¹Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
²Division of Dermatology, University of Calgary, Calgary, AB, Canada
³Beacon Dermatology, Calgary, AB, Canada

Conflict of interest: Leah Johnston does not have any conflicts of interest to disclose. Andrei Metelitsa has been an advisor and speaker for AbbVie, Eli Lilly, Galderma, Leo, Pfizer, Sanofi. Susan Poelman has been an advisor and speaker for AbbVie, Eli Lilly, Galderma, Leo, Pfizer, Sanofi.
Funding sources: None.

Abstract:
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that impacts approximately 10-15% of the population in the United States and Canada. Lebrikizumab is a novel systemic human monoclonal immunoglobulin G4 antibody that inhibits the activity of interleukin-13. In June 2024, lebrikizumab was approved by Health Canada for the treatment of moderate-to-severe AD in adults and adolescents who are 12 years of age and older, followed by US Food and Drug Administration approval in September 2024. This review provides an overview of data from clinical trials on the efficacy and safety of lebrikizumab in adult patients.

Keywords:atopic dermatitis, lebrikizumab, interleukin-13, IL-13, biologics, eczema, dermatitis

Introduction

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that presents with pruritic, erythematous, eczematous patches and plaques that has a predilection for flexural sites. The estimated prevalence of AD in Canada and the United States is 8-16% in adolescents aged 12-17 years and 2-11% in adults.^1-7 Approximately 40% of AD patients have moderate-to-severe disease.⁷ AD has a significant negative impact on quality of life in individuals with the condition and is associated with increased rates of anxiety, depression, and sleep disturbances.⁸ Additionally, AD can be costly to manage for both patients and the healthcare system at large, and previous studies have found that AD has a major adverse impact on workplace productivity and absenteeism.⁸

First-line treatments for AD include emollients with use of wet wraps and topical agents including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and Janus kinase (JAK) inhibitors.⁹ Patients who do not achieve an adequate improvement with topical therapies alone or have severe, widespread AD at baseline may require narrowband phototherapy or systemic therapies to improve disease control.¹⁰ Currently, three monoclonal antibodies and two small molecule inhibitors have received Health Canada approval for the treatment of moderate-to-severe AD (Table 1).¹⁰ This review presents efficacy and safety data from clinical trials of lebrikizumab, the most recently approved treatment for AD in patients ≥12 years of age.

Table 1

Mechanism of Action

AD has numerous predisposing genetic and environmental factors that lead to a predominantly T‐helper type 2 (Th2) cell and type 2 innate lymphoid cell (ILC2)‐driven inflammatory response. Activation of Th2 and ILC2 cells leads to an increase in type 2 inflammatory cytokines, including interleukin (IL)‐4, IL‐5, IL‐13, and IL‐31.¹¹ IL‐4 is thought to primarily exert central effects by regulating the development of immune cells, such as Th2 cells, and promoting production of immunoglobulin E (IgE) by B cells. Conversely, IL‐13 primarily acts in the periphery and both cytokines are implicated in the pathogenesis of AD.¹² IL‐13 is overexpressed in AD lesions and non‐lesional skin compared to healthy controls and levels of IL‐13 in lesional skin correlate with AD severity.¹² IL‐4 and IL‐13 also contribute to cutaneous microbial dysbiosis and disruption of the skin barrier, with IL‐13 predominantly stimulating decreases in antimicrobial peptide and filaggrin protein levels and increasing local expression of IgE and migration of eosinophils.^11,13 Both IL‐4 and IL‐13 can bind to IL‐13 receptor α1 (IL‐13Rα1), inducing the formation of a heterodimeric receptor with the IL‐4 receptor α (IL‐4Rα) subunit and subsequently activating downstream JAK1 and tyrosine kinase 2 (TYK2)‐mediated pro‐inflammatory pathways.¹¹ IL‐13 also binds to IL‐13Rα2, which plays a negative regulatory role by stimulating IL‐13 degradation.^12‐14 Different IL‐13Rα2 receptor epitopes affect IL‐13 clearance rates, which has been observed in asthma studies.¹² Dupilumab binds to IL‐4Rα in IL‐4Rα/IL‐13Rα1 receptor complexes and decreases receptor signaling.^11,15 Although both lebrikizumab and tralokinumab are monoclonal antibodies that bind to IL‐13, lebrikizumab is known to have the highest binding affinity for IL‐13.¹² Lebrikizumab‐bound IL‐13 can still bind to IL‐13Rα1, but formation of IL‐4Rα/IL‐13Rα1 receptor complexes is blocked by lebrikizumab (Figure 1). Tralokinumab prevents IL‐13 from binding to IL‐13Rα1, which also subsequently inhibits IL‐4Rα/IL‐ 13Rα1 heterodimerization.^11,12,16 Tralokinumab also inhibits binding of IL‐13 to IL‐13Rα2, which does not occur with lebrikizumab.¹² In contrast, lebrikizumab‐bound IL‐13 is transported intracellularly after binding to Il‐13Rα2, where it co‐localizes and is subsequently degraded by lysosomes.¹² This mechanism promotes for clearance of IL‐13, while the underlying mechanism of tralokinumab inhibits this process and may lead to persistence of elevated IL‐13 levels.¹²

Figure 1

Production, Administration, Ingredients, Storage and Dosing

Lebrikizumab is a humanized IgG4 monoclonal antibody that consists of two identical heavy gamma chains and two identical light chains.¹⁷ Recombinant DNA technology is used to produce lebrikizumab in Chinese Hamster Ovary cells.¹⁷

Lebrikizumab is administered via subcutaneous (SC) 125 mg/mL (250 mg in 2 mL sterile solution) injections using either pre‐filled syringes or pre‐filled pens.¹⁷ The sterile solution in lebrikizumab is comprised of acetic acid, histidine, polysorbate 20, sucrose, and water. The medication should be stored in a refrigerator with a temperature between 2 and 8 degrees Celsius.

The initial loading dose of lebrikizumab is 500 mg (two injections) at baseline and 2 weeks,¹⁷ followed by administration every 2 weeks in 250 mg SC doses until 16 weeks. After 16 weeks, the dosing frequency can be decreased to every 4 weeks.¹⁷ In some cases, patients who achieved partial responses may be recommended to continue 250 mg every 2 weeks until 24 weeks.¹⁸

Pharmacokinetics

Serum levels of lebrikizumab peak at 7-8 days after SC injections and the estimated bioavailability is 86%.^17,19 Metabolism of lebrikizumab is theorized to occur through the same protein catabolism pathways that typically degrade endogenous antibodies.^19,20 No dose adjustments are required for patients with hepatic or renal insufficiency, or geriatric patients (≥65 years of age).¹⁷

Contraindications to Lebrikizumab

Lebrikizumab is contraindicated in patients with known allergies or hypersensitivity to any ingredients in its formulation.¹⁷ Clinical trials for lebrikizumab have not been conducted in pediatric patients <12 years of age or >12 years who weigh less than 40 kg, and therefore, it is not currently approved by Health Canada for use in these individuals.¹⁷ Lebrikizumab is not currently recommended in pregnant individuals due to a lack of safety data in humans.¹⁷ As lebrikizumab is an IgG4 antibody, it is able to cross the placenta. However, studies in pregnant monkeys that tested lebrikizumab at exposure levels that were 18 to 22‐fold higher than the dosages used in humans, no adverse fetal effects were observed.¹⁷ Fetal serum levels of lebrikizumab were approximately 30% of maternal serum levels.¹⁷ Recent clinical practice guidelines suggest that dupilumab is likely to be safe during pregnancy and other biologics targeting similar pathways are expected to have similar pregnancy safety profiles, though this conclusion cannot be drawn due to the current lack of safety data.²¹

Clinician-Reported Efficacy Data from Phase 2 and 3 Clinical Trials in AD

Three phase 2 clinical trials have been conducted to evaluate the efficacy of lebrikizumab in adults with moderate-to-severe AD (Table 2).^16,22,23 Following completion of phase 2 trials, which demonstrated efficacy for improving AD as well as high safety and tolerability, six phase 3 clinical trials of lebrikizumab have been completed.^24-31 Additional long-term phase 3 efficacy and safety trials are currently being conducted.^32,33

Table 2

The ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) monotherapy, randomized, phase 3 placebo-controlled trials further demonstrated the efficacy of lebrikizumab as a treatment for AD.^24-26 The ADvocate trials enrolled both adolescents ≥12 years of age and adults.^24-26 The primary outcome in both trials was the proportion of participants who achieved an Investigator Global Assessment score (IGA) of 0 or 1 at 16 weeks, representing complete or near complete clearance of AD.²⁴ The secondary efficacy outcome was the proportion of participants who achieved Eczema Area and Severity Index (EASI)-75, indicating ≥75% improvement from baseline, at 16 weeks. In ADvocate1, 43.1% of the lebrikizumab group and 12.7% of the placebo group achieved an IGA score of 0 or 1 at 16 weeks (P < 0.001).²⁴ EASI-75 was achieved by 58.8% and 16.2%, respectively (P < 0.001).²⁴ In ADvocate2, 33.2% of the lebrikizumab group and 10.8% of the placebo group had IGA 0/1 scores at 16 weeks (P < 0.001), and EASI-75 was achieved in 52.1% and 18.1%, respectively (P < 0.001).²⁴ After 16 weeks, patients in the ADvocate1 and ADvocate2 trials who received treatment with lebrikizumab were randomized to either continue 250 mg every 2 weeks, switch to lebrikizumab 250 mg every 4 weeks, or discontinue treatment with lebrikizumab.²⁵ The primary efficacy endpoint, IGA 0/1, was maintained in 71.2% of the lebrikizumab every 2 weeks group, 76.9% of the lebrikizumab every 4 weeks group, and 47.9% of the group that was switched to placebo after week 16.²⁶ The group that received lebrikizumab 250 mg every 4 weeks had the highest proportion of participants who maintained EASI-75 at the end of 52 weeks of treatment (81.7%), compared to 78.4% of patients in the lebrikizumab 250 mg every 2 weeks group and 66.4% of the lebrikizumab discontinuation group.²⁵ No fluctuations in maintenance of EASI-75 occurred in 70.8% of the lebrikizumab every 2 weeks group, 71.2% of the lebrikizumab every 4 weeks group, and 60.0% of the lebrikizumab withdrawal group.²⁶ During the maintenance treatment period (weeks 16 to 52) in the ADvocate1 and ADvocate2 trials, 12.4% of the lebrikizumab every 2 weeks group, 16.1% of the lebrikizumab every 4 weeks group, and 18.3% of the lebrikizumab withdrawal group required treatment with topical therapies to optimize control of their AD.²⁵

The ADhere trial (NCT04250337) was a 16‐week, phase 3 randomized, placebo‐controlled trial of lebrikizumab, combined with low to mid‐potency topical corticosteroids and/or topical calcineurin inhibitors, which participants were instructed to use on an as‐needed basis.²⁷ The primary endpoint, attainment of IGA 0/1 at 16 weeks, occurred in 41.2% of patients in the lebrikizumab 250 mg every 2 weeks group and 22.1% of the placebo injection group (P = 0.01).²⁷ EASI‐75 was achieved in 69.5% of lebrikizumab and 42.2% of placebo group patients (P < 0.001).²⁷ The mean proportion of topical therapy‐free days at 16 weeks was numerically greater in the lebrikizumab group, but this difference was not statistically significant.²⁷

The ADjoin (NCT04392154) trial is a phase 3, long-term, efficacy and safety trial that is pending completion. Preliminary data from this trial demonstrated that 76% of the ADvocate1 and ADvocate2 trial participants and 79% of the ADhere trial participants maintained IGA 0/1 after 2 years of treatment with lebrikizumab at 250 mg every 4 weeks maintenance dosing.²⁸ This data suggests that lebrikizumab is an effective long-term therapy for maintaining complete or near-complete clearance of AD in patients who have optimal responses at 16 weeks.²⁸

Clinician-Reported Efficacy Data from Phase 3 Trials in Pediatric Patients with AD

