A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
David H. Miller, M.D., Omar A. Khan, M.D., William A. Sheremata, M.D., Lance D. Blumhardt, M.D., George P.A. Rice, M.D., Michele A. Libonati, M.S., Allison J. Willmer-Hulme, Ph.D., Catherine M. Dalton, M.B., Katherine A. Miszkiel, M.B., Paul W. O'Connor, M.D., for the International Natalizumab Multiple Sclerosis Trial Group
Background In patients with multiple sclerosis, inflammatorybrain lesions appear to arise from autoimmune responses involvingactivated lymphocytes and monocytes. The glycoprotein 4 integrinis expressed on the surface of these cells and plays a criticalpart in their adhesion to the vascular endothelium and migrationinto the parenchyma. Natalizumab is an 4 integrin antagonistthat reduced the development of brain lesions in experimentalmodels and in a preliminary study of patients with multiplesclerosis.
Methods In a randomized, double-blind trial, we randomly assigneda total of 213 patients with relapsing–remitting or relapsingsecondary progressive multiple sclerosis to receive 3 mg ofintravenous natalizumab per kilogram of body weight (68 patients),6 mg per kilogram (74 patients), or placebo (71 patients) every28 days for 6 months. The primary end point was the number ofnew brain lesions on monthly gadolinium-enhanced magnetic resonanceimaging during the six-month treatment period. Clinical outcomesincluded relapses and self-reported well-being.
Results There were marked reductions in the mean number of newlesions in both natalizumab groups: 9.6 per patient in the placebogroup, as compared with 0.7 in the group given 3 mg of natalizumabper kilogram (P<0.001) and 1.1 in the group given 6 mg ofnatalizumab per kilogram (P<0.001). Twenty-seven patientsin the placebo group had relapses, as compared with 13 in thegroup given 3 mg of natalizumab per kilogram (P=0.02) and 14in the group given 6 mg of natalizumab per kilogram (P=0.02).The placebo group reported a slight worsening in well-being(a mean decrease of 1.38 mm on a 100-mm visual-analogue scale),whereas the natalizumab groups reported an improvement (meanincrease of 9.49 mm in the group given 3 mg of natalizumab perkilogram and 6.21 mm in the group given 6 mg of natalizumabper kilogram).
Conclusions In a placebo-controlled trial, treatment with natalizumabled to fewer inflammatory brain lesions and fewer relapses overa six-month period in patients with relapsing multiple sclerosis.
Multiple sclerosis is a leading cause of chronic neurologicdisability.1 Several new therapies have been introduced in thepast decade,2,3,4,5 but additional effective treatments areneeded to slow disease progression and reduce disability. Thepathological hallmark of multiple sclerosis is multiple fociof inflammation and demyelination within the white matter ofthe central nervous system. The formation of these lesions mayinvolve lymphocytes and monocytes that gain access to the brainparenchyma from the circulation by first adhering to vascularendothelial cells in regions of inflammation.6 The glycoprotein41 integrin, also known as very late antigen 4, or VLA-4, isexpressed on the surface of lymphocytes and monocytes and isan important mediator of cell adhesion and transendothelialmigration, as well as a regulator of immune-cell activationwithin inflamed tissue.7,8
Brain lesions in patients with multiple sclerosis are readilydetected with T2-weighted magnetic resonance imaging (MRI).New lesions with features of inflammation can be detected bygadolinium-enhanced T1-weighted MRI,9,10,11,12 and this approachhas been used to assess disease activity in clinical trials.
Treatment with an antibody against 4 integrin reduced signsof disease activity and inflammation in mice with experimentallyinduced allergic encephalomyelitis, a rodent model of multiplesclerosis.13,14,15 Natalizumab (Antegren, Elan Pharmaceuticalsand Biogen), a humanized monoclonal antibody, is an 4 integrinantagonist in a class of agents known as selective adhesion-moleculeinhibitors. In a small, placebo-controlled study of patientswith multiple sclerosis, natalizumab reduced the frequency ofnew gadolinium-enhancing lesions.16 Because the patients receivedonly two infusions one month apart, the longer-term effectsof antagonism of 4 integrin on the formation of brain lesionsand various clinical outcomes are unknown. Therefore, we conducteda randomized, placebo-controlled trial of six months of treatmentwith natalizumab in patients with relapsing multiple sclerosis.
