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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Research Article

Changes in John Cunningham Virus Index in Multiple Sclerosis Patients Treated with Different Disease-Modifying Therapies

Author(s): Eleonora Sgarlata, Clara Grazia Chisari, Simona Toscano, Chiara Finocchiaro, Salvatore Lo Fermo, Enrico Millefiorini and Francesco Patti*

Volume 20, Issue 10, 2022

Published on: 21 April, 2022

Page: [1978 - 1987] Pages: 10

DOI: 10.2174/1570159X19666211111123202

Price: $65

Abstract

Background: Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection caused by John Cunningham virus (JCV) reactivation, potentially associated with natalizumab (NTZ) treatment for Multiple Sclerosis (MS). The anti-JCV antibodies titre (JCV index) increases during NTZ treatment; however, the effects of other disease-modifying therapies (DMTs) on the JCV index have not been fully explored.

Objective: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs.

Methods: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1).

Results: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index <0.90 was found to be significantly increased in the ALM group (16.7 % versus 66.7 %, p = 0.05), while the percentage of patients with JCV index >1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index <0.90 was also found (23.5 % versus 1.4 %, p = 0.0006). The mean JCV index was reduced in the RTX/OCR and ALM groups, while a significant increase was observed in the FTY group.

Conclusion: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk.

Keywords: Multiple sclerosis, JCV index, disease-modifying therapies, T cells depleting drugs, B cells depleting drugs, PML risk, treatment strategy.