The ADore trial (NCT04250350) analyzed the effects of lebrikizumab exclusively in adolescent patients between 12 and 17 years of age with moderate‐to‐severe AD.²⁹ Patients received 500 mg loading doses of lebrikizumab at baseline and week 2, followed by 250 mg every 2 weeks throughout the 52‐week trial.²⁹ The primary endpoint was safety and the proportion of participants who discontinued lebrikizumab due to adverse events. At 4 weeks, 28.6% of patients achieved EASI‐75, which rose to 73.2% at week 16 and continued to steadily increase to 81.9% at the end of the 52‐week trial.²⁹ IGA 0/1 was achieved in 14.4% at week 4, 46.3% at week 16, and 62.6% at week 52.²⁹ Rescue therapies were needed in 27.2% of participants.²⁹ The ADorabale‐1 (NCT05559359) and ADorable‐2 (NCT05735483) trials, two phase 3 placebo‐controlled randomized controlled trials (RCTs) in children aged ≥6 months, are currently in progress.^32,33

Subset efficacy analyses from the ADvocate1, ADvocate2, and ADhere trials found that data collected from adolescent patients were consistent with overall population outcomes.³⁰

Effects of Lebrikizumab on Vaccine-Induced Immune Responses

The ADOPT-VA trial (NCT04626297) was a phase 3 placebo-controlled RCT that was conducted to analyze responses to non-live vaccines in patients receiving treatment for AD with lebrikizumab.³¹ No differences in response rates between the lebrikizumab and placebo groups were observed following the meningococcal conjugate vaccine and the tetanus toxoid booster vaccine.³¹ Improvements in AD severity and symptoms were similar to results from other lebrikizumab trials.³¹

It is recommended that patients receive age-appropriate live vaccinations prior to starting lebrikizumab, as they are contraindicated during treatment.¹⁷

Patient‐Reported Outcomes

Across published phase 2 and 3 trials, patients who received lebrikizumab 250 mg every 2 weeks had significantly higher rates of achieving a ≥4‐point decrease in Pruritus Numerical Rating Scale severity scores compared to the placebo groups.^16,24,27,31 At 52 weeks, more than 60% of participants in the ADvocate1 and ADvocate2 trials maintained this improvement.²⁶ Additionally, sleep loss and the interference of pruritus with sleep were significantly better with lebrikizumab compared to placebo,³⁴ Furthermore, these improvements were associated with higher Dermatology Life Quality Index ratings.³⁵ Patients in the ADvocate1 and ADvocate2 trials who received treatment with lebrikizumab also experienced significant improvements in depression and anxiety ratings compared to placebo.³⁶

Safety Data

A pooled safety analysis of the eight clinical trials of lebrikizumab for AD found that the rates of adverse events (AEs) were 49.2% in participants who were treated with lebrikizumab 250 mg every 2 weeks and 53.1% in participants who received treatment with a placebo, of which 2.3% and 4.4% were classified as severe AEs, respectively.³⁷ AEs leading to treatment discontinuation occurred in 2.3% of lebrikizumab 250 mg every 2 weeks and 1.4% of placebo group participants.³⁷

Conjunctivitis was the most common treatment-emergent adverse event (TEAE) in the lebrikizumab groups (6.5%).³⁷ Allergic conjunctivitis was reported in 1.8% of the lebrikizumab 250 mg every 2 weeks groups and in the TREBLE RCT, more than half (53%, n=8/15) of all instances of conjunctivitis were allergy-related.^22,37 Approximately 20% of patients in both the lebrikizumab and placebo groups had a past history of conjunctivitis at baseline, but only 1.8% of the placebo groups developed the condition during the trials.³⁷ Targeting IL-13 signaling is theorized to interfere with maintenance of the conjunctival mucosa by decreasing levels of conjunctival goblet cells, thereby increasing the risk of conjunctivitis.³⁷ Other TEAEs that were more common in participants who received lebrikizumab included nasopharyngitis (4.4%), headache (4.4%), dry eye (1.4%), allergic rhinitis (1.0%), and injection site reactions (2.5%).³⁷ No participants developed anaphylaxis or hypersensitivity reactions.³⁷ Eosinophilia occurred more frequently in the placebo groups (0.8%) than the lebrikizumab every 2 weeks groups (0.6%).³⁷

The lebrikizumab every 2 weeks groups developed herpes zoster (0.6%) and herpes simplex (0.3%) infections at higher rates compared to the placebo groups, in which no cases were reported.³⁷ Eczema herpeticum was not reported in patients receiving lebrikizumab every 2 weeks, while the incidence was 0.7% in the placebo groups.³⁷ Lebrikizumab could theoretically increase the risk of helminth infections, though this was not observed in the lebrikizumab every 2 weeks trial groups.^17,37 No confirmed opportunistic infections occurred in any of the lebrikizumab or placebo groups.

Non‐melanoma skin cancers (NMSC) occurred in 0.3% of the lebrikizumab 250 mg every 2 week groups and 0.5% of the placebo groups.³⁷ No other malignancies were observed during the 16‐week trial period in the lebrikizumab 250 mg every 2 weeks and placebo groups.³⁷ In a pooled analysis of all participants who received lebrikizumab with any dosing protocol (including a single dose at baseline), 0.3% of participants developed NMSC and 0.4% developed other malignancies, including prostate cancer (n=1), cutaneous T‐cell lymphoma (n=2), endometrial adenocarcinoma (n=1), invasive breast cancer (n=1), a neuroendocrine tumor (n=1), and metastatic pancreatic carcinoma (n=1).³⁷ All malignancies were classified as unrelated to lebrikizumab by the study investigators and were similar to expected malignancy rates.³⁷

Data from Clinical Trials for Asthma

Asthma is a common comorbidity of AD and in patients with both moderate‐to‐severe asthma and AD, consideration should be given to systemic therapies that can optimize management of both conditions. Some phase 2 and 3 trials of lebrikizumab found reductions in rates of asthma exacerbations and hospitalizations in adolescents and adults with poorly controlled asthma, though other studies have failed to demonstrate consistently significant results.^38‐40

Efficacy Comparison of Lebrikizumab to Other Biologics and Small Molecule Inhibitors for AD

A 2024 network meta‐analysis of RCTs that investigated biologics and small molecule inhibitors for moderate‐to‐severe AD found that lebrikizumab, along with dupilumab and tralokinumab, had intermediate efficacy and the most favorable safety profiles.⁴¹ While JAK inhibitors, including upadacitinib and abrocitinib, have demonstrated the highest efficacy in improving AD, they were associated with significantly higher rates of AEs. Compared to dupilumab, lebrikizumab has shown a slightly reduced but non‐significant difference in reducing EASI scores from baseline, though dupilumab was associated with a higher chance of achieving EASI‐50 and IGA 0/1 at 16 weeks.^42,43 Lebrikizumab showed comparable or superior performance to tralokinumab for clinician and patient‐reported efficacy measures.^41,42

A comparative study that analyzed propensity‐matched participant cohorts based on week 16 EASI and % BSA scores from the ADvocate trials and the SOLO‐CONTINUE dupilumab phase 3 RCT found that lebrikizumab every 4 weeks showed comparable or superior maintenance of efficacy outcomes between week 16 and week 52.⁴³ Lebrikizumab may be advantageous due to the less frequent dosing schedule during the maintenance phase, as the FDA‐approved maintenance frequency of dupilumab is every 2 weeks.⁴³

Conclusion

Lebrikizumab is a novel monoclonal IgG4 antibody that targets IL‐13 and prevents IL‐4Rα/IL‐13Rα1 receptor signaling and is approved by Health Canada for the treatment of moderate‐to‐severe AD in adolescents 12 years or older and adults. Lebrikizumab has comparable efficacy to other monoclonal antibody treatments for AD, including dupilumab and tralokinumab, requires less frequent monthly maintenance doses than dupilumab after 16 weeks, and is associated with a lower rate of adverse events compared to JAK inhibitors. Lebrikizumab is a promising option for the treatment of moderate‐to‐severe AD given its favorable safety profile, durable efficacy in long‐term follow‐up studies, and major improvements in pruritus, sleep, and overall quality of life in patients with AD.

Purchase Article PDF for $1.99

¹School of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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

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

Introduction

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

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

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

IL-31 Pathway and Mechanism of Nemolizumab

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

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

Phase 3 Clinical Trials for Prurigo Nodularis

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

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

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

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

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

Table 1.

Phase 3 Clinical Trials for Atopic Dermatitis

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

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

Table 2.

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

Conclusion

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

Purchase Article PDF for $1.99

Abstract

Background: Atopic dermatitis (AD) is a heterogeneous disease characterised by epidermal barrier dysfunction and immune dysregulation. It commonly presents with pruritus and eczematous lesions that significantly impact quality of life. Abrocitinib is a JAK inhibitor approved for treatment of refractory, moderate-to-severe AD in patients 12 years and older.

Objectives: This real-world case series intends to illustrate a variety of moderate-to-severe AD patient cases to help guide discussions around abrocitinib and describe its treatment strategies used by experts in the field.

Methods: Expert panel members were recruited from across Canada to discuss varying clinical AD phenotypes seen in their clinic. Guided by literature, the panel shared their opinions and insights to provide a holistic view of the overarching question, “Which patients are good abrocitinib candidates?”

Results: The panel reported on ten real-world patient cases that detailed the use of abrocitinib in biologic naïve patients, refractory AD patients, complex medical patients, and those with differing treatment goals. Cases aim to demonstrate the broad use of abrocitinib in patients with AD, offering a learning point with each real-world case.

Conclusions: Each presented real-world case reflects the panel’s clinical experience. Panel members concluded that abrocitinib is a fast-acting, safe, and efficacious therapy for a wide variety of AD patients with differing disease severities and comorbidities. Treatment with abrocitinib may cause transient nausea that frequently resolves by taking it with food. Overall, patients are highly satisfied with the treatment.

Keywords: atopic dermatitis, real-world cases, JAK inhibitor, abrocitinib

Disclosures and Acknowledgment: The authors conducted the real-world series, supported by an educational grant from Pfizer Canada. The authors acknowledge and thank Sophie Guénin, MSc, for her assistance in preparing this manuscript.

PDF Download

Introduction

Atopic dermatitis (AD) is a heterogeneous, chronic inflammatory skin disease characterized by epidermal barrier breakdown, immune dysregulation, and significantly reduced quality of life (QoL).¹ Approximately 3.5% of the total Canadian population and 25.4% of the pediatric Canadian population is affected with AD.^1,2 This relapsing condition may present as dry, erythematous, sensitive skin or pruritic, excoriated, eczematous, and painful patches with weeping erosions and prurigo nodules.¹ About one-third of AD patients are affected by atopic comorbidities such as asthma, food allergy, and hay fever.³

Patients with AD report impaired quality of life that limits their daily lives and social interactions.³ Pruritus is reported as the most burdensome symptom of AD, with 95% of patients reporting itch as the most important indicator of treatment response.⁴ Other burdensome symptoms included excessive dryness, scaling, inflamed skin, skin pain, and sleep disturbance.⁴ Impaired barrier function in AD is largely attributed to filaggrin dysfunction.⁵ Meanwhile, immune dysregulation in AD largely stems from T-helper (Th)2 cell cytokines, interleukin (IL)-4 and IL-13, in its acute phase and Th1 skewing in chronic disease.⁶ IL-22 and IL-17-producing T cells have also been implicated in the pathogenesis of AD.⁶

Systemic Treatment for Moderate-to-Severe AD

The consensus-based European guidelines for the treatment of AD recommend proactive therapy with topical calcineurin inhibitor (TCI) or topical glucocorticosteroids (TCS) for moderate AD along with narrow band (nb) UVB phototherapy, psychosomatic counseling, and climate therapy.⁶ For severe AD, the guidelines recommend hospitalization in specific cases, systemic immunosuppression with cyclosporine, short-course oral glucocorticosteroids, methotrexate, azathioprine, or mycophenolate mofetil.⁷ Biologic monoclonal antibody therapies such as dupilumab are also recommended for severe AD patients.⁷

Dupilumab is an anti-IL-4-receptor α monoclonal antibody that inhibits the signaling of both IL-4 and IL-13.⁶ Since the guidelines were published in 2018, an additional monoclonal antibody therapy, tralokinumab, an IL-13 inhibitor, has been approved for AD treatment in Canada, as well as two janus kinase inhibitors (JAK) inhibitors (JAKi): abrocitinib and upadacitinib.⁶

