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Conclusion:    Click on the link at left to go to your desired page:  Introduction  Page 2  Page 3  Study 1  Study 2  Conclusion  Post-Test

Most studies conducted on treatment options for MS are generally less than two years in duration.  This is considered relatively short-term to learn about achieving long-term effects.  Because of this, the American Academy of Neurology and the MS Council for Clinical Practice Guidelines recommend primary endpoints that can reflect shorter-term changes such as serial MRI tests for new and changing lesions along with clinical evaluations to further verify objective findings. 


In addition to the use of MRI for objective measures and primary endpoints for treatment research, the National Multiple Sclerosis Society’s Clinical Outcomes Assessment Task Force has recommended use of the MS Function Composite (MSFC) assessment in the place of the previously used Kurtzke Expanded Disability Status Scale (EDSS).  The former is based on quantitative measures while the latter was based on qualitative neurologic examination.  The MFSC has been cross-validated with the EDSS, health-related quality of life (HRQOL) scale based on patient self-report, and magnetic resonance imaging (MRI) for objective evaluation of brain lesions and atrophy.  A recent trial of IFN β-1a compared the use of the MSFC to EDSS.11  While most studies reported to date have used the EDSS it is likely that the criteria for evaluation will switch to the MFSC methods in future studies, which may limit some comparisons to previous studies that used EDSS. 


Categories of treatments outlined by the Task Force guidelines include immunosuppressive, immunomodulatory, and anti-inflammatory.  Two types of therapies have been reviewed in this Journal Club from the immunomodulatory category: interferon β-1a and natalizumab. 


In the study comparing two different regimens of interferon β-1a differences were attributed to dose levels (44 mcg versus 30 mcg) but were not separated out to determine the effects of other factors in the Rebif versus the Avonex regimens, such as route of administration (subcutaneous versus intramuscular), the frequency of dosing (three times per week versus once per week), and total weekly dose (132 mcg versus 30 mcg). The results were mixed with significantly fewer new lesions and relapses seen during the treatment phases for the Rebif arm compared to the Avonex arm while additional adverse effects and development of NAb were seen in the Rebif regimen.  Authors noted that longer-term observation is needed to determine any clinically important effects on therapy efficacy by the presence or level of NAb.


Natalizumab (Antegren) is an experimental treatment for MS that has recently been investigated in both MS and Crohn’s disease.  Natalizumab therapy is based on the potential for binding with α4 integrin molecules to keep them from allowing the adhesion of lymphocytes and monocytes to endothelial cells on vascular walls.  While this normally allows the immune cell to slow down and roll along the wall, signaling chemokines can switch the integrins to “high-affinity,” which allows the cell to stop and flatten in a favorable position to migrate across the endothelial barrier.  In the case of MS, this migration occurs across the blood-brain barrier.  Natalizumab is an anti α4 integrin molecule that can affect the signaling of immune cells to adhere and cross the blood brain barrier.  The study described in this Journal Club is a follow-up to promising preliminary work that suggested a beneficial effect on reducing the numbers of new and continuing lesions.  The follow-up study suggested that two levels of dosing showed similar profiles for such benefits over placebo, and may favorably compare to other treatments such as interferon β-1a and glatiramer acetate.  The authors also suggested that there might be a better saturation of α4 integrin receptors using the higher dose and a potential for a more sustained effect.  The development of NAb to natalizumab did not have any apparent limiting effect in this study, but may require longer-term studies to fully determine any such limitations for natalizumab therapy in MS.


Proposed treatments for MS continue to evolve with carefully designed research guided by the American Academy of Neurology and the MS Council for Clinical Practice Guidelines criteria for reporting research results.  While it is likely that MS treatment will be individualized according to patient needs, evidence-based practice guidelines will continue to be revised and refined according to new research over the next few years in order to improve patient outcomes while minimizing the potential for adverse effects.



1 Goodin DS, Frohman EM, Garmany GP, Halper J, Likosky WH, Lublin FD, Silberberg DH, Stuart WH, van den Noort S. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58(2):169-178.

2 Based on: Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, Gotzsche PC, Lang T for the CONSORT Group. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Int Med. 2001;134:663-694. Access at

3 Biogen, Inc. 14 Cambridge Center, Cambridge, MA 02142. 800-456-2255.

4 Serono Laboratories, Inc. 100 Longwater Circle, Norwell, MA 02061; 800-283-8088.

5 Elan Pharmaceuticals, Inc. 800 Gateway Blvd, South San Francisco, CA 94080. 888-638-7605.

6 IFNB MS Study Group. University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon ß-1a in relapsing MS. Neurology. 2001;56:1628-1636.

7 PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon ß-1a in relapsing MS. Neurology. 2001;56:1628-1636.

8 Drug description information accessed June 6, 2003 at and Elan Pharmaceuticals at

9 Von Andrian UH, Engelhardt B. α4-integrins as therapeutic targets in autoimmune disease. N Engl J Med. 348(1):68-72.

10 Turbridy N, Behan PO, Capildeo R, Chaudhuri A, Forbes R, Hawkins CP, Hughes RAC, Palace J, Sharrack B, Swingler R, Young MC, Moseley IF, MacManus DG, Donoghue S, Miller DH and the UK Antegren Study Group. The effect of anti-α4 integrin antibody in brain lesion activity in MS. Neurology. 1999;53:466-472.

11 Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, Sandrock AW, Rudick RA, Simon JH, Simonian NA, Tsao EC, Whitaker JN for the IMPACT Investigators. Benefit of interferon ß-1a on MSFC progression in secondary progressive MS.  Neurology. 2002;59:679-687.


Click on the link at left to go to your desired page:  Introduction  Page 2  Page 3  Study 1  Study 2  Conclusion  Post-Test

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