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[1]
Hauser, S.L.; Cree, B.A.C. Treatment of Multiple Sclerosis: A Review. Am. J. Med., 2020, 133(12), 1380-1390.e2.
[http://dx.doi.org/10.1016/j.amjmed.2020.05.049] [PMID: 32682869]
[2]
Cree, B.A.C.; Mares, J.; Hartung, H.P. Current therapeutic landscape in multiple sclerosis: An evolving treatment paradigm. Curr. Opin. Neurol., 2019, 32(3), 365-377.
[http://dx.doi.org/10.1097/WCO.0000000000000700] [PMID: 30985372]
[3]
Baldwin, K.J.; Hogg, J.P. Progressive multifocal leukoencephalopathy in patients with multiple sclerosis. Curr. Opin. Neurol., 2013, 26(3), 318-323.
[http://dx.doi.org/10.1097/WCO.0b013e328360279f] [PMID: 23493158]
[4]
Sørensen, P.S.; Bertolotto, A.; Edan, G.; Giovannoni, G.; Gold, R.; Havrdova, E.; Kappos, L.; Kieseier, B.C.; Montalban, X.; Olsson, T. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult. Scler., 2012, 18(2), 143-152.
[http://dx.doi.org/10.1177/1352458511435105] [PMID: 22312009]
[5]
Major, E.O.; Yousry, T.A.; Clifford, D.B. Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: A decade of lessons learned. Lancet Neurol., 2018, 17(5), 467-480.
[http://dx.doi.org/10.1016/S1474-4422(18)30040-1] [PMID: 29656742]
[6]
Kartau, M.; Sipilä, J.O.; Auvinen, E.; Palomäki, M.; Verkkoniemi-Ahola, A. Progressive Multifocal Leukoencephalopathy: Current Insights. Degener. Neurol. Neuromuscul. Dis., 2019, 9, 109-121.
[http://dx.doi.org/10.2147/DNND.S203405] [PMID: 31819703]
[7]
Berger, J.R.; Aksamit, A.J.; Clifford, D.B.; Davis, L.; Koralnik, I.J.; Sejvar, J.J.; Bartt, R.; Major, E.O.; Nath, A. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology, 2013, 80(15), 1430-1438.
[http://dx.doi.org/10.1212/WNL.0b013e31828c2fa1] [PMID: 23568998]
[8]
Koralnik, I.J. Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? Ann. Neurol., 2006, 60(2), 162-173.
[http://dx.doi.org/10.1002/ana.20933] [PMID: 16862584]
[9]
Wollebo, H.S.; White, M.K.; Gordon, J.; Berger, J.R.; Khalili, K. Persistence and pathogenesis of the neurotropic polyomavirus JC. Ann. Neurol., 2015, 77(4), 560-570.
[http://dx.doi.org/10.1002/ana.24371] [PMID: 25623836]
[10]
Steiner, I.; Berger, J.R. Update on progressive multifocal leukoencephalopathy. Curr. Neurol. Neurosci. Rep., 2012, 12(6), 680-686.
[http://dx.doi.org/10.1007/s11910-012-0313-4] [PMID: 22991070]
[11]
Oshima, Y.; Tanimoto, T.; Yuji, K.; Tojo, A. Drug-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients. Mult. Scler., 2019, 25(8), 1141-1149.
[http://dx.doi.org/10.1177/1352458518786075] [PMID: 29985084]
[12]
Patel, A.; Sul, J.; Gordon, M.L.; Steinklein, J.; Sanguinetti, S.; Pramanik, B.; Purohit, D.; Haroutunian, V.; Williamson, A.; Koralnik, I.; Harel, A. Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy. JAMA Neurol., 2021, 78(6), 736-740.
[http://dx.doi.org/10.1001/jamaneurol.2021.0627] [PMID: 33724354]
[13]
Toorop, A.A.; van Lierop, Z.Y.G.; Strijbis, E.E.M.; Teunissen, C.E.; Petzold, A.; Wattjes, M.P.; Barkhof, F.; de Jong, B.A.; van Kempen, Z.L.E.; Killestein, J. Mild progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab. Neurol. Neuroimmunol. Neuroinflamm., 2020, 8(1), e904.
[http://dx.doi.org/10.1212/NXI.0000000000000904] [PMID: 33051344]
[14]
Gerevini, S.; Capra, R.; Bertoli, D.; Sottini, A.; Imberti, L. Immune profiling of a patient with alemtuzumab-associated progressive multifocal leukoencephalopathy. Mult. Scler., 2019, 25(8), 1196-1201.
[http://dx.doi.org/10.1177/1352458519832259] [PMID: 30964396]
[15]
Jalkh, G.; Abi Nahed, R.; Macaron, G.; Rensel, M. Safety of newer disease modifying therapies in multiple sclerosis. Vaccines (Basel), 2020, 9(1), 12.
[http://dx.doi.org/10.3390/vaccines9010012] [PMID: 33375365]
[16]
