Pub Date : 2025-01-01Epub Date: 2024-08-27DOI: 10.1002/art.42964
Christine Ehlers, Thea Thiele, Hannah Biermann, Stephan Traidl, Luzia Bruns, Annett Ziegler, Matthias Schefzyk, Lea M Bartsch, Ulrich Kalinke, Torsten Witte, Theresa Graalmann
Objective: Systemic sclerosis (SSc) is a severe rheumatic disease causing fibrotic tissue rearrangement. Aberrant toll-like receptor (TLR) 8 transcripts in plasmacytoid dendritic cells (pDCs) were recently linked to SSc pathogenesis, which is at least partially mediated by increased type I interferon (IFN-I) responses. Here, we addressed the functional role of TLR8 signaling in different immune cell subsets of patients with SSc.
Methods: Monocytes, conventional dendritic cells (cDCs), and pDCs from the blood and skin of patients with SSc were analyzed for TLR8 protein expression. To assess TLR function, cytokine responses upon TLR7 and TLR8 stimulation were studied. To identify relevant alterations specific for patients with SSc (n = 16), patients with primary Sjögren disease (pSS; n = 10) and healthy controls (HCs; n = 13) were included into the study.
Results: In all individuals, TLR8 was expressed in monocytes and cDCs but not in pDCs. The TLR8 expression levels were overall similar in patients with SSc and pSS and HCs. Additionally, in all study participants, TLR8 stimulation of pDCs did not induce IFN-I expression. In contrast, monocytes from patients with SSc revealed increased interleukin (IL)-10 responses upon TLR8 (patients with SSc vs HCs, P = 0.0126) and TLR7/8 stimulation (patients with SSc vs HCs, P = 0.0170).
Conclusion: TLR8 protein is not expressed in pDCs of patients with SSc. Accordingly, they do not respond to TLR8 stimulation. In contrast, monocytes of patients with SSc respond to TLR8 stimulation with increased IL-10 responses. Therefore, TLR8 signaling in monocytes participates in SSc pathogenesis by conferring aberrant IL-10 expression.
{"title":"Toll-Like Receptor 8 is Expressed in Monocytes in Contrast to Plasmacytoid Dendritic Cells and Mediates Aberrant Interleukin-10 Responses in Patients With Systemic Sclerosis.","authors":"Christine Ehlers, Thea Thiele, Hannah Biermann, Stephan Traidl, Luzia Bruns, Annett Ziegler, Matthias Schefzyk, Lea M Bartsch, Ulrich Kalinke, Torsten Witte, Theresa Graalmann","doi":"10.1002/art.42964","DOIUrl":"10.1002/art.42964","url":null,"abstract":"<p><strong>Objective: </strong>Systemic sclerosis (SSc) is a severe rheumatic disease causing fibrotic tissue rearrangement. Aberrant toll-like receptor (TLR) 8 transcripts in plasmacytoid dendritic cells (pDCs) were recently linked to SSc pathogenesis, which is at least partially mediated by increased type I interferon (IFN-I) responses. Here, we addressed the functional role of TLR8 signaling in different immune cell subsets of patients with SSc.</p><p><strong>Methods: </strong>Monocytes, conventional dendritic cells (cDCs), and pDCs from the blood and skin of patients with SSc were analyzed for TLR8 protein expression. To assess TLR function, cytokine responses upon TLR7 and TLR8 stimulation were studied. To identify relevant alterations specific for patients with SSc (n = 16), patients with primary Sjögren disease (pSS; n = 10) and healthy controls (HCs; n = 13) were included into the study.