Abstract

Background: Psoriasis vulgaris, or plaque psoriasis, is a chronic systemic inflammatory disease characterized by scaly, erythematous plaques. It is associated with comorbidities such as cardiovascular disease, metabolic syndrome, depression, and anxiety, significantly affecting patients’ quality of life. Tildrakizumab, an IL-23 inhibitor, is approved for treating adults with moderate-to-severe plaque psoriasis.

Objectives: This real-world case series aims to illustrate diverse cases of moderate-to-severe psoriasis to highlight the clinical use of tildrakizumab by expert dermatologists. It seeks to answer: (1) How are experienced specialists utilizing tildrakizumab? (2) What are the patient outcomes on this injection regimen?

Methods: Expert dermatologists from four Canadian provinces (Saskatchewan, Alberta, Quebec, Ontario) contributed two patient cases each, ensuring diverse clinical settings and patient populations. Cases included the specialists’ clinical reasoning and patient outcomes at weeks 0, 4, 8, 12, and 16 post-tildrakizumab initiation.

Results: Seven real-world cases demonstrated the effective use of tildrakizumab in Canadian patients with psoriasis, including those with metabolic syndrome, psoriatic arthritis, malignancy history, and refractory disease. All patients experienced psoriasis improvement over the treatment period without notable adverse events.

Conclusions: Experts agreed that tildrakizumab is a safe, effective, and convenient treatment for psoriasis in Canada. Patients were highly satisfied with their outcomes and the therapy’s ease of use. These real-world cases provide valuable guidance for selecting tildrakizumab candidates seeking effective treatment with infrequent dosing suitable for various age groups, comorbidities, and busy lifestyles.

Keywords: psoriasis, real-world cases, IL-23 inhibitor, tildrakizumab

Funding/Disclosures: An unrestricted educational grant from SunPharma Canada supported the real-world case series. All authors contributed to the cases and development of the manuscript, reviewed it, and agreed with its content and publication.

PDF Download

Introduction

Psoriasis is a systemic inflammatory disease with a heterogeneous skin presentation, affecting approximately 125 million people worldwide. ¹ Psoriasis vulgaris, the most common variant, accounts for approximately 85% of psoriasis cases in Canadians.² It typically presents as red, scaly, well-demarcated plaques or patches on the skin, which may appear violaceous or hyperpigmented in darker skin types.³ These plaques can affect the entire body but are frequently found on the scalp, face, intertriginous regions, nails, palms, and soles.⁴ The disease commonly manifests in adolescence or middle age (50–60 years) and follows a chronic course, rarely improving without treatment.¹

The etiology of psoriasis involves genetic, environmental, infectious, and lifestyle factors that contribute to the overactivation of the adaptive immune system. This leads to hyperproliferation of epidermal keratinocytes, vascular hyperplasia, and infiltration of T lymphocytes, neutrophils, and other immune mediators.^5-6 Interleukin 23 (IL-23) dysregulation has been identified as a key driver of psoriasis and autoimmune inflammation. Upon exposure to a trigger, TNF-α is released in the skin, activating dermal dendritic cells (DCs), which in turn produce IL-23. This cytokine activates Th17 cells and other inflammatory cells.⁷ Activated Th17 cells release pro-inflammatory cytokines—IL-17A/F, IL-22, IL-26, IFNγ, IL-6, TNF-α, and GM-CSF—resulting in keratinocyte hyperproliferation and an amplified inflammatory response.⁸ Notably, IL-23 plays a crucial role in both initiating and maintaining Th17 cell activation, IL-17 production, and the inflammatory feedback loop (Figure 1).⁸

Psoriatic arthritis (PsA), which shares a similar pathogenic mechanism, is the most prevalent comorbid condition, developing in up to 30% of psoriasis patients and potentially leading to joint destruction and lifelong disability.⁹ Furthermore, nearly half of psoriasis patients have been reported to have comorbid conditions such as cardiovascular disease (CVD), metabolic syndrome (MetS), anxiety, and depression.¹⁰ Systemic IL-23/Th17 inflammation in psoriasis has been linked to other inflammatory diseases, including CVD and MetS.⁹ Elevated Th17 and IL-17 levels have been observed in atherosclerosis patients, correlating with vascular inflammation, endothelial dysfunction, and atherosclerotic plaque formation.^11-12 Additionally, IL-23 and IL-23R levels are elevated within atherosclerotic plaques, indicating a role in disease progression.¹⁰ This corresponds with the increased incidence of myocardial infarction, ischemic heart disease, and severe vascular events in psoriasis patients.¹⁰

Obesity (BMI >30) has also been associated with psoriasis due to pro-inflammatory signaling from adipocytes, which contribute to disease pathogenesis via increased IL-6 and TNF-α production.¹³ These cytokines also promote insulin resistance, further exacerbating MetS and CVD.¹³ Given these systemic implications, effective psoriasis treatment may provide additional benefits, such as improving lipid-rich atherosclerosis and reducing non-calcified coronary plaque burden.¹²

Existing Treatments, Gaps, and Needs

Psoriasis has traditionally been managed with topical corticosteroids, but increasing recognition of its systemic nature necessitates systemic treatments. For mild psoriatic disease (3–5% body surface area [BSA]), topical corticosteroids, vitamin D3 analogs, calcineurin inhibitors, keratolytics, and phototherapy remain standard therapies.¹⁴ In moderate (BSA 5–10%) to severe (>10% BSA) cases, systemic treatments such as methotrexate, cyclosporine, and biologics targeting TNF-α (adalimumab, infliximab), IL-17 (secukinumab, ixekizumab, brodalumab), IL-12/23 (ustekinumab) and IL-23 (guselkumab, tildrakizumab, risankizumab) are commonly used. Additionally, small-molecule Janus kinase inhibitors such as deucravacitinib (approved for psoriasis) and tofacitinib as well as upadacitinib (approved for PsA) have expanded treatment options.¹⁵

Despite these advances, Canadian psoriasis patients remain largely dissatisfied with current treatments. In an online survey assessing awareness and use of available therapies, only 24% of respondents reported being “very satisfied” with their current regimen.¹⁶ Among Canadian dermatologists, key challenges in managing moderate psoriasis included treatment access, time to treatment, limited treatment choices, comorbidities, and patient acceptance.¹⁷ Notably, topical treatments remain the predominant approach for moderate psoriasis in Canada, whereas systemic therapies (including biologics) are underutilized. This contrasts with a study of 150 U.S. dermatologists, in which approximately 50% of moderate psoriasis patients were prescribed biologics.¹⁸

Tildrakizumab as a Psoriasis Treatment

Tildrakizumab is a high-affinity, humanized IgG1K monoclonal antibody that selectively targets IL-23 via its p19 subunit (Figure 1). It is indicated for adults with moderate-to-severe plaque psoriasis and is administered via subcutaneous injection every 12 weeks. The pivotal reSURFACE1 and reSURFACE2 phase 3, double-blind, randomized clinical trials evaluated the efficacy of tildrakizumab (100 mg and 200 mg) compared to placebo and the TNF-α inhibitor, etanercept.¹⁹ Patients received tildrakizumab at weeks 0, 4, and 16, while etanercept was administered twice weekly for the first four weeks and weekly thereafter. The primary endpoints included:

1. 1. The proportion of participants achieving ≥75% improvement in the Psoriasis Area and Severity Index (PASI 75).
   2. The proportion achieving a Physician’s Global Assessment (PGA) score of “clear” or “minimal,” with a ≥2-grade reduction from baseline at week 12.

In reSURFACE1, 59% of participants receiving tildrakizumab 200 mg, 55% receiving tildrakizumab 100 mg, 4% receiving placebo, and 48% receiving etanercept achieved a PGA 0/1 at week 12.¹⁹ Similar results were observed in reSURFACE2. Furthermore, pooled data revealed that tildrakizumab-treated patients with or without MetS had comparable response rates, making it a viable option for this population.¹⁹

Long-term data confirm tildrakizumab’s sustained efficacy. In the long-term extension trial, week 244 (5 years), 88.7%, 93.1%, and 114.7% of patients maintained PASI75, PASI90, and PASI100 responses, respectively.²⁰ Pooled phase 2 and 3 data indicate a favorable safety profile, with serious adverse events occurring in only 1.4% of tildrakizumab-treated patients versus 1.7% in the placebo group.^20-22 The most common adverse events were upper respiratory infections, injection reactions, and diarrhea.^21-22 Importantly, no increased risk was observed for cardiac disease, malignancy, suicidal ideation, inflammatory bowel disease, or demyelinating disorders.^21-22

Real-world evidence supports tildrakizumab’s effectiveness for moderate-to-severe plaque psoriasis in Canada.^{24, 25} In a 75-patient retrospective study, Abu-Hilal et al. demonstrated PASI75 in 95.7% of patients by week 48, regardless of prior biologic expsoure.²⁴ Long-term data confirm tildrakizumab’s sustained efficacy. At week 244 (5 years), 88.7%, 93.1%, and 114.7% of patients maintained PASI75, PASI90, and PASI100 responses, respectively.²⁰ Pooled phase 2 and 3 data indicate a favorable safety profile, with serious adverse events occurring in only 1.4% of tildrakizumab-treated patients versus 1.7% in the placebo group.^20-22 The most common adverse events were upper respiratory infections, injection reactions, and diarrhea.^21-22 Importantly, no increased risk was observed for cardiac disease, malignancy, suicidal ideation, inflammatory bowel disease, or demyelinating disorders.^21-22

Patients in these real-world studies also saw significant improvement in nail and scalp psoriasis during tildrakizumab treatment.^24,25 Gebauer et al. conducted a multicenter, randomized, double-blind, placebo-controlled, phase 3b study which showed that tildrakizumab was effective in treatment of scalp psoriasis with 49.4% of tildrakizumab-treated patients achieving a >2 improvement in Investigator Global Assessment (IGA) score by week 12 compared to 7.3% in the placebo group.²³

Considering psoriasis’ severe impact on quality of life, Costanzo et al. evaluated tildrakizumab’s effect on health-related quality of life metrics.²⁷ Their study revealed significant improvements in sleep, work productivity, and daily activities, with over 93% of patients expressing confidence in the treatment and an improved ability to lead a normal life.²⁷

Moderate-to-severe psoriasis is a systemic disease that warrants systemic, efficacious, and safe treatments to improve patient symptoms, quality of life, and overall health. Real-world cases provide invaluable guidance for both patients and physicians. Here, we illustrate how shared decision-making, and real-world clinical experience can facilitate successful tildrakizumab therapy across diverse patient populations in Canada.

Methods

Aim of the Project

This real-world case series is designed to illustrate a variety of patients with moderate-to-severe psoriasis treated with tildrakizumab in Canada. Cases showcase leading Canadian dermatologists’ real-world use of tildrakizumab, an advanced treatment for psoriasis. This series aim to answer the questions: 1) How are experienced specialist using tildrakizumab, and 2) How are their patients doing on the injection regimen? Expert dermatologists’ thought-process, reasoning, and rationales are detailed in the patient cases to serve as a guide for licensed providers who treat patients with moderate-to-severe psoriasis in Canada.

Steps in the Process

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

Role of the Panel

Our expert dermatologist panel consisted of 5 dermatologists practicing in Canada with extensive experience in caring for patients with moderate-to-severe psoriasis. Dermatologists were from 4 different Canadian provinces (Saskatchewan, Alberta, Quebec, Ontario) to capture geographical and provincial differences in dermatological practice. During an advisory meeting on November 17th, 2024, in Montreal, Quebec, expert dermatologists met to report on and discuss clinical cases using tildrakizumab in their clinical practice.

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

a) Initial Steps in Treatment
____i. Patient-Focused Treatment Strategies
b) Treatment Options
c) Special Considerations
d) Advantages of Tildrakizumab for these Cases

Experts were asked to select two patient cases from their clinical practice to share and discuss. In the second half of the meeting, experts examined and collaborated to select seven real-world cases for inclusion in this publication. Experts agreed that real-world cases should represent common patient presentations and comorbidities to best illustrate tildrakizumab use in a wide range of patients. The publication was prepared and reviewed by the panel.

Tildrakizumab Administration

Before initiating tildrakizumab treatment, all patients completed a 28-day washout period for any prior systemic psoriasis therapies. Tildrakizumab was administered according to the prescribing information.²¹ Patients received two initial doses at weeks 0 and 4, followed by a dose at week 16 and subsequent doses every 12 weeks. All 100 mg doses were administered subcutaneously at the patient’s preferred injection site.

Experience Gathering and Psoriasis Outcome Measures

Suggested information and outcome measures to present included patient demographics, sex, weight, relevant medical history, concomitant medications, and comorbidities. In addition, patient psoriasis history was elicited by asking about the onset of psoriasis, type of psoriasis, location, and tried and failed therapies. At baseline, the patient’s psoriasis was evaluated using BSA and PASI scores. In addition, dermatologists were encouraged to ask patients how their psoriasis impacted their daily activities, social life, and self-image. Patients were evaluated at week 0 (baseline), week 4, week 8, week 12, and week 16 using BSA, PASI, and patient-reported qualitative measures such as treatment satisfaction and improvement in quality of life. Any adverse reactions were recorded and reported at each visit.

Body Surface Area (BSA)

BSA is a measure of the extent of skin involvement by psoriasis. According to the Joint American Academy of Dermatology-National Psoriasis Foundation guidelines, one severity measurement of psoriasis can be based on the percentage of BSA affected: less than 3% BSA is considered mild, 3-10% BSA is considered moderate and more than 10% BSA is considered severe.²⁹

Psoriasis Area Severity Index (PASI)

Another severity measurement is PASI which quantifies the extent and severity of psoriasis by accounting for intensity of redness, scaling, and plaque thickness. Scoring in each category will produce a score from 0 (no disease) to 72 (maximal disease severity).²⁹

Results

Selected Real-World Cases

The expert dermatologists selected seven cases to demonstrate the real-world use of tildrakizumab in a diverse group of patients with varying skin concerns, past treatment failures, severity, and comorbidities (Table 1).

Table 1. Summary of Real-World Patient Cases

Case 1. Use of Tildrakizumab in Previous Secukinumab Failure

A 34-year-old male, Fitzpatrick Skin Types (FST) IV, presented with severe plaque psoriasis involving his hands, legs, and arms. At baseline, he had a BSA of 12% and PASI score of 13.3. He had been diagnosed 3 years prior and had previously tried topical corticosteroids, methotrexate, phototherapy, and secukinumab, but his psoriasis persisted. The patient was also overweight and had psoriatic arthritis for which he took hydroxychloroquine and ibuprofen. He reported feeling self-conscious about his skin and stated that the itching affected his sleep. He avoided participating in sports due to fear of exposing his skin in public. The patient received his first dose of 100mg tildrakizumab. At week 4, he returned for his second 100mg loading dose but had not seen any improvement in his psoriasis (BSA 13%, PASI 15.6). By week 8, he noticed a reduction in plaque redness, though his BSA remained unchanged (BSA 13%, PASI 9.6). No further improvement was seen at week 12. The patient felt his condition had slightly improved and reported no discomfort or adverse events in the first 3 months of treatment. By week 16, he showed significant improvement with noticeable reductions in plaque redness, scaling, and thickness (BSA 3%, PASI 1.8) (Figure 2). The patient strongly agreed that his condition had improved and was satisfied with the treatment. Additionally, his psoriatic arthritis remained stable while on tildrakizumab, and he maintained his hydroxychloroquine regimen, despite the potential to exacerbate psoriasis, without any reported adverse effects.