Methods
Patients
Twenty-six clinical centers in the United States, Canada, andthe United Kingdom enrolled 213 patients from September 1999until May 2000. The protocol was reviewed and approved by centraland local ethics committees. Before providing informed consent,all patients were told by the investigator of the alternativeeffective therapies available to them, and any who wished totry one of these therapies were encouraged to do so. All patientsgave written informed consent. The study was overseen by anindependent data and safety monitoring committee. The studydata were gathered by the investigators and by an independentorganization (PPD Development); the data were held and analyzedby Elan and Biogen. The principal investigators on the writingteam had access to all data.
Eligible patients were 18 through 65 years of age, met the criteriaof Poser et al. for clinically definite or laboratory-supporteddefinite multiple sclerosis17 — either relapsing–remittingor secondary progressive multiple sclerosis18 — had hadat least two relapses within the previous two years, had a base-linescore on the Kurtzke Expanded Disability Status Scale19 between2 and 6.5 (scores can range from 0 to 10, with higher scoresindicating more severe disease), and had had a minimum of threelesions on T2-weighted MRI of the brain. Patients were ineligibleif they had received immunosuppressive or immunomodulating treatmentswithin the preceding 3 months or had had a relapse or receivedsystemic corticosteroids within the preceding 30 days.
Study Design and Randomization
Patients were randomly assigned to one of three treatments —3 mg of natalizumab per kilogram of body weight, 6 mg of natalizumabper kilogram, or placebo — with use of a computer-generatedblock randomization schedule. Randomization was performed centrallyby PPD Development. Patients received an intravenous infusionevery 28 days for 6 months and were then monitored for an additional6 months for adverse effects. Neither the study personnel northe patients were aware of the blinded treatment assignments.
Study Procedures and End Points
Unenhanced proton-density, T2-weighted MRI and gadolinium-enhancedT1-weighted MRI scans were obtained during the screening phase(one month before randomization), immediately before each treatment(months 0 through 5), and one month after the last treatment(month 6). Follow-up scans were obtained at months 9 and 12.Forty-six contiguous, 3-mm-thick, axial slices were acquiredthrough the brain. MRI analysis was performed by a single centerwhose members were unaware of the patients' treatment and history.Two experienced clinicians identified the lesions on hard-copyimages after reaching a consensus.
The primary outcome measure was the number of new gadolinium-enhancinglesions over the six-month treatment period, defined as theperiod following the first infusion (month 1) to one month afterthe last infusion (month 6). Other MRI outcomes included thenumber of persistent enhancing lesions (enhancing lesions thathad also been present on the previous monthly scan); the volumeof enhancing lesions (measured with use of a semiautomated method20);the number of new active lesions (the number of new enhancinglesions plus the number of new or newly enlarging, nonenhancinglesions on T2-weighted MRI); and the number of scans showingone or more new enhancing lesions.
Secondary and tertiary clinical end points included the frequencyof relapse, changes in the scores on the Kurtzke Expanded DisabilityStatus Scale, and patients' own assessments of well-being. Alladverse events were recorded. Patients were examined at scheduledintervals — and at unscheduled visits in the case of asuspected relapse — by the treating and evaluating neurologists,both of whom were unaware of the patients' treatment assignments.The treating neurologist obtained a medical history and, ateach monthly visit, conducted physical and neurologic examinationsand recorded adverse events. The evaluating neurologist assessedeach patient's neurologic status at quarterly intervals andat unscheduled visits and assigned each a score on the ExpandedDisability Status Scale without knowledge of the patient's historyor prior scores.
An objective relapse, determined by the evaluating neurologist,was defined as the occurrence of an acute episode of new orworsening symptoms of multiple sclerosis that lasted at least48 hours after a stable period of at least 30 days and was accompaniedby an increase from base line of at least one point in the scoreon the Expanded Disability Status Scale, at least one pointon two functional system scores, or at least two points on onefunctional system score. Neurologic symptoms that did not meetthe above criteria for relapse but were judged by the treatingneurologist to constitute a relapse were also recorded (andincluded in the total number of relapses).
