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.

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.

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.

Biological disease-modifying antirheumatic drugs may mitigate the risk of psoriatic arthritis in patients with chronic plaque psoriasis.

OBJECTIVE: To estimate the incidence of psoriatic arthritis (PsA) in patients with psoriasis who had received a continuous treatment with biological disease-modifying antirheumatic drugs (bDMARDs) compared with phototherapy. METHODS: A retrospective non-randomised study involving patients with moderate-to-severe plaque psoriasis, who were prescribed at least 5 years of bDMARDs or at least three narrow-band ultraviolet light B (nb-UVB) phototherapy courses, and did not have a diagnosis of PsA at enrolment. Development of PsA in each patient was assessed by a rheumatologist according to the Classification for Psoriatic Arthritis criteria. The annual and cumulative incidence rate of PsA was estimated by using an event per person-years analysis. Cox proportional hazards models were undertaken to assess the hazard risk (HR) of PsA after adjustment for confounders. RESULTS: A total of 464 psoriatic patients (bDMARDs, n=234 and nb-UVB, n=230) were followed between January 2012 and September 2020 (corresponding to 1584 and 1478 person year of follow-up for the two groups, respectively). The annual incidence rate of PsA was 1.20 cases (95% CI 0.77 to 1.89) versus 2.17 cases (95% CI 1.53 to 3.06) per 100 patients/year in the bDMARDs versus phototherapy group, respectively (HR 0.29, 0.12-0.70; p=0.006). The variables independently associated with higher risk of PsA were older age (adjusted HR 1.04, 1.02-1.07), nail psoriasis (adjusted HR 3.15, 1.63-6.06) and psoriasis duration >10 years (adjusted HR 2.02, 1.09-3.76); notably, bDMARDs treatment was associated with a lower risk of incident PsA (adjusted HR 0.27, 0.11-0.66). CONCLUSIONS: bDMARDs treatment may delay or reduce the risk of incident PsA in patients with moderate-to-severe chronic plaque psoriasis.

Risk of lymphohematologic malignancies in patients with chronic plaque psoriasis: A systematic review with meta-analysis.

BACKGROUND: The association between chronic plaque psoriasis and lymphohematologic malignancies (LHMs) remains controversial. OBJECTIVE: To investigate the risk of LHMs in patients with psoriasis according to the best evidence. METHODS: A systematic review and meta-analysis of observational cohort studies was undertaken to assess the association of psoriasis with different LHMs. A literature search for relevant studies was performed on February 28, 2021. The random-effects model in conducting meta-analyses was applied. To evaluate the risk of bias, the Newcastle-Ottawa Scale was employed. RESULTS: A total of 25 observational studies were selected, comprising collectively 2,501,652 subjects. A significantly increased risk for LHM (hazard ratio [HR], 1.55; 1.24-2.94) and lymphoma (HR, 1.27; 1.08-1.50) in patients with moderate-to-severe plaque psoriasis compared to the general population was found. In detail, increased risks for Hodgkin lymphoma (HR, 1.71; 1.27-2.30), non-Hodgkin lymphoma (HR, 1.27; 1.08-1.50), multiple myeloma (HR, 1.32; 1.03-1.69), and leukemia (HR, 1.28; 1.00-1.65) were found. The risk of cutaneous T-cell lymphoma was markedly augmented in patients with psoriasis (HR, 6.22; 3.39-11.42). LIMITATIONS: Possible ascertainment bias related to the diagnosis of LHMs. CONCLUSION: The increased risk of LHMs, particularly cutaneous T-cell lymphoma, in patients with psoriasis could be related to exposure to systemic immunosuppressive therapies, comorbidities, and sustained immune activation, particularly in the skin.

Hypochondriasis and Personality Traits of Patients with Chronic Plaque Psoriasis.

