Over the past two decades, treatment options for patients with multiple sclerosis (MS) have increased exponentially. In the current therapeutic landscape, “no evidence of MS disease activity” is within reach in many of our patients. Minimizing risks of complications, improving treatment convenience, and decreasing health care costs are goals that are yet to be reached. One way to optimize MS therapy is to implement personalized or extended interval dosing. Monoclonal antibodies are suitable candidates for personalized dosing (by therapeutic drug monitoring) or extended interval dosing. An increasing number of studies are performed and underway reporting on altered dosing intervals of anti-α4β1-integrin treatment (natalizumab) and anti-CD20 treatment (ocrelizumab, rituximab, and ofatumumab) in MS. In this review, current available evidence regarding personalized and extended interval dosing of monoclonal antibodies in MS is discussed with recommendations for future research and clinical practice.
SheremataWAVollmerTLStoneLA, et al. A safety and pharmacokinetic study of intravenous natalizumab in patients with MS. Neurology1999; 52: 1072–1074.
2.
O’ConnorPWGoodmanAWillmer-HulmeAJ, et al. Randomized multicenter trial of natalizumab in acute MS relapses: Clinical and MRI effects. Neurology2004; 62: 2038–2043.
3.
MillerDHKhanOASheremataWA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med2003; 348: 15–23.
4.
PolmanCHO’ConnorPWHavrdovaE, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med2006; 354: 899–910.
5.
PlavinaTFoxEJLucasN, et al. A randomized trial evaluating various administration routes of natalizumab in multiple sclerosis. J Clin Pharmacol2016; 56(10): 1254–1262.
6.
TrojanoMRamio-TorrentaLGrimaldiLM, et al. A randomized study of natalizumab dosing regimens for relapsing-remitting multiple sclerosis. Mult Scler2021; 27(14): 2240–2253.
7.
Bar-OrACalabresiPAArnoldD, et al. Rituximab in relapsing-remitting multiple sclerosis: A 72-week, open-label, phase I trial. Ann Neurol2008; 63(3): 395–400.
8.
HauserSLWaubantEArnoldDL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med2008; 358: 676–688.
9.
NaismithRTPiccioLLyonsJA, et al. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: A 52-week phase II trial. Neurology2010; 74: 1860–1867.
10.
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.
11.
SalzerJSvenningssonRAlpingP, et al. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology2016; 87: 2074–2081.
12.
KapposLLiDCalabresiPA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: A phase 2, randomised, placebo-controlled, multicentre trial. Lancet2011; 378: 1779–1787.
13.
MontalbanXHauserSLKapposL, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med2017; 376: 209–220.
14.
HauserSLBar-OrAComiG, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med2017; 376: 221–234.
15.
SorensenPSLisbySGroveR, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 study. Neurology2014; 82: 573–581.
16.
Bar-OrAGroveRAAustinDJ, et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology2018; 90: e1805–e1814.
17.
HauserSLBar-OrACohenJA, et al. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med2020; 383: 546–557.
18.
MuralidharanKKKuestersGPlavinaT, et al. Population pharmacokinetics and target engagement of natalizumab in patients with multiple sclerosis. J Clin Pharmacol2017; 57(8): 1017–1030.
19.
DerfussTKovarikJMKapposL, et al. Alpha4-integrin receptor desaturation and disease activity return after natalizumab cessation. Neurol Neuroimmunol Neuroinflamm2017; 4: e388.
20.
PlavinaTMuralidharanKKKuestersG, et al. Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients. Neurology2017; 89: 1584–1593.
21.
van KempenZLLeursCEWitteBI, et al. The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing. Mult Scler2018; 24: 805–810.
22.
Zhovtis RyersonLLiXGoldbergJD, et al. Pharmacodynamics of natalizumab extended interval dosing in MS. Neurol Neuroimmunol Neuroinflamm2020; 7(2): e672.
23.
GhezziAComiGGrimaldiLM, et al. Pharmacokinetics and pharmacodynamics of natalizumab in pediatric patients with RRMS. Neurol Neuroimmunol Neuroinflamm2019; 6(5): e591.
24.
van KempenZLEHoogervorstELJWattjesMP, et al. Personalized extended interval dosing of natalizumab in MS: A prospective multicenter trial. Neurology2020; 95: e745-e54.
25.