On a visual-analogue scale, patients marked a point along a100-mm line that reflected their assessment of overall well-beingat base line and after three and six months of treatment. Higherscores reflected a greater sense of well-being.
Serum samples were collected at each visit and analyzed forbinding antibodies against natalizumab with use of an enzyme-linkedimmunosorbent assay. Serum levels of natalizumab and the extentof 4 integrin–receptor occupancy by natalizumab were measuredin a subgroup of 12 to 14 patients per treatment group beforeeach infusion and 2 hours, 24 hours, and one, two, and threeweeks after the first and last infusions. Patients were followedclinically to month 12. Patients who discontinued treatmentprematurely were encouraged to return for follow-up assessments.
Statistical Analysis
Estimates of sample size were based on the number of new enhancinglesions observed during the first 12 weeks after the first infusionin a previous clinical trial of natalizumab.16 Using methodsbased on the Wilcoxon–Mann–Whitney statistic21 appropriatefor a two-group comparison at a two-sided level of significanceof 5 percent, we calculated that approximately 73 patients wereneeded in each group for the study to have 80 percent power.
The primary comparison of the number of new enhancing lesionswas evaluated with use of the Wilcoxon–Mann–Whitneyrank-sum test. Given the short-term effects of corticosteroidson gadolinium-enhancing lesions, MRI scans obtained from patientswho had received systemic corticosteroids within the previous30 days were discarded and treated as missing values to avoidconfounding of the efficacy analyses. We imputed these missingvalues and those due to one or more scans' not being performedby replacing the missing value with the average number of lesionson available scans obtained at months 1 through 6 for that patient.This type of imputation was performed for the primary end pointas well as all other end points involving lesion counts duringthe six-month treatment phase. According to the prespecifiedanalysis, the imputation of lesion volume and scores on theExpanded Disability Status Scale followed the principle of thelast observation carried forward. No imputation method was specifiedfor the analyses of relapses at any point during the study andMRI data after month 6; therefore, missing data were excludedfrom these analyses during the corresponding period.
Demographic and base-line clinical characteristics were comparedwith use of a two-way analysis of variance, with site and groupincluded as independent variables, for continuous data and Fisher'sexact test for categorical data. Base-line MRI characteristicswere compared with use of the Kruskal–Wallis test. Foranalysis of the end points, we used the Wilcoxon–Mann–Whitneyrank-sum test for all analyses involving lesion counts, includingthe primary end point. Averaged scores were assigned to tiedrank values. Lesion volumes, the mean percentage of scans showingactivity, and changes from base line in the scores for the ExpandedDisability Status Scale and visual-analogue scale were analyzedwith the use of two-way analysis of variance, with site andgroup included as independent variables. Fisher's exact testwas used to compare the proportions of patients in each groupwho had one or more relapses. When no data were available todetermine whether a relapse could be objectively confirmed,that relapse was excluded from the analysis of objective relapses.
All analyses followed the intention-to-treat principle. Allreported P values are two-tailed. No interim analyses were performedbefore the primary end point was analyzed.
Results
Among the 213 patients, 71 were randomly assigned to receiveplacebo, 68 to receive 3 mg of natalizumab per kilogram, and74 to receive 6 mg of natalizumab per kilogram. There were nosignificant differences in clinical or MRI characteristics atbase line (Table 1).
Table 1. Base-Line Characteristics of the Patients.
All the patients received at least one dose of the assigneddrug. Five patients in the placebo group, five in the groupgiven 3 mg of natalizumab per kilogram, and eight in the groupgiven 6 mg of natalizumab per kilogram discontinued treatmentprematurely. Of these patients, three in the placebo group,four in the 3-mg group, and one in the 6-mg group remained inthe study until the end of the treatment period. In the analysisof the primary end point during the treatment period, 6.3 percentof the values were imputed: the distribution of imputed valueswas 8.2 percent of those in the placebo group, 2.9 percent ofthose in the 3-mg group, and 7.7 percent of those in the 6-mggroup.
