Early Intervention and Cumulative Life Course Impairment in psoriasis: a Review.

Psoriasis is a chronic, systemic, inflammatory disease affecting the skin, joints, and other organs. Psoriasis negatively affects patients' quality of life, causing social anxiety and negative coping, thus determining a cumulative life course impairment (CLCI). The concept of CLCI in psoriasis is reinforced by the understanding that psoriasis-associated comorbidities and stigma accumulate over a patient's life course, resulting from an interaction between the burden of stigmatization, physical and psychological co-morbidities, coping strategies, and external factors. The concept may help identify more vulnerable patients and facilitate more appropriate treatment decisions or earlier referrals. Although some potential risk factors for CLCI have been clarified, no all-encompassing screening tools are available. Patients at risk for CLCI should be identified by applying clinical, personal and psychosocial indicators and predictors individually. Early intervention in psoriasis treatment could improve long-term patient outcomes and modify the disease course. However, more research is needed to define what constitutes "early" intervention clearly and to identify the most effective strategies for implementation. From a preventive point of view, it is helpful to identify early interventions aimed at reducing the risk of CLCI and establishing a new life course trajectory in patients with psoriasis. This review summarizes the state of the art on CLCI and psoriasis, highlighting knowledge gaps and future directions to make CLCI control a possible goal for therapies.

Tildrakizumab in moderate-to-severe plaque psoriasis: A multicenter, retrospective, real-life study.

New biologic agents targeting interleukin (IL)23/T-helper17 axis, such as tildrakizumab, have been developed for the treatment of plaque psoriasis. To analyze the efficacy and safety of tildrakizumab in a real life setting of patients affected by moderate-to-severe psoriasis over a 28-week treatment period. A multicentric retrospective study was conducted in patients who initiated tildrakizumab between February 2020 and March 2021. Psoriasis Area and Severity Index-PASI was measured at baseline and after 4, 16 and 28 weeks. The percentage change in PASI value from baseline to the considered time-points, proportion of patients with absolute PASI <3 at week 28 and the percentages of achieving a PASI75 or PASI90 response were assessed. Data about potential safety issues and adverse events (AEs) were collected. Statistical analysis were performed for establish clinical efficacy and for variables predicting clinical response. Fifty nine patients with psoriasis were included. Overall mean PASI percentage reduction was of 88% from baseline to week 28 and 47 out of 59 patients (79.7%) at week 28 had an absolute PASI <3. PASI75 and PASI90 responses at week 28 were achieved by 48 (81.40%) patients and 38 (64.4.0%) patients, respectively. No substantial associations between gender, body mass index - BMI, PASI at baseline and prior exposition to biological therapies and the efficacy endpoints were retrieved. No serious safety issues or discontinuations related to adverse events were reported. In our real-life study, tildrakizumab showed high efficacy and a favorable safety profile, regardless of patient- and disease-related factors.

Risankizumab for the treatment of moderate-to-severe psoriasis: A multicenter, retrospective, 1 year real-life study.

Several new biologic agents targeting IL23/Th17 axis, such as risankizumab, have been developed for the treatment of psoriasis. The aim of the present study was to analyze the efficacy and safety of risankizumab in patients with moderate-to-severe psoriasis over a 52-week period. A multicentric retrospective study was conducted in patients who initiated risankizumab between July 2019 and December 2020. Psoriasis Area and Severity Index-PASI was measured at baseline and after 4, 16, 28 and 52 weeks. Clinical responses were evaluated by PASI75, PASI90 and PASI100 at the same timepoints. Potential safety issues and adverse events (AEs) were collected. Univariable and multivariable logistic regressions were performed for variables predicting clinical response. One hundred and twelve patients with psoriasis were included. PASI90 response was achieved by 17.86% of patients at week 4, 72.22% at week 16, 91.0% at week 28 and 95.24% at week 52 (as observed analysis). No associations between the considered variables and the efficacy endpoints were retrieved, influence of variables such as Body Mass Index (BMI), baseline PASI or previous biologics were not shown. No serious safety issues or discontinuations related to adverse events were reported. Risankizumab showed high efficacy and a favorable safety profile, regardless of patient- and disease-related factors.

Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% of children and 10% of adults in high-income countries. The prevalence and incidence of AD have increased in recent years. The onset of AD mostly occurs in childhood, although in some cases AD may persist in adult life or even manifest in middle age (adult-onset AD). AD pathophysiology is made of a complex net, in which genetic background, skin barrier dysfunction, innate and adaptive immune responses, as well as itch contribute to disease development, progression, and chronicization. One of the most important features of AD is skin dehydration, which is mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, and antigen penetration. In accordance with the "outside-inside" theory of AD pathogenesis, in a context of an altered epidermal barrier, antigens encounter epidermal antigen presentation cells (APCs), such as epidermal Langerhans cells and inflammatory epidermal dendritic cells, leading to their maturation and Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), which induce IgE-mediated sensitizations as part of pathogenic mechanisms leading to AD. In this review, we discuss the role of cytokines in the pathogenesis of AD, considering patients with various clinical AD phenotypes. Moreover, we describe the cytokine patterns in patients with AD at different phases of the disease evolution, as well as in relation to different phenotypes/endotypes, including age, race, and intrinsic/extrinsic subtypes. We also discuss the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. A deep insight into the correlation between cytokine patterns and the related clinical forms of AD is a crucial step towards increasingly personalized, and therefore more efficient therapy.

Adalimumab in severe plaque psoriasis of childhood: A multi-center, retrospective real-life study up to 52 weeks observation.

The objective of this study is to determine drug effectiveness and safety of the tumor necrosis factor-alpha blocker monoclonal antibody adalimumab in a real-life cohort of 54 children and/or adolescents with severe plaque psoriasis. Retrospective, multicenter analysis over a 52-week period is discussed in this study. Efficacy was determined by the percentage of patients achieving Psoriasis Area Severity Index (PASI 75) and PASI 90 at weeks 16, 24, and 52 and the response in biologic-naïve versus non-naïve patients. Safety was assessed by the number of patients experiencing at least one adverse event. At week 16, 29.6% of patients achieved a 90% PASI score reduction (PASI 90), while 55.5% of patients achieved a 75% PASI score reduction (PASI 75). Effectiveness was sustained through week 24, since PASI 90 response increased to 55.5% and PASI 75 response increased to 74.0% of patients. The PASI response rates did not differ between biologic-naïve and non-naïve patients. The drug was well tolerated and no serious infections were observed. Adalimumab was effective and safe in this cohort of children with severe plaque psoriasis in a 52-week observation. Effectiveness did not differ between biologic-naïve and non-naïve patients.

Treatment of severe psoriasis in children: recommendations of an Italian expert group.

This article provides comprehensive recommendations for the systemic treatment of severe pediatric psoriasis based on evidence obtained from a systematic review of the literature and the consensus opinion of expert dermatologists and pediatricians. For each systemic treatment, the grade of recommendation (A, B, C) based on the treatment's approval by the European Medicines Agency for childhood psoriasis and the experts' opinions is discussed. The grade of recommendation for narrow-band-ultraviolet B phototherapy, cyclosporine, and retinoids is C, while that for methotrexate is C/B. The use of adalimumab, etanercept, and ustekinumab has a grade A recommendation. No conventional systemic treatments are approved for pediatric psoriasis. Adalimumab is approved by the European Medicines Agency as a first-line treatment for severe chronic plaque psoriasis in children (≥ 4 years old) and adolescents. Etanercept and ustekinumab are approved as second-line therapy in children ≥ 6 and ≥ 12 years, respectively. CONCLUSION: A treatment algorithm as well as practical tools (i.e., tabular summaries of differential diagnoses, treatment mechanism of actions, dosing regimens, control parameters) are provided to assist in therapeutic reasoning and decision-making for individual patients. These treatment recommendations are endorsed by major Italian Pediatric and Dermatology Societies. What is Known: • Guidelines for the treatment of severe pediatric psoriasis are lacking and most traditional systemic treatments are not approved for use in young patients. Although there has been decades of experience with some of the traditional agents such as phototherapy, acitretin, and cyclosporine in children, there are no RCTs on their pediatric use while RCTs investigating new biologic agents have been performed. What is New: • In this manuscript, an Italian multidisciplinary team of experts focused on treatment recommendations for severe forms of psoriasis in children based on an up-to-date review of the literature and experts' opinions.

