Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis

Izanne Roos; Stella Hughes; Gavin McDonnell; Charles B Malpas; Sifat Sharmin; Cavit Boz; Raed Alroughani; Serkan Ozakbas; Katherine Buzzard; Olga Skibina; Anneke van der Walt; Helmut Butzkueven; Jeannette Lechner-Scott; Jens Kuhle; Murat Terzi; Guy Laureys; Liesbeth Van Hijfte; Nevin John; Pierre Grammond; Francois Grand'Maison; Aysun Soysal; Ana Voldsgaard Jensen; Peter Vestergaard Rasmussen; Kristina Bacher Svendsen; Ismael Barzinji; Helle Hvilsted Nielsen; Tobias Sejbæk; Sivagini Prakash; Morten Leif Munding Stilund; Arkadiusz Weglewski; Nadia Mubder Issa; Matthias Kant; Finn Sellebjerg; Orla Gray; Melinda Magyari; Tomas Kalincik; MSBase Study GroupDanish MS Registry Study Group

doi:10.1001/jamaneurol.2023.1625

Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis

Izanne Roos, Stella Hughes, Gavin McDonnell, Charles B Malpas, Sifat Sharmin, Cavit Boz, Raed Alroughani, Serkan Ozakbas, Katherine Buzzard, Olga Skibina, Anneke van der Walt, Helmut Butzkueven, Jeannette Lechner-Scott, Jens Kuhle, Murat Terzi, Guy Laureys, Liesbeth Van Hijfte, Nevin John, Pierre Grammond, Francois Grand'MaisonAysun Soysal, Ana Voldsgaard Jensen, Peter Vestergaard Rasmussen, Kristina Bacher Svendsen, Ismael Barzinji, Helle Hvilsted Nielsen, Tobias Sejbæk, Sivagini Prakash, Morten Leif Munding Stilund, Arkadiusz Weglewski, Nadia Mubder Issa, Matthias Kant, Finn Sellebjerg, Orla Gray, Melinda Magyari, Tomas Kalincik, MSBase Study GroupDanish MS Registry Study Group

Abstract

IMPORTANCE: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab.

OBJECTIVE: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS.

DESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country.

EXPOSURE: Treatment with ocrelizumab or rituximab after 2015.

MAIN OUTCOMES AND MEASURES: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups.

RESULTS: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses.

CONCLUSION: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.

Original language	English
Journal	JAMA Neurology
Volume	80
Issue number	8
Pages (from-to)	789-797
Number of pages	9
ISSN	2168-6149
DOIs	https://doi.org/10.1001/jamaneurol.2023.1625
Publication status	Published - 1 Aug 2023

Keywords

Cohort Studies
Female
Humans
Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging
Multiple Sclerosis/drug therapy
Neoplasm Recurrence, Local
Rituximab/therapeutic use

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10.1001/jamaneurol.2023.1625

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Roos, I., Hughes, S., McDonnell, G., Malpas, C. B., Sharmin, S., Boz, C., Alroughani, R., Ozakbas, S., Buzzard, K., Skibina, O., van der Walt, A., Butzkueven, H., Lechner-Scott, J., Kuhle, J., Terzi, M., Laureys, G., Van Hijfte, L., John, N., Grammond, P., ... MSBase Study GroupDanish MS Registry Study Group (2023). Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis. JAMA Neurology, 80(8), 789-797. https://doi.org/10.1001/jamaneurol.2023.1625

Roos, I, Hughes, S, McDonnell, G, Malpas, CB, Sharmin, S, Boz, C, Alroughani, R, Ozakbas, S, Buzzard, K, Skibina, O, van der Walt, A, Butzkueven, H, Lechner-Scott, J, Kuhle, J, Terzi, M, Laureys, G, Van Hijfte, L, John, N, Grammond, P, Grand'Maison, F, Soysal, A, Jensen, AV, Rasmussen, PV, Svendsen, KB, Barzinji, I, Nielsen, HH, Sejbæk, T, Prakash, S, Stilund, MLM, Weglewski, A , Issa, NM, Kant, M, Sellebjerg, F, Gray, O, Magyari, M, Kalincik, T & MSBase Study GroupDanish MS Registry Study Group 2023, 'Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis', JAMA Neurology, vol. 80, no. 8, pp. 789-797. https://doi.org/10.1001/jamaneurol.2023.1625

