¹SKiN Centre for Dermatology Peterborough, ON, Canada
²Probity Medical Research, Peterborough, ON, Canada
³Queen’s University, Kingston, ON, Canada

Conflict of interest: MG has been an investigator, speaker and advisory board member for Arcutis.

Adapted from O’Toole A, Gooderham M. Topical Roflumilast for Plaque Psoriasis. Skin Therapy Lett. 2023 Sep;28(5):1-4. PMID: 37734074. Copyright 2023 by the Skincareguide.com Limited. Reprinted with permission.

PDF Download

Case Presentations

Case #1

A 62-year-old female postal carrier presents with a 15-year history of plaque psoriasis which involves her elbows, dorsal hands, under the breasts and on the forehead and around the ears, total body surface area (BSA) of 3.5%. She has used numerous topical agents over the years, but most recently was prescribed hydrocortisone valerate 0.2% cream and clotrimazole for under the breasts, off-label tacrolimus 0.1% ointment for the face and ears and betamethasone valerate/calcipotriol foam for the elbows and hands. She reports using the topicals ‘when needed’ and presents with ongoing plaques in all described areas. She does admit she should probably be more consistent, but she has a busy life. Her past medical history is significant for obesity and hypertension. Her work uniform is uncomfortable and does not cover the visible areas of psoriasis making her very self-conscious. She books an appointment to discuss other options.

Case #2

A 38-year-old mechanic has a 10-year history of moderate-to-severe plaque psoriasis which requires systemic therapy. He has tried and failed methotrexate and acitretin in the past, and more recently has had success with an interleukin (IL)-23 inhibiting biologic agent started by his dermatologist. His body psoriasis cleared with the biologic, but he continues to have fissured plaques on his hands which is painful and interferes with his ability to work. He has been prescribed potent topical corticosteroid products in the past, including combination products, but he reports they are greasy, and he’s concerned about using steroids long-term. You see him in follow up, and he asks you for any other solutions.

Introduction

Plaque psoriasis is a chronic inflammatory skin condition with an estimated prevalence of 3%¹ and is characterized by scaly plaques which can be red to violaceous depending on the background skin tone. Psoriasis most commonly presents on the extensor surfaces but can involve anywhere on the body, including the scalp, face, and intertriginous areas (groin, under breasts or pannus, axillae). Most cases of plaque psoriasis are mild to moderate in severity, where half of patients have a BSA ≤3%.¹ Psoriasis significantly impacts quality of life, with the majority of patients reporting a “large impact” on their everyday life, even in those with limited BSA involvement.² Impact on quality of life is greater with special site involvement (i.e., face, groin, palms/soles) compared to no special site involvement.³ Itch is considered the most bothersome symptom in plaque psoriasis by almost half of patients.^3,4

The mainstay of treatment is topical including steroids, vitamin D analogs, retinoids, and calcineurin inhibitors (used off label), whether used as monotherapy in mild to moderate disease or as concomitant therapy with systemic agents in moderate to severe disease. Current topical therapies have limitations, however, including messy or greasy texture, complex or timeconsuming application, local side effects, or perceived inefficacy, which can all lead to lack of adherence to treatment and poor outcomes.⁵

Pathophysiology of Psoriasis and Role of Phosphodiesterase-4

Psoriasis is a chronic inflammatory disease influenced by environmental, genetic, and immunologic factors, characterized by rapid keratinocyte proliferation. The enzyme phosphodiesterase-4 (PDE4) plays a crucial role in immune cell regulation, with elevated activity in psoriatic skin promoting inflammation.⁶ PDE4 inhibitors, such as oral apremilast for moderate to severe psoriasis and crisaborole ointment for mild to moderate atopic dermatitis, are approved for use. Roflumilast, a potent PDE4 inhibitor, increases cyclic AMP, thereby reducing pro-inflammatory mediators like IL-17, IL-23, IFN-gamma, and TNF-alpha, thus normalizing immune response and keratinocyte differentiation.⁷ Roflumilast has greater affinity for PDE4 than the other currently available PDE4 inhibitors; depending on the comparator and isoform analyzed, it is approximately 25-300 times more potent than apremilast and crisaborole.^7-9

Topical Roflumilast Cream

Topical roflumilast 0.3% cream (Zoryve^TM) was approved for the treatment of plaque psoriasis including intertriginous psoriasis in adolescents (aged ≥12 years) and adults by the FDA in July 2022 and by Health Canada in April 2023; In October 2023, the FDA approved the expanded indication to include children 6-11 years of age as well. It is uniquely formulated as an emollient water-based cream designed to deliver the roflumilast molecule throughout the epidermis without disrupting the skin’s barrier function. A unique and patented emulsifier blend (Crodafos^TM CES) maintains the integrity of the lipid bilayer while facilitating delivery of roflumilast. The formulation does not contain sensitizing or irritating ingredients such as propylene glycol or fragrance, resulting in improved tolerability (compared to some other topicals currently available). Topical roflumilast 0.3% cream is also found in higher concentrations in the skin compared to that expected with oral dosing, with levels 62- to 126-fold higher in the skin compared to plasma.¹⁰ Its lipophilic and protein-affinity properties allow it to form a reservoir in the stratum corneum, enabling prolonged release. With a long half-life of 4 days, it allows for once-daily dosing, ensuring high efficacy and improved tolerability.¹⁰

Clinical Trials: Efficacy and Safety of Roflumilast

Phase 1 and 2 trials

A Phase 1/2a randomized controlled trial (NCT03392168) tested roflumilast cream 0.5%, 0.15% vs. vehicle for 28 days in patients with ≤5% BSA.¹¹ The primary endpoint was met with significant improvement in the Target Plaque Severity Score (TPSS) x target plaque area (TPA) with roflumilast 0.5% (P = .0007) and 0.15% cream (P = .0011) vs. vehicle; 66%-67% improvement from baseline to week 4 was noted with roflumilast vs. 38% for vehicle.¹¹

In a Phase 2b randomized controlled trial (NCT03638258), 331 adult patients were randomized to receive roflumilast cream 0.3%, 0.15%, or vehicle once daily for 12 weeks. The primary endpoint at 6 weeks of an Investigator Global Assessment (IGA) score of clear or almost clear (0 or 1) was reached by 28% in the roflumilast 0.3% group (P < .001), 23% in the roflumilast 0.15% group (P = .004), and 8% in the vehicle group (Figure 1A). Important secondary endpoints included an intertriginous IGA (I-IGA) response (clear or almost clear and ≥2 grade improvement from baseline) in 73% of the roflumilast 0.3% group, 44% of the roflumilast 0.15% group, and 29% of the vehicle group in the subgroup of participants with at least mild IGA intertriginous involvement (~15% of trial population).¹² Itch and itch-related sleep loss were also improved in subjects receiving roflumilast. Subjects with a baseline worst itch numeric rating scale (WI-NRS) ≥6 treated with roflumilast 0.3% cream achieved ≥4-point improvement compared with vehicle, which was significant at all time points between week 2 and week 12 (all P < .05).¹³ The least squares mean improvement in itch-related sleep loss was statistically significant for both doses of roflumilast as early as week 6 and maintained through week 12.¹³

Phase 3 trials

Two identical pivotal Phase 3 trials, DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389), enrolled patients older than 2 years of age, with 2% to 20% BSA and an IGA of at least 2 (mild).¹⁴ A total of 439 and 442 subjects were enrolled (DERMIS-1 and DERMIS-2, respectively) and randomized to receive roflumilast cream 0.3% or vehicle. The primary endpoint was achieving IGA success (clear or almost clear [0 or 1] with ≥2 grade improvement from baseline) at 8 weeks. IGA success was achieved by participants receiving roflumilast 0.3% cream vs. vehicle by 42.4% and 6.1% (DERMIS-1) and by 37.5% and 6.9% (DERMIS-2), respectively (P < .001 for both) as shown in Figure 1B. Important secondary endpoints included I-IGA success at week 8, 75% improvement in Psoriasis Area and Severity Index (PASI75) at week 8, and itch improvement as measured by WI-NRS at weeks 2, 4, and 8. In participants with an I-IGA score of at least 2 at baseline (approximately 20% of trial population), I-IGA success at week 8 was achieved by 71.2% vs. 13.8% (DERMIS-1) and 68.1% vs. 18.5% (DERMIS-2) in roflumilast 0.3% cream vs. vehicle, respectively.¹⁴ The majority of patients achieving I-IGA success also achieved an I-IGA score of clear (0) with 63.5% vs. 10.3% (DERMIS-1) and 57.4% vs. 7.4% (DERMIS-2) (P < .001) clearing intertriginous areas with roflumilast 0.3% vs. vehicle, respectively. PASI75 was reached with roflumilast 0.3% vs. vehicle in 41.6% vs. 7.6% (P <.001) and 39% vs. 5.3% (P < .001) in DERMIS-1 and DERMIS-2, respectively. Itch, the most bothersome symptom of psoriasis, also improved in patients with a baseline WI-NRS score of ≥4 at baseline. WI-NRS reduction of at least 4 points from baseline was achieved as early as week 2 in 34.9% vs. 22% (DERMIS-1, P = .12) and 41.9% vs. 21.1% (DERMIS-2, P = .003) and at week 8 in 67.5% vs. 26.8% (DERMIS-1, P < .001) and 69.4% vs. 35.6% (DERMIS-2, P < .001).¹⁴

Topical roflumilast was well tolerated with rates of treatment emergent adverse effects (TEAEs) similar in both groups: DERMIS-1 (roflumilast: 25.2% and vehicle: 23.5%) and DERMIS-2 (roflumilast: 25.9% and vehicle: 18.9%).¹⁴ Less than 1% of patients in any group experienced a serious adverse event. Rates of discontinuation due to TEAEs were low and similar between groups. The most commonly reported TEAEs were headache and diarrhea consistent with the effects of oral PDE4 inhibition, but present at much lower rates than seen with oral agents. Diarrhea was mild to moderate and reported in 3.5% and 2.8% of participants receiving roflumilast in DERMIS-1 and DERMIS-2, respectively, compared to none in the vehicle group. No patients interrupted therapy or discontinued due to diarrhea.¹⁴ Headache was reported in 1% and 3.8% in the roflumilast groups and 1.3% and 0.7% in the vehicle groups. The cream was well tolerated with low rates of application site pain: DERMIS-1 (roflumilast: 0.7% and vehicle: 0.7%) and DERMIS-2 (roflumilast: 1.4% and vehicle: 0%). Investigator-rated tolerability was consistent with patient-rated tolerability, with 98- 99% of roflumilast patients and 98% of vehicle patients showing no signs of irritation and 99% of patients reporting ‘no or mild’ sensation with application when assessed at both weeks 4 and 8.¹⁴

Long-term Use of Topical Roflumilast

Long-term use of roflumilast was investigated in a 52-week open-label extension (OLE) of the Phase 2b study.¹⁵ There were two cohorts in the OLE: cohort 1 (n=230) was comprised of patients who completed the initial 12-week phase of the Phase 2b study (for a total of 64 weeks of therapy), and cohort 2 (n=102) had naïve patients with a diagnosis of at least mild psoriasis for a minimum of 6 months. The completion rate after 52 weeks was 73.5%, with low rates of discontinuation due to TEAEs or inefficacy, and the majority of discontinuations were due to withdrawal or loss of follow-up considering these trials were conducted during the COVID pandemic. The proportion of patients achieving IGA success was consistent over time, with 34.8% of cohort 1 patients and 39.5% of cohort 2 patients achieving IGA success with 64 weeks and 52 weeks of as-needed therapy, respectively. I-IGA success was achieved by 60% at week 12 and maintained by 66.7% of cohort 2 patients by week 52 but was not recorded in cohort 1 patients. Of the patients who achieved clear or almost clear skin during the open label portion, the mean durability of maintaining their response was 10 months.¹⁶ Topical roflumilast was well tolerated in the OLE, with the majority of TEAEs rated mild or moderate, 97% considered unrelated to treatment, and ≥97% showed no signs of irritation on physician assessment.¹⁵

Discussion

PDE4 inhibition with topical roflumilast is a promising nonsteroidal option for patients with plaque psoriasis of varying severities. Key data from the pivotal trials, DERMIS-1 and DERMIS-2, report IGA success in approximately 40% of study participants with psoriasis ranging from mild to severe. Results are supported by earlier phase studies measured at earlier time points. IGA success was noted as early as week 4, and responses were maintained to week 64 with as-needed use, suggesting that once a response is obtained, it can likely be sustained over time. Itch, the most bothersome symptom of plaque psoriasis, improved by 2 weeks (the first assessed time point) in all studies and itch improvement maintained over time. Itch-related sleep loss also improved compared to vehicle. Early responses such as itch and sleep improvement can encourage adherence to therapy and improve outcomes.

Given the spectrum of obstacles in the treatment of plaque psoriasis, including patient adherence and tolerance with topical therapies, as well as the management of itch and special sites (e.g., face and intertriginous areas), topical roflumilast appears to address these challenges. Individuals with psoriasis are often prescribed multiple topical medications to treat different skin areas, which contributes to a complicated treatment regimen and patient non-adherence. Topical roflumilast addresses this significant unmet need with its once-daily, non-steroidal and carefully designed vehicle that is appropriate for use on most body areas, avoiding the need for multiple prescriptions and simplifying the treatment regimen. A foam formulation is also being developed for use on the body and scalp.

