There are 6 US Food and Drug Administration (FDA)-approved DMTs in the United States at this time.  These DMTs are IFN beta-1a (intramuscular or subcutaneous), IFN beta-1b, glatiramer acetate, mitoxantrone, and natalizumab.  All of these treatments have shown significant reduction of relapse rate and MRI lesions compared with controls.  There are some data from pivotal studies to suggest a reduction of disability but long-term prevention of disability needs further evaluation.

Because cognitive dysfunction is the main cause of disability in patients with MS, and brain atrophy is highly associated with cognitive dysfunction, reduction of brain atrophy is a potentially important marker for the prevention of disability -- more important than the

fraction (BPF) reduction in patients receiving natalizumab compared with patients receiving placebo during the first year (0.56 vs 0.24%) than the second year (0.24% vs 0.43%). The question of why this may have occurred includes a time lag between inflammation and subsequent tissue loss (or atrophy in which the decrease in BPF during the first year may be an inevitable consequence of inflammation and tissue damage that occurred prior to initiation of treatment) or "pseudoatrophy" as an initial decrease in BPF from resolution of edema and inflammatory infiltrate rather than actual tissue loss.

To answer these questions, an analysis was conducted on the kinetics of brain atrophy during the first year of treatment with natalizumab from the AFFIRM study. Drs. Fisher and Rudick from the Cleveland Clinic Foundation, Cleveland, Ohio, presented further evaluation of the kinetics of brain atrophy and the relationship between inflammatory lesions and BPF during natalizumab treatment.   The study was a randomized, double-blind, placebo-controlled, phase 2 study of 213 patients, of which 148 (100 natalizumab, 48 placebo) had analyzable MRI scans.  The scans were performed at 1 month prior to the study, at month 0 (baseline), monthly for 6 months, and at months 9 and 12. The 2 treatment arms of natalizumab (3 mg/kg and 6 mg/kg) were combined for all statistical analyses.

The results showed an initial decrease in BPF in the early treatment period, followed by a levelling off after month 4 to the end of the treatment period (month 12).  This pattern of BPF change is most suggestive of pseudoatrophy, which is consistent with an anti-inflammatory effect followed by a reduced atrophy rate in the late treatment phase.  Therefore, this pattern of decrease in brain volume during the study suggests that natalizumab may have a beneficial effect on brain atrophy, beginning about 4 months after treatment initiation.

As of September 21, 2007, a total of 26,200 patients have been exposed to natalizumab, with no new cases of progressive multifocal leukoencephalopathy reported.  Seventeen thousand patients remain on natalizumab as of October 2007.  The overall rate of serious hypersensitivity reactions is 0.64%, usually at the second infusion. Testing for the presence of persistent antibodies to natalizumab (detected on 2 occasions at least 6 weeks apart) prior to re-dosing following a prolonged dose interruption is recommended because reduced efficacy and increased risk for hypersensitivity reactions are more common in these patients.  Twenty-four women in the United States and Austria with MS and exposure to natalizumab at any time during the first 3 months of pregnancy have enrolled in a pregnancy registry.  Twenty-one pregnancies were ongoing as of August 23, 2007 with 1 live birth, 1