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

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

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

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

Introduction

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

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

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

Patients and Methods

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

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

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

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

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

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

Results

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

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

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

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

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

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

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

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

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

Discussion

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

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

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

Strengths and Limitations

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

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

Conclusion

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

Acknowledgements

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

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¹Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Lynde Institute for Dermatology (Private Practice), Markham, ON, Canada
³Division of Dermatology, University of Toronto, ON, Canada

Funding Sources: None

Conflict of interest:
Cindy Kang and Monica Shah have no conflicts of interest to disclose. Charles Lynde has acted as a principal investigator, speaker and/or consultant and/or advisory board member for AbbVie, Amgen, AnaptysBio, Arcutis, Avillon, Bristol-Myers Squibb, Celgene, Cipher, Eli Lilly, Galderma, Genentech, GlenMark, Incyte, Janssen, Kyowa, Leo Pharma, L’Oréal, Merck, Novartis, Pfizer, Sanofi and Valeant. Patrick Fleming has received honorarium and/or consulting and/or advisory boards and/or speaking fees for AbbVie, Altius, Amgen, Aralez, Bausch Health, Cipher, Eli Lilly, Galderma, Janssen, Leo Pharma, L’Oréal, Novartis, Pfizer, Sanofi-Genzyme and UCB.

Abstract:
Hair removal practices have evolved from adhering to social, cultural, and religious traditions to meeting aesthetic standards. Hair removal methods can be divided into two categories: 1) depilation, which involves removing the hair shaft and includes shaving and chemical depilatories, and 2) epilation, which involves removing the hair shaft, follicle, and bulb, and includes plucking, threading, waxing, sugaring, lasers, intense pulsed light system, electrolysis, and photodynamic therapy. Furthermore, an eflornithine hydrochloride 13.9% cream (Vaniqa®, neither an epilatory or depilatory technique), has been US FDA- and Health Canada-approved to slow the rate of facial hair growth and to be used in combination with other hair removal methods. Most methods are temporary except for electrolysis and laser therapy for some individuals, and each technique has advantages and disadvantages in terms of efficacy and adverse events. Importantly, most studies examining the efficacy of hair removal techniques are limited to darker hair and fairer skin, and further research is required especially for those with light-colored hair.

Key Words:
chemical depilatories, depilation, electrolysis, epilation, hair removal, laser hair removal, photodynamic therapy, plucking, shaving, sugaring, threading, Vaniqa, waxing

Introduction

Hair removal methods fall under two categories of depilation and epilation, each with distinctive advantages, disadvantages, and adverse events (Table 1).¹ Depilation removes the hair shaft and includes techniques such as shaving and chemical depilatories. Epilation removes the hair shaft, follicle, and bulb, and includes techniques such as plucking, threading, waxing, sugaring, lasers, intense pulsed light system (IPL), electrolysis, and photodynamic therapy (PDT).¹ In the 2000s, eflornithine hydrochloride cream 13.9% (Vaniqa®) was US FDA and Health Canada approved. Topical eflornithine is not considered an epilatory or depilatory technique but slows the rate of facial hair growth when used in conjunction with other methods.²

Table 1: Hair removal methods – advantages, disadvantages, adverse events, and permanency

Hair Removal Methods

Depilation

Shaving

Shaving is a cost-efficient and popular technique for male facial hair and female underarm and leg hair removal.^1,3 The two methods include: 1) wet shaving with a safety razor and 2) dry shaving with an electric razor.^1,3 The first razors used in the 17th century had straight, fixed blades made of tempered steel which were dangerous to use and required regular maintenance (honing and stropping). In 1903, the revolutionary King Camp Gillette T-shape razor was introduced with the first double-edged disposable blade which did not require honing and stropping, but still needed direct handling for blade replacement. In the 1920s, the disposable injector blade was introduced, a safer and more convenient method without direct handling. In 1931, the razor blade was again revolutionized by the electric razor blade, which was costlier, but provided enhanced safety (the blade never directly touched the skin) and convenience (long-lasting and eliminated the need for shaving cream).^3,4 Finally, in 1970, hoe-shaped safety razors with disposable cartridges were launched, and in 1975, the disposable razor was introduced. Both were safe to use, inexpensive, and convenient, with the disposable razor the most convenient of all models.⁵

Shaving (wet or dry) does not interrupt the anagen phase and, therefore, is a temporary hair removal method that necessitates frequent treatment.^1,6 Shaving is convenient and inexpensive, but may cause irritation, skin abrasions, and pseudofolliculitis.^1,7 Moreover, shaving does not change hair thickness or growth rate and leaves a blunt tip that appears to be thicker than uncut hair;³ thus, it is uncommon for facial hair removal in females.¹

Chemical Depilatories

Chemical depilatories are made as powders, pastes, creams, or lotions,^1,6,8 and used for the legs, bikini area, and face.³ Examples include detergents, hair-shaft-swelling agents, adhesives, pH adjusters, and bond-breaking agents, which disrupt disulfide bonds within keratin and provide temporary hair removal.³ The most common chemical depilatories are substituted mercaptans, 2% to 10% thioglycolates, mixed with 2% to 6% of sodium hydroxide or calcium hydroxide to increase pH.^3,6,8 Sulfide depilatories and sodium hydroxide depilatories are unpopular as they cause greater irritant dermatitis and skin damage.³ Depilatories are applied to hairs for 3 to 15 minutes to dissolve the hair shaft, and are then washed off with soap and water.^6,8

While chemical depilatories are easy to use, painless, have a slower regrowth than shaving, and do not result in stiffness of hairs post-treatment,³ they have unpleasant odors and may cause irritant contact dermatitis due to the alkalinity and allergic contact dermatitis due to fragrances.^3,7 Thus, less than 1% of patients find facial application tolerable.⁷ Moreover, chemical depilatories are less effective in removing darkly pigmented and coarse hair.³

Epilation

Plucking

Plucking with tweezers temporarily removes hairs in small areas, and is most effective at removing terminal as opposed to vellus hairs, with the latter tending to break near the skin surface.^1,3 Plucking is simple, inexpensive, causes minimal skin damage, and affords a longer regrowth period (2 to 12 weeks).³ However, plucking does not alter hair growth rate unless hairs are in the anagen phase, and can be a tedious process, making it impractical for use over larger areas.¹ Plucking can cause discomfort or pain, and its efficacy is dependent on user tolerance and technique.¹ Other drawbacks include folliculitis, follicular distortion, hyperpigmentation, erythema, and scarring.^6-8

