The Role of Natalizumab in the Treatment of Multiple Sclerosis

Abstract

Natalizumab is an α4-integrin antagonist, the first in its class for the treatment of multiple sclerosis (MS). Although multiple mechanisms have been proposed for the efficacy of natalizumab in MS, the most likely explanation is that it interferes with the migration of immune cells into the central nervous system. It does this by binding to the α4 subunit of α4β1-integrin and preventing leukocyte adhesion to endothelial vascular cell adhesion molecule-1. The efficacy of natalizumab in relapsing-remitting MS has been demonstrated in several double-blind, placebo-controlled trials. Natalizumab has been shown to slow the progression of disability in relapsing-remitting MS significantly better than placebo, and to reduce the number of new and enlarging T2 hyperintense and gadolinium-enhanced magnetic resonance imaging lesions. In a post hoc analysis, the proportion of patients with relapsing-remitting MS free of disease activity was significantly greater with natalizumab compared with placebo. Due to the rare risk of progressive multifocal leukoencephalopathy as a complication, natalizumab is primarily recommended in patients who fail, or cannot tolerate, treatment with interferon (IFN) beta or glatiramer acetate (GA). Stratification of those patients most likely to benefit from natalizumab treatment-such as those with highly active disease, severe disease, or extensive functional loss, or those who have failed or cannot tolerate IFN beta or GA therapy-would help define natalizumab's appropriate place in therapy.

(Am J Manag Care. 2010;16:S164-S170)

Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by immune activation with damage to the CNS components including myelin, axons, oligodendrocytes, and neurons.¹ The course of MS is quite variable. MS can range from very mild to very severe. The most common course of the disease in most untreated patients involves a relapsing pattern, which later transitions to a slow, worsening progressive pattern in most untreated patients.² If initial onset is progressive, disability will typically occur more rapidly and with greater severity.³

The effect of MS on lifespan is also quite heterogeneous. The period from symptom onset to death has been estimated to range from 20 to 45 years.⁴ Ultimately, the average person with untreated MS may be expected to lose 5 to 10 years off their natural lifespan. Onset of MS generally occurs in young and early middle-aged adults, with peak onset between the ages of 20 and 40 years.^5,6 Women are at least 2 times more likely than men to develop MS, and this trend is increasing.⁷

Pathophysiology of MS

MS is a chronic disease distinguished by waves of activity that damage the CNS. Disease activity is evident on a macroscopic level (ie, detection of MS lesions using magnetic resonance imaging [MRI]) and a cellular level. The process by which MS lesions form is complex and includes multiple factors (eg, cytokines, chemokines, and immunoglobulins). There is focal breach of the blood-brain barrier (BBB), penetration of systemic immune cells, and local immune activation and responses leading to damage of the CNS tissue.^8,9 Microglial and oligodendrocyte changes may occur that prime this immune response.

Permeability of the BBB allows more T cells to enter into the CNS.⁹ These T cells produce cytokines which activate macrophages-white blood cells that consume other cells that they "perceive" to be invasive or harmful. Resident macrophages in the brain and spinal cord-called microglia cells-are activated and attack the myelin sheath.¹⁰ The myelin sheath insulates nerve fibers (axons) and speeds up the impulses that travel along these axons. As the microglia cells attack the myelin sheath, it gradually breaks down in a process known as demyelination. Areas where the myelin sheath and surrounding tissue have been damaged form lesions. These lesions can be visualized using MRI. While remyelination processes are activated to repair the damage to the myelin sheath, in MS, this process is inadequate.⁹ In addition to the gradual demyelination just described, there is neurodegeneration (damage to axons and neurons), with consequent emergent symptoms.

MS Lesions and Detection Using MRI

MRI is used to visualize and determine the characteristics of MS lesions. T1-weighted imaging and T2-weighted imaging are the most common techniques employed to assess MS lesions. Scarred lesions are evident as white, bright (ie, hyperintense) areas on T2 images.^11,12 T1 images identify areas where nerve fibers have died; these areas are less dense (ie, hypointense) and are commonly referred to as "black holes." Gadolinium is used as a contrast agent to identify areas of active disease; it will leak into the brain tissue when there are breaks in the BBB.¹² These areas will be hyperintense on T1-weighted images, and are referred to as "gadolinium-enhancing" lesions.

