Esraa Eloseily, Alex Pickering, Sanjeev Dhakal, Nicolino Ruperto, Hermine I Brunner, Alexi A Grom, Sherry Thornton
{"title":"托法替尼治疗幼年特发性关节炎的转录谱分析:治疗反应预测的意义。","authors":"Esraa Eloseily, Alex Pickering, Sanjeev Dhakal, Nicolino Ruperto, Hermine I Brunner, Alexi A Grom, Sherry Thornton","doi":"10.1002/acr.25459","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>To assess changes in gene expression following tofacitinib treatment and investigate transcription patterns as potential predictors of treatment response in patients with active juvenile idiopathic arthritis (JIA).</p><p><strong>Methods: </strong>Whole blood samples were collected from JIA patients at baseline and after 18 weeks of open-label tofacitinib treatment (clinical trial NCT02592434). Patients who achieved a JIA-American College of Rheumatology (ACR) response of 70 or above at week 18 were classified as treatment-responders (TR) while those with at most a JIA-ACR30 response were classified as poor-responders (PR). Differential gene expression and gene ontology (GO) over-representation analyses were performed to compare RNA expression between week 18 and baseline samples, as well as between PR and TR samples at baseline.</p><p><strong>Results: </strong>Samples from 67 patients at baseline and 60 at week 18 were analyzed. Following 18 weeks of tofacitinib treatment across all JIA subjects, 883 genes showed significant differential expression (week 18 - baseline). The most strongly downregulated genes were over-represented within IL-7, type I, and type II interferon pathways, while upregulated genes were enriched in ontologies related to neuronal cell processes and cell signaling. Comparing PR and TR at baseline, 663 genes showed differential expression. Upregulated genes were over-represented within ontologies including activation of MAPK activity (p=9.40x10<sup>-5</sup>), myeloid cell development (p=8.13 x10<sup>-5</sup>), activation of GTPase activity (p=0.00015), and organelle transport along microtubules (p=0.00021).</p><p><strong>Conclusions: </strong>Tofacitinib treatment in JIA downregulated genes in interferon and IL-7 signaling pathways regardless of effectiveness. Furthermore, baseline upregulation of MAPK signaling may predict poor response to tofacitinib treatment in JIA.</p>","PeriodicalId":8406,"journal":{"name":"Arthritis Care & Research","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Transcriptional Profiling of Tofacitinib Treatment in Juvenile Idiopathic Arthritis: Implications for Treatment Response Prediction.\",\"authors\":\"Esraa Eloseily, Alex Pickering, Sanjeev Dhakal, Nicolino Ruperto, Hermine I Brunner, Alexi A Grom, Sherry Thornton\",\"doi\":\"10.1002/acr.25459\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>To assess changes in gene expression following tofacitinib treatment and investigate transcription patterns as potential predictors of treatment response in patients with active juvenile idiopathic arthritis (JIA).</p><p><strong>Methods: </strong>Whole blood samples were collected from JIA patients at baseline and after 18 weeks of open-label tofacitinib treatment (clinical trial NCT02592434). Patients who achieved a JIA-American College of Rheumatology (ACR) response of 70 or above at week 18 were classified as treatment-responders (TR) while those with at most a JIA-ACR30 response were classified as poor-responders (PR). Differential gene expression and gene ontology (GO) over-representation analyses were performed to compare RNA expression between week 18 and baseline samples, as well as between PR and TR samples at baseline.</p><p><strong>Results: </strong>Samples from 67 patients at baseline and 60 at week 18 were analyzed. Following 18 weeks of tofacitinib treatment across all JIA subjects, 883 genes showed significant differential expression (week 18 - baseline). The most strongly downregulated genes were over-represented within IL-7, type I, and type II interferon pathways, while upregulated genes were enriched in ontologies related to neuronal cell processes and cell signaling. Comparing PR and TR at baseline, 663 genes showed differential expression. Upregulated genes were over-represented within ontologies including activation of MAPK activity (p=9.40x10<sup>-5</sup>), myeloid cell development (p=8.13 x10<sup>-5</sup>), activation of GTPase activity (p=0.00015), and organelle transport along microtubules (p=0.00021).</p><p><strong>Conclusions: </strong>Tofacitinib treatment in JIA downregulated genes in interferon and IL-7 signaling pathways regardless of effectiveness. Furthermore, baseline upregulation of MAPK signaling may predict poor response to tofacitinib treatment in JIA.</p>\",\"PeriodicalId\":8406,\"journal\":{\"name\":\"Arthritis Care & Research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-11-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Arthritis Care & Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/acr.25459\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arthritis Care & Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/acr.25459","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Transcriptional Profiling of Tofacitinib Treatment in Juvenile Idiopathic Arthritis: Implications for Treatment Response Prediction.
Objectives: To assess changes in gene expression following tofacitinib treatment and investigate transcription patterns as potential predictors of treatment response in patients with active juvenile idiopathic arthritis (JIA).
Methods: Whole blood samples were collected from JIA patients at baseline and after 18 weeks of open-label tofacitinib treatment (clinical trial NCT02592434). Patients who achieved a JIA-American College of Rheumatology (ACR) response of 70 or above at week 18 were classified as treatment-responders (TR) while those with at most a JIA-ACR30 response were classified as poor-responders (PR). Differential gene expression and gene ontology (GO) over-representation analyses were performed to compare RNA expression between week 18 and baseline samples, as well as between PR and TR samples at baseline.
Results: Samples from 67 patients at baseline and 60 at week 18 were analyzed. Following 18 weeks of tofacitinib treatment across all JIA subjects, 883 genes showed significant differential expression (week 18 - baseline). The most strongly downregulated genes were over-represented within IL-7, type I, and type II interferon pathways, while upregulated genes were enriched in ontologies related to neuronal cell processes and cell signaling. Comparing PR and TR at baseline, 663 genes showed differential expression. Upregulated genes were over-represented within ontologies including activation of MAPK activity (p=9.40x10-5), myeloid cell development (p=8.13 x10-5), activation of GTPase activity (p=0.00015), and organelle transport along microtubules (p=0.00021).
Conclusions: Tofacitinib treatment in JIA downregulated genes in interferon and IL-7 signaling pathways regardless of effectiveness. Furthermore, baseline upregulation of MAPK signaling may predict poor response to tofacitinib treatment in JIA.
期刊介绍:
Arthritis Care & Research, an official journal of the American College of Rheumatology and the Association of Rheumatology Health Professionals (a division of the College), is a peer-reviewed publication that publishes original research, review articles, and editorials that promote excellence in the clinical practice of rheumatology. Relevant to the care of individuals with rheumatic diseases, major topics are evidence-based practice studies, clinical problems, practice guidelines, educational, social, and public health issues, health economics, health care policy, and future trends in rheumatology practice.