Patient Preferences in the Treatment of Moderate-to-severe Atopic Dermatitis.

Atopic dermatitis is a chronic, inflammatory skin disease. A variety of systemic treatments are available for patients with moderate-to-severe atopic dermatitis. The efficacy, safety and administration profile of these treatments vary, and determining the optimal treatment strategy may require weighing the benefits and drawbacks of therapies with diverse characteristics. This study used an online discrete choice experiment survey to investigate treatment preferences among adults with atopic dermatitis from Denmark, France, the UK, or Canada. Participants were identified through existing online panels. The survey included questions regarding different treatment attributes, defined based on currently approved treatments for moderate to severe atopic dermatitis. Treatment preferences were measured as the relative importance of different treatment attributes. A total of 713 respondents met the inclusion criteria and completed the survey. The discrete choice experiment identified a significant preference for avoiding the risk of severe adverse events, and for oral pill every day compared with biweekly injections. The time to full effect was not rated as being important. These findings suggest that patients with moderate-to-severe atopic dermatitis prioritize safety as most important, followed by ease of administration in their treatment preferences, while time to full effect and monitoring requirements were the least important attributes.

Combining treat-to-target principles and shared decision-making: International expert consensus-based recommendations with a novel concept for minimal disease activity criteria in atopic dermatitis.

BACKGROUND: Current treat-to-target recommendations for atopic dermatitis (AD) may not include high enough treatment targets and do not fully consider patient needs. OBJECTIVE: To develop recommendations for optimized AD management, including disease severity assessments, treatment goals and targets, and guidance for treatment escalation/modification. METHODS: An international group of expert dermatologists drafted a series of recommendations for AD management using insights from a global patient study and 87 expert dermatologists from 44 countries. Experts voted on recommendations using a modified eDelphi voting process. RESULTS: The Aiming High in Eczema/Atopic Dermatitis (AHEAD) recommendations establish a novel approach to AD management, incorporating shared decision-making and a concept for minimal disease activity (MDA). Consensus (≥70% agreement) was reached for all recommendations in 1 round of voting; strong consensus (≥90% agreement) was reached for 30/34 recommendations. In the AHEAD approach, patients select their most troublesome AD feature(s); the clinician chooses a corresponding patient-reported severity measure and objective severity measure. Treatment targets are chosen from a list of 'moderate' and 'optimal' targets, with achievement of 'optimal' targets defined as MDA. CONCLUSIONS: Patient and expert insights led to the development of AHEAD recommendations, which establish a novel approach to AD management. Patients were not involved in the eDelphi voting process used to generate consensus on each recommendation. However, patient perspectives were captured in a global, qualitative patient research study that was considered by the experts in their initial drafting of the recommendations.

Canalicular obstruction associated with dupilumab.

PURPOSE: Dupilumab is a novel treatment for severe atopic dermatitis and is associated with a range of ocular complications such as blepharoconjunctivitis, keratitis, cicatricial ectropion and punctal stenosis. METHODS: We report 4 patients with canalicular obstruction in association with dupilumab therapy, and we describe their treatment and outcomes in each case. RESULTS: Canalicular obstruction was diagnosed by an oculoplastic consultant between 3 years and 3 months and 4 years and 9 months after the commencement of dupilumab therapy. Case 1 underwent nasolacrimal intubation, case 2 was treated conservatively, and case 4 underwent endonasal dacryocystorhinostomy and these patients' symptoms resolved. Unfortunately, in case 3 despite endonasal dacryocystorhinostomy with stenting they remained symptomatic. CONCLUSION: This case series adds to the growing number of ocular complications associated with dupilumab therapy, and there is yet an optimal treatment strategy to mitigate these complications. It is possible that simple conservative measures such as discontinuation of dupilumab and topical treatments with steroids can eventually lead to some form of recovery and recanalisation of the canalicular system. Early referral to an ophthalmologist prior to the development of canalicular obstruction to control the inflammatory ocular surface could reduce the risks of cicatricial sequelae from dupilumab, and temporary stenting of the canalicular system could be attempted as a method to keep the canalicular system patent, whilst the patient remained on treatment.

A Real-World Data Study on the Healthcare Resource Use for Uncontrolled Moderate-to-Severe Atopic Dermatitis in Secondary Care in the United Kingdom Prior to the Introduction of Biologic Treatment.

