Expert consensus on the systemic treatment of atopic dermatitis in special populations.

With the increasing number of options for the treatment of moderate-to-severe atopic dermatitis, clinicians need guidance on a practical approach to selecting a systemic agent for specific patient populations. We convened an expert panel consisting of 12 members to conduct a literature review and summarize relevant data related to six scenarios of clinical interest: comorbid asthma, ocular surface disease, history of cancer, past and ongoing infections of interest (including herpes simplex virus, herpes zoster, hepatitis B, and tuberculosis), pregnancy and lactation, and the elderly. We performed a literature search and examined each clinical scenario with respect to three major categories of available systemic agents: traditional systemics (azathioprine, cyclosporine A, methotrexate, and mycophenolate mofetil), Janus kinase inhibitors (abrocitinib, baricitinib, and upadacitinib), and biologics (dupilumab, lebrikizumab, and tralokinumab). The expert panel and steering committee met virtually to review the data and discuss the drafted consensus statements. A modified Delphi process was used to arrive at a set of final consensus statements related to the systemic treatment of AD in these specific patient populations. To provide practical guidance on the choice of systemic therapy for atopic dermatitis in these six topics of clinical interest, 25 expert consensus statements and a summary of the supporting data are presented herein.

Position statement for a pragmatic approach to immunotherapeutics in patients with inflammatory skin diseases during the coronavirus disease 2019 pandemic and beyond.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel RNA virus that was declared a global pandemic on 11 March 2020. The efficiency of infection with SARS-CoV-2 is reflected by its rapid global spread. The SARS-CoV-2 pandemic has implications for patients with inflammatory skin diseases on systemic immunotherapy who may be at increased risk of infection or more severe infection. This position paper is a focused examination of current evidence considering the mechanisms of action of immunotherapeutic drugs in relation to immune response to SARS-CoV-2. We aim to provide practical guidance for dermatologists managing patients with inflammatory skin conditions on systemic therapies during the current pandemic and beyond. Considering the limited and rapidly evolving evidence, mechanisms of action of therapies, and current knowledge of SARS-CoV-2 infection, we propose that systemic immunotherapy can be continued, with special considerations for at risk patients or those presenting with symptoms.

Topical treatment of psoriasis: questionnaire results on topical therapy as long-term continuous treatment and use on specific body sites.

BACKGROUND: Currently, no formalized international consensus guidelines exist to direct optimal topical treatment including long-term treatment. OBJECTIVE: In this survey, we aim to examine if and which topicals are used in clinical practice in long-term continuous treatment of psoriasis and how topicals are used in treating specific sites of the body. METHODS: A questionnaire was distributed electronically to dermatologists from the International Psoriasis Council (IPC) representing 26 countries. RESULTS: The top three topicals used across all severities of disease were topical corticosteroids, vitamin D analogs, and potent topical corticosteroids in combination with vitamin D analogs. On locations where the skin is thin, flexural and genital psoriasis, lower potency topical corticosteroids were used, whereas on other sites, in particular in palmoplantar psoriasis, superpotent topical corticosteroids and combination vitamin D analogs/corticosteroids were used. CONCLUSIONS: It is relevant to optimize localized therapy for all severities of psoriasis reconciling disease activity (stable vs. unstable disease), localization of the lesions and the individual patient and his/her perspectives on disease control. Topical therapies are valuable treatments for classical mild disease and may have a position in some patients with more severe manifestations.

Shifting the focus - the primary role of IL-23 in psoriasis and other inflammatory disorders.

Insights into the pathophysiology of autoimmune inflammatory diseases including psoriasis have advanced considerably in recent years, and in parallel, so too have the available treatment options. Current clinical paradigms for the treatment of psoriasis have evolved to include targeted biologic therapies, starting with tumour necrosis factor-alpha (TNF-α) inhibitors and later, agents targeting interleukin (IL)-12/23 and IL-17. The most recent evidence suggests that IL-23 might be an even more potent target for the effective treatment of psoriasis and other autoimmune inflammatory disorders. This review will describe recent developments leading to the current understanding of the key role of IL-23 as a 'master regulator' of autoimmune inflammation and the clinical evidence for agents that specifically target this modulator in the context of treating psoriasis, spondyloarthropathy and inflammatory bowel disease.

