Pub Date : 2024-01-17DOI: 10.1101/2024.01.15.24301339
Iago Pinal-Fernandez, Sandra Muñoz-Braceras, Maria Casal-Dominguez, Katherine Pak, Jiram Torres-Ruiz, Jon Musai, Stefania Dell’Orso, Faiza Naz, Shamima Islam, Gustavo Gutierrez-Cruz, Maria Dolores Cano, Ana Matas-Garcia, Joan Padrosa, Esther Tobías-Baraja, Gloria Garrabou, Iban Aldecoa, Gerard Espinosa, Carmen Pilar Simeon-Aznar, Alfredo Guillen-Del-Castillo, Albert Gil-Vila, Ernesto Trallero-Araguas, Lisa Christopher-Stine, Thomas E. Lloyd, Teerin Liewluck, Elie Naddaf, Werner Stenzel, Steven A. Greenberg, Josep Maria Grau, Albert Selva-O’Callaghan, Jose C. Milisenda, Andrew L. Mammen
Objectives Myositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has been unclear. This study aimed to determine whether myositis autoantibodies reach their autoantigen targets within muscle cells and disrupt the normal function of these proteins.
{"title":"Pathogenic autoantibody internalization in myositis","authors":"Iago Pinal-Fernandez, Sandra Muñoz-Braceras, Maria Casal-Dominguez, Katherine Pak, Jiram Torres-Ruiz, Jon Musai, Stefania Dell’Orso, Faiza Naz, Shamima Islam, Gustavo Gutierrez-Cruz, Maria Dolores Cano, Ana Matas-Garcia, Joan Padrosa, Esther Tobías-Baraja, Gloria Garrabou, Iban Aldecoa, Gerard Espinosa, Carmen Pilar Simeon-Aznar, Alfredo Guillen-Del-Castillo, Albert Gil-Vila, Ernesto Trallero-Araguas, Lisa Christopher-Stine, Thomas E. Lloyd, Teerin Liewluck, Elie Naddaf, Werner Stenzel, Steven A. Greenberg, Josep Maria Grau, Albert Selva-O’Callaghan, Jose C. Milisenda, Andrew L. Mammen","doi":"10.1101/2024.01.15.24301339","DOIUrl":"https://doi.org/10.1101/2024.01.15.24301339","url":null,"abstract":"<strong>Objectives</strong> Myositis is a heterogeneous family of autoimmune muscle diseases. As myositis autoantibodies recognize intracellular proteins, their role in disease pathogenesis has been unclear. This study aimed to determine whether myositis autoantibodies reach their autoantigen targets within muscle cells and disrupt the normal function of these proteins.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139518628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-17DOI: 10.1101/2024.01.16.24301351
Zhengjun Zhang
Motivation Systemic lupus erythematosus (SLE) is an autoimmune disease and a long-term condition affecting many body parts. Autoimmune diseases are affecting more people for reasons unknown, and the causes of these diseases remain a mystery.
