A novel mutation in the SCN9A gene associated with congenital insensitivity to pain, anhidrosis, and mild cognitive impairment.

Congenital insensitivity to pain (CIP) is a rare phenotype characterized by the inability to perceive pain stimuli with subsequent self-injuries, whereas CIP associated with anhidrosis (CIPA) is an overlapping phenotype mainly characterized by insensitivity to noxious stimuli and anhidrosis. CIP is primarily associated with pathogenetic variants in the SCN9A gene while CIPA is associated with pathogenetic variants in NGF and NRTK genes. However, in recent years, a significant overlap between these two disorders has been observed highlighting the presence of anhidrosis in SCN9A variants. We report the cases of two siblings (age 4 and 6 years) born from consanguineous parents presenting with a previously undescribed phenotype due to a novel pathogenic variant in SCN9A clinically characterized by congenital insensitivity to pain, anhidrosis, and mild cognitive impairment.

Whole-genome sequencing of hMPXV1 in five Italian cases confirms the occurrence of the predominant epidemic lineage.

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.

Characterisation of IL-1 family members in Sweet syndrome highlights the overexpression of IL-1ß and IL-1R3 as possible therapeutic targets.

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-1ß, IL-36γ, IL-33 and IL-1R3 (IL-1RaP) in SS. The expression profile of IL-1ß, 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-1ß 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-1ß. This study shows that IL-1ß 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.

Clinical and Molecular Characterization of Hidradenitis Suppurativa: A Practical Framework for Novel Therapeutic Targets.

BACKGROUND: The pathophysiological picture underlying hidradenitis suppurativa (HS) and its syndromic forms is still patchy, thus presenting a great challenge for dermatologists and researchers since just by better understanding the pathogenesis of disease we could identify novel therapeutic targets. METHODS: We propose a practical framework to improve subcategorization of HS patients and support the genotype-phenotype correlation, useful for endotype-directed therapies development. RESULTS: This framework includes (i) clinical work-up that involves the collection of demographic, lifestyle, and clinical data as well as the collection of different biological samples; (ii) genetic-molecular work-up, based on multi-omics analysis in combination with bioinformatics pipelines to unravel the complex etiology of HS and its syndromic forms; (iii) functional studies, - represented by skin fibroblast cell cultures, reconstructed epidermal models (both 2D and 3D) and organoids -, of candidate biomarkers and genetic findings necessary to validate novel potential molecular mechanisms possibly involved and druggable in HS; (iv) genotype-phenotype correlation and clinical translation in tailored targeted therapies. CONCLUSION: Omic findings should be merged and integrated with clinical data; moreover, the skin-omic profiles from each HS patient should be matched and integrated with the ones already reported in public repositories, supporting the efforts of the researchers and clinicians to discover novel biomarkers and molecular pathways with the ultimate goal of providing faster development of novel patient-tailored therapeutic approaches.

SARS-CoV-2 Detection by Digital Polymerase Chain Reaction and Immunohistochemistry in Skin Biopsies from 52 Patients with Different COVID-19-Associated Cutaneous Phenotypes.

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.

External Validation of the IHS4-55 in a European Antibiotic-Treated Hidradenitis Suppurativa Cohort.

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.

Disseminated superficial actinic porokeratosis following hydroxyurea treatment: A case report.

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.

Urticarial vasculitis: Clinical and laboratory findings with a particular emphasis on differential diagnosis.

Urticarial vasculitis (UV) is a rare cutaneous vasculitis of small vessels characterized by recurrent episodes of wheal-like lesions that tend to last more than 24 hours, healing with a residual ecchymotic postinflammatory hyperpigmentation. The histopathologic pattern of UV is that of leukocytoclastic vasculitis, consisting of fibrinoid necrosis of dermal vessels' walls and neutrophil-rich perivascular inflammatory infiltrates. Although its etiopahogenesis remains still undefined, UV is now regarded as an immune complex-driven disease with activation of the complement cascade, leading to exaggerated production of anaphylatoxins that are responsible for neutrophil recruitment and activation. This condition can be categorized into 2 main entities according to serum complement levels: normocomplementemic UV and hypocomplementemic UV, the latter being associated with circulating anti-C1q autoantibodies and possible extracutaneous manifestations. Systemic multiorgan involvement may be seen particularly in syndromic hypocomplementemic UV, also known as McDuffie syndrome. This review summarizes the clinicopathological and laboratory features as well as the underlying pathophysiological mechanisms of UV. A focus on its main differential diagnoses is provided, that is, chronic spontaneous urticaria, bullous pemphigoid, IgA (Henoch-Schönlein purpura) and IgM/IgG immune complex vasculitis, lupus erythematous tumidus, Wells syndrome, erythema multiforme, cutaneous mastocytosis, cryopyrin-associated periodic syndromes, and coronavirus disease 2019-associated and anti-severe acute respiratory syndrome coronavirus 2-vaccine-associated urticarial eruptions.

