avoid sun exposure and discontinue sunscreen on irradiated area until the reaction is over. Use saline compresses on the areas with moist desquamation. Continue TCS in the surrounding area of moist desquamation Use a wound dressing for bullae and erosions, and select the type of dressing according to the wound bed condition and the exudate production. Consider putting radiation treatment on hold.

Figure 3: RD Treatment according to presentation

Grading according to CTCAE v5¹⁹

Education on Prevention and Treatment of RD

Education on the type of radiation treatment, on preventive and on treatment measures for RD is essential for both clinicians and patients.^13,25 Before starting the treatment, a therapeutic relationship with the patient should be built, supporting the patients’ active participation in their cancer treatment.¹³ As outlined in two previous publications by the CaSMO group, a detailed discussion between the patient, treating physician, and nurse or other team members includes explaining the radiation treatment protocol, potential side effects, hospital visits, diagnostic tests, management of AEs, and prophylactic and preventative measures.^8,13 It is recommended to provide the patients with details on who to contact in the early stages of RD to enable addressing the AEs as early as possible.^8,13 It is recommended to support education given to patients verbally by printed or online information (Box 2).^8,13

Education on general measures include avoiding skin irritants, products with an elevated pH (>7), scented products and temperature extremes.^8,13 Further skin trauma should be avoided such as the use of adhesive bandages and tape, rubbing, scratching and massaging the skin within the treatment area. The patient should be recommended to wear loose fitting cotton clothing which may help avoid traumatic shearing and friction injuries.

Patients should also be recommended to use electric shavers for hair removal. Wax or other depilatory creams and pre-shave liquids and aftershave are discouraged, as they can irritate the irradiated skin.

Patients should be asked not to shave the axilla if it is within the treatment field but may continue to use antiperspirants or deodorants during radiation therapy on dry intact skin.

Box 2: Resources and information

Sun Avoidance and Sun Protection

Patients should be educated on radiation treatment-induced photosensitivity which can result in symptoms such as severe sunburn, pruritus, erythema, or edema. It should be explained that phototoxicity may occur, primarily induced by UVA exposure.^8,13

Phototoxicity symptoms may appear on the exposed area within a few minutes to several hours after exposure to UV light.^3-5,8,13

Patients should be educated on sun avoidance as part of a healthy lifestyle, and the use of sun-protective clothing [e.g., brim hats and sunglasses].^8,13 During the course of radiation and while skin is healing the patient should keep the treatment field out of direct sunlight. ^3-5,8,13 After the skin has healed, it may be more sun sensitive and therefore requires diligent protection from sunlight and tanning beds should be avoided.^8,13

Most dermatologists recommend daily sunscreen of SPF 30 or higher, especially for sun-exposed areas. Special populations that are at higher risk for sun-induced toxicities and neoplasms are advised to avoid sun exposure by using para-aminobenzoic acid (PABA) free UVA and UVB protection as well as sun-protective clothing.^8,13 Sunscreen should be reapplied as needed (e.g. after swimming or heavy perspiration) (Box 3).

Patients may continue to swim in chlorinated pools but should rinse afterwards with a gentle cleanser followed by immediately applying a moisturizer. If RD has progressed beyond dry desquamation (CTCAE grade 1) swimming should be avoided.

Box 3: Information on photoprotection and sunscreen application

Assessment of Skin Condition

Upon presentation of a patient with RD, it is important to check the location, size of the affected area, erythema, dry desquamation, moist desquamation, exudate, signs of infection, and discomfort (burning, pruritus, pulling, tenderness, dryness, scaling, flaking, peeling).^3-5,8,13,19 Similarly, the healthcare provider should check for the presence of fever, pain, mucosal involvement and if there are significant blood laboratory abnormalities. The clinician must establish whether the AE is possibly dangerous or life threatening such as in the case of skin necrosis, ulceration of the full thickness dermis or spontaneous bleeding,^13,19 and seek urgent care via a dermatologist, or emergency room for these patients.^13,19 The patient must be asked about the duration of the AE and what products were used for cleansing, moisturizing, or dressings for erosions or bullae.^3-5,8,13,19

Finally, the impact of RD on the patients’ daily activities, sleeping, eating or drinking must be verified. In the context of the assessment, the date of the last radiation or chemotherapy treatment, as well as concurrent medication use (analgesic, antibiotic, antifungal) and efficacy must be verified.^3-5,13,19

Skincare Using Cleansers and Moisturizers

Skincare using OTC products comprises cleansers and moisturizers (Box 4).^8,13 Although evidence is lacking on the best choice of product, basic recommendations on supportive measures using OTC skincare are given in various cancer treatment guidelines and consensus papers (Table 4).^{3,9-13,22,23,25-33}

Box 4: Criteria and application of cleansers and moisturizers

Table 4: Systematic literature reviews, consensus papers, guidelines and algorithms

Rosenthal and colleagues recommended a treatment algorithm for RD that included basic hygiene measures using mild soap and lukewarm water.³ A consensus paper and skincare algorithm by the CaSMO group recommended a daily skincare regime focusing on: hygiene, moisturization, sun protection, and, if applicable, camouflage products.^8,13 They recommended to encourage patients to keep their skin moisturized using gentle products to prevent pruritus and xerosis.^8,13

The skincare formulations used for patients with RD should be safe, effective, free of additives, fragrances, perfumes, sensitizing agents, and should have a near physiologic stratum corneum (SC) pH.^8,13 To support adherence to the skincare regime, products should be cosmetically pleasant and easy to use.^8,13

