Dupilumab in real-life settings: a review of adverse events and their pathogenesis.

INTRODUCTION: Dupilumab is a safe and effective biological drug that revolutionized the treatment of atopic dermatitis (AD). Concerning adverse events (AEs), the most commonly reported included ocular involvement, nasopharyngitis, and injection site reactions in clinical trials. Anyway, its use in daily practice is revealing novel dupilumab-induced manifestations. AREAS COVERED: Relevant English literature (real-life studies, case series, reviews, and meta-analyses) regarding real-life adverse events induced by dupilumab were searched for up to 10 June 2023. EXPERT OPINION: Dupilumab is an effective treatment for AD, showing favorable safety profile since no routine laboratory monitoring is recommended. However, several cutaneous and extracutaneous AEs have been reported in real-life setting expanding the pool emerged from clinical trials. In detail, dupilumab may determine de-novo onset or exacerbation of preexisting conditions, whose pathogenesis is still unclear and seems to involve Th1/Th2 and Th2/Th17 immune-response imbalance. Also, the heterogeneity and the variable onset time of AEs with respect to dupilumab initiation warrant a thorough patients' history collection and strict short- and long-term monitoring. Finally, the most appropriate management of patients with AEs related to dupilumab should take into consideration efficacy for AD as well as severity and nature of the AE, available treatment and patients' preferences.

Efficacy and safety of spesolimab for the management of generalized pustular psoriasis: a drug safety evaluation.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare form of psoriasis (less of 1% of cases). Currently, GPP is recognized as a clinical entity, distinguished from plaque psoriasis. However, there are not guidelines for GPP management and treatments are often derived from plaque psoriasis. Therefore, conventional systemic drugs are usually used as first-line treatment options, and biologics are still used off label. Recently, spesolimab, an anti-IL36 receptor humanized IgG1 monoclonal antibody, has been specifically approved for GPP disease, revolutionizing treatment scenario. AREAS COVERED: The aim of this review is to investigate current literature on the use of spesolimab for GPP management to underline its potential role in GPP and offer a current clinical perspective. Literature research using the Google Scholar, Pubmed, Embase, Cochrane Skin, and clinicaltrials.gov databases was performed, selecting the most relevant manuscripts. EXPERT OPINION: Spesolimab is efficacious and has a consistent and favorable safety profile in patients presenting with a GPP flare. However, despite excellent results in terms of safety and efficacy have been reported by both clinical trials and very limited real-life experiences, long-term data, especially in flare-up prevention, are scant. Thus, while the available data are encouraging, further research is warranted to understand the efficacy, safety, and long-term outcomes associated with spesolimab treatment in GPP.

Biologics for the Management of Erythrodermic Psoriasis: An Updated Review.

Erythrodermic psoriasis (EP) is a severe and rare variant of psoriasis (less than 3% of cases), characterized by generalized scaling and erythema affecting more than 90% of body surface area. Several systemic symptoms can be present in patients with EP such as lymphadenopathy, arthralgia, fever, fatigue, dehydration, serum electrolyte disturbances, and tachycardia making this condition a possible life-threatening disease, particularly if appropriate treatments are not performed. In this scenario, effective and safe therapies are required. Unfortunately, the rarity of EP makes head-to-head Phase III trials challenging, leading to the lack of established guidelines for its management. Globally, conventional systemic drugs such as cyclosporine, methotrexate, and retinoids often have contraindications linked to patients' comorbidities and have not shown a high profile of efficacy and safety. Recently, the development of biologic drugs including anti-tumor necrosis factor-α and anti-interleukin 12-23, 23, and 17 has revealed favorable results for the management of plaque psoriasis, making them also a possible therapeutic option for EP disease. However, their use in EP is still off-label. The aim of our study was to review current literature on the use of biologic drugs for the treatment of EPs in order to offer a wide perspective on their possible application in EP management.