The PASI75 responses noted with topical roflumilast were also comparable with a recent trial of oral apremilast for patients with mild to moderate psoriasis (ADVANCE trial, NCT03721172).¹⁷ With similar baseline characteristics (PASI 6-7, BSA 6-7% and the majority of patients with IGA 3 or moderate severity) in DERMIS-1/ DERMIS-2 and the ADVANCE trial, the proportion of patients achieving PASI75 were similar or better with roflumilast compared to oral apremilast. The comparability of a topical therapy demonstrating efficacy that is similar to or better than an oral PDE4 agent such as apremilast, can be explained by the properties of topical roflumilast, which include the lipophilicity and reservoir in the stratum corneum combined with the higher affinity of roflumilast for PDE4. In patients with mild to moderate psoriasis, topical roflumilast may potentially delay or even avoid the need for oral therapy by providing similar efficacy. The limitation will be patients with higher BSA where the risk of TEAEs, such as diarrhea, may be higher or those with psoriatic arthritis where a systemic therapy may be preferred.

Case Follow Up

Case #1 continued

After further discussion of options, this 62-year-old woman does not wish to start a systemic medication and would like to continue with topical therapy. For more effective control, she requires a more simplified treatment regimen and more education on how to use topical therapies effectively. Reducing the number of prescriptions and applications per day can simplify her busy life, so topical roflumilast 0.3% cream is one product that she can use on all areas of psoriasis once a day, making this convenient and easy for her. Alternatively, she could reduce her current regimen and use off-label tacrolimus 0.1% ointment twice daily on the face, ears, and body folds and the betamethasone dipropionate/calcipotriol foam once daily on the hands and elbows. Education on optimal use of these products is required to inform that they need to be continued until the skin is clear and then used as needed.

Case #2 continued

The 38-year-old male is looking for optimization of his current biologic therapy to improve the residual psoriasis on his hands and his preference is to not use steroids. Current options include: adding a non-steroidal, non-greasy, once-daily topical, such as roflumilast 0.3% cream; adding back an oral systemic medication such as acitretin in addition to his biologic; or increasing the frequency of his biologic injection. His preference is to try a new topical agent to avoid taking more systemic medication. After 4 months of follow up of using roflumilast 0.3% cream, his fissures have healed and his hands are almost clear. Not only does he feel better at work, but he has been able to re-join his softball league this year.

Conclusion

Targeting PDE4 with a highly selective inhibitor such as roflumilast is a proven effective strategy for the treatment of plaque psoriasis. Topical roflumilast cream 0.3%, already approved by Health Canada and the FDA for use in adolescents and adults, has demonstrated efficacy and tolerability. It is nonsteroidal, administered once daily, and highly potent, yet delivered in a cosmetically elegant formulation that is well tolerated by patients. It can be used on most body areas, including the sensitive intertriginous regions and face, making one product suitable for treating all areas of involvement. Topical roflumilast will offer patients and their health care providers a simple, convenient, safe, effective, and durable therapeutic option for the management of psoriasis.

¹Faculté de médecine, Université de Montréal, Montréal, Québec
²Division of Dermatology, McGill University, Montreal, Quebec

Conflicts of Interest: Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Other authors declare no competing financial interests.

Introduction

Human Papillomavirus (HPV) is the most common sexually transmitted disease. Its lifetime
prevalence is >75% and this rate continues to increase.¹ This virus infects keratinocytes and is primarily transmitted by skin-to-skin contact.²

Chronic HPV infection, especially from low-risk strains such as 6, 11, 42, 43, and 44, plays an important role in the pathogenesis of cutaneous warts.³ For example, HPV strains 6 and 11 are responsible for 90% of anogenital warts (condyloma acuminate).⁴ Warts can also be found in the mouth, throat, penis/vagina and elsewhere on the skin.⁵

While many HPV infections are asymptomatic⁶, some can result in malignancies. A classic example of this in the skin is represented by carcinoma cuniculatum, a rare form of squamous cell carcinoma (SCC) that often presents on feet in the setting of a longstanding exophytic plantar wart, several decades after the initial infection.⁷ High-risks strains with the potential to lead to cancer or squamous intraepithelial lesions include 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 70.³ The Canadian Cancer Society lists HPV as the fifth most preventable cause of cancer.⁸ However, this ranking likely underestimates the role of HPV in carcinogenesis since cutaneous SCCs, where HPV is recognized as a co-carcinogen, are not included in cancer statistics. Cutaneous SCCs and Basal Cell Carcinomas (BCCs), together called keratinocyte carcinomas, are the most common cancers with an estimated ~5.4 million new cases diagnosed every year in the United States alone.⁹

Notably, a high proportion of HPV-associated cancers are diagnosed in males.¹⁰ Since males are under-vaccinated and are increasingly disproportionately affected by certain HPV-associated cancers, namely oropharyngeal and penile cancers, current vaccination efforts should be refocused on male patients.^6,11-13 Effective vaccination protocols can help promote both physical health as well as mental health since male patients with HPV often encounter numerous psychosocial impacts secondary to their infection, namely depression, reduction in quality of life and sexual dysfunction.⁶

Male HPV Vaccination Statistics and Guidelines

HPV vaccination programs and guidelines have changed several times in the past decade, causing important gaps in vaccination rates between males vs. females. In 2007, the first Canadian vaccination program for school-aged females was implemented, and by 2010 all Canadian provinces had established vaccination programs for females.⁶ In Alberta, before the start of the vaccination program for school-aged males, 98.3% of vaccinated individuals were females.¹⁴ The first Canadian public vaccination program for males was launched in 2012, while national coverage for the vaccine was only established in 2017.⁶ In Ontario, even after the sex-neutral school vaccination programs were created, there was still a gap in HPV vaccination rates between males and females.⁶ Hence, most males remain unvaccinated for HPV, especially the middle age population, which is at risk of developing the aforementioned cancers in the future. One narrative review investigating reasons for suboptimal vaccination in males found that lack of information, the misconception that the virus only affects females, vaccine hesitancy, lack of recommendations from healthcare providers, costs and logistics all acted as barriers to vaccination.¹⁵

According to the National Advisory Committee on Immunization (NACI) of Canada, the HPV vaccine was previously only recommended for males ages 9 through 26 years to prevent anogenital warts and other HPV-associated cancers.¹⁶ However, now there is no age limit on receiving a quadrivalent or nonavalent HPV vaccine. While the vaccine before was not routinely recommended for males ages 27 to 45 years, the guidelines state that the vaccine may be administered to this age group if there is an ongoing risk of HPV exposure,⁶ for example, healthcare providers treating warts.¹⁷ Recent reports, however, strongly argued that this vaccine should be given to middle aged males.¹⁸ On the other hand, there is currently insufficient research to encourage HPV vaccination in males over 45 years of age.

Natural Immunity Post HPV Exposure in Males and Cancer Risks

There are important differences between males and females regarding their immune response to HPV. A study has shown that males are 4 to 10 times less likely to seroconvert after an HPV infection, regardless of the infected anatomic site.¹⁹ In fact, within 36 months after HPV DNA was detected as a result of an oral, anal or genital HPV infection (strains 6, 11, 16, 18), only 7.7% of men developed detectable serum HPV antibodies.¹⁹ In the same study, the seroconversion rate following a genital HPV 16 infection was only 4.1% in males compared to 60% in females.¹⁹ Further, the HPV in Men (HIM) study showed that healthy males do not have a reduced risk of subsequent HPV oral infection from natural HPV L1 antibodies (immunoglobulin G antibodies to the L1 capsid protein in serum) following an HPV infection, as it was previously thought.²⁰ Thus, these antibodies are not protective against future HPV infection and, unlike females, males are at risk of reinfection with the same HPV strain.²⁰ On the other hand, females’ existing antibodies confer partial immunity.¹⁹ As such, males acquire HPV infections at a steady rate.²¹ The prevalence of male genital HPV infections, which do not decrease with age (Figure 1), highlights the suboptimal natural immunity against HPV in males.

Importantly, in recent years the number of oropharyngeal SCC cancers has surpassed the number of cervical cancers caused by HPV. In fact, most of the oropharyngeal SCC cancer patients are males (Figure 2).²² Cervical cancer rates are declining, whereas oropharyngeal cancer rates in Canadian males are on the rise (Figure 3).¹² Anal cancer rates are also on the rise, while the incidence rates of penile and oral cancers, unfortunately, remain unchanged (Figure 3).^11-13

Some males are at a particularly higher risk for HPV-associated cancers. Males who have sex with males (MSM), especially MSM who have Human immunodeficiency virus (HIV), have higher rates of anal carcinoma.²³ Males who are solid organ transplant recipients also have higher rates of penile and anal cancer.²³ Additionally, there is currently no approved HPV DNA test for males in Canada.²⁴ In contrast, females who get a Pap test can be co-tested for HPV using a sample of cervical cells taken at the same visit.²⁵

Recommendations for Vaccinations Should Focus on Males and Health Care Professionals at Risk of HPV Exposure

Side Effects of Spironolactone

Taking into consideration the above important points, we recommend that all males at risk of exposure to HPV between the ages of 9 and 45 receive the vaccine. Sufficient data exists to update the current guidelines, which only recommend vaccination for males between the ages of 9 and 27.⁶ The recommended vaccine is HPV9 (GARDASIL^®9) a nonavalent vaccine that prevents HPV infections caused by strains 6, 11, 16, 18, 31, 33, 45, 52 and 58²⁶ and received in 2022 Health Canada approval for the prevention of oropharyngeal cancer and other head & neck cancers (along with the prevention of cervical, vulvar, vaginal and anal intraepithelial neoplasia) caused by HPV.²⁷ The nonavalent vaccine is preferred to the quadrivalent vaccine since it protects against a wider range of high-risk strains.²⁸

The effectiveness of the vaccine in males aged 27 to 45 is inferred from the efficiency data in females of the same age and by the immunogenicity data from the Mid-Adult-Aged Men (MAM) Trial.²⁹ The MAM Trial evaluating response to the quadrivalent vaccine showed a 100% seroconversion rate 6 months after vaccination in 150 males between the ages of 27 and 45.²⁸ Another study reported 95% seroconversion rate 28 weeks following the quadrivalent vaccine administered in males with HIV between the ages of 22 and 61.³⁰

The vaccine is also proven to be safe. In fact, a study demonstrating the safety profile of the quadrivalent HPV vaccine in adult men 27 to 45 years of age with HIV-1 found no grade 4 (life-threatening) or 5 (death) adverse events.²⁹ Most adverse events were of either mild or moderate intensity.²⁹ Given these promising results, the vaccine should be strongly recommended to unvaccinated males aged 27 to 45.

HPV Vaccination for Healthcare Professionals

HPV vaccination is also recommended to all physicians, nurses and residents in obstetrics and gynecology, oncology, dermatology and any staff that treat patients with warts.³¹ HPV DNA was found in the vapour of 62% and 57% of plantar warts treated with ablative laser and electrocautery, respectively.³² Normal non-lesioned skin was shown to contain in >60% of cases pathogenic HPV strains.³³ Hence, use of cautery on normal skin can too produce plume with HPV particles. This poses an occupational risk for dermatologists and other health care providers,¹⁷ which is why the vaccine is highly recommended in this group. In addition, reports indicate that (1) using local exhaust ventilation, (2) general room ventilation and (3) full personal protective equipment including a fit tested particulate respirator of at least N95 grade can decrease operator from HPV inhalation exposure.³⁴ Another study mentions that even though protective equipment, mainly gloves, can get contaminated with HPV, transmissions to medical professional is less likely to occur if the equipment is disposed of properly.³⁵

Conclusion

While the incidence of cervical cancer is decreasing in females, the incidence of oropharyngeal and other HPV-driven cancers is increasing at an alarming rate, especially in males. As such, vaccination efforts should be aimed at addressing this important public health concern. Males are significantly under-vaccinated compared to females and acquire HPV infections at a steady rate, with a very low rate of seroconversion following infection. Therefore, we advocate to provide routine vaccination against HPV in all males between the ages of 27 and 45, and continue to actively vaccinate males ages 9 to 26. Vaccines are effective, as shown by the high rate of post-vaccination seroconversion, which is an important factor in preventing oropharyngeal SCCs and other HPV-related cancers. Finally, it is crucial to routinely promote the HPV vaccination for all patients and healthcare professionals at risk of exposure to HPV, the same way we promote sun safety for all.

Introduction

Acne is a common chronic inflammatory disease of the pilosebaceous unit. It can cause physical disfigurement and scarring and is also associated with depression, anxiety and social isolation.¹ Although its prevalence is highest in adolescence, acne often persists into adulthood, especially in women. More than 50% of women in their 20s and 35% in their 30s experience acne.² Given that long-term treatment is frequently required, topical therapy plays a pivotal role in its management. Topical retinoids are recommended as first line therapy for most acne patients by evidence-based guidelines in the US, Europe and Canada.^3-5 Although utilization of retinoids has increased over time, a claims-based study of data obtained from a large US database indicated that of all patients seen by a dermatologist for acne, only 59% were prescribed either an oral or topical retinoid. Nondermatologist physicians prescribed a retinoid to 32% of acne patients.⁶ Retinoid use is limited in part due to their tendency to cause irritation of the skin.⁷ Novel retinoid formulations may improve tolerability and increase use.

