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.

Age affects drug survival rates of interleukin (IL)-17 and IL-23 inhibitors in patients with plaque psoriasis: Results from a retrospective, multicentric, multi-country, cohort study.

BACKGROUND: Scarce data related to the drug survival of biologic agents in psoriasis patients aged ≥65 years is available. OBJECTIVES: To evaluate the drug survival of interleukin (IL)-23 or the IL-17 inhibitors approved for the treatment of moderate-to-severe psoriasis in elderly patients (aged ≥65 years), compared with younger adult patients (aged <65 years), and to identify clinical predictors that can influence the drug survival. METHODS: This retrospective multicentric cohort study included adult patients with moderate-to-severe psoriasis, dissecting two-patient subcohorts based on age: elderly versus younger adults. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. RESULTS: We included 4178 patients and 4866 treatment courses; 934 were elderly (1072 treatment courses), and 3244 were younger patients (3794 treatment courses). Drug survival, considering all causes of interruption, was higher in patients aged <65 years than in elderly patients overall (log-rank p < 0.006). This difference was significant for treatment courses involving IL-23 inhibitors (p < 0.001) but not for those with IL-17 inhibitors (p = 0.2). According to both uni- and multi-variable models, elder age was associated with an increased risk of treatment discontinuation (univariable analysis: HR: 1.229, 95% CI 1.062-1.422; p < 0.006; multivariable analysis: HR: 1.199, 95% CI 1.010-1.422; p = 0.0377). Anti-IL-23 agents were associated with a reduced likelihood of treatment discontinuation after adjusting for other variables (HR: 0.520, 95% CI 0.368-0.735; p < 0.001). Being previously treated with IL-17 inhibitors increased the probability of discontinuation. CONCLUSION: Elderly patients with psoriasis have an increased risk of biologic treatment discontinuation compared with younger adult patients, particularly, if being treated with IL-23 inhibitors. However, in stratified analyses conducted in elderly patients, IL-23 inhibitors showed higher drug survival rates than IL-17 inhibitors.

The "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) Project: An Expert Panel Opinion.

Actinic keratosis (AK) is an intraepithelial condition characterized by the development of scaly, erythematous lesions after repeated exposure to ultraviolet radiation. Significant immunosuppression is a risk factor for the development of AK and subsequent lesion progression to squamous cell carcinoma. Immunocompromised patients (ICPs), particularly organ transplant recipients, often have more advanced or complex AK presentations and an increased risk of skin carcinomas versus non-ICPs with AK, making lesions more difficult to treat and resulting in worse treatment outcomes. The recent "Personalising Actinic Keratosis Treatment" (PAKT) consensus reported that delivering patient-centric care may play a role in supporting better clinical outcomes and patient satisfaction with treatments for chronic dermatologic conditions such as AK, which require repeated cycles of treatment. Additionally, currently published guidance and recommendations were considered by the PAKT panel to be overly broad for managing ICPs with their unique and complex needs. Therefore, the "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) panel was established to build upon general recommendations from the PAKT consensus. The panel identified current gaps in guidance for AK care in ICPs, offered practical care approaches based on typical ICP scenarios, and highlighted the need to adapt AK management to optimize care and improve treatment outcomes in ICPs. In particular, dermatologists should establish collaborative and transparent relationships with patients' multidisciplinary teams to enhance overall care for patients' comorbidities: given their increased risk of progression to malignancy, earlier assessments/interventions and frequent follow-ups are vital.The panel also developed a novel "triage" tool outlining effective treatment follow-up and disease surveillance plans tailored to patients' risk profiles, guided by current clinical presentation and relevant medical history. Additionally, we present the panel's expert opinion on three fictional ICP scenarios to explain their decision-making process for assessing and managing typical ICPs that they may encounter in clinical practice.

OPT-In; Optimized Patient Treatment Outcomes in Plaque Psoriasis: A 3-Year State-Transition Treatment-Sequencing Model in the Italian Setting.