Newer topicals such as the topical PDE4 inhibitor, crisaborole, has also been recently introduced for AD treatment, and ruxolitinib, a topical JAK inhibitor, not yet available in Canada.^6,7

Abrocitinib & JAK Inhibitors (JAKis)

JAKis are a new class of systemic treatments for AD that function by blocking downstream cytokine inflammatory signaling.⁶ Abrocitinib and upadacitinib are once daily, oral JAK1 inhibitors that block IL-4 and IL-13, cytokines involved in the pathogenesis of AD, downstream.^8,9 Abrocitinib is available in three doses: 50 mg, 100 mg, and 200 mg, and is approved for moderate-to-severe AD patients aged 12 and older.⁹ In pivotal trials JADE MONO-1 and JADE-MONO-2, abrocitinib demonstrated significant pruritus reduction within two weeks.^10,11 In a phase 3 comparative clinical trial, JADE-COMPARE, abrocitinib 200 mg demonstrated greater IGA response and itch response at endpoint than dupilumab.¹² As with all JAK inhibitors, abrocitinib has inherited a black box warning for thrombosis, major adverse cardiovascular events (MACE), and malignancy. Despite this, clinical trial safety analysis at 48 weeks of both the 100 mg and 200 mg abrocitinib dosage groups showed only 0% to 0.3% incidence of the following: nonmelanoma skin cancer (NMSC), malignancy, MACE, or VTEs.¹³

Upadacitinib is approved for the treatment of AD, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondylarthritis.⁹ In refractory moderate-to-severe AD, upadacitinib is approved in Canada for ages 12 and up with two dosing options: 15 mg and 30 mg; recommendations suggest initiating treatment at 15 mg prior to titrating up to 30 mg.¹⁴

As more treatments become available, it will be important for clinicians to partner with patients in a treat-to-target (TTT) paradigm to identify the optimal AD treatment for each patient.¹⁵

Methods

Aim of the Project

This real-world case series illustrates a variety of patients with moderate-to-severe AD treated with abrocitinib. The cases outline the TTT paradigm and demonstrate patient-provider partnerships that highlight patient priorities and ideal treatment options. Expert panelists’ thought processes, reasoning, and rationales are detailed in the following patient cases to serve as a guide for licensed providers who treat patients with AD.

Steps in the Process

The project was conducted in the following five steps: 1) project definition and expert panel selection 2) data collection and preparation of patient cases, 3) patient case discussion and selection for publication 4) literature review to support selected cases 5) drafting, review, and finalization of the manuscript.

Role of the Panel

The panel consisted of 10 dermatologists practicing in Canada who commonly care for patients with AD. Panelists were chosen from 3 provinces in Canada to capture geographical and provincial differences in dermatological practice. During the Dermatology Update conference on April 30^th, 2023, in Vancouver, panelists met to report on and discuss clinical cases of AD patients who were suitable candidates for abrocitinib treatment.

The panel used the following template to gather insight through a case-based approach:

Panelists were asked to select two patient cases from their clinical practice to share and discuss. In the second half of the meeting, panelists examined and collaborated to select ten real-world cases for inclusion in the publication. Panel members agreed that real-world cases should focus on common AD scenarios encountered in the clinic. The publication was prepared and reviewed by the panel.

Experience Gathering and Atopic Dermatitis Outcome Measures

Suggested information and outcome measures to present included patient demographics, concomitant medications, comorbidities and Investigators’ Global Assessment (IGA) score, Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (PP-NRS), and patient-reported Dermatology Life Quality Index (DLQI) at weeks 0, 2, and 4 (+/- 5 days) of abrocitinib treatment (Appendix 1). Panelists were also requested to report patient compliance, treatment satisfaction, and any adverse events experienced.

Results

Selected Real-World Cases

The panel selected ten cases to demonstrate the real-world use of abrocitinib in a diverse group of patients with varying skin concerns, past treatment failures, severity, and comorbidities. The findings reflect real-world clinical use of oral abrocitinib and patient treatment outcomes.

Case 1: The recalcitrant, severe AD patient with intense pruritus

A 31-year-old Caucasian, Fitzpatrick Skin Type (FST) 1, female struggling with severe, recalcitrant AD for the past 18 years presented with reported worsening anxiety, avoidance of social activities, and sleep interruption due to debilitating pruritus. Intense pruritus led to diffuse excoriations and multiple skin infections. Her EASI was 22, and DLQI 20. Over the years, the patient had tried TCS, TCI, crisaborole, nbUVB phototherapy, and systemic therapies: prednisone, methotrexate, and intramuscular triamcinolone injection. She had developed striae on her abdomen and arms from frequent TCS use and continued to suffer from intractable itch. The patient started dupilumab but discontinued it after three months due to repeated flu-like symptoms and nasopharyngitis. Having failed first, second-, and third-line therapies for AD, the patient was started on abrocitinib, 200 mg daily. The rationale for beginning abrocitinib at the higher dose was the failure of previous treatment and the patient’s primary complaint of incessant itch. Within eight weeks, she saw rapid improvement; her EASI was 8 and DLQI 4. At week 16, her EASI was 2 and DLQI 0. When asked about her experience, the patient reported that abrocitinib had “life-changing” effects after only one month of treatment. No adverse events occurred, and the patient was reduced to 100 mg abrocitinib daily without exacerbation.

Learning point: Abrocitinib is a fast-acting, effective, and safe treatment option for patients with longstanding, recalcitrant AD. It may be an option for patients who have failed many prior therapies. Abrocitinib therapy can improve patients’ QoL and reduce the need for TCS and other adjunct therapies, thereby sparing patients from the undesirable adverse effects of these treatments.

Case 2. The biologic-naïve patient

Since early childhood, a 55-year-old Caucasian (FST1) salesman with hypertension, hypercholesterolemia, and prediabetes had suffered from severe AD that affected extensive parts of his head, neck, trunk, and extremities. Since starting amlodipine and rosuvastatin for his comorbid conditions, the patient reported worsening xerosis and diffuse erythema.

While biologic naïve, he had previously tried various moisturizers, TCS, TCI, phototherapy, and oral antihistamines with only modest benefit. Despite the multimodal treatment approach, the patient continued to have frequent visits to the Emergency for infections and exacerbations. His condition greatly impacted his work and social interactions as well as his psychological and sexual health. Given his frequent business travel, busy family life, and needle aversion, the patient expressed interest in a convenient, effective treatment that would improve his worsening xerosis and eliminate the requirement for additional therapies. For these reasons, the patient was started on 100 mg abrocitinib. Within two weeks, the patient’s IGA score reduced from 3 to 2, EASI score from 4 to 2 and PP-NRS score from 8 to 3. Two weeks later, the patient saw continued improvement with an IGA score of 1, EASI score of 1, and PP-NRS score of 2. Rapid reduction in itch made the patient extremely satisfied with abrocitinib monotherapy. He did not experience any adverse events and was “thrilled” with his outcome. The patient remains on abrocitinib 100 mg with the option to increase to 200 mg, if necessary.

Learning point: JAKi is an option for biologic-naïve patients for whom self-injection does not correspond to their lifestyle. Patients who travel frequently or lead busy lifestyles may have difficulty transporting subcutaneous injections that must be stored in cool temperatures or having the proper setting to self-inject. Further, some patients are needle-phobic and would prefer an effective, oral treatment option.

Case 3. The patient with post-inflammatory hyperpigmentation

A 29-year-old Southeast Asian (FST4) female presented with sensitive skin, longstanding AD and significant post-inflammatory hyperpigmentation (PIH) around her eyes and on her arms. She had been treated with multiple courses of prednisone with a good response but would predictably flare 2-4 weeks after steroid discontinuation. Having suffered from AD since infancy, she reported the post-inflammatory hyperpigmentation from AD as her most bothersome symptom. Previous treatments included TCS, TCI, and crisaborole. She saw a slight improvement in her skin and pruritus with topical therapy in conjunction with oral antihistamines. Despite mild improvement, she was still desperate for a long-term, effective solution. Her primary care physician had recently made her aware of abrocitinib and encouraged her to seek evaluation by a dermatologist. As a young, single female without any plans for pregnancy in the near future, the patient was a good candidate for abrocitinib and was started on abrocitinib 100 mg. Her IGA was 3 at baseline, EASI score was 4, and PP-NRS score was 8. By week 4, her IGA, EASI, and PP-NRS scores were all 1, and she felt happy and hopeful that PIH marks would continue to fade with time. No compliance issues or adverse reactions were reported.

Learning point: Patients with skin of colour are at increased risk for PIH. Consistent AD treatment with abrocitinib and control of AD, results in PIH improvement and improved mood and QoL. It also reduces inappropriate, long-term use of oral corticosteroids. In females of childbearing age, it is also important to inquire about pregnancy and/or contraceptive use. Pregnancy is a contraindication for abrocitinib use. It should be recognized that contraceptive use may lead to low risk of VTE. Family planning should be discussed with all patients of childbearing potential who are contemplating treatment with abrocitinib.

Case 4. The atopic patient with barriers to treatment access

A 22-year-old (FST2) male with lifelong AD and comorbid atopic diseases (hay fever, asthma, and urticaria) presented with worsening pruritus. Physical exam revealed symmetric, generalized excoriated red, scaly patches with significant lichenification on his bilateral extremities, face, scalp, and back. Working as a dishwasher, the patient reported wearing gloves most of the day to protect his skin from irritating soaps or dryness. Despite his precautions, his skin began impacting his ability to work. He reported skin burning, discomfort, unbearable itch, and skin pain, which frequently disrupted his sleep. At presentation, while on methotrexate, his EASI was 23, IGA score 4, and DLQI 18, with 31% of his body surface area (BSA) affected by AD (Figure 1A [back – face]). Throughout his lifetime, the patient had tried lifestyle modifications such as fragrance-free, hypoallergenic detergent, gentle cleansers, moisturizer application every 2 hours as well as TCS, TCI, calcipotriol gels, oral antihistamines, systemic corticosteroids, and 1-year of methotrexate. Given the severity of the patient’s AD and worsening QoL, the plan was to begin biologic monoclonal antibody therapy. Unfortunately, the patient could not gain access to dupilumab or tralokinumab through his insurance, compassionate drug program, or patient assistance programs. Fortunately, the patient was able to access 100 mg abrocitinib and was thus started on this oral therapy in lieu of biologic therapy. The 100 mg dose was chosen since the patient and his mother were risk-averse and wished to try the 100 mg dose first, increasing to 200 mg only if the 100 mg dose was not sufficient. Two weeks prior to starting abrocitinib, the patient was given his first shingles vaccine. At his 11-week follow-up visit, the patient reported no skin pain and minimal itch with only slight residual erythema on his face (EASI 1.1, IGA 1) (Figure 1B [face – back]). He reported that he could sleep through the night and was able to stop using topical therapies and antihistamines. Of note, the patient experienced mild initial nausea and abdominal pain that abated within the first few weeks of treatment. He had his second shingles vaccine after commencing abrocinitib treatment.

Learning point: Abrocitinib is readily accessible to some patients who are unable to gain coverage for monoclonal antibody therapies such as dupilumab and tralokinumab. While addressing itch, abrocitinib also effectively targets skin pain. It is important to consider shingles vaccination prior to abrocitinib start. The second dose of the vaccine can be given 1-6 months later.¹⁶ Nausea may also be an important adverse effect to discuss with patients. Nausea is frequently transient and can be improved by taking abrocitinib with food.

Figure 1: 22-year-old male with severe AD
(Photos courtesy of Lyn Guenther MD, FRCPC)

Case 5. The complex medical patient with persistent AD-related pruritus

The retired aerospace worker, two-time widower, and former smoker the 63-year-old man, has atopic triad and comorbid anxiety, depression, hyperlipidemia, hypertension, and a history of stroke. He presented with persistent AD, severe pruritus, and atopic keratoconjunctivitis (AKC). His concomitant medications included: citalopram, atorvastatin, ezetimibe, perindopril, and clopidogrel. Despite his other conditions, the patient was most concerned with his pruritus as it had prevented him from sleeping, exercising, socializing, dating, and working. He had only slept through the night three times in the past year. Embarrassed by his skin, he has not been in a swimming pool for over ten years. His EASI was 50, DLQI 26, IGA 4, PP-NRS 10, and BSA 49% (Figure 2A [face – back – legs]).