Background

Topical retinoids target multiple pathophysiologic processes that contribute to acne. They decrease follicular occlusion and hence comedone and microcomedone formation. Retinoids also have anti-inflammatory effects.⁸ In addition, they may improve acne indirectly by enhancing penetration of other topicals, reducing postinflammatory hyperpigmentation, and improving acne scarring.⁷

Four topical retinoids have been approved by the United States Food and Drug Administration (FDA) for the treatment of acne: adapalene, tazarotene, and trifarotene. Studies comparing the efficacy and tolerability of tretinoin, adapalene and tazarotene have shown mixed results.^9-12 Whereas some of these studies have shown comparable efficacy and tolerability, others have shown greater efficacy but lower tolerability with tazarotene 0.1% cream, gel or foam. Studies comparing trifarotene to other topical retinoids have not yet been published.

Tazarotene 0.1% cream, gel and foam are FDA approved for the treatment of acne, initially in 1997. Although effective, cutaneous irritation has limited their clinical use.¹³ In an effort to improve tolerability and maintain efficacy, tazarotene has been reformulated at a lower concentration into a non-greasy lotion vehicle. Tazarotene 0.045% lotion was approved for the treatment of acne for patients 9 years and older by the FDA in 2019 and by Health Canada for those 10 years and older in 2021. Health Canada recommends use only on the face in those 10 to <12 due to increased systemic absorption in this age group. This new formulation utilizes polymeric emulsion technology, which encapsulates tazarotene within oil droplets along with moisturizing ingredients. These oil droplets are dispersed in an oil-in-water emulsion containing more hydrating ingredients that are trapped within a honeycomb matrix. This allows for a uniform distribution of tazarotene and moisturizing excipients on the skin, which should lead to more efficient drug delivery into the epidermis and reduced irritation.¹⁴

Phase 2 Data Comparing Different Formulations of Topical Tazarotene

A phase 2 multicenter, double-blind, randomized, vehicle-controlled study compared tazarotene 0.045% lotion and tazarotene 0.1% cream to their respective vehicles.15 A total of 210 patients 12 years and older were enrolled in the 12 week trial. Tazarotene 0.045% lotion showed statistically significant superiority in reducing both inflammatory and noninflammatory lesion counts compared to its vehicle. The mean percentage changes in inflammatory lesion counts from baseline to week 12 were 63.8% with tazarotene lotion versus 51.4% with vehicle, and in noninflammatory lesion counts 56.9% with tazarotene lotion versus 35.2% with vehicle. Tazarotene lotion showed a numerically greater reduction in both inflammatory and noninflammatory lesions than tazarotene cream but the differences were not statistically significant. Both formulations of tazarotene were well tolerated, although more treatment-related adverse effects were reported with tazarotene cream (5.6% versus 2.9%). The only treatment-related adverse effect with tazarotene lotion was application site pain, reported in 2 patients.

Phase 3 Data on the Efficacy and Safety of Tazarotene Lotion in the Treatment of Acne

Two phase 3 multicenter, double-blind, randomized, vehicle-controlled trials studied the efficacy, safety and tolerability of tazarotene 0.045% lotion in the treatment of acne.¹⁶ A total of 1614 subjects with moderate to severe facial acne who were 9 years or older were enrolled. Subjects were randomized 1:1 to receive tazarotene 0.045% lotion or vehicle once daily for 12 weeks. The co-primary efficacy endpoints were inflammatory and noninflammatory lesion counts and Evaluator Global Severity Score (EGSS). Treatment success was defined as a minimum 2-grade improvement in EGSS and achievement of either clear or almost clear.

Tazarotene 0.045% lotion showed statistically significant superiority to vehicle in reducing both inflammatory and noninflammatory lesions in both trials (P<0.001). The mean percent reductions in inflammatory and noninflammatory lesions from baseline were 55.5% and 51.4% with tazarotene lotion in Study 1 (versus 45.7% and 41.5% with vehicle) and 59.5% and 60.0% with tazarotene lotion in Study 2 (versus 49.0% and 41.6% with vehicle)(Figure 1 and 2). Tazarotene lotion was also significantly more likely than vehicle to achieve treatment success (P<0.001). Treatment success was achieved by 25.5% in Study 1 and 29.6% in Study 2 of subjects treated with tazarotene lotion, compared with 13.0% and 17.3% receiving vehicle in the respective studies.

Treatment-related adverse effects were reported in 11.3% (88/779) of subjects receiving tazarotene lotion. The most common were application site pain (5.3%), dryness (3.6%), exfoliation (2.1%) and erythema (1.8%). Most adverse effects were mild, peaked at week 2 and returned to baseline by week 12. The authors commented that application site reactions were less common than those reported previously with tazarotene 0.1% gel, cream and foam, which may be due to the formulation of the lotion and its lower concentration of tazarotene.

Sensitization and Tolerability Studies

In two phase 1 dermal safety studies of tazarotene lotion conducted in healthy adults, no participants developed dermal sensitization.¹⁷ Likewise, no cases of allergic contact dermatitis were reported in tazarotene-treated subjects in the phase 2 and 3 trials. In the phase 1 cumulative irritation patch test study which compared tazarotene 0.045% lotion to vehicle lotion, saline solution, and sodium lauryl sulfate (SLS), tazarotene lotion was deemed to be “slightly irritating”. Although the mean irritation score for tazarotene lotion was statistically greater than that of the SLS positive control, this was felt to be due to the exaggerated dosing conditions employed. The authors commented that the cumulative irritancy score for tazarotene 0.045% lotion was less than half of those reported previously in other studies with tazarotene 0.1% gel, cream and foam.

Clinical Use

Tazarotene is contraindicated in pregnancy. Although pharmacokinetic studies show low systemic exposure with use of topical tazarotene, exposure levels that could lead to teratogenicity in humans are unknown and there is currently very limited data regarding pregnancy outcomes after in utero exposure.¹⁸

As with all topical retinoids, topical tazarotene may increase sun sensitivity and sun protection is recommended with its use. Concomitant application of oxidizing agents such as benzoyl peroxide is not recommended to avoid potential degradation of the retinoid.¹⁹

When prescribing a topical retinoid, it is important to counsel patients on strategies to minimize irritation including:

• Use of mild cleansers
• Use of small amounts of retinoid
• Starting with every other day use and increasing to daily use if tolerated
• Applying a moisturizer before or after use

Conclusions

Topical retinoids are recommended as first line therapy for most patients with acne. Despite strong data supporting their pivotal role in acne management, topical retinods continue to be underutilized. An important reason for this underuse is irritation. Although comparative studies have shown similar or better efficacy of tazarotene compared to other retinoids, higher rates of irritation have limited the use of older formulations of topical tazarotene. Tazarotene 0.045% lotion is a novel formulation that utilizes polymeric emulsion technology to improve tolerability and epidermal penetration. Despite the lower concentration of tazarotene in the lotion formulation, which likely also contributes to improved tolerability, tazarotene 0.045% lotion is at least as effective as tazarotene 0.1% cream. Given its effectiveness and improved tolerability, tazarotene 0.045% lotion is a useful addition to our armamentarium of topical retinoids for the treatment of acne.

Professor of Dermatology, Western University, London ON, Canada
President, Guenther Research Inc., London ON, Canada

Conflict of interest:
Dr. Guenther has been a consultant, speaker, and clinical investigator for Bausch Health.

Introduction

A fixed combination halobetasol propionate and tazarotene lotion was launched in Canada in 2020, to treat moderate to severe plaque psoriasis in adults.¹ It contains the super-potent corticosteroid halobetasol propionate (HP) 0.01% and the retinoid (vitamin A derivative) tazarotene (TAZ) 0.045% (HP/TAZ) in a moisturizing base.¹ With the use of polymeric emulsion technology, there is uniform distribution of HP and TAZ and excipients on the skin and improved skin moisturization.² It is a once daily fixed combination lotion that does not drip. Unlike HP cream and ointment which have a 2-week limitation before re-evaluation,³ there is no maximum treatment duration with HP/TAZ lotion. The product is supplied in a 100 g aluminum tube which should last at least 2 weeks.¹ The lotion is hydrating and decreases transepidermal water loss.² The non-medicinal ingredients are: carbomer copolymer type B, carbomer homopolymer type A, diethyl sebacate, edetate disodium dihydrate, light mineral oil, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitan monooleate and sorbitol solution 70%.¹ HP/TAZ lotion should not be used in pregnancy or in women who may become pregnant since it contains the retinoid tazarotene and retinoids are teratogenic.¹

Background

Topical therapy is the mainstay of treatment for psoriasis. It is more convenient to apply one topical than two which may lead to improved adherence. Topical corticosteroids are most commonly applied, however psoriasis quickly relapses upon discontinuation and they may cause atrophy which is seen clinically as wrinkled or shiny skin.

TAZ is the only topical retinoid approved for use in psoriasis, however TAZ cream and gel are rarely used due to irritation. In an attempt to minimize irritation, TAZ is typically used with a topical corticosteroid.⁴ The once daily fixed combination HP/TAZ lotion is a convenient formulation that delivers TAZ and a topical corticosteroid.¹ TAZ reduces inflammation and keratinocyte hyperproliferation, and normalizes the abnormal differentiation seen in psoriasis.¹

In contrast to topical corticosteroids, improvement associated with TAZ therapy often persists after TAZ is stopped.⁵ Concomitant use of a mid- to higher-potency corticosteroid with tazarotene does not compromise the sustained posttreatment improvement seen with TAZ.⁶ In addition, use of a mid- to higher-potency corticosteroid with tazarotene halves the rate of burning compared to that seen with tazarotene and placebo.⁶ TAZ can also minimize corticosteroid induced atrophy. In a 4-week study, the corticosteroid diflorasone diacetate ointment decreased epidermal thickness by 43%, but when it was used with TAZ 0.1% gel, there was only a 28% reduction (p ≤ 0.003).⁷

Clinical Trials with HP/TAZ Lotion

The fixed combination HP/ TAZ lotion provides synergistic efficacy and greater efficacy than the individual ingredients.⁸ In a phase 2 multicenter, randomized, double-blind vehicle-controlled study, more participants in the HP/TAZ arm were clear/almost clear with a 2-grade or greater improvement in Investigator Global Assessment (IGA) after 8 weeks of treatment (52.5% vs. 33.3% with HP (p=0.033), 18.6% with TAZ (p<0.001), and 9.7% with vehicle (p<0.001).^8,9 Improvement was noted as early as week 2 (the first visit after baseline).¹⁰ Itching, dryness and burning/stinging also improved with HP/TAZ at week 2, to a similar degree to that seen with HP but greater degree than that seen with TAZ.¹⁰ The improvement with HP/TAZ at week 8 was maintained four weeks after treatment discontinuation.¹¹

In two phase 3 clinical trials, HP/TAZ was more efficacious than vehicle at week 2. After 8 weeks of therapy, 35.8% (study 1) and 45.3% (study 2) were clear/almost clear with at least a 2-grade improvement in IGA.¹²

HP/TAZ has been used in individuals with skin of colour. In a phase 3 clinical trial, a 58-year-old black man with post-inflammatory hyperpigmentation was almost clear after 4 weeks of treatment and after 8 weeks, the affected body surface area was one half that at baseline. During weeks 2-8, he developed hypopigmentation which resolved 4 weeks after treatment.¹³

A 1-year open-label phase 3 study involving 555 adults with moderate-to-severe psoriasis affecting 3-12% body surface area (BSA) showed that HP/TAZ can be safely used long-term. In this study, initially patients were treated once daily for 8 weeks, then as needed in 4-week intervals with a maximum of 24 weeks continuous treatment at any point in the study. If an IGA of clear/almost clear (treatment success) was achieved, treatment was discontinued, however if it was not, it was resumed. At some point in the study, 57.8% achieved treatment success.¹⁴ Persistence of improvement was noted in many individuals. After treatment discontinuation, 55.3% did not require retreatment for >4 weeks, 28.3% for >8 weeks, 19.5% for >12 weeks, and 12.4% for >16 weeks. More than half of participants had treatment-emergent adverse events (TEAEs) during the 1-year clinical trial, particularly during the first 12 weeks. Seven and one-half percent discontinued the clinical trial due to TEAEs. Mild to moderate application site dermatitis, pruritus, pain and irritation were the most common TEAEs. Skin atrophy led to study discontinuation in one individual and was noted in 0.5% at baseline, 1.7% at week 12, 1.4% at week 24 and 0% at week 52. Striae were noted in 1.1% at baseline, 1.3% at week 12, 0.8% at week 24 and 0.7% at week 52.

Application Counselling: Practical Tips to Optimize Treatment and Minimize Irritation (see Figure 1)

A thin coat, just enough to cover the psoriatic plaques, should be applied once daily, then gently rubbed in. Patients should be shown where the psoriasis lesions are and where they should apply HP/TAZ. Less frequent applications should be considered for patients with sensitive skin (e.g., 1-3 times a week initially), then increasing the frequency as tolerated. If HP/TAZ is to be applied after bathing, the patient should wait until the skin is completely dry before applying.

