An update on the safety of treating relapsing-remitting multiple sclerosis

References

• Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14:183–193.
   PubMed Web of Science ®Google Scholar
• Degenhardt A, Ramagopalan SV, Scalfari A, et al. Clinical prognostic factors in multiple sclerosis: a natural history review. Nat Rev Neurol. 2009;5:672–682.
   PubMed Web of Science ®Google Scholar
• Jacques FH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2015;84:963.
   PubMed Web of Science ®Google Scholar
• Winkelmann A, Loebermann M, Reisinger EC, et al. Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol. 2016;12:217–233.
   PubMed Web of Science ®Google Scholar
• Kyritsis AP, Boussios S, Pavlidis N. Cancer specific risk in multiple sclerosis patients. Crit Rev Oncol Hematol. 2016;98:29–34.
   PubMed Web of Science ®Google Scholar
• Ghezzi A. European and American guidelines for multiple sclerosis treatment. Neurol Ther. 2018;7:189–194.
   PubMedGoogle Scholar
• Comi G, Radaelli M, Soelberg Sørensen P. Evolving concepts in the treatment of relapsing multiple sclerosis. Lancet Lond Engl. 2017;389:1347–1356.
   PubMed Web of Science ®Google Scholar
• Jakimovski D, Kolb C, Ramanathan M, et al. Interferon β for multiple sclerosis. Cold Spring Harb Perspect Med. 2018 Nov 1;8(11).
   PubMed Web of Science ®Google Scholar
• O’Connor P, Filippi M, Arnason B, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8:889–897.
   PubMed Web of Science ®Google Scholar
• Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242–1249.
   PubMed Web of Science ®Google Scholar
• Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European study group on interferon beta-1b in secondary progressive MS. Lancet Lond Engl. 1998;352:1491–1497.
   PubMedGoogle Scholar
• Panitch H, Miller A, Paty D, et al. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology. 2004;63:1788–1795.
   PubMed Web of Science ®Google Scholar
• Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The multiple sclerosis collaborative research group (MSCRG). Ann Neurol. 1996;39:285–294.
   PubMed Web of Science ®Google Scholar
• Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group N Engl J Med. 2000;343:898–904.
   PubMed Web of Science ®Google Scholar
• Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of relapses and disability by interferon beta-1a subcutaneously in multiple sclerosis) study group. Lancet Lond Engl. 1998;352:1498–1504.
   PubMed Web of Science ®Google Scholar
• Clanet M, Radue EW, Kappos L, et al. A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology. 2002;59:1507–1517.
   PubMed Web of Science ®Google Scholar
• Sormani MP, Li DK, Bruzzi P, et al. Combined MRI lesions and relapses as a surrogate for disability in multiple sclerosis. Neurology. 2011;77:1684–1690.
   PubMed Web of Science ®Google Scholar
• Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet Lond Engl. 2001;357:1576–1582.
   PubMed Web of Science ®Google Scholar
• Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012;11:33–41.
   PubMed Web of Science ®Google Scholar
• Secondary Progressive efficacy clinical trial of recombinant interferon-Beta-1a in MS (SPECTRIMS) study group.Randomized controlled trial of interferon- beta-1a in secondary progressive MS: clinical results. Neurology. 2001;56:1496–1504.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology. 2002;59:679–687.
   PubMed Web of Science ®Google Scholar
• Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014;13:657–665.
   PubMed Web of Science ®Google Scholar
• Einarson TR, Bereza BG, Machado M. Comparative effectiveness of interferons in relapsing-remitting multiple sclerosis: a meta-analysis of real-world studies. Curr Med Res Opin. 2017;33:579–593.
   PubMed Web of Science ®Google Scholar
• Patti F, Nicoletti A, Pappalardo A, et al. Frequency and severity of headache is worsened by Interferon-β therapy in patients with multiple sclerosis. Acta Neurol Scand. 2012;125:91–95.
   PubMed Web of Science ®Google Scholar
• Menzin J, Caon C, Nichols C, et al. Narrative review of the literature on adherence to disease-modifying therapies among patients with multiple sclerosis. J Manag Care Pharm JMCP. 2013;19:S24–40.
   PubMed Web of Science ®Google Scholar
• Patti F, Pappalardo A, Florio C, et al. Effects of interferon beta-1a and −1b over time: 6-year results of an observational head-to-head study. Acta Neurol Scand. 2006;113:241–247.
   PubMed Web of Science ®Google Scholar
• Avonex | European Medicines Agency [Internet]. [cited 2019 Feb 2]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/avonex
   Google Scholar
• Rieckmann P, O’Connor P, Francis GS, et al. Haematological effects of interferon-beta-1a (Rebif) therapy in multiple sclerosis. Drug Saf. 2004;27:745–756.
   PubMed Web of Science ®Google Scholar
• Koudriavtseva T, Plantone D, Renna R, et al. Interferon-β therapy and risk of thrombocytopenia in multiple sclerosis patients. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2015;36:2263–2268.
   Google Scholar
• Tremlett HL, Yoshida EM, Oger J. Liver injury associated with the beta-interferons for MS: a comparison between the three products. Neurology. 2004;62:628–631.
   PubMed Web of Science ®Google Scholar
• Frisullo G, Calabrese M, Tortorella C, et al. Thyroid autoimmunity and dysfunction in multiple sclerosis patients during long-term treatment with interferon beta or glatiramer acetate: an Italian multicenter study. Mult Scler. 2014;20:1265–1268.
   PubMed Web of Science ®Google Scholar
• Ozturk M, Basoglu F, Yilmaz M, et al. Interferon β associated nephropathy in a multiple sclerosis patient: A case and review. Mult Scler Relat Disord. 2016;9:50–53.
   PubMed Web of Science ®Google Scholar
• Bloomgren G, Sperling B, Cushing K, et al. Assessment of malignancy risk in patients with multiple sclerosis treated with intramuscular interferon beta-1a: retrospective evaluation using a health insurance claims database and postmarketing surveillance data. Ther Clin Risk Manag. 2012;8:313–321.
