Pub Date : 2024-09-30DOI: 10.1186/s13075-024-03403-9
Lei Ding, Daniel H. Park, Bo Gao, Lingyuan Wu, Meizhang Li, Haitham Abedelhakim, Ming Zhang
CXC chemokine CXCL12 is involved in the pathological development of rheumatoid arthritis (RA) through abnormal migration of peripheral immune cells in the joint. Although low dose methotrexate (MTX) is clinically used to treat RA patients, CXCL12 signaling responses to MTX-mediated treatments is still not well understood. In this study, we examined the expression of CXCR4 (cognatic receptor for CXCL12) in peripheral T cells from RA patients and arthritis mice models received from low dose MTX therapies. The effects of low dose MTX on CXCR4 were further determined via both in vitro CD3+ T cells and Cxcr4 conditional knockout (CKO) arthritis mice models. Our clinical data shows that low dose MTX treatment was clinically associated with down-regulated expression of chemokine receptor CXCR4 on patient peripheral T cells. In vitro, low dose MTX significantly decreased cell transmigration through down-regulated CXCR4’s expression in CD3+ T cells. Consistently, CD3+ T cells treated with low dose MTX demonstrated an increased genomic hypermethylation across the promoter region of Cxcr4 gene. Furthermore, our preclinical studies showed that low dose MTX-mediated downregulation of CXCR4 significantly improved the pathological development in mouse arthritis models. Conditional disruption of the Cxcr4 gene in peripheral immune cells potentially alleviated inflammation of joints and lung tissue in the arthritis mice, though genetic modification itself overall did not change their clinical scores of arthritis, except for a significant improvement on day 45 in CXCR4 CKO arthritis mice models during the recovery phase. Our findings suggest that the effect of low dose MTX treatment could serve to eliminate inflammation in RA patients through impairment of immune cell transmigration mediated by CXCR4.
CXC趋化因子CXCL12通过外周免疫细胞在关节中的异常迁移参与了类风湿性关节炎（RA）的病理发展。尽管低剂量甲氨蝶呤（MTX）被临床用于治疗类风湿性关节炎患者，但CXCL12信号对MTX介导的治疗反应仍不甚了解。在这项研究中，我们检测了接受低剂量 MTX 治疗的 RA 患者和关节炎小鼠模型的外周 T 细胞中 CXCR4（CXCL12 的认知受体）的表达。通过体外 CD3+ T 细胞和 Cxcr4 条件性基因敲除（CKO）关节炎小鼠模型，进一步确定了低剂量 MTX 对 CXCR4 的影响。我们的临床数据显示，低剂量 MTX 治疗与患者外周 T 细胞中趋化因子受体 CXCR4 的表达下调有关。在体外，低剂量 MTX 通过下调 CD3+ T 细胞中 CXCR4 的表达，显著减少了细胞的迁移。同样，经低剂量 MTX 处理的 CD3+ T 细胞显示，Cxcr4 基因启动子区域的基因组超甲基化增加。此外，我们的临床前研究表明，低剂量 MTX 介导的 CXCR4 下调能显著改善小鼠关节炎模型的病理发展。外周免疫细胞中 Cxcr4 基因的条件性破坏有可能减轻关节炎小鼠的关节和肺组织炎症，但基因修饰本身总体上并没有改变关节炎小鼠的临床评分，只是在恢复阶段，CXCR4 CKO 关节炎小鼠模型的临床评分在第 45 天有明显改善。我们的研究结果表明，低剂量MTX治疗可通过抑制CXCR4介导的免疫细胞转运来消除RA患者的炎症。
{"title":"Low dose methotrexate impaired T cell transmigration through down-regulating CXCR4 expression in rheumatoid arthritis (RA)","authors":"Lei Ding, Daniel H. Park, Bo Gao, Lingyuan Wu, Meizhang Li, Haitham Abedelhakim, Ming Zhang","doi":"10.1186/s13075-024-03403-9","DOIUrl":"https://doi.org/10.1186/s13075-024-03403-9","url":null,"abstract":"CXC chemokine CXCL12 is involved in the pathological development of rheumatoid arthritis (RA) through abnormal migration of peripheral immune cells in the joint. Although low dose methotrexate (MTX) is clinically used to treat RA patients, CXCL12 signaling responses to MTX-mediated treatments is still not well understood. In this study, we examined the expression of CXCR4 (cognatic receptor for CXCL12) in peripheral T cells from RA patients and arthritis mice models received from low dose MTX therapies. The effects of low dose MTX on CXCR4 were further determined via both in vitro CD3+ T cells and Cxcr4 conditional knockout (CKO) arthritis mice models. Our clinical data shows that low dose MTX treatment was clinically associated with down-regulated expression of chemokine receptor CXCR4 on patient peripheral T cells. In vitro, low dose MTX significantly decreased cell transmigration through down-regulated CXCR4’s expression in CD3+ T cells. Consistently, CD3+ T cells treated with low dose MTX demonstrated an increased genomic hypermethylation across the promoter region of Cxcr4 gene. Furthermore, our preclinical studies showed that low dose MTX-mediated downregulation of CXCR4 significantly improved the pathological development in mouse arthritis models. Conditional disruption of the Cxcr4 gene in peripheral immune cells potentially alleviated inflammation of joints and lung tissue in the arthritis mice, though genetic modification itself overall did not change their clinical scores of arthritis, except for a significant improvement on day 45 in CXCR4 CKO arthritis mice models during the recovery phase. Our findings suggest that the effect of low dose MTX treatment could serve to eliminate inflammation in RA patients through impairment of immune cell transmigration mediated by CXCR4.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"14 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330052","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}
Based on the recent evidence of IL-1 inhibition in patients with rheumatoid arthritis (RA) and concomitant type 2 diabetes (T2D), we evaluated the synovial tissue expression of IL-1 related genes in relationship to the ubiquitin–proteasome system and the effects of insulin on ubiquitinated proteins in fibroblast-like synoviocytes (FLSs). The synovial expression of IL-1 pathway genes was compared in early (< 1 year) treatment-naïve RA patients with T2D (RA/T2D n = 16) and age- and sex-matched RA patients without T2D (n = 16), enrolled in the Pathobiology of Early Arthritis Cohort (PEAC). The synovial expression of ubiquitin in macrophages and synovial lining fibroblasts was also assessed by Immunohistochemistry/immunofluorescence and correlated with synovial pathotypes. Finally, FLSs from RA patients (n = 5) were isolated and treated with human insulin (200 and 500 nM) and ubiquitinated proteins were assessed by western blot. Synovial tissues of RA/T2D patients were characterised by a consistent reduced expression of ubiquitin–proteasome genes. More specifically, ubiquitin genes (UBB, UBC, and UBA52) and genes codifying proteasome subunits (PSMA2, PSMA6, PSMA7, PSMB1, PSMB3, PSMB4, PSMB6, PSMB8, PSMB9, PSMB10, PSMC1, PSMD9, PSME1, and PSME2) were significantly lower in RA/T2D patients. On the contrary, genes regulating fibroblast functions (FGF7, FGF10, FRS2, FGFR3, and SOS1), and genes linked to IL-1 pathway hyper-activity (APP, IRAK2, and OSMR) were upregulated in RA/T2D. Immunohistochemistry showed a significant reduction of the percentage of ubiquitin-positive cells in synovial tissues of RA/T2D patients. Ubiquitin-positive cells were also increased in patients with a lympho-myeloid pathotype compared to diffuse myeloid or pauci-immune-fibroid. Finally, in vitro experiments showed a reduction of ubiquitinated proteins in RA-FLSs treated with a high concentration of insulin (500 nM). A different IL-1 pathway gene expression was observed in the synovial tissues of early treatment-naïve RA/T2D patients, linked to decreased expression of the ubiquitin–proteasome system. These findings may provide a mechanistic explanation of the observed clinical benefits of IL-1 inhibition in patients with RA and concomitant T2D.
