The significance of early initiation of high-efficacy therapy in light of recent clinical evidence on ocrelizumab Review article
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Published:
Mar 31, 2026
Keywords:
multiple sclerosis, benign multiple sclerosis, ocrelizumab, high-efficacy therapy, PIRA
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Abstract
Early initiation of high-efficacy therapies (HETs) has emerged as a key strategy in the management of relapsing forms of multiple sclerosis (MS), aiming to limit progresion of the disease. Ocrelizumab, a humanized monoclonal antibody targeting CD20-positive B cells, has demonstrated robust efficacy across both relapsing and primary progressive multiple sclerosis phenotypes in pivotal and extension clinical trials.
This article present the impact of early treatment initiation with ocrelizumab on disease activity, disability progression, and neurodegeneration. Data from randomized controlled trials and real-world studies consistently indicate that patients treated earlier in the disease course experience lower annualized relapse rates, reduced accumulation of new or enlarging T2 lesions, and delayed confirmed disability progression compared to those receiving delayed or escalation therapy. Furthermore, early use of ocrelizumab has been associated with favourable effects on brain volume loss, suggesting a potential role in mitigating neuroaxonal damage from the earliest stages of disease. Emerging long-term extension data support the durability of these benefits, with sustained disease control and a manageable safety profile.
Current evidence underscores the clinical importance of early intervention with high-efficacy therapies such as ocrelizumab. Initiating treatment at earlier stages of multiple sclerosis may optimize long-term outcomes. These findings support a paradigm shift toward early, targeted use of high-efficacy therapies in appropriately selected patients.
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References
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13. Simonsen CS, Flemmen HØ, Broch L et al. Early High Efficacy Treatment in Multiple Sclerosis Is the Best Predictor of Future Disease Activity Over 1 and 2 Years in a Norwegian Population-Based Registry. Front Neurol. 2021; 12: 693017.
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27. Kappos L, Radue EW, Comi G et al. Ocrelizumab exposure in relapsing–remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension. J Neurol. 2023; 270(11): 5509-21.
28. Kappos L, Wolinsky JS, Giovannoni G et al. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. 2020; 77(9): 1132-40.
29. Ingwersen J, Aktas O, Kuempfel T et al. Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials. Sci Rep. 2023; 13(1): 14940.
30. Cerqueira JJ, Compston DAS, Geraldes R et al. Long-Term Treatment With Ocrelizumab in Patients With Early-Stage Relapsing MS: Nine-Year Data From the OPERA Studies Open-Label Extension. Neurology. 2025; 104(3): e210142.
31. Bermel R, Hartung HP, Brochet B et al. Low Disease Activity Over 4 Years of Ocrelizumab Therapy in Treatment-Naive Patients With Early-Stage Relapsing- Remitting Multiple Sclerosis; the Phase IIIb ENSEMBLE Study (S46.004). MS Therapeutics and Clinical Decision Making. 2023; 100(17, suppl. 2): 1928.
32. Hartung HP, Aktas O, Boyko AN et al. Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial. Neurology. 2024; 103(8): e210049.
33. Buttmann M, Brück W, Hecker M et al. CONFIDENCE treatment success: long-term real-world effectiveness and safety of ocrelizumab in Germany. Front Neurol. 2025; 16: 1564327.
34. Lanzillo R, Sparaco M, Lavorgna L et al. Prognostic Markers of Ocrelizumab Effectiveness in Multiple Sclerosis: A Real World Observational Multicenter Study. J Clin Med. 2022; 11(8): 2081.
35. Cellerino M, Cordano C, Boffa G et al. Predictors of Ocrelizumab Effectiveness in Patients with Multiple Sclerosis. Neurotherapeutics. 2021; 18(4): 2579-88.
36. Guerra T, Coppola L, Maida E et al. Long-Term Evaluation of Effectiveness and Immunological Implications of Ocrelizumab in a Real-World Cohort. Drug Saf. 2025; 48(2): 1-13.
37. Hauser SL, Kappos L, Montalban X et al. Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis. Neurology. 2021; 97(16): e1546-59.
2. Hartung HP, Meuth SG, Aktas O et al. Paradigm shifts: early initiation of high-efficacy disease-modifying treatment in multiple sclerosis. Mult Scler. 2021; 27(13): 1985-97.
3. Filippi M, Amato MP, Centonze D et al. Early use of high-efficacy disease-modifying therapies makes the difference in people with multiple sclerosis: an expert opinion. J Neurol. 2022; 269(10): 5382-94.
4. Lamb YN. Ocrelizumab: A Review in Multiple Sclerosis. Drugs. 2022; 82(3): 323-34.
5. Kułakowska A, Mirowska-Guzel D, Kalinowska A et al. Disease-modifying therapy in multiple sclerosis: recommendations of Multiple Sclerosis and Neuroimmunology Section of Polish Neurological Society. Neurol Neurochir Pol. 2024; 58(6): 569-85.
6. Freedman MS, Devonshire V, Duquette P et al. Treatment Optimization in Multiple Sclerosis: Canadian MS Working Group Recommendations. Can J Neurol Sci. 2020; 47(4): 437-55.
7. Kappos L, De Stefano N, Freedman MS et al. Inclusion of brain volume loss in a revised measure of ‚no evidence of disease activity’ (NEDA-4) in relapsing- remitting multiple sclerosis. Mult Scler. 2016; 22(10): 1297-305.
