Correspondence
Natalizumab for Relapsing Multiple Sclerosis
N Engl J Med 2003; 348:1598-1599April 17, 2003
- Article
To the Editor:
As participants in the original exploratory study,1 we did not find that treatment with anti–α4 integrin antibody was of clinical benefit. Miller and colleagues ( Jan. 2 issue)2 report that monthly natalizumab infusions in patients with multiple sclerosis significantly reduced relapse rates and enhancing lesions on magnetic resonance imaging (MRI), but this effect was not carried forward in the six months after treatment. The treatment had no effect on the disability score (on the Kurtzke Expanded Disability Status Scale). There was no evidence that long-term natalizumab infusions modify the course of multiple sclerosis.
Epidemiologic studies have shown a biologic dissociation between relapses and progressive disability once a score of 4 to 4.5 on the Expanded Disability Status Scale is reached.3 It may be argued that all patients with multiple sclerosis should start receiving natalizumab at the time of their first clinical presentation; however, the effects of pregnancy in multiple sclerosis clearly indicate that the progression of disability is independent of clinical relapses.4 Longitudinal MRI studies show that perivenous inflammatory changes are associated with local alterations in the blood–brain barrier and are not obligatory events in the evolution of the plaques in multiple sclerosis.5
The results of immunotherapy trials in multiple sclerosis suggest that although such treatments may reduce relapse rates, they do not modify progressive loss of function. In a three-year follow-up of a trial of treatment for acute optic neuritis, a benefit of antiinflammatory treatment was not evident.6 We are not convinced that the effects of natalizumab on relapsing multiple sclerosis are any exception.
6 ReferencesAbhijit Chaudhuri, D.M., M.D.
Peter O. Behan, D.Sc.
University of Glasgow, Glasgow G51 4TF, United Kingdom
ac54p@udcf.gla. ac. uk 1
Tubridy N ,Behan PO ,Capildeo R , et al. The effect of anti-alpha4-integrin antibody on brain lesion activity in MS. Neurology 1999;53:466-472
Web of Science | Medline2
Miller DH ,Khan OA ,Sheremata WA , et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15-23
Full Text | Web of Science | Medline3
Confavreux C ,Vukusic S ,Moreau T ,Adeleine P . Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438
Full Text | Web of Science | Medline4
Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, Pregnancy in Multiple Sclerosis Group
Full Text | Web of Science | Medline5
Narayana PA ,Doyle TJ ,Lai D ,Wolinsky JS . Serial proton magnetic resonance spectroscopic imaging, contrast-enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis. Ann Neurol 1998;43:56-71
CrossRef | Web of Science | Medline6
Beck RW . The optic neuritis treatment trial: three-year follow-up results. Arch Ophthalmol 1995;113:136-137
Web of Science | Medline
Author/Editor Response
Chaudhuri and Behan refer to an early exploratory study of natalizumab in multiple sclerosis. This was a study of 72 patients, of whom 37 were randomly assigned to receive two doses of natalizumab, one month apart (and 35 to receive placebo).1 There was a significant decrease in the number of new gadolinium-enhanced lesions on MRI during the 12 weeks after the first dose of natalizumab, as compared with placebo. Given the small size of the study and the limited duration of treatment, however, it is not surprising that no clinical benefit was observed. The positive MRI result did, however, provide us with a reason to undertake our six-month study. Although this study was powered only to investigate the effect of treatment on MRI activity, it showed a significant treatment-associated reduction in relapses. It is not surprising that there was no significant change in disability in either the treated groups or the placebo group over a six-month period.
The mechanisms by which irreversible disability develops in multiple sclerosis are not well understood. Chaudhuri and Behan cite evidence supporting the independence of the progression of disability and relapses,2,3 but these events are not completely unrelated. Incomplete recovery from relapses is one mechanism of permanent disability. The effect of natalizumab on long-term progression of disability can be addressed only by larger, longer-term, phase 3 studies. Two such studies designed to investigate this issue are currently under way.
In our article, we omitted acknowledgment of J. O'Riordan and J. Parratt (Ninewells Hospital, Dundee, United Kingdom), who were investigators in the trial, and Dr. Martin Sanders, who provided helpful comments on the manuscript.
3 ReferencesDavid H. Miller, M.D.
Institute of Neurology, London WC1N 3BG, United Kingdom
d.miller@ion. ucl. ac. uk Paul W. O'Connor, M.D.
University of Toronto, Toronto, ON M5B 1W8, Canada1
Tubridy N ,Behan PO ,Capildeo R , et al. The effect of anti-alpha4-integrin antibody on brain lesion activity in MS. Neurology 1999;53:466-472
Web of Science | Medline2
Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, Pregnancy in Multiple Sclerosis Group
Full Text | Web of Science | Medline3
Confavreux C ,Vukusic S ,Moreau T ,Adeleine P . Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438
Full Text | Web of Science | Medline
- Citing Articles (8)
Citing Articles
1
Y. Miyazaki, S. Miyake, A. Chiba, O. Lantz, T. Yamamura. (2011) Mucosal-associated invariant T cells regulate Th1 response in multiple sclerosis. International Immunology 23:9, 529-535
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James T Rosenbaum. (2010) Future for biological therapy for uveitis. Current Opinion in Ophthalmology 21:6, 473-477
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O. Barreiro, P. Martin, R. Gonzalez-Amaro, F. Sanchez-Madrid. (2010) Molecular cues guiding inflammatory responses. Cardiovascular Research 86:2, 174-182
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Olga Barreiro, Francisco Sánchez-Madrid. (2009) Bases moleculares de las interacciones leucocito-endotelio durante la respuesta inflamatoria. Revista Española de Cardiología 62:5, 552-562
CrossRef5
Olga Barreiro, Hortensia de la Fuente, María Mittelbrunn, Francisco Sánchez-Madrid. (2007) Functional insights on the polarized redistribution of leukocyte integrins and their ligands during leukocyte migration and immune interactions. Immunological Reviews 218:1, 147-164
CrossRef6
María Mittelbrunn, Carlos Cabanas, Francisco Sanchez-Madrid. (2006) Integrin alpha 4. AfCS-Nature Molecule Pages
CrossRef7
Charo, Israel F., Ransohoff, Richard M., . (2006) The Many Roles of Chemokines and Chemokine Receptors in Inflammation. New England Journal of Medicine 354:6, 610-621
Full Text8
Roberto Gonzalez-Amaro, Maria Mittelbrunn, Francisco Sanchez-Madrid. (2005) Therapeutic anti-integrin (alpha4 and alphaL) monoclonal antibodies: two-edged swords?. Immunology 116:3, 289-296
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