   PubMed Web of Science ®Google Scholar
• Sandberg-Wollheim M, Kornmann G, Bischof D, et al. The risk of malignancy is not increased in patients with multiple sclerosis treated with subcutaneous interferon beta-la: analysis of data from clinical trial and post-marketing surveillance settings. Mult Scler. 2011;17:431–440.
   PubMed Web of Science ®Google Scholar
• Reder AT, Oger JF, Kappos L, et al. Short-term and long-term safety and tolerability of interferon β-1b in multiple sclerosis. Mult Scler Relat Disord. 2014;3:294–302.
   PubMed Web of Science ®Google Scholar
• Amato MP, Portaccio E, Ghezzi A, et al. Pregnancy and fetal outcomes after interferon-β exposure in multiple sclerosis. Neurology. 2010;75:1794–1802.
   PubMed Web of Science ®Google Scholar
• Thiel S, Langer-Gould A, Rockhoff M, et al. Interferon-beta exposure during first trimester is safe in women with multiple sclerosis-A prospective cohort study from the German multiple sclerosis and pregnancy registry. Mult Scler. 2016;22:801–809.
   PubMed Web of Science ®Google Scholar
• Coyle PK, Sinclair SM, Scheuerle AE, et al. Final results from the Betaseron (interferon β-1b) pregnancy registry: a prospective observational study of birth defects and pregnancy-related adverse events. BMJ Open. 2014;4:e004536.
   PubMed Web of Science ®Google Scholar
• Hellwig K, Geissbuehler Y, Sabidó M, et al. Pregnancy and infant outcomes with interferon beta: data from the European interferon beta pregnancy registry and population based registries in Finland and Sweden. Mult Scler Relat Disord. 2018;26:240.
   Google Scholar
• Niemczyk G1, Begus-Nahrmann Y2, Herold S2, et al. Pregnancy reports and outcomes from multiple sclerosis patients primarily treated with the disease-modifying therapies peginterferon beta-1a and delayed-release dimethyl fumarate in Germany. ECTRIMS Online Library. Mäurer M. 2018;229121;P1281
   Google Scholar
• Alroughani R, Altintas A, Al Jumah M, et al. Pregnancy and the use of disease-modifying therapies in patients with multiple sclerosis: benefits versus risks. Mult Scler Int. 2016;2016:1034912.
   PubMed Web of Science ®Google Scholar
• Betaseron Prescribing Information. [cited 2019 June 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103471s5193lbl.pdf
   Google Scholar
• Pellegrino P, Carnovale C, Perrone V, et al. Efficacy of vaccination against influenza in patients with multiple sclerosis: The role of concomitant therapies. Vaccine. 2014;32:4730–4735.
   PubMed Web of Science ®Google Scholar
• Metze C, Winkelmann A, Loebermann M, et al. Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies. CNS Neurosci Ther. 2019;25:245–254.
   PubMed Web of Science ®Google Scholar
• Olberg HK, Cox RJ, Nostbakken JK, et al. Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study. Mult Scler. 2014;20:1074–1080.
   PubMed Web of Science ®Google Scholar
• Mehling M, Fritz S, Hafner P, et al. Preserved antigen-specific immune response in patients with multiple sclerosis responding to IFNβ-therapy. PloS One. 2013;8:e78532.
   PubMed Web of Science ®Google Scholar
• Olberg HK, Eide GE, Cox RJ, et al. Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy. Eur J Neurol. 2018;25:527–534.
   PubMed Web of Science ®Google Scholar
• Schwid SR, Decker MD, Lopez-Bresnahan M, et al. Immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta-1a. Neurology. 2005;65:1964–1966.
   PubMed Web of Science ®Google Scholar
• Davis MD, Ashtamker N, Steinerman JR, et al. Time course of glatiramer acetate efficacy in patients with RRMS in the GALA study Internet]. 2017 [cited 2019 Jul 25];4. Available from. Neurol Neuroimmunol Neuroinflammation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299631/
   Google Scholar
• Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 multiple sclerosis study group. Neurology. 1995;45:1268–1276.
   PubMed Web of Science ®Google Scholar
• Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2009;374:1503–1511.
   PubMed Web of Science ®Google Scholar
• Comi G, Amato MP, Bertolotto A, et al. The heritage of glatiramer acetate and its use in multiple sclerosis. Mult Scler Demyelinating Disord. 2016;1:6.
   Google Scholar
• Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs glatiramer acetate in relapsing MS disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7:903–914.
   PubMed Web of Science ®Google Scholar
• Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72:1976–1983.
   PubMed Web of Science ®Google Scholar
• Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087–1097.
   PubMed Web of Science ®Google Scholar
• Khan O, Rieckmann P, Boyko A, et al. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73:705–713.
   PubMed Web of Science ®Google Scholar
• Kolitz S, Hasson T, Towfic F, et al. Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids Internet]. 2015 [cited 2019 Jan 27];5. Available from. Sci Rep. [];. : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441120/
   Web of Science ®Google Scholar
• Borchard G, Crommelin DJA. Equivalence of glatiramer acetate products: challenges in assessing pharmaceutical equivalence and critical clinical performance attributes. Expert Opin Drug Deliv. 2018;15:247–259.
   PubMed Web of Science ®Google Scholar
• D’Alessandro JS, Duffner J, Pradines J, et al. Equivalent gene expression profiles between Glatopatm and Copaxone®. PloS One. 2015;10:e0140299.
   PubMed Web of Science ®Google Scholar
• Annovazzi P, Bertolotto A, Brescia Morra V, et al. A comprehensive review on Copemyl®. Neurol Ther. 2017;6:161–173.
   PubMed Web of Science ®Google Scholar
• Cohen J, Belova A, Selmaj K, et al. Equivalence of generic glatiramer acetate in multiple sclerosis: a randomized clinical trial. JAMA Neurol. 2015;72:1433–1441.
   PubMed Web of Science ®Google Scholar
• Selmaj K, Barkhof F, Belova AN, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler. 2017;23:1909–1917.
   PubMed Web of Science ®Google Scholar
• Ford C, Goodman AD, Johnson K, et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler. 2010;16:342–350.