{"title":"cg05883128 (DDX60) and NR3C2 (CD4 T-cells and B-cells) to Be the Genetic Roots of Systemic Lupus Erythematosus","authors":"Zhengjun Zhang","doi":"10.1101/2024.01.16.24301351","DOIUrl":"https://doi.org/10.1101/2024.01.16.24301351","url":null,"abstract":"<strong>Motivation</strong> Systemic lupus erythematosus (SLE) is an autoimmune disease and a long-term condition affecting many body parts. Autoimmune diseases are affecting more people for reasons unknown, and the causes of these diseases remain a mystery.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139510512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-18DOI: 10.1101/2023.12.15.23299947
Abhishek Abhishek, Matthew J Grainge, Tim Card, Hywel C Williams, Maarten W Taal, Guruprasad P Aithal, Christopher P Fox, Christian D Mallen, Matthew D Stevenson, Georgina Nakafero, Richard D Riley
Background: Sulfasalazine induced cytopenia, nephrotoxicity, and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend three monthly monitoring blood-tests indefinitely while others recommend stopping monitoring after one year. To rationalise monitoring we developed and validated a prognostic model for clinically significant blood, liver, or kidney toxicity during established sulfasalazine treatment. Design: Retrospective cohort study. Setting: UK primary-care. Data from Clinical Practice Research Datalink Gold and Aurum formed independent development and validation cohorts. Participants: Age ≥18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription. Study period: 01/01/2007 to 31/12/2019. Outcome: Sulfasalazine discontinuation with abnormal monitoring blood-test result. Analysis: Patients were followed-up from six months after first primary-care prescription to the earliest of outcome, drug discontinuation, death, 5 years, or 31/12/2019.Penalised Cox regression was performed to develop the risk equation. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination. Results: 8,936 participants were included in the development cohort (473 events, 23,299 person-years) and 5,203 participants were included in the validation cohort (280 events, 12,867 person-years).Nine candidate predictors were included. The optimism adjusted R2D and Royston D statistic in the development data were 0.13 and 0.79 respectively. The calibration slope (95% confidence interval (CI)) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96-1.43) and 0.87 (0.67-1.07) respectively. Conclusion: This prognostic model for sulfasalazine toxicity utilises readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment.
{"title":"Risk-stratified monitoring for sulfasalazine toxicity: prognostic model development and validation.","authors":"Abhishek Abhishek, Matthew J Grainge, Tim Card, Hywel C Williams, Maarten W Taal, Guruprasad P Aithal, Christopher P Fox, Christian D Mallen, Matthew D Stevenson, Georgina Nakafero, Richard D Riley","doi":"10.1101/2023.12.15.23299947","DOIUrl":"https://doi.org/10.1101/2023.12.15.23299947","url":null,"abstract":"Background: Sulfasalazine induced cytopenia, nephrotoxicity, and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend three monthly monitoring blood-tests indefinitely while others recommend stopping monitoring after one year. To rationalise monitoring we developed and validated a prognostic model for clinically significant blood, liver, or kidney toxicity during established sulfasalazine treatment.\u0000Design: Retrospective cohort study.\u0000Setting: UK primary-care. Data from Clinical Practice Research Datalink Gold and Aurum formed independent development and validation cohorts.\u0000Participants: Age ≥18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription.\u0000Study period: 01/01/2007 to 31/12/2019.\u0000Outcome: Sulfasalazine discontinuation with abnormal monitoring blood-test result.\u0000Analysis: Patients were followed-up from six months after first primary-care prescription to the earliest of outcome, drug discontinuation, death, 5 years, or 31/12/2019.Penalised Cox regression was performed to develop the risk equation. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination.\u0000Results: 8,936 participants were included in the development cohort (473 events, 23,299 person-years) and 5,203 participants were included in the validation cohort (280 events, 12,867 person-years).Nine candidate predictors were included. The optimism adjusted R2D and Royston D statistic in the development data were 0.13 and 0.79 respectively. The calibration slope (95% confidence interval (CI)) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96-1.43) and 0.87 (0.67-1.07) respectively.\u0000Conclusion: This prognostic model for sulfasalazine toxicity utilises readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"96 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138745849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-08DOI: 10.1101/2023.12.06.23299609
Vidya Ambati, Praveen Yerramothu, Ranjith Konduri, Joseph Nguyen, Bradley D Gelfand, Brian C Werner, Ethan W Taylor, Shao-bin Wang
Gout is the most prevalent form of inflammatory arthritis in the world. Although multiple treatments exist, many patients are poorly responsive. Here we report, using a health insurance database analysis, that use of the anti-psychotic haloperidol is associated with a reduced risk of incident gout. Haloperidol inhibits ASC speck formation, caspase-1 activation, and release of IL-1beta; and IL-6, suggesting that it inhibits NLRP3 inflammasome activation and downstream cytokine responses. We also identified LAMTOR1 as a novel binding partner for haloperidol and demonstrate that haloperidol inhibits the aggregation of LAMTOR1 and NLRP3. Since NLRP3 inflammasome activation has been implicated in gout, these data provide a foundation for exploring haloperidol as a potential therapy.
