Rituximab, a chimeric anti-CD20-antibody, attracts increasing attention as a treatment option for multiple sclerosis (MS). Apart from smaller controlled trials, an increasing number of studies in real-world populations indicate high efficacy based on clinical and neuroradiological outcomes for rituximab in relapsing-remitting MS patients. Additional evidence also demonstrates efficacy of rituximab with treatment of progressive MS phenotypes. In this topical review, we summarize and discuss current evidence on mechanisms of action, efficacy, safety, tolerance and other clinical aspects of rituximab in the treatment of MS. Finally, we will highlight current knowledge gaps and the need for comparative studies with other disease-modifying therapies in MS.
MyhrKMTorkildsenOLossiusA, et al. B cell depletion in the treatment of multiple sclerosis. Expert Opin Biol Ther2019; 19: 261–271.
2.
MaloneyDGGrillo-LopezAJBodkinDJ, et al. IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol1997; 15(10): 3266–3274.
3.
PiccioLNaismithRTTrinkausK, et al. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis. Arch Neurol2010; 67(6): 707–714.
4.
SalzerJSvenningssonRAlpingP, et al. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology2016; 87: 2074–2081.
5.
Bar-OrAFawazLFanB, et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS. Ann Neurol2010; 67(4): 452–461.
6.
LiRRezkAMiyazakiY, et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med2015; 7(310): 310ra166.
7.
JelcicIAlNimerFWangJ, et al. Memory B cells activate brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell2018; 175(1): 85–100.e23.
8.
PalanichamyAJahnSNicklesD, et al. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol2014; 193(2): 580–586.
9.
GravesJVinayagasundaramUMowryEM, et al. Effects of rituximab on lymphocytes in multiple sclerosis and neuromyelitis optica. Mult Scler Relat Disord2014; 3(2): 244–252.
10.
Von EssenMRAmmitzbollCHansenRH, et al. Proinflammatory CD20+ T cells in the pathogenesis of multiple sclerosis. Brain2019; 142(1): 120–132.
11.
GuanYJakimovskiDRamanathanM, et al. The role of Epstein-Barr virus in multiple sclerosis: From molecular pathophysiology to in vivo imaging. Neural Regen Res2019; 14(3): 373–386.
12.
OlssonTBarcellosLFAlfredssonL.Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol2017; 13(1): 25–36.
13.
HawkerKO’ConnorPFreedmanMS, et al. Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol2009; 66(4): 460–471.
14.
Bar-OrACalabresiPAArnoldD, et al. Rituximab in relapsing-remitting multiple sclerosis: A 72-week, open-label, phase I trial. Ann Neurol2008; 63(3): 395–400.
15.
EllrichmannGBolzJPeschkeM, et al. 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 Neurol2019; 266: 57–67.
16.
RollPMahmoodZMuhammadK, et al. Long-term repopulation of peripheral B-cell subsets after single and repeated rituximab infusions in patients with rheumatoid arthritis. Clin Exp Rheumatol2015; 33(3): 347–353.
17.
BakerDMartaMPryceG, et al. Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine2017; 16: 41–50.
18.
TernantDBejan-AngoulvantTPassotC, et al. Clinical pharmacokinetics and pharmacodynamics of monoclonal antibodies approved to treat rheumatoid arthritis. Clin Pharmacokinet2015; 54(11): 1107–1123.
19.
NgCMBrunoRCombsD, et al. Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial. J Clin Pharmacol2005; 45(7): 792–801.
HagensMHKillesteinJYaqubMM, et al. Cerebral rituximab uptake in multiple sclerosis: A 89Zr-immunoPET pilot study. Mult Scler2018; 24: 543–545.
22.
PetereitHFRubbert-RothA.Rituximab levels in cerebrospinal fluid of patients with neurological autoimmune disorders. Mult Scler2009; 15(2): 189–192.
23.
ToppingJDobsonRLapinS, et al. The effects of intrathecal rituximab on biomarkers in multiple sclerosis. Mult Scler Relat Disord2016; 6: 49–53.
24.
KomoriMLinYCCorteseI, et al. Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol2016; 3(3): 166–179.
25.
SvenningssonABergmanJDringA, et al. Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally. Neurol Neuroimmunol Neuroinflamm2015; 2(2): e79.
26.
BergmanJBurmanJGilthorpeJD, et al. Intrathecal treatment trial of rituximab in progressive MS: An open-label phase 1b study. Neurology2018; 91(20): e1893–e1901.
27.
RubensteinJLFridlyandJAbreyL, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol2007; 25(11): 1350–1356.
28.
SchlachetzkiFZhuCPardridgeWM.Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem2002; 81(1): 203–206.
29.
