Beyond Clinical Efficacy: A Stage-Specific Comparative Framework for Evaluating Multiple Sclerosis Therapies
DOI:
https://doi.org/10.58445/rars.3985Keywords:
immunomodulation, multiple sclerosis, patient care, patient burden, clinically isolated syndrome, primary progressive multiple sclerosis, immune disease, neurodegenerationAbstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by inflammatory demyelination and progressive neurodegeneration. Because disease mechanisms evolve from early inflammatory activity to later irreversible neuronal loss, therapeutic effectiveness varies substantially across disease stages.
This review comparatively evaluated major therapeutic strategies used in clinically isolated syndrome (CIS) and primary progressive multiple sclerosis (PPMS), examining their mechanisms of action, clinical efficacy, treatment burden, and accessibility. In addition to conventional literature synthesis, treatments were evaluated using a novel Stage-Specific Ideal Treatment Proximity Score (SITPS), an exploratory composite metric integrating efficacy, evidence status, cost accessibility, administration frequency, and route of administration through disease-specific weighting to estimate each therapy's proximity to an ideal treatment profile.
Immune-targeting therapies demonstrated the greatest benefit during early disease. Interferon β-1b and glatiramer acetate reduced progression from CIS to clinically definite MS by approximately 50% and 45%, respectively, whereas ocrelizumab slowed disability progression in PPMS by approximately 24%. Potassium-channel blockade improved neurological function but did not modify disease progression. SITPS analysis further demonstrated that highly effective therapies were often associated with greater treatment burden, while lower-burden interventions generally provided less disease modification. Overall SITPS values were consistently lower for PPMS therapies than for CIS therapies, reflecting the persistent therapeutic gap in progressive disease.
These findings support a stage-specific, patient-centered approach to MS management in which treatment selection considers not only biological efficacy but also accessibility, administration burden, and quality of life. The SITPS framework provides an exploratory method for integrating these factors into comparative therapeutic evaluation and may inform future patient-centered decision-making and refinement of treatment assessment models.
References
Aljagthmi, A. A., & Abdel-Aziz, A. K. (2025). Hematopoietic stem cells: Understanding the mechanisms to unleash the therapeutic potential of hematopoietic stem cell transplantation. Stem Cell Research & Therapy, 16(1), 60. https://doi.org/10.1186/s13287-024-04126-z
Comi, G., Martinelli, V., Rodegher, M., Moiola, L., Bajenaru, O., Carra, A., Elovaara, I., Fazekas, F., Hartung, H., Hillert, J., King, J., Komoly, S., Lubetzki, C., Montalban, X., Myhr, K., Ravnborg, M., Rieckmann, P., Wynn, D., Young, C., & Filippi, M. (2009). Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): A randomized, double-blind, placebo-controlled trial. The Lancet, 374(9700), 1503–1511. https://doi.org/10.1016/S0140-6736(09)61259-9
Compston, A., & Coles, A. (2008). Multiple sclerosis. The Lancet, 372(9648), 1502–1517. https://doi.org/10.1016/S0140-6736(08)61620-7
Dendrou, C. A., Fugger, L., & Friese, M. A. (2015). Immunopathology of multiple sclerosis. Nature Reviews Immunology, 15(9), 545–558. https://doi.org/10.1038/nri3871
Franklin, R. J. M., & ffrench-Constant, C. (2017). Regenerating CNS myelin—From mechanisms to experimental medicines. Nature Reviews Neuroscience, 18(12), 753–769. https://doi.org/10.1038/nrn.2017.136
Hauser, S. L., & Cree, B. A. C. (2020). Treatment of multiple sclerosis: A review. The American Journal of Medicine, 133(12), 1380–1390.e2. https://doi.org/10.1016/j.amjmed.2020.05.049
Judge, S. I. V., & Bever, C. T. (2006). Potassium channel blockers in multiple sclerosis: Neuronal Kv channels and effects of symptomatic treatment. Pharmacology & Therapeutics, 111(1), 224–259. https://doi.org/10.1016/j.pharmthera.2005.10.006
