Managing the Patient with Psoriasis and Metabolic Comorbidities.

Epidemiological data demonstrate strong associations between psoriasis and metabolic comorbidities, including obesity, hypertension, diabetes mellitus, dyslipidemia, and non-alcoholic fatty liver disease. The presence of metabolic comorbidities significantly influences the selection and effectiveness of pharmacological treatments. Some drugs should be prescribed with caution in patients with metabolic comorbidities because of an increased risk of adverse events, while others could have a reduced effectiveness. The aim of this narrative review is to highlight the challenges that healthcare professionals may face regarding the management of psoriasis in patients with metabolic comorbidities. In the first part of the article, the epidemiological association between psoriasis and metabolic comorbidities and their pathogenetic mechanisms is summarized. The second part describes the efficacy and safety profile of conventional and biologic drugs in patients with selected metabolic comorbidities including obesity, non-alcoholic fatty liver disease/hepatic steatosis, and diabetes. Finally, the role of pharmacological and non-pharmacological interventions, such as diet, alcohol abstinence, physical activity, and smoking avoidance is discussed. In conclusion, the choice of the best approach to manage patients with psoriasis with metabolic comorbidities should encompass both tailored pharmacological and individualized non-pharmacological interventions.

Infectious events in patients with alopecia areata treated with JAK inhibitors: low burden and minimal impact on persistence in treatment.

BACKGROUND: Alopecia areata (AA) is a non-scarring disorder characterized by hair loss that greatly affects patients' quality of life and has a chronic, recurring course. This disease is marked by an inflammatory process, mainly on an autoimmune basis primarily regulated by Janus kinase (JAK). RESEARCH DESIGN AND METHODS: We conducted a retrospective study evaluating the safety of JAKi in a real-world setting in 91 AA patients, with a specific focus on the assessment of infectious events. RESULTS: Overall, 34 infectious events were observed in 28 patients (30.8%), among them 17 patients (60.7%) suspended treatment with JAKi until the infection was clinically resolved. Only in one case the infectious event led to a permanent discontinuation of the treatment. The data we observed in the study are consistent with results reported in clinical trials. CONCLUSION: It can be stated that, during treatment with JAKi in AA patients, infectious events may occur, but in most cases these events are easily manageable and do not result in permanent discontinuation of the drug.

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 characterised, 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. 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 towards 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 one 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.

Generalized pustular psoriasis successfully treated with spesolimab: A case report.

Generalized pustular psoriasis is defined as a primary, sterile, macroscopically visible pustular eruption on non-acral skin, which can occur with or without systemic inflammation and/or psoriasis vulgaris, and can either be relapsing or be persistent, according to the European Rare and Severe Psoriasis Expert Network. The treatment of generalized pustular psoriasis may be challenging. We describe a 48-year-old woman with a 15-year history of severe generalized pustular psoriasis and plaque psoriasis resistant to multiple courses of treatments with conventional and biological agents who had a rapid, complete and durable (up to 12 months) clinical remission with spesolimab, an anti-interleukin-36 receptor antagonist monoclonal antibody recently approved for the treatment of generalized pustular psoriasis flares.

Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines.

This study explores the impact of antiretroviral administration on the expression of human endogenous retroviruses (HERVs), cell growth, and invasive capability of human melanoma cell lines in culture. We investigated three antiretrovirals-lamivudine, doravirine, and cabotegravir-in A375, FO-1, and SK-Mel-28, BRAF-mutated, and in MeWo, P53-mutated, melanoma cell lines. The findings indicate a general capability of these drugs to downregulate the expression of HERV-K Pol and Env genes and hinder cell viability, mobility, and colony formation capacity of melanoma cells. The antiretroviral drugs also demonstrate selectivity against malignant cells, sparing normal human epithelial melanocytes. The study reveals that the integrase inhibitor cabotegravir is particularly effective in inhibiting cell growth and invasion across different cell lines in comparison with lamivudine and doravirine, which are inhibitors of the viral reverse transcriptase enzyme. The investigation further delves into the molecular mechanisms underlying the observed effects, highlighting the potential induction of ferroptosis, apoptosis, and alterations in cell cycle regulatory proteins. Our findings showed cytostatic effects principally revealed in A375, and SK-Mel-28 cell lines through a downregulation of retinoblastoma protein phosphorylation and/or cyclin D1 expression. Signs of ferroptosis were detected in both A375 cells and FO-1 cells by a decrease in glutathione peroxidase 4 and ferritin expression, as well as by an increase in transferrin protein levels. Apoptosis was also detected in FO-1 and SK-Mel-28, but only with cabotegravir treatment. Moreover, we explored the expression and activity of the stimulator of interferon genes (STING) protein and its correlation with programmed death-ligand 1 (PD-L1) expression. Both the STING activity and PD-L1 expression were decreased, suggesting that the antiretroviral treatments may counteract the detrimental effects of PD-L1 expression activation through the STING/interferon pathway triggered by HERV-K. Finally, this study underscores the potential therapeutic significance of cabotegravir in melanoma treatment. The findings also raise the prospect of using antiretroviral drugs to downregulate PD-L1 expression, potentially enhancing the therapeutic responses of immune checkpoint inhibitors.

