Pub Date : 2024-07-18DOI: 10.1186/s13075-024-03363-0
Panagiota Xanthouli, Paul Uesbeck, Hanns-Martin Lorenz, Norbert Blank, Christina A Eichstaedt, Satenik Harutyunova, Benjamin Egenlauf, Jerry G Coghlan, Christopher P Denton, Ekkehard Grünig, Nicola Benjamin
Background: In the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy.
Methods: Patients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition.
Results: Of 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (p < 0.0001).
Conclusion: In SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.
{"title":"Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study.","authors":"Panagiota Xanthouli, Paul Uesbeck, Hanns-Martin Lorenz, Norbert Blank, Christina A Eichstaedt, Satenik Harutyunova, Benjamin Egenlauf, Jerry G Coghlan, Christopher P Denton, Ekkehard Grünig, Nicola Benjamin","doi":"10.1186/s13075-024-03363-0","DOIUrl":"10.1186/s13075-024-03363-0","url":null,"abstract":"<p><strong>Background: </strong>In the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy.</p><p><strong>Methods: </strong>Patients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition.</p><p><strong>Results: </strong>Of 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (p < 0.0001).</p><p><strong>Conclusion: </strong>In SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.</p>","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"26 1","pages":"136"},"PeriodicalIF":4.9,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1186/s13075-024-03374-x
Jing Luo, Jing Zhang, Bomiao Ju, Yanhua Wang, Nan Hu, Qian Li, Qianyun Xu, Dan Pu, Zhiming Hao, Yongwei Huo, Xiaohong Lv, Lan He
To investigate the distribution and activation of B-cell subpopulations in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) and to analyze their correlation with disease remission. Peripheral blood samples were collected from 23 adult healthy controls and 58 RA patients, 31 of whom were treated with JAKis and assessed during a 24-month follow-up. The number of peripheral B-cell subpopulations (including naive B cells, nonswitched memory B (NSMB) cells, switched memory B cells, and double-negative B cells), their activation, and phosphorylation of SYK and AKT upon B-cell receptor (BCR) stimulation in each population were analyzed by flow cytometry. Compared with that in healthy controls, the frequency of NSMB cells was significantly lower in new-onset untreated RA patients. However, expression of CD40, CD80, CD95, CD21low and pAKT significantly increased in these NSMB cells. Additionally, the number of NSMB cells correlated negatively with DAS28-ESR and IgG and IgA levels in these patients; expression of CD80, CD95 and CD21low on NSMB cells correlated positively with DAS28-ESR and IgG and IgA levels. After treatment with JAKis, the serum IgG concentration significantly decreased in RA patients in remission, but CD40, CD95 and pAKT levels in NSMB cells significantly decreased. RA patients present different B-cell subpopulations, in which the frequency of NSMB cells is negatively associated with disease activity. However, treatment with JAKis can inhibit activation of NSMB cells, restore the balance of kinase phosphorylation, and facilitate disease remission in RA patients.
研究类风湿性关节炎（RA）患者接受 Janus 激酶抑制剂（JAKis）治疗后 B 细胞亚群的分布和活化情况，并分析其与疾病缓解的相关性。研究人员采集了23名成年健康对照者和58名类风湿关节炎患者的外周血样本，其中31人接受了JAKis治疗，并在24个月的随访期间进行了评估。流式细胞术分析了外周 B 细胞亚群（包括幼稚 B 细胞、非开关记忆 B 细胞（NSMB）、开关记忆 B 细胞和双阴性 B 细胞）的数量、其活化情况以及每个亚群在 B 细胞受体（BCR）刺激下的 SYK 和 AKT 磷酸化情况。与健康对照组相比，新发未经治疗的RA患者中NSMB细胞的频率明显降低。但是，CD40、CD80、CD95、CD21low 和 pAKT 在这些 NSMB 细胞中的表达明显增加。此外，在这些患者中，NSMB细胞的数量与DAS28-ESR以及IgG和IgA水平呈负相关；NSMB细胞上CD80、CD95和CD21low的表达与DAS28-ESR以及IgG和IgA水平呈正相关。使用 JAKis 治疗后，缓解期 RA 患者的血清 IgG 浓度明显降低，但 NSMB 细胞中的 CD40、CD95 和 pAKT 水平明显下降。RA 患者有不同的 B 细胞亚群，其中 NSMB 细胞的频率与疾病活动性呈负相关。然而，使用 JAKis 治疗可以抑制 NSMB 细胞的活化，恢复激酶磷酸化的平衡，促进 RA 患者的疾病缓解。
{"title":"JAK inhibitors attenuate hyperactivation of nonswitched memory B cells in rheumatoid arthritis patients in remission","authors":"Jing Luo, Jing Zhang, Bomiao Ju, Yanhua Wang, Nan Hu, Qian Li, Qianyun Xu, Dan Pu, Zhiming Hao, Yongwei Huo, Xiaohong Lv, Lan He","doi":"10.1186/s13075-024-03374-x","DOIUrl":"https://doi.org/10.1186/s13075-024-03374-x","url":null,"abstract":"To investigate the distribution and activation of B-cell subpopulations in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) and to analyze their correlation with disease remission. Peripheral blood samples were collected from 23 adult healthy controls and 58 RA patients, 31 of whom were treated with JAKis and assessed during a 24-month follow-up. The number of peripheral B-cell subpopulations (including naive B cells, nonswitched memory B (NSMB) cells, switched memory B cells, and double-negative B cells), their activation, and phosphorylation of SYK and AKT upon B-cell receptor (BCR) stimulation in each population were analyzed by flow cytometry. Compared with that in healthy controls, the frequency of NSMB cells was significantly lower in new-onset untreated RA patients. However, expression of CD40, CD80, CD95, CD21low and pAKT significantly increased in these NSMB cells. Additionally, the number of NSMB cells correlated negatively with DAS28-ESR and IgG and IgA levels in these patients; expression of CD80, CD95 and CD21low on NSMB cells correlated positively with DAS28-ESR and IgG and IgA levels. After treatment with JAKis, the serum IgG concentration significantly decreased in RA patients in remission, but CD40, CD95 and pAKT levels in NSMB cells significantly decreased. RA patients present different B-cell subpopulations, in which the frequency of NSMB cells is negatively associated with disease activity. However, treatment with JAKis can inhibit activation of NSMB cells, restore the balance of kinase phosphorylation, and facilitate disease remission in RA patients.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"28 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141631555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16DOI: 10.1186/s13075-024-03366-x