Threading

Threading involves the use of a twisted loop of cotton thread, with ends held by hand and teeth,³ that is pressed against the skin to trap and pull hairs.^1,6 Threading is used in men to remove cheek, ear, and forehead hairs, and in women to remove facial hair.^1,3, Threading is a temporary hair removal technique widely practiced in the Middle East and dates back to antiquity, also known as fatlah in Egypt, that has gained popularity in Western cultures due to its precision in shaping eyebrows.¹ Threading, however, can be painful, tedious, and typically requires an esthetician with expertise.¹

Waxing

Waxing is a popular, temporary hair removal method resulting in hair-free skin for 2 to 6 weeks depending on the individual’s hair growth rate and body site.^1,3,7 Waxing is commonly used for larger areas.⁹ Wax is composed of beeswax and rosin with additives, essential oils, chemicals, and preservatives. Hot wax is preferred over cold wax especially in beauty salons⁹ as the heat dilates the follicular opening to facilitate hair removal.^1,3,7 Once the wax cools and hardens, the strip is removed quickly in the direction opposite of hair growth.^1,9

Waxing removes both vellus and terminal hairs in large areas, and is longer-lasting than shaving or chemical depilatories as hairs are removed from the bulb.^1,3 Repeated waxing can cause follicular trauma and reduce hair regrowth over time.^7,9 Other adverse events include folliculitis, thermal injury, skin irritation, scars,^7,9 and allergic reactions to the additives.^1,7 Patients using systemic retinoids are advised not to wax due to increased risk of scarring.

Sugaring

Sugaring is an ancient hair removal technique used in the Middle East and Egypt¹ involving a paste composed of sugar, lemon juice, and water¹⁰ applied to skin in the direction of hair growth, then removed in the opposite direction with cloth.¹⁰ Sugaring has a similar application to waxing, but may remove shorter hairs (1/16 inch versus ¼ inch) as water-based pastes can more easily penetrate follicles.¹⁰ Moreover, sugaring is safe (utilizes natural ingredients), cost-effective, hydrating, painless, and can be used for larger areas,⁷ and reduces the risk of skin redness, trauma, and scarring compared to shaving or hot waxing.¹⁰ However, sugaring may cause skin irritation and allergic reactions¹ and can only remove hairs of sufficient length.

Lasers

Laser hair removal can be permanent for some individuals,¹¹ and involves selective photothermolysis that emits a light at a specific wavelength (nm), pulse duration, and fluence, causing thermal injury without damaging the skin.^1,12 Light is either directly absorbed by melanin within the hair bulb and shaft⁶ or by an exogenous chromophore applied topically then absorbed by the follicle.^1,6,12 Lasers are more effective when the pigmented hair shaft is intact; thus, plucking and waxing are discouraged, whereas depilation (e.g., shaving) is recommended pretreatment.^1,12

Laser types include the ruby laser (694 nm),^1,6,13 diode laser (800 nm),^1,6,13-21 alexandrite laser (795 nm),^1,18,22,23 and neodymium:yttrium-aluminum-garnet (Nd:YAG) laser (1064 nm),^6,12,24,25 and efficacy depends on laser fluence, spot size, number of treatments and individual factors (e.g., skin type, hair type and hormonal status).26 Lasers work best for dark, thick terminal hairs, light/fair skin, and a normal hormonal status, but are ineffective for thin vellus hairs, and white, grey, or red hairs.²⁶ Longer wavelengths reduce epidermal damage due to poor absorption and are therefore safe and effective in darker skin types. Cooling devices should also be used to reduce skin damage.¹⁶ Adverse events include immediate erythema,¹³edema, first- and second- degree burns,^19,20 folliculitis,^22,23 skin damage, pigmentation changes, blisters, and crust formation, and are more likely to occur in darker skin types [Fitzpatrick skin type (FST) III to VI].^6,24

Intense Pulsed Light (IPL) System

The IPL system is a non-laser source of polychromatic light (550 nm to 1200 nm)⁶ tailored to individual skin type and hair color.^1,6,24 Multiple treatments are typically required,¹ however, results (60% hair reduction) may last up to 12 weeks after one session.²⁷ For optimal results, individuals should avoid tanning but should shave prior to treatment to prevent conducting thermal energy to adjacent epidermis.¹ IPL is most effective in individuals with the combination of darker hair and lighter skin.¹

IPL has several advantages, including lower cost compared to laser hair removal and the ability to treat large surface areas (back, chest, and legs). However, IPL is generally less effective than laser hair removal, requires more treatment sessions,²⁸ and the IPL device is bulky, heavy, and difficult to maneuver as it houses a lamp and cooling device.¹⁸ Adverse events include pain, edema, erythema, hypopigmentation, and hyperpigmentation.^1,18,24 IPL devices can emit inconsistent fluence and wavelengths from pulse to pulse, making it difficult to predict efficacy.¹⁸

Electrolysis

Electrolysis is a permanent method of hair removal,^1,6,8 but patients with hirsutism will experience conversion of vellus to terminal hairs in treatment areas. The three types of electrolysis [1) galvanic (direct current) electrolysis, 2) thermolysis (alternating current), and 3) combination/blend method] all involve inserting a probe to deliver electric currents that destroy and prevent regrowth of hair follicles.¹

Galvanic electrolysis treatment is slow (15 seconds to 3 minute application per hair) with multiple treatments required; however, it can reduce the number of active hair follicles by 80% to 90%.¹ This technique is tedious, time-consuming, painful, and can cause post-inflammatory hyperpigmentation and scarring, and is not recommended for larger areas requiring hair removal.⁸ In contrast, thermolysis is faster than galvanic electrolysis due to a shorter skin contact time, but generally less effective – hair has been found to regrow in 20% to 40% of follicles post-treatment.¹ The blend method (combination of galvanic electrolysis and thermolysis) is considered the most effective form, as it is as fast as thermolysis and less painful than galvanic electrolysis.¹

Adverse events of electrolysis depend on current type, duration, and intensity, but include pain, scarring/keloid formation in susceptible patients, and post-inflammatory hypo- or hyperpigmentation. Topical anesthetics can be offered before treatment, however maintaining sensation is preferred as pain is related to skin damage.⁶ Erythema and edema are common but transient, and crusting or follicular nodules may form with repeated insertion of a needle into the same follicle. There is also risk of local infection if instruments are not cleaned properly; operators should wear gloves at all times and apply antibacterial ointment to the area post-treatment.⁶ The efficacy of electrolysis depends largely on the operator’s skills, and unfortunately there is no standardization of licensure to practice this technique.^1,6