   PubMed Web of Science ®Google Scholar
• MS-UK. Copaxone use during pregnancy by relapsing MS patients now possible in EU (08/12/16) [Internet]. [cited 2019 Jul 24]. Available from: https://www.ms-uk.org/copaxone-use-during-pregnancy-relapsing-ms-patients-now-possible-eu-081216
   Google Scholar
• Sandberg-Wollheim M, Neudorfer O, Grinspan A, et al. Pregnancy outcomes from the branded glatiramer acetate pregnancy database. Int J MS Care. 2018;20:9–14.
   PubMedGoogle Scholar
• Giannini M, Portaccio E, Ghezzi A, et al. Pregnancy and fetal outcomes after glatiramer acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. BMC Neurol. 2012;12:124.
   PubMed Web of Science ®Google Scholar
• Almas S, Vance J, Baker T, et al. Management of multiple sclerosis in the breastfeeding mother. Mult Scler Int. 2016;2016:6527458.
   PubMed Web of Science ®Google Scholar
• D’Amico E, Leone C, Caserta C, et al. Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal. Expert Rev Neurother. 2015;15:803–824.
   PubMed Web of Science ®Google Scholar
• Oh J, O’Connor PW. Teriflunomide in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord. 2014;7:239–252.
   PubMed Web of Science ®Google Scholar
• O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293–1303.
   PubMed Web of Science ®Google Scholar
• Confavreux C, O’Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:247–256.
   PubMed Web of Science ®Google Scholar
• Miller AE, Wolinsky JS, Kappos L, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:977–986.
   PubMed Web of Science ®Google Scholar
• O’Connor P, Comi G, Freedman MS, et al. Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. Neurology. 2016;86:920–930.
   PubMed Web of Science ®Google Scholar
• Confavreux C, Li DK, Freedman MS, et al. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Mult Scler. 2012;18:1278–1289.
   PubMed Web of Science ®Google Scholar
• Miller AE. Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. Clin Ther. 2015;37:2366–2380.
   PubMed Web of Science ®Google Scholar
• Aubagio | European Medicines Agency [Internet]. [cited 2019 Jan 29]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/aubagio
   Google Scholar
• Comi G, Freedman MS, Kappos L, et al. Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions. Mult Scler Relat Disord. 2016;5:97–104.
   PubMed Web of Science ®Google Scholar
• Epstein DJ, Dunn J, Deresinski S. Infectious complications of multiple sclerosis therapies: implications for screening, prophylaxis, and management. Open Forum Infect Dis. 2018;5. ofy174.
   PubMed Web of Science ®Google Scholar
• Aly L, Hemmer B, Korn T. From leflunomide to teriflunomide: drug development and immunosuppressive oral drugs in the treatment of multiple sclerosis. Curr Neuropharmacol. 2017;15:874–891.
   PubMed Web of Science ®Google Scholar
• Lorefice L, Fenu G, Gerevini S, et al. PML in a person with multiple sclerosis: Is teriflunomide the felon? Neurology. 2018;90:83–85.
   PubMed Web of Science ®Google Scholar
• Bar-Or A, Freedman MS, Kremenchutzky M, et al. Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis. Neurology. 2013;81:552–558.
   PubMed Web of Science ®Google Scholar
• Lebrun C, Rocher F. Cancer risk in patients with multiple sclerosis: potential impact of disease-modifying drugs. CNS Drugs. 2018;32:939–949.
   PubMed Web of Science ®Google Scholar
• Vukusic S, Coyle PK, Jurgensen S, et al. Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience. Mult Scler. 2019. 1352458519843055.
   Google Scholar
• Kieseier BC, Benamor M. Pregnancy outcomes following maternal and paternal exposure to teriflunomide during treatment for relapsing-remitting multiple sclerosis. Neurol Ther. 2014;3:133–138.
   PubMedGoogle Scholar
• Faissner S, Gold R. Efficacy and safety of the newer multiple sclerosis drugs approved since 2010. CNS Drugs. 2018;32:269–287.
   PubMed Web of Science ®Google Scholar
• Guarnera C, Bramanti P, Mazzon E. Comparison of efficacy and safety of oral agents for the treatment of relapsing-remitting multiple sclerosis. Drug Des Devel Ther. 2017;11:2193–2207.
   PubMed Web of Science ®Google Scholar
• Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–1107.
   PubMed Web of Science ®Google Scholar
• Gold R, Arnold DL, Bar-Or A, et al. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study. Mult Scler. 2017;23:253–265.
   PubMed Web of Science ®Google Scholar
• Fernández Ó, Giovannoni G, Fox RJ, et al. Efficacy and safety of delayed-release Dimethyl fumarate for relapsing-remitting multiple sclerosis in prior interferon users: an integrated analysis of DEFINE and CONFIRM. Clin Ther. 2017;39:1671–1679.
   PubMed Web of Science ®Google Scholar
• Linker RA, Haghikia A. Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy. Ther Adv Chronic Dis. 2016;7:198–207.
   PubMed Web of Science ®Google Scholar
• Diebold M, Altersberger V, Décard BF, et al. A case of progressive multifocal leukoencephalopathy under dimethyl fumarate treatment without severe lymphopenia or immunosenescence. Mult Scler. 2019;1352458519852100.
   Google Scholar
• von Hehn C, Howard J, Liu S, et al. Immune response to vaccines is maintained in patients treated with dimethyl fumarate. Neurol Neuroimmunol Neuroinflammation. 2018;5:e409.
   PubMed Web of Science ®Google Scholar
• Fox RJ, Chan A, Gold R, et al. Characterizing absolute lymphocyte count profiles in dimethyl fumarate-treated patients with MS: Patient management considerations. Neurol Clin Pract. 2016;6:220–229.
   PubMedGoogle Scholar
• Prosperini L, Pontecorvo S. Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations. Ther Clin Risk Manag. 2016;12:339–350.
   PubMed Web of Science ®Google Scholar
• Tecfidera | European Medicines Agency [Internet]. [cited 2019 Jan 29]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/tecfidera
   Google Scholar
• Everage NJ1, Jones CC1, Hellwig K2, et al. Pregnancy outcomes from an international registry of patients treated with delayed-release dimethyl Fumarate. Rev Neurol (Paris). 2019;175:S94.
