Highlights
- •Rituximab is a commonly used off-label treatment of multiple sclerosis (MS).
- •Mainly observational data suggested high efficacy of rituximab across different MS populations.
- •The optimal dosing regimen and duration of rituximab for MS are still inconclusive.
- •Biosimilars may be a cost-effective option in resource-limited settings.
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central
nervous system. The immunopathology of MS involves both T and B lymphocytes. Rituximab
is one of the anti-CD20 monoclonal antibody therapies which deplete B-cells. Although
some anti-CD20 therapies have been approved by the Food and Drug Administration for
treatment of MS, rituximab is used off-label. Several studies have shown that rituximab
has a good efficacy and safety in MS, including certain specific patient conditions
such as treatment-naïve patients, treatment-switching patients, and the Asian population.
However, there are still questions about the optimal dose and duration of rituximab
in MS due to the different dosing regimens used in each study. Moreover, many biosimilars
have become available at a lower cost with comparable physicochemical properties,
pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. Thus, rituximab
may be considered as a potential therapeutic option for patients without access to
standard treatment. This narrative review summarized the evidence of both original
and biosimilars of rituximab in MS treatment including pharmacokinetics, pharmacodynamics,
clinical efficacy, safety, and dosing regimen.
Keywords
Abbreviations:
DMTs (Disease-modifying therapies), MS (Multiple sclerosis)To read this article in full you will need to make a payment
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References
- Rituximab in the treatment of multiple sclerosis in the Hospital District of Southwest Finland.Mult. Scler. Relat. Disord. 2020; 40101980
- Treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing-remitting multiple sclerosis is effective and safe.J. Neurol. 2019; 266: 726-734
- Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: a hospital-based study.J. Neurol. 2018; 265: 1690-1697
- Safety and efficacy of rituximab: experience of a single multiple sclerosis center.Clin. Neuropharmacol. 2018; 41: 56-59
- Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.Ann. Neurol. 2016; 79: 950-958
- Cancer risk for fingolimod, natalizumab, and rituximab in multiple sclerosis patients.Ann. Neurol. 2020; 87 (May): 688-699
- It's time for combination therapies: in multiple sclerosis.Innov. Clin. Neurosci. 2017; 14: 28
- Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial.Ann. Neurol. 2008; 63: 395-400
- Experience with long-term rituximab use in a multiple sclerosis clinic.Mult. Scler. J. Exp. Transl. Clin. 2016; 2 (Oct 9)2055217316672100
- Treatment of multiple sclerosis with anti-CD20 antibodies.Clin. Immunol. 2012; 142: 31-37
- Experience with rituximab therapy in a real-life sample of multiple sclerosis patients.Neurol. Sci. 2020; 41: 2939-2945
- Progressive multifocal leukoencephalopathy in patients treated with rituximab: a 20-year review from the Southern Network on Adverse Reactions.Lancet Haematol. 2021; 8 (Aug 1): e593-e604
- Rescue therapy using rituximab for multiple sclerosis.Clin. Neuropharmacol. 2016; 39: 178-181
- Association of serum Rituximab (IDEC–C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma.Ann. Oncol. 1998; 9 (Sep 1): 995-1001
- Rapidly increasing off-label use of rituximab in multiple sclerosis in Sweden-outlier or predecessor?.Acta Neurol. Scand. 2018; 138: 327-331
- Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis.Eur. J. Neurol. 2019; 26: 1060-1067
- Discontinuation and dose reduction of rituximab in relapsing-remitting multiple sclerosis.J. Neurol. 2021; 268 (Jun): 2161-2168
Briumv® [package Insert]. Morrisville: TG Therapeutics, Inc; 2022.
- Incidence of infusion-associated reactions with rituximab for treating multiple sclerosis.Drug Saf. 2011; 34 (Feb): 117-123
- Rituximab and glatiramer-acetate in secondary-progressive multiple sclerosis: a randomized-clinical trial.Acta Neurol. Scand. 2021; 143: 178-187
ClinicalTrials.gov. COMparison Between All immunoTherapies for Multiple Sclerosis. (COMBAT-MS) [ClinicalTrials.gov Identifier: NCT03193866]. https://clinicaltrials.gov/ct2/show/NCT03193866. Accessed February 11, 2022.
ClinicalTrials.gov. Non-inferiority Study of Ocrelizumab and Rituximab in Active Multiple Sclerosis (DanNORMS) [ClinicalTrials.gov Identifier: NCT04688788]. https://clinicaltrials.gov/ct2/show/NCT04688788. Accessed February 11, 2022.
