n  report  n

The Role of Natalizumab in the Treatment of Multiple Sclerosis
Patricia K. Coyle, MD

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, placebocontrolled 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 relapsingremitting 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)


ultiple 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

For author information and disclosures, see end of text.

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
  n  www.ajmc.com  n

© Managed Care & Healthcare Communications, LLC


june 2010

these areas are less dense (ie. with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 6 (mean score. and the secondary end points were: (1) number of new or enlarging MRI-detected hyperintense T2 lesions. A murine version of natalizumab.12 T1 images identify areas where nerve fibers have died. AN100226m.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. there is neurodegeneration (damage to axons and neurons).The Role of Natalizumab in the Treatment of Multiple Sclerosis lesions. respectively—a reduction of 59% over 2 years (P <. experimental allergic encephalomyelitis (EAE).11.20 AFFIRM was a 2-year trial conducted in 99 clinical centers in North America.0 on the EDSS among patients with a baseline EDSS score of at least 1. known as AFFIRM. hyperintense) areas on T2 images.18 Finally. 2. and (4) disability progression as measured by the Multiple Sclerosis Functional Composite (MSFC).17.9 In addition to the gradual demyelination just described. P <. the primary end point was clinical relapse rate.81. While remyelination processes are activated to repair the damage to the myelin sheath.0. Disability progression was defined as an increase of at least 1. at year 2. The study design of AFFIRM included primary and secondary end points at years 1 and 2. in MS. the proportions were 67% and 41%. with consequent emergent symptoms. and (3) proportion of patients who were relapsefree.17 Similarly.3). At year 1.20 At year 2. this process is inadequate. and Australia. New lesion development follows infiltration of activated lymphocytes through the BBB. a protein involved in endothelial cell and leukocyte adhesion.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. No. thereby reducing the inflammatory response. (2) volume of T2-weighted lesions. At year 1. Similar results have been observed in studies of EAE in rats. (3) number of new hypointense T1 lesions. Role of α4-integrin Antagonism in the Treatment of MS Although the exact mechanism of action of natalizumab in MS is unknown. New Zealand. several explanations have been suggested.19 Clinical Efficacy of Natalizumab MRI is used to visualize and determine the characteristics of MS lesions. it has been suggested that the clinical efficacy of natalizumab in MS may be due to its ability to induce apoptosis in T cells. Scarred lesions are evident as white. respectively. thereby preventing leukocyte adhesion to endothelial VCAM-1. hypointense) and are commonly referred to as “black holes.26 vs 0. bright (ie. One such effect relates to the role of fibronectin. MS Lesions and Detection Using MRI binding to fibronectin.20 The annualized relapse rate at year 1 was significantly lower in the natalizumab group compared with the placebo group (0. This benefit was sustained over 2 years.16 By VOL. the primary end point was the cumulative probability of sustained disability progression over a 12-week period. 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.001). which facilitates lymphocytic penetration of the BBB.” Gadolinium is used as a contrast agent to identify areas of active disease. natalizumab interrupts α4β1-integrin binding. T1-weighted imaging and T2-weighted imaging are the most common techniques employed to assess MS lesions.15 Several other effects of natalizumab have been offered as explanations for its efficacy in MS. were randomized in a 2:1 ratio to receive either natalizumab 300 mg (n = 627) or placebo (n = 315) intravenously every 4 weeks. 77% of patients given natalizumab were relapse free compared with 56% of those given placebo.) At year 2.001 for both years). has been shown to have a powerful limiting effect on leukocyte infiltration into the CNS of guinea pigs in a preclinical model of MS.5. which requires the adhesion of lymphocytes to vascular endothelial cells. and are referred to as “gadoliniumenhancing” lesions. (2) number of gadolinium-enhanced MRI lesions. placebo-controlled trial: the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis study. (Patients with a baseline EDSS score of 0 were defined as experiencing disability progression if their EDSS score increased by at least 1. These lesions can be visualized using MRI. with a 68% relative reduction in the relapse rate among patients given natalizumab compared with those giv- The American Journal of Managed Care  n S165 . 36 years). A total of 942 patients between the ages of 18 and 50 years (mean age. it will leak into the brain tissue when there are breaks in the BBB. Natalizumab was significantly more effective than placebo. 6 n  The clinical efficacy of natalizumab was established in a double-blind. a reduction in the inflammatory response appears to result from the binding of natalizumab to osteopontin. Europe.20 Patients were evaluated every 12 weeks.12 These areas will be hyperintense on T1-weighted images. secondary end points were: (1) clinical relapse rate. 16.9 This process involves binding of vascular cell adhesion molecule (VCAM)-1 to α4β1-integrin located on the lymphocytes.