Background: Whilst there is international evidence around the high healthcare resource utilization (HRU) associated with atopic dermatitis (AD), there is a lack of published data from the United Kingdom (UK). Methods: A retrospective, descriptive, observational study was conducted to evaluate the burden of moderate-to-severe AD on the National Health Service (NHS) in an adult UK population treated with traditional standard of care prior to the introduction of biologics. Patients (n=59) were recruited from 6 UK NHS Hospital Trusts and observed over three years. Results: 707 dermatology clinic visits were recorded over the observation period, amounting to 6.6 visits per patient-year, most commonly for routine check-ups most of which involved dermatology consultants (n=469, 66%). Physicians were the most consulted healthcare professional (n=652, 92%); emollients were the most common treatment (n=80 courses). 174 flares requiring additional medical advice were recorded in total (1.6 per patient-year). Discussion/Conclusions: Complex treatment pathways for adult patients in the UK with moderate-to-severe AD incur considerable HRU, particularly for those patients non-responsive to systemic therapies with broad immunosuppressant action. Recent advances in biologics-based AD management could possibly have a significant positive impact on HRU through significant reduction in the number of NHS touch points identified in this study.

Perception and Experience of Biologic Therapy in Atopic Dermatitis: A Qualitative Focus Group Study of Physicians and Patients in Europe and Canada.

INTRODUCTION: The Biologics in Atopic Dermatitis: Experiences & Learnings (BADEL) project aims to improve real-life understanding of how, where, and when biologics can play a role in the treatment of atopic dermatitis (AD) from the perspective of healthcare professionals (HCPs) and patients. METHODS: Individual experiences of 24 patients with moderate-to-severe AD and who had been treated with biologic therapy (dupilumab) for ≥ 3-6 months, and 20 HCPs with a sub-specialty interest in AD were collected by means of focus groups held in Canada, Germany, France, Italy and the United Kingdom. Dupilumab was the only biologic therapy available at the time of the study. RESULTS: Most patients had suffered from AD for many years, particularly from itch and psychosocial issues, with AD negatively impacting all aspects of their life. They had experienced a long treatment journey and seen many dermatologists, enduring treatment delays and failures. They had been prescribed various therapies without long-term success. Biologics provided symptom improvement, offering many patients a near-normal quality of life. Side effects, especially conjunctivitis, were the greatest drawback, and there were a few issues with incomplete or unreliable efficacy. HCPs agreed that biologic therapy for AD in the majority of patients demonstrated rapid onset, good efficacy and tolerability, and are a viable option in patients who had exhausted all other treatment options. However, those patients who failed to sufficiently respond or developed intolerable adverse effects, particularly ocular symptoms, require alternative therapeutic options. CONCLUSION: Biologics can provide a near-normal quality of life for many patients with AD. Patients with AD who have failed conventional therapies should be offered all such novel therapies. Education and good patient-HCP communication will enable patients to manage their disease and treatment expectations. Patients and HCPs alike eagerly await alternative targeted therapies, which will offer greater choice and flexibility.

Clinical and Economic Burden of Mild-to-Moderate Atopic Dermatitis in the UK: A Propensity-Score-Matched Case-Control Study.

INTRODUCTION: The burden of mild-to-moderate atopic dermatitis (AD) in the United Kingdom (UK) is not well understood. Long-lasting AD flares may lead to systemic inflammation resulting in reversible progression from mild to more severe AD. This study aimed to assess the clinical and economic burden of mild-to-moderate AD in the UK. METHODS: AD patients were identified in the Health Improvement Network (THIN) from 2013 to 2017 and propensity score matched to non-AD controls by demographics. Patients were identified based on continuous disease activity using validated algorithms and sufficient patient status to fully validate data integrity for the entire period. Mild-to-moderate AD patients were identified by using treatment as a surrogate. Demographics, clinical characteristics and healthcare resource use (HCRU) were obtained from THIN. Literature reviews were conducted to obtain additional outcomes. A cost-of-illness model was developed to extrapolate the burden in 2017 to the UK population and in subsequent years (2018-2022). RESULTS: In 2017, the prevalence of mild-to-moderate AD in THIN was 1.28%. These patients reported higher comorbidity rates and significantly higher (p < 0.0001) HCRU, encompassing mean general practitioner visits (5.57 versus 3.59), AD-related prescriptions (5.85 versus 0.68) and total referrals (0.97 versus 0.82) versus matched non-AD controls. The model projected total HCRU and drug excess costs of €462.99M over the 5 years. The excess cost decreased to €417.35M after excluding patients on very potent topical corticosteroids, who most likely had at least moderate disease. The excess costs increased to €1.21B and €7.06B when considering comorbidity burden and productivity losses, respectively. CONCLUSION: Mild-to-moderate AD patients had higher comorbidity burden, HCRU and cost compared with matched non-AD controls. Overall, UK country-based economic burden was high given partly the high prevalence of this disease. Moreover, productivity burden and comorbidities had considerable impact on the economic burden, which further suggests the importance of optimal disease management.