Photodynamic Therapy (PDT)

PDT involves the application of a topical photosensitizer⁶ and subsequent exposure to nonionizing radiation of red light (635 nm) through a projector, broadband light device, or laser.²⁹ Light is absorbed by a photosensitizer, subsequently forming singlet oxygen that causes lipid peroxidation of follicular cell membranes and protein damage,^6,8 resulting in phototoxic effects on hairs.³⁰ The most common topical agents used for PDT are 10% or 20% topical 5-aminolevulinic acid (5-ALA) and methyl aminolevulinate – prodrugs that lead to the formation of a photosensitizer, protoporphyrin IX (PPIX). PDT treatment duration is dependent on the incubation time of 5-ALA, which should be sufficient to allow for its conversion to PPIX. The incubation period for 5-ALA is typically 3 hours²⁹ followed by brief light exposure.³¹ PDT can be used in all skin and hair types as its mechanism of action is independent of melanin concentration and has minimal side-effects.³⁰ Uebelhoer et al. described a 40% hair reduction at 6 months of wax epilated areas after ALA application for 3 hours with one treatment of irradiation with continuous wave 630 nm red light.³² Moreover, in a recent study by Comacchi et al. on the use of PDT in idiopathic hirsutism and hypertrichosis, two to five treatments (with a 1 month period between treatments) led to a 75% hair reduction at 12 months.³⁰ Since PDT is primarily used to treat cutaneous malignancy, its use in hair removal is limited and further investigations are required.^8,12

Other

Topical Eflornithine Hydrochloride

Eflornithine hydrochloride 13.9% cream (Vaniqa®), is a topical prescription medication that is not meant to be used alone and should be combined with another hair removal technique. Topical eflornithine does not fall under epilation or depilation as it does not remove hair but rather slows facial hair growth, and inhibition of ornithine decarboxylase is the postulated mechanism of action. If applied twice daily at least 8 hours apart, results may be seen as early as 4 to 8 weeks. Adverse event rates include acne, folliculitis, stinging or burning, dry skin, itching, tingling, redness or irritation, indigestion, rash, and dizziness. Patients should consult their physician before using eflornithine if pregnant, planning pregnancy, or breastfeeding.²

Conclusion

This article is a general overview of hair removal practices, which have evolved from utilizing waxes and blades, to advanced lasers and electrolysis, with further advancements still being studied.¹ Residual, unwanted hair is a common problem for many individuals and traditional methods of hair removal (e.g., shaving and waxing) have provided temporary solutions and unsatisfactory results. Laser therapy is a safe modality that can produce permanent results in some individuals.^11,12 Electrolysis is a permanent hair removal method but can be tedious and associated with several adverse events. A relatively recent FDA and Health Canada approved treatment, eflornithine hydrochloride 13.9% cream, can be used in combination with another hair removal technique to slow the rate of facial hair growth. Importantly, studies examining hair removal efficacy are limited to individuals with darker hair and fairer skin, whereby precautionary measures such as cooling devices are recommended for safe treatment. Further research is required to develop safe and effective treatments for those with lighter-colored hair.¹²

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¹Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Division of Dermatology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada

Conflict of interest:
Funding sources: None. Conflicts of interest: Sara Mirali has no conflicts of interest to declare. Patrick Fleming has received honorarium and/or consulting and/or advisory boards and/or speaking fees for AbbVie, Altius, Amgen, Aralez, Bausch Health, Cipher, Galderma, Eli Lilly, L’Oréal, UCB, Janssen, Novartis, Pfizer, and Sanofi-Genzyme. Charles Lynde has acted as a principal investigator, speaker and/or consultant and/or advisory board member for AbbVie, Amgen, AnaptysBio, Avillon, Arcutis, Bristol-Myers Squibb, Celgene, Cipher, Genentech, GlenMark, Incyte, Janssen, Leo Pharma, L’Oréal, Kyowa, Pfizer, Merck, Novartis, and Sanofi.

Abstract:
During the COVID-19 pandemic, prolonged usage of personal protective equipment (PPE) and frequent handwashing has exacerbated or caused skin diseases, particularly amongst frontline workers. Skin conditions, such as atopic dermatitis, irritant contact dermatitis, and hand eczema, affect patients’ quality of life and their ability to work. These conditions can be managed by frequent moisturization and washing with gentle cleansers. In this review, we discuss the properties of effective moisturizers and cleansers for patients with skin diseases related to enhanced infection control procedures.

Key Words:
COVID-19, personal protective equipment, PPE, skin pH, eczema, atopic dermatitis, irritant contact dermatitis, acne, hand eczema

Table of Content:

1. Introduction
2. PPE-related Dermatitis
3. Moisturizers
4. Hand Eczema
5. Cleansers
6. Conclusion

Introduction

During the COVID-19 pandemic caused by the novel coronavirus SARS-CoV2, health authorities advised frontline workers and the public to take infection control precautions. Current evidence suggests that COVID-19 is transmitted through respiratory droplets and contact with contaminated surfaces.¹ To prevent transmission, frequent handwashing and prolonged usage of personal protective equipment (PPE), such as goggles, masks, face shields, and gloves, are recommended. These enhanced precautions can cause or exacerbate inflammatory skin conditions, which impact patients’ quality of life and, in some cases, their ability to work.² Moreover, associated symptoms, such as pruritis affecting the face, increase the risk of transmission.

Recent studies have shown that 75-97% of healthcare workers (HCWs) treating COVID-19 patients suffered from adverse skin reactions, including contact and pressure urticaria, rosacea, perioral dermatitis, contact dermatitis, or aggravation of preexisting skin disorders. The most commonly affected areas were the hands, cheeks, and nasal bridge.^2,3 These adverse effects are not restricted to HCWs4 and are mainly caused by the hyperhydration effects of PPE, friction, epidermal barrier breakdown, and contact reactions. All of these can aggravate preexisting skin diseases or cause new skin diseases, many of which can be controlled with proper moisturization. In this review, we discuss the role of moisturizers and cleansers in the management of skin conditions caused by frequent handwashing and PPE.

