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关键词： Atopic dermatitis   JAK inhibitors   Body mass index   Obesity   Real-world study   Upadacitinib   Abrocitinib   Baricitinib   Treatment efficacy   Dermatology  

摘要： Introduction: Janus kinase (JAK) inhibitors are effective systemic treatments for moderate-to-severe atopic dermatitis (AD), rapidly controlling symptoms and improving quality of life. However, the impact of body mass index (BMI) on therapeutic response remains unclear. Methods: This multicenter retrospective study analyzed data from 388 adult AD patients treated with upadacitinib, abrocitinib, or baricitinib across 25 Italian dermatology centers between May 2022 and July 2024. Patients were classified as overweight (BMI >= 25) or non-overweight (BMI < 25), with disease severity assessed using EASI, IGA, and Numerical Rating Scales (NRS) for pruritus and sleep disturbance over 104 weeks. The effect of different treatment dosages was also evaluated. Results: No significant BMI-related differences in clinical outcomes were noted at most timepoints. However, in the upadacitinib 15 mg group, non-overweight patients showed greater EASI and pruritus improvements at Week 4 (p = 0.037, p = 0.039), although these differences resolved subsequently. At Week 104, higher BMI modestly reduced EASI improvement (p = 0.045) in multivariable analysis. Conclusions: Treatment dosage consistently influenced clinical improvement regardless of BMI. These findings confirm the efficacy of JAK inhibitors across BMI categories, suggesting minimal short-term BMI influence but highlighting potential long-term considerations in overweight patients, emphasizing personalized dosing strategies and prolonged monitoring.

关键词： Ulcerative colitis   IL-10   Mitochondrial function   Intestinal barrier   Autophagy   ISG15  

摘要： Background: Interleukin-10 (IL-10), an anti-inflammatory cytokine, has shown therapeutic effect on autoimmune diseases, yet its effects on UC remain unclear. This study aims to investigate whether the administration of IL-10 can suppress disease flares in ulcerative colitis (UC). Methods: A UC model was established in mice using dextran sulfate sodium (DSS) to evaluate the therapeutic effect of IL-10. LPS-stimulated Caco-2 cells were utilized to explore the underlying molecular mechanisms, focusing on apoptosis, inflammation, and oxidative stress. Results: IL-10 administration significantly alleviated clinical symptoms in DSS-induced colitis, including promoting body weight recovery, increasing colon length, and reducing disease activity index scores. IL-10 repaired the intestinal mucosal barrier by inhibiting apoptosis of intestinal epithelial cells, downregulating proinflammatory cytokines (IL-6, Interferon-gamma, and IL-1 beta), and modulating oxidative stress markers, such as malondialdehyde (MDA) and superoxide dismutase (SOD). In LPS-stimulated Caco-2 cells, IL-10 protected against apoptosis, oxidative stress, and inflammation. Bioinformatics analysis of control and IL-10 knockout mice showed a significant upregulation of Interferon-Stimulated Gene 15 (ISG15) after IL-10 knockout. In contrast, ISG15 expression was downregulated in the LPS + IL-10 group but upregulated in LPS-stimulated Caco-2 cells. These results suggest that ISG15 is a target gene of IL-10 and plays a role in autophagy regulation. Furthermore, IL-10 enhanced autophagy by increasing the protein expression of ATG7, and the LC3-II/LC3-I ratio, thereby reducing apoptosis and oxidative stress in Caco-2 cells. Autophagy inhibition with 3-Methyladenine or overexpression of ISG15 diminished IL-10's protective effects. Conclusion: This study demonstrates that IL-10 administration inhibits the progression of UC by activating autophagy and modulating ISG15 expression. In the future, targeted delivery of

摘要： Pharmacodynamic (PD) biomarkers can support biosimilarity assessment, potentially reducing the need for comparative clinical efficacy studies. This study aimed to characterize previously identified proteomic PD biomarker candidates for Interferon beta-1a (IFN beta-1a, n = 248) and pegylated IFN beta-1a (pegIFN beta-1a, n = 528) biologics at therapeutic doses, to further evaluate the utility of proteomics in biosimilar development. Here, we reproduced the results at lower doses and characterized PD responses across multiple doses using criteria for justifying PD biomarker use in biosimilar development. We analyzed candidate proteins from longitudinal proteomics data (SomaScan (TM) Assay v4.1) from 48 healthy subjects administered intermediate or low doses of IFN beta-1a (15, 7.5 mu g) or pegIFN beta-1a (62.5, 31.25 mu g) in an FDA-sponsored study, alongside previously published therapeutic dose and placebo data. EDTA plasma samples were collected at 0, 0.125, 0.33, 0.67, 1.33, 2, 3, 4, 5, 6 days and at 9, 13 days additionally for pegIFN beta-1a. Prioritization criteria included significant differential expression at the intermediate dose vs. placebo, >= 20% response difference from placebo, significant baseline-adjusted area under the effect curve (AUEC) and a monotonic dose-response relationship across all doses. Among the candidates, 165 and 323 were differentially expressed at intermediate doses of IFN beta-1a and pegIFN beta-1a respectively. Nine PD biomarkers, including C-X-C motif chemokine 11 (I-TAC), Lymphocyte activation gene 3 protein (LAG3), and Granulins (GRN), were prioritized as common to both biologics. Most candidates followed the Emax dose-response model. I-TAC showed the strongest response, and LAG-3 showed the least variability in AUEC. Our study identified several suitable plasma PD biomarkers for IFN beta-1a and pegIFN beta-1a biologics with potential utility in biosimilar development programs.

关键词： HLA‐C*08:294   novel allele   sequencing‐based typing  

摘要： HLA-C*08:294 allele differs from HLA-C*08:01:01:01 by a single non-synonymous nucleotide change in exon 3.

摘要： [This corrects the article DOI: 10.7759/cureus.44901.].

关键词： HLA‐A*32:187   HLA   next‐generation sequencing   novel allele  

摘要： HLA-A*32:187 differs from HLA-A*32:01:01:01 by one nucleotide substitution in codon 211 in exon 4.

关键词： HLA‐C*12:72   Indian   next generation sequencing   novel allele  

摘要： The HLA-C*12:72 allele, differs from HLA-C*12:02:02:01, by one nonsynonymous substitution, c.312C>A in exon 2.

关键词： HLA‐DQB1*06:528   novel allele   sequencing‐based typing  

摘要： HLA-DQB1*06:528 differs from HLA-DQB1*06:09:01:01 by a single non-synonymous nucleotide change in exon 2.

关键词： allele variant   next generation sequencing   novel allele  

摘要： The novel allele HLA-B*50:01:01:14 displays a single polymorphism in the 5'UTR when compared to HLA-B*50:01:01:01.