{"title":"Diminished expression of the ubiquitin-proteasome system in early treatment-naïve patients with rheumatoid arthritis and concomitant type 2 diabetes may be linked to IL-1 pathway hyper-activity; results from PEAC cohort","authors":"Piero Ruscitti, Damiano Currado, Felice Rivellese, Marta Vomero, Luca Navarini, Paola Cipriani, Costantino Pitzalis, Roberto Giacomelli","doi":"10.1186/s13075-024-03392-9","DOIUrl":"https://doi.org/10.1186/s13075-024-03392-9","url":null,"abstract":"Based on the recent evidence of IL-1 inhibition in patients with rheumatoid arthritis (RA) and concomitant type 2 diabetes (T2D), we evaluated the synovial tissue expression of IL-1 related genes in relationship to the ubiquitin–proteasome system and the effects of insulin on ubiquitinated proteins in fibroblast-like synoviocytes (FLSs). The synovial expression of IL-1 pathway genes was compared in early (< 1 year) treatment-naïve RA patients with T2D (RA/T2D n = 16) and age- and sex-matched RA patients without T2D (n = 16), enrolled in the Pathobiology of Early Arthritis Cohort (PEAC). The synovial expression of ubiquitin in macrophages and synovial lining fibroblasts was also assessed by Immunohistochemistry/immunofluorescence and correlated with synovial pathotypes. Finally, FLSs from RA patients (n = 5) were isolated and treated with human insulin (200 and 500 nM) and ubiquitinated proteins were assessed by western blot. Synovial tissues of RA/T2D patients were characterised by a consistent reduced expression of ubiquitin–proteasome genes. More specifically, ubiquitin genes (UBB, UBC, and UBA52) and genes codifying proteasome subunits (PSMA2, PSMA6, PSMA7, PSMB1, PSMB3, PSMB4, PSMB6, PSMB8, PSMB9, PSMB10, PSMC1, PSMD9, PSME1, and PSME2) were significantly lower in RA/T2D patients. On the contrary, genes regulating fibroblast functions (FGF7, FGF10, FRS2, FGFR3, and SOS1), and genes linked to IL-1 pathway hyper-activity (APP, IRAK2, and OSMR) were upregulated in RA/T2D. Immunohistochemistry showed a significant reduction of the percentage of ubiquitin-positive cells in synovial tissues of RA/T2D patients. Ubiquitin-positive cells were also increased in patients with a lympho-myeloid pathotype compared to diffuse myeloid or pauci-immune-fibroid. Finally, in vitro experiments showed a reduction of ubiquitinated proteins in RA-FLSs treated with a high concentration of insulin (500 nM). A different IL-1 pathway gene expression was observed in the synovial tissues of early treatment-naïve RA/T2D patients, linked to decreased expression of the ubiquitin–proteasome system. These findings may provide a mechanistic explanation of the observed clinical benefits of IL-1 inhibition in patients with RA and concomitant T2D.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"7 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328866","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 : 2024-09-28DOI: 10.1186/s13075-024-03401-x
Roberta Ramonda, Mariagrazia Lorenzin, Maria Sole Chimenti, Fabiola Atzeni, Angelo Semeraro, Salvatore D’Angelo, Carlo Selmi, Augusta Ortolan, Antonio Marchesoni, Maria Manara, Michele Maria Luchetti Gentiloni, Leonardo Santo, Carlo Salvarani, Alberto Cauli, Maurizio Rossini, Giorgio Amato, Giacomo Cozzi, Laura Scagnellato, Mario Ferraioli, Antonio Carriero, Elena Fracassi, Francesco Giorgio, Andrea Doria, Rosario Foti, Antonio Carletto
to evaluate over a 48-month follow-up period the: 1) long-term effectiveness and safety; 2) drug retention rate (DRR); 3) impact of comorbidities and bDMARDs line on MDA and DAPSA remission/low disease activity (LDA) of secukinumab in a multicenter Italian cohort of PsA patients. Consecutive PsA patients receiving secukinumab were followed prospectively in Italian centers between 2016 and 2023. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were recorded. Treatment response was evaluated at 6 and 12 months after initiation, and every year up to 48 months (T48). DRR was assessed according to clinical and demographic features, comorbidities and bDMARDs line. Adverse events (AE) were recorded. Six hundred eighty-five patients [42.5% male] were enrolled; 32.9% naïve received secukinumab; 74.2% had ≥ 1 comorbidity. Overall, secukinumab yielded improved outcomes at T48: naïve maintained lower disease activity vs. non-naïve [DAPSA 4.0 (1.4–8.1) vs. 6.0 (2.2–10.4);p = 0.04]; 76.9% naïve and 66.2% non-naïve achieved MDA; MDA no comorbidities vs. 1–3 comorbidities 78.8% vs. 73.3% (p < 0.05), and MDA no comorbidities vs. > 3 comorbidities 78.8% vs. 48.7% (p < 0.001). DAPSA-REM and DAPSA-LDA rates were higher in naïve patients, albeit similar between those without comorbidities vs. 1–3 comorbidities, and slightly lower in those with > 3 comorbidities. Treatment was discontinued in 233 patients due to loss of effectiveness, and in 41 due to AE. The overall DRR at T48 was 66%, with differences according to bDMARDs line (p < 0.001), use of combined csDMARDs (p = 0.016), BMI (p = 0.037) and mono/oligoarthritis vs. polyarthritis (p = 0.012). Secukinumab proved safe and effective, and patients achieved sustained remission with a notable drug retention rate at 4 years. What is already known on this topic? • Secukinumab is a novel drug for psoriatic arthritis (PsA), but real-life long-term safety and effectiveness data are lacking. What this study adds? • Our findings confirmed the safety and notable effectiveness on all PsA domains (arthritis, enthesitis, dactylitis, spinal symptoms, psoriasis, PROs and inflammatory markers), over a 48-month follow-up period. • The drug retention rate (DRR) is considerably high at 48 months. The main clinical disease pattern (peripheral/axial involvement), male gender, age, and the presence of comorbidities do not influence the DRR of secukinumab over time. • The first line of bDMARDs seems to favor MDA and remission/low disease activity DAPSA achievement and drug retention, while fewer than 3 comorbidities have no impact on these outcomes. How this study might affect research, practice or policy • This study supports the effectiveness of secukinumab, which also seems to be a valid option for multi-drug failure patients; the safety of secukinumab means it can be used in patients with comorbidities, older age, higher BMI, and in particular cardiovascular conditions and metabolic syndrome.
