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.

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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.

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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.^2,3,4 Oats were introduced into North America in the 17th 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 of its 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 results in the eczematous pruritic 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 NFKB in keratinocytes and inhibition of the release of the proinflammatory 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. Nonprescription 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.

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

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

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

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

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

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

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

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

Introduction

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

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

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

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

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

Methods

Aim of the Project

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

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

Steps in the Process

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

Role of the Panel

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

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

Topical Treatment for Mild-To-Moderate AD

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

Skincare Using Gentle Cleansers and Moisturizers

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

TCS and TCI

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

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

Systemic Therapy

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

Crisaborole Ointment

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

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

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

Data Gathering of Real-World Cases on Crisaborole Ointment Use

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

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

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

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

Selected Real-World Cases

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

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

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

Figure 1A – 1D

Figure 1E and 1F

Figure 1G and 1H

Figure 1I and 1G

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

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

Figure 2A and 2B

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

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

Figure 3A and 3B

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

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

Figure 4A and 4D

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

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

Figure 5A and 5D

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

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

Figure 6A and 6B

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

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

Figure 7A and 7B

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

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

Figure 8A and 8D

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

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

Figure 9A and 9B

Figure 9C and 9E

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

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

Figure 10A and 10G

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

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

Figure 11A and 11E

Discussion

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

Steroid Phobia

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

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

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

Irritation, Burning and Stinging

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

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

Antibiotic Resistance

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

Combination Treatment

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

Specific Body Locations

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

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

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

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

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

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

Maintenance Therapy

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

Conclusion

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

Acknowledgement

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

Limitations

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

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

Introduction

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

Prevalence

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

Pathogenesis

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

Clinical Features

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

Diagnosis

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

Co-Morbidities

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

• Obesity

Treatment

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

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

Education

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

Emollients

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

Topical Anti-Inflammatories

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

TCSs

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

TCIs

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

PDE4 Inhibitors

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

Further Options

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

Practical Tips

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

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

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

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

Conclusion

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

¹Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
²Division of Dermatology, University of Alberta, Edmonton, AB, Canada

Conflict of interest:
The authors have no conflicts to declare for this work.

Abstract
Atopic dermatitis is a common cutaneous disease with significant morbidity affecting children and adults. The mainstay of atopic dermatitis therapy has typically included emollients, topical corticosteroids, and topical calcineurin inhibitors. Among the newer advances recently introduced is crisaborole (Eucrisa™), a phosphodiesterase type-4 inhibitor (PDE-4) for the treatment of mild moderate atopic dermatitis. Evidence from phase 3 trials demonstrates crisaborole as an efficacious topical agent with a favorable safety profile and limited systemic exposure. While the efficacy of crisaborole compared to existing therapies remains unknown, crisaborole is a promising candidate in the treatment of atopic dermatitis.

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

Introduction

Atopic dermatitis (AD) is a chronic inflammatory cutaneous condition associated with significant morbidity and stigma in affected patients.¹ AD is characterized by the sudden onset of a recurrent, pruritic, erythematous and fissured dermatoses. It is estimated to affect up to 15-30% of children and up to 10% of adults living in industrialized countries.² In the United States alone, AD imposes a considerable economic burden, with an estimated cost of up to $3.8 billion annually.^1,3 Clinical features differ with age. The flexural surfaces of upper and lower extremities and face are most often affected during childhood, whereas hands and feet are more commonly involved in adult patients.⁴ AD can be associated with serious comorbidities including allergic rhinitis, asthma, hay fever, urticaria and asthma.^3,5 Patients with genodermatoses, such as Wiskott-Aldrich syndrome, may show an AD like skin condition.⁶ Individuals with AD are more prone to cutaneous secondary infections by pathogens including Staphylococcus aureus, which is also a leading cause of soft-tissue infections. Moreover, secondary skin infection can lead to exacerbation of AD disease severity.⁷

As the frequency of AD continues to rise, renewed focused on treatment and management is increasingly important.¹ As no curative options exist, therapy centers on controlling disease progression, reducing flares and providing relief from symptoms, including pain and pruritus.^8,9 The mainstays of such therapies include the use of emollients, cosmeceuticals, topical and systemic corticosteroids, as well as topical calcineurin inhibitors (TCIs).² Treatment options are predicated on age and AD severity. For instance, mild to moderate AD may be treated with TCIs or corticosteroids such as desonide 0.05% or fluocinolone 0.01%.⁸ In patients with moderate to severe AD who are recalcitrant to topical therapy, systemic treatment may include dupilumab administered at 300 mg subcutaneously once weekly or every other week for adults.^10,11 Proactive therapy with tacrolimus 0.1% ointment or pimecrolimus 2% twice daily⁹ may be employed to prevent relapses and extend periods without recurrence in patients who experience frequent exacerbations. TCIs have been issued a black box warning based on theoretical concerns that their use may be linked to lymphoma,¹² however, long-term surveillance has not substantiated this risk. Moreover, prolonged use of topical corticosteroids has been associated with cutaneous atrophy, telangiectasia, and striae formation.⁸ This has led to the development of new therapies, particularly aimed at the pediatric population. Crisaborole (formerly known as AN2728) is a novel, boron-based phosphodiesterase-4 (PDE-4) inhibitor developed to treat this populace.^8,13

A Novel Treatment for Mild-Moderate AD

Crisaborole (Eucrisa™) 2% ointment is indicated as a topical treatment for patients aged ≥2 years with mild to moderate AD. Early phase 1 and 2 studies provided evidence that showed the potential for crisaborole to be an efficacious and noncarcinogenic treatment option with a positive safety profile.^14-16 Approved in December of 2016 by the US FDA and June 2018 by Health Canada, it is the first topical PDE-4 inhibitor to be indicated for AD.

Mechanism of Action

In patients with AD, elevation of PDE-4 is associated with increased inflammatory mediators leading to a chronic inflammatory state.¹⁷ PDE-4 facilitates this inflammatory process through the degradation of 3’5’-cyclic adenosine monophosphate (cAMP). Crisaborole works through the selective inhibition of PDE-4, preventing the breakdown of cAMP, leading to an accumulation of cellular cAMP, suppression of pro-inflammatory cytokines, and reduction in inflammatory pathways.^8,17,18 Specifically, elevated levels of cAMP result in further activation of protein kinase A and inhibition of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) signaling pathways. Crisaborole targets the underlying mechanism of the disease through suppression of pro-inflammatory cytokines, including interleukin (IL)-2, IL-5, interferon-γ, and tumor necrosis factor-α.^17-19 Of note, this mechanism of cytokine-production inhibition by crisaborole is distinct from that of corticosteroids.¹⁷

Phase 3 Clinical Trials

The efficacy and safety of crisaborole was evaluated through two randomized, double-blind controlled phase 3 clinical trials, which included a total of 1522 patients ≥2 years of age with mild to moderate AD.²⁰ Although both pediatric and adult patients were represented in the study population, the mean age of the crisaborole ointment treatment groups was 12 and 12.6 in both studies. Adult patients (≥18 years of age) constituted 12.9% and 15% of the crisaborole treatment groups. The efficacy of crisaborole within these studies was determined by the clearance or almost clearance of AD with a 2-grade or more improvement from baseline using the Investigator’s Static Global Assessment (ISGA). In both studies, more crisaborole-treated patients showed improvement in the ISGA score at day 29 (32.8%, 31.4%) as compared against vehicle-treated patients (25.4%, 18%), respectively. Furthermore, patients in the crisaboroletreated group achieved success in the ISGA score earlier than the control. Pooled data between the two studies demonstrated an improvement in disease severity, as measured by the reduction in signs and symptoms, including erythema, exudation, excoriations, induration/papulation and lichenification. Improvement and sustained relief of pruritus was achieved earlier in crisaboroletreated patients (1.37 vs. 1.7 days, p=0.001).²⁰ A secondary analysis of the phase 3 trials performed by Yosipovitch et al.21 confirmed the early improvement in pruritus for the treatment cohort compared to control (56.6% vs. 39.5%; p<0.001).

