Pub Date : 2024-10-22DOI: 10.1016/S2665-9913(24)00199-1
Hong Zhang, Qianqian Li, Cuiyun Li, Min Wu, Hong Chen, Yang Li, Feng You, Yanshi Zhao, Jing Jin, Xiaoguang Chen, Yanhua Ding
<p><strong>Background: </strong>Proximod is a selective agonist of sphingosine-1-phosphate receptor-1 (S1PR1). It acts by redirecting lymphocytes from the circulation to secondary lymph nodes, and is under development as an immunomodulator for rheumatoid arthritis. We aimed to evaluate the safety, pharmacokinetics, and preliminary efficacy of proximod in healthy volunteers and patients with rheumatoid arthritis.</p><p><strong>Methods: </strong>We did a two part, phase 1, double-blind, randomised, placebo-controlled, ascending dose trial at a single centre in China. Eligible participants were adults aged 18-50 years with a BMI of 18-28 kg/m<sup>2</sup> for healthy volunteers and aged 18-70 years with a BMI of 18-30 kg/m<sup>2</sup> for patients with rheumatoid arthritis. In part 1, healthy volunteers were randomly assigned within ten cohorts to receive a single oral dose of proximod (0·125 mg, 0·25 mg, 0·5 mg, 1 mg, 1·5 mg, 2 mg, 3 mg, 5 mg, 10 mg, or 15 mg in cohorts 1-10) or placebo. In part 2, healthy volunteers were randomly assigned to receive once-daily doses of proximod 5 mg or placebo, and patients with rheumatoid arthritis were randomly assigned to receive once-daily doses of proximod 5 mg, proximod 10 mg, or placebo, for 28 days. Patients and investigators were masked to treatment assignment. The primary outcomes were safety, tolerability, and pharmacokinetic profile of proximod for 72 days in healthy volunteers and for 48 days in patients with rhematoid arthritis, assessed in all treated participants. This trial is registered with ClinicalTrials.gov (NCT06361199, NCT06361186), and is complete.</p><p><strong>Findings: </strong>Between Nov 1, 2017, and June 22, 2021, 124 healthy volunteers were randomly assigned in part 1 of the study and 124 were included in the analyses (mean age 34·3 years [SD 6·9], 62 [50%] of 124 participants were women and 62 [50%] were men, and 116 [94%] were Han Chinese ethnicity). Between Feb 16, 2022, and Oct 8, 2023, 113 participants were screened for inclusion in part 2 (80 healthy volunteers and 33 patients with rheumatoid arthritis). 79 participants were excluded and 34 were randomly assigned (10 healthy participants and 24 patients with rheumatoid arthritis), 34 of whom were included in the analyses. Ten (100%) of ten healthy participants were Han Chinese ethnicity, with a mean age of 39·9 years (SD 7·3). Five (50%) of ten healthy volunteers were women and five (50%) were men). 22 (92%) of 24 participants with rheumatoid arthritis were Han Chinese ethnicity, with a mean age of 52·7 years (SD 6·8). 22 (92%) of 24 patients with rheumatoid arthritis were women and two (8%) were men. In part 1, all doses of proximod were well tolerated, with no dose-related adverse reactions or serious adverse events observed. In part 2, 74 adverse reactions were reported in eight (80%) of ten healthy volunteers and 22 (92%) of 24 patients with rheumatoid arthritis. Adverse events associated with proximod were predominantly mil
{"title":"Evaluation of proximod, a selective agonist of sphingosine-1-phosphate receptor-1, in healthy volunteers and patients with rheumatoid arthritis: a phase 1, double-blind, randomised, placebo-controlled, ascending dose trial.","authors":"Hong Zhang, Qianqian Li, Cuiyun Li, Min Wu, Hong Chen, Yang Li, Feng You, Yanshi Zhao, Jing Jin, Xiaoguang Chen, Yanhua Ding","doi":"10.1016/S2665-9913(24)00199-1","DOIUrl":"https://doi.org/10.1016/S2665-9913(24)00199-1","url":null,"abstract":"<p><strong>Background: </strong>Proximod is a selective agonist of sphingosine-1-phosphate receptor-1 (S1PR1). It acts by redirecting lymphocytes from the circulation to secondary lymph nodes, and is under development as an immunomodulator for rheumatoid arthritis. We aimed to evaluate the safety, pharmacokinetics, and preliminary efficacy of proximod in healthy volunteers and patients with rheumatoid arthritis.</p><p><strong>Methods: </strong>We did a two part, phase 1, double-blind, randomised, placebo-controlled, ascending dose trial at a single centre in China. Eligible participants were adults aged 18-50 years with a BMI of 18-28 kg/m<sup>2</sup> for healthy volunteers and aged 18-70 years with a BMI of 18-30 kg/m<sup>2</sup> for patients with rheumatoid arthritis. In part 1, healthy volunteers were randomly assigned within ten cohorts to receive a single oral dose of proximod (0·125 mg, 0·25 mg, 0·5 mg, 1 mg, 1·5 mg, 2 mg, 3 mg, 5 mg, 10 mg, or 15 mg in cohorts 1-10) or placebo. In part 2, healthy volunteers were randomly assigned to receive once-daily doses of proximod 5 mg or placebo, and patients with rheumatoid arthritis were randomly assigned to receive once-daily doses of proximod 5 mg, proximod 10 mg, or placebo, for 28 days. Patients and investigators were masked to treatment assignment. The primary outcomes were safety, tolerability, and pharmacokinetic profile of proximod for 72 days in healthy volunteers and for 48 days in patients with rhematoid arthritis, assessed in all treated participants. This trial is registered with ClinicalTrials.gov (NCT06361199, NCT06361186), and is complete.