{"title":"Four-year effectiveness, safety and drug retention rate of secukinumab in psoriatic arthritis: a real-life Italian multicenter cohort","authors":"Roberta Ramonda, Mariagrazia Lorenzin, Maria Sole Chimenti, Fabiola Atzeni, Angelo Semeraro, Salvatore D’Angelo, Carlo Selmi, Augusta Ortolan, Antonio Marchesoni, Maria Manara, Michele Maria Luchetti Gentiloni, Leonardo Santo, Carlo Salvarani, Alberto Cauli, Maurizio Rossini, Giorgio Amato, Giacomo Cozzi, Laura Scagnellato, Mario Ferraioli, Antonio Carriero, Elena Fracassi, Francesco Giorgio, Andrea Doria, Rosario Foti, Antonio Carletto","doi":"10.1186/s13075-024-03401-x","DOIUrl":"https://doi.org/10.1186/s13075-024-03401-x","url":null,"abstract":"to evaluate over a 48-month follow-up period the: 1) long-term effectiveness and safety; 2) drug retention rate (DRR); 3) impact of comorbidities and bDMARDs line on MDA and DAPSA remission/low disease activity (LDA) of secukinumab in a multicenter Italian cohort of PsA patients. Consecutive PsA patients receiving secukinumab were followed prospectively in Italian centers between 2016 and 2023. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were recorded. Treatment response was evaluated at 6 and 12 months after initiation, and every year up to 48 months (T48). DRR was assessed according to clinical and demographic features, comorbidities and bDMARDs line. Adverse events (AE) were recorded. Six hundred eighty-five patients [42.5% male] were enrolled; 32.9% naïve received secukinumab; 74.2% had ≥ 1 comorbidity. Overall, secukinumab yielded improved outcomes at T48: naïve maintained lower disease activity vs. non-naïve [DAPSA 4.0 (1.4–8.1) vs. 6.0 (2.2–10.4);p = 0.04]; 76.9% naïve and 66.2% non-naïve achieved MDA; MDA no comorbidities vs. 1–3 comorbidities 78.8% vs. 73.3% (p < 0.05), and MDA no comorbidities vs. > 3 comorbidities 78.8% vs. 48.7% (p < 0.001). DAPSA-REM and DAPSA-LDA rates were higher in naïve patients, albeit similar between those without comorbidities vs. 1–3 comorbidities, and slightly lower in those with > 3 comorbidities. Treatment was discontinued in 233 patients due to loss of effectiveness, and in 41 due to AE. The overall DRR at T48 was 66%, with differences according to bDMARDs line (p < 0.001), use of combined csDMARDs (p = 0.016), BMI (p = 0.037) and mono/oligoarthritis vs. polyarthritis (p = 0.012). Secukinumab proved safe and effective, and patients achieved sustained remission with a notable drug retention rate at 4 years. What is already known on this topic? • Secukinumab is a novel drug for psoriatic arthritis (PsA), but real-life long-term safety and effectiveness data are lacking. What this study adds? • Our findings confirmed the safety and notable effectiveness on all PsA domains (arthritis, enthesitis, dactylitis, spinal symptoms, psoriasis, PROs and inflammatory markers), over a 48-month follow-up period. • The drug retention rate (DRR) is considerably high at 48 months. The main clinical disease pattern (peripheral/axial involvement), male gender, age, and the presence of comorbidities do not influence the DRR of secukinumab over time. • The first line of bDMARDs seems to favor MDA and remission/low disease activity DAPSA achievement and drug retention, while fewer than 3 comorbidities have no impact on these outcomes. How this study might affect research, practice or policy • This study supports the effectiveness of secukinumab, which also seems to be a valid option for multi-drug failure patients; the safety of secukinumab means it can be used in patients with comorbidities, older age, higher BMI, and in particular cardiovascular conditions and metabolic syndrome.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"40 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328904","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 : 2024-09-28DOI: 10.1186/s13075-024-03402-w
Yan Du, Shuo Wang, Fanlei Yang, Hao Xu, Yu Cheng, Jia Yu
Untreated acute ankle sprains often result in chronic ankle instability (CAI) and can ultimately lead to the development of post-traumatic osteoarthritis (PTOA). At present, a typical animal model of ankle instability in mice is established by transecting the ligaments around the ankle joint. This study aimed to establish a grade I acute ankle sprain animal model by rapid stretching of peri-ankle joint ligaments. Furthermore, we tried to explore the pathophysiological mechanism of ankle osteoarthritis. In all, 18 male C57BL/6 J mice (7 weeks) were randomly divided into three groups: calcaneofibular ligament (CFL) laxity group, deltoid ligament (DL) laxity group, and SHAM group. One week after the surgical procedure, all mice were trained to run in the mouse rotation fatigue machine daily. The mice were tested on the balance beam before surgery and three days, 4 weeks, 8 weeks, and 12 weeks after surgery. Footprint analyses were performed on each mouse before surgery and 12 weeks after surgery. Micro-CT scanning was then performed to evaluate the degeneration of ankle joints and histological staining was performed to analyze and evaluate PTOA caused by ankle joint instability. After surgery, the mice in the CFL and DL laxity groups took longer to cross the balance beam and slipped more often than those in the SHAM group (p < 0.05). The step length and width in the CFL and DL laxity groups were significantly shorter and smaller than those in the SHAM group 12 weeks after surgery (p < 0.05). There was a significant increase in the bone volume fraction (BV/TV) in the CFL and DL laxity groups compared with the SHAM group (p < 0.05). Histological staining results suggested obvious signs of PTOA in the CFL and DL laxity groups. Based on CFL and DL laxity in a mouse ankle instability model, this study suggests that grade I ankle sprain can contribute to chronic ankle instability, impair motor coordination and balance, and eventually lead to PTOA of ankle with significant degeneration of its adjacent joints.