Having tried numerous moisturizers, TCS, 12 years of nbUVB phototherapy, antihistamines (up to 4 times approved dosing), and multiple cycles of prednisone, he continued to suffer from his skin condition. He was enrolled in a lebrikizumab clinical trial, which helped his AD and pruritus but did not clear his face and neck. However, during the clinical trial, he suffered a non-treatment-related posterior cerebral artery infarct, which has deterred him from future biologic use. The patient redeveloped generalized erythema, lichenification, and scaling off the biologic.

The rationale for starting abrocitinib stemmed from numerous conversations with the patient, during which he highlighted his preference for QoL over mere survival. He was desperately seeking to sleep through the night and regain control of his life. Use of immunosuppressants such as methotrexate and cyclosporine were contraindicated in this patient due to his heavy alcohol use and hypertension, respectively. Given his AKC, dupilumab, and tralokinumab were eliminated as options to reduce the risk of worsening his ocular involvement. The lower perceived rates of MACE and VTE events with abrocitinib compared to upadacitinib led to the patient being started on abrocitinib. Two weeks prior to starting abrocitinib, he received his first dose of the shingles vaccine. The decision was made to start at 50 mg of abrocitinib to mitigate any potential risk for drug interactions or adverse cardiovascular events. He reported that during his first week on abrocitinib, he was able to sleep itch-free every night and noticed smoother skin texture. After one month of monitoring without any adverse events nor appreciable changes in blood values, the patient was increased to 100 mg abrocitinib. After two weeks on 100 mg abrocitinib, the patient’s EASI was reduced to 6.4, DLQI to 6, IGA to 2, PP-NRS to 1.5, and BSA to 10% (Figure 2B [face – back – legs]). The patient remains on 100 mg of abrocitinib with good control of AD, itch, and good tolerability.

Learning point: Assessment of risks and benefits with a patient remains an important consideration in the TTT paradigm for AD treatment. While extra precautions must be considered in a complex medical patient, their complexity does not preclude them from abrocitinib therapy. Titration of the abrocitinib dose, starting at 50 mg, may also help minimize any potential risk while simultaneously allowing patients to benefit from treatment.

Figure 2: 63-year-old medically complex male with anxiety, depression, hyperlipidemia, hypertension, and a history of stroke
(Photos courtesy of Lyn Guenther MD, FRCPC)

Case 6. The busy professional biologic naïve patient needing a fast-acting therapy

A 38-year-old lawyer of Asian (FST4) descent presented to the clinic in search of a rapid solution for his AD. He had no significant past medical history other than lifelong AD. At presentation, his DLQI was 28, EASI was 50, and IGA was 4 (Figure 3A [face – legs]). He had only previously tried betamethasone 0.1% cream and prednisone with mild, transient improvement after each therapy. Despite being naïve to systemic therapies beyond prednisone, he wanted a quick, easy solution to his skin condition that would not impact his busy schedule and allow him to enter conference rooms with confidence. Understanding the patient’s aggressive treatment goals, the provider started him on 200 mg of abrocitinib with concomitant use of tacrolimus ointment 0.1% twice daily, as needed. Four weeks later, the patient returned with 90% skin clearance, including complete clearance on his face and only post-inflammatory erythema remaining on his extremities (Figure 3B face – legs]. At his 6-month follow-up, he had clear skin (Figure 3C [legs]). While he was given the option to reduce to the 100 mg dose, the patient has been reluctant to decrease the dosage given his rapid, lasting response to the current abrocitinib 200 mg regimen.

Learning point: The 200 mg dose of abrocitinib may be an optimal first-choice therapy for select patients. The JAKi allows for fast results, and the ease of a once-daily pill makes it an ideal option for working professionals with hectic lives. The 100 mg and 200 mg abrocitinib dosing options also allow patients to choose how aggressively they would like to treat their AD while relying on their provider to help them weigh the risks and benefits.

Figure 3: 38-year-old biologic naïve male
(Photos courtesy of Andrei Metelitsa MD, FRCPC)

Case 7. The dupilumab failure AD patient

A 62-year-old (FST3) male with generalized AD since adolescence was initiated on 100 mg of abrocitinib therapy. Having struggled most of his adult life with daily TCS and emollient regimens, the patient was frustrated as his AD had a determinantal impact on his daily activity, social life, sports participation, and sleep. He had previously tried one year of dupilumab treatment with an inadequate response. Prior to starting abrocitinib, his EASI was 12, IGA 3, and PP-NRS 8. After two weeks on abrocitinib, the patient had an EASI of 3.2, IGA 1, and PP-NRS of 1. Despite reporting nausea from therapy, he expressed 8 out of 10 satisfaction, given his dramatic skin response. At his 4-week follow-up, the patient had an EASI of 2.1, IGA 1, and PP-NRS of 1, with resolution of his nausea and no further adverse events.

Learning Point: Abrocitinib is an ideal step-up therapy for patients who have an inadequate response to dupilumab. The differing mechanisms of action of abrocitinib and dupilumab make the trial of abrocitinib worthwhile in a patient who may have failed IL-4 receptor blockade. Nausea, when and if it occurs, often resolves spontaneously.

Case 8. The patient intolerant to dupilumab

Struggling with AD since childhood, a 47-year-old female (FST4) with mild asthma and severe AD presented after 16 months of dupilumab therapy. While dupilumab was effective for the first year, her skin failed to maintain its initial response. She had also developed persistent conjunctivitis secondary to dupilumab use. AD covered her trunk, face, and proximal extremities and often caused her to miss work and avoid romantic and social relationships. She struggled to sleep through the night without scratching. In the past, she had tried topical tacrolimus and clobetasol without any lasting improvements. The rationale for starting 100 mg abrocitinib was intolerance and failure to maintain response to dupilumab. On Day 0, her EASI was 35, IGA 4, and PP-NRS score 8. Upon starting abrocitinib treatment, the patient reported mild nausea that improved when the tablet was taken with food. By week 4, the nausea had resolved, and the patient had an EASI of 16, IGA of 2, and PP-NRS of 3. She reported feeling more confident in her skin, with reduced pruritus and improved sleep and quality of life. Without experiencing any other side effects, the patient remains on 100 mg of abrocitinib and is highly satisfied with the treatment.

Learning Point: The side effect profile for abrocitinib does not include conjunctivitis or any other ocular effects, making it ideal for patients sensitive to the adverse reaction of dupilumab or tralokinumab or patients with comorbid ocular conditions. Lastly, nausea is a common adverse effect of abrocitinib therapy that usually resolves with time and may be mitigated by taking the medication with food.

Case 9. The patient with adult-onset AD

The 49-year-old (FST2) male presented with a 4-year history of adult-onset AD. He had a remote history of alcohol-induced pancreatitis but no other comorbidities. Expressing high levels of frustration with his inadequate sleep and intractable itch, the patient wanted rapid control of his pruritic skin. He had tried TCS, TCI, and cyclosporine without sustained skin improvement, and he experienced deterioration of his kidney function from cyclosporine. His EASI was 25, IGA 4, and PP-NRS score 9. The rationale for starting abrocitinib was that the patient was desperate for rapid control. While upadacitinib was considered for rapid pruritus relief, the patient’s history of alcoholism made abrocitinib a safer option as it does not require monitoring of liver function tests. After four weeks of abrocitinib 100 mg daily use, the patient no longer required use of TCS and had an EASI of 1.2, IGA of 2 and PP-NRS of 4. He was extremely satisfied with treatment and tolerated the treatment without any adverse events.

Learning Point: Immunosuppressants such as cyclosporine and methotrexate have long been used to treat AD, although Health Canada does not approve them for treating AD. In addition, these immunosuppressants are often associated with kidney toxicity (cyclosporine), liver and bone marrow toxicity (methotrexate) as well as malignancy (both medications). Thus, long-term use of these immunosuppressants is not appropriate for long-term use in AD patients. In addition, the increasing availability of efficacious, safe, and targeted treatments for AD makes the use of broad immunosuppressants inappropriate.

Case 10. The AD patient switching from another JAK inhibitor

The 21-year-old (FST4) male university student presented with severe AD involving his torso and limbs. His AD first presented in childhood. He had a positive family history of atopic disease. Having tried TCS, crisaborole, and a 2-year course of methotrexate without improvement, the patient was started on upadacitinib. While the upadacitinib helped to significantly clear his skin, he developed acneiform lesions on his face which led to treatment cessation. His AD returned upon upadacitinib cessation (EASI 24, IGA 4, and BSA 30%). A healthy young man, the patient was offered to start at the higher 200 mg dose of abrocitinib, which should allow for faster control of his AD and a quicker return time to being more productive at school. At his 4-week follow-up, the patient had an EASI of 1.2, IGA of 2, and BSA of 3%, with the most considerable improvement on his face and neck. The patient reported mild nausea a few hours after taking abrocitinib; however, the nausea abated when he started taking it with food. Interestingly, he did not experience acne on abrocitinib.

Learning Point: Abrocitinib is a good treatment option for patients who had adverse reactions to another JAKi. There is a low risk of acne as an adverse reaction to abrocitinib versus upadacitinib. Thus, if a patient develops acne on one JAKi, it does not preclude them from trying abrocitinib.

Discussion

Real-world cases provide highly impactful insight into patient and provider experience with a new treatment. Without a cure, the AD treatment goal is aimed at reducing symptoms to a level that has minimal or no impact on patient QoL. In the patient cases discussed above, all patients had previously tried and failed topical therapies such as TCS, TCI, and various emollients and moisturizers. While some had tried systemic therapies, a few were naïve to systemic AD therapies prior to starting abrocitinib. Each patient discussed had a complete or near complete response by week 4 of abrocitinib therapy and reported significant satisfaction with treatment. This real-world case discussion provides invaluable insight into abrocitinib use in a diverse population of Canadian patients suffering from moderate-to-severe AD.

Biologic Naïve Patients

The 2018 consensus-based European guidelines for the treatment of adult AD only recommend the use of dupilumab in severe AD.⁶ While JAKi’s were not yet approved when these guidelines were released, clinical experience suggests that many practices do not recommend JAKi until a patient has failed all other standard therapies, such as dupilumab and other immunosuppressants. However, panel members discussed five cases of biologic-naïve patients with safe, efficacious, and accessible treatment with abrocitinib. The patients’ successful treatment with abrocitinib as a second-line therapy after topicals suggests that requiring a patient to cycle through a biologic prior to a JAKi may be unnecessary. Biologic naïve patients reported being “thrilled” and “very satisfied” with abrocitinib oral dosing that provided rapid itch relief and improvement in QoL.

Dupilumab Failed/Intolerant Patients

Another recurring rationale for initiating a patient on abrocitinib therapy was previous inadequate response or intolerance to dupilumab treatment. Three patients presented had previously been on dupilumab and stopped either due to inefficacy, failure to maintain response, or secondary conjunctivitis. Switching to abrocitinib after prior dupilumab therapy had no effect on the JAKi’s efficacy. Each patient saw near complete response to abrocitinib on either 100 mg and 200 mg dosing approaches. Failure to maintain response to dupilumab may stem from the monoclonal antibody’s ability to trigger the development of anti-drug antibodies (ADA).¹⁷ Some reports show a 7.61% ADA incidence in dupilumab studies, which may be higher in sporadic dupilumab injectors.¹⁸ Abrocitinib, a small-molecule JAK inhibitor, does not trigger the production of ADAs, which may contribute to greater maintenance of initial response.¹⁸ In one-year clinical trials, JADE EXTEND for abrocitinib and LIBERTY AD CHRONOS for dupilumab, 60.5% of patients on abrocitinib 200 mg exhibited an IGA 0/1 at week 48 while only 40% of patients on dupilumab 300 mg weekly and 36% of patients on dupilumab 300 mg biweekly exhibited an IGA score of 0/1 at week 52.^19,20

Jumping JAKi’s and Adverse Reactions

To date, two systemic JAKi’s, upadacitinib and abrocitinib, are indicated in Canada for AD treatment. The most common adverse reactions to abrocitinib include nasopharyngitis, nausea, headache, herpes simplex, increase in blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, and vomiting. Acne occurred in 4.7% of patients on 200 mg abrocitinib and 1.6% of patients on 100 mg abrocitinib in placebo-controlled trials.⁸ While upadacitinib shares many similar adverse reactions to abrocitinib, 16% of patients on 30 mg and 10% on 15 mg of upadacitinib developed acne during placebo-controlled clinical trials.¹⁴ Case 10 illustrates that patients who develop acne on upadacitinib may not have this adverse event on abrocitinib.