Apremilast for the treatment of moderate-to-severe palmoplantar psoriasis: results from a double-blind, placebo-controlled, randomized study.

BACKGROUND: Palmoplantar psoriasis is a variant of psoriasis vulgaris which can severely impair quality of life. OBJECTIVES: The main objectives of this double-blind, placebo-controlled, randomized study were to assess the efficacy and impact on quality of life and work productivity of apremilast for the treatment of moderate-to-severe palmoplantar psoriasis. METHODS: A total of 100 patients with moderate-to-severe palmoplantar psoriasis were randomized to either apremilast 30 mg bid or placebo for 16 weeks. At Week 16, all patients received apremilast 30 mg bid until Week 32. The primary endpoint was the proportion of patients who achieved a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) of 0/1 at Week 16. RESULTS: There was no significant difference in the proportion of patients who achieved a PPPGA of 0/1 at Week 16 between patients randomized to apremilast (14%) and placebo (4%; P = 0.1595). After 32 weeks of treatment with apremilast, 24% of patients achieved a PPGA of 0/1. In addition, apremilast was superior to placebo in achieving Palmoplantar Psoriasis Area Severity Index (PPPASI) 75 (apremilast: 22%; placebo: 8%; P = 0.0499), in improving PPPASI (apremilast: -7.4 ± 7.1; placebo: -3.6 ± 5.9; P = 0.0167), Dermatology Life Quality Index score (apremilast: -4.3 ± 5.1; placebo: -0.8 ± 4.5; P = 0.0004) and in reducing activity impairment (apremilast: -11.0 ± 22.3; placebo: 2.5 ± 25.5; P = 0.0063). CONCLUSION: Despite the absence of a significant difference between apremilast and placebo in proportion of patients achieving a PPPGA of 0/1, the presence of significant differences observed for several secondary endpoints suggests that apremilast may have a role in the treatment of moderate-to-severe palmoplantar psoriasis.

Topical treatment of psoriasis: questionnaire results on topical therapy accessibility and influence of body surface area on usage.

BACKGROUND: Topical treatment of mild to moderate psoriasis is first-line treatment and exhibits varying degrees of success across patient groups. Key factors influencing treatment success are physician topical treatment choice (high efficacy, low adverse events) and strict patient adherence. Currently, no formalized, international consensus guidelines exist to direct optimal topical treatment, although many countries have national guidelines. OBJECTIVE: To describe and analyse cross-regional variations in the use and access of psoriasis topical therapies. METHODS: The study was conducted as an observational cross-sectional study. A survey was distributed to dermatologists from the International Psoriasis Council (IPC) to assess topical therapy accessibility in 26 countries and to understand how body surface area (BSA) categories guide clinical decisions on topical use. RESULTS: Variation in the availability of tars, topical retinoids, dithranol and balneotherapy was reported. The vast majority of respondents (100% and 88.4%) used topical therapy as first-line monotherapy in situations with BSA < 3% and BSA between 3% and 10%, respectively. However, with disease severity increasing to BSA > 10%, the number of respondents who prescribe topical therapy decreased considerably. In addition, combination therapy of a topical drug and a systemic drug was frequently reported when BSA measured >10%. CONCLUSION: This physician survey provides new evidence on topical access and the influence of disease severity on topical usage in an effort to improve treatment strategies on a global level.

Tofacitinib in the Treatment of Rheumatoid Arthritis and Chronic Plaque Psoriasis.