Louise Koller-Smith, Ahmed Mehdi, Lyn March, Leigh Tooth, Gita D. Mishra, Ranjeny Thomas
Most estimates of rheumatoid arthritis (RA) prevalence, including all official figures in Australia and many other countries, are based on self-report. Self-report has been shown to overestimate RA, but the ‘gold standard’ of reviewing individual medical records is costly, time-consuming and impractical for large-scale research and population monitoring. This study provides an algorithm to estimate RA cases using administrative data that can be adjusted for use in multiple contexts to provide the first approximate RA cohort in Australia that does not rely on self-report. Survey data on self-reported RA and medications from 25 467 respondents of the Australian Longitudinal Study on Women’s Health (ALSWH) were linked with data from the national medication reimbursement database, hospital and emergency department (ED) episodes, and Medicare Benefits codes. RA prevalence was calculated for self-reported RA, self-reported RA medications, dispensed RA medications, and hospital/ED RA presentations. Linked data were used to exclude individuals with confounding autoimmune conditions. Of 25 467 survey respondents, 1367 (5·4%) women self-reported disease. Of the 26 840 women with hospital or ED presentations, 292 (1·1%) received ICD-10 codes for RA. There were 1038 (2·8%) cases by the medication database definition, and 294 cases (1·5%) by the self-reported medication definition. After excluding individuals with other rheumatic conditions, prevalence was 3·9% for self-reported RA, 1·9% based on the medication database definition and 0·5% by self-reported medication definition. This confirms the overestimation of RA based on self-reporting. We provide an algorithm for identifying individuals with RA, which could be used for population studies and monitoring RA in Australia and, with adjustments, internationally. Its balance of accuracy and practicality will be useful for health service planning using relatively easily accessible input data.
对类风湿性关节炎（RA）患病率的大多数估计，包括澳大利亚和许多其他国家的所有官方数字，都是基于自我报告。自我报告已被证明会高估类风湿关节炎的患病率，但审查个人医疗记录这一 "黄金标准 "成本高昂、耗时长，对于大规模研究和人口监测来说并不实用。本研究提供了一种利用行政数据估算RA病例的算法，该算法可根据多种情况进行调整，从而提供澳大利亚首个不依赖自我报告的RA近似队列。澳大利亚妇女健康纵向研究（ALSWH）的25 467名受访者自我报告的RA和药物调查数据与来自国家药物报销数据库、医院和急诊科（ED）病例以及医疗保险福利代码的数据进行了关联。根据自我报告的RA、自我报告的RA药物、配发的RA药物以及医院/急诊科的RA病例计算RA患病率。使用关联数据排除了患有自身免疫性疾病的混杂个体。在 25 467 名调查对象中，1367 名（5-4%）女性自我报告患有疾病。在 26 840 名曾在医院或急诊室就诊的女性中，有 292 人（1-1%）获得了 ICD-10 的 RA 代码。根据药物数据库定义的病例有 1038 例（2-8%），根据自我报告的药物定义的病例有 294 例（1-5%）。排除患有其他风湿病的患者后，自我报告的 RA 患病率为 3-9%，根据药物数据库的定义为 1-9%，根据自我报告的药物定义为 0-5%。这证实了基于自我报告的 RA 患病率被高估。我们提供了一种识别RA患者的算法，可用于澳大利亚的人口研究和RA监测，经调整后也可用于国际研究。该算法兼顾了准确性和实用性，将有助于利用相对容易获取的输入数据进行医疗服务规划。
{"title":"A novel method to monitor rheumatoid arthritis prevalence using hospital and medication databases","authors":"Louise Koller-Smith, Ahmed Mehdi, Lyn March, Leigh Tooth, Gita D. Mishra, Ranjeny Thomas","doi":"10.1186/s13075-024-03366-x","DOIUrl":"https://doi.org/10.1186/s13075-024-03366-x","url":null,"abstract":"Most estimates of rheumatoid arthritis (RA) prevalence, including all official figures in Australia and many other countries, are based on self-report. Self-report has been shown to overestimate RA, but the ‘gold standard’ of reviewing individual medical records is costly, time-consuming and impractical for large-scale research and population monitoring. This study provides an algorithm to estimate RA cases using administrative data that can be adjusted for use in multiple contexts to provide the first approximate RA cohort in Australia that does not rely on self-report. Survey data on self-reported RA and medications from 25 467 respondents of the Australian Longitudinal Study on Women’s Health (ALSWH) were linked with data from the national medication reimbursement database, hospital and emergency department (ED) episodes, and Medicare Benefits codes. RA prevalence was calculated for self-reported RA, self-reported RA medications, dispensed RA medications, and hospital/ED RA presentations. Linked data were used to exclude individuals with confounding autoimmune conditions. Of 25 467 survey respondents, 1367 (5·4%) women self-reported disease. Of the 26 840 women with hospital or ED presentations, 292 (1·1%) received ICD-10 codes for RA. There were 1038 (2·8%) cases by the medication database definition, and 294 cases (1·5%) by the self-reported medication definition. After excluding individuals with other rheumatic conditions, prevalence was 3·9% for self-reported RA, 1·9% based on the medication database definition and 0·5% by self-reported medication definition. This confirms the overestimation of RA based on self-reporting. We provide an algorithm for identifying individuals with RA, which could be used for population studies and monitoring RA in Australia and, with adjustments, internationally. Its balance of accuracy and practicality will be useful for health service planning using relatively easily accessible input data.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"6 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141624888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-16DOI: 10.1186/s13075-024-03368-9
