Bayram Farisogullari, Saskia Lawson-Tovey, Kimme L Hyrich, Laure Gossec, Loreto Carmona, Anja Strangfeld, Elsa F Mateus, Martin Schäfer, Ana Rodrigues, Eric Hachulla, Jose A Gomez-Puerta, Marta Mosca, Patrick Durez, Ludovic Trefond, Tiphaine Goulenok, Martina Cornalba, Emoke Stenova, Inita Bulina, Eva Strakova, Julija Zepa, Nicolas Roux, Olivier Brocq, Eric Veillard, Bernd Raffeiner, Gerd R Burmester, Xavier Mariette, Pedro M Machado
Objectives: To investigate the frequency and factors associated with disease flare following vaccination against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal diseases (I-RMDs).
Methods: Data from the European Alliance of Associations for Rheumatology Coronavirus Vaccine physician-reported registry were used. Factors associated with flare in patients with I-RMDs were investigated using multivariable logistic regression adjusted for demographic and clinical factors.
Results: The study included 7336 patients with I-RMD, with 272 of 7336 (3.7%) experiencing flares and 121 of 7336 (1.6%) experiencing flares requiring starting a new medication or increasing the dosage of an existing medication. Factors independently associated with increased odds of flare were: female sex (OR=1.40, 95% CI=1.05 to 1.87), active disease at the time of vaccination (low disease activity (LDA), OR=1.45, 95% CI=1.08 to 1.94; moderate/high disease activity (M/HDA), OR=1.37, 95% CI=0.97 to 1.95; vs remission), and cessation/reduction of antirheumatic medication before or after vaccination (OR=4.76, 95% CI=3.44 to 6.58); factors associated with decreased odds of flare were: higher age (OR=0.90, 95% CI=0.83 to 0.98), non-Pfizer/AstraZeneca/Moderna vaccines (OR=0.10, 95% CI=0.01 to 0.74; vs Pfizer), and exposure to methotrexate (OR=0.57, 95% CI=0.37 to 0.90), tumour necrosis factor inhibitors (OR=0.55, 95% CI=0.36 to 0.85) or rituximab (OR=0.27, 95% CI=0.11 to 0.66), versus no antirheumatic treatment. In a multivariable model using new medication or dosage increase due to flare as the dependent variable, only the following independent associations were observed: active disease (LDA, OR=1.47, 95% CI=0.94 to 2.29; M/HDA, OR=3.08, 95% CI=1.91 to 4.97; vs remission), cessation/reduction of antirheumatic medication before or after vaccination (OR=2.24, 95% CI=1.33 to 3.78), and exposure to methotrexate (OR=0.48, 95% CI=0.26 to 0.89) or rituximab (OR=0.10, 95% CI=0.01 to 0.77), versus no antirheumatic treatment.
Conclusion: I-RMD flares following SARS-CoV-2 vaccination were uncommon. Factors associated with flares were identified, namely higher disease activity and cessation/reduction of antirheumatic medications before or after vaccination.
