Recent Advancements in the Atopic Dermatitis Mechanism.

Atopic dermatitis (AD) is a recurrent, chronic, inflammatory, itchy skin disorder that affects up to 20% of the pediatric population and 10% of the adult population worldwide. Onset typically occurs early in life, and although cardinal disease features are similar across all ages, different age groups and ethnicities present distinct clinical characteristics. The disease imposes a significant burden in all health-related quality of life domains, both in children and adults, and a substantial economic cost both at individual and national levels. The pathophysiology of AD includes a complex and multifaceted interplay between the impaired dysfunctional epidermal barrier, genetic predisposition, and environmental contributors, such as chemical and/or biological pollutants and allergens, in the context of dysregulated TH2 and TH17 skewed immune response. Regarding the genetic component, the loss of function mutations encoding structural proteins such as filaggrin, a fundamental epidermal protein, and the more recently identified variations in the epidermal differentiation complex are well-established determinants resulting in an impaired skin barrier in AD. More recently, epigenetic factors have facilitated AD development, including the dysbiotic skin microbiome and the effect of the external exposome, combined with dietary disorders. Notably, the interleukin (IL)-31 network, comprising several cell types, including macrophages, basophils, and the generated cytokines involved in the pathogenesis of itch in AD, has recently been explored. Unraveling the specific AD endotypes, highlighting the implicated molecular pathogenetic mechanisms of clinically relevant AD phenotypes, has emerged as a crucial step toward targeted therapies for personalized treatment in AD patients. This review aims to present state-of-the-art knowledge regarding the multifactorial and interactive pathophysiological mechanisms in AD.

Hair Dyes Sensitization and Cross-Reactions: Challenges and Solutions: A Systematic Review of Hair Dye Allergens' Prevalence.

Widespread use of oxidative hair dyes during the past decades has raised questions on the potential allergy reactions and their management, as well as prevention measures for both professionals and consumers. Allergic contact dermatitis can be elicited by various hair dye-related allergens, though the main problem remains with p-phenylenediamine and related aromatic amines. If allergy is suspected, patch testing identifies the responsible hapten. Individuals sensitized to specific permanent hair dyes substances should avoid the exposure to these chemicals, but also be aware of possible cross-sensitization to other similar compounds. Cross-reactions detected in patch-tested populations indicate that one cannot safely use alternatives, although cross-reactivity is not always clinically relevant. An open application hair dye allergy self-test is recommended by manufacturers for early detection of allergy predisposition in consumers, although the lack of standardized conditions makes the efficacy of this process doubtful. Appropriate use of hand gloves, especially nitrile, is the most efficient prevention measure for professional hand eczema. In this systematic review, we focus on cross-reactions among hair dye-related allergens and make an attempt to answer some, frequently encountered by physicians, questions, while presenting the prevalence of the hair dye-related allergens.

Adalimumab-Induced Paradoxical Psoriasis Treated with Biologics Targeting the IL-17/IL-23 Axis in Patients with Hidradenitis Suppurativa.

BACKGROUND: Paradoxical psoriasis (PP) has been mainly described in patients receiving tumor necrosis factor-α (TNFα) inhibitors for inflammatory bowel disease or psoriasis vulgaris, while such data in the context of hidradenitis suppurativa (HS) are scarce. The purpose of this study was to demonstrate the course of PP and the underlying HS upon switching from adalimumab to a biologic agent targeting the interleukin (IL)-17/IL-23 axis. METHODS: The electronic medical database of the outpatient department for HS of a tertiary hospital for skin diseases was searched to identify patients with moderate-to-severe HS under treatment with adalimumab, who developed PP and were switched to biological therapy with an IL-17 or IL-23 inhibitor between February 2016 and January 2022. Disease assessment scores were evaluated at baseline, at time of PP development, as well as six and 12 months thereafter. RESULTS: Among the 83 patients who received adalimumab for the treatment of HS between February 2016 and January 2022, 10 patients (12%) developed paradoxical psoriasiform skin reactions after a median time of seven (range, 2-48) months. There were four females (40%) and six males (60%) with a median age of 42.5 (range, 33-56) years. Five patients presented with plaque psoriasis and five with palmoplantar pustulosis, while four had intertriginous and three nail involvement. In most of the patients, HS responded well to adalimumab at onset of PP. Eight patients were changed to secukinumab, one to ustekinumab, and one to risankizumab. HS further improved in all but 2 patients, one receiving secukinumab and one receiving risankizumab. In addition, all patients achieved improvement of PP. CONCLUSION: Despite the small number of patients, this study provides support that patients with adalimumab-induced PP may benefit from biologics targeting the IL-17/IL-23 axis. Further studies are needed to establish the optimal therapeutic strategy of the anti-TNFα-induced PP in the context of HS.

