{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T23:03:25Z","timestamp":1788476605996,"version":"build-2803163510"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T00:00:00Z","timestamp":1707436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Forty-two RRMS patients (30F\/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The \u2018no evidence of disease activity\u2019 (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug\u2019s effect on chronic macrophage and microglia activation deserves further evaluation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1343892","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T14:45:21Z","timestamp":1707489921000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis"],"prefix":"10.3389","volume":"15","author":[{"given":"Damiano","family":"Marastoni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Foschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Eccher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Crescenzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Mazziotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnese","family":"Tamanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albulena","family":"Bajrami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Camera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Ziccardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddalena","family":"Guandalini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bosello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Anni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Virla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ermanna","family":"Turano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Romoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Mariotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Benedetta","family":"Pizzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Bonetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Calabrese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000560","article-title":"Defining the clinical course of multiple sclerosis: the 2013 revisions","volume":"83","author":"Lublin","year":"2014","journal-title":"Neurology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30470-2","article-title":"Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria","volume":"17","author":"Thompson","year":"2018","journal-title":"Lancet Neurol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa251","article-title":"Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis","volume":"143","author":"Amato","year":"2020","journal-title":"Brain"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.20588","article-title":"Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis","volume":"321","author":"Brown","year":"2019","journal-title":"JAMA"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207664","article-title":"Association of very early treatment initiation with the risk of long-term disability in patients with a first demyelinating event","volume":"101","author":"Cobo-Calvo","year":"2023","journal-title":"Neurology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s41582-019-0170-8","article-title":"Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis","volume":"15","author":"Rotstein","year":"2019","journal-title":"Nat Rev Neurol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25786","article-title":"The CSF profile linked to cortical damage predicts multiple sclerosis activity","volume":"88","author":"Magliozzi","year":"2020","journal-title":"Ann Neurol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"17562864221092124","DOI":"10.1177\/17562864221092124","article-title":"CSF TNF and osteopontin levels correlate with the response to dimethyl fumarate in early multiple sclerosis","volume":"15","author":"Marastoni","year":"2022","journal-title":"Ther Adv Neurol Disord"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0902533","article-title":"A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis","volume":"362","author":"Giovannoni","year":"2010","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70023-0","article-title":"Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis","volume":"10","author":"Giovannoni","year":"2011","journal-title":"Lancet Neurol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517727603","article-title":"Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study","volume":"24","author":"Giovannoni","year":"2018","journal-title":"Mult Scler"},{"key":"B12","doi-asserted-by":"publisher","first-page":"104491","DOI":"10.1016\/j.msard.2022.104491","article-title":"Real-world experience of cladribine treatment in relapsing-remitting multiple sclerosis: A Danish nationwide study","volume":"70","author":"Sorensen","year":"2023","journal-title":"Mult Scler Relat Disord"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-023-11700-7","article-title":"Effectiveness and safety profile of cladribine in an Italian real-life cohort of relapsing-remitting multiple sclerosis patients: a monocentric longitudinal observational study","volume":"270","author":"Zanetta","year":"2023","journal-title":"J Neurol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-020-01422-9","article-title":"The development of cladribine tablets for the treatment of multiple sclerosis: A comprehensive review","volume":"80","author":"Rammohan","year":"2020","journal-title":"Drugs"},{"key":"B15","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41582-021-00498-5","article-title":"B cells in multiple sclerosis - from targeted depletion to immune reconstitution therapies","volume":"17","author":"Cencioni","year":"2021","journal-title":"Nat Rev Neurol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1756286419854986","DOI":"10.1177\/1756286419854986","article-title":"Effects of cladribine tablets on lymphocyte subsets in patients with multiple sclerosis: an extended analysis of surface markers","volume":"12","author":"Stuve","year":"2019","journal-title":"Ther Adv Neurol Disord"},{"key":"B17","article-title":"Oral cladribine in the treatment of multiple sclerosis-data from the national registry ReMuS (R) registry","volume":"84","author":"Hor\u00e1kov\u00e1","year":"2021","journal-title":"CESKA A SLOVENSKA Neurol A NEUROCHIRURGIE"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2021.118113","article-title":"Real