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The definition of paradoxical psoriasis (PP) encompasses 2 main scenarios, namely, (i) new-onset psoriasis in patients treated for a different disease and (ii) worsening as well as phenotypical change of pre-existing psoriasis. Originally restricted to the appearance of an untoward psoriasiform reaction under TNF inhibitors, the term has gained new meaning, with the progressive observation of psoriasis-like eruptions also with other medications. Although the conceptual framework of PP has expanded, a molecular and clinicotherapeutic classification is still lacking. In addition, a certain degree of confusion surrounds the correct terminology to indicate these eruptions. In this paper, evidence on the epidemiology, clinical features, pathogenesis, and treatment of PP is reviewed, providing a perspective on possible pathogenesis-driven therapeutic approaches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aims: Aquaporin-3 (AQP3) is an aquaglyceroporin and peroxiporin that plays a crucial role in skin barrier homeostasis. Dysregulated AQP3 expression has been observed in different inflammatory skin conditions. Hidradenitis Suppurativa (HS) is an autoinflammatory keratinization disease that typically appears between 10 and 21 years of age, characterized by alteration of skin barrier homeostasis., Methods: To evaluate in vitro the role of AQP3 in the development of HS, we performed real-time PCR and Western blot to analyze gene and protein levels in human keratinocyte cell lines knock-out (KO) for NCSTN and PSENEN genes, simulating genetic-associated HS. Additionally, we investigated the impact of Glyceryl Glucoside (GG) on biological processes by performing MTT, scratch, proliferation assays and proteome studies., Results: We detected a significant decrease of the levels of AQP3 gene and protein in KO cell lines. GG effectively elevated the levels of mRNA and protein, significantly decreased the hyperproliferation rate, and enhanced cell migration in our in vitro model of genetic Hidradenitis Suppurativa. Pathway enrichment analysis further confirmed GG's role in the migration and proliferation pathways of keratinocytes., Conclusion: Our results suggest that AQP3 may act as a new novel actor in HS etio-pathogenesis, and GG could be further explored as potential treatment option for managing HS in patients., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Long COVID affects both children and adults, including subjects who experienced severe, mild, or even asymptomatic SARS-CoV-2 infection. We have provided a comprehensive overview of the incidence, clinical characteristics, risk factors, and outcomes of persistent COVID-19 symptoms in both children and adults, encompassing vulnerable populations, such as pregnant women and oncological patients. Our objective is to emphasize the critical significance of adopting an integrated approach for the early detection and appropriate management of long COVID. The incidence and severity of long COVID symptoms can have a significant impact on the quality of life of patients and the course of disease in the case of pre-existing pathologies. Particularly, in fragile and vulnerable patients, the presence of PASC is related to significantly worse survival, independent from pre-existing vulnerabilities and treatment. It is important try to achieve an early recognition and management. Various mechanisms are implicated, resulting in a wide range of clinical presentations. Understanding the specific mechanisms and risk factors involved in long COVID is crucial for tailoring effective interventions and support strategies. Management approaches involve comprehensive biopsychosocial assessments and treatment of symptoms and comorbidities, such as autonomic dysfunction, as well as multidisciplinary rehabilitation. The overall course of long COVID is one of gradual improvement, with recovery observed in the majority, though not all, of patients. As the research on long-COVID continues to evolve, ongoing studies are likely to shed more light on the intricate relationship between chronic diseases, such as oncological status, cardiovascular diseases, psychiatric disorders, and the persistent effects of SARS-CoV-2 infection. This information could guide healthcare providers, researchers, and policymakers in developing targeted interventions.

Introduction: Hidradenitis suppurativa (HS) is an autoinflammatory skin disease with a high unmet need for effective medical management. Clinically, it is characterized by inflammatory nodules that may progress into abscesses, draining tunnels and extensive scarring, mainly affecting apocrine gland-bearing areas., Areas Covered: Treatment options include topical and systemic medications and a variety of surgical procedures. The anti-TNF-α antibody adalimumab and the anti-IL-17 secukinumab are the only two approved biologics for HS, showing moderate efficacy. HS research is a rapidly growing field, with a wide range of agents leveraging distinct mechanisms of action currently under development. Drugs targeting the IL-17 and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are the most advanced in both ongoing and completed Phase 3 studies, promising deeper levels of response. Use of other, off-label biologics is also discussed., Expert Opinion: A therapeutic algorithm is proposed based on comorbidities and existing evidence. Patient-tailored combinations between biologics and other biologics or small molecules will hopefully allow clinicians to target most events in HS pathophysiology in a complementary way while obtaining a meaningful effect on their devastating manifestations.

