Neutrophilic Activity Biomarkers (Plasma Neutrophil Extracellular Traps and Calprotectin) in Established Patients with Rheumatoid Arthritis Receiving Biological or JAK Inhibitors: A Clinical and Ultrasonographic Study.

IF 2.9 3区 医学 Q2 RHEUMATOLOGY Rheumatology and Therapy Pub Date : 2024-06-01 Epub Date: 2024-03-02 DOI:10.1007/s40744-024-00650-9
Beatriz Frade-Sosa, Andrés Ponce, Estíbaliz Ruiz-Ortiz, Noemí De Moner, María J Gómara, Ana Belén Azuaga, Juan C Sarmiento-Monroy, Rosa Morlà, Virginia Ruiz-Esquide, Laura Macías, Nuria Sapena, Lola Tobalina, Julio Ramirez, Juan D Cañete, Jordi Yague, Josep M Auge, José A Gomez-Puerta, Odette Viñas, Isabel Haro, Raimon Sanmarti
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Abstract

Introduction: This study assesses the accuracy of neutrophil activation markers, including neutrophil extracellular traps (NETs) and calprotectin, as biomarkers of disease activity in patients with established rheumatoid arthritis (RA). We also analyse the relationship between NETs and various types of therapies as well as their association with autoimmunity.

Methods: Observational cross-sectional study of patients with RA receiving treatment with biological disease-modifying antirheumatic drugs or Janus kinase inhibitors (JAK-inhibitors) for at least 3 months. Plasma calprotectin levels were measured using an enzyme-linked immunosorbent assay test kit and NETs by measuring their remnants in plasma (neutrophil elastase-DNA and histone-DNA complexes). We also assessed clinical disease activity, joint ultrasound findings and autoantibody status [reumatoid factor (RF), anti-citrullinated peptide/protein antibodies (ACPAs) and anti-carbamylated protein (anti-CarP)]. Associations between neutrophilic biomarkers and clinical or ultrasound scores were sought using correlation analysis. The discriminatory capacity of both neutrophilic biomarkers to detect ultrasound synovitis was analysed through receiver-operating characteristic (ROC) curves.

Results: One hundred fourteen patients were included. Two control groups were included to compare NET levels. The active control group consisted of 15 patients. The second control group consisted of 30 healthy subjects. Plasma NET levels did not correlate with clinical disease status, regardless of the clinic index analysed or the biological therapy administered. No significant correlation was observed between NET remnants and ultrasound synovitis. There was no correlation between plasma NET and autoantibodies. In contrast, plasma calprotectin positively correlated with clinical parameters (swollen joint count [SJC] rho = 0.49; P < 0.001, Clinical Disease Activity Index [CDAI] rho = 0.30; P < 0.001) and ultrasound parameters (rho > 0.50; P < 0.001). Notably, this correlation was stronger than that observed with acute phase reactants.

Conclusion: While NET formation induced by neutrophils may play a role in RA pathogenesis, our study raises questions about the utility of NET remnants in peripheral circulation as a biomarker for inflammatory activity. In contrast, this study strongly supports the usefulness of calprotectin as a biomarker of inflammatory activity in patients with RA.