Case 2. Biologic-Naïve Patient with Long-Standing, Severe Psoriasis

A 50-year-old female, FST III, presented with long-standing severe psoriasis. Diagnosed at age 14, she had previously tried topical corticosteroids, calcineurin inhibitors, vitamin D analogs, acitretin, and methotrexate without significant or lasting improvement. At presentation, her BSA was 40% and her PASI score was 16, with plaques affecting her torso, nails, and scalp. She avoided social activities, carefully selected clothes to hide her skin, and became less intimate with her husband due to embarrassment. The patient had developed depression due to her inability to live normally with her condition. She was started on tildrakizumab as a first-line biologic. At her week 4 visit, she reported modest improvement in plaque thickness and scaliness, with a 10% reduction in BSA (BSA 30%, PASI 12). Improvement continued at week 8 (BSA 20%, PASI 9) and week 12 (BSA 6%, PASI 4). By week 16, she had seen significant improvement with a BSA of 2% and PASI of 2 (Figure 3). She experienced no adverse events and tolerated the treatment without issues. The patient felt much more confident in her skin and was very satisfied with the therapy.

Case 3. Breast Cancer Survivor with Chronic, Lifelong Psoriasis

A 66-year-old overweight female, FST II, presented with lifelong psoriasis affecting her back and torso. She had suffered from psoriasis since her teenage years and had never achieved reliable control with any therapy. Previously, she had tried methotrexate, apremilast, phototherapy, topical corticosteroids, vitamin D analogs, and topical roflumilast. Additionally, the patient was a two-time breast cancer survivor, currently in remission for the past 10 years. She was apprehensive about starting systemic medications that might jeopardize her cancer remission, but she also felt very self-conscious about her skin and wanted to treat her psoriasis. Given tildrakizumab’s favorable safety profile, her dermatologist suggested trying the therapy. At baseline, the patient had a 10% BSA with a PASI score of 10.4. At week 4, she returned for her second loading dose and showed mild improvement, with a BSA of 8.5% and PASI of 8.4. Further improvement was noted by week 8 (BSA 2.5%, PASI 2) (Figure 4). At this time, she developed generalized pruritus, likely due to concomitant rosuvastatin use. The itching subsided after discontinuing rosuvastatin. The patient tolerated the treatment without any further adverse effects.

Case 4. Suboptimal Results with Tildrakizumab after Etanercept (TNF-α) Failure

A 65-year-old male presents to the clinic with refractory psoriasis. The patient has suffered from psoriasis for more than 30 years and had tried topical corticosteroids, tar, and vitamin D analogs as well as systemic etanercept. Topical treatments had provided some relief, but he had been on etanercept since 2004. In 2024, his psoriasis flared despite ongoing therapy. At that time, he had started a beta-blocker, bisoprolol and had been taking naproxen for PsA joint pain. Beta-blockers such as bisoprolol and non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, have been associated with increased risk of psoriasis and psoriasis flares.^{30, 31} The patient felt severely impacted by his psoriasis, which caused skin pain that affected his work, sleep, and daily activities. At his baseline visit, his BSA was 14%, and his PASI score was 15, with primarily extensor surface involvement and foot/sole involvement. He was started on tildrakizumab. At week 4, his BSA decreased to 9%, and his PASI score was 6.4. Despite mild improvement, the patient felt his condition was not improving and was dissatisfied with the effects of the first dose. He also developed cracks on his fingers that made holding objects uncomfortable. By week 8, the patient experienced significant improvement, with a BSA of 1.5% and PASI of 1.8. Although still not fully satisfied with the therapy, he reported dramatic improvement in his quality of life and felt less negatively impacted by his skin. At week 12, the patient had a flare with a BSA of 7% and PASI of 6.8. However, by week 16, his psoriasis had begun to resolve, with a BSA of 3% and PASI of 3.6 (Figure 5). Overall, he acknowledged mild improvement but expressed frustration with suboptimal results and continued psoriasis flares despite ongoing treatment.

Case 5. Tildrakizumab Used as a Safe and Effective Alternative to Systemic Immunosuppression

A 35-year-old male, FST IV, presented with a 4-year history of psoriasis. He had no other medical conditions. Since diagnosis, the patient had tried methotrexate, cyclosporine, topical calcineurin inhibitors (tacrolimus), and topical corticosteroids and vitamin D analogs. While on cyclosporine, the patient was concerned about the numerous side effects associated with the medication, and the other treatments were ineffective. At baseline, the patient had severe psoriasis affecting his torso, with a BSA of 55% and a PASI score of 29.8. His skin condition had a significant impact on his social life, self-image, and daily activities. He was started on tildrakizumab. By week 4, the patient saw improvements, with a reduction in BSA to 35% and a PASI score of 3.0. Continued improvement was observed at week 8, with a BSA of 10% and PASI of 2.9. By week 12, the patient was clear of psoriasis, with a BSA and PASI of 0 (Figure 6). He was very satisfied with the treatment and did not experience any adverse effects. He maintained these results through week 16 and continues to be treated with tildrakizumab.

Case 6. Tildrakizumab Used in Biologic-Naïve Patient with History of Prostate Cancer and Non-Hodgkin’s Lymphoma

A 69-year-old male, FST II, presented with long-standing plaque psoriasis. He was diagnosed about 15 years prior to presentation and had a 15% BSA and PASI score of 14.5. The psoriasis affected his feet, hands, elbows, legs and scalp. At the same time, the patient also had a history of hypertension, gastric reflux, non-Hodgkin’s lymphoma, and prostate cancer for which he was taking the following medications: pantoprazole, furosemide, candesartan, aspirin, and goserelin acetate. For his psoriasis, he had tried acitretin, calcipotriene/betamethasone, and clobetasol ointment. The patient was very bothered by his current regimen of topicals as the creams and ointments often rubbed off on his sheets and clothing. In addition, he often had people asking him about his skin and being concerned about it being infectious. At this time, he was started on tildrakizumab. Four weeks later, the patient began seeing some improvement in the scaling of his plaques. While his BSA remained unchanged, he saw reduction in PASI score to 10.7. He continued to see improvement and at week 8, he had a BSA of 8% and PASI score of 3.6. At week 12, the patient saw a reduction in BSA to 2% and a PASI score of 2.4. He eventually achieved a PASI score of 1 and BSA 1% by week 16 of treatment (Figure 7). No adverse effects were reported during his treatment.

Case 7. Tildrakizumab Used in Active Smoker with Severe Psoriasis

A 47-year-old female, FST II, presented with severe psoriasis affecting her back, nails, feet, legs, buttocks, and scalp. She had suffered from psoriasis for the past 25 years and had tried various topicals including calcipotriene/betamethasone foam, clobetasol ointment, tazarotene cream, coal tar, UV-B phototherapy and systemic treatments such as methotrexate. She also continued to smoke tobacco products and had hypertension, attention-deficit hyperactivity disorder (ADHD), and obesity. At baseline, the patient had a BSA of 26% and PASI score of 25.8. She felt very self-conscious about her skin and never thought that it would be possible for her to have clear skin. At this time, the patient was started on tildrakizumab. By week 4, the patient saw mild improvement in her psoriasis with a reduction in scaling; however, her BSA increased to 28%. The patient continued with treatment and saw noticeable results at week 8 when she returned to the office and was found to have a BSA of 22% and PASI score of 17.4 (Figure 8). At week 12, she had a BSA of 16% and PASI score of 8.7. By week 16, she further improved to have a BSA of 14% and PASI score of 8 (Figure 8). The patient was very enthusiastic about her results and felt hopeful about continuing with the treatment.

Discussion

This real-world case discussion provides valuable insights into the use of tildrakizumab as a safe, effective, and convenient therapy for Canadian patients suffering from moderate-to-severe psoriasis. All patients presented showed significant reductions in BSA and PASI by week 8 or week 16 of treatment.

In pivotal trials, 64% and 61% of patients on tildrakizumab (100mg) achieved PASI 75 by week 12 in reSURFACE1 and reSURFACE2, respectively This mirrors results from the real world, with 6 of the 7 patient cases showing significant improvement by week 12 or earlier. In reSURFACE2, etanercept was compared to tildrakizumab and demonstrated inferior results to tildrakizumab with only 48% of the etanercept group achieving PASI 75 compared to the 61% in the tildrakizumab group. One partial tildrakizumab responder in our series failed to respond to etanercept; however, he had mild improvements in his psoriasis after starting tildrakizumab demonstrating that IL-23 blockade may be more efficacious than TNF-α inhibition in some patients. Similarly, another patient had previously failed adalimumab before trying tildrakizumab. Our real-world cases, along with multiple real-world retrospective studies also confirm tildrakizumab efficacy in special psoriasis sites such as scalp, nails, palms and soles.^23-26 Importantly, tildrakizumab was also effective in patients with multiple comorbidities and refractory psoriasis. It also proved to be an effective treatment in overweight patients with BMI>25, which is critical in that approximately a third of patients with psoriasis meet criteria for MetS.³² Preliminary results from a recent study suggests that tildrakizumab may be effective in obesity by reducing levels of adipokines, immune modulating cytokines originating from adipocytes.³³ Taken together, tildrakizumab should be considered a first-line biologic given its efficacity in a variety of patients, psoriasis presentations, and safety profile.

Unlike many existing therapies, tildrakizumab has a highly favorable safety profile. In clinical trials, there were no serious adverse events, and the most common adverse events included upper respiratory illness and injection site reactions.²¹ A pooled analysis of three randomized controlled clinical trials demonstrates that the rates of treatment-emergent adverse events (TEAE), serious TAE, and discontinuations due to adverse events were similar in both the tildrakizumab treatment and placebo group. Moreover, no reported cases of inflammatory bowel disease, candida infections or suicides were reported which are key counseling points for patients starting anti-IL-17 biologics. Additionally, no increased risk of malignancy was observed during tildrakizumab treatment. This is significant, as psoriasis increases the risk of lymphohematopoietic, head and neck, and gastrointestinal cancers, as well as non-melanoma skin cancers in patients who have previously received psoralen ultraviolet-A treatment. The increased cancer risk in this population makes carcinogenic treatments like methotrexate and cyclosporine less ideal compared to tildrakizumab.

Tildrakizumab does not harbor risks for MACE, VTE, or malignancy which makes it an appropriate first-line treatment for biologic-naïve and biologic-experienced patients.²¹ It may also be especially helpful in adult patients over the age of 50 with multiple comorbidities such as existing CVD, history of stroke or previous malignancies. One expert suggested tildrakizumab to be the ideal treatment for such as patient: the 70-year-old male with complex medical history including cardiovascular and cancer history (and perhaps a current smoker) who is seeking something to relieve his psoriasis symptoms and improve his quality of life. This is supported by pooled analyses of reSURFACE1 and reSURFACE2 which demonstrates efficacy, safety, and sustained responses in patients > 65 years through 244 weeks.³⁵ Safe use of tildrakizumab in the elderly population makes it an invaluable treatment for a population with high prevalence of comorbidities and polypharmacy. Experts agree that the only drawback of tildrakizumab is that some patients may require multiple doses before experiencing significant effects. This delay can be frustrating for patients who are hoping for quicker skin clearance.

Despite slow onset of action, patients are generally highly satisfied with tildrakizumab treatment. In the TRIBUTE study, researchers measured tildrakizumab impact on health-related quality of life and found that patients had significant improvement in their skin as well as their sleep, work productivity, activity level, and absenteeism.²⁷ Tildrakizumab is also convenient, with every 12-week dosing making it suitable for patients with busy work schedules or those who live between multiple locations. In Canada, it is ideal for the “snowbird” population who leave for months at a time to escape the winter. Most other biologics are dosed every 2, 4, or 8 weeks, which may impose time constraints on certain patients and their lifestyles. Less frequent dosing reduces the healthcare burden in Canada by decreasing the number of treatment administration visits.

Table 2. Clinical Pearls from Expert Canadian Dermatologists

Conclusion

The presented real-world cases reflect expert dermatologists’ clinical experience with tildrakizumab in treating Canadian patients with moderate-to-severe plaque psoriasis. The collective experience of these dermatologists suggests that tildrakizumab is a safe, effective, and durable treatment for a variety of patients. Tildrakizumab is an ideal therapy for older patients with multiple comorbidities who may not be candidates for therapies with a less favorable safety profile. The onset of action with tildrakizumab may vary, with some patients responding quickly while others may only experience results after 12 or 16 weeks. No adverse effects were reported in any of the patients.

Limitations

These patient cases represent outcomes under real-world conditions in patients with differing lifestyles and environments. The reported symptoms and measures were provided by dermatologists in their clinics and represent real-world data, rather than data from a randomized clinical trial under controlled conditions. Results are only reported up to the 16-week time point, which may not capture patients who required more doses of tildrakizumab to see improvement. Furthermore, the 16-week time frame does not account for potential future psoriasis flares.

Acknowledgement

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

References

¹Center for Clinical Studies, Webster, TX, USA
²Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there is no conflict of interest.
Funding sources: None.

Abstract:
Nanodermatology has been an emerging area of research and drug development in the last two decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has yielded potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery. Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been more frequently explored for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been increasingly investigated to improve efficacy of various drugs via enhanced delivery to the target site. Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but these formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to boost drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects. Enhanced drug delivery utilizing nanoparticles has been successfully trialed for treatment of psoriasis, vitiligo, acne vulgaris, and atopic dermatitis in many research studies, however more investigation is needed prior to utilization in humans.

Keywords:nanodermatology, nanoparticles, enhanced drug delivery, nanocarriers

Introduction

Nanodermatology has been an emerging area of research and drug development in the last decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has exhibited potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery.¹

Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been increasingly investigated for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been more frequently explored in order to improve the efficacy of various drugs via enhance delivery to the target site.

Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but topical formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to increase drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects.²

This article will discuss the promising application of nanotechnology as a route of increased transdermal drug delivery in order to treat various common dermatological conditions, including psoriasis, vitiligo, acne vulgaris and atopic dermatitis, as well as nanoparticle utilization in sun protection.

Psoriasis

Psoriasis is a common inflammatory skin disorder, affecting over 125 million people worldwide, that can range in presentation from erythematous plaques to pustules. Traditionally, mild psoriasis can be treated with topical medications, including corticosteroids, betamethasone/calcipotriol, calcineurin inhibitors, and retinoids.³ However, moderate to severe disease often requires systemic treatments such as methotrexate, cyclosporine, and biologic agents. These systemic treatments often come with the risk of significant adverse effects.

Multiple drug‐loaded nanoparticles and nanocarriers have been found to have promising potential in the treatment of psoriasis, while minimizing the risk for adverse effects and maximizing transdermal drug delivery.⁴ Tazarotene (TZ), a topical antipsoriatic retinoid with significant irritation potential, was loaded into fluidized spanlastic nanovesicles that measured about 260 nanometers. When compared to commercially available topical tazarotene, researchers found that the nanovesicles not only showed higher antipsoriatic activity in human subjects but also demonstrated deeper penetration during ex vivo testing.⁵ Tacrolimus, an immunosuppressive agent that has often been used topically to treat psoriasis, exhibits poor cutaneous bioavailability, particularly in hyperkeratotic plaques. Therefore, topical tacrolimus ointment was compared to a micelle nanocarrier tacrolimus formula. The micelle formula showed increased tacrolimus delivery into the stratum corneum and epidermis when compared to the traditional topical tacrolimus ointment.⁶

In addition to improved delivery of classic topical treatments, researchers have been utilizing nanotechnology to investigate the transdermal delivery potential of drugs traditionally used as systemic therapy, such as methotrexate and cyclosporine. Both methotrexate and cyclosporine are typically reserved for severe psoriasis due to the significant risks of toxicity and adverse effects. However, when combined with nanotechnology, these drugs can be applied topically, therefore greatly minimizing the risk for systemic adverse effects.⁴

Cyclosporine, a calcineurin inhibitor, is incredibly effective as a systemic therapy for psoriasis, but unfortunately, its use comes with risks of nephrotoxicity, neurotoxicity, metabolic disruptions, and immunosuppression.⁷ In an imiquimod induced psoriatic plaque on mice, cyclosporine‐loaded liposomes were more effective at reducing psoriatic features than cyclosporine gel.⁸

Like cyclosporine, systemic methotrexate has shown great utility in the treatment of psoriasis, however there is risk of significant side effects. In an in vivo skin deposition study, methotrexate niosomes, or non‐ionic surfactant vesicles, resulted in a greater percentage of drug deposition in the skin when compared to a simple methotrexate topical solution.⁹ Similarly, gold nanoparticles loaded with methotrexate led to improvement of scaling, erythema, epidermal thickness, and parakeratosis in mice models with imiquimod induced psoriasis. The methotrexate‐gold nanoparticles also showed deeper penetration when compared to topical methotrexate. Additionally, after treatment there was no significant difference in the blood count, AST, and ALT of the treatment group when compared to the control.¹⁰

Nanoparticles have not only allowed for greater skin penetration and drug delivery than classical topical treatments, but they have also allowed researchers to create topical formulations of systemic medications that come with risk of significant adverse effects. More research is needed to compare the efficacy of systemic therapy with nanoparticle formulations.