MicroRNAs (miRNAs) play a crucial role in the early diagnosis of autoinflammatory diseases, with Hidradenitis Suppurativa (HS) being a notable example. HS, an autoinflammatory skin disease affecting the pilosebaceous unit, profoundly impacts patients' quality of life. Its hidden nature, with insidious initial symptoms and patient reluctance to seek medical consultation, often leads to a diagnostic delay of up to 7 years. Recognizing the urgency for early diagnostic tools, recent research identified significant differences in circulating miRNA expression, including miR-24-1-5p, miR-146a-5p, miR26a-5p, miR-206, miR338-3p, and miR-338-5p, between HS patients and healthy controls. These miRNAs serve as potential biomarkers for earlier disease detection. Traditional molecular biology techniques, like reverse transcription quantitative-polymerase chain reaction (RT-qPCR), are employed for their detection using specific primers and probes. Alternatively, short peptides offer a versatile and effective means for capturing miRNAs, providing specificity, ease of synthesis, stability, and multiplexing potential. In this context, we present a computational simulation pipeline designed for crafting peptide sequences that can capture circulating miRNAs in the blood of patients with autoinflammatory skin diseases, including HS. This innovative approach aims to expedite early diagnosis and enhance therapeutic follow-up, addressing the critical need for timely intervention in HS and similar conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Moltrasio, Silva, Tricarico, Marzano, Sueleman and Crovella.)

Hidradenitis suppurativa (HS) is an autoinflammatory skin disorder of the terminal hair follicle, which can present in sporadic, familial, or syndromic form. A classification has been proposed for the latter, distinguishing cases associated with a known genetic condition, with follicular keratinization disorders or with autoinflammatory diseases. This review focuses on the clinical and genetic features of those entities (ie, pyoderma gangrenosum [PG], acne and HS; PG, acne, pyogenic arthritis and HS; psoriatic arthritis, PG, acne and HS; synovitis, acne, pustulosis, hyperostosis, osteitis; and so forth) for which the collective term HS-related autoinflammatory syndromes is proposed., Competing Interests: Disclosure The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This perspective delves into the integration of artificial intelligence (AI) to enhance early diagnosis in hidradenitis suppurativa (HS). Despite significantly impacting Quality of Life, HS presents diagnostic challenges leading to treatment delays. We present a viewpoint on AI-powered clinical decision support system designed for HS, emphasizing the transformative potential of AI in dermatology. HS diagnosis, primarily reliant on clinical evaluation and visual inspection, often results in late-stage identification with substantial tissue damage. The incorporation of AI, utilizing machine learning and deep learning algorithms, addresses this challenge by excelling in image analysis. AI adeptly recognizes subtle patterns in skin lesions, providing objective and standardized analyses to mitigate subjectivity in traditional diagnostic approaches. The AI integration encompasses diverse datasets, including clinical records, images, biochemical and immunological data and OMICs data. AI algorithms enable nuanced comprehension, allowing for precise and customized diagnoses. We underscore AI's potential for continuous learning and adaptation, refining recommendations based on evolving data. Challenges in AI integration, such as data privacy, algorithm bias, and interpretability, are addressed, emphasizing the ethical considerations of responsible AI deployment, including transparency, human oversight, and striking a balance between automation and human intervention. From the dermatologists' standpoint, we illustrate how AI enhances diagnostic accuracy, treatment planning, and long-term follow-up in HS management. Dermatologists leverage AI to analyze clinical records, dermatological images, and various data types, facilitating a proactive and personalized approach. AI's dynamic nature supports continuous learning, refining diagnostic and treatment strategies, ultimately reshaping standards of care in dermatology.

Background: Obsessive-compulsive disorder (OCD) is a psychiatric disorder whose etiopathogenesis, according to various neuroimaging studies, seems to be linked to selective dysfunctions in regions within the cortico-striatal-thalamo-cortical circuit. Selective Serotonin Reuptake Inhibitors (SSRIs) are the first-line therapy for OCD but their neurobiological effects on the brain is only partially understood. Therefore, the aim of this review is to highlight structural and functional brain imaging modifications induced by SSRIs treatment., Methods: A literature search on PubMed, Psych-Info and Embase database was performed. Studies including patients with OCD that analyzed the effect of SSRIs through structural and functional Magnetic Resonance Imaging were selected. Seven relevant studies were considered eligible for the present review., Results: Overall, the results of the reviewed studies showed that SSRIs treatment seems to normalize structural, in terms of the white matter and gray matter volumes, and functional activity alterations observed in OCD patients, especially in regions within the prefrontal cortex and striatum., Limitations: The poor design of the studies, the small and heterogeneous samples, differences in age, gender, illness course, comorbidities, treatment protocols and the different magnetic fields used make it difficult to generalize the results., Conclusions: From the available evidence it emerged that SSRIs treatment has proven to be effective in normalizing brain structural and functional alterations observed in OCD patients. However, future neuroimaging investigations should focus on long-term effects of drugs on brain structure and function in OCD patients through longitudinal approaches in order to identify more effective treatments for these patients., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cutaneous manifestations of hematologic malignancy represent both a clinical challenge for the treating physician and a pathophysiological model for advancing the knowledge on individual neoplasms. Indeed, a growing body of evidence supports the concept of recurrent molecular defects associating with specific clinical features, as best exemplified by VEXAS. Herein neutrophilic and eosinophilic dermatoses of potential interest for both hematologists and dermatologists will be reviewed, including subcorneal pustular dermatosis-type IgA pemphigus, neutrophilic eccrine hidradenitis, Sweet's syndrome as well as myelodysplasia cutis and VEXAS, pyoderma gangrenosum, eosinophilic annular erythema, eosinophilic dermatosis of hematological malignancy, Wells syndrome and cutaneous involvement in hypereosinophilic syndromes. Possible management approaches are discussed for each, emphasizing scenarios that require treatment of the underlying condition to achieve remission at the skin level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Maronese, Derlino, Moltrasio, Cattaneo, Iurlo and Marzano.)

Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder, which typically occurs during puberty or early adulthood. The pathogenesis of HS is complex and multifactorial; a close interaction between hormonal, genetic, epigenetics factors, host-specific aspects, and environmental influences contributes to the susceptibility, onset, severity, and clinical course of this disease, although the exact molecular mechanisms are still being explored. Epigenetics is currently emerging as an interesting field of investigation that could potentially shed light on the molecular intricacies underlying HS, but there is much still to uncover on the subject. The aim of this work is to provide an overview of the epigenetic landscape involved in HS. Specifically, in this in-depth review we provide a comprehensive overview of DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs (such as microRNA-miRNA-132, miRNA-200c, miRNA-30a-3p, miRNA-100-5b, miRNA-155-5p, miRNA-338-5p) dysregulation in HS patients. An interesting element of epigenetic regulation in HS is that the persistent inflammatory milieu observed in HS lesional skin could be exacerbated by an altered methylation profile and histone acetylation pattern associated with key inflammatory genes. Deepening our knowledge on the subject could enable the development of targeted epigenetic therapies to potentially restore normal gene expression patterns, and subsequentially ameliorate, or even reverse, the progression of the disease. By deciphering the epigenetic code governing HS, we strive to usher in a new era of personalized and effective interventions for this enigmatic dermatological condition.

Hidradenitis suppurativa (HS) is a chronic-relapsing inflammatory skin disease. It usually appears in the second and third decades, but a smaller proportion of patients develop late-onset HS. Geriatric HS, defined as the persistence or the development of HS after the age of 65 years, has been poorly explored. This study aimed to investigate the clinical features, treatment management and response to therapies of HS elderly subjects (≥65 years old). We designed a multicentric observational study, gathering data from seven Italian university hospitals. Demographic and clinical data of HS patients aged over 65 years were collected at baseline, week 12 and week 24. Overall, 57 elderly subjects suffering from HS were enrolled. At baseline, disease severity was predominantly moderate-to-severe, with 45.6% of patients classified as Hurley III. The gluteal phenotype was the most frequently observed; it also appeared to affect patients' quality of life more than other phenotypes. Gluteal involvement was detected in about half (49.1%) of cases and associated with severe stages of the disease. In terms of therapeutic response, Hurley III patients showed the persistency of higher values of mean IHS4, DLQI, itch- and pain-NRS scores compared to Hurley I/II. In conclusion, disease severity in this subpopulation appears high and treatment is often challenging.