RubensteinJLCombsDRosenbergJ, et al. Rituximab therapy for CNS lymphomas: Targeting the leptomeningeal compartment. Blood2003; 101(2): 466–468.
30.
RizviSABashirK.Other therapy options and future strategies for treating patients with multiple sclerosis. Neurology2004; 63(12 Suppl. 6): S47–S54.
31.
EdwardsJCCambridgeG.Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology2001; 40(2): 205–211.
32.
BarraMESoniDVoKH, et al. Experience with long-term rituximab use in a multiple sclerosis clinic. Mult Scler J Exp Transl Clin2016; 2: DOI: 10.1177/2055217316672100.
33.
CreeBLambSChinA, et al. Tolerability and effects of rituximab (anti-CD20 antibody) in neuromyelitis optica (NMO) and rapidly worsening multiple sclerosis (MS). Neurology2004; 62: A492.
34.
HauserSLWaubantEArnoldDL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med2008; 358: 676–688.
35.
BerntssonSGKristofferssonABostromI, et al. Rapidly increasing off—label use of rituximab in multiple sclerosis in Sweden—outlier or predecessor?Acta Neurol Scand2018; 138: 327–331.
36.
GranqvistMBoremalmMPoorghobadA, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol2018; 75(3): 320–327.
37.
SpelmanTFrisellTPiehlF, et al. Comparative effectiveness of rituximab relative to IFN-beta or glatiramer acetate in relapsing-remitting MS from the Swedish MS registry. Mult Scler2018; 24(8): 1087–1095.
38.
AlpingPFrisellTNovakovaL, et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol2016; 79(6): 950–958.
39.
DurozardPMaaroufABoutiereC, et al. Efficacy of rituximab in refractory RRMS. Mult Scler2019; 25: 828–836.
40.
De FlonPGunnarssonMLaurellK, et al. Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab. Neurology2016; 87(2): 141–147.
41.
MontalbanXHauserSLKapposL, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med2017; 376(3): 209–220.
42.
MontserratE.Rituximab in chronic lymphocytic leukemia. Semin Hematol2003; 30: 34–39.
43.
DunnNJutoARynerM, et al. Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies. Mult Scler2018; 24(9): 1224–1233.
44.
BoremalmMJutoAAxelssonM, et al. Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis. Eur J Neurol. Epub ahead of print 14 February 2019. DOI: 10.1111/ene.13936.
45.
MemonABJavedACaonC, et al. Long-term safety of rituximab induced peripheral B-cell depletion in autoimmune neurological diseases. PLoS ONE2018; 13(1): e0190425.
46.
AlcalaCGasconFPerez-MirallesF, et al. Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: A hospital-based study. J Neurol2018; 265(7): 1690–1697.
47.
KimSHKimWLiXF, et al. Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years. Arch Neurol2011; 68(11): 1412–1420.
48.
BrownBATorabiM.Incidence of infusion-associated reactions with rituximab for treating multiple sclerosis: A retrospective analysis of patients treated at a US centre. Drug Saf2011; 34(2): 117–123.
49.
JoergerM.Prevention and handling of acute allergic and infusion reactions in oncology. Ann Oncol2012; 23(Suppl. 10): x313–x319.
50.
GottenbergJERavaudPBardinT, et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum2010; 62(9): 2625–2632.
51.
KeystoneEFleischmannREmeryP, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: An open-label extension analysis. Arthritis Rheum2007; 56(12): 3896–3908.
52.
RommerPSDornerTFreivogelK, et al. Safety and clinical outcomes of rituximab treatment in patients with multiple sclerosis and neuromyelitis optica: Experience from a National Online Registry (GRAID). J Neuroimmune Pharmacol2016; 11(1): 1–8.
53.
AlldredgeBJordanAImitolaJ, et al. Safety and efficacy of rituximab: Experience of a Single Multiple Sclerosis Center. Clin Neuropharmacol2018; 41(2): 56–59.
54.
MarcinnoAMarnettoFValentinoP, et al. Rituximab-induced hypogammaglobulinemia in patients with neuromyelitis optica spectrum disorders. Neurol Neuroimmunol Neuroinflamm2018; 5(6): e498.
55.
BoletoGAvouacJWipffJ, et al. Predictors of hypogammaglobulinemia during rituximab maintenance therapy in rheumatoid arthritis: A 12-year longitudinal multi-center study. Semin Arthritis Rheum2018; 48(2): 149–154.
56.
IsvyAMeunierMGobeaux-ChenevierC, et al. Safety of rituximab in rheumatoid arthritis: A long-term prospective single-center study of gammaglobulin concentrations and infections. Joint Bone Spine2012; 79(4): 365–369.
57.