Role of α4-integrin Antagonism in the Treatment of MS

Although the exact mechanism of action of natalizumab in MS is unknown, several explanations have been suggested. New lesion development follows infiltration of activated lymphocytes through the BBB, which requires the adhesion of lymphocytes to vascular endothelial cells.⁹ This process involves binding of vascular cell adhesion molecule (VCAM)-1 to α4β1-integrin located on the lymphocytes, which facilitates lymphocytic penetration of the BBB.¹³ It is generally believed that the primary mechanistic explanation for the efficacy of natalizumab is that it interferes with the migration of immune cells into the CNS by binding to the α4 subunit of α4β1-integrin, thereby preventing leukocyte adhesion to endothelial VCAM-1.

A murine version of natalizumab, AN100226m, has been shown to have a powerful limiting effect on leukocyte infiltration into the CNS of guinea pigs in a preclinical model of MS, experimental allergic encephalomyelitis (EAE).¹⁴ The rapid clearance of leukocytes from the CNS was associated with a reduction in disease progression and a substantial decrease in the incidence of demyelination. Similar results have been observed in studies of EAE in rats.¹⁵

Several other effects of natalizumab have been offered as explanations for its efficacy in MS. One such effect relates to the role of fibronectin, a component of the extracellular matrix to which α4β1-integrin binds in the course of migrating to inflammatory sites as part of the immune response.¹⁶ By binding to fibronectin, natalizumab interrupts α4β1-integrin binding, thereby reducing the inflammatory response.¹⁷ Similarly, a reduction in the inflammatory response appears to result from the binding of natalizumab to osteopontin, a protein involved in endothelial cell and leukocyte adhesion. ^17,18 Finally, it has been suggested that the clinical efficacy of natalizumab in MS may be due to its ability to induce apoptosis in T cells.¹⁹

Clinical Efficacy of Natalizumab

The clinical efficacy of natalizumab was established in a double-blind, placebo-controlled trial: the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis study, known as AFFIRM.²⁰ AFFIRM was a 2-year trial conducted in 99 clinical centers in North America, Europe, New Zealand, and Australia. A total of 942 patients between the ages of 18 and 50 years (mean age, 36 years), with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 6 (mean score, 2.3), were randomized in a 2:1 ratio to receive either natalizumab 300 mg (n = 627) or placebo (n = 315) intravenously every 4 weeks.²⁰ Patients were evaluated every 12 weeks.

The study design of AFFIRM included primary and secondary end points at years 1 and 2. At year 1, the primary end point was clinical relapse rate, and the secondary end points were: (1) number of new or enlarging MRI-detected hyperintense T2 lesions, (2) number of gadolinium-enhanced MRI lesions, and (3) proportion of patients who were relapse-free.²⁰ At year 2, the primary end point was the cumulative probability of sustained disability progression over a 12-week period. Disability progression was defined as an increase of at least 1.0 on the EDSS among patients with a baseline EDSS score of at least 1.0. (Patients with a baseline EDSS score of 0 were defined as experiencing disability progression if their EDSS score increased by at least 1.5.) At year 2, secondary end points were: (1) clinical relapse rate, (2) volume of T2-weighted lesions, (3) number of new hypointense T1 lesions, and (4) disability progression as measured by the Multiple Sclerosis Functional Composite (MSFC).

