Short-, mid- and long-term efficacy of dupilumab in moderate to severe atopic dermatitis: a real life multicenter Italian study on 2576 patients.

BACKGROUND: The efficacy and safety of dupilumab in atopic dermatitis (AD) have been defined in clinical trials but limited real-world evidence on long term treatment outcomes are currently available to inform clinical decisions. OBJECTIVES: to describe long-term effectiveness and safety of dupilumab up to 48 months in patients with moderate-to-severe AD. METHODS: a multicenter, retrospective, dynamic cohort study was conducted to assess long term effectiveness and safety of dupilumab in patients with moderate to severe AD in a real-world setting. Predictors of minimal disease activity (MDA) optimal treatment target criteria (defined as the simultaneous achievement of EASI90, itch NRS score ≤1, sleep NRS score ≤1 and DLQI ≤1) were investigated. RESULTS: 2576 patients were enrolled from June 2018 to July 2022. MDA optimal treatment target criteria were achieved by 506 (21.91%), 769 (40.63%), 628 (50.36%), 330 (55.37%) and 58 (54.72%) of those that reached 4, 12, 24, 36 and 48 months of follow-up, respectively. Logistic regression revealed a negative effect on MDA achievement for conjunctivitis and food allergy at all timepoints. Adverse events (AE) were mild and were observed in 373 (15.78%), 166 (7.02%), 83 (6.43%), 27 (4.50%) and 5 (4.55%) of those that reached 4, 12, 24, 36 and 48 months of follow-up. Conjunctivitis was the most frequently reported AE during the available follow-up. AE led to treatment discontinuation in <1% of patients during the evaluated time periods. CONCLUSION: High long-term effectiveness and safety of dupilumab were confirmed in this dynamic cohort of patients with moderate to severe AD, regardless of clinical phenotype and course at baseline. Further research will be needed to investigate the effect of Th2 comorbidities and disease duration on the response to dupilumab and other newer therapeutics for AD.

Autoreactivity to self-antigens LL37 and ADAMTSL5 influences the clinical response to risankizumab in psoriatic patients.

The autoantigens LL37 and ADAMTSL5 contribute to induce pathogenetic T-cells responses in a subset of psoriatic patients. Whether the presence of LL37-and/or ADAMTS5-reactive T-cells influences the clinical response to treatment is still unknown. The aim of the study is to evaluate the clinical responses to the anti-IL-23 risankizumab in LL37 and/or ADAMTSL5-reactive patients in comparison with non-reactive ones and to assess whether genetics (HLA-Cw06.02) or BMI influences the response to treatment. Patients were screened at baseline for the presence of circulating LL37 or/and ADAMTSL5-reactive T-cells and were treated as per protocol with risankizumab. Effectiveness data (PASI scores) were collected at weeks 4, 16, 28, 40 and 52. Data were also analyzed based on HLA-Cw06.02 status and BMI. The overall response to treatment of patients with autoreactivity to LL37 or ADAMTSL5 did not differ compared to the non-reactive cohort as measured as PASI75/90/100 at different time points; however, subjects that had autoreactive T-cells to both LL37 and ADAMTS5 demonstrated suboptimal response to treatment starting at week16. HLA-Cw06:02+ patients demonstrated faster response to risankizumab at week 4 compared to HLA-Cw06:02-. Additionally, the response to treatment was influenced by the BMI with slower responses seen in overweight and obese patients at week 4 and week16. In conclusion, while the presence of either LL37-and ADAMTS5-reactive circulating T-cells do not influence the clinical response to risankizumab, the presence of the double reactivity to both LL37 and ADAMTS5 decreases the clinical responses. Moreover, we evidenced that HLA-Cw06+ respond faster to IL-23 inhibition and that BMI, associated to autoreactivity, can influence the speed in response.

Efficacy of Siltuximab and 1,927 nm Fractional Laser for the Treatment of Cutaneous Manifestations in Castleman's Disease: The Role of Dermoscopy and Reflectance Confocal Microscopy for Lesion Evaluation.

Introduction: Multicentric Castleman's disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman's disease (CD) is usually a challenge, especially in case of cutaneous involvement. Case Presentation: We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. Conclusion: We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings.

Bone marrow metastases: a systematic review of a neglected involvement in malignant melanoma.