   Google Scholar
• Gold R, Phillips JT, Havrdova E, et al. Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience. Neurol Ther. 2015;4:93–104.
   PubMed Web of Science ®Google Scholar
• Kappos L, Radue E-W, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–415.
   PubMed Web of Science ®Google Scholar
• Calabresi PA, Radue E-W, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13:545–556.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Khatri B, Barkhof F, et al. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. J Neurol Neurosurg Psychiatry. 2016;87:468–475.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69:759–777.
   PubMed Web of Science ®Google Scholar
• Dooley J, Pauwels I, Franckaert D, et al. Immunologic profiles of multiple sclerosis treatments reveal shared early B cell alterations. Neurol Neuroimmunol Neuroinflammation. 2016;3:e240.
   PubMed Web of Science ®Google Scholar
• Kappos L, Cohen J, Collins W, et al. Fingolimod in relapsing multiple sclerosis: an integrated analysis of safety findings. Mult Scler Relat Disord. 2014;3:494–504.
   PubMed Web of Science ®Google Scholar
• Ward MD, Jones DE, Goldman MD. Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis. Expert Opin Drug Saf. 2014;13:989–998.
   PubMed Web of Science ®Google Scholar
• Nakahara J, Tomaske L, Kume K, et al. Three cases of non-carryover fingolimod-PML Internet]. 2019 [cited 2019 Jul 15];6. Available from. Neurol Neuroimmunol Neuroinflammation. [];. : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467684/
   PubMed Web of Science ®Google Scholar
• Francis G, Kappos L, O’Connor P, et al. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler. 2014;20:471–480.
   PubMed Web of Science ®Google Scholar
• Kappos L, O’Connor P, Radue E-W, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;84:1582–1591.
   PubMed Web of Science ®Google Scholar
• Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416–426.
   PubMed Web of Science ®Google Scholar
• Cook S, Vermersch P, Comi G, et al. Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine tablets treating multiple sclerosis orallY) study. Mult Scler. 2011;17:578–593.
   PubMed Web of Science ®Google Scholar
• Kappos L, Mehling M, Arroyo R, et al. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology. 2015;84:872–879.
   PubMed Web of Science ®Google Scholar
• Gilenya | European Medicines Agency [Internet]. [cited 2019 Jan 29]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/gilenya
   Google Scholar
• Benedetti MD, Marangi A, Bozzetti S, et al. HPV-related papillary squamous cell carcinoma of the tonsil during treatment with fingolimod. Mult Scler Relat Disord. 2018;23:24–26.
   PubMed Web of Science ®Google Scholar
• Abstract: association between fingolimod and HPV-related complications in women with MS (2017 Annual Meeting of the Consortium of Multiple Sclerosis Centers) [Internet]. [cited 2019 Apr 24]. Available from: https://cmsc.confex.com/cmsc/2017/webprogram/Paper4860.html
   Google Scholar
• Karlsson G, Francis G, Koren G, et al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology. 2014;82:674–680.
   PubMed Web of Science ®Google Scholar
• Geissbühler Y, Vile J, Koren G, et al. Evaluation of pregnancy outcomes in patients with multiple sclerosis after fingolimod exposure Internet]. 2018 [cited 2019 Jul 17];11. Available from. Ther Adv Neurol Disord. [];. : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236588/
   PubMed Web of Science ®Google Scholar
• Dobson R, Dassan P, Roberts M, et al. UK consensus on pregnancy in multiple sclerosis: “Association of British Neurologists” guidelines. Pract Neurol. 2019;19:106–114.
   PubMedGoogle Scholar
• Yednock TA, Cannon C, Fritz LC, et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992;356:63–66.
   PubMed Web of Science ®Google Scholar
• Niino M, Bodner C, Simard M-L, et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol. 2006;59:748–754.
   PubMed Web of Science ®Google Scholar
• Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354:899–910.
   PubMed Web of Science ®Google Scholar
• Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354:911–923.
   PubMed Web of Science ®Google Scholar
• Svenningsson A, Sundstrom P, Salzer J, et al. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology. 2014;83:2099–2100.
   PubMedGoogle Scholar
• Kappos L, Radue E-W, Comi G, et al. Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS. Neurology. 2015;85:29–39.
   PubMed Web of Science ®Google Scholar
• Iaffaldano P, Lucisano G, Pozzilli C, et al. Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis. Brain J Neurol. 2015;138:3275–3286.
   Web of Science ®Google Scholar
• Calabresi PA, Giovannoni G, Confavreux C, et al. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology. 2007;69:1391–1403.
   PubMed Web of Science ®Google Scholar
• Clerico M, Artusi CA, Di Liberto A, et al. Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2017;16:963–972.
   PubMed Web of Science ®Google Scholar
• Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med. 2010;61:35–47.
   PubMed Web of Science ®Google Scholar
• Avasarala J. The TOUCH program and natalizumab: fundamental flaw in patient protection. F1000Res. 2015;4:1450.
   PubMedGoogle Scholar
• Biogen. Biogen-Medical Information TYSABRI® (natalizumab): PML Incidence in Patients Receiving TYSABRI (EMA region). 2019.
   Google Scholar
• Biogen, TYSABRI® (natalizumab): PML Incidence in Patients Receiving TYSABRI (EMA region), U.S.S. 2018, Editor. 2018.
   Google Scholar
• Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–1880.
   PubMed Web of Science ®Google Scholar
• Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87:885–889.
   PubMed Web of Science ®Google Scholar
• A study to evaluate efficacy, safety, and tolerability of 6-week extended interval dosing of natalizumab (BG00002) in participants with relapsing-remitting multiple sclerosis (RRMS) switching from treatment with 4-week natalizumab standard interval dosing (SID) in relation to continued SID treatment - full text view - clinicalTrials.gov [Internet]. [cited 2019 Aug 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT03689972
   Google Scholar
• Gundacker ND, Jordan SJ, Jones BA, et al. Acute cryptococcal immune reconstitution inflammatory syndrome in a patient on natalizumab. Open Forum Infect Dis. 2016;3:ofw038.