Safety and Long-term Complications

Unlike topical corticosteroids and calcineurin inhibitors, which have potential adverse side effects with continued use, crisaborole demonstrates a promising safety profile. Crisaborole effectively penetrates through the skin due to its low molecular weight (251 Da) and lipophilic properties,¹⁷ with only trace amounts reaching the systemic circulation.²² Steady-state levels of crisaborole and its metabolites were reached in a pharmacokinetic 8-day trial under maximal-use conditions.²² In this study, the mean maximum plasma concentration of crisaborole remained stable with a mean maximum concentration of 127 ng/mL seen on day 8. Once in the bloodstream, the drug is quickly metabolized into inactive metabolites, limiting the systemic impact of crisaborole to the site of application.^17,22 Whereas nausea, emesis, and/or diarrhea are side effects associated with oral PDE-4 inhibitors, similar symptoms are uncommonly observed with topical use.^20,23,24 The majority of adverse events include burning or stinging at the site of application.²⁰ Of these adverse events, 77.6% of patients experienced resolution within 1 day of onset. No serious adverse events were recorded. Lastly, the low discontinuation rates (1.2%, pooled data) that were observed in phase 3 trials may indicate the potential for higher treatment compliance.

After completion of a 28-day phase 3 pivotal study, a longitudinal multicenter, open-label trial was conducted that followed 517 patients over 48 weeks to assess the long-term safety of crisaborole.²⁴ Only 10.3% of patients experienced treatmentrelated adverse events. Of these, the vast majority of adverse events were considered mild (51.2%) or moderate (44.6%). The most common events reported were atopic dermatitis (3.1%), application-site pain (2.3%) and application-site infection (1.2%). No change in the frequency of adverse events was observed throughout the study. Rescue therapy with a topical corticosteroid or TCI was required in 22.2% of patients, with the majority (79%) resuming crisaborole after the end of rescue therapy.

Conclusion

Crisaborole represents a novel and efficacious therapeutic approach for the treatment of mild to moderate AD. Through the inhibition of PDE-4 and reduction of local inflammation, crisaborole has been shown to provide a significant improvement in the management of AD.^14-16,20,22 Furthermore, crisaborole demonstrates early and continued decrease in pruritus, which improves quality of life and reduces the potential risk of infection and scarring.^24,25 The small size of the crisaborole molecule allows for effective skin penetration, while its quick metabolism in the bloodstream limits systemic exposure, which is associated with the long-term use of topical corticosteroids and TCIs.²² Further studies comparing crisaborole against topical corticosteroids or TCIs are warranted to establish it role in the treatment paradigm for mild to moderate AD, as well as its utility in children <2 years of age.

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Skin Centre for Dermatology, Peterborough, ON, Canada; Probity Medical Research, Waterloo, ON, Canada; Queen’s University, Kingston, ON, Canada

Conflict of interest:
Melinda Gooderham has been a speaker for Actelion and an investigator, speaker and advisor for Janssen.

Abstract
Chronic hand dermatitis is a debilitating inflammatory dermatosis that has a significant impact on the quality of life of those affected. Alitretinoin is an oral retinoid which has proven efficacy and safety in the treatment of chronic hand dermatitis through randomized controlled trials. Real-world evidence, information gathered in the clinic or community setting, as opposed to a research environment, can complement knowledge gained from clinical trials. Herein, real-world evidence supporting the safety and effectiveness of alitretinoin in the management of chronic hand dermatitis will be reviewed.

Key Words:
alitretinoin, Toctino®, chronic hand dermatitis, chronic hand eczema, retinoid

Chronic hand dermatitis (CHD) has a negative impact on the quality of life of those affected, leading to social and psychological distress and a reduction in productivity.^{1, 2} CHD is common and has a 1-year prevalence of 10% and a lifetime prevalence of up to 15% in the general population.³ Although CHD is notoriously difficult to treat, the endogenous retinoid alitretinoin (9-cisretinoic acid, Toctino®), has proven to be an effective and safe therapeutic option.^4-7 In the pivotal randomized, double-blind, multicenter, placebo-controlled Phase 3 BACH trial, the treatment group receiving alitretinoin 30 mg daily had up to a 75% median reduction in signs and symptoms and 48% were clear or almost clear at the week 24 time point.⁷ Of the patients that achieved remission after 24 weeks, the majority did not require long-term management. However, for those who did relapse and required retreatment, many recaptured their response6 and of those patients who required a second course of therapy, there were no safety concerns.⁵

Real-world evidence is information gathered in clinical care or the community setting, as opposed to a research environment.⁸ It can be derived from electronic health records, claims databases, registries or personal devices and is important because information collected post-marketing can complement knowledge gained from clinical trials.⁸ The realworld effectiveness and safety of alitretinoin has previously been reported and will be reviewed here (see Table 2).^9-14 The TOCCATA non-interventional, observational study reported on the use of alitretinoin in ‘real life’ daily practice in Germany, enrolling 680 adult patients with CHD who were treated with alitretinoin.⁹ Global assessment was performed and reported 56.7% of patients reaching clear or almost clear at week 24.⁹ These real-world results were better than the pivotal trial, likely because participants could continue concomitant therapies, which were not permitted in the BACH trial.⁹ Safety was similar to previous reports and the most common adverse events were headache, hypertriglyceridemia and hypercholesterolemia, as expected with the retinoid class. The FUGETTA study, a second observational study in Germany, explored the effectiveness and impact on quality of life in 658 adults with CHD treated with 10 mg or 30 mg of alitretinoin daily.¹⁵ It reported similar results to the BACH trial, with 48% of participants with severe CHD at baseline reaching clear or almost clear at the final visit for both doses, however, 45% of patients withdrew before the 24 weeks mainly because of hand dermatitis clearing.¹⁵ There was a mean reduction in the Dermatology Life Quality Index (DLQI) score of 58% and 70% for the 30 mg and 10 mg group, respectively.¹⁵ The treatment was well tolerated, with the majority of patients and physicians rating the effectiveness and tolerability of alitretinoin as ‘good’ or ‘very good’.¹⁵ The PASSION study, a third postmarketing observational study performed in Germany, enrolled 631 patients with CHD and, unlike previous trials, 17.7% had already been exposed to alitretinoin within the past 12 months.¹³ The main focus of this trial was to look at the impact of oral alitretinoin on quality of life and work productivity. It was shown that alitretinoin significantly improved quality of life and reduced work incapacity as the number of patients rated as ‘disabled’ reduced from 12.4% at baseline to 2.2% at week 24, and those reporting ‘no work impairment’ increased from 2.7% at baseline to 63.7% at week 24.¹³ The limitation of these observational studies is the short duration of 24 weeks.⁹ Gulliver and Baker (2012) reported on longer-term therapy in 3 patients who took alitretinoin continuously for 36 months with maintained efficacy and no new safety concerns.¹⁰

A recently published chart review includes a follow-up of a previous patient cohort from a 2014 Canadian dermatology practice chart review, which demonstrated that alitretinoin was a safe and well-tolerated treatment in real-world practice.^11,14 The participants in the original chart review were CHD patients who were prescribed alitretinoin from November 2010 until August 2013,¹¹ and their course was further reported until a second cutoff date of January 2017.¹⁴ Participants were prescribed alitretinoin (10 mg or 30 mg daily), and laboratory assessments were conducted approximately every 2 months. As previously reported, the average age was 57.3 ± 12.2 years, and 60% were male (Table 1).¹⁴ The patient cohort included several types of CHD, such as hyperkeratotic, dyshidrotic, fingertip, psoriasiform dermatitis, chronic actinic dermatitis, asteatotic dermatitis, and palmoplantar dermatitis. Of the 80 patients with CHD originally prescribed alitretinoin, 25 (31.3%) did not take the treatment, 53 (96.4%) patients started at 30 mg and 2 (3.6%) patients started at the 10 mg daily (see Figure 1 for patient disposition). Two additional patients from this cohort started alitretinoin therapy since the cutoff in August 2013: 1 patient at 30 mg and the other at 10 mg daily.¹⁴ Of the 55 (68.8%) participants who took alitretinoin, the median time of treatment was 10 months, the average was 12.6 months, and the ongoing maximum was 71 months. Up to January 2017, 44 (55%) patients discontinued treatment for various reasons (see Figure 2). Sixteen (29%) patients who discontinued therapy elected to restart therapy because of recurrence of disease. There were 17 (30.9%) patients who reduced the dose from 30 mg to 10 mg and the main reason was clearance of symptoms. The most common side effects were headaches, nausea and joint pain/stiffness. Less common side effects included depression, elevated triglycerides or cholesterol, blurred vision, hand numbness, and edema. One patient who started at 10 mg increased the dose to 30 mg during the follow-up period to increase effectiveness. During the follow-up period, 4 (7.3%) additional patients from the cohort stopped alitretinoin due to abnormal laboratory values: 1 (1.8%) with elevated triglycerides and 3 (5.5%) with elevated transaminases. Thirteen (23.6%) patients remain on long-term therapy with good control of their disease.¹⁴

Conclusion

Alitretinoin has proven to be a safe and effective treatment option for CHD in both clinical trials and the real-world setting. A quarter of patients in this cohort required ongoing alitretinoin therapy for chronic control of disease, and no increase in safety signals were noted with long-term therapy. Side effects were uncommon and not a frequent cause for discontinuation; the most common reason for dose reduction was clearance of symptoms. These findings, in combination with those of three real-world trials from Germany, support the use of alitretinoin in the management of CHD. Gathering real-world evidence of alitretinoin use in a community setting can complement information gained from the well-controlled pivotal trials of shorter duration.