world experience with Cladribine at S. Andrea Hospital of Rome","volume":"429","author":"Barbuti","year":"2021","journal-title":"J Neurological Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s40120-022-00364-6","article-title":"Two year relapse-free and NEDA status with Cladribine in a real life population: a multicentre study","volume":"11","author":"Annovazzi","year":"2021","journal-title":"MULTIPLE SCLEROSIS J"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s40120-022-00364-6","article-title":"Predictors of cladribine effectiveness and safety in multiple sclerosis: A real-world, multicenter, 2-year follow-up study","volume":"11","author":"Petracca","year":"2022","journal-title":"Neurol Ther"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.33.11.1444","article-title":"Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410130302","article-title":"New diagnostic criteria for multiple sclerosis: guidelines for research protocols","volume":"13","author":"Poser","year":"1983","journal-title":"Ann Neurol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517703193","article-title":"\u201cNo evident disease activity\u201d: The use of combined assessments in the management of patients with multiple sclerosis","volume":"23","author":"Giovannoni","year":"2017","journal-title":"Mult Scler"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181c47cc2","article-title":"A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking","volume":"73","author":"Teunissen","year":"2009","journal-title":"Neurology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25197","article-title":"Inflammatory intrathecal profiles and cortical damage in multiple sclerosis","volume":"83","author":"Magliozzi","year":"2018","journal-title":"Ann Neurol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31820a0cc4","article-title":"Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI","volume":"76","author":"Geurts","year":"2011","journal-title":"Neurology"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.4905","article-title":"Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis","volume":"76","author":"Harding","year":"2019","journal-title":"JAMA Neurol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30391-6","article-title":"Advances in oral immunomodulating therapies in relapsing multiple sclerosis","volume":"19","author":"Derfuss","year":"2020","journal-title":"Lancet Neurol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2018.11.021","article-title":"A multicentre, real-life study on the risk of lymphopenia and infections discloses a favourable safety profile of cladribine in ms patients","volume":"29","author":"Margoni","year":"2020","journal-title":"MULTIPLE SCLEROSIS J"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-018-0695-9","article-title":"The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis","volume":"58","author":"Hermann","year":"2019","journal-title":"Clin Pharmacokinet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1756286420970833","DOI":"10.1177\/1756286420970833","article-title":"Cerebrospinal fluid inflammatory biomarkers predicting interferon-beta response in MS patients","volume":"13","author":"Stampanoni Bassi","year":"2020","journal-title":"Ther Adv Neurol Disord"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e200050","DOI":"10.1212\/NXI.0000000000200050","article-title":"Serum levels of CXCL13 are associated with teriflunomide response in patients with multiple sclerosis","volume":"10","author":"Fissolo","year":"2023","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2016.12.006","article-title":"Chitinase 3-like 1 is associated with the response to interferon-beta treatment in multiple sclerosis","volume":"303","author":"Matute-Blanch","year":"2017","journal-title":"J neuroimmunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e921","DOI":"10.1212\/NXI.0000000000000921","article-title":"Chitinases and chitinase-like proteins as biomarkers in neurologic disorders","volume":"8","author":"Pinteac","year":"2021","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e1082","DOI":"10.1212\/NXI.0000000000001082","article-title":"CSF chitinase 3\u2013like 2 is associated with long-term disability progression in patients with progressive multiple sclerosis","volume":"8","author":"Comabella","year":"2021","journal-title":"Neurology-Neuroimmunology Neuroinflamm"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13045-017-0408-0","article-title":"Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein","volume":"10","author":"Chen","year":"2017","journal-title":"J Hematol Oncol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/s41467-017-02731-6","article-title":"Regulation of chitinase-3-like-1 in T cell elicits Th1 and cytotoxic responses to inhibit lung metastasis","volume":"9","author":"Kim","year":"2018","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1177\/13524585211010082","article-title":"CSF chitinase 3-like 1 is associated with iron rims in patients with a first demyelinating event","volume":"28","author":"Comabella","year":"2022","journal-title":"Multiple Sclerosis J"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2019.2399","article-title":"Association of chronic active multiple sclerosis lesions with disability in vivo","volume":"76","author":"Absinta","year":"2019","journal-title":"JAMA Neurol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1818-y","article-title":"Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis","volume":"135","author":"Luchetti","year":"2018","journal-title":"Acta neuropathologica"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1233546","article-title":"Molecular signature associated with cladribine treatment in patients with multiple sclerosis","volume":"14","author":"Fissolo","year":"2023","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1343892\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T14:45:24Z","timestamp":1707489924000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1343892\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,9]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2024.1343892"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1343892","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,9]]},"article-number":"1343892"}}