{"title":"Factors associated with disease flare following SARS-CoV-2 vaccination in people with inflammatory rheumatic and musculoskeletal diseases: results from the physician-reported EULAR Coronavirus Vaccine (COVAX) Registry.","authors":"Bayram Farisogullari, Saskia Lawson-Tovey, Kimme L Hyrich, Laure Gossec, Loreto Carmona, Anja Strangfeld, Elsa F Mateus, Martin Schäfer, Ana Rodrigues, Eric Hachulla, Jose A Gomez-Puerta, Marta Mosca, Patrick Durez, Ludovic Trefond, Tiphaine Goulenok, Martina Cornalba, Emoke Stenova, Inita Bulina, Eva Strakova, Julija Zepa, Nicolas Roux, Olivier Brocq, Eric Veillard, Bernd Raffeiner, Gerd R Burmester, Xavier Mariette, Pedro M Machado","doi":"10.1136/ard-2024-225869","DOIUrl":"https://doi.org/10.1136/ard-2024-225869","url":null,"abstract":"<p><strong>Objectives: </strong>To investigate the frequency and factors associated with disease flare following vaccination against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal diseases (I-RMDs).</p><p><strong>Methods: </strong>Data from the European Alliance of Associations for Rheumatology Coronavirus Vaccine physician-reported registry were used. Factors associated with flare in patients with I-RMDs were investigated using multivariable logistic regression adjusted for demographic and clinical factors.</p><p><strong>Results: </strong>The study included 7336 patients with I-RMD, with 272 of 7336 (3.7%) experiencing flares and 121 of 7336 (1.6%) experiencing flares requiring starting a new medication or increasing the dosage of an existing medication. Factors independently associated with increased odds of flare were: female sex (OR=1.40, 95% CI=1.05 to 1.87), active disease at the time of vaccination (low disease activity (LDA), OR=1.45, 95% CI=1.08 to 1.94; moderate/high disease activity (M/HDA), OR=1.37, 95% CI=0.97 to 1.95; vs remission), and cessation/reduction of antirheumatic medication before or after vaccination (OR=4.76, 95% CI=3.44 to 6.58); factors associated with decreased odds of flare were: higher age (OR=0.90, 95% CI=0.83 to 0.98), non-Pfizer/AstraZeneca/Moderna vaccines (OR=0.10, 95% CI=0.01 to 0.74; vs Pfizer), and exposure to methotrexate (OR=0.57, 95% CI=0.37 to 0.90), tumour necrosis factor inhibitors (OR=0.55, 95% CI=0.36 to 0.85) or rituximab (OR=0.27, 95% CI=0.11 to 0.66), versus no antirheumatic treatment. In a multivariable model using new medication or dosage increase due to flare as the dependent variable, only the following independent associations were observed: active disease (LDA, OR=1.47, 95% CI=0.94 to 2.29; M/HDA, OR=3.08, 95% CI=1.91 to 4.97; vs remission), cessation/reduction of antirheumatic medication before or after vaccination (OR=2.24, 95% CI=1.33 to 3.78), and exposure to methotrexate (OR=0.48, 95% CI=0.26 to 0.89) or rituximab (OR=0.10, 95% CI=0.01 to 0.77), versus no antirheumatic treatment.</p><p><strong>Conclusion: </strong>I-RMD flares following SARS-CoV-2 vaccination were uncommon. Factors associated with flares were identified, namely higher disease activity and cessation/reduction of antirheumatic medications before or after vaccination.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178724","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}
Huai Leng Pisaniello, Susan Elizabeth Lester, Oscar Russell, Rachel Black, Joanna Tieu, Bethan Richards, Claire Barrett, Marissa Lassere, Lyn March, Rachelle Buchbinder, Catherine Hill, Samuel Lawrance Whittle
{"title":"The associations between poorer pain-related health status and increased hospitalisations and excess mortality in patients with rheumatoid arthritis (RA): a prospective cohort analysis using the Australian Rheumatology Association Database (ARAD).","authors":"Huai Leng Pisaniello, Susan Elizabeth Lester, Oscar Russell, Rachel Black, Joanna Tieu, Bethan Richards, Claire Barrett, Marissa Lassere, Lyn March, Rachelle Buchbinder, Catherine Hill, Samuel Lawrance Whittle","doi":"10.1136/ard-2024-225696","DOIUrl":"https://doi.org/10.1136/ard-2024-225696","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174581","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}
Daniele Mauro, Xiang Lin, Elena Pontarini, Pascale Wehr, Giuliana Guggino, Yuan Tang, Chong Deng, Saviana Gandolfo, Fan Xiao, Ke Rui, Enyu Huang, Jie Tian, Stefania Raimondo, Maureen Rischmueller, Jane Boroky, Sarah Downie-Doyle, Hendrik Nel, Adriana Baz-Morelli, Arthur Hsu, Eugene Maraskovsky, Adele Barr, Patrice Hemon, Loukas Chatzis, Ciro Emiliano Boschetti, Giuseppe Colella, Riccardo Alessandro, Aroldo Rizzo, Jacques-Olivier Pers, Michele Bombardieri, Ranjeny Thomas, Liwei Lu, Francesco Ciccia
Objective: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS).
