Natalizumab for relapsing-remitting multiple sclerosis in adults
- Michael J Olek, DO
Michael J Olek, DO
- Associate Professor of Neurology
- Loma Linda University Medical Center
Natalizumab is an effective drug for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, its use is associated with the development of progressive multifocal leukoencephalopathy (PML), a potentially fatal complication.
This topic will review issues related to the use of natalizumab for the treatment of RRMS in adults. Other disease-modifying treatment for relapsing forms of MS are discussed in detail separately. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults".)
Natalizumab is a recombinant monoclonal antibody directed against alpha-4 integrins. The formation of inflammatory lesions in patients with multiple sclerosis (MS) may involve lymphocytes and monocytes that gain access to the brain parenchyma from the circulation by first adhering to vascular endothelial cells [1,2]. Alpha-4 integrin is expressed on the surface of inflammatory lymphocytes and monocytes and may play a critical role in their adhesion to the vascular endothelium.
Treatment with alpha-4 integrin antagonists in rodent models of MS led to reduced signs of disease activity and inflammation [3-5]. In a preliminary six-month clinical trial of 213 patients with MS, natalizumab treatment was associated with significantly fewer new enhancing brain lesions on MRI and significantly fewer relapses compared with placebo . In patients with MS, natalizumab treatment is associated with a diminished migratory capacity of immune cells and a prolonged decrease in lymphocyte counts in the cerebrospinal fluid [7,8].
Natalizumab is one of several disease-modifying agents that effectively reduce the relapse rate for patients with relapsing-remitting multiple sclerosis (RRMS). The main concern with natalizumab therapy is the risk of developing progressive multifocal leukoencephalopathy (PML). The choice of a specific agent for patients with RRMS should be individualized according to disease activity and patient values and preferences (algorithm 1), as discussed in detail elsewhere (see "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults"). In this context, we suggest infusion therapy with natalizumab for patients with more active RRMS and for those who value effectiveness above safety and convenience, including use of natalizumab as a first-line agent. In contrast, earlier guidelines (published in 2008) by the American Academy of Neurology (AAN) recommended that natalizumab be reserved for patients with RRMS who failed other therapies because of continued disease activity or medication intolerance, or who had a very aggressive initial disease course . As of June 2016, approximately 153,000 patients had received natalizumab with over 487,000 patients-years of exposure .
- Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 2005; 64:1336.
- Hynes RO. Integrins: a family of cell surface receptors. Cell 1987; 48:549.
- 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.
- Kent SJ, Karlik SJ, Cannon C, et al. A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis. J Neuroimmunol 1995; 58:1.
- Kent SJ, Karlik SJ, Rice GP, Horner HC. A monoclonal antibody to alpha 4-integrin reverses the MR-detectable signs of experimental allergic encephalomyelitis in the guinea pig. J Magn Reson Imaging 1995; 5:535.
- Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348:15.
- Niino M, Bodner C, Simard ML, et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol 2006; 59:748.
- Stüve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006; 59:743.
- Goodin DS, Cohen BA, O'Connor P, et al. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008; 71:766.
- Tysabri® (natalizumab) safety update. https://medinfo.biogen.com (Accessed on July 21, 2016).
- Kappos L, Bates D, Hartung HP, et al. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol 2007; 6:431.
- Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J Med 2007; 356:2622.
- Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev 2011; :CD007621.
- 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.
- Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354:911.
- Rudick RA, Miller D, Hass S, et al. Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann Neurol 2007; 62:335.
- Ropper AH. Selective treatment of multiple sclerosis. N Engl J Med 2006; 354:965.
- Zintzaras E, Doxani C, Mprotsis T, et al. Network analysis of randomized controlled trials in multiple sclerosis. Clin Ther 2012; 34:857.
- Tramacere I, Del Giovane C, Salanti G, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev 2015; :CD011381.
- Barbin L, Rousseau C, Jousset N, et al. Comparative efficacy of fingolimod vs natalizumab: A French multicenter observational study. Neurology 2016; 86:771.
- Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005; 353:375.
- Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353:369.
- Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab--unforeseen consequences. N Engl J Med 2005; 353:414.
- Kappos L, Bates D, Edan G, et al. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol 2011; 10:745.
