Istituto Dermopatico dell'Immacolata

VEGF-A exerts complex immunomodulatory effects that foster an immunosuppressive tumour microenvironment, including impaired dendritic cell (DC) maturation, expansion of regulatory T cells (Tregs), and induction of T-cell exhaustion, while transiently enhancing effector T-cell responses. This dual activity underscores the need to clarify the immunosuppressive versus immunostimulatory consequences of VEGF-A receptor activation to optimise selective inhibition. This proof-of-concept study evaluated whether selective VEGFR-1 blockade can counteract VEGF-A-driven immunosuppression in human immune cells using the monoclonal antibody (mAb) D16F7, which inhibits membrane-bound VEGFR-1 while preserving the decoy and anti-angiogenic activity of its soluble form. The impact of VEGFR-1 blockade by D16F7 mAb on VEGF-A-mediated immune modulation was assessed by multiparametric flow cytometry using primary immune cells from healthy donors. Human DCs were generated from CD14+ monocytes and cultured with VEGF-A; tolerogenic and pro-exhaustion activity was evaluated via maturation markers (CD80, CD83, HLA-DR) and PD-1 expression on DC-stimulated T cells after 14days. Short-term effects on effector T cells, stratified by PD-1 and CD28 expression, were analysed by intracellular cytokine staining at 5-6 and 18h. Purified Tregs, isolated via a two-step magnetic separation, were cultured for 1week to assess the acquisition of an immunosuppressive phenotype by measuring the expression of checkpoint markers (PD-1, ICOS, TIM-3). D16F7 reversed VEGF-A-induced DC maturation defects, reduced DC-mediated T-cell tolerance, and attenuated the emergence of a highly immunosuppressive Treg phenotype, while largely preserving short-term effector T-cell function. Despite the limitations of an in vitro PBMC-based system, selective VEGFR-1 blockade by D16F7 mAb alleviates VEGF-A-driven immune tolerance while preserving T-cell activation, supporting its translational potential as a complementary immunomodulatory approach.

Psoriasis is a chronic inflammatory skin disease associated with significant physical and psychological burden. Tildrakizumab, an interleukin-23 p19 inhibitor, has demonstrated efficacy in treating moderate-to-severe plaque psoriasis both in clinical trials and real-world setting. However, limited data are available on the impact of the effective treatment of psoriasis on the psychological health of patients. The aim of this study was to assess changes in psychological well-being, as well as clinical and quality-of-life outcomes, in patients with moderate-to-severe plaque psoriasis treated with tildrakizumab in routine clinical practice in Italy. This was an interim analysis (IA) of a 52-week multicenter, prospective, observational study. Adults with moderate-to-severe plaque psoriasis initiating tildrakizumab were enrolled. Endpoints focused on well-being and psychological health and included changes, from baseline to week28, in Depression, Anxiety, and Stress Scale-21 (DASS-21) scores, Dermatology Life Quality Index (DLQI), European Social Survey (ESS) items, and World Health Organization-Five Well-Being Index (WHO-5). Effectiveness was also monitored via Psoriasis Area and Severity Index (PASI), and safety via treatment-emergent adverse event reporting. A total of 115 patients were included (mean age 52.5years, 60.8% male), 102 receiving ≥ 1 dose of tildrakizumab and completing DASS-21 evaluations at baseline and week28. At week28, improvements were observed in DASS-21 subscales [depression (-2.6, 95%CI -2.0 to -1.0), anxiety (-2.3, 95%CI -2.0 to -1.0), and stress (-3.4, 95%CI -4.0 to -2.0)], accompanied by marked PASI reduction (-13.7, 95%CI -12.8 to -10.1). DLQI, ESS, and WHO-5 scores also improved. Adverse events were generally mild or moderate, with no unexpected safety signals. In this real-world IA, tildrakizumab was observed to improve the psychological well-being of patients, reflected by a reduction in all items of the DASS-21 scale and, in parallel, confirmed its effectiveness in managing physical symptoms of psoriasis, establishing its role in the holistic management of psoriasis.

Autoimmune blistering diseases (AIBDs) in children and adolescents present a major challenge in diagnosis and management because of their rarity and the presence of other differential diagnoses with blistering. They are potentially serious, and timely diagnosis and optimal management can help prevent morbidity related to both the diseases and their treatments. The Autoimmune Blistering Diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated evidence-based, expert-informed clinical guidelines for the diagnosis, treatment and monitoring of paediatric AIBDs. A writing group conducted a systematic review of the available literature on AIBDs in children and adolescents, and since there is limited strong evidence in the literature, recommendations were formulated by consensus over three rounds of structured feedback and revision by the Core Group and Expert Group of the task force (32 voting experts; >75% agreement threshold). Although all AIBDs-including intra-epidermal and subepidermal blistering disorders-are reported in children, linear IgA dermatosis (LAD) is the most common (42-83%). The diagnostic approach in the paediatric age group does not differ from that in adults. Treatment recommendations are tailored to paediatric patients, taking into account developmental pharmacokinetics, potential adverse effects and the impact of disease and therapy on quality of life. These guidelines provide the first comprehensive, paediatric-focused framework for the diagnosis and management of AIBDs. Implementing the recommendations should harmonize care, reduce treatment-related toxicity and improve quality of life for affected children while steering future research towards critical knowledge gaps.