HLA-Cw6 allele, NFkB1 and NFkBIA polymorphisms play no role in predicting response to etanercept in psoriatic patients.

OBJECTIVE: This retrospective study aimed to evaluate the role of NFKB1-94 insertion/deletion ATTG (rs28362491) and NFkBIA 2758 A>G (rs696) polymorphisms and HLA-Cw6 allele in predicting the response to etanercept, a TNF-α blocker, in a population of psoriatic patients naive to biologics. METHODS: Genomic DNA was extracted from whole blood in a series of 96 psoriatic patients who received etanercept for at least 3 months. Patients were classified as responders if they achieved a Psoriasis Area and Severity Index improvement of at least 75% after 12 weeks of etanercept treatment and as nonresponders if Psoriasis Area and Severity Index improvement was less than 75%. Genotyping was performed using the PCR-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: We did not find any significant role of NFKB1-94 insertion/deletion ATTG (rs28362491) and NFkBIA 2758 A>G (rs696) polymorphisms and the HLA-Cw6 allele in predicting the response to etanercept. CONCLUSION: Our findings suggest that NFKB1 and NFkBIA polymorphisms are not related to the response to etanercept. They also indicate that the therapeutic response to etanercept is not influenced by the presence of the HLA-Cw6 allele, in contrast with previous evidence on ustekinumab, suggesting that such an association is related more to drug than to disease characteristics.

A possible role of polycystic ovary syndrome for pregnancy complications in women with psoriasis.

Psoriasis is a common, chronic, relapsing immune-mediated inflammatory disease (IMID) of the skin. IMIDs are multifactorial diseases characterized by common molecular pathways leading to a systemic inflammation. Patients with an IMID are also at higher risk of developing co-morbidities, such as adverse pregnancy outcomes, than the general population. A higher rate of pregnancy complications have been seen in inflammatory bowel disease and rheumatoid arthritis. The data for psoriasis are inconsistent but it appears that women with moderate-to-severe psoriasis may also have an increased risk of poor pregnancy outcomes. The cause of this association is unknown, although it may be related to elevated proinflammatory cytokines such as IL-6 and TNF-α, the high prevalence of comorbidities and other unhealthy behaviours, or the high prevalence of polycystic ovary syndrome (PCOS). In a recent study, PCOS prevalence in a psoriatic cohort (n = 51) was higher than in non-psoriatic women (n = 102) (47% versus 11%), and women with PCOS and psoriasis had a greater probability of insulin resistance, hyperinsulinaemia, and dyslipidaemia as well as a more severe skin condition, than those with psoriasis alone. Further studies are necessary to clarify the impact of psoriasis on pregnancy and in particular if these effects are mediated by concomitant PCOS.

Long-Term Effectiveness of Brodalumab for the Treatment of Moderate-To-Severe Psoriasis: A Real-Life Multicenter Study of Up to 3 Years in a Real-Life Italian Cohort.

INTRODUCTION: Data about the long-term effectiveness of brodalumab could be valuable in assessing patient adherence to treatment and improving psoriasis management. OBJECTIVE: The aim of our study was to evaluate the drug survival of brodalumab and identify any predictive factors for discontinuation. METHODS: A multicenter retrospective study was conducted in patients with moderate-to-severe psoriasis who were treated for up to 3 years. We extracted data from patient files, related to the characteristics of the patients and the disease. Drug survival analysis was descriptively analyzed using Kaplan-Meier survival curves. Univariable and multivariable analyses were performed to assess baseline patient characteristics that predicted clinical response. RESULTS: The study included 90 patients. Among them, 28 (31.1%) suspended brodalumab through the observation period. At weeks 52, 104 and 156 the median PASI score were 0.0 [0.0 - 0.8], 0.0 [0.0 - 1.0] and 0.0 [0.0 - 0.0], respectively. The estimated cumulative survival rates at weeks 52 and 104 were 86.32% and 78.09%, respectively. In the multivariable survival analysis, predictor factors for overall discontinuation included body mass index (BMI) (OR 1.10, 95% CI 1.03 - 1.18), baseline PASI (OR 1.06, 95% CI 1.02 - 1.10), and psoriatic arthritis (OR 5.05, 95% CI 0.89 - 13.50). CONCLUSIONS: Brodalumab has shown long-term effectiveness for up to 3 years. Considering baseline disease severity and patient characteristics could aid in optimizing the long-term management of psoriasis.