BACKGROUND: Plaque psoriasis has been associated with anxiety, depression, suicidal ideation and various personality traits. However, studies on hypochondriasis, i.e. the belief of serious illness despite having no or only mild symptoms, are currently scarce. OBJECTIVE: The aim of this study was to assess hypochondriasis and personality traits in psoriasis patients using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). METHODS: We conducted an observational study on patients with plaque psoriasis who underwent MMPI-2 testing. Demographic and clinical data, including comorbidities, alcohol consumption, and smoking, were collected. RESULTS: A total of 136 consecutive psoriatic patients were included. The mean age (±SD) was 53.7 (±13.5), mean PASI (Psoriasis Area Severity Index) was 12.4 (±9.9), and mean disease duration was 23.3 (±15.7) years. Pathologically elevated scores in the Hypochondriasis scale were observed in 27.9% of patients. Furthermore, in a few other MMPI-2 scales (Anxiety, Fears and Negative Treatment Indicators) ≥25% of patients obtained pathologically elevated scores. Conversely, the scales that had the highest proportion of low scorers were Ego Strength and Dominance. At regression analysis, higher psoriasis severity and female gender were associated with higher scores in the Hypochondriasis scale (p = 0.03 and 0.001). Finally, 72.8% reported any alcohol consumption and 8.1% heavy alcohol consumption. CONCLUSION: About one third of patients with psoriasis have high scores in the MMPI-2 hypochondriasis evaluation scale. Poor individual coping resources also appeared to be distinctive psychological features in a significant proportion of psoriatic patients.

Non-Alcoholic Fatty Liver Disease Is Associated With Reduced Glomerular Filtration Rate in Patients With Chronic Plaque Psoriasis.

BACKGROUND: Chronic plaque psoriasis has been associated with metabolic comorbidities, including non-alcoholic fatty liver disease (NAFLD). A causal relationship between NAFLD and chronic kidney disease (CKD) is debated. OBJECTIVES: To assess whether NAFLD is associated with impaired renal function in patients with psoriasis. METHODS: A multicenter, retrospective, observational study including 337 patients with moderate-to-severe chronic plaque psoriasis, who had no history of excessive alcohol consumption or other secondary causes of chronic liver and renal diseases was conducted. NAFLD was diagnosed by ultrasonography, and CKD stage ≥2 or stage ≥3 were defined by an estimated glomerular filtration rate (e-GFR) of <90 ml min-1 1.73 m-2 or <60 ml min-1 1.73 m-2, respectively. Logistic and linear regression analyses were undertaken to assess the independent association of NAFLD with CKD or eGFR levels. RESULTS: Patients with NAFLD (n = 212, 62.9% of total) had significantly lower e-GFR levels (83.4 ± 18.0 vs. 93.5 ± 15.8 ml min-1 1.73 m-2, P<.001) and a remarkably higher prevalence of both CKD stage ≥2 (56.1% vs. 30.4%, P<.0001) and CKD stage ≥3 (10.4% vs. 3.2%, P<.0001) compared with their counterparts without NAFLD. Multivariable logistic regression analysis showed that NAFLD was associated with a nearly 2.5-fold increased risk of prevalent CKD stage ≥2 (adjusted-odds ratio= 2.60 95% confidence intervals 1.4-4.8, P=.02), independently of components of metabolic syndrome, psoriasis severity, and psoriatic arthritis. CONCLUSIONS: Ultrasound-diagnosed NAFLD is strongly associated with a reduced eGFR in patients with moderate-to-severe psoriasis, independently of cardiometabolic risk factors and psoriasis-related variables.

Could Targeted Pharmacotherapies Exert a "Disease Modification Effect" in Patients with Chronic Plaque Psoriasis?