21 Natalizumab was associated with significant improvement compared with placebo for all measurements of disease activity.21 Differences were seen for each measure of disease activity.0001).com  n . respectively.46. a reduction of 76% (P <. respectively. natalizumab was associated with an 83% reduction in the number of new or enlarging T2 hyperintense lesions compared with placebo. natalizumab was associated with a 54% reduction in risk (HR. et al. P <.0001) (Figure 2). 354:899-910. The subgroups were defined as follows: (1) number of relapses occurring during the year prior to enrollment (1.001). 0. but has not been an expected outcome for the majority of MS patients receiving therapy.64.5. This difference represents a 42% reduction in risk of disability progression with natalizumab. no clinical disease activity was defined as the absence of both relapse and of disability progression (sustained for at least 12 weeks). P <.2 placebo.58. >3.33-0. Similarly.3 placebo) and year 2 (0. 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 <. patient characteristics were similar to those in the overall population.1 0. When a stricter definition of disability progression was applied (sustained progression for 24 weeks). natalizumab was significantly better than placebo for the measures of no relapses and no disability progression for 12 weeks (P <. significantly more natalizumab-treated patients experienced no clinical disease activity compared with those given placebo (64% vs 39%.1 natalizumab vs 1. P <.001) (Figure 1). P <. Time to Sustained Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis Given Natalizumab in AFFIRM Proportion of Patients With Sustained Progression of Disability 0.ajmc.12. 0.21 A state of no overt disease activity is clearly an ideal treatment goal.001 for both). 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]. P <.20 After 2 years. sustained disability progression rate. After 2 years.4 P <.001).21) Of the original 942 patients enrolled in the AFFIRM trial. 0.23 vs 0. mean T2 lesion volume was significantly lower in patients treated with natalizumab compared with those given placebo. 2. significantly fewer patients given natalizumab experienced either measure of radiologic disease activity (new gadolinium-enhancing lesions and new or enlarging T2 hyperintense lesions) (P <. was also significantly lower in natalizumab-treated patients compared with those receiving placebo.0001 for both). there was a 92% reduction in lesions detected by gadolinium-enhancing MRI among natalizumab-treated patients compared with placebo at year 1 (0.430. (2) EDSS score (<3.6 in the placebo group.0 0 12 24 36 48 60 72 84 96 108 120 Weeks 264 248 240 229 216 208 567 546 525 517 503 490 200 199 478 473 No. 0.Reports n  Figure 1. 95% confidence interval [CI]. In this post hoc analysis. Compared with placebo. 95% CI.73. respectively. P <. In parallel with clinical measurements. the MRI data also reflected significantly better outcomes associated with nata­ l­ izumab treatment. The 2-year primary end point. N Engl J Med.77. and the mean number of T1 hypointense lesions in the natalizumab group was 1.2 Natalizumab 0.0001).21 Even more pronounced was the absence of radiologic disease activity in patients given natalizumab compared with those given placebo (58% vs 14%. P <.001 for both).0001 for both). at Risk Placebo Natalizumab 315 296 283 627 601 582 Reprinted with permission from Polman CH. One of the most compelling is an analysis conducted by Havrdova et al which examined the proportion of patients free of disease activity. (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. en placebo (0. No radiologic disease activity was defined as the absence of gadolinium-enhancing lesions and the absence of both new and enlarging T2 hyperintense lesions.12 Several post hoc analyses of data from the AFFIRM study have provided additional insight into the benefits of nata­ lizumab monotherapy in relapsing-remitting MS.1 compared with 4. Subgroup Analyses From AFFIRM Hutchinson and colleagues conducted an extensive analysis of data from predefined patient subgroups in the AFFIRM trial.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%.3 0. (3) number of T2 lesions june 2010 S166   n  www. 2006. data from 917 patients were available for analysis of disease activity. >3).5). At 2 years.001).1 natalizumab vs 1.001 Placebo 0.