Real-world evidence of biologic treatments in moderate-severe psoriasis in Italy: Results of the CANOVA (EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: An obserVAtional longitudinal study of real-life clinical practice) study.

EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: An obserVAtional (CANOVA) study was aimed at providing real-world evidence of the effectiveness of biologics in Italian patients with moderate-severe psoriasis. It was an observational, retro-prospective cohort study conducted in 17 Italian dermatology clinics. Adult patients with moderate-severe plaque psoriasis, who started a biologic treatment between 24 weeks and 24 months before enrolment, were included. With a follow-up visit at 6 months after enrolment, each patient had at least 12 months of observation. The primary objective was to describe the clinical response rates (PASI 75) after 16/24/52 weeks from biologic treatment start. Secondary outcomes were sustained response, quality of life, and treatment satisfaction. Of the 669 eligible patients (64% males), 52% were naïve to biologics, though a mean duration of psoriasis since first diagnosis of 18.6 years (SD 13.2). The most frequently prescribed biologics were secukinumab (41%), ustekinumab (25%), TNF-inhibitors (22%) and ixekizumab (12%). PASI 75 was achieved by 86% of patients (95% CI: 82%-89%) at 16 weeks, 90% (87%-93%) at 24 weeks, and 91% (89%-94%) at 52 weeks. Patients achieving PASI 90 and PASI 100 at 52 weeks were 75% (71%-79%) and 53% (49%-57%), respectively. Sustained PASI 75 response after 1 year from treatment start was achieved by 78% (74%-82%) of patients. Mean DLQI total score was 2.3 (SD 3.9) at enrollment and decreased at the final visit to 1.8 (3.6). A high level of treatment satisfaction was expressed by patients over the study period. This large real-world study confirms in the clinical practice the good effectiveness and acceptability of biologics in psoriasis patients.

Multisystem Inflammatory Syndrome in Children Associated with COVID-19: A Review with an Emphasis on Mucocutaneous and Kawasaki Disease-Like Findings.

BACKGROUND: COronaVIrus Disease 2019 (COVID-19) affects children with less severe symptoms than adults. However, severe COVID-19 paediatric cases are increasingly reported, including patients with Kawasaki disease (KD) or a multisystem inflammatory syndrome (MIS-C) that can present with features resembling KD. SUMMARY: MIS-C is an emerging severe paediatric syndrome associated with COVID-19 that can show overlapping features of KD, KD shock syndrome, and toxic shock syndrome. MIS-C might be an inflammatory disease distinct from KD resulting from an exaggerated immune response. A high prevalence of mucocutaneous manifestations - in addition to gastrointestinal and cardiovascular involvements - was found in MIS-C. The most frequent mucocutaneous findings were conjunctivitis and rash, often described as macular and/or papular or polymorphous. In this article, we present a brief overview of MIS-C with an emphasis on mucocutaneous findings and the relationship with KD.

Whole-Exome Sequencing in 10 Unrelated Patients with Syndromic Hidradenitis Suppurativa: A Preliminary Step for a Genotype-Phenotype Correlation.

BACKGROUND: The genetics of syndromic hidradenitis suppurativa (HS), an immune-mediated condition associated with systemic comorbidities such as inflammatory bowel diseases and arthritis, has not been completely elucidated. OBJECTIVE: To describe clinical features and genetic signature of patients with the main syndromic HS forms, i.e., PASH, PAPASH, and PASH/SAPHO overlapping. METHODS: Whole-exome sequencing (WES) approach was performed in ten patients with syndromic HS. RESULTS: Three clinical settings have been identified based on presence/absence of gut and joint inflammation. Four PASH patients who had also gut inflammation showed three different variants in NOD2 gene, two variants in OTULIN, and a variant in GJB2, respectively. Three PAPASH and three PASH/SAPHO overlapping patients who had also joint inflammation showed two different variants in NCSTN, one in WDR1 and PSTPIP1, and two variants in NLRC4, one of whom was present in a patient with a mixed phenotype characterized by gut and joint inflammation. LIMITATIONS: Limited number of patients that can be counterbalanced by the rarity of syndromic HS. CONCLUSION: Syndromic HS can be considered as a polygenic autoinflammatory condition; currently WES is a diagnostic tool allowing more accurate genotype-phenotype correlation.

