{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:07:31Z","timestamp":1784095651644,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T00:00:00Z","timestamp":1783814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Progression independent of relapse activity (PIRA) and smouldering multiple sclerosis (MS) represent major unmet challenges in contemporary MS care. Disability may accumulate independently of clinical relapses, driven in part by chronic compartmentalised inflammation behind a relatively intact blood\u2013brain barrier and incompletely captured by conventional monitoring tools. This narrative review synthesises evidence across four complementary biomarker domains for detecting smouldering MS and PIRA: advanced MRI (paramagnetic rim lesions [PRLs], slowly expanding lesions, deep grey matter atrophy, quantitative susceptibility mapping); fluid biomarkers (serum glial fibrillary acidic protein [sGFAP], serum neurofilament light chain [sNfL]); retinal optical coherence tomography (ganglion cell\u2013inner plexiform layer thinning); and digital health metrics (wearable accelerometry, digital Symbol Digit Modalities Test). In a single prospective cohort, combined elevation of sGFAP and sNfL conferred a 4.71-fold increased hazard for PIRA (HR 4.71; 95% CI 2.05\u20139.77); independent data suggest sGFAP may carry selectivity for progression beyond sNfL, although this remains to be confirmed. No single domain sufficiently characterises smouldering pathology. We therefore propose a hypothesis-generating Multimodal PIRA Score (MPS) as a conceptual validation scaffold intended to structure\u2014rather than inform\u2014prospective multicentre evaluation against a long-horizon disability endpoint. Harmonisation of acquisition protocols, reference ranges, and digital phenotyping algorithms remains a prerequisite.<\/jats:p>","DOI":"10.3390\/brainsci16070735","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T09:51:09Z","timestamp":1783936269000},"page":"735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Relapses: A Multimodal Biomarker Framework for Progression Independent of Relapse Activity and Smouldering Multiple Sclerosis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4297-7111","authenticated-orcid":false,"given":"Nayeli Alejandra","family":"S\u00e1nchez-Rosales","sequence":"first","affiliation":[{"name":"Departamento de Neurolog\u00eda, Unidad de Alta Especialidad M\u00e9dica (UMAE), Centro M\u00e9dico Nacional de Occidente (CMNO), Instituto Mexicano Del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0936-7525","authenticated-orcid":false,"given":"Edgar Ricardo","family":"Valdivia-Tangarife","sequence":"additional","affiliation":[{"name":"Departamento de Neurociencias, Centro Universitario de Ciencias de La Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2233-571X","authenticated-orcid":false,"given":"Blanca Miriam","family":"Torres-Mendoza","sequence":"additional","affiliation":[{"name":"Departamento de Disciplinas Filos\u00f3ficas, Metodol\u00f3gicas e Instrumentales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Divisi\u00f3n de Neurociencias, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Instituto Mexicano Del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5540-1923","authenticated-orcid":false,"given":"Antonio","family":"Kobayashi-Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Neurociencias, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Instituto Mexicano Del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico"},{"name":"Departamento de Medicina Interna, Unidad de Alta Especialidad M\u00e9dica (UMAE), Centro M\u00e9dico Nacional de Occidente (CMNO), Instituto Mexicano Del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Javier","family":"Fr\u00edas-M\u00e1rquez","sequence":"additional","affiliation":[{"name":"Departamento de Neurolog\u00eda, Unidad de Alta Especialidad M\u00e9dica (UMAE), Centro M\u00e9dico Nacional de Occidente (CMNO), Instituto Mexicano Del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betsabe","family":"Contreras-Haro","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Centro Universitario Tonal\u00e1, Universidad de Guadalajara, Tonal\u00e1 45425, Jalisco, Mexico"},{"name":"Unidad de Investigaci\u00f3n Biom\u00e9dica 02, Instituto Mexicano Del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4757-4792","authenticated-orcid":false,"given":"Martha Roc\u00edo","family":"Hern\u00e1ndez-Preciado","sequence":"additional","affiliation":[{"name":"Departamento de Disciplinas Filos\u00f3ficas, Metodol\u00f3gicas e Instrumentales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Unidad M\u00e9dica de Alta Especialidad, Hospital Pedi\u00e1trico, Centro 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