Efficacy of imipenem therapy for Nocardia actinomycetomas refractory to sulfonamides.

BACKGROUND: Actinomycetomas are chronic, granulomatous, subcutaneous infections caused by actinomycetes bacteria. Despite prolonged high-dose and combination antibiotic therapies, some cases remain resistant with risks of bone and visceral involvement. OBJECTIVES: We sought to evaluate the efficacy and safety of imipenem monotherapy, and in combination with amikacin for the treatment of severe and refractory disease, and to identify the disease characteristics that might predict therapy failure with first-line sulfonamides. METHODS: A retrospective study was performed of all microbiologically confirmed cases of actinomycetomas treated since 1995 at a tertiary center for mycology. Eleven patients (Nocardia, n = 10) were treated with sulfonamide combinations (trimethoprim/sulfamethoxazole and dapsone). Eight patients (Nocardia, n = 7) refractory to previous therapies including sulfonamides received a 3-week course of either parenteral imipenem monotherapy (1.5 g daily, n = 3) or combination therapy with amikacin (1 g daily, n = 5), which was repeated at 6-month intervals. RESULTS: Eleven patients with limited disease and mean disease duration of 1.7 years responded successfully to sulfonamides after a mean treatment period of 15 months (range 6-48 months). Patients receiving imipenem had mean disease duration of 10 years, with visceral and bone involvement in 4 patients. Imipenem treatment was well tolerated, and 4 patients achieved clinical and microbiological cure after one to two courses of treatment, the others demonstrating greater than 75% clinical improvement and negative culture results. LIMITATIONS: Patient cohorts in this study were small because strict criteria for inclusion included species identification and adequate follow-up periods. The efficacy data for imipenem +/- amikacin therapy cannot be extrapolated to all Nocardia mycetomas, as the cohort treated in this study had particularly refractory infection. CONCLUSIONS: Sulfonamides are effective for limited disease of relatively short duration. Imipenem monotherapy or in combination with amikacin is well tolerated and demonstrates efficacy in severe disease refractory to sulfonamides.

Managing mycetomas.

Mycetomas are chronic, granulomatous, subcutaneous infections caused by traumatic inoculation into the skin of either the actinomycetes bacteria or the eumycetes fungi, giving rise to actinomycetomas and eumycetomas, respectively. They are endemic in the tropics afflicting mainly those of low socio-economic status and men working in agriculture. The disease is slowly progressive and can cause bone involvement, which can result in considerable disability. Late presentation is not uncommon making them notoriously difficult to manage. This article highlights the important aspects of their management and developments in drug therapy.

Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis.

The PSORS1 locus in the major histocompatibility complex region is the major genetic determinant for psoriasis vulgaris. Within the PSORS1 region reside at least three potential candidate genes for psoriasis susceptibility. Specific allelic variants of the genes HLA-Cw*6, HCR*WWCC, and CDSN*5 are strongly associated with psoriasis vulgaris and are in strong linkage disequilibrium with each other. We have genotyped the three psoriasis vulgaris susceptibility alleles of the PSORS1 locus in two clinical variants of psoriasis (guttate psoriasis and palmoplantar pustulosis) to study whether PSORS1 is also involved in the pathogenesis of these variants. We also asked whether these two clinical subgroups could help us to distinguish the causative gene within the high-risk PSORS1 haplotype. The association of guttate psoriasis with the three PSORS1 susceptibility alleles was similar and even stronger than seen with psoriasis vulgaris. Palmoplantar pustulosis, however, did not show association with any of the three candidate genes at this locus. Finally, no correlation with the age of onset for disease was observed. Our results show conclusively that psoriasis vulgaris and guttate psoriasis have a similar genetic basis for their association to PSORS1, whereas palmoplantar pustulosis appears to be a distinct disorder.