</p><p><strong>Results: </strong>In all individuals, TLR8 was expressed in monocytes and cDCs but not in pDCs. The TLR8 expression levels were overall similar in patients with SSc and pSS and HCs. Additionally, in all study participants, TLR8 stimulation of pDCs did not induce IFN-I expression. In contrast, monocytes from patients with SSc revealed increased interleukin (IL)-10 responses upon TLR8 (patients with SSc vs HCs, P = 0.0126) and TLR7/8 stimulation (patients with SSc vs HCs, P = 0.0170).</p><p><strong>Conclusion: </strong>TLR8 protein is not expressed in pDCs of patients with SSc. Accordingly, they do not respond to TLR8 stimulation. In contrast, monocytes of patients with SSc respond to TLR8 stimulation with increased IL-10 responses. Therefore, TLR8 signaling in monocytes participates in SSc pathogenesis by conferring aberrant IL-10 expression.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":"59-66"},"PeriodicalIF":11.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11685002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900246","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}
Pub Date : 2025-01-01Epub Date: 2024-09-18DOI: 10.1002/art.42973
Sei Muraoka, William D Brodie, Megan N Mattichak, Mikel Gurrea-Rubio, Yuzo Ikari, Caroline Foster, M Asif Amin, Neha Khanna, Hafsa Amin, Phillip L Campbell, Sirapa Vichaikul, Ellen N Model, Morgan M Omara, Steven Petrovski, Karly Kozicki, Camilia Amarista, Anna Webber, Mustafa Ali, Pamela J Palisoc, Jonatan Hervoso, Jeffrey H Ruth, Lam C Tsoi, John Varga, Johann E Gudjonsson, Dinesh Khanna, David A Fox, Pei-Suen Tsou
Objective: Systemic sclerosis (SSc) is an autoimmune multisystem disease with poorly understood pathogenesis and ineffective treatment options. Soluble CD13 (sCD13), generated by the cleavage of cell surface CD13 via matrix metalloproteinase 14 (MMP14), signals through the bradykinin receptor B1 (B1R) to elicit pro-inflammatory, pro-arthritic, and pro-angiogenic responses. In this study, we explored the antifibrotic potential of targeting the sCD13-B1R axis in SSc.
Methods: The expression of CD13, B1R, and MMP14 was examined in SSc skin and explanted dermal fibroblasts. The efficacy of B1R antagonists in the inhibition on fibrosis was determined in vitro and in vivo.
Results: Expression of the genes for CD13, B1R, and MMP14 was elevated in skin biopsies from patients with diffuse cutaneous (dc) SSc. Notably, single-cell analysis of SSc skin biopsies revealed the highest BDKRB1 expression in COL8A1-positive myofibroblasts, a population exclusively seen in SSc. Transforming growth factor beta (TGFβ) induced the expression of BDKRB1 and production of sCD13 by dcSSc skin fibroblasts. Treatment of dcSSc fibroblasts with sCD13 promoted fibrotic gene expression, signaling, cell proliferation, migration, and gel contraction. The pro-fibrotic responses of sCD13 or TGFβ were prevented by a B1R antagonist. Mice lacking Cd13 or Bdkrb1 were resistant to bleomycin-induced skin fibrosis and inflammation. Pharmacological B1R inhibition had a comparable antifibrotic effect.
Conclusion: These results are the first to demonstrate a key role for sCD13 in SSc skin fibrosis and suggest that targeting the sCD13-B1R signaling axis is a promising novel therapeutic approach for SSc.