- Fox RJ, Rudick RA. Risk stratification and patient counseling for natalizumab in multiple sclerosis. Neurology 2012; 78:436.
- Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366:1870.
- McGuigan C, Craner M, Guadagno J, et al. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry 2016; 87:117.
- Berger JR, Fox RJ. Reassessing the risk of natalizumab-associated PML. J Neurovirol 2016; 22:533.
- Gagne Brosseau MS, Stobbe G, Wundes A. Natalizumab-related PML 2 weeks after negative anti-JCV antibody assay. Neurology 2016; 86:484.
- Plavina T, Subramanyam M, Bloomgren G, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2014; 76:802.
- Kuesters G, Plavina T, Lee S, et al. Anti-JC virus (JCV) antibody index differentiates risk of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated multiple sclerosis (MS) patients with no prior immunosuppressant (IS) use: An updated analysis. Poster presentation, 67th American Academy of Neurology Annual Meeting, April 22, 2015 Washington DC, USA. www.abstracts2view.com/aan/view.php?nu=AAN15L1_P4.031 (Accessed on February 04, 2016).
- Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009; 361:1067.
- Rudick RA, O'Connor PW, Polman CH, et al. Assessment of JC virus DNA in blood and urine from natalizumab-treated patients. Ann Neurol 2010; 68:304.
- Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010; 68:295.
- Trampe AK, Hemmelmann C, Stroet A, et al. Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort. Neurology 2012; 78:1736.
- Outteryck O, Zéphir H, Salleron J, et al. JC-virus seroconversion in multiple sclerosis patients receiving natalizumab. Mult Scler 2014; 20:822.
- Schwab N, Schneider-Hohendorf T, Pignolet B, et al. Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values. Neurol Neuroimmunol Neuroinflamm 2016; 3:e195.
- Raffel J, Gafson AR, Malik O, Nicholas R. Anti-JC virus antibody titres increase over time with natalizumab treatment. Mult Scler 2015; 21:1833.
- Wijburg MT, Witte BI, Vennegoor A, et al. MRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance. J Neurol Neurosurg Psychiatry 2016; 87:1138.
- US Food and Drug Administration. Tysabri risk minimization action plan: summary of TOUCH. www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM107197.pdf (Accessed on February 09, 2016).
- Butzkueven H, Kappos L, Pellegrini F, et al. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry 2014; 85:1190.
- Freedman MS. Present and emerging therapies for multiple sclerosis. Continuum (Minneap Minn) 2013; 19:968.
- Kwiatkowski A, Gallois J, Bilbault N, et al. Herpes encephalitis during natalizumab treatment in multiple sclerosis. Mult Scler 2012; 18:909.
- Dahdaleh D, Altmann DM, Malik O, Nicholas RS. Breathlessness, night sweats, and weight loss on natalizumab. Lancet 2012; 380:726.
- Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med 2008; 358:647.
- US Food and Drug Administration. Tysabri (natalizumab) Feb 2008. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm110608.htm (Accessed on October 28, 2010).
- Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther 2010; 31:1028.
- Abbas M, Lalive PH, Chofflon M, et al. Hypereosinophilia in patients with multiple sclerosis treated with natalizumab. Neurology 2011; 77:1561.
- 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.
- Berger JR, Centonze D, Comi G, et al. Considerations on discontinuing natalizumab for the treatment of multiple sclerosis. Ann Neurol 2010; 68:409.
- O'Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011; 76:1858.
- Stüve O, Cravens PD, Frohman EM, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 2009; 72:396.
- West TW, Cree BA. Natalizumab dosage suspension: are we helping or hurting? Ann Neurol 2010; 68:395.
- Miravalle A, Jensen R, Kinkel RP. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol 2011; 68:186.
- Killestein J, Vennegoor A, Strijbis EM, et al. Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol 2010; 68:392.
- Rigau V, Mania A, Béfort P, et al. Lethal multiple sclerosis relapse after natalizumab withdrawal. Neurology 2012; 79:2214.
- Kappos L, Radue EW, Comi G, et al. Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS. Neurology 2015; 85:29.
- Zhovtis Ryerson L, Frohman TC, Foley J, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016; 87:885.