PPE-related Dermatitis

Atopic dermatitis (AD) and irritant contact dermatitis (ICD) are common types of eczema that are characterized by pruritus, eczematous lesions, xerosis, and lichenification. AD is a chronic relapsing inflammatory skin condition that often develops at a young age, while ICD is caused by direct contact of the skin with environmental, chemical, or physical agents that disrupt the epidermal barrier.^5,6 AD and ICD can be exacerbated or caused by wearing PPE for long periods of time.^2,3

Prolonged usage of PPE can also exacerbate or cause acne vulgaris.^7,8 The tight seal and humid environment created by masks, particularly N95s, aggravates acne (also known colloquially as maskne). This is likely because pressure on the skin can rupture comedones and block pilosebaceous ducts. Moreover, the humid microclimate within the mask is ideal for bacterial growth and prevents filaggrin (FLG) breakdown, which contributes to skin barrier disruption.^8,9 In addition to AD and acne, masks can exacerbate other inflammatory skin disorders, such as rosacea and perioral dermatitis.^7,8

Moisturizers

Moisturizers are widely used to treat AD and ICD. Moisturizers treat damaged skin by repairing the stratum corneum, increasing hydration, and reducing transepidermal water loss (TEWL). In addition to restoring the skin barrier and relieving symptoms, frequent use of moisturizers can reduce the need for topical steroids.¹⁰ While steroids may reduce inflammation, they can also compromise the skin barrier and increase TEWL.¹¹

An effective moisturizer should contain an occlusive barrier, humectants, and emollients (Table 1). Occlusives block TEWL by forming a film on the surface of the skin, while humectants retain moisture by attracting water from the environment and from the dermis. Emollients soften the skin by repairing the stratum corneum’s lipid-rich matrix and filling the spaces between desquamating corneocytes.

Table 1: Basic properties of an effective moisturizer

PCA = pyrrolidine carboxylic acid; TEWL = transepidermal water loss

Treatment with moisturizers is largely based on patient compliance. Consumer preferences must be taken into account as compliance will likely be poor if patients are unsatisfied with the treatment.¹² An ideal moisturizer should be non-irritating, hydrating, cosmetically appealing, pH balanced, and contain ceramides.^10,13,14 Moreover, an ideal moisturizer should be inexpensive and widely available.

Non-irritating

Sensory reactions are a common adverse effect of moisturizers. Sensory reactions consist of burning or stinging sensations without evidence of inflammation.¹⁵ Although urea, lactic acid, and pyrrolidine carboxylic acid (PCA) are clinically effective humectants, they cause irritation in some patients, particularly in those with damaged skin.^12,16,17 In contrast, the humectant glycerin is well-tolerated.¹⁶ Preservatives, such as benzoic acid and sorbic acid, can also cause irritation (Table 2).^12,17

Table 2: Side effects of moisturizers and potential causes

Adapted from Lynde et al.²³
PCA = pyrrolidine carboxylic acid
MCI/MI = methylchloroisothiazolinone/methylisothiazolinone

Fragrances are the most common allergen found in moisturizers and are the most frequent cosmetic cause of allergic contact dermatitis.^18,19 Fragrances can also cause photo contact dermatitis and contact urticaria.²⁰ Moisturizers should be fragrance-free and fragrance-related allergens, such as benzyl alcohols, essential oils, and biologic additives should also be avoided.¹⁸ dermatitis and contact urticaria.²⁰ Moisturizers should be fragrance-free and fragrance-related allergens, such as benzyl alcohols, essential oils, and biologic additives should also be avoided.¹⁸

Moisturizers may contain or be used alongside treatments for acne vulgaris, such as retinoids and benzoyl peroxide. These compounds can disrupt the skin barrier and cause further irritation, particularly if patients recently integrated them into their skincare routine.²¹ To prevent maskne, skincare routines should be limited to a pH-balanced gentle non-soap cleanser and mild moisturizer free of irritants. Products with a physiological skin surface pH (4.0-6.0) should be used to reduce inflammation and improve skin barrier function.²² Changes in skincare routine (i.e., addition of a retinol) should be incorporated with caution because mask occlusion may worsen irritation from new products. Likewise, cosmetic products should not be used as mask occlusion will intensify product delivery to the skin, increasing irritation and maskne.

Hydrating Properties

Moisturizers derive their hydrating properties from humectants that attract water from the dermis and from the external environment. Within the stratum corneum, corneocytes contain natural moisturizing factors (NMF), a humectant mixture derived from amino acids and salts. NMF are made of amino acids produced by the breakdown of the protein FLG, which retains water within the corneocytes and maintains skin hydration.²⁴ Patients suffering from AD are deficient in FLG, resulting in increased TEWL and impaired skin barrier function.²⁵ Moisturizers containing FLG breakdown products have been shown to improve barrier function in AD patients.²⁶

Commonly used humectants include the FLG breakdown products lactic acid and PCA, as well as urea. Another frequently used humectant is hyaluronic acid, which has been shown to be efficacious in mild-to-moderate AD.²⁷ If patients are sensitive to these humectants, a moisturizer with glycerin should be considered. Glycerin is an effective humectant that is inexpensive and well-tolerated.¹⁶ Because humectants draw up water from the dermis, they must be used in combination with an occlusive agent to prevent TEWL.²⁸

Cosmetically Appealing

Moisturizers are formulated to be non-greasy, non-comedogenic, and smoothing. The consistency of a moisturizer depends on its emulsification. Creams are available as water-in-oil (W/O) or oil-in-water (O/W) emulsions. O/W emulsions are less viscous compared to W/O emulsions, which have an oil content between 15-30%. A higher oil content retains more moisture but increases the greasiness of the product.¹⁵

New emulsion technologies allow for better delivery of active ingredients. Multivesicular emulsions (MVE^®) are multi-lamellar emulsions with a series of concentric spheres containing oil and water. Ingredients are stored within the oil or water phases and layers are released slowly over time. While traditional emulsions release all of their ingredients at once, MVEs^® allows for sustained release, increasing the effective duration of the product.²⁹

pH Balanced

Normal physiological skin surface pH ranges from 4.0-6.0 but is elevated in AD, ICD, and acne.^30-32 Elevated skin pH can result in inflammation, disrupted stratum corneum cohesion, and impaired skin permeability. Moreover, for individuals with acne-prone skin, high pH moisturizers can interfere with the efficacy of topical acne treatments.^22,33 To improve skin barrier function, moisturizers at physiological skin surface pH (4.0-6.0) should be used, although there is limited clinical evidence directly linking low pH moisturizers and reduced irritation.