Ultraviolet A phototest positivity is associated with higher free erythrocyte protoporphyrin IX concentration and lower transferrin saturation values in erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited. METHODS: To investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment-naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25-hydroxyvitamin D, and liver enzyme levels. RESULTS: Median FEP concentration at the time of phototesting was 57.50 (IQR: 34.58-102.70) µg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest-positive patients than in those negative (64.37 [IQR: 57.45-121.82] vs 45.35 [IQR: 24.53-74.61] µg/g of Hb, respectively; P = .04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR: 33.5-84] µg/dL vs 109 [IQR: 63.25-154] µg/dL, respectively; P = .01862) and transferrin saturation values (15.005 [IQR: 7.0775-18.41] % vs 29.645 [IQR: 17.8225-34.3575] %; P = .0109) than those negative. CONCLUSIONS: Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP.

Epigenetic Mechanisms of Epidermal Differentiation.

Keratinocyte differentiation is an essential process for epidermal stratification and stratum corneum formation. Keratinocytes proliferate in the basal layer of the epidermis and start their differentiation by changing their functional or phenotypical type; this process is regulated via induction or repression of epidermal differentiation complex (EDC) genes that play a pivotal role in epidermal development. Epidermal development and the keratinocyte differentiation program are orchestrated by several transcription factors, signaling pathways, and epigenetic regulators. The latter exhibits both activating and repressive effects on chromatin in keratinocytes via the ATP-dependent chromatin remodelers, histone demethylases, and genome organizers that promote terminal keratinocyte differentiation, and the DNA methyltransferases, histone deacetylases, and Polycomb components that stimulate proliferation of progenitor cells and inhibit premature activation of terminal differentiation-associated genes. In addition, microRNAs are involved in different processes between proliferation and differentiation during the program of epidermal development. Here, we bring together current knowledge of the mechanisms controlling gene expression during keratinocyte differentiation. An awareness of epigenetic mechanisms and their alterations in health and disease will help to bridge the gap between our current knowledge and potential applications for epigenetic regulators in clinical practice to pave the way for promising target therapies.

Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis.

The challenge of unravelling the molecular basis of multifactorial disorders nowadays cannot rely just on association studies searching for potential causative variants shared by groups of patients and not present in healthy individuals; indeed, association studies have as a main limitation the lack of information on the interactions between the disease-causing variants. Thus, new genomic analysis tools focusing on disrupted pathways rather than associated gene variants are required to better understand the complexity of a disease. Therefore, we developed the Variant Enrichment Analysis (VEA) workflow, a tool applicable for whole exome sequencing data, able to find differences between the numbers of genetic variants in a given pathway in comparison with a reference dataset. In this study, we applied VEA to discover novel pathways altered in patients with complex autoinflammatory skin disorders, namely PASH (n = 9), 3 of whom are overlapping with SAPHO) and PAPASH (n = 3). With this approach we have been able to identify pathways related to neutrophil and endothelial cells homeostasis/activations, as disrupted in our patients. We hypothesized that unregulated neutrophil transendothelial migration could elicit increased neutrophil infiltration and tissue damage. Based on our findings, VEA, in our experimental dataset, allowed us to predict novel pathways impaired in subjects with autoinflammatory skin disorders.

The clinical spectrum of COVID-19-associated cutaneous manifestations: An Italian multicenter study of 200 adult patients.