Figure 1

Natalizumab was significantly more effective than placebo. At year 1, 77% of patients given natalizumab were relapse free compared with 56% of those given placebo; at year 2, the proportions were 67% and 41%, respectively-a reduction of 59% over 2 years (P <.001 for both years).²⁰ The annualized relapse rate at year 1 was significantly lower in the natalizumab group compared with the placebo group (0.26 vs 0.81, respectively; P <.001). This benefit was sustained over 2 years, with a 68% relative reduction in the relapse rate among patients given natalizumab compared with those given placebo (0.23 vs 0.73, respectively; P <.001). The 2-year primary end point, sustained disability progression rate, was also significantly lower in natalizumab-treated patients compared with those receiving placebo; the cumulative probability of 12-week sustained progression of disability was 17% in the natalizumab group versus 29% in the placebo group (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.43- 0.77; P <.001) (). This difference represents a 42% reduction in risk of disability progression with natalizumab. When a stricter definition of disability progression was applied (sustained progression for 24 weeks), natalizumab was associated with a 54% reduction in risk (HR, 0.46; 95% CI, 0.33-0.64; P <.001).

In parallel with clinical measurements, the MRI data also reflected significantly better outcomes associated with natalizumab treatment. The mean number of new or enlarging T2 hyperintense lesions was significantly less in the natalizumab group compared with the placebo group at years 1 and 2 (P <.001 for both).^12,20 After 2 years, natalizumab was associated with an 83% reduction in the number of new or enlarging T2 hyperintense lesions compared with placebo. Similarly, there was a 92% reduction in lesions detected by gadolinium-enhancing MRI among natalizumab-treated patients compared with placebo at year 1 (0.1 natalizumab vs 1.3 placebo) and year 2 (0.1 natalizumab vs 1.2 placebo; P <.001 for both). After 2 years, mean T2 lesion volume was significantly lower in patients treated with natalizumab compared with those given placebo, and the mean number of T1 hypointense lesions in the natalizumab group was 1.1 compared with 4.6 in the placebo group, a reduction of 76% (P <.001).¹²

Several post hoc analyses of data from the AFFIRM study have provided additional insight into the benefits of natalizumab monotherapy in relapsing-remitting MS. One of the most compelling is an analysis conducted by Havrdova et al which examined the proportion of patients free of disease activity.²¹ A state of no overt disease activity is clearly an ideal treatment goal, but has not been an expected outcome for the majority of MS patients receiving therapy. In this post hoc analysis, no clinical disease activity was defined as the absence of both relapse and of disability progression (sustained for at least 12 weeks). No radiologic disease activity was defined as the absence of gadolinium-enhancing lesions and the absence of both new and enlarging T2 hyperintense lesions. (T1 hypointense lesions were excluded from these criteria due to challenges in their quantification and in the detection of lesion conversion based on annual MRIs.²¹) Of the original 942 patients enrolled in the AFFIRM trial, data from 917 patients were available for analysis of disease activity; patient characteristics were similar to those in the overall population.²¹

Figure 2

Natalizumab was associated with significant improvement compared with placebo for all measurements of disease activity. At 2 years, significantly more natalizumab-treated patients experienced no clinical disease activity compared with those given placebo (64% vs 39%, respectively; P <.0001).²¹ Differences were seen for each measure of disease activity; natalizumab was significantly better than placebo for the measures of no relapses and no disability progression for 12 weeks (P <.0001 for both).²¹ Even more pronounced was the absence of radiologic disease activity in patients given natalizumab compared with those given placebo (58% vs 14%, respectively; P <.0001). Compared with placebo, significantly fewer patients given natalizumab experienced either measure of radiologic disease activity (new gadolinium-enhancing lesions and new or enlarging T2 hyperintense lesions) (P <.0001 for both).²¹ Patients given natalizumab were also significantly more likely to have no evidence of either clinical or MRI disease activity (37%) than those given placebo (7%; P <.0001) ().

Subgroup Analyses From AFFIRM

Hutchinson and colleagues conducted an extensive analysis of data from predefined patient subgroups in the AFFIRM trial. The subgroups were defined as follows: (1) number of relapses occurring during the year prior to enrollment (1, 2, >3); (2) EDSS score (<3.5, >3.5); (3) number of T2 lesions (<9, >9); (4) presence of gadolinium-enhancing lesions (0, >1); (5) age (<40, >40 years); (6) and sex.²² Compared with placebo, natalizumab was associated with a significant reduction in the risk of disability progression in most subgroups, with the exception of the following: patients with 2 relapses prior to the start of the study, those with a baseline EDSS score of more than 3.5 (37 given placebo, 79 given natalizumab), patients with less than 9 T2 lesions (15 given placebo, 29 given natalizumab), males, and those 40 years or older.²² The annualized relapse rate was lower with natalizumab therapy in every subgroup and failed to meet statistical significance only in the small subgroup of patients with fewer than 9 T2 lesions at baseline. A reason for this might be the small number of patients in this subgroup (52 given placebo, 67 given natalizumab).