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¹Hospital for Sick Children, Toronto, ON, Canada
²University of Calgary, Calgary, AB, Canada
³University of British Columbia, Vancouver, BC, Canada
⁴Toronto Western Hospital, University Health Network, Toronto, ON, Canada and Department of Dermatology, Brown University, Providence, RI, USA
⁵University Health Network, Toronto, ON, Canada
⁶Centre hospitalier universitaire Sainte-Justine, Montreal, QC, Canada
⁷British Columbia Children’s Hospital, Vancouver, BC, Canada
⁸Eczema Society of Canada / Société canadienne de l’eczéma, Keswick, ON, Canada

This manuscript was previously disseminated by Eczema Society of Canada Copyright© by the Eczema Society of Canada / Société canadienne de l’eczéma July 2016; revised 2017. All rights reserved. Third Edition

About Atopic Dermatitis

Eczema (atopic dermatitis), is a chronic, pruritic inflammatory skin condition that follows a relapsing course affecting people of all ages, although it is more frequent in children. Eczema is most often diagnosed and managed by primary care providers. This article aims to provide practical guidance to primary healthcare practitioners who care for patients with eczema. The Eczema Society of Canada/Société canadienne de l’eczéma convened a group of Canadian dermatologists with extensive experience in managing paediatric and adult patients with atopic dermatitis, to develop practical recommendations for the management of atopic dermatitis. They developed clinical recommendations based on expert consensus opinion and the best available medical evidence. The experts developed recommendations that focus on three key areas of managing patients with eczema: (1) patient/caregiver education, (2) addressing skin barrier dysfunction and (3) inflammation control. Therapeutic education directed to the patient or main caregiver(s) has been demonstrated to improve QoL.¹ While complete guidelines on AD are available,^2-5 these guidelines may not be practical for everyday clinical practice in primary care, nor are they specific to the Canadian healthcare system.

Abbreviations: AD – Atopic Dermatitis, QoL – Quality of Life, SOA – Sedating Oral Antihistamine, TCI – Topical Calcineurin Inhibitors, TCS – Topical Corticosteroids

Background

• Atopic dermatitis (AD)-also commonly referred to as eczema or atopic eczema-is a chronic, pruritic, relapsing inflammatory skin condition that impacts quality of life (QoL) and places a significant burden on patients and families.
• It can affect people of all ages but it is more frequent in children.
• Eczema is characterized by periods of acute worsening symptoms, known as flares, alternating with periods of symptom remission, but some patients do not have any remission.
• Patients often have associated atopic disorders, such as allergic rhinoconjuncitivitis, food allergies and/or asthma.
• The onset of eczema is typically between 2 and 6 months of age, although it can begin at any age. It was previously thought that eczema resolved or improved by adulthood in most cases, but evidence suggests that it is a chronic condition that may persist into adulthood.^6-8
• Eczema is caused by a dysfunctional skin barrier and dysregulation of the immune system, due to genetic, immunologic, and environmental factors. Pruritus is the most notable feature of eczema, which is at the centre of much of the disease burden for patients and their families.

Diagnosis & Assessment

• Eczema is most often diagnosed and managed by primary care providers.⁹
• Eczema is diagnosed based on the morphology and distribution of the patient’s skin lesions, associated clinical signs, and family history (Table 1).¹⁰ Eczema can range from mild to severe, based on body surface area involvement, extent of eczematous lesions, and the impact on a patient’s QoL.
• At this time, eczema remains a clinical diagnosis. In select cases additional testing may be performed, such as a biopsy or patch testing, to rule out other conditions, but this is usually unnecessary. If the diagnosis is unclear, referral to a dermatologist should be considered.

Quality of Life in Eczema Assessment

• Eczema has a significant impact on QoL for patients and their families. Physicians should consider addressing this impact on QoL with their patients and patients’ families, in addition to assessing the signs and symptoms of the disease.
• Sleep is disturbed, often for the whole family. Healthcare providers should address itch, sleep loss, and disease impact on mood, activities, behaviour and self-esteem, when diagnosing eczema and formulating a management plan.
• The impact of AD on QoL for the patient and his or her family is often very significant. The level of impact has been found to be similar and at times can surpass the effect that diabetes has on the family.¹¹

Minimizing and Controlling Flares

• Eczema is a relapsing-remitting, chronic disease with cyclical periods of relative quiescence and periods of flares.
• Currently, there is no cure for eczema. As such, the main goal of eczema management is to improve baseline inflammation and xerosis and to reduce the frequency and severity of flares. For some patients, treating baseline disease activity will involve emollient use only. For others it will involve the use of emollients and topical anti-inflammatory medications to any inflamed areas. In periods of flare, treatment needs to be increased beyond this baseline.
• For those mild disease and mild flares, adding a topical anti-inflammatory medication to their emollient regimen may be necessary.
• For others with more severe eczema, a temporary increase in the potency of topical anti-inflammatory medications may be required.
• For patients with frequent flares and flares that require high-potency topical corticosteroids, referral to a dermatologist is recommended.

Patient Education

• Suboptimal treatment and poor adherence to therapy are common in patients with eczema, much like in patients with other chronic diseases that require regular intervention. Therefore, therapeutic education is particularly important in the face of many sources of potentially misleading or inaccurate information, or patient misconceptions and fears present in the community.¹²
• Patient and caregiver education is a key aspect of successful eczema management.¹³ Studies have demonstrated that therapeutic patient education increases adherence to therapy, increases the use of moisturizers, and decreases fear of medications.^14-16

Patient counselling should focus on the following key points:

• Eczema is a chronic disease. There is no cure, but control of the disease can be achieved. Eczema typically goes through periods of flares and remissions. Moisturizing is the mainstay of therapy during remission, and prescription treatments are needed for any areas of inflammation.
• Eczema flares can be managed by hydrating the skin (bathing and moisturizing appropriately) and reducing inflammation with topical medication.
• Undertreating, starting treatment too late, or stopping treatment too soon, should be avoided. Treatment of eczema flares should begin at the first sign of inflammation. Patients and caregivers often stop treatment before the skin is fully clear of lesions, mistakenly believing that the vast improvement they have seen means the skin is “clear enough.”
• Clinicians should encourage patients and caregivers to make sure the skin is completely clear of lesions before stopping treatment, since even though eczema flares may seem to be much less severe, the patient still has chronic active inflammation, and often the skin rapidly becomes worse.
• Patients need to be counselled on how to apply the medication, as applying the treatment sparingly may contribute to under treatment.
• Adherence to therapy is essential for the optimal management of eczema. Poor adherence may be the most significant barrier to optimal care in eczema. In a survey of 200 eczema outpatients, 24% admitted that they did not adhere to treatment, and experts estimate this percentage could be significantly higher.⁵ Healthcare providers should counsel patients and caregivers about the importance of adhering to treatment.
• Trigger avoidance:
  • Patients should be counselled to attempt to identify and avoid their triggers, and to understand that some eczema flares occur despite strict trigger avoidance and diligent skin care. This is often a source of frustration for patients.
  • Many eczema flares do result from some environmental trigger. Common triggers include harsh or fragranced soaps and self-care products, rough fabrics, overheating and sweating, and winter weather. Often these triggers can be identified but not avoided, such as weather changes.
  • Lifestyle can impact eczema as well, such as sweating for a young athlete. Instead of advising the patient to avoid pleasurable activities, help the patient learn about ways to manage the eczema flare that may follow an activity or exposure to an eczema trigger.
  • Additional actions can be taken to help the condition, such as keeping nails trimmed short and filed smooth to help reduce damage done by scratching.
  • Distraction can also be helpful during episodes of acute itch, particularly activities that keep the hands busy.
• Patients and caregivers often seek causes or cures for eczema, which diverts attention away from the treatment plan. Patients should be counselled on the chronicity of atopic dermatitis, and reminded that broad panel allergy testing and restrictive diets are not recommended in the absence of signs and symptoms consistent with an IgE-mediated allergy.
• For additional patient support, information and education, recommend reliable sources, such as the Eczema Society of Canada/ Société canadienne de l’eczéma, Canadian Dermatology Association, American Academy of Dermatology, National Eczema Association (USA), or National Eczema Society (UK)

Written Eczema Care Plans

• A written eczema care plan is a recommended tool to improve therapeutic outcomes.^{17, 18} Patients and caregivers may benefit from having a written plan in order to carry out the multi-step plan of caring for eczema, which often includes specific bathing and moisturizing recommendations and instructions for using prescription medications (type and dosage). For a sample written eczema care plan, see Figure 1.