Genetic basis of psoriasis vulgaris and its pharmacogenetic potential.

Psoriasis vulgaris is one of the most prevalent T cell-mediated inflammatory diseases in humans. It is multifactorial in origin and shows polygenic inheritance. Systemic immunosuppressive therapies play an important role in management of severe disease cases but are associated with variable response and toxicity. Within the last decade there have been significant advances in our understanding of the genetic basis of this complex disease and polymorphic candidate genes have been proposed. Susceptibility gene characterization together with an explosion in knowledge of its primary immune basis will further define disease pathways involved in psoriasis pathogenesis. This holds the promise of rational design of new therapeutic agents and pharmacogenetic testing to predict responders from non-responders and those at risk of toxicity.

Microsporum spp. onychomycosis: disease presentation, risk factors and treatment responses in an urban population.

BACKGROUND: Dermatophytes are the main causative agent of all onychomycosis, but genus Microsporum is infrequent and the risk of acquiring the infection is often associated with exposure to risk factors. OBJECTIVES: To describe clinical characteristics of onychomycosis due to Microsporum onychomycosis in an urban population. METHODS: This was a retrospective analysis of the epidemiological and clinical features of 18 Microsporum onychomycosis cases of a total of 4220 of onychomycosis cases diagnosed between May 2008 and September 2011 at the tertiary referral center for mycology in Guatemala. RESULTS: Eighteen cases of Microsporum onychomycosis (M. canis, n=10; M. gypseum, n=7; M. nanum, n=1) were identified (prevalence=0.43%). Infection was limited to nails only and disease duration ranged from 1 month to 20 years (mean=6.55 years). The toenails were affected in all cases except for a single M. gypseum case of fingernail. The most common clinical presentation was distal lateral subungual onychomycosis (12/18) followed by total dystrophic onychomycosis (5/18), and superficial white onychomycosis (1/18). M. gypseum presented in 6 cases as distal lateral subungual onychomycosis and in 1 case like total dystrophic onychomycosis. Five cases (27.78%) were associated with hypertension, diabetes, and psoriasis. Treatment with terbinafine or itraconazole was effective. Two cases of M. canis distal lateral subungual onychomycosis responded to photodynamic therapy. CONCLUSION: This is the largest reported series of Microsporum onychomycosis and demonstrates such a disease in an urban population. In 27.78% of the cases risk factors for infection were associated to comorbid states. We also report the first 2 cases of successfully treated M. canis onychomycosis with photodynamic therapy and a rare case of M. canis associated dermatophytoma.

Successful treatment of Nocardia actinomycetoma with meropenem and amikacin combination therapy.

BACKGROUND: Actinomycetomas are chronic, granulomatous, subcutaneous infections caused by the traumatic inoculation of actinomycetes bacteria into the skin which produces nodular lesions with draining sinuses and discharging grains. Actinomycetomas can cause profound disability, and despite long-term chemotherapy, treatment failure is common. AIMS: We investigated the efficacy of a novel drug regimen for the treatment of a severe case of Nocardia actinomycetoma of the leg. MATERIAL AND METHODS: A 31-year-old man was treated with an initial three-week parenteral course of meropenem and amikacin combination therapy followed by long term oral sulphonamides. RESULTS: Treatment was well-tolerated with no adverse effects, and there was complete clinical and microbiological cure with no recurrence. CONCLUSION: Meropenem and amikacin combination therapy represents an important addition to the currently available treatments for actinomycetomas.

Cutaneous markers of HIV infection and progression.