Falk Schumacher, Maximilian Zimmermann, Malte Kanbach, Wigbert Schulze, Maximilian Wollsching-Strobel, Doreen Kroppen, Sarah Bettina Stanzel, Daniel Majorski, Wolfram Windisch, Johannes Strunk, Melanie Berger
The increased availability of myositis autoantibodies represents new possibilities and challenges in clinical practice (Lundberg IE, Tjärnlund A, Bottai M, Werth VP, Pilkington C, de Visser M, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. 2017;76:1955–64. https://doi.org/10.1136/annrheumdis-2017-211468 .). The aim of this study was to perform a retrospective data analysis of patient cases with positive myositis autoantibodies to analyse their significance in routine rheumatology practice. A monocentric analysis of all the orders used to determine myositis autoantibodies from July 2019 to May 2022 in the Department of Rheumatology, Krankenhaus Porz am Rhein, Cologne, Germany, was carried out. In the defined time interval, a total of 71,597 laboratory values for the antibodies mentioned above were obtained. A total of 238 different positive autoantibodies were detected in 209 patients. Idiopathic inflammatory myopathy was diagnosed in 37 patients (18%), and inflammatory rheumatic diseases other than idiopathic inflammatory myopathy were diagnosed in 90 patients (43%). No inflammatory rheumatic disease was diagnosed in 82 patients (39%). General clusters of clinical manifestations were observed. In our cohort, we were able to show that a relevant proportion of patients with positive myositis antibodies did not have idiopathic inflammatory myopathies or inflammatory rheumatic diseases. This finding indicates the importance of myositis autoantibodies in this group of patients. However, further studies on the course of symptoms and examination results in patients without inflammatory rheumatic diseases and with positive myositis antibodies are necessary.
{"title":"Clinical relevance of positively determined myositis antibodies in rheumatology: a retrospective monocentric analysis","authors":"Falk Schumacher, Maximilian Zimmermann, Malte Kanbach, Wigbert Schulze, Maximilian Wollsching-Strobel, Doreen Kroppen, Sarah Bettina Stanzel, Daniel Majorski, Wolfram Windisch, Johannes Strunk, Melanie Berger","doi":"10.1186/s13075-024-03368-9","DOIUrl":"https://doi.org/10.1186/s13075-024-03368-9","url":null,"abstract":"The increased availability of myositis autoantibodies represents new possibilities and challenges in clinical practice (Lundberg IE, Tjärnlund A, Bottai M, Werth VP, Pilkington C, de Visser M, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis. 2017;76:1955–64. https://doi.org/10.1136/annrheumdis-2017-211468 .). The aim of this study was to perform a retrospective data analysis of patient cases with positive myositis autoantibodies to analyse their significance in routine rheumatology practice. A monocentric analysis of all the orders used to determine myositis autoantibodies from July 2019 to May 2022 in the Department of Rheumatology, Krankenhaus Porz am Rhein, Cologne, Germany, was carried out. In the defined time interval, a total of 71,597 laboratory values for the antibodies mentioned above were obtained. A total of 238 different positive autoantibodies were detected in 209 patients. Idiopathic inflammatory myopathy was diagnosed in 37 patients (18%), and inflammatory rheumatic diseases other than idiopathic inflammatory myopathy were diagnosed in 90 patients (43%). No inflammatory rheumatic disease was diagnosed in 82 patients (39%). General clusters of clinical manifestations were observed. In our cohort, we were able to show that a relevant proportion of patients with positive myositis antibodies did not have idiopathic inflammatory myopathies or inflammatory rheumatic diseases. This finding indicates the importance of myositis autoantibodies in this group of patients. However, further studies on the course of symptoms and examination results in patients without inflammatory rheumatic diseases and with positive myositis antibodies are necessary.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"33 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141624887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-15DOI: 10.1186/s13075-024-03370-1
Marc Lauraine, Maxence de Taffin de Tilques, Dganit Melamed-Kadosh, Bilade Cherqaoui, Vincent Rincheval, Erwan Prevost, Aurore Rincheval-Arnold, Eneida Cela, Arie Admon, Isabelle Guénal, Luiza M. Araujo, Maxime Breban
Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-β2 microglobulin (hβ2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype. Genetic interaction was studied between activin/transforming growth factor β (TGFβ) pathway and HLA-B27/hβ2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hβ2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFβ pathways induced by its ligands, and the transcript level of target genes of the TGFβ pathway, were evaluated. In HLA-B27/hβ2m transgenic Drosophila, inappropriate signalling through the activin/TGFβ pathway, involving Baboon (Babo), the type I activin/TGFβ receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hβ2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hβ2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFβ receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFβ1 was increased in T cells from B27 rats, showing evidence for deregulated TGFβ pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFβ exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. This study shows that HLA-B27 alters the TGFβ pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats.