The occurrence of bone marrow metastases (BMM) in melanoma patients is often underestimated, with only 7% detected during in-vivo staging procedures but rising to 45% in autopsy cases. This systematic review aims to shed light on the clinical and laboratory features of BMM in melanoma by analyzing 73 studies selected from 2 482 initially retrieved from PubMed, Embase , and Cochrane CENTRAL databases. Our findings reveal a slight male predominance, with a median age at BMM diagnosis of 56 years. Primary melanoma sites included the skin (52%), mucosa (8.8%), uvea (20.5%) and unidentified (19%). BMM was preceded by lymph node involvement in 36.5% of cases, whereas 63% showed no nodal metastases, with direct BMM occurring in 22.5% and metastases to other sites in 41%. Common BMM symptoms included pain (60.7%), anemia (80%), thrombocytopenia, leukoerythroblastosis, pancytopenia and leukopenia, while disseminated intravascular coagulation was detected in 11% of cases. In 23.6% of cases, BMM was amelanotic. The prognosis for BMM is grim, with a median survival of only 2 months. Conventional therapies for BMM remain largely ineffective, emphasizing the importance of considering bone marrow as a potential metastatic site in melanoma patients.

Burden of Disease in the Real-Life Setting of Patients with Atopic Dermatitis: Italian Data From the MEASURE-AD Study.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease that negatively impacts the quality of life and work productivity of patients. OBJECTIVES: We sought to evaluate the real-world burden of AD patients in Italy. METHODS: This sub-analysis of the MEASURE-AD multicountry study conducted between December 2019-2020 included patients diagnosed with moderate-to-severe AD eligible for or receiving systemic therapy in the previous 6 months. During a single visit, physician and patient-reported questionnaires were used. RESULTS: A total of 118 adult patients were enrolled and 57.6% (N = 68) of patients had moderate-to-severe AD at the time of enrolment according to the Eczema Area and Severity Index. Sleep disorders interfered with daily function in the previous week in 58.5% (N = 69) of patients, pruritus was severe in 50% (N = 59) and 42.4% (N = 50) reported a flare lasting >7 days in the previous 6 months. According to the Dermatology Quality of Life Index, 37.3% (N = 44) of patients reported a severe impact of AD and approximately 10% had clinical depression/anxiety. Current drug therapy was considered inadequate in controlling AD in 26.3% (N=31) of patients. Work activity impairment was 38.6±31.7% and monthly AD-related expenses were 148.6±134.6 Euros per patient. CONCLUSIONS: This real-life study documents a high burden of disease in patients with moderate-severe AD in Italy.

Anifrolumab for Moderate and Severe Muco-Cutaneous Lupus Erythematosus: A Monocentric Experience and Review of the Current Literature.

Refractory cutaneous manifestations constitute a significant unmet need in patients with cutaneous lupus (CLE), even in the setting of systemic lupus erythematosus (SLE) with otherwise good control of inflammatory manifestations. Anifrolumab, an anti-interferon I receptor monoclonal antibody has recently been approved for serologically positive SLE with or without CLE, but real-life efficacy and safety data are currently limited. In addition, relatively limited evidence exists about the spectrum of cutaneous manifestations potentially benefitting from anifrolumab treatment and about the optimal clinimetrics to monitor treatment efficacy. While summarising current evidence on the topic in the literature, we report on four patients with SLE and refractory CLE who were successfully treated with anifrolumab. We also describe the potential usefulness and complementarity of the cutaneous lupus activity investigator's global assessment (CLA-IGA) in assessing cutaneous activity in patients treated with anifrolumab.

Cutaneous Toll-like Receptor 9 Pre-Defines Hydroxychloroquine Dosage in Patients with Both Discoid and Subacute Lupus Erythematosus.