Skin Care

Moisturizers

• Frequent application of moisturizers is the cornerstone of eczema management,¹⁹ helping to decrease itch, preventing and reducing flares, and decreasing the need for prescription medications.
• Xerosis results from skin barrier dysfunction and is present to some degree in most patients with eczema. Moisturizers are used to reduce xerosis, which reduces itching, and they also reduce transepidermal water loss.²⁰
• For patients with mild eczema, frequent and consistent use of moisturizers may sufficiently manage the disease. In moderate to severe disease, moisturizing is still a fundamental part of treatment. Patients may need to be explicitly counselled on how to use moisturizers in conjunction with other topical prescription treatments.
• Patients should select moisturizers that are soothing and do not irritate the skin. Ideal moisturizers contain varying amounts of emollient, occlusive and humectant ingredients. While thicker products that both moisturize and provide a barrier are recommended, there are many moisturizers to choose from and patient preference is important.
• The consistent use of a moisturizer that is well-tolerated by a patient is more important than the specific product selected.
• There is insufficient evidence to recommend a specific optimal regimen for use of moisturizers. However, this consensus group suggests that generous application, one to several times a day, is necessary to help minimize skin dryness. It is highly recommended to apply moisturizers immediately after bathing or any water exposure to improve skin hydration.^{21, 22}

Barrier Repair & Barrier Repair Products

• Patients with atopic dermatitis have impaired skin barrier function, partly due to deficiencies in ceramides (lipids) and filaggrin (a protein), components of the outer skin barrier. These deficiencies contribute to a degraded skin barrier that allows bacteria, irritants, and allergens to enter the skin, and also allows moisture to escape.²³ To address this, ceramides are increasingly available in over-the-counter moisturizers, as well as one prescription barrier repair treatment.

Bathing & Showering

• Daily bathing is often recommended for patients with eczema; however, there is no evidence to support a standard recommendation for the frequency, duration or the method of bathing. Moisturizing after bathing is strongly recommended.^{21, 22}
• Clinicians can recommend that patients bathe or shower (5-10 minutes) in warm, plain water once daily, or every other day, based on patient preference (e.g., baths may sting open eczema lesions making daily bathing challenging).
• Gentle cleansers may be used only on areas that need cleaning, and should be used at the end of the bath or shower. Bathing using this method should not aggravate eczema.
• Moisturizing should immediately follow bathing or showering, since exposure to water can exacerbate eczema if the skin is not moisturized soon after exiting the water.
• Evidence is lacking to support the use of bath additives such as oils, emollients, bath salts, and most other products.

Inflammation Control

Topical Corticosteroids

• Appropriate use of topical corticosteroids (TCS) is a safe and effective first-line therapy in the treatment of the inflammatory component of eczema.²⁴
• Consider factors such as the age of the patient, areas of the body to be treated, xerosis, and patient preference when prescribing appropriate topical corticosteroids.
• Selecting the appropriate agent, including the appropriate strength, can be challenging. In general, low potency TCS (classes VI and VII) are recommended for the face, neck, skin folds, and groin, for both paediatric and adult patients.
• Moderately potent medications (classes III, IV, and V) are recommended for the trunk and extremities. Higher potency TCS may be required for refractory eczema or lichenified areas.
• Consider referral to a dermatologist in these cases.
• Once to twice daily application of TCS are the generally recommended treatment during an acute eczema flare.
• Treatment should be stopped once the affected areas are smooth to the touch and no longer itchy or red.
• If no response to treatment is seen after 1 to 2 weeks, re-evaluate to consider other diagnoses or treatment plans. With appropriate use, the incidence of adverse events is minimal.²⁵
• When prescribing combination treatments, TCS strength should be taken into consideration, as the TCS could be of higher potency than is appropriate.
• Patients and caregivers may fear the side effects of pharmacological treatments. Fear of topical corticosteroids is common and should be recognized and addressed. This may be particularly important for paediatric patients.
• Addressing fears and concerns may help improve adherence and avoid under-treatment or non-treatment.
• Patients who are using corticosteroids over the long term should be monitored, and should have regular physical examinations to watch for cutaneous side effects. Monitoring of eczema patients for systemic side effects from topical corticosteroids is not routinely recommended.^{26, 27}
• In patients who have good adherence to their treatment plan and experience periods of remission, but flare frequently in predictable areas, maintenance treatment with topical corticosteroids may be suitable. Intermittent application (one application 1 to 2 times a week) of a moderately potent topical corticosteroid is recommended for proactive treatment on areas that are commonly at risk of flare.²⁸

Topical Corticosteroid Side Effects

• As with all medications, TCS can have side effects (Table 2). However, when they are used appropriately, the incidence of side effects is low, and patients should be counselled accordingly.²⁹
• The burden of under- and untreated eczema usually outweighs the risks associated with TCS.³⁰

Topical Calcineurin Inhibitors

• Topical calcineurin inhibitors (TCI) (i.e. tacrolimus and pimecrolimus) are a class of anti-inflammatory medications that are a recommended safe and effective second-line therapy option for treatment of acute flares of eczema.³¹
• Whereas TCS are generally considered first-line topical treatment for eczema, TCI can also be used off-label as first-line therapy in select cases, particularly for areas that are sensitive to the adverse effects of TCS, such as the eyelids.
• TCI are also appropriate second-line therapy for eczema that does not respond to TCS or in patients intolerant of TCS.
• TCI can also be used as a preventive therapy, 2 to 3 times a week in areas of predictable flares similar to the preventative strategy described for TCS above.³²
• Proactive, intermittent use of TCI has been shown to be more effective than the use of emollients alone.^{33, 34}

Topical Calcineurin Inhibitor Side Effects

• Mild to moderate burning or stinging sensation of the skin can occur with TCI use, and patients and caregivers should be counselled about this possible reaction.
• Patients who use tacrolimus may have flushing of the face when they consume alcohol.
• Based on concerns about an increased risk of cancer with the use of TCI use, the US Food and Drug Administration (FDA) issued a black-box warning shortly after the class of medications came on to the market. Shortly after the FDA warning was issued, Health Canada issued a similar warning. However, TCI have been available for over 15 years and recently published data does not support those concerns.^35-39 Healthcare providers should be aware of the black-box warning and discuss it with patients.

Adjunctive Therapies

Antimicrobials

• Skin infections can worsen eczema and should be addressed when present.
• Clinical signs of infected eczema include crusting, oozing, and pus.
• Gram-positive bacteria, in particular Staphylococcus aureus, is frequently found on the skin in eczema.⁴⁰
• Mild infection may be treated with a topical antibiotic adjunctively with a topical anti-inflammatory agent.
• The routine use of topical antistaphylococcal antibiotic treatment in the absence of clinical signs of infection is not recommended.⁴¹
• When clinical signs of bacterial infection are seen, swabs for culture and sensitivity should be considered, partly because of the increased prevalence of resistant organisms, and empiric oral antibiotics targeting streptococcal and staphylococcal infections can be started.
• In patients who frequently show clinical signs of secondary bacterial infection, consider bleach baths as prophylactic therapy.⁴²

Bleach Baths

• In patients where infections are common, bleach baths can be done once to twice per week, and consist of bathing in a dilute solution of bleach and clear warm water.⁴³
• Patients and/or caregivers can create a dilute bleach bath at home by adding 120 mL (1/2 a cup) of regular strength household bleach (6% sodium hypochlorite) to a full standard-size bathtub of warm water (which is usually about 150 litres). This concentration of bleach is quite low (0.005%).
• For smaller bathtubs, patients may use 1 teaspoon (5 mL) of regular bleach for every 5 litres of water.⁴²
• The bleach and clear water should be mixed well, and the patient should bathe in the solution for 5 to 10 minutes, thoroughly rinsing the skin after with warm clear water.
• Rinsing should be immediately followed by application of prescription treatments, if needed, and moisturizers.
• Patients and caregivers should be explicitly counselled on how to perform the bleach bath, including how to select the correct concentration of bleach and safe dilution practices.