P <. natalizumab was 22 associated with a 64% reduction in risk (P <.029). natalizumab-treated patients experienced a also favored natalizumab-treated patients. Lancet Neurol. as measured by Sloan low-contrast the BEYOND (Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in Multiple Sclerosis Patients) study. 29 given natalizumab). a post hoc analysis was conducted in the early stages of successful treatment with MS agents due using data from patients in the AFFIRM trial.23 Exploratory Analyses From AFFIRM Brain atrophy over time is a further means of determining deterioration in MS. Sloan low-contrast acuity has been demonMS agents. The cumuHigh-contrast visual acuity was also measured during this lative probability of relapse over the 2-year study was 75% study. >1). >40 years). whereas paprednisolone. and those 40 years or older. at the 1. where visual to a reduction in edema and inflammation.008). and has been described as pseudoatrophy.8:254-260.008 vs placebo). patients with less than 9 T2 282/604 50 lesions (15 given placebo. Overall risk of sustained visual acuity loss mulative probability of sustained disability progression for that was considered clinically meaningful (sustained reduc12 weeks was 29% with placebo compared with 14% with tion by 2 or more lines in scores sustained over 12 weeks) natalizumab. representing a 53% reduction in risk (P <. was significantly greater in patients given placebo at both When a stricter definition of disability progression was apthe 2.5% and 1. 79 60 given natalizumab). (5) age (<40. >9). (6) and Activity Based on Composite Clinical and Radiologic Criteria sex.5% contrast charts at 12-week the first year of the study.27 Similarly. (4) presence of gadolinium-enhancing n  Figure 2. et al.23 At the 2. ized relapse rate was reduced by 81% (P <.001). in some cases. in whom annual35% reduced risk of visual acuity loss (P <. the cuDifferences between the 2 groups were significant at nearly every time point. 6 n  The American Journal of Managed Care  n S167 . natalizumab was asPlacebo sociated with a significant reduction in the risk of Natalizumab 100 disability progression in most subgroups. analysis of outcomes in patients with highly active disease.22 were observed.22 The annualized 30 relapse rate was lower with natalizumab therapy in 20 47/305 37/284 every subgroup and failed to meet statistical signifi22/304 10 cance only in the small subgroup of patients with 0 0-1 1-2 0-2 fewer than 9 T2 lesions at baseline. 220/600 40 males. patients treated with natalizumab Patients Without Combined Disease Activity (%) VOL. although this measure is somewhat conTo evaluate the effect of treatment on loss or reduction founded by the fact that there can be a loss of brain volume of visual function in MS.25% contrast charts and 2. showed improvements. those with a baseline 372/544 70 EDSS score of more than 3. The anlevel. Hutchinson et al also conducted a post hoc Reprinted with permission from Havrdova E. A reason for Years this might be the small number of patients in this subgroup (52 given placebo.26 Initial brain atrophy study.25 In strated to be effective in determining visual dysfunction in MS.The Role of Natalizumab in the Treatment of Multiple Sclerosis (<9.5 (37 given placebo.23 at study entry.22 Compared with placebo. has been shown to correlate with EDSS and MSFC both interferon (IFN) beta-1b and glatiramer acetate (GA) in MS.25% contrast levels. with the 90 exception of the following: patients with 2 relapses 80 prior to the start of the study. Patients receiving placebo experienced progressive worsening (negative changes from baseline in Z scores) has also been seen in patients with MS treated with methylof low-contrast visual acuity over the 2 years.001 vs placebo). natalizumab was associated with a 47% reduction in risk of visual acuity loss (P <. but no significant differences between the 2 groups lower in the natalizumab group compared with placebo. 2009. 16. Low-contrast visual acuity was measured using both treatment resulted in substantial loss of brain volume during 1.22 Over the course of the 2-year study. No. Proportion of Patients in AFFIRM With No Disease lesions (0.25% nualized relapse rate in patients with highly active disease contrast level. This phenomfunction was measured using the Sloan low-contrast letter 23 enon has been observed with initial treatment with several acuity chart .24 Visual acuity. a loss that was recovered by the intervals for the entire 2-year duration of the AFFIRM end of the second year of treatment. charts.0001 for all time periods. 67 given natalizumab). defined as at least 2 relapses during the year prior tients receiving natalizumab generally maintained their to study entry and at least 1 gadolinium-enhancing lesion visual acuity and.5% contrast plied (sustained progression for 24 weeks).