Background: Borderline personality disorder (BPD) is a severe psychiatric disorder characterized by emotion dysregulation, impulsivity, and interpersonal disturbances. Several structural and functional neuroimaging abnormalities have been described in BPD. In particular, resting-state functional magnetic resonance imaging (rs-fMRI) studies have recently suggested various connectivity alterations within and between large-scale brain networks in BPD. This review aimed at providing an updated summary of the evidence reported by the available rs-fMRI studies in BPD individuals., Methods: A search on PubMed, Scopus, and Web of Science was performed to identify rs-fMRI alterations in BPD. A total of 15 studies met our inclusion criteria., Results: Overall, aberrant resting-state functional connectivity (rs-FC) within and between default mode network (DMN), salience network (SN), and central executive network (CEN) were observed in BPD compared to healthy controls, as well as selective functional impairments in bilateral amygdala, anterior and posterior cingulate cortex, hippocampus, and prefrontal cortex., Limitations: The observational design, small sample size, prevalence of females, high rates of concurrent comorbidities and medications, and heterogeneity across imaging methodologies limit the generalizability of the results., Conclusions: The identification of altered patterns of rs-FC within and between selective brain networks, including DMN, SN, and CEN, could further our knowledge of the clinical symptoms of BPD, and therefore, future studies with multimodal methodologies and longitudinal designs are warranted to further explore the neural correlates of this disorder., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Sweet syndrome (SS) as a prototypic neutrophilic dermatosis (NDs) shares certain clinical and histologic features with monogenic auto-inflammatory disorders in which interleukin (IL)-1 cytokine family members play an important role. This has led to the proposal that NDs are polygenic auto-inflammatory diseases and has fuelled research to further understand the role of IL-1 family members in the pathogenesis of NDs. The aim of this study was to characterise the expression of the IL-1 family members IL-1β, IL-36γ, IL-33 and IL-1R3 (IL-1RaP) in SS. The expression profile of IL-1β, IL-33, IL-36γ and their common co-receptor IL-1R3 was analysed by immunohistochemistry, in situ hybridisation and double immunofluorescence (IF) in healthy control skin (HC) and lesional skin samples of SS. Marked overexpression of IL-1β in the dermis of SS (p < 0.001), and a non-significant increase in dermal (p = 0.087) and epidermal (p = 0.345) IL-36γ expression compared to HC was observed. Significantly increased IL-1R3 expression within the dermal infiltrate of SS skin samples (p = 0.02) was also observed, whereas no difference in IL-33 expression was found between SS and HC (p = 0.7139). In situ hybridisation revealed a good correlation between gene expression levels and the above protein expression levels. Double IF identifies neutrophils and macrophages as the predominant sources of IL-1β. This study shows that IL-1β produced by macrophages and neutrophils and IL-1R3 are significantly overexpressed in SS, thereby indicating a potential pathogenic role for this cytokine and receptor in SS., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Introduction: Major Depression Disorder (MDD) and pain appear to be reciprocal risk factors and sharing common neuroanatomical pathways and biological substrates. However, the role of MDD on pain processing remains still unclear. Therefore, this review aims to focus on the effect of depression on pain anticipation, and perception, before and after treatment, through functional magnetic resonance imaging (fMRI)., Methods: A bibliographic search was conducted on PubMed, Scopus and Web of Science, looking for fMRI studies exploring pain processing in MDD patients., Results: Amongst the 602 studies retrieved, 12 met the inclusion criteria. In terms of pain perception, studies evidenced that MDD patients generally presented increased activation in brain regions within the prefrontal cortex, insula and in the limbic system (such as amygdala, hippocampus) and occipital cortex. The studies investigating the effect of antidepressant treatment evidenced a reduced activation in areas such as insula, anterior cingulate, and prefrontal cortices. In terms of pain anticipation, contrasting results were evidenced in MDD patients, which presented both increased and decreased activity in the prefrontal cortex, the insula and the temporal lobe, alongside with increased activity in the anterior cingulate cortex, the frontal gyrus and occipital lobes., Limitations: The small number of included studies, the heterogeneous approaches of the studies might limit the conclusions of this review., Conclusions: Acute pain processing in MDD patients seems to involve numerous and different brain areas. However, more specific fMRI studies with a more homogeneous population and rigorous approach should be conducted to better highlight the effect of depression on pain processing., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Borderline Personality Disorder (BPD) is characterized by impulsiveness, interpersonal difficulties, emotional instability and dysfunctional cognitive processes. In addition to these symptoms, anger rumination is a cognitive mechanism often prominent in BPD patients and it has been found to be associated with maladaptive outcomes, such as increasing anger feelings, aggressive and impulsive behaviors. In this context, the aim of our review is to synthesize results on the relationship between emotional dysregulation and anger rumination in BPD with the final goal to get more information about possible psychotherapeutic methods in the treatment of BPD., Methods: A comprehensive search on BPD and anger rumination was performed on PubMed, Embase and Scopus. The search identified 8 articles meeting our inclusion criteria., Results: Most of the studies reported a correlation between BPD emotional instability and dyscontrolled behaviors, anger and depressive rumination. Specifically, from the reviewed studies, it emerged that the tendency to use dysfunctional cognitive strategies, such as anger rumination, predicted aggressive behavior above and beyond emotion dysregulation, ultimately suggesting that anger rumination mediates the relationship between emotional dysregulation and aggression proneness., Limitations: The cross-sectional design and the inclusion of subjects without a definite diagnosis of BPD (e.g., university students), may have decreased the generalizability of the results to the clinical populations and limited the possibility to explore the effect of anger rumination over time in BPD., Conclusions: From the reviewed studies emerged that the identification of anger rumination as a proximal process with respect to BPD may have the potential to expand and support psychotherapeutic treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The global outbreak of human monkeypox virus (hMPXV1) in 2022 highlighted the usefulness of dermatological manifestations for its diagnosis. Infection by the human monkeypox virus thus necessitated inclusion in the diagnostic repertoire of dermatopathology. To assess the histopathological and microscopical findings of cutaneous lesions related to hMPXV infection, we analyzed skin biopsies from patients with positive MPXV DNA polymerase chain reaction presenting with a typical course of hMPXV1 infection. The most prominent histopathological findings were ascribable to a pustular stage in which epidermal necrosis with areas of non-viable keratinocytes and a "shadow cell" appearance were evident; in some cases, the deep portion of the hair follicle and the acrosyringial epithelium were affected. The main cytopathic modifications included ballooning keratinocytes, followed by Guarnieri bodies and a ground glass appearance of the keratinocytes' nuclei, together with a dense mixed inflammatory cell infiltrate with prominent neutrophil exocytosis. Transmission electron microscopy analysis demonstrated viral particle aggregates in the cytoplasm of keratinocytes, without any involvement of the nucleus. Interestingly, we also found the presence of viral particles in infected mesenchymal cells, although to a lesser extent than in epithelial cells. Through this study, we contributed to expanding the histological and microscopic knowledge of the human mpox virus, a key step to understanding current and potential future trends of the disease, as well as of other Orthopoxvirus infections.