Effectiveness of risankizumab in the treatment of palmoplantar psoriasis: a 52-week Italian real-life experience.

Background: Data on the treatment of palmoplantar psoriasis (PP) are scarce, representing a therapeutic challenge. This study aims to assess the efficacy and safety of risankizumab in a population of patients with psoriasis with a palmoplantar involvement, over a 52-week treatment period. Methods: We performed a retrospective analysis in a cohort of patients with PP, with or without involvement of other skin sites. Palmoplantar Psoriasis Area and Severity Index (ppPASI) was assessed at baseline and after 4, 16, 28 and 52 weeks, to evaluate the PP severity. Results: Sixteen patients were enrolled. The rates of ppPASI90 responses constantly increased during the period of observation and were 18.7%, 62.2%, 75.0% and 81.2% at weeks 4, 16, 28 and 52, respectively. Only two patients suspended treatment because of ineffectiveness at week 16. Conclusion: Our data from a series of 16 patients reveal that risankizumab could represent an effective and safe therapeutic choice in patients with PP.

Analysis of predictive factors influencing dupilumab continuation rate in adult patients with atopic dermatitis: results from an Italian multicenter study.

OBJECTIVES: The purpose of this study was to analyze the drug survival rate of dupilumab up to 2 years in a large real-world cohort of adult patients affected by moderate/severe atopic dermatitis (AD), and to investigate the clinical, demographic and predictive factors influencing the patients' treatment persistence. MATERIAL AND METHODS: This study included adult patients affected by moderate-to-severe AD treated with dupilumab for at least 16 weeks who visited 7 dermatologic outpatient clinics in Lazio, Italy, from January 2019 until August 2021. RESULTS: A total of 659 adult patients (345 male [52.3%], mean age: 42.8 years) with an average treatment duration of 23.3 months were enrolled in the study. Overall, 88.6% and 76.1% of patients were still on treatment after 12 and 24 months, respectively. The drug survival rate for discontinuation due to AEs and dupilumab ineffectiveness was 95.0% at 12 months and 90.0% at 24 months. The main reasons for drug discontinuation included inefficacy (29.6%), failed compliance (17.4%), persistent efficacy (20.4%) and adverse events (7.8%). Adult AD onset (≥18 years) and EASI score severity measured at the last follow-up visit were the only factors significantly associated with lower drug survival. CONCLUSION: This study revealed an increased cumulative probability of dupilumab survival at 2 years, reflected by a sustained effectiveness and a favorable safety profile of the drug.

Attitudes among dermatologists regarding actinic keratosis treatment options.

Actinic keratosis (AK) is considered a precancerous lesion that can develop into invasive squamous cell carcinoma. Its prevalence is increasing, and it is estimated that it affects between 1% and 44% of the adult population worldwide. Advanced age, fair skin phototypes, and cumulative sun exposure are the main risk factors for AK. Therapies for AK consists of lesion-directed treatment (i.e., cryotherapy, curettage, electrocoagulation, and laser therapy) or field therapy [i.e., photodynamic therapy (PDT), 5-fluorouracil (5-FU), diclofenac sodium (DIC), imiquimod (IMQ), and ingenol mebutate (Ing Meb)]. The type of therapy chosen is determined by the number and location of AKs, the patient's condition, and the patient's tolerability and compliance. In this survey, we collected information from 110 Italian dermatologists about their knowledge and attitudes toward various AK therapeutic approaches. In our study, we discovered that cryotherapy and PDT are the most used treatments for AK, while surgery and laser therapy are the least commonly used. The most commonly used topical therapies are DIC and IMQ 3.75 percent cream, followed by IMQ 5 percent cream, Ing Meb, and 5-FU. The correct treatment for AK can be difficult to choose, but adherence to therapy is critical for good results. Given the high and continuing rise in the incidence of AK, dermatologists' knowledge of various therapeutic approaches is critical.