Cambridge. S168   n  www. 2009. MA: Biogen Idec Inc. Adverse Events Occurring in the AFFIRM Trial Adverse Reactions (Preferred Term) General    Headache    Fatigue    Arthralgia    Chest discomfort    Acute hypersensitivity reactionsa    Other hypersensitivity reactionsa    Seasonal allergy    Rigors    Weight increased    Weight decreased Infection    Urinary tract infection    Lower respiratory tract infection    Gastroenteritis    Vaginitisb    Tooth infections    Herpes    Tonsillitis Psychiatric    Depression Musculoskeletal/connective tissue disorders    Pain in extremity    Muscle cramp    Joint swelling Gastrointestinal    Abdominal discomfort    Diarrhea NOS    Abnormal liver function test Skin    Rash    Dermatitis    Pruritus    Night sweats Menstrual disorders b    Irregular menstruation    Dysmenorrhea    Amenorrhea    Ovarian cyst Neurologic disorders    Somnolence    Vertigo Renal and urinary disorders    Urinary incontinence    Urinary urgency/frequency Injury    Limb injury NOS    Skin laceration    Thermal burn Tysabri (N = 627) Percentage 38 27 19 5 4 5 3 3 2 2 21 17 11 10 9 8 7 19 16 5 2 11 10 5 12 7 4 1 5 3 2 2 2 6 4 9 3 2 1 Placebo (N = 312) Percentage 33 21 14 3 <1 2 2 <1 <1 <1 17 16 9 6 7 7 5 16 14 3 1 10 9 4 9 4 2 0 4 <1 1 <1 <1 5 3 7 2 <1 <1 NOS indicates not otherwise specified.ajmc. . Reprinted from Tysabri [package insert].Reports n Table.com  n june 2010 . b Percentage based on female patients only. a Acute versus other hypersensitivity reactions are defined as occurring within 2 hours postinfusion versus more than 2 hours.