Tofacitinib is an oral immunosuppressant approved for the treatment of rheumatoid arthritis (RA) and is currently undergoing investigation (Phase III trials) for treating chronic plaque psoriasis. Tofacitinib inhibits Janus kinases (JAKs), which are essential for the signaling of multiple inflammatory pathways and have been implicated in the pathogenesis of RA and psoriasis. The efficacy and safety of tofacitinib in the treatment of RA and psoriasis have been demonstrated in Phase III trials. Across all studies, the efficacy of tofacitinib in alleviating symptoms of RA and psoriasis were superior to placebo. Moreover, treatment was generally well-tolerated, with the most frequently reported adverse events, for both RA and psoriasis, being nasopharyngitis and upper respiratory tract infection. As such, tofacitinib proves to be an effective therapeutic option for RA and a promising new therapy for psoriasis.

The prevalence of unsuspected onychomycosis and its causative organisms in a multicentre Canadian sample of 30 000 patients visiting physicians' offices.

BACKGROUND: Onychomycosis is difficult to treat and a concern for many patients. Prevalence estimates of onychomycosis in North American clinic samples have been higher than what has been reported for general populations. OBJECTIVE: A large, multicentre study was conducted to estimate the prevalence of toenail onychomycosis in the Canadian population. METHODS: Patients were recruited from the offices of three dermatologists and one family physician in Ontario, Canada. Nail samples for mycological testing were obtained from normal and abnormal-looking nails. This sample of 32 193 patients includes our previous published study of 15 000 patients. RESULTS: Abnormal nails were observed in 4350 patients. Of these, the prevalence of culture-confirmed toenail onychomycosis was estimated to be 6.7% (95% CI, 6.41-6.96%). Following sex and age adjustments for the general population, the estimated prevalence of toenail onychomycosis in Canada was 6.4% (95% CI, 6.12%-6.65%). The distribution of fungal organisms in culture-confirmed onychomycosis was 71.9% dermatophytes, 20.4% non-dermatophyte moulds and 7.6% yeasts. Toenail onychomycosis was four times more prevalent in those over the age of 60 years than below the age of 60 years. CONCLUSION: The present data highlights that onychomycosis may be a growing medical concern among ageing patients.

Identification of key research needs for topical therapy treatment of psoriasis - a consensus paper by the International Psoriasis Council.

In this age of expanding choices of therapy for psoriasis, topical therapies still play an important part in the management of patients. There are many knowledge gaps in topical therapy for psoriasis with regard to efficacy and safety as well as various combinations including topical therapy with phototherapy or with systemic agents. Councillors of the International Psoriasis Council comprised a topical therapy working group to describe these gaps in order to help direct future research endeavours. Herein, we present the results of this analysis, discuss topical agents in clinical development and the attributes of the ideal topical treatment for psoriasis.

Non-melanoma skin cancer in Canada chapter 1: introduction to the guidelines

BACKGROUND: Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma, represents the most common malignancy. OBJECTIVE: The aim of this document is to provide guidance to Canadian health care practitioners on NMSC management. METHODS: After conducting a literature review, the group developed recommendations for prevention, management, and treatment of basal cell carcinomas, squamous cell carcinomas, and actinic keratoses. These tumour types are considered separately in the accompanying articles. The Grading of Recommendations Assessment, Development and Evaluation system was used to assign strength to each recommendation. RESULTS: This introduction describes the scope and structure of the guidelines and the methods used to develop them. The epidemiology of NMSC is reviewed, as are the pathophysiologic changes occurring with damage to the skin, which lead to the formation of actinic keratoses and invasive squamous or basal cell carcinomas. CONCLUSIONS: This introduction describes the need for primary prevention and offers an overview of treatment options that are discussed in later chapters of the guidelines.(AU)

Etanercept for patients with psoriasis who did not respond or who lost their response to adalimumab or infliximab.