HLA-B27与脊柱关节炎（Spondyloarthritis，SpA）的关系已经存在了50年，但至今仍未解释清楚。我们最近发现，在HLA-B27/人β2微球蛋白（hβ2m）转基因果蝇的翅胚盘中表达的HLA-B27通过与I型BMP受体（BMPR1）Saxophone（Sax）发生物理相互作用，从而干扰了骨形态发生蛋白（BMP）通路，导致无交叉脉表型。研究了转基因果蝇翅膀中活化素/转化生长因子β（TGFβ）通路与HLA-B27/hβ2m之间的遗传相互作用。研究人员对翅膀显像盘中与HLA-B27结合的肽组进行了表征。在HLA-B27/hβ2m大鼠（B27大鼠）的肠系膜淋巴结（mLN）T细胞中，评估了HLA-B27与活化素受体样激酶-2（ALK2）、ALK3和ALK5 BMPR1s之间的物理相互作用、其配体诱导的抗断头小母（SMADs）和非经典BMP/TGFβ通路蛋白的磷酸化以及TGFβ通路靶基因的转录水平。在HLA-B27/hβ2m转基因果蝇中，除了BMP通路失调外，通过I型激活素/TGFβ受体巴布（Babo）参与的激活素/TGFβ通路的不恰当信号传导也导致了无横纹表型。我们在HLA-B27/hβ2m转基因果蝇翼像盘中发现了与HLA-B27结合的具有典型结合基序的肽。我们在 B27 大鼠的 mLN 细胞中证实了 HLA-B27/hβ2m 与哺乳动物 Sax 和 Babo 的直向同源物，即 ALK2 和 ALK5（即 TGFβ 受体 I）之间的特异性物理相互作用。在 B27 大鼠的 T 细胞中，SMAD2/3 对 TGFβ1 的磷酸化程度增加，表明 TGFβ 通路失调。相应地，在基础条件下和/或暴露于 TGFβ 后，B27 大鼠 T 细胞中该通路的几个靶基因（包括 Foxp3、Rorc、Runx1 和 Maf）的表达增加。有趣的是，B27 大鼠的幼稚 T 细胞中 Tgfb1 的表达减少，甚至在发病前也是如此，这一观察结果与促炎模式一致。这项研究表明，HLA-B27 改变了果蝇和 B27 大鼠的 TGFβ 通路。鉴于该通路在 CD4 + T 细胞分化和调节中的重要性，它的干扰可能会导致 B27 大鼠中观察到的促炎性 T 辅助细胞 17 的异常扩增和调节性 T 细胞表型的改变。
{"title":"TGFβ signaling pathway is altered by HLA-B27 expression, resulting in pathogenic consequences relevant for spondyloarthritis","authors":"Marc Lauraine, Maxence de Taffin de Tilques, Dganit Melamed-Kadosh, Bilade Cherqaoui, Vincent Rincheval, Erwan Prevost, Aurore Rincheval-Arnold, Eneida Cela, Arie Admon, Isabelle Guénal, Luiza M. Araujo, Maxime Breban","doi":"10.1186/s13075-024-03370-1","DOIUrl":"https://doi.org/10.1186/s13075-024-03370-1","url":null,"abstract":"Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-β2 microglobulin (hβ2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype. Genetic interaction was studied between activin/transforming growth factor β (TGFβ) pathway and HLA-B27/hβ2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hβ2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFβ pathways induced by its ligands, and the transcript level of target genes of the TGFβ pathway, were evaluated. In HLA-B27/hβ2m transgenic Drosophila, inappropriate signalling through the activin/TGFβ pathway, involving Baboon (Babo), the type I activin/TGFβ receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hβ2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hβ2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFβ receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFβ1 was increased in T cells from B27 rats, showing evidence for deregulated TGFβ pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFβ exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. This study shows that HLA-B27 alters the TGFβ pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"44 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The aim of this prospective observational cohort study was to unveil the predictors of treatment response to tocilizumab (TCZ) therapy in rheumatoid arthritis (RA) patients, in terms of clinical characteristics and serum proinflammatory cytokines, especially to explore the predictive value of granulocyte macrophage-colony stimulating factor (GM-CSF). Active adult RA patients with inadequate response to MTX intending to receive TCZ therapy were recruited prospectively in the study. A total of 174 severe RA patients were included for the identification of the associations between treatment response and the following characteristic features: demographics, medications, disease activity, serum proinflammatory cytokines and so on. Disease duration (OR = 0.996), tender joint count (TJC)/68 (OR = 0.943), neutrophil ratio (W4/baseline) (OR = 0.224), the high level of GM-CSF > 5 ng/ml (OR = 0.414) at baseline were the independent adverse predictors of good response assessed by clinical disease activity index (CDAI) at week 24 (W24) for TCZ therapy in RA patients. Moreover, DAS28-ESR (OR = 2.951, P = 0.002) and the high level of GM-CSF > 10 ng/ml at baseline (OR = 5.419, P = 0.002) were independent predictors of poor response, but not the high level of GM-CSF > 5 ng/ml (OR = 2.713, P = 0.054). The patients in the high GM-CSF group had significantly higher DAS28-ESR and serum levels of cytokines (IL-17A, IL-1β, IL-6, TNF-α) at baseline, as well as significantly higher rate of non-good response (62.8% vs. 39.4%, P = 0.010) and poor response (27.9% vs. 9.1%, P = 0.004) than the low GM-CSF group at W24. In addition, poor responders had significantly higher levels of GM-CSF with concomitant increase in the serum levels of IL-17A and IL-1β at baseline than those in moderate and good response groups, while serum levels of IL-6 and TNF-α at baseline were not significantly different in three response groups. The high levels of GM-CSF (> 5 ng/ml and > 10 ng/ml) at baseline were the independent predictors of non-good response and poor response to TCZ at W24 respectively. The high level of GM-CSF at baseline is a marker of high disease activity and a predictor of poor response to TCZ in severe RA patients, which may facilitate the development of individualized treatment strategies for refractory RA.