BACKGROUND: COVID-19 is associated with a wide range of skin manifestations. OBJECTIVE: To describe the clinical characteristics of COVID-19-associated skin manifestations and explore the relationships among the 6 main cutaneous phenotypes and systemic findings. METHODS: Twenty-one Italian Dermatology Units were asked to collect the demographic, clinical, and histopathologic data of 200 patients with COVID-19-associated skin manifestations. The severity of COVID-19 was classified as asymptomatic, mild, moderate, or severe. RESULTS: A chilblain-like acral pattern was significantly associated with a younger age (P < .0001) and, after adjusting for age, significantly associated with less severe COVID-19 (P = .0009). However, the median duration of chilblain-like lesions was significantly longer than that of the other cutaneous manifestations taken together (P < .0001). Patients with moderate/severe COVID-19 were more represented than those with asymptomatic/mild COVID-19 among the patients with cutaneous manifestations other than chilblain-like lesions, but only the confluent erythematous/maculo-papular/morbilliform phenotype was significantly associated with more severe COVID-19 (P = .015), and this significance disappeared after adjustment for age. LIMITATIONS: Laboratory confirmation of COVID-19 was not possible in all cases. CONCLUSIONS: After adjustment for age, there was no clear-cut spectrum of COVID-19 severity in patients with COVID-19-related skin manifestations, although chilblain-like acral lesions were more frequent in younger patients with asymptomatic/pauci-symptomatic COVID-19.

The efficacy and tolerability of tetracyclines and clindamycin plus rifampicin for the treatment of hidradenitis suppurativa: Results of a prospective European cohort study.

BACKGROUND: Tetracyclines and clindamycin plus rifampicin combination therapy are both considered first-line therapy in current hidradenitis suppurativa guidelines. However, evidence for their efficacy is drawn from small studies, often without validated outcomes. OBJECTIVE: To assess the 12-week efficacy of oral tetracyclines and a combination of clindamycin and rifampicin. METHODS: A prospective, international cohort study performed between October 2018 and August 2019. RESULTS: In total, 63.6% of the included 283 patients received oral tetracyclines, and 36.4% were treated with clindamycin and rifampicin. Both groups showed a significant decrease in International Hidradenitis Suppurativa Severity Score System from baseline (both P < .001). The Hidradenitis Suppurativa Clinical Response (HiSCR) was achieved in 40.1% and 48.2% of patients, respectively (P = .26). Patient characteristics or disease severity were not associated with the attainment of HiSCR or the minimal clinically important differences for the Dermatology Life Quality Index and pain. LIMITATIONS: Cohort study. Respectively, 23.9% and 19.4% of patients had to be excluded from the HiSCR analysis for the tetracycline and combination therapy group because of a low abscess and nodule count at baseline. CONCLUSION: This study shows significant efficacy of both tetracycline treatment and clindamycin and rifampicin combination therapy after 12 weeks in patients with hidradenitis suppurativa. No significant differences in efficacy were observed between the 2 treatments, regardless of disease severity.

Vascularization and fibrosis are important ultrasonographic tools for assessing response to adalimumab in hidradenitis suppurativa: Prospective study of 32 patients.

Hidradenitis suppurativa (HS) is a debilitating skin disease presenting with nodules, abscesses, and fistulae preferentially in the main folds. Adalimumab is the only licensed biologic for moderate-to-severe HS. Ultrasound demonstrated good sensitivity to provide anatomic and functional information in HS; in particular assessing vascularization, related to inflammation, and fibrosis in HS lesions before and after adalimumab treatment with ultrasound and Color Doppler may integrate clinical evaluation with imaging. Patients with moderate-to-severe HS were enrolled in this observational prospective study. Clinical evaluation (according to Hurley classification and International Hidradenitis Suppurativa Severity Score System score) and ultrasound (according to US HS-PGA)/Color Doppler were performed at baseline and after 12 weeks of adalimumab. Ultrasound was used for assessing fibrosis and Color Doppler for vascularization. For each patient, the three most severe lesions among abscesses and fistulae were chosen for total 96 lesions. Thirty-two patients were included, 18 men (56%) and 14 women (44%) with mean age 41.2. Mean IHS4 was 22.4 at baseline and dropped to 14.7 at week 12. Based on US HS-PGA, 14 out of 32 patients fell down by one or more classes of severity. Interestingly, adalimumab led to overall decrease in vascularization, particularly in lesions with intense vascular flow, which were 78 (81.3%) at baseline and became only 25 (26.04%). Finally, marked increase in fibrosis was seen after adalimumab, notably in lesions without fibrosis, which were 81 (84.4%) at baseline and became 15 (15.6%). This study confirms the efficacy of adalimumab in HS and provides value for vascularization and fibrosis as important ultrasonographic tools integrating clinical scores.

