{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:24:46Z","timestamp":1787199886940,"version":"build-2736575974"},"reference-count":42,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["PNRR\u2010MCNT2\u20102023\u201012377850"],"award-info":[{"award-number":["PNRR\u2010MCNT2\u20102023\u201012377850"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007366","name":"Fondazione Italiana Sclerosi Multipla","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007366","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Progression independent of relapse activity is a major determinant of long\u2010term disability in multiple sclerosis, but its immunopathologic basis remains incompletely understood. We investigated whether relapse\u2010independent progression in radiologically stable relapsing\u2013remitting multiple sclerosis is associated with distinct cerebrospinal fluid inflammatory profiles and whether cytokine\u2010network features provide information beyond single\u2010mediator levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this prospective observational cohort study, baseline cerebrospinal fluid cytokine and chemokine profiling was performed in 346 RRMS patients, 61 primary progressive multiple sclerosis (PPMS) patients, and 196 neurological controls without inflammatory or neurodegenerative central nervous system disease. After 2\u2010year clinical and MRI follow\u2010up, 37 RRMS patients with clinical relapse and\/or MRI activity were excluded, leaving 309 relapse\u2010free and MRI\u2010stable RRMS patients classified as stable RRMS (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009241) or RRMS with PIRMA (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200968). Cytokines were analyzed using two\u2010part hurdle models, cytokine interactomes, and machine\u2010learning classifiers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Quantitative cytokine analyses distinguished multiple sclerosis from controls but showed substantial overlap across multiple sclerosis phenotypes. RRMS with PIRMA showed higher cerebrospinal fluid levels of tumor necrosis factor\u2010\u03b1, interleukin\u201017, and RANTES than stable RRMS. Network analyses showed a more integrated cytokine interactome in RRMS with PIRMA. The network\u2010level model best distinguished RRMS with PIRMA from stable RRMS, with an area under the curve of 0.86, sensitivity of 77%, and specificity of 76%.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Relapse\u2010independent progression in multiple sclerosis is associated with selective cytokine changes and broader reorganization of inflammatory network architecture, supporting cerebrospinal fluid cytokine interactome profiling as a translational approach to immune stratification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70502","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T03:52:24Z","timestamp":1787197944000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>CSF<\/scp>\n                    Cytokine Network Organization Predicts Progression Independent of Relapse and\n                    <scp>MRI<\/scp>\n                    Activity in Multiple Sclerosis"],"prefix":"10.1002","author":[{"given":"Antonio","family":"Bruno","sequence":"first","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2879-2209","authenticated-orcid":false,"given":"Matteo","family":"Conti","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome Tor Vergata  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Dolcetti","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Azzolini","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Borrelli","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Fantozzi","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Stampanoni Bassi","sequence":"additional","affiliation":[{"name":"Faculty of Psychology Uninettuno Telematic International University  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Galifi","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"},{"name":"Department of Systems Medicine University of Rome Tor Vergata  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Maccarrone","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome Tor Vergata  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Montaguti","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome Tor Vergata  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Cervigni","sequence":"additional","affiliation":[{"name":"Clinica Neurologica, Azienda Ospedaliero Universitaria Delle Marche Universit\u00e0 Politecnica Delle Marche  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddalena Dal","family":"Pozzo","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome Tor Vergata  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7376-9425","authenticated-orcid":false,"given":"Roberto","family":"Furlan","sequence":"additional","affiliation":[{"name":"Clinical Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Finardi","sequence":"additional","affiliation":[{"name":"Clinical Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girolama Alessandra","family":"Marfia","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome Tor Vergata  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Salvetti","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"},{"name":"Department of Human Neurosciences Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6338-2961","authenticated-orcid":false,"given":"Antonella","family":"Conte","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"},{"name":"Department of Human Neurosciences Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Buttari","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed  Pozzilli (IS) Italy"},{"name":"Department of Systems Medicine University of Rome Tor Vergata  Rome 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