{"title":"Targeting CD13/Aminopeptidase N as a Novel Therapeutic Approach for Scleroderma Fibrosis.","authors":"Sei Muraoka, William D Brodie, Megan N Mattichak, Mikel Gurrea-Rubio, Yuzo Ikari, Caroline Foster, M Asif Amin, Neha Khanna, Hafsa Amin, Phillip L Campbell, Sirapa Vichaikul, Ellen N Model, Morgan M Omara, Steven Petrovski, Karly Kozicki, Camilia Amarista, Anna Webber, Mustafa Ali, Pamela J Palisoc, Jonatan Hervoso, Jeffrey H Ruth, Lam C Tsoi, John Varga, Johann E Gudjonsson, Dinesh Khanna, David A Fox, Pei-Suen Tsou","doi":"10.1002/art.42973","DOIUrl":"10.1002/art.42973","url":null,"abstract":"<p><strong>Objective: </strong>Systemic sclerosis (SSc) is an autoimmune multisystem disease with poorly understood pathogenesis and ineffective treatment options. Soluble CD13 (sCD13), generated by the cleavage of cell surface CD13 via matrix metalloproteinase 14 (MMP14), signals through the bradykinin receptor B1 (B1R) to elicit pro-inflammatory, pro-arthritic, and pro-angiogenic responses. In this study, we explored the antifibrotic potential of targeting the sCD13-B1R axis in SSc.</p><p><strong>Methods: </strong>The expression of CD13, B1R, and MMP14 was examined in SSc skin and explanted dermal fibroblasts. The efficacy of B1R antagonists in the inhibition on fibrosis was determined in vitro and in vivo.</p><p><strong>Results: </strong>Expression of the genes for CD13, B1R, and MMP14 was elevated in skin biopsies from patients with diffuse cutaneous (dc) SSc. Notably, single-cell analysis of SSc skin biopsies revealed the highest BDKRB1 expression in COL8A1-positive myofibroblasts, a population exclusively seen in SSc. Transforming growth factor beta (TGFβ) induced the expression of BDKRB1 and production of sCD13 by dcSSc skin fibroblasts. Treatment of dcSSc fibroblasts with sCD13 promoted fibrotic gene expression, signaling, cell proliferation, migration, and gel contraction. The pro-fibrotic responses of sCD13 or TGFβ were prevented by a B1R antagonist. Mice lacking Cd13 or Bdkrb1 were resistant to bleomycin-induced skin fibrosis and inflammation. Pharmacological B1R inhibition had a comparable antifibrotic effect.</p><p><strong>Conclusion: </strong>These results are the first to demonstrate a key role for sCD13 in SSc skin fibrosis and suggest that targeting the sCD13-B1R signaling axis is a promising novel therapeutic approach for SSc.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":"80-91"},"PeriodicalIF":11.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034630","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}
Pub Date : 2025-01-01Epub Date: 2024-09-18DOI: 10.1002/art.42968
Elvira D'Andrea, Sebastian Schneeweiss, Jessica M Franklin, Seoyoung C Kim, Robert J Glynn, Su Been Lee, Shirley V Wang
Objective: The objective of this study is to evaluate the concordance of results between the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON)-Pivotal Fracture Trial (PFT) and a nonrandomized database study designed to emulate the trial.
Methods: HORIZON-PFT evaluated the efficacy of zoledronic acid versus placebo in reducing the risk of hip fractures and found a 41% risk reduction over a three-year treatment period (hazard ratio [HR] = 0.59; 95% confidence interval [95% CI] 0.42-0.83). Using two US claims databases from August 2007 to December 2020 or June 2021, we applied eligibility criteria from HORIZON-PFT and identified women with osteoporosis who initiated zoledronic acid or raloxifene as a proxy for placebo. The study protocol was registered on ClinicalTrials.gov (NCT04736693) before inferential analyses. We compared HORIZON-PFT and database study results using prespecified metrics.
Results: Because of low adherence in clinical practice, on-treatment follow-up was truncated at 18 months in the database study. The hip fracture risk after 18 months was 9.3 in 1,000 in the trial and 8.3 in 1,000 in the database analysis. In the database study, zoledronic acid was associated with a 28% reduction in hip fractures risk compared with raloxifene (HR = 0.72; 95% CI 0.51-0.92). The attenuated effect of zoledronic acid in the database study may be explained by its shorter follow-up, because the interpolated estimate of the effect in HORIZON-PFT at 18 months was HRRCT (randomized controlled trial), 0.74, nearly identical to the observational estimate HRdatabase 0.72.
Conclusion: Real-world emulation of the HORIZON-PFT found that zoledronic acid reduced hip fractures risk over an 18-month follow-up period. Limited adherence in clinical practice diminished the magnitude of its preventive effect and precluded long-term estimation of effectiveness in this setting.