{"title":"Effects of chronic ankle instability after grade I ankle sprain on the post-traumatic osteoarthritis","authors":"Yan Du, Shuo Wang, Fanlei Yang, Hao Xu, Yu Cheng, Jia Yu","doi":"10.1186/s13075-024-03402-w","DOIUrl":"https://doi.org/10.1186/s13075-024-03402-w","url":null,"abstract":"Untreated acute ankle sprains often result in chronic ankle instability (CAI) and can ultimately lead to the development of post-traumatic osteoarthritis (PTOA). At present, a typical animal model of ankle instability in mice is established by transecting the ligaments around the ankle joint. This study aimed to establish a grade I acute ankle sprain animal model by rapid stretching of peri-ankle joint ligaments. Furthermore, we tried to explore the pathophysiological mechanism of ankle osteoarthritis. In all, 18 male C57BL/6 J mice (7 weeks) were randomly divided into three groups: calcaneofibular ligament (CFL) laxity group, deltoid ligament (DL) laxity group, and SHAM group. One week after the surgical procedure, all mice were trained to run in the mouse rotation fatigue machine daily. The mice were tested on the balance beam before surgery and three days, 4 weeks, 8 weeks, and 12 weeks after surgery. Footprint analyses were performed on each mouse before surgery and 12 weeks after surgery. Micro-CT scanning was then performed to evaluate the degeneration of ankle joints and histological staining was performed to analyze and evaluate PTOA caused by ankle joint instability. After surgery, the mice in the CFL and DL laxity groups took longer to cross the balance beam and slipped more often than those in the SHAM group (p < 0.05). The step length and width in the CFL and DL laxity groups were significantly shorter and smaller than those in the SHAM group 12 weeks after surgery (p < 0.05). There was a significant increase in the bone volume fraction (BV/TV) in the CFL and DL laxity groups compared with the SHAM group (p < 0.05). Histological staining results suggested obvious signs of PTOA in the CFL and DL laxity groups. Based on CFL and DL laxity in a mouse ankle instability model, this study suggests that grade I ankle sprain can contribute to chronic ankle instability, impair motor coordination and balance, and eventually lead to PTOA of ankle with significant degeneration of its adjacent joints.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"25 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328869","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 : 2024-09-28DOI: 10.1186/s13075-024-03398-3
Sabha Asghar, Gary J. Litherland, John J. Cole, Iain B. McInnes, R. M. D. Meek, John C. Lockhart, Carl S. Goodyear, Anne Crilly
Small extracellular vesicles (sEV) derived from synovial fibroblasts (SF) represent a novel molecular mechanism regulating cartilage erosion in osteoarthritis (OA). However, a comprehensive evaluation using disease relevant cells has not been undertaken. The aim of this study was to isolate and characterise sEV from OA SF and to look at their ability to regulate OA chondrocyte effector responses relevant to disease. Profiling of micro (mi) RNA signatures in sEV and parental OA SF cells was performed. SF and chondrocytes were isolated from OA synovial membrane and cartilage respectively (n = 9). sEV were isolated from OA SF (± IL-1β) conditioned media by ultracentrifugation and characterised using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Particle size was confirmed by nanoparticle tracking analysis (NTA). sEV regulation of OA chondrocyte and cartilage effector response was evaluated using qPCR, ELISA and sulphated glycosaminoglycan assay (sGAG). RNA-sequencing was used to establish miRNA signatures in isolated sEV from OA SF. OA SF derived sEV were readily taken up by OA chondrocytes, with increased expression of the catabolic gene MMP 13 (p < 0.01) and decreased expression of the anabolic genes aggrecan and COL2A1 (p < 0.01) observed. Treatment with sEV derived from IL-1β stimulated OA SF significantly decreased expression of aggrecan and COL2A1 (p < 0.001) and increased SOX 9 gene expression (p < 0.05). OA chondrocytes cultured with sEV from either non-stimulated or IL-1β treated OA SF, resulted in a significant increase in the secretion of IL-6, IL-8 and MMP-3 (p < 0.01). Cartilage explants cultured with sEV from SF (± IL-1β) had a significant increase in the release of sGAG (p < 0.01). miRNA signatures differed between parental SF cells and isolated sEV. The recently identified osteoclastogenic regulator miR182, along with miR4472-2, miR1302-3, miR6720, miR6087 and miR4532 were enriched in sEV compared to parental cells, p < 0.01. Signatures were similar in sEVs derived from non-stimulated or IL-1β stimulated SF. OA SF sEV regulate chondrocyte inflammatory and remodelling responses. OA SF sEV have unique signatures compared to parental cells which do not alter with IL-1β stimulation. This study provides insight into a novel regulatory mechanism within the OA joint which could inform future targeted therapy.