Remind patients that more medication is not better; more medication is more irritating. A thin coat is all that is required. The medication should not be applied to skin without psoriasis. The medication should be dry before putting on clothes to prevent spread to unaffected skin. 50 g (i.e. one half of a 100 g tube) is the maximum recommended weekly dose.¹

Healthcare providers should warn patients that irritation may occur particularly around the plaques. If this happens, before applying HP/TAZ, moisturizer should be applied either all over, OR just around psoriasis lesions and/or the frequency of application of HP/TAZ should be decreased to every 2-3 days until it settles.

Once psoriasis lesions have cleared, HP/TAZ should be discontinued. If the psoriasis lesions cannot be felt when the eyes are closed, it is time to stop. The medication should not be applied to: (1) sensitive areas such as the face, anogenital areas, and intertriginous areas (where two areas of skin touch or rub), (2) sites with erosions, ulcers, or fissures; and (3) skin with eczema. DO NOT use in pregnancy or in women who may become pregnant.¹

Conclusion

HP (a superpotent corticosteroid) /TAZ (a retinoid) is a convenient once daily fixed combination lotion for moderate to severe psoriasis. TAZ minimizes the atrophic potential of HP, and HP reduces the irritancy potential of TAZ. It has synergistic efficacy that is rapid and sustained. Intermittent treatment over 1 year is safe and efficacious. Application counselling improves tolerability and should be offered to all patients.

Charles W Lynde MD, FRCPC¹, James Bergman MD, FRCPC², Loretta Fiorillo MD³, Lyn Guenther MD, FRCPC⁴, Marissa Joseph MD, FRCPC, FAAD⁵, Jill Keddy-Grant MD⁶, Ian Landells MD, FRCPC⁷, Danielle Marcoux MD, FRCPC⁸, Catherine McCuaig MD, FRCPC⁹, Michele Ramien MD¹⁰, Wingfield Rehmus MD MPH FAAD¹¹

Introduction

Atopic dermatitis (AD) is a lifelong pruritic, inflammatory skin disease associated with altered immune function and epidermal barrier dysfunction.^1-3 The chronic and recurring cyclic waxing and waning nature of AD leads the patient to treatment fatigue and imposes a significant burden on both the patients’ and caregivers’ quality of life (QoL).¹ AD frequently appears early in childhood and affects over 20% of children and up to 3.5% of adults.^2,3 Measurements of the prevalence of AD can differ, and this variability can be impacted by geographic location, population studied, and definition of AD used. A Canadian study showed that the adult prevalence of AD is up to 3.5% and that AD may be more prevalent among First Nations populations.² This research further revealed that men were less affected than women and that AD decreases with age. Additionally, the study noted that the severity of AD varies per region.² In many countries, the prevalence of AD is on the rise, especially in young children from developing lower-income countries in South East Asia and Latin America.⁴ Although the role of race and ethnicity in the pathophysiology of AD remains unclear, a higher incidence of AD was observed in Black American children (17.3%) compared to White children (10.4%).⁴

The pathophysiology includes skin barrier defects, inflammatory cytokines, and immune abnormalities. ADs’ etiology is multifactorial and involves an incompletely understood interaction between genetic factors, immune system dysfunction, skin barrier disorders, genetic and environmental stressors.^5,6 Most of the patients with AD have mild disease; however, 10% – 20% of children with AD are categorized as severe, and these rates are slightly higher in adults.²

There is a need for a variety of therapeutics targeted to different levels of severity.^6,7 A treatment paradigm that recognizes that patients may oscillate between degrees of severity and integrates topical and systemic therapies may align more closely with clinical reality.^8,9 AD treatment is often challenging due to the disease itself, treatment fatigue, and patient/caregiver concerns. Patients and caregivers frequently have concerns about medication safety and adverse events (AEs) as well as the long-term use of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI).⁹ Crisaborole ointment is an effective and safe alternative to TCS and TCI.⁹ Sharing best clinical practice standards, addressing challenges in treatment application, and methods to improve patient adherence to therapy may improve treatment results.⁹

This paper aims to review best clinical practices in treating AD patients, explore optimal use of crisaborole in mild to moderate disease, and provide expert guidance for the real-world use of crisaborole ointment to improve patient outcomes. This papers’ target audience is general practitioners, pediatricians, pediatric dermatologists, and dermatologists who treat patients with AD.

Methods

The project used a modified Delphi communication technique for interactive decision-making for medical projects, adapted from face-to-face meetings to suit a virtual platform.^10-12 The meeting was virtually convened on May 8, 2021, and the expert panel consisted of eleven dermatologists, including nine pediatric dermatologists from diverse geographical regions within Canada, who commonly treat patients with AD. In preparation for the meeting, a literature review surrounding crisaborole for the treatment of mild-moderate AD was conducted, and the panel members were surveyed regarding the use of crisaborole ointment for the treatment of AD.

The literature review and the pre-meeting survey results were presented at the virtual meeting. During the meeting, the experts were divided into three breakout groups to discuss and adopt draft recommendations for the real-world use of crisaborole ointment that were prepared from the literature searches by CWL and AA. The three groups presented their adapted versions of the recommendations to the larger group following the breakout session. The adapted recommendations were then collated and edited if necessary. The panel then voted and adopted the recommendations using evidence coupled with expert opinion based on the clinical experience of the advisors. The meeting summary and subsequent review of the manuscript were performed online (Figure 1).

Literature Review

Searches for English-language literature [2015– 2020] took place on April 14, 2021, on PubMed and Google Scholar as a secondary source. The data gathered by the literature review prioritized clinical studies published on the use of crisaborole, articles describing the current best practice in AD, and the most recent clinical guidelines, consensus papers and, algorithms. Excluded were duplications, articles of insufficient quality [small sample size, flawed methodology], and the most recent reviews were used in the case of review articles.

The searches yielded sixty-two papers deemed clinically relevant to current best practices of crisaborole use in AD. After removing duplicates and articles of insufficient quality, thirty publications remained: Four on epidemiology, ten reviews, three consensus papers and algorithms, four guidelines, five clinical studies, and four systematic reviews, meta-analyses, or posthoc analyses.

Results

The literature review indicated that the guidelines, algorithms, and consensus papers for topical AD treatment had not changed significantly over the past decade apart from adding crisaborole ointment and removing the black box for topical calcineurin inhibitor (TCI) treatment.^{7-9, 13-21}

A consensus paper and algorithm that explored the need for practical solutions to improve AD care was developed and published by the authors’ panel.⁸ The consensus statements and algorithm for topical treatment and maintenance of AD were integrated into the panels’ recommendations presented in this publication.

The DERMA (D: Diagnosis/Distribution; E: Education/Emollients; R: Red/Itchy; M: Medication/Maintenance; A: Assessment /Adherence) AD Algorithm targets a broad base of health care professionals treating patients with AD. The consensus statements and DERMA AD algorithm for topical treatment and maintenance of AD reflected current practice and were integrated into the panels’ recommendations (Figure 2).

Clinical Evidence of Crisaborole

Crisaborole is a small molecule, anti-inflammatory nonsteroidal PDE4-I inhibitor for the treatment of AD, which has demonstrated safety and efficacy in patients with mild-to-moderate AD.^22-30 Two percent crisaborole ointment was first approved by the American Food and Drug Administration (FDA) in December 2016 and then in 2018 by Health Canada for mild-to-moderate AD patients aged 2 years and over and in March 2020 (USA) and May 2021 (Canada) for patients aged 3 months and over.²⁵

The efficacy and safety studies on crisaborole used various clinical assessment scales such as Investigator Static Global Assessment (ISGA), Atopic Dermatitis Severity Index (ADSI), Eczema Area, and Severity Index (EASI) score, and Patient-Oriented Eczema Measure (POEM).

A randomized, double-blind, intra-patient controlled study (for the first 14 days) was continued as an open-label study applying crisaborole to all lesions. The study, including 40 patients of 18 years-old and older, demonstrated significant changes from baseline in crisaborole-treated lesions, ISGA, and pruritus NRS improvement from day fifteen assessment onwards.²³ The study also showed normalization of the genomic skin profile (approximated normal skin), inhibition of inflammatory genes known to be induced through degradation of cAMP by PDE4, and reduction in epidermal hyperplasia and TEWL.²³

The safety and efficacy of crisaborole treatment over 28 days were shown in two identical randomized, double-blind, vehicle-controlled studies including 1,522 patients with mild-to-moderate AD of 2 years and over.²² Significantly more patients treated with crisaborole than vehicle reached the primary endpoint (ISGA: clear, almost clear) than those treated with the vehicle at day 29 assessment.²² A long-term, open-label, single-arm 48 weeks safety study that included 517 patients of 2 years and over showed similar safety results as in a previous study that included adult AD patients.^22,24 In the long-term open-label study, nine patients (1.7%) withdrew due to AEs such as a stinging sensation after applying the ointment.²⁴ Another phase four open-label, single-arm study on 137 infants aged 3 months to less than 24 months of age demonstrated that crisaborole is safe and effective. ISGA of clear or almost clear was achieved at day 29 assessment by 30.2% of patients.²⁵ The study further indicated that improvements exceeded the minimal clinically significant difference in total POEM score at day eight and day twenty-nine.²⁵ The POEM subscale data further revealed improved sleep and pruritus, markedly improving patients’ and their caregivers’ quality of life.²⁵ Crisaborole yielded a rapid and statistically significant reduction in pruritus within four days.^26-28 Notably, in two vehicle-controlled studies, the vehicle effect on pruritus was considerable.^26,28

A pooled analysis of four studies of mild-to-moderate AD patients demonstrated efficacy and local tolerability of crisaborole treatment. After crisaborole use, most patients had mild to no pruritus from the first assessment through the remainder of treatment.²⁷

In a further study, treatment with crisaborole resulted in a marked improvement in QoL for patients and their parents, caregivers, and families.²⁸

A post hoc analysis of 2 phase 3 studies showed the effectiveness of crisaborole compared to the vehicle in significantly alleviating mild-to-moderate AD severity (per ADSI), and percentage of body surface area (%BSA) affected.²⁹

Finally, a systematic literature review and network meta-analysis comparing efficacy and safety profiles of crisaborole ointment, 2%, versus other topical treatments for mild-to-moderate AD showed crisaborole was superior to vehicle and pimecrolimus 1% cream, and comparable to tacrolimus, 0.1% or 0.03% ointments, concerning ISGA 0/1 at 28-42 days.³⁰ Additionally, the systematic review showed that the AEs rates for application site burning/stinging were much higher for TCIs than for crisaborole.³⁰ The studies included different patients, and endpoints varied, so comparative assessment of medications from this meta-analysis is difficult. Head to head comparative studies are needed to see objective scientifically-grounded efficacy comparison.

Crisaborole works better for mild than moderate disease, where it provides a faster reduction of pruritus and other AD symptoms relieve.^9,25-30 Crisaborole is not typically used with TCI due to potential irritation, but the combination may be suitable for steroid-phobic patients and those at high risk of sequelae.⁹

It is advisable to avoid crisaborole application on significantly flared skin due to possible irritation. Crisaborole ointment can be beneficial for dermatitis of the hands and feet due to the potential for deeper penetration into inflamed, thicker lichenified skin as a result of the smaller molecular size of crisaborole. There appears to be less irritation of the hands and feet, and the good safety profile of crisaborole justifies application in infants and children.^9,25-30

Statements and Recommendations

Statement 1: Atopic dermatitis (AD) is a lifelong inflammatory skin condition associated with epidermal barrier dysfunction and altered immune function. When AD is not controlled by behavioral measures such as skincare and avoidance of triggers, treatments such as TCS, TCI, and more recently, PDE4-I should be considered. It is important to use topical agents in conjunction with moisturizers and gentle cleansers.