{"title":"Efficacy Versus Effectiveness: The HORIZON-Pivotal Fracture Trial and Its Emulation in Claims Data.","authors":"Elvira D'Andrea, Sebastian Schneeweiss, Jessica M Franklin, Seoyoung C Kim, Robert J Glynn, Su Been Lee, Shirley V Wang","doi":"10.1002/art.42968","DOIUrl":"10.1002/art.42968","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study is to evaluate the concordance of results between the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON)-Pivotal Fracture Trial (PFT) and a nonrandomized database study designed to emulate the trial.</p><p><strong>Methods: </strong>HORIZON-PFT evaluated the efficacy of zoledronic acid versus placebo in reducing the risk of hip fractures and found a 41% risk reduction over a three-year treatment period (hazard ratio [HR] = 0.59; 95% confidence interval [95% CI] 0.42-0.83). Using two US claims databases from August 2007 to December 2020 or June 2021, we applied eligibility criteria from HORIZON-PFT and identified women with osteoporosis who initiated zoledronic acid or raloxifene as a proxy for placebo. The study protocol was registered on ClinicalTrials.gov (NCT04736693) before inferential analyses. We compared HORIZON-PFT and database study results using prespecified metrics.</p><p><strong>Results: </strong>Because of low adherence in clinical practice, on-treatment follow-up was truncated at 18 months in the database study. The hip fracture risk after 18 months was 9.3 in 1,000 in the trial and 8.3 in 1,000 in the database analysis. In the database study, zoledronic acid was associated with a 28% reduction in hip fractures risk compared with raloxifene (HR = 0.72; 95% CI 0.51-0.92). The attenuated effect of zoledronic acid in the database study may be explained by its shorter follow-up, because the interpolated estimate of the effect in HORIZON-PFT at 18 months was HR<sub>RCT</sub> (randomized controlled trial), 0.74, nearly identical to the observational estimate HR<sub>database</sub> 0.72.</p><p><strong>Conclusion: </strong>Real-world emulation of the HORIZON-PFT found that zoledronic acid reduced hip fractures risk over an 18-month follow-up period. Limited adherence in clinical practice diminished the magnitude of its preventive effect and precluded long-term estimation of effectiveness in this setting.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":"12-21"},"PeriodicalIF":11.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915577","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 : 2025-01-01Epub Date: 2024-10-20DOI: 10.1002/art.42979
Christina Bergmann, Sara Chenguiti Fakhouri, Thuong Trinh-Minh, Tim Filla, Aleix Rius Rigau, Arif B Ekici, Benita Merlevede, Ludwig Hallenberger, Honglin Zhu, Clara Dees, Alexandru-Emil Matei, Janina Auth, Andrea-Hermina Györfi, Xiang Zhou, Simon Rauber, Aline Bozec, Nicholas Dickel, Chunguang Liang, Meik Kunz, Georg Schett, Jörg H W Distler
Objective: Deregulation of the cJUN/AP-1 and hedgehog/GLI2 signaling pathways has been implicated in fibroblast activation in systemic sclerosis (SSc). However, the consequences of their concomitant up-regulation are unknown. Here, we tested the hypothesis that mutual amplification of both pathways might drive persistent fibroblast activation.
Methods: Cultured fibroblasts and skin sections of patients with diffuse SSc and healthy volunteers were analyzed. cJUN/AP-1 signaling and hedgehog/GLI2 signaling were inhibited using knockdown and pharmacologic approaches. Hedgehog signaling was activated in mice by fibroblast-specific overexpression of constitutively active Smoothened.
Results: cJUN and GLI2 are concomitantly up-regulated and colocalize in fibroblasts of patients with SSc compared to healthy controls. Activation of hedgehog/GLI2 signaling induces the expression of cJUN in vitro and in vivo, whereas inactivation of GLI2 inhibits cJUN expression. Likewise, inactivation of cJUN impairs the expression of GLI2. This mutual regulation occurs at the level of transcription with binding of cJUN and GLI2 to specific binding motifs. Interference with this mutual amplification of cJUN signaling and GLI2 signaling inhibits fibroblast activation and collagen release: Inhibition of cJUN/AP-1 signaling ameliorates hedgehog-induced fibroblast activation and skin fibrosis in SmoACT mice with a reduction of skin thickness of 103% (P = 0.0043) in the treatment group compared to the fibrotic control group. Moreover, combined pharmacologic inhibition of cJUN/AP-1 and hedgehog/GLI2 exerts additive antifibrotic effects in a model of TGFβ-driven experimental fibrosis (TBRACT mice).