Methods: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration.
Results: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8+CD103+CD69+ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8+ CD103+ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8+ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3+CD8+ SG T cells. In the SG of ESS, CD8+CD69+CD103+ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow.
Conclusions: CD103+CD8+Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.
{"title":"CD8<sup>+</sup> tissue-resident memory T cells are expanded in primary Sjögren's disease and can be therapeutically targeted by CD103 blockade.","authors":"Daniele Mauro, Xiang Lin, Elena Pontarini, Pascale Wehr, Giuliana Guggino, Yuan Tang, Chong Deng, Saviana Gandolfo, Fan Xiao, Ke Rui, Enyu Huang, Jie Tian, Stefania Raimondo, Maureen Rischmueller, Jane Boroky, Sarah Downie-Doyle, Hendrik Nel, Adriana Baz-Morelli, Arthur Hsu, Eugene Maraskovsky, Adele Barr, Patrice Hemon, Loukas Chatzis, Ciro Emiliano Boschetti, Giuseppe Colella, Riccardo Alessandro, Aroldo Rizzo, Jacques-Olivier Pers, Michele Bombardieri, Ranjeny Thomas, Liwei Lu, Francesco Ciccia","doi":"10.1136/ard-2023-225069","DOIUrl":"https://doi.org/10.1136/ard-2023-225069","url":null,"abstract":"<p><strong>Objective: </strong>Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS).</p><p><strong>Methods: </strong>In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration.</p><p><strong>Results: </strong>Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8<sup>+</sup>CD103<sup>+</sup>CD69<sup>+</sup> cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8<sup>+</sup> CD103<sup>+</sup> Trm contributed to the secretion of granzyme-B and interferon-γ, CD8<sup>+</sup> Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of <i>CD69, ITGAE, GZMB, GZMK</i> and <i>HLA-DRB1</i> among CD3<sup>+</sup>CD8<sup>+</sup> SG T cells. In the SG of ESS, CD8<sup>+</sup>CD69<sup>+</sup>CD103<sup>+</sup> Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow.</p><p><strong>Conclusions: </strong>CD103<sup>+</sup>CD8<sup>+</sup>Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079518","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}
Philip Rask Lage-Hansen, Nikoletta Svendsen, Jamie Kirkham, Sabrina Mai Nielsen, Kirstine Amris, Maarten de Wit, Maarten Boers, Torkell Ellingsen, Robin Christensen
Objectives: To explore which core domain is best associated with the American College of Rheumatology (ACR) 20% response in trials assessing the effect of targeted interventions in rheumatoid arthritis (RA).
Methods: A meta-epidemiological study was performed on randomised trials investigating biologics and targeted agents compared with placebo or conventional disease-modifying antirheumatic drugs in patients with RA. The main outcome measures were ORs for the ACR 20% response and at least one of the eight core domains according to the existing RA core outcome set (COS) analysed based on standardised mean differences.
Results: 115 trials involving 55 422 patients with RA were eligible. The OR for achieving ACR 20% response was 3.19 (95% CI 2.96 to 3.44) for the experimental interventions relative to the comparators. The median number of COS domains reported was 6; 18 trials reported only 1 domain, 17 all 8. Univariable meta-regression analyses indicated that each of the eight core domains was significantly associated with ACR 20% response, yet improvements in physical disability explain a successful ACR 20% response the most. Including only trials reporting on all eight core domains, univariable meta-regression analyses proved improvement in fatigue to explain a successful ACR 20% response the most.