The complex multifactorial pathogenesis of AD includes genetic and environmental factors.⁵ The skin barrier in AD is dysfunctional, and this defective skin barrier leads to water loss from the skin and the ingress of irritants, pathogens and allergens resulting in further inflammation.⁷ As the dysfunctional barrier at baseline is further disrupted, an inflammatory immune response is upregulated, which further disrupts the barrier leading to a feedback loop.^6,31,5,6

AD presents clinically as recurrent scaly erythematous and pruritic papules and plaques of skin with varying severity. This morphology, in addition to pruritus and family history of atopy, are important diagnostic criteria.^7,32 Specific signs of AD include oozing, scaling, crusting, erythema, edema, and lichenification, which, together with the body surface area involved and the impairment of daily activities, help determine AD severity (Figure 3-5).
Most patients with AD present with mild disease and can be adequately treated with frequent moisturization and topical therapy such as TCS, TCI, or crisaborole.^{3,5,7,8,12-21}

Educating patients and caregivers about the condition, avoiding triggers, and daily skincare regime, including gentle cleansers and moisturizers, is a vital part of the approach.^{7-9, 13-21}

AD is a chronic disease, and as a result, adherence to therapy is a major obstacle. Education and patient support and can improve adherence and, in turn, outcomes. It is important to remember that AD education is not a one-and-done phenomenon. Ongoing reinforcement of the treatment plan and goals is needed. Clinicians need to explain the condition, the rationale for treatment, optimal treatment use, and demonstrate the application process in their office.^8,9 During the detailed conversation, solicit the patients’ or caregivers’ input and questions to enable their active role in the process.⁹ This will help manage expectations, adherence to treatment, and maintenance of the lifelong chronic disease.⁹ Actions to improve patient adherence with treatment include detailed but easy to follow information and options to revisit the information by reading materials or trusted websites (Box 1).^8,9,15,19

Box 1: Patient and caregivers information and education about crisaborole

Statement 2: Crisaborole, 1% ointment, is a nonsteroidal anti-inflammatory PDE4-I with demonstrated efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any body site. It may be especially beneficial for:

• Sensitive areas prone to thinning from TCS such as the face, intertriginous areas, and genitals
• Hand, feet, palms, and soles, where the small molecular size may allow potential deeper penetration

A previous publication by the panel reviewed various cases that reflect real-world clinical use of crisaborole aimed to clarify its optimal use as monotherapy, combination therapy, sequential therapy, and maintenance therapy.⁹ Crisaborole can provide a good and safe alternative to TCS and TCI, such as in cases of steroid or TCI avoidance, and can be used in mild-to-moderate AD patients from 3 months of age upwards.²⁵

The case studies discussed in the article suggested that crisaborole treatment was effective and well-tolerated for pediatric AD of the face, hands, and feet of infants, toddlers, young children, and adults where therapy with TCS or TCI had failed.⁹ One of the cases was a 5-year-old boy with moderate-to-severe AD of his hands that was painful and severely impacting daily activities, such as playing and interacting with other children. After eight weeks of crisaborole use, his hand palms and wrists involvement had almost entirely cleared.⁹

The advisors recommend that the smaller molecular size of crisaborole may allow better penetration into the skin to the site of inflammation.⁹ The advisors also indicated that there might be a cumulative effect of adding crisaborole for hands and feet that can benefit from its optimal penetration as part of a combination regimen with TCS and TCI in moderate-to-severe AD cases.⁹

Statement 3: Crisaborole may be used as a first-line topical agent and is also a good choice when previous treatment has yielded suboptimal results when TCS side effects constitute a significant concern, and in the case of TCS/TCI phobia.

TCS and TCI hesitancy exists among all cultures and likely contribute to AD treatment failure.³³ Widely available biased unreliable, and inaccurate sources of information about eczema and topical therapies such as TCS and TCI are not helpful for AD patients and hinder physicians ability to educate and treat appropriately.³³ Clinicians must inquire about and if present must thoroughly discuss the patients and caregivers’ concerns about TCS and TCI and emphasize that these treatments are vital and, if used appropriately, safe and effective.^{5,7,8,9,12-21} Providing the patient with trusted websites can give balanced information, thus addressing the issues that are adding to patients concerns, especially in those with TCS and TCI phobia.^15,19

If patients or caregivers continue to have safety concerns surrounding TCS/TCI treatment, then crisaborole can offer a safe alternative even in infants as young as three months of age.²⁵ In this situation, offering a safe and effective alternative to TCS or TCI may improve treatment adherence and patient outcomes.⁹

Statement 4: When starting topical therapies such as crisaborole, consider the following:

• Test the patients’ tolerability with a sample before a prescription to determine the degree of stinging
• Avoid its initial use on severely inflamed or open areas of skin
• Limit its use to areas less likely to sting/burn
• Use the product in combination with a refrigerated moisturizer

The recommendations are supported by the advisors’ clinical experience⁹, a post hoc analysis of 2 phase 3 studies²⁹, and a systematic literature review comparing efficacy and safety profiles of crisaborole and other topical treatments in mild-to-moderate AD.³⁰ Crisaborole is used in mild-to-moderate AD, but it is best to avoid application on severely inflamed and open areas if possible to minimize stinging.^29,30

Testing the patients’ tolerability in-office before prescribing crisaborole provides an opportunity to teach the patient about the appropriate application of the medication and identifies the uncommon patient who has more prominent stinging and thus may not tolerate the medication. The application also helps to identify the patient who has mild discomfort. Proper education and guidance can minimize the symptoms and allow then to get past the short-term symptom. Application in the office and identifying these subgroups will instill greater confidence in the medication and make it more likely that the prescription will be filled and utilized rather than abandoned after one application.

Improved knowledge about the central roles a defective skin barrier and dry skin may play in AD increasingly recognizes the benefits of daily and ongoing use of mild cleansers and moisturizers.³⁴ The use of a gentle cleanser that employs advanced vehicles with a near-physiologic pH (4.0–6.0) may help maintain skin barrier function by optimizing skin surface pH levels.³⁴ Utilizing moisturizers to optimize the barrier decreases water loss, decreases inflammation, and improves the skin’s barrier and natural moisturizing factors. Moisturizers that contain skin lipids such as ceramides have shown benefits over standard emollients when used for AD patients.³⁵

In an algorithm for South and East Asian AD patients, moisturizers were included as a standard measure when using topical treatments for AD, such as pimecrolimus.³⁶ A refrigerated moisturizer used in combination with crisaborole ointment may prevent irritation, burning, or stinging.⁹

Statement 5: TCS, TCIs, and PDE4-I may induce application site pain such as burning and stinging. Information and education on measures to prevent or treat these side-effects, such as testing/limiting application sites and concomitant use of a refrigerated moisturizer, can help optimize results and decrease skin irritation.

Few AEs such as irritation, burning, and stinging were reported in clinical studies using crisaborole but seem to be occurring more frequently in clinical practice.^16,9

Clinical trials report stinging or burning occurring in up to 8%, but the symptoms are usually transient, and 1.7% of patients withdrew due to these symptoms. In practice, clinicians have anecdotally noted that the rate of stinging seems to be greater than that reported in clinical trials, but generally, the stinging is mild and transient.^16,9 Topical medications can sting due to the stabilizers and preservatives in the vehicle cream or due to the medication itself. TCIs can sting, and this stinging is often correlated to the degree of inflammation in the area. Clinicians often apply TCS initially to calm down the AD, after which the TCI is better tolerated. Whether this technique applies to crisaborole is not clear but should be answered by future reports/ studies.^8,9

Before starting crisaborole therapy, inform and educate the patient and caregiver on measures that may prevent or quickly resolve irritation, burning, or stinging if it occurs.⁹ Best practice tips of the panel include the use of crisaborole with daily skincare, such as a gentle cleanser and a refrigerated moisturizer.⁹ Apply a patient age-appropriate regimen and patient education.⁹ Identifying patients prone to skin irritation may benefit from an in-office trial with a sample before prescribing the ointment.

Survey Results

A pre-meeting survey was conducted among the panel to share best practice standards and clinical pearls they use in prescribing crisaborole to mild-to-moderate AD patients. All eleven advisors completed the survey. Demographics, number of visits of AD patients, the severity of AD, and treatment are shown in Table 1. When asked: If Crisaborole is not your first choice, indicate why not? stinging (63% [7]), burning (40% [4]) and costs (91% [10]) were frequently mentioned. Six physicians also answered crisaborole was not used for other reasons, which included: Lack of payer coverage, Need to be off-flare to initiate the treatment to get a good response, It is not as effective and does not work as quickly as TCS or TCI, Other medications are effective and more readily available and with which there is more clinical experience. The advisors noted to specifically use crisaborole for various body locations such as the face (72% [8]), hands (91% [10]), eyelids (55% [6]), intertriginous areas (63% [7]), genitals (63% [7]), and feet (81% [9]). According to the advisors, they hypothesize that the small molecular size of crisaborole appears to allow better penetration on areas with thicker skin.

Table 1: Pre-meeting survey results
N=11
Topical corticosteroid (TCS), atopic dermatitis (AD)

When asked the main reasons to prescribe crisaborole, all (100% [11]) answered that there is a need for a nonsteroidal alternative. Other answers included TCS phobia (91% [10]) and TCI phobia (63% [7]) and suboptimal results with previous therapy (63% [7]).

When stinging or burning occurred with crisaborole use, the advisors discontinued the treatment more frequently in children than adults. For preventing and managing AEs, the advisors provided education before starting crisaborole treatment. Some tested patients’ tolerability to the treatment in the office prior to a prescription to determine the degree of stinging. Further, they recommended measures to reduce stinging, such as concomitant use of a gentle cleanser and refrigerated moisturizer, cooling the ointment in the fridge, and concomitant TCS or TCI use (Figure 6). Finally, the advisors agreed to avoid the application of crisaborole on severely flaring skin.

When asked about the patients’ response to crisaborole treatment within four weeks, forty percent of responders noted that on average, 20-50% of patients had improved, and 50% of the panel noted an improvement in over 50% of their patients (Figure 7 and 8).

Limitations

Measures to reduce burning and stinging that may occur when using crisaborole were developed using the authors’ expert opinion and clinical experience, and further studies are needed to support the possible benefits of these measures.

Conclusions

The review explored best clinical practices of crisaborole for mild to moderate AD patients and provided expert guidance for the real-world use of crisaborole ointment.

Atopic dermatitis is a common chronic inflammatory disorder in which patients experience a waxing and waning disease state that is punctuated by episodes of flares. If their disease is quiescent, then the patient continues good skincare by utilizing moisturizers and avoiding irritants. Patients will escalate and add topical medications at the first sign of a flare. Since every patient has a distinct disease course, some patients may never be fully clear while others clear between episodes. Recognition that patients with AD have a disease that often varies in severity and location on their body allows physicians to choose the appropriate treatments based on their clinical experience. The physician needs to educate their patient to escalate therapy accordingly at the first sign of disease in order to prevent severe flares. An eczema treatment plan is a necessity to ensure a smooth transition of therapy from baseline to flare. For mild to moderate AD patients, three topical options can be prescribed to control inflammation. Traditionally these medications have been divided into first and second-line therapy. However, the expert panel believes that the choice of a specific agent should be decided by the clinician based on factors such as disease severity, location, physician experience with the product, cost, and patient preference.

Crisaborole is a nonsteroidal PDE4-I with demonstrated safety and efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any cutaneous non-mucosal body site. It may be especially beneficial for areas with thicker skin, such as hands and feet, possibly due to improved penetration to the site of inflammation as a result of its small molecular size. There are no concerning serious safety signals associated with crisaborole. Crisaborole does cause a burning sensation in 8% of patients, but this is usually transient and may be minimized by the concomitant application of cool moisturizers. Consideration of in-clinic test site application of crisaborole to high-risk individuals may help identify those at risk and allow patient education, which may decrease the side effect and in turn improve adherence and outcome.

Introduction

Psoriasis vulgaris (PsO) is a common immune-directed disorder that affects approximately 1 million Canadians.¹ Spontaneous, durable remission is rare, and patients and physicians should expect PsO to persist throughout life, with unpredictable periods of improvement or flares/exacerbations.²

Psoriasis can be difficult to manage; daily treatment application may be challenging despite the proven efficacy and safety of topical formulations. Randomized clinical trials have demonstrated that topical aerosol foam therapy offers patients a combination of higher efficacy and better patient acceptability, with easier application to enhance patient adherence. In a small real-world patient case review study, dermatologists tested the efficacy, safety and patient preference of Enstilar^®, a calcipotriol-betamethasone dipropionate (Cal/BD) aerosol foam, in patients with moderate-to-severe scalp PsO or mild-to-severe plaque PsO on the body, who had previously used Cal/BD gel and/or ointment formulations with sub-optimal response. Cases included in this article were selected prospectively from patients presenting at Winnipeg, Manitoba area dermatology practices.