滑膜成纤维细胞（SF）产生的小细胞外囊泡（sEV）是调节骨关节炎（OA）软骨侵蚀的一种新型分子机制。然而，目前尚未使用与疾病相关的细胞进行全面评估。本研究的目的是从 OA SF 中分离出 sEV 并对其进行表征，研究它们调节与疾病相关的 OA 软骨细胞效应反应的能力。研究人员对 sEV 和亲代 OA SF 细胞中的微 (mi) RNA 特征进行了分析。SF和软骨细胞分别从OA滑膜和软骨中分离出来（n = 9）。sEV通过超速离心从OA SF（± IL-1β）条件培养基中分离出来，并使用扫描电子显微镜（SEM）和透射电子显微镜（TEM）进行表征。使用 qPCR、ELISA 和硫酸化糖胺聚糖检测法（sGAG）评估了 sEV 对 OA 软骨细胞和软骨效应因子反应的调控。RNA 测序用于确定从 OA SF 分离的 sEV 中的 miRNA 特征。OA SF 衍生的 sEV 很容易被 OA 软骨细胞吸收，观察到分解基因 MMP 13 的表达增加（p < 0.01），合成基因 aggrecan 和 COL2A1 的表达减少（p < 0.01）。用来源于 IL-1β 刺激的 OA SF 的 sEV 处理可显著降低 aggrecan 和 COL2A1 的表达（p < 0.001），增加 SOX 9 基因的表达（p < 0.05）。用未经刺激或经 IL-1β 处理的 OA SF 的 sEV 培养 OA 软骨细胞，会导致 IL-6、IL-8 和 MMP-3 的分泌明显增加（p < 0.01）。用 SF 的 sEV（± IL-1β）培养的软骨外植体释放的 sGAG 显著增加（p < 0.01）。与亲代细胞相比，最近发现的破骨细胞生成调节因子 miR182 以及 miR4472-2、miR1302-3、miR6720、miR6087 和 miR4532 在 sEV 中富集，p < 0.01。未受刺激或受 IL-1β 刺激的 SF sEV 中的特征相似。OA SF sEV 可调节软骨细胞的炎症和重塑反应。与亲代细胞相比，OA SF sEV 具有独特的特征，这些特征不会随着 IL-1β 的刺激而改变。这项研究深入揭示了 OA 关节内的新型调控机制，可为未来的靶向治疗提供依据。
{"title":"Small extracellular vesicles derived from synovial fibroblasts contain distinct miRNA profiles and contribute to chondrocyte damage in osteoarthritis","authors":"Sabha Asghar, Gary J. Litherland, John J. Cole, Iain B. McInnes, R. M. D. Meek, John C. Lockhart, Carl S. Goodyear, Anne Crilly","doi":"10.1186/s13075-024-03398-3","DOIUrl":"https://doi.org/10.1186/s13075-024-03398-3","url":null,"abstract":"Small extracellular vesicles (sEV) derived from synovial fibroblasts (SF) represent a novel molecular mechanism regulating cartilage erosion in osteoarthritis (OA). However, a comprehensive evaluation using disease relevant cells has not been undertaken. The aim of this study was to isolate and characterise sEV from OA SF and to look at their ability to regulate OA chondrocyte effector responses relevant to disease. Profiling of micro (mi) RNA signatures in sEV and parental OA SF cells was performed. SF and chondrocytes were isolated from OA synovial membrane and cartilage respectively (n = 9). sEV were isolated from OA SF (± IL-1β) conditioned media by ultracentrifugation and characterised using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Particle size was confirmed by nanoparticle tracking analysis (NTA). sEV regulation of OA chondrocyte and cartilage effector response was evaluated using qPCR, ELISA and sulphated glycosaminoglycan assay (sGAG). RNA-sequencing was used to establish miRNA signatures in isolated sEV from OA SF. OA SF derived sEV were readily taken up by OA chondrocytes, with increased expression of the catabolic gene MMP 13 (p < 0.01) and decreased expression of the anabolic genes aggrecan and COL2A1 (p < 0.01) observed. Treatment with sEV derived from IL-1β stimulated OA SF significantly decreased expression of aggrecan and COL2A1 (p < 0.001) and increased SOX 9 gene expression (p < 0.05). OA chondrocytes cultured with sEV from either non-stimulated or IL-1β treated OA SF, resulted in a significant increase in the secretion of IL-6, IL-8 and MMP-3 (p < 0.01). Cartilage explants cultured with sEV from SF (± IL-1β) had a significant increase in the release of sGAG (p < 0.01). miRNA signatures differed between parental SF cells and isolated sEV. The recently identified osteoclastogenic regulator miR182, along with miR4472-2, miR1302-3, miR6720, miR6087 and miR4532 were enriched in sEV compared to parental cells, p < 0.01. Signatures were similar in sEVs derived from non-stimulated or IL-1β stimulated SF. OA SF sEV regulate chondrocyte inflammatory and remodelling responses. OA SF sEV have unique signatures compared to parental cells which do not alter with IL-1β stimulation. This study provides insight into a novel regulatory mechanism within the OA joint which could inform future targeted therapy.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"7 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328870","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 : 2024-09-28DOI: 10.1186/s13075-024-03397-4
Carlos Rafael-Vidal, Sara Martínez-Ramos, Beatriz Malvar-Fernández, Irene Altabás-González, Coral Mouriño, Pablo Pazos-López, Arturo Fraga-Bau, José María Pego Reigosa, Samuel García
Endothelial progenitor cells (EPCs) are essential for maintenance of vascular homeostasis and stability, key processes in the pathogenesis of systemic lupus erythematosus (SLE). However, the role and phenotypic characterization of EPCs populations in SLE have not been completely elucidated. To identify EPCs specific subpopulations in patients with SLE using a novel flow cytometry tool. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SLE and healthy controls (HC). mRNA and surface protein expression were determined by quantitative PCR (qPCR) and flow cytometry. Clusters identification and characterization were performed using tSNE-CUDA dimensionality reduction algorithms. tSNE-CUDA analysis identified eight different clusters in PBMCs from HC and patients with SLE. Three of these clusters had EPC-like phenotype and the expression was elevated in patients with SLE. Moreover, four SLE-associated subclusters were found mainly expressed in patients with SLE, being only present in patients in remission with SLE and significantly associated with the 2021 Definition of Remission in SLE. Importantly, we also identified specific clusters in SLE patients with organ damage, according to the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI). These clusters showed an EPC-like phenotype, but the expression of angiogenic markers was lower compared to HC or patients without organ damage, suggesting an impaired angiogenic function. Our novel approach identified clusters of EPCs in patients with SLE that are associated with remission and damage. Therefore, these clusters might be useful biomarkers to predict disease progression and severity in SLE pathogenesis.