ClinicalTrials.gov. Ocrelizumab VErsus Rituximab Off-Label at the Onset of Relapsing MS Disease (OVERLORD-MS) [ClinicalTrials.gov Identifier: NCT04578639]. https://clinicaltrials.gov/ct2/show/NCT04578639. Accessed February 11, 2022.
ClinicalTrials.gov. Rituximab long-term DOSE trial in multiple sclerosis – RIDOSE-MS (RIDOSE-MS) [ClinicalTrials.gov Identifier: NCT03979456]. https://clinicaltrials.gov/ct2/show/study/NCT03979456. Accessed February 11, 2022.
- Pharmacokinetics, efficacy, and safety of the rituximab biosimilar CT-P10.Expert Rev. Clin. Pharmacol. 2017; 10 (Sep 2): 923-933
- Age at disability milestones in multiple sclerosis.Brain. 2006; 129 (Mar): 595-605
- Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients.J. Neuroimmunol. 2006; 180: 63-70
- Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS.Mult. Scler. 2017; 23: 1249-1257
- Simultaneous monitoring of monoclonal antibody variants by strong cation-exchange chromatography hyphenated to mass spectrometry to assess quality attributes of rituximab-based biotherapeutics.Int. J. Mol. Sci. 2021; 22 (Jan): 9072
- De-escalating rituximab dose results in stability of clinical, radiological, and serum neurofilament levels in multiple sclerosis.Mult. Scler. J. 2021; 27 (Jul): 1230-1239
- Rituximab in multiple sclerosis: frequency and clinical relevance of anti-drug antibodies.Mult. Scler. 2018; 24 (Aug): 1224-1233
- Efficacy of rituximab in refractory RRMS.Mult. Scler. 2019; 25: 828-836
- Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders.J. Neurol. 2019; 266 (Jan): 57-67
- Multiple sclerosis epidemiology in east Asia, south east Asia and south Asia: a systematic review.Neuroepidemiology. 2016; 46: 209-221
- Multiple sclerosis epidemiology in Asia and Oceania; a systematic review and meta-analysis.Mult. Scler. Relat. Disord. 2021; 54 (Sep 1)103119
- A milestone in multiple sclerosis therapy: monoclonal antibodies against CD20-yet progress continues.Neurotherapeutics. 2021; (Apr 20): 1-21
- The role of B cells in the immunopathogenesis of multiple sclerosis.Immunology. 2020; 160 (Aug): 325-335
- Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics.MAbs. 2013; 5 (Nov-Dec): 826-837
- Population pharmacokinetics of Reditux™, a biosimilar Rituximab, in diffuse large B-cell lymphoma.Cancer Chemother. Pharmacol. 2016; 78 (Aug): 353-359
- Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis.JAMA Neurol. 2018; 75: 320-327
- Cerebral rituximab uptake in multiple sclerosis: a 89Zr-immunoPET pilot study.Mult. Scler. 2018; 24: 543-545
- Treatment of multiple sclerosis: a review.Am. J. Med. 2020; 133: 1380-1390.e2
- B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.N. Engl. J. Med. 2008; 358: 676-688
- Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial.Ann. Neurol. 2009; 66: 460-471
- Rituximab in multiple sclerosis at general hospital level.Acta Neurol. Scand. 2020; 141: 491-499
- Rituximab vs placebo induction prior to glatiramer acetate monotherapy in multiple sclerosis.Neurology. 2019; 92: 723-732
- Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study.Lancet Haematol. 2017; 4 (Aug 1): e350-e361
- Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity.Mult. Scler. Relat. Disord. 2020; 37 (Jan)101468
Kesimpta® [package Insert]. East Hanover: Novartis Pharmaceuticals Corporation; 2020.