INTRODUCTION: There are several treatment options for plaque psoriasis (PsO), but uncertainty remains around the optimal sequencing of treatments. The aims of this study were to investigate how adopting a best-treatment-first treatment sequence impacts patient outcomes and healthcare systems and to quantify the cost of treatment failure to the healthcare system. METHODS: A 3-year state-transition treatment-sequencing model which identifies all possible treatment sequences in PsO was adapted to the Italian healthcare setting. Treatments considered in the model are those with European Medicines Agency marketing authorization and reimbursement in Italy as of December 2022. Italian market share data (2019-2021) and list prices (2022) informed the current prescribed sequences; these sequences were compared against all possible sequences to determine opportunities for improvement. Both the national perspective in Italy as well as the local perspective from seven regions were considered. The cost of treatment failure was informed through a questionnaire circulated to Italian dermatologists. RESULTS: Overall, 1284 possible treatment sequences are possible when four lines of treatment are considered for patients with moderate-to-severe PsO in Italy. Within the estimated range of treatment failures across those sequences (0.97-2.56 per patient over 3 years), current prescribing behavior from the national perspective suggests patients will face 1.44 failures on average; this highlights the potential for improvement. For every treatment failure, the cost borne by the Italian National Healthcare Service (NHS) is €676.80. Overall, prescribing more optimized treatment sequences results in a 22.95% reduction in failures with a 2.27% increase in costs. The regional analyses found similar trends. CONCLUSIONS: Results suggest that selecting the most effective treatment sequences for incident patients provides the greatest opportunity to reduce treatment failures and maximize patient outcomes with a modest impact on costs. While regional variations exist, there is room for improvement across the board, which could translate to more efficient local healthcare systems.

Ablative CO2-Assisted Laser for Topical Drug Delivery in Nail Psoriasis: A Systematic Review.

Background: Nail psoriasis poses challenges for effective treatment, and topical drug delivery through the nail plate is limited. A novel approach to address this challenge involves the use of ablative fractional laser as a pretreatment strategy to enhance topical drug delivery for nail psoriasis. Summary: This systematic review, conducted in accordance with PRISMA guidelines, involved an extensive literature search across PubMed/MEDLINE, EMBASE, and the Cochrane Library up to July 2023. The primary focus was on exploring studies that investigated the application of ablative laser technology to augment drug delivery for nail psoriasis. Key Messages: (1) The review included seven randomized controlled trials, all examining the combination of fractional CO2 laser with topical treatments. These trials demonstrated varying degrees of improvement in nail psoriasis. (2) Patients undergoing laser treatment reported experiencing moderate levels of pain, effectively managed through the application of topical anesthesia. (3) Commonly observed side effects included erythema, swelling, and crusting, with the Koebner phenomenon being a rare occurrence. (4) Notably, patient satisfaction levels with the combined approach of laser and topical treatments were consistently high. In conclusion, the utilization of ablative CO2-assisted laser pretreatment, when used in conjunction with topical therapy, appears to be both effective and well-tolerated for the treatment of nail psoriasis. However, the establishment of optimal parameters and treatment intervals for fractional laser therapy remains an area for further research. Standardized studies are imperative to identify the most effective strategy for enhancing topical drug delivery in the context of nail psoriasis treatment.

Epidemiology, Characteristics of Disease, and Unmet Needs of Patients with Generalized Pustular Psoriasis: A Large Italian Delphi Consensus.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare and chronic, debilitating skin condition characterized, in its acute flare phase, by clinically severe and potentially life-threatening systemic manifestations. Data on GPP are still scanty, particularly in Europe and at a national level. The aim of this study was to provide expert indications on several disease-related and patient-related aspects of GPP, with specific focus to the Italian context. METHODS: We conducted an iterative eDelphi study following the recommended criteria for reporting methods and results. After a thorough bibliographic review aimed to identify unknown or controversial issues in GPP, the following areas were investigated through a few specific questions/statements for each area: (1) disease epidemiology; (2) disease characteristics, with specific interest toward GPP flares; (3) diagnosis and diagnostic delay; (4) GPP treatment; (5) GPP patient journey and use of healthcare resources in Italy; (6) unmet needs and quality of life. An Executive Board of 9 principal investigators revised and approved the topics to be examined and overviewed the whole project. A total of 35 experts from different Italian areas, including 34 board-certified Italian dermatologists and 1 representative of patients' associations, took part in the study. RESULTS: A high agreement in responses from Italian experts emerged during two eDelphi iterations on - among several other aspects - GPP prevalence and incidence in Italy, use of European Rare and Severe Psoriasis Expert Network diagnostic criteria, flare frequency and duration, best diagnostic and care pathway, and main unmet needs of Italian patients. On the other hand, a broad spectrum of treatments (of different drug classes) was reported both in the acute and chronic phases of GPP, and no consensus on the issue was thus achieved. CONCLUSIONS: Consensus findings from this Delphi study of GPP experts may be useful to fill gaps of knowledge and improve awareness of this rare disease, as well as to help clinical and public health management of GPP in Italy.

Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.

Kaposi's Sarcoma: Evaluation of Clinical Features, Treatment Outcomes, and Prognosis in a Single-Center Retrospective Case Series.