Vitiligo

Vitiligo, an acquired disorder characterized by the development of depigmented macules, is thought to be caused by autoimmune destruction of melanocytes. Treatment is typically focused on preventing progression and inducing some degree of repigmentation. Recent investigation into the utility of nanodermatology has led to exciting treatment potential.

Berberine, an isoquinoline alkaloid, despite exhibiting potential benefit as a topical vitiligo treatment, has limited utility due to its poor skin permeability. In order to improve delivery, berberine was loaded into hyalurosomes, which are modified nanovesicles that have enhanced skin penetration abilities and are non‐irritating. In human skin studies, berberine hyalurosomes showed greater permeability and greater drug retention when compared to a conventional berberine gel. In a vitiligo‐induced mouse model, the berberine loaded hyalurosomes showed a significant return of normal pigmentation that was greater than the conventional berberine gel.¹¹

Psoralen in combination with ultraviolet light (PUVA) is a common treatment for vitiligo. However, psoralen has weak percutaneous permeability. Resveratrol, a sirtuin activator, has the potential to manage vitiligo by reducing oxidative stress, therefore psoralen and resveratrol were loaded into ultra deformable liposomes and used as combination antioxidants in PUVA therapy for vitiligo. This combination not only demonstrated greater skin penetration but also showed significant melanin stimulation and tyrosinase activity. Administration of a nanocarrier loaded with resveratrol and psoralen in combination with UV light therapy stimulated pigment and reduced oxidative stress, making it a promising potential therapy for vitiligo.¹²

While the mechanism of vitiligo is not completely understood, oxidative stress is believed to play a significant role in the disease. Platinum and palladium have been investigated for their strong antioxidant properties as they are inducers of superoxide dismutase.¹³ PAPLAL, a topical cream consisting of platinum and palladium nanoparticles, has been shown to be an effective treatment for vitiligo that was refractory to first‐line therapies including narrow band UVB and topical corticosteroids.¹⁴

Acne Vulgaris

Acne vulgaris is one of the most common skin conditions, affecting up to 90 percent of adolescents with presentation ranging from mild to severe. The pathophysiology is multifactorial, making treatment complicated. Therapeutic options for mild to moderate acne typically consists of topical agents, including retinoids, antibiotics, benzoyl peroxide, and salicylic acid, whereas treatment for severe acne consists of oral therapy with isotretinoin, antibiotics, or hormonal agents.¹⁵

While topical tretinoin is an effective treatment, its use is limited by low water solubility and high instability in air and heat. Its use also comes with the risk of significant skin irritation and dryness. Therefore, nanocarriers have been investigated to achieve greater photostability and lower irritation potential. Tretinoin was encapsulated into solid lipid nanoparticles which improved its photostability and showed significantly less irritation when compared to the gel formula in an animal model.¹⁶

Similar to tretinoin, adapalene has been widely used in the treatment of acne vulgaris since gaining US FDA approval in 2016, however it has limited bioavailability in the hair follicle and its use also comes with the risk of irritation and dryness. Adapalene was successfully encapsulated into tyrosine derived nanospheres (TyroSphere™). In ex vivo follicular penetration studies, the tyrospheres significantly enhanced adapalene delivery to the pilosebaceous unit, when compared with commercially available adapalene. In vitro irritation studies also demonstrated decreased irritation potential of the tyrosphere formula.¹⁷

Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that presents with dry, eczematous, erythematous patches, and pruritus. AD is likely mediated by a combination of epidermal changes, increased immunoglobulin E levels, and T-helper 1 and 2 proliferation which leads to elevated levels of inflammatory cytokines. Traditionally, topical corticosteroids have been the treatment of choice for acute flares, however long-term use of topical corticosteroids can cause skin atrophy.

Liposomes, composed of phospholipids, have a strong affinity for the stratum corneum, allowing for increased skin permeability and uptake. Both betamethasone 17‐valerate (BMV), a moderate potency corticosteroid, and diflucortolone valerate (DFV), a high potency corticosteroid, were loaded into liposomes. The liposomes showed 2.68 to 3.22 times greater retention in the stratum corneum and epidermis when compared to the commercially available BMV and DFV creams. In pharmacodynamic evaluation, the liposome formula showed greater anti‐inflammatory activity when compared to the commercial creams, despite the liposome gel having 10 percent less active drug than the commercial cream. This result was thought to be due to enhanced delivery and decreased systemic absorption. Finally, in rat models, AD was induced by dinitrofluorobenzene, and the liposomes formulas not only showed lower erythema, edema, and scratching behaviors, but also to the commercial creams.¹⁸

In a similar study, chitosan nanoparticles were loaded with hydrocortisone (HC) and hydroxytyrosol (HT). These nanoparticles exhibited deeper penetration and a higher concentration of drug in the epidermal layer. This could reduce the dose and frequency of drug application needed for effective treatment, which could decrease the risk of adverse effects. Systemic adverse effects of glucocorticoids include hypocalcemia and hyperglycemia. When commercially available hydrocortisone was repeatedly applied to rat models, they showed a significant decrease in serum calcium concentration and an increase in serum glucose concentration, while the HC‐HT nanoparticle solution did not cause any biochemical derangements. This demonstrates that utilizing a nanoparticle drug delivery system could potentially reduce systemic adverse effects of glucocorticoids, while also increasing skin penetration.¹⁹

While corticosteroids have been considered the first‐line for AD, other topical calcineurin inhibitors, like tacrolimus and pimecrolimus, are being increasingly utilized in AD. Calcineurin inhibitors are often considered safer for long‐term use and use on sensitive areas like the face, but they often cause an uncomfortable burning sensation at the site of application. Tacrolimus has a high molecular weight and poor water solubility which limits its permeability. To reach therapeutic dosing, larger quantities of topical tacrolimus must be applied, which increases the risk of irritation. Chitosan nanoparticles were used as the carrier for tacrolimus. The nanoparticle solution led to greater drug retention in the stratum corneum, epidermis, and dermis than the commercially available cream. In AD induced rat models, AD was successfully managed with the nanoparticle solution containing one‐third the dose in the commercially available cream.²⁰

Sunscreen

Sunscreen commonly contains minerals like zinc oxide and titanium dioxide as the primary active sun protection agents. However, sunscreens with these ingredients are typically opaque and white, which lends cosmetic concerns to many users. Many cosmeceutical companies have begun incorporating nanoparticles into their sunscreens in an attempt to create a more desirable and better tolerated formula.

Sunscreens with zinc oxide and titanium dioxide nanoparticles have been shown, in an in vitro study, to provide enhanced sun protection. Additionally, sunscreen containing nanoparticles demonstrated improved texture with no residual white cast when compared to creams with zinc oxide and titanium dioxide particles.²¹

However, some studies have shown that zinc oxide and titanium dioxide nanoparticles lead to an alteration in the recommended UVA/UVB ratio. Currently, the FDA recommends that at least one‐third of the overall sun protection factor should be against UVA. Reducing the size of the zinc oxide and titanium dioxide particles confers an increased UVB protection at the expense of UVA protection. In order to mitigate this, some researchers have recommended that using various sizes of particles in one formulation, for example using micro and nano zinc oxide (20‐ 200 nanometers) particles and nano titanium dioxide (20‐35 nanometers) particles may remedy this discrepancy. However, more research is needed to determine the ideal size of particles to adhere to the recommended 3 to 1 UVB/UVA ratio.²²

Concerns

As nanoparticle use increases both in treatment of skin disease and in cosmetics, there are concerns regarding the long-term health effects and potential toxicities. The potential for nanoparticles to accumulate in the skin and contain harmful impurities are important considerations regarding toxicity.²³

Due to rising concerns that nanoparticles are depositing into deeper layers of the skin and causing cellular damage, multiple studies have sought to determine the long-term effects of utilizing nanoparticles in various formulations. One study found that both coated and uncoated zinc oxide nanoparticles localized primarily in the stratum corneum with limited penetration into viable epidermis. This study also found that the nanoparticles did not alter the skin barrier function or the redox state of the viable epidermis.²⁴ There are also concerns regarding the ability of titanium dioxide to induce DNA damage and potentially act as a carcinogen.²⁵ However, the carcinogenic effects of titanium dioxide are typically seen after subcutaneous injection or inhalation of nanoparticles.²⁶

There is conflicting data regarding the penetration of zinc and titanium nanoparticles, and thus the ability for these nanoparticles to cause damage. However, despite the conflicting data, the consensus appears to be that nanoparticles in sunscreens and skin care do not pose a health risk, however more research and collaboration is needed between the scientific and cosmetic communities as many cosmetic companies do not advertise their products as containing nanoparticles.^25,27

Conclusion

Nanoparticles, defined as a particle ranging from 1 to 1000 nanometers, have shown extremely encouraging potential in targeted drug delivery systems in the treatment of various dermatologic diseases and conditions. Not only do nanoparticles or nanocarriers exhibit increased penetration and retention of existing topical drugs, but they also have been employed to create topical formulations of drugs that are primarily given as systemic therapy. This allows drugs like methotrexate and cyclosporine to be used topically and without the risk of severe adverse effects. Overall, the utilization of nanoparticles as an enhanced drug delivery system is an incredibly promising area of research with exciting implications in the treatment of many common dermatologic conditions. Nanocarriers appear to be safe, however more research and development is needed as the majority of current research is being done in animal models. It is also important for cosmeceutical and scientific communities to collaborate on research, particularly when it comes to utilization of nanoparticles in sunscreens. Cosmetic companies should also be encouraged to publish or advertise the use of nanoparticles in their products.

Purchase Article PDF for $1.99

Abstract

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

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

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

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

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

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

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

PDF Download

Introduction

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

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

Systemic Treatment for Moderate-to-Severe AD

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

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

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

Abrocitinib & JAK Inhibitors (JAKis)

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

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

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

Methods

Aim of the Project

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

Steps in the Process

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

Role of the Panel

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

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

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

Experience Gathering and Atopic Dermatitis Outcome Measures

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

Results

Selected Real-World Cases

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

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

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

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

Case 2. The biologic-naïve patient

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

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

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

Case 3. The patient with post-inflammatory hyperpigmentation

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

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

Case 4. The atopic patient with barriers to treatment access

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

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

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

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

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

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

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

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

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

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

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

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

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

Case 7. The dupilumab failure AD patient

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

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

Case 8. The patient intolerant to dupilumab

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

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

Case 9. The patient with adult-onset AD

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

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

Case 10. The AD patient switching from another JAK inhibitor

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

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

Discussion

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

Biologic Naïve Patients

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

Dupilumab Failed/Intolerant Patients

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

Jumping JAKi’s and Adverse Reactions

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

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

Dosing Approach

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

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

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

Future Directions

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

Conclusion

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

Limitations

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

¹Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
²Carilion Clinic Dermatology and Mohs Surgery, Roanoke, VA, USA

Conflict of interest: Mariana Phillips is an investigator for Castle Biosciences. Neha Singh has no disclosures.

Abstract: Toxic epidermal necrolysis (TEN) is an immune mediated, severe cutaneous adverse drug reaction characterized by epidermal detachment affecting greater than 30% body surface area. The mortality rate of TEN exceeds 20% and is usually caused by infection and respiratory compromise. Withdrawal of the causative drug, supportive care, and adjuvant therapy improve prognosis. Over the past decade, randomized controlled trials and meta-analyses have supported a role for cyclosporine, tumor necrosis factor alpha inhibitors, and combination therapy with intravenous immune globulin and corticosteroids. This review summarizes the medical management of TEN in adult patients.

Key Words: toxic epidermal necrolysis, TEN, Stevens-Johnson syndrome, SJS, intravenous immunoglobulin, IVIG, etanercept, cyclosporine, corticosteroids

Introduction

Toxic epidermal necrolysis (TEN) is a severe, life-threatening, adverse drug reaction characterized by widespread epidermal necrosis. The global mortality rate for TEN approaches 20-40%.^1-5 Stevens-Johnson syndrome (SJS) and TEN are on the same spectrum and are clinically distinguished by percentage of body surface area detached. Patients are classified as SJS, SJS/TEN, or TEN if there is <10%, 10-30%, and >30% skin detachment, respectively.⁶

Initial manifestations of SJS and TEN include a prodrome of high fever and flu-like symptoms for 1-3 days followed by rapidly progressive mucocutaneous involvement. Ill-defined, targetoid, dusky macules that coalesce to form flaccid vesicles and bullae that eventually slough are typical. Blistering and detachment of the epidermis at the dermal epidermal junction can be induced with light pressure.⁷ Epidermal detachment may occur anywhere on the skin and mucosa, and commonly involves the ocular and respiratory epithelium. Complications include sepsis from loss of the skin barrier and respiratory compromise. Individuals with compromised immune systems (i.e., malignancies, human immunodeficiency virus (HIV), etc.) are at greater risk of developing TEN. Advanced age and comorbidities are associated with increased mortality.⁸

The exact pathogenesis of TEN remains unclear. It is traditionally considered to be a delayed type IV hypersensitivity immune reaction that results in cytotoxic CD8 T-cell mediated keratinocyte apoptosis.^9-12

Drugs commonly associated with TEN include antibiotics like sulfonamides, tetracyclines, quinolones, as well as antiepileptics, antivirals, non-steroidal anti-inflammatory drugs (NSAIDs), and allopurinol.⁴ In the pediatric population, a TEN-like clinical presentation can be associated with Mycoplasma pneumoniae. Pharmacogenetic susceptibility to the development of TEN is present in certain populations. The human leukocyte antigen (HLA) B 15:02 confers an increased risk of TEN in Asian patients taking carbamazepine.¹⁰ Another allele, HLA-B 58:01, has been linked with allopurinol-induced TEN in European and Asian populations.¹¹

The severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is a well-validated specific predictor of mortality for patients with TEN.^12-15 Aside from supportive care, the medical management of TEN is dependent upon the clinician’s critical appraisal of the available literature, and availability of various treatments.^16-20 The primary purpose of this article is to provide a concise but comprehensive review on the medical management of SJS/TEN and TEN.

Treatment Modalities

Supportive Measures

Due to the rapid progression and complex nature of TEN, early intervention, close surveillance and multidisciplinary support are key to management. Patients may require observation in the intensive care and/or burn units.^21-23 Supportive measures are aimed at maintaining thermoregulation and pain control, preventing major fluid loss, electrolyte imbalance, secondary infection, and scarring. Patients should be closely monitored for signs and symptoms of infection. Empiric antibiotics are associated with a poor prognosis and are therefore not indicated in the management of TEN. The most common organisms causing early infection are Staphylococcus aureus and Pseudomonas aeruginosa. Despite the importance in supportive measures, there is a lack of standardization among treating centers.²⁴

Intravenous Immunoglobulin (IVIG)

Enthusiasm for IVIG in the treatment of TEN resulted from an initial study published by Viard et al., that showed IVIG preparations containing Fas-blocking antibodies could effectively inhibit the interaction of the Fas-ligand (FasL) with Fas-receptor, an established pathway of keratinocyte apoptosis.²⁵ The same group reported an open, uncontrolled trial of 10 TEN patients who received 0.2-0.75 g/kg of IVIG per day for 4 consecutive days (Table 1). In all patients, disease progression ceased within 48 hours and rapid skin healing was noted.²⁶ The popularity of IVIG for TEN increased since its introduction in 1998 and became the standard treatment for many years.