{"title":"Haloperidol inhibits inflammasome activation via LAMTOR1 and reduces the risk of arthritides","authors":"Vidya Ambati, Praveen Yerramothu, Ranjith Konduri, Joseph Nguyen, Bradley D Gelfand, Brian C Werner, Ethan W Taylor, Shao-bin Wang","doi":"10.1101/2023.12.06.23299609","DOIUrl":"https://doi.org/10.1101/2023.12.06.23299609","url":null,"abstract":"Gout is the most prevalent form of inflammatory arthritis in the world. Although multiple treatments exist, many patients are poorly responsive. Here we report, using a health insurance database analysis, that use of the anti-psychotic haloperidol is associated with a reduced risk of incident gout. Haloperidol inhibits ASC speck formation, caspase-1 activation, and release of IL-1beta; and IL-6, suggesting that it inhibits NLRP3 inflammasome activation and downstream cytokine responses. We also identified LAMTOR1 as a novel binding partner for haloperidol and demonstrate that haloperidol inhibits the aggregation of LAMTOR1 and NLRP3. Since NLRP3 inflammasome activation has been implicated in gout, these data provide a foundation for exploring haloperidol as a potential therapy.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138561165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Prior studies indicated improved survival in systemic sclerosis-associated pulmonary arterial hypertension (PAH) patients, but trends in systemic lupus erythematosus-associated PAH (SLE-PAH) survival remained unclear. Methods: Analyzing SLE-PAH patients from the nationwide CSTAR-PAH cohort, we divided them into two cohorts: A (2011-2016) and B (2016-2021), based on baseline right heart catheterization dates. We compared clinical characteristics, mortality, and treatment outcomes between these cohorts and with idiopathic PAH (IPAH) patients. Results: We enrolled 610 and 104 patients with SLE-PAH and IPAH, respectively. Patients with SLE-PAH were younger, had a higher proportion of low-risk patients, and had a significantly higher 10-year survival rate than those with IPAH (66.6% vs. 44.1%, p < 0.001). Cohort B had a longer 6-min walk distance, lower mean pulmonary arterial pressure and pulmonary vascular resistance, a better-preserved cardiac index, and less right ventricular dilation than cohort A. More patients in cohort B received intensive immunosuppressant- and PAH-targeted therapies. The 5-year survival rate was significantly higher in cohort B (88.1% vs. 77.5%, p = 0.006). Reaching low-risk profile of PAH (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.15-0.79, p = 0.012) and reaching lupus low-disease-activity state (HR 0.33, 95% CI 0.14-0.82, p = 0.016) were independent predictors of survival. The rate of achieving low-risk profile for PAH was considerably higher in patients initially treated with intensive immunosuppressive and dual-PAH-targeted therapies. Conclusions: Over the last decade in China, the clinical characteristics of patients with SLE-PAH have evolved and survival has improved. Early PAH detection and dual treatment-to-target strategies for both PAH and SLE have contributed to this improvement in survival.