Primary Outcome
The placebo group had a mean of 9.6 new gadolinium-enhancinglesions per patient during the treatment period. The correspondingmeans were 0.7 in the group given 3 mg of natalizumab per kilogram(P<0.001) and 1.1 in the group given 6 mg of natalizumabper kilogram (P<0.001) (Table 2 and Figure 1). There wasno significant difference in values between the two natalizumabgroups. A sensitivity analysis, performed with and without imputedvalues (the latter including actual counts on MRI scans obtainedwithin 30 days after corticosteroid treatment), yielded consistent,statistically significant results.
Figure 1. Cumulative Mean Number of New Gadolinium-Enhancing Lesions on MRI in Each Group during Treatment.
The subgroup of patients with relapsing–remitting multiplesclerosis had significantly fewer new enhancing lesions witheither dose of natalizumab than with placebo (mean, 12.1 inthe placebo group, as compared with 0.6 in the group given 3mg of natalizumab per kilogram [P<0.001] and 0.6 in the groupgiven 6 mg of natalizumab per kilogram [P<0.001]). The subgroupof patients with secondary progressive multiple sclerosis hadfewer new enhancing lesions with natalizumab than with placebo,and the difference was statistically significant in the groupgiven 3 mg of natalizumab per kilogram (mean, 5.4 in the placebogroup, as compared with 1.0 in the group given 3 mg of natalizumabper kilogram [P=0.005] and 2.0 in the group given 6 mg of natalizumabper kilogram [P=0.08]).
Secondary MRI Outcomes
There was a marked reduction in the number of persistent enhancinglesions, the number of new active lesions, the total volumeof enhancing lesions, and the percentage of scans showing activityin each natalizumab group as compared with the placebo group(Table 2).
Clinical Outcomes
During the six-month treatment period, 36 relapses were reportedin 27 of the 71 patients in the placebo group (38 percent),as compared with 18 in 13 of the 68 patients receiving 3 mgof natalizumab per kilogram (19 percent, P=0.02) and 15 in 14of the 74 patients receiving 6 mg of natalizumab per kilogram(19 percent, P=0.02). Using the objective criteria, we identified18 relapses in 15 patients in the placebo group (21 percent),as compared with 3 in 3 patients receiving 3 mg of natalizumabper kilogram (4 percent, P=0.004) and 8 in 8 patients receiving6 mg of natalizumab per kilogram (11 percent, P=0.11). Sensitivityanalyses were performed in which patients with data missingwere counted as either having had a relapse or not having hada relapse; all three approaches yielded consistent results.More patients in the placebo group than in either of the natalizumabgroups received corticosteroid treatment (using the permittedregimen of 1 g of intravenous methylprednisolone per day forthree or five days) for relapse: 22 of 27 (81 percent), as comparedwith 5 of 13 in the group given 3 mg of natalizumab per kilogram(38 percent, P<0.001) and 7 of 14 in the group given 6 mgof natalizumab per kilogram (50 percent, P=0.002) (Table 3).
The visual-analogue scores of well-being at month 6 were comparedwith base-line scores. The placebo group reported a slight worsening(mean decrease of 1.38 mm on a 100-mm scale), whereas the groupgiven 3 mg of natalizumab per kilogram and that given 6 mg ofnatalizumab per kilogram reported an improvement (mean increase,9.49 mm [P=0.04] and 6.21 mm [P=0.03], respectively). No significantchanges in the scores on the Expanded Disability Status Scalewere observed in any group during the six-month treatment period(mean increase of 0.03 in the placebo group and mean decreaseof 0.14 and 0.03 in 3-mg and 6-mg groups, respectively).
Pharmacodynamics
Total white-cell counts increased in both natalizumab groupswithin the first month of treatment and remained elevated untilmonth 7 in the group given 3 mg of natalizumab per kilogramand month 8 in the group given 6 mg of natalizumab per kilogram.There were increases in the lymphocyte, monocyte, and eosinophilcounts in both natalizumab groups, but the mean values werenot beyond the normal range and returned to base line by month9. There was no increase in neutrophil counts.