Kaposi's sarcoma (KS) is a rare angioproliferative tumor classified in four different clinical-epidemiological forms. The diagnosis is based on histopathological and immunohistochemical analyses. The treatment is heterogeneous and includes several local and systemic therapeutic strategies. Methods: This is a retrospective cohort study including 86 KS patients treated between 1993 and 2022 at the University Hospital of Padua (AOPD) and at the Veneto Institute of Oncology (IOV). The data were extracted from an electronic database. Survival curves were generated using the Kaplan-Meier method, and Cox regression models were employed to explore associations with overall and disease-free survival. The male sex (89.53%), classical variant (43.02%), and cutaneous involvement (77.9%) were predominant. More than 61.6% of patients received a single treatment. Surgery, antiretroviral therapy, and chemotherapy were the mostly adopted approaches. A persistent response was observed in approximately 65% of patients, with a 22% relapse rate (at least 2 years). The overall survival ranges from 90 to 70% at 2 to 10 years after the diagnosis. Iatrogenic KS demonstrated a higher mortality (52.9%). This study reflects our experience in the management of KS. Comorbidities are very frequent, and treatments are heterogeneous. A multidisciplinary approach involving multiple referral specialists is essential for the appropriate management of this disease during diagnosis, treatment, and follow-up.

Coronary Microvascular Dysfunction in Asymptomatic Patients with Severe Psoriasis.

Severe psoriasis is associated with an increased cardiovascular risk, which may be independent of the traditional risk factors. Coronary microvascular dysfunction (CMD) has been shown to predict a poor cardiovascular prognosis in the general population and in patients with psoriasis. In this study, we assessed the prevalence and predictors of CMD in a large cohort of patients with psoriasis without clinical cardiovascular disease. A total of 503 patients with psoriasis were enrolled and underwent transthoracic Doppler echocardiography to evaluate coronary microcirculation. Of these, 55 patients were excluded from the analyses because of missing data. Of the 448 patients in this study, 31.5% showed CMD. Higher PASI, longer disease duration, the presence of psoriatic arthritis, and hypertension were independently associated with CMD. An increase of 1 point of PASI and 1 year of psoriasis duration were associated with a 5.8% and 4.6% increased risk of CMD, respectively. In our study, CMD was associated with the severity and duration of psoriasis. This supports the role of systemic inflammation in CMD and suggests that the coronary microcirculation may represent an extracutaneous site involved in the immune-mediated injury of psoriasis. We should diagnose and actively search for CMD in patients with severe psoriasis.

Comparative effectiveness of biologics for patients with moderate-to-severe psoriasis and special area involvement: week 12 results from the observational Psoriasis Study of Health Outcomes (PSoHO).

Introduction: Psoriasis localized at the scalp, face, nails, genitalia, palms, and soles can exacerbate the disease burden. Real-world studies comparing the effectiveness of treatments for these special areas are limited. Methods: Psoriasis Study of Health Outcomes (PSoHO) is an international, prospective, non-interventional, study comparing the effectiveness of anti-interleukin (IL)-17A biologics (ixekizumab and secukinumab) compared to other approved biologics and the pairwise comparative effectiveness of ixekizumab relative to five other individual biologics for patients with moderate-to-severe psoriasis. To determine special area involvement, physicians answered binary questions at baseline and week 12. The proportion of patients who achieved special area clearance at week 12 was assessed. Missing outcome data were imputed as non-response. Comparative treatment analyses were conducted using frequentist model averaging. Results: Of the 1,978 patients included, 83.4% had at least one special area involved at baseline with the scalp (66.7%) as the most frequently affected part, followed by nails (37.9%), face/neck (36.9%), genitalia (25.6%), and palms and/or soles (22.2%). Patients with scalp, nail, or genital, but not palmoplantar or face/neck psoriasis, had significantly higher odds of achieving clearance at week 12 in the anti-IL-17A cohort compared to the other biologics cohort. Patients with scalp psoriasis had a 10-20% higher response rate and significantly greater odds (1.8-2.3) of achieving clearance at week 12 with ixekizumab compared to included biologics. Conclusion: Biologics demonstrate a high level of clearance of special areas at week 12 in a real-world setting. Patients with scalp, nail, or genital involvement have significantly higher odds of clearance at week 12 with anti-IL-17A biologics compared to other biologics.

Insulin Stimulates IL-23 Expression in Human Adipocytes: A Possible Explanation for the Higher Prevalence of Psoriasis in Obesity.