背景：先前的研究表明，系统性硬化症相关性肺动脉高压（PAH）患者的生存率有所提高，但系统性红斑狼疮相关性肺动脉高压（SLE-PAH）患者的生存率趋势仍不明确：分析全国范围内的 CSTAR-PAH 队列中的系统性红斑狼疮相关 PAH 患者，我们将其分为两个队列：根据基线右心导管检查日期，我们将其分为 A 组（2011-2016 年）和 B 组（2016-2021 年）。我们比较了这些队列与特发性 PAH（IPAH）患者的临床特征、死亡率和治疗效果：我们分别招募了 610 名和 104 名 SLE-PAH 和 IPAH 患者。SLE-PAH患者更年轻，低风险患者比例更高，10年生存率明显高于IPAH患者（66.6% vs. 44.1%，p <0.001）。与 A 组相比，B 组患者的 6 分钟步行距离更长，平均肺动脉压和肺血管阻力更低，心脏指数保存得更好，右心室扩张更少。B 组患者的 5 年生存率明显更高（88.1% 对 77.5%，P = 0.006）。达到PAH低风险状态（危险比[HR] 0.34，95% 置信区间[CI] 0.15-0.79，p = 0.012）和达到狼疮低疾病活动状态（HR 0.33，95% CI 0.14-0.82，p = 0.016）是生存率的独立预测因素。在最初接受强化免疫抑制和双PAH靶向治疗的患者中，达到PAH低危状态的比例要高得多：结论：近十年来，中国系统性红斑狼疮-PAH患者的临床特征发生了变化，生存率也有所提高。PAH的早期发现以及针对PAH和系统性红斑狼疮的双重治疗策略为生存率的提高做出了贡献。
{"title":"Improvements and challenges of long-term survival in patients with systemic lupus erythematosus-associated pulmonary arterial hypertension: A 10-year multi-center cohort study","authors":"Xingbei Dong, Jiuliang Zhao, Junyan Qian, Wei Wei, Miaojia Zhang, Xiao Zhang, Xiaofei Shi, Yisha Li, Xiaoping Hong, Qiang Shu, Shuhong Chi, Xin Dong, Ping Zhu, Rong Zhang, Zhuoli Zhang, Hongfeng feng Zhang, Xinwang Duan, Jing Xue, Shuhong Zhou, Hongbin Li, Dan Chen, Junwei Zhang, Yanhong WANG, Zhuang Tian, Yong-Tai Liu, Mengtao Li, Xiaofeng ZENG, Qian Wang","doi":"10.1101/2023.12.05.23299536","DOIUrl":"https://doi.org/10.1101/2023.12.05.23299536","url":null,"abstract":"Background: Prior studies indicated improved survival in systemic sclerosis-associated pulmonary arterial hypertension (PAH) patients, but trends in systemic lupus erythematosus-associated PAH (SLE-PAH) survival remained unclear.\u0000Methods: Analyzing SLE-PAH patients from the nationwide CSTAR-PAH cohort, we divided them into two cohorts: A (2011-2016) and B (2016-2021), based on baseline right heart catheterization dates. We compared clinical characteristics, mortality, and treatment outcomes between these cohorts and with idiopathic PAH (IPAH) patients.\u0000Results: We enrolled 610 and 104 patients with SLE-PAH and IPAH, respectively. Patients with SLE-PAH were younger, had a higher proportion of low-risk patients, and had a significantly higher 10-year survival rate than those with IPAH (66.6% vs. 44.1%, p < 0.001). Cohort B had a longer 6-min walk distance, lower mean pulmonary arterial pressure and pulmonary vascular resistance, a better-preserved cardiac index, and less right ventricular dilation than cohort A. More patients in cohort B received intensive immunosuppressant- and PAH-targeted therapies. The 5-year survival rate was significantly higher in cohort B (88.1% vs. 77.5%, p = 0.006). Reaching low-risk profile of PAH (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.15-0.79, p = 0.012) and reaching lupus low-disease-activity state (HR 0.33, 95% CI 0.14-0.82, p = 0.016) were independent predictors of survival. The rate of achieving low-risk profile for PAH was considerably higher in patients initially treated with intensive immunosuppressive and dual-PAH-targeted therapies.\u0000Conclusions: Over the last decade in China, the clinical characteristics of patients with SLE-PAH have evolved and survival has improved. Early PAH detection and dual treatment-to-target strategies for both PAH and SLE have contributed to this improvement in survival.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"251 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138553252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-05DOI: 10.1101/2023.12.05.23299396
Desire Casares-Marfil, Manuel Martinez-Bueno, Maria Orietta Borghi, Guillermo Pons-Estel, PRECISESADS Clinical Consortium, Guillermo Reales, Yu Zuo, Gerard Espinosa, Timothy R.D.J. Radstake, Lucas L. van den Hoogen, Chris Wallace, Joel Guthridge, Judith James, Ricard Cervera, Pier Luigi Luigi Meroni, Javier Martín, Jason Knight, Marta Alarcon-Riquelme, Amr H Sawalha
Objectives: Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS. Methods: We performed a genome-wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta-analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune-mediated diseases. Results: We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near HLA-DRA and in STAT4 with a genome-wide level of significance. 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele in the HLA class II locus is associated with overexpression of HLA-DRB6, HLA-DRB9, HLA-DPB2, HLA-DQA2 and HLA-DQB2, and is independent of the association between PAPS and HLA-DRB1*1302. Functional analyses highlighted immune and nervous system related pathways in PAPS-associated loci. The comparison with other immune-mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjogren syndrome, suggesting colocalized causal variations close to STAT4, TNPO3, and BLK. Conclusions: This study represents a comprehensive large-scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease.
