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Understanding the compartmentalized pathophysiology of MS would enhance comprehension of disease progression mechanisms, overcoming the traditional distinction in phenotypes. Smoldering MS activity is thought to be maintained by a continuous interaction between the parenchymal chronic processes of neuroinflammation and neurodegeneration and the intrathecal compartment. This review provides a comprehensive and up-to-date overview of the neuropathological and immunological evidence related to the mechanisms underlying PIRA phenomena in MS, with a focus on studies investigating the impact of currently available therapies on these complex mechanisms.<\/jats:p>","DOI":"10.3390\/ijms26030884","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T11:47:32Z","timestamp":1737460052000},"page":"884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A Window into New Insights on Progression Independent of Relapse Activity in Multiple Sclerosis: Role of Therapies and Current Perspective"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5248-5981","authenticated-orcid":false,"given":"Tommaso","family":"Guerra","sequence":"first","affiliation":[{"name":"Department of Translational Biomedicine and Neurosciences (DiBraiN), University of Bari \u201cAldo Moro\u201d, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Iaffaldano","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neurosciences (DiBraiN), University of Bari \u201cAldo Moro\u201d, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0140-6736(23)01473-3","article-title":"Multiple sclerosis","volume":"403","author":"Jakimovski","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"278","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":"ref_3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1080\/14737175.2021.1829478","article-title":"Newly approved agents for relapsing remitting multiple sclerosis: How real-world evidence compares with randomized clinical trials?","volume":"21","author":"Comi","year":"2021","journal-title":"Expert Rev. 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