@article{18518d67358e4f4c94df6e6810886a0e,

title = "Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis",

abstract = "IMPORTANCE: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab.OBJECTIVE: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS.DESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country.EXPOSURE: Treatment with ocrelizumab or rituximab after 2015.MAIN OUTCOMES AND MEASURES: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups.RESULTS: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses.CONCLUSION: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.",

keywords = "Cohort Studies, Female, Humans, Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging, Multiple Sclerosis/drug therapy, Neoplasm Recurrence, Local, Rituximab/therapeutic use",

author = "Izanne Roos and Stella Hughes and Gavin McDonnell and Malpas, {Charles B} and Sifat Sharmin and Cavit Boz and Raed Alroughani and Serkan Ozakbas and Katherine Buzzard and Olga Skibina and {van der Walt}, Anneke and Helmut Butzkueven and Jeannette Lechner-Scott and Jens Kuhle and Murat Terzi and Guy Laureys and {Van Hijfte}, Liesbeth and Nevin John and Pierre Grammond and Francois Grand'Maison and Aysun Soysal and Jensen, {Ana Voldsgaard} and Rasmussen, {Peter Vestergaard} and Svendsen, {Kristina Bacher} and Ismael Barzinji and Nielsen, {Helle Hvilsted} and Tobias Sejb{\ae}k and Sivagini Prakash and Stilund, {Morten Leif Munding} and Arkadiusz Weglewski and Issa, {Nadia Mubder} and Matthias Kant and Finn Sellebjerg and Orla Gray and Melinda Magyari and Tomas Kalincik and {MSBase Study GroupDanish MS Registry Study Group}",

year = "2023",

month = aug,

day = "1",

doi = "10.1001/jamaneurol.2023.1625",

language = "English",

volume = "80",

pages = "789--797",

journal = "JAMA Neurology",

issn = "2168-6149",

publisher = "American Medical Association",

number = "8",

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TY - JOUR

T1 - Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis

AU - Roos, Izanne

AU - Hughes, Stella

AU - McDonnell, Gavin

AU - Malpas, Charles B

AU - Sharmin, Sifat

AU - Boz, Cavit

AU - Alroughani, Raed

AU - Ozakbas, Serkan

AU - Buzzard, Katherine

AU - Skibina, Olga

AU - van der Walt, Anneke

AU - Butzkueven, Helmut

AU - Lechner-Scott, Jeannette

AU - Kuhle, Jens

AU - Terzi, Murat

AU - Laureys, Guy

AU - Van Hijfte, Liesbeth

AU - John, Nevin

AU - Grammond, Pierre

AU - Grand'Maison, Francois

AU - Soysal, Aysun

AU - Jensen, Ana Voldsgaard

AU - Rasmussen, Peter Vestergaard

AU - Svendsen, Kristina Bacher

AU - Barzinji, Ismael

AU - Nielsen, Helle Hvilsted

AU - Sejbæk, Tobias

AU - Prakash, Sivagini

AU - Stilund, Morten Leif Munding

AU - Weglewski, Arkadiusz

AU - Issa, Nadia Mubder

AU - Kant, Matthias

AU - Sellebjerg, Finn

AU - Gray, Orla

AU - Magyari, Melinda

AU - Kalincik, Tomas

AU - MSBase Study GroupDanish MS Registry Study Group

PY - 2023/8/1

Y1 - 2023/8/1

N2 - IMPORTANCE: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab.OBJECTIVE: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS.DESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country.EXPOSURE: Treatment with ocrelizumab or rituximab after 2015.MAIN OUTCOMES AND MEASURES: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups.RESULTS: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses.CONCLUSION: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.

AB - IMPORTANCE: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab.OBJECTIVE: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS.DESIGN, SETTING, AND PARTICIPANTS: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country.EXPOSURE: Treatment with ocrelizumab or rituximab after 2015.MAIN OUTCOMES AND MEASURES: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups.RESULTS: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses.CONCLUSION: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.

KW - Cohort Studies

KW - Female

KW - Humans

KW - Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging

KW - Multiple Sclerosis/drug therapy

KW - Neoplasm Recurrence, Local

KW - Rituximab/therapeutic use

UR - http://www.scopus.com/inward/record.url?scp=85168221913&partnerID=8YFLogxK

U2 - 10.1001/jamaneurol.2023.1625

DO - 10.1001/jamaneurol.2023.1625

M3 - Journal article

C2 - 37307006

SN - 2168-6149

VL - 80

SP - 789

EP - 797

JO - JAMA Neurology

JF - JAMA Neurology

IS - 8

ER -

Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis

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