{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T05:32:37Z","timestamp":1793424757811,"version":"4.5.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Rheumatol"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, partly driven by chronic systemic inflammation. Neutrophil extracellular traps (NETs) have emerged as important mechanistic links between sustained immune activation and early vascular injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To evaluate changes in NET-associated activity following initiation of biologic therapy in patients with RA and to investigate the relationship between treatment- associated changes in NETs, lipid profile, and subclinical atherosclerosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this prospective single-arm observational study, 36 patients with RA initiating biologic therapy were evaluated at baseline and after 6 months of treatment. Disease activity was assessed using DAS28-CRP, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Circulating citrullinated histone H3 (CitH3) levels were measured by ELISA as a robust marker of NETs. Carotid intima-media thickness (cIMT) was assessed using high-resolution B-mode ultrasonography. Linear regression analyses were performed to investigate the relationship between NETs activity, inflammatory burden, lipid profile, and subclinical atherosclerosis, both cross-sectionally and longitudinally following biologic therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Following initiation of biologic therapy, disease activity and inflammatory markers improved significantly. Circulating CitH3 levels decreased from a median 3.89 (0.11\u201332.78) to 2.56 (0.07\u20138.39;\n                      <jats:italic>p<\/jats:italic>\n                      -value 0.025) while cIMT decreased from a median 1 (0.7\u20131.6) mm to 0.75 (0.6\u20131.3 mm;\n                      <jats:italic>p<\/jats:italic>\n                      -value\u2009&lt;\u20090.001) after 6 months of treatment. HDL cholesterol increased significantly from 56.36\u2009\u00b1\u200916.21 to 67.47\u2009\u00b1\u200917.56 mg\/dL (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). At follow-up, CitH3 levels were independently associated with ESR (\u03b2\u2009=\u20090.448,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.018), indicating a relationship between NETs and systemic inflammatory burden. Longitudinal analyses demonstrated that changes in HDL cholesterol were independently associated with changes in CitH3 (\u03b2\u2009=\u2009\u2009\u2212\u20090.505,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003), whereas changes in DAS28, CRP, ESR, oxLDL, and cIMT were not independently associated with \u0394CitH3. No significant differences in \u0394CitH3 were observed between anti-TNF and non-anti-TNF therapies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In this prospective observational cohort, initiation of biologic therapy was associated with reduced circulating CitH3 levels, alongside improvements in disease activity, inflammatory markers, HDL cholesterol, and cIMT. The longitudinal association between increases in HDL cholesterol and reductions in CitH3 was independent of changes in disease activity and cIMT, generating a hypothesis regarding a potential immunometabolic relationship between HDL cholesterol and NET-associated activity. These findings should be considered exploratory and require confirmation in larger, controlled prospective studies.\n                      <jats:table-wrap>\n                        <jats:table>\n                          <jats:tbody>\n                            <jats:tr>\n                              <jats:td align=\"left\" colspan=\"2\">\n                                <jats:bold>Key Points<\/jats:bold>\n                                \u2022\n                                <jats:italic>Biologic therapy was associated with a significant reduction in circulating CitH3 levels, consistent with reduced NET-associated activity in patients with RA.<\/jats:italic>\n                                \u2022\n                                <jats:italic>Changes in HDL cholesterol independently predict changes in NETs, suggesting a possible HDL\u2013NETs immunometabolic axis in RA patients under biologic treatment.<\/jats:italic>\n                                \u2022\n                                <jats:italic>Concurrent improvement in NETs and subclinical atherosclerosis supports a potential role for NETs in RA-associated cardiovascular risk.<\/jats:italic>\n                                \u2022\n                                <jats:italic>Similar reductions in CitH3 were observed across biologic treatment classes; however, the small and unequal subgroup sizes limit the ability to draw conclusions regarding class-specific effects.<\/jats:italic>\n                              <\/jats:td>\n                            <\/jats:tr>\n                          <\/jats:tbody>\n                        <\/jats:table>\n                      <\/jats:table-wrap>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10067-026-08454-8","type":"journal-article","created":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T07:11:43Z","timestamp":1791011503000},"page":"6573-6581","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neutrophil extracellular trap suppression in rheumatoid arthritis patients treated with biologic therapy: a prospective observational study"],"prefix":"10.1007","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5297-1705","authenticated-orcid":false,"given":"Georgios V.","family":"Papamichail","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0325-6146","authenticated-orcid":false,"given":"Akrivi","family":"Chrysanthopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8099-0105","authenticated-orcid":false,"given":"Nikolaos A.","family":"Georgiadis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9263-4771","authenticated-orcid":false,"given":"Christina A.","family":"Kapsali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1475-9021","authenticated-orcid":false,"given":"Vasileios G.","family":"Xydis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8330-9000","authenticated-orcid":false,"given":"Athanasios","family":"Kitsakos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2232-0326","authenticated-orcid":false,"given":"Alexandros A.","family":"Drosos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5193-2284","authenticated-orcid":false,"given":"Paraskevi V.","family":"Voulgari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"key":"8454_CR1","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","volume":"388","author":"JS Smolen","year":"2016","unstructured":"Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. 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The study protocol was approved by the Institutional Ethics Committee of the University Hospital of Ioannina (Approval No. 6\/11\u201303-2025).","order":1,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"No part of the manuscript has been copied from previously published material or published elsewhere, and all relevant sources have been appropriately acknowledged and cited. During the preparation and revision of the manuscript, ChatGPT (OpenAI) was used solely as an editorial and language-support tool to assist with wording, clarity, and readability. It was not used for data collection, statistical analysis, generation or interpretation of results, or formulation of the study conclusions.","order":2,"name":"Ethics","label":"Disclaimer","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"Written informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":4,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"All authors meet the four ICMJE authorship criteria, contributed substantially to the work, approved the final version of the manuscript, and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.","order":5,"name":"Ethics","label":"Authorship statement","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}}]}}