Conclusions: Within this dataset, it is evident that the conclusions concerning our primary objective were significantly influenced by both the amount and characteristics of missing data. Our data suggest that fatigue could be more important for the primary endpoint than previously assumed, but this is based on limited data.
目的探讨在评估类风湿关节炎(RA)靶向干预效果的试验中,哪个核心领域与美国风湿病学会(ACR)20%的反应最相关:对研究生物制剂和靶向药物的随机试验进行了荟萃流行病学研究,并将其与安慰剂或传统的改善类风湿关节炎患者病情的抗风湿药物进行了比较。主要结果指标是ACR 20%反应的ORs,以及根据现有RA核心结果集(COS)分析的8个核心领域中至少一个领域的ORs:涉及55 422名RA患者的115项试验符合条件。试验性干预措施相对于比较者达到 ACR 20% 反应的 OR 为 3.19(95% CI 2.96 至 3.44)。报告的 COS 领域中位数为 6 个;18 项试验仅报告了 1 个领域,17 项试验报告了全部 8 个领域。单变量元回归分析表明,8个核心领域中的每一个都与ACR 20%反应显著相关,但肢体残疾的改善最能解释ACR 20%反应成功的原因。仅包括报告所有八个核心领域的试验,单变量元回归分析证明,疲劳程度的改善最能解释 ACR 20% 成功应答的原因:在这一数据集中,有关我们主要目标的结论显然受到缺失数据的数量和特征的显著影响。我们的数据表明,疲劳对主要终点的影响可能比之前假设的更重要,但这是基于有限的数据。
{"title":"Exploring the effect on primary endpoints in trials testing targeted therapy interventions for rheumatoid arthritis: a meta-epidemiological study on the appropriate use of a core outcome set.","authors":"Philip Rask Lage-Hansen, Nikoletta Svendsen, Jamie Kirkham, Sabrina Mai Nielsen, Kirstine Amris, Maarten de Wit, Maarten Boers, Torkell Ellingsen, Robin Christensen","doi":"10.1136/ard-2024-225523","DOIUrl":"https://doi.org/10.1136/ard-2024-225523","url":null,"abstract":"<p><strong>Objectives: </strong>To explore which core domain is best associated with the American College of Rheumatology (ACR) 20% response in trials assessing the effect of targeted interventions in rheumatoid arthritis (RA).</p><p><strong>Methods: </strong>A meta-epidemiological study was performed on randomised trials investigating biologics and targeted agents compared with placebo or conventional disease-modifying antirheumatic drugs in patients with RA. The main outcome measures were ORs for the ACR 20% response and at least one of the eight core domains according to the existing RA core outcome set (COS) analysed based on standardised mean differences.</p><p><strong>Results: </strong>115 trials involving 55 422 patients with RA were eligible. The OR for achieving ACR 20% response was 3.19 (95% CI 2.96 to 3.44) for the experimental interventions relative to the comparators. The median number of COS domains reported was 6; 18 trials reported only 1 domain, 17 all 8. Univariable meta-regression analyses indicated that each of the eight core domains was significantly associated with ACR 20% response, yet improvements in physical disability explain a successful ACR 20% response the most. Including only trials reporting on all eight core domains, univariable meta-regression analyses proved improvement in fatigue to explain a successful ACR 20% response the most.</p><p><strong>Conclusions: </strong>Within this dataset, it is evident that the conclusions concerning our primary objective were significantly influenced by both the amount and characteristics of missing data. Our data suggest that fatigue could be more important for the primary endpoint than previously assumed, but this is based on limited data.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079638","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}
Myrto Kostopoulou, Chetan B Mukhtyar, George Bertsias, Dimitrios T Boumpas, Antonis Fanouriakis
Objectives: To analyse the new evidence (2018-2022) for the management of systemic lupus erythematosus (SLE) to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations.