Skin and mucosal diseases can be the first manifestation of asymptomatic HIV infection, may indicate advancing immunodeficiency, or may represent systemic opportunistic infections or neoplasms. Mucocutaneous diseases are highly prevalent in the HIV-infected population and multiple pathologies are common particularly with advanced immunosuppression. The dominant HIV-associated skin diseases are infectious and inflammatory and they can cause significant morbidity. Although skin cancers are less common their prognosis is often worse. Clinical presentations are often atypical and may vary depending on the level of immunosuppression. Managing skin disease in the context of advanced immunosuppression is challenging and they often respond poorly to conventional therapies. This improves with the commencement of antiretrovirals (ARVs) and immune restoration. Despite the significant decline in HIV-related skin diseases with ARVs, the drugs themselves have brought with them a range of other skin-associated problems: adverse effects, an increased risk of drug reactions, and immune reconstitution-associated skin diseases. Therefore, the burden of skin disease remains high even in the era ARVs and the aim of this review is to equip physicians managing HIV-infected patients with knowledge of the spectrum of skin disorders associated with HIV-related immunosuppression.

Epidemiology of superficial fungal infections.

Fungal infections of the skin, hair, and nails are common worldwide, and their incidence continues to increase. The principal causative agents are dermatophytes, and their geographic distribution is variable. This is reflected in the differing patterns of dermatophytoses seen in different parts of the world. The epidemiology of dermatophyte infection has changed as a result of migration, lifestyle, drug therapy, and socioeconomic conditions. This contribution discusses global patterns of dermatophyte infection and the changing epidemiology of the causative agents.

Cutaneous and mucocutaneous leishmaniasis: emerging therapies and progress in disease management.

IMPORTANCE OF THE FIELD: Cutaneous leishmaniasis (CL) is a major tropical skin disease. Its incidence continues to increase, and disease control and management are challenging. Available therapies remain inadequate and are associated with low efficacy, toxicity, difficulties with administration, or are expensive. AREAS COVERED IN THIS REVIEW: This article describes progress in the therapeutics of CL since 2006. Clinical trials have provided further evidence for the use of alternative systemic agents to first-line antimonials, an enhanced topical paromomycin preparation, the efficacy of thermotherapy, photodynamic therapy as an emerging physical therapy, and the role of immunotherapy and immunomodulators as adjuncts to chemotherapy. In addition, in vitro studies have demonstrated the anti-leishmanial effects of several drugs, which might represent potential future therapeutic agents for CL. WHAT THE READER WILL GAIN: An overview of the magnitude and complexity of this heterogenous disease, and an update on recent advances in therapeutics and future directions for new drug development. TAKE HOME MESSAGE: Drug therapy for CL must be tailored according to infective species, endemic region, and host responses; a range of different therapies and modalities is therefore required. The impetus for new drug development must continue, combination therapies need to be evaluated, and robust and comparative trials of existing agents are required to adequately assess their efficacy and tolerability.

Managing chromoblastomycosis.

Chromoblastomycosis is a subcutaneous fungal infection caused by the traumatic inoculation of the skin with pigmented saprophytic moulds. Although infection is rarely fatal, it is characteristically chronic and can be complicated by lymphatic damage and malignant transformation. Despite a variety of treatment modalities, which are often combined and include long courses of antifungals, surgical excision and destructive physical therapies, it remains one of the most difficult deep mycotic infections to eradicate.

Oral ivermectin for treatment of pediculosis capitis.

BACKGROUND: Pediculosis capitis is a highly transmissible infestation prevalent worldwide. It is an important public health problem mainly affecting children. The emergence of drug resistance and high rates of treatment failure with several topical agents makes ivermectin, an antiparasitic drug, an attractive therapeutic option for lice control. OBJECTIVE: To evaluate the efficacy and safety of oral ivermectin in the treatment of a pediatric population with pediculosis capitis. METHODS: Children with pediculosis capitis from the ages of 6 to 15 years were recruited from an indigenous community in Mexico, and were treated with a single dose of oral ivermectin at 200 µg/kg. They were treated with a second dose of ivermectin 1 week later if there was evidence of persistent infestation. RESULTS: Forty-four children (mean age, 9.8 years) with active infestation were treated. A single approximately 200-µg/kg dose of ivermectin eradicated adult lice in all children. Forty-one percent (n = 18) required a second dose because of the presence of viable nits. At the third visit, 2 weeks after commencement of treatment there was no evidence of viable nits, and there was complete resolution of excoriations in all children and minimal or no symptoms of pruritus were reported in 93% (n = 41). There were no significant adverse effects due to ivermectin administration. CONCLUSIONS: Ivermectin demonstrates high efficacy and tolerability in the treatment of pediculosis capitis in children. A significant number of children required a second dose to ensure complete eradication.