Intrinsic Effects of Exposome in Atopic Dermatitis: Genomics, Epigenomics and Regulatory Layers.

Atopic dermatitis (AD) or atopic eczema is an increasingly manifested inflammatory skin disorder of complex etiology which is modulated by both extrinsic and intrinsic factors. The exposome includes a person's lifetime exposures and their effects. We recently reviewed the extrinsic exposome's environmental risk factors that contribute to AD. The periods of pregnancy, infancy, and teenage years are recognized as crucial stages in the formation of AD, where the exposome leads to enduring impacts on the immune system. However, research is now focusing on the interactions between intrinsic pathways that are modulated by the extrinsic exposome, including genetic variation, epigenetic modifications, and signals, such as diet, stress, and microbiome interactions. As a result, immune dysregulation, barrier dysfunction, hormonal fluctuations, and skin microbiome dysbiosis are important factors contributing to AD development, and their in-depth understanding is crucial not only for AD treatment but also for similar inflammatory disorders.

Prevalence of adult self-reported atopic dermatitis in Greece: results from a nationwide survey

Background: Atopic dermatitis (AD) is a common chronic inflammatory skin disorder. In Greece, there is a lack of data on AD epidemiology. Objectives: The objective of the present study was to estimate the self-reported prevalence of AD and the prevalence of moderate/severe AD in the adult population in Greece. Materials & Methods: A nationwide cross-sectional survey with a structured questionnaire was conducted, between June 17th, 2021 and July 12th, 2021, using Computer Assisted Telephone Interviewing (CATI) and Computer Assisted web Interviewing (CAWI) data collection methods. Several different self-reported AD definitions, as extracted from the literature, were used. Self-reported moderate/severe atopic dermatitis was estimated using the Patient Oriented Eczema Measure (POEM). Results: More than 30,500 persons were invited to participate; among them, 3,001 were recruited for the survey. The 12-month self-reported AD prevalence in Greece ranged from 1.7% to 6.4%, while lifetime prevalence reached 11.4%. At least half of the responders who identified with AD during the last 12 months had moderate to very severe eczema. The multivariate analysis confirmed that age, atopy-related comorbidities (asthma, allergies, and rhinitis), a family history of AD, rhinitis, and asthma were factors that are independently associated with AD, irrespective of the definition used. Conclusion: The 12-month and lifetime prevalence of AD in adults in Greece ranges from 1.7% to 6.4% and 3.7% to 11.4%, respectively. At least half of the adults with AD suffer from moderate-to-severe disease. Our study is a first step in understanding AD epidemiology in Greece and may provide useful insights for healthcare decision makers.

Burden of Atopic Dermatitis in Adults in Greece: Results from a Nationwide Survey.