Evidence levels of components of topical treatments is shown in Table 5.^{3,8,13,26-28,34-59} A systematic review³ of topical agents for the treatment of RD reported no benefits from formulations containing aloe vera²⁶, chamomile^3,37, ascorbic acid, pantothenic acid, and trolamine.⁴⁹ However, benefits or potential benefits were shown when using formulations containing hyaluronic acid (HA)^{27,28, 34,54} epidermal growth factor EGF3,^39,51 granulocyte-macrophage colony stimulating factor (GM-CSF), topical corticosteroids (TCS) 40-45 or statins.⁵⁸

Table 5: Evidence levels of components of topical treatments

Topical agents that have common ingredients known as soothing may be beneficial for the reduction of symptoms such as niacinamide, panthenol, squalene, glycerin, and allantoin.^8,13 A skincare kit including all the products needed may be easy to use for the patients supporting adherence to the regimen.^8,13 A thermal water containing skincare regime (La Roche-Posay) comprising two types of cleansers, a moisturizer, a healing baume, and an SPF50+ sunscreen was shown to be beneficial for RD prevention and treatment.⁸ The regimen was evaluated in two-hundred-fifty-three women with mostly stage I (International Union Against Cancer (UICC) /American Joint Committee on Cancer (AJCC)) breast cancer undergoing radiotherapy. The frequent users who daily used the total skincare regime showed significantly (p ≤ 0.0001) less severe RD than those who used parts of the skincare regimen infrequently.⁸

Contrary to the advice some cancer patients may receive when undergoing radiation treatment, skincare does not interfere with or increase the radiation dose to the skin and can be used in moderation before daily radiation treatments.⁶⁰ Even if applied shortly before radiation treatment, thin or moderately applied skincare may have minimal influence on skin radiation dose regardless of beam energy or beam incidence.⁶⁰ Patients are frequently concerned about toxic effects on the skin.^60,61 Allowing patients to apply skincare throughout their radiation treatment period will simplify patient instructions and reduce patient confusion and anxiety.^60,61 Allowing patients to apply skincare daily and liberally without restrictions on application timing is likely to improve patient quality of life and adherence to the prevention and management of cutaneous AEs using skincare.^60-62

Topical Pharmaceuticals

Topical corticosteroids (TCS) have anti-inflammatory effects and may be used for the prevention and treatment of RD.^{3,4,25,28,40-45,59} A meta-analysis confirmed that TCS, ranging from mild to potent, significantly prevented the incidence of wet desquamation and reduced the mean RD score.²⁸ Various studies confirmed the efficacy of mild TCS decreasing moist desquamation, lowering the incidence of severe RD and delaying time to development of grade three RD.^41-44 Extensive and inappropriate use especially of high potency TCS on the face, neck or genitalia can cause AEs including skin atrophy, permanent striae, hematomas and tearing of the skin, telangiectasia, hypertrichosis, local and systemic infections, and rarely adrenal suppression.^8,13

Although the efficacy of TCS is established in RD such as in breast cancer²⁸, it is currently under evaluation in head and neck cancer where the use of TCS is frequently associated with the onset of clinically relevant adverse events.^22,42,59 In particular, the prolonged use of TCS leads to skin atrophy, which may be particularly contraindicated in this condition.⁵⁹

Topical use of statins may be beneficial for RD as the product may display some anti-inflammatory, immunomodulatory, antioxidant, metabolic, and antibacterial properties.⁴⁸

Although topical trolamine (doxepin) is extensively used for the management of RD, its efficacy for RD has not been established.⁴⁹

Wound Healing Products

Wound healing products and barrier films are widely used, as well, in oncology for cracked skin, erosion, bullae and more severe RD healing by secondary intention. Depending on the wound bed condition and exudate levels, various dressings may be used, such as a foam dressing or a non-adherent wound contact layer, including silicone-coated dressings. The frequency of dressing changes depends on exudate level and are typically twice weekly. The evidence supporting the efficacy of various dressings is scarce. Silicone based agents may have anti-inflammatory properties and are available as a gel or as coated wound dressings.^35,36,46-48

Prophylactic topical antibiotics should be avoided to comply with antimicrobial stewardship preventing antibiotic resistance.

The Multidisciplinary Team

Prevention and treatment of RD is a multidisciplinary effort involving radiation oncologists, dermatologists, nurses, and advanced practitioners (APPs). Collaboration and an interprofessional approach between oncology and dermatology is effective in connecting cancer patients with dermatological care from the start of their radiation treatment through to completion.^8,13,63-68

Timely intervention by a radiation-oncologist or dermatologist trained in supportive dermatology for oncology patients is critical to preventing avoidable treatment interruptions.^8,13,63-68 Moreover, almost equally important is an oncology specialists’ ability to improve quality of life-related to RD and may be able to preserve cancer treatment through managing RD early.^8,13

Limitations

Statements used and recommendations given in the algorithm were based on a mix of data and expert opinion. While it is possible that alternatives for RD could exist, the recommendations are suggestions for best practice developed from a panel of expert clinicians that are supported by peer-reviewed literature.

A small panel of physicians developed the algorithm, representing a few centers, and did not include patients in the development. Although limited evidence was available to guide the development, the project will hopefully encourage more skincare studies to prevent, treat and maintain RD.

Conclusions

A multidisciplinary team treating and guiding the cancer patient who receives radiation treatment may improve cancer treatment tolerance. The CaSMO algorithm on acute radiation dermatitis and general preventive measures, including cleansers and moisturizers to prevent or reduce the severity of acute radiation dermatitis, may increase awareness and help improve cancer patient outcomes.