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接受生物或 JAK 抑制剂治疗的已确诊类风湿性关节炎患者的中性粒细胞活性生物标志物(血浆中性粒细胞胞外捕获物和钙蛋白):临床和超声波研究。
简介本研究评估了中性粒细胞活化标志物(包括中性粒细胞胞外捕获物(NETs)和钙蛋白)作为类风湿关节炎(RA)已确诊患者疾病活动性生物标志物的准确性。我们还分析了NETs与各类疗法之间的关系及其与自身免疫的关联:观察性横断面研究:对接受生物改变病情抗风湿药或Janus激酶抑制剂(JAK-抑制剂)治疗至少3个月的RA患者进行观察。使用酶联免疫吸附试验试剂盒测量血浆钙蛋白水平,通过测量血浆中的NET残留物(中性粒细胞弹性蛋白酶-DNA和组蛋白-DNA复合物)测量NET水平。我们还评估了临床疾病活动性、关节超声检查结果和自身抗体状态[类风湿因子(RF)、抗瓜氨酸肽/蛋白抗体(ACPA)和抗氨甲酰蛋白(抗CarP)]。中性粒细胞生物标志物与临床或超声评分之间的相关性是通过相关分析来寻找的。两种中性粒细胞生物标记物检测超声滑膜炎的判别能力通过接收器操作特征曲线(ROC)进行分析:结果:共纳入了 114 名患者。为比较NET水平,纳入了两个对照组。主动对照组由 15 名患者组成。第二个对照组由 30 名健康人组成。无论分析的临床指标或采用的生物疗法如何,血浆NET水平都与临床疾病状况无关。NET残留物与超声滑膜炎之间没有明显的相关性。血浆NET与自身抗体之间也没有相关性。相反,血浆钙蛋白与临床参数呈正相关(关节肿胀计数[SJC] rho = 0.49;P 0.50;P 结论:血浆钙蛋白与临床参数呈正相关(关节肿胀计数[SJC] rho = 0.49;P 0.50;P 结论):虽然中性粒细胞诱导的NET形成可能在RA发病机制中发挥作用,但我们的研究对外周循环中的NET残留物作为炎症活动生物标志物的效用提出了质疑。与此相反,本研究强烈支持将钙蛋白作为 RA 患者炎症活动的生物标志物。
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来源期刊
Rheumatology and Therapy
Rheumatology and Therapy RHEUMATOLOGY-
CiteScore
6.00
自引率
5.30%
发文量
91
审稿时长
6 weeks
期刊介绍: Aims and Scope Rheumatology and Therapy is an international, open access, peer reviewed, rapid publication journal dedicated to the publication of high-quality clinical (all phases), observational, real-world and health outcomes research around the discovery, development, and use of rheumatologic therapies. Studies relating to diagnosis, pharmacoeconomics, public health, quality of life, and patient care, management, and education are also welcomed. Areas of focus include, but are not limited to, rheumatoid arthritis, gout, gouty arthritis, psoriatic arthritis, osteoarthritis, juvenile idiopathic/rheumatoid arthritis, systemic lupus erythematosus, axial spondyloarthritis, Pompe’s disease, inflammatory joint conditions, musculoskeletal conditions, systemic sclerosis, and fibromyalgia. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, case reports, trial protocols, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Rheumatology and Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research. Ethics and Disclosures The journal is a member of the Committee on Publication Ethics (COPE) and subscribes to its principles on how to deal with acts of misconduct thereby committing to investigate allegations of misconduct in order to ensure the integrity of research. Content in this journal is peer-reviewed (Single-blind). For more information on our publishing ethics policies, please see here: https://www.springer.com/gp/editorial-policies Rapid Publication The journal’s rapid publication timelines aim for a peer review decision within 2 weeks of submission. If an article is accepted it will be published online 3-4 weeks from acceptance. These rapid timelines are achieved through the combination of a dedicated in-house editorial team, who closely manage article workflow, and an extensive Editorial and Advisory Board who assist with rapid peer review. This allows the journal to support the rapid dissemination of research, whilst still providing robust peer review. Combined with the journal’s open access model this allows for the rapid and efficient communication of the latest research and reviews, allowing the advancement of rheumatologic therapies. Personal Service The journal’s dedicated in-house editorial team offer a personal “concierge service” meaning that authors will always have a personal point of contact able to update them on the status of their manuscript. The editorial team check all manuscripts to ensure that articles conform to the most recent COPE, GPP and ICMJE publishing guidelines. This supports the publication of ethically sound and transparent research. We also encourage pre-submission enquiries and are always happy to provide a confidential assessment of manuscripts. Digital Features Rheumatology and Therapy offers a range of additional features designed to increase the visibility, readership and educational value of the journal’s content. Each article is accompanied by key summary points, giving a time-efficient overview of the content to a wide readership. Articles may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand the scientific content and overall implications of the article. The journal also provides the option to include various types of digital features including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations. All additional features are peer reviewed to the same high standard as the article itself. If you consider that your paper would benefit from the inclusion of a digital feature, please let us know. Our editorial team are able to create high-quality slide decks and infographics in-house, and video abstracts through our partner Research Square, and would be happy to assist in any way we can. For further information about digital features, please contact the journal editor (see ‘Contact the Journal’ for email address), and see the ‘Guidelines for digital features and plain language summaries’ document under ‘Submission guidelines’. For examples of digital features please visit: https://springerhealthcare.com/expertise/publishing-digital-features/ Preprints We encourage posting of preprints of primary research manuscripts on preprint servers, authors'' or institutional websites, and open communications between researchers whether on community preprint servers or preprint commenting platforms. Posting of preprints is not considered prior publication and will not jeopardize consideration in our journals. Authors should disclose details of preprint posting during the submission process or at any other point during consideration in the journal. Once the manuscript is published, it is the author''s responsibility to ensure that the preprint record is updated with a publication reference, including the DOI and a URL link to the published version of the article on the journal website. Please see here for further information on preprint sharing: https://www.springer.com/gp/authors-editors/journal-author/journal-author-helpdesk/submission/1302#c16721550 Peer Review Process Upon submission, manuscripts are assessed by the editorial team to ensure they fit within the aims and scope of the journal and are also checked for plagiarism. All suitable submissions are then subject to a comprehensive single-blind peer review. Reviewers are selected based on their relevant expertise and publication history in the subject area. The journal has an extensive pool of editorial and advisory board members who have been selected to assist with peer review based on the afore-mentioned criteria. At least two extensive reviews are required to make the editorial decision. Where reviewer recommendations are conflicted, the editorial board will be contacted for further advice and a presiding decision. Manuscripts are then either accepted, rejected or authors are required to make major or minor revisions (both reviewer comments and editorial comments may need to be addressed). Once a revised manuscript is re-submitted, it is assessed along with the responses to reviewer comments and if it has been adequately revised it will be accepted for publication. Accepted manuscripts are then copyedited and typeset by the production team before online publication. Appeals against decisions following peer review are considered on a case-by-case basis and should be sent to the journal editor, and authors are welcome to make rebuttals against individual reviewer comments if appropriate. Considering the time and effort required for a detailed peer review we reward our regular reviewers with the opportunity to publish without publication fees (pending peer review) for every three reviews completed per calendar year. Copyright Rheumatology and Therapy is published under the Creative Commons Attribution-Noncommercial License, which allows users to read, copy, distribute, and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited. The author assigns the exclusive right to any commercial use of the article to Springer. For more information about the Creative Commons Attribution-Noncommercial License, click here: http://creativecommons.org/licenses/by-nc/4.0. Publication Fees Upon acceptance of an article, authors will be required to pay the mandatory Rapid Service Fee of €5,250/$6,000/£4,300. The journal will consider fee discounts and waivers for developing countries and this is decided on a case-by-case basis. Open Access All articles published by Rheumatology and Therapy are published open access. Contact For more information about the journal, including pre-submission enquiries, please contact charlotte.maddocks@springernature.com.
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