Background: Although many studies reported the neuropsychiatric involvement of testosterone (T) levels in the development of mood disorders, its role in this disabling disorder is still not well understood. Therefore, in this review, we aim to summarize the current literature exploring serum testosterone levels in both major depressive disorder (MDD) and bipolar disorder (BD), with particular attention given to the possible causal relationship between pathological mood alterations and T levels., Methods: We selected 9 original studies from a bibliographic search on PubMed, excluding studies on hormonal therapy and other psychiatric disorders other than mood disorders., Results: The results reported by the reviewed studies were conflicting especially with regards to the presence of dysfunctional levels of T in patients with BD. Specifically, while MDD was found to be associated with low levels of T compared to healthy controls (HC), in BD the results were highly heterogeneous, with a mixed picture of reduced, increased or no difference in T levels in BD patients compared to HC., Limitations: Studies were highly heterogeneous in terms of samples employed, psychometric scales used for assessing depressive symptoms, T assay methods and therapeutic regimens., Conclusions: Overall, T levels were shown to be reduced in both MDD and BD patients, ultimately suggesting that T could be useful as a biomarker in mood disorders and provide guidance for future research., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disease, clinically characterized by chronic and recurrent episodes of osteoarticular inflammation, that generally presents in children and adolescents. From a dermatological point-of-view, CMRO can be associated with skin rashes mainly including psoriasis, palmoplantar pustulosis and acne. Pyoderma gangrenosum (PG) is a rare immune-mediated inflammatory skin disease classified within the spectrum of neutrophilic dermatoses that, in some cases, has been reported as cutaneous manifestation in CMRO patients. This paper presents a 16-year female patient diagnosed with CMRO, who presented PG lesions located on the lower leg, that arose after the administration of the tumour necrosis factor (TNF)-α inhibitor adalimumab. Cases of PG have been reported in patients being treated with certain medications, including TNF-α antagonists, leading to classified them in a setting aptly termed "drug-induced PG." In this paper, we discuss the co-occurrence of PG and CRMO, in the light of recent evidence on the pathogenesis of both diseases and giving ample space to a literature review on drug induced PG. In our case, it is plausible that PG could be considered a cutaneous manifestation of CRMO, although the mechanisms underlying this intriguingly relationship remain to be fully unraveled., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Romagnuolo, Moltrasio, Iannone, Gattinara, Cambiaghi and Marzano.)

Effective options in the quiescent, scantily inflammatory phase of localized scleroderma (morphea) are lacking. A cohort study in patients with histologically confirmed fibroatrophic morphea explored the therapeutic value of the anti-dystrophic A2A adenosine agonist polydeoxyribonucleotide (PDRN, one daily 5.625 mg/3 mL ampoule for 90 days with a three-month follow-up). Primary efficacy endpoints: Localized Scleroderma Cutaneous Assessment Tool mLoSSI and mLoSDI subscores for disease activity and damage in eighteen areas; Physicians Global Assessment for Activity (PGA-A) and Damage (PGA-D) VAS scores; skin echography. Secondary efficacy endpoints: mLoSSI, mLoSDI, PGA-A, PGA-D, and morphea areas (photographs) over time; Dermatology Life Quality Index (DLQI); skin biopsy scores and induration over time. Twenty-five patients enrolled; 20 completed the follow-up period. Highly significant improvements at the end of the 3-month treatment period: mLoSSI-73.7%, mLoSDI-43.9%, PGA-A-60.4%, PGA-D-40.3%, with further improvements at follow-up visit for all disease activity and damage indexes. Overall, the outcomes suggest that a daily PDRN ampoule intramuscularly for 90 days reduces disease activity and damage rapidly and significantly in quiescent, modestly inflammatory morphea with few currently therapeutic options. The COVID-19 pandemic and lockdowns caused difficulties in enrollment, and some patients were lost to follow-up. Due to low final enrollment, the study outcomes may have only an exploratory value, yet they appear impressive. The anti-dystrophic potential of the PDRN A2A adenosine agonist deserves further in-depth exploration.

Pyoderma gangrenosum (PG) is a rare inflammatory skin disease classified within the spectrum of neutrophilic dermatoses. The pathophysiology of PG is yet incompletely understood but a prominent role of genetics facilitating immune dysregulation has been proposed. This study investigated the potential contribution of disrupted molecular pathways in determining the susceptibility and clinical severity of PG. Variant Enrichment Analysis, a bioinformatic pipeline applicable for Whole Exome Sequencing data was performed in unrelated PG patients. Eleven patients were enrolled, including 5 with unilesional and 6 with multilesional PG. Fourteen pathways were exclusively enriched in the "multilesional" group, mainly related to immune system (i.e., type I interferon signaling pathway), cell metabolism and structural functions. In the "unilesional" group, nine pathways were found to be exclusively enriched, mostly related to cell signaling and cell metabolism. Genetically altered pathways involved in immune system biology and wound repair appear to be nodal pathogenic drivers in PG pathogenesis., (© 2023. The Author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Competing Interests: Conflict of interest: The authors declare that they have no conflicts of interest.