Background and Objectives: Cutaneous lupus erythematosus (CLE) presents clinically heterogeneous manifestations, partially explained by the different expression of Toll-like receptors (TLRs) type 8 and 9, located to endosomal compartments where they are poised to recognize microbial nucleic acids. This disease is empirically treated with hydroxychloroquine (HCQ), which is hallmarked with a safe and effective profile, but induces a slow and sometimes clinically insufficient therapeutic response. Currently, no biomarkers predictive of response are validated or even proposed in the scientific literature. We aimed to evaluate endosomal TLR type 7, 8 and 9 as predictive biomarkers of HCQ efficacy. Materials and Methods: We conducted a case-control study comparing CLE patients retrospectively assigned to three subgroups based on 3-6-month Cutaneous LE Disease Area and Severity Index (CLASI) reduction upon treatment with HCQ (I = <40% vs. II = 40-80% vs. III = >80%). Before HCQ, lesional skin specimens were collected in untreated CLE and through immunohistochemistry; TLR-7, -8 and -9 expression was evaluated in the epidermis and the lymphocytic infiltrate was evaluated in the dermis. Results: Sixty-six lesional skin biopsies were compared with healthy controls. CLE patients displayed lower epidermal expression of total TLR 8 and 9 as well as infiltrating TLR-8, TLR9 + lymphocytes compared to controls. High HCQ responders differed from low responders for TLR-9 positivity (high vs. low) and for the lymphocytic dermal infiltrate (high vs. low). Conclusions: TLR9 could be envisaged as a possible biomarker to predict HCQ response level and dosage in CLE patients.

Exclusive and Solitary Facial Porokeratosis: Pathogenesis and Literature Reappraisal of a Rare Entity.

Porokeratosis is a group of well-known clinically distinct entities, characterised by different clinical aspects, but sharing a single common histological aspect, namely the cornoid lamella. Usually, porokeratosis occurs in the limbs and trunk, while it rarely involves the face, especially as an exclusive, single, and solitary lesion. We report the case of a 52-year-old Caucasian woman, with an 11-month history of a 2-cm slowly growing solitary, keratotic lesion on her left cheekbone. The patient did not present other cutaneous lesions on the face, as well as in other body sites. A cutaneous biopsy showed epidermal hyperplasia with multiple, sharply defined cornoid lamella, associated with an underlying attenuation of the granular layer and scattered dyskeratotic cells in the spinous layer. The superficial dermis underneath showed a mild lymphocytic infiltrate and fibrosis with remodelled collagen bundles. A final diagnosis of solitary facial porokeratosis was made.

Combination treatment of dupilumab with bortezomib in a patient with IgG kappa gammopathy of renal significance, uremic pruritus and chronic lichenoid dermatitis.

Chronic pruritus (CP) is one of the most frequent symptoms among dermatological conditions, capable of reducing the quality of life (QoL). CP may be induced by atopic dermatitis or other dermatological and/or non-dermatological conditions. In this article, we report the case of a patient affected by generalized CP, characterised by multiple papulo-nodular and escoriatic lesions, developed after the onset of an immunoglobulin G (IgG) kappa monoclonal gammopathy of renal significance (MGRS), associated with renal insufficiency. Therefore, a combined treatment with dupilumab for CP and bortezomib for the hematologic malignancy was administered to the patient. The present case report highlights the efficacy of dupilumab for the treatment of CP. Moreover, no relevant side effects were recorded during the treatment in combination with other systemic biological drugs for other systemic pathologies.

The Prevalent Comorbidome at the Onset of Psoriasis Diagnosis.

INTRODUCTION: Psoriasis (PsO) is currently regarded as a systemic inflammatory disease with a growing burden of post-diagnosis associated comorbidities. To determine the initial burden of comorbiditis we evaluated the comorbidome at PsO onset. METHODS: In a matched case-control study, we extracted data on 57,228 patients and 125 morbidities from the Clalit Health Services Israeli insurance database. PsO cases were matched with control individuals by sex and age at enrolment. As pre-existing comorbidities, we considered all conditions already present in controls at the same age as the matched PsO case at the time of their diagnosis. To test for differences in the odds of comorbidities between the case and control groups, logistic regression analyses were run to calculate the odds ratio (OR) for each comorbidity, after which the comorbidome was graphically represented. RESULTS: In this study we enrolled 28,614 PsO patients and 28,614 controls with an average age of 45.3 ± 19.6 years. At the time of diagnosis, PsO patients were more likely to be diagnosed with 2-4 comorbidities (28.8% vs 23.8%) and > 5 (19.6% vs 12.9%,). PsO patients' specific comorbidomes evidenced several pathological cores: autoimmune and inflammatory systemic diseases [i.e., hidradenitis suppurativa (OR 3.55, 95% CI 1.88-7.28) or polymyalgia rheumatica (OR 3.01 95% CI 1.96-4.77)], inflammatory bowel diseases [i.e., Crohn's disease (OR 2.99 95% CI 2.20-4.13)], pulmonary inflammatory diseases [i.e., chronic obstructive pulmonary disease (OR 1.81 95% CI 1.61-2.04)], hepatological diseases [i.e., cirrhosis (OR 2.00 95% CI 1.36-3.00)], endocrine diseases [dysthyroidisms (OR 1.82 95% CI 1.30-2.59)], mental disorders [i.e., depression (OR 1.72 95% CI 1.57-1.87)], and cardiovascular diseases (i.e., hypertension (OR 1.47 95% CI 1.41-1.53)]. CONCLUSION: The PsO-onset comorbidome may help health professionals plan more comprehensive patient management. By screening for these common PsO-linked conditions, early diagnosis and treatment may become more frequent, thus greatly benefiting patients on their medical journey.