Aside from the pediatric population where IVIG is considered safe and effective, recent studies have challenged the use of IVIG in the management of TEN.^27-29 Selected publications examining the use of IVIG for TEN are summarized in Table 1. Although IVIG was once considered the first-line treatment for SJS/TEN, a large meta-analysis concluded that administration of IVIG does not correlate with mortality reduction in multivariate regression analysis when adjusting for age, total body surface area involved, and delay in treatment compared to predicted mortality in adult patients.³⁰ One prospective study examined the efficacy of a total dose of 2 g/kg IVIG (infused at a rate of 1 g/kg/day to 0.4 g/kg/day dependent on renal function) in 34 patients (9 with SJS, 5 with SJS/TEN, and 20 with TEN). No significant reduction in SCORTEN predicted mortality was noted (11 observed vs. 8.2 predicted). Disease progression was not interrupted by IVIG administration.³¹ Furthermore, a multicenter study that reviewed 377 SJS/TEN patients from 18 academic medical centers between 2000 and 2015 found no significant difference in mortality between treatment subgroups which included steroid monotherapy, IVIG monotherapy, and the combination of IVIG and corticosteroids.³² In one of the largest network meta-analyses to date, IVIG monotherapy showed no improvement in mortality rate when compared to supportive care.²⁷ This network meta-analysis incorporated 67 studies published between 1999 to 2019 and included 2079 patients with SJS/TEN overlap or TEN. Regarding mortality rate and standardized mortality ratio, the surface under the cumulative ranking curve (SUCRA) score for IVIG rated below supportive care.²⁷ Overall, the efficacy of IVIG in treating TEN remains uncertain and further prospective evaluation is warranted.

Table 1. Summary of studies reporting IVIG use in TEN*

Systemic Corticosteroid Therapy

Systemic steroids may be effective in treating SJS/TEN by the following mechanisms: 1) rapid acting: inhibiting the arachidonic acid cascade signaling pathway resulting in suppression of the inflammatory response and 2) slow acting: promoting transcription factors that suppress expression of inflammatory cytokines.⁴¹

The use of high-dose steroids in early SJS/TEN inhibits inflammation and decreases biomarkers of inflammation.⁴² Among 96 studies reviewed in a meta-analysis between the years 1990-2012, three studies suggested the benefit of corticosteroid treatment when compared to supportive care.⁴³ Studies were variable in the duration of corticosteroids administration, most ranging from days 1-5 with an average of 3 days. A separate European multicenter retrospective study and meta-analysis of observational studies also highlighted the benefits of steroids.^37,43

In contrast, several studies report no difference in prognosis between corticosteroid therapy and supportive care, due to the increased risk of infection caused by the immunosuppressive agent.^2,44 More recently, a retrospective SCORTEN-based comparison was performed on patients who received low-doses (<2 mg/kg/day) and high-doses (>2 mg/kg/day) of either prednisone, or prednisone-equivalents of methylprednisolone, hydroprednisone, or dexamethasone (Table 2). Results revealed lower mortality rates in the low-dose steroid treatment group than those predicted by SCORTEN.⁴⁵ In the high-dose steroid group, difference between the expected and actual mortality was not statistically significant; however, the actual mortality rate was 40% lower than the expected rate. A large retrospective study analyzing 366 patients for ocular sequelae found no benefit to steroid therapy.⁴⁶

Table 2. Summary of studies reporting corticosteroid use in TEN

Currently, there is conflicting data on the benefit of corticosteroids in SJS/TEN. The beneficial effects of high-dose steroids must be weighed against the risk of complications including gastrointestinal (GI) bleeds, prolonged wound healing thus increasing the risk of infection, and increased mortality.

Cyclosporine

Cyclosporine, a calcineurin inhibitor, has been reported to have therapeutic benefit in the setting of SJS/TEN. This drug works by inhibiting activation of T cells and thus downstream mediators including FasL, nuclear factor-kB, and tumor necrosis factor alpha (TNF-α).^48,49 Although less studied in comparison to other modalities discussed previously, cyclosporine has been shown to slow the progression of TEN and promote re-epithelialization.^50,51

Several studies have shown favorable outcomes in patients receiving cyclosporine (Table 3). Lee et al., reported 24 patients who received 3 mg/kg/day of cyclosporine for 10 days. Three deaths occurred in contrast to the SCORTEN-predicted mortality of 5.9.⁵² Valeyrie-Allanore et al., investigated the same dosage of cyclosporine and found that rate of disease progression decreased; 62% of patients receiving cyclosporine experienced no disease progression at day 3.⁵³ No deaths occurred in this study cohort which favorably contrasted with the SCORTEN-predicted mortality of 2.75.⁵³ In a meta-analysis of 9 studies comparing cyclosporine with supportive care, a survival benefit for patients treated with cyclosporine was found.⁵⁴ Cyclosporine is associated with hypertension and renal toxicity and both should be monitored during treatment.⁵⁵ In one trial with 29 patients, only 26 were able to complete treatment due to side effects. Reported adverse reactions included neutropenia, leukoencephalopathy, and severe infection.⁵³ Contraindications to cyclosporine include severe infections, internal malignancy, and renal dysfunction.⁵⁴ Due to the small number of patients reported, further studies are needed to validate the efficacy of cyclosporine as a therapeutic agent for TEN.

Table 3. Summary of studies reporting cyclosporine use in TEN

Plasmapheresis

The mechanism of action of plasmapheresis involves clearing the circulating pathogenic metabolites including drugs, FasL, and TEN-induced cytokines from the patient’s blood. These sessions are typically carried out daily or every other day until patients show no signs of disease progression. The safety profile of plasmapheresis makes this therapeutic modality particularly attractive.^50,51,61-65 Reported adverse events included transient paresthesias and urticaria. Most data on use of plasmapheresis in TEN come from case series and show improvement of disease progression (Table 4). In one case series involving 4 patients, those receiving plasmapheresis after unsuccessful treatment with corticosteroids and IVIG showed marked clinical improvement. Skin sloughing was interrupted and skin lesions began to heal after an average of 5.25 sessions.⁶⁶ This treatment modality is not widely available, thus limiting its use.

Table 4. Summary of studies reporting plasmapheresis use in TEN

TNF-α Inhibitors

Skin lesions and blister fluid in TEN are known to contain high levels of TNF-α which prompted the use TNF-α inhibitors in patients with SJS/TEN.^68,69 Both infliximab and etanercept have shown benefit.^50,51,70-78

One case series published in 2014 included 10 patients who received a single dose of etanercept, 50 mg, subcutaneously (Table 5). All patients responded without any complications or adverse effects.⁷² The median time to healing was 8.5 days. Wang et al. studied etanercept 25 mg or 50 mg twice weekly compared with steroids in 96 SJS/TEN patients in a randomized controlled trial (RCT) and found that re-epithelialization occurred more quickly in the etanercept group (14 days for etanercept vs. 19 days for steroids). Additionally, etanercept was associated with a 9.4% reduction in SCORTEN predicated mortality and a lower actual mortality (8.3% with etanercept vs. 17.7% with steroid treatment) and fewer adverse events (GI hemorrhage).⁷⁹ In the largest network metanalyses to date, etanercept was ranked the best among 10 treatments based on the SUCRA score for mortality rate.²⁷ The SUCRA score is a metric used to evaluate which treatment in a network meta-analyses is likely to be the most efficacious. Although there are case reports to support the use of infliximab, this medication has not been as well studied.⁷³

Table 5. Summary of studies reporting use of TNF-α inhibitors in TEN

Combination Therapies

The combination of IVIG and corticosteroids has shown promise in patients with SJS/TEN.27,55,82 One retrospective study included 39 patients who received an initial dose of 1.5 mg/ kg/day of methylprednisolone for 3 to 5 days combined with a total dose of 2 g/kg IVIG for 5 days.⁸³ Mortality rate with steroid monotherapy was 31% compared to 13% with combination therapy. Similarly, a network meta-analysis (2021) concluded that the combination of IVIG and corticosteroids was the only treatment that reduced the standardized mortality ratio with statistical significance.²⁷ Additionally, following etanercept, the combination of corticosteroids and IVIG was calculated to have the second highest SUCRA score for mortality rate. These results were supported by another meta-analysis of 24 studies suggesting combination therapy (IVIG + steroids) had better therapeutic effect compared to either therapy alone.⁸² Additional studies support these findings.^27,32,84,85 The combination of IVIG with etanercept was evaluated in 13 patients at a single institution from 2015 to 2018. There was no significant difference in mortality when compared to IVIG monotherapy. A systematic review supported the combination of corticosteroids and cyclosporine, although these findings warrant further investigation.³⁹ The combination of TNF-α inhibitors with a steroid was investigated in 25 patients with SJS/TEN. Ten patients received methylprednisolone (equivalent to 1 to 1.5 mg/kg/day of prednisolone) and 15 patients received the steroid regimen in combination with 25 mg of etanercept twice weekly.⁸⁶ Combination therapy significantly shortened the course of initial steroid treatment and time until skin re-epithelialization (median, 12 days) compared to steroid monotherapy (median, 16 days).

Conclusion

Over the past decade, there have been several meta-analyses detailing the efficacy of various treatments that serve to guide clinicians in the management of SJS/TEN and TEN.^{27,30,40,43,82,84} Early intervention is paramount. As soon as the diagnosis is considered, all potential offending drugs must be stopped. Transfer to a burn center and administration of systemic therapy should be considered. Management is heavily dependent on disease severity and rate of progression, patient comorbidities, available evidence, and physician experience.

Due to the complexity of the data and often conflicting results, no one treatment can be recommended at this time. Currently, there is not enough evidence to recommend IVIG or steroid monotherapy for adult patients with TEN. However, IVIG is still considered a safe and effective option for pediatric patients.^28,29 Several network meta-analyses suggest that combination therapy with corticosteroids and IVIG, cyclosporine, and/or etanercept can reduce mortality of TEN.^{27,30,40,43,82,84} These treatment recommendations are summarized in Table 6.

Table 6. Summary of therapies for TEN that have been shown to be more efficacious than supportive measures in reducing mortality

Purchase Article PDF for $1.99

¹Faculty of Medicine, University of Toronto, Toronto, ON, Canada
²Windsor Clinical Research, Windsor, ON, Canada
³Western University, Schulich School of Medicine, Windsor, ON, Canada

Conflict of interest:
Cindy Kang and Monica Shah have no conflicts of interest to disclose. Jerry Tan has been a consultant, investigator and/or speaker for Almirall, Bausch, Boots/Walgreens, Cipher, Galderma, L’Oréal, Promius, Sun and Vichy. Disclaimers: This manuscript is an original submission. Views expressed in the submitted article are our own and not official positions of our institutions.

Abstract:
The diagnosis and classification of rosacea has been modified to reflect presenting features. On exclusion of differentials, the diagnosis of rosacea is based on the presence of either (1) phymatous changes, or (2) centrofacial persistent erythema. In their absence, diagnosis can be established by presence of any two of: flushing/transient erythema, papules and pustules, telangiectases, or ocular manifestations. Management of rosacea depends on presenting feature(s), their severity, and impact. General management includes gentle skin care, sun protection, and trigger avoidance. Evidence-based treatment recommendations include topical brimonidine and oxymetazoline for persistent erythema; topical azelaic acid, ivermectin, metronidazole, minocycline and oral doxycycline, tetracycline and isotretinoin for papules and pustules; vascular lasers and light devices for telangiectases; and omega-3 fatty acids and cyclosporine ophthalmic emulsion for ocular rosacea. While surgical or laser therapy can be considered for clinically noninflamed phyma, there are no trials on their utility. Combination therapies include topical brimonidine with topical ivermectin, or topical metronidazole with oral doxycycline. Topical metronidazole, topical ivermectin, and topical azelaic acid are appropriate for maintenance therapy. In conclusion, the updated phenotype approach, based on presenting clinical features, is the foundation for current diagnosis, classification, and treatment of rosacea.

Key Words:
alpha-adrenergic agonist, anti-parasitic, antibiotic, diagnosis, dicarboxylic acid, erythema, laser therapy, management, phenotype approach, phyma, retinoids, rosacea, telangiectasia

Table of Content:

1. Introduction
2. Quality of Evidence
3. Diagnosis
4. Evaluation and Differential Diagnosis
5. Associated Comorbidities
6. Management
7. Conclusion

Introduction

Rosacea is a chronic inflammatory dermatosis affecting the centrofacial region (cheeks, chin, nose, and central forehead), with a prevalence of 5.5% of the adult population.¹ While rosacea has been considered to primarily affect fair-skinned individuals, this may be due to difficulty in detecting facial redness in darker skin types. Nevertheless, rosacea patients of Asian, Hispanic, or African ancestry have been described in literature.² Women are more likely to develop rosacea, however, when present in men, the disease tends to be more severe.³ The typical age of onset is after 30 years old;^4,5 however, ocular rosacea can occur as early as 22 months of age.⁶ Pediatric rosacea is rare and is usually associated with a family history of the condition.^6,7 Ocular manifestations of rosacea occur in more than 50% of rosacea patients.⁸

There are several flare triggers in patients with rosacea including temperature changes, heat, cold, exercise, ultraviolet radiation, spicy food, and alcoholic beverages.⁹ Microbes have also been implicated in the pathophysiology of rosacea, including Demodex species, Bacillus oleronius, Staphylococcus epidermidis, Helicobacter pylori, and Bartonella quintana.¹⁰ The immune system, neurogenic inflammation, and vascular hyperreactivity are central to the pathophysiology of rosacea. Specifically, innate immune system activation via toll-like receptor 2 (TLR2), transient receptor potential (TRP) ion channels, and proinflammatory cytokines contribute to clinical manifestations of rosacea.¹¹

Rosacea has a significant impact on the emotional, social, and occupational wellbeing of affected individuals. Due to the altered facial features characterising this disease, patients with rosacea frequently experience stigmatization. Consequently, they can suffer from depression and anxiety and tend to avoid social situations.¹²

The phenotype approach establishes diagnosis and management based on the presenting features of the individual.¹³ While previously classified according to subtypes, each potentially comprising multiple signs and symptoms, this nomenclature should be abandoned as it limits the ability to study, evaluate, and treat individual features.¹³ The phenotype approach more accurately addresses patient features and can facilitate focused treatment on those of greatest severity and impact.¹³ Thus, this review provides an overview of the updated phenotype approach in the diagnosis and management of rosacea.

Quality of Evidence

The PubMed database was searched for systematic reviews, meta-analyses, and guidelines on the diagnosis, classification, and management of rosacea, with a focus on phenotypes. Key words included “rosacea” and “diagnosis” or “classification” or “management” or “guidelines” or “treatment”. There were no limits on age, sex, or nationality or year of publication. Only studies published in English on human subjects were included.