Chisari, C.G.; Toscano, S.; D’Amico, E.; Lo Fermo, S.; Zanghì, A.; Arena, S.; Zappia, M.; Patti, F. An update on the safety of treating relapsing-remitting multiple sclerosis. Expert Opin. Drug Saf., 2019, 18(10), 925-948.
[http://dx.doi.org/10.1080/14740338.2019.1658741] [PMID: 31429602]
[17]
Pavlovic, D.; Patel, M.A.; Patera, A.C.; Peterson, I. T cell deficiencies as a common risk factor for drug associated progressive multifocal leukoencephalopathy. Immunobiology, 2018, 223(6-7), 508-517.
[http://dx.doi.org/10.1016/j.imbio.2018.01.002] [PMID: 29472141]
[18]
Monaco, M.C.; Major, E.O. Immune system involvement in the pathogenesis of JC virus induced PML: What is learned from studies of patients with underlying diseases and therapies as risk factors. Front. Immunol., 2015, 6, 159.
[http://dx.doi.org/10.3389/fimmu.2015.00159] [PMID: 25972864]
[19]
Khoy, K.; Mariotte, D.; Defer, G.; Petit, G.; Toutirais, O.; Le Mauff, B. Natalizumab in multiple sclerosis treatment: From biological effects to immune monitoring. Front. Immunol., 2020, 11, 549842.
[http://dx.doi.org/10.3389/fimmu.2020.549842] [PMID: 33072089]
[20]
Bloomgren, G.; Richman, S.; Hotermans, C.; Subramanyam, M.; Goelz, S.; Natarajan, A.; Lee, S.; Plavina, T.; Scanlon, J.V.; Sandrock, A.; Bozic, C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N. Engl. J. Med., 2012, 366(20), 1870-1880.
[http://dx.doi.org/10.1056/NEJMoa1107829] [PMID: 22591293]
[21]
Plavina, T.; Subramanyam, M.; Bloomgren, G.; Richman, S.; Pace, A.; Lee, S.; Schlain, B.; Campagnolo, D.; Belachew, S.; Ticho, B. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann. Neurol., 2014, 76(6), 802-812.
[http://dx.doi.org/10.1002/ana.24286] [PMID: 25273271]
[22]
Ho, P.R.; Koendgen, H.; Campbell, N.; Haddock, B.; Richman, S.; Chang, I. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: A retrospective analysis of data from four clinical studies. Lancet Neurol., 2017, 16(11), 925-933.
[http://dx.doi.org/10.1016/S1474-4422(17)30282-X] [PMID: 28969984]
[23]
Chisari, C.G.; Grimaldi, L.M.; Salemi, G.; Ragonese, P.; Iaffaldano, P.; Bonavita, S.; Sparaco, M.; Rovaris, M.; D’Arma, A.; Lugaresi, A.; Ferrò, M.T.; Grossi, P.; Di Sapio, A.; Cocco, E.; Granella, F.; Curti, E.; Lepore, V.; Trojano, M.; Patti, F.; Italian, M.S.R.S.G. Clinical effectiveness of different natalizumab interval dosing schedules in a large Italian population of patients with multiple sclerosis. J. Neurol. Neurosurg. Psychiatry, 2020, 91(12), 1297-1303.
[http://dx.doi.org/10.1136/jnnp-2020-323472] [PMID: 33055141]
[24]
Berger, J.R. Classifying PML risk with disease modifying therapies. Mult. Scler. Relat. Disord., 2017, 12, 59-63.
[http://dx.doi.org/10.1016/j.msard.2017.01.006] [PMID: 28283109]
[25]
Sgarlata, E.; Chisari, C.G.; D’Amico, E.; Millefiorini, E.; Patti, F. Changes in anti-JCV antibody status in a large population of multiple sclerosis patients treated with natalizumab. CNS Drugs, 2020, 34(5), 535-543.
[http://dx.doi.org/10.1007/s40263-020-00716-6] [PMID: 32221861]
[26]
Thompson, A.J.; Banwell, B.L.; Barkhof, F.; Carroll, W.M.; Coetzee, T.; Comi, G.; Correale, J.; Fazekas, F.; Filippi, M.; Freedman, M.S.; Fujihara, K.; Galetta, S.L.; Hartung, H.P.; Kappos, L.; Lublin, F.D.; Marrie, R.A.; Miller, A.E.; Miller, D.H.; Montalban, X.; Mowry, E.M.; Sorensen, P.S.; Tintoré, M.; Traboulsee, A.L.; Trojano, M.; Uitdehaag, B.M.J.; Vukusic, S.; Waubant, E.; Weinshenker, B.G.; Reingold, S.C.; Cohen, J.A. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol., 2018, 17(2), 162-173.
[http://dx.doi.org/10.1016/S1474-4422(17)30470-2] [PMID: 29275977]
[27]
Lee, P.; Plavina, T.; Castro, A.; Berman, M.; Jaiswal, D.; Rivas, S.; Schlain, B.; Subramanyam, M. A second-generation ELISA (STRATIFY JCV™ DxSelect™) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J. Clin. Virol., 2013, 57(2), 141-146.