Treatment of Psoriasis Patients with Latent Tuberculosis Using IL-17 and IL-23 Inhibitors: A Retrospective, Multinational, Multicentre Study.

BACKGROUND: Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed. Available evidence from clinical trials and real-world studies suggests that IL-17 and IL-23 inhibitors do not increase the risk of tuberculosis reactivation. OBJECTIVE: To evaluate psoriasis patients with treated or untreated newly diagnosed LTBI who received IL-17 and IL-23 inhibitors and the tolerability/safety of tuberculosis chemoprophylaxis. METHODS: This is a retrospective, observational, multinational study from a series of 14 dermatology centres based in Portugal, Spain, Italy, Greece and Brazil, which included adult patients with moderate-to-severe chronic plaque psoriasis and newly diagnosed LTBI who were treated with IL-23 or IL-17 inhibitors between January 2015 and March 2022. LTBI was diagnosed in the case of tuberculin skin test and/or interferon gamma release assay positivity, according to local guideline, prior to initiating IL-23 or IL-17 inhibitor. Patients with prior diagnosis of LTBI (treated or untreated) or treated active infection were excluded. RESULTS: A total of 405 patients were included; complete/incomplete/no chemoprophylaxis was administered in 62.2, 10.1 and 27.7% of patients, respectively. The main reason for not receiving or interrupting chemoprophylaxis was perceived heightened risk of liver toxicity and hepatotoxicity, respectively. The mean duration of biological treatment was 32.87 ± 20.95 months, and only one case of active tuberculosis infection (ATBI) was observed, after 14 months of treatment with ixekizumab. The proportion of ATBI associated with ixekizumab was 1.64% [95% confidence interval (CI): 0-5.43%] and 0% for all other agents and 0.46% (95% CI 0-1.06%) and 0% for IL-17 and IL-23 inhibitors, respectively (not statistically significant). CONCLUSIONS: The risk of tuberculosis reactivation in patients with psoriasis and LTBI does not seem to increase with IL-17 or IL-23 inhibitors. IL-17 or IL-23 inhibitors should be preferred over TNF antagonists when concerns regarding tuberculosis reactivation exists. In patients with LTBI considered at high risk for developing complications related to chemoprophylaxis, this preventive strategy may be waived before initiating treatment with IL-17 inhibitors and especially IL-23 inhibitors.

Multi-failure psoriasis patients: characterization of the patients and response to biological therapy in a multicenter Italian cohort.

INTRODUCTION: Patients with psoriasis who have failed multiple biologic drugs have been defined as "multi-failure," although there are no clear data on the characteristics, comorbidities, and best treatment strategies for this population. Nowadays, given the next generation and the number of biologics available, patients are considered multi-failure when ≥4 biologics fail to achieve a good response. METHODS: Demographic characteristics and efficacy of anti-interleukin drugs in multi-failure patients were compared to a cohort of general psoriatic patients treated with IL-23 or IL-17 inhibitors. RESULTS: In total 97 multi-failure patients (≥4 lines of biologics) were compared with 1,057 patients in the general cohort. The current drugs in the multi-failure group were risankizumab (34), ixekizumab (23), guselkumab (21), brodalumab (7), tildrakizumab (5), ustekinumab (4), secukinumab (2), and certolizumab pegol (1). A significant difference was found in the multi-failure cohort for age of psoriasis onset (mean 29.7 vs. 35.1, P < 0.001), concurrent psoriatic arthritis (45.4 vs. 26.9%, P < 0.001), diabetes mellitus (30.9 vs. 10.9%, P < 0.001), and cardiovascular comorbidity (54.6 vs. 39.8%, P = 0.005). In multi-failure patients, current biological therapy showed a good initial response (PASI 90 and 100 of 41.24 and 27.84%, respectively, at 16 weeks); the response tended to decline after 40 weeks. Anti-IL-17 agents showed clinical superiority over IL-23 agents in terms of achieving PASI90 at 28 weeks (P < 0.001) and 40 weeks (P = 0.007), after which they reached a plateau. In contrast, IL-23 agents showed a slower but progressive improvement that was maintained for up to 52 weeks. A similar trend was also seen for PASI100 (28 weeks P = 0.032; 40 weeks P = 0.121). CONCLUSIONS: The multi-failure patient is characterized by many comorbidities and longstanding inflammatory disease that frequently precedes the introduction of systemic biologic therapy. Further studies are needed to identify more specific criteria that could be applied as a guideline by clinicians.

