Pub Date : 2024-10-22DOI: 10.1016/S2665-9913(24)00199-1
Hong Zhang MD , Qianqian Li MSc , Cuiyun Li MSc , Min Wu MSc , Hong Chen MSc , Yang Li MSc , Feng You PhD , Yanshi Zhao BS , Jing Jin PhD , Xiaoguang Chen PhD , Prof Yanhua Ding MD
<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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 <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (<span><span>NCT06361199</span><svg><path></path></svg></span>, <span><span>NCT06361186</span><svg><path></path></svg></span>), and is complete.</div></div><div><h3>Findings</h3><div>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 i
{"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 MD , Qianqian Li MSc , Cuiyun Li MSc , Min Wu MSc , Hong Chen MSc , Yang Li MSc , Feng You PhD , Yanshi Zhao BS , Jing Jin PhD , Xiaoguang Chen PhD , Prof Yanhua Ding MD","doi":"10.1016/S2665-9913(24)00199-1","DOIUrl":"10.1016/S2665-9913(24)00199-1","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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 <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (<span><span>NCT06361199</span><svg><path></path></svg></span>, <span><span>NCT06361186</span><svg><path></path></svg></span>), and is complete.</div></div><div><h3>Findings</h3><div>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 i","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"6 12","pages":"Pages e837-e847"},"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 : 2024-10-11DOI: 10.1016/S2665-9913(24)00223-6
Amanda Malone PhD , Mark M Kowalski MD , James Helliwell MD , Sidsel Lynggaard Boll MD , Helene Rovsing MD , Kathrine Moriat MD , Alejandro Castillo Mondragón MD , Yanqi Li PhD , Claire Prener Miller MD , Asger Reinstrup Bihlet PhD , Christine Dobek MSc , Vik Peck BSc , Mike Wilmink MD , Lee S Simon MD , Prof Philip G Conaghan MBBS
<div><h3>Background</h3><div>Corticosteroids are among the few effective treatments for knee osteoarthritis, but short duration of action limits their utility. EP-104IAR, a long-acting formulation of fluticasone propionate for intra-articular injection, optimises the action of fluticasone propionate through novel diffusion-based extended-release technology. The SPRINGBOARD trial assessed the efficacy, safety, and pharmacokinetics of EP-104IAR in people with knee osteoarthritis.</div></div><div><h3>Methods</h3><div>SPRINGBOARD was a randomised, vehicle-controlled, double-blind, phase 2 trial done at 12 research sites in Denmark, Poland, and Czech Republic. We recruited adults aged 40 years or older with primary knee osteoarthritis (Kellgren–Lawrence grade 2–3) who reported Western Ontario and McMaster Universities Osteoarthritis Arthritis Index (WOMAC) pain scores of at least 4 and no more than 9 out of 10. Participants were randomly assigned (1:1) to receive one intra-articular dose of 25 mg EP-104IAR or vehicle control. Randomisation was done via interactive web-based access to a central predefined computer-generated list with block size of six (allocated by clinical site). Participants and assessors were masked to treatment allocation. Participants were followed up for 24 weeks. The primary outcome was the difference between groups in change in WOMAC pain score from baseline to week 12, analysed in all participants who were randomly assigned and received treatment. Safety, including laboratory analyses, and pharmacokinetics from quantification of fluticasone propionate in peripheral blood were assessed in all participants who received a dose of randomly assigned treatment. A person with lived experience of knee osteoarthritis was involved in study interpretation and writing of the report. This trial is registered with <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span>, <span><span>NCT04120402</span><svg><path></path></svg></span>, and the EU Clinical Trials Register, EudraCT 2021-000859-39, and is complete.</div></div><div><h3>Findings</h3><div>Between Sept 10, 2021, and Nov 16, 2022, 1294 people were screened for eligibility, and 319 were randomly assigned to EP-104IAR (n=164) or vehicle control (n=155). One participant in the EP-104IAR group was excluded from all analyses because treatment was not administered due to an adverse event. 318 participants (135 [42%] male and 183 [58%] female, 315 [99%] White) received randomly assigned treatment and were included in the primary analysis and safety analysis (EP-104IAR, n=163; vehicle control, n=155). At week 12, least squares mean change in WOMAC pain score from baseline was –2·89 (95% CI –3·22 to –2·56) in the EP-104IAR group and –2·23 (–2·56 to –1·89) in the vehicle control group, with a between-group difference of –0·66 (–1·11 to –0·21; p=0·0044); a significant between-group difference persisted to week 14. 106 (65%) of 163 participants in the EP-104IAR group had one or more t