Diagnosis

The diagnosis of rosacea is clinical and based on specific features according to the ROSacea COnsensus expert panel (ROSCO)¹³ and the National Rosacea Society (NRS).¹⁴ On clinical exclusion of other conditions with similar presenting features, the diagnosis of rosacea is established with either: (1) phymatous changes, or (2) centrofacial persistent erythema (Table 1).^13,15 In their absence, diagnosis can be established by the presence of any two of the following major features: flushing/transient erythema, papules and pustules, telangiectases (Table 1), or ocular rosacea (Table 2).^13,15 Minor features, such as burning, stinging, dry sensation of the skin, or edema are not diagnostic of rosacea (Table 1).¹⁵ The diagnosis of rosacea in darker skin types (Fitzpatrick phototypes V and VI) is difficult as erythema and telangiectasia may not be readily visible, and a high level of suspicion based on minor features is required. A less common variant of rosacea is granulomatous rosacea, with multiple brown, yellow, or red cutaneous papules of uniform size. Occasionally, skin biopsy may be useful for diagnostic support.¹³

Table 1: Descriptions of cutaneous rosacea features by consensus

Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1273.¹⁵

Table 2: Descriptions of ocular rosacea features

Note that these are recommendations rather than consensus due to n = 2. Both ophthalmologists voted ‘Agree’ or ‘Strongly agree’ to the descriptions.
Consensus of an expert panel of 19 dermatologists from Argentina (n = 1), Brazil (n = 1), Canada (n = 1), France (n = 1), Germany (n = 2), India (n = 1), Italy (n = 1), the Netherlands (n = 1), Qatar (n = 1), Singapore (n = 1), South Africa (n = 1), the U.K. (n = 1) and the U.S.A. (n = 6); and two ophthalmologists from Germany (n = 1) and the U.S.A (n = 1). Some panellists abstained when their clinical expertise did not extend to a particular subject.
Reprinted from Schaller M. et al., 2019, Br J Dermatol, 176, p. 1274.¹⁵

Evaluation and Differential Diagnosis

Differential diagnoses of rosacea depend on the clinical feature(s) present (Table 3). Examples include contact dermatitis, photodermatitis, seborrheic dermatitis, and systemic lupus erythromatous for facial erythema; perimenopausal flushing, emotional flushing, carcinoid syndrome, and mastocytosis for flushing; and acne vulgaris and folliculitis for papules and pustules.¹⁶ Exclusion of mimics can be established by taking an adequate history, performing a directed physical evaluation for distinguishing features, and further testing as required.

Table 3: Differential diagnoses of rosacea

Information from Asai et al., 2016,¹⁶ Ogé et al., 2015,¹⁹ Scheinfeld et al., 2010,⁵⁵ and Izikson et al., 2006.⁵⁶

Associated Comorbidities

Associations between rosacea and metabolic, cardiovascular, gastrointestinal (GI), neurologic, and psychiatric diseases have been established (Table 4).¹⁷ Some of these share common innate inflammatory elements with rosacea, such as macrophage and macrophage-derived mediators, reactive oxygen species, matrix metalloproteinases, interleukin-1b (IL-1b), and tumor-necrosis-factor (TNF).¹⁸

Table 4: Rosacea and associated comorbidities

CI = confidence interval, N/A = not available, OR = odds ratio, P = probability

Management

The goals of rosacea treatment are to reduce the severity of features and the frequency and intensity of flares.¹³ General management includes routine skin care: gentle cleansers, moisturizers, sun protection, and avoidance of triggers.^16,19 Specific treatments should be targeted at clinical features (Table 5 on pages 7-8). If multiple features are present, combination treatment should be considered.¹⁶ The phenotype approach allows for such feature-based treatment according to the severity and impact of the presentation.²⁰ An updated systematic review of rosacea treatment based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, is outlined below (Table 5).²¹

Table 5: Treatment recommendations and certainty of evidence

CI = confidence interval, Er:YAG = erbium-doped yttrium aluminium garnet, I2 = heterogeneity, IPL = intense pulsed light, MD = mean difference, MR = modified release, N/A = not available, Nd:YAG = neodymium-doped yttrium aluminum garnet, NNTB = number needed to benefit, NNTH = number needed to harm, PDL = pulsed dye laser, P = probability, RCT = randomized controlled trial, RR = relative risk
Information from van Zuuren et al., 2019.²¹

Flushing/Transient Erythema

No randomized controlled trials available.

Persistent Erythema

Evidence to support the efficacy and safety in transient reduction of persistent erythema was derived from two randomized vehicle-controlled trials for topical brimonidine 0.33% gel²² and topical oxymetazoline 1% cream.^23,24 Quality of evidence for efficacy was reported as high-certainty for brimonidine 0.33% gel and moderate-certainty for oxymetazoline 1% cream.²¹ Adverse event frequency was similar to vehicle for both brimonidine²² (moderate-certainty evidence)²¹ and for oxymetazoline^23,24 (moderate-certainty evidence).²¹ In both, there is ongoing concern about the potential risk of worsening erythema with repeated use.^25,26

Papules and Pustules

Dicarboxylic Acids

Topical azelaic acid 15% foam twice daily is a safe and effective treatment for papules and pustules^27,28 (high-certainty evidence)²¹ with an adverse event frequency similar to vehicle^27,28 (moderate-certainty evidence)²¹ according to two randomized vehicle-controlled trials.^27,28

Another randomized controlled trial showed that azelaic acid 15% gel may be more effective in reducing mean nominal lesion count than metronidazole 0.75% gel²⁹ (moderate-certainty evidence).²¹ These differences, however, were not reproducible and were considered to be unimportant.^30,31

Antiparasitics

Topical ivermectin 1% cream once daily is more effective in the treatment of papules and pustules compared to vehicle³² (high-certainty evidence),²¹ and compared to metronidazole 0.75% cream twice daily³³ (moderate-certainty evidence).²¹ Adverse event rates for topical ivermectin were similar compared to vehicle³² (moderate-certainty evidence)²¹ and topical metronidazole.³³

Retinoids

In two randomized controlled trials, low-dose oral isotretinoin 0.25 mg/kg and low-dose oral isotretinoin 0.30 mg/kg were more effective than placebo³⁴ (high-certainty evidence)²¹ and oral doxycycline (100 mg for 14 days, then tapered to 50 mg)³⁵ (moderate-certainty evidence),²¹ respectively. The frequency of adverse events was higher for isotretinoin compared to placebo³⁴ (moderate-certainty evidence),²¹ but similar to oral doxycycline³⁵ (moderate-certainty evidence).²¹

Antibiotics

Several randomized vehicle- or placebo-controlled trials demonstrated the efficacy of topical metronidazole 1% cream,^36-38 topical minocycline 1.5% and 3% foam,³⁹ oral doxycycline 40 mg modified-release (MR),⁴⁰ and oral tetracycline 250 mg twice daily^41,42 in the treatment of papules and pustules. The quality of evidence for efficacy was moderate-certainty for the first three treatments, but low-certainty for oral tetracycline.²¹ Adverse event frequency was similar to vehicle/placebo for topical metronidazole^36-38 (moderate-certainty evidence),²¹ oral doxycycline,⁴⁰ and oral tetracycline,^41,42 but higher than vehicle for topical minocycline39 (moderate-certainty evidence).²¹ Topical clindamycin 1% cream or gel was found to be no more effective than vehicle for any outcome⁴³ (low-to-moderate certainty evidence).²¹ Compared to oral doxycycline 40 mg MR, oral minocycline 100 mg is similarly effective⁴⁴ (moderate-certainty evidence)²¹ with no differences in the rate of adverse events⁴⁴ (low-certainty evidence).²¹ Compared to oral doxycycline 100 mg, oral azithromycin 500 mg three times a week then tapered is similarly effective in reducing lesion counts⁴⁵ (very low-certainty evidence).²¹ Finally, 40 mg MR doxycycline is as effective as 100 mg with fewer side effects.⁴⁶

Telangiectases

There is low-to-moderate certainty evidence that long pulsed dye laser (PDL), neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and intense pulsed light (IPL) therapy reduce telangiectasia.²¹

Clinically Non-inflamed Phyma

Physical modalities, such as ablative laser surgery using carbon dioxide or erbium-doped yttrium aluminium garnet (Er:YAG) modalities, electrosurgery, or cryosurgery, may improve clinically noninflamed phyma.¹⁶ However, it is difficult to determine their effectiveness due to the lack of evaluation by randomized controlled trials.^16,21

Clinically Inflamed Phyma

While there are no randomized controlled trials evaluating the efficacy of treatments for clinically inflamed phyma, oral doxycycline or oral isotretinoin are still recommended.^16,21

Ocular Rosacea

One randomized placebo-controlled trial supported omega-3 fatty acids (180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid) one capsule twice daily⁴⁷ (moderate-certainty evidence)²¹ in the treatment of ocular rosacea. Another randomized controlled trial supported cyclosporine ophthalmic emulsion 0.05% twice daily versus artificial tears⁴⁸ (low-certainty evidence)²¹ and versus oral doxycycline 100 mg twice daily for the first month followed by 2 months once daily⁴⁹ (low-certainty evidence).²¹ For the cyclosporine ophthalmic emulsion, there were no differences in the rate of adverse events compared to artificial tears (low-certainty evidence).²¹ For severe ocular rosacea or when there is diagnostic uncertainty, referral to an ophthalmologist should be arranged.²¹

Combination Therapies

Treatment combinations may address several different clinical features of rosacea. For example, compared to vehicle, topical brimonidine 0.33% gel with topical ivermectin 1% cream can effectively reduce both erythema and papules and pustules.⁵⁰ Compared to metronidazole 1% gel alone, metronidazole 1% gel with oral doxycycline 40 mg MR can reduce lesion counts to a greater extent.⁵¹

Finally, randomized controlled trials reported no difference in efficacy between oral minocycline 45 mg with or without topical azelaic acid 15% gel⁵² (moderate-certainty evidence)²¹ or between topical clindamycin phosphate 1.2% with tretinoin 0.025% gel compared to placebo⁵³ (moderate-certainty evidence).²¹ However, in the latter, there was a higher rate of adverse events in the topical clindamycin/tretinoin group compared to placebo (moderate-certainty evidence).²¹

Maintenance Therapies

Topical metronidazole 0.75% gel, ivermectin 1% cream, and azelaic acid 15% gel are reported as effective and safe for maintenance therapy of papules and pustules.^21,54

Conclusion

The diagnosis and classification of rosacea has evolved to a phenotype approach to accurately address the clinical features presenting in an individual and to advance epidemiological and clinical trials research.¹³ This review details the rosacea phenotype approach to diagnosis and classification, and summarizes current evidence-based treatment recommendations for individual features. There is no singularly effective treatment for all features of rosacea. There is an unmet need for high quality investigations for treatment of inflamed phyma, flushing/transient erythema, and ocular rosacea.

Purchase Article PDF for $1.99

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.

Purchase Article PDF for $1.99

CONFLICTS of INTEREST:
Rajani Katta reports no relevant conflicts of interest. Mary Jo Kramer reports no relevant conflicts of interest.

ABSTRACT:
An increasing body of research indicates that dietary change may serve as a component of therapy for certain skin conditions. This includes conditions such as acne, atopic dermatitis, aging skin, psoriasis, and rosacea. Certain nutrients, foods, or dietary patterns may act as disease “triggers”, while others may prove beneficial. Avoidance or elimination diets may be helpful in some conditions, although testing may be recommended first. In terms of beneficial effects, an eating pattern that emphasizes the consumption of whole foods over highly processed foods may help in the treatment of certain skin conditions, and will certainly help in the prevention of associated co-morbidities.

KEY WORDS:
diet, elimination diet, skin, whole foods

TABLE OF CONTENT:

1. Introduction
2. Diet and Acne
3. Diet and Aging Skin
4. Diet and Atopic Dermatitis
5. Diet and Psoriasis
6. Diet and Rosacea
7. Conclusion

Introduction

Dietary change has long been considered an important treatment strategy for certain skin conditions. For example, dermatologists have long discussed the role of dietary triggers in rosacea and insulin resistance in acanthosis nigricans. As an increasing body of research has demonstrated, dietary change may play a role in treatment strategies for other skin diseases as well.

In this review, we focus on five major skin conditions for which dietary change may be advised as one component of treatment. As a quick Internet search will reveal, there is much misinformation on the link between skin and diet. Some recommendations are ineffective, while others are potentially harmful, such as untested dietary supplements or severely restrictive elimination diets. It is critical, therefore, that physicians be well-informed in this area in order to provide evidence-based recommendations.

In this article, we review information on specific nutrients, foods, or dietary patterns that may act as disease “triggers”, as well as those that may prove beneficial in therapy. This review provides a synopsis, highlighting promising research findings.

Diet and Acne

Triggers

The strongest evidence to date on dietary triggers for acne is for high-glycemic-load diets. In a randomized controlled trial (RCT), acne patients demonstrated significant improvement after 12 weeks of a low-glycemic-load diet.¹ Later studies documented that this dietary pattern resulted in lower androgen bioavailability and altered skin sebum production.^2,3 In another RCT, a 10-week low-glycemic-load diet improved acne, and histopathological exam revealed decreased skin inflammation and reduced sebaceous gland size.⁴

Some studies have demonstrated an epidemiologically weak association between acne and dairy consumption, possibly more so with skim milk.^5,7 While further research is needed, it may play a role in some patients, as in a report of five teenagers who developed treatment-resistant acne after starting whey protein supplements.⁸

Beneficial Measures

Studies in humans are limited and, therefore, despite promising in vitro, animal, or anecdotal reports, recommendations for foods or supplements containing probiotics, omega-3 fatty acids, zinc, antioxidants, fiber, and vitamin A cannot be made with certainty at this time.⁹ Omega-3 fatty acids warrant further study; in one 10-week RCT, omega-3 fatty acid supplements and gammalinolenic acid supplements both resulted in clinical and histopathological improvement in acne lesions.¹⁰ Probiotics warrant further study as well; in one RT, minocycline with probiotic supplementation resulted in a lower total lesion count as compared to antibiotics alone.¹¹

Zinc bears special mention, as it has been studied in several RCTs. While some trials have not been successful, others have demonstrated efficacy in acne treatment.^12,13 Further research is warranted, as published trials have utilized multiple dosages and forms of zinc, including zinc gluconate, zinc sulphate, and methionine-bound zinc, among others. Some formulations have better absorption and result in less gastrointestinal side effects. Other factors that impact zinc absorption include age and meal components.¹⁴ In addition, some successful trials have utilized zinc in combination with other components, such as antioxidants and lactoferrin.^15,16 Future research must account for these multiple factors.

Diet and Aging Skin

Triggers

For patients who present for cosmetic treatment of aging skin, lifestyle factors that impact this process are an important aspect of treatment. While smoking and sun protection are commonly reviewed, dietary factors should be as well.

While it has long been recognized that diabetics experience poor wound healing, there is now a greater recognition that these effects on collagen can promote skin wrinkling. Higher levels of blood sugar can result in the production of advanced glycation end products (known as AGEs) via glycation and cross-linking of collagen fibers, which ultimately results in a loss of elasticity.¹⁷ Consumption of pre-formed AGEs, created during certain cooking processes such as deep-frying, can also be detrimental.¹⁸

Even in non-diabetics, effects on collagen may be seen. Even after accounting for degree of sun damage and smoking, as study subjects’ blood glucose level increased, their perceived age increased.¹⁹

Beneficial Measures

Many laboratory and animal studies have found that multiple different antioxidants (AOs), found in foods ranging from various fruits and vegetables to tea leaves and seeds, act to limit the damaging cutaneous effects of ultraviolet (UV) radiation.²⁰ Experimental human studies of a few AOs have noted the same, as in one study in which subjects consuming tomato paste daily for 12 weeks experienced less UV-induced erythema, as well as lower levels of UV-induced matrix metalloproteinase.²¹ It is important to note that research indicates AOs consumed via dietary sources appear to function in a different fashion than those found in isolated supplements.²²

Other human studies suggest that a diet high in phytonutrients can limit photodamage. One study reported higher intake of vegetables, legumes, and olive oil appeared to protect against actinic damage.²³ In another study of over 4000 women, patients’ skin was analyzed for features of skin aging. After controlling for other factors, a diet reported as high in potassium and vitamins A and C correlated to fewer wrinkles.²⁴

Diet and Atopic Dermatitis

Triggers

Food allergies are highly correlated with atopic dermatitis (AD). In some cases, they are causative.²⁵ Foods may trigger an AD flare via three main mechanisms.²⁶

Immunoglobulin E (IgE)-mediated allergy, also known as Type 1 or immediate-type hypersensitivity, may trigger a flare within minutes to hours.²⁷ The six common trigger foods are milk, eggs, wheat, soy, seafood, and nuts. Testing with skin prick test or blood test may screen for this allergy, but due to a high rate of false positive results, confirmation requires double-blind, placebo-controlled food challenge (DBPCFC).