The objective was to describe the AD burden in terms of quality of life (QoL), sleep, social life, work productivity, and resource utilization in Greece and assess the impact of disease severity. A nationwide cross-sectional survey was conducted. The questionnaire consisted of socioeconomic factors, medical history, AD screening, AD severity, QoL, sleep difficulties, social activities, and work productivity questions. AD was defined using the UK Working Party criteria (UKWP cohort) and a patient-reported AD diagnosis from a physician (Expert Diagnosis cohort). Self-reported moderate/severe AD was estimated using the Patient-Oriented Eczema Measure (POEM). In the UKWP cohort, the AD effect on QoL was moderate/extremely large in 84.3% of moderate/severe AD (vs. 55.7% in mild; p = 0.016), while in the Expert Diagnosis cohort, it was 72.2% (vs. 22.8%; p < 0.001). Disease severity was associated with a higher impact on sleep and social activities. Overall work impairment was high in both mild (32.7%) and moderate/severe (48.5%) AD of the UKWP cohort, while among the Expert Diagnosis cohort, it was significantly higher among those with moderate/severe (31.2%) versus mild AD (11.9%; p < 0.001). The AD burden in Greece is significant, especially for those in moderate/severe AD stages. Acknowledging this burden is the first step toward applying healthcare decisions that will benefit patients and the community.

Atopic Dermatitis and Food Allergy: A Complex Interplay What We Know and What We Would Like to Learn.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense pruritus, eczematous lesions, and relapsing course. It presents with great clinical heterogeneity, while underlying pathogenetic mechanisms involve a complex interplay between a dysfunctional skin barrier, immune dysregulation, microbiome dysbiosis, genetic and environmental factors. All these interactions are shaping the landscape of AD endotypes and phenotypes. In the "era of allergy epidemic", the role of food allergy (FA) in the prevention and management of AD is a recently explored "era". Increasing evidence supports that AD predisposes to FA and not vice versa, while food allergens are presumed as one of the triggers of AD exacerbations. AD management should focus on skin care combined with topical and/or systemic treatments; however, in the presence of suspected food allergy, a thorough allergy evaluation should be performed. Food-elimination diets in food-allergic cases may have a beneficial effect on AD morbidity; however, prolonged, unnecessary diets are highly discouraged since they can lead to loss of tolerance and potentially increase the risk of IgE-mediated food allergy. Preventive AD strategies with the use of topical emollients and anti-inflammatory agents as well as early introduction of food allergens in high-risk infants seem promising in managing and preventing food allergy in AD patients. The current review aims to overview data on the complex AD/FA relationship and provide the most recent developments on whether food allergy interventions change the AD course and vice versa.

Botulinum Toxin Type A for Treatment of Forehead Hyperhidrosis: Multicenter Clinical Experience and Review from Literature.

Among the forms of idiopathic hyperhidrosis, those involving the forehead have the greatest impact on patients' quality of life, as symptoms are not very controllable and are difficult to mask for patients. Although the local injection therapy with Incobotulinum toxin type A (IncoBTX-A therapy) can be considered a rational treatment, data from the literature describing both efficacy and safety of the treatment over the long term are poor. The aim of this report is to describe the single-center experience of five patients seeking treatment, for forehead hyperhidrosis with IncoBTX-A. To evaluate the benefits, safety profile and duration of anhidrosis, patients were treated following a standardized procedure and then followed until clinical relapse. The amount of sweating was measured by gravimetric testing, the extension of hyperhidrosis area was measured through Minor's iodine starch test, and response to the treatment was evaluated using the Hyperhidrosis Disease Severity Scale (HDSS) and the Dermatology Life Quality Index (DLQI). In all treated patients, a significant anhidrotic effect was observed 4 weeks after the treatment and lasted for approximately 36 weeks. The reduction in sweat production was associated with significant amelioration of symptoms and quality of life for all treated patients. No serious side effects occurred; one patient complained of a mild transient bilateral ptosis. Although further wider studies are required, our preliminary results seem to encourage the use of IncoBTX-A in forehead hyperhidrosis.

The pharmacological treatment and management of hyperhidrosis.