Managing Viral Infections

• Viral infection with herpes simplex virus can cause eczema herpeticum, a potentially life-threatening condition.
• Swabs for viral detection (such as viral culture, or polymerase chain reaction) should be performed in suspected cases of eczema herpeticum, in addition to initiation of treatment with an appropriate antiviral agent.⁴⁴
• Eczema coxsackium is a form of hand-foot-and-mouth disease in patients with eczema that is more extensive than routine hand-foot-and-mouth disease, and can look similar to eczema herpeticum.
• Molluscum contagiosum occurs more commonly in eczema patients and the presence of the virus can lead to eczema surrounding the mollusca, potentially exacerbating an eczema flare.

Antihistamines

• Due to a lack of evidence of their efficacy in patients with eczema, non-sedating oral antihistamines are not recommended for use.⁴⁵
• Sedating oral antihistamines (SOA), such as hydroxyzine and diphenhydramine, can be used in patients whose disease significantly interferes with sleep.
• It should be noted that long-term use of SOA may lead to a reduction in the efficacy and sedative effects of the treatment.⁴⁶
• Control of inflammation and itch, through the use of previously discussed prescription anti-inflammatory medications and appropriate bathing and moisturizing may mitigate the need for sedating antihistamines in many patients.
• Patient reliance upon regular antihistamine use should be an indication that the treatment plan is not optimally managing the condition.⁴⁷

Allergy Testing & Restrictive Diets

• The relationship between eczema and allergy is complex. While children with eczema have a significantly higher incidence of food allergies, food does not cause eczema flares for most patients.
• In an AD patient who has confirmed food allergies, exposure to the allergenic foods can induce urticaria, which can indirectly worsen the eczema.
• If a patient shows true allergic signs and symptoms such as urticaria or anaphylaxis to a food, that food should be avoided and an epinephrine auto injector should be prescribed, until an allergist/immunologist can be consulted.
• Routine allergy testing with eczema as the only symptom is not currently recommended.
• Broad spectrum panel testing for a variety of foods is not recommended, as it often leads to a number of false positive results.⁴⁸
• Food elimination diets or restrictive diets are not recommended as an eczema intervention.
• Excessive, prolonged food elimination diets, especially in children, may lead to weight loss, poor growth, and nutritional deficiency.⁴⁹

Supplements & Alternative Therapies

• There is limited evidence to support the routine use of dietary supplements and alternative medicines for the treatment of eczema. However, some patients may find dietary supplements or alternative interventions to be helpful.
• If the dietary supplements or interventions are not harmful, the patient should be counselled and supported accordingly. However, if these interventions could be harmful, patients should be counselled and cautioned.
• Extra caution should be taken in the case of infants and children.

Refractory and Severe Eczema

• Phototherapy⁵⁰ and/or systemic immunomodulatory agents may be necessary for refractory and severe eczema, and they should be used by health care providers versed in their use.⁵¹
• Phototherapy, specifically broad- and narrow-band UVB, can be used for pediatric and adult patients with AD. It is a safe and effective treatment for most patients, but a major barrier to its use is accessibility as it requires visits to a physician’s office multiple times per week. Furthermore, long term side effects, such as skin cancer, have not been well-established in the paediatric population.
• Cyclosporine, methotrexate, azathioprine and mycophenolate mofetil are the systemic agents commonly used for atopic dermatitis. All of these agents may cause significant adverse events and require regular monitoring, so they should be used with caution and after appropriate discussion of their risks and benefits with patients and their families. Specific guidelines for their use, including dosing schedules and adverse effects, are beyond the scope of this review.
• Referral to a dermatologist should be considered in patients with refractory eczema in whom systemic therapy is being contemplated.

Systemic Corticosteroids

• Systemic corticosteroids, such as prednisone, are not recommended for the routine management of atopic dermatitis.
• While systemic corticosteroids can rapidly ameliorate the signs and symptoms of an acute eczema flare, patients often have a disease flare upon withdrawal of the corticosteroid.
• Given the long-term consequences of chronic systemic corticosteroid use, they should be avoided whenever possible in patients with atopic dermatitis.⁵²

Conflicts of Interest:
Dr. Tyring and Dr. Vangipuram have served as investigators for Regeneron Pharmaceuticals.

ABSTRACT
Atopic dermatitis (AD) is the most common chronic inflammatory disease affecting 2-10% of adults and up to 15-30% of children. Despite a rising prevalence, effective and safe therapeutics for patients with moderate-to-severe AD are limited due to toxicity and side effects. Dupilumab, an interleukin (IL)-4 and IL-13 antagonist that limits type 2 T helper (Th2) driven inflammatory activity, is a promising therapeutic option. In clinical trials, it has demonstrated efficacy by reducing clinical activity and symptoms, and showed improvement in the AD genomic phenotype, including a significant reduction in Th2 chemokines and reversal of key epidermal markers of AD. It also has a favorable safety profile. This review discusses the role of dupilumab in treating Th2 related inflammation, and its efficacy and safety, as demonstrated in clinical trials. Dupilumab (Dupixent®) recently gained US FDA approval for patients with moderate-to-severe AD, and is poised to revolutionize the management of this chronic, relapsing condition. 

Key Words:
atopic dermatitis, biologics, dupilumab, eczema, Th2 related inflammation

Introduction

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease with a prevalence of 2-10% among adults and up to 15-30% among children.^1,2 It is a chronic, relapsing inflammatory skin disorder characterized by intensely pruritic scaly and dry eczematous lesions. AD is often associated with other atopic disorders, such as allergic rhinitis and asthma. It causes substantial morbidity and greatly impacts the quality of life of affected individuals and their families.³ While around 85% of patients first develop the disease in childhood, adult-onset AD has also been recognized.^4,5 The incidence of AD has been rising over the last decades, especially in industrialized nations.¹ One-third of all adults with AD are classified as having moderate-to-severe disease, representing a large and unmet need for safe, effective and reliable treatments.⁶

Pathogenesis of Atopic Dermatitis

The pathogenesis of AD is complex and includes immunological abnormalities, an impaired epidermal barrier, and altered skin microbiota.^7-10 An increased susceptibility to infections is also observed in patients with AD.^9,10 Immunologically, AD is characterized by excessive T-cell activation, with significant skin infiltration by T-cells and dendritic cells (DCs). There is increased expression of Th2 cytokines in the acute lesional skin of AD patients, with a corresponding decrease in the T helper type 1 (Th1) cytokines.^7,8 T helper type 2 (Th2) cells produce interleukin (IL)-4, IL-5 and IL-13; and activate eosinophils, basophils and mast cells, as well as immunoglobulin E (IgE)-producing B cells, which are all involved in allergic reactions.

In addition, the Th2 cytokines have specific effects on the epidermis, including suppression of keratinocyte differentiation and antimicrobial peptide (AMP) production, which contribute to the AD skin phenotype.⁸ High levels of the Th2 cytokines IL-4 and IL-13 in AD skin have been shown to act as inhibitors of both epidermal differentiation and production of AMPs.⁸

Current Treatments

Despite the high prevalence of AD, treatment options for patients with moderate-to-severe disease are limited. Current therapies for AD provide symptomatic relief, in the form of topical emollients and topical anti-inflammatory agents, with limited, nonspecific options for moderate-to-severe disease. Immunosuppressive agents such as cyclosporine, methotrexate, and systemic corticosteroids can only be used as short-term options due to their side effect profile. Off label agents such as mycophenolate mofetil and azathioprine are used when all available options have been exhausted. Narrow band ultraviolet B (UVB) phototherapy is another option; however, it is time-consuming and inconvenient. There is a great unmet need for safe and efficacious longterm therapy for the management of moderate-to-severe AD. Dupilumab is a promising alternative.