Ceramide Content

The stratum corneum’s lipid-rich matrix is composed of approximately 50% ceramides, 25% cholesterol, and 10-20% fatty acids.³⁴ Ceramides are synthesized in keratinocytes and play an important role in skin barrier maintenance, cell adhesion, and epidermal differentiation. Reductions in ceramide correlate with clinical irritation and barrier disruption.³⁵ Natural ceramides are expensive to synthesize but moisturizers containing synthetic ceramides have been shown to reduce symptoms and improve quality of life in patients with AD and ICD.^10,13,14,36

Hand Eczema

Hand eczema (HE) is the most common form of ICD.³⁷ Anionic surfactants, commonly found in hand soaps, disrupt the stratum corneum by damaging proteins and the processing of new lipids, allowing for greater penetration of irritants and TEWL.³⁸ Likewise, extended exposure to water disrupts the stratum corneum’s lipid structure and increases skin permeability.³⁹ Other irritants, such as organic solvents used in hand sanitizers, strip away lipids from the stratum corneum, although they are less damaging compared to harsh detergents.⁴⁰

Cleansers

Cleansers are mainly available as soaps, combars, and synthetic detergents (syndets) (Table 3 & Table 4). Soaps are typically very alkaline and range from pH 9.0-10.0. In contrast, syndets contain synthetic detergents and are acidic or neutral (pH 5.5- 7.0). Combars are a combination of soaps and syndets.⁴¹ While soaps are more effective at removing soluble proteins and lipids, their high pH disrupts the skin barrier and causes irritation.⁴² Fragrance-free, hypoallergenic, non-soap cleansers that are neutral to low pH are recommended.⁴³ Frequent handwashing with low pH cleansers is preferred as they have been shown to be less irritating.⁴⁴

Table 3: Cleanser categories

Table 4: Allergens in cleansers

Adapted from Rundle et al.⁴⁰

Conclusion

Prolonged PPE usage and frequent handwashing increases the risk of developing or aggravating skin diseases, such as AD, ICD, acne, and HE. Routine moisturization with non-irritating, pH-adjusted, ceramide-based products and gentle cleansing with a pH-adjusted cleanser can treat the unique dermatological challenges posed by COVID-19 (Table 5).

Table 5: Ideal characteristics of moisturizers/cleansers and summary of recommendations

AD = atopic dermatitis; FLG = filaggrin; PCA = pyrrolidine carboxylic acid; TEWL = transepidermal water loss

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¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Division of Dermatology, University of Toronto, Toronto, ON, Canada
³The Lynde Institute of Dermatology, Markham, ON, Canada

Conflict of interest:
All of the authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract:
Prurigo nodularis (PN) is a chronic, recalcitrant inflammatory skin condition characterized by the presence of pruritic nodules. The exact pathogenesis of the disease is unknown, although immune and neural dysregulation are indicated in driving the itch-scratch cycle. Specifically, interleukin-4 and interleukin-31 pathways have been recently implicated in transmission of the pruritic sensation. There are currently no US FDA-approved targeted therapies for the treatment of PN. This article aims to review our present understanding of the disease pathogenesis and treatments, with a focus on emerging therapeutics. Specifically, this article explores the developing use of monoclonal antibodies nemolizumab and dupilumab, opioid receptor modulation and cannabinoids as potential treatments for PN.

Key Words:
prurigo nodularis, nemolizumab, dupilumab, chronic pruritus

Clinical Presentation

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by the presence of pruritic nodules. Lesions vary in size from a few millimeters to 2-3 cm in diameter, and range in number from a few to hundreds.¹ Nodules may be flesh-colored, erythematous, or hyperpigmented (depending on skin type), and are typically located in symmetric linear arrangements along extensor surfaces.¹ PN has some predilection for elderly patients and individuals with dark skin, particularly persons of African ancestry.^2,3 Although the disease affects patients of either sex, some research suggests women may be disproportionately affected in terms of frequency, age of onset, and severity.⁴ Numerous risk factors have been elucidated prior to development of PN, including eczemas, psychiatric diagnoses, and chronic medical diseases such as malignancy, liver failure, chronic renal failure, diabetes and human immunodeficiency virus (HIV) infection.^3,5-7

Pathophysiology

The pathogenesis of PN is thought to be characterized by a cutaneous reaction pattern due to chronic itching and repeated scratching, otherwise termed the “itch-scratch cycle.” Although the exact pathogenesis of PN is unknown, immune and neural dysregulation drive the pruritic cycle.⁸

Histopathologic studies investigating the immune response of PN have demonstrated increased infiltrate in the dermis of PN lesions consisting of increased T lymphocytes, mast cells and eosinophilic granulocytes.^8,9 The intense itch is created by an inflammatory response in the skin through mediators such as interleukin (IL)-31, tryptase, eosinophil cationic protein, histamine, prostaglandins and neuropeptides.^8,9 Specifically, eosinophils and IL-31 are particularly implicated in the pathogenesis of the disease through their increased expression and pathologic mechanisms in the dermis of PN lesioned skin.^8-13

Neuronal dysregulation has also been demonstrated in PN; studies have shown differences in nerve fiber density between the dermis and epidermis in individuals with PN.¹¹ Further, dysregulation of neuropeptides has been implicated in the pathogenesis, with particular increases in calcitonin gene-related peptide and substance P in dermal PN skin.^8-11,14 Although these changes may be secondary to repeated mechanical scratching, they still contribute to the pruritic cycle through regulation of eosinophils, mast cells, effects on endorphins and mu- and kappa-opioid receptors.^8,9,11

Regardless of the aforementioned potential triggering pathologies, central nervous system functioning is essential for transmitting the itch signal from the periphery. Recent seminal findings by Oetjen and colleagues have demonstrated that the IL-4 receptor is directly expressed on sensory neurons in the dorsal root ganglia of both humans and mice. This receptor is directly activated by expression of type 2 cytokines, such as IL-4, IL-13 and IL-31.¹⁵ Most importantly, the authors demonstrated that ablating the IL-4 receptor in a mouse model significantly diminished chronic pruritus, and treating human patients with recalcitrant chronic itch that failed other immunosuppressive therapies with inhibitors of the type 2 cytokine pathway (Janus kinase – JAK – inhibitors) markedly improved their symptoms.¹⁵ Taken together, therapeutics targeting the inhibition of this central nervous system pathway may potentially be groundbreaking in the treatment of PN.