Background: The spreading of the SARS-CoV-2 Omicron variant is probably due to its increased transmissibility and ability to escape from neutralising antibodies. Cutaneous manifestations have been reported after infection with the Omicron strain, consisting mainly of generalised urticarial eruption and prickly heat rash, also known as miliaria, that can persist for several days. Here the impact of Omicron SARS-CoV-2 on skin was investigated., Methods: The case series of 10 patients with SARS-CoV-2 Omicron variant-related cutaneous manifestations were described; moreover, skin derived cells were challenged in vitro with SARS-CoV-2 Omicron variant., Results: The main clinical cutaneous features observed were urticarial lesions lasting more than 24 h, mainly involving the trunk and sometimes extending to the extremities, and miliaria presenting with clusters of small sweat-filled vesicles, sometimes surrounded by slight erythema. HaCaT keratinocytes, BJ fibroblast cell lines and outer root sheath (ORS) keratinocytes were not susceptible to SARS-CoV-2 Omicron variant infection; they also did not present any evident cytopathic effect or modification of cells viability., Conclusion: Our findings suggests that, despite the high number of nucleotide mutations in the spike protein of SARS-CoV-2 Omicron variant, responsible to the higher transmissibility of this virus, and the increased reports of cutaneous manifestation in COVID-19 affected patients, the virus is not able to directly infect and damage the keratinocytes and fibroblasts, thus suggesting an indirect virus-induced activation of the immune system as the major pathogenetic driver.

Adverse cutaneous reactions after COVID-19 vaccinations have increased, highlighting not only how SARS-CoV-2 infection but also COVID-19 vaccines may induce adverse cutaneous manifestations. We evaluated the clinical and pathologic spectrum of mucocutaneous reactions after COVID-19 vaccinations, observed consecutively within three large tertiary centers of the Metropolitan City of Milan (Lombardy), comparing our results with the currently available literature. We retrospectively reviewed medical records and skin biopsies of patients diagnosed with mucocutaneous adverse events after COVID-19 vaccinations and followed at three Italian tertiary referral centers in the Metropolitan City of Milan. One hundred twelve patients (77 women and 35 men (112 total); median age, 60 years) have been included in the present study; a cutaneous biopsy was performed in 41 cases (36%). The trunk and arms were the most involved anatomic areas. Autoimmune reactions after COVID-19 vaccinations, urticaria, morbilliform eruptions, and eczematous dermatitis have been the most commonly diagnosed disorders. Compared to the currently available literature, we performed many more histologic examinations, allowing us to make more precise diagnoses. Most of the cutaneous reactions were self-healing and/or responded to topical and systemic steroids and systemic antihistamines, thus not discouraging the general population from carrying out vaccinations, which currently have a good safety profile., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Porokeratosis encompass a group of acquired and familial, preneoplastic, keratinization disorders, clinically characterized by atrophic macules or patches with a peripheral keratotic rim, the cornoid lamella. Genetic background is recognized as crucial in its pathophysiology, while immunosuppression and ultraviolet radiation represent triggering factors. We report the case of a woman who developed disseminate superficial actinic porokeratosis following the intake of hydroxyurea for a polycythaemia vera. Clinical, dermoscopic and histopathology data are showed, and the role of drug as a second-hit mutation trigger is discussed., (© 2022 The Authors. Australasian Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Australasian College of Dermatologists.)

The ongoing outbreak of monkeypox virus (hMPXV1) is the largest recorded in historically nonendemic countries. Genomic surveillance has emerged as a pivotal tool to track the spread and monitor the evolution of viral pathogens. Therefore, to assess the genetic diversity of circulating hMPXV1 in northern Italy in June to July 2022, we sequenced and analyzed five complete genomes of viruses sampled from patients presenting with a typical course of hMPXV1 infection. Phylogenetic analysis confirmed that all five genomes belong to the predominant epidemic lineage (B.1). Inspection of genetic changes and comparison with the reference sequence showed the presence of 12 nucleotide substitutions. Seven are nonsynonymous mutations leading to amino acid changes in six proteins belonging to different functional classes. Moreover, 11 of these 12 nucleotide mutations involve GA>AA or TC>TT replacements, suggesting that host APOBEC3 enzymes are responsible for the generation of substitutions in circulating viruses. Finally, metagenomic analysis evidenced bacterial superinfection (Streptococcus pyogenes) in one patient. Through this study, we contributed to expand the number of complete genomes of viruses circulating in Italy and characterize them as belonging to the predominant outbreak lineage., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: AIM2 is a key cytoplasmatic pathogen-sensor that detects foreign DNA from viruses and bacteria; it can also recognize damaged or anomalous presence of DNA, promoting inflammasome assembly and activation with the secretion of IL-1β, thus sustaining a chronic inflammatory state, potentially leading to the onset of autoinflammatory skin diseases. Given the implication of the IL-1β pathway in the pathogenesis of syndromic hidradenitis suppurativa (HS), an autoinflammatory immune-mediated skin condition, the potential involvement of AIM2 was investigated., Methods: Sequencing of the whole coding region of the AIM2 gene, comprising 5'- and 3' UTR and a region upstream of the first exon of ~800 bp was performed in twelve syndromic HS patients., Results: Six out of twelve syndromic HS patients carried a heterozygous variant c.-208 A ≥ C (rs41264459), located on the promoter region of the AIM2 gene, with a minor allele frequency of 0.25, which is much higher than that reported in 1000 G and GnomAD (0.075 and 0.094, respectively). The same variant was found at a lower allelic frequency in sporadic HS and isolated pyoderma gangrenosum (PG) (0.125 and 0.065, respectively)., Conclusion: Our data suggest that this variant might play a role in susceptibility to develop syndromic forms of HS but not to progress to sporadic HS and PG. Furthermore, epigenetic and/or somatic variations could affect AIM2 expression leading to different, context-dependent responses.