Background

• Plaque PsO is distinguished by the presence of red, erythematous plaques, usually covered with silver, flaking scales, with a tendency to be itchy or painful; depending on their extent and location.²
• Overall, the prevalence of PsO has been estimated to be about 2%;^3–5 In 2015, an Ontario study identified a PsO prevalence of 2.5% for individuals aged ≥20 years of age.⁶
• PsO is a chronic inflammatory skin disease that requires ongoing, lifelong care,⁷ with a burden of disease that extends far beyond the physical dermatological symptoms. Indeed, PsO has an impact on physical and mental function as well as health-related quality of life (HRQoL) similar to that of cancer, arthritis, hypertension, heart disease, diabetes, and depression.^8–13
• Clinical trial and real-world evidence indicate that psoriatic patients have high rates of depression and anxiety, challenges at work, and difficulties with interpersonal relationships and intimacy.^14,15
• PsO is associated with a large socioeconomic burden including loss of productivity,^5,16–18 and cost of treatment may be significant. Treatments are broadly categorized into three main types: topical treatments, phototherapy, and systemic medications.^1,25 For patients with more severe PsO, the treatment costs associated with biologic agents are considerably higher than costs associated with topical therapies.^5,16,19
• A reliable assessment of PsO requires the use of several independent simultaneous evaluations to minimize the subjective perceptions of physicians.²⁰ Two assessments for severity (Psoriasis Area and Severity Index [PASI] and Body Surface Area [BSA]), and one for impact on quality of life (Dermatology Life Quality Index [DLQI]) were used during the collection of cases as presented here. PASI is evaluated on a scale of 0 (no disease) to 72 (very severe disease) and examines extent of disease and severity by three measures (redness, induration, scaling).^21,22 BSA ranges from 0-100% with less than 3% being considered mild, 3-10% being moderate, and greater than 10% considered severe.²³ DLQI is a short, 10 question survey that covers impact on quality of life and ranges from 0 (no impact) to 30 (extremely large impact).²⁴
• Data supports that about 75% of patients with moderate-to-severe plaque psoriasis manage their disease with topical therapies, either alone or in combination with other modalities,²⁶ which may lead to quicker treatment fatigue as a daily topical treatment regimen can be cumbersome and time consuming.³ There is considerable evidence from clinical trials that dermatology patients commonly self-undertreat, while inflating their reported use of the assigned treatment.^27,28
• Evidence suggests that changes in drug formulation may make patients more willing to use the treatment as instructed, leading to a sudden dramatic increase in treatment effectiveness.²
• Cal/BD aerosol foam (Enstilar^®) is indicated for the topical treatment of psoriasis vulgaris in adults for up to 4 weeks. This fixed dose Cal/BD combination is formulated as a pressurized aerosol foam, comprised of an emollient vehicle base and the active ingredients dissolved in a mixture of volatile propellants. The propellants evaporate rapidly after spray application, creating a stable solution of active ingredients on the skin; this formulation leads to greater skin penetration of the active ingredients.²⁹

Patient Case Review

Cases included in this review were selected prospectively from patients presenting at Winnipeg, Manitoba area dermatology practices. Patients reviewed presented with moderate-to-severe scalp PsO or mild-to-severe plaque PsO on the body and all had previously tried and did not obtain optimal results using the Cal/BD gel and/or ointment formulations. Following baseline assessment, patients were prescribed Cal/BD aerosol foam and then returned in four weeks for follow-up assessment.

Case 1

A 41-year old female had scalp, body and face PsO for 12 years, with significant impact on HRQoL.

Patient treatment history included very potent topical steroids, coal tar (for 5 or more years), fluocinolone acetonide (5 years of therapy), Cal/BD gel/ointment (5 years of treatment). At the time of the baseline visit the patient had been using Cal/BD gel with limited success.

Physical examination revealed psoriasis on both elbows and on the face and scalp around both left and right ears (Figure 1) and on both elbows (Figure 2). The estimated body surface area (BSA) was 5 to 9.9%, with PASI score of 8.8. The Dermatology Life Quality index (DLQI) score was 14, suggesting a significant impact on quality of life (QoL) for this patient.

Although the patient was eligible for treatment using systemic therapy, she preferred topical therapy due to personal preferences and financial considerations. The patient was prescribed 1 can (60 g) of Cal/BD aerosol foam to apply to arms, face/neck and scalp, continuing to use the product until the plaques were clear.

Following 4-weeks of treatment, the patient had used less than 1 can of product. BSA was reduced to <5%, and PASI decreased to 1.4. The DLQI was markedly improved with a 10-point reduction to 4 (a small impact on the patient’s HRQoL). The patient expressed high satisfaction with the treatment, reporting improvement in itch and overall disease. She described the treatment as cool and moisturizing, and felt the product was superior to all other topicals she had previously tried.

Case 2

A 31-year old woman had PsO affecting the scalp, knees and elbows for 3 years. She had been treated with various topical treatments including Cal/BD gel, very potent topical corticosteroids, as well as liberal and longstanding use of moisturizing gels.

Physical examination identified psoriatic lesions on both left and right elbows (Figure 3) and both left and right knees (Figure 4). PASI was calculated as 4, with a BSA estimated to be less than 5%. The DLQI score was 8, indicating moderate impact on QoL. The patient was prescribed Cal/BD aerosol foam (1 can of 60 g) and instructed to use the product for 4 weeks or until the plaques were visually clear.

At the 4-week follow-up assessment, the patient reported using the foam product only intermittently, with lapses when she forgot to apply the product as directed. Despite these lapses, she experienced marked improvement including resolution of her psoriasis, with only post-inflammatory changes remaining in some areas. PASI was reduced to 1.2 and DLQI score was reduced by 5 to a final score of 3. The patient expressed high satisfaction with Cal/BD aerosol foam, reporting both improved disease and improved itch.

Discussion

• These cases provide real-world clinical data supporting the benefits of Cal/BD aerosol foam for patients with either long- or short-duration disease, who were unable to gain satisfactory response with other topical treatment. Improvements were noted for both the objective disease measures (i.e., PASI and BSA) as well as the more subjective measures (i.e., DLQI and symptom impact).
• Robust clinical evidence has demonstrated that the Cal/BD aerosol foam is an effective treatment for patients with PsO, with many healthcare providers prescribing the aerosol foam due to its clinical efficacy versus other formulations.³⁰ This efficacy has been demonstrated in several randomized phase II and III clinical trials, including a 4 week, head-to-head comparison of the aerosol foam and ointment in 376 patients, which demonstrated significantly improved treatment success (54.6% vs 43% (p < 0.05)).³¹ A phase III study in 463 patients demonstrated significantly higher treatment success rates following 4 weeks of treatment, with 38% of patients achieving treatment success when using the Cal/BD aerosol foam formulation compared with only 22% using the gel formulation at 8 weeks (p < 0.001).³²
• A pooled analysis of randomized phase II and III clinical trials demonstrated that Cal/BD aerosol foam has a positive benefit-risk profile for the treatment of psoriasis vulgaris; importantly, the superior efficacy versus Cal/BD ointment or the individual active ingredients, is not associated with poorer tolerability.³³
• Patient preference and acceptance of treatment is a strong indicator of adherence to the prescribed treatment regimen. Patient adherence to topical PsO therapy is generally low.³⁵ The high burden of treatment and the substantial effort required to maintain ongoing therapy often leads to treatment fatigue.³⁶ A recent survey of Canadian patients identifying attitudes towards PsO and their views regarding topical therapies found that patients were generally more satisfied with an aerosol foam formulation and more likely to use the product, which could lead to improved treatment outcomes.^37,38 Clinical data supports that the aerosol foam formulation is an appropriate topical therapy option for patients with PsO of any severity.³⁹ Aerosol foam vehicles were developed to address several needs beyond the effective delivery of active ingredients: ease of application over large areas; gentle application, and cosmetic factors (no greasy film on the skin, no greasy feeling).³⁶ Patients are typically more satisfied with the aerosol foam formulation than other formulations and vehicles used.⁴⁰ Both patients described in this clinical review expressed very high satisfaction with the treatment.
• There remains an inequity in the accessibility to the Cal/BD aerosol foam formulation between Canadian provinces. It has been added to formulary in most provinces, including Quebec, Ontario, Newfoundland and Labrador, Saskatchewan, Alberta, New Brunswick, and Nova Scotia, and Manitoba, as well as federally. British Columbia does not yet list the product in their formulary.

Conclusion

This patient case review provides real-world clinical practice data supporting the benefits of calcipotriol-betamethasone aerosol foam formulation.

Patients reported that the aerosol foam formulation was the preferred treatment they had used and they were very satisfied with their treatment outcomes. This demonstrates that there is a clear need for alternative topical formulations in patients with PsO.

Introduction

Topical retinoids have been used for almost half a century and remain a mainstay in the treatment of acne. They target two of the pathogenic processes in acne: The abnormal keratinization in the pilosebaceous apparatus and inflammation. They act on existing acne lesions and prevent new lesions by targeting the microcomedo and by reducing inflammation. Yet they are underutilized in the treatment acne among generalist physicians. A new topical retinoid, trifarotene, the first fourth-generation retinoid, is now available in Canada for the treatment of moderate facial and truncal acne. It selectively binds to the retinoic acid receptor (RAR)-γ making for an efficacious and safe new option and is the only topical acne therapy to have been rigorously studied in truncal acne.

Background

Acne is a chronic inflammatory skin disease that mostly affects teenagers and young adults and can lead to permanent physical and psychological scarring.

50 years after Kligman described the use of tretinoin in the treatment of acne¹, a new fourth-generation topical retinoid, trifarotene, is now available in Canada for the treatment of facial and truncal acne. It is a potent and selective RAR gamma agonist.

Though most patients present with facial acne, 50-60% of them are also afflicted with truncal acne.² Acne severity was found to have a higher correlation between chest and back acne than face/back or face/chest combinations. Recognition of truncal acne can be problematic as patients often fail to report it, making clinical evaluation of the trunk necessary in acne assessment. Despite the fact that patients may not report its presence, most of them are interested in treating it.³

The key pathogenic mechanisms involved in the production of acne include:

• Increased sebum production under androgen control
• Proliferation of Cutibacterium acnes (formerly Propionibacterium acnes)
• Abnormal keratinization in the pilosebaceous apparatus
• Inflammation mostly via innate immunity

Topical Retinoids

Topical retinoids are critical in the treatment of acne. They are recommended by acne guidelines to be used first line and in the maintenance of all forms of acne.^4,5 They are the cornerstone of acne treatment because of their comedolytic and anti-comedogenic effects which are brought about by their ability to modify cellular proliferation and differentiation, and because of their anti-inflammatory properties. Some of these anti-inflammatory activities include blocking inflammation via toll-like receptor-2, inhibiting neutrophil chemotaxis and blocking the AP-1 pathway, thus reducing the production of inflammatory cytokines.⁶ They also have other effects such as the prevention and reduction of acne scarring^7,8 and improvement of hyperpigmentation.^9,10

Retinoids are a group of compounds that resemble the Vitamin A molecule retinol. Their effects are mediated by two types of nuclear hormone receptors, the retinoid A receptors (RARs: alpha, beta and gamma) and the second receptor system, the retinoid X receptors (RXRs: alpha, beta and gamma).

The first-generation retinoids include tretinoin (retinoic acid) and isotretinoin; they bind all three retinoid A receptors: RAR-α, RAR-β and RAR-γ. The second-generation retinoids are not used in acne. The third-generation retinoids include adapalene and tazarotene; they selectively bind both RAR-β and RAR-γ. The only fourth-generation retinoid is trifarotene; it selectively binds to the retinoic acid receptor (RAR)-γ. RAR-γ is abundantly expressed in the skin¹¹ and is the most important receptor involved in epidermal differentiation.¹²

The different molecular structures of these retinoids and the different receptors they bind will affect their impact on acne. For instance, the third-generation retinoid adapalene was found to have more potent anti-inflammatory effects in vitro and in animal studies than the first-generation all-trans retinoic acid and 13-cis retinoic acid.¹³

Trifarotene

Trifarotene was designed for metabolic stability in the skin, while being rapidly metabolized in human liver microsomes with a halflife (t ½) of five minutes. It should result in low systemic levels, while retaining strong cutaneous activity. These properties are particularly important when treating large body surface areas such as the face, chest and back. In ex-vivo cultured human skin, trifarotene was three times more potent than tazarotene. In vivo, trifarotene eliminated almost all comedones from the classical retinoid-responsive rhino mouse model, with a dose ten times lower than that required for tazarotene. The rapid in vivo anti-pigmenting activity of trifarotene is another useful advantage of this molecule that may reduce the hyperpigmentation that is seen secondary to acne.¹⁴

Two multicentre, double-blind, randomized, vehicle-controlled, 12-week phase 3 trials were undertaken to study trifarotene.¹⁵ Of note, these were the first-ever large-scale randomized trials to simultaneously evaluate a topical therapy for facial and truncal acne treatment.

The study subjects, all of whom had moderate acne vulgaris on the face and trunk, ranged in age from 9 to 58 years, with a mean age of 19 years. They were randomized to once-daily application of trifarotene cream or its vehicle in the evening.

The primary efficacy end points on the face were achievement of Investigator Global Assessment (IGA) success as defined by a score of 0 or 1, meaning clear or almost clear, coupled with at least a 2-grade improvement from baseline to week 12. Another primary endpoint was the absolute reduction from baseline in facial inflammatory and non-inflammatory acne lesions. The secondary end points were similar but as applied to truncal acne from baseline to week 12. Safety was assessed through adverse events, local tolerability, vital signs, and routine laboratory testing results.

In both studies response rates were significantly better than in the vehicle-treated controls. For the 1214 patients treated with trifarotene and 1206 treated with vehicle, the week 12 facial success rates according to the IGA were 29.4% in the first trial and 42.3% in the second (vs 19.5% and 25.7% for vehicle [p < .001]). Trifarotene treatment also achieved significantly superior reductions in facial acne lesion counts in both studies, with statistical differences apparent as early as weeks one or two. With trifarotene treatment, the mean absolute inflammatory lesion counts were reduced by 19.0 and 24.2 in trial one and two respectively (vs by 15.4 and 18.7 with vehicle [p < .001]) and the mean absolute non-inflammatory lesion counts were reduced by 25.0 and 30.1 (vs by 17.9 and 21.6 with vehicle [p < .001]).

The rates of success with trifarotene at week 12 according to the truncal PGA (Physician’s Global Assessment) were 35.7% in the first trial and 42.6% in the second (vs 25.0% and 29.9%, respectively for vehicle [each p < .001]). In both trials, trifarotene was statistically significantly superior in reducing both inflammatory and non-inflammatory lesions on the trunk starting by week 4 in the first trial and by week 2 in the second. Rates of success on the trunk were statistically significant for trifarotene versus vehicle starting at week 8 in both trials.