Hutchinson et al also conducted a post hoc analysis of outcomes in patients with highly active disease, defined as at least 2 relapses during the year prior to study entry and at least 1 gadolinium-enhancing lesion at study entry.²² Over the course of the 2-year study, the cumulative probability of sustained disability progression for 12 weeks was 29% with placebo compared with 14% with natalizumab, representing a 53% reduction in risk (P <.029). When a stricter definition of disability progression was applied (sustained progression for 24 weeks), natalizumab was associated with a 64% reduction in risk (P <.008).²² The annualized relapse rate in patients with highly active disease also favored natalizumab-treated patients, in whom annualized relapse rate was reduced by 81% (P <.001). The cumulative probability of relapse over the 2-year study was 75% lower in the natalizumab group compared with placebo.²²

Exploratory Analyses From AFFIRM

To evaluate the effect of treatment on loss or reduction of visual function in MS, a post hoc analysis was conducted using data from patients in the AFFIRM trial, where visual function was measured using the Sloan low-contrast letter acuity chart²³; Sloan low-contrast acuity has been demonstrated to be effective in determining visual dysfunction in MS.²⁴ Visual acuity, as measured by Sloan low-contrast charts, has been shown to correlate with EDSS and MSFC in MS. Low-contrast visual acuity was measured using both 1.25% contrast charts and 2.5% contrast charts at 12-week intervals for the entire 2-year duration of the AFFIRM study. Patients receiving placebo experienced progressive worsening (negative changes from baseline in Z scores) of low-contrast visual acuity over the 2 years, whereas patients receiving natalizumab generally maintained their visual acuity and, in some cases, showed improvements.²³ Differences between the 2 groups were significant at nearly every time point. Overall risk of sustained visual acuity loss that was considered clinically meaningful (sustained reduction by 2 or more lines in scores sustained over 12 weeks) was significantly greater in patients given placebo at both the 2.5% and 1.25% contrast levels.²³ At the 2.5% contrast level, natalizumab was associated with a 47% reduction in risk of visual acuity loss (P <.001 vs placebo); at the 1.25% contrast level, natalizumab-treated patients experienced a 35% reduced risk of visual acuity loss (P <.008 vs placebo). High-contrast visual acuity was also measured during this study, but no significant differences between the 2 groups were observed.²³

Brain atrophy over time is a further means of determining deterioration in MS, although this measure is somewhat confounded by the fact that there can be a loss of brain volume in the early stages of successful treatment with MS agents due to a reduction in edema and inflammation. This phenomenon has been observed with initial treatment with several MS agents, and has been described as pseudoatrophy.²⁵ In the BEYOND (Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in Multiple Sclerosis Patients) study, both interferon (IFN) beta-1b and glatiramer acetate (GA) treatment resulted in substantial loss of brain volume during the first year of the study, a loss that was recovered by the end of the second year of treatment.²⁶ Initial brain atrophy has also been seen in patients with MS treated with methylprednisolone.²⁷ Similarly, patients treated with natalizumab in AFFIRM experienced some degree of brain atrophy at year 1, but at the end of 2 years, brain atrophy was significantly less among patients given natalizumab compared with those receiving placebo.¹²

Taken together, these data confirm the efficacy of natalizumab in relapsing-remitting MS based on both clinical and radiologic criteria. The AFFIRM data are noteworthy because across clinical measurements, including relapse rate, disability progression, and proportion of patients who were relapse-free, patients given natalizumab consistently achieved significantly better results than those given placebo. The MRI data were similarly remarkable, as natalizumab was consistently associated with a significant reduction in the number of gadolinium-enhancing and T2 lesions. Of interest is that the study design of AFF IRM did not allow confirmation of disability progression within 4 weeks of initiation of a relapse, thereby constituting a higher threshold for the achievement of efficacy than that of other clinical trials.^28-31