   PubMed Web of Science ®Google Scholar
• Fine AJ, Sorbello A, Kortepeter C, et al. Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis Off Publ Infect Dis Soc Am. 2013;57:849–852.
   PubMed Web of Science ®Google Scholar
• Vågberg M, Kumlin U, Svenningsson A. Humoral immune response to influenza vaccine in natalizumab-treated MS patients. Neurol Res. 2012;34:730–733.
   PubMed Web of Science ®Google Scholar
• Kaufman M, Pardo G, Rossman H, et al. Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis. J Neurol Sci. 2014;341:22–27.
   PubMed Web of Science ®Google Scholar
• Bezabeh S, Flowers CM, Kortepeter C, et al. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther. 2010;31:1028–1035.
   PubMed Web of Science ®Google Scholar
• Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med. 2008;358:647–648.
   PubMed Web of Science ®Google Scholar
• Na A, Hall N, Kavar B, et al. Central nervous system lymphoma associated with natalizumab. J Clin Neurosci Off J Neurosurg Soc Australas. 2014;21:1068–1070.
   PubMed Web of Science ®Google Scholar
• Schowinsky J, Corboy J, Vollmer T, et al. Natalizumab-associated complication? First case of peripheral T cell lymphoma. Acta Neuropathol (Berl). 2012;123:751–752.
   PubMed Web of Science ®Google Scholar
• Proschmann U, Thomas K, Thiel S, et al. Natalizumab during pregnancy and lactation. Mult Scler. 2018;24:1627–1634.
   PubMed Web of Science ®Google Scholar
• Ebrahimi N, Herbstritt S, Gold R, et al. Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study. Mult Scler Houndmills Basingstoke Engl. 2015;21:198–205.
   PubMed Web of Science ®Google Scholar
• Friend S, Richman S, Bloomgren G, et al. Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study. BMC Neurol. 2016;16:150.
   PubMed Web of Science ®Google Scholar
• Peng A, Qiu X, Zhang L, et al. Natalizumab exposure during pregnancy in multiple sclerosis: a systematic review. J Neurol Sci. 2019;396:202–205.
   PubMed Web of Science ®Google Scholar
• Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: fetal risks. Neurology. 2018;90:e823–e831.
   PubMed Web of Science ®Google Scholar
• Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90:e832–e839.
   PubMed Web of Science ®Google Scholar
• Haghikia A, Langer-Gould A, Rellensmann G, et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol. 2014;71:891–895.
   PubMed Web of Science ®Google Scholar
• Anonymous. Tysabri [Internet]. Eur Med Agency. 2018. [cited 2019 Jul 19]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/tysabri
   Google Scholar
• Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet Lond Engl. 2012;380:1829–1839.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet Lond Engl. 2012;380:1819–1828.
   PubMed Web of Science ®Google Scholar
• Ruck T, Bittner S, Wiendl H, et al. Alemtuzumab in multiple sclerosis: mechanism of action and beyond. Int J Mol Sci. 2015;16:16414–16439.
   PubMed Web of Science ®Google Scholar
• Thompson SAJ, Jones JL, Cox AL, et al. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J Clin Immunol. 2010;30:99–105.
   PubMed Web of Science ®Google Scholar
• McCall B. Alemtuzumab to be restricted pending review, says EMA. Lancet Lond Engl. 2019;393:1683.
   PubMed Web of Science ®Google Scholar
• Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord. 2017;10:343–359.
   PubMed Web of Science ®Google Scholar
• Lemtrada | European Medicines Agency [Internet]. [cited 2019 Jan 29]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/lemtrada
   Google Scholar
• Pariani N, Willis M, Muller I, et al. Alemtuzumab-induced thyroid dysfunction exhibits distinctive clinical and immunological features. J Clin Endocrinol Metab. 2018;103:3010–3018.
   PubMed Web of Science ®Google Scholar
• Muller I, Willis M, Healy S, et al. Longitudinal characterization of autoantibodies to the thyrotropin receptor (TRAb) during alemtuzumab therapy: evidence that TRAb may precede thyroid dysfunction by many years. Thyroid Off J Am Thyroid Assoc. 2018;28:1682–1693.
   PubMed Web of Science ®Google Scholar
• Devonshire V, Phillips R, Wass H, et al. Monitoring and management of autoimmunity in multiple sclerosis patients treated with alemtuzumab: practical recommendations. J Neurol. 2018;265:2494–2505.
   PubMed Web of Science ®Google Scholar
• Wray S, Havrdova E, Snydman DR, et al. Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study. Mult Scler. 2018;1352458518796675.
   Google Scholar
• Rau D, Lang M, Harth A, et al. Listeria meningitis complicating alemtuzumab treatment in multiple sclerosis—report of two cases. Int J Mol Sci. 2015;16:14669–14676.
   PubMed Web of Science ®Google Scholar
• Pappolla A, Midaglia L, Boix Rodríguez CP, et al. Simultaneous CMV and listeria infection following alemtuzumab treatment for multiple sclerosis. Neurology. 2019;92(6):296–298.
   PubMed Web of Science ®Google Scholar
• Brownlee WJ, Chataway J. Opportunistic infections after alemtuzumab: New cases of norcardial infection and cytomegalovirus syndrome. Mult Scler. 2017;23:876–877.
   PubMed Web of Science ®Google Scholar
• Coles AJ, Cohen JA, Fox EJ, et al. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology. 2017;89:1117–1126.
   PubMed Web of Science ®Google Scholar
• Havrdova E, Arnold DL, Cohen JA, et al. Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology. 2017;89:1107–1116.
   PubMed Web of Science ®Google Scholar
• McCarthy CL, Tuohy O, Compston DAS, et al. Immune competence after alemtuzumab treatment of multiple sclerosis. Neurology. 2013;81:872–876.
   PubMed Web of Science ®Google Scholar
• Haghikia A, Dendrou CA, Schneider R, et al. Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy. Lancet Neurol. 2017;16:104–106.