Prevalence of Non-Alcoholic Fatty Liver Disease in Adult Individuals with Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: There are no published studies on the prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with atopic dermatitis (AD). OBJECTIVES: To estimate the prevalence of NAFLD (assessed via liver ultrasonography) in adults with moderate-to-severe AD. METHODS: We performed a retrospective, cross-sectional, observational study including adult patients affected by moderate-to-severe AD, moderate-to-severe chronic plaque psoriasis, or a previous diagnosis of thin melanoma in situ (considered as the control group) who attended the Verona University Hospital between January 2022 and April 2023. Fatty liver was assessed via liver ultrasonography. RESULTS: A total of 144 adults with AD, 466 with chronic plaque psoriasis, and 99 with thin melanoma were included. The prevalence rates of ultrasound-detected NAFLD among patients with in situ melanoma, those with moderate-to-severe AD, and those with moderate-to-severe chronic plaque psoriasis were 23.2% (23 out of 99), 24.1% (36 out of 144), and 49.8% (228 out of 466), respectively (p < 0.01). Logistic regression analysis revealed that being of male sex, a higher age, a higher body mass index, and psoriasis were independently associated with NAFLD, whereas AD was not. CONCLUSIONS: Our findings show that the prevalence of ultrasound-detected NAFLD in patients with moderate-to-severe AD was comparable to that of patients with a previous diagnosis of in situ melanoma. It is plausible to hypothesize that the Th2-type inflammation typically characterizing AD is not a risk factor for NAFLD. Patients with moderate-to-severe psoriasis, but not those with AD, should be screened for NAFLD and other metabolic comorbidities.

Comparative dermoscopy assessment of nevus-associated versus de novo in situ melanoma.

BACKGROUND: Dermoscopic features differentiating in situ nevus-associated melanoma (NAM) versus in situ de novo melanoma (DNM) are inconclusive. OBJECTIVES: The aim of the study was to investigate the dermoscopic features associated with in situ NAM versus DNM. MATERIALS & METHODS: This was a retrospective observational study. All consecutive in situ melanomas diagnosed in adult patients were retrieved and stratified as NAM vs DNM, and clinical and dermoscopic data were compared between the two. RESULTS: A total of 183 patients with in situ melanoma were collected, of whom 98 (54%) were male with a mean age of 64±14 years. For 129 patients, standardized dermoscopic images were collected (51 for NAM and 78 for de novo MM). The most common dermoscopic features were an atypical pigment network (85%), atypical globules (63%) and regression (42%). No significant differences were found except for regression, which was detected in 54.9% NAM vs 33.3% DNM (p=0.016). Multivariate logistic regression confirmed the association between dermoscopic regression and NAM (OR=2.34, 95% CI: 1.15-4.91). CONCLUSION: Currently, the use of dermoscopy to determine whether a melanoma is associated with a nevus is unreliable, however, the presence of regression adjacent to atypical lesions may raise suspicion of in situ NAM.

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.

Central Pain Sensitization in Patients with Chronic Plaque Psoriasis.

