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Article History

Received: 17 June 2025

Revised: 19 March 2026

Accepted: 4 April 2026

First Online: 2 May 2026

Compliance with ethical standards

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: The scientific guarantor of this publication is Dr. ir. Hugo Vrenken of Amsterdam UMC.

: R.M.M. has received research support from Merck. I.B. has received research support from Merck, Novartis, Teva, and the Dutch MS Research Foundation. F.B. is a steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena; Consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics; Research agreements with Merck, Biogen, GE Healthcare, Roche; Co-founder and shareholder of Queen Square Analytics LTD. H.V. has received research support from Merck, Novartis, Pfizer, and Teva, consulting fees from Merck, and speaker honoraria from Novartis; all funds were paid to his institution. F.A.G., R.A.v.S., and H.J.M.M.M. report no disclosures.

: No complex statistical methods were necessary for this paper.

: Written informed consent was obtained from all subjects (patients) in this study.

: Institutional Review Board approval was obtained.

: Some study subjects or cohorts have been previously reported in: Battaglini, M., Vrenken, H., Tappa Brocci, R., Gentile, G., Luchetti, L., Versteeg, A., Freedman, M. S., Uitdehaag, B. M. J., Kappos, L., Comi, G., Seitzinger, A., Jack, D., Sormani, M. P., Barkhof, F., & De Stefano, N. (2022); Evolution from a first clinical demyelinating event to multiple sclerosis in the REFLEX trial: Regional susceptibility in the conversion to multiple sclerosis at disease onset and its amenability to subcutaneous interferon beta-1a. European journal of neurology, 29(7), 2024–2035. ; Comi, G., De Stefano, N., Freedman, M. S., Barkhof, F., Uitdehaag, B. M. J., de Vos, M., Marhardt, K., Chen, L., Issard, D., & Kappos, L. (2017). Subcutaneous interferon β-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. Journal of neurology, neurosurgery, and psychiatry, 88(4), 285–294. ; De Stefano, N., Comi, G., Kappos, L., Freedman, M. S., Polman, C. H., Uitdehaag, B. M. J., Hennessy, B., Casset-Semanaz, F., Lehr, L., Stubinski, B., Jack, D. L., & Barkhof, F. (2014). Efficacy of subcutaneous interferon β-1a on MRI outcomes in a randomized controlled trial of patients with clinically isolated syndromes. Journal of neurology, neurosurgery, and psychiatry, 85(6), 647–653. ; Gentile, G., Mattiesing, R. M., Brouwer, I., van Schijndel, R. A., Uitdehaag, B. M. J., Twisk, J. W. R., Kappos, L., Freedman, M. S., Comi, G., Jack, D., Barkhof, F., De Stefano, N., Vrenken, H., & Battaglini, M. (2023). The spatio-temporal relationship between concurrent lesion and brain atrophy changes in early multiple sclerosis: A post-hoc analysis of the REFLEXION study. NeuroImage. Clinical, 38, 103397. ; Mattiesing, R. M., Gentile, G., Brouwer, I., van Schijndel, R. A., Uitdehaag, B. M. J., Twisk, J. W. R., Kappos, L., Freedman, M. S., Comi, G., Jack, D., De Stefano, N., Barkhof, F., Battaglini, M., & Vrenken, H. (2022). The spatio-temporal relationship between white matter lesion volume changes and brain atrophy in clinically isolated syndrome and early multiple sclerosis. NeuroImage. Clinical, 36, 103220. ; Vrenken, H., Battaglini, M., de Vos, M. L., Nagtegaal, G. J., Teixeira, B. C. A., Seitzinger, A., Jack, D., Sormani, M. P., Uitdehaag, B. M. J., Versteeg, A., Comi, G., Kappos, L., De Stefano, N., & Barkhof, F. (2023). Temporal evolution of new T1-weighted hypo-intense lesions and central brain atrophy in patients with a first clinical demyelinating event treated with subcutaneous interferon β-1a. Journal of Neurology, 270(4), 2271–2282. ; Mattiesing, R. M., Kramer, E., Strijbis, E. M., Brouwer, I., van Schijndel, R. A., Gentile, G., Battaglini, M., De Stefano, N., Uitdehaag, B. M. J., Barkhof, F., Vrenken, H., & Schoonheim, M. M. (2024). Disease progression in the first 5 years of treatment in multiple sclerosis: Predictive value of early brain and lesion volume changes. Multiple Sclerosis Journal, 30(1), 44–54. ; Mattiesing, R. M., Stel, S., Mangroe, A. S., Brouwer, I., Versteeg, A., van Schijndel, R. A., Uitdehaag, B. M. J., Barkhof, F., Vrenken, H., & Kuijer, J. P. A. (2024). Validation of a semi-automated method to quantify lesion volume changes in multiple sclerosis on 2D proton-density-weighted scans based on image subtraction. Neuroimage: Reports, 4(1), 100194.

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