BACKGROUND: There is a paucity of data on the use of etanercept in patients who have previously failed a different tumour necrosis factor (TNF) alpha antagonist. OBJECTIVES: To study etanercept in patients who did not achieve a satisfactory response to adalimumab or who lost their response to adalimumab or infliximab and to explore the role of anti-adalimumab and anti-infliximab antibodies in etanercept response. METHODS: Patients with psoriasis who did not achieve a satisfactory response to adalimumab or who lost their response to adalimumab or infliximab were included. All patients received etanercept 50 mg twice a week for 12 weeks followed by 50 mg once a week for 12 more weeks. Anti-infliximab and anti-adalimumab antibodies were measured at baseline. The primary objective was to study the efficacy of etanercept using the proportion of patients who achieved a physician global assessment (PGA) of 0 or 1. RESULTS: A total of 81 patients were included. The proportion of patients who achieved a PGA of 0 or 1 after 24 weeks of etanercept was 20.0% (95% CI 4.8-35.2%) for patients who had an unsatisfactory response to adalimumab, 35.1% (95% CI 19.0-51.3%) and 35.7% (95% CI 7.0-64.4%) for patients who lost their response to adalimumab and infliximab respectively. The proportion of patients who achieved a PGA of 0 or 1 at week 24 was numerically higher for patients who had anti-adalimumab or anti-infliximab antibodies (36.5%) as compared to those without (17.2%; P = 0.08). CONCLUSIONS: Etanercept can be effective in patients with psoriasis who failed a previous TNF alpha antagonist.

Improvements in patient-reported outcomes in patients with psoriasis receiving etanercept plus topical therapies: results from REFINE.

BACKGROUND: The REFINE study examined the efficacy and safety of adding topical corticosteroid therapy to etanercept when stepping down from the initial dose of etanercept to the maintenance dose. Clinical responses were shown to be similar in patients who remained on etanercept 50 mg twice weekly (BIW) and those who received etanercept 50 mg once weekly (QW) plus topical therapies through week 24. OBJECTIVE: The purpose of this analysis was to evaluate the effect of treatment on health-related quality of life (HRQoL) for patients in REFINE. METHODS: All patients received etanercept 50 mg BIW for 12 weeks and were then randomized to etanercept 50 mg BIW or etanercept 50 mg QW plus topical corticosteroid as required to clear through week 24. HRQoL measures included the Dermatology Life Quality Index (DLQI), Treatment Satisfaction Questionnaire for Medication (TSQM) and the Economic Implications of Psoriasis Patient Questionnaire. No comparative testing was performed for this descriptive analysis. Missing data were imputed using the last observation carried forward. RESULTS: For 287 randomized patients (144 etanercept; 143 etanercept plus topical), the mean change [standard deviation (SD)] in DLQI from baseline to week 24 was 10.7 (7.8) for etanercept and 9.9 (6.9) for etanercept plus topical. Mean change (SD) in TSQM effectiveness, convenience, side-effects and global satisfaction was 27.1 (36.1), 14.8 (25.9), -0.7 (22.0) and 26.7 (32.5) for the etanercept arm and 32.5 (40.3), 18.5 (29.0), 1.3 (19.4) and 28.4 (35.9) for etanercept plus topical. Economic implications, including healthcare visits, employment status, work productivity, ability to perform daily activities and out-of-pocket expenses were similar between treatment arms. CONCLUSION: At week 24 of REFINE, measures of HRQoL were numerically similar in patients who stayed on etanercept 50 mg BIW and patients who received etanercept 50 mg QW plus topical therapies.

A Randomized, blinded assessor study to Evaluate the efFIcacy and safety of etanercept 50 mg once weekly plus as Needed topical agent vs. Etanercept 50 mg twice weekly in patients with moderate to severe plaque psoriasis (REFINE).