Actinic keratoses (AKs) are ultraviolet (UV)-induced skin lesions that may progress to invasive squamous cell carcinoma. Hyperkeratotic AKs hinder line-field confocal optical coherence tomography (LC-OCT) imaging, limiting assessment of the dermal-epidermal junction (DEJ) and PRO-score, a histopathological index of dermal invasion. The aim of this study was to evaluate whether moisturization improves DEJ visualization and PRO-score evaluation in hyperkeratotic AKs using LC-OCT. Fifty-nine hyperkeratotic AKs were randomized to receive either 20-min tap water occlusion or 20% salicylic acid ointment (SAO). LC-OCT scans were taken before and after treatment. DEJ visibility, PRO-score (0-3), and confidence in PRO assignment (cPRO) were rated by blinded evaluators. DEJ visibility significantly increased posttreatment (from 39.0% to 86.4%, p = 0.015), with no significant difference between water and salicylic acid ointment (SAO). Confidence in PRO-scoring also improved (p < 0.001), and 39.1% of lesions with initial scores were reclassified. G2 AKs had higher DEJ visibility than G3 both before and after treatment. Moisturization enhances LC-OCT evaluation of hyperkeratotic AKs, improving DEJ visualization and diagnostic confidence.

BackgroundSkin diseases are symptomatic, visible, and stigmatizing and it is acknowledged that they can be associated with stress. However, large studies comparing disease-specific stress are scarce.ObjectivesTo investigate stress in a large, diverse sample of patients with different skin conditions and identify predictors of stress.MethodsA cross-sectional, multicenter study was conducted in 22 dermatology clinics across 17 European countries (response rate 82.4%). The study included 5487 patients diagnosed with various dermatological conditions and 2808 skin-healthy controls. The Perceived Stress Scale, 10 items was used to measure stress.ResultsPatients reported significantly higher stress levels, more stressful life events during the last 6 months, and more economic difficulties than controls. Patients with psychodermatological conditions, hyperhidrosis, hidradenitis suppurativa, atopic dermatitis, acne, and urticaria experienced the highest stress levels. 44% of the variance of perceived stress in patients with skin conditions could be predicted by sociodemographic data and disease-related and psychological variables (depression, anxiety, stigmatization, and body dysmorphic concerns).LimitationsAs with all cross-sectional studies, causality and directionality cannot be inferred.ConclusionStress poses a significant psychosocial burden to dermatological patients, especially to vulnerable subgroups. Health interventions targeting stress may be essential to improve clinical outcomes.

In the latest issue of JEADV, Hrvatin Stancic et al.1 present a systematic review and meta-analysis exploring the relationship between skin conditions and completed suicide in adult patients. Drawing on data from over 3.8 million patients and more than 33.7 million controls, the study offers a critical statistical analysis that addresses a significant gap in the existing literature. Briefly, the authors identify hidradenitis suppurativa (HS) and melanoma as dermatological conditions strongly associated with an elevated suicide risk, emphasizing the need for enhanced mental health monitoring. Conversely, the results for other skin diseases, such as psoriasis and dermatitis/eczema, remain inconclusive. Dermatologists should be mindful that skin diseases can significantly impact health-related quality of life (QoL), affecting social interactions, emotional well-being and psychological health. HS, in particular, is associated with the highest comorbidity burden and the lowest QoL among skin conditions, even below psoriasis.2 Moreover, it is one of the most painful conditions treated by dermatologists yet lacking a standardized pain treatment algorithm. It is important to acknowledge the bidirectional relationship between pain and mental health disorders: chronic pain can exacerbate anxiety, depression and other psychiatric conditions, while mental health issues may intensify the perception of pain, thus creating a vicious cycle.3 Both depression and anxiety are recognized as risk factors for suicide.4 Moreover, the psychosocial burden, particularly the stigmatization associated with visible conditions such as HS, may lead to psychological stress, which can contribute to an increased risk of suicide by exacerbating depression and hopelessness. Another hypothesis on the link between suicide and skin conditions is that mental disorders may be associated with the underlying pathological factors of skin diseases, particularly systemic inflammation. For instance, a systematic review by Miná et al.5 reported elevated cytokine levels in the cerebrospinal fluid of suicide victims and attempters, suggesting a potential biological connection between inflammatory skin disorders and completed suicide. However, this connection remains speculative and warrants further research. Special attention should be given to oncological patients, as individuals with melanoma are nearly three times more likely to die by suicide, primarily due to the psychological distress associated with the diagnosis.1 Anxiety, depression and suicidal thoughts often stem from concerns about cancer progression, treatment side effects and changes in body image. Altogether, these findings highlight the critical need for a comprehensive, multidisciplinary approach to optimize patient outcomes and enhance overall QoL. This holistic approach is especially important for patients with skin diseases, particularly HS and melanoma. The psychological impact of these conditions should be carefully considered in patient management, with regular monitoring of psychiatric health to support treatment adherence and well-being. Collaborative care models involving dermatologists, psychiatrists and pain specialists could enhance early intervention strategies, improving both dermatological and psychological outcomes. Moreover, patient education and support groups may help mitigate feelings of isolation and stigma, fostering resilience and better coping mechanisms. Additionally, dermatologists must be aware of how pharmacologic therapies may affect mental health, particularly those that could influence suicidality. None. None for the authors to disclose. Not applicable. Not applicable. Data sharing not applicable to this article as no data sets were generated or analysed during this study.