HLA-DR6 association confers increased resistance to T. rubrum onychomycosis in Mexican Mestizos.

BACKGROUND: Onychomycosis is multifactorial in origin. Studies have suggested an autosomal dominant pattern of inheritance and human leukocyte antigen DR4 (HLA-DR4) has been shown to protect against onychomycosis in an Ashkenazi Jewish population. AIM: This study investigates HLA class II association in a Mexican Mestizo population with Trichophyton rubrum onychomycosis. METHODS: This was a prospective case-control study. Mexican Mestizos with a clinical diagnosis of onychomycosis and culture positive for T. rubrum were recruited, together with age- and sex-matched controls. First-degree relatives were also investigated for onychomycosis. Case-control samples were HLA typed by polymerase chain reaction sequence-specific primer based analysis. RESULTS: Twenty-one cases and 42 controls were recruited with a mean age of 40 years (range: 18-58 years). HLA-DR6 was found in seven (33%) cases and 19 (45%) controls [P < 0.023, odds ratio (OR) = 0.088, 95% confidence interval (CI): 0.01-0.71]. Six (29%) cases and three (7%) controls had an affected child (P < 0.043, OR = 9.15, 95% CI: 1.07-78.31), and 13 (62%) cases and 12 (29%) controls had an affected first-degree relative (P < 0.02, OR = 4.0, 95% CI: 1.1-14.3). CONCLUSIONS: These results suggest that HLA-DR6 confers protection against the development of onychomycosis in a Mexican Mestizo population. Having an affected first-degree relative significantly increases the risk of onychomycosis, suggesting genetic susceptibility.

Cutaneous leishmaniasis: disease susceptibility and pharmacogenetic implications.

Cutaneous leishmaniasis is a major tropical infection of public health importance caused by a number of vector-borne Leishmania protozoa species. Evidence supports a highly complex etiology. Environmental, parasite and host factors determine pathogenesis, and result in a diverse clinical spectrum of disease. Disease susceptibility, clinical course, prognosis and therapy response are highly variable, suggesting a genetic basis. Epidemiological studies have demonstrated familial aggregation, and family and association studies have identified HLA and non-HLA gene associations. Further progress in susceptibility gene identification for leishmaniasis would require genome-wide scans and candidate gene-association studies in large cohorts. Correlation between host genotype and therapy response has important pharmacogenetic implications, especially as current therapies for leishmaniasis are inadequate and progress in new drug development has been poor.

Microsporum spp. onychomycosis: disease presentation, risk factors and treatment responses in an urban population

BACKGROUND: Dermatophytes are the main causative agent of all onychomycosis, but genus Microsporum is infrequent and the risk of acquiring the infection is often associated with exposure to risk factors. OBJECTIVES: To describe clinical characteristics of onychomycosis due to Microsporum onychomycosis in an urban population. METHODS: This was a retrospective analysis of the epidemiological and clinical features of 18Microsporum onychomycosis cases of a total of 4220 of onychomycosis cases diagnosed between May 2008 and September 2011 at the tertiary referral center for mycology in Guatemala. RESULTS: Eighteen cases of Microsporum onychomycosis (M. canis, n=10; M. gypseum, n=7; M. nanum, n=1) were identified (prevalence=0.43%). Infection was limited to nails only and disease duration ranged from 1 month to 20 years (mean=6.55 years). The toenails were affected in all cases except for a single M. gypseum case of fingernail. The most common clinical presentation was distal lateral subungual onychomycosis (12/18) followed by total dystrophic onychomycosis (5/18), and superficial white onychomycosis (1/18). M. gypseumpresented in 6 cases as distal lateral subungual onychomycosis and in 1 case like total dystrophic onychomycosis. Five cases (27.78%) were associated with hypertension, diabetes, and psoriasis. Treatment with terbinafine or itraconazole was effective. Two cases of M. canisdistal lateral subungual onychomycosis responded to photodynamic therapy. CONCLUSION: This is the largest reported series of Microsporum onychomycosis and demonstrates such a disease in an urban population. In 27.78% of the cases risk factors for infection were associated to comorbid states. We also report the first 2 cases of successfully treated M. canis onychomycosis with photodynamic therapy and a rare case of M. canis associated dermatophytoma. .