Methods: Systematic literature reviews were performed in the Medline and the Cochrane Library databases capturing publications from 1 January 2018 through 31 December 2022, according to the EULAR standardised operating procedures. The research questions focused on five different domains, namely the benefit/harm of SLE treatments, the benefits from the attainment of remission/low disease activity, the risk/benefit from treatment tapering/withdrawal, the management of SLE with antiphospholipid syndrome and the safety of immunisations against varicella zoster virus and SARS-CoV2 infection. A Population, Intervention, Comparison and Outcome framework was used to develop search strings for each research topic.
Results: We identified 439 relevant articles, the majority being observational studies of low or moderate quality. High-quality randomised controlled trials (RCTs) documented the efficacy of the type 1 interferon receptor inhibitor, anifrolumab, in non-renal SLE, and belimumab and voclosporin, a novel calcineurin inhibitor, in lupus nephritis (LN), when compared with standard of care. For the treatment of specific organ manifestations outside LN, a lack of high-quality data was documented. Multiple observational studies confirmed the beneficial effects of attaining clinical remission or low disease activity, reducing the risk for multiple adverse outcomes. Two randomised trials with some concerns regarding risk of bias found higher rates of relapse in patients who discontinued glucocorticoids (GC) or immunosuppressants in SLE and LN, respectively, yet observational cohort studies suggest that treatment withdrawal might be feasible in a subset of patients.
Conclusion: Anifrolumab and belimumab achieve better disease control than standard of care in extrarenal SLE, while combination therapies with belimumab and voclosporin attained higher response rates in high-quality RCTs in LN. Remission and low disease activity are associated with favourable long-term outcomes. In patients achieving these targets, GC and immunosuppressive therapy may gradually be tapered. Cite Now.
{"title":"Management of systemic lupus erythematosus: a systematic literature review informing the 2023 update of the EULAR recommendations.","authors":"Myrto Kostopoulou, Chetan B Mukhtyar, George Bertsias, Dimitrios T Boumpas, Antonis Fanouriakis","doi":"10.1136/ard-2023-225319","DOIUrl":"https://doi.org/10.1136/ard-2023-225319","url":null,"abstract":"<p><strong>Objectives: </strong>To analyse the new evidence (2018-2022) for the management of systemic lupus erythematosus (SLE) to inform the 2023 update of the European League Against Rheumatism (EULAR) recommendations.</p><p><strong>Methods: </strong>Systematic literature reviews were performed in the Medline and the Cochrane Library databases capturing publications from 1 January 2018 through 31 December 2022, according to the EULAR standardised operating procedures. The research questions focused on five different domains, namely the benefit/harm of SLE treatments, the benefits from the attainment of remission/low disease activity, the risk/benefit from treatment tapering/withdrawal, the management of SLE with antiphospholipid syndrome and the safety of immunisations against varicella zoster virus and SARS-CoV2 infection. A Population, Intervention, Comparison and Outcome framework was used to develop search strings for each research topic.</p><p><strong>Results: </strong>We identified 439 relevant articles, the majority being observational studies of low or moderate quality. High-quality randomised controlled trials (RCTs) documented the efficacy of the type 1 interferon receptor inhibitor, anifrolumab, in non-renal SLE, and belimumab and voclosporin, a novel calcineurin inhibitor, in lupus nephritis (LN), when compared with standard of care. For the treatment of specific organ manifestations outside LN, a lack of high-quality data was documented. Multiple observational studies confirmed the beneficial effects of attaining clinical remission or low disease activity, reducing the risk for multiple adverse outcomes. Two randomised trials with some concerns regarding risk of bias found higher rates of relapse in patients who discontinued glucocorticoids (GC) or immunosuppressants in SLE and LN, respectively, yet observational cohort studies suggest that treatment withdrawal might be feasible in a subset of patients.