the US Food and Drug Administration–approved labeling for natalizu­ mab recommends. and approval of final version of manuscript. Acknowledgment: Editorial support for this manuscript was provided by James Borwick. The most common serious AE was relapsing MS (6% with natalizumab. more functional loss. Biogen Idec. The MRI data were similarly remarkable. No. Stony Brook. as well as the risk of disability progression. thereby constituting a higher threshold for the achievement of efficacy than that of other clinical trials. and Teva. but as a first-line therapy for those patients with greater disease severity. only fatigue (natalizumab 27% vs placebo 21%. and that the cate­ gorization of natalizumab as a second-line therapy is largely a consequence of the occurrence of progressive multifocal leukoencephalopathy (PML). Authorship Information: Concept and design. these data confirm the efficacy of nata­ lizumab in relapsing-remitting MS based on both clinical and radiologic criteria. P = . Bayer. The status of natalizumab as a secondline therapy is based on the risk of PML. 2010. and perhaps those who are phenotypically less likely to respond to other treatments. Biogen Idec. Such a stratification process would consider nata­ lizumab not simply as a backup treatment. and Teva. Novartis. a rare but severe infection.06). although does not mandate. drafting of the manuscript.20 Ultimately.The Role of Natalizumab in the Treatment of Multiple Sclerosis in AFFIRM experienced some degree of brain atrophy at year 1. P = . or those who cannot tolerate such agents. Conclusion Natalizumab monotherapy is approved for the treatment of relapsing forms of MS.012) were significantly different. Pfizer. Of interest is that the study design of AFFIRM did not allow confirmation of disability progression within 4 weeks of initiation of a relapse. there were 49 confirmed cases of PML among patients who received natalizumab worldwide. including honoraria. a demyelinating disease of the CNS caused by lytic infection of oligodendrocytes by the papovavirus JC that causes death or severe disability.33 Although the risk of PML may be a disincentive to treat with natalizumab. 16. All other serious AEs occurred in less than 1% of each treatment group. 13% with placebo. Author Affiliation: From the Department of Neurology. As of VOL. Indeed. however. The efficacy of natalizumab in treating patients with MS is compelling. With this in mind. The AFFIRM data are noteworthy because across clinical measurements. more disease activity.048) and allergic reaction (natalizumab 9% vs placebo 4%.20 The Table provides a full list of AEs occurring in the AFFIRM trial. Dr Coyle has also received grants from Novartis and sanofi-aventis as well as honoraria and lectureship fees from Bayer. disability progression. The American Journal of Managed Care  n S169 . Author Disclosures: The author reports board membership at Bayer and Novartis.12 Taken together. P = . as natalizumab was consistently associated with a significant reduction in the number of gadolinium-enhancing and T2 lesions. 6 n  Natalizumab is an effective agent in the treatment of relapsing-remitting MS. particularly in light of the post hoc analysis from AFFIRM. The demonstrated efficacy of natalizumab in reducing relapses. and proportion of patients who were relapse-free. EMD Serono. was provided by Biogen Idec. Pfizer. Nearly all patients in both groups experienced some type of adverse event (AE). which demonstrated that natalizumab produced no overt disease activity in this subset of patients. consultancy/advisory board membership at Acorda. NY. P <. it is worth considering the benefits nata­ lizumab may provide in the treatment of MS. patients with active disease may be considered a group for whom natalizumab therapy would be very beneficial.20 The incidence of serious AEs was similar between natalizumab and placebo (19% vs 24%. analysis and interpretation of data.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. Funding Source: Financial support for this work. patients given natalizumab consistently achieved significantly better results than those given placebo. EMD Serono. including relapse rate.32 It should be noted that some practitioners do employ natalizumab as first-line therapy. and clinicians must weigh this benefit against the risks of nata­ lizumab.001). natalizumab is widely regarded as a second-line therapy for MS that can be used if treatment with IFN beta or GA fails. Role of Natalizumab in Clinical Practice May 6.28-31 Safety of Natalizumab in AFFIRM Safety results from AFFIRM were similar between nata­ lizumab and placebo. Stony Brook University Medical Center and Stony Brook MS Comprehensive Care Center. but at the end of 2 years. critical revision of the manuscript for important intellectual content. the place of natalizumab in therapy requires appropriate stratification of patients to identify those who will likely respond and benefit from natalizumab treatment. At present. respectively.22 Natalizumab therapy may be considered in patients with an inadequate response to IFN beta (-1a or -1b) or GA. brain atrophy was significantly less among patients given natalizumab compared with those receiving placebo. substantiates its use in patients whose functionality has deteriorated and who may not have other promising treatment options. sanofi-aventis. its use in cases of inadequate response or intolerability to alternate MS therapies. sanofi-aventis.12.