Current Treatments

Currently, there are no US Food and Drug Administration (FDA) approved targeted treatments for PN. Although the treatment goal is to break the itch-scratch cycle to allow the nodules to heal, there is a high degree of variability between providers and treatment regimens in the use of off-label therapies.^8,16 A recent systematic review assigned level of evidence ratings to the current treatment options for PN (Table 1). The review found that many current therapies have low efficacy or a high frequency of side effects, limiting their effectiveness. Further, there was a paucity of randomized control trials (8 RCTs, with only 3/8 having >22 participants with PN) and quality studies looking at treatment of PN. Overall, topical agents, including corticosteroids, calcineurin inhibitors, calcipotriol, and capsaicin, had the highest evidence ratings, with some beneficial effects.¹⁷ The majority of studies investigating phototherapy and photochemotherapy reported mild side effects and demonstrated good partial response rates, as did thalidomide, although it had poorer quality studies and a large side effect profile. Antiepileptics and antidepressants, such as pregabalin, amitriptyline, paroxetine, fluvoxamine, and neurokinin-1 receptor antagonists had strong evidence ratings with promising treatment results and low risks of side effects. Lastly, systemic immunomodulatory therapies, such as cyclosporine and methotrexate, demonstrated some benefit in a limited number of low evidence level studies. However, these systemic treatments had poor safety profiles.¹⁷

The lack of success with current treatments is likely due to the heterogeneity of disease and dearth of regimens addressing the immunologic and neural pathophysiologic components of PN.^8,17

Emerging Treatments

Currently, several new treatments are being explored for itch pathogenesis in PN (Table 2).

Nemolizumab

Nemolizumab is a new drug designed to interrupt the itch-scratch cycle in PN. Considering that up-regulation of IL-31 messenger RNA has been reported in PN lesions compared to healthy skin biopsies, a drug interrupting this increase could be beneficial.¹³ Nemolizumab was designed as a humanized anti-human IL-31 receptor A monocloncal antibody. This monoclonal antibody disrupts the binding of IL-31 to its receptor, and in doing so inhibits part of the cascade of inflammatory events causing the itch sensation.^18,19

Results of a phase 2 trial of nemolizumab on adults with moderate-to-severe PN were recently published. Moderate-to-severe PN was defined as 20 or more nodules, while severe PN was characterized as a mean score of at least 7 (range 0-10) for the worst daily intensity of pruritus. PN patients were randomly equally assigned to receive subcutaneous injections of nemolizumab 0.5 mg/kg (n=34), or matching placebo (n=36).²⁰ Three total injections were administered at baseline, week 4 and week 8, with three more visits at weeks 12, 16 and 18. At week 4 there was a 53% reduction from baseline in peak pruritus score (4.5 points) in the nemoluzimab group, compared to a 20% reduction in the placebo group (1.7 points). Reductions were maintained throughout the trial period.²⁰ The mean number of prurigo lesions decreased by a greater proportion in the nemolizumab group compared to the placebo group at week 12. Other secondary outcome measures such as assessments investigators’ global assessments, sleep quality and Dermatology Life Quality Index also demonstrated greater improvements in the nemolizumab group compared to placebo.²⁰ Nemolizumab was associated with more side effects than placebo, namely abdominal symptoms such as abdominal pain and diarrhea, as well as nonspecific musculoskeletal symptoms.²⁰

Based on these strong and promising results for treatment of PN, the FDA recently approved nemolizumab for Breakthrough Therapy status, thus expediting its development and approval process.²¹ Phase 3 trials are currently underway (NCT03989206).

Dupilumab

Similar to nemolizumab, dupilumab is a monoclonal antibody antagonist of the IL-4 receptor, another integral component of the neural pathway for pruritus.¹⁵ Further, it has already been approved by the FDA for three indications including treatment of moderate-to-severe atopic dermatitis.²²

The largest recently published case series has demonstrated the benefit of dupilumab in the treatment of chronic pruritus. Twenty recalcitrant pruritus patients at a tertiary care center were treated with off-label dupilumab at standard atopic dermatitis dosing. Promising results were observed, with complete resolution obtained in 12/20 patients and an overall mean reduction of 7.⁵⁵ points on the numeric rating scale for itch intensity (range 0-10). Specifically, 9 patients in this series had PN, and reported a mean reduction in itch ratings of 7.89. Further, the drug was well tolerated in all patients and no significant adverse events were reported.²² The same authors have also reported success in its specific use for PN in a previously published case series.²³ Several other case series and reports all published within the last year have also described the benefit of dupilumab for treatment of PN.^24-28

Further, a recent retrospective cohort study examined the effectiveness of dupilumab in treating adults affected by persistent atopic dermatitis with clinical features of generalized PN. A total of 90 atopic dermatitis patients were treated, of which 9 patients demonstrated generalized PN. Significant improvements in Eczema Area and Severity Index, Dermatology Quality of Life Index, and pruritus visual analogue scale score were observed after treatment.²⁹ Another recent retrospective cohort study of 16 adult patients with chronic PN refractory to multimodal treatment regimens reported similar results.³⁰ Taken together with the evidence from the case series, the use of dupilumab in treatment of PN shows promise, and warrants further research with randomized control trials.

Opioid Receptor Modulation: Nalbuphine, Butorphanol, Naloxone and Naltrexone

Other research has examined the efficacy of opioid receptor modulating drugs in the treatment of pruritus. Considering that imbalances between mu- and kappa-opioid signalling have been indicated in generalized itch pathogenesis, mixed kappa-opioid agonist/mu-opioid antagonists may interrupt this cycle.³¹ The mechanisms of nalbuphine and butorphanol both act as such, and each have been demonstrated to have some beneficial effects on reducing pruritus. Specifically, one study examined the effects of nalbuphine in hemodialysis patients on treating uremic pruritus, and found discernable reductions in measures of itch severity with increasing dosage.³² Further, case investigations examining the effects of butorphanol on intractable pruritus have also demonstrated its benefit.³¹ Importantly, a recent multicenter, double-blind randomized control trial examined the effects of nalbuphine on itch severity in PN, as well as evaluated the safety and tolerability of the drug in this population. Phase 2 results have been released, but not yet published, and demonstrated promising beneficial effects of nalbuphine in reducing pruritus (NCT02174419).

Intravenous naloxone and oral naltrexone, both mu-opioid receptor antagonists, have also demonstrated antipruritic effects in select PN patients.^33,34 A double-blind, randomized control trial investigating the use of naloxone infusions in patients with pruritus of cholestasis (n=29) found that it was associated with reduced pruritic perception and actual reduction of scratching.³⁵ Further, another trial of 65 patients examined the effects of naltrexone on pruritus, and found significant benefits including lesion healing and symptom reduction.³⁶ Further studies examining the efficacy of opioid receptor modulation in pruritic pathways are warranted given these promising combined results.