VassilopoulosDDelichaEMSettasL, et al. Safety profile of repeated rituximab cycles in unselected rheumatoid arthritis patients: A long-term, prospective real-life study. Clin Exp Rheumatol2016; 34(5): 893–900.
58.
SchneiderPMacKayFSteinerV, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med1999; 189(11): 1747–1756.
59.
IrelandSMonsonN.Potential impact of B cells on T cell function in multiple sclerosis. Mult Scler Int2011; 2011: 423971.
60.
ParodisISoderFFaustiniF, et al. Rituximab-mediated late-onset neutropenia in systemic lupus erythematosus—distinct roles of BAFF and APRIL. Lupus2018; 27(9): 1470–1478.
61.
OshimaYTanimotoTYujiK, et al. Drug-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients. Mult Scler2019; 25(8): 1141–1149.
62.
MokCC.Rituximab for the treatment of rheumatoid arthritis: An update. Drug Des Devel Ther2013; 8: 87–100.
63.
YamoutBIEl-AyoubiNKNicolasJ, et al. Safety and efficacy of rituximab in multiple sclerosis: A retrospective observational study. J Immunol Res2018; 2018: 9084759.
64.
WadstromHFrisellTAsklingJ.Malignant neoplasms in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors, tocilizumab, abatacept, or rituximab in clinical practice: A nationwide cohort study from Sweden. JAMA Intern Med2017; 177(11): 1605–1612.
65.
AlpingPPiehlFFrisellT.Cancer risk among Swedish multiple sclerosis patients: A nationwide cohort study comparing rituximab, fingolimod and natalizumab. Mult Scler J2018; 24: 8–120.
66.
Van VollenhovenRFFleischmannRMFurstDE, et al. Longterm safety of rituximab: Final report of the rheumatoid arthritis global clinical trial program over 11 years. J Rheumatol2015; 42(10): 1761–1766.
67.
DasGDamotteVGelfandJM, et al. Rituximab before and during pregnancy: A systematic review, and a case series in MS and NMOSD. Neurol Neuroimmunol Neuroinflamm2018; 5(3): e453.
68.
KlinkDTvanElburgRMSchreursMW, et al. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development. Clin Dev Immunol2008; 2008: 271363.
69.
BragnesYBoshuizenRdeVriesA, et al. Low level of rituximab in human breast milk in a patient treated during lactation. Rheumatology2017; 56(6): 1047–1048.
70.
VaidyanathanAMcKeeverKAnandB, et al. Developmental immunotoxicology assessment of rituximab in cynomolgus monkeys. Toxicol Sci2011; 119(1): 116–125.
71.
ChitnisTArnoldDLBanwellB, et al. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med2018; 379(11): 1017–1027.
72.
SalzerJLyckeJWickstromR, et al. Rituximab in paediatric onset multiple sclerosis: A case series. J Neurol2016; 263(2): 322–326.
73.
Langer-GouldAPiehlFSmithJ, et al. Mortality rates in large US and Swedish rituximab-treated multiple sclerosis cohorts. Mult Scler J2018; 24: 231830.
74.
D’AmicoEZanghiAChisariCG, et al. Effectiveness and safety of rituximab in demyelinating diseases spectrum: An Italian experience. Mult Scler Relat Disord2019; 27: 324–326.
75.
HonceJMNairKVSillauS, et al. Rituximab vs placebo induction prior to glatiramer acetate monotherapy in multiple sclerosis. Neurology2019; 92: e723–e732.
76.
MocciaMdeStefanoNBarkhofF.Imaging outcome measures for progressive multiple sclerosis trials. Mult Scler2017; 23(12): 1614–1626.
77.
FilippiMBruckWChardD, et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol2019; 18: 198–210.
78.
AlvarezEPiccioLMikesellRJ, et al. Predicting optimal response to B-cell depletion with rituximab in multiple sclerosis using CXCL13 index, magnetic resonance imaging and clinical measures. Mult Scler J Exp Transl Clin2015; 1. DOI: 10.1177/2055217315623800.
79.
BergmanJDringAZetterbergH, et al. Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS. Neurol Neuroimmunol Neuroinflamm2016; 3(5): e271.
80.
AxelssonMMalmestromCGunnarssonM, et al. Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis. Mult Scler2014; 20(1): 43–50.
81.
De FlonPSoderstromLLaurellK, et al. Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls. PLoS ONE2018; 13(2): e0192516.
82.
KhalilMTeunissenCEOttoM, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol2018; 14(10): 577–589.
83.
VillarLMCasanovaBOuamaraN, et al. Immunoglobulin M oligoclonal bands: Biomarker of targetable inflammation in primary progressive multiple sclerosis. Ann Neurol2014; 76(2): 231–240.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