Treatment-emergent adverse events leading to study discontinuation were low. They occurred in 1.9% of trifarotene-treated patients in one trial and 1% in the other. The typical adverse effects of retinoids include local skin irritation such as redness, peeling, dryness, stinging and burning.

Retinoid cutaneous reactions are typically dependent on concentration and formulation of the retinoid but more importantly may be related to the sensitivity of the patient’s skin.¹⁶ There are various strategies to improve retinoid tolerability. A clinical trial looking at four different regimens showed that adding a moisturizer to the treatment regime improved dryness and scaling while every other night application improved stinging and burning sensations as well as erythema.¹⁷

In the long-term safety study (52-week trial) trifarotene was found to be well tolerated and efficacious in moderate facial and truncal acne.¹⁸

Conclusions

Retinoids are essential in the treatment of acne, but they are generally under prescribed by physicians.¹⁹ There are many ways to improve the tolerability of topical retinoids, allowing the majority of acne sufferers access to this crucial therapy. The practice of altering treatment regimens has been shown to improve local tolerability, which may in turn improve overall adherence to treatment. Using these techniques to help patients tolerate the first 4-6 weeks of retinoid use will help patients stay with this most effective therapy.²⁰ Now Canadians will have a new fourth-generation topical retinoid, trifarotene, for the treatment of moderate facial and truncal acne.

Lynde Institute for Dermatology, Markham, ON, Canada

Introduction

Patients often seek natural approaches to treating skin disease. Colloidal oatmeal has been used for decades to improve atopic dermatitis and soothe other pruritic and xerotic dermatologic conditions.¹ Although initially developed because of historical use, data is growing supporting its myriad benefits.

Background

• Oats have long been used as treatment for skin disorders and to beautify the skin.
  • The oldest oat grains were found in Egypt around 2000 BC^2,3 and the nutritional value of oatmeal and its topical benefits have been recognized since Roman times.^2-4
  • Oats were introduced into North America in the 17^th century.²
• In 1945 a ready to use colloidal oatmeal for skin care became available.³
  • Colloidal oatmeal is produced by grinding fine granules of oatmeal and subsequently boiling it to extract the colloidal material.
  • A colloid is a substance microscopically dispersed evenly throughout another substance.
• Colloidal oatmeal was approved by the Food and Drug Administration (FDA) as a skin protectant agent for over-the-counter use in 2003.⁵
  • One approved listings is that it “temporarily protects and helps relieve minor skin irritation and itching”.⁵
• It is recognized as a natural health product skin protectant ingredient by Health Canada.⁶
• Atopic dermatitis (AD) is a common, chronic, pruritic skin condition with a high prevalence in children.
  • Although AD has a complex pathogenesis there is substantial evidence that a genetically impaired skin barrier plays a role in its development.^1,7,8
  • The defective barrier allows irritants and antigens to penetrate leading to inflammation.⁹
  • Decreased stratum corneum hydration also leads to skin inflammation.¹⁰
  • This leads to the itchy eczematous lesions of AD.
  • Thus, restoration of skin barrier and stratum corneum hydration, soothing of itch and reduction of inflammation are critical for improvement of AD and quality of life for the patient and their families.¹
  • Moisturization and barrier protection play a central role in the treatment of AD.
  • They are recommended as first line and adjunctive agents for the management of AD.^11,12

Oatmeal Properties

• Colloidal oatmeal has multiple properties that make it ideal for managing AD and other xerotic and pruritic skin conditions.
• The small particles of the oat proteins form an occlusive barrier, protecting the skin from external agents^1,13 and preventing moisture loss.
• It contains high concentrations of starches and beta-glucan that create an occlusive film and exhibit water-absorbing properties.¹⁴ It also has antioxidant (e.g. avenanthramides, vitamin E, ferulic acid, caffeic acid)^3,4,15 and anti-inflammatory properties.^16,17
• Aventhramides are phenolic compounds with potent anti-inflammatory activity, through inhibition of NF-KB in keratinocytes and inhibition of the release of the pro-inflammatory cytokine IL-8.¹⁸
  • The level of anti-inflammatory effect is similar to that of topical 1% hydrocortisone.¹⁸
  • Colloidal oatmeal can also act as a skin buffer, restoring the pH of the skin to normal.⁴

Efficacy

• The benefits of colloidal oatmeal have been known for decades and several studies as early as the 1950s have reported the hydrating, soothing, protective and anti-irritant properties in AD.^1,19-21
• In the study by Nebus et al.,²² twenty-five patients aged 12 to 60 years were enrolled in the 8-week study.
  • Inclusion criteria included mild to moderate AD with at least 5% body surface area (BSA).
  • They used a topical regimen of twice-daily oat-based occlusive cream and a once-daily oat-based body wash.
  • Patients were permitted to continue their topical prescription AD treatments, however, patients on systemic medications for their AD were excluded.

• The results demonstrated that daily use of the adjunctive oat-based regimen significantly improved AD outcomes at all time points compared to baseline: Investigators Global Assessment (IGA), Eczema Area and Severity Index (EASI), and itching. Dermatology Life Quality Index (DLQI) was significantly improved from baseline at weeks 4 and 8.
• Some patients became clear of eczema as early as week 2 of use and over 45% of patients were clear or almost clear by week 8.
• Safety assessments revealed the regimen was well tolerated and compatible with various topical prescription medications.
• In another study by Nebus et al.,²³ twenty-three babies and children (3 months to 5 years of age) were enrolled in a 4-week study.
  • Similarly, patients must have mild to moderate AD and at least 5% BSA involvement.
  • Patients applied an occlusive colloidal oatmeal cream twice daily on the entire body and a colloidal oatmeal-based glycerin cleanser for all routine bathing.
  • Patients could continue any topical prescription AD medication already in use but must discontinue any previous cleansers or moisturizers.
  • The oat-based regimen was well tolerated and significantly reduced itching by over 45% (mean) as early as week 2 of use.
  • IGA and EASI were significantly improved from baseline at both week 2 and 4.
  • Over 60% of patients were categorized as clear or almost clear by the end of the study.
  • Baby/Child Quality of Life Index was also significantly improved by week 4.
• In another clinical study,²⁴ 21 patients age 15 to 60 years with mild to moderate AD and at least 5% BSA were entered in this 14-day study.
  • Patients used the oatmeal-based body wash once daily and applied the oatmeal-based therapeutic cream to the body twice daily.
  • They were permitted to continue prescription topical treatments for AD.
  • Itching was significantly improved at weeks 1 and 2, with over 40% improvement in the mean itch score at week 1.
  • Investigator evaluations showed a significant improvement in the mean eczema severity score after 2 weeks of regimen use, with 62% of patients showing improvement from baseline.
• In a 6-week randomized, controlled study involving 173 infants under 12 months of age with moderate to severe AD, an emollient containing colloidal oatmeal was shown to reduce the use of topical steroids.²⁵
  • High-potency topical steroid usage significantly decreased by 42%
  • The SCORAD index, and infants’ and parents’ quality of life significantly improved (p < 0.0001) in both groups.

Microbiome

• The microbiome has been implicated in many different dramatological conditions.
• In AD the microbiome of lesional skin differs from that of non-lesional skin.²⁶
  • In lesional skin there tends to be less microbial diversity and we see this as lesions which are often colonized preferentially with staph aureus.
• A 14-day study with 65 adult subjects (mean age=34.5y) was conducted to look at the effects of a colloidal oatmeal cream versus a moisturizing lotion without oatmeal.²⁶
  • Subjects used assigned product to the body twice daily.
  • The study showed significant improvement in transepidermal water loss (TEWL), skin hydration as well as itch.
  • As expected, non-lesional skin had greater microbial diversity than lesional skin at both groups at baseline.
  • Over the course of the study, subjects treated with the oatmeal-based cream had increased microbial diversity of lesional skin that approached that of non-lesional skin.
  • This diversity was lost when the product was discontinued.
  • The product that did not contain oatmeal did not improve microbial diversity of lesional skin at any point during the study.

Safety

• Products containing colloidal oatmeal are very well tolerated.
  • Although more than 8 million oat-based cosmetics are sold yearly, there are very few reports of allergic contact dermatitis or contact urticaria.²⁷
  • In the very few patients with cutaneous adverse effects to topical oats the reactions are generally very mild and did not recur with repeat application.²⁸
• In a series of studies, the safety of topical products containing oatmeal were assessed for irritant and allergenic potential on repeat insult patch testing, in safety-in-use and ocular studies using subjects with non-sensitive and sensitive skin.²⁸
  • Low-level reactions were documented in 1.0% of subjects during the induction phase of repeat insult patch testing;
  • one of 2291 subjects developed a persistent but doubtful low-level reaction involving edema during the challenge phase in repeat insult patch testing.²⁸
  • No allergies were reported by 80 subjects after patch testing after in-use application.²⁸

Conclusion

Moisturizers are essential in the management of AD. Non-prescription ingredients such as colloidal oatmeal have been used for years as an adjunct to provide further benefits. There is mounting evidence that colloidal oatmeal can safely enhance skin hydration and even help resolve clinical lesions through anti-inflammatory effects and by modulation of the microbiome. Currently, there are oat-based skin products available OTC, including Aveeno by Johnson & Johnson.

¹Medical Student, University of Pittsburgh, Pennsylvania, USA
²Board Certified Dermatologist & Clinical Professor, University of Alberta, Alberta, Canada

Introduction

Onychomycosis, also known as tinea unguium, is a progressive fungal infection of the nails resulting in discoloration, nail plate thickening, and onycholysis. This infection is caused by dermatophytes, nondermatophyte molds, and yeasts. It accounts for up to 90% of toenail and 50% of fingernail infections in North America.¹ Onychomycosis afflicts 10% of the general population, 20% of those older than 60 years, and 50% of those older than 70 years. Risk factors include peripheral vascular disease, diabetes mellitus, immunologic disorders, hyperhidrosis, obesity, concurrent fungal infections, and nail trauma.^2,3 As per the Canadian clinical pathway, treatment of onychomycosis needs to start as soon as the infection is diagnosed.^4,5 Especially in diabetic and immunocompromised patients, treatment of onychomycosis is medically indicated, as untreated onychomycosis affects quality of life and often leads to secondary infections as abrasions or ulcerations created by sharp onychomycotic nails allow bacterial and fungal entry.⁶ Efinaconazole is a novel topical azole that has shown promising and superior activity against dermatophytes, non-dermatophytes, and yeasts causing onychomycosis.^7-9

Diagnostic and Clinical Features

• Onychomycosis has several different clinical presentations including distal lateral subungual, proximal subungual, superficial white, and total dystrophic forms.³ Although onychomycosis accounts for about 50% of the nail abnormalities, establishing a differential diagnosis is important to rule out other nail pathologies.¹⁰ Differential diagnoses include other infections (both fungal and bacterial), primary cutaneous dermatoses (such as psoriasis, lichen planus or dermatitis), trauma, and tumors such as melanomas, fibromas, and carcinomas.^3,12
• Accurate diagnosis requires visual identification of physical changes as well as positive laboratory analysis of nail clippings and subungual debris. Laboratory analysis includes microscopy using KOH (potassium hydroxide) and then subsequent culture and/or histological evaluations of negative microscopy results.³ As per product monographs of the approved medications for onychomycosis in Canada, positive laboratory analysis are required prior to starting an oral treatment, though it is not required before starting a topical treatment.

Background on Efinaconazole 10% (w/w) Solution

• Efinaconazole is a topical triazole that has been shown to have superior antifungal potency in vitro and in vivo, when compared to the other commonly used onychomycosis topical therapies such as ciclopirox nail lacquer.^7,8
• The treatment inhibits fungal lanosterol 14α-demethylase in the ergosterol biosynthesis pathway, which is a structural component in fungal cell membranes. The accumulation of 14α-methyl sterols and subsequent loss of ergosterol in the fungi cell wall may be responsible for the fungistatic and fungicidal activity of efinaconazole. This activity has been shown to be effective against dermatophytes, non-dermatophytes and yeasts.^8,13
• Efinaconazole 10% w/w topical solution grants easier and more convenient administration, which is important for compliance with its daily application regimen.
  • Its low molecular weight allows it to penetrate easily through the nail plate and even through nail polish.¹⁴
  • Its non-lacquer profile avoids buildup and does not require nail debridement⁷, an added benefit when compared to other topical treatments, e.g. Ciclopirox lacquer.¹⁵
  • It is also easy to administer by patients simply by gently squeezing the bottle in upside-down position to wet the flowthrough applicator brush attached to the bottle and spreading the solution to the affected region.¹⁶ One application on each affected toenail and 2 applications on the big toenail, once daily.
• Its low surface tension and low keratin affinity allows it to permeate through the nail plate more efficiently than Ciclopirox, contributing to higher fungicidal activity underneath and within the nail plate.¹⁷
• The recommended treatment regimen is once daily topical application for 48 weeks to the nail plate surface, lateral and proximal nailfolds, hyponychium, underside of nail plate, and surrounding skin.^7,16 A complete cure may be seen some months after mycological cure is achieved.

Combining Modalities

Several studies have found that combining different modalities of treatment with topical Efinaconazole may provide a synergism that increases fungicidal efficacy and cure rates. Faster visible results and increased efficacy may enhance compliance by inspiring patients to adhere to the combination regimen.