In the real-world cases presented, nausea was the most common adverse event experienced by four patients in the series. The nausea was reported to subside over time or when counseled to take abrocitinib with food. Reactivation of the varicella-zoster virus (VZV) has also been reported in approximately 1% of abrocitinib-treated patients.¹³ The panel suggests shingles vaccination in conjunction with JAKi use. Two presented cases reported that first dose shingles vaccination occurred two weeks prior to abrocitinib start.

Dosing Approach

Abrocitinib is unique in that it offers three potential dosing strategies: 50 mg, 100 mg, and 200 mg.⁸ Depending on preference, patients and providers may choose to start at a higher dose and titrate down or start at a lower dose and titrate up. Considering patient factors, disease factors, and concomitant medications, providers should work with their patients to choose the best dosing strategy for them.

Abrocitinib is predominately metabolized by CYP2C19 (~53%) and CYP2C9 (~30%); thus, co-administration of abrocitinib with a strong CYP2C19 and CYP2C9 inhibitor is not recommended and may increase the risk of adverse reaction to abrocitinib.⁸ Case 5 had a history of cerebral infarct and anxiety treated with CYP2C19 inhibitor, clopidogrel, and CYP2C19 substrate, citalopram, respectively. Despite his complex medical history, because of the impact of his severe AD on his QoL and sleep (he only slept three nights/year pre-abrocitinib), he was initiated on 50 mg of abrocitinib to assess safety. He tolerated the regimen without any adverse reactions. The 50 mg abrocitinib allows for further dose titration in patients with poor renal function or who are poor CYP2C19 metabolizers.

While extra caution must be taken, the panel agreed that patients with complex medical histories should not be excluded as potential candidates for abrocitinib without first evaluating the risks and benefits and having a thorough discussion with these patients.

Future Directions

The panel agreed that patient testimonials are highly impactful and educational. Patients are often enthusiastic about sharing their experiences. In the future, it will be important to direct discussions toward more complex AD cases to help healthcare providers choose appropriate dosing strategies and treatment regimens with the proper precautions. Further investigation into AD-associated PIH in individuals with sensitive skin may also help elucidate therapy plans for all skin types. Lastly, one panel member suggested further training of other medical specialties outside of dermatology in order to earlier recognize and appropriately treat AD patients. In particular, emergency medicine (EM) practitioners come in frequent contact with AD patients suffering from recurrent infections or exacerbations. Educating EM providers may allow for faster AD treatment and reduced patient suffering.

Conclusion

The real-world cases presented reflect the expert panel’s clinical experience with abrocitinib for the treatment of patients with moderate-to-severe AD. The panel’s cumulative insight suggests that abrocitinib is a safe, effective, and rapid-acting AD therapy that may be used in all Fitzpatrick skin types and disease stages. Through a multi-option dosing approach, abrocitinib fosters a TTT paradigm that allows patients and providers to form successful, individualized AD treatment plans.

Limitations

The presented cases represent real-world experience with abrocitinib. All outcome measures were reported from providers in the clinic and reflect real-life data rather than data from a controlled, clinical trial environment. Actual experience with abrocitinib may differ with each patient and/or provider. Our expert panel included general dermatologists and did not include specialized pediatric dermatologists. Thus, this discussion does not provide real-world experience in a pediatric setting. Off-label use of abrocitinib is up to the discretion of treating healthcare providers.

¹Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
²Brunswick Dermatology Center, Fredericton, NB, Canada;
³Skin Investigation Network of Canada (SkIN Canada), Toronto, ON, Canada; ⁴Dalhousie University, Halifax, NS, Canada; ⁵Probity Medical Research, Waterloo, ON, Canada

Conflict of interest: Nadia Kashetsky reports no conflicts of interest. Irina Turchin was a consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Novartis, Pfizer, Sanofi, UCB.

Abstract:
As systemic administration of Janus kinase-inhibitors is associated with safety concerns, local alternatives, such as topical ruxolitinib, have been developed. This review summarizes utilization of topical ruxolitinib in dermatology. A literature search was performed of studies reporting topical use of ruxolitinib in dermatologic conditions. Twenty-four articles were included, representing 2618 patients. Results show improvement with topical ruxolitinib formulations in atopic dermatitis, vitiligo, psoriasis, and lichen planus. Results are conflicting in alopecia areata. Minimal bioavailability and low rates of mild-to-moderate treatment-related adverse events support a favorable safety profile and higher tolerability of topical ruxolitinib compared to oral Janus kinase-inhibitors.

Keywords: ruxolitinib, topical, Opzelura™, Janus kinase-inhibitors, JAK-inhibitors, vitiligo, atopic dermatitis, eczema, psoriasis, alopecia areata, lichen planus

Introduction

Immune-mediated skin conditions are common and cause significant morbidity and healthcare utilization.^1,2 Treatment of these conditions was previously focused on symptom management and nonspecific immunosuppression, however, recent advances in understanding the pathogenesis of immunologic disease has led to novel therapeutic targets.^2,3

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, shown to be vital in downstream signaling of inflammatory cytokines, is amongst these novel therapeutic targets, for which JAK-inhibitors have been developed.^4-6 JAK-dependent cytokines are important in the immunopathology of diverse immune-mediated skin diseases, leading to the utilization of JAK-inhibitors in dermatology.^4,6 However, as systemic administration of JAK-inhibitors are associated with safety concerns, local alternatives, such as topical ruxolitinib (RUX), have been developed.^7,8 Topical 1.5% RUX cream was US FDA approved for AD in September 2021 and nonsegmental vitiligo in July 2022.⁹

Although several systematic reviews have described the utilization of JAK-inhibitors in dermatology, a summary of topical RUX in dermatology is lacking.^10-12 Accordingly, this review comprehensively summarizes the available data on efficacy and safety outcomes of topical RUX in dermatological conditions.

Methods

A literature search was performed of studies reporting topical RUX utilization in dermatologic conditions (Figure 1).

Results

Twenty-five articles were included in this review, representing 2618 patients (Table 1). Articles reported data on topical RUX use in atopic dermatitis (AD, n=8), vitiligo (n=6), alopecia areata (AA, n=5), psoriasis (n=2), and lichen planus (LP), necrobiosis lipoidica, discoid lupus erythematosus, and seborrheic dermatitis (n=1 each).

Efficacy

Atopic Dermatitis

A 4-week, phase I, open-label, maximum-use trial investigated efficacy of RUX cream in patients with AD, aged 12-65 years, disease duration ≥2 years, Investigator’s Global Assessment (IGA) score ≥2, and ≥25% body surface area (BSA) involvement (n=41).^13,14 Patients applied 1.5% RUX cream twice-daily (BID) for 4 weeks. An extension period to week 8 was completed by 37 patients. IGA treatment success (an IGA score of 0/1 with a ≥2-grade improvement from baseline) was reported in 20% of patients at day 15, 35.9% of patients at day 28, and 56.8% of patients at day 56. Mean standard deviation (SD) BSA decreased from 38.1% (16.3%) at baseline to 6.5% (8.2%) at day 28 and 3.1% (5.4%) at day 56; 79.5% and 94.6% of patients achieved ≥75% improvement in Eczema Area and Severity Index (EASI-75) at day 28 and day 56; and 82.6% and 90.5% of patients achieved ≥4-point improvement in the itch Numerical Rating Scale (NRS) at days 28 and 56, respectively. The mean daily application amount of RUX cream over the first 4 weeks was 20.2 g compared to 5.4 g in the phase III studies.^13,14

An 8-week, phase II, randomized study with vehicle control and active control (0.1% triamcinolone acetonide cream) investigated efficacy of RUX cream in patients with AD, aged 18-70 years, disease duration ≥2 years, IGA score 2-3, and 3%-20% BSA (n=307).¹⁵ Patients were randomly assigned to 1.5% RUX cream BID (n=50), 1.5% daily (n=52), 0.5% daily (n=51), 0.15% daily (n=51), 0.1% triamcinolone BID for 4 weeks then vehicle for 4 weeks (n=51), or vehicle BID (n=52). Mean percentage change in EASI score from baseline at week 4 was 71.6% versus 15.5% for 1.5% RUX cream BID versus vehicle (P<0.0001). At week 4, IGA response defined as a patient achieving an IGA score of 0 to 1, with 2 or more points improvement from baseline was achieved by 38% of patients in the RUX 1.5% arm compared to 25.5% of patients in the 0.1% triamcinolone arm.

Within 36 hours after the first 1.5% RUX cream application BID, itch NRS was significantly reduced compared to vehicle (-1.8 versus -0.2, P<0.0001), and significantly more patients achieved minimally clinically important difference (42.5% versus 13.6%, P<0.01).¹⁶ Within 2 weeks, all RUX cream regimens decreased itch NRS and achieved significant improvements in quality of life as measured by Skindex-16.¹⁶

Two, 8-week, phase III, randomized, double-blind, vehicle-controlled studies of identical study design, investigated efficacy of RUX cream in patients with AD, aged ≥12 years, disease duration ≥2 years, IGA score 2-3, and 3%-20% BSA (n=631/n=618 in Study 1/2).^17,18 Patients were randomized to apply 1.5% RUX cream BID (n=253/n=246), 0.75% BID (n=252/n=248), or vehicle cream BID (n=126/n=124). IGA treatment success at week 8 was achieved by significantly more patients in both Study 1 and Study 2 with 1.5% RUX cream (53.8%/51.3%) and 0.75% RUX cream (50.0%/39.0%) compared to vehicle (15.1%/7.6%, all P<0.0001).

Pooled data demonstrated significant rapid itch reduction within 12 hours of 1.5%/0.75% RUX cream application (-0.5/-0.4, versus -0.1 for vehicle; both P<0.02).¹⁹ At 36 hours, a ≥4-point itch NRS improvement was achieved by significantly more patients with 1.5%/0.75% RUX cream (11.2%/8.9%, versus 2.1% for vehicle; both P<0.005),¹⁹ and significantly more patients achieved an itch free state versus vehicle.²⁰

At week 8, significant impact on work productivity and activity impairment were achieved.²¹ Estimated incremental annual indirect cost savings for patients were US$5302/US$4228 for 1.5%/0.75% RUX cream.²¹

Long-term safety and efficacy of 1.5% and 0.75% RUX cream was further investigated in the long-term extension of the phase III studies.²² Patients initially randomized to twice-daily 0.75%/1.5% cream were maintained in their assigned arms for 44 weeks, and patients randomized to vehicle were re-assigned at week 8 to either RUX cream strength. At week 52 of as-needed treatment, 74.1%-77.8% of patients had IGA0/1, and a mean affected BSA was low (1.4%-1.8%).

Vitiligo

A 20-week, phase II, open-label proof-of-concept study investigated efficacy of RUX cream in patients with vitiligo, ≥18 years, with ≥1% BSA (n=11).²³ Patients applied 1.5% RUX cream BID for 20 weeks.²³ Mean improvement in Vitiligo Area Scoring Index (VASI) at week 20 was significant (23%, P=0.02). An extension of this study included 8 patients without previous response, and showed significant overall mean improvement from baseline at 52 weeks (37.6%, P=0.011).²⁴

A 52-week, phase II, randomized, double-blind, dose-ranging study investigated the efficacy of RUX cream in patients with vitiligo, aged 18-75 years, 0.5% facial BSA, and ≥3% non-facial BSA (n=157).^25,26 Patients were randomly assigned to 1.5% RUX cream BID (n=33), 1.5% daily (n=30), 0.5% daily (n=31), 0.15% daily (n=31), or vehicle cream BID (n=32). A ≥50% improvement in facial Vitiligo Area Scoring Index (F-VASI50) at week 24, was achieved by 50%/45% of patients with 1.5% RUX daily/BID versus 3% with vehicle (P<0.001/P=0.001). In patients who received 1.5% RUX cream BID in this trial, a sub-analysis indicated a larger proportion of F-VASI50 responders were aged ≤50 years, women, had baseline ≤1.5% facial BSA, disease duration >20 years, and received previous phototherapy.²⁷ All body areas had repigmentation, including difficult to treat acral areas.²⁷

Following the double-blind period of this phase II study, an open-label phase assessed the efficacy of RUX cream with narrowband ultraviolet B (NB-UVB) (n=19).²⁸ At week 104, overall mean improvement was 50.1% for F-VASI and 29.5% for total body VASI (T-VASI) versus the last visit before adding NB-UVB.