{"title":"Efficacy and safety of a diffusion-based extended-release fluticasone propionate intra-articular injection (EP-104IAR) in knee osteoarthritis (SPRINGBOARD): a 24-week, multicentre, randomised, double-blind, vehicle-controlled, phase 2 trial","authors":"Amanda Malone PhD , Mark M Kowalski MD , James Helliwell MD , Sidsel Lynggaard Boll MD , Helene Rovsing MD , Kathrine Moriat MD , Alejandro Castillo Mondragón MD , Yanqi Li PhD , Claire Prener Miller MD , Asger Reinstrup Bihlet PhD , Christine Dobek MSc , Vik Peck BSc , Mike Wilmink MD , Lee S Simon MD , Prof Philip G Conaghan MBBS","doi":"10.1016/S2665-9913(24)00223-6","DOIUrl":"10.1016/S2665-9913(24)00223-6","url":null,"abstract":"<div><h3>Background</h3><div>Corticosteroids are among the few effective treatments for knee osteoarthritis, but short duration of action limits their utility. EP-104IAR, a long-acting formulation of fluticasone propionate for intra-articular injection, optimises the action of fluticasone propionate through novel diffusion-based extended-release technology. The SPRINGBOARD trial assessed the efficacy, safety, and pharmacokinetics of EP-104IAR in people with knee osteoarthritis.</div></div><div><h3>Methods</h3><div>SPRINGBOARD was a randomised, vehicle-controlled, double-blind, phase 2 trial done at 12 research sites in Denmark, Poland, and Czech Republic. We recruited adults aged 40 years or older with primary knee osteoarthritis (Kellgren–Lawrence grade 2–3) who reported Western Ontario and McMaster Universities Osteoarthritis Arthritis Index (WOMAC) pain scores of at least 4 and no more than 9 out of 10. Participants were randomly assigned (1:1) to receive one intra-articular dose of 25 mg EP-104IAR or vehicle control. Randomisation was done via interactive web-based access to a central predefined computer-generated list with block size of six (allocated by clinical site). Participants and assessors were masked to treatment allocation. Participants were followed up for 24 weeks. The primary outcome was the difference between groups in change in WOMAC pain score from baseline to week 12, analysed in all participants who were randomly assigned and received treatment. Safety, including laboratory analyses, and pharmacokinetics from quantification of fluticasone propionate in peripheral blood were assessed in all participants who received a dose of randomly assigned treatment. A person with lived experience of knee osteoarthritis was involved in study interpretation and writing of the report. This trial is registered with <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span>, <span><span>NCT04120402</span><svg><path></path></svg></span>, and the EU Clinical Trials Register, EudraCT 2021-000859-39, and is complete.</div></div><div><h3>Findings</h3><div>Between Sept 10, 2021, and Nov 16, 2022, 1294 people were screened for eligibility, and 319 were randomly assigned to EP-104IAR (n=164) or vehicle control (n=155). One participant in the EP-104IAR group was excluded from all analyses because treatment was not administered due to an adverse event. 318 participants (135 [42%] male and 183 [58%] female, 315 [99%] White) received randomly assigned treatment and were included in the primary analysis and safety analysis (EP-104IAR, n=163; vehicle control, n=155). At week 12, least squares mean change in WOMAC pain score from baseline was –2·89 (95% CI –3·22 to –2·56) in the EP-104IAR group and –2·23 (–2·56 to –1·89) in the vehicle control group, with a between-group difference of –0·66 (–1·11 to –0·21; p=0·0044); a significant between-group difference persisted to week 14. 106 (65%) of 163 participants in the EP-104IAR group had one or more t","PeriodicalId":48540,"journal":{"name":"Lancet Rheumatology","volume":"6 12","pages":"Pages e860-e870"},"PeriodicalIF":15.0,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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