Cannabinoids

Cannabinoid receptor (CB)1 and CB2 are expressed on cutaneous nerve fibers, with agonists of these receptors diminishing histamine-induced excitation and leading to reduction of itch.^37,38 As such, these cannabinoid receptors are thought to contribute to the pruritic sensation. A recent systematic review examined the efficacy of cannabinoids for the treatment of chronic refractory pruritus. Only 5 studies were included in the analysis, but all reported a reduction in itch intensity following cannabinoid therapy.³⁹ Considering the recent growth in acceptance of use and favorable legislation of medical marijuana, further research is warranted to explore its potential use in PN.⁴⁰

Conclusion

Novel therapeutics are currently being explored for the treatment of PN. It is important for treatments to consider targeting both the neural and immunologic components of the itch-scratch cycle. Nemolizumab and dupilumab both demonstrate promise in inhibiting specific central nervous system pathways responsible for transmission of the pruritic sensation. Moving forward it is important for clinicians to better understand the pathogenesis of PN, and apply an integrated approach to treatment of this chronic, recalcitrant condition.

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¹Northern Ontario School of Medicine, Thunder Bay, ON, Canada
²Faculty of Medicine, University of Toronto, Toronto, ON, Canada
³Department of Family & Community Medicine, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
⁴Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest:
Jeremy Strain has no conflicts of interest to disclose. Maria Leis has no conflicts of interest to disclose. Kyle O. Lee has received honoraria and/or consulting fees and/or advisory board fees for Bausch Health, Eli Lilly, Eisai, Elvium, and Pfizer for work unrelated to this manuscript. Patrick Fleming has received honoraria and/or consulting fees and/or advisory board fees for AbbVie, Altius, Aralez, Bausch Health, Cipher, Galderma, Eli Lilly, UCB, Novartis, Pfizer, and Sanofi-Genzyme for work unrelated to this manuscript.

Abstract:
Psoriasis is a chronic, immune-mediated skin condition which commonly affects women of childbearing age. Certolizumab pegol (CZP) is an anti-tumor necrosis factor-alpha (anti-TNFα) agent that has demonstrated long-term safety and efficacy in treating moderate-to-severe plaque psoriasis. Previously, there has been limited safety data surrounding its use in pregnancy. The objective of this article is to review pivotal clinical trial data for CZP and explore safety considerations for this agent in pregnancy. This review demonstrates that CZP offers a safe and effective treatment option for women during childbearing years based on pharmacokinetics and available safety data. The observed occurrence of major congenital malformations and miscarriages appears to be no greater than the background occurrence of those in the general population, and risks to the mother are minimal based on its known safety profile. The use of CZP for treatment of plaque psoriasis should be considered and discussed with patients considering childbearing or whom are currently pregnant or breastfeeding.

Key Words:
psoriasis, certolizumab, Cimzia, biologics, anti-TNF agents, pregnancy, obstetrics

Introduction

Plaque psoriasis is a chronic inflammatory immune-mediated skin disorder associated with genetic and environmental factors. The global prevalence of psoriasis is approximately 2% with some regional variation.^1,2 Although psoriasis primarily affects the skin, it also has widespread systemic effects including psoriatic arthritis, depression, and cardiovascular disease.²

Over the past two decades our understanding of the pathogenesis of psoriasis has been largely elucidated. Research has demonstrated that the disease is primarily driven through a mediated pathogenic T-cell pathway. Specifically, high levels of interleukin (IL)-23/T-helper type 17 T-cell are thought to stimulate release of IL-17.³ IL-17 upregulation in turn leads to a “feed forward” cycle, including inflammatory responses in keratinocytes which further drive the development of psoriatic plaques by inducing characteristic changes such as epidermal hyperplasia and cell proliferation and leukocyte recruitment.³

TNFα is a pro-inflammatory cytokine further implicated in the immunopathogenesis of psoriasis.³ The upregulation of TNFα leads to increased production of IL-23, further stimulating the psoriatic pathway. Additionally, TNFα works synergistically with IL-17 to upregulate transcription of many pro-inflammatory genes. Increased understanding of these inflammatory pathways has led to the advent of biologic therapies, including TNFα inhibitors, which have revolutionized the treatment of psoriasis.³

Although advances in our understanding of the disease pathogenesis have spawned the development of targeted biologic therapies, research is limited on the use of these medications in specific subpopulations. Considering that psoriasis often affects women of childbearing age, effective and safe treatment options during pregnancy are an important consideration.⁴ The objective of this article is to review pivotal clinical trial data for certolizumab pegol (CZP), a PEGylated anti-TNFα biologic agent, and explore safety considerations for this treatment option in pregnancy.

Certolizumab Pegol and Early Clinical Trials

CZP (Cimzia®) is a recombinant humanized monoclonal anti- TNFα antibody approved to treat plaque psoriasis, psoriatic arthritis, Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, and axial spondyloarthritis. CZP contains the antigen-binding fragment (Fab) of an immunoglobulin G (IgG) antibody and lacks the fragment crystallizable (Fc) region.⁵ A single cysteine residue allows the Fab portion to be conjugated with polyethylene glycol (PEG) to form CZP, increasing its halflife to 14 days while maintaining its ability to avidly bind TNFα.⁵

Two phase III double-blind randomized placebo-controlled studies (CIMPASI-1 and CIMPASI-2) using CZP for moderate-severe plaque psoriasis found biweekly doses of either 200 mg or 400 mg led to significantly improved responses of the Psoriasis Area and Severity Index (PASI) PASI-75, PASI-90, and Physician’s Global Assessment (PGA) 0/1, when compared to placebo.⁶ The pooled data from CIMPASI-1 and CIMPASI-2 show that after 16 weeks, CZP 200 mg q2w resulted in PASI-75 of 76.7% (P<0.0001), PGA 0/1 of 56.8% (P<0.0001), and PASI-90 of 45.9% (P<0.0001), while CZP 400 mg q2w showed PASI-75 of 82% (P<0.0001), PGA 0/1 of 65.3% (P<0.0001), and PASI-90 of 52.2% (P<0.0001) (supplemental Table 1).⁶ A similar study (CIMPACT) compared its use to etanercept, also a TNFα inhibitor, with CZP 200 mg q2w showing a PASI-75 of 61.3%, with 8% higher when compared to etanercept (P<0.1523).7 Similarly, CZP 400 mg q2w showed a PASI-75 responder rate of 66.7%, with 13.4% higher responder rate when compared to etanercept (P<0.0152) (supplemental Table 2), with efficacy either comparable or superior to etanercept in psoriasis.⁷ However, pregnant and breastfeeding patients were excluded in these initial studies.^6,7