{"title":"Novel endothelial progenitor cells populations as biomarkers of damage and remission in systemic lupus erythematosus","authors":"Carlos Rafael-Vidal, Sara Martínez-Ramos, Beatriz Malvar-Fernández, Irene Altabás-González, Coral Mouriño, Pablo Pazos-López, Arturo Fraga-Bau, José María Pego Reigosa, Samuel García","doi":"10.1186/s13075-024-03397-4","DOIUrl":"https://doi.org/10.1186/s13075-024-03397-4","url":null,"abstract":"Endothelial progenitor cells (EPCs) are essential for maintenance of vascular homeostasis and stability, key processes in the pathogenesis of systemic lupus erythematosus (SLE). However, the role and phenotypic characterization of EPCs populations in SLE have not been completely elucidated. To identify EPCs specific subpopulations in patients with SLE using a novel flow cytometry tool. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SLE and healthy controls (HC). mRNA and surface protein expression were determined by quantitative PCR (qPCR) and flow cytometry. Clusters identification and characterization were performed using tSNE-CUDA dimensionality reduction algorithms. tSNE-CUDA analysis identified eight different clusters in PBMCs from HC and patients with SLE. Three of these clusters had EPC-like phenotype and the expression was elevated in patients with SLE. Moreover, four SLE-associated subclusters were found mainly expressed in patients with SLE, being only present in patients in remission with SLE and significantly associated with the 2021 Definition of Remission in SLE. Importantly, we also identified specific clusters in SLE patients with organ damage, according to the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI). These clusters showed an EPC-like phenotype, but the expression of angiogenic markers was lower compared to HC or patients without organ damage, suggesting an impaired angiogenic function. Our novel approach identified clusters of EPCs in patients with SLE that are associated with remission and damage. Therefore, these clusters might be useful biomarkers to predict disease progression and severity in SLE pathogenesis. ","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328867","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 : 2024-09-28DOI: 10.1186/s13075-024-03404-8
Angelika Lackner, Barbara Dreo, Josef Hermann, Sabine Zenz, Johannes Fessler, Jens Thiel, Martin Helmut Stradner
Little is known about the symptoms at the onset of Sjögren’s Disease (SjD) and it is unclear whether SjD starts with characteristic symptoms that could be differentiated from dryness of other origin (sicca syndrome). The aim of this study was to investigate patients’ recollection of initial events and first symptoms of SjD. The second aim was to verify and quantify these aspects in a representative cohort. All SjD patients fulfilled the EULAR/ACR 2016 classification criteria. In the first part of the study, consecutive SjD patients were recruited for individual, semi-structured interviews. All interviews were audio-recorded and transcribed verbatim, and an inductive thematic data analysis was performed. In the second part, the identified aspects of the qualitative analysis were grouped into a checklist with ten items. One-hundred and thirty-four patients participated in the study. 31 SjD patients completed the qualitative part. Major aspects emerged of how patients experienced the beginning and first symptoms of SjD: (1) “classic” SjD symptoms (fatigue, pain, dryness) (2), sicca symptoms started after initial swelling of parotid and/or lymph nodes (3), after hormonal transition or infections before the onset of SjD symptoms. In the second part of the study, the previous identified major aspects were verified in an independent cohort of 103 SjD patients. The main symptom before diagnosis was dryness (n = 77, 74.8%) with migratory joint pain (n = 51, 49.5%) and fatigue (n = 47, 45.6%). In 38.8% (n = 40), patients reported a swelling/inflammation of the parotid gland at the onset of disease. We describe patients’ recollection of the onset of SjD. Raising awareness of the symptoms identified among physicians and among the general public may allow earlier diagnosis of SjD.
{"title":"Patients’ recollection about the onset of Sjögren’s disease – a mixed methods study on the patients’ perspective","authors":"Angelika Lackner, Barbara Dreo, Josef Hermann, Sabine Zenz, Johannes Fessler, Jens Thiel, Martin Helmut Stradner","doi":"10.1186/s13075-024-03404-8","DOIUrl":"https://doi.org/10.1186/s13075-024-03404-8","url":null,"abstract":"Little is known about the symptoms at the onset of Sjögren’s Disease (SjD) and it is unclear whether SjD starts with characteristic symptoms that could be differentiated from dryness of other origin (sicca syndrome). The aim of this study was to investigate patients’ recollection of initial events and first symptoms of SjD. The second aim was to verify and quantify these aspects in a representative cohort. All SjD patients fulfilled the EULAR/ACR 2016 classification criteria. In the first part of the study, consecutive SjD patients were recruited for individual, semi-structured interviews. All interviews were audio-recorded and transcribed verbatim, and an inductive thematic data analysis was performed. In the second part, the identified aspects of the qualitative analysis were grouped into a checklist with ten items. One-hundred and thirty-four patients participated in the study. 31 SjD patients completed the qualitative part. Major aspects emerged of how patients experienced the beginning and first symptoms of SjD: (1) “classic” SjD symptoms (fatigue, pain, dryness) (2), sicca symptoms started after initial swelling of parotid and/or lymph nodes (3), after hormonal transition or infections before the onset of SjD symptoms. In the second part of the study, the previous identified major aspects were verified in an independent cohort of 103 SjD patients. The main symptom before diagnosis was dryness (n = 77, 74.8%) with migratory joint pain (n = 51, 49.5%) and fatigue (n = 47, 45.6%). In 38.8% (n = 40), patients reported a swelling/inflammation of the parotid gland at the onset of disease. We describe patients’ recollection of the onset of SjD. Raising awareness of the symptoms identified among physicians and among the general public may allow earlier diagnosis of SjD.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"1 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328868","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 : 2024-09-20DOI: 10.1186/s13075-024-03400-y
Konstantinos Triantafyllias, Khalid K. Altamimi, Florian Schederecker, Andreas Schwarting