Biological Matrices from Cairina moschata as Non-Destructive Biomonitoring Tools to Study Environmental Quality of Urban and Extra-Urban Areas: A Case Study of Palermo (Sicily, Italy).

Biomonitoring is the qualitative observation and the measurement of biosphere parameters aimed at modelling the environment, evaluating its quality, and studying the effects of alterations on different ecological levels. In this work, trace metal concentrations were assessed using non-destructive biomonitoring tools as blood and feathers of the allochthonous aquatic bird Cairina moschata, collected within two areas of the Palermo metropolitan area, Sicily, differently exposed to air pollution: Parco D'Orleans, in a central urban location, and Monreale, southwest of the city centre. Higher concentrations in both blood and feathers collected in Parco D' Orleans were found for lead, tin and selenium, but the same was not observed for other metals. The concentrations were not above physiological tolerance in any case. The comparison between blood and feathers allowed to realize that the latter are more useful for biomonitoring analyses, as they are indicative of both external contamination and bioaccumulation. Treatment with nitric acid highlighted that the feathers collected in Parco D' Orleans had higher metal bioaccumulation than the ones collected in Monreale; however, the treatment needs standardization. The present study confirms that feathers and blood from C. moschata are a convenient and non-destructive sampling tool for metal contamination analysis.

Reflectance Confocal Microscopy of Skin after the Sting of the Jellyfish Pelagia noctiluca.

Jellyfish are aquatic animals of the phylum Cnidaria found in seas all over the world. They are characterized by the presence of cnidocytes, cells that contain a secretory organelle, the cnidocyst, mainly used for predation and defense purposes. An adult female patient presented to our Unit of Dermatology, for a 10 days-old history of macular-erythematous lesions in her right upper limb, due to a sting by a mauve stinger Pelagia noctiluca. Dermoscopy showed a general pinkish background surmounted by numerous brown dots and lines, distributed along the surface of the skin. Reflectance confocal microscopy (RCM) showed the presence of multiple partially hyperreflective, highly coiled, hollow, and harpoonlike structures through the epidermis but without the barbed tubes found in a previous RCM report, likely due to a greater time elapsed between the sting and the dermatological visit. This case highlights how dermoscopy and RCM may help clinicians for the diagnosis of jellyfish stings.

Hidradenitis suppurativa presents a methylome dysregulation capable to explain the pro-inflammatory microenvironment: Are these DNA methylations potential therapeutic targets?

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, systemic, inflammatory skin condition with elusive pathogenesis that affects therapeutic intervention directly. OBJECTIVE: To characterize epigenetic variations in cytokines genes contributing to HS. METHODS: Epigenome-wide DNA methylation profiling with the Illumina Epic array was performed on blood DNA samples from 24 HS patients and 24 age- and sex-matched controls to explore DNA methylation changes in cytokine genes. RESULTS: We identified 170 cytokine genes including 27 hypermethylated CpG sites and 143 genes with hypomethylated sites respectively. Hypermethylated genes, including LIF, HLA-DRB1, HLA-G, MTOR, FADD, TGFB3, MALAT1 and CCL28; hypomethylated genes, including NCSTN, SMAD3, IGF1R, IL1F9, NOD2, NOD1, YY1, DLL1 and BCL2 may contribute to the pathogenesis of HS. These genes were enriched in the 117 different pathways (FDR p-values ≤ 0.05), including IL-4/IL-13 pathways and Wnt/ß-catenin signalling. CONCLUSIONS: The lack of wound healing, microbiome dysbiosis and increased tumour susceptibility are all sustained by these dysfunctional methylomes, hopefully, capable to be targeted in the next future. Since methylome describes and summarizes genetic and environmental contributions, these data may represent a further step towards a feasible precision medicine also for HS patients.