Real-world outcomes in patients with moderate-to-severe plaque psoriasis treated with guselkumab for up to 1 year.

BACKGROUND: Real-world data on guselkumab, especially at times >6 months, are limited. RESEARCH DESIGN AND METHODS: We performed a longitudinal, retrospective analysis on 307 patients with moderate-severe chronic plaque psoriasis (Psoriasis Area Severity Index [PASI] >10) treated with guselkumab for up to 12 months. MAIN OUTCOME MEASURES: PASI 75, PASI 90, and PASI 100 were assessed at baseline and at 4, 12, 20, 28, 36, 44, and 52 weeks. RESULTS: At 12 weeks, PASI 75, PASI 90, and PASI 100 were achieved in 56.4%, 33.6%, and 24.1% of patients, respectively. At 52 weeks, PASI 75, PASI 90, and PASI 100 were achieved in 82.7%, 68.7%, and 51.1% of patients, respectively. Patients without comorbidities and those naïve to previous biological therapy had better responses. The mean Dermatology Life Quality Index score decreased from 14.0 at baseline to 3.1 at 12 weeks and 1.6 at 6 months, which was maintained at later times. Similar improvements were seen in pruritus visual analog scale. CONCLUSIONS: Guselkumab maintains its efficacy for up to 12 months among responders in a real-world cohort of patients with moderate-severe plaque psoriasis, confirming data from prior real-world studies with smaller cohorts and shorter duration of follow-up.

Attitudes among dermatologists regarding non-melanoma skin cancer treatment options.

Non-melanoma skin cancers include basal and squamous cell carcinoma. These tumors have become an important health issue for their high incidence and for the morbidity, especially if untreated for a long period. Over the last 20 years, therapeutic approaches for these tumours have been improved and tailored. In this survey we provided data from one hundred and ten Italian dermatologists regarding knowledge and attitude towards different therapeutic approaches on non-melanoma skin cancers. In our study, we observed that surgery and imiquimod 5% cream were the most used treatment by dermatologists for basal cell carcinoma, while, surgery was the most common treatment for cutaneous squamous cell carcinoma. Furthermore, we observed some differences regarding the prescribed therapies in the different Italian geographical areas (i.e., Mohs' surgery and electrochemotherapy were more frequently used in Northern compared to Central and Southern Italy whereas immunotherapy was more used in Southern compared to Northern and Central Italy) and even considering the year of specialization of the dermatologists (i.e., immunotherapy with cemiplimab was prescribed mainly by dermatologists with 10-19 years of specialization). However, for locally advanced and metastatic forms of basal and squamous cell carcinoma, Hedgehog Pathway Inhibitors and anti- Programmed cell death protein antibody treatment, respectively, were used in line with the newest evolution of therapies regarding this topic. Considering the importance of skin cancers and its progressive increase in incidence, it is crucial to improve the knowledge of different therapeutic approaches among dermatologists.

Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare and extremely aggressive neuroendocrine carcinoma of the skin, with increasing incidence worldwide. This review intends to propose a comprehensive evaluation of MCC epidemiology, clinical features, pathogenetic mechanisms, diagnosis, and therapies. A section is dedicated to immunological aspects and another to the involvement of angiogenesis and angiogenic growth factors in MCC progression, proposing novel diagnostic and therapeutic approaches. Advanced MCC tumors have been treated with immune checkpoint inhibitors with effective results. Therefore, the state of art of this immunotherapy is also examined, reporting on the most recent clinical trials in the field. We conclude by underlining the achievements in the understanding of MCC pathology and indicating the present needs for effective diagnosis and therapeutic management of the disease.