[http://dx.doi.org/10.1016/j.jcv.2013.02.002] [PMID: 23465394]
[28]
Reuwer, A.Q.; Heron, M.; van der Dussen, D.; Schneider-Hohendorf, T.; Murk, J.L. The clinical utility of JC virus antibody index measurements in the context of progressive multifocal leukoencephalopathy. Acta Neurol. Scand., 2017, 136(Suppl. 201), 37-44.
[http://dx.doi.org/10.1111/ane.12840] [PMID: 29068484]
[29]
Lehmann-Horn, K.; Kronsbein, H.C.; Weber, M.S. Targeting B cells in the treatment of multiple sclerosis: recent advances and remaining challenges. Ther. Adv. Neurol. Disord., 2013, 6(3), 161-173.
[http://dx.doi.org/10.1177/1756285612474333] [PMID: 23634189]
[30]
Duddy, M.; Niino, M.; Adatia, F.; Hebert, S.; Freedman, M.; Atkins, H.; Kim, H.J.; Bar-Or, A. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J. Immunol., 2007, 178(10), 6092-6099.
[http://dx.doi.org/10.4049/jimmunol.178.10.6092] [PMID: 17475834]
[31]
Harp, C.T.; Ireland, S.; Davis, L.S.; Remington, G.; Cassidy, B.; Cravens, P.D.; Stuve, O.; Lovett-Racke, A.E.; Eagar, T.N.; Greenberg, B.M.; Racke, M.K.; Cowell, L.G.; Karandikar, N.J.; Frohman, E.M.; Monson, N.L. Memory B cells from a subset of treatment-naïve relapsing-remitting multiple sclerosis patients elicit CD4(+) T-cell proliferation and IFN-γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Eur. J. Immunol., 2010, 40(10), 2942-2956.
[http://dx.doi.org/10.1002/eji.201040516] [PMID: 20812237]
[32]
Baker, D.; Marta, M.; Pryce, G.; Giovannoni, G.; Schmierer, K.; Memory, B.; Memory, B. Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine, 2017, 16, 41-50.
[http://dx.doi.org/10.1016/j.ebiom.2017.01.042] [PMID: 28161400]
[33]
Havrdova, E.; Horakova, D.; Kovarova, I. Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use. Ther. Adv. Neurol. Disord., 2015, 8(1), 31-45.
[http://dx.doi.org/10.1177/1756285614563522] [PMID: 25584072]
[34]
Chisari, C.G.; Sgarlata, E.; Arena, S.; Toscano, S.; Luca, M.; Patti, F. Rituximab for the treatment of multiple sclerosis: A review. J. Neurol., 2022, 269(1), 159-183.
[http://dx.doi.org/10.1007/s00415-020-10362-z] [PMID: 33416999]
[35]
Palanichamy, A.; Jahn, S.; Nickles, D.; Derstine, M.; Abounasr, A.; Hauser, S.L.; Baranzini, S.E.; Leppert, D.; von Büdingen, H.C. Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J. Immunol., 2014, 193(2), 580-586.
[http://dx.doi.org/10.4049/jimmunol.1400118] [PMID: 24928997]
[36]
Ceronie, B.; Jacobs, B.M.; Baker, D.; Dubuisson, N.; Mao, Z.; Ammoscato, F.; Lock, H.; Longhurst, H.J.; Giovannoni, G.; Schmierer, K. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J. Neurol., 2018, 265(5), 1199-1209.
[http://dx.doi.org/10.1007/s00415-018-8830-y] [PMID: 29550884]
[37]
Jelcic, I.; Jelcic, I.; Kempf, C.; Largey, F.; Planas, R.; Schippling, S.; Budka, H.; Sospedra, M.; Martin, R. Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant. Ann. Neurol., 2016, 79(3), 404-418.
[http://dx.doi.org/10.1002/ana.24574] [PMID: 26874214]
[38]
Scarpazza, C.; De Rossi, N.; Tabiadon, G.; Turrini, M.V.; Gerevini, S.; Capra, R. Four cases of natalizumab-related PML: A less severe course in extended interval dosing? Neurol. Sci., 2019, 40(10), 2119-2124.
[http://dx.doi.org/10.1007/s10072-019-03959-4] [PMID: 31175467]
[39]
Rolla, S.; Maglione, A.; De Mercanti, S.F.; Clerico, M. The meaning of immune reconstitution after alemtuzumab therapy in multiple sclerosis. Cells, 2020, 9(6), E1396.
[http://dx.doi.org/10.3390/cells9061396] [PMID: 32503344]
[40]
Rommer, P.S.; Milo, R.; Han, M.H.; Satyanarayan, S.; Sellner, J.; Hauer, L.; Illes, Z.; Warnke, C.; Laurent, S.; Weber, M.S.; Zhang, Y.; Stuve, O. Immunological aspects of approved MS therapeutics. Front. Immunol., 2019, 10, 1564.
[http://dx.doi.org/10.3389/fimmu.2019.01564] [PMID: 31354720]
[41]