{"title":"A genome-wide association study suggests new susceptibility loci for primary antiphospholipid syndrome","authors":"Desire Casares-Marfil, Manuel Martinez-Bueno, Maria Orietta Borghi, Guillermo Pons-Estel, PRECISESADS Clinical Consortium, Guillermo Reales, Yu Zuo, Gerard Espinosa, Timothy R.D.J. Radstake, Lucas L. van den Hoogen, Chris Wallace, Joel Guthridge, Judith James, Ricard Cervera, Pier Luigi Luigi Meroni, Javier Martín, Jason Knight, Marta Alarcon-Riquelme, Amr H Sawalha","doi":"10.1101/2023.12.05.23299396","DOIUrl":"https://doi.org/10.1101/2023.12.05.23299396","url":null,"abstract":"Objectives: Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS. Methods: We performed a genome-wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta-analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune-mediated diseases. Results: We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near HLA-DRA and in STAT4 with a genome-wide level of significance. 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele in the HLA class II locus is associated with overexpression of HLA-DRB6, HLA-DRB9, HLA-DPB2, HLA-DQA2 and HLA-DQB2, and is independent of the association between PAPS and HLA-DRB1*1302. Functional analyses highlighted immune and nervous system related pathways in PAPS-associated loci. The comparison with other immune-mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjogren syndrome, suggesting colocalized causal variations close to STAT4, TNPO3, and BLK.\u0000Conclusions: This study represents a comprehensive large-scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138511520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-03DOI: 10.1101/2023.12.02.23299318
Michele Fresneda Alarcon, Genna Ali Abdullah, Andrew H Nolan, Christina Linford, Marie M Phelan, Helen L Wright
Neutrophils are key effector leukocytes of the innate immune system and play a pivotal role in defending the host against microbial infections. Recent studies have identified a crucial link between glycolysis and neutrophil cellular functions. Using human neutrophils, we have investigated the intricate relationship between glycolysis, extracellular glucose availability, and the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), in the regulation of reactive oxygen species (ROS) and neutrophil extracellular trap (NET) production. We have identified that PFKFB3 activity is a key regulator of neutrophil ROS and NET production, cytotoxic molecules which are both implicated in the pathogenesis of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA). Targeted inhibition of PFKFB3 expression blocked the production of ROS and NETs in a dose-dependent manner in both RA and HC neutrophils (p<0.01). RA neutrophils were more sensitive to lower concentrations of PFKFB3 inhibition. We also demonstrated that RA neutrophils retain ROS and NET production in culture conditions which mimic the low glucose environments encountered in the RA synovial joint. By dissecting the intricate interplay between PFKFB3, glycolysis, and neutrophil effector functions, this study advances the understanding of the molecular mechanisms governing innate immune responses and identifies PFKF3B as a potential therapeutic target for conditions characterized by dysregulated neutrophil activity.