Late eczematous reactions, due to the same trigger foods, may cause an AD flare up to 48 hours later.²⁸ As the immunological mechanism is unknown, testing requires DBPCFC.

Systemic contact dermatitis, screened for by patch testing, is a T-cell mediated reaction. In balsam of Peru allergy, some persons allergic to fragrance additives may experience a cutaneous flare following ingestion of certain foods, including tomatoes, citrus, and cinnamon.²⁹

An expert panel, representing 34 agencies and groups, published guidelines on food allergy, and concluded that elimination diets are not recommended in unselected AD patients.³⁰ In other words, dietary changes should be guided by results of testing. If suspected by history, though, a single food elimination diet for 6 weeks may be attempted in adults.

Beneficial Measures

Synbiotics, which are probiotics in combination with prebiotics, have shown promise in the treatment of AD. Probiotics are live bacteria, similar to those found naturally in the human body, and which may be beneficial to health. They may be found in supplements or in certain foods containing live, active cultures.³¹ Prebiotics, such as certain plant fiber, are defined as nondigestible carbohydrates that stimulate the growth of probiotic bacteria in the intestine.³² A meta-analysis of synbiotics in AD treatment found the most promise with a combination of different strains of bacteria and when used for at least 8 weeks in adults and children over the age of 1 year.³³ However, the optimal dose, bacterial strains, and treatment duration remains unclear.

Vitamin D has not been shown to be helpful in most AD patients, but further research is recommended for certain groups, specifically those with very low levels of vitamin D, those with food allergies, and those with frequent bacterial skin infections.^34,35 Studies of evening primrose oil and borage seed oil have been disappointing, while studies of Chinese herbal medicine have either not shown efficacy, or have been of low quality.^36,37 Limited research is available for fish oil supplements.³⁸

Diet and Psoriasis

The importance of diet should be emphasized to all psoriasis patients, primarily due to the higher risk of comorbid conditions, including diabetes, hypertension, and cardiovascular disease, that may be prevented or ameliorated by dietary approaches.³⁹ In addition, dietary change leading to weight loss has resulted in better treatment efficacy, as well as improved psoriasis area and severity index (PASI) scores in some patients.

Triggers

It is well recognized that smoking and increased alcohol intake are associated with psoriasis, and all psoriatic patients should be advised of their potential role.^40,41

Dietary factors may also play a role. Gluten-containing foods may act as a trigger in some patients, and testing for celiac antibodies is warranted in those who report gastrointestinal symptoms. While estimates vary, one large study found a 2.2 fold higher risk of celiac disease as compared to matched controls, while a meta-analysis found a 2.4 fold higher risk of certain celiac antibodies.^42,43 In such patients, a gluten-free diet may result in psoriasis improvement, as demonstrated in small trials and case reports, although further studies are required to confirm.^43,44

Beneficial Measures

In a systematic literature review, increased severity of psoriasis appeared to correlate with a higher body mass index (BMI), although the authors noted the difficulty in determination of temporality due to study designs.⁴⁵ It is believed that obesity likely predisposes to psoriasis, and vice versa.⁴⁶ While the reasons for this are multifactorial, it has been shown that weight loss can improve response to systemic psoriasis therapies and improve disease severity.

An excellent review article summarizes the effects of weight loss interventions in psoriasis.⁴⁷ In a meta-analysis of five RCTs of lifestyle intervention via diet or exercise in overweight or obese psoriasis patients, a greater reduction in PASI score was seen in weight loss intervention groups.⁴⁸ In a limited number of case reports and retrospective studies, some obese patients have experienced significant improvements in psoriasis following gastric bypass surgery.⁴⁹

Weight loss has also improved response to systemic therapy, as in one RT trial of patients on cyclosporine.⁵⁰ In examining factors associated with response to biologic therapy, one analysis found that BMI had the strongest effect across studies, although several studies found no association.^47,51

While specific dietary recommendations are not clear, one observational study found an inverse association between PASI score and degree of adherence to the Mediterranean diet.⁵²

In terms of nutritional supplements, Millsop et al. summarized multiple studies and found that further investigation was needed, with fish oil showing the most promise and oral vitamin D demonstrating some promise in open label studies. There was limited evidence for benefit of vitamin B12 and selenium
supplementation.⁵³

Diet and Rosacea

Triggers

Although dermatologists frequently counsel rosacea patients on avoidance of dietary triggers, there is a lack of research in this area. In one survey of patients by the National Rosacea Society, 78% had altered their diet, and 95% of this group reported subsequent reduction in flares.⁵⁴

In this group, 75% were affected by spices and 54% by hot sauce. Other trigger foods included tomatoes (30%), chocolate (23%), and citrus (22%). Alcohol was another frequent trigger, including wine (52%) and hard liquor (42%), as well as hot beverages such as coffee (33%) and tea (30%).

While the underlying pathophysiologic mechanism of these reported triggers is unknown, transient receptor potential (TRP) channels may play a role. These are expressed throughout the body, including on neuronal tissues, and may be activated by cold or hot temperatures, as well as certain foods.⁵⁵ Specific dietary activators include capsaicin and cinnamaldehyde, which act on certain of these channels to stimulate an increase in skin blood flow via neurogenic vasodilatation.⁵⁵ Capsaicin is found in some spices, while cinnamaldehyde is found in cinnamon, tomatoes, citrus, and chocolate.⁵⁶

Beneficial Measures

Research indicates the possible role of a gut-skin connection in rosacea. In a population-based cohort study of close to 50,000 patients with rosacea, the prevalence of celiac disease, Crohn’s disease, ulcerative colitis, Helicobacter pylori infection, small intestinal bacterial overgrowth (SIBO), and irritable bowel syndrome were all higher among patients with rosacea as compared with control subjects.⁵⁷

Although research is ongoing, the pathogenic link remains unknown. One intriguing study found that patients with rosacea were 13 times more likely to have SIBO, with a suspected role for increasing circulating cytokines.⁵⁸ Treatment of SIBO with antibiotics in 40 patients led to remission of rosacea in all cases, which persisted in the majority at 3-year follow-up.

In one case report, a reduction of gut transit time via a high-fiber intervention resulted in improvement of rosacea.⁵⁸ As SIBO has been linked to decreased gut motility, further research on such intervention is warranted.

Conclusion

This article is intended as a general overview. There are several other conditions (not touched upon here) for which dietary intervention may be considered. For example, emerging research indicates that patients with hidradenitis suppurativa have a higher risk of adverse cardiovascular events, which may necessitate dietary change.⁶⁰ In the arena of prevention, research continues into the role of diet and supplement use in skin cancer prevention. As research continues, dietary interventions may play a role in other dermatologic diseases as well.

The five conditions reviewed here are very disparate, and yet patients with each often seek dietary advice. In discussing the link between skin and diet, it is important to recognize and convey the limitations of nutritional research. Specifically, such research may not lead to definitive answers applicable to every patient, but rather general recommendations.

This is in part due to the notable variability of individual responses to different foods and nutrients, as in marked differences in blood glucose responses to the same quantity of carbohydrates.⁶¹ Confounding factors present a notable research challenge, as does the fact that many health effects may take months to years to manifest, which makes valid controlled dietary trials extremely challenging. Despite these challenges, nutritional research can indicate directions for further study, or add to an increasing body of evidence to support specific recommendations.

Based on research findings to date, certain dietary recommendations are suitable for patients with multiple different types of skin disease.

1. The results of research support the promotion of eating patterns over specific foods or nutrients.
2. An eating pattern that emphasizes the consumption of whole foods over highly processed foods may help in the treatment of certain skin diseases. It will certainly help in the prevention of associated comorbidities.
3. Multiple eating plans emphasize whole foods as a foundational approach, and may be recommended to patients with skin disease. Such eating plans, rich in dietary antioxidants, fiber, and other phytonutrients, have demonstrated multiple overall health benefits. These may be either cuisine-based, such as the Mediterranean diet, or guideline-based, such as the DASH diet. These particular plans have been shown to reduce the risks of cardiovascular disease and hypertension, respectively.^62,63
4. An increased intake of fiber is seen as one key benefit of these whole foods diets. Some plant-derived fiber serves as a prebiotic, which may promote a healthy gut microbiome. Given an increasing body of research demonstrating a gut-skin connection, this may benefit certain inflammatory skin diseases.
5. For some skin diseases, specific dietary “triggers” should be reviewed. Some patients may choose a trial of an elimination diet, such as avoidance of high-glycemic-load foods in acne or vasodilating foods in rosacea. For other conditions, medical testing may be recommended prior to dietary change, as in testing for celiac disease in psoriasis.
6. Dietary supplements, used in the absence of a documented nutrient deficiency, have been demonstrated as beneficial in only a few very specific instances. Despite the marketing of many over-the-counter supplements for the treatment of skin disease, the vast majority of these are not supported by evidence.
7. Referral to integrative physicians, dieticians, or nutritionists may be recommended to help implement and tailor dietary approaches according to food allergies, personal or cultural preferences, and other medical conditions.

Purchase Article PDF for $1.99

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, pruritic, inflammatory condition involving the skin which can have a significant impact on the quality of life (QoL).^1,2 Although many patients may be controlled with topical therapy, a subset of those affected will require systemic therapy to control their disease.³ There are currently no approved systemic therapies in North America for the long-term management of moderate-to-severe atopic dermatitis and many treatments are currently being used off-label. This article will guide the family practitioner on how to manage adults with moderate-to-severe AD and when to refer for specialist management.

Abbreviations: AD – atopic dermatitis; ADHD – attention deficit hyperactivity disorder; BSA – body surface area; HPA – hypothalamic-pituitary-adrenal, HTN – hypertension; IL – interleukin; PGA – Physician’s Global Assessment; QoL – quality of life; TCI – topical calcineurin inhibitors; TCS – topical corticosteroids; Th2 – T helper cell type 2; TPMT – thiopurine methyltransferase

Background

• Atopic dermatitis is a common chronic inflammatory disease in both children and adults.
• In developed countries, it is a common skin disorder, affecting up to 20% of children and 1% to 3% of adults.⁴
• Approximately 10% of adults are not controlled with topical therapy alone and require systemic therapy for disease control.³
• Many immunosuppressants are used off-label to control this disease. Cyclosporine is approved for use in AD only in Europe and Japan.^5,6
• The pathogenesis of AD is thought to be due to a defect in the skin barrier primarily through abnormal filaggrin and alterations of the innate and acquired immune system, with interleukin (IL) 4 and 13 as key players.⁷
• Increased knowledge of the immunopathogenesis of AD has allowed for the development of new, targeted therapies.⁸

The Burden of AD

• Up to two thirds of patients with AD also suffer from other atopic comorbidities including asthma, rhinitis and food allergies.^9-11
• A recent epidemiologic study from Germany showed that in addition to atopic comorbidities, patients with AD have a two-fold increased risk of developing ADHD.¹¹
• In one Phase 2b study, 86% of patients reported daily pruritus and 55% reported that itch disturbed their sleep 5-7 nights per week.¹²
• AD has a significant impact on patients and their families: itch, sleep disturbance, anxiety and depression can lead to a reduced QoL and stress on the family.¹³
• Risk factors for depression in patients with AD include an increasing severity of AD, female gender and increasing age. In addition to depression, there is also an increased risk of suicidality in this population and therefore, patients should be screened appropriately.¹³
• In a large US study, (2013 National Health and Wellness Survey:N=75,000), patients with AD reported overall lost work productivity of 30% compared to 16% in those workers without AD; an even greater loss of work productivity was noted when moderate-to-severe patients were compared to those with mild AD, 37% versus 23%, respectively.¹⁴

AD Management

• Non-prescription therapies are often used to help control the disease: moisturizers and emollients should be the cornerstone of any AD regimen.^15,16
• Controlling itch is also key for management as frequent scratching may put the patient at risk for infection.
• Dilute bleach baths can be helpful for patients who suffer from frequent bacterial infections due to their anti-staphylococcal activity, when used in conjunction with intranasal mupirocin. To prepare a bleach bath see Tip #1.^15,17
• Wet wrap therapy can also be an effective treatment to manage flares. This involves applying a wetted layer of gauze where TCS or TCI have been applied to the skin, and then cover with a second, outer dry layer of gauze. Wet wrap therapy provides more rapid improvement as it will increase medication penetration and provide a barrier to scratching.¹⁸

Tip #1: Dilute bleach baths at a concentration of 0.005% – 0.009% can help reduce colonization and recurrent infections in patients with AD.^15,17

How to prepare a bleach bath

• ¼ cup of bleach in a half tub of water to ½ cup bleach in a full bath tub of water
• Repeat 2 times per week

Topical Treatment and Phototherapy

• The gold standard of topical therapy is treatment with TCS and/or TCI.^15,16
• Both TCS and TCI can be used twice daily as needed for acute flares, or as maintenance therapy with a scheduled reduced frequency of application, such as 2-3 days per week.¹⁵
• Topical antihistamines and topical antimicrobials are not recommended for use in AD due to lack of efficacy and risk of contact dermatitis.¹⁵
• If available, phototherapy can be used in both the acute situation for management of flares, and as maintenance therapy for refractory or chronic disease; attention should be paid to any concomitant photosensitizing medications and underlying skin cancer risk.¹⁹

Tip #2: Topical or systemic antihistamines are NOT recommended for the routine care of patients with AD.

Candidates for systemic therapy have

• Moderate-to-severe atopic dermatitis
• Body surface area involvement ≥ 10%
• Areas with significant burden: involvement of face, hands or genitals
• Significant impact on QoL
• Ongoing pruritus
• Failed an adequate trial of TCS or TCI
• Failed phototherapy or cannot access it

Patient Selection for Systemic Therapy

• Patients with moderate-to-severe AD (PGA score ≥ 3) should be considered for systemic therapy when they have the following:
  • At least 10% body surface area (BSA) involvement
  • Ongoing significant impairment in QoL
  • Ongoing pruritus
  • Disease is not controlled with TCS or TCI or topical therapy is not appropriate
  • Treatment failure with phototherapy or phototherapy is not accessible
• Topical therapy is not appropriate if there is a history of adverse effects from TCS such as atrophy, telangiectasia and striae.¹⁵
• TCS are not appropriate if there is a need for application to large areas with a risk of absorption and hypothalamic-pituitary-adrenal (HPA) axis suppression.¹⁵
• TCI therapy can cause transient burning and stinging with application that may not be tolerated by some patients and, therefore, not considered an appropriate therapy.
• Special situations where systemic therapy may be considered appropriate include involvement of areas such as the face, hands or genitals, or when AD has a significant impact on a patient’s daily functioning due to lack of sleep, fatigue, intractable pruritus or significant psychological distress.^19,20

Systemic Therapy

• Antihistamines are not recommended; antihistamines used for the sedating effects have little to no impact on itch and may lead to disturbed sleep, so these are not typically recommended for regular use.^15,19
• Many immunosuppressants are used off label; the most commonly prescribed are cyclosporine, methotrexate, azathioprine and mycophenolate mofetil.³
• Evidence supporting use of these agents is lacking due to methodological limitations in most trials, small numbers and short duration of therapy.^3,21
• The best evidence available supports the use of cyclosporine as first-line therapy for short-term use (Table 1).³
• Systemic therapy is often limited by intolerance to common side effects (nausea, vomiting, headache) or by potential end-organ toxicity and sequelae of immunosuppression.²¹
• Routine monitoring of these agents for adverse events is required.¹⁹
• Oral corticosteroids should be considered as a rescue intervention for severe exacerbations and are not a suitable treatment option for the ongoing management of patients with AD.¹⁹

Tip #3: Avoid the use of systemic corticosteroids in the management of AD unless required as a rescue or salvage therapy of acute severe exacerbations of disease.