</p><p><strong>Findings: </strong>Between Nov 1, 2017, and June 22, 2021, 124 healthy volunteers were randomly assigned in part 1 of the study and 124 were included in the analyses (mean age 34·3 years [SD 6·9], 62 [50%] of 124 participants were women and 62 [50%] were men, and 116 [94%] were Han Chinese ethnicity). Between Feb 16, 2022, and Oct 8, 2023, 113 participants were screened for inclusion in part 2 (80 healthy volunteers and 33 patients with rheumatoid arthritis). 79 participants were excluded and 34 were randomly assigned (10 healthy participants and 24 patients with rheumatoid arthritis), 34 of whom were included in the analyses. Ten (100%) of ten healthy participants were Han Chinese ethnicity, with a mean age of 39·9 years (SD 7·3). Five (50%) of ten healthy volunteers were women and five (50%) were men). 22 (92%) of 24 participants with rheumatoid arthritis were Han Chinese ethnicity, with a mean age of 52·7 years (SD 6·8). 22 (92%) of 24 patients with rheumatoid arthritis were women and two (8%) were men. In part 1, all doses of proximod were well tolerated, with no dose-related adverse reactions or serious adverse events observed. In part 2, 74 adverse reactions were reported in eight (80%) of ten healthy volunteers and 22 (92%) of 24 patients with rheumatoid arthritis. Adverse events associated with proximod were predominantly mil","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142510631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21DOI: 10.1016/S2665-9913(24)00308-4
The Lancet Rheumatology
{"title":"The 2024 US election—voting for equitable health care","authors":"The Lancet Rheumatology","doi":"10.1016/S2665-9913(24)00308-4","DOIUrl":"10.1016/S2665-9913(24)00308-4","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"6 11","pages":"Page e733"},"PeriodicalIF":15.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142510637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21DOI: 10.1016/S2665-9913(24)00281-9
Marita Cross , Kanyin Liane Ong , Hailey Hagins , Ewerton Cousin , Lyn March , Anthony Woolf
{"title":"Gout in central Asia: a few things make a big difference – Authors' reply","authors":"Marita Cross , Kanyin Liane Ong , Hailey Hagins , Ewerton Cousin , Lyn March , Anthony Woolf","doi":"10.1016/S2665-9913(24)00281-9","DOIUrl":"10.1016/S2665-9913(24)00281-9","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"6 11","pages":"Page e748"},"PeriodicalIF":15.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142510635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21DOI: 10.1016/S2665-9913(24)00280-7
Chokan Baimukhamedov , Galymzhan Togizbayev
{"title":"Gout in central Asia: a few things make a big difference","authors":"Chokan Baimukhamedov , Galymzhan Togizbayev","doi":"10.1016/S2665-9913(24)00280-7","DOIUrl":"10.1016/S2665-9913(24)00280-7","url":null,"abstract":"","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"6 11","pages":"Pages e747-e748"},"PeriodicalIF":15.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142510636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1016/S2665-9913(24)00225-X
Yujie Shen, Jinchao Jia, Jialin Teng, Chengde Yang, Qiongyi Hu
Still's disease, a systemic autoinflammatory disorder with a classic multigenetic background, is characterised by polyarthritis, high-spiking fever, salmon-like evanescent skin rash, and hyperferritinaemia. Although the exact cause of Still's disease remains unclear, it is believed to be influenced by genetic factors, infections, and immune dysregulation. Current studies indicate that neutrophils and macrophages play crucial roles in the pathogenesis of Still's disease, along with involvement of natural killer cells, T cells, and B cells. Advances in biologic agents have expanded treatment strategies beyond conventional approaches, with cytokine-targeted agents showing promise in the management of Still's disease. Some cytokine-targeting biologic agents can be developed based on clinical manifestations, complications, immune cells, and molecular networks. Emphasis of immunophenotyping for precise clinical subtyping and targeted molecular therapies based on these findings is crucial for optimising treatment outcomes. In this Review, we discuss the latest advancements in the understanding of Still's disease pathogenesis and corresponding therapeutic approaches.