{"title":"PFKFB3 is a critical regulator of neutrophil metabolism and function in rheumatoid arthritis","authors":"Michele Fresneda Alarcon, Genna Ali Abdullah, Andrew H Nolan, Christina Linford, Marie M Phelan, Helen L Wright","doi":"10.1101/2023.12.02.23299318","DOIUrl":"https://doi.org/10.1101/2023.12.02.23299318","url":null,"abstract":"Neutrophils are key effector leukocytes of the innate immune system and play a pivotal role in defending the host against microbial infections. Recent studies have identified a crucial link between glycolysis and neutrophil cellular functions. Using human neutrophils, we have investigated the intricate relationship between glycolysis, extracellular glucose availability, and the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), in the regulation of reactive oxygen species (ROS) and neutrophil extracellular trap (NET) production. We have identified that PFKFB3 activity is a key regulator of neutrophil ROS and NET production, cytotoxic molecules which are both implicated in the pathogenesis of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA). Targeted inhibition of PFKFB3 expression blocked the production of ROS and NETs in a dose-dependent manner in both RA and HC neutrophils (p<0.01). RA neutrophils were more sensitive to lower concentrations of PFKFB3 inhibition. We also demonstrated that RA neutrophils retain ROS and NET production in culture conditions which mimic the low glucose environments encountered in the RA synovial joint. By dissecting the intricate interplay between PFKFB3, glycolysis, and neutrophil effector functions, this study advances the understanding of the molecular mechanisms governing innate immune responses and identifies PFKF3B as a potential therapeutic target for conditions characterized by dysregulated neutrophil activity.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138511521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-15DOI: 10.1101/2023.11.15.23298534
Katie Fishpool, George Young, Coziana Ciurtin, Fiona Cramp, Emmanuel Erhieyovwe, Bayram Farisogullari, Gary J Macfarlane, Pedro Machado, Jennifer Pearson, Eduardo Santos, Emma Dures
Introduction Fatigue is an important and distressing symptom for many people living with chronic musculoskeletal (MSK) conditions. Many non-pharmacological interventions have been investigated in recent years and some have been demonstrated to be effective in reducing fatigue and fatigue impact, however there is limited guidance for clinicians to follow regarding the most appropriate management options. The objective of this scoping review is to understand and map the extent of evidence in relation to the impact of non-pharmacological interventions on MSK condition-related fatigue across the lifespan. Methods and analysis This scoping review will include evidence relating to people of all ages living with chronic MSK conditions who have been offered a non-pharmacological intervention with either the intention or effect of reducing fatigue and its impact. Databases including AMED, PsycINFO, CINAHLPlus, MEDLINE, EMBASE and Scopus will be searched for peer reviewed primary research studies published after 1st January 2007 in English language. These findings will be used to identify factors associated with successful interventions and to map gaps in knowledge. Ethics and dissemination Ethical approval was not required for this review. Findings will be disseminated by journal publication, conference presentation and by communicating with relevant healthcare and charity organisations.
{"title":"Factors influencing the outcomes of non-pharmacological interventions for managing fatigue across the lifespan of people living with musculoskeletal (MSK) conditions: a scoping review protocol","authors":"Katie Fishpool, George Young, Coziana Ciurtin, Fiona Cramp, Emmanuel Erhieyovwe, Bayram Farisogullari, Gary J Macfarlane, Pedro Machado, Jennifer Pearson, Eduardo Santos, Emma Dures","doi":"10.1101/2023.11.15.23298534","DOIUrl":"https://doi.org/10.1101/2023.11.15.23298534","url":null,"abstract":"Introduction\u0000Fatigue is an important and distressing symptom for many people living with chronic musculoskeletal (MSK) conditions. Many non-pharmacological interventions have been investigated in recent years and some have been demonstrated to be effective in reducing fatigue and fatigue impact, however there is limited guidance for clinicians to follow regarding the most appropriate management options. The objective of this scoping review is to understand and map the extent of evidence in relation to the impact of non-pharmacological interventions on MSK condition-related fatigue across the lifespan. Methods and analysis\u0000This scoping review will include evidence relating to people of all ages living with chronic MSK conditions who have been offered a non-pharmacological intervention with either the intention or effect of reducing fatigue and its impact. Databases including AMED, PsycINFO, CINAHLPlus, MEDLINE, EMBASE