{"title":"Serum GM-CSF level is a predictor of treatment response to tocilizumab in rheumatoid arthritis patients: a prospective observational cohort study","authors":"Jingbo Su, Wenlu Hu, Yanxia Ding, Panpan Zhang, Tianfang Li, Shengyun Liu, Lihua Xing","doi":"10.1186/s13075-024-03373-y","DOIUrl":"https://doi.org/10.1186/s13075-024-03373-y","url":null,"abstract":"The aim of this prospective observational cohort study was to unveil the predictors of treatment response to tocilizumab (TCZ) therapy in rheumatoid arthritis (RA) patients, in terms of clinical characteristics and serum proinflammatory cytokines, especially to explore the predictive value of granulocyte macrophage-colony stimulating factor (GM-CSF). Active adult RA patients with inadequate response to MTX intending to receive TCZ therapy were recruited prospectively in the study. A total of 174 severe RA patients were included for the identification of the associations between treatment response and the following characteristic features: demographics, medications, disease activity, serum proinflammatory cytokines and so on. Disease duration (OR = 0.996), tender joint count (TJC)/68 (OR = 0.943), neutrophil ratio (W4/baseline) (OR = 0.224), the high level of GM-CSF > 5 ng/ml (OR = 0.414) at baseline were the independent adverse predictors of good response assessed by clinical disease activity index (CDAI) at week 24 (W24) for TCZ therapy in RA patients. Moreover, DAS28-ESR (OR = 2.951, P = 0.002) and the high level of GM-CSF > 10 ng/ml at baseline (OR = 5.419, P = 0.002) were independent predictors of poor response, but not the high level of GM-CSF > 5 ng/ml (OR = 2.713, P = 0.054). The patients in the high GM-CSF group had significantly higher DAS28-ESR and serum levels of cytokines (IL-17A, IL-1β, IL-6, TNF-α) at baseline, as well as significantly higher rate of non-good response (62.8% vs. 39.4%, P = 0.010) and poor response (27.9% vs. 9.1%, P = 0.004) than the low GM-CSF group at W24. In addition, poor responders had significantly higher levels of GM-CSF with concomitant increase in the serum levels of IL-17A and IL-1β at baseline than those in moderate and good response groups, while serum levels of IL-6 and TNF-α at baseline were not significantly different in three response groups. The high levels of GM-CSF (> 5 ng/ml and > 10 ng/ml) at baseline were the independent predictors of non-good response and poor response to TCZ at W24 respectively. The high level of GM-CSF at baseline is a marker of high disease activity and a predictor of poor response to TCZ in severe RA patients, which may facilitate the development of individualized treatment strategies for refractory RA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"71 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-12DOI: 10.1186/s13075-024-03361-2
Khaled Elhady Mohamed, Anna Thorsø Larsen, Simone Melander, Frederik Andersen, Ellen Barendorff Kerrn, Morten Asser Karsdal, Kim Henriksen
Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats. We evaluated KBP-336’s effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology. After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues. Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.
尽管对改善骨关节炎疾病的药物（DMOAD）进行了广泛的研究，但目前仍没有一种DMOAD获得批准。双淀粉样蛋白和降钙素受体激动剂（DACRA）在抗痛觉和潜在的结构保护作用的同时，还能促进新陈代谢。在这些研究中，我们在半月板切除（MNX）大鼠的 OA 代谢模型中测试了一种名为 KBP-336 的 DACRA。我们评估了 KBP-336 对高脂饮食（HFD）的 Sprague Dawley（SD）大鼠疼痛类症状的影响，这些大鼠接受了半月板切除术，我们使用 von Frey 试验测量了 50%的爪退缩阈值（PWT），并使用单因素方差分析进行了分析。短期体内研究和体外细胞受体表达系统用于说明受体药理学。雌性 MNX 动物接受 KBP-336 4.5 nmol/Kg/72 h 高频分解膳食 30 周（包括 8 周治疗）后，体重低于接受车辆治疗的动物，脂肪组织也较小。服用高纤维食物 20 周（包括 8 周治疗）后，接受 KBP-336 治疗的雄性大鼠的体重低于车辆组。在雌性和雄性大鼠中，接受 KBP-336 治疗的 MNX 组的脉搏波速度高于接受车辆治疗的 MNX 组。为了确定影响疼痛缓解的受体，KBP-336 与长效人降钙素（hCTA）进行了比较。对 12 周大雄性大鼠进行的单剂量研究表明，hCTA 可降低 CTX-I，但不影响食物摄入量，这证实了其降钙素受体的选择性。在高密度脂蛋白膳食 18 周（包括 6 周治疗）的代谢性 OA 模型中，100 nmol/Kg/24 h 的 hCTA 和 0.5、1.5 和 4.5 nmol/Kg/72 h 的 KBP-336 可使 MNX 动物的脉搏波速度显著高于接受车辆治疗的 MNX 动物。总体而言，KBP-336 可改善代谢性 OA 模型中观察到的疼痛。事实证明，降钙素受体激活在这种抗痛觉效应中至关重要。
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Pub Date : 2024-07-09DOI: 10.1186/s13075-024-03357-y
Javier Narvaez, Elena Canadillas, Ivan Castellvi, Juan Jose Alegre, Vanesa Vicens‑Zygmunt, Guadalupe Bermudo, Paola Vidal-Montal, Maria Molina Molina, Joan Miquel Nolla
Correction: Arthritis Res Ther 26, 122 (2024)
https://doi.org/10.1186/s13075-024-03353-2
Following publication of the original article [1], the authors identified an error in the author name of Vanesa Vicens‑Zygmunt.