The aims of this study were to suggest patient-adjusted optical spectral transmission (OST) cut-off values for the first time and to develop clinical models that predict the probability of an early rheumatoid arthritis (RA) diagnosis based on OST findings and the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria as a reference standard. OST examinations were performed in newly diagnosed RA patients and healthy controls by the HandScan device. Moreover, RA patients underwent a full clinical [tender/swollen joint counts (TJC/SJC), disease activity score-28 (DAS28)] and laboratory evaluation. OST confounding factors were examined via logistic multivariate regression analyses and patient-adjusted OST-cut-offs were subsequently determined. Furthermore, statistical models to calculate the probability of an RA diagnosis, based on the measured OST values and the presence of OST influencing factors, were developed. Finally, correlations of OST with RA activity parameters were assessed. 1.584 joints of 72 early RA patients were examined via OST and compared to 2.200 joints of 100 healthy controls and 1.166 joints of 53 patients with non-inflammatory arthralgia (NIA), respectively. Overall OST diagnostic performance was excellent in the whole cohort between RA- and healthy control-group [Area-Under-the-Curve (AUC): 0.810 (95%CI: 0.746–0.873); p < 0.0001], and further improved in RA-patients with ≥ 1 swollen wrist/finger joint(s) [AUC: 0.841 (95%CI: 0.773–0.908); p < 0.0001]. Comparison between RA patients and patients with non-inflammatory arthralgia showed similar results by an AUC of 0.788 (95%-CI: 0.709–0.867; p < 0.0001), and further improved in RA patients with ≥ 1 swollen wrist/finger joint(s) [AUC: 0.822 (95%CI: 0.74–0.90); p < 0.0001]. For the assessment of an adjusted RA diagnosis probability, two gender-specific statistical models were developed, based on OST values and patient age. OST cut-off values of 11.2 and 18.21 were calculated for female and male patients with active disease (sensitivity 93% and 67%; specificity 71.2% and 90%), respectively. Among RA patients, OST was associated moderately/significantly with DAS28 (r = 0.42,p < 0.001) and swollen joint count (rho = 0.355,p = 0.002). The development of patient-adjusted OST cut-off values and the suggested statistical models significantly enhance OST’s diagnostic performance, supporting its utility in differentiating between RA and non-inflammatory conditions. Future research should include a broader spectrum of arthritis types to validate OST’s comprehensive diagnostic utility also across various inflammatory arthritides. DRKS00016752 (German Registry of Clinical Trials)
本研究的目的是首次提出经患者调整的光学光谱透射率（OST）临界值，并根据 OST 检查结果和 2010 年美国风湿病学会/欧洲抗风湿联盟（ACR/EULAR）分类标准作为参考标准，建立预测早期类风湿性关节炎（RA）诊断概率的临床模型。新诊断的 RA 患者和健康对照组使用 HandScan 设备进行了 OST 检查。此外，RA 患者还接受了全面的临床[触痛/肿胀关节计数（TJC/SJC）、疾病活动度评分-28（DAS28）]和实验室评估。通过逻辑多元回归分析研究了OST混杂因素，随后确定了患者调整后的OST截断值。此外，还根据 OST 测量值和 OST 影响因素的存在情况，建立了计算 RA 诊断概率的统计模型。最后，还评估了 OST 与 RA 活动参数的相关性。通过 OST 检查了 72 名早期 RA 患者的 1.584 个关节，并分别与 100 名健康对照者的 2.200 个关节和 53 名非炎症性关节痛（NIA）患者的 1.166 个关节进行了比较。在整个队列中，RA 患者和健康对照组之间的 OST 诊断效果非常好[曲线下面积 (AUC)：0.810 (95%CI: 0.746-0.873); p < 0.0001]，在腕关节/手指关节肿胀≥1 个的 RA 患者中，OST 诊断效果进一步提高[AUC：0.841 (95%CI: 0.773-0.908); p < 0.0001]。对 RA 患者和非炎症性关节痛患者进行比较后发现，两者的 AUC 值为 0.788（95%CI：0.709-0.867；p <0.0001），结果相似，而腕关节/手指关节肿胀≥1 个的 RA 患者的 AUC 值进一步提高[AUC：0.822（95%CI：0.74-0.90）；p <0.0001]。为了评估调整后的 RA 诊断概率，根据 OST 值和患者年龄建立了两个性别特异性统计模型。计算出女性和男性活动性疾病患者的 OST 临界值分别为 11.2 和 18.21（敏感性分别为 93% 和 67%；特异性分别为 71.2% 和 90%）。在 RA 患者中，OST 与 DAS28（r = 0.42，p < 0.001）和关节肿胀计数（rho = 0.355，p = 0.002）呈中度/显著相关。患者调整的OST临界值和建议的统计模型的开发大大提高了OST的诊断性能，支持其在区分RA和非炎症性疾病方面的实用性。未来的研究应包括更广泛的关节炎类型，以验证 OST 在各种炎症性关节炎中的综合诊断效用。DRKS00016752（德国临床试验登记处）
{"title":"Increased predictive value of optical spectral transmission in early rheumatoid arthritis through use of patient-adjusted cut-off scores","authors":"Konstantinos Triantafyllias, Khalid K. Altamimi, Florian Schederecker, Andreas Schwarting","doi":"10.1186/s13075-024-03400-y","DOIUrl":"https://doi.org/10.1186/s13075-024-03400-y","url":null,"abstract":"The aims of this study were to suggest patient-adjusted optical spectral transmission (OST) cut-off values for the first time and to develop clinical models that predict the probability of an early rheumatoid arthritis (RA) diagnosis based on OST findings and the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria as a reference standard. OST examinations were performed in newly diagnosed RA patients and healthy controls by the HandScan device. Moreover, RA patients underwent a full clinical [tender/swollen joint counts (TJC/SJC), disease activity score-28 (DAS28)] and laboratory evaluation. OST confounding factors were examined via logistic multivariate regression analyses and patient-adjusted OST-cut-offs were subsequently determined. Furthermore, statistical models to calculate the probability of an RA diagnosis, based on the measured OST values and the presence of OST influencing factors, were developed. Finally, correlations of OST with RA activity parameters were assessed. 1.584 joints of 72 early RA patients were examined via OST and compared to 2.200 joints of 100 healthy controls and 1.166 joints of 53 patients with non-inflammatory arthralgia (NIA), respectively. Overall OST diagnostic performance was excellent in the whole cohort between RA- and healthy control-group [Area-Under-the-Curve (AUC): 0.810 (95%CI: 0.746–0.873); p < 0.0001], and further improved in RA-patients with ≥ 1 swollen wrist/finger joint(s) [AUC: 0.841 (95%CI: 0.773–0.908); p < 0.0001]. Comparison between RA patients and patients with non-inflammatory arthralgia showed similar results by an AUC of 0.788 (95%-CI: 0.709–0.867; p < 0.0001), and further improved in RA patients with ≥ 1 swollen wrist/finger joint(s) [AUC: 0.822 (95%CI: 0.74–0.90); p < 0.0001]. For the assessment of an adjusted RA diagnosis probability, two gender-specific statistical models were developed, based on OST values and patient age. OST cut-off values of 11.2 and 18.21 were calculated for female and male patients with active disease (sensitivity 93% and 67%; specificity 71.2% and 90%), respectively. Among RA patients, OST was associated moderately/significantly with DAS28 (r = 0.42,p < 0.001) and swollen joint count (rho = 0.355,p = 0.002). The development of patient-adjusted OST cut-off values and the suggested statistical models significantly enhance OST’s diagnostic performance, supporting its utility in differentiating between RA and non-inflammatory conditions. Future research should include a broader spectrum of arthritis types to validate OST’s comprehensive diagnostic utility also across various inflammatory arthritides. DRKS00016752 (German Registry of Clinical Trials)","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"272 1","pages":"165"},"PeriodicalIF":4.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276047","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 : 2024-09-20DOI: 10.1186/s13075-024-03393-8
Taejun Yoon, Jang Woo Ha, Jung Yoon Pyo, Eunhee Ko, Sung Soo Ahn, Jason Jungsik Song, Yong-Beom Park, Sang-Won Lee
This study investigated whether serum syndecan1 at diagnosis reflects activity at diagnosis and predicts poor outcomes during follow-up in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The study included 79 patients with AAV from the cohort of Korean patients diagnosed with AAV. AAV-specific indices, including the Birmingham vasculitis activity score (BVAS), five-factor score (FFS), 36-item short-form survey (SF-36) physical and mental component summary (PCS and MCS), and vasculitis damage index (VDI), were assessed. Laboratory data including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were also collected. The highest tertile and upper half of the BVAS were tentatively defined as having high AAV activity. Serum syndecan1 levels were measured in sera stored at diagnosis. Serum syndecan1 at diagnosis was significantly correlated with AAV activity and functional status, as assessed by BVAS, FFS, SF-36 PCS, MCS, and acute-phase reactants, including ESR and CRP. Patients with serum syndecan1 ≥ 76.1 ng/mL at diagnosis, and those with serum syndecan1 ≥ 60.0 ng/mL at diagnosis showed significantly higher risks for the highest tertile and the upper half of BVAS at diagnosis than those without, respectively. Patients with serum syndecan1 ≥ 120.1 ng/mL at diagnosis had a significantly higher risk for all-cause mortality during follow-up than those without, and further, exhibited a significantly lower cumulative patients’ survival rate than those without. Serum syndecan1 at diagnosis may not only reflect AAV activity at diagnosis but may also be associated with all-cause mortality during follow-up.