INTRODUCTION: Idiopathic hyperhidrosis is a dysfunctional disorder involving eccrine sweat glands, and its impact on patients' daily quality of life is well known. Unlike some years ago, when only poor effective and safe therapeutic alternatives were available, nowadays, several emerging pharmacological active substances have gained significant space as treatment options. AREAS COVERED: The authors report on, in this narrative review, the emerging data from the literature focusing on the pharmacological treatments to draw up a drug treatment flow chart for patients with idiopathic hyperhidrosis, taking into consideration specific differences among axillary, palmoplantar, and craniofacial hyperhidrosis. EXPERT OPINION: Idiopathic hyperhidrosis, regardless of the site of involvement, remains a functional disorder that places a significant burden on patients. After balancing efficacy against adverse events, systemic therapy, although off-label for all forms of hyperhidrosis, can be an added therapeutic option for patients with insufficient response to topical treatment. Until the pathophysiological mechanisms underlying hyperhidrosis are clear and the etiological therapeutic approach becomes realistic, the greatest challenge in the therapeutic management of hyperhidrotic patients seems to be the search for the most convenient combination between different therapeutic modalities (topical and systemic agents, and botulinum toxins) to achieve long-term control of the disease symptoms.

Saliva Proteomics as Fluid Signature of Inflammatory and Immune-Mediated Skin Diseases.

Saliva is easy to access, non-invasive and a useful source of information useful for the diagnosis of serval inflammatory and immune-mediated diseases. Following the advent of genomic technologies and -omic research, studies based on saliva testing have rapidly increased and human salivary proteome has been partially characterized. As a proteomic protocol to analyze the whole saliva proteome is not currently available, the most common aim of the proteomic analysis is to discriminate between physiological and pathological conditions. The salivary proteome has been initially investigated in several diseases: oral squamous cell carcinoma and oral leukoplakia, chronic graft-versus-host disease, and Sjögren's syndrome. Otherwise, salivary proteomics studies in the dermatological field are still in the initial phase, thus the aim of this review is to collect the best research evidence on the role of saliva proteomics analysis in immune-mediated skin diseases to understand the direction of research in this field. The results of PRISMA analysis reported herein suggest that human saliva analysis could provide significant data for the diagnosis and prognosis of several immune-mediated and inflammatory skin diseases in the next future.

Cost per PASI-75 responder of calcipotriol plus betamethasone dipropionate cutaneous foam versus nonbiologic systemic therapies for the treatment of plaque psoriasis in seven European countries.

PURPOSE: To compare the short-term cost and effectiveness of calcipotriol/betamethasone dipropionate (Cal/BD) cutaneous foam against nonbiologic systemics in psoriasis patients for whom oral systemic or topical therapy is considered appropriate in seven European countries. METHODS: Matching-adjusted indirect comparisons of four-week PASI-75 responses of Cal/BD foam were performed versus 12-week responses of methotrexate, acitretin, fumaric acid esters (FAE) and 16-week responses of apremilast. Analyses took a payer perspective and included drug, physician visit and monitoring costs. RESULTS: In all countries, Cal/BD foam generated the lowest cost per responder (CPR). Against methotrexate, apremilast and acitretin, Cal/BD foam generated response for less than €190 in Italy, €195 in Portugal, €216 in Greece, £218 in the United Kingdom, €250 in Belgium, €319 in Spain, and €359 in the Netherlands. Relative to treatment with FAE, Cal/BD foam resulted in response for less than €298, €430, €382 and £262 in Belgium, the Netherlands, Spain and the United Kingdom, respectively. For Cal/BD foam, apremilast and FAE, total costs were driven by drug costs; for methotrexate and acitretin, by monitoring. CONCLUSIONS: Driven by its lower costs and high response rates, Cal/BD foam is likely to be a cost-effective option over the short-term in the investigated psoriasis population.

Incidence of anogenital warts: epidemiological risk factors and real-life impact of human papillomavirus vaccination.