New Onset and Exacerbation of Psoriasis Following COVID-19 Vaccination: A Review of the Current Knowledge.

COVID-19 vaccination was the main measure to overcome the pandemic. As with other drugs and vaccines, mild to moderate adverse events have been reported following vaccination. In addition, several cutaneous reactions have been described. In particular, there are several reports investigating de novo psoriasis or the exacerbation of psoriasis following COVID-19 vaccination. However, data on the possible pathogenetic mechanisms as well as comprehensive manuscripts on the topic are scant. Thus, the aim of our manuscript was to perform a review of the current literature on post-COVID-19 vaccination exacerbations and new-onset psoriasis in order to offer a wide perspective on this area and to point out possible pathogenetic mechanisms. Research on the current literature was performed following PRISMA guidelines. In total, 49 studies involving 134 patients developing new-onset psoriasis (n = 27, 20.1%) or psoriasis exacerbation (n = 107, 79.9%) were collected. Although cases of de novo psoriasis or a worsening of psoriasis have been reported following vaccination, all of the cases have been successfully treated while overall benefit-risk profile of COVID-19 vaccination does not justify vaccine hesitancy due to the risk of psoriasis being developed or worsening. Certainly, further studies are needed to identify possible pathogenetic mechanisms in order to identify "at-risk" patients. Finally, vaccination should not be discouraged.

Development of a Patient-Reported Outcome Measure (PROM) for Dysgeusia During Treatment With Smoothened (SMO) Inhibitors for Basal Cell Carcinomas: The SMO-iD Questionnaire.

INTRODUCTION: Dysgeusia may occur during conventional or target-therapies and affect patients adherence-to-treatment. Therefore, it should be monitored to improve clinical outcome. To date, available questionnaires on dysgeusia relate to traditional antineoplastics and do not apply to target-therapies as the pathogenetic mechanism and clinical expression differ. OBJECTIVES: To develop a patient-reported outcome measure (PROM) to screen for and monitor the occurrence and severity of dysgeusia in patients under Smoothened (SMO) inhibitors: the SMO-iD questionnaire. METHODS: Patients with locally advanced basal cell carcinomas referring dysgeusia under SMO inhibitors at the University Hospital of Naples Federico II, were enrolled between January-December 2020. The PROM was elaborated based on chemotherapy-induced dysgeusia (CiTas) scale (development phase) and then validated by measuring internal consistency and reliability (validation phase). RESULTS: Thirty-nine patients were enrolled and interviewed every 8 weeks. In the first phase, 160 CiTas questionnaires were collected, and the SMO-iD questionnaire was developed. In the second phase, 195 SMO-iD questionnaires were recorded, and reliability and validity assessed. Cronbach alpha was 0.89. CONCLUSIONS: The SMO-iD questionnaire is a validated questionnaire that shows high face and content validity as well as high internal consistency and reliability. Hence, it may be introduced in daily clinical setting to monitor dysgeusia in patients under SMO-inhibitors.

Use of Biological Therapies for the Management of Pustular Psoriasis: A New Era?

Generalized pustular psoriasis (GPP) is a severe and rare form of psoriasis, being a potentially life-threatening condition, characterized by recurring episodes or flares of widespread cutaneous erythema with macroscopic sterile pustules. An irregular innate immune response is linked to GPP, which is considered an auto-inflammatory disorder, while innate and adaptive immunopathogenic responses are involved in psoriasis pathogenesis. In consequence, different cytokine cascades have been suggested to be mainly involved in the pathogenesis of each different psoriasis form, with the interleukin (IL)23/IL17 axis implied in plaque psoriasis, and the IL36 pathway in the GPP. As regards GPP treatment, conventional systemic drugs available for plaque psoriasis are usually used as the first-line treatment option. However, contraindications and adverse events often limit the use of these therapies. In this scenario, biologic drugs may represent a promising treatment option. To date, even if 12 different biologics have been approved for plaque psoriasis, none of these is approved for GPP where they are employed off-label. Recently, spesolimab, an anti-IL36 receptor monoclonal antibody, has been recently approved for GPP. The purpose of this article is to assess the current literature about the use of biological therapies for the treatment of GPP to establish the basis for a shared GPP management algorithm.