8. Bose G, Healy BC, Saxena S et al. Precision medicine in the multiple sclerosis clinic: Selecting the right patient for the right treatment. Mult Scler. 2020; 26(12): 1555-64.
9. Wijmeersch BV, Vermersch P, Hartung HP et al. Using personalized prognosis in the treatment of relapsing multiple sclerosis: A practical guide. Front Immunol. 2022; 13: 991291.
10. Morgan J, Huynh W, Barnett MH et al. The benefits and risks of escalation versus early highly effective treatment in patients with multiple sclerosis. Expert Rev Neurother. 2023; 23(6): 549-62.
11. Fernandez O. Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS? Mult Scler Relat Disord. 2017; 17: 75-83.
12. Iaffaldano P, Lucisano G, Caputo F et al. Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies. Ther Adv Neurol Disord. 2021; 14: 17562864211019574.
13. Simonsen CS, Flemmen HØ, Broch L et al. Early High Efficacy Treatment in Multiple Sclerosis Is the Best Predictor of Future Disease Activity Over 1 and 2 Years in a Norwegian Population-Based Registry. Front Neurol. 2021; 12: 693017.
14. Hawkins SA, Mcdonnell GV. Benign multiple sclerosis? Clinical course, long term follow up and assessment of prognostic factors. J Neurol Neurosurg Psychiatry. 1999; 67(2): 148-52.
15. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996; 46(4): 907-11.
16. Ramsaransing GSM, De Keyser J. Benign course in multiple sclerosis: a review. Acta Neurol Scand. 2006; 113: 359-69.
17. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33(11): 1444-52.
18. Tallantyre EC, Causon EG, Harding KE et al. How common is truly benign MS in a UK population? J Neurol Neurosurg Psychiatry. 2019; 90(5): 522-28.
19. Ellenberger D, Flachenecker P, Haas J et al. Is benign MS really benign? What a meaningful classification beyond the EDSS must take into consideration. Mult Scler Relat Disord. 2020; 46: 102485.
20. Matas E, Bau L, Romero-Pinel L et al. Benign multiple sclerosis and long-term outcomes after 30 years. J Neurol. 2025; 272(11): 747.
21. Amato MP, Prestipino E, Bellinvia A. Truly benign multiple sclerosis is rare: let’s stop fooling ourselves – Yes. Mult Scler. 2012; 18(1): 15-7.
22. Sharmin S, Leocani L, Hillert J et al. Standardized definition of progression independent of relapse activity (PIRA) in relapsingremitting multiple sclerosis. JAMA Neurol. 2025; 82(2): 1-9.
23. Cagol A, Schaedelin S, Barakovic M et al. Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis. JAMA Neurol. 2022; 79(7): 682-92.
24. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015; 14(2): 183-93.
25. Portaccio E, Bellinvia A, Fonderico M et al. Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression. J Neurol. 2024; 271(7): 4528-38.
26. Massacesi L, Tramacere I, Amoroso S et al. Relevance of Pathogenetic Mechanisms to Clinical Effectiveness of B-Cell-Depleting Monoclonal Antibodies in Multiple Sclerosis. J Clin Med. 2022; 11(15): 4288.
27. Kappos L, Radue EW, Comi G et al. Ocrelizumab exposure in relapsing–remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension. J Neurol. 2023; 270(11): 5509-21.
28. Kappos L, Wolinsky JS, Giovannoni G et al. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials. JAMA Neurol. 2020; 77(9): 1132-40.
29. Ingwersen J, Aktas O, Kuempfel T et al. Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials. Sci Rep. 2023; 13(1): 14940.
30. Cerqueira JJ, Compston DAS, Geraldes R et al. Long-Term Treatment With Ocrelizumab in Patients With Early-Stage Relapsing MS: Nine-Year Data From the OPERA Studies Open-Label Extension. Neurology. 2025; 104(3): e210142.
31. Bermel R, Hartung HP, Brochet B et al. Low Disease Activity Over 4 Years of Ocrelizumab Therapy in Treatment-Naive Patients With Early-Stage Relapsing- Remitting Multiple Sclerosis; the Phase IIIb ENSEMBLE Study (S46.004). MS Therapeutics and Clinical Decision Making. 2023; 100(17, suppl. 2): 1928.
32. Hartung HP, Aktas O, Boyko AN et al. Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial. Neurology. 2024; 103(8): e210049.
33. Buttmann M, Brück W, Hecker M et al. CONFIDENCE treatment success: long-term real-world effectiveness and safety of ocrelizumab in Germany. Front Neurol. 2025; 16: 1564327.
34. Lanzillo R, Sparaco M, Lavorgna L et al. Prognostic Markers of Ocrelizumab Effectiveness in Multiple Sclerosis: A Real World Observational Multicenter Study. J Clin Med. 2022; 11(8): 2081.
35. Cellerino M, Cordano C, Boffa G et al. Predictors of Ocrelizumab Effectiveness in Patients with Multiple Sclerosis. Neurotherapeutics. 2021; 18(4): 2579-88.
36. Guerra T, Coppola L, Maida E et al. Long-Term Evaluation of Effectiveness and Immunological Implications of Ocrelizumab in a Real-World Cohort. Drug Saf. 2025; 48(2): 1-13.
37. Hauser SL, Kappos L, Montalban X et al. Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis. Neurology. 2021; 97(16): e1546-59.