BACKGROUND: Topical corticosteroids are used with systemic therapies for treatment of plaque psoriasis, but data from randomized clinical trials to document efficacy of combination therapy are lacking. OBJECTIVE: To evaluate efficacy and safety of adding topical corticosteroid therapy from the time that etanercept dosage is reduced from initial label dose [50 mg twice weekly (BIW)] to maintenance dose [50 mg once weekly (QW)]. METHODS: In this phase 3b, multicentre, randomized, open-label study, patients with moderate-to-severe plaque psoriasis received etanercept 50 mg BIW for 12 weeks, and then were randomized to etanercept 50 mg BIW or 50 mg QW plus topical agent as needed to achieve static physician global assessment (sPGA) status of clear for 12 weeks. Endpoints included percentage change in Psoriasis Area and Severity Index (PASI) score from week 12 to week 24 (primary endpoint); proportion of patients achieving 50% improvement in (PASI 50), PASI 75 and PASI 90; patients achieving sPGA of clear/almost clear; and change in affected body surface area (BSA). RESULTS: Mean difference [95% confidence interval (CI)] between etanercept arm (n = 140) and etanercept plus topical arm (n = 142) in change in PASI score from week 12 to week 24 was 16.2% (-3.5%, 35.8%). PASI response rates were similar between groups. Percentage (95% CI) of patients achieving sPGA status of clear/almost clear was 40.6% (32.5%, 48.6%) and 45.8% (37.6%, 54.0%) at week 12 for patients in etanercept and etanercept plus topical arms, respectively, and 53.5% (45.3%, 61.7%) and 45.4% (37.2%, 53.6%) at week 24. Difference (95% CI) between groups in change in affected BSA from week 12 to week 24 was 4.9% (-23.4%, 33.2%). CONCLUSION: Patients who received etanercept 50 mg QW at week 12 plus as-needed topical therapy and those who stayed on etanercept 50 mg BIW maintained clinical response through week 24 with no notable differences in PASI responses.

Increased expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled trial.

BACKGROUND: Palmo-plantar pustular psoriasis (PPPP) and palmo-plantar pustulosis (PPP) are chronic skin diseases with significant impact on quality of life. OBJECTIVES: The purpose of this study was to study the efficacy of ustekinumab in PPPP and PPP and gain more knowledge on the pathophysiology and the role of the interleukin-23 (IL-23) signalling pathway in these diseases. METHODS: Thirty-three patients with either PPPP (20) or PPP (13) and seven volunteers with normal palmo-plantar skin were recruited. Patients with PPP or PPPP were randomised (1 : 1) to receive either an anti IL-12/IL-23 antibody (ustekinumab 45 mg) or placebo at day 0 and week 4 with subsequent placebo cross-over to ustekinumab at week 16. The primary endpoint was the proportion of patients randomized to ustekinumab achieving a 50% improvement in the Palmo-Plantar Pustular Area and Severity Index (PPPASI-50) as compared to placebo. Skin biopsies of the palms and soles of normal subjects and patients with PPP or PPPP were performed and analysed by RT-PCR and immunohistochemistry. RESULTS: There was no statistically significant difference in the proportion of patients randomised to ustekinumab as compared to those randomised to placebo achieving PPPASI-50 at week 16 for patients with PPPP (10%, 20%; P = 1.000) or PPP (20%, 37.5%; P = 1.000) respectively. Compared to normal subjects an 89-fold increase in IL-17A expression was found in palms/soles of patients with PPPP (P = 0.006) and a 190-fold increase for patients with PPP (P = 0.051). There were no statistically significant changes in cytokine expression at week 16 in the palms and soles of patients with PPP or PPPP. CONCLUSION: Taken together these results suggest that ustekinumab at a dose of 45 mg has limited efficacy in PPPP and PPP. IL-17A may have a more important role than IL-23 in patients with PPPP and PPP. Conclusions are limited by the small sample size of this study.

Acitretin revisited.

Acitretin over the last 20 years has proven useful in a number of dermatologic diseases. Evidence of efficacy, side-effect profile, and approach to its use will be reviewed.

Treatment of palmoplantar psoriasis with infliximab: a randomized, double-blind placebo-controlled study.