Conclusion: The transcription factors cJUN and GLI2 reinforce each other's activity to promote fibroblast activation in SSc. Interruption of this crosstalk by combined inhibition of both pathways exerts additive antifibrotic effects at well-tolerated doses.
{"title":"Mutual Amplification of GLI2/Hedgehog and Transcription Factor JUN/AP-1 Signaling in Fibroblasts in Systemic Sclerosis: Potential Implications for Combined Therapies.","authors":"Christina Bergmann, Sara Chenguiti Fakhouri, Thuong Trinh-Minh, Tim Filla, Aleix Rius Rigau, Arif B Ekici, Benita Merlevede, Ludwig Hallenberger, Honglin Zhu, Clara Dees, Alexandru-Emil Matei, Janina Auth, Andrea-Hermina Györfi, Xiang Zhou, Simon Rauber, Aline Bozec, Nicholas Dickel, Chunguang Liang, Meik Kunz, Georg Schett, Jörg H W Distler","doi":"10.1002/art.42979","DOIUrl":"10.1002/art.42979","url":null,"abstract":"<p><strong>Objective: </strong>Deregulation of the cJUN/AP-1 and hedgehog/GLI2 signaling pathways has been implicated in fibroblast activation in systemic sclerosis (SSc). However, the consequences of their concomitant up-regulation are unknown. Here, we tested the hypothesis that mutual amplification of both pathways might drive persistent fibroblast activation.</p><p><strong>Methods: </strong>Cultured fibroblasts and skin sections of patients with diffuse SSc and healthy volunteers were analyzed. cJUN/AP-1 signaling and hedgehog/GLI2 signaling were inhibited using knockdown and pharmacologic approaches. Hedgehog signaling was activated in mice by fibroblast-specific overexpression of constitutively active Smoothened.</p><p><strong>Results: </strong>cJUN and GLI2 are concomitantly up-regulated and colocalize in fibroblasts of patients with SSc compared to healthy controls. Activation of hedgehog/GLI2 signaling induces the expression of cJUN in vitro and in vivo, whereas inactivation of GLI2 inhibits cJUN expression. Likewise, inactivation of cJUN impairs the expression of GLI2. This mutual regulation occurs at the level of transcription with binding of cJUN and GLI2 to specific binding motifs. Interference with this mutual amplification of cJUN signaling and GLI2 signaling inhibits fibroblast activation and collagen release: Inhibition of cJUN/AP-1 signaling ameliorates hedgehog-induced fibroblast activation and skin fibrosis in Smo<sup>ACT</sup> mice with a reduction of skin thickness of 103% (P = 0.0043) in the treatment group compared to the fibrotic control group. Moreover, combined pharmacologic inhibition of cJUN/AP-1 and hedgehog/GLI2 exerts additive antifibrotic effects in a model of TGFβ-driven experimental fibrosis (TBR<sup>ACT</sup> mice).</p><p><strong>Conclusion: </strong>The transcription factors cJUN and GLI2 reinforce each other's activity to promote fibroblast activation in SSc. Interruption of this crosstalk by combined inhibition of both pathways exerts additive antifibrotic effects at well-tolerated doses.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":"92-98"},"PeriodicalIF":11.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071519","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}
Yann Nguyen, Maxime Beydon, Jacques‐Eric Gottenberg, Jacques Morel, Aleth Perdriger, Emmanuelle Dernis, Divi Cornec, Valérie Devauchelle‐Pensec, Damien Sène, Philippe Dieudé, Marion Couderc, Anne‐Laure Fauchais, Claire Larroche, Olivier Vittecoq, Carine Salliot, Eric Hachulla, Véronique Le Guern, Xavier Mariette, Raphaèle Seror, Gaëtane Nocturne
