BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is characterized by skin fragility, extensive wounding, and systemic complications. While inflammation contributes to disease severity, its pattern, longitudi...BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is characterized by skin fragility, extensive wounding, and systemic complications. While inflammation contributes to disease severity, its pattern, longitudinal dynamics and clinical correlates remain poorly defined. OBJECTIVE: To characterize the course of systemic inflammatory markers over time in patients with RDEB and explore their associations with clinical, microbiological, and laboratory parameters. METHODS: This retrospective longitudinal study analyzed clinical and laboratory data of 120 visits within 5 years from 44 patients with intermediate (N=22) and severe (N=22) RDEB. Acute-phase proteins (CRP, IL-6, SAA), neutrophil to lymphocyte ratio (NLR), leukocytes, thrombocytes and ferritin were examined in relation to wound body surface area, mucosal involvement, collagen VII (C7) protein expression levels, squamous cell carcinoma (SCC) presence, nutritional status, anemia markers, wound microbiology and immunoglobulins. RESULTS: Severe RDEB showed an early and sustained systemic inflammatory profile, with CRP, IL-6, and SAA elevated >3.5-fold from early childhood, plateauing in mid-adulthood. Intermediate RDEB maintained low inflammatory activity throughout life. Acute phase proteins and NLR were significantly elevated in the presence of SCC (CRP: p<0.001; IL-6: p=0.002; SAA: p=0.011; NLR: p=0.004), collagen VII absence (CRP: p=0.002), and colonization by Pseudomonas (CRP, IL-6: p<0.001) or fungi (CRP: p=0.006). CRP and age were the most robust independent predictors of SCC risk. Streptococcus, Pseudomonas, fungi, or polymicrobial colonization were associated with a broader systemic inflammatory response, when compared to infections with Staphylococcus. Hypoalbuminemia and elevated immunoglobulins correlated with inflammatory markers and anemia of chronic disease was reflected by declining iron and increased ferritin levels. In multivariable models, reduced C7 expression, wound burden and SCC were the strongest independent predictors of acute phase inflammation. CONCLUSIONS: This study reveals that severe RDEB involves early-onset, progressive systemic inflammation that peaks in mid-adulthood and then plateaus, suggesting a critical window for therapeutic intervention. In contrast, intermediate RDEB shows minimal systemic inflammation. The findings support a three-tiered treatment approach-wound burden reduction through curative/corrective interventions, antimicrobial strategies and anti-inflammatory therapy -aligned with standard of care and nutritional supplementation.
BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory skin condition that is associated with a prolonged diagnostic delay of approximately 7-10 years. The diagnostic delay can be attributed to various factors, inc...BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory skin condition that is associated with a prolonged diagnostic delay of approximately 7-10 years. The diagnostic delay can be attributed to various factors, including low awareness of diagnostic criteria among nondermatological healthcare professionals often leading to misdiagnosis. Screening questionnaires have been proposed for the diagnosis of HS. One such questionnaire has been validated and used in the Global Hidradenitis Suppurativa Atlas (GHiSA) Global Prevalence Study (GPS). OBJECTIVES: To evaluate and provide a summary of the diagnostic accuracy measures (pooled sensitivity and specificity) of the screening questionnaire employed in the GHiSA GPS. METHODS: All studies that adhered to the methodology specified by the GHiSA and provided diagnostic accuracy data were eligible for inclusion. Data on geographical location and diagnostic accuracy parameters (true positive, false positive, true negative and false negative) were extracted from the included studies and entered in duplicate into Microsoft Excel independently by two authors. The quality of the studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. RESULTS: Data from 25 studies carried out in 23 countries were included in the pooled analysis. The QUADAS-2 assessment revealed a high risk of bias in the domains 'reference standard' and 'patient flow'. For the applicability of the studies, there were concerns about 'patient selection'. Substantial variations in sensitivity (0.43-1.00) and specificity (0.15-1.00) values were observed globally. A bivariate random effects model showed a pooled sensitivity of 0.88 [95% confidence interval (CI) 0.80-0.94] and a pooled specificity of 0.86 (95% CI 0.78-0.91). The summary receiver operating curve revealed a clustering of studies in the upper left corner, indicating a sensitivity and specificity close to 1. The area under the curve was 0.93, suggesting excellent accuracy. CONCLUSIONS: Despite substantial variations in diagnostic estimates around the world, the pooled analysis indicated that the accuracy of the GHiSA screening questionnaire was excellent. The screening questionnaire may prove useful for triage, ensuring that only individuals fitting the criteria for HS see specialized dermatological care.