The incorrect author name is: Vanesa Vincens‑Zygmunt.
The correct author name is: Vanesa Vicens‑Zygmunt.
The author group has been updated above and the original article [1] has been corrected.
Narváez J, Cañadillas E, Castellví I, et al. Rituximab in the treatment of progressive interstitial lung disease associated with the antisynthetase syndrome. Arthritis Res Ther. 2024;26:122. https://doi.org/10.1186/s13075-024-03353-2.
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Authors and Affiliations
Department of Rheumatology, Hospital Universitario de Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga, s/n, Hospitalet de Llobregat, Barcelona, 08907, Spain
Javier Narvaez, Paola Vidal-Montal & Joan Miquel Nolla
Department of Rheumatology, Hospital Cl?nico, Universitario Lozano Blesa, Zaragoza, Spain
Elena Canadillas
Department of Rheumatology. Hospital, Universitario de la Santa Creu i Sant Pau, Barcelona, Spain
Ivan Castellvi
Department of Rheumatology. Hospital, Universitario Dr Peset, Valencia, Spain
Juan Jose Alegre
Interstitial Lung Disease Unit, Department of Pneumology. Hospital, Universitario de Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
Vanesa Vicens‑Zygmunt, Guadalupe Bermudo & Maria Molina Molina
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Paola Vidal-Mont
更正：Arthritis Res Ther 26, 122 (2024)https://doi.org/10.1186/s13075-024-03353-2Following 原文[1]发表后，作者发现Vanesa Vicens-Zygmunt的作者姓名有误。错误的作者姓名是Vanesa Vincens-Zygmunt。正确的作者姓名是Vanesa Vicens-Zygmunt。Narváez J, Cañadillas E, Castellví I, et al. Rituximab in the treatment of progressive interstitial lung disease associated with the antisynthetase syndrome.Arthritis Res Ther.2024;26:122. https://doi.org/10.1186/s13075-024-03353-2.Article CAS PubMed PubMed Central Google Scholar 下载参考文献作者及工作单位贝尔维日大学医院风湿病科。Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga, s/n, Hospitalet de Llobregat, Barcelona, 08907, SpainJavier Narvaez, Paola Vidal-Montal & Joan Miquel NollaDepartment of Rheumatology, Hospital Cl?nico, Universitario Lozano Blesa, Zaragoza, SpainElena CanadillasDepartment of Rheumatology.西班牙巴塞罗那圣克鲁伊圣保大学医院风湿病科。西班牙巴伦西亚佩塞特博士大学医院胡安-何塞-阿莱格里肺病科间质性肺病室。贝尔维日大学医院。西班牙巴塞罗那 Bellvitge 生物医学研究所（IDIBELL）Vanesa Vicens-Zygmunt、Guadalupe Bermudo &；Maria Molina Molina作者Javier Narvaez查看作者发表的论文您也可以在PubMed谷歌学术中搜索该作者Elena Canadillas查看作者发表的论文您也可以在PubMed谷歌学术中搜索该作者Ivan Castellvi查看作者发表的论文您也可以在PubMed谷歌学术中搜索该作者ScholarJuan Jose Alegre查看作者发表的作品您也可以在 PubMed Google ScholarVanesa Vicens-Zygmunt查看作者发表的作品您也可以在 PubMed Google ScholarGuadalupe Bermudo查看作者发表的作品您也可以在 PubMed Google ScholarPaola Vidal- 查看作者发表的作品MontalView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Maria Molina MolinaView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Joan Miquel NollaView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者通信作者Javier Narvaez的通信。出版者注Springer Nature对出版地图中的管辖权主张和机构隶属关系保持中立。原文的在线版本可在以下网址找到：https://doi.org/10.1186/s13075-024-03353-2.Open Access 本文采用知识共享署名 4.0 国际许可协议进行许可，该协议允许以任何媒介或格式使用、共享、改编、分发和复制，只要您适当注明原作者和来源，提供知识共享许可协议的链接，并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中，除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中，且您打算使用的材料不符合法律规定或超出许可使用范围，则您需要直接从版权所有者处获得许可。如需查看该许可的副本，请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明，否则知识共享公共领域专用免责声明 (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据。转载与许可引用本文Narvaez, J., Canadillas, E., Castellvi, I. et al. Correction：利妥昔单抗治疗与抗异烟酸酶综合征相关的进行性间质性肺病。Arthritis Res Ther 26, 128 (2024). https://doi.org/10.1186/s13075-024-03357-yDownload citationPublished: 09 July 2024DOI: https://doi.org/10.1186/s13075-024-03357-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative
{"title":"Correction: Rituximab in the treatment of progressive interstitial lung disease associated with the antisynthetase syndrome","authors":"Javier Narvaez, Elena Canadillas, Ivan Castellvi, Juan Jose Alegre, Vanesa Vicens‑Zygmunt, Guadalupe Bermudo, Paola Vidal-Montal, Maria Molina Molina, Joan Miquel Nolla","doi":"10.1186/s13075-024-03357-y","DOIUrl":"https://doi.org/10.1186/s13075-024-03357-y","url":null,"abstract":"<p><b>Correction: Arthritis Res Ther 26, 122 (2024)</b></p><p><b>https://doi.org/10.1186/s13075-024-03353-2</b></p><p>Following publication of the original article [1], the authors identified an error in the author name of Vanesa Vicens‑Zygmunt.</p><p> The incorrect author name is: Vanesa Vincens‑Zygmunt.</p><p> The correct author name is: Vanesa Vicens‑Zygmunt.</p><p> The author group has been updated above and the original article [1] has been corrected.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Narváez J, Cañadillas E, Castellví I, et al. Rituximab in the treatment of progressive interstitial lung disease associated with the antisynthetase syndrome. Arthritis Res Ther. 2024;26:122. https://doi.org/10.1186/s13075-024-03353-2.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations</h3><ol><li><p>Department of Rheumatology, Hospital Universitario de Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), Feixa Llarga, s/n, Hospitalet de Llobregat, Barcelona, 08907, Spain</p><p>Javier Narvaez, Paola Vidal-Montal & Joan Miquel Nolla</p></li><li><p>Department of Rheumatology, Hospital Cl?nico, Universitario Lozano Blesa, Zaragoza, Spain</p><p>Elena Canadillas</p></li><li><p>Department of Rheumatology. Hospital, Universitario de la Santa Creu i Sant Pau, Barcelona, Spain</p><p>Ivan Castellvi</p></li><li><p>Department of Rheumatology. Hospital, Universitario Dr Peset, Valencia, Spain</p><p>Juan Jose Alegre</p></li><li><p>Interstitial Lung Disease Unit, Department of Pneumology. Hospital, Universitario de Bellvitge. Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain</p><p>Vanesa Vicens‑Zygmunt, Guadalupe Bermudo & Maria Molina Molina</p></li></ol><span>Authors</span><ol><li><span>Javier Narvaez</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Elena Canadillas</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Ivan Castellvi</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Juan Jose Alegre</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Vanesa Vicens‑Zygmunt</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Guadalupe Bermudo</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Paola Vidal-Mont","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"39 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-08DOI: 10.1186/s13075-024-03360-3
Marta Hernández-Díaz, Dara Rodríguez-González, Elena Heras-Recuero, Fuensanta Gómez-Bernal, Juan Carlos Quevedo-Abeledo, Agustín F. González-Rivero, Elena González-López, J. Gonzalo Ocejo-Vinyals, Alejandro Jimenez-Sosa, Miguel Ángel González-Gay, Iván Ferraz-Amaro
Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) events and CV mortality. Subclinical carotid atherosclerosis is independently associated with rates of incident CV events among patients with RA. The complement system has been related to both the etiopathogenesis of RA and CV disease. In this study, we aimed to evaluate the association between a comprehensive assessment of the complement system and carotid intima media thickness and carotid plaque in patients with RA. 430 patients with RA were recruited. Functional assays of the three pathways of the complement system, utilizing new-generation techniques, were assessed. Additionally, serum levels of individual components of the complement system belonging to the three pathways were measured: C1q (classical), lectin (lectin), C2, C4, and C4b (classical and lectin), factor D and properdin (alternative), C3 and C3a (common), C5, C5a, and C9 (terminal), as well as regulators factor I and C1-inhibitor. Subclinical carotid atherosclerosis was evaluated by ultrasonography. Multivariable linear regression analysis was conducted to investigate the association between the complement system and carotid intima media thickness and carotid plaque. After multivariable adjustment, which included traditional CV risk factors and disease-related data, C3a and C5a exhibited significant positive correlations with carotid intima media thickness. Additionally, higher values of C1-inhibitor, properdin, C3, C5, and C5a were independently associated with the presence of carotid plaque. The complement system and subclinical carotid atherosclerosis are linked in patients with RA.