斯蒂尔病是一种具有典型多基因遗传背景的系统性自身炎症性疾病，其特征是多关节炎、高热、鲑鱼状皮疹和高铁蛋白血症。尽管 Still's 病的确切病因仍不清楚，但据信它受到遗传因素、感染和免疫失调的影响。目前的研究表明，中性粒细胞和巨噬细胞在 Still's 病的发病机制中起着关键作用，自然杀伤细胞、T 细胞和 B 细胞也参与其中。生物制剂的进步使治疗策略超越了传统方法，细胞因子靶向制剂在治疗斯蒂尔病方面大有可为。一些细胞因子靶向生物制剂可根据临床表现、并发症、免疫细胞和分子网络进行开发。强调通过免疫分型进行精确的临床亚型分析，并根据这些发现进行有针对性的分子治疗，对于优化治疗效果至关重要。在本综述中，我们将讨论在了解斯蒂尔病发病机制和相应治疗方法方面取得的最新进展。
{"title":"Advancing personalised precision treatment for Still's disease based on molecular characteristics and disease progression.","authors":"Yujie Shen, Jinchao Jia, Jialin Teng, Chengde Yang, Qiongyi Hu","doi":"10.1016/S2665-9913(24)00225-X","DOIUrl":"https://doi.org/10.1016/S2665-9913(24)00225-X","url":null,"abstract":"<p><p>Still's disease, a systemic autoinflammatory disorder with a classic multigenetic background, is characterised by polyarthritis, high-spiking fever, salmon-like evanescent skin rash, and hyperferritinaemia. Although the exact cause of Still's disease remains unclear, it is believed to be influenced by genetic factors, infections, and immune dysregulation. Current studies indicate that neutrophils and macrophages play crucial roles in the pathogenesis of Still's disease, along with involvement of natural killer cells, T cells, and B cells. Advances in biologic agents have expanded treatment strategies beyond conventional approaches, with cytokine-targeted agents showing promise in the management of Still's disease. Some cytokine-targeting biologic agents can be developed based on clinical manifestations, complications, immune cells, and molecular networks. Emphasis of immunophenotyping for precise clinical subtyping and targeted molecular therapies based on these findings is crucial for optimising treatment outcomes. In this Review, we discuss the latest advancements in the understanding of Still's disease pathogenesis and corresponding therapeutic approaches.</p>","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1016/S2665-9913(24)00221-2
Mark D Russell, Mark Gibson, Benjamin Zuckerman, Kanta Kumar, Shirish Dubey, Maryam A Adas, Edward Alveyn, Samir Patel, Zijing Yang, Katie Bechman, Elizabeth Price, Sarah Gallagher, Andrew P Cope, Sam Norton, James B Galloway
<p><strong>Background: </strong>Quantifying health-care inequality is essential to addressing the imbalance in outcomes attributable to age, sex, race or ethnicity, and multimorbidity. In this study, we analysed differences in the initiation of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis within the universal health-care system of England and Wales, UK.</p><p><strong>Methods: </strong>An observational cohort study was conducted using the National Early Inflammatory Arthritis Audit (NEIAA) dataset. We included all patients with rheumatoid arthritis who were enrolled in NEIAA between May 8, 2018, and April 30, 2022, and who had 12-month follow-up data available. Modified Poisson regression was used to explore factors associated with the initiation of biological and targeted synthetic DMARDs within 12 months of initial rheumatology assessment. The factors evaluated included age, sex, ethnicity, socioeconomic status (index of multiple deprivation), smoking status, and relevant comorbidities (lung disease, cardiovascular disease, cancer, and depression). NEIAA is supported by people with lived experience of rheumatoid arthritis, who contributed to study design and the interpretation of findings.</p><p><strong>Findings: </strong>6098 patients in NEIAA had new diagnoses of rheumatoid arthritis and available follow-up data. The mean age was 59·2 years (SD 14·9); 3912 (64·2%) patients were women and 2186 (35·8%) were men. 6047 (99·2%) patients had available ethnicity data, of whom 5215 (86·2%) were White, 152 (2·5%) were Black, 478 (7·9%) were Asian, and 202 (3·3%) were of mixed or other ethnicities. 508 (8·3%) of 6098 patients initiated biological and targeted synthetic DMARDs within 12 months. Patients younger than 40 years were more likely to be initiated on biological and targeted synthetic DMARDs than individuals older than 65 years (multivariable-adjusted risk ratio 2·41 [95% CI 1·83-3·19]; p<0·0001). Asian individuals were less likely to be initiated on biological and targeted synthetic DMARDs than White individuals (0·52 [0·36-0·76]; p=0·0007), which persisted after adjustment for socioeconomic status, comorbidities, baseline disease severity, and the initial response to conventional synthetic DMARDs. These differences were evident for Asian women but not Asian men. Black individuals were more likely to be initiated on biological and targeted synthetic DMARDs than White individuals (1·54 [1·10-2·16]; p=0·012), which became non-significant after adjusting for baseline disease severity and autoantibody status.