A 2-year multimodal prospective cohort study to predict sustained progression independent of relapse activity in multiple sclerosis
5 affiliations
- 1Research Group in Immunotherapy and Biomodels for Autoimmunity, Instituto de Investigación Sanitaria La Fe
- 2Department of Neurology, Hospital Dr. Peset
- 3Department of Neurology, Hospital Universitario Vega Baja
- 4Clinical Memory Research Unit, Department of Clinical Sciences, Lund University
- 5Division of Hematology and Oncology, Department of Medicine, Columbia Initiative in Cell Engineering and Therapy (CICET), Columbia University Irving Medical Center
Abstract
Background: Disability accrual in multiple sclerosis (MS) is heterogeneous. We assessed whether a 2-year multimodal evaluation could identify patients who were developing progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW).
Methods: Among the 81 MS patients with a 2-year follow-up and outcomes determined through 5 years, a composite for PIRA was developed using Firth’s penalized logistic regression analysis; discrimination was calculated as the area under the curve (AUC) using repeated stratified nested cross-validation.
Results: In total, 21 patients (25.9%) met the PIRA criteria, 9 (11.1%) met the RAW criteria, and 1 met both criteria. A multivariate Firth regression analysis selected two variables associated with PIRA after adjustment: Modified Fatigue Impact Scale (MFIS) total score (OR 2.04, 95% CI 1.17–3.83; p = 0.011) and cerebrospinal fluid (CSF) chitinase-3-like protein 1 (CHI3L1) (OR 2.00, 95% CI 1.11–5.26; p = 0.018). Notably, the Symbol Digit Modalities Test (ΔSDMT) showed an association in the univariate analysis (OR 0.47, 95% CI 0.23–0.82; p = 0.006) but was attenuated in the multivariate analysis [odds ratio (OR) 0.64; p = 0.141]. Oligoclonal immunoglobulin G band (OCB) positivity was universal in PIRA, but the findings are inconclusive due to sparse OCB-negative observations and incomplete OCB data. Worsening gait [ΔTimed 25-Foot Walk (ΔT25FW)] and new T2 lesions showed associations in the univariate analysis that were not retained in the multivariate analysis. None of the variables had a p -value of less than 0.10 for RAW. The median out-of-sample AUC was 0.74 (95% CI 0.68–0.78).
Conclusion: A two-year multimodal assessment identified a biologically coherent PIRA composite driven by intrathecal neuroinflammation and fatigue. No reliable RAW predictor was found, and external validation is warranted.
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BibTeX
@article{solistarazona20262year,
title = {{A 2-year multimodal prospective cohort study to predict sustained progression independent of relapse activity in multiple sclerosis}},
author = {Luis Rafael Solís-Tarazona and Salma Reddam and Ana Merchán-Cabanillas and Silvia Navarro-Quevedo and Lars Lau Raket and Sara Gil-Perotin},
journal = {Frontiers in Neurology},
year = {2026},
month = oct,
doi = {10.3389/fneur.2026.1902455},
url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1902455/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A 2-year multimodal prospective cohort study to predict sustained progression independent of relapse activity in multiple sclerosis
AU - Luis Rafael Solís-Tarazona
AU - Salma Reddam
AU - Ana Merchán-Cabanillas
AU - Silvia Navarro-Quevedo
AU - Lars Lau Raket
AU - Sara Gil-Perotin
PY - 2026
DA - 2026/10/13
JO - Frontiers in Neurology
DO - 10.3389/fneur.2026.1902455
UR - https://www.frontiersin.org/articles/10.3389/fneur.2026.1902455/full
AB - Background: Disability accrual in multiple sclerosis (MS) is heterogeneous. We assessed whether a 2-year multimodal evaluation could identify patients who were developing progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW). Methods: Among the 81 MS patients with a 2-year follow-up and outcomes determined through 5 years, a composite for PIRA was developed using Firth’s penalized logistic regression analysis; discrimination was calculated as the area under the curve (AUC) using repeated stratified nested cross-validation. Results: In total, 21 patients (25.9%) met the PIRA criteria, 9 (11.1%) met the RAW criteria, and 1 met both criteria. A multivariate Firth regression analysis selected two variables associated with PIRA after adjustment: Modified Fatigue Impact Scale (MFIS) total score (OR 2.04, 95% CI 1.17–3.83; p = 0.011) and cerebrospinal fluid (CSF) chitinase-3-like protein 1 (CHI3L1) (OR 2.00, 95% CI 1.11–5.26; p = 0.018). Notably, the Symbol Digit Modalities Test (ΔSDMT) showed an association in the univariate analysis (OR 0.47, 95% CI 0.23–0.82; p = 0.006) but was attenuated in the multivariate analysis [odds ratio (OR) 0.64; p = 0.141]. Oligoclonal immunoglobulin G band (OCB) positivity was universal in PIRA, but the findings are inconclusive due to sparse OCB-negative observations and incomplete OCB data. Worsening gait [ΔTimed 25-Foot Walk (ΔT25FW)] and new T2 lesions showed associations in the univariate analysis that were not retained in the multivariate analysis. None of the variables had a p -value of less than 0.10 for RAW. The median out-of-sample AUC was 0.74 (95% CI 0.68–0.78). Conclusion: A two-year multimodal assessment identified a biologically coherent PIRA composite driven by intrathecal neuroinflammation and fatigue. No reliable RAW predictor was found, and external validation is warranted.
SN - 1664-2295
ER -