   PubMed Web of Science ®Google Scholar
• Research C for DE and. FDA warns about rare but serious risks of stroke and blood vessel wall tears with multiple sclerosis drug Lemtrada (alemtuzumab). FDA [Internet]. 2019 [cited 2019 Jul 20]; Available from: http://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-serious-risks-stroke-and-blood-vessel-wall-tears-multiple-sclerosis-drug
   Google Scholar
• Lemtrada [Internet]. Eur. Med. Agency. 2019 [cited 2019 Jul]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/lemtrada
   Google Scholar
• Myro AZ, Bjerke G, Zarnovicky S, et al. Diffuse alveolar hemorrhage during alemtuzumab infusion in a patient with multiple sclerosis: a case report. BMC Pharmacol Toxicol. 2018;19:75.
   PubMed Web of Science ®Google Scholar
• Romba MC, Newsome SD, McArthur JC. Acute myocardial infarction associated with initial alemtuzumab infusion cycle in relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2019;34:100–102.
   PubMedGoogle Scholar
• Azevedo CJ, Kutz C, Dix A, et al. Intracerebral haemorrhage during alemtuzumab administration. Lancet Neurol. 2019;18:329–331.
   PubMed Web of Science ®Google Scholar
• Durand-Dubief F, Marignier R, Berthezene Y, et al. Spontaneous multiple cervical artery dissections after alemtuzumab. Mult Scler. 2019;1352458519828663.
   Google Scholar
• Saarela M, Senthil K, Jones J, et al. Hemophagocytic lymphohistiocytosis in 2 patients with multiple sclerosis treated with alemtuzumab. Neurology. 2018;90:849–851.
   PubMed Web of Science ®Google Scholar
• Beattie W, Yan B, Sood S. Acute severe hepatitis with alemtuzumab and rechallenge after a year. J Clin Neurosci Off J Neurosurg Soc Australas. 2019;60:158–160.
   PubMed Web of Science ®Google Scholar
• Rog D, Chambers C, McCombe P, et al. Pregnancy outcomes in alemtuzumab-treated patients with Rrms. J Neurol Neurosurg Psychiatry. 2016;87:e1–e1.
   PubMed Web of Science ®Google Scholar
• LEMTRADA pregnancy registry in multiple sclerosis - full text view - clinicalTrials.gov [Internet]. [cited 2019 Jul 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT03774914
   Google Scholar
• Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017;376:221–234.
   PubMed Web of Science ®Google Scholar
• Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376:209–220.
   PubMed Web of Science ®Google Scholar
• D’Amico E, Patti F, Zanghì A, et al. A personalized approach in progressive multiple sclerosis: the current status of disease modifying therapies (DMTs) and future perspectives Internet]. 2016 [cited 2019 Aug 16];17. Available from. Int J Mol Sci. [];. : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085756/
   Web of Science ®Google Scholar
• Hultin LE, Hausner MA, Hultin PM, et al. Cd20 (pan-B cell) antigen is expressed at a low level on a subpopulation of human T lymphocytes. Cytometry. 1993;14:196–204.
   PubMedGoogle Scholar
• Palanichamy A, Jahn S, Nickles D, et al. Rituximab efficiently depletes increased CD20 expressing T cells in multiple sclerosis patients. J Immunol (Baltimore, MD). 1950;2014(193):580–586.
   Google Scholar
• Gingele S, Jacobus TL, Konen FF, et al. Ocrelizumab depletes CD20+ T cells in multiple sclerosis patients. Cells. 2018;8(1). pii: E12.
   PubMed Web of Science ®Google Scholar
• Klein C, Lammens A, Schäfer W, et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. mAbs. 2013;5:22–33.
   PubMed Web of Science ®Google Scholar
• Ocrevus | European Medicines Agency [Internet]. [cited 2019 Jan 29]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ocrevus
   Google Scholar
• Cohen BA. Late-onset neutropenia following ocrelizumab therapy for multiple sclerosis. Neurology. 2019;92:435–436.
   PubMed Web of Science ®Google Scholar
• Bittner S, Ruck T, Wiendl H, et al. Targeting B cells in relapsing-remitting multiple sclerosis: from pathophysiology to optimal clinical management. Ther Adv Neurol Disord. 2017;10:51–66.
   PubMed Web of Science ®Google Scholar
• Kado R, Sanders G, McCune WJ. Diagnostic and therapeutic considerations in patients with hypogammaglobulinemia after rituximab therapy. Curr Opin Rheumatol. 2017;29:228–233.
   PubMed Web of Science ®Google Scholar
• Hu Y, Jayagopal LA, Persenaire M, et al. Effects of ocrelizumab on immune parameters in a cohort of MS patients (P4.2-049). Neurology. 2019;92:P4.2–049.
   Web of Science ®Google Scholar
• Roche. OCREVUS® (ocrelizumab). Medical information website. [Internet]. 2019. [updated 2019 Feb 1; cited 2019 Feb 1]. https://www.ocrelizumabinfo.global/. Available from: https://www.ocrelizumabinfo.com/content/dam/gene/ocrelizumabinfo/pdfs/progressive-multifocal-leukoencephalopathy.pdf
   Google Scholar
• Stokmaier D, Winthrop K, Chognot C, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis. Neurology. 2018;90:S36.002.
   Google Scholar
• Westra J, van Assen S, Wilting KR, et al. Rituximab impairs immunoglobulin (Ig)M and IgG (subclass) responses after influenza vaccination in rheumatoid arthritis patients. Clin Exp Immunol. 2014;178:40–47.
   PubMed Web of Science ®Google Scholar
• Wormser D, Engel P, Hahn K, et al. Design of the ocrelizumab pregnancy registry to assess maternal, fetal and infant outcomes in women with multiple sclerosis who were exposed to ocrelizumab during, or within 6 months before, pregnancy. Neurology. 2018;90:P4.367.
   Web of Science ®Google Scholar
• Gelfand JM, Cree BAC, Hauser SL. Ocrelizumab and other CD20+ B-cell-depleting therapies in multiple sclerosis. Neurotherapeutics. 2017;14:835–841.