</p><p><strong>Interpretation: </strong>The initiation of biological and targeted synthetic DMARDs for patients with newly diagnosed rheumatoid arthritis varies markedly by ethnicity and age in the universal health-care system of England and Wales. This study demonstrates the importance of providing tailored information and ensuring equitable access to high-quality care fo
{"title":"Factors associated with biological and targeted synthetic disease-modifying antirheumatic drug initiation for rheumatoid arthritis in underserved patient groups in England and Wales, UK: a national cohort study.","authors":"Mark D Russell, Mark Gibson, Benjamin Zuckerman, Kanta Kumar, Shirish Dubey, Maryam A Adas, Edward Alveyn, Samir Patel, Zijing Yang, Katie Bechman, Elizabeth Price, Sarah Gallagher, Andrew P Cope, Sam Norton, James B Galloway","doi":"10.1016/S2665-9913(24)00221-2","DOIUrl":"https://doi.org/10.1016/S2665-9913(24)00221-2","url":null,"abstract":"<p><strong>Background: </strong>Quantifying health-care inequality is essential to addressing the imbalance in outcomes attributable to age, sex, race or ethnicity, and multimorbidity. In this study, we analysed differences in the initiation of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis within the universal health-care system of England and Wales, UK.</p><p><strong>Methods: </strong>An observational cohort study was conducted using the National Early Inflammatory Arthritis Audit (NEIAA) dataset. We included all patients with rheumatoid arthritis who were enrolled in NEIAA between May 8, 2018, and April 30, 2022, and who had 12-month follow-up data available. Modified Poisson regression was used to explore factors associated with the initiation of biological and targeted synthetic DMARDs within 12 months of initial rheumatology assessment. The factors evaluated included age, sex, ethnicity, socioeconomic status (index of multiple deprivation), smoking status, and relevant comorbidities (lung disease, cardiovascular disease, cancer, and depression). NEIAA is supported by people with lived experience of rheumatoid arthritis, who contributed to study design and the interpretation of findings.</p><p><strong>Findings: </strong>6098 patients in NEIAA had new diagnoses of rheumatoid arthritis and available follow-up data. The mean age was 59·2 years (SD 14·9); 3912 (64·2%) patients were women and 2186 (35·8%) were men. 6047 (99·2%) patients had available ethnicity data, of whom 5215 (86·2%) were White, 152 (2·5%) were Black, 478 (7·9%) were Asian, and 202 (3·3%) were of mixed or other ethnicities. 508 (8·3%) of 6098 patients initiated biological and targeted synthetic DMARDs within 12 months. Patients younger than 40 years were more likely to be initiated on biological and targeted synthetic DMARDs than individuals older than 65 years (multivariable-adjusted risk ratio 2·41 [95% CI 1·83-3·19]; p<0·0001). Asian individuals were less likely to be initiated on biological and targeted synthetic DMARDs than White individuals (0·52 [0·36-0·76]; p=0·0007), which persisted after adjustment for socioeconomic status, comorbidities, baseline disease severity, and the initial response to conventional synthetic DMARDs. These differences were evident for Asian women but not Asian men. Black individuals were more likely to be initiated on biological and targeted synthetic DMARDs than White individuals (1·54 [1·10-2·16]; p=0·012), which became non-significant after adjusting for baseline disease severity and autoantibody status.</p><p><strong>Interpretation: </strong>The initiation of biological and targeted synthetic DMARDs for patients with newly diagnosed rheumatoid arthritis varies markedly by ethnicity and age in the universal health-care system of England and Wales. This study demonstrates the importance of providing tailored information and ensuring equitable access to high-quality care fo","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":" ","pages":""},"PeriodicalIF":15.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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