BACKGROUND: Pyoderma gangrenosum (PG) is a rare, painful neutrophilic dermatosis with a profound impact on patient quality of life. Its management is hindered by a lack of approved therapies, limited clinical trials, and...BACKGROUND: Pyoderma gangrenosum (PG) is a rare, painful neutrophilic dermatosis with a profound impact on patient quality of life. Its management is hindered by a lack of approved therapies, limited clinical trials, and low-quality evidence. The rarity of the disease and funding constraints have impeded research progress and the development of standardized outcome measures. Patient data registries offer a promising solution to these challenges, providing essential infrastructure to improve evidence generation and clinical care. OBJECTIVE: To develop a consensus-based minimum data set for an international treatment effectiveness registry for pyoderma gangrenosum, informed by real-world clinical data. METHODS: An initial list of candidate domain items was generated based on a systematic literature review following a previously published protocol. An international, multi-stakeholder panel of 45 participants-including patients with PG, clinicians, researchers, methodologists, and industry representatives-was convened from 97 invited experts. Through three rounds of modified Delphi surveys and a virtual consensus meeting, items were ranked using predefined criteria: "consensus in" (≥70% scoring 7-9 and ≤15% scoring 1-3), "consensus out" (≥70% scoring 1-3 and ≤15% scoring 7-9), and "no consensus." A final verification survey confirmed inclusion if <30% of participants voted "no." RESULTS: All 45 stakeholders completed all three Delphi rounds (0% dropout). Thirty-four (76%) participated in the consensus meeting, and 42 (93%) completed the final verification survey. Of 143 initial items across 24 domains, 118 items across 26 domains achieved consensus for inclusion in the minimum data set. CONCLUSIONS: This international consensus establishes a standardized framework for collecting real-world data on PG. The resulting registry will serve as a critical resource for evaluating treatment effectiveness, understanding disease progression, and improving patient outcomes. It will also support future clinical trials, guideline development, quality improvement initiatives, and global patient recruitment efforts.
Hodgson K, Inns J, Reynolds G
… +19 more, Stephenson E, Paul A, Sinclair N, Berretta G, Lawson C, Frey AM, Ivanova I, Adam E, Lord CJ, Cockell S, Coxhead J, Nagy N, Adams D, Szell M, Trost M, Haniffa M, Mackay SP, Perkins N, Rajan N
Br J Dermatol
· 2026 May · PMID 41779628
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BACKGROUND: CYLD cutaneous syndrome (CCS) skin tumours develop from puberty onwards, can number in the hundreds and progressively grow over time. Patients with CCS lack medical therapies and require repeated surgery to c...BACKGROUND: CYLD cutaneous syndrome (CCS) skin tumours develop from puberty onwards, can number in the hundreds and progressively grow over time. Patients with CCS lack medical therapies and require repeated surgery to control tumour burden. CYLD loss of heterozygosity drives tumour growth, and CCS tumours have previously been shown to demonstrate increased canonical nuclear factor kappa B (NF-κB) and Wnt signalling. OBJECTIVES: To investigate NF-κB signalling in CCS tumours and CCS tumour keratinocytes, with the aim of identifying druggable targets. METHODS: We used complementary bulk transcriptomics and proteomics in patient-derived CCS tumour cell fractions, as well as single-cell RNA sequencing of CCS tumour cells to investigate aberrant NF-κB signalling. We developed a patient-derived CCS tumour spheroid culture model to determine the utility of targeting aberrant NF-κB cell signalling. RESULTS: We demonstrate evidence of non-canonical NF-κB signalling in CCS tumour keratinocytes, with increased p100 to p52 processing and RelB protein expression compared with normal skin. We identify IκB kinase alpha (IKKα) as a candidate target in the noncanonical NF-κB signalling pathway. A novel, highly selective IKKα inhibitor (SU1644) used in patient-derived CCS tumour spheroid cultures demonstrated that IKKα inhibition reduced tumour spheroid viability. CONCLUSIONS: These data provide the preclinical rationale for the assessment of topical IKKα inhibitors as a novel preventive treatment for CCS.