Topical Antifungals

• Fungal infections of the skin surrounding the toenail can often lead to or perpetuate onychomycosis.¹⁸ In a survey of 2761 patient with toenail onychomycosis, 42.8% had some other concomitant fungal infection. Of these, tinea pedis was the most common and accounted for 80% of concomitant infections.¹⁹
• Several studies have documented higher onychomycosis cure rates with the treatment of concomitant tinea pedis. For example, one study found that treatment of concomitant tinea pedis resulted in a complete cure of 29.4% and mycological cure of 56.2% compared to a complete cure of 16.1% and mycological cure of 45.2% in the control of no concomitant tinea pedis treatment.^20,21

Oral/Systemic Antifungals

• Oral therapies have been recorded to have high cure rates for onychomycosis. However, hepatotoxicity, adverse effects, drug interactions and the need for bloodwork monitoring may limit the viable population while also incurring greater burdens on the patient to comply with regular monitoring practices.⁷
• A systematic review of 26 studies found that combined systemic and topical treatment regimens resulted in a higher complete cure rate of 80.8% compared to the 70.8% complete cure rate in systemic treatment alone.²²

Laser Therapy

• Laser treatments for onychomycosis are currently approved by the FDA only as a temporary solution to increase the clear nail surface area. Currently, laser studies primarily provide evidence for aesthetic endpoints rather than medical endpoints.²³
• However, some studies have found that combined use of laser treatments with topical therapy have high cure rates, with clinical efficacy rates ranging from 70% – 90% and mycological cure rates ranging from 57% – 70%.^24-28
• Others have also found that this combined modality has decreased rate of reinfection.²⁸

Managing Patient Expectations

Efinaconazole treatment, given its relatively high efficacy, has been documented to have positive impact on patient satisfaction and quality of life measures. Importantly, this impact was greatest in patients who were considered clinically improved and correlated inversely with percent of nail affected.²⁹ It is important to adequately manage patient expectations in the treatment of onychomycosis, and the following suggestions may help physicians to accomplish this goal:

Laser Therapy

• While Efinaconazole has been shown to be a superior topical treatment, physicians should clearly convey to patients the mycological and complete cure rates so that patients can have realistic expectations for treatment outcome. In two Phase III studies conducted on 1655 patients, at the end of the study at week 52, they found:⁷
  • Mycological cure rates: 55.2% and 53.4%
  • Complete cure rates: 17.8% and 15.2%

Explain Prognostic Factors

• Physicians should educate patients on factors that affect response
  to treatment and prognosis.¹³ These include:
  • Patient demographics:
    • Gender³⁰, advancing age, and history of nail trauma
  • Comorbidities:
    • Diabetes mellitus, liver or kidney transplantation, immunosuppression, cancer, neutrophil defects, chronic steroid therapy, and peripheral vascular disease
  • Nail characteristics and disease severity:
    • Distal lateral subungual onychomycosis, proximal subungual onychomycosis, total dystrophic onychomycosis, dermatophytoma, severe onycholysis, two feet-one hand syndrome, slow nail growth, and lengthy disease duration
  • Co-infection with other pathogenic organisms:
    • Mixed bacterial and fungal infections, yeasts, and nondermatophytes

Detail Recurrence Rates

Physicians should also educate patients on the recalcitrant nature of the disease and high rates of recurrence. Indeed, recurrence rates vary from 20% to 25%.^31,32

Preparation for Appropriate Therapy Duration

• Physicians should also explain the long duration of treatment for the topical solution, i.e. at least 48 weeks. It may work well to justify this lengthier treatment by explaining the limitations of oral treatments. That is, although generally efficacious, systemic medications are limited by drug interactions and potential hepatotoxicity which may require regular monitoring.⁷
• The rate of nail clearance is dependent on slow toenail regrowth in healthy subjects. With a growth rate of 1 to 2 mm per month, it may take up to 4-6 months for fingernail clearance and 12-18 months for toenail clearance. Slower growth occurs in patients with comorbidities and older patients.³³

Encouraging Compliance

Patient compliance is essential to positive treatment outcomes and is consistently a struggle with a variety of therapies. It has been shown that up to 80% of patients are non-adherent to drug treatments independent of diagnosis or prognosis.³⁴ One study found that up to 95% of dermatology patients underdose on topical treatments.³⁵ Nonadherence is particularly concerning with onychomycosis treatment. The following suggestions may assist physicians to improve compliance in their onychomycosis patients:

Remind Patients of the Consequences of Noncompliance

• Issues with medical adherence such as early termination, incorrect or irregular dosing, and missed dosing are serious risk factors in poor response to treatment.³
• Afflicted nails, if left unattended, can become increasingly discolored, thickened, flaky, separated from the nail bed, and painful. Severe onychomycosis can also hinder mobility and thus occupational functions, as well as lead to cellulitis in older adults and foot ulcers in diabetics.^3,36 Moreover, serious cases might require surgery.³⁷

Use Visual Aids to Demonstrate the Potential for Treatment Success

• Visual aids can significantly increase comprehension of treatment schedules and improve patient compliance.³⁸ Physicians should consider using a “before-and-after” set of pictures taken at intermittent intervals in the treatment process (e.g. baseline, 6 months and 1 year) (see Figure 1). This discussion can be paired with charts showing Efinaconazole cure rates and nail clearance over time (see Figures 2 & 3). Showing patients pictures of positive results, while still managing expectations, can help them visualize potential success with compliance to proper treatment.
• Additionally, physicians can utilize visual aids to help patients better understand the pathology of onychomycosis (see Figure 4), which has similarly been shown to increase compliance.³⁸
• A patient toolkit may be beneficial in packaging together a comprehensive and encouraging onychomycosis treatment plan, with explanations and visualizations of disease pathology, treatment mechanism, and treatment regimen and trajectories.

Conclusions

• Efinaconazole 10% solution is an effective and convenient topical antifungal treatment for onychomycosis, with toenail mycological cure rates between 53.4% and 55.2% and complete cure rates between 15.2% and 17.8%.
• Treatment may be more effective when combining Efinaconazole with other modalities such as topical antifungals for the management of tinea pedis on adjacent skin, oral antifungals, and laser treatment.
• Patient adherence is the cornerstone of treatment success. It is crucial that patients adhere to daily application of efinaconazole throughout the treatment course. Compliance should be encouraged by emphasizing the consequences of nonadherence, using visual guides to aid in understanding of disease pathology and treatment mechanisms, and inspiring a motivated outlook on treatment trajectory.

¹Lecturer, Department of Family and Community Medicine, St. Michael’s Hospital, Toronto, ON, Canada
²Assistant Professor, Division of Dermatology, University of Toronto, Toronto, ON, Canada
³Associate Professor, Division of Dermatology, University of Toronto, Toronto, ON, Canada

Introduction

Atopic dermatitis (AD) is a chronic and pruritic inflammatory disease that affects a wide age range of patients causing significant impact on their quality of life. There has been a recently updated consensus paper on the treatment of mild-to-moderate AD published by an expert panel of dermatologists and pediatricians.¹ The primary objective of this article is to review the prevalence, pathophysiology, clinical features, diagnosis and treatment options for atopic dermatitis. The secondary objective is to disseminate the updated treatment algorithm suggested by the authors of the consensus paper for the primary care providers.

Prevalence

• Atopic dermatitis affects both pediatric and adult populations.
• Up to 20% of children have been reported to suffer from AD.²
• AD is more common in patients with a history of atopy such as allergic rhinitis or asthma.
• The majority of patients with AD have a positive family history of atopy.³

Pathogenesis

• AD is associated with impaired skin barrier, increased inflammation and altered microbiome.⁴
• A mutation in the filaggrin (FLG) gene that affects the natural skin barrier function is the most important genetic association.⁵
• There has been further evidence to suggest that there is a complex mechanism involving the JAK-STAT pathway and other immune responses via TH₂ and TH₂₂.
• Finally, AD is also associated with overproduction of phosphodiesterase 4 (PDE4) and subsequent pro-inflammatory cytokines.⁶

Clinical Features

• Atopic dermatitis has an intermittent nature and variable distribution that may change with age.
• Common clinical features include dry skin, pruritus and hyperreactivity to environmental exposures.
• The characteristic lesions of atopic dermatitis are ill-defined, erythematous, scaly, vesicular, excoriated and/or oozing papules and plaques that may become lichenified and fissured.
• In infants, AD often affects head, neck and extensor surfaces.
• In older children and adults, the antecubital/popliteal fossae, wrists and ankles are most commonly affected.

Diagnosis

• Atopic dermatitis is a clinical diagnosis. In unusual cases, a punch biopsy may help rule out potential mimics. Patch testing may help diagnose allergic contact dermatitis.
• The differential diagnosis for AD includes:
  • Irritant contact dermatitis
  • Allergic contact dermatitis
  • Seborrheic dermatitis
  • Plaque psoriasis
  • Scabies
• The most widely accepted diagnostic criteria by Williams et al.⁷ include:
  • Evidence of itchy skin AND three or more of:
    • Involvement of creases
    • History of asthma or hay fever (or history of atopic disease in children under four years of age)
    • Visible dermatitis involving flexural surfaces (including cheeks or forehead and outer aspects of limbs in children under four years of age)
    • Personal or family history of asthma or hay fever
    • Generally dry skin in the past year
    •  Onset in a child under two years of age
  • Severity scales for atopic dermatitis are available but not widely used by clinicians

Co-Morbidities

• Psychiatric disorders
  • Depression⁸
  • Suicide⁹
  • Attention deficit hyperactive disorder¹⁰

• Obesity

Treatment

The new DERMA Atopic Dermatitis Algorithm was developed for management of AD (Figure 1).

Diagnosis/Distribution
Education/ Emollients
Red/Itchy
Medication/Maintenance
Assessment /Adherence

Education

• The mainstay of treatment is patient education.
• Counselling should include:
  • Consistent use of emollients
  • Luke-warm bathing (with non-soap cleansers)
  • Avoidance of irritants such as fragrance

Emollients

• Emollients control xerosis and improve the epidermal barrier, with some suggesting products with humectants, lipids and/or ceramides.¹¹
• Application of moisturizers should be done immediately after bathing.

Topical Anti-Inflammatories

• The majority of AD patients have mild-to-moderate disease and only require topical therapies.
• Topical therapies include anti-inflammatory agents such as topical corticosteroids (TCSs), topical calcineurin inhibitors (TCIs) or phosphodiesterase-4 (PDE4) inhibitors in various vehicles.
• Ointments are generally better tolerated for nonintact “raw” skin as they do not contain preservatives, tend not to sting and can be more potent.
• Creams are often more cosmetically appealing but can sting on nonintact skin.
• Gels, sprays, lotions and foams may be useful for hair-bearing sites.
• Providers should re-assess patients for adherence, severity, and diagnosis after four weeks of continuous topical anti-inflammatory use.

TCSs

• Corticosteroids remain effective first-line treatments.
• Long-term adverse effects in sensitive areas include:
  • Local cutaneous atrophy
  • Striae formation
  • Telangiectasia
  • Impaired wound healing
  • Acneiform eruptions
  • Allergic contact dermatitis

TCIs

• Pimecrolimus 1% and tacrolimus 0.03% or 0.1% are safe and approved for children over age two.
• Common side effects are burning or stinging sensation on applications that subside over time.
• There exists a black box warning for possible lymphoma risk. However, patients should be counselled that causal relationship for this is unclear.¹²

PDE4 Inhibitors

• Crisaborole 2% ointment (Eucrisa©) is a novel topical applied twice daily to reduce symptoms of mild-to-moderate atopic dermatitis approved for patients two years and older.¹³
• Crisaborole showed efficacy by day 8 in clinical trials compared to vehicle and itch improves in less than two days.¹⁴
• Since there is no risk of steroid-atrophy, PDE4 inhibitors may be applied on the face and other sensitive areas of the body. Similar to TCIs, crisaborole is an alternative for steroid-phobic patients and/or caregivers.
• The most common side effect is application site burning, which is temporary.

Further Options

For severe AD, treatment options beyond topical therapies may involve phototherapy and/or systemic therapies such as cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, or dupilumab.

Practical Tips

What about oral antihistamines?
A recent systemic review showed a lack of consistent evidence for use of oral antihistamines (e.g. cetirizine, loratadine, fexofenadine) when compared to placebo in decreasing symptoms of atopic dermatitis.¹⁵

What about food allergens?
Although patients with AD often have food allergies to cow’s milk, egg, wheat and peanut, there is no evidence that dietary interventions provide any benefit in the treatment of AD.¹⁶

What about bath additives?
Although some guidelines in Europe support the use of bath additives, there is no consistent data to demonstrate its efficacy in controlling pruritus.¹⁷

What about allergy testing?
Patch testing is not required to diagnose atopic dermatitis. It is only necessary for excluding the alternative diagnosis of irritant contact dermatitis.¹⁸

Conclusion

There are several topical therapy options available for the management of AD such as TCIs and PDE4 inhibitor. Family physicians are well equipped to manage mild-to-moderate AD in the majority of cases, but referral to dermatologists may be required in severe cases or alternative diagnoses.