   PubMed Web of Science ®Google Scholar
• Ocrevus Prescribing Information. [cited 2017 May 31]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761053lbl.pdf
   Google Scholar
• Kim W, Zandoná ME, Kim S-H, et al. Oral disease-modifying therapies for multiple sclerosis. J Clin Neurol Seoul Korea. 2015;11:9–19.
   PubMed Web of Science ®Google Scholar
• Leist TP, Weissert R. Cladribine: mode of action and implications for treatment of multiple sclerosis. Clin Neuropharmacol. 2011;34:28–35.
   PubMed Web of Science ®Google Scholar
• Press Release Template - Cladribine Tablets EMA Deu.pdf [cited 2017 Apr 14].
   Google Scholar
• Giovannoni G, Cook S, Rammohan K, et al. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol. 2011;10:329–337.
   PubMed Web of Science ®Google Scholar
• Comi G, Cook SD, Giovannoni G, et al. MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study. J Neurol. 2013;260:1136–1146.
   PubMed Web of Science ®Google Scholar
• De Stefano N, Giorgio A, Battaglini M, et al. Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets. Mult Scler. 2018;24:222–226.
   PubMed Web of Science ®Google Scholar
• Leist TP, Comi G, Cree BAC, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014;13:257–267.
   PubMed Web of Science ®Google Scholar
• Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Trials - Full Text View - ClinicalTrials.gov [Internet]. [cited 2019 Feb 2]. Available from: https://clinicaltrials.gov/ct2/show/NCT01013350
   Google Scholar
• Carson DA, Wasson DB, Taetle R, et al. Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood. 1983;62:737–743.
   PubMed Web of Science ®Google Scholar
• UMC | VigiBase, t. W.H.O.W., international databse of suspected adverse drug reactions. [Internet]. 2017. [updated 2017 Jul 12; cited 2019 Feb 2]. Available from: https://www.who-umc.org/vigibase/vigibase/
   Google Scholar
• Cladribine (Litak, Leustat) for leukaemia: reports of progressive multifocal encephalopathy (PML); stop treatment if PML suspected [Internet]. GOV.UK. [cited 2019 Jun 28]. Available from: https://www.gov.uk/drug-safety-update/cladribine-litak-leustat-for-leukaemia-reports-of-progressive-multifocal-encephalopathy-pml-stop-treatment-if-pml-suspected
   Google Scholar
• Leustat injection. - summary of product characteristics (SmPC) - (eMC) [Internet]. [cited 2019 Feb 2]. Available from: https://www.medicines.org.uk/emc/product/1438/smpc#CLINICAL_PRECAUTIONS
   Google Scholar
• Pakpoor J, Disanto G, Altmann DR, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflammation. 2015;2:e158.
   PubMed Web of Science ®Google Scholar
• Anonymous. Mavenclad [Internet]. Eur Med Agency. 2018. [cited 2019 Apr 24]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/mavenclad
   Google Scholar
• Orlowski RZ. Successful pregnancy after cladribine therapy for hairy cell leukemia. Leuk Lymphoma. 2004;45:187–188.
   PubMed Web of Science ®Google Scholar
• Galazka A, Nolting A. Pregnancy outcomes during the clinical development of cladribine in multiple sclerosis: an integrated analysis of safety. Mult Scler Relat Disord. 2018;26:260–261.
   Google Scholar
• D’Amico E, Leone C, Graziano G, et al. The use of immunosuppressant therapy for multiple sclerosis in italy: a multicenter retroprospective study. PloS One. 2016;11:e0157721.
   PubMed Web of Science ®Google Scholar
• Massacesi L, Tramacere I, Amoroso S, et al. Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial. PloS One. 2014;9:e113371.
   PubMed Web of Science ®Google Scholar
• Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev. 2007;(4):CD003982.
   PubMed Web of Science ®Google Scholar
• La Mantia L, Mascoli N, Azathioprine MC. Safety profile in multiple sclerosis patients. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2007;28:299–303.
   Google Scholar
• Confavreux C, Saddier P, Grimaud J, et al. Risk of cancer from azathioprine therapy in multiple sclerosis: a case-control study. Neurology. 1996;46:1607–1612.
   PubMed Web of Science ®Google Scholar
• Azathioprine 50 mg tablets - summary of product characteristics (SmPC) - (eMC) [Internet]. [cited 2019 Jan 31]. Available from: https://www.medicines.org.uk/emc/product/3301/smpc
   Google Scholar
• Stankiewicz JM, Kolb H, Karni A, et al. Role of immunosuppressive therapy for the treatment of multiple sclerosis. Neurother J Am Soc Exp Neurother. 2013;10:77–88.
   Google Scholar
• La Mantia L, Milanese C, Mascoli N, et al. Cyclophosphamide for multiple sclerosis. Cochrane Database Syst Rev. 2007;(1):CD002819.
   PubMed Web of Science ®Google Scholar
• Weinstock-Guttman B, Kinkel RP, Cohen JA, et al. Treatment of fulminant multiple sclerosis with intravenous cyclophosphamide. Neurologist. 1997;3:178.
   Web of Science ®Google Scholar
• Manova MG, Kostadinova II, Rangelov AA. Clinico-laboratory study of methylprednisolone and cyclophosphamide treatment in patients with multiple sclerosis relapse. Folia Med (Plovdiv). 2000;42:20–25.
   PubMedGoogle Scholar
• Patti F, Reggio E, Palermo F, et al. Stabilization of rapidly worsening multiple sclerosis for 36 months in patients treated with interferon beta plus cyclophosphamide followed by interferon beta. J Neurol. 2004;251:1502–1506.
   PubMed Web of Science ®Google Scholar
• Gonsette RE, Demonty L, Delmotte P. Intensive immunosuppression with cyclophosphamide in multiple sclerosis. Follow up of 110 patients for 2-6 years. J Neurol. 1977;214:173–181.
   PubMed Web of Science ®Google Scholar
• Patti F, Lo Fermo S. Lights and shadows of cyclophosphamide in the treatment of multiple sclerosis. Autoimmune Dis. 2011;2011:961702.