Kappos, L., Freedman, M. S., Polman, C. H., Edan, G., Hartung, H.-P., Miller, D. H., Montalbán, X., Barkhof, F., Radü, E.-W., Metzig, C., Bauer, L., Lanius, V., Sandbrink, R., & Pohl, C. (2009). Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. The Lancet Neurology, 8(11), 987–997. https://doi.org/10.1016/S1474-4422(09)70237-6
Kappos, L., Polman, C. H., Freedman, M. S., Edan, G., Hartung, H. P., Miller, D. H., Montalban, X., Barkhof, F., Bauer, L., Jakobs, P., Pohl, C., & Sandbrink, R. (2006). Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology, 67(7), 1242–1249. https://doi.org/10.1212/01.WNL.0000237641.33768.8D
Kosa, P., Wu, T., Phillips, J., Leinonen, M., Masvekar, R., Komori, M., Wichman, A., Sandford, M., & Bielekova, B. (2020). Idebenone does not inhibit disability progression in primary progressive multiple sclerosis. Multiple Sclerosis and Related Disorders, 45, 102434. https://doi.org/10.1016/j.msard.2020.102434
Lassmann, H. (2018). Multiple sclerosis pathology. Cold Spring Harbor Perspectives in Medicine, 8(3), a028936. https://doi.org/10.1101/cshperspect.a028936
Lublin, F. D., Reingold, S. C., Cohen, J. A., Cutter, G. R., Sørensen, P. S., Thompson, A. J., Wolinsky, J. S., Balcer, L. J., Banwell, B., Barkhof, F., Bebo, B., Calabresi, P. A., Clanet, M., Comi, G., Fox, R. J., Freedman, M. S., Goodman, A. D., Inglese, M., Kappos, L., ... Polman, C. H. (2014). Defining the clinical course of multiple sclerosis. Neurology, 83(3), 278–286. https://doi.org/10.1212/WNL.0000000000000560
Montalban, X., Hauser, S. L., Kappos, L., Arnold, D. L., Bar-Or, A., Comi, G., de Seze, J., Giovannoni, G., Hartung, H.-P., Hemmer, B., Lublin, F., Rammohan, K. W., Selmaj, K., Traboulsee, A., Sauter, A., Masterman, D., Fontoura, P., Belachew, S., Garren, H., ... Wolinsky, J. S. (2017). Ocrelizumab versus placebo in primary progressive multiple sclerosis. The New England Journal of Medicine, 376(3), 209–220. https://doi.org/10.1056/NEJMoa1606468
Motl, R. W., & Pilutti, L. A. (2024). Advancements and challenges in exercise training for multiple sclerosis: Comprehensive review and future directions for randomized controlled trials. Neurology and Therapy, 13(6), 1559–1569. https://doi.org/10.1007/s40120-024-00656-z
Nave, K.-A., & Werner, H. B. (2014). Myelination of the nervous system: Mechanisms and functions. Annual Review of Cell and Developmental Biology, 30, 503–533. https://doi.org/10.1146/annurev-cellbio-100913-013101
Polman, C. H., O’Connor, P. W., Havrdova, E., Hutchinson, M., Kappos, L., Miller, D. H., Phillips, J. T., Lublin, F. D., Giovannoni, G., Wajgt, A., Toal, M., Lynn, F., Panzara, M. A., & Sandrock, A. W. (2006). A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. The New England Journal of Medicine, 354(9), 899–910. https://doi.org/10.1056/NEJMoa044397
Reich, D. S., Lucchinetti, C. F., & Calabresi, P. A. (2018). Multiple sclerosis. The New England Journal of Medicine, 378(2), 169–180. https://doi.org/10.1056/NEJMra1401483
Thompson, A. J., Banwell, B. L., Barkhof, F., Carroll, W. M., Coetzee, T., Comi, G., Correale, J., Fazekas, F., Filippi, M., Freedman, M. S., Fujihara, K., Galetta, S. L., Hartung, H. P., Kappos, L., Lublin, F. D., Marrie, R. A., Miller, A. E., Miller, D. H., Montalban, X., ... Cohen, J. A. (2018). Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology, 17(2), 162–173. https://doi.org/10.1016/S1474-4422(17)30470-2
Thouvenot, E., Laplaud, D., Lebrun-Frenay, C., Derache, N., le Page, E., Maillart, E., Froment-Tilikete, C., Castelnovo, G., Casez, O., Coustans, M., Guennoc, A.-M., Heinzlef, O., Magy, L., Nifle, C., Ayrignac, X., Fromont, A., Gaillard, N., Caucheteux, N., Patry, I., ... Durand-Dubief, F. (2025). High-dose vitamin D in clinically isolated syndrome typical of multiple sclerosis. JAMA, 333(16), 1413–1423. https://doi.org/10.1001/jama.2025.1604
Zanetta, C., Rocca, M. A., & Filippi, M. (2026). BTK inhibitors in multiple sclerosis: Emerging evidence and future directions. Expert Opinion on Pharmacotherapy, 27(2), 111–122. https://doi.org/10.1080/14656566.2026.2634204
Downloads
Posted
Categories
License
Copyright (c) 2026 Research Archive of Rising Scholars
This work is licensed under a Creative Commons Attribution 4.0 International License.