Chronic plaque psoriasis is an immune-mediated skin disease with a chronic relapsing course, affecting up to ~2-3% of the general adult population worldwide. The interleukin (IL)-23/Th17 axis plays a key role in the pathogenesis of this skin disease and may represent a critical target for new targeted pharmacotherapies. Cutaneous lesions tend to recur in the same body areas, likely because of the reactivation of tissue-resident memory T cells. The spillover of different pro-inflammatory cytokines into systemic circulation can promote the onset of different comorbidities, including psoriatic arthritis. New targeted pharmacotherapies may lead to almost complete skin clearance and significant improvements in the patient's quality of life. Accumulating evidence supports the notion that early intervention with targeted pharmacotherapies could beneficially affect the clinical course of psoriatic disease at three different levels: (1) influencing the immune cells infiltrating the skin and gene expression, (2) the prevention of psoriasis-related comorbidities, especially psoriatic arthritis, and (3) the improvement of the patient's quality of life and reduction of cumulative life course impairment. The main aim of this narrative review is to summarize the effects that new targeted pharmacotherapies for psoriasis may have on the immune scar, both at the molecular and cellular level, on psoriatic arthritis and on the patient's quality of life.

The safety profile of hydroxychloroquine: major cutaneous and extracutaneous adverse events.

Hydroxychloroquine is an established therapy for several rheumatological disorders, and very recently it has been proposed as a possible treatment for the new coronavirus disease 2019 even if recent randomised trials did not prove any benefit. Notably, hydroxychloroquine has been associated with a heterogeneous range of cutaneous and extra-cutaneous adverse events. We carried out a narrative review of the literature up to November 1st, 2020, related to the safety of hydroxychloroquine. In particular, cutaneous and extra-cutaneous adverse events associated with hydroxychloroquine were reviewed. The following databases were consulted: PubMed, Embase, Google Scholar and ResearchGate. The research of articles was conducted by using the following search terms: ''hydroxychloroquine," ''adverse event/effect,'' "cutaneous", "skin", "cardiotoxicity", "retinopathy", gastrointestinal and neurological toxicity". The main indication for which hydroxychloroquine was used in the reports was an immune mediated disorder. Adverse events were described mostly in females over 50 years of age. The most common cutaneous adverse effect was maculopapular and erythematous rash occurring within 4 weeks of initiating hydroxychloroquine and disappearing within few weeks of discontinuation. Gastrointestinal symptoms and headache were the most frequent extracutaneous manifestations. Rarer cutaneous manifestations include hyperpigmentation, psoriasiform dermatitis, photodermatitis, stomatitis, melanonychia and hair loss. More severe conditions were acute generalised exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis, and among extra-cutaneous adverse events cardiotoxicity and retinopathy. Since hydroxychloroquine is widely prescribed in rheumatology, it is important for rheumatologists to be familiar with its safety profile.

IL-17A inhibitors in patients with chronic plaque psoriasis and history of malignancy: A case series with systematic literature review.

The treatment of moderate to severe plaque psoriasis in patients with history of malignancy is challenging. To review the studies reporting the experience with IL-17A inhibitors in patients with psoriasis and history of malignancy; secondly, to investigate cancer recurrence in a series of patients with a prior malignancy and plaque psoriasis treated with IL-17A inhibitors. A systematic literature review and an observational retrospective analysis of patients with history of malignancy and plaque psoriasis treated with IL-17A inhibitors was performed. About 5 original articles out of 601 were retrieved, reporting a total of 10 patients with a median age of 59 years, interquartile range (IQR) 50-63. Seven patients were treated with secukinumab, one with ixekizumab and two with both sequentially. Although the stage ranged from in situ to IV stage, most of the cases were early-stage neoplasm. The IL-17A inhibitor was initiated after a median of 10 months, interquartile range (IQR) 5-30 (range 0-144) from the diagnosis of malignancy. In addition, a series of 12 patients with history of malignancy were identified from the University Hospital of Verona, including 9 cases with cancer in clinical remission and 3 with advanced disease at time of initiating IL-17 inhibitor. No malignancy recurrence was reported within a median of 12 (IQR 6-23) and 46 (IQR 36-48) months follow up in case series from literature and our experience, respectively. Data on use of IL-17A inhibitors in patients with chronic plaque psoriasis and history of malignancy are limited. Registries and proactive pharmacovigilance activities are needed to guide clinical practice.

Methotrexate vs secukinumab safety in psoriasis patients with metabolic syndrome.