ObjectiveRecently, three distinct phenotypes of Sjögren's disease (SjD) patients have been described, based on cluster analysis: B‐cell active with low symptoms (BALS), high systemic activity (HSA), and low systemic activity with high symptoms (LSAHS). We aimed to assess whether these clusters were associated with distinct biomarkers and the prognostic value of IFN signature.MethodsThe ASSESS cohort is a 20‐year prospective cohort of SjD patients. The following biomarkers were compared: IFN‐α2, IFN‐γ, CXCL10, CXCL13, BAFF, IL7, FLT3, CCL19, and TNFRII. IFN signature was assessed using transcriptomic analysis. We then compared systemic and symptomatic evolution, and the risk of new immunosuppressant prescription and of lymphoma, according to the IFN signature across the three clusters.Results395 patients (94% female, median age 53 [43‐63] years) were included. Higher levels of CXCL‐13, IL7, and TNF‐RII levels were found in the BALS and HSA clusters compared to the LSAHS cluster. A high IFN signature was mainly found in the BALS cluster (57%, vs. 48%, and 38% in the HSA and LSAHS clusters, respectively). This IFN signature was mainly driven by type I IFN, with higher levels of IFN‐ α2. In the BALS cluster, a high IFN signature was associated with a higher risk of new immunosuppressant treatment (HR 9.38; 95% CI 1.22‐72.16). All lymphoma occurred in patients with high IFN signature.ConclusionThe three SjD clusters displayed distinct expression of IFN signature, and markers of T‐ and B‐cell activation, confirming distinct pathophysiological mechanisms. High IFN signature could predict systemic evolution in the BALS cluster.
{"title":"Distinct pathophysiological pathways support stratification of Sjögren's disease based on symptoms, clinical, and routine biological data","authors":"Yann Nguyen, Maxime Beydon, Jacques‐Eric Gottenberg, Jacques Morel, Aleth Perdriger, Emmanuelle Dernis, Divi Cornec, Valérie Devauchelle‐Pensec, Damien Sène, Philippe Dieudé, Marion Couderc, Anne‐Laure Fauchais, Claire Larroche, Olivier Vittecoq, Carine Salliot, Eric Hachulla, Véronique Le Guern, Xavier Mariette, Raphaèle Seror, Gaëtane Nocturne","doi":"10.1002/art.43096","DOIUrl":"https://doi.org/10.1002/art.43096","url":null,"abstract":"ObjectiveRecently, three distinct phenotypes of Sjögren's disease (SjD) patients have been described, based on cluster analysis: B‐cell active with low symptoms (BALS), high systemic activity (HSA), and low systemic activity with high symptoms (LSAHS). We aimed to assess whether these clusters were associated with distinct biomarkers and the prognostic value of IFN signature.MethodsThe ASSESS cohort is a 20‐year prospective cohort of SjD patients. The following biomarkers were compared: IFN‐α2, IFN‐γ, CXCL10, CXCL13, BAFF, IL7, FLT3, CCL19, and TNFRII. IFN signature was assessed using transcriptomic analysis. We then compared systemic and symptomatic evolution, and the risk of new immunosuppressant prescription and of lymphoma, according to the IFN signature across the three clusters.Results395 patients (94% female, median age 53 [43‐63] years) were included. Higher levels of CXCL‐13, IL7, and TNF‐RII levels were found in the BALS and HSA clusters compared to the LSAHS cluster. A high IFN signature was mainly found in the BALS cluster (57%, vs. 48%, and 38% in the HSA and LSAHS clusters, respectively). This IFN signature was mainly driven by type I IFN, with higher levels of IFN‐ α2. In the BALS cluster, a high IFN signature was associated with a higher risk of new immunosuppressant treatment (HR 9.38; 95% CI 1.22‐72.16). All lymphoma occurred in patients with high IFN signature.ConclusionThe three SjD clusters displayed distinct expression of IFN signature, and markers of T‐ and B‐cell activation, confirming distinct pathophysiological mechanisms. High IFN signature could predict systemic evolution in the BALS cluster.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"3 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887007","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}
Nikolaos Papazoglou, Petros P. Sfikakis, Maria G. Tektonidou