Phase 1 and 2 Studies

Dupilumab is a fully human monoclonal antibody that binds to the shared alpha chain subunit of the IL-4 receptor, and blocks both IL-4 and IL-13 signaling. Early-phase studies showed the efficacy of dupilumab in patients with asthma^11,12 and chronic sinusitis with nasal polyposis¹³, which are both driven by Th2 cytokines. It is administered subcutaneously. Beck et al. published the first trials involving dupilumab in AD patients in 2014.¹⁴ They conducted four randomized, double-blind, placebo-controlled trials in patients with refractory moderate-to-severe AD. Two of the studies evaluated the safety of dupilumab monotherapy for 4 weeks. Efficacy measurements were obtained as the secondary endpoints of the study. The third study assessed the safety and efficacy of dupilumab monotherapy for 12 weeks, as primary and secondary endpoints, respectively. The fourth study evaluated the incidence and severity of adverse events associated with combination therapy with topical steroids for 4 weeks. Patients who were treated with dupilumab in all four trials experienced rapid improvement in AD disease activity. In the 4-week monotherapy studies, 59% of patients on dupilumab achieved a 50% reduction in the Eczema Area and Severity Index (EASI-50) as compared to 19% of patients on placebo (p<0.05).¹⁴ In the 12-week monotherapy trial, 85% of patients in the dupilumab arm reached EASI-50 as compared to 35% in the placebo arm (p<0.001).¹⁴ When combined with topical glucocorticoids, all patients treated with dupilumab reached EASI-50, compared with only half of those receiving topical glucocorticoids plus placebo (p=0.002).¹⁴ Notably, patients receiving dupilumab used less than half the glucocorticoid therapy compared with those who were on placebo (p=0.16).¹⁴

Hamilton et al. studied the effects of IL-4/IL-13 blockade at the molecular level, via transcriptomic analyses of pre-treatment and post-treatment skin biopsies from 18 patients with moderate-to-severe AD.¹⁵ All subjects received weekly treatment with 150 mg or 300 mg of dupilumab or placebo in the aforementioned 4-week monotherapy trials. Dupilumab improved the AD signature in a dose-dependent manner, with a measurable response after 4 weeks of treatment.¹⁵ The molecular changes paralleled improvements in clinical scores. Dupilumab suppressed mRNA expression of genes related to activation of T cells, DCs, eosinophils, inflammatory pathways, and Th2-inducing chemokines in skin lesions.¹⁵ Moreover, dupilumab reversed the epidermal phenotype of Th2 driven skin lesions of AD, without major effects on the Th1 axis.¹⁵ On the other hand, exacerbation of the AD transcriptome was observed in placebo-treated patients.¹⁵ Thaçi et al. studied the efficacy of dupilumab in 380 patients in a randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial in adult patients with moderate-to-severe AD ¹⁶ Patients were randomly assigned to receive 300 mg of dupilumab once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or a placebo. Patients were required to apply a topical emollient twice a day for the first few weeks of the study, and could continue using a topical emollient during the study.In the highest dosage group (300 mg once a week), 73.7% of patients achieved the primary endpoint of EASI-50. In addition, 68.2% of patients in the second highest dosage group (300 mg every 2 weeks), and 44.8% in the lowest dosage group (100 mg every 4 weeks) also achieved EASI-50, compared to 18.1% of placebo patients.¹⁶ The strong placebo effect could be partly explained by the mandatory use of an emollient. Changes in clinical assessment and symptom reduction were noted during the first week of treatment, with the greatest improvement in symptoms achieved with 4 weeks of treatment. This study showed the clinical efficacy of dupilumab at five different dose regimens in moderate-to-severe AD patients, with the most consistent benefits recorded at the higher dose regimens (300 mg once a week and 300 mg every 2 weeks).

Phase 3 Studies

Simpson et al. reported the findings from two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2).¹⁷ Dupilumab 300 mg or placebo was injected subcutaneously weekly or every other week for 16 weeks, in 671 patients in SOLO 1 and 708 patients in SOLO 2. Enrolled patients had moderate-to-severe AD that was inadequately controlled by topical treatment. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment (IGA) and a reduction of 2 points or more in that score from baseline at week 16. In SOLO 1, 37% patients who received dupilumab weekly and 38% of patients who received dupilumab every other week achieved an IGA of 0 or 1, as compared with 10% of patients who received placebo (p<0.001 for both comparisons with placebo).¹⁷ Similar results were reported in SOLO 2, with 36% of patients who received dupilumab weekly and 36% of patients who received dupilumab every other week achieved an IGA of 0 or 1, compared to 8% of patients who received placebo (p<0.001 for both comparisons).¹⁷ Additionally, in both trials, an improvement from baseline to week 16 of at least 75% on the EASI was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (p<0.001 for all comparisons).¹⁷

Patient Reported Outcomes

Patients who received dupilumab in clinical trials consistently reported a rapid and substantial reduction in pruritus, as well as improvement in anxiety and depression symptoms and overall quality of life, which further solidifies dupilumab’s role in the management of moderate-to-severe AD. In the early phase trials conducted by Beck et al., patients treated with dupilumab also experienced a notable reduction in pruritus when compared to those on placebo, as measured by the pruritus Numerical Rating Scale (NRS) (56% vs. 15%, respectively; p<0.05).¹⁴ Similar results were reported by Thaçi et al. in their phase 2 trial, in which treatment with dupilumab resulted in marked improvement in pruritus NRS scores at week 16, with significant reduction as early as week 1.¹⁵ Improvement in pruritus symptoms was dosedependent. Additionally, dupilumab resulted in improvement of patients’ assessment for quality of life: dupilumab improved Dermatology Life Quality Index (DLQI) scores from baseline to week 16 in a dose-dependent manner for all dose regimens (p<0.0001) except 100 mg every 4 weeks.¹⁵

Patient-reported outcomes obtained in Thaçi et al.’s phase 2b trial were further analyzed by Simpson et al.¹⁸ Dupilumab led to rapid and persistent patient-reported and clinically relevant improvements in sleep, mental health, and health-related quality of life, which was most pronounced with the two 300 mg dose regimens. All dupilumab doses except 100 mg every 4 weeks also significantly improved other skin symptoms, such as itchy, bleeding, oozing, cracked, flaking, and dry/rough skin, at 16 weeks when compared to placebo (p<0.0001).¹⁸ Among patients who reported moderate or severe pain/discomfort at baseline, 57.4% on the 300 mg weekly dose, 51.2% on the 300 mg every 2 weeks dose, and 53.8% on the 200 mg every 2 weeks dose reported no pain/discomfort at week 16, compared with 20.5% of patients on placebo (p<0.005 vs. placebo for all 3 doses).¹⁸ Patients receiving dupilumab also reported significant improvement in sleep relative to placebo (p<0.05) starting at week 1, which was maintained over the treatment duration at all doses except 100 mg every 4 weeks.¹⁸ Patients treated with dupilumab reported significant improvements in psychological symptoms at 16 weeks as indicated by reductions in Hospital Anxiety and Depression Scale (HADS) total score. In addition, all dupilumab doses except 100 mg every 4 weeks resulted in consistent and significant (p<0.05) improvements on each of the six DLQI domains (symptoms and feelings, daily activities, leisure, work and school, personal relationships, treatment) relative to placebo at week 16.¹⁸

In the SOLO 1 and SOLO 2 phase 3 trials, dupilumab was associated with improvements in pruritus, symptoms of anxiety or depression, and quality of life. By week 2, patient-reported scores with respect to itching were markedly better among patients receiving dupilumab than among those receiving placebo.¹⁷ In these trials, dupilumab significantly reduced patient-reported symptoms of AD and its effect on sleep, anxiety or depression, and quality of life.

Safety

In the phase 1 trials conducted by Beck et al., adverse events occurred with a similar frequency in the placebo and dupilumab groups. Most were graded as mild or moderate in severity and self-limited. However, nasopharyngitis and headache were observed more commonly in dupilumab patients than placebo.¹⁴ These findings were also reported at a higher frequency in patients taking dupilumab for asthma and elevated eosinophil levels.¹¹ Injection-site reactions were observed more frequently in the dupilumab group. Severe adverse events were reported by 11.2% of placebo patients, compared to 1.5% of dupilumab patients.¹⁴ The majority of these severe adverse events were related to a greater number of skin infections and exacerbations of AD in the placebo groups, which led the authors to speculate that dupilumab improves the skin-barrier function.¹⁴

In the trial reported by Thaçi and colleagues, in which safety outcomes were monitored from baseline until week 32, the dupilumab and placebo treatment groups had similar rates of treatment-emergent adverse events.¹⁵ Dupilumab was well tolerated in this study, with most adverse events classified as mild or moderate. These included nasopharyngitis, exacerbation of AD, headache and upper respiratory tract infection.¹⁵ Injectionsite reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups; however, the rate of serious treatment-emergent adverse events was higher in the placebo group (7%) than in the dupilumab groups (4%).¹⁵ Herpes viral infections were more frequent in patients given dupilumab vs. placebo (8% vs. 2%, respectively);¹⁵ this finding was not reported in the first four phase 1 and 2 studies. All herpes viral infections were mild to moderate, and most cases were confined to the perioral area.