The Natural Evolution of Nevi with Peripheral Globules.

BACKGROUND: Peripheral globules (PG) in melanocytic lesions represent a concerning dermoscopic feature since they might be present in growing nevi and melanomas. Their natural evolution has not been fully elucidated, and an age-based management approach has been recommended. OBJECTIVES: The aim of this study was to calculate the growth rate of lesions with PG and investigate possible association with age, sex, location, and the global dermoscopic pattern. METHODS: We retrospectively selected the lesions of interest from a cohort of Caucasian patients who underwent sequential digital dermoscopy monitoring. Lesions with PG distributed at 75% or more of their circumference with available follow-up images or histopathologic report were included. The surface area was automatically calculated with the help of an incorporated tool used in the acquisition of the images. The images were also evaluated by independent investigators for the presence of pre-defined criteria. Growth-curve models were used to assess the growth rate. The outcome variable was the area of nevi in mm2, and scatterplots with Lowess curves were used to present the mean change of nevi during follow-up. RESULTS: A total of 208 lesions from 98 patients with a median age of 36 years (range 15-75) were included. The median follow-up time was 18 months (range 4-48). The mean growth rate for all nevi was 0.16 mm2/month (95% CI, 0.14-0.18, p < 0.001), ranging from -0.29 to 0.61 mm2/month. The growth rate was higher in nevi with a homogeneous dermoscopic pattern (p < 0.001). The number of peripheral globules during follow-up varied from increasing to complete disappearance. None of the lesions developed any melanoma-specific structure at follow-up. CONCLUSION: Nevi with PG grew at a mean rate of 0.16 mm2/month, and the growth rate was independent of age, gender, or anatomic location. Nevi with homogeneous pattern demonstrated the highest growth rate in our cohort. None of the monitored nevi with PG developed melanoma-specific criteria at follow-up.

Acral Melanocytic Nevi in a High-Risk Population: Prevalence, Clinical Characteristics and Dermatoscopic Patterns.

BACKGROUND: The prevalence of acral nevi and their dermatoscopic patterns have been mainly studied in Asian populations. Few data exist on the prevalence and clinico-dermatoscopic morphology of acral nevi in white populations. OBJECTIVES: The aim of this study was to assess the prevalence of acral nevi and evaluate their features in a cohort of Caucasian individuals at high risk for skin cancer. METHODS: We prospectively examined the palms and soles of 680 high-risk patients who underwent total body clinical and dermatoscopic documentation, as a part of their routine follow-up, between January 2016 and March 2020 at a skin cancer referral center in Greece. RESULTS: Overall, 334 acral lesions were detected in 217 (37.0%) of 585 patients in the study. The presence of acral nevi was associated with 2.6 higher odds of a total nevus count higher than 50 (OR: 2.6, p < 0.05, confidence intervals [CI]: 1.11-6.09). Of 334 acral nevi, 65.0% were clinically flat and 35.0% were clinically palpable. Palpable lesion had 19-fold higher probability of being located on the sole (OR: 19.44, p < 0.05, CI: 3.91-96.7). The parallel furrow pattern was present in 147 lesions (44.0%). In 76 lesions (22.8%), we observed a previously undefined pattern consisting of wavy lines, which was correlated with clinically palpable lesions (p < 0.001). The third most common pattern was homogeneous (10.5%), followed by the fibrillar (8.7%), the lattice-like (7.2%), the reticular (3.6%), and globular (3.3%). CONCLUSION: We observed a higher prevalence of benign acral melanocytic lesions than expected, probably related to our cohort selection of patients at high risk for developing skin cancer. Our study confirms the previously described dermatoscopic patterns and provides novel insights into the dermatoscopic morphology of acral palpable nevi, for which we described a new benign pattern consisting of wavy lines.