Anogenital warts (AGWs) rank among the most frequent sexually transmitted infections in young adults. They are benign lesions, but they pose a significant economic cost to health care systems and a substantial psychological burden on patients, who need evidence-based counselling. Human papillomavirus (HPV) vaccination has shown very high protection rates against AGWs in clinical trials and real-world settings but vaccination coverage remains low in many countries. The aim of this review is to summarize the current evidence on the risk factors for AGW development and to present the available real-life data on the impact of HPV vaccination on AGW incidence. An increased number of lifetime sexual partners, a new sexual partner in the last 12 months, smoking, and immunosuppression have been associated with increased risk for AGWs. HPV vaccination has led to a dramatic decline in AGW incidence in populations that have achieved high vaccination rates. These conclusions can contribute to primary prevention of AGWs and evidence-based counselling of AGW patients.

Impact of vitamin D receptor gene polymorphisms on vitiligo susceptibility and clinical features in a Southeastern European Caucasian population.

An association of vitamin D receptor (VDR) polymorphisms and vitiligo has been suggested. However, previous studies have reported contradictory results while including limited data among Caucasians. The aim of this single­center study was to evaluate the effect of three common VDR gene polymorphisms (FokI, TaqI and BsmI) on susceptibility and clinical aspects of vitiligo in a Southeastern European Caucasian population. A total of 110 unrelated vitiligo cases and 509 general population controls were enrolled from October 2018 to November 2019. Genomic DNA was extracted from whole blood after de­identification and anonymization of the samples and genotyped for the selected VDR polymorphisms by the qPCR (melting curve analysis). Subgroup analysis by clinical features among subsets of patients indicated that, compared to subjects with the FokI TT genotype or T allele, carriers of the FokI CC genotype or C allele exhibited significantly decreased risk of developing vitiligo before the age of 30 [TT vs. CC: odds ratio (OR)=0.286, 95% confidence interval (CI): 0.083­0.984, P=0.041; T vs. C: OR=0.545, 95% CI: 0.313­0.948, P=0.031]. Intra­patient analysis also revealed that, compared to T allele, the presence of TaqI C allele was adversely associated with the incidence of concurrent leukotrichia (T vs. C: OR=1.874, 95% CI: 1.018­3.451, P=0.042). Comparisons between the case and control groups showed no evidence to support an association between susceptibility to vitiligo and the VDR BsmI, TaqI, and FokI polymorphisms in this cohort. Thus, the studied VDR polymorphisms might indirectly impact the clinical course and treatment decision­making despite their lack of association with vitiligo per se. Further research with larger sample sizes, especially across Caucasian individuals, should be performed to confirm these findings.

Occupational and non-occupational allergic contact dermatitis to hair dyes in Greece. A 10-year retrospective study.

BACKGROUND: Oxidative hair dyes are an important source of chemical exposure and a major risk factor for the development of occupational and non-occupational allergic contact dermatitis (ACD) worldwide. OBJECTIVE: To identify the frequency of common allergens associated with occupational and non-occupational ACD to hair dyes during the last 10 years, in Greece. METHODS: We retrospectively reviewed the medical records of patients with suspected ACD to hair dyes from 2010-2019. All patients with patch-test-confirmed ACD to hair dyes were evaluated. RESULTS: Out of 501 patients with suspected ACD to hair dyes, 362 had at least one positive reaction to hair dye allergens (62.4% were customers and 37.6% were hairdressers). The mean age of customers and hairdressers was 43.8 years and 30.8 years, respectively. Of the customers, 58.9% were exposed to dyes for >10 years and 61% of hairdressers for <5 years. The most common site of ACD among customers was the scalp (85%) and among hairdressers the hands (90%). p-Phenylenediamine (PPD) was the most common contact allergen (52.2%), followed by toluene-2,5-diamine, p-aminophenol, m-aminophenol, and ammonium persulfate. CONCLUSIONS: Sensitization prevalences for PPD and cross-reacting allergens have increased in Greece during the last decade, regardless of occupational or non-occupational exposure to hair dyes.

