Sustained Low Relapse Rate With Highly Variable B-Cell Repopulation Dynamics With Extended Rituximab Dosing Intervals in Multiple Sclerosis.
Journal
Neurology(R) neuroimmunology & neuroinflammation
ISSN: 2332-7812
Titre abrégé: Neurol Neuroimmunol Neuroinflamm
Pays: United States
ID NLM: 101636388
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
10
05
2022
accepted:
16
09
2022
entrez:
21
11
2022
pubmed:
22
11
2022
medline:
24
11
2022
Statut:
epublish
Résumé
B cell-depleting therapies are highly effective in relapsing-remitting multiple sclerosis (RRMS) but are associated with increased infection risk and blunted humoral vaccination responses. Extension of dosing intervals may mitigate such negative effects, but its consequences on MS disease activity are yet to be ascertained. The objective of this study was to determine clinical and neuroradiologic disease activity, as well as B-cell repopulation dynamics, after implementation of extended rituximab dosing in RRMS. We conducted a prospective observational study in a specialized-care, single-center setting, including patients with RRMS participating in the COMBAT-MS and MultipleMS observational drug trials, who had received at least 2 courses of rituximab (median follow-up 4.2 years, range 0.1-8.9 years). Using Cox regression, hazard ratios (HRs) of clinical relapse and/or contrast-enhancing lesions on MRI were calculated in relation to time since last dose of rituximab. A total of 3,904 dose intervals were accumulated in 718 patients and stratified into 4 intervals: <8, ≥8 to 12, ≥12 to 18, and ≥18 months. We identified 24 relapses of which 20 occurred within 8 months since previous infusion and 4 with intervals over 8 months. HRs for relapse when comparing ≥8 to 12, ≥12 to 18, and ≥18 months with <8 months since last dose were 0.28 (95% CI 0.04-2.10), 0.38 (95% CI 0.05-2.94), and 0.89 (95% CI 0.20-4.04), respectively, and thus nonsignificant. Neuroradiologic outcomes mirrored relapse rates. Dynamics of total B-cell reconstitution varied considerably, but median total B-cell counts reached lower level of normal after 12 months and median memory B-cell counts after 16 months. In this prospective cohort of rituximab-treated patients with RRMS exposed to extended dosing intervals, we could not detect a relation between clinical or neuroradiologic disease activity and time since last infusion. Total B- and memory B-cell repopulation kinetics varied considerably. These findings, relevant for assessing risk-mitigation strategies with anti-CD20 therapies in RRMS, suggest that relapse risk remains low with extended infusion intervals. Further studies are needed to investigate the relation between B-cell repopulation dynamics and adverse event risks associated with B-cell depletion.
Sections du résumé
BACKGROUND AND OBJECTIVES
B cell-depleting therapies are highly effective in relapsing-remitting multiple sclerosis (RRMS) but are associated with increased infection risk and blunted humoral vaccination responses. Extension of dosing intervals may mitigate such negative effects, but its consequences on MS disease activity are yet to be ascertained. The objective of this study was to determine clinical and neuroradiologic disease activity, as well as B-cell repopulation dynamics, after implementation of extended rituximab dosing in RRMS.
METHODS
We conducted a prospective observational study in a specialized-care, single-center setting, including patients with RRMS participating in the COMBAT-MS and MultipleMS observational drug trials, who had received at least 2 courses of rituximab (median follow-up 4.2 years, range 0.1-8.9 years). Using Cox regression, hazard ratios (HRs) of clinical relapse and/or contrast-enhancing lesions on MRI were calculated in relation to time since last dose of rituximab.
RESULTS
A total of 3,904 dose intervals were accumulated in 718 patients and stratified into 4 intervals: <8, ≥8 to 12, ≥12 to 18, and ≥18 months. We identified 24 relapses of which 20 occurred within 8 months since previous infusion and 4 with intervals over 8 months. HRs for relapse when comparing ≥8 to 12, ≥12 to 18, and ≥18 months with <8 months since last dose were 0.28 (95% CI 0.04-2.10), 0.38 (95% CI 0.05-2.94), and 0.89 (95% CI 0.20-4.04), respectively, and thus nonsignificant. Neuroradiologic outcomes mirrored relapse rates. Dynamics of total B-cell reconstitution varied considerably, but median total B-cell counts reached lower level of normal after 12 months and median memory B-cell counts after 16 months.
DISCUSSION
In this prospective cohort of rituximab-treated patients with RRMS exposed to extended dosing intervals, we could not detect a relation between clinical or neuroradiologic disease activity and time since last infusion. Total B- and memory B-cell repopulation kinetics varied considerably. These findings, relevant for assessing risk-mitigation strategies with anti-CD20 therapies in RRMS, suggest that relapse risk remains low with extended infusion intervals. Further studies are needed to investigate the relation between B-cell repopulation dynamics and adverse event risks associated with B-cell depletion.
Identifiants
pubmed: 36411076
pii: 10/1/e200056
doi: 10.1212/NXI.0000000000200056
pmc: PMC9749930
pii:
doi:
Substances chimiques
Rituximab
4F4X42SYQ6
Immunologic Factors
0
Types de publication
Observational Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Références
Mult Scler. 2022 Jun;28(7):1121-1125
pubmed: 34240631
JAMA Neurol. 2021 Jun 1;78(6):699-708
pubmed: 33739362
J Neurol. 2021 Jun;268(6):2161-2168
pubmed: 33475825
Neurol Neuroimmunol Neuroinflamm. 2021 Jul 14;8(5):
pubmed: 34261812
iScience. 2021 Sep 24;24(9):103078
pubmed: 34490414
Mult Scler Relat Disord. 2020 Sep;44:102279
pubmed: 32645640
Neurol Neuroimmunol Neuroinflamm. 2020 Aug 4;7(5):
pubmed: 32753406
Neurology. 2021 Nov 9;97(19):e1870-e1885
pubmed: 34610987
JAMA Neurol. 2020 Feb 1;77(2):184-191
pubmed: 31589278
Epidemiology. 2019 Mar;30(2):230-233
pubmed: 30721167
Nat Rev Drug Discov. 2021 Mar;20(3):179-199
pubmed: 33324003
Ann Clin Transl Neurol. 2020 Sep;7(9):1477-1487
pubmed: 32767531
Acta Neurol Scand. 2017 Jan;135(1):17-24
pubmed: 27558404
Mult Scler Relat Disord. 2022 Jan;57:103358
pubmed: 35158467
N Engl J Med. 2008 Feb 14;358(7):676-88
pubmed: 18272891
Nat Med. 2021 Nov;27(11):1990-2001
pubmed: 34522051
Sci Transl Med. 2015 Oct 21;7(310):310ra166
pubmed: 26491076
Cell. 2018 Sep 20;175(1):85-100.e23
pubmed: 30173916
N Engl J Med. 2020 Aug 6;383(6):546-557
pubmed: 32757523
Mult Scler Relat Disord. 2020 Jan;37:101468
pubmed: 31683231
Mult Scler. 2020 Dec;26(14):1816-1821
pubmed: 33174475
Mult Scler Relat Disord. 2020 Aug;43:102175
pubmed: 32417664
Neurology. 2020 Oct 6;95(14):e1999-e2008
pubmed: 32727835
J Exp Med. 2012 May 7;209(5):1001-10
pubmed: 22547654
Eur J Neurol. 2022 Nov;29(11):3317-3328
pubmed: 35808856
N Engl J Med. 2017 Jan 19;376(3):221-234
pubmed: 28002679
Neurol Neuroimmunol Neuroinflamm. 2020 Oct 21;7(6):
pubmed: 33087582