Binding antibodies against natalizumab developed in 15 patientsin the natalizumab groups (11 percent) — 13 during thetreatment period and 2 during the post-treatment follow-up period.Pharmacokinetic analysis showed that serum levels of natalizumabwere proportional to the dose given. Patients who received 3mg of natalizumab per kilogram had more than 80 percent saturationof the 4 integrin receptors on peripheral-blood leukocytes duringthe treatment period; receptor occupancy was approximately 90percent and was more prolonged in those receiving 6 mg of natalizumabper kilogram.
Safety and Tolerability
Similar numbers of patients in each group had adverse eventsduring treatment (Table 4). Eleven serious adverse events occurredin seven patients in the placebo group, five serious eventsoccurred in five patients who were receiving 3 mg of natalizumabper kilogram, and four such events occurred in three patientswho were receiving 6 mg of natalizumab per kilogram. Four ofthese events were considered to be immune-mediated and relatedto the study drug. One patient who was receiving 3 mg of natalizumabper kilogram had an anaphylactoid reaction with urticaria andbronchospasm, which was rapidly reversed with antihistaminesand corticosteroids. There were three reports of serum sickness,one in each group. Only one of these events was accompaniedby a change in complement levels, and all three occurred ata single study site. These events complicated fewer than 1 in250 infusions. Treatment was discontinued because of an adverseevent in three patients in the placebo group, four in the groupgiven 3 mg of natalizumab per kilogram, and three in the groupgiven 6 mg of natalizumab per kilogram. One patient in the placebogroup died of pleural carcinomatosis complicated by hemothorax.
When the values obtained at month 9 and month 12 were combined,the number of new enhancing lesions and scans showing activitywere similar in all three groups (Table 2). After treatment,there was no significant difference among the three groups eitherin the total number of relapses or in those objectively confirmed(Table 3).
Discussion
Our study provides MRI and clinical evidence that selectiveinhibition of 4 integrin–mediated adhesion and migrationof leukocytes is an effective approach to the treatment of multiplesclerosis. The 4 integrin–specific humanized monoclonalantibody natalizumab suppressed the formation of gadolinium-enhancinginflammatory brain lesions over the six-month treatment period.This effect was evident one month after the first infusion andwas sustained throughout the treatment period. The reductionin the formation of lesions was approximately 90 percent ata dose of both 3 mg per kilogram and 6 mg per kilogram and wasthus greater than the reduction of 50 to 80 percent reportedwith the -interferons and the reduction of approximately 30percent reported with glatiramer acetate.3,22,23
Although the intent of our study was not to demonstrate thatnatalizumab affected clinical outcomes, treatment neverthelessresulted in a significant reduction in the frequency of relapseand an increased perception of well-being among the patients.The magnitude of the reduction in both total and objectivelyconfirmed relapses exceeded that of the currently approved treatmentsfor multiple sclerosis, which is approximately 30 percent.2,3,4,5Just as important, although new lesions developed on MRI andrelapses recurred after treatment ended, there was no reboundabove the level seen in patients who received placebo.
The improved perception of well-being among natalizumab-treatedpatients should be interpreted with caution, since the visual-analoguescale used to assess well-being has not been widely used. Ifconfirmed, this finding may reflect the decreased frequencyof relapses and severity of fatigue and the increased clinicalstability associated with natalizumab therapy. Monthly infusionsof natalizumab for six months were well tolerated and were associatedwith a safety profile similar to that of placebo. There wasa trend toward an increased rate of infections in the natalizumab-treatedpatients, the clinical significance of which is unclear. Theeffects of 4 integrin blockade on human adaptive responses areunknown. Ongoing longer-term studies of natalizumab will providemore definitive data.