Background/Objectives: Sulfated hyaluronic acid (sHA) is a chemically modified derivative of native hyaluronic acid (HA), characterized by enhanced physicochemical stability and increased biological activity. Glycosaminoglycans (GAGs), including HA, are key regulators of skin structure, hydration, and immune homeostasis. This review aims to critically summarize current knowledge on the structural and functional properties of GAGs—particularly HA and its sulfated forms—and to explore their potential dermatological applications in skin aging and inflammatory diseases such as atopic dermatitis, psoriasis, and acne. Methods: A narrative literature review was conducted using PubMed and Scopus databases up to June 2025, including experimental, preclinical, and clinical studies investigating the biological effects, mechanisms of action, and dermatological uses of sHA compared with native HA and other HA derivatives. Results: Compared with HA, sHA demonstrates increased enzymatic resistance, higher charge density, and improved water-binding and antioxidant capacity. These properties contribute to the restoration of skin barrier function, modulation of oxidative stress and inflammation, and promotion of extracellular matrix remodeling. Preclinical evidence supports the efficacy of sHA in reducing dryness, irritation, and inflammatory responses in atopic dermatitis, psoriasis, and acne. Preliminary findings also suggest potential benefits in wound healing and skin barrier repair. Conclusions: sHA represents a promising multifunctional molecule in dermatology and cosmetology, capable of reducing inflammation and supporting tissue regeneration. However, current evidence remains limited to preliminary studies. Future controlled clinical trials are required to confirm efficacy, optimize formulations, and establish standardized treatment protocols.

Psoriasis is a chronic inflammatory skin disease whose pathogenesis involves not only cutaneous inflammation but also intestinal dysbiosis and oxidative stress (OxS). Monoclonal antibodies targeting interleukin (IL)-17 and IL-23 have demonstrated significant immunomodulatory effects; however, their impact on systemic parameters requires further investigation. We conducted a study on 33 patients with plaque psoriasis treated with anti-IL-17 or anti-IL-23 monoclonal antibodies. Dermatological parameters (Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI)), biomarkers of intestinal dysbiosis (trimethylamine-N-oxide (TMAO)) and OxS (reactive oxygen metabolites (d-ROMs) and oxidized LDL (oxLDL)) were evaluated. Anthropometric, metabolic, and adipose-derived hormonal parameters (adipokines) were also monitored. After 16 weeks of therapy, significant improvements were observed in PASI and DLQI scores (p < 0.001). TMAO levels were significantly reduced (p = 0.02), as were d-ROMs and oxLDL (p < 0.001). No significant changes were found in weight, body mass index, lipid profile, or adipokine levels (visfatin, leptin and adiponectin). Our data indicate that monoclonal antibody therapy not only improves psoriasis severity but also exerts beneficial effects on systemic biomarkers of dysbiosis and OxS, independent of metabolic or hormonal changes. These findings suggest a systemic mechanism of action, supporting a multifactorial therapeutic effect with potential implications for the prevention of cardiovascular risk.