- Tolerability and safety of rituximab (MabThera®).Cancer Treat. Rev. 2005; 31 (Oct 1): 456-473
- Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties.MAbs. 2013; 5 (Jan): 22-33
- Multiple sclerosis pathology.Cold Spring Harb. Perspect. Med. 2018; 8 (Mar 1)a028936
- Targets of therapy in progressive MS.Mult. Scler. 2017; 23: 1593-1599
- Rituximab and hepatitis B reactivation in HBsAg-negative/anti-HBc-positive kidney transplant recipients.Nephrol. Dial. Transplant. 2017; 32 (Apr 1): 722-729
- A retrospective observational study of rituximab treatment in multiple sclerosis patients in Cyprus.Postgrad. Med. 2019; 131: 486-489
- The FCGR3A polymorphism predicts the response to rituximab-based therapy in patients with non-Hodgkin lymphoma: a meta-analysis.Ann. Hematol. 2016; 95 (Sep): 1483-1490
- Defining the clinical course of multiple sclerosis: the 2013 revisions.Neurology. 2014; 83: 278-286
- The pathology of multiple sclerosis.Neurol. Clin. 2005; 23 (Febvi): 77-105
- Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies.JAMA Neurol. 2020; 77: 184-191
MabThera ® [package Insert]. Grenzach-Wyhlen: Roche Pharma AG; 2019.
- Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology.Brain. 2007; 130: 1089-1104
- Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes.QJM. 2014; 107 (Oct): 821-828
- Efficacy and safety of rituximab in multiple sclerosis: experience from a developing country.Mult. Scler. Relat. Disord. 2020; 43102210
- Effect of rituximab on expanded disability status scale and relapse rate in multiple sclerosis patients.J. Mol. Neurosci. 2020; 70: 1165-1168
- Evaluating the efficacy and safety of ZytuxTM (Rituximab, AryoGen pharmed) in Iranian multiple sclerosis patients: an observational study.Mult. Scler. Relat. Disord. 2019; 36101419
- ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis.Mult. Scler. 2018; 24: 96-120
MSIF Off-Label Treatments (MOLT) Panel. Guideline for the use of off-label azathioprine and rituximab for the treatment of multiple sclerosis in low-resource settings. 2022. https://www.msif.org/wp-content/uploads/2022/11/MOLT_EtD-and-recommendations_public_301122.pdf. Accessed 12.30.2022.
- Reactivation of hepatitis B virus: a review of clinical guidelines.Clin. Liver Dis. 2020; 15 (Apr): 162
- Association of rituximab treatment with disability progression among patients with secondary progressive multiple sclerosis.JAMA Neurol. 2019; 76: 274-281
- Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial.Neurology. 2010; 74: 1860-1867
- The role of B cells in multiple sclerosis: current and future therapies.Cell. Immunol. 2019; 339 (May 1): 10-23
- Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial.J. Clin. Pharmacol. 2005; 45 (Jul): 792-801
- Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis.Nat. Med. 2008; 14: 688-693
- Proinflammatory CD20+ T cells contribute to CNS-directed autoimmunity.Sci. Transl. Med. 2022; 14 (Mar 30): eabi4632
Ocrevus® [package Insert]. South San Francisco: Genentech, Inc; 2020.
- Drug-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients.Mult. Scler. 2019; 25 (Jul): 1141-1149
- Efficacy and safety of switching from innovator rituximab to biosimilar CT-P10 compared with continued treatment with CT-P10: results of a 56-week open-label study in patients with rheumatoid arthritis.BioDrugs. 2017; 31 (Aug): 369-377
- Efficacy and safety of rituximab in central nervous system demyelinating disorders.Ann. Indian Acad. Neurol. 2021; 24 (Sep-Oct): 732-739
- Comparison of rituximab originator (MabThera®) to biosimilar (Truxima®) in patients with multiple sclerosis.Mult. Scler. 2021; 27 (Apr): 585-592
- Hypogammaglobulinemia and infections in patients with multiple sclerosis treated with rituximab.Neurol. Neuroimmunol. Neuroinflamm. 2021; 9: e1115
- Rituximab levels in cerebrospinal fluid of patients with neurological autoimmune disorders.Mult. Scler. 2009; 15 (Feb): 189-192
- Past, present, and future of rituximab-The World's first oncology monoclonal antibody therapy.Front. Oncol. 2018; 8 (Jun 4): 163
- Pharmacokinetic behavior of rituximab: a study of different schedules of administration for heterogeneous clinical settings.Ther. Drug Monit. 2005; 27 (Dec 1): 785-792
Rituxan® [package Insert]. South San Francisco: Biogen and Genentech, Inc; 2020.