   PubMedGoogle Scholar
• Cyclophosphamide 500 mg powder for solution for injection or infusion - summary of product characteristics (SmPC) - (eMC) [Internet]. [cited 2019 Feb 1]. Available from: https://www.medicines.org.uk/emc/product/3526/smpc
   Google Scholar
• Awad A, Stüve O. Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms. Ther Adv Neurol Disord. 2009;2:50–61.
   PubMedGoogle Scholar
• De Ridder D, van Poppel H, Demonty L, et al. Bladder cancer in patients with multiple sclerosis treated with cyclophosphamide. J Urol. 1998;159:1881–1884.
   PubMed Web of Science ®Google Scholar
• Fox EJ. Mechanism of action of mitoxantrone. Neurology. 2004;63:S15–18.
   PubMed Web of Science ®Google Scholar
• Novantrone and associated names | European Medicines Agency [Internet]. [cited 2019 Feb 1]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/novantrone-associated-names
   Google Scholar
• Hartung H-P, Gonsette R, König N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet Lond Engl. 2002;360:2018–2025.
   PubMed Web of Science ®Google Scholar
• Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 1997;62:112–118.
   PubMed Web of Science ®Google Scholar
• Zaffaroni M, Ghezzi A, Comi G. Intensive immunosuppression in multiple sclerosis. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2006;27(Suppl 1):S13–17.
   Google Scholar
• Martinelli V, Cocco E, Capra R, et al. Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology. 2011;77:1887–1895.
   PubMed Web of Science ®Google Scholar
• Koyama A, Tanaka A, To H. Daily oral administration of low-dose methotrexate has greater antirheumatic effects in collagen-induced arthritis rats. J Pharm Pharmacol. 2017;69:1145–1154.
   PubMed Web of Science ®Google Scholar
• Calabresi PA, Wilterdink JL, Rogg JM, et al. An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS. Neurology. 2002;58:314–317.
   PubMed Web of Science ®Google Scholar
• Currier RD, Haerer AF, Meydrech EF. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry. 1993;56:1217–1218.
   PubMed Web of Science ®Google Scholar
• Fernández O, Fernández V, De Ramón E. Azathioprine and methotrexate in multiple sclerosis. J Neurol Sci. 2004;223:29–34.
   PubMed Web of Science ®Google Scholar
• Methotrexate 2.5mg tablets - Summary of product characteristics (SmPC) - (eMC) [Internet]. [cited 2019 Jan 31]. Available from: https://www.medicines.org.uk/emc/product/511/smpc
   Google Scholar
• Rommer PS, Zettl UK. Managing the side effects of multiple sclerosis therapy: pharmacotherapy options for patients. Expert Opin Pharmacother. 2018;19:483–498.
   PubMed Web of Science ®Google Scholar
• Zecca C, Disanto G, Sacco R, et al. Use of glatiramer acetate between 2010-2015: effectiveness, safety and reasons to start GA as first or second line treatment in Swiss multiple sclerosis patients. BMC Neurol. 2019;19:159.
   PubMed Web of Science ®Google Scholar
• Bartolomé-García E, Usarralde-Pérez Á, Sanmartín-Fenollera P, et al. Persistence and adherence to interferon and glatiramer acetate in patients with multiple sclerosis. Eur J Hosp Pharm Sci Pract. 2019;26:23–28.
   PubMedGoogle Scholar
• Zettl UK, Hecker M, Aktas O, et al. Interferon β-1a and β-1b for patients with multiple sclerosis: updates to current knowledge. Expert Rev Clin Immunol. 2018;14:137–153.
   PubMed Web of Science ®Google Scholar
• Dubey D, Cano CA, Stüve O. Update on monitoring and adverse effects of first generation disease modifying therapies and their recently approved versions in relapsing forms of multiple sclerosis. Curr Opin Neurol. 2016;29:272–277.
   PubMed Web of Science ®Google Scholar
• MacDonald SC, McElrath TF, Hernández-Díaz S. Use and safety of disease-modifying therapy in pregnant women with multiple sclerosis. Pharmacoepidemiol Drug Saf. 2019;28:556–560.
   PubMed Web of Science ®Google Scholar
• Wynn DR. Enduring clinical value of Copaxone® (Glatiramer Acetate) in multiple sclerosis after 20 years of use. Mult Scler Int. 2019;2019:7151685.
   PubMedGoogle Scholar
• Aramideh Khouy R, Karampoor S, Keyvani H, et al. The frequency of varicella-zoster virus infection in patients with multiple sclerosis receiving fingolimod. J Neuroimmunol. 2019;328:94–97.
   PubMed Web of Science ®Google Scholar
• 2014 joint ACTRIMS-ECTRIMS meeting (MSBoston 2014): oral presentations. Mult Scler Houndmills Basingstoke Engl. 2014;20:14–66.
   Google Scholar
• Movectro Withdrawal EPAR clean - WC500104393.pdf [cited 2017 Apr]. 2014
   Google Scholar
• Research C for DE and. Drug Safety and Availability - FDA working with manufacturers to withdraw Zinbryta from the market in the United States [Internet]. [cited 2019 Feb 2]. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm600999.htm
   Google Scholar
• Avasarala J. Dress syndrome and daclizumab failure—Were potentially dangerous signs missed in clinical trials? Drug Target Insights. Internet]. 2018 [cited 2019 Jul 26];12. Available from. [];. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043933/
   PubMed Web of Science ®Google Scholar
• Amato MP, Portaccio E. Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs. CNS Drugs. 2015;29:207–220.
   PubMed Web of Science ®Google Scholar
• Pozzilli C, Pugliatti M, ParadigMS Group. An overview of pregnancy-related issues in patients with multiple sclerosis. Eur J Neurol. 2015;22(Suppl 2):34–39.
   PubMedGoogle Scholar
• Iannazzo S, Iliza A-C PL. Disease-modifying therapies for multiple sclerosis: a systematic literature review of cost-effectiveness studies. PharmacoEconomics. 2018;36:189–204.
   PubMed Web of Science ®Google Scholar