Systemic Agents on the Horizon

• Due to an increased understanding of the pathogenesis of AD, several targeted therapies are being developed.²¹ Monoclonal antibodies are among them, as they can provide reduced toxicity and improved efficacy compared to oral systemic agents that may have unintended effects and end organ toxicity.⁸
• A number of small molecule targets and monoclonal antibodies which target Th2 cytokines such as IL-4, IL-5, IL-13 and IL-31, or their receptors, are in development.⁸
• Dupilumab, a human monoclonal antibody against the receptor for IL-4 and IL-13 is the first agent to have demonstrated safety and efficacy in phase 3 trials.^21,22
• Dupilumab is furthest along in development and poised to be the first commercially available biologic for AD.
• Tralokinumab and lebrikizumab, which target IL-13, mepolizumab which targets IL-5, and nemolizumab which targets the IL-31 receptor, are also in earlier stages of development.⁷

Next Steps

• When your patient presents with ongoing difficulties managing AD, it is important to review their current treatment regimen and rule out other diagnoses, such as contact dermatitis.²³
• Encourage regular and generous use of emollients.
• Discuss adherence to the application of topical medications; TCS and TCI should be applied twice daily when there is an acute flare, and when controlled, applied on a schedule of 2-3 times weekly for maintenance, to prolong the flare-free period.^15,16
• During flares, consider wet wrap therapy to improve the efficacy of the applied topical agents, TCS and TCI, and reduce scratching.¹⁸
• If available and convenient, consider phototherapy for widespread acute or chronic disease.¹⁹
• For patients experiencing frequent skin infections, consider dilute bleach baths with intranasal mupirocin to reduce Staphylococcal colonization and infection.¹⁷
• Assess the patient for sleep loss, pruritus, and the impact on QoL and consider screening for depression, anxiety and suicidality.¹³
• If the disease cannot be controlled by these measures, the patient should be managed with systemic medication such as cyclosporine, azathioprine or methotrexate.^3,21
• For physicians not familiar with prescribing immunosuppressive medications, a referral to a dermatologist should be made for the systemic management of AD.

Conclusion

HD can have a significant burden on the patient with an impact on QoL. Early diagnosis of acute or chronic HD is important for optimal management. Other conditions such as tinea manuum and psoriasis need to be ruled out and managed appropriately. Once a diagnosis of HD is confirmed, treatment depends on the severity of the disease. A treatment algorithm has been developed to assist the general practitioner to make a diagnosis and either refer or treat accordingly. Whichever treatment option is prescribed, all patients should be educated on emollient therapy, hand protection and avoidance of irritants or allergens, which may be contributing to their disease.

References

1. Silverberg JI, Hanifin JM. J Allergy Clin Immunol. 2013 Nov;132(5):1132-8.
2. Lundberg L, Johannesson M, Silverdahl M, et al. Acta Derm Venerol. 2000 Nov;80(6):430-4.
3. Roekevisch E, Spuls PI, Kuester D, et al. J Allergy Clin Immunol. 2014 Feb;133(2):429-38.
4. Williams H, Robertson C, Stewart A, et al. J Allergy Clin Immunol. 1999 Jan;103(1):125-38.
5. Bieber T, Straeter B. Allergy. 2015 Jan;70(1):6-11.
6. Saeki H, Nakahara T, Tanaka A, et al. J Dermatol. 2016 Oct;43(10):1117-45.
7. Gandhi NA, Bennett BL, Graham NMH, et al. Nat Rev Drug Discov. 2016 Jan;15(1):35-50.
8. Harskamp C, Armstrong A. Semin Cutan Med Surg. 2013 Sep;32(3):132-9.
9. Zeppa L, Bellini V, Lisi P. Dermatitis. 2011;22(1):40-6.
10. Langenbruch A, Radtke M, Franzke N, et al. J Eur Acad Dermatol Venereol. 2014 Jun;28(6):719-26.
11. Radtke MA, Schäfer I, Glaeske G, et al. J Eur Acad Dermatol Venereol. 2017 Jan;31(1):151-7.
12. Simpson EL, Bieber T, Eckert L, et al. J Am Acad Dermatol. 2016 Mar;74(3):491-8.
13. Nicholas MN, Gooderham MJ. Atopic Dermatitis, depression, and Suicidality. J of Cutaneous Med Surg. 2017 Jan 9:1203475416685078.
14. Whiteley J, Emir B, Seitzman R, et al. Curr Med Res Opin. 2016 Jun;32(10):1645-51.
15. Eichenfield LF, Tom WL, Berger TG, et al. J Am Acad Dermatol. 2014;71(6):116-32.
16. Lynde C, Barber K, Claveau J, et al. J Cutan Med Surg. 2005;8(suppl 5):1-9.
17. Ryan C, Shaw RE, Cockerell CJ, et al. Pediatr Dermatol. 2013;30(3):308-15.
18. Devillers ACA, Oranje AP. Br J Dermatol. 2006;154(4):579-85.
19. Sidbury R, Davis DM, Cohen DE, et al. J Am Acad Dermatol. 2014;71(6):327-49.
20. Evers AW, Lu Y, Duller P, et al. Br J Dermatol. 2005 Jun;152(6):1275-81.
21. Gooderham M, Lynde CW, Papp K, et al. J Cutan Med Surg. 2016;21(1):31-9.
22. Simpson EL, Bieber T, Guttman-Yassky E, et al. N Engl J Med. 2016; 375(24):2335-48.
23. Eichenfield LF, Tom WL, Chamlin SL, et al. J Am Acad Dermatol. 2014;70:338-51.

¹Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
²Division of Dermatology, St. Paul’s Hospital, Vancouver, BC, Canada

Conflicts of interest:
None Reported.

ABSTRACT
Dermatologists have within their armamentarium numerous immunosuppressant agents, both traditional and new, that are useful in the treatment of chronic cutaneous disorders such as autoimmune bullous diseases and psoriasis. It is imperative that users of these agents are aware of potential sequelae from therapy, particularly infections. In this review, we summarize the most common immunosuppressant medications currently used in dermatology, and provide recommendations for infection screening prior to initiating treatment.

Key Words:
immunosuppression, infection, TNF-α inhibitors, IL-12/23 inhibitors, IL-17 inhibitors, clinical protocol, drug therapy, skin diseases

Introduction

Psoriasis, connective tissue diseases, and autoimmune bullous diseases such as bullous pemphigoid and pemphigus are but a few examples of the dermatological indications for which immunomodulatory/immunosuppressive therapy may be indicated. Treating patients with these inflammatory cutaneous diseases often involves one or more immunosuppressive agents, either sequentially or in combination, which increases the risk of infection-related morbidity and mortality. One of the main safety concerns for the dermatologist prior to initiating therapy is the risk of infection. Risk factors for infection include age, medical comorbidities, travel history, location of residence, occupation, as well as the type, duration and extent of immunosuppression. Although pretreatment infection-testing guidelines exist for the disciplines of gastroenterology, hepatology, rheumatology, and transplant medicine, no specific guidelines have been developed for the dermatologist wishing to begin immunosuppressive therapy. This discussion is timely and of interest within the dermatology literature, as multiple publications have emerged within the last 5 years.^1-3 The dermatologist has a therapeutic armamentarium of immunosuppressive drugs including traditional therapies such as systemic corticosteroids, methotrexate, cyclosporine, azathioprine, mycophenolate mofetil as well as novel therapeutics known as biologics. Within the last decade or so there has been an emergence of novel biologic therapeutics including inhibitors of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, CD20, p40 subunit of IL-12/23, and more recently IL-17. Herein, we discuss the current pre-treatment infection guidelines for the dermatologist prior to beginning immunosuppressive therapy.

Non-biologic immunosuppressive therapy

The non-biologic immunosuppressive therapies that will be discussed are corticosteroids, methotrexate, azathioprine, cyclosporine and mycophenolate mofetil (Table 1). Since their introduction in the 1950s, corticosteroids have revolutionized the management of inflammatory diseases.⁴ Corticosteroids are among the oldest immunosuppressants; their mechanism of action is through inhibition of gene transcription and downregulation of secreted inflammatory cytokines.^5,6 The risk of infection with corticosteroid use depends upon the patient’s underlying disease state, duration, dose and route of administration.⁷ A lower dose of corticosteroids as well as a shorter duration are associated with a reduction in infectious complications.⁸ Corticosteroid use in combination with other immunosuppressive agents, such as methotrexate or azathioprine, increases the risk of serious infections as evidenced in inflammatory bowel disease and rheumatoid arthritis.⁹ However, given the short half-life of systemic corticosteroids (e.g., prednisone plasma half-life is 60 minutes, prednisolone plasma half-life is 115-212 minutes), it is reasonable to start these medications, if needed, while awaiting infection screening results.

Azathioprine and its derivative 6-mercatopurine are structurally similar to the endogenous purines adenine and guanine. The exact mechanism of action of this immunosuppressive agent is unknown, however it is thought that the structural similarity to endogenous purines allows it to be incorporated into DNA and RNA with subsequent inhibition of purine metabolism and cell division. Azathioprine use is associated with increased bacterial, fungal and viral infections.¹⁰ Prior to initiating azathioprine, the dermatologist should ascertain whether the patient has been immunized or previously infected with varicella zoster virus and if not, immunization prior to commencing immunosuppression should be recommended.¹⁰ Furthermore, azathioprine in combination with prednisolone is associated with an increased risk of infection which can be fatal in the elderly.¹¹

Methotrexate is a potent competitive inhibitor of dihydrofolate reductase and a partially reversible inhibitor of thymidylate synthetase, which ultimately acts by inhibiting purine synthesis. However, the definitive mechanism of action of methotrexate is, to date, incompletely understood, as novel modes of action continue to be published; most recently its role as a Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway inhibitor has been described.¹² In patients receiving long-term treatment with methotrexate, hepatotoxicity is an important consideration and patients should be screened for hepatitis B and C infection prior to initiating treatment. In addition, untreated chronic tuberculosis and active tuberculosis infections are contraindications to treating with methotrexate.

Cyclosporine is postulated to act by inhibition of the intracellular enzyme calcineurin, resulting in reduced activity of the transcription factor nuclear factor of activated T-cells (NFAT-1). With decreased NFAT-1 activity, the transcription of a number of downstream cytokine genes, most notably IL-2, are suppressed. Furthermore, impaired production of IL-2 leads to a decline in the number of activated T-cells within the epidermis. Thus, cyclosporine results in decreased functional T-cell mediated immunity, leading to increased susceptibility to cytosolic microorganisms, including atypical Mycobacterium, and viruses.^13,14

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase (IMPDH). Inhibition of this critical enzyme, IMPDH, subsequently deprives T- and B-cells of purine metabolites necessary for growth and replication. The net effect is selective immunosuppression. MMF is associated with an increased risk of infection especially when doses in excess of 2 g daily are used.^15,16 Serious infections are most common in renal and cardiac (2%) and hepatic (5%) transplant patients at doses of 2-3 g daily. Viral (herpes zoster, herpes simplex), bacterial, atypical mycobacterial and fungal infections have been reported in the literature.^17-20

Biologic Immunosuppressive Therapy

The biologics account for a relatively novel class of medications refered to as specialty drugs or specialty pharmaceuticals.²¹ Biologics are derived from living cells and are administered by injection, infusion or oral route, and are used to treat a variety of rare conditions. Biologic immunosuppressive therapies include TNF-α inhibitors (infliximab, adalimumab, etanercept), IL-12/23 inhibitors (ustekinumab), CD20 inhibitors (rituximab) and most recently the IL-17 pathway inhibitors (secukinumab, ixekizumab, brodalumab) (Table 2). Given the relative success of TNF-α inhibitors and ustekinumab in the treatment of psoriasis, there has been an emergence of biologics targeting various other cytokines. Inhibitors of IL-17 are the latest wave of therapeutics developed for the treatment of psoriasis and psoriatic arthritis, which deplete the Th17 population of T-cells. Other types of IL-17 inhibitors are currently in various phases of clinical trials for psoriasis and psoriatic arthritis.²² The clinical trials for these agents are currently ongoing and data pertaining to incidence and type of infections have not yet been published.

Rituximab, a biologic that targets the B-cell surface antigen CD20, can be used in several dermatologic conditions including pemphigus vulgaris. Rituximab became the first monoclonal antibody approved by the US FDA for the treatment of cancer. Since rituximab depletes CD20+ B-cells, it should not be administered to patients with active infections. Live vaccines should not be given to patients taking rituximab, and recombinant or killed vaccines should be given at least 4 weeks prior to initiating treatment. Patients should undergo screening for active and latent infections. Rituximab has been associated in particular with reactivation of hepatitis B virus (HBV).²³ The time from last rituximab dose to reactivation of HBV was 3 months, although 29% occurred >6 months after last rituximab. Patients with previous exposure to HBV should be screened prior to initiating rituximab. Carriers should be closely monitored for clinical and laboratory signs of infection as reactivation may lead to liver failure and death in the months following therapy. There is an argument for the consideration of prophylactic treatment in selected patients.²⁴ Reactivation of the JC virus (a type of human polyomavirus), leading to progressive multifocal leukoencephalopathy (PML) has also been associated with rituximab treatment.²⁵ Among human immunodeficiency virus (HIV)-negative patients, the median time to diagnosis of PML was 5.5 months following the last dose of rituximab and a 90% fatality was reported. These data warrant vigilant monitoring for new onset neurologic findings during and after the course of treatment.

Pretreatment Infection Workup

Recent publications within the dermatology literature have provided recommendations for an infection workup for the dermatologist prior to initiating immunosuppressive agents.^2,3 In general, the suggested steps apply to all immunosuppressants, whether non-biologic or biologic. Table 3 provides a summary of these and our recommendations.

Although the morbidity and mortality from infectious complications can be significant, careful patient selection and monitoring can mitigate risk and reduce potential harm. General recommendations include conducting a thorough history and physical exam, with particular focus on country of birth and residence, travel history, sexual and social risk factors and exposure to sick contacts. Vaccination records should be reviewed and, if feasible, age-appropriate vaccinations should be updated prior to initiating immunosuppressive therapy. Patients should be educated on the importance of general hygiene (i.e., handwashing), signs and symptoms of early infection and when they should seek urgent medical care. Likewise, the dermatologist should be vigilant for early signs and symptoms of infection, and have a low threshold to treat bacterial, fungal and viral illness. Physicians should assess patients at each visit for impetiginization and treat appropriately.

All patients should undergo HIV, HBV, and hepatitis C virus (HCV) testing. Furthermore, testing and diagnosis of tuberculosis should be undertaken as per Centers for Disease Control and Prevention (CDC) and Health Canada recommendations and CDC: http://www.cdc.gov/tb/topic/testing/).
Testing for parasitic infections, particularly Strongyloides stercoralis (S. stercoralis) should be considered and done on an individualized basis. Infection with S. stercoralis is usually chronic and asymptomatic in immunocompetent patients and may persist undetected for many years. In immunosuppressed patients, strongyloidiasis can cause hyperinfection and dessimination and carries a high mortality rate. It is reasonable to screen those who have resided in an endemic area for a prolonged period even if it was in the distant past (i.e., southeastern United States and subtropical areas, Europe) and those who possess other risk factors (i.e., occupation, activities). Unexplained hypereosinophilia should also trigger the physician to screen for Strongyloides. Conversely, the physician should be mindful that prolonged corticosteroid use can suppress hypereosinophilia. Stool microscopy for ova and parasites is currently the gold standard for diagnosis, however, up to seven collections may be required in order to reach a sensitivity of 100%.²⁶ A single stool sample collection has a low sensitivity of 30-75%.^27,28 Sensitivity for the enzyme-linked immunosorbent assay (ELISA) for S. stercoralis serology is 83-93% with 95-97% specificity.²⁹

Conclusion

We have provided an overview of some of the major immunosuppressant drugs used in dermatology and have presented a summary of recommendations prior to initiating these medications (Table 3). Regardless of the immunosuppressive agent used, the type of infections that the dermatologist needs to screen for and prevent are similar. Overall, the risk of infection is likely to be directly proportional to the dose and duration of immunosuppressant therapy.