类风湿性关节炎（RA）患者发生心血管事件和心血管死亡的风险增加。亚临床颈动脉粥样硬化与类风湿性关节炎患者的心血管事件发生率独立相关。补体系统与 RA 和心血管疾病的发病机制都有关系。在这项研究中，我们旨在评估补体系统综合评估与 RA 患者颈动脉内膜厚度和颈动脉斑块之间的关联。我们招募了 430 名 RA 患者。利用新一代技术对补体系统的三个途径进行了功能评估。此外，还测量了属于三种途径的补体系统各成分的血清水平：C1q（经典）、凝集素（凝集素）、C2、C4 和 C4b（经典和凝集素）、因子 D 和 properdin（替代）、C3 和 C3a（普通）、C5、C5a 和 C9（末端）以及调节因子 I 和 C1 抑制剂。通过超声波检查评估了亚临床颈动脉粥样硬化。对补体系统与颈动脉内膜厚度和颈动脉斑块之间的关系进行了多变量线性回归分析。经过多变量调整（包括传统的冠心病风险因素和疾病相关数据）后，C3a和C5a与颈动脉内膜厚度呈显著正相关。此外，较高的C1-抑制因子、properdin、C3、C5和C5a值与颈动脉斑块的存在也有独立关联。RA患者的补体系统与亚临床颈动脉粥样硬化有关。
{"title":"The Relationship between the complement system and subclinical carotid atherosclerosis in patients with rheumatoid arthritis","authors":"Marta Hernández-Díaz, Dara Rodríguez-González, Elena Heras-Recuero, Fuensanta Gómez-Bernal, Juan Carlos Quevedo-Abeledo, Agustín F. González-Rivero, Elena González-López, J. Gonzalo Ocejo-Vinyals, Alejandro Jimenez-Sosa, Miguel Ángel González-Gay, Iván Ferraz-Amaro","doi":"10.1186/s13075-024-03360-3","DOIUrl":"https://doi.org/10.1186/s13075-024-03360-3","url":null,"abstract":"Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular (CV) events and CV mortality. Subclinical carotid atherosclerosis is independently associated with rates of incident CV events among patients with RA. The complement system has been related to both the etiopathogenesis of RA and CV disease. In this study, we aimed to evaluate the association between a comprehensive assessment of the complement system and carotid intima media thickness and carotid plaque in patients with RA. 430 patients with RA were recruited. Functional assays of the three pathways of the complement system, utilizing new-generation techniques, were assessed. Additionally, serum levels of individual components of the complement system belonging to the three pathways were measured: C1q (classical), lectin (lectin), C2, C4, and C4b (classical and lectin), factor D and properdin (alternative), C3 and C3a (common), C5, C5a, and C9 (terminal), as well as regulators factor I and C1-inhibitor. Subclinical carotid atherosclerosis was evaluated by ultrasonography. Multivariable linear regression analysis was conducted to investigate the association between the complement system and carotid intima media thickness and carotid plaque. After multivariable adjustment, which included traditional CV risk factors and disease-related data, C3a and C5a exhibited significant positive correlations with carotid intima media thickness. Additionally, higher values of C1-inhibitor, properdin, C3, C5, and C5a were independently associated with the presence of carotid plaque. The complement system and subclinical carotid atherosclerosis are linked in patients with RA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"45 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-03DOI: 10.1186/s13075-024-03356-z
Li Zhang, Qing Yan, Miao Lin, Juanjuan He, Jie Tian, Zhihan Chen, Fuyuan Hong
Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) with poor treatment outcomes. The role and underlying mechanisms of ferroptosis in LN remain largely unknown. We aimed to explore ferroptosis-related molecular subtypes and assess their prognostic value in LN patients. Molecular subtypes were classified on the basis of differentially expressed ferroptosis-related genes (FRGs) via the Consensus ClusterPlus package. The enriched functions and pathways, immune infiltrating levels, immune scores, and immune checkpoints were compared between the subgroups. A scoring algorithm based on the subtype-specific feature genes identified by artificial neural network machine learning, referred to as the NeuraLN, was established, and its immunological features, clinical value, and predictive value were evaluated in patients with LN. Finally, immunohistochemical analysis was performed to validate the expression and role of feature genes in glomerular tissues from LN patients and controls. A total of 10 differentially expressed FRGs were identified, most of which showed significant correlation. Based on the 10 FRGs, LN patients were classified into two ferroptosis subtypes, which exhibited significant differences in immune cell abundances, immune scores, and immune checkpoint expression. A NeuraLN-related protective model was established based on nine subtype-specific genes, and it exhibited a robustly predictive value in LN. The nomogram and calibration curves demonstrated the clinical benefits of the protective model. The high-NeuraLN group was closely associated with immune activation. Clinical specimens demonstrated the alterations of ALB, BHMT, GAMT, GSTA1, and HAO2 were in accordance with bioinformatics analysis results, GSTA1 and BHMT were negatively correlated with the severity of LN. The classification of ferroptosis subtypes and the establishment of a protective model may form a foundation for the personalized treatment of LN patients.
{"title":"Investigation of ferroptosis-associated molecular subtypes and immunological characteristics in lupus nephritis based on artificial neural network learning","authors":"Li Zhang, Qing Yan, Miao Lin, Juanjuan He, Jie Tian, Zhihan Chen, Fuyuan Hong","doi":"10.1186/s13075-024-03356-z","DOIUrl":"https://doi.org/10.1186/s13075-024-03356-z","url":null,"abstract":"Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) with poor treatment outcomes. The role and underlying mechanisms of ferroptosis in LN remain largely unknown. We aimed to explore ferroptosis-related molecular subtypes and assess their prognostic value in LN patients. Molecular subtypes were classified on the basis of differentially expressed ferroptosis-related genes (FRGs) via the Consensus ClusterPlus package. The enriched functions and pathways, immune infiltrating levels, immune scores, and immune checkpoints were compared between the subgroups. A scoring algorithm based on the subtype-specific feature genes identified by artificial neural network machine learning, referred to as the NeuraLN, was established, and its immunological features, clinical value, and predictive value were evaluated in patients with LN. Finally, immunohistochemical analysis was performed to validate the expression and role of feature genes in glomerular tissues from LN patients and controls. A total of 10 differentially expressed FRGs were identified, most of which showed significant correlation. Based on the 10 FRGs, LN patients were classified into two ferroptosis subtypes, which exhibited significant differences in immune cell abundances, immune scores, and immune checkpoint expression. A NeuraLN-related protective model was established based on nine subtype-specific genes, and it exhibited a robustly predictive value in LN. The nomogram and calibration curves demonstrated the clinical benefits of the protective model. The high-NeuraLN group was closely associated with immune activation. Clinical specimens demonstrated the alterations of ALB, BHMT, GAMT, GSTA1, and HAO2 were in accordance with bioinformatics analysis results, GSTA1 and BHMT were negatively correlated with the severity of LN. The classification of ferroptosis subtypes and the establishment of a protective model may form a foundation for the personalized treatment of LN patients.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"34 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141495887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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