BACKGROUND: Palmoplantar psoriasis is a difficult to treat variant of plaque psoriasis. OBJECTIVE: To study the safety and efficacy of infliximab in non-pustular palmoplantar psoriasis. METHODS: Patients with non-pustular palmoplantar psoriasis affecting at least 10% of their palms and soles and with a modified palmoplantar psoriasis area and severity index (m-PPPASI) of at least eight were recruited. Patients were randomized (1:1) to receive infliximab 5 mg/kg or placebo at weeks 0, 2 and 6. Patients initially randomized to placebo received infliximab at weeks 14, 16 and 20 whereas patients randomized to infliximab received additional infliximab infusions every 8 weeks until week 22. RESULTS: Twenty four (24) patients were randomized in this study. At week 14, 33.3% and 66.7% of patients treated with infliximab achieved m-PPPASI 75 and m-PPPASI 50 respectively compared to 8.3% for both m-PPPASI 75 (P = 0.317) and m-PPPASI 50 (P = 0.009) for patients randomized to placebo. A reduction of 50.3% in the mean surface area of palms and soles affected with psoriasis was seen at week 14 in patients randomized to infliximab as compared to an increase of 14.9% in patients randomized to placebo (P = 0.009). CONCLUSIONS: This pilot study did not reach its primary endpoint of m-PPPASI 75 at week 14. However, infliximab was observed to be more efficacious than placebo in improving PPSA and with respect to the percentage of patients reaching m-PPPASI 50 at week 14. Larger and longer term studies are needed for severe patients to better assess the efficacy of infliximab in palmoplantar psoriasis.

Predictive testing of the melanocortin 1 receptor for skin cancer and photoaging.

Genetic predisposition to melanoma and nonmelanoma skin cancer extends far beyond the Fitzpatrick phenotype classification scheme. Specific alleles of the gene that codes for the malnocortin 1 receptor are predictive of skin cancer risk independent of skin type and hair color. The ability to identify high risk patients independent of the red hair phenotype may help to modify routine sun and skin monitoring behaviors. In addition, as this increased skin cancer risk is likely due to impaired UVA and UVB defence mechanisms, consideration of genetic predisposition may also be appropriate for patients undergoing psoralen + UVA (PUVA) or UVB treatments for various cutaneous disorders, such as psoriasis, eczema, and vitiligo. Testing aimed at improving prognostication may serve to limit the influence of certain risk factors.

Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double-blind, placebo-controlled phase III study.

BACKGROUND: The use of systemic calcineurin inhibitors for the treatment of patients with psoriasis is limited by toxicity, particularly nephrotoxicity. ISA247, a novel inhibitor, was effective and well tolerated in a phase II study of patients with plaque psoriasis. Therefore its efficacy was assessed in this phase III study. METHODS: 451 patients aged 18-65 years with plaque psoriasis involving at least 10% of the body surface area were randomly assigned in equal proportions to receive placebo or ISA247 at 0.2 mg/kg, 0.3 mg/kg, or 0.4 mg/kg orally twice a day in dermatology clinics. The primary endpoint was a 75% reduction in the psoriasis area and severity index (PASI 75) score at week 12. Treatment allocation was concealed from patient and physicians doing the assessments by use of sealed envelopes. The method of analysis was by modified intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00244842. FINDINGS: 107, 113, and 116 patients were assigned to the ISA247 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg groups, respectively, and 115 to the placebo group. At week 12, PASI 75 scores were achieved in the ISA247 0.2 mg/kg, 0.3 mg/kg, and 0.4 mg/kg groups by 14 (16%; 95% CI 9-24) of 105, 26 (25%; 17-24) of 111, and 44 (47%; 27-57) of 113 patients, respectively, and in the placebo group by 4 (4%; 0-8) of 113 patients. Efficacy was maintained during 24 weeks. Mild to moderate glomerular filtration rate reductions were noted in seven patients in the ISA247 0.4 mg/kg group and in one in the ISA247 0.3 mg/kg group. ISA247 blood concentrations showed a strong correlation with mean percentage reduction in PASI. INTERPRETATION: ISA247 was safe and effective in the treatment of patients with moderate to severe psoriasis during 24 weeks, with the highest dose providing the best efficacy. The strong correlation between ISA247 concentrations and efficacy might allow for accurate dosing of patients compared with existing calcineurin inhibitors.

Novel agents for intractable itch.

There exists a multitude of medical conditions that cause intractable itch, or pruritus. The successful management of this symptom depends explicitly on establishing the underlying cause. Studies have shown that drugs not traditionally used in the treatment of cutaneous disorders, such as opiate receptor antagonists, antidepressants, and antiepileptics, can provide symptomatic relief of intractable itch. These novel antipruritic agents will be explored in this review.