Natalizumab binds to 4 integrin and is an antagonist of integrinheterodimers containing the 4 integrin subunit. One such heterodimeris 41 integrin, which is expressed on the surface of activatedlymphocytes and monocytes — cells that have been implicatedin the pathogenesis of acute inflammatory lesions and the breakdownof the blood–brain barrier in patients with multiple sclerosis.24,25Our results provide evidence of a role of 4 integrin —and the immune cells that express it — in the pathogenesisof acute inflammatory lesions in patients with multiple sclerosis.The increase in circulating lymphocytes in patients treatedwith natalizumab is consistent with a mechanism involving theantagonism of 4 integrin–dependent adhesion of leukocytesthat migrate to regions of inflammation. Binding of natalizumabto 41 integrin may also inhibit the activation of T lymphocytesor eliminate autoreactive T lymphocytes, and both doses of natalizumabwere associated with near-saturation of the 41 integrin receptor.The reduction in the number of new enhancing lesions was evidentafter one month of treatment, suggesting that natalizumab actsrapidly to prevent the development of lesions.
In summary, natalizumab had beneficial effects on clinical andimaging outcomes in patients with relapsing multiple sclerosis.Therapy was well tolerated during the six-month trial. Promisingresults with this agent have also been obtained in a randomizedcontrolled trial of patients with Crohn's disease.26 Althoughour results are encouraging, longer-term data are needed. Theeffect of natalizumab on the progression of disability and itseffect in direct comparison with existing therapies are notyet known.
Sponsored by Elan Pharmaceuticals, South San Francisco, California,and Biogen, Cambridge, Mass.
Dr. Miller has reported receiving grant support from Elan, Schering,and Biogen; honorariums for giving expert advice to Biogen,Wyeth, and Bristol-Myers Squibb; and lecture fees from Serono.Dr. Khan has reported receiving grant support or honorariumsfrom Elan, Teva Neuroscience, Biogen, Serono, and Berlex. Dr.Sheremata has reported receiving grant support from Elan, TevaNeuroscience, Serono, and Biogen. Dr. Blumhardt has reportedreceiving honorariums from Serono, Teva Neuroscience, and Bayerfor giving lectures and expert advice. Dr. Rice has reportedreceiving grant support from Elan and honorariums from Elanfor giving expert advice. Dr. O'Connor has reported receivinggrant support from Elan, Biogen, Athena Neurosciences, Aventis,Berlex, Serono, Teva Neurosciences, Angiotech, and Amgen. Dr.Dalton has reported receiving salary support from Elan (througha grant held by the Institute of Neurology) to analyze the MRIdata. The MRI group at the Institute of Neurology is also supportedby the Multiple Sclerosis Society of Great Britain and NorthernIreland.
We are indebted to Drs. Kenneth Johnson, Stephen Donoghue, andCarol Greenlees for their valuable contributions during theconduct of this study; to Dr. Michael Panzara for many helpfulsuggestions and enthusiastic support during the preparationof the manuscript; to Dr. Alfred Sandrock for helpful comments;and to Dr. Charles Davis, Donald Bennett, Frances Lynn, andMinhua Yang for statistical advice and analysis.
* Members of the International Natalizumab Multiple SclerosisTrial Group are listed in the Appendix.
Source Information
From the Institute of Neurology, London (D.H.M., C.M.D., K.A.M.); Wayne State University School of Medicine, Detroit (O.A.K.); the University of Miami School of Medicine, Miami (W.A.S.); University Hospital, Nottingham, United Kingdom (L.D.B.); the London Multiple Sclerosis Clinic, London, Ont., Canada (G.P.A.R.); Elan Pharmaceuticals, San Francisco (M.A.L., A.J.W.-H.); and St. Michael's Hospital, University of Toronto, Toronto (P.W.O.).
Address reprint requests to Dr. Miller at the Department of Neuroinflammation, Institute of Neurology, Queen Sq., London WC1N 3BG, United Kingdom, or at d.miller{at}ion.ucl.ac.uk.
