British Journal of Dermatology最新文献

Background: The Checkmate 067 randomized controlled trial, published in 2015, demonstrated improved progression-free survival and numerically, although not statistically, superior overall survival for ipilimumab + nivolumab. The objective of this study was to compare the efficacy and safety of nivolumab to ipilimumab + nivolumab as first-line treatment for metastatic melanoma in a real-world setting.

Methods: Patients were prospectively included in the French Melbase cohort from 2013 to 2022. Eligible patients were those in first-line treatment for stage-IIIc or -IV melanoma, undergoing immunotherapy with nivolumab or ipilimumab + nivolumab. The primary endpoint was overall survival at 36 months. The secondary endpoints included progression-free survival at 36 months, best radiological response, and safety analyses. We conducted a propensity score using the IPTW method to overcome the various confounding factors and also a subgroup analysis (brain metastasis, LDH levels, and BRAF mutation status).

Results: A total of 406 patients were treated with nivolumab, and 416 with ipilimumab + nivolumab. Overall survival at 36 months was higher in the ipilimumab + nivolumab group (57.1%, ([95%CI 50.7-64.2]) than in the nivolumab group (46.6% [95%CI 41.6-52.1]), HR 1.4[1.1;1.8]. Progression-free survival at 36 months was significantly improved in the ipilimumab + nivolumab group (42.3%) compared to the nivolumab group (21.9%), with a HR 1.6[1.4;1.9]. The objective response rate was similar for the two groups (44%). The overall incidence of side effects was comparable (82 vs. 84%), and severe toxicity (grade ≥ 3) was more frequent, though not significantly so, in the ipilimumab + nivolumab arm (29% vs. 41%).

Conclusions: Our results are consistent with those from the Checkmate 067 study, except for the objective response rate and the incidence of toxicities, which proved to be lower in our analysis.

Background: Growing evidence has shown that cholesterol metabolism abnormalities involve carcinogenesis. Proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors have been reported to inhibit tumor progression and prevent ultraviolet-related skin damage.

Objective: To investigate the association of PCSK9 inhibitors with the risk of nonmelanoma skin cancer (NMSC).

Methods: This retrospective cohort study analyzed data from the US Collaborative Network in the TriNetX database. Adults aged ≥40 years with atherosclerotic cardiovascular disease (ASCVD) under statin therapy between 2016 and 2022 were identified. A target trial design was used to compare the risk of NMSC, including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), among patients additionally treated with PCSK9 inhibitors or continuing statin therapy (the control group). Each head-to-head comparison involved propensity score matching. Hazard ratios (HRs) were estimated using Cox proportional hazard models. Stratified analyses based on age, sex, Fitzpatrick skin type, and immune status were also performed.

Results: A total of 73,636 patients with ASCVD were analyzed. Compared with the control group, the ASCVD patients initiating PCSK9 inhibitors were associated with lower risks of NMSC (HR: 0.78; 95%CI: 0.71-0.87), BCC (HR: 0.78; 95%CI: 0.69-0.89), and cSCC (HR: 0.79; 95%CI: 0.67-0.93). Subanalyses revealed the reduced risk of NMSC observed with each PCSK9 inhibitor, namely, evolocumab and alirocumab. Stratified analyses showed similar results among patients aged 65-79 years, those more than 80 years, and male patients.

Conclusions: Our study indicated ASCVD patients with PCSK9 inhibitors have a lower risk of incident NMSC than those without PCSK9 inhibitors.

Background: Polymorphic light eruption (PLE) is the most frequent photodermatosis in Europe with an estimated prevalence of 10 to 20%, particularly in temperate climates. Itching or burning lesions appear only in sun-exposed areas, predominantly on the chest, the arms and forearms within a few hours following exposure. The disease's cause is still unknown, yet studies have suggested that skin microbial elements may play a role in its pathogenesis.

Objectives: We investigated in this cohort the skin microbiome of PLE patients upon exposure to ultraviolet radiation (UVR), to assess its role in the onset of PLE lesions.

Methods: Forty-one skin swabs have been collected from eleven PLE patients at baseline and following a three-day exposure to UVR and from healthy controls. The collected swabs were analyzed for their microbial composition using a 16S amplicon sequencing approach.

Results: The PLE skin showed a dysbalanced microbiome, already at baseline, with significantly reduced microbial diversity and noticeable colonization by bacterial pathogens as Staphylococcus aureus. Upon UVR exposure, the PLE microbiome exhibited a further loss of diversity and decline of beneficial skin commensals. In line with this, we observed that UVR exerted strong antimicrobial effects in vitro against representative skin residents.

Conclusions: Taken together, UVR can lead to profound skin microbiome changes, allowing the proliferation of dysbiotic members that can release a variety of elements able to trigger PLE lesions. This is the first study investigating the cutaneous microbiome changes in PLE patients upon UVR, offering new insights into disease pathogenesis, so far unexplored.

Background: The pathogenesis of psoriasis, an inflammatory skin disease, is incompletely understood. Growing evidence substantiates the involvement of stromal cells in the inflammatory process.

Objectives: To investigate the roles of stromal cells, including fibroblasts, vascular endothelial cells (VECs) and smooth muscle cells (VSMCs), in the psoriatic inflammatory microenvironment and the possible underlying mechanisms involved.

Methods: This study employed combination of single-cell, spatial transcriptome and bulk RNA sequencing using lesional and nonlesional skin samples from patients with psoriasis vulgaris (PV) and healthy skin samples from unaffected individuals.

Results: Through the analysis of transcriptome from 364,098 single cells, we uncovered WNT5A+ fibroblasts, ITIH5+ VECs and VCAN+ VSMCs with the significantly increased cell proportions in the papillary dermis of lesional skin. We defined eight unique subclusters of fibroblasts in the skin and observed a shift of WIF1+ fibroblasts towards WNT5A+ fibroblasts, with abnormal activation of the non-canonical Wnt signaling pathway and increased capabilities of angiogenesis and pro-inflammatory. For the microvascular cells, VSMCs could undergo phenotypic transformation from a contractile phenotype to a synthetic phenotype in the development of psoriatic inflammation. ITIH5+ VECs and VCAN+ VSMCs were identified with an essential role in regulating angiogenesis and vascular remodeling involved in the mechanism of psoriatic pathological changes. Ligand receptor analyses demonstrated WNT5A+ fibroblasts were extensively implicated in interactions with various cell types in skin, especially with ITIH5+ VECs and VCAN+ VSMCs within the papillary dermis.

Conclusions: Interactions of stromal cells in the papillary dermis were identified as possible pathogenic elements in psoriasis vulgaris. Improving the inflammatory microenvironment by targeting stromal cells might be a potential treatment strategy for psoriasis.