Venomous Bites, Stings and Poisoning by European Vertebrates as an Overlooked and Emerging Medical Problem: Recognition, Clinical Aspects and Therapeutic Management.

Europe presents a high number of venomous and poisonous animals able to elicit medically relevant symptoms in humans. However, since most of the accidents involving venomous or poisonous animals in Europe are unreported, their incidence and morbidity are severely overlooked. Here we provide an overview of the European vertebrate species of greatest toxicological interest, the clinical manifestations their toxins can cause, and their treatment. We report the clinical symptoms induced by envenomations and poisoning caused by reptiles, fishes, amphibians and mammals in Europe, ranging from mild, local symptoms (e.g., erythema, edema) to systemic and potentially deadly. The present work constitutes a tool for physicians to recognize envenomation/poisoning symptoms caused by the most medically relevant European vertebrates and to decide which approach is the most appropriate to treat them.

Adult-Onset Linear Morphea (en coupe de sabre) of the Face Successfully Treated with Photoactivated Low-Temperature Platelet-Rich Plasma: A Valid Therapeutic Option.

Localized scleroderma (also known as morphea) is a chronic autoimmune disorder characterized by depressed, fibrotic, and dyschromic cutaneous lesions. It has a significant impact on the patient's daily life due to the unaesthetic evolution of the cutaneous lesions. Morphea is clinically divided into linear, circumscribed (plaque), generalized, pansclerotic, and mixed forms. Linear morphea en coupe de sabre (LM) usually arises in childhood. However, in about 32% of cases, it may arise in adulthood, showing a more aggressive course with also an increased risk of systemic involvement. Methotrexate is the first-line treatment for LM, although systemic steroids, topical agents (corticosteroids and calcineurin inhibitors), hyaluronic acid injections, and hydroxychloroquine or mycophenolate mofetil are valid therapeutic options. In any case, these treatments are not always effective and sometimes can be associated with important side effects and/or not tolerated by the patients. In this spectrum, platelet-rich plasma (PRP) injection can be considered a valid and safe alternative since PRP injections in the skin induce the release of anti-inflammatory cytokines and growth factors, thus reducing inflammation and increasing collagen remodeling. Herein, we describe a successful treatment of an adult-onset LM en coupe de sabre with photoactivated low-temperature PRP (Meta Cell Technology Plasma) sessions, showing an important local improvement of the lesion and patient satisfaction.

Carbapenem Resistance in Gram-Negative Bacteria: A Hospital-Based Study in Egypt.

Background and Objectives: The global spread of carbapenem resistance and the resulting increase in mortality forced the World Health Organization (WHO) to claim carbapenem-resistant enterobacteriaceae (CRE) as global priority pathogens. Our study aimed to determine the prevalence of carbapenemase-encoding genes and major plasmid incompatibility groups among Gram-negative hospital-based isolates in Egypt. Material and Methods: This cross-sectional study was carried out at Mansoura University Hospitals over 12 months, from January to December 2019. All the isolates were tested for carbapenem resistance. The selected isolates were screened by conventional polymerase chain reaction (PCR) for the presence of carbapenemase genes, namely blaKPC, blaIMP, blaVIM, and blaNDM-1. PCR-based plasmid replicon typing was performed using the commercial PBRT kit. Results: Out of 150 isolates, only 30 (20.0%) demonstrated carbapenem resistance. Klebsiella pneumoniae was the most resistant of all isolated bacteria, and blaNDM was the predominant carbapenemases gene, while the most prevalent plasmid replicons were the F replicon combination (FIA, FIB, and FII) and A/C. Plasmids were detected only in Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, and Pseudomonas aeruginosa. Remarkably, we found a statistically significant association between carbapenemase genes and plasmid replicons, including blaNDM, IncA/C, and IncX. Conclusions: Our study demonstrated an alarming rise of plasmid-mediated carbapenem-resistant bacteria in our locality. The coexistence of resistance genes and plasmids highlights the importance of a targeted antibiotic surveillance program and the development of alternative therapeutic options at the local and international levels. Based on our results, we suggest a large-scale study with more Enterobacteriaceae isolates, testing other carbapenemase-encoding genes, and comparing the replicon typing method with other plasmid detection methods. We also recommend a national action plan to control the irrational use of antibiotics in Egypt.