Two 24-week, phase III, double-blind, vehicle-controlled trials of identical study design investigated the efficacy of RUX cream in patients with vitiligo, aged ≥12 years, ≤10% BSA, ≥0.5% facial BSA, and ≥3% non-facial BSA (n=330/n=344 in Study 1/2).^29,30 Patients were randomized to apply 1.5% RUX cream BID (n=221/n=229) or vehicle cream BID (n=109/n=115) for 24 weeks. At week 24, F-VASI75 was achieved by 29.8%/30.9% of patients in the RUX cream arms compared to vehicle (7.4%/11.4%, P<0.001).

Alopecia Areata

A 28-week, phase I, prospective, double-blind, placebo controlled, pilot study investigated the efficacy of 1% RUX ointment, 2% tofacitinib ointment, 0.05% clobetasol dipropionate ointment, and vehicle in patients with alopecia areata (AA) (n=16).³¹ All 4 ointments were applied to designated areas BID. Partial regrowth was achieved in 5/6/10/2 patients treated with 1% RUX/2% tofacitinib/0.05% clobetasol dipropionate/vehicle.

A phase II, 2-part, double-blind, randomized, vehicle-controlled study, investigated the efficacy of RUX cream in patients with AA, aged 18-70 years, Severity of Alopecia Tool (SALT) score 25%-99% (Part A: n=12; Part B: n=78).³² In Part A patients applied 1.5% RUX cream BID for 24 weeks. A ≥50% improvement in SALT (SALT50) was achieved by 50% of patients at week 24. In Part B patients were randomized to 1.5% RUX cream BID (n=39) or vehicle BID (n=39) for 24 weeks. Percentage of patients achieving SALT50 between RUX cream and vehicle at week 24 was not significant (12.8% versus 12.8%, P=0.99).

Moreover, 4 case reports utilizing RUX cream in patients with AA demonstrate conflicting results. A teenaged female had marked improvement with 0.6% RUX cream BID for 12 weeks,³³ whereas a 66-year-old female who exhibited lack of improvement with 0.6% RUX cream daily for 8 weeks, increased to BID for 6 weeks.³⁴ Finally, 2 patients, a 17-year-old female, and 4-year-old male, showed partial and no regrowth, with 1% RUX in a liposomal base BID for 18 months, and 2% RUX in a liposomal base BID then 1% tofacitinib liposomal base BID for 3 months, respectively.³⁵

Psoriasis

A 4-week, phase II, double-blind, vehicle or active comparator study assessed efficacy of RUX cream in patients with stable and active plaque psoriasis, aged 18-75 years, <20% BSA (n=29).³⁶ Patients were randomized to 0.5% or 1.0% RUX cream daily, 1.5% RUX BID, vehicle daily or BID, 0.005% calcipotriene cream BID, or 0.05% betamethasone dipropionate cream BID for 4 weeks. At 4 weeks, mean total lesion score decreased by 53%/54% for 1.0% RUX daily/1.5% RUX BID versus vehicle (32%, P=0.033/P=0.056).

A 4-week, phase II, open-label, multicenter, cohort, doseescalation study evaluated efficacy of RUX cream in patients with stable and active psoriasis, aged 12-65 years (n=25).³⁷ Patients applied 1.0% or 1.5% RUX cream daily or BID for 4 weeks to 2%-20% BSA. In all cohorts, at 4 weeks, mean total lesion scores decreased and PGA scores improved.

Other

An 8-week, phase II, single-arm, open-label trial investigated the efficacy of RUX cream in patients with biopsy proven lichen planus (LP), aged ≥18 years, ≤20% BSA and ≥4 lesions (n=12).³⁸ Patients applied 1.5% RUX cream BID for 8 weeks. At week 4, lesion count significantly decreased by a median of 50 lesions (P<0.001); and mean modified Composite Assessment of Index Lesion Severity of index versus control lesions decreased significantly by a mean of 7.6 points (P=0.016).

A 19-year-old female with refractory necrobiosis lipoidica showed marked improvement with 1.5% RUX cream BID for 3 months.³⁹ A 28-year-old female with discoid lupus erythematosus exhibited improvement of scalp lesions with 1.5% RUX cream daily for 2 months.⁴⁰ A 74-year-old male with seborrheic dermatitis and rosacea showed complete and partial response, respectively, with 1.5% RUX cream BID for 2 weeks.⁴¹

Safety and Tolerability

Bioavailability of RUX cream was limited.^{13,14,25,36,37,42,43} The highest strength average steady-state trough plasma concentrations were well below clinically relevant systemic pharmacological activity, remaining below the half-maximal inhibitory concentration of JAK-mediated myelosuppression.^{13,14,25,36,37,42,43}

No serious treatment related adverse events (TRAE) were reported across all topical RUX data. Mild-to-moderate TRAE were reported in minority of patients, most commonly including application-site pain, pruritus, acne, erythema, and hyperpigmentation. Rare treatment-emergent adverse events included increase in aspartate aminotransferase and alanine aminotransferase, leukopenia, hemoglobin decrease, mild reticulocytosis, dyspnea, abnormal taste, and transient hypoaesthesia of the fingertips.

Discussion

This review summarizes the utilization of topical RUX in dermatological conditions. Results show improvement with topical RUX formulations in AD, vitiligo, psoriasis, and LP. Results are conflicting in AA. Minimal bioavailability and low rates of mild-to-moderate TRAEs support higher tolerability of topical RUX as compared to oral JAK-inhibitors.

RUX is a targeted inhibitor of JAK1/2, selectively interrupting effects of the cytokines which signal through JAK1/2 proteins.⁴⁴ AD pathogenesis involves JAK1/2 mediated cytokines interleukin (IL)-4, IL-13, IL-31, and IL-33.^6,45 Vitiligo and AA, both involve JAK1/2 mediated interferon (IFN)-gamma and IL-15 in their pathogenesis.⁶ IFN-gamma is also important in the pathogenesis of LP and psoriasis.^4,6,38 Psoriasis pathogenesis also has shown involvement of other JAK1/2 mediated cytokines including IL-6, IL-21, IL-22, and IL-23.^4,6

Conclusion

Available clinical trial data support the efficacy of topical RUX in AD, vitiligo, psoriasis, and LP with a favorable safety profile and tolerability compared to oral JAK-inhibitors suggesting that topical RUX is a promising new therapy in dermatology.

Purchase Article PDF for $1.99

¹Faculty of Medicine, University of Western Ontario, London, ON, Canada
²Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
³Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
⁴Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁵Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁶Probity Medical Research, Waterloo, ON, Canada
⁷Dermatology Research Institute, Calgary, AB, Canada
⁸Skin Health & Wellness Centre, Calgary, AB, Canada
⁹Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹⁰Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest:
Abrahim Abduelmula has no relevant disclosures. Brian D. Rankin has no relevant disclosures. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant.

Funding sources: None.

Abstract:
Atopic dermatitis (AD) is a common, chronic, recurrent, immune-mediated inflammatory skin disease. Targeted treatment options remain limited. Tralokinumab (Adtralza^®) is a promising, new systemic therapy that inhibits interleukin-13. It was recently approved by Health Canada and the US FDA for the treatment of moderate-to-severe AD in adults and may be used alone or with topical corticosteroids. Herein, we review the efficacy and safety of tralokinumab in adults, as demonstrated in clinical trials.

Keywords:
Adtralza^®, tralokinumab, immunomodulator, therapeutics, biologic, atopic dermatitis, eczema, clinical trial

Introduction

Atopic dermatitis (AD) is a common, chronic, recurrent, immune-mediated inflammatory skin disorder affecting between 5-10% of adults, with moderate-to-severe disease accounting for approximately 20-30% of cases.^1,2 This condition can have a significant negative impact on psychosocial well-being, health-related quality of life (QoL), and work/school productivity. In addition, uncontrolled AD is associated with a substantial financial burden on the patient and their family as well as the health care system.³

Topical therapies are employed as first-line treatment for the majority of AD cases, but lack of response can necessitate the use of phototherapy and/or systemic therapies. With respect to systemic therapies, recent advances have led to the development of new targeted treatments, of which four are now approved by Health Canada and the US FDA for moderate-to-severe AD. This includes two biologics (dupilumab [Dupixent^®], an interleukin (IL)-4/IL-13 inhibitor, and tralokinumab [Adtralza^®], an IL-13 inhibitor) and two small molecules (upadacitinib [Rinvoq^®] and abrocitinib [Cibinqo^®], both selective Janus kinase 1 [JAK1] inhibitors).

Background

Tralokinumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds with high affinity to IL-13, thereby blocking its interaction with the IL-13Rα1/IL-4Rα1 heterodimer and IL-13Rα2 homodimer receptor complexes and subsequently leading to downstream STAT-6 inhibition.⁴ The latter results in reduced inflammation, improved skin barrier function (reductions in epidermal thickness and increased epithelial barrier integrity), as well as restoration of the microbiome (a near 10-fold reduction in Staphylococcus aureus colonization of the skin).^4,5

Tralokinumab may be given alone or in combination with a topical corticosteroid (TCS).^6,7 It was approved by both Health Canada and the US FDA in 2021 for the treatment of moderate-to-severe AD in adult patients whose disease is not adequately controlled with prescription topical therapies or when those prescription topical therapies are not advisable.⁶ Available as a single-use prefilled syringe containing 150 mg of tralokinumab in 1 mL solution (150 mg/mL), tralokinumab is administered as a subcutaneous (SC) injection.⁶ The recommended dosage for adult patients is an initial 600 mg loading dose followed by 300 mg maintenance doses every other week (Q2W). According to the product monograph, the prescriber may choose to administer tralokinumab every fourth week (Q4W) in adult patients who achieve clear or almost clear skin after 16 weeks of treatment; however, there is an increased probability that maintenance efficacy may be decreased with Q4W dosing.⁶

Non-medicinal ingredients of the product include acetic acid, polysorbate 80, sodium acetate trihydrate, sodium chloride, and water. No published data is currently available for its use in pediatric or pregnant patients, and, as such, tralokinumab has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended for pregnant women.⁶

Supporting Evidence from Clinical Trials (Figures 1-5)

Results from Pivotal Phase 3 Monotherapy Studies

In a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=802) with moderate-to-severe AD (ECZTRA 1), the efficacy and safety of tralokinumab 300 mg SC Q2W (n=603) versus placebo (n=199) was evaluated.⁸ At week 16: the primary endpoint of an Investigator Global Assessment (IGA) score of clear or almost clear (IGA 0/1) was achieved by 15.8% and 7.1% of patients treated with tralokinumab and placebo, respectively (p<0.002) (Figure 1); an improvement of ≥75% and ≥90% in the Eczema Area and Severity Index (EASI75 and EASI90, respectively) was achieved by 25.0% and 14.5% of patients treated with tralokinumab versus 12.7% and 4.1% of patients treated with placebo (p<0.001 and p<0.05, respectively) (Figure 2); pruritus Numerical Rating Scale (NRS) improved by 20.0% with tralokinumab versus 10.3% with placebo (p=0.002); and there was a reduction in Dermatology Life Quality Index (DLQI) scores by 7.1 with tralokinumab and 5.0 with placebo, respectively (p=0.002) (Figure 3). Safety evaluation revealed similar adverse event (AE) profiles between the tralokinumab and placebo groups, with the majority of treatment-emergent AEs (TEAEs) being mild and self-limiting in nature. The most observed TEAEs with tralokinumab included viral upper respiratory tract infection (URTI) (23.1%), conjunctivitis (10.0%), and eczema herpeticum (0.5%). One case of conjunctivitis led to treatment discontinuation. No injection-site reactions (ISRs) were observed in either treatment group.⁸