BACKGROUND: following a first cutaneous squamous cell carcinoma (CSCC), approximately one-third of patients develop new primaries, escalating their risk of metastasis and poor outcomes. However, current follow-up strateg...BACKGROUND: following a first cutaneous squamous cell carcinoma (CSCC), approximately one-third of patients develop new primaries, escalating their risk of metastasis and poor outcomes. However, current follow-up strategies lack risk stratification, representing a critical gap in patient management. OBJECTIVE: to develop and validate a prognostic model to quantify individualized absolute risk of a first metachronous CSCC after an index tumor, accurately accounting for the high competing risk of mortality in this typically elderly population. METHODS: we conducted a nationwide, population-based cohort study of 11,737 patients with a first histologically confirmed CSCC (Netherlands Cancer Registry, 2007-2008) with up to 10 years of follow-up. Subsequent tumors were identified via linkage to the Automated National Pathological Anatomy Archive (Palga). A Fine-Gray competing-risk model was developed using routinely available clinical and pathological predictors. Model performance was assessed 10-fold cross-validation, quantifying discrimination (time-dependent area under the receiving operator characteristic curve [AUCt]) and calibration. Clinical utility was evaluated using Decision Curve Analysis (DCA) and tertile risk stratification. RESULTS: during follow-up, 3,288 (28%) developed a first metachronous CSCC. Key predictors included markers of cumulative UV-exposure (included AK history, ≥5 prior BCCs), and chronic lymphocytic leukaemia/small lymphocytic leukaemia (CLL/SLL). Male sex and presence of synchronous CSCC at baseline were also associated with higher risk. While discrimination was modest (cross-validated 5-year AUCt: 0.64), the model demonstrated excellent calibration across all predictor subgroups. DCA showed modest net benefit for predicted probabilities between 18% and 45%. Risk stratification into tertiles revealed a nearly five-fold acceleration: the high-risk tertile reached a 15% cumulative incidence in 1.4 years, compared to 6.9 years for the low-risk tertile. CONCLUSIONS: this competing-risk model provides individualized, well-calibrated absolute risk estimates for a first metachronous CSCC. Based on routinely available clinical features, it offers insight into how established predictors shape risk in this high-susceptibility population and quantifies relative risk acceleration. External validation and the identification of novel predictors are necessary to further refine the model and support personalized surveillance strategies.
Oashi K, Ogata D, Yokoyama M
… +23 more, Sano Y, Fukuda H, Hiura A, Nakamura Y, Uehara J, Takahashi A, Namikawa K, Mori S, Nakano E, Maeda T, Miyagawa T, Yoshino K, Funakoshi T, Kiniwa Y, Nakagawa T, Shibayama Y, Uchi H, Maeda T, Muto I, Maruyama A, Takenouchi T, Hatta N, Yamazaki N
BACKGROUND: Paclitaxel is a standard first-line chemotherapy for primary cutaneous angiosarcoma. However, there is no established second-line treatment after paclitaxel. OBJECTIVES: The aim of the JCOG1605 study was to e...BACKGROUND: Paclitaxel is a standard first-line chemotherapy for primary cutaneous angiosarcoma. However, there is no established second-line treatment after paclitaxel. OBJECTIVES: The aim of the JCOG1605 study was to evaluate the efficacy and safety of second-line pazopanib for primary cutaneous angiosarcoma. METHODS: This multi-institutional, single-arm, confirmatory trial was conducted in Japan. Patients with cutaneous angiosarcoma not associated with lymphedema or radiation exposure were included in this study. Pazopanib was administered orally at an initial dose of 800 mg, once daily. The primary endpoint was progression-free survival. Retrospective data on second-line docetaxel following first-line paclitaxel treatment were used as a historical control. This trial was registered in the UMIN Clinical Trials Registry (UMIN000031438 [http://www.umin.ac.jp/ctr/index.htm]). RESULTS: Thirty patients were enrolled from 15 institutes and received pazopanib (n = 30). The median progression-free survival and overall survival were 2.8 months (80% CI: 2.1-3.9) and 12.1 months (95% CI: 8.9-28.8), respectively. The response and disease control rates were 31.8% (95% CI: 13.9-54.9) and 63.6% (95% CI: 40.7-82.8), respectively. Twenty-eight (93.3%) and 21 (70%) patients experienced grade ≥2 and grade ≥3 non-hematologic adverse events, respectively. No treatment-related deaths occurred. CONCLUSIONS: The primary endpoint progression-free survival did not meet the predefined threshold. However, the response rate and overall survival were better than expected, and there were no safety issues. Therefore, pazopanib may be a treatment option for patients with paclitaxel-pretreated primary cutaneous angiosarcoma. (231/350 words).