and Scopus will be searched for peer reviewed primary research studies published after 1st January 2007 in English language. These findings will be used to identify factors associated with successful interventions and to map gaps in knowledge. Ethics and dissemination\u0000Ethical approval was not required for this review. Findings will be disseminated by journal publication, conference presentation and by communicating with relevant healthcare and charity organisations.","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"22 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138511519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background. Disease relapse remains a major problem in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, HLA-DPB1*04:01 is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between HLA-DRB1*09:01 and DQB1*03:03 with susceptibility to, and DRB1*13:02 with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of DQA1*03:02, which is in strong linkage disequilibrium with HLA-DRB1*09:01 and DQB1*03:03, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether HLA-class II is associated with the risk of relapse in MPO-AAV. Methods. First, the association of HLA-DQA1*03:02 with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported DRB1*09:01 and DQB1*03:03 were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method. Results. The association of DQA1*(03:02 with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8x10-7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: Puncorr=1.1x10-5, OR 1.71, 95%CI 1.34-2.17). DQA1*03:02 was in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03 and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of DRB1*09:01 (Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87), DQA1*03:02 (Puncorr=0.020, Q=0.22, HR:2.11) and DQB1*03:03 (Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including DRB1*13:02 carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combining DQA1*03:02 and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr
{"title":"Association of HLA-class II alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population.","authors":"Aya Kawasaki, Ken-Ei Sada, Premita Ari Kusumawati, Fumio Hirano, Shigeto Kobayashi, Kenji Nagasaka, Takahiko Sugihara, Nobuyuki Ono, Takashi Fujimoto, Makio Kusaoi, Naoto Tamura, Yasuyoshi Kusanagi, Kenji Itoh, Takayuki Sumida, Kunihiro Yamagata, Hiroshi Hashimoto, Hirofumi Makino, Yoshihiro Arimura, Masayoshi Harigai, Naoyuki Tsuchiya","doi":"10.1101/2022.12.28.22283983","DOIUrl":"https://doi.org/10.1101/2022.12.28.22283983","url":null,"abstract":"<strong>Background.</strong>\u0000Disease relapse remains a major problem in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, <em>HLA-DPB1<sup>*</sup>04:01</em> is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between <em>HLA-DRB1<sup>*</sup>09:01</em> and <em>DQB1<sup>*</sup>03:03</em> with susceptibility to, and <em>DRB1<sup>*</sup>13:02</em> with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of <em>DQA1<sup>*</sup>03:02</em>, which is in strong linkage disequilibrium with <em>HLA-DRB1<sup>*</sup>09:01</em> and <em>DQB1<sup>*</sup>03:03</em>, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether HLA-class II is associated with the risk of relapse in MPO-AAV.\u0000<strong>Methods.</strong>\u0000First, the association of <em>HLA-DQA1<sup>*</sup>03:02</em> with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported <em>DRB1<sup>*</sup>09:01</em> and <em>DQB1<sup>*</sup>03:03 </em> were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (P<sub>uncorr</sub>) were corrected for multiple comparisons in each analysis using the false discovery rate method.\u0000<strong>Results.</strong>\u0000The association of <em>DQA1<sup>*(</sup>03:02</em> with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: P<sub>uncorr</sub>=5.8x10<sup>-7</sup>, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: P<sub>uncorr</sub>=1.1x10<sup>-5</sup>, OR 1.71, 95%CI 1.34-2.17). <em>DQA1<sup>*</sup>03:02</em> was in strong linkage disequilibrium with <em>DRB1<sup>*</sup>09:01</em> and <em>DQB1<sup>*</sup>03:03</em> and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of <em>DRB1<sup>*</sup>09:01</em> (P<sub>uncorr</sub>=0.049, Q=0.42, hazard ratio [HR]:1.87), <em>DQA1<sup>*</sup>03:02</em> (P<sub>uncorr</sub>=0.020, Q=0.22, HR:2.11) and <em>DQB1<sup>*</sup>03:03</em> (Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including <em>DRB1<sup>*</sup>13:02</em> carriers, showed longer relapse-free survival with nominal significance (P<sub>uncorr</sub>=0.010, Q=0.42, HR:0.31). By combining <em>DQA1<sup>*</sup>03:02</em> and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (P<sub>uncorr</s","PeriodicalId":501212,"journal":{"name":"medRxiv - Rheumatology","volume":"44 3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138530889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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