{"title":"Serum syndecan1 has the potential to reflect activity at diagnosis and predict death during follow-up in patients with ANCA-associated vasculitis","authors":"Taejun Yoon, Jang Woo Ha, Jung Yoon Pyo, Eunhee Ko, Sung Soo Ahn, Jason Jungsik Song, Yong-Beom Park, Sang-Won Lee","doi":"10.1186/s13075-024-03393-8","DOIUrl":"https://doi.org/10.1186/s13075-024-03393-8","url":null,"abstract":"This study investigated whether serum syndecan1 at diagnosis reflects activity at diagnosis and predicts poor outcomes during follow-up in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The study included 79 patients with AAV from the cohort of Korean patients diagnosed with AAV. AAV-specific indices, including the Birmingham vasculitis activity score (BVAS), five-factor score (FFS), 36-item short-form survey (SF-36) physical and mental component summary (PCS and MCS), and vasculitis damage index (VDI), were assessed. Laboratory data including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were also collected. The highest tertile and upper half of the BVAS were tentatively defined as having high AAV activity. Serum syndecan1 levels were measured in sera stored at diagnosis. Serum syndecan1 at diagnosis was significantly correlated with AAV activity and functional status, as assessed by BVAS, FFS, SF-36 PCS, MCS, and acute-phase reactants, including ESR and CRP. Patients with serum syndecan1 ≥ 76.1 ng/mL at diagnosis, and those with serum syndecan1 ≥ 60.0 ng/mL at diagnosis showed significantly higher risks for the highest tertile and the upper half of BVAS at diagnosis than those without, respectively. Patients with serum syndecan1 ≥ 120.1 ng/mL at diagnosis had a significantly higher risk for all-cause mortality during follow-up than those without, and further, exhibited a significantly lower cumulative patients’ survival rate than those without. Serum syndecan1 at diagnosis may not only reflect AAV activity at diagnosis but may also be associated with all-cause mortality during follow-up.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"13 1","pages":"166"},"PeriodicalIF":4.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276045","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 : 2024-09-18DOI: 10.1186/s13075-024-03399-2
Yukai Wang, Shaoqi Chen, Shaoyu Zheng, Zexuan Zhou, Weijin Zhang, Guangzhou Du, Angelina Mikish, Barbara Ruaro, Cosimo Bruni, Anna-Maria Hoffmann-Vold, Luna Gargani, Marco Matucci-Cerinic, Daniel E Furst
Systemic autoimmune rheumatic diseases (SARDs) related pulmonary disease is highly prevalent, with variable clinical presentation and behavior, and thus is associated with poor outcomes and negatively impacts quality of life. Chest high resolution computed tomography (HRCT) is still considered a fundamental imaging tool in the screening, diagnosis, and follow-up of pulmonary disease in patients with SARDs. However, radiation exposure, economic burden, as well as lack of point-of-care CT equipment limits its application in some clinical situation. Ultrasound has found a place in numerous aspects of the rheumatic diseases, including the vasculature, skin, muscle, joints, kidneys and in screening for malignancies. Likewise it has found increasing use in the lungs. In the past two decades, lung ultrasound has started to be used for pulmonary parenchymal diseases such as pneumonia, pulmonary edema, lung fibrosis, pneumothorax, and pleural lesions, although the lung parenchymal was once considered off-limits to ultrasound. Lung ultrasound B-lines and irregularities of the pleural line are now regarded two important sonographic artefacts related to diffuse parenchymal lung disease and they could reflect the lesion extent and severity. However, its role in the management of SARDs related pulmonary involvement has not been fully investigated. This review article will focus on the potential applications of lung ultrasound in different pulmonary scenarios related with SARDs, such as interstitial lung disease, diffuse alveolar hemorrhage, diaphragmatic involvement, and pulmonary infection, in order to explore its value in clinical daily practice.
{"title":"A versatile role for lung ultrasound in systemic autoimmune rheumatic diseases related pulmonary involvement: a narrative review","authors":"Yukai Wang, Shaoqi Chen, Shaoyu Zheng, Zexuan Zhou, Weijin Zhang, Guangzhou Du, Angelina Mikish, Barbara Ruaro, Cosimo Bruni, Anna-Maria Hoffmann-Vold, Luna Gargani, Marco Matucci-Cerinic, Daniel E Furst","doi":"10.1186/s13075-024-03399-2","DOIUrl":"https://doi.org/10.1186/s13075-024-03399-2","url":null,"abstract":"Systemic autoimmune rheumatic diseases (SARDs) related pulmonary disease is highly prevalent, with variable clinical presentation and behavior, and thus is associated with poor outcomes and negatively impacts quality of life. Chest high resolution computed tomography (HRCT) is still considered a fundamental imaging tool in the screening, diagnosis, and follow-up of pulmonary disease in patients with SARDs. However, radiation exposure, economic burden, as well as lack of point-of-care CT equipment limits its application in some clinical situation. Ultrasound has found a place in numerous aspects of the rheumatic diseases, including the vasculature, skin, muscle, joints, kidneys and in screening for malignancies. Likewise it has found increasing use in the lungs. In the past two decades, lung ultrasound has started to be used for pulmonary parenchymal diseases such as pneumonia, pulmonary edema, lung fibrosis, pneumothorax, and pleural lesions, although the lung parenchymal was once considered off-limits to ultrasound. Lung ultrasound B-lines and irregularities of the pleural line are now regarded two important sonographic artefacts related to diffuse parenchymal lung disease and they could reflect the lesion extent and severity. However, its role in the management of SARDs related pulmonary involvement has not been fully investigated. This review article will focus on the potential applications of lung ultrasound in different pulmonary scenarios related with SARDs, such as interstitial lung disease, diffuse alveolar hemorrhage, diaphragmatic involvement, and pulmonary infection, in order to explore its value in clinical daily practice.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"7 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236433","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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