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
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.
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.
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