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关键词： Crohns disease   ustekinumab   real world evidence comparison  

摘要： Background The prospective RUN-CD registry investigates the effectiveness of ustekinumab (UST) and other biologics in Crohn's disease (CD) across Germany. Based on data from the registry, this study presents the maintenance phase results of a 12-month real-world-evidence (RWE) comparison of CD patients initiating new biologic therapies with UST or *** After excluding patients using biologics other than UST and anti-TNF and those with missing outcomes, the final sample consisted of 618 CD patients. Clinical remission (CR), defined as a Harvey-Bradshaw Index (HBI) <= 4, was the prespecified endpoint at 12 months. Switching to another biologic therapy was considered an outcome failure. Propensity score adjustment was used to reduce the effect of *** The study included 343 CD patients treated with UST and 264 treated with anti-TNF. Over 12 months, the frequency of therapy switches was significantly higher for infliximab (28%) compared with UST (17%) and adalimumab (17%) (P =.045). There was no significant difference in CR rates at 12 months between the UST and anti-TNF groups (65.8% vs 60.0%, P =.262). However, in week-16 responders, CR rates at 12 months were significantly higher with UST (77.6%) versus anti-TNF (65.4%) (P =.041). The change in EQ-VAS (QoL) scores between UST and anti-TNF showed a 5.1-point difference favoring UST (P =.002).Conclusions In this 12-month RWE comparison, overall CR rates were similar between UST and anti-TNF. However, among week-16 responders, CR rates were significantly higher with UST. Additionally, UST was associated with a significantly greater improvement in QoL compared with anti-TNF.

关键词： HLA   HLA-DQB1*06:02:49   novel allele   sequence-based typing   Taiwanese  

摘要： One nucleotide substitution at nucleotide 36 of HLA-DQB1*06:02:01:01 results in a novel allele HLA-DQB1*06:02:49.

关键词： Cytokines   Proteineprotein interaction inhibitors   Dermatology   Arthritis   Interleukins   Inflammation  

摘要： T-helper 17 (Th17) cells produce homodimeric IL17A/A and IL17F/F cytokines as well as the heterodimeric IL17A/F isoform, all having well known roles in defense against extracellular pathogens including fungal infection. Antibodies targeting IL17A (such as secukinumab and ixekizumab) have been approved to treat psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis and are under further investigation as therapies in inflammatory disorders such as hidradenitis suppurativa and giant cell arteritis. Because many patients dislike injections with needles, orally bioavailable small molecule IL17 antagonists are desirable as next-generation drugs as long as they can replicate the degree of efficacy observed with anti-IL17A biologics. We recently described novel small molecules binding as 2 copies to the IL17A/A homodimer with only weak effects on the IL17A/F heterodimer. Because approved antibodies binding IL17A neutralize both IL17A/A and IL17A/F, we assessed whether targeting IL17A/A would be sufficient to bring efficacy comparable to IL17A biologics. In comparison to IL17A/F and IL17F/F, we found that the IL17A/A homodimer is the strongest initiator of signaling and that comparable IL17A/A to IL17A/F ratios are expressed in Th17 cells and in human psoriatic skin tissue. Furthermore, our IL17A/A-specific small molecules block the effects of Th17 cell supernatants on keratinocytes to similar maximal responses as anti-IL17A. Our IL17A/A-selective antagonists deliver comparable efficacy to anti-IL17A biologics in several rodent inflammatory models of psoriasiform dermatitis and arthritis. These results support neutralizing IL17A/A with oral small molecule antagonists is an attractive approach to provide differentiated, next-generation therapies for inflammatory disorders. Significance Statement: This study found that orally active small molecule antagonists of the proinflammatory cytokine IL17A that preferentially bind the IL17A/A form produced e

关键词： HLA-DQA1   HLA-DQA1*05:01:21   NGS   novel HLA allele  

摘要： HLA-DQA1*05:01:21 differs from HLA-DQA1*05:01:01:02 by one nucleotide substitution in codon 198 (TGC > TGT) in exon 4.

关键词： vulvovaginal candidiasis   Card9 deficiency   IL-17   tight junction   antimicrobial peptide  

摘要： Vulvovaginal candidiasis (VVC) is an inflammation caused by Candida albicans with a higher recurrence rate in individuals deficient in Card9. This study aimed to elucidate the mechanisms underlying this increased susceptibility. Estrogen-treated Card9-/- mice infected with C. albicans were used to model Card9 deficiency-related VVC. Our findings indicate that Card9 deficiency leads to a reduction in Th17 cells, interleukin (IL)-17-producing gamma delta T cells, and IL-17A secretion, weakens epithelial tight junctions, and reduces antimicrobial peptide secretion, leading to persistent fungal invasion. This persistent invasion results in excessive neutrophil recruitment and activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) and absent in melanoma 2 inflammasomes (AIM2), causing mucosal damage. In conclusion, Card9 deficiency compromises the vaginal epithelial barrier, prolongs C. albicans infection, and increases inflammation, highlighting the critical role of Card9 in maintaining immune function of vaginal mucosa. Vulvovaginal candidiasis (VVC) is an inflammation caused by Candida albicans. Key findings reveal that Card9 deficiency disrupts the interleukin-17 production, weakens epithelial tight junctions, and reduces antimicrobial peptide secretion, resulting in exacerbation of VVC.

关键词： HLA-A   Indian   next-generation sequencing   novel allele  

摘要： HLA-A*01:474 differs from HLA-A*01:01:01:01 by a single nucleotide substitution at codon 132 in exon 3.

关键词： IL-27   AMPK/SIRT1 pathway   Sepsis   Acute liver injury   Macrophage polarization   Pyroptosis   Caspase-11  

摘要： Objectives: Our aim was to explore the IL-27 effect in sepsis (SP)-related acute hepatic injury (AHI) as well as its possible mechanism. Materials and methods: Herein, we utilized both wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R- /- ) mice alongside RAW264.7 cells. Our study established an SP-associated AHI model through the intraperitoneal injections of lipopolysaccharide (LPS) + D-galactosamine (D-G). For examining the IL-27 impact on AHI, mice serum and liver tissue samples were gathered. Inflammatory factor levels in the liver and serum were detected using ELISA and immunohistochemistry. Immunofluorescence and Western blot techniques were employed for the detection of protein expression associated with polarization and pyroptosis in the liver, including iNOS, ARG1, caspase-11, RAGE, and GSDMD. To further verify the IL-27 effects on macrophage polarization and pyroptosis and explore possible mechanisms involved, we used LPS-triggered RAW264.7 macrophages to assess AMPK/ SIRT1 expression after IL-27 intervention. This study utilized Compound C (CC) to block the AMPK/SIRT1 pathway. The inflammatory response level and protein expression related to macrophage polarization and pyroptosis were measured again to reveal IL-27 implication in AHI and determine whether its role is associated with the AMPK/SIRT1 pathway. Results: The results revealed that IL-27 exacerbated systemic inflammation and liver damage in AHI mice by promoting M1 macrophage polarization, thereby increasing pro-inflammatory phenotype macrophages (M1). This further exacerbated the inflammatory response and pyroptosis in vivo and in vitro. Additionally, IL-27 down- regulated p-AMPK and SIRT1 protein expression while overexpressing macrophage inflammatory mediators including IL-1 beta/6 and TNF alpha. Furthermore, IL-27 promoted increased RAGE and caspase-11 protein expression, aggravating macrophage pyroptosis. Employing CC to block the AMPK pathway further aggravated M1 macrophage pola

关键词： acute hepatitis   cytokines   interleukin 18   interleukin-18 binding protein   liver immunology