References

1. Keith PJ, Wetter DA, Wilson JW, et al. Evidence-based guidelines for laboratory screening for infectious diseases before initiation of systemic immunosuppressive agents in patients with autoimmune bullous dermatoses. Br J Dermatol. 2014 Dec;171(6):1307-17.
2. Lehman JS, Wetter DA, Davis MD, et al. Anticipating and preventing infection in patients treated with immunosuppressive medications for dermatologic indications: a dermatologist’s checklist. J Am Acad Dermatol. 2014 Oct; 71(4):e125-6.
3. Lehman JS, Murrell DF, Camilleri MJ, et al. Infection and infection prevention in patients treated with immunosuppressive medications for autoimmune bullous disorders. Dermatol Clin. 2011 Oct;29(4):591-8.
4. Hench PS, Kendall EC, Slocumb CH, et al. Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch Intern Med (Chic). 1950 Apr;85(4):545-666.
5. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med. 2005 Oct 20;353(16):1711-23.
6. Buttgereit F, Straub RH, Wehling M, et al. Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action. Arthritis Rheum. 2004 Nov;50(11):3408-17.
7. Cutolo M, Seriolo B, Pizzorni C, et al. Use of glucocorticoids and risk of infections. Autoimmun Rev. 2008 Dec;8(2):153-5.
8. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis. 1989 Nov-Dec;11(6):954-63.
9. Stein RB, Hanauer SB. Comparative tolerability of treatments for inflammatory bowel disease. Drug Saf. 2000 Nov;23(5):429-48.
10. Meggitt SJ, Anstey AV, Mohd Mustapa MF, et al. British Association of Dermatologists’ guidelines for the safe and effective prescribing of azathioprine 2011. Br J Dermatol. 2011 Oct;165(4):711-34.
11. Wojnarowska F, Kirtschig G, Highet AS, et al. British Association of Dermatologists. Guidelines for the management of bullous pemphigoid. Br J Dermatol. 2002 Aug;147(2):214-21.
12. Thomas S, Fisher KH, Snowden JA, et al. Methotrexate Is a JAK/STAT Pathway Inhibitor. PLoS One. 2015 Jul 1;10(7):e0130078.
13. Amor KT, Ryan C, Menter A. The use of cyclosporine in dermatology: part I. J Am Acad Dermatol. 2010 Dec;63(6):925-46; quiz 47-8.
14. Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: part II. J Am Acad Dermatol. 2010 Dec;63(6):949-72; quiz 73-4.
15. Beissert S, Mimouni D, Kanwar AJ, et al. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebocontrolled trial. J Invest Dermatol. 2010 Aug;130(8):2041-8.
16. Powell AM, Albert S, Al Fares S, et al. An evaluation of the usefulness of mycophenolate mofetil in pemphigus. Br J Dermatol. 2003 Jul;149(1):138-45.
17. Murray ML, Cohen JB. Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol. 2007 Jan;32(1):23-7.
18. Benez A, Fierlbeck G. Successful long-term treatment of severe atopic dermatitis with mycophenolate mofetil. Br J Dermatol. 2001 Mar;144(3):638-9.
19. Rowin J, Amato AA, Deisher N, et al. Mycophenolate mofetil in dermatomyositis: is it safe? Neurology. 2006 Apr 25;66(8):1245-7.
20. Saha M, Black MM, Groves RW. Risk of herpes zoster infection in patients with pemphigus on mycophenolate mofetil. Br J Dermatol. 2008 Nov;159(5):1212-3.
21. Gleason PP, Alexander GC, Starner CI, et al. Health plan utilization and costs of specialty drugs within 4 chronic conditions. J Manag Care Pharm. 2013 Sep;19(7):542-8.
22. Mease PJ. Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol. 2015 Mar;27(2):127-33.
23. Evens AM, Jovanovic BD, Su YC, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011 May;22(5):1170-80.
24. Leung C, Tsoi E, Burns G, et al. An argument for the universal prophylaxis of hepatitis B infection in patients receiving rituximab: a 7-year institutional experience of hepatitis screening. Oncologist. 2011;16(5):579-84.
25. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009 May 14;113(20):4834-40.
26. Sarubbi FA. Hyperinfection with Strongyloides during treatment of pemphigus vulgaris. Arch Dermatol. 1987 Jul;123(7):864-5.
27. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis. 2001 Oct 1;33(7):1040-7.
28. Cartwright CP. Utility of multiple-stool-specimen ova and parasite examinations in a high-prevalence setting. J Clin Microbiol. 1999 Aug;37(8):2408-11.
29. Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep. 2000 Oct;49(RR-10):1-125, CE1-7.

Introduction

Hand dermatitis (HD) can have a significant impact on quality of life of those affected. It may interfere with activities both at work and in the home and can be associated with social and psychological distress.^1,2 The chronic form, chronic hand dermatitis (CHD) affects up to 10% of the population, which can have a considerable societal impact.² Canadian Guidelines for the management of chronic hand dermatitis have been published to help guide management of this burdensome condition.³ This article provides helpful practical guidance for the general practitioner in the management of patients with HD.

Abbreviations: CHD – chronic hand dermatitis; ENT – ear, nose, and throat; HD – hand dermatitis; KOH – potassium hydroxide; QoL – quality of life; TCI – topical calcineurin inhibitors; TCS – topical corticosteroid(s)

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 exposure to irritants? Frequent handwashing?
• Do a skin scraping for fungal KOH and culture to rule out tinea manuum as needed.

Figure 1.
Examples of hand dermatitis(HD)

Determining if HD is Acute or Chronic

Figure 2.
Establish diagnosis of acute hand dermatitis and chronic hand dermatitis (CHD). HD – hand dermatitis

• It is important to first differentiate between acute and chronic forms of HD, as the treatment options may vary.
• Acute HD lasts less than 3 months or occurs only once in a calendar year.
• CHD lasts for at least 3 months and/or patients experience at least 2 relapses in a calendar year.

TIP: Could This Be Tinea?

• Check the feet for signs of tinea pedis and onychomycosis.
• Look for an active border suggestive of tinea.
• Take a skin scraping for KOH microscopy and culture.

TIP: Could This Be Psoriasis?

• Check the feet, scalp, elbows, knees, gluteal cleft and umbilicus for signs of psoriasis.
• Check the nails for signs of psoriasis: pitting, onycholysis, subungual hyperkeratosis, splinter hemorrhages, salmon patches (oil drops).

Prevention, Avoidance and Patient Education

• Every patient with HD, whether acute or chronic, should protect their hands and avoid irritants and exacerbating factors.
• Avoid wet work, frequent hand washing and alcohol-based hand sanitizers.
• Gloves should be worn to protect the hands: cotton gloves at home, or during the night; gel padded gloves for friction and protective gloves for wet work and irritant exposure.
• The following tips are provided for patients on what to use, what to avoid and helpful common practices.

Assessing and Encouraging Patient Adherence

• Ask patients to bring products and prescriptions to follow up appointments to assess usage.
• More frequent patient follow up visits improve adherence.
• Provide education on the disease, treatment options and potential side effects of therapy.
• Choose treatment in agreement with the patient.
• Suggest joining a support group or organization, such as the Eczema society of Canada ( https://eczemahelp.ca/).

Emollient Therapy

• All patients with HD should use a bland, rich emollient to help restore the skin barrier, and apply frequently throughout the day.
• Regular application may prevent itching and reduce the number of flares.
• For hyperkeratotic eczema, patients should use an emollient with keratolytic agent (salicylic acid 10-20% or urea 5-10%).
• Unscented petroleum jelly is inexpensive and helpful for many patients.

Management of Acute HD

• It is important to make a diagnosis of acute HD so that treatment can be started as quickly as possible to maximize the outcome and prevent chronic involvement.
• Patients with HD should be adequately counselled on prevention and avoidance strategies.
• Avoidance of irritants, potential allergens and regular use of emollients is essential.
• Early treatment includes control of flares with a potent or super-potent topical corticosteroid (TCS) applied twice daily. For example, clobetasol propionate 0.05% ointment applied twice daily is generally effective in acute flares.
• For less severe flares, consider betamethasone valerate 0.1% ointment applied twice daily until controlled.
• In more severe cases, systemic steroids (prednisone, intramuscular triamcinolone) should be considered. Prednisone starting at 40-50 mg orally once a day and tapering over three weeks is an effective treatment course.
• Avoid short courses of prednisone as the condition may flare again, so a tapering dose is advised.
• Look for signs of infection and treat concomitantly.
• Try to identify any allergen exposures and recommend avoidance. If allergy is suspected, the patient should be referred for patch testing.
• Once controlled, consider maintenance therapy with topical calcineurin inhibitors (TCIs), such as tacrolimus 0.1% ointment twice daily when necessary, or twice weekly as maintenance therapy.

Figure 3.
Severity-based treatment algorithm for the management of hand dermatitis (HD). CS – corticosteroid; TCS – topical corticosteroid

QoL Consideration

• Patients with mild or moderate CHD who have a significant impact on QoL should be managed as severe CHD.

Did You Know?

• Hydrocortisone topical agents should not be recommended for most cases of HD because it is rarely effective and patients may become sensitized.
• Hydrocortisone is responsible for the majority of allergies to topical steroid products.

Management of Chronic HD

• The treatment plan for CHD depends on whether it is mild, moderate or severe.

Management of Mild CHD

• Patients with mild CHD should be educated on proper prevention and avoidance strategies as outlined earlier.
• Regular emollient therapy should be used to restore and maintain the skin barrier.
• TCS therapy should be initiated with betamethasone valerate 0.1% ointment twice daily for 4-8 weeks.
• If not responding, adherence to the treatment plan should be assessed. Ask the patient to bring medication to follow up appointment to assess amount of product actually used.
• The patient can then be counselled on proper use of the product and provide support for ongoing management.
• If not responding with an adequate trial, a higher potency TCS, such as clobetasol priopionate 0.05% ointment should be prescribed as next line therapy. Reassess after 2 weeks. If not responding to an adequate trial of a potent or super potent TCS, the patient should be considered to have moderate CHD.

Figure 4.
Treatment algorithm for the management of mild chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

TIP: Always assess adherence, reconsider the diagnosis and rule out contact allergens, concomitant infection or colonization when patients do not respond to therapy.

Management of Moderate CHD

• In addition to regular use of emollients, patients with a diagnosis of moderate CHD should be given a 4-8 week trial of a moderate TCS, such as betamethasone valerate 0.1% ointment, or a super potent TCS, clobetasol propionate 0.05% ointment for a 2-week trial. If improved, the patient can continue this as necessary, for control of the condition.
• Another option is maintenance with a TCI, such as tacrolimus 0.1% ointment twice a day as needed, or twice weekly for maintenance. If not improved, reconsider the diagnosis and assess the patient for adherence.
• If a diagnosis of moderate CHD is confirmed, consider treating the patient with a course of phototherapy, if accessible. If unavailable or the patient does not respond, consider treating as severe CHD.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 5.
Treatment algorithm for the management of moderate chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Safety Tip

When patients show signs of adverse effects to TCS, including
atrophy or telangiectasias or they cannot tolerate topical steroid
use, consider TCI (tacrolimus ointment 0.1%) as a non-steroid
topical therapy option for treatment and maintenance.

When to Refer

• Patients with CHD should be referred to a dermatologist when:
  • They may require patch testing
  • They are not responding to therapy
  • Condition is worsening instead of improving
  • Require phototherapy

Management of Severe CHD

• Patients who are diagnosed with severe CHD, patients with mild to moderate CHD who have failed an adequate trial on therapy, or patients who have a significant impact on the QoL, should be treated as having severe CHD.
• Treatment should be initiated with a potent or super-potent TCS, such as clobetasol propionate 0.05% ointment twice a day for 4-8 weeks (2 weeks on dorsal hands if super potent). If improved, patients may continue to use on an as needed basis, or switch to a TCI for ongoing maintenance therapy.
• Patients should be reassessed at 4-8 weeks. If they are not responding to therapy, consider adherence and review proper care.
• A course of phototherapy may also be considered if available.
• Treatment with oral alitretinoin (30 mg orally, once a day) is the next line of therapy based on best available evidence.⁴ Alitretinoin should be prescribed by those who are comfortable with prescribing retinoids.
• As with all retinoids, caution should be used in females of child bearing potential due to teratogenic potential. Monitoring of therapy with regular blood tests for hepatotoxicity and alterations in lipid profile is also recommended.
• If the patient responds to therapy, it should be continued for 3-6 months and reassessed at that time. Patients may discontinue therapy at this point, and continue with ongoing maintenance with topical therapy. If, in the future, they experience a flare, they can be retreated with alitretinoin.⁵
• If a patient does not respond to 12 weeks of alitretinoin, they should be referred for confirmation of diagnosis and other treatment options, which would include treatment with immunosuppressive therapy such as cyclosporine, methotrexate, mycophenolate mofetil or azathioprine.

*Ensure patient education and check compliance. Consider reassessment to rule out infection and infestation, or consider differential diagnosis.

Figure 6.
Treatment algorithm for the management of severe chronic hand dermatitis (HD). CHD – chronic hand dermatitis; TCS – topical corticosteroid

Conclusion

HD can have a significant burden on the patient with an impact on
QoL. Early diagnosis of acute or chronic HD is important for optimal
management. Other conditions such as tinea manuum and psoriasis
need to be ruled out and managed appropriately. Once a diagnosis of
HD is confirmed, treatment depends on the severity of the disease.
A treatment algorithm has been developed to assist the general
practitioner to make a diagnosis and either refer or treat accordingly.
Whichever treatment option is prescribed, all patients should be
educated on emollient therapy, hand protection and avoidance of
irritants or allergens, which may be contributing to their disease.

References

1. Diepgen TL, Agner T, Aberer W, et al. Management of chronic hand eczema. Contact Dermatitis 2007;57:203-10, doi:10.1111/j.1600- 0536.2007.01179.x.
2. Agner T. Hand eczema. In: Johansen JD, Frosch PJ, Lepoittevin J-P, editors. Contact dermatitis. 5th ed. Berlin: Springer-Verlag; 2011. p. 395-406
3. Lynde C, Guenther L, Diepgen TL, Sasseville D, Poulin Y, Gulliver W, Agner T, Barber K, Bissonnette R, Ho V, Shear NH, and Toole J. Canadian Hand Dermatitis Management Guidelines. J Cut Med Surg 2010; 14(6): 267-284
4. Ruzicka T, Lynde CW, Jemec GB, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebocontrolled, multicentre trial. Br J Dermatol 2008;158:808-17, doi:10.1111/j.1365- 2133.2008.08487.x.
5. Bissonnette R, Worm M, Gerlach B, et al. Successful retreatment with alitretinoin in patients with relapsed chronic hand eczema. Br J Dermatol 2009;162:420-6, doi:10.1111/j.1365-2133.2009.09572.x.
6. Veien NK, Larsen P, Thestrup-Pedersen K, and Schou G. Long-term, intermittent treatment of chronic hand eczema with mometasone furoate British Journal of Dermatology Volume 140( 5): 882-886, May 1999
7. Krejci-Manwaring J, McCarty MA, Camacho F, Manuel J, Hartle J, Fleischer A Jr and Feldman SR: Topical tacrolimus 0.1% improves symptoms of hand dermatitis in patients treated with a prednisone taper. J Drugs Dermatol. 7:643-646. 2008. PubMed/NCBI
8. Thestrup-Pedersen K, Andersen KE, Menne T, and Veien NK. Treatment of hyperkeratotic dermatitis of the palms (eczema keratoticum) with oral acitretin. A single blind placebo controlled study. Acta Derm Venereol 2001; 81: 353-355
9. Granlund H, Erkko P , Eriksson E , and Reitamo S. Comparison of cyclosporine and topical betamethasone-17,21-dipropionate in the treatment of severe chronic hand eczema. Acta Dermato-venereologica [1996, 76(5):371-376]