ObjectiveCardiovascular disease is a leading cause of mortality in Systemic Lupus Erythematosus (SLE). We assessed atherosclerotic plaque progression and incident cardiovascular events in SLE patients over a 10‐year follow‐up.MethodsWe prospectively analyzed 738 carotid ultrasound measurements (413 in SLE patients and 325 in age/sex‐matched healthy controls [HC]) to assess new plaque development from baseline to 3‐, 7‐, and 10‐year follow‐up. Multivariate mixed Poisson regression models examined potential predictors of plaque progression, including patient characteristics, Systemic Coronary Risk Evaluation (SCORE), traditional cardiovascular risk factor (CVRF) target attainment, Definition of Remission in SLE (DORIS), medications, and persistent triple antiphospholipid antibody (aPL) positivity during follow‐up. Ten‐year incident cardiovascular events were recorded, and univariate Cox regression analysis assessed potential associations.ResultsSLE patients had a 2.3‐fold higher risk of carotid plaque progression than HC (Incidence Rate Ratio [IRR]: 2.26; p=0.002). Plaque progression risk in SLE was reduced by 32% (IRR: 0.68, p=0.004) per each sustainedly attained CVRF target during follow‐up, including blood pressure, lipids, smoking, body weight, and physical activity. DORIS achievement ≥75% of follow‐up was associated with a 43% decrease in atherosclerosis progression risk (IRR: 0.57; p=0.033). Ten‐year risk of incident cardiovascular events was higher in SLE than HC individuals (eight versus one event, permutation‐based log‐rank p=0.036) and was associated with persistent triple aPL positivity.ConclusionPatients with SLE experience a 2.3‐fold higher 10‐year atherosclerosis progression risk than HC, mitigated by sustained CVRF control and prolonged clinical remission. Persistent triple aPL positivity is associated with increased incidence of CVD events.
{"title":"Atherosclerotic plaque progression and incident cardiovascular events in a 10‐year prospective study of patients with Systemic Lupus Erythematosus: the impact of persistent cardiovascular risk factor target attainment and sustained DORIS remission","authors":"Nikolaos Papazoglou, Petros P. Sfikakis, Maria G. Tektonidou","doi":"10.1002/art.43097","DOIUrl":"https://doi.org/10.1002/art.43097","url":null,"abstract":"ObjectiveCardiovascular disease is a leading cause of mortality in Systemic Lupus Erythematosus (SLE). We assessed atherosclerotic plaque progression and incident cardiovascular events in SLE patients over a 10‐year follow‐up.MethodsWe prospectively analyzed 738 carotid ultrasound measurements (413 in SLE patients and 325 in age/sex‐matched healthy controls [HC]) to assess new plaque development from baseline to 3‐, 7‐, and 10‐year follow‐up. Multivariate mixed Poisson regression models examined potential predictors of plaque progression, including patient characteristics, Systemic Coronary Risk Evaluation (SCORE), traditional cardiovascular risk factor (CVRF) target attainment, Definition of Remission in SLE (DORIS), medications, and persistent triple antiphospholipid antibody (aPL) positivity during follow‐up. Ten‐year incident cardiovascular events were recorded, and univariate Cox regression analysis assessed potential associations.ResultsSLE patients had a 2.3‐fold higher risk of carotid plaque progression than HC (Incidence Rate Ratio [IRR]: 2.26; p=0.002). Plaque progression risk in SLE was reduced by 32% (IRR: 0.68, p=0.004) per each sustainedly attained CVRF target during follow‐up, including blood pressure, lipids, smoking, body weight, and physical activity. DORIS achievement ≥75% of follow‐up was associated with a 43% decrease in atherosclerosis progression risk (IRR: 0.57; p=0.033). Ten‐year risk of incident cardiovascular events was higher in SLE than HC individuals (eight versus one event, permutation‐based log‐rank p=0.036) and was associated with persistent triple aPL positivity.ConclusionPatients with SLE experience a 2.3‐fold higher 10‐year atherosclerosis progression risk than HC, mitigated by sustained CVRF control and prolonged clinical remission. Persistent triple aPL positivity is associated with increased incidence of CVD events.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"8 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887008","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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