BACKGROUND: Large-to-giant congenital melanocytic naevi (LGCMNs) often develop nodules that contain ectopic tissues (hamartomas), which are rarely observed in small-to-medium congenital melanocytic naevi (SMCMNs). The or...BACKGROUND: Large-to-giant congenital melanocytic naevi (LGCMNs) often develop nodules that contain ectopic tissues (hamartomas), which are rarely observed in small-to-medium congenital melanocytic naevi (SMCMNs). The origin and mechanism of the hamartomas formed in LGCMNs remain unknown. OBJECTIVES: To investigate the origin and mechanism of hamartoma formation in LGCMNs, and to evaluate the stemness and multipotency of LGCMNs. METHODS: A total of 276 congenital melanocytic naevi (CMNs) of different sizes were included in this study. LGCMNs with diverse hamartomas were identified and analysed by histology and immunofluorescence. Whole-exome sequencing (WES) of matched healthy skin, LGCMN and hamartoma tissues assessed mutational overlap. RNA sequencing (RNAseq), immunohistochemistry and immunocytochemistry evaluated multipotency pathways and stem markers across CMN sizes. LGCMN and SMCMN cells were assayed for clonogenicity and induced to differentiate along osteogenic, chondrogenic, adipogenic and neurogenic lineages in vitro. Three-dimensional spheroid cultures and cell-derived xenograft (CDX) models tested LGCMN multilineage differentiation in vivo. Single-cell RNAseq (scRNAseq) of patient-derived hamartomas delineated intermediate differentiation states and active pathways. RESULTS: We found that LGCMN lesions harboured bone, cartilage, adipose and neural hamartomas with intermixed naevocytes. WES revealed 35-92% overlap of somatic mutations (including driver mutations) between LGCMN and hamartoma tissue, indicating a common origin. Immunofluorescence identified cells in hamartoma co-expressing lineage-specific and naevocyte markers, indicating intermediate differentiation states. RNAseq, immunohistochemistry and immunocytochemistry showed that LGCMNs were enriched for multipotency pathways and expressed higher levels of stem cell markers than SMCMNs. LGCMNs showed greater clonogenicity in vitro, and all LGCMNs robustly differentiated into osteocytes, chondrocytes, adipocytes and neuronal cells/astrocytes, whereas SMCMNs or healthy melanocytes largely failed. Intriguingly, in three-dimensional cultures and CDX models, LGCMNs were able to form lineage-specific hamartomas. scRNAseq identified intermediate differentiation clusters that co-expressed melanocytic and multilineage markers, confirming the transdifferentiation. Upregulation of neuroactive ligand-receptor signalling was identified as the common feature during differentiation. CONCLUSIONS: Hamartomas in LGCMNs originate from the LGCMN cells themselves, which undergo multipotent differentiation. LGCMNs have markedly greater stemness and multipotency than SMCMNs. Our data implicate the neuroactive ligand-receptor pathway in mediating LGCMN transdifferentiation. These findings shed light on LGCMN development and suggest that modulating differentiation pathways might offer new therapeutic approaches.
Booth L, Chen X, Stoker K
… +13 more, McCraw A, Tahiri M, Wu Y, Geh JLC, MacKenzie Ross AD, Lloyd-Hughes H, Lacy KE, Whittaker S, Jacków-Malinowska J, Van Hemelrijck M, Tull TJ, Tsoka S, Karagiannis SN
Br J Dermatol
· 2026 May · PMID 41742701
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BACKGROUND: The clinical significance of B cells and the antibodies they express is increasingly appreciated in melanoma, a highly immunogenic tumour, for which immune checkpoint inhibitor (ICI) therapy is the standard c...BACKGROUND: The clinical significance of B cells and the antibodies they express is increasingly appreciated in melanoma, a highly immunogenic tumour, for which immune checkpoint inhibitor (ICI) therapy is the standard care for advanced disease. OBJECTIVES: To evaluate the phenotypes and roles of B cells and antibodies in patients with melanoma, and their prognostic and predictive value, in a scoping review following PRISMA-ScR reporting guidelines. METHODS: Using three search engines, we conducted literature searches for full-text studies written in English from 1 January 2000 to 9 October 2024. Three reviewers conducted title and abstract screening, followed by full-text paper assessment by two independent reviewers. This study was registered with PROSPERO (CRD42024592965). RESULTS: Of 4667 identified studies (PubMed, n = 827; Scopus, n = 2759; Ovid MEDLINE, n = 1081), 1659 were duplicates. The titles and abstracts of the remaining 3008 were screened to yield 251 full-text papers, resulting in the inclusion of 80 studies. Our search identified increased naïve, alternatively activated and regulatory B cells in blood, and a bias towards differentiated and class-switched B-cell infiltrates in tumours. Consistent associations were found between B-cell density in tumours, particularly the abundance of memory B cells and more favourable survival outcomes. Despite tumour and immune response heterogeneity, collectively, enriched B-cell signatures such as B-cell abundance, B-cell receptor diversity and immunoglobulin gene rearrangement in tumours correlated with better ICI response. Antibody dysregulation favouring the anti-inflammatory IgG4 isotype was associated with less-favourable outcomes, while class switching to immune-stimulating isotypes such as IgG1 correlated with better clinical outcomes and ICI response. Antibody reactivity and autoantibody analysis revealed distinct isotype signatures in patients, the presence of cancer antigen-reactive antibodies and an association between increased autoantibody production on treatment with ICIs and the development of toxicity (immune-related adverse events; irAEs). CONCLUSIONS: We draw consensus for associations between class-switched B cells and immune-active antibody isotypes that indicate heightened classical immunity, with improved immunotherapy response. Alternatively activated, regulatory B cells and immune-inert antibody isotypes are associated with immunosuppression and less-favourable clinical outcomes. We reveal aspects of humoral immunity that offer opportunities to identify predictive biomarkers of immunotherapy response and irAEs.