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Appendix
In addition to the authors, the following investigators participatedin the International Natalizumab Multiple Sclerosis Trial (principalinvestigators are in boldface type): Institute of Neurology,London (MRI Analysis Center) — G.J. Barker, D.G. MacManus,C. Webb, C. Middleditch, S. Lewis, T. Pepple, E. Riddle, C.Coombs; University of California at Davis, Sacramento —M. Agius, D. Richman, J. Adams, M. Buonocore; University ofNebraska Medical Center, Omaha — J. Al-Omaishi, K. Markopoulou,K. Healey, P. Sorensen; Royal Victoria Infirmary, Newcastleupon Tyne, United Kingdom — D. Bates, J. Forsyth, J. Curlis,P. English; University Hospital Queens Medical Centre, Nottingham,United Kingdom — V. Orpe, T. Jaspen; University of Washington,Seattle — J. Bowen, M. Chang, H. Lew, M. Burke, T. Richards;Mayo Clinic, Scottsdale, Ariz. — J.L. Carter, D. Dodick,J. Takata, M. Malikowski, K. Nelson; Washington University Schoolof Medicine, St. Louis — D.A.H. Cross, J. Trotter, D.Derrington, J. Lauber, C. Martinez, G. Foster, T. Conturo; Universityof British Columbia, Vancouver, Canada — V. Devonshire,J. Oger, L. Wang, W. Morrison, L. Costley; North StaffordshireRoyal Infirmary, Stoke on Trent, United Kingdom — C. Hawkins,C. Mathews, C. Gibson; Hospital for Joint Diseases, New York— J. Hebert, I. Rozentsvit, L. Capolino, J.P. Kelly; CarolinasMedical Center, Charlotte, N.C. — M. Kaufman, S. Putman,A. Diedrich, R. Follmer, S. Dombrowski, C. Graves, B. Harwick;Wayne State University, Detroit — A.C. Tselis, M. Din,C. Caon, M. Cochran, Z. Latif, R.P. Lisak, M. Zvartau-Hinds;Foothills Hospital, Calgary, Alta., Canada — L. Metz,J. Scott, D. Patry, M. Yeung, J. Heuser, C. Wallace, S. Curtis;Maimonides Medical Center, Brooklyn, N.Y. — A. Miller,E. Drexler, M.J. Keilson, K. Bruining, A. Schneider, R. Wolintz,L. Sciarra, H. Oltazewska; Rocky Mountain Multiple SclerosisCenter, Englewood, Colo. — R.S. Murray, A. Bowling, R.E.Kramer, K. Bracht, C. O'Brien, L. Seeberger, J. Leitch, E. Prenger,R. Gagnon; St. Michael's Hospital, Toronto — M. Hohol,T. Gray, E. Viara, B. Gray, L. Lewin, J. Rainford; RadcliffeInfirmary, Oxford, United Kingdom — J. Palace, A. Cavey,V. Moody; Texas Neurology, Dallas — J.T. Phillips, A.Martin, D. Hietzman, S. O'Leary, J. Phillips, M. Newsome; LehighValley Hospital, Allentown, Pa. — A. Rae-Grant, J.E. Castaldo,G. Mackin, N.J. Eckert, E. Shoemaker, L. Fowler-Blatt; Universityof Chicago, Chicago — A. Reder, B. Arnason, A. Noronha,P. Manning, V. Edmonds, B. Jamison, R. Ladsaria; London HealthScience Center, London, Ont., Canada — P. Mandalfino,D. Wingerchuk, M. Nicolle, M. Hopkins, D. Lee, E. Buchner, K.Kennedy; Guy's Hospital, London — M. Sharief, K. Wilson,S. Soudain, J. Bingham, P. Graves; University of Miami Schoolof Medicine, Miami — A. Minegar, M. Martinez, G. Calabro,S. Falcone; Ninewells Hospital, Dundee, United Kingdom —R. Swingler, S. Wilson, W. Milne; Yale University School ofMedicine, New Haven, Conn. — T. Vollmer, M.A. Rizzo, M.Carrithers, G. Blonco, H. Sarofin; Walton Centre for Neurologyand Neurosurgery, Liverpool, United Kingdom — C. Young,L. Owens, C. Dickinson.
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Glasner, J., Blum, H., Wehner, V., Stilz, H. U., Humphries, J. D., Curley, G. P., Mould, A. P., Humphries, M. J., Hallmann, R., Rollinghoff, M., Gessner, A.
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4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an 
1 integrin, also known as very late antigen 4, or VLA-4, is expressed on the surface of lymphocytes and monocytes and is an important mediator of cell adhesion and transendothelial migration, as well as a regulator of immune-cell activation within inflamed tissue.7,8 
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