Mucous membrane pemphigoid (MMP) is a rare autoimmune blistering disease targeting components of the basement membrane zone (BMZ), including BP180, BP230, laminin 332, type VII collagen, and α6β4 integrin [1]. In a subset of MMP, known as oral pemphigoid (OP), erosions affect exclusively the oral mucosa, without any involvement of the skin [1]. In 2006, Rashid et al. proposed α6 integrin subunit as the main antigen in OP patients [2]. In this paper, 20 sera from OP patients showed immunological reactivity against the extracellular domain of α6 integrin, and the immunodominant region (A2) was identified [2]. However, a more recent study highlighted the presence of immunoglobulin (Ig)G anti-BP180 antibodies in the sera of a large percentage of MMP patients (71%) with oropharyngeal involvement, without showing the anti-α6 integrin immunoreactivity [3]. Currently, searching for anti-α6 integrin antibodies is not recommended for diagnosing MMP. However, recent European guidelines encourage further research to better understand and clarify this issue [1]. Aiming at finding out the prevalence of IgG anti-α6 integrin antibodies, we analyzed sera from an Italian cohort of 17 OP patients using immunoblotting (IB). The patients had a mean age of 68.1 ± 11.2 years and a male to female ratio of 1:7.5. The diagnosis was confirmed by clinical features and positive direct immunofluorescence results. Sera from OP and healthy donors (HD) were obtained in accordance with the local Ethics Committee and the Declaration of Helsinki. Cell lysate from cultured keratinocytes and DU145 cells, prepared as previously reported [4], was used by IB to analyze 17 OP sera. Likewise, the nucleotide sequence of α6 integrin extracellular fragment A2, coding for amino acid residues 217–462 [2], was cloned in plasmid pET-45b(+) and expressed in E. coli BL21. The recombinant protein, purified on nickel-nitrilotriacetic (Ni-NTA) Agarose, was employed to screen the immunological reactivity of sera (Figure 1a). In IB experiments with keratinocyte lysate as substrate, 3/17 OP (17.6%) showed binding to the α6 integrin heavy chain, generated by a proteolytic cleavage during its biosynthesis, which migrated as a 120 kDa protein (Figure 1b). Moreover, 5/17 OP (29.4%), three of which were also positive with keratinocyte extracts, detected the 120 kDa band using DU145 cell lysate (Figure 1c). A2 fragment (Figure 1d) was stained by only two of 17 sera tested (11.8%). As for BP180-NC16a and BP230 reactivity, seven and three of 17 sera were positive by commercial enzyme-linked immunosorbent assays (ELISAs) (41.2% and 17.6%, respectively) (Table 1). Finally, 6/17 OP sera bound the extracellular domain of BP180 (ECD-BP180) by in-house ELISA (35.3%) [5] (Table 1). In the present study, we identified a small fraction of OP sera positive for α6 integrin using lysates from both keratinocyte and DU145 cells (3/17 and 5/17 sera, respectively). The different reactivity observed with these substrates could depend on a higher α6 integrin expression by DU145 cells. The extracellular portion of α6 (A2), previously identified as the immunodominant region [2], was detected by only two sera, one of which also bound α6 in DU145 cell lysate, suggesting the presence of other relevant epitopes that have not yet been identified. In addition, overall BP180 immunoreactivity, assessed using ELISAs (BP180-NC16a and ECD-BP180), was found in 47.1% of OP sera, compared to 35.3% of sera positive for α6 integrin (heavy chain and/or A2 α6 integrin), highlighting the importance of BP180 antigen and downplaying the role of α6 integrin in these patients. Notably, only two sera bound exclusively to α6 integrin. Our results outline the need for additional studies to clarify the prevalence of reactivity against α6 integrin and to evaluate the diagnostic relevance of this antigen. IDI-IRCCS is a healthcare provider of the European Reference Network (ERN)-Skin. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

To uncover substrates mediating the oncogenic activity of WWP1 in acute myeloid leukemia (AML), we performed a proteomic analysis that identified the histone demethylase KDM5B/JARID1B as a candidate target. Of note, JARID1B is indispensable for efficient recruitment of several DNA damage repair factors and for damage resolution, thus negatively influencing the sensitivity of cancer cells to chemo- and radiation therapies. Validation of JARID1B as a substrate of WWP1 revealed a positive regulation of JARID1B half-life by WWP1 through the establishment of K63-linked polyubiquitin chains. As a result, downregulation of JARID1B rising from WWP1 inactivation was associated with higher H3K4me3 enrichment at JARID1B target genes in WWP1-depleted relatively to control AML cells. Integration of RNA-seq and H3K4me3 ChIP-seq data uncovered a highly significant overlap between upregulated gene expression and enriched H3K4me3 peaks after shWWP1 inactivation. We confirmed transcriptional activation of JARID1B targets in WWP1-depleted cells, supporting a role for WWP1 in regulating JARID1B activity. Coherently, upon WWP1 inactivation, we observed a defective recruitment of repair proteins after DNA damage, with subsequent reduced DNA damage repair efficiency and enhanced sensitization of AML cells to the cytotoxic activity of chemotherapeutic drugs. All together, these data identify JARID1B as a bona fide target of WWP1 and imply that WWP1-mediated regulation of JARID1B impacts its ability to modify chromatin and to recruit DNA damage repair factors, thus ultimately affecting chemosensitivity of AML cells.