Background: Chronic spontaneous urticaria (CSU) is defined as the recurrence of unprovoked transient wheals and itch for more than 6 weeks. Currently, there is an unmet need concerning response prediction in CSU. The present study investigated biomarkers of type I and type IIb autoimmunity as potential predictors of response to omalizumab in CSU. Materials and methods: Differences in levels of IgG and IgE autoantibodies targeting the high- and low-affinity IgE receptors (FcεRI and FcεRII, respectively), as well as spontaneous and specifically triggered leukotriene C (LTC)4 release by basophils from the investigated subjects, were evaluated in 18 consecutive, prospectively enrolled CSU patients and 18 age- and sex-matched, healthy non-atopic controls. Results: The patients with CSU had higher levels of anti-FcεRI IgE (542 (386.25-776.5) vs. 375 (355-418), optical density (OD), p = 0.008), and IgG (297 (214.5-431.25) vs. 193.5 (118-275) OD, p = 0.004) autoantibodies relative to the controls. Simultaneous anti-FcεRI IgG and IgE positivity (i.e., both autoantibody levels above the respective cut-offs) was recorded only in late- and non-responders (3/8 and 1/2, respectively). Discussion: Significantly higher anti-FcεRI IgE autoantibody levels were found in the CSU patients as compared to the controls, supporting FcεRI as an autoallergic target of IgE (autoallergen) in the complex pathophysiological scenario of CSU. The co-occurrence of anti-FcεRI IgG and IgE autoantibodies was documented only in late- and non-responders, but not in early ones, crediting the co-existence of autoimmune and autoallergic mechanisms as a driver of late/poor response to omalizumab.

Background: COronaVIrus Disease 19 (COVID-19) is associated with a wide spectrum of skin manifestations, but SARS-CoV-2 RNA in lesional skin has been demonstrated only in few cases., Objective: The objective of this study was to demonstrate SARS-CoV-2 presence in skin samples from patients with different COVID-19-related cutaneous phenotypes., Methods: Demographic and clinical data from 52 patients with COVID-19-associated cutaneous manifestations were collected. Immunohistochemistry and digital PCR (dPCR) were performed in all skin samples. RNA in situ hybridization (ISH) was used to confirm the presence of SARS-CoV-2 RNA., Results: Twenty out of 52 (38%) patients presented SARS-CoV-2 positivity in the skin. Among these, 10/52 (19%) patients tested positive for spike protein on immunohistochemistry, five of whom had also positive testing on dPCR. Of the latter, one tested positive both for ISH and ACE-2 on immunohistochemistry while another one tested positive for nucleocapsid protein. Twelve patients showed positivity only for nucleocapsid protein on immunohistochemistry., Conclusions: SARS-CoV-2 was detected only in 38% of patients, without any association with a specific cutaneous phenotype, suggesting that the pathophysiology of cutaneous lesions mostly depends on the activation of the immune system. The combination of spike and nucleocapsid immunohistochemistry has higher diagnostic yield than dPCR. Skin persistence of SARS-CoV-2 may depend on timing of skin lesions, viral load, and immune response., (© 2023 S. Karger AG, Basel.)

