Chronic hand eczema is a multifactorial disease that can impact quality of life considerably. This observational questionnaire study aimed to investigate real-world treatments and patients’ experiences of disease burden across the broad severity spectrum represent-ed by the general chronic hand eczema population. The study included 1,948 individuals from 6 countries (mean age 43.2 years; 64.5% females) with self-reported physician-diagnosed chronic hand eczema. Ongoing treatment was reported in 68.6%, which included systemics or phototherapy (with or without topicals; 10.7%), topical corticosteroids (with or without additional topicals; 36.0%) and other topical treatments (no topical corticosteroids; 21.8%). At survey time, 43.0% were in flare state. About half, 51.1%, reported moderate to severe disease signs (past week). Treatment with topical corticosteroids was suboptimal in 9.7% of those with moderate to severe disease. Experience of symptoms was common, particularly itch. Symptom burden differed significantly between groups with different treatments and severity levels; it was highest among those reporting systemics/phototherapy and those for whom topical corticosteroids were suboptimal. The results indicate that, despite a high treatment rate, chronic hand eczema is associated with a considerable disease burden that varies significantly across the severity spectrum. A particularly high burden in treatment stages beyond topical corticosteroids indicates a need for more effective management of symptoms.
Cutaneous melanoma is a highly aggressive skin cancer prone to relapse and metastasis. Surgery is often curative when combined with early screening and prevention. However, in recurrent or advanced disease, the development of new targeted and immune therapies has demonstrated promising clinical outcomes, although the acquisition of resistance limits their effectiveness. Thus, new therapeutic approaches are needed. Emerging data indicate that the Hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly reactivated in melanoma and may represent a promising therapeutic target. Here, we demonstrate its chronic up-modulation in a panel of patient-derived cell lines and, by investigating the underlying molecular mechanisms, we excluded mutations in the principal components of the pathway. We observed reduced PTCH1 and SUFU repressors expression and GLI2 upregulation as common melanoma features. At the same time, copious SHH release, the principal PTCH1 ligand, evidenced autocrine Hh signaling activation. Consistently, a tendency of greater level of this factor resulted higher in the blood of patients compared to controls, confirming the relevance of ligand-dependent trigger in melanoma. The therapeutic potential of inhibiting the Hh pathway is highlighted by the reduced proliferation and migration observed in the presence of clinically approved pharmacological Hh antagonists. Profiling inflammatory mediators revealed significant modulation upon treatment with SMO inhibitors, possibly affecting chemotactic and immune functions. Collectively, these findings provide deeper insight into the role of the Hh pathway in melanoma and support the potential repurposing of Hh inhibitors as therapeutic agents for melanoma.
Background:Difficult-to-treat psoriatic arthritis (D2T PsA) represents a challenging condition characterized by inadequate response to multiple therapeutic agents. Real-world data on the effectiveness of Janus kinase inhibitors (JAKi) in this population remain limited. Objective:To evaluate the effectiveness, safety, and treatment persistence of Upadacitinib (UPA) in patients with D2T PsA using both clinical and ultrasound assessments. Patients and Methods:This observational retrospective study included patients with PsA who failed at least one conventional DMARD and two biologic DMARDs with different mechanisms of action. All patients received UPA 15 mg once daily as monotherapy. Treatment persistence was assessed over 140 weeks, while effectiveness data were collected at four time points following baseline (12, 24, 48, and 104 weeks). Clinical measures included: PASI; cDAPSA score; swollen/tender joints count; assessment of enthesitis and dactylitis; VAS scores for disease activity/pain; HAQ. At baseline and during the follow-up, ultrasound imaging was performed according to the EULAR-OMERACT ultrasound score. Results:Twenty-five patients were enrolled. After 140 weeks, treatment persistence was 68%. A rapid and sustained improvement in disease activity was observed, with mean cDAPSA decreasing from 27.88±5.2 at baseline to 12.04±8.17 at week 12 and 4.88±4.54 at week 52. At one year, 70.6% of patients achieved complete remission and 23.6% low disease activity. Ultrasound findings confirmed the clinical improvement, with a significant reduction in the EULAR-OMERACT score and complete resolution of enthesitis after one year of treatment. Most patients (94.1%) maintained complete remission or low disease activity up to week 104. Skin condition also improved significantly as demonstrated by the marked reduction in PASI score which decreased from a baseline value of 2.22 ± 2.62 to 0.21 ± 0.36 after 52 weeks of treatment. The safety profile was favorable, with mild lipid and CPK abnormalities being the most common adverse events. Conclusion:In this real-world cohort of patients with D2T PsA, UPA demonstrated sustained clinical and ultrasound effectiveness with a favorable safety profile and good long-term treatment persistence.