In another phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=794) with moderate-to-severe AD (ECZTRA 2), the efficacy and safety of tralokinumab 300 mg SC Q2W (n=593) versus placebo (n=201) was evaluated.⁸ At week 16: the primary endpoint of IGA 0/1 was achieved by 22.2% and 10.9% of patients treated with tralokinumab and placebo, respectively (p<0.001) (Figure 1); EASI75 and EASI90 were achieved by 33.2% and 18.3% of patients treated with tralokinumab versus 11.4% and 5.5% of patients treated with placebo (p<0.001 and p<0.05, respectively) (Figure 2); pruritus NRS improved by 25.0% with tralokinumab versus 9.5% with placebo (p<0.001); and there was a reduction in DLQI by 8.8 with tralokinumab and 4.9 with placebo, respectively (p<0.001) (Figure 3). Safety evaluation revealed similar AE profiles between the tralokinumab and placebo groups, with the majority of TEAEs being mild and self-limiting in nature. The most observed TEAEs with tralokinumab included URTI (8.3%), conjunctivitis (5.2%), and eczema herpeticum (0.3%). No cases of conjunctivitis led to discontinuation. In addition, no ISRs were observed in either treatment group.⁸

By week 52, IGA 0/1 responses achieved at week 16 with tralokinumab Q2W were maintained, without any rescue therapy (including TCS), by 51% (ECZTRA 1) and 59% (ECZTRA 2) of patients who continued to receive tralokinumab Q2W versus 47% (ECZTRA 1) and 25% (ECZTRA 2) of patients who were rerandomized from tralokinumab Q2W to placebo (p=0.60 and p=0.004, respectively) (Figure 4). In addition, by week 52, EASI75 responses achieved at week 16 with tralokinumab Q2W were maintained by 60% (ECZTRA 1) and 56% (ECZTRA 2) of patients who continued to receive tralokinumab Q2W versus 33% (ECZTRA 1) and 21% (ECZTRA 2) of patients who were rerandomized from tralokinumab Q2W to placebo (p=0.056 and p<0.001, respectively) (Figure 5).⁸ A subset of patients following week 16 were downdosed from Q2W to Q4W dosing of tralokinumab. By week 52, 39% (ECZTRA 1) and 45% (ECZTRA 2) of patients maintained their week 16 IGA 0/1 responses despite being switched from Q2W to Q4W dosing (Figure 4). In addition, by week 52, 49% (ECZTRA 1) and 51% (ECZTRA 2) of patients maintained their week 16 EASI75 responses despite being switched from Q2W to Q4W dosing (Figure 5).

Results from Pivotal Phase 3 Combination Therapy Studies

In a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=380) with moderate-to-severe AD (ECZTRA 3), the efficacy and safety of tralokinumab 300 mg SC Q2W + TCS (n=253) versus placebo + TCS (n=127) was evaluated. The TCS utilized was mometasone furoate 0.1% cream. At week 16: the primary endpoint of IGA 0/1 was achieved by 38.9% and 26.2% of patients treated with tralokinumab + TCS and placebo + TCS, respectively (p=0.015) (Figure 1); EASI75 and EASI90 were achieved by 56.0% and 32.9% of patients treated with tralokinumab + TCS versus 35.7% and 21.4% of patients treated with placebo + TCS (p<0.001 and p<0.022, respectively) (Figure 2); pruritus NRS improved by 45.5% with tralokinumab + TCS versus 34.1% with placebo + TCS (p=0.037); and there was a reduction in DLQI by 11.7 with tralokinumab + TCS and 8.8 with placebo + TCS, respectively (p<0.001) (Figure 3). By week 32, in patients receiving tralokinumab Q2W + TCS, 89.6% and 92.5% maintained their week 16 IGA 0/1 and EASI75 responses, respectively (Figure 4 and 5, respectively). A subset of patients following week 16 were downdosed from tralokinumab Q2W to Q4W dosing. At week 32, 77.6% and 90.8% of patients maintained their week 16 IGA 0/1 and EASI75 responses, respectively, despite being switched from Q2W to Q4W dosing (Figure 4 and 5, respectively).⁹ Safety evaluation revealed similar AE profiles between the tralokinumab + TCS and placebo + TCS groups, with the majority of TEAEs being non-serious and self-limiting in nature. The most observed TEAEs with tralokinumab + TCS included URTI (19.4%), conjunctivitis (13.1%), and eczema herpeticum (0.4%). Six patients permanently discontinued treatment with tralokinumab due to non-serious AEs, one of which was conjunctivitis.⁹ No ISRs were observed in either treatment group.

In another phase 3 multicenter, parallel, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=277) with moderate-to-severe AD (ECZTRA 7), the efficacy and safety of tralokinumab 300 mg SC Q2W + TCS (n=140) versus placebo + TCS (n=137) was evaluated. The TCS utilized was mometasone furoate 0.1% cream.¹⁰ At week 16: the primary endpoint of EASI75 was achieved by 64.2% and 50.5% of patients treated with tralokinumab + TCS and placebo + TCS, respectively (p=0.018) (Figure 2); EASI90 was achieved by 41.1% of patients treated with tralokinumab + TCS versus 29.3% of patients treated with placebo + TCS (p<0.001) (Figure 2); pruritus NRS was reduced by 4 with tralokinumab + TCS versus 3.1 with placebo + TCS (p<0.001); and there was a reduction in DLQI by 11.2 with tralokinumab + TCS and 9.6 with placebo + TCS, respectively (p=0.009) (Figure 3). By week 26, in patients receiving tralokinumab + TCS, 68.8% achieved EASI75 and 48.6% achieved EASI90, compared with 55.3% and 36.4% for placebo + TCS (p=0.014 and p=0.027, respectively) (Figure 5). Safety evaluation once again showed similar AE profiles between the tralokinumab and placebo groups, with the majority of TEAEs being non-serious and self-limiting in nature. The most observed TEAEs with tralokinumab included URTI (26.8%), conjunctivitis (9.4%), and eczema herpeticum (0.7%). One patient permanently discontinued treatment with tralokinumab due to an AE that was not deemed serious.¹⁰ No ISRs were observed in either treatment group.

Summary of Results from Pivotal Phase 3 Monotherapy and Combination Therapy Study Results and Additional Analyses

In summary, tralokinumab was more effective than placebo in both monotherapy and combination therapy studies, with tralokinumab demonstrating greater efficacy than placebo for patients with moderate-to-severe AD across all phase 3 clinical trials. Interestingly, rates of eczema herpeticum were higher in the placebo groups as opposed to the tralokinumab groups.^8-10 An additional pooled analysis (n=1605) of five completed double-blind, randomized, placebo-controlled, phase 2 and 3 clinical trials of tralokinumab in adult patients with moderateto- severe AD examined the rates of conjunctivitis within these studies; it was found that tralokinumab had a slightly higher incidence of conjunctivitis (7.5%) in comparison to placebo (3.2%), with the majority of cases being mild-to-moderate in severity and 75% of events resolving before the treatment period was over in both groups.¹¹

Tralokinumab was also shown to have a significant impact on health-related QoL in a phase 2b randomized, double-blind, placebo-controlled clinical trial involving adult patients (n=204) with moderate-to-severe AD. At week 6, a 5.4-point reduction in DLQI was observed with tralokinumab monotherapy, while a 2.3-point reduction in DLQI was observed with placebo (p=0.05). At week 16, a 6.8-point reduction in DLQI was observed with tralokinumab monotherapy, while a 3.5-point reduction in DLQI was observed with placebo (p=0.006) (Figure 3).¹²

Tralokinumab may also help resolve other IL-13-associated skin abnormalities. In a phase 2 randomized, double-blind, placebo-controlled study (n=204), adult patients with moderate-to-severe AD treated with tralokinumab had lower rates of Staphylococcus aureus colonization, fewer skin infections requiring systemic antimicrobial therapy, and a lower frequency of eczema herpeticum when compared to placebo groups.⁷ In another phase 2, 30-week, double-blind, randomized, placebo-controlled clinical trial (n=215), it was shown that tralokinumab did not impair vaccine-induced immune responses in adult patients receiving tetanus-diphtheria-pertussis (Tdap) or meningococcal vaccines.¹³

Special Populations

Tralokinumab has not been approved for utilization in children/ adolescents (<18 years of age), although a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial in adolescent patients (12-17 years of age) with moderate-to-severe AD is still ongoing.¹⁴ Tralokinumab is currently not recommended in pregnant or breastfeeding women. It remains unknown if the drug is excreted in breast milk. There were no differences in terms of efficacy or safety with use in elderly patients (≥65 years of age).⁶

Table 1. Summary of the efficacy and quality of life data for tralokinumab from pivotal phase 2 and 3 clinical trials in adult patients with moderate-to-severe AD

Counselling: Practical Tips to Optimize Administration

Tralokinumab is administered as an SC injection. Optimal anatomic sites for the SC injection include the lower limb (specifically thigh) or trunk (specifically abdomen, excluding a 5 cm radius around the navel); the upper limb (specifically lateral upper arm) may also be used if another individual can administer the medication. Multiple doses should be delivered in the same anatomic site but at different points within that anatomic site. Doses should be rotated to different anatomic sites with each subsequent set of SC injections. Tralokinumab should not be injected into tender or damaged skin. If a patient and/or a caregiver wishes to administer the SC injection, proper training should be provided. If a dose is missed, the missed dose should be administered as soon as possible and the scheduled dosing regimen continued.⁶

Conclusion

Tralokinumab is an effective and safe treatment for adult patients with moderate-to-severe AD. It may be used alone or in combination with TCS. This biologic can be considered first-line treatment after failure of or intolerance to topical therapies, and, as such, represents an important tool in our therapeutic armamentarium.

Purchase Article PDF for $1.99

Abstract

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

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

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

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

PDF Download

Background

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

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

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

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

Methods

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

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

Literature Review

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

The Nomenclature Used for the Searches

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

Search Terms

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

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

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

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

Role of the Panel

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

Results

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 1: Cleanser and moisturizer use

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

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

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

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

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

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

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

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

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

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

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

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

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

Limitations

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

Conclusions

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

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.

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

Purchase Article PDF for $1.99

¹Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
²Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest:
Joseph Lam has served as an advisory board member for Bausch Health, Leo Pharma, Pfizer Canada and Sanofi-Genzyme.
He is on the speaker’s bureau for Pfizer Canada. He has received a research grant from the Eczema Society of Canada. Aryan Riahi has no conflicts to declare.

Abstract:
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory condition marked by pruritus and traditionally treated with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Crisaborole 2% ointment (a topical phosphodiesterase-4 inhibitor) is a newer topical agent for the treatment of AD. Crisaborole is indicated for treating mild-to-moderate AD and evidence from phase 3 and phase 4 trials show that crisaborole is an effective agent with a well-tolerated side effect profile for children >2 years of age. The most common side effects are pain and paresthesia at the application site. Treatments with tolerable safety profiles such as crisaborole may provide an alternative to patients with TCS phobia. The role of crisaborole in AD therapy may become clearer as multiple phase 4 trials are currently underway and their results are poised to answer more questions, including its safety profile for patients as young as 3 months of age, potential use as a steroid-sparing agent, and direct comparisons to TCS and TCI, which are the current mainstay treatments of mild-to-moderate AD.