</p><p><strong>Conclusion: </strong>Anifrolumab and belimumab achieve better disease control than standard of care in extrarenal SLE, while combination therapies with belimumab and voclosporin attained higher response rates in high-quality RCTs in LN. Remission and low disease activity are associated with favourable long-term outcomes. In patients achieving these targets, GC and immunosuppressive therapy may gradually be tapered. Cite Now.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079639","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}
Jerome Hadjadj, Yann Nguyen, Dalila Mouloudj, Rim Bourguiba, Mael Heiblig, Hassina Aloui, Chloe McAvoy, Valentin Lacombe, Samuel Ardois, Corrado Campochiaro, Alexandre Maria, Cyrille Coustal, Thibault Comont, Estibaliz Lazaro, Francois Lifermann, Guillaume Le Guenno, Hervé Lobbes, Vincent Grobost, Roderau Outh, Julien Campagne, Anais Dor-Etienne, Alice Garnier, Yvan Jamilloux, Antoine Dossier, Maxime Samson, Sylvain Audia, Barbara Nicolas, Alexis Mathian, Baptiste de Maleprade, Benjamin De Sainte-Marie, Benoit Faucher, Jean-David Bouaziz, Jonathan Broner, Cyril Dumain, Carole Antoine, Benjamin Carpentier, Brice Castel, Celine Lartigau-Roussin, Etienne Crickx, Geoffroy Volle, Damien Fayard, Paul Decker, Thomas Moulinet, Anael Dumont, Alexandre Nguyen, Achille Aouba, Jean-Philippe Martellosio, Matthieu Levavasseur, Sebastien Puigrenier, Pascale Antoine, Jean-Thomas Giraud, Olivier Hermine, Carole Lacout, Nihal Martis, Jean-Denis Karam, Francois Chasset, Laurent Arnaud, Paola Marianetti, Christophe Deligny, Thibaud Chazal, Pascal Woaye-Hune, Murielle Roux-Sauvat, Aurore Meyer, Pierre Sujobert, Pierre Hirsch, Noemie Abisror, Pierre Fenaux, Olivier Kosmider, Vincent Jachiet, Olivier Fain, Benjamin Terrier, Arsène Mekinian, Sophie Georgin-Lavialle
Objectives: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies.
Methods: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose.
Results: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors.
Conclusions: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.
{"title":"Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX.","authors":"Jerome Hadjadj, Yann Nguyen, Dalila Mouloudj, Rim Bourguiba, Mael Heiblig, Hassina Aloui, Chloe McAvoy, Valentin Lacombe, Samuel Ardois, Corrado Campochiaro, Alexandre Maria, Cyrille Coustal, Thibault Comont, Estibaliz Lazaro, Francois Lifermann, Guillaume Le Guenno, Hervé Lobbes, Vincent Grobost, Roderau Outh, Julien Campagne, Anais Dor-Etienne, Alice Garnier, Yvan Jamilloux, Antoine Dossier, Maxime Samson, Sylvain Audia, Barbara Nicolas, Alexis Mathian, Baptiste de Maleprade, Benjamin De Sainte-Marie, Benoit Faucher, Jean-David Bouaziz, Jonathan Broner, Cyril Dumain, Carole Antoine, Benjamin Carpentier, Brice Castel, Celine Lartigau-Roussin, Etienne Crickx, Geoffroy Volle, Damien Fayard, Paul Decker, Thomas Moulinet, Anael Dumont, Alexandre Nguyen, Achille Aouba, Jean-Philippe Martellosio, Matthieu Levavasseur, Sebastien Puigrenier, Pascale Antoine, Jean-Thomas Giraud, Olivier Hermine, Carole Lacout, Nihal Martis, Jean-Denis Karam, Francois Chasset, Laurent Arnaud, Paola Marianetti, Christophe Deligny, Thibaud Chazal, Pascal Woaye-Hune, Murielle Roux-Sauvat, Aurore Meyer, Pierre Sujobert, Pierre Hirsch, Noemie Abisror, Pierre Fenaux, Olivier Kosmider, Vincent Jachiet, Olivier Fain, Benjamin Terrier, Arsène Mekinian, Sophie Georgin-Lavialle","doi":"10.1136/ard-2024-225640","DOIUrl":"https://doi.org/10.1136/ard-2024-225640","url":null,"abstract":"<p><strong>Objectives: </strong>Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies.</p><p><strong>Methods: </strong>Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose.</p><p><strong>Results: </strong>110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors.</p><p><strong>Conclusions: </strong>This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141079566","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}
Objectives: Vasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved.