Actinic keratosis (AK) represents an early stage of keratinocyte carcinogenesis and has long been attributed primarily to cumulative ultraviolet (UV) radiation-induced genetic damage. However, increasing evidence suggests that AK arises within a complex cutaneous microenvironment, in which chronic inflammation, oxidative stress, immune dysregulation, and alterations of the skin microbiota interact to promote and sustain field cancerization. UV exposure not only drives mutational events in epidermal keratinocytes, but also disrupts barrier integrity and local immune surveillance, reshaping microbial community structure on photodamaged skin. Recent studies reveal a characteristic profile in AK, characterized by reduced microbial diversity, depletion of protective commensals, and enrichment of opportunistic taxa, most notably Staphylococcus aureus. Experimental and clinical data suggest that S. aureus may act as a microbial cofactor in AK by amplifying proinflammatory and pro-oxidant signaling, inducing genotoxic stress, impairing DNA repair pathways, and modulating local immune responses in a manner consistent with early carcinogenic progression. Concurrent loss of commensal bacteria and fungi with immunomodulatory functions may further destabilize epidermal homeostasis, potentially reinforcing a self-perpetuating inflammatory loop. This perspective review synthesizes current molecular, immunologic, and microbial evidence to elucidate the role of host–microbe interactions in AK arising on chronically UV-exposed skin. Finally, we discuss how targeting inflammation–microbiota crosstalk may open new opportunities for risk stratification, prevention, and therapeutic intervention across the AK–cutaneous squamous cell carcinoma spectrum.
Unlike many other solid tumors, melanoma cells possess a remarkable ability to dynamically transition between distinct transcriptional states in response to environmental cues or therapeutic pressure. Among the adaptive mechanisms underlying this plasticity, the epithelial-to-mesenchymal transition (EMT) has garnered increasing attention, as it facilitates the shift from a proliferative, epithelial-like phenotype to a more invasive, mesenchymal-like phenotype frequently associated with cellular dormancy, quiescence and resistance to therapy. Despite growing interest in this phenomenon, the characterization of dormant cellular phenotypes and their clinical significance remains incomplete. In this study, we adopted a comprehensive approach integrating patient-derived melanoma cell lines, bulk RNA sequencing from tumor biopsies and analysis of independent bulk and single-cell public datasets. This multi-dimensional strategy enabled the identification of a reproducible dichotomy between “proliferative” and “dormant” phenotypes, characterized by distinct levels of mitotic activity and mesenchymal gene expression profiles. By leveraging an eight-gene transcriptional signature, we constructed a “dormancy score” able to stratify tumors along a dormancy–proliferation axis, revealing strong associations with clinical outcomes such as progression-free survival (PFS), overall survival (OS) and response to immunotherapy. Within the dormant-associated gene module, the surface glycoprotein TACSTD2 (TROP2) emerged as a central hub gene. TROP2 expression was consistently upregulated in the dormant-like transcriptional state. Supporting these findings, single-cell RNA sequencing data confirmed that TROP2 marks a rare subpopulation of malignant cells that may constitute a quiescent, therapy-resistant niche. Besides, results highlight a predominant intracellular expression of TROP2 in the dormant phenotype. Together, these findings define a robust dormant phenotype in melanoma with both molecular and clinical significance and evaluate TROP2 as a potential biomarker and therapeutic target for identifying and eradicating dormant and treatment-refractory tumor cells.