The safety of methotrexate in psoriasis patients with metabolic syndrome could be argued because of increased risk of liver toxicity. The aim of the study was to investigate the safety of methotrexate compared with secukinumab in psoriasis patients with metabolic syndrome. A controlled, open trial in psoriasis patients with metabolic syndrome, candidate to methotrexate, or secukinumab. Primary end point of the study was investigating any variations in waist circumference, body mass index, blood pressure, fasting glucose, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, creatinine levels between baseline and month-6 and 12 of follow-up in the two treatment cohorts. A total of 130 (110 male and 20 female) patients were consecutively assigned in a 1:1 ratio to treatment with methotrexate (n = 64) dosed 15 mg weekly or secukinumab (n = 66) at standard dose. At month-6 and month-12 serum levels of liver enzymes were significantly increased only in patients treated with methotrexate (P < .01). Three times elevation of liver enzymes was reported in 4 of 64 patients receiving methotrexate, causing drug withdrawal. No significant changes in other parameters were observed. Methotrexate could induce a liver enzyme increase whereas secukinumab has a neutral effect.

Disease Severity Is Associated with Alexithymia in Patients with Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder that is associated with higher rates of psychological disorders, but limited evidence supported the association with alexithymia, a psychoaffective dysfunction. OBJECTIVES: This study was aimed to investigate the occurrence of alexithymia in AD patients, compared to healthy subjects. METHODS: This cross-sectional study assessed AD severity by the Eczema Area and Severity Index (EASI) score, sleeplessness and itch by a numeric rating scale (NRS), and alexithymia by the 20-item Toronto Alexithymia Scale (TAS-20) score. The association between disease characteristics and alexithymia was evaluated through several logistic regression models. RESULTS: 202 AD patients and 240 healthy subjects were included in this study. The alexithymic personality trait (TAS-20 ≥51) was more frequently observed among AD patients compared to the control group (62.4% [126/202] vs. 29.2% [70/240], p < 0.0001). In particular, alexithymia (TAS-20 score ≥61) was detected in a significantly higher number of AD patients than in the controls (27.7% [56/202] vs. 7.5% [18/240]; p < 0.0001), whereas borderline alexithymia was detected in 34.6% (70/202) of AD patients compared to 21.7% of healthy controls. Alexithymia was more common among severe AD patients (43.6%) compared to mild AD patients (15.6%) and correlated with itch intensity and sleep disturbances. Among clinical variables, ordered logistic regression analyses revealed disease severity as predictor of alexithymia. Indeed, univariate analysis showed EASI score, sleep NRS, and itch NRS being significantly associated with alexithymia, while a multivariate model identified increased EASI score values as predicting factor. CONCLUSION: This study described alexithymia in AD patients correlating its occurrence with clinical AD severity markers (EASI score, itch, and sleeplessness) and identifying the increase in EASI score as predicting factor.

Clinical features and treatments of transient acantholytic dermatosis (Grover's disease): a systematic review.

Grover's disease (GD) is an itchy acantholytic disorder occurring on the trunk of middle-aged men. Based on the best evidence, this study aimed to provide a summary of the clinical characteristics, disease course and treatments of GD. A systematic review was performed according to PRISMA guidelines for original articles published between 01.01.1970-08.15.2019, assessing clinical features and/or any type of intervention for GD. A total of 263 articles were retrieved, and 116 original reports that were deemed relevant and satisfied the inclusion criteria were included in the analysis (88 case reports, 26 case series and two retrospective reviews). From these articles, 317 patients were identified, with a male-to-female ratio of 3.95. The mean age was 59 years (range 11-92). Typical lesions were itchy papules and vesicle-papules, generally located on the trunk. Spontaneous resolution within one week to eight months was described in 42 % of cases. Topical corticosteroids (TCSs) were the most frequent treatment (response rate of 70 %) followed by systemic retinoids and corticosteroids with response rates of 86 % and 64 %, respectively. According to the results of this review, TCS appears to be the most frequently employed treatment, and we suggest TCS as first-line therapy. Second-line treatments could include systemic retinoids or systemic corticosteroids.