Purpose: Psoriasis is a chronic systemic inflammatory disease involving the production of many pro-inflammatory cytokines derived from immune cells and interacting with different tissues leading to the typical skin lesions. Psoriasis shows a higher prevalence and a worse progression in obese than in lean subjects. The IL-23/IL-17 immune axis has a pivotal role in the pathogenesis of psoriasis and anti-IL-23 monoclonal antibodies are highly effective in its treatment. Since obesity in frequently associated with elevated insulin plasma levels, we have investigated the ability of in vitro differentiated human adipocytes to produce IL-23 at basal conditions and after insulin stimulation. Material and Methods: In vitro differentiated human adipocytes were incubated in the absence and presence of different insulin concentrations and the expression of IL-23 was analyzed by real-time PCR and Western blotting. Results: The results of this study show that in vitro differentiated human adipocytes spontaneously express IL-23 mRNA and protein being stimulated by insulin in a dose-dependent manner. The stimulatory effects of insulin on IL-23 expression were specific since it did not stimulate the expression of other well-known cytokines involved in psoriasis pathogenesis such as Il-22 nor LL-37. Furthermore, lipopolysaccharide did not stimulate IL-23 expression in human adipocytes, thus highlightening the specific effects of insulin in the stimulation of IL-23 expression in human adipocytes. Conclusion: Here we show that human adipocytes spontaneously express IL-23 and that insulin stimulates IL-23 production by these cells in a specific manner as other stimuli, known to be involved in psoriasis pathophysiology, are ineffective. These observations could explain the association between psoriasis and obesity, a condition frequently characterized by a state of insulin hypersecretion.

Real-World Experience of Methotrexate in the Treatment of Skin Diseases: an Italian Delphi Consensus.

BACKGROUND: After decades of use, methotrexate displays an established safety and efficacy profile in both in-hospital and outpatient settings. Despite its widespread use, there is surprisingly little clinical evidence to guide daily practice with methotrexate in dermatology. OBJECTIVES: To provide guidance for clinicians in daily practice for areas in which there is limited guidance. METHODS: A Delphi consensus exercise on 23 statements was carried out on the use of methotrexate in dermatological routine settings. RESULTS: Consensus was reached on statements that cover six main areas: (1) pre-screening exams and monitoring of therapy; (2) dosing and administration in patients naïve to methotrexate; (3) optimal strategy for patients in remission; (4) use of folic acid; (5) safety; and (6) predictors of toxicity and efficacy. Specific recommendations are provided for all 23 statements. CONCLUSIONS: In order to optimize methotrexate efficacy, it is essential to optimize treatment using appropriate dosages, carrying out a rapid drug-based step-up on a treat-to-target strategy and preferably using the subcutaneous formulation. To manage safety aspects appropriately, it is essential to evaluate patients' risk factors and carry out proper monitoring during the course of treatment.

Characteristics of Patients Experiencing a Flare of Generalized Pustular Psoriasis: A Multicenter Observational Study.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, severe inflammatory skin disease characterized by recurrent episodes of flares. Characteristics of patients experiencing a flare are hardly described in a real-life setting. The aim of the study is to investigate the clinical characteristics of patients experiencing a flare of GPP. METHODS: Multicenter retrospective observational study on consecutive patients experiencing a flare of GPP between 2018 and 2022. Disease severity and quality of life were assessed by Generalized Pustular Psoriasis Area, Body Surface Area (BSA), and Severity Index (GPPASI), and Dermatology life quality index (DLQI) questionnaire, respectively. Visual analogue scale (VAS) of itch and pain, triggers, complications, comorbidities, pharmacological therapies, and outcome were collected. RESULTS: A total of 66 patients, 45 (68.2%) females, mean age 58.1 ± 14.9 years, were included. The GPPASI, BSA, and DLQI were 22.9 ± 13.5 (mean ± standard deviation), 47.9 ± 29.1, and 21.0 ± 5.0, respectively. The VAS of itch and pain were 6.2 ± 3.3 and 6.2 ± 3.0, respectively. Fever (>38 °C) and leukocytosis (WBC > 12 × 109/L) were found in 26 (39.4%) and 39 (59.1%) patients, respectively. Precipitating triggers were identified in 24 (36.3%) and included infections (15.9%), drugs (10.6%), stressful life events (7.6%), and corticosteroids withdrawal (3.0%). Fourteen (21.2%) patients were hospitalized because of complications including infections in 9 (13.6%) leading to death in one case and hepatitis in 3 (4.5%). CONCLUSIONS: GPP flares can be severe and cause severe pain and itch with significant impact on the quality of life. In about one-third of patients the flare may have a persistent course and, with complications, lead to hospitalization.