- Comparison of the efficacy and safety of Rituximab (MabtheraTM) and its biosimilar (RedituxTM) in diffuse large B-cell lymphoma patients treated with chemo-immunotherapy: A retrospective analysis.Indian J Med Paediatr Oncol. 2013 Oct; 34: 292-298
- B-cell therapies in multiple sclerosis.Cold Spring Harb. Perspect. Med. 2019; 9 (Feb 1)a032037
- Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy.Neurology. 2016; 87: 2074-2081
- Features of Human CD3+CD20+ T Cells.J. Immunol. 2016; 197 (Aug 15): 1111-1117
- Effectiveness and safety of Rituximab in multiple sclerosis: an observational study from Southern Switzerland.PLoS ONE. 2018; 13e0197415
- Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis.Brain Pathol. 2004; 14: 164-174
- Efficacy and safety of switching from rituximab to biosimilar CT-P10 in rheumatoid arthritis: 72-week data from a randomized Phase 3 trial.Rheumatology. 2019; 58 (Oxford)Dec 1: 2193-2202
- Efficacy and safety of Sandoz biosimilar rituximab for active rheumatoid arthritis: 52-week results from the randomized controlled ASSIST-RA trial.Rheumatology. 2021; 60 (Oxford)Jan: 256-262
- Comparative effectiveness of rituximab relative to IFN-β or glatiramer acetate in relapsing-remitting MS from the Swedish MS registry.Mult. Scler. 2018; 24: 1087-1095
- Long-term efficacy and safety of biosimilar CT-P10 versus innovator rituximab in rheumatoid arthritis: 48-week results from a randomized phase III trial.BioDrugs. 2019; 33 (Feb): 79-91
- Brief report: safety and immunogenicity of rituximab biosimilar GP 2013 after switch from reference rituximab in patients with active rheumatoid arthritis.Arthritis Care Res. 2019; 71 (Jan 1): 88-94
Tout M, Passot C, Cartron G, Paintaud G, Ternant D. Gota et al. on their article "the pharmacokinetics of Reditux™, a biosimilar of rituximab". Cancer Chemother Pharmacol. 2016 Dec;78(6):1317-1318.
- Torkildsen Ø. Safety and efficacy of rituximab as first-and second line treatment in multiple sclerosis–a cohort study.Mult. Scler. J. Exp. Transl. Clin. 2021; 72055217320973049
- Long-term safety of rituximab (risks of viral and opportunistic infections).Curr. Rheumatol. Rep. 2021; 23 (Sep): 1-6
- Biosimilars: part 1: proposed regulatory criteria for FDA approval.P T. 2013; 38 (May): 270
- Physicochemical and functional comparability between the proposed biosimilar rituximab GP2013 and originator rituximab.BioDrugs. 2013 Oct; 27: 495-507
- Rituximab versus natalizumab, fingolimod, and dimethyl fumarate in multiple sclerosis treatment.Ann. Clin. Transl. Neurol. 2020; 7: 1466-1476
- Serious safety events in rituximab-treated multiple sclerosis and related disorders.Ann. Clin. Transl. Neurol. 2020; 7 (Sep): 1477-1487
- Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS.Mult. Scler. 2020; 26: 1816-1821
- Rituximab in neurological disease: principles, evidence and practice.Pract. Neurol. 2019; 19: 5-20
- Depletion of functionally active CD20+ T cells by rituximab treatment.Arthritis Rheumatol. 2009; 60: 3563-3571
- Safety and efficacy of rituximab in multiple sclerosis: a retrospective observational study.J. Immunol. Res. 2018; 2018: 9084759
- A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis.Ann. Rheum. Dis. 2017; 76 (Mar 1): 566-570
- Efficacy, safety and pharmacokinetics of up to two courses of the rituximab biosimilar CT-P10 versus innovator rituximab in patients with rheumatoid arthritis: results up to week 72 of a phase I randomized controlled trial.BioDrugs. 2017; 31 (Aug): 357-367
- A pharmacokinetic evaluation of the rituximab biosimilar CT-P10 in the treatment of rheumatoid arthritis.Expert Opin. Drug Metab. Toxicol. 2020; 16 (Dec 1): 1125-1132
- The pharmacogenetics of rituximab: potential implications for anti-CD20 therapies in multiple sclerosis.Neurotherapeutics. 2020; 17 (Oct): 1768-1784
- Treatment of multiple sclerosis with rituximab: a multicentric Italian-Swiss experience.Mult. Scler. 2020; 26: 1519-1531
Article info
Publication history
Published online: April 23, 2023
Accepted:
April 22,
2023
Received in revised form:
April 15,
2023
Received:
November 22,
2022
Identification
Copyright
© 2023 Elsevier B.V. All rights reserved.