Background: Previously, a new dichotomous outcome was developed, calculated as 55% reduction in the International Hidradenitis Suppurativa 4 (IHS4-55) score. It was validated in datasets of adalimumab and placebo-treated HS patients. External validation is an important aspect of clinical outcomes., Objectives: We aimed to externally validate the novel dichotomous IHS4-55 in a non-biologic treated dataset of HS patients., Methods: Data from a previously published European-wide prospective clinical study of antibiotic treatment of HS patients were used to assess the association of IHS4-55 achievement with individual reduction in inflammatory nodules, abscesses, and draining tunnels. Moreover, the associations between IHS4-55 positivity and achievement of the minimal clinically important differences (MCIDs) for Dermatology Life Quality Index (DLQI), Numerical Rating Scale (NRS) Pain, and NRS Pruritus were analyzed., Results: Data were obtained from 283 individual patients, of which 36.4% (103/283) were treated with clindamycin and rifampicin and 63.6% (180/283) with tetracyclines for 12 weeks. Achievers of the IHS4-55 demonstrated a significant reduction the counts of inflammatory nodules, abscesses, and draining tunnels (all p < 0.001). Additionally, IHS4-55 achievers had an odds ratio for achieving the MCID of DLQI, NRS Pain, and NRS Pruritus of 2.16 (95% CI 1.28-3.65, p < 0.01), 1.79 (95% CI 1.10-2.91, p < 0.05), and 1.95 (95% CI 1.18-3.22, p < 0.01), respectively., Conclusions: This study shows the external validity of the novel IHS4-55 by demonstrating a significant association between IHS4-55 achievement and a reduction in inflammatory lesion counts as well as achievement of MCIDs for DLQI, NRS Pain, and NRS Pruritus in an antibiotic-treated cohort. These findings support the use of the IHS4-55 as a novel primary outcome measure in clinical trials., (© 2023 S. Karger AG, Basel.)

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin's physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tricarico, Gratton, Santos-Silva, Moura, Ura, Sommella, Campiglia, Del Vecchio, Moltrasio, Berti, D’Adamo, Elsherbini, Staudenmaier, Chersi, Boniotto, Krismer, Schittek and Crovella.)

Background: Brunsting-Perry pemphigoid (BPP) is a rare, autoimmune bullous skin disorder classified within the spectrum of mucous membrane pemphigoid (MMP)., Materials and Methods: An a priori protocol was designed based on PRISMA guidelines. PubMed and Scopus databases were searched for English-language articles concerning BPP published between 1950 and July 2021., Results: Thirty-six articles including 63 BPP patients were analyzed. The mean age at diagnosis was 62.9 years (range: 27-86). BPP was shown to be characterized by vesiculobullous lesions (46/63, 73.0%) on an erythematous base, erosions or ulcerations (27/63, 42.9%), atrophic scars (49/63, 77.8%), and milia (4/63, 6.3%). Exclusive oral mucosal involvement was documented in 22.2% of cases, usually manifesting after the cutaneous onset of the disease. Subepidermal blistering was a constant finding, often with an eosinophil-rich inflammatory infiltrate (21/58, 36.2%). Positive direct immunofluorescence was found in 92.0% of patients, almost always with linear IgG ± C3 deposits along the basement membrane (43/46, 93.5%). BP180 (12/15, 80.0%), BP230 (5/15, 33.3%), and laminin 332 (3/15, 20.0%) were the most frequently identified target antigens., Conclusions: BPP nosologic position remains uncertain, given the overlap with other autoimmune bullous diseases, such as MMP, bullous pemphigoid, and epidermolysis bullosa acquisita, particularly in its BPP-like variant. Nonpredominant oral mucosal lesions may appear during the course of the disease, generally after cutaneous manifestations. Positivity of DIF and anti-BP180/230 autoantibodies detected on ELISA/immunoblotting in the absence of anticollagen VII antibodies may provide guidance in diagnosing BPP., (© 2022 the International Society of Dermatology.)

The NLRP3 inflammasome is one of the NOD-like receptor family members with the most functional characterization and acts as a key player in innate immune system, participating in several physiological processes including, among others, the modulation of the immune system response and the coordination of host defences. Activation of the inflammasome is a crucial signaling mechanism that promotes both an acute and a chronic inflammatory response, which can accelerate the production of pro-inflammatory cytokines, mainly Interleukin (IL)-1β and IL-18, leading to an exacerbated inflammatory network. Cryopyrin associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder, clinically characterized by cutaneous and systemic, musculoskeletal, and central nervous system inflammation. Gain-of-function mutations in NLRP3 gene are causative of signs and inflammatory symptoms in CAPS patients, in which an abnormal activation of the NLRP3 inflammasome, resulting in an inappropriate release of IL-1β and gasdermin-D-dependent pyroptosis, has been demonstrated both in in vitro and in ex vivo studies. During recent years, two new hereditary NLRP3-related disorders have been described, deafness autosomal dominant 34 (DFN34) and keratitis fugax hereditaria (KFH), with an exclusive cochlear- and anterior eye- restricted autoinflammation, respectively, and caused by mutations in NLRP3 gene, thus expanding the clinical and genetic spectrum of NLRP3-associated autoinflammatory diseases. Several crucial mechanisms involved in the control of activation and regulation of the NLRP3 inflammasome have been identified and researchers took advantage of this to develop novel target therapies with a significant improvement of clinical signs and symptoms of NLRP3-associated diseases. This review provides a broad overview of NLRP3 inflammasome biology with particular emphasis on CAPS, whose clinical, genetic, and therapeutic aspects will be explored in depth. The latest evidence on two "new" diseases, DFN34 and KFH, caused by mutations in NLRP3 is also described., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moltrasio, Romagnuolo and Marzano.)