Panagiotis Garantziotis, Georgia Savina Moysidou, Noemin Kapsala, Sofia Flouda, Dionysis Nikolopoulos, Katerina Chavatza, George Sentis, Anastasia Filia, Nikos Malissovas, Antigone Pieta, Agellos Banos, Spyridon Katechis, Antonis Fanouriakis, George Bertsias, Dimitrios T Boumpas
{"title":"通过转录组分析破译系统性红斑狼疮治疗反应的分子基础。","authors":"Panagiotis Garantziotis, Georgia Savina Moysidou, Noemin Kapsala, Sofia Flouda, Dionysis Nikolopoulos, Katerina Chavatza, George Sentis, Anastasia Filia, Nikos Malissovas, Antigone Pieta, Agellos Banos, Spyridon Katechis, Antonis Fanouriakis, George Bertsias, Dimitrios T Boumpas","doi":"10.1136/rmdopen-2024-005050","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by variable treatment responses. We investigated the transcriptional landscape associated with treatment response and resistance in SLE.</p><p><strong>Methods: </strong>Blood was collected from 92 active patients with SLE at baseline and after 6 months (n=32 paired samples) of treatment with cyclophosphamide (n=40), rituximab (n=20), belimumab (n=23), mycophenolate mofetil (n=8) or azathioprine (n=1) and was subjected to RNA sequencing. The response was defined by the Lupus Low Disease Activity State. We identified differentially expressed genes and co-expressed transcript modules.</p><p><strong>Results: </strong>Achieving response, irrespective of treatment, was accompanied by downregulation of B cell immunity-related and complement activation-related signatures. Rituximab led to the most profound decrease in the activity of the B cell pathway, while cyclophosphamide uniquely downregulated neutrophil activation pathways. Responders, regardless of medication, showed increased activity in pathways related to neutrophil migration, type I interferon signalling, complement activation and B cell function prior to treatment. A 539-gene signature, enriched in processes related to chemokine signalling, characterised patients with insufficient response to treatment.</p><p><strong>Conclusions: </strong>Baseline B cell immunity transcriptional signatures correlate with favourable treatment outcomes-accounting for better responses in serologically active patients in SLE clinical trials-with effective treatment reversing the B cell immunity signature. Cyclophosphamide uniquely targets a neutrophil gene signature linked to severe SLE. Alterations in chemotaxis may represent a mechanism driving resistance to treatment in SLE.</p>","PeriodicalId":21396,"journal":{"name":"RMD Open","volume":"11 1","pages":""},"PeriodicalIF":5.1000,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Transcriptome analysis to decipher the molecular underpinnings of response to treatment in systemic lupus erythematosus.\",\"authors\":\"Panagiotis Garantziotis, Georgia Savina Moysidou, Noemin Kapsala, Sofia Flouda, Dionysis Nikolopoulos, Katerina Chavatza, George Sentis, Anastasia Filia, Nikos Malissovas, Antigone Pieta, Agellos Banos, Spyridon Katechis, Antonis Fanouriakis, George Bertsias, Dimitrios T Boumpas\",\"doi\":\"10.1136/rmdopen-2024-005050\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by variable treatment responses. We investigated the transcriptional landscape associated with treatment response and resistance in SLE.</p><p><strong>Methods: </strong>Blood was collected from 92 active patients with SLE at baseline and after 6 months (n=32 paired samples) of treatment with cyclophosphamide (n=40), rituximab (n=20), belimumab (n=23), mycophenolate mofetil (n=8) or azathioprine (n=1) and was subjected to RNA sequencing. The response was defined by the Lupus Low Disease Activity State. We identified differentially expressed genes and co-expressed transcript modules.</p><p><strong>Results: </strong>Achieving response, irrespective of treatment, was accompanied by downregulation of B cell immunity-related and complement activation-related signatures. Rituximab led to the most profound decrease in the activity of the B cell pathway, while cyclophosphamide uniquely downregulated neutrophil activation pathways. Responders, regardless of medication, showed increased activity in pathways related to neutrophil migration, type I interferon signalling, complement activation and B cell function prior to treatment. A 539-gene signature, enriched in processes related to chemokine signalling, characterised patients with insufficient response to treatment.</p><p><strong>Conclusions: </strong>Baseline B cell immunity transcriptional signatures correlate with favourable treatment outcomes-accounting for better responses in serologically active patients in SLE clinical trials-with effective treatment reversing the B cell immunity signature. Cyclophosphamide uniquely targets a neutrophil gene signature linked to severe SLE. Alterations in chemotaxis may represent a mechanism driving resistance to treatment in SLE.</p>\",\"PeriodicalId\":21396,\"journal\":{\"name\":\"RMD Open\",\"volume\":\"11 1\",\"pages\":\"\"},\"PeriodicalIF\":5.1000,\"publicationDate\":\"2025-03-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"RMD Open\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/rmdopen-2024-005050\",\"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":"RMD Open","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/rmdopen-2024-005050","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Transcriptome analysis to decipher the molecular underpinnings of response to treatment in systemic lupus erythematosus.
Objective: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by variable treatment responses. We investigated the transcriptional landscape associated with treatment response and resistance in SLE.
Methods: Blood was collected from 92 active patients with SLE at baseline and after 6 months (n=32 paired samples) of treatment with cyclophosphamide (n=40), rituximab (n=20), belimumab (n=23), mycophenolate mofetil (n=8) or azathioprine (n=1) and was subjected to RNA sequencing. The response was defined by the Lupus Low Disease Activity State. We identified differentially expressed genes and co-expressed transcript modules.
Results: Achieving response, irrespective of treatment, was accompanied by downregulation of B cell immunity-related and complement activation-related signatures. Rituximab led to the most profound decrease in the activity of the B cell pathway, while cyclophosphamide uniquely downregulated neutrophil activation pathways. Responders, regardless of medication, showed increased activity in pathways related to neutrophil migration, type I interferon signalling, complement activation and B cell function prior to treatment. A 539-gene signature, enriched in processes related to chemokine signalling, characterised patients with insufficient response to treatment.
Conclusions: Baseline B cell immunity transcriptional signatures correlate with favourable treatment outcomes-accounting for better responses in serologically active patients in SLE clinical trials-with effective treatment reversing the B cell immunity signature. Cyclophosphamide uniquely targets a neutrophil gene signature linked to severe SLE. Alterations in chemotaxis may represent a mechanism driving resistance to treatment in SLE.
期刊介绍:
RMD Open publishes high quality peer-reviewed original research covering the full spectrum of musculoskeletal disorders, rheumatism and connective tissue diseases, including osteoporosis, spine and rehabilitation. Clinical and epidemiological research, basic and translational medicine, interesting clinical cases, and smaller studies that add to the literature are all considered.