Similarly, in the phase 3 trials, the overall incidence of adverse events was similar in the dupilumab and the placebo groups. The most common adverse events in the two trials were exacerbations of AD, injection-site reactions, and nasopharyngitis.¹⁷ The incidence of nasopharyngitis was generally equal across the dupilumab and placebo groups.¹⁷ Dupilumab was associated with a higher rate of injection-site reactions, most of which were mild or moderate. Exacerbations of AD and most types of skin infections were more common in the placebo groups. The rates of conjunctivitis with an unspecified cause and allergic conjunctivitis were higher in the dupilumab groups than in the placebo groups. Herpes infections were reported in 7% of patients receiving dupilumab every week, 4% of dupilumab every other week, and 4% of placebo in SOLO 1. In SOLO 2, herpes infections were reported in 4% of patients receiving dupilumab every week, 5% of dupilumab every other week, and 3% of placebo.¹⁷

In all reported trials, laboratory values, vital signs, and electrocardiographic assessments did not significantly differ among treatment groups.^14,16,17

Long-term Efficacy and Safety

In a long-term open label study, dupilumab demonstrated sustained efficacy and safety through 52 weeks of treatment.¹⁹ The percentage of dupilumab-naïve patients or those re-treated with dupilumab, who maintained an IGA of 0-1 at week 52 was approximately equal (49.1% and 50.7%, respectively).¹⁹ Moreover, 73.3% and 80.6% of dupilumab-naïve and re-treated patients, respectively, sustained EASI-75.¹⁹ The decrease in peak pruritus NRS and DLQI were also sustained over the treatment period.

Safety analyses through week 52, which included 459 subjects, did not identify any concerns associated with long-term treatment.¹⁹ The rate of previously noted adverse events (nasopharyngitis, exacerbation of AD, conjunctivitis, and herpes labialis infections) did not increased with long-term treatment; moreover, there were no new side effects or adverse events identified through week 52.

Pediatric Patients and Future Trials

The results of a phase 2a, open-label, ascending-dose, sequentialcohort trial among AD pediatric patients who failed topical corticosteroid therapy recently became available.²⁰ Up to 20% of these patients previously failed non-steroidal systemic medications. There were four cohorts, which were stratified based on age (age 6 to 11 with an IGA of 4; age 12-17 with an IGA of 3-4) and dosage (2 mg/kg and 4 mg/kg). The study was divided into two parts: in part A, subjects were given one dose and followed for 8 weeks; in part B, subjects were given four weekly doses and followed for 8 weeks. The primary objective of the study was to characterize the pharmacokinetic (PK) profile of dupilumab in the pediatric AD population. Secondary endpoints included the rate of adverse events, percent change from baseline EASI, and percent change in baseline peak pruritus NRS score. Based on the analysis of 77 subjects, the PK profile of dupilumab in pediatric patients with AD was consistent with that observed in adults with moderate-to-severe AD; moreover, it correlated with improvements in EASI score and reduction in pruritus.²⁰ Both the 2 mg/kg and 4 mg/kg dose regimens showed comparable responses in clinical endpoints; however, the 4 mg/kg dosage was associated with a higher frequency of adverse events, including nasopharyngitis, exacerbation of AD, injection-site reaction, infections, and conjunctivitis.

Future trials for dupilumab include a long-term, open-label extension of the pediatric phase 2a study to assess safety²⁰, a phase 3 placebo-controlled trial to investigate the efficacy and safety of dupilumab monotherapy in pediatric patients >12 years of age²¹, and a study comparing a dupilumab auto-injector device to a pre-filled syringe²².

Conclusion

Dupilumab is a promising therapeutic option for patients with moderate-to-severe AD. The remarkable and rapid onset of efficacy has been clearly demonstrated in published trials. Moreover, dupilumab has produced significant and sustained improvements in the symptomatology of AD, and has improved the quality of life for patients suffering from this disease. Its approval by the US FDA was based on the efficacy and safety results of phase 3 trials. While investigations of longer duration are needed to further characterize the long-term effectiveness and safety of this drug, especially in the pediatric population, dupilumab is poised to revolutionize the management of moderate-to-severe AD.

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¹Skin Centre for Dermatology, Peterborough, ON and Queen’s University, Kingston, ON, Canada
²Associate Professor, University of Toronto, ON, Canada
³Lynde Institute for Dermatology, Markham, ON, Canada
⁴Clinical Instructor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁵Assistant Professor in Clinical Teaching faculty of medicine, Sherbrooke University, Sherbrooke, QC, Canada
⁶Assistant Professor, Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
⁷Dermatology, CHU de Québec-Université Laval, Quebéc, QC, Canada
⁸Centre hospitalier universitaire Dr-Georges-L.-Dumont, Moncton, NB, Canada
⁹Assistant Professor, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
¹⁰Queen’s University, Kingston, ON, Canada
¹¹Clinical Associate Professor, Memorial University of Newfoundland, St. John’s, NL, Canada
¹²Clinical Assistant Professor, Discipline of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
¹³Associate Clinical Professor Dermatology, University of Calgary, AB, Canada
¹⁴Associate Professor, Dalhousie University, Halifax, NS, Canada
¹⁵Université de Montréal, Montréal and Dermatologie Sima Recherches, Verdun, QC, Canada
¹⁶Dermatology, CHU de Québec-Université Laval, Québec, QC, Canada
¹⁷Ottawa, ON, Canada
¹⁸Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada
¹⁹Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Introduction

Chronic hand dermatitis (CHD) can affect up to 10% of the population and have a significant impact on quality of life (QoL).^1-3 It presents as a chronic, recurrent, inflammatory condition with erythema, scaling, fissuring, pruritus and lichenification of the hands. The etiology is multi-factorial and includes both genetic and environmental factors.¹Treatment is notoriously difficult as symptoms frequently recur despite standard therapy. Undertreated CHD can lead to a substantial burden on patients as well as an economic burden on society due to reduced work productivity and many work-related compensation claims.^2-5

Recently, practical guidelines for the management of CHD were published in the Skin Therapy Letter, Family Practice Edition (October 2016).⁶ This series of cases using alitretinoin (Toctino®, GlaxoSmithKline and distributed by Actelion, Laval, QC) is a follow on to that publication to put the guidelines into context.

Abbreviations: AEs – adverse events, CHD – chronic hand dermatitis, ENT – ear, nose, and throat, HD – hand dermatitis, QoL – quality of life

Diagnosing HD – Important points to cover

• Determine if the patient has eczema, or a childhood history of eczema (erythematous, scaling patches with some fissuring in typical locations).
• Ask about a personal or family history of atopy, including asthma, seasonal ENT allergies, nasal polyps.
• Ask about a history of psoriasis and comorbidities such as psoriatic arthritis.
• Does the patient have occupational exposures that could lead to allergic or irritant contact dermatitis?
• Has the patient had any recent exposures to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum, as needed.

Case

Case 1:

A 39-year old dairy farmer presented with a 15-year history of redness, scaling and painful fissuring of the hands. He has used multiple potent topical steroids over the years with only temporary benefit. Despite the continued use of topical steroids he reported that his symptoms always return. After a skin scraping for fungal culture was taken and reported negative, he was referred to a dermatologist for assessment.

A diagnosis of CHD was confirmed. Given the failure of potent topical steroids for >8 weeks and inability to attend regular phototherapy sessions, his dermatologist started him on alitretinoin 30 mg PO QD for a 6-month course. By week 12, his hands were almost clear and by week 24, his hands were clear. He stopped the medication after a 6-month course of alitretinoin and entered into remission. At follow up appointments at year 5 and year 11, his hands remained clear. (Figure 1 and 2)

• Alitretinoin (9-cis retinoic acid) is an endogenous retinoid (physiological vitamin A derivative) and is the only systemic agent approved for CHD. It has proven to be safe and effective for the treatment of CHD in controlled clinical trials7-10 and in real-world experience.^11-15
• In the pivotal BACH trial, 1032 patients with CHD were treated with alitretinoin (10 mg, 30 mg) or placebo for up to 24 weeks. The group that received alitretinoin 30 mg QD had up to a 75% median reduction in signs and symptoms and 48% were clear or almost clear at the week 24 time point.⁸
• In patients who were clear/almost clear, 67% did not relapse within 24 weeks off therapy. In those patients who did relapse, 80% of those re-treated with 30 mg QD recaptured their response.⁹
• Approximately half of those patients receiving 10 mg QD and 40% of those receiving 30 mg QD who did not initially respond to alitretinoin, did respond to retreatment with the 30 mg QD dose for an additional 24 weeks.¹⁰
• The majority of patients do not require long-term management with alitretinoin as some patients enter a remission period with 24 weeks of therapy. For those who relapse and require re-treatment, the majority recapture their response⁹ and in those patients who require ongoing therapy, there are no safety concerns with continuous dosing.^10,12,13

Figure 2. No further prescribed systemic or topical treatments since 2005. (2A) Year 5, (2B) Year 11.Photos courtesy of Dr. Yves Poulin

Case 2:

A 52-year old female teacher presented with a 15-year history of recurrent CHD. She had tried numerous moisturizers and mild to superpotent topical steroids over the years without relief. She tried 6 months of narrowband UVB phototherapy with only partial resolution. She was frustrated and looking for a better solution. Her past medical history is significant for obesity and hypothyroidism. Her dermatologist started her on alitretinoin 30 mg PO QD with excellent response. However, her baseline liver enzymes were 1.5 times the upper limit of normal and 2 months after initiating therapy, increased to 3 times the upper limit so the alitretinoin was discontinued.

