Ocrelizumab Reduces Thalamic Volume Loss in Patients with RMS and PPMS

Overview

Journal Mult Scler

Publisher Sage Publications

Specialty Neurology

Date 2022 Jun 8

PMID 35672926

Authors

Douglas L Arnold

Till Sprenger

Amit Bar-Or

Jerry S Wolinsky

Ludwig Kappos

Shannon Kolind

Ulrike Bonati

Stefano Magon

Johan van Beek

Harold Koendgen

Oscar Bortolami

Corrado Bernasconi

Laura Gaetano

Anthony Traboulsee

Affiliations

Soon will be listed here.

Abstract

Background: In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic neuronal projections.

Objective: To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNβ1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570).

Methods: Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model.

Results: Over the double-blind period, ocrelizumab treatment significantly reduced thalamic volume loss with the largest effect size (Cohen's : RMS: 0.561 at week 96; PPMS: 0.427 at week 120) compared with whole brain, cortical gray matter, and white matter volume loss. At the end of up to 7 years of follow-up, patients initially randomized to ocrelizumab still showed less thalamic volume loss than those switching from IFNβ1a ( < 0.001) or placebo ( < 0.001).

Conclusion: Ocrelizumab effectively reduced thalamic volume loss compared with IFNβ1a/placebo. Early treatment effects on thalamic tissue preservation persisted over time. Thalamic volume loss could be a potential sensitive marker of persisting tissue damage.

Citing Articles

The effect of ibudilast on thalamic volume in progressive multiple sclerosis.

Nicholson S, Russo A, Brewer K, Bien H, Tobyne S, Eloyan A Mult Scler. 2023; 29(14):1819-1830.

PMID: 37947294 PMC: 10841081. DOI: 10.1177/13524585231204710.

Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis.

Nakamura K, Zheng Y, Mahajan K, Cohen J, Fox R, Ontaneda D Mult Scler. 2023; 29(10):1257-1265.

PMID: 37537928 PMC: 11130979. DOI: 10.1177/13524585231187289.

Deviation From Normative Whole Brain and Deep Gray Matter Growth in Children With MOGAD, MS, and Monophasic Seronegative Demyelination.

Fadda G, Cardenas de La Parra A, OMahony J, Waters P, Yeh E, Bar-Or A Neurology. 2023; 101(4):e425-e437.

PMID: 37258297 PMC: 10435061. DOI: 10.1212/WNL.0000000000207429.

References

Kipp M, Wagenknecht N, Beyer C, Samer S, Wuerfel J, Nikoubashman O . Thalamus pathology in multiple sclerosis: from biology to clinical application. Cell Mol Life Sci. 2014; 72(6):1127-47. PMC: 11113280. DOI: 10.1007/s00018-014-1787-9. View

Azevedo C, Cen S, Khadka S, Liu S, Kornak J, Shi Y . Thalamic atrophy in multiple sclerosis: A magnetic resonance imaging marker of neurodegeneration throughout disease. Ann Neurol. 2018; 83(2):223-234. PMC: 6317847. DOI: 10.1002/ana.25150. View

Polman C, Reingold S, Edan G, Filippi M, Hartung H, Kappos L . Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005; 58(6):840-6. DOI: 10.1002/ana.20703. View

Vercellino M, Plano F, Votta B, Mutani R, Giordana M, Cavalla P . Grey matter pathology in multiple sclerosis. J Neuropathol Exp Neurol. 2005; 64(12):1101-7. DOI: 10.1097/01.jnen.0000190067.20935.42. View

Henry R, Shieh M, Amirbekian B, Chung S, Okuda D, Pelletier D . Connecting white matter injury and thalamic atrophy in clinically isolated syndromes. J Neurol Sci. 2009; 282(1-2):61-6. DOI: 10.1016/j.jns.2009.02.379. View

Gaetano L, Haring D, Radue E, Mueller-Lenke N, Thakur A, Tomic D . Fingolimod effect on gray matter, thalamus, and white matter in patients with multiple sclerosis. Neurology. 2018; 90(15):e1324-e1332. DOI: 10.1212/WNL.0000000000005292. View

Sotirchos E, Gonzalez-Caldito N, Dewey B, Fitzgerald K, Glaister J, Filippatou A . Effect of disease-modifying therapies on subcortical gray matter atrophy in multiple sclerosis. Mult Scler. 2019; 26(3):312-321. PMC: 6689465. DOI: 10.1177/1352458519826364. View

Hauser S, Bar-Or A, Comi G, Giovannoni G, Hartung H, Hemmer B . Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2016; 376(3):221-234. DOI: 10.1056/NEJMoa1601277. View

Nakamura K, Guizard N, Fonov V, Narayanan S, Collins D, Arnold D . Jacobian integration method increases the statistical power to measure gray matter atrophy in multiple sclerosis. Neuroimage Clin. 2013; 4:10-7. PMC: 3830061. DOI: 10.1016/j.nicl.2013.10.015. View

10.

Rudick R, Fisher E, Lee J, Simon J, Jacobs L . Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 1999; 53(8):1698-704. DOI: 10.1212/wnl.53.8.1698. View

11.

Mahajan K, Nakamura K, Cohen J, Trapp B, Ontaneda D . Intrinsic and Extrinsic Mechanisms of Thalamic Pathology in Multiple Sclerosis. Ann Neurol. 2020; 88(1):81-92. PMC: 8291218. DOI: 10.1002/ana.25743. View

12.

Trapp B, Peterson J, Ransohoff R, Rudick R, Mork S, Bo L . Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998; 338(5):278-85. DOI: 10.1056/NEJM199801293380502. View

13.

Wolinsky J, Arnold D, Brochet B, Hartung H, Montalban X, Naismith R . Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2020; 19(12):998-1009. DOI: 10.1016/S1474-4422(20)30342-2. View

14.

Magon S, Chakravarty M, Amann M, Weier K, Naegelin Y, Andelova M . Label-fusion-segmentation and deformation-based shape analysis of deep gray matter in multiple sclerosis: the impact of thalamic subnuclei on disability. Hum Brain Mapp. 2014; 35(8):4193-203. PMC: 6869820. DOI: 10.1002/hbm.22470. View

15.

Azevedo C, Overton E, Khadka S, Buckley J, Liu S, Sampat M . Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflamm. 2015; 2(3):e102. PMC: 4396526. DOI: 10.1212/NXI.0000000000000102. View

16.

Borges I, Shea C, Ohayon J, Jones B, Stone R, Ostuni J . The effect of daclizumab on brain atrophy in relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2013; 2(2):133-140. PMC: 3619446. DOI: 10.1016/j.msard.2012.10.002. View

17.

Polman C, Reingold S, Banwell B, Clanet M, Cohen J, Filippi M . Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69(2):292-302. PMC: 3084507. DOI: 10.1002/ana.22366. View

18.

Hauser S, Kappos L, Arnold D, Bar-Or A, Brochet B, Naismith R . Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology. 2020; 95(13):e1854-e1867. PMC: 7682822. DOI: 10.1212/WNL.0000000000010376. View

19.

Filippi M, Rocca M, Pagani E, De Stefano N, Jeffery D, Kappos L . Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry. 2013; 85(8):851-8. DOI: 10.1136/jnnp-2013-306132. View

20.

Houtchens M, Benedict R, Killiany R, Sharma J, Jaisani Z, Singh B . Thalamic atrophy and cognition in multiple sclerosis. Neurology. 2007; 69(12):1213-23. DOI: 10.1212/01.wnl.0000276992.17011.b5. View