Safety of Natalizumab in AFFIRM

Table

Safety results from AFFIRM were similar between natalizumab and placebo. Nearly all patients in both groups experienced some type of adverse event (AE); however, only fatigue (natalizumab 27% vs placebo 21%; P = .048) and allergic reaction (natalizumab 9% vs placebo 4%; P = .012) were significantly different.²⁰ The incidence of serious AEs was similar between natalizumab and placebo (19% vs 24%, respectively; P = .06).²⁰ The provides a full list of AEs occurring in the AFFIRM trial. The most common serious AE was relapsing MS (6% with natalizumab, 13% with placebo; P <.001). All other serious AEs occurred in less than 1% of each treatment group.

Role of Natalizumab in Clinical Practice

Natalizumab monotherapy is approved for the treatment of relapsing forms of MS. At present, natalizumab is widely regarded as a second-line therapy for MS that can be used if treatment with IFN beta or GA fails. Indeed, the US Food and Drug Administration-approved labeling for natalizumab recommends, although does not mandate, its use in cases of inadequate response or intolerability to alternate MS therapies.³² It should be noted that some practitioners do employ natalizumab as first-line therapy, and that the categorization of natalizumab as a second-line therapy is largely a consequence of the occurrence of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS caused by lytic infection of oligodendrocytes by the papovavirus JC that causes death or severe disability. As of May 6, 2010, there were 49 confirmed cases of PML among patients who received natalizumab worldwide.³³

Although the risk of PML may be a disincentive to treat with natalizumab, it is worth considering the benefits natalizumab may provide in the treatment of MS. The efficacy of natalizumab in treating patients with MS is compelling, and clinicians must weigh this benefit against the risks of natalizumab. With this in mind, patients with active disease may be considered a group for whom natalizumab therapy would be very beneficial, particularly in light of the post hoc analysis from AFFIRM, which demonstrated that natalizumab produced no overt disease activity in this subset of patients.²² Natalizumab therapy may be considered in patients with an inadequate response to IFN beta (-1a or -1b) or GA, or those who cannot tolerate such agents. The demonstrated efficacy of natalizumab in reducing relapses, as well as the risk of disability progression, substantiates its use in patients whose functionality has deteriorated and who may not have other promising treatment options.^12,20

Ultimately, the place of natalizumab in therapy requires appropriate stratification of patients to identify those who will likely respond and benefit from natalizumab treatment. Such a stratification process would consider natalizumab not simply as a backup treatment, but as a first-line therapy for those patients with greater disease severity, more disease activity, more functional loss, and perhaps those who are phenotypically less likely to respond to other treatments.

Conclusion

Natalizumab is an effective agent in the treatment of relapsing- remitting MS. The status of natalizumab as a second-line therapy is based on the risk of PML, a rare but severe infection.³³ Appropriate stratification of patients could better refine the place of natalizumab in MS treatment and identify those patients for whom first-line initiation of natalizumab therapy may be appropriate.

Acknowledgment: Editorial support for this manuscript was provided by James Borwick.

Author Affiliation: From the Department of Neurology, Stony Brook University Medical Center and Stony Brook MS Comprehensive Care Center, Stony Brook, NY.

Funding Source: Financial support for this work, including honoraria, was provided by Biogen Idec.

Author Disclosures: The author reports board membership at Bayer and Novartis; consultancy/advisory board membership at Acorda, Bayer, Biogen Idec, EMD Serono, Pfizer, sanofi-aventis, and Teva. Dr Coyle has also received grants from Novartis and sanofi-aventis as well as honoraria and lectureship fees from Bayer, Biogen Idec, EMD Serono, Novartis, Pfizer, sanofi-aventis, and Teva.