The holistic approach to psoriasis patients with comorbidities: the role of investigational drugs.

INTRODUCTION: Psoriasis is a high-burden syndrome characterized by cutaneous and extracutaneous manifestations that profoundly reduce patients' quality of life. The presence of concomitant comorbidities often represents a limit to the most appropriate psoriasis treatment that will be overcome by the development of drugs effective for diseases with common pathogenetic pathways. AREAS COVERED: The current review summarizes the latest findings on investigational drugs for psoriasis and their role on potentially concomitant diseases that share similar pathogenetic pathways. EXPERT OPINION: The development of novel drugs that target key-molecules in the pathogenesis of several diseases, including psoriasis, will impact on the reduction of polypharmacy and drug interaction with increased patients' compliance to treatment, wellbeing, and quality of life. Certainly, the efficacy and safety profile of each novel agent must be defined and evaluated in real-life since the performance may vary according to comorbidities and their severity. Anyway, future is now, and research must continue in this direction.

Dermoscopic Clues of Histopathologically Aggressive Basal Cell Carcinoma Subtypes.

Background: The group of histopathologically aggressive BCC subtypes includes morpheaform, micronodular, infiltrative and metatypical BCC. Since these tumors are at increased risk of recurring, micrographically controlled surgery is considered the best therapeutic option. Although dermoscopy significantly improves the clinical recognition of BCC, scarce evidence exists on their dermoscopic criteria. Aim: To investigate the dermoscopic characteristics of histopathologically aggressive BCC subtypes. Materials and Methods: Dermoscopic images of morpheaform, micronodular, infiltrative and metatypical BCC were analyzed for the presence of predefined variables. Descriptive and analytical statistics were performed. Results: Most histopathologically aggressive BCCs were located on the head and neck. Infiltrative was the most common subtype. All subtypes, except micronodular BCC, rarely displayed dermoscopic pigmentation. The most frequent dermoscopic features of infiltrative BCC were arborizing vessels (67.1%), shiny white structures (48.6%) and ulceration (52.9%). The features prevailing in morpheaform BCC were arborizing vessels (68.4%), ulceration (n = 12, 63.2%) and white porcelain areas (47.4%). Micronodular BCC was typified by milky red structureless areas (53.8%), arborizing vessels (53.8%), short fine telangiectasias (50%), ulceration (46.2%) and blue structures (57.7%). The most common findings in metatypical BCC were arborizing vessels (77.8%), shiny white structures (66.7%), ulceration (62.9%) and keratin mass (29.6%). Limitations: Study population of only white skin and relatively small sample size in some groups. Conclusions: Our study provided data on the clinical, dermoscopic and epidemiological characteristics of histopathologically aggressive BCCs.

Efficacy and safety of biologics and small molecules for psoriasis in pediatric and geriatric populations. Part II: focus on elderly patients.

INTRODUCTION: The management of moderate-to-severe forms of psoriasis is becoming a frequent concern in geriatric age due to the higher risk to develop treatment adverse events, logistic issues, vulnerability to immune-related diseases and cancer, presence of comorbidities and the risk of drug interactions. In this context, traditional systemic treatments are often contraindicated, and biologic drugs and small molecules seem to be a valuable option. However, data on their effectiveness and safety in elderly patients are scant. AREAS COVERED: The aim of this review is to analyze the current literature in order to point out data on the efficacy and safety of biologic drugs and small molecules for the management of psoriasis in elderly patients in order to put the basis for universally shared treatment algorithm following available evidence. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used for the literature research. EXPERT OPINION/COMMENTARY: Our review suggests biologics and small molecules as an effective and safe option for the management of moderate-to-severe forms of psoriasis in elderly patients.