Certolizumab Pegol in Pregnancy

Psoriasis commonly affects women during childbearing years, making safe and effective treatment in this population important.^4,8,9 Up to 32% of women may have worsening or ongoing high disease activity during pregnancy,¹⁰ with increased psoriatic disease linked to adverse outcomes such as low birth weight, preterm delivery, preeclampsia, small for gestational age and fetal loss.⁴ Following, control of psoriatic disease during pregnancy leads to improved pregnancy outcomes, such as reducing preterm delivery, fetal loss, and low birth rates.⁴ Disease control prior to pregnancy and into the postpartum period are also important to maternal and fetal outcomes.¹⁰

Most anti-TNF agents (infliximab, adalimumab, golimumab, etanercept) have a classical IgG structure with an Fc region which can attach to the neonatal Fc receptor for IgG (FcRn) and cross the placenta.¹¹ In particular, circulating maternal IgG antibodies are actively transported across the placenta in the second half of pregnancy, facilitated by FcRn¹¹ Importantly, IgG levels at term in the newborn are higher than maternal levels, with a half-life approximately twice as long as that in the mother.^11-13 Unlike other anti-TNF agents, CZP lacks the Fc-binding property. Results from CZP nonclinical and human placental perfusion data demonstrate that in fact CZP does not bind to FcRn, and consequently suggest that there is no active FcRn-mediated placental transport.^5,14

Several studies have specifically examined the use of CZP during pregnancy. The CRIB study (n=16 mother-infant pairs) measured any potential placental transfer of CZP from mothers to infants at birth, along with concentrations of CZP in the plasma of mothers at delivery and umbilical cords at birth.¹⁵ Maternal CZP plasma levels at delivery were within the expected range (median = 24.4 μg/mL), and infant levels were below the lower limit of quantitation (0.032 μg/mL). Further, the investigators found that gestational age and weight at birth of all infants were within the expected range for healthy infants.¹⁵ Safety data was consistent with the known safety profile of CZP for mothers, and clinical events by infants did not show any patterns of clusters of events suggesting a specific adverse safety signal.¹⁵ The CRIB study provides evidence that levels of CZP are not present in sufficient amounts in infants to cause treatment emergent adverse effects.

Similarly, a recent pooled analysis of n=11,317 patients in clinical trials examined the long-term safety of CZP in rheumatoid arthritis, psoriatic arthritis, psoriasis and Crohn’s disease.¹⁶ With regards to its use during pregnancy, the study concluded there is no to minimal placental transfer from mothers to infants (suggesting a lack of in utero exposure during the third trimester), with the median Relative Infant Dose of CZP in breastmilk (0.125%) considered to be in the safe range for breastfeeding (<10%). The authors concluded that the safety profile of CZP is in line with that of other anti-TNF agents in all indications¹⁶

The CRADLE study (n=18 mothers, n=17 infants) examined the concentration of CZP in mature human breast milk, and assessed safety profiles in both mothers and infants.¹⁷ The study demonstrated almost all breast milk concentrations were less than two times the lower limit of quantification. Further, adverse events in mothers and infants were mostly mild to moderate in intensity (mothers: 3 mild, 6 moderate; infants: 6 mild, 2 moderate). No serious adverse events were reported in infants, and no hospitalizations or deaths in mothers or infants occurred.¹⁷ Overall, this study suggests very low to undetectable levels of CZP in breast milk, which corresponded with no increased risk for breastfeeding infants of mothers using CZP.

A recent review by Clowse and colleagues examined pregnancy outcomes, including major congenital malformations, in women receiving CZP, with a specific focus on the timing of exposure. This analysis represents the largest published cohort (n=538) of pregnant women with known outcomes exposed to CZP for the management of chronic inflammatory diseases.¹⁸ Results demonstrated that most maternally CZP-exposed pregnancies resulted in live births (Figure 1), with miscarriage, induced abortion and stillbirth representing trends similar to the general population (Figure 2). Timing-wise, maternal exposure to CZP occurred during at least the first trimester for 367 of the 452 prospective pregnancies (81.2%) and almost half of the pregnant women (44.5%) were exposed to CZP during all three trimesters. Eight major congenital malformations were observed (Table 1).¹⁸ Further, serious maternal infections occurred in 22 (4.2%) pregnancies, and among those which resulted in a live birth, maternal comorbidities were due to preeclampsia (5 patients, 1.1%) and gestational diabetes (6 patients, 1.3%).¹⁸ Overall, the results suggest there is no increased teratogenic effect of CZP compared to the general population, nor a greater incidence of fetal death. Maternal complications are similar to the general population. Important limitations include a lack of an untreated control group for comparison, lack of follow up for a third of cases, and numbers of pregnancy outcomes in patients receiving an anti-TNF therapy are relatively small for less common birth characteristics.

The above studies provide evidence that CZP use during the third trimester of pregnancy has low or undetectable levels of CZP in infants’ blood, low to undetectable levels of CZP are present in breastmilk, and observed occurrence of major congenital malformations and miscarriages is no greater than that of the general population in mothers using CZP. Considering these findings and the increasingly emergent use of anti-TNF biologics in pregnancy, a Canadian consensus paper on management of plaque psoriasis in women of child-bearing potential was recently published.¹⁹ A panel of nine Canadian dermatologists managing psoriasis reviewed the relevant literature, focusing on TNF-α inhibitors, IL-23 inhibitors, IL-12/23 inhibitors, and IL-17 inhibitors. With respect to CZP, three main conclusions were drawn. First, CZP is the only biologic demonstrating no active placental transport throughout pregnancy due to the lack of the Fc portion, and as such can be used throughout all three trimesters. Second, CZP is the only biologic for psoriasis for which infants exposed have no detectable drug levels. Third, CZP has the most evidence of all biologics reviewed suggesting no to minimal exposure for the fetus and infant.¹⁹ Taken together, these results provide evidence for the safety of CZP throughout all three trimesters of pregnancy and during the breastfeeding period.

Conclusion

Psoriasis is a common condition affecting women during childbearing years, with untreated disease contributing to adverse events for both the mother and infant. CZP appears to offer a safe and effective treatment for patients who are considering pregnancy, pregnant, or lactating based on its pharmacokinetics and available safety data. Importantly, the observed occurrence of major congenital malformations and miscarriages appears to be no greater than the background occurrence of those in the general population, and risks to the mother are minimal based on its known safety profile. The use of CZP for treatment of plaque psoriasis should be considered and discussed with patients considering childbearing or whom are currently pregnant or breastfeeding.

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