BACKGROUND: Central sensitization (CS) is a condition characterized by a disproportionate response to pain stimuli, and is associated with chronic pain conditions such as fibromyalgia, but also with inflammatory arthropathies such as rheumatoid arthritis and psoriatic arthritis (PsA). CS has never been investigated in patients with psoriasis. The aim of this study is to investigate CS in patients with chronic plaque psoriasis. METHODS: This research involved a cross-sectional observational study of adult patients with moderate-to-severe psoriasis consecutively attending the outpatient clinic of the University Hospital of Verona. Demography, measures of disease severity or activity [i.e., Psoriasis Area and Severity Index (PASI), Disease Activity in Psoriatic Arthritis (DAPSA)], diagnosis of PsA, hypertension, and diabetes were collected. Central Sensitization Inventory (CSI), Dermatology Life Quality Index (DLQI), General Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) were administered. RESULTS: A total of 194 patients, including 115 (59%) men, with mean age of 54 ± 13 years, mean PASI of 12.7 ± 6.7, and mean DAPSA of 14.4 ± 3.8 were included. In total, 134 patients (79%) had only psoriasis while 60 (31%) had psoriasis and PsA; 19 (10%) patients had CSI score ≥ 40, which is the threshold for diagnosing CS. The proportion of CS ≥ 40 was higher in patients with PsA compared with psoriasis (17% versus 7%, p = 0.031). The mean CSI score in patients with PsA was higher compared with those with only psoriasis (27.5 ± 13.5 versus 20.7 ± 13.7, p = 0.002). An association between CSI and DLQI [ß = 1.25 (95% CI 0.85-1.66)], PASI [ß = 1.22 (95% CI 0.74-1.65)], GAD-7 [ß = 2.07 (95% CI 1.69-2.45)] and PHQ-9 [ß = 2.16 (95% CI 1.76-2.54)] was found independently from age, gender, diabetes, and PsA. CONCLUSIONS: Central sensitization may be associated with psoriasis, particularly in those with high PASI, concomitant PsA, anxiety, depression, and severe quality of life impairment.

Association between short-term exposure to environmental air pollution and atopic dermatitis flare in patients treated with dupilumab.

Background: The magnitude of short/medium-term air pollution exposure on atopic dermatitis (AD) flare has not been fully investigated. The aim of the study was to investigate the association of short/medium-term exposure to airborne pollution on AD flares in patients treated with dupilumab. Methods: Observational case-crossover study. Patients with moderate-to-severe AD under treatment with dupilumab were included. The exposure of interest was the mean concentrations of coarse and fine particulate matter (PM10, PM2.5), nitrogen dioxide, and oxides (NO2, NOx). Different intervals were considered at 1 to 60 days before the AD flare and control visit, defined as the visit with the highest Eczema Area and Severity Index scores >8 and ≤7, respectively. A conditional logistic regression analysis adjusted for systemic treatments was employed to estimate the incremental odds (%) of flare every 10 µg/m3 pollutant concentration. Results: Data on 169 of 528 patients with AD having 1130 follow-up visits and 5840 air pollutant concentration measurements were retrieved. The mean age was 41.4 ± 20.3 years; 94 (55%) men. The incremental odds curve indicated a significant positive trend of AD flare for all pollutants in all time windows. At 60 days, every 10 µg/m3 PM10, PM2.5, NOx, and NO2 increase concentration was associated with 82%, 67%, 28%, and 113% odds of flare, respectively. Conclusions: In patients treated with dupilumab, acute air pollution exposure is associated with an increased risk for AD flare with a dose-response relationship.

Optimization of long-range PCR protocol to prepare filaggrin exon 3 libraries for PacBio long-read sequencing.

BACKGROUND: The filaggrin (FLG) protein, encoded by the FLG gene, is an intermediate filament-associated protein that plays a crucial role in the terminal stages of human epidermal differentiation. Loss-of-function mutations in the FLG exon 3 have been associated with skin diseases. The identification of causative mutations is challenging, due to the high sequence homology within its exon 3 (12,753 bp), which includes 10 to 12 filaggrin tandem repeats. With this study we aimed to obtain the whole FLG exon 3 sequence through PacBio technology, once 13-kb amplicons have been generated. METHODS AND RESULTS: For the preparation of SMRTbell libraries to be sequenced using PacBio technology, we focused on optimizing a 2-step long-range PCR protocol to generate 13-kb amplicons covering the whole FLG exon 3 sequence. The performance of three long-range DNA polymerases was assessed in an attempt to improve the PCR conditions required for the enzymes to function properly. We focused on optimization of the input template DNA concentration and thermocycling parameters to correctly amplify the entire FLG exon 3 sequence, minimizing non-specific amplification. CONCLUSIONS: Taken together, our findings suggested that the PrimeSTAR protocol is suitable for producing the amplicons of the 13-kb FLG whole exon 3 to prepare SMRTbell libraries. We suggest that sequencing the generated amplicons may be useful for identifying LoF variants that are causative of the patients' disorders.