Efficacy and safety of biologics and small molecules for psoriasis in pediatric and geriatric populations. Part I: focus on pediatric patients.

INTRODUCTION: Psoriasis management is challenging, especially in pediatric age for different factors. The introduction of biologic drugs and oral small molecules (OSM) revolutionized the armamentarium of available weapons in psoriasis treatment. Despite the use of these drugs in adult patients has been widely investigated, pediatric patients have often been unconsidered in clinical trials and real-life studies. However, the high efficacy and speed of action, the safety profile and the ease-to-use administration make these innovative drugs an invaluable therapeutic opportunity. AREAS COVERED: The aim of this manuscript is to perform a review of the current literature examining data on the effectiveness and safety of biologic drugs and OSM for the management of psoriasis in pediatric patients in order to put the basis for universally shared treatment algorithm following available evidence. PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines were used for the literature research. EXPERT OPINION/COMMENTARY: Our review based on currently available evidence suggests biologics and OSM as an ideal treatment option for pediatric patients, with an excellent profile in terms of efficacy and safety as compared to traditional systemic drugs.

Drug safety evaluation of tildrakizumab for psoriasis: a review of the current knowledge.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease that may have an important negative impact on a patient's quality of life. Biological agents deeply changed the management of its moderate-to-severe forms. Interleukin-23 inhibitors represent the latest biologics class approved for the treatment of moderate-to-severe psoriasis. In particular, tildrakizumab, the latest available anti-interleukin-23 on the Italian market, is a humanized monoclonal antibody specifically targeting the p19 subunit of IL-23. AREAS COVERED: The objective of this review is to evaluate the safety profile of tildrakizumab in moderate-to-severe psoriasis patients. A literature review included articles until July 2022. EXPERT OPINION: Our analysis showed tildrakizumab as a generally safe option for the treatment of psoriasis, with most of the reported adverse events being classified as mild or moderate, and rarely requiring treatment discontinuation. Furthermore, in line with other interleukin-23 inhibitor, no concerns have been raised for tildrakizumab in regard to inflammatory bowel diseases, which represent a significant comorbidity to investigate before starting other biologics (IL-17 inhibitors). However, more real-life long-term data are needed to confirm trial results to further confirm tildrakizumab as a generally safe treatment option for psoriasis.

Towards Personalized Medicine in Psoriasis: Current Progress.

Although innovative targeted therapies have positively revolutionized psoriasis treatment shifting treatment goals to complete or almost complete skin clearance, primary or secondary lack of efficacy is still possible. Hence, identifying robust biomarkers that reflect the various clinical psoriasis phenotypes would allow stratify patients in subgroups or endotypes, and tailor treatments according to the characteristics of each individual (precision medicine). To sum up the current progress in personalized medicine for psoriasis, we performed a review on the available evidence on biomarkers predictive of response to psoriasis treatments, with focus on phototherapy and systemic agents. Relevant literature published in English was searched for using the following databases from the last five years up to March 20, 2022: PubMed, Embase, Google Scholar, EBSCO, MEDLINE, and the Cochrane library. Currently, more evidence exists towards biologicals, as justified by the huge health care costs as compared to phototherapy or conventional systemic drugs. Among them, most of the studies focused on anti-TNF and IL12/23, with still few on IL17 (mainly secukinumab). The most discussed biomarker gene is the HLA-C*02:06 status that has been shown to be associated with psoriasis, and also differential response to biologicals. Although its positivity is associated with great response to MTX, debatable results were retrieved concerning both anti-TNF and IL12/23 while it seems not to affect secukinumab response. Personalized treatment in psoriasis would provide excellent outcome minimizing the risk of side effects. To date, although several candidates were proposed and assessed, the scarcity and heterogeneity of the results do not allow the identification of the gold-standard biomarker per each treatment. Anyway, the creation of a more comprehensive panel would be more reliable for the treatment decision process.