Skin Manifestations Associated with COVID-19: Current Knowledge and Future Perspectives.

BACKGROUND: Coronavirus disease-19 (COVID-19) is an ongoing global pandemic caused by the "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), which was isolated for the first time in Wuhan (China) in December 2019. Common symptoms include fever, cough, fatigue, dyspnea and hypogeusia/hyposmia. Among extrapulmonary signs associated with COVID-19, dermatological manifestations have been increasingly reported in the last few months. SUMMARY: The polymorphic nature of COVID-19-associated cutaneous manifestations led our group to propose a classification, which distinguishes the following six main clinical patterns: (i) urticarial rash, (ii) confluent erythematous/maculopapular/morbilliform rash, (iii) papulovesicular exanthem, (iv) chilblain-like acral pattern, (v) livedo reticularis/racemosa-like pattern, (vi) purpuric "vasculitic" pattern. This review summarizes the current knowledge on COVID-19-associated cutaneous manifestations, focusing on clinical features and therapeutic management of each category and attempting to give an overview of the hypothesized pathophysiological mechanisms of these conditions.

A real-world economic analysis of biologic therapies for moderate-to-severe plaque psoriasis in Italy: results of the CANOVA observational longitudinal study.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease which can also involve joints. It is often associated with burdensome comorbidities which negatively impact prognosis and quality of life (QoL). Biologic agents have been shown to be effective in controlling disease progression, but their use is associated with higher costs compared with traditional systemic treatments. The economic analysis of the CANOVA (EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: an obserVAtional longitudinal study of real-life clinical practice) study aims to assess the costs and cost-effectiveness of biologics in a real-world context in Italy. METHODS: The annualised overall direct costs of moderate-to-severe plaque psoriasis management, the annualised cost of biologic drugs and the cost per responder in the Italian National Health System perspective were assessed. More specifically, the cost per response and cost per sustained response of the most prescribed biologic therapies for the treatment of moderate-to-severe plaque psoriasis within the CANOVA study were assessed using the Psoriasis Area Severity Index (PASI) at several score levels (75, 90 and 100%). RESULTS: The most frequently used biologic therapies for plaque psoriasis were secukinumab, ustekinumab, adalimumab originator, and ixekizumab. Cost of biologics was the driver of expenditure, accounting for about 98% of total costs. Adalimumab originator was the biologic with the lowest cost per responder ratio (range: €7848 - €31,378), followed by secukinumab (range: €9015 - €33,419). Ustekinumab (range: €11,689 - €39,280) and ixekizumab (range: €11,092 - €34,289) ranked respectively third and fourth, in terms of cost-effectiveness ratio. As concerns the cost per sustained response analysis, secukinumab showed the lowest value observed (€21,375) over the other options, because of its high response rate (86% vs. 60-80%), which was achieved early in time. CONCLUSION: Biologic therapy is a valuable asset for the treatment of moderate-to-severe plaque psoriasis. Concomitant assessment of treatment costs against the expected therapeutic response over time can provide physicians and payers additional insights which can complement the traditional risk-benefit profile assessment and drive treatment decisions.

Cutaneous-group histiocytoses associated with myeloid malignancies: A systematic review of 102 cases.

BACKGROUND: Histiocytoses are haematological disorders of bone marrow origin that share many biological and clinical features with haematological neoplasms. The association between histiocytoses of the cutaneous-group and myeloid malignancies is a poorly investigated topic of high biological and clinical impact. METHODS: We performed a systematic review of the scientific literature, compliant with PRISMA guidelines, to unravel the clinical and pathological features of this intriguing association. FINDINGS: We gathered and analysed 102 patients. Most were children with generalised cutaneous eruptions and displayed risk organ involvement (i.e. bone marrow, spleen, liver). Interestingly, all these features are uncommonly encountered in C-group histiocytosis not associated with haematological neoplasms. CONCLUSIONS: Our review shows that generalised eruptions and risk organ involvement in cutaneous-group histiocytosis should raise a suspicion for a concomitant myeloid neoplasm both in children and in adults and warrant further investigations. A rapid recognition of this association is required to start a prompt and effective therapeutic management given the aggressive behaviour of the associated myeloid neoplasm in most instances.