Chemical Peels in Skin Cancer: A Review.

Background: Chemexfoliation is widely used to reverse signs of photodamage. Although photodamage can eventually lead to skin cancer, it remains unclear whether chemical peels also affect photocarcinogenesis. Moreover, concerns about the systemic and/or cutaneous toxicity of peeling agents have already arisen. Objective: This review sought primarily to summarize the data available on the effects of chemical peels on ultraviolet-induced skin carcinogenesis, focusing particular attention on actinic keratoses and cutaneous field cancerization. In addition, considerations about the systemic and/or cutaneous toxicity of peeling agents, particularly trichloracetic acid, are briefly discussed. Methods: The PubMed, MEDLINE, and SCOPUS databases were searched using the keywords "chemical peeling," "actinic keratosis," "cutaneous field cancerization," "skin cancer," "skin cancer prevention," and "cutaneous and systemic carcinogenicity," both alone and in combination with one another. Additional relevant references were also isolated from citations in the reviewed literature. Results: A total of 42 articles involving both in-vitro and in-vivo human and animal models were included for analysis. The data were mainly confined to laboratory animals. Conclusion: Apart from efficacy in clearing visible actinic keratoses, the findings point towards the possible clinical use of chemical peeling for the prevention of skin cancer. To date, no evidence on systemic toxicity following dermal exposure of humans to chemical peels has been identified.

Prevalence of Cervico-vaginal High-risk HPV Types and Other Sexually Transmitted Pathogens in Anogenital Warts Patients.

AIM: To investigate the prevalence of cervico-vaginal co-infection with high-risk (HR) HPV types and other sexually transmitted pathogens (STPs) in women with anogenital warts (AGWs). PATIENTS AND METHODS: In this cross-sectional study, cervico-vaginal smears of women with AGWs were examined with real-time polymerase chain reaction for the presence of HR-HPV types and common STPs. Women with recent cervical HPV infection and general population were used for comparisons. RESULTS: A total of 689 women participated in the study. Among the examined groups, higher rates of cervico-vaginal co-infection with HR-HPV types and other STPs collectively were recorded in women with AGWs (p=0.0049 and p<0.004, respectively). Within the AGWs group, cervical co-infection with HR-HPV types was detected more often in women with recurrent disease (p<0.001). CONCLUSION: The higher rates of cervico-vaginal co-infection with HR-HPV types and common STPs in women with AGWs may affect their risk for cervical carcinogenesis and the natural course of their disease.

The Rising Incidence of Allergic Contact Dermatitis to Acrylates.

BACKGROUND: Allergic contact dermatitis (ACD) caused by (meth)acrylates used in nail products is being increasingly reported in nail technicians and consumers. OBJECTIVES: The aim of the study was to assess the incidence of sensitization to (meth)acrylates in technicians and users of nail products with ACD, referred for patch testing in a tertiary center, during the last 10 years. METHODS: All patients with ACD, who reported a profession associated with cosmetic nail procedures or use of such services and were referred for patch tests in our department between January 2009 and December 2018, were identified. The incidence of positive sensitization to (meth)acrylates was assessed. RESULTS: Contact allergy to 1 or more (meth)acrylates was found in 116 (74.4%) of 156 nail technicians or nail product users, all women. One hundred thirty-eight (88.5%) were occupationally exposed, and 18 (11.5%) were consumers. In addition, there was a statistically significant increase in (meth)acrylate ACD during 2014-2018 (100/127 cases [79%]) when compared with 2009-2013 (16/29 cases [55%]). The most common sensitizer among the 156 allergic individuals was ethylene glycol dimethacrylate, which was positive in 113 cases (72.4%), and among patients with acrylate-positive patch test, the rate was 97.4%. CONCLUSIONS: Our experience confirms the worldwide changing landscape of rising (meth)acrylate sensitization in nail technicians and nail products users with ACD. Efforts to improve prevention are needed, and clinicians should have a high index for suspicion in this occupational group.