Methods: Transcriptomes and chromatin accessibility were assessed by single-cell RNA sequencing and single-nucleus transposase-accessible chromatin sequencing. Immunofluorescent staining of skin and proteomics assay were employed to confirm the altered SSc EC phenotypes. Gain-of-function assay was used to evaluate the effects of ETS transcription factors on human dermal ECs (hDECs).
Results: Both control and SSc ECs shared transcriptomic signatures of vascular linages (arterial, capillary and venous ECs) and lymphatic ECs. Arterial ECs in SSc showed reduced number and increased expression of genes associated with apoptosis. Two distinct EC subpopulations, tip and proliferating ECs, were markedly upregulated in SSc, indicating enhanced proangiogenic and proliferative activities. Molecular features of aberrant SSc-ECs were associated with disease pathogenesis and clinical traits of SSc, such as skin fibrosis and digital ulcers. Ligand-receptor analysis demonstrated altered intercellular networks of SSc EC subpopulations with perivascular and immune cells. Furthermore, the integration of open chromatin profiles with transcriptomic analysis suggested an increased accessibility of regulatory elements for ETS family transcription factors in SSc ECs. Overexpression of ETS genes in hDECs suggested ELK4, ERF and ETS1 may orchestrate arterial apoptosis and dysregulated angiogenesis in SSc.
Conclusions: This study unveils transcriptional and chromatin alterations in driving endovascular dysregulation in SSc, proposing ELK4, ERF and ETS1 as novel targets in ECs for addressing vascular complications in the condition.
{"title":"Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis.","authors":"Mengqi Huang, Tracy Tabib, Dinesh Khanna, Shervin Assassi, Robyn Domsic, Robert Lafyatis","doi":"10.1136/ard-2023-225415","DOIUrl":"https://doi.org/10.1136/ard-2023-225415","url":null,"abstract":"<p><strong>Objectives: </strong>Vasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved.</p><p><strong>Methods: </strong>Transcriptomes and chromatin accessibility were assessed by single-cell RNA sequencing and single-nucleus transposase-accessible chromatin sequencing. Immunofluorescent staining of skin and proteomics assay were employed to confirm the altered SSc EC phenotypes. Gain-of-function assay was used to evaluate the effects of ETS transcription factors on human dermal ECs (hDECs).</p><p><strong>Results: </strong>Both control and SSc ECs shared transcriptomic signatures of vascular linages (arterial, capillary and venous ECs) and lymphatic ECs. Arterial ECs in SSc showed reduced number and increased expression of genes associated with apoptosis. Two distinct EC subpopulations, tip and proliferating ECs, were markedly upregulated in SSc, indicating enhanced proangiogenic and proliferative activities. Molecular features of aberrant SSc-ECs were associated with disease pathogenesis and clinical traits of SSc, such as skin fibrosis and digital ulcers. Ligand-receptor analysis demonstrated altered intercellular networks of SSc EC subpopulations with perivascular and immune cells. Furthermore, the integration of open chromatin profiles with transcriptomic analysis suggested an increased accessibility of regulatory elements for ETS family transcription factors in SSc ECs. Overexpression of ETS genes in hDECs suggested ELK4, ERF and ETS1 may orchestrate arterial apoptosis and dysregulated angiogenesis in SSc.</p><p><strong>Conclusions: </strong>This study unveils transcriptional and chromatin alterations in driving endovascular dysregulation in SSc, proposing ELK4, ERF and ETS1 as novel targets in ECs for addressing vascular complications in the condition.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955451","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}
