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While comorbidities are common in MS and linked to disability progression, their role in PIRA remains unclear. We investigated whether comorbidities at treatment initiation could predict PIRA in RRMS patients receiving B\u2010cell depleting therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This population\u2010based cohort study included RRMS patients initiating rituximab between August 2010 and April 2019, without relapses during six\u2010year follow\u2010up. PIRA was defined as confirmed disability worsening (Expanded Disability Status Scale). We performed hypothesis\u2010driven analysis of pre\u2010specified comorbidities and data\u2010driven analysis of all ICD\u201010 codes from secondary care. Comorbidity\u2010PIRA associations were assessed using adjusted logistic regression. Predictive performance for elastic net, random forest, XGBoost, and neural networks was evaluated as the area under the curve (AUC) and Brier score through nested cross\u2010validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 2837 patients, 563 (20%) experienced PIRA within 6\u2009years. The most prevalent comorbidities were depression\/anxiety (36%), hypertension (15%), and headache (8%). No pre\u2010specified comorbidities were statistically significant predictors of PIRA. Among all diagnosis codes, only neuromuscular bladder dysfunction reached significance after multiple comparison correction. Predictive models demonstrated modest performance (AUC 0.563\u20130.652) and adding comorbidities did not improve prediction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this rituximab\u2010treated RRMS cohort, comorbidities at therapy start were not associated with higher PIRA risk when accounting for MS\u2010associated disability. The association with bladder dysfunction likely reflects spinal tract engagement rather than an independent comorbidity effect.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ene.70656","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:17:16Z","timestamp":1780377436000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comorbidities for Predicting Progression Independent of Relapse Activity in Multiple Sclerosis Treated With B\u2010Cell Depletion"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4710-6326","authenticated-orcid":false,"given":"Peter","family":"Alping","sequence":"first","affiliation":[{"name":"Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet  Stockholm 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