GibianskyEPetryCMercierF, et al. Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO. Br J Clin Pharmacol2021; 87: 2511–2520.
26.
KletzlHGibianskyEPetryC, et al. Pharmacokinetics, pharmacodynamics and exposure-response analyses of ocrelizumab in patients with multiple sclerosis. In: Presented at AAN annual meeting, South San Francisco, CA, 7 May 2019.
27.
BakerDPryceGJamesLK, et al. The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis. Mult Scler Relat Disord2020; 44: 102279.
28.
RyersonLZFoleyJChangI, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology2019; 93: e1452–e1462.
29.
BomprezziRPawateS. Extended interval dosing of natalizumab: A two-center, 7-year experience. Ther Adv Neurol Disord2014; 7(5): 227–231.
30.
ClericoMDe MercantiSFSignoriA, et al. Extending the interval of natalizumab dosing: Is efficacy preserved?Neurotherapeutics2020; 17(1): 200–207.
31.
YamoutBISahraianMAAyoubiNE, et al. Efficacy and safety of natalizumab extended interval dosing. Mult Scler Relat Disord2018; 24: 113–116.
32.
De MercantiSFSignoriACordioliC, et al. MRI activity and extended interval of natalizumab dosing regimen: A multicentre Italian study. J Neurol Sci2021; 424: 117385.
33.
RianchoJSetienSSanchez de la TorreJR, et al. Does extended interval dosing natalizumab preserve effectiveness in multiple sclerosis? A 7 year-retrospective observational study. Front Immunol2021; 12: 614715.
34.
Zhovtis RyersonLFrohmanTCFoleyJ, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry2016; 87: 885–889.
35.
ChisariCGGrimaldiLMSalemiG, et al. Clinical effectiveness of different natalizumab interval dosing schedules in a large Italian population of patients with multiple sclerosis. J Neurol Neurosurg Psychiatry2020; 91(12): 1297–1303.
36.
ZeccaCBovisFNoviG, et al. Treatment of multiple sclerosis with rituximab: A multicentric Italian-Swiss experience. Mult Scler2020; 26(12): 1519–1531.
37.
DisantoGRipellinoPRiccitelliGC, et al. De-escalating rituximab dose results in stability of clinical, radiological, and serum neurofilament levels in multiple sclerosis. Mult Scler2021; 27: 1230–1239.
38.
NoviGBovisFFabbriS, et al. Tailoring B cell depletion therapy in MS according to memory B cell monitoring. Neurol Neuroimmunol Neuroinflamm2020; 7(5): e845.
39.
BarunBGabelicTAdamecI, et al. Influence of delaying ocrelizumab dosing in multiple sclerosis due to COVID-19 pandemics on clinical and laboratory effectiveness. Mult Scler Relat Disord2021; 48: 102704.
40.
TazzaFLapucciCCellerinoM, et al. Personalizing ocrelizumab treatment in multiple sclerosis: What can we learn from Sars-Cov2 pandemic?J Neurol Sci2021; 427: 117501.
41.
van LieropZYTooropAAvan BallegoijWJ, et al. Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic. Mult Scler. Epub ahead of print 9 July 2021. DOI: 10.1177/13524585211028833.
42.
RolfesLPawlitzkiMPfeufferS, et al. Ocrelizumab extended interval dosing in multiple sclerosis in times of COVID-19. Neurol Neuroimmunol Neuroinflamm2021; 8(5): e1035.
43.
Bar-OrACalkwoodJCChognotC, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology2020; 95: e1999–e2008.
44.
OksbjergNRNielsenSDBlinkenbergM, et al. Anti-CD20 antibody therapy and risk of infection in patients with demyelinating diseases. Mult Scler Relat Disord2021; 52: 102988.
45.
BoremalmMSundstromPSalzerJ. Discontinuation and dose reduction of rituximab in relapsing-remitting multiple sclerosis. J Neurol2021; 268: 2161–2168.
AchironAMandelMDreyer-AlsterS, et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord2021; 14: 17562864211012835.
48.
RudickRAStuartWHCalabresiPA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med2006; 354: 911–23
49.
de FlonPGunnarssonMLaurellK, et al. Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab. Neurology2016; 87: 141–7
50.
MaaroufARicoABoutiereC, et al. Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?Neurol Neuroimmunol Neuroinflamm2020; 7