Key Words:
crisaborole, Eucrisa, atopic dermatitis, eczema, topical treatment, phosphodiesterase-4 inhibitor, corticosteroids

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, and inflammatory condition affecting the skin. Clinical features include xerosis, oozing, crusting, and erythema. Pruritus is a hallmark manifestation of AD that can cause frequent scratching, leading to skin infections and lichenification.¹ The face, scalp and extensor surfaces are commonly involved in infancy, while there is prominent flexural involvement in older children and adults.² While some patients experience resolution by adolescence, others have symptoms that persist into adulthood.³ AD has been estimated to affect 15-30% of children and 10% of adults in industrialized nations.⁴ The economic burden of AD has been estimated to be $3.8 billion per year.⁵ Due to the chronic nature of AD and limitations of current available topical agents, especially for pediatric use, there remains an unmet need for novel AD therapies to address long-standing treatment gaps. Crisaborole 2% ointment (Eucrisa™) is a Health Canada and US FDA-approved topical phosphodiesterase-4 (PDE4) inhibitor for treating mild-to-moderate AD. Evidence from phase 3 and 4 trials demonstrate crisaborole is an effective agent with a well-tolerated side effect profile for children >2 years of age.⁶

Overview: Diagnosis and Pathogenesis

The diagnosis of AD is clinical. Skin biopsy and laboratory testing such as serum immunoglobulin E (IgE) levels are not routinely performed in the evaluation of suspected AD, but may be useful in ruling out other skin conditions.⁷ Adverse impacts from AD are wide ranging and include impairments to general health, quality of life, and mental health, with the financial cost of disease management posing a significant concern for patients and their families. Scratching may expose patients to secondary infections, which can exacerbate the severity of AD.⁸ The differential diagnosis for AD includes irritant or allergic contact dermatitis, serborrheic dermatitis, psoriasis, and scabies. Intractable, chronic itch is a hallmark of AD. Scratching may expose patients to secondary infections, which can exacerbate the disease severity.⁶

The pathogenesis of AD is determined by numerous factors including abnormalities in the skin barrier, a skewed T helper type 2 (Th2) immune response, impaired innate immunity, and changes in the resident microbial flora of the skin.⁹ The epidermis of patients with AD is prone to increased transepidermal water loss.¹⁰ The filaggrin (FLG) protein, which is produced by keratinocytes and encoded by the FLG gene, serves a critical role in skin barrier formation.¹¹ Patients with AD have lower levels of expression of skin barrier-related proteins including FLG-2, corneodesmosin, and enzymes necessary for skin hydration and water retention at the stratum corneum.¹² In addition to a barrier defect, the underlying immune system is also dysregulated in patients with AD. The innate immune response depends on toll-like receptors, which are stimulated by tissue damage and microorganisms, and enhance the strength of tight junctions to prevent allergen and microorganism penetration.¹³ Grouping patients with AD into one endotype may be overly simplistic. AD has a variety of endotypes depending on age groups, ethnicities, FLG mutations, and IgE levels.¹⁴ These include Asian versus European American, adults versus children, and presence or absence of family history of FLG mutations.¹⁴ Since increased Th2 cell levels are common across the spectrum of AD, targeting this factor should theoretically be therapeutic for all phenotypes of AD. However, phase 3 trials of dupilumab, an interleukin (IL)-4 and IL-13 blocker targeting the Th2-mediated pathway, was only able to reduce the Investigator’s Global Assessment score of patients down to 1 or 0 in 36-38% of cases.¹⁵ This suggests that other immune mediators outside of Th2 cells may be involved in the pathogenesis and treatment of AD.

Treatment Options for Atopic Dermatitis

The goals of treatment for AD are to achieve symptom reduction and prevent exacerbations. This approach is balanced with minimizing the risks of therapy. The mainstay therapy of AD is topical corticosteroids (TCS).¹⁶ An alternative to TCS is topical calcineurin inhibitors (TCI). Both treatments elicit potential side effects if used improperly. The face and skin folds are areas at high risk for atrophy with inappropriate use of TCS. High potency TCS also pose the risk of systemic toxicity, such as adrenal suppression in pediatric populations, especially if used under occlusion, e.g., diapered area.^17,18 TCI medications such as topical tacrolimus ointment and pimecrolimus cream do not carry the risk of skin atrophy, but may burn and sting on application. Patient education is needed as topical tacrolimus and pimecrolimus come with an FDA black box warning for increased risk of malignancies such as lymphoma.^19,20 Since the regulatory manadate to include the black box warning was institued in 2005, there has been mounting evidence to support the safe use of TCIs and the increased risk of malignancy remains theoretical. Prior to topical crisaborole, no new topical molecules have been approved to treat AD over the last 15 years.

Severe AD may warrant the use of ultraviolet-B (UVB) phototherapy or systemic immunosuppressant therapy such as cyclosporine, methotrexate, or mycophenolate mofetil when the patient is refractory to topical treatments.²¹ In 2019, both the FDA and Health Canada approved dupilumab for treating patients with AD >12 years of age who suffer from moderate-to-severe AD when topical therapies are ineffective or not advised.^22-24 Dupilumab is a fully human monoclonal antibody that binds to the IL-4 receptor and inhibits signaling of IL-4 and IL-13.²⁵

Crisaborole 2% is a topical PDE4 inhibitor indicated for the treatment of mild-to-moderate AD. Studies have shown that crisaborole 2% ointment improves AD signs such as exudation, excoriation, lichenification, and especially pruritus. Unlike TCS and TCI therapies, systemic exposure to crisaborole is limited.²⁶ The most common side effects are pain and paresthesia at the application site.²⁷

Crisaborole‘s Mechanism of Action

Crisaborole inhibits the action of PDE4. Pharmaceutical interest in phosphodiesterase enzymes, including crisaborole, was sparked by their role in nucleotide signaling pathways, leading to the development of specific novel inhibitors.²⁸ Elevated PDE4 enzyme levels have been associated with a chronic inflammatory state.²⁹ Since PDE4 is expressed by immune cells and keratinocytes, inhibition of PDE4 increases intracellular levels of cyclic adenosine monophosphate (cAMP) which inhibits the nuclear factor kappa B (NF-kB) pathway and the release of tumor necrosis factor (TNF)-alpha and pro-inflammatory cytokines that have a causal role in AD and psoriasis.²⁹

Crisaborole’s boron chemistry allows for formation of a low molecular weight molecule that penetrates human skin effectively.³⁰ Systemic exposure and risk of adverse effects from crisaborole is generally avoided due to the molecule’s rapid metabolism to inactive metabolites that do not affect cytokine release or the activity of PDE4.²⁹

Completed and Ongoing Studies of Crisaborole

Crisaborole’s safety profile and efficacy has been evaluated through 2 double-blind vehicle-controlled controlled phase 3 clinical trials. These studies assigned patients aged 2 years and older with mild or moderate AD as per Investigator’s Static Global Assessment (ISGA) scoring for treatment with either 2% crisaborole ointment or vehicle for 28 days. Results collected on day 29 demonstrated that 51.7% of patients receiving crisaborole had an ISGA of clear (0) compared to 40.6% of vehicle-treated patients (P = 0.05) and 48.5% of patients had ISGA of almost clear (1) compared to 29.7% of those treated with vehicle (P < 0.001).⁷

Two randomized, double-blind, vehicle controlled phase 3 studies with 759 and 763 participants demonstrated that crisaborole improves pruritus compared with vehicle (56.6% vs. 39.5%; P < 0.001) as early as day 2 of therapy (34.3% vs. 27.3%; P = 0.013).³¹

TCS are routinely used as therapy for flare-ups in AD.³² However, only short-term TCS use is recommended to minimize local and systemic adverse effects such as striae, telangiectasia, cutaneous atrophy, and acne.³³ As for TCI, both Health Canada and FDA initially advised against the use of long-term TCI therapy due to the unclear risk of malignancy.^19,20 Health Canada has subsequently removed the black box label for primecrolimus.³⁴ However, patients may continue to be apprehensive about using TCIs given their previous black box labeling. More research, including investigations on long-term maintenance, is needed to determine optimal topical treatment options for AD with favorable safety profiles. There is a phase 3 randomized, double-blind, vehicle-controlled study being conducted with 700 patients with mild-to-moderate AD.³⁵ Patients will receive crisaborole twice a day for a maximum of 8 weeks to identify responders, defined as ISGA score of 0 or 1 with 2-grade improvement from baseline or 50% improvement from baseline based on Eczema Area and Severity Index (EASI50) scoring. Non-responders will be discontinued after the 8-week run-in period. Maintenance treatment consists of once daily administration of crisaborole QD. Flares defined as ISGA ≥2 will be treated with twice daily crisaborole for up to 12 weeks. Completion of the trial is anticipated by July 2022.³⁵

The efficacy and safety profile of crisaborole is currently being investigated in phase 4 trials. A randomized, double-blind, vehicle-controlled study is evaluating the efficacy and safety of 3 different application rates of crisaborole ointment 2% in adults with mild-to-moderate AD.³⁶ Each patient will have 4 application areas and receive 1 of 4 treatments ranging from vehicle to 3 different application rates of crisaborole. Patients will be randomly assigned to treatment with topical crisaborole (application rates A, B, or C) or vehicle, once daily, for 2 weeks. The results of this study, with a projected completion of June 2020, may demonstrate whether the efficacy and safety of crisaborole is dose dependent. The results may be compared and contrasted with TCS use, which has a well-known dose dependent effect (e.g., anti-inflammatory effects at lower doses, immunosuppressive activity at higher doses) as well as dose dependent adverse effects (e.g., ecchymosis, parchment-like skin, and sleep disturbances).³⁶

Long-term topical treatment is often required for the management of a chronic inflammatory skin conditions like AD. Crisaborole’s long-term safety was evaluated in an open-label extension study of 517 patients with mild-to-moderate AD who used crisaborole for 48 additional weeks after the 28-day phase 3 study. The most frequently reported treatment related adverse effect (AE) were AD (3.1%), pain at the site of application (2.3%), and localized infection (1.2%).²⁷

The treatment options for patients under 2 years of age with AD are sparse. Pimecrolimus has recently been approved for infants as young as 3 months.³⁷ However, having a wider array of therapeutic strategies would be ideal for this demographic. A phase 4 multicenter, open-label, single arm investigation called the CrisADe CARE 1 study evaluated the safety, efficacy, and pharmacokinetics of crisaborole 2% ointment applied twice daily on 125 pediatric patients between 3-24 months of age.³⁸ These patients had extensive AD involving at least 5% of body surface area (BSA) except for the scalp. A total of 29.93% of patients reported non-serious AEs. The most common side effect was pyrexia (9.49%). The study found a total of 1 (0.73%) serious AE involving a febrile convulsion. The study did not comment on whether this AE was related to the use of crisaborole. No deaths occurred. This study is the first to evaluate the safety profile of crisaborole in children less than 24 months of age.

Crisaborole may have the potential of decreasing steroid use in patients with AD. Side effects of TCS can range from cutaneous atrophy to suppression of the hypothalamic-pituitary-axis.³⁹ Misunderstandings and steroid phobia can interfere with patient compliance, which in turn negatively affect disease control.⁴⁰ Currently, a proof-of-concept phase 4 clinical trial with 60 children between 2-18 years with mild-moderate AD is underway to determine whether crisaborole is an effective steroid reducing agent. The trial will be completed by November 2020.⁴¹ Similarly, a single-center observational prospective cohort study aimed to evaluate the efficacy and safety profile of crisaborole ointment 2% and a TCI versus crisaborole alone over 8 weeks. The study included participants aged 2-79 with mild-tomoderate AD and the projected completion was March 2020.⁴²

While high-quality phase 3 studies have demonstrated the efficacy of crisaborole compared to vehicle, head-to-head studies comparing crisaborole with TCS or TCI are needed to better define its role in the management of AD. A phase 4 multicenter, randomized, vehicle versus active (TCS and TCI) controlled study is being conducted on 600 patients with mild-to-moderate AD over 4 weeks to evaluate the safety and efficacy of crisaborole 2% ointment, crisaborole vehicle, TCS, and TCI applied BID in patients over 2 years of age.⁴³ Inclusion criteria include patients with AD involving at least 5% of BSA except for the scalp. The primary efficacy endpoint is change from the patient’s baseline in the EASI score by Day 29. The study will be completed by March 2021. This will be the first study to directly compare crisaborole to the current mainstay treatments of mild-to-moderate AD.

Conclusion

Crisaborole provides a novel and safe treatment option for mild-to-moderate AD. Crisaborole’s boron chemistry allows for formation of a low molecular weight molecule that penetrates human skin effectively but is inactivated and metabolized rapidly.³⁰ Crisaborole therapy has been shown to decrease pruritus, which disrupts the itch-scratch cycle that exacerbates signs of AD, improve quality of life, and decrease the risk of infection and scarring.⁴⁴ Adverse events related to crisaborole 2% are overall infrequent and range from mild-to-moderate in severity. Studies are currently underway to determine whether crisaborole can be used as long-term maintenance therapy for patients who respond to treatment. Furthermore, while crisaborole’s side effect profile is generally well tolerated, new head-to-head studies comparing crisaborole with TCS or TCI are underway to better define its role in the management of AD.

Purchase Article PDF for $1.99

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.