Neurology. Contrast letter acuity ology of multiple sclerosis in US veterans. References 1. A randomized. 1995. et al. Hutchinson M. Accessed May 10. 7. Bö L. Zivadinov R. a product of their environment. NY 11794-8121. et al. ulation on cells of the central nervous system. Reder AT. Anti-alpha 4 integrin antibody induces apoptosis in murine thymocytes and staphylococcal enterotoxin B-activated lymph node T cells. ans of the Vietnam era and later military service: race. 15. Immunology. Sandrock A. The natural history of multiple sclerosis: a geographically based study.92(3):321-327. 1998. Age at onset in mul6. Savettieri G. Salemi G. et al. et al. 1997. 2007.43:655-661. Natalizumab reduces visual loss in patients with relapsing multiple sclerosis.112:1419-1428. Cannon C. 24. randomised.com/ [registration required]. Norman JE Jr. Brain. 14. Neurology. 28. S170   n  www. 25. Randomised double-blind placebo- 12. disease-modifying agents and brain volume changes in multiple sclerosis. Neurology. Chan PY. Galetta SL. Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. MD. 5. 2009. et al. Differential mechanisms of action of interferon-beta and glatiramer acetate in MS. Department of Neurology. 1993. Wallin MT.59(5):688-694. et al. Neurol Neurosci Rep. Cambridge.256(3):405-415. Stony Brook. Soon D. 1992. Neurol Sci. 1992. 4. Predictive value of the early clinical course. Sobel DF. 2007. et al. Ann Neurol. Davis GE. Effect of natalizu­ mab 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. controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Johnson KP. Kent SJ.5(3):239-244. Bayless KJ. Steinman L. 16. Sriram S. N Engl J Med. Deng X. 2009.11:226-235. sex. Richert N. The Copolymer 1 Multiple Sclerosis Study Group. Cannon C. Jenkinson EJ. double-blind. 9.61(10):1367-1373. Role of microglia in multiple sclerosis. PRISMS Study Group. O’Connor PW. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter. Cell Mol Life Sci. 2008. et al. Aruffo A. Yong VW.68:1390-1401. 32. Benveniste EN. 2002. et al.com  n june 2010 . 19. Aridon P. Tchilian EZ. Page WF.ajmc. 1996.4:571-580. et al. 2. Hypointense and hyper- on brain volume and enhancing lesions in MS before and during IFNbeta-1b. J Neurol.71(2):136-144. Fritz LC. Kurtzke JF. Scholtz JM. Peterson J. nist selective adhesion molecule inhibitors for MS. Balcer LJ. Neuroepidemiology. Ransohoff RM. Rice GP. Adams HP. 1989. 27. 2008. Wagner S. Astrocytes in multiple sclerosis: 26. Prevention of experimental autoimmune encephalo- myelitis by antibodies against alpha 4 beta 1 integrin. Fernando KT. Neurology. I. 2. Howard T. Nair A.edu. 2008.98:77-88. Lancet. Owen JJ. Calabresi PA. The efficacy Mortality in multiple sclerosis: a review. Frederick TJ. Karlik SJ. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective. Filippi M. Arch Neurol.352:1498-1504. 2005.sunysb. Karin N. 2006. Methylprednisolone effect 10. Adhesion molecule expression and reg- 29. Curr 11. Sanchez-Madrid F. Baier ML. relapsing multiple sclerosis. et al. Nature.42(1):52-63. et al. 31.15: 123-127. O’Connor P. Cohen JA. N Engl J Med. The IFNB Multiple Sclerosis Study Group. Rudick RA. 1998. A monoclonal antibody to 13. https://medinfo. Meininger GA. Tysabri [package insert]. Page WF. Biernacki K.58:1-10.338(5):278-285. D’Amelio M. Trapp BD. Lancet Neurol.268:24655-24664. Bass B. J Neuroimmunol. 1999. Cookfair DL. multicentre study. Multiple sclerosis in US veter- as a visual component for the Multiple Sclerosis Functional Composite. 2010. 2005. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). HSC T-12 – 20. Epidemi­ 23. 2009. Marrosu MG. Miller DH.354(9):899-910. Balcer LJ. Clinical results of a multicenter. and geography. Neurology. Yednock TA. Mechanisms of action of 8. 3. Havrdova E. Brooks BR. 1993. Expert Rev Neurother. Hutchinson M.45:1268-1276.356:63-66. 18. Kurtzke JF. Polman CH. Miller SD.111(pt 9):1165-1174. of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL.21(suppl 2):825-829. Filippi M. 30. Weinshenker BG. Coyle.Reports Address correspondence to: Patricia K. et al. Havrdova E. 17. tiple sclerosis. et al.8:254-260. Rudick RA. Rao AB. 2002. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Ann Neurol. et al. double-blind placebo-controlled trial. AFFIRM Investi­ gators. Osteopontin is a ligand for the alpha4beta1 integrin. Eur Neurol. J Cell Sci. E-mail: pcoyle@notes. 22. 1999. Pugliatti M. 21. Eur J Neurol. Lee SJ. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. randomized. 20. VLA-4 integrin mediates lymphocyte migration on the inducible endothelial cell ligand VCAM-1 and the extracellular matrix ligand fibronectin. Age at onset. State University of New York. Murphy FM. intense lesions on magnetic resonance imaging in secondaryprogressive MS patients.65(17): 2702-2720. Ragonese P.8(10):889-897. placebo-controlled trial of natalizu­ mab for Axonal transection in the lesions of multiple sclerosis. Neurology. 2000. 4. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. 33. Kappos L. Rudick R. Blain M. Natalizumab: alpha 4-integrin antago- 2009.62:563-568. IFNB Multiple Sclerosis Study Group. Arnason B. Antel JP.cc. Lancet Neurol. PML incidence in patients receiving Tysabri. Neurology. J Neuroimmunol.68:1299-1304. Calabresi PA. Jacobs LD. 2004. 1995. biogenidec.59(6):802-808. 2003. placebo-controlled trial. et al.39:285-294. Mörk S. 2004. J Biol Chem. Liguori M. Cohen JA. alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis. MA: Biogen Idec Inc.55:65-71. Neurology. Galetta S. 1998.