{"title":"Treatment of recalcitrant psoriasis and psoriatic arthritis with a combination of a biologic plus an oral JAK or TYK2 inhibitor: a case series.","authors":"M Grace Hren, Saakshi Khattri","doi":"10.1136/ard-2024-225800","DOIUrl":"https://doi.org/10.1136/ard-2024-225800","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955455","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}
Megan R W Barber, Manuel Francisco Ugarte-Gil, John G Hanly, Murray B Urowitz, Yvan St-Pierre, Caroline Gordon, Sang-Cheol Bae, Juanita Romero-Diaz, Jorge Sanchez-Guerrero, Sasha Bernatsky, Daniel J Wallace, David A Isenberg, Anisur Rahman, Joan T Merrill, Paul R Fortin, Dafna D Gladman, Ian N Bruce, Michelle Petri, Ellen M Ginzler, Mary Anne Dooley, Rosalind Ramsey-Goldman, Susan Manzi, Andreas Jönsen, Ronald F van Vollenhoven, Cynthia Aranow, Meggan Mackay, Guillermo Ruiz-Irastorza, S Sam Lim, Murat Inanc, Kenneth C Kalunian, Søren Jacobsen, Christine A Peschken, Diane L Kamen, Anca Askanase, Bernardo A Pons-Estel, Francesca S Cardwell, Graciela S Alarcón, Ann E Clarke
Objectives: This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort.
Methods: Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions.
Results: 1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC -$C1372; IC -$C2507), remission on-treatment (DC -$C973; IC -$C2604,) LDA-TC (DC -$C1158) and mLLDAS (DC -$C1040). There were no cost differences between remission/LDA states.
Conclusions: Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity.
{"title":"Remission and low disease activity are associated with lower healthcare costs: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort.","authors":"Megan R W Barber, Manuel Francisco Ugarte-Gil, John G Hanly, Murray B Urowitz, Yvan St-Pierre, Caroline Gordon, Sang-Cheol Bae, Juanita Romero-Diaz, Jorge Sanchez-Guerrero, Sasha Bernatsky, Daniel J Wallace, David A Isenberg, Anisur Rahman, Joan T Merrill, Paul R Fortin, Dafna D Gladman, Ian N Bruce, Michelle Petri, Ellen M Ginzler, Mary Anne Dooley, Rosalind Ramsey-Goldman, Susan Manzi, Andreas Jönsen, Ronald F van Vollenhoven, Cynthia Aranow, Meggan Mackay, Guillermo Ruiz-Irastorza, S Sam Lim, Murat Inanc, Kenneth C Kalunian, Søren Jacobsen, Christine A Peschken, Diane L Kamen, Anca Askanase, Bernardo A Pons-Estel, Francesca S Cardwell, Graciela S Alarcón, Ann E Clarke","doi":"10.1136/ard-2024-225613","DOIUrl":"https://doi.org/10.1136/ard-2024-225613","url":null,"abstract":"<p><strong>Objectives: </strong>This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort.</p><p><strong>Methods: </strong>Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions.</p><p><strong>Results: </strong>1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC -$C1372; IC -$C2507), remission on-treatment (DC -$C973; IC -$C2604,) LDA-TC (DC -$C1158) and mLLDAS (DC -$C1040). There were no cost differences between remission/LDA states.</p><p><strong>Conclusions: </strong>Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":27.4,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140955191","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}
{"title":"Response to: Correspondence on 'SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy' by Zhao <i>et al</i>.","authors":"Yuan-Yuan Qi","doi":"10.1136/ard-2023-225255","DOIUrl":"10.1136/ard-2023-225255","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139085627","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}