Li, Z.; Richards, S.; Surks, H.K.; Jacobs, A.; Panzara, M.A. Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis. Clin. Exp. Immunol., 2018, 194(3), 295-314.
[http://dx.doi.org/10.1111/cei.13208] [PMID: 30144037]
[42]
Durali, D.; de Goër de Herve, M.G.; Gasnault, J.; Taoufik, Y. B cells and progressive multifocal leukoencephalopathy: search for the missing link. Front. Immunol., 2015, 6, 241.
[http://dx.doi.org/10.3389/fimmu.2015.00241] [PMID: 26042124]
[43]
Meltzer, E.; Campbell, S.; Ehrenfeld, B.; Cruz, R.A.; Steinman, L.; Parsons, M.S.; Zamvil, S.S.; Frohman, E.M.; Frohman, T.C. Mitigating alemtuzumab-associated autoimmunity in MS: A “whack-a-mole” B-cell depletion strategy. Neurol. Neuroimmunol. Neuroinflamm., 2020, 7(6), e868.
[http://dx.doi.org/10.1212/NXI.0000000000000868] [PMID: 32769201]
[44]
Baber, U.; Bouley, A.; Egnor, E.; Sloane, J.A. Anti-JC virus antibody index changes in rituximab-treated multiple sclerosis patients. J. Neurol., 2018, 265(10), 2342-2345.
[http://dx.doi.org/10.1007/s00415-018-8996-3] [PMID: 30109480]
[45]
Focosi, D.; Tuccori, M.; Maggi, F. Progressive multifocal leukoencephalopathy and anti-CD20 monoclonal antibodies: What do we know after 20 years of rituximab. Rev. Med. Virol., 2019, 29(6), e2077.
[http://dx.doi.org/10.1002/rmv.2077] [PMID: 31369199]
[46]
Hermann, R.; Karlsson, M.O.; Novakovic, A.M.; Terranova, N.; Fluck, M.; Munafo, A. The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis. Clin. Pharmacokinet., 2019, 58(3), 283-297.
[http://dx.doi.org/10.1007/s40262-018-0695-9] [PMID: 29987837]
[47]
Subei, A.M.; Cohen, J.A. Sphingosine 1-phosphate receptor modulators in multiple sclerosis. CNS Drugs, 2015, 29(7), 565-575.
[http://dx.doi.org/10.1007/s40263-015-0261-z] [PMID: 26239599]
[48]
Blumenfeld-Kan, S.; Staun-Ram, E.; Miller, A. Fingolimod reduces CXCR4-mediated B cell migration and induces regulatory B cells-mediated anti-inflammatory immune repertoire. Mult. Scler. Relat. Disord., 2019, 34, 29-37.
[http://dx.doi.org/10.1016/j.msard.2019.06.016] [PMID: 31228713]
[49]
Matloubian, M.; Lo, C.G.; Cinamon, G.; Lesneski, M.J.; Xu, Y.; Brinkmann, V.; Allende, M.L.; Proia, R.L.; Cyster, J.G. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature, 2004, 427(6972), 355-360.
[http://dx.doi.org/10.1038/nature02284] [PMID: 14737169]
[50]
Longbrake, E.E.; Cross, A.H. Effect of multiple sclerosis disease-modifying therapies on B cells and humoral immunity. JAMA Neurol., 2016, 73(2), 219-225.
[http://dx.doi.org/10.1001/jamaneurol.2015.3977] [PMID: 26720195]
[51]
Montalban, X.; Gold, R.; Thompson, A.J.; Otero-Romero, S.; Amato, M.P.; Chandraratna, D.; Clanet, M.; Comi, G.; Derfuss, T.; Fazekas, F.; Hartung, H.P.; Havrdova, E.; Hemmer, B.; Kappos, L.; Liblau, R.; Lubetzki, C.; Marcus, E.; Miller, D.H.; Olsson, T.; Pilling, S.; Selmaj, K.; Siva, A.; Sorensen, P.S.; Sormani, M.P.; Thalheim, C.; Wiendl, H.; Zipp, F. ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult. Scler., 2018, 24(2), 96-120.
[http://dx.doi.org/10.1177/1352458517751049] [PMID: 29353550]
[52]
Chisari, C.G.; Comi, G.; Filippi, M.; Paolicelli, D.; Iaffaldano, P.; Zaffaroni, M.; Brescia, M.V.; Cocco, E.; Marfia, G.A.; Grimaldi, L.M.; Inglese, M.; Bonavita, S.; Lugaresi, A.; Salemi, G.; De Luca, G.; Cottone, S.; Conte, A.; Sola, P.; Aguglia, U.; Maniscalco, G.T.; Gasperini, C.; Ferrò, M.T.; Pesci, I.; Amato, M.P.; Rovaris, M.; Solaro, C.; Lus, G.; Maimone, D.; Bergamaschi, R.; Granella, F.; Di Sapio, A.; Bertolotto, A.; Totaro, R.; Vianello, M.; Cavalla, P.; Bellantonio, P.; Lepore, V.; Patti, F. PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study. J. Neurol., 2022, 269(2), 933-944.
[http://dx.doi.org/10.1007/s00415-021-10676-6] [PMID: 34181077]

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