Authorship Information: Concept and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and approval of final version of manuscript.

Address correspondence to: Patricia K. Coyle, MD, Department of Neurology, HSC T-12 - 20, State University of New York, Stony Brook, NY 11794-8121. E-mail: pcoyle@notes.cc.sunysb.edu.

1. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278-285.

2. Biernacki K, Antel JP, Blain M, et al. Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch Neurol. 2005;62:563-568.

3. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain. 1989;112:1419-1428.

4. Ragonese P, Aridon P, Salemi G, D'Amelio M, Savettieri G. Mortality in multiple sclerosis: a review. Eur J Neurol. 2008;15:123-127.

5. Liguori M, Marrosu MG, Pugliatti M, et al. Age at onset in multiple sclerosis. Neurol Sci. 2000;21(suppl 2):825-829.

6. Kurtzke JF, Page WF, Murphy FM, Norman JE Jr. Epidemiology of multiple sclerosis in US veterans. 4. Age at onset. Neuroepidemiology. 1992;11:226-235.

7. Wallin MT, Page WF, Kurtzke JF. Multiple sclerosis in US veterans of the Vietnam era and later military service: race, sex, and geography. Ann Neurol. 2004;55:65-71.

8. Yong VW. Differential mechanisms of action of interferon-beta and glatiramer acetate in MS. Neurology. 2002;59(6):802-808.

9. Nair A, Frederick TJ, Miller SD. Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci. 2008;65(17):2702-2720.

10. Deng X, Sriram S. Role of microglia in multiple sclerosis. Curr Neurol Neurosci Rep. 2005;5(3):239-244.

11. Adams HP, Wagner S, Sobel DF, et al. Hypointense and hyperintense lesions on magnetic resonance imaging in secondary-progressive MS patients. Eur Neurol. 1999;42(1):52-63.

12. Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68:1390-1401.

13. Lee SJ, Benveniste EN. Adhesion molecule expression and regulation on cells of the central nervous system. J Neuroimmunol. 1999;98:77-88.

14. 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;58:1-10.

15. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992;356:63-66.

16. Chan PY, Aruffo A. VLA-4 integrin mediates lymphocyte migration on the inducible endothelial cell ligand VCAM-1 and the extracellular matrix ligand fibronectin. J Biol Chem. 1993;268:24655-24664.

17. Rudick RA, Sandrock A. Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS. Expert Rev Neurother. 2004;4:571-580.

18. Bayless KJ, Meininger GA, Scholtz JM, Davis GE. Osteopontin is a ligand for the alpha4beta1 integrin. J Cell Sci. 1998;111(pt 9):1165-1174.

19. Tchilian EZ, Owen JJ, Jenkinson EJ. Anti-alpha 4 integrin antibody induces apoptosis in murine thymocytes and staphylococcal enterotoxin B-activated lymph node T cells. Immunology. 1997;92(3):321-327.

20. Polman CH, O'Connor PW, Havrdova E, et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910.

21. Havrdova E, Galetta S, Hutchinson M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8:254-260.

22. Hutchinson M, Kappos L, Calabresi PA, et al. The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol. 2009;256(3):405-415.

23. Balcer LJ, Galetta SL, Calabresi PA, et al. Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology. 2007;68:1299-1304.

24. Balcer LJ, Baier ML, Cohen JA, et al. Contrast letter acuity as a visual component for the Multiple Sclerosis Functional Composite. Neurology. 2003;61(10):1367-1373.

25. Zivadinov R, Reder AT, Filippi M, et al. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology. 2008;71(2):136-144.

26. 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(10):889-897.

27. Rao AB, Richert N, Howard T, et al. Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFNbeta-1b. Neurology. 2002;59(5):688-694.

28. PRISMS Study Group. 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. 1998;352:1498-1504.

29. 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.

30. 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.

31. IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:655-661.

32. Tysabri [package insert]. Cambridge, MA: Biogen Idec Inc; 2009.

33. PML incidence in patients receiving Tysabri. https://medinfo.biogenidec.com/ [registration required]. Accessed May 10, 2010.

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