Ultrasound demonstrated fatty liver and further work up revealed diabetes. After initiation of metformin and 10 kg of weight loss, the patient’s transaminases returned to within the normal range but her CHD flared. A repeat course of phototherapy and superpotent topical steroids failed again. Slow re-introduction of alitretinoin at 10 mg, followed by 20 mg and then 30 mg led to recapture of response and her transaminases have remained within normal range throughout a continued 3-year course of therapy with alitretinoin.

• In clinical trials, alitretinoin was well tolerated by the majority of patients, although a dose dependent effect was noted with the AE of headache (up to 21.6% with 30 mg dose, 11.6% with 10 mg dose) and with mucocutaneous side effects.^8-10
• Laboratory abnormalities consistent with a retinoid class effect were noted in the trials, with dose dependent elevations in serum cholesterol and triglycerides most commonly noted; reduced thyroid stimulating hormone was reported, but there were no cases of clinical hypothyroidism.^8-10
• A hepatic effect of alitretinoin was not identified in the clinical trials^8-10 or in real-world studies,^11,14 however transient and reversible increases in transaminases have been noted in the product monograph.¹⁶ In the case presented, her transaminitis was likely related to her underlying fatty liver; she had no further issues with ongoing alitretinoin use, once she had proper management of her comorbid conditions (obesity, diabetes). If persistent elevations in transaminases are noted, reduction of the dose or discontinuation should be considered.¹⁶
• Post-marketing surveillance of the use of alitretinoin has identified AEs of special interest in the retinoid class that were not identified in clinical trials. Depression has been reported as well as very rare cases of inflammatory bowel disease and benign intracranial hypertension.¹⁴
• Work-up and monitoring for patients taking alitretinoin is similar to other commonly used retinoids (isotretinoin, acitretin) and should include: baseline hepatic transaminases and lipid profiles, repeated at one month, and then every 2-3 months during therapy. Beta-HCG should be done in women of child-bearing potential prior to initiation of therapy and repeated monthly during therapy and one month after discontinuation.¹⁶
• Retinoids are potent teratogens so practitioners should follow the Pregnancy Prevention Program,¹⁶ and women of child-bearing potential should be counselled on strict pregnancy prevention, use of two highly effective forms of birth control simultaneously and be monitored monthly with a serum pregnancy test.¹⁶
• Of 2 pregnancies reported in the clinical trials and 12 in post-marketing reports, 13 pregnancies were terminated early (elective or spontaneous abortion) and one healthy baby was born. No congenital abnormalities have been reported to date.¹⁴

Case 3:

A 68-year old retired woman had been suffering from hand dermatitis for the past 3 years since she had been at home caring for her elderly husband. She had been applying emollients throughout the day and trying to avoid frequent hand washing. Neither the potent topical corticosteroid nor the topical calcineurin inhibitor prescribed for her have helped. She was finding chores at home difficult with fissured finger tips and could not enjoy her hobbies of knitting or gardening because of the painful fissures. She was started on alitretinoin at 30 mg PO QD and noted good response, however she suffered from frequent headaches. Her dose was reduced to 10 mg PO QD with partial return of her CHD symptoms. Addition of a potent topical steroid and a course of narrowband UVB phototherapy to the alitretinoin 10 mg QD provided an effective combination regimen to control her CHD.

• Although clinical trials excluded concomitant therapy with topical medications or phototherapy, these concomitant treatments are often continued or added in real-world practice.^11,13
• Narrowband UVB phototherapy has been shown to be effective in CHD.¹⁷
• We know from vast experience in treating psoriasis, the combination of retinoids and UVB phototherapy is a very safe and effective way to optimize treatment outcomes and can reduce the cumulative dose of UVB exposure.^18,19
• According to expert opinion based on the experiences of the authors, combination of alitretinoin with topical corticosteroids or phototherapy is safe, can improve responses and may be a good option for patients who can only tolerate the 10 mg QD dose or who have not reached clear/almost clear status with the 30 mg QD dose.¹³
• Regardless of the combination of treatments selected, always remember to assess adherence and counsel each patient on appropriate prevention and avoidance strategies, regular moisturization and proper use of medications.⁶ (see Figure 3)

Case 4:

A 34-year-old mechanic presented with a 3.5-year history of CHD. His job is dependent on the use of his hands and he has a young family to support. He responded poorly to multiple courses of mid to superpotent topical steroids and a topical calcineurin inhibitor. Contact dermatitis was suspected and he was referred to a dermatologist for patch testing.

Patch testing with the North American Contact Dermatitis Group standard series revealed a positive reaction to methylisothiazolinone, which happened to be an ingredient in the citrus hand scrub he used at work and in the wet wipes he used when changing his child’s diaper. Modification of his home and work place environment to avoid this allergen has improved his CHD somewhat but it is not clear and is still causing problems at work. He was fearful of jeopardizing his employment and requested further treatment. A course of alitretinoin at 30 mg QD was initiated with good response and he continued to avoid methylisothiazolinone at work and home.

• CHD may be related to a contact dermatitis, which can be either irritant contact dermatitis or in some cases allergic contact dermatitis.²⁰ Many times patients also have an underlying atopic diathesis putting them at increased risk of developing hand dermatitis.²¹
• Contact dermatitis should be suspected when patients are not responding to treatment or worsening despite therapy; these patients should be referred for patch testing.^20,21
• Many different allergens can be responsible for the onset or exacerbation of CHD. In this particular patient’s case, methylisothizolinene, a common preservative in personal care products,^21-23 was a factor. This outlines the importance of patch testing, and considering contact dermatitis in the differential diagnosis.
• Whether the patient has CHD of unknown etiology or due to irritant contact dermatitis, allergic contact dermatitis or underlying atopic dermatitis, alitretinoin is still an option for management as second line therapy after failure of potent or superpotent topical steroids. Patch testing can help determine if an allergen should be avoided as part of the management plan, although lengthy wait times for this test in some jurisdictions should not delay therapy. In some cases, once identified, allergen avoidance may be all that is necessary for symptom resolution.
• In the real-world observational study, PASSION, it was shown that treating CHD with alitretinoin resulted in significant and rapid improvement in symptoms, increased QoL and reduced work impairment. The number of patients rated as ‘disabled’ was reduced from 12.4% at baseline to 2.2% at week 24, and those reporting no work impairment increased from 2.7% at baseline to 63.7% at week 24, showing that alitretinoin can significantly reduce work incapacity.¹⁵

Conclusions

CHD is a common condition causing a significant impact on quality of life and an economic burden due to reduced productivity and cause for disability. Many patients do not respond to standard treatments, making it a challenging condition to manage. This case series is a follow on to a recent publication of practical guidelines for the general practitioner on the management of CHD, to put the use of alitretinoin in context. The addition of alitretinoin to our therapeutic armamentarium has changed the way we are able to manage patients who suffer from this condition, providing a safe and effective treatment option to improve QoL and reduce work impairment. When managing patients with CHD, we must always remember to confirm the diagnosis, assess adherence, counsel our patients on prevention and avoidance strategies, encourage moisturization and proper use of medications and refer patients for patch testing if a contact allergy is suspected.

Patient Resources:
https://eczemahelp.ca/
http://www.eczemacanada.ca/

Acknowledgement

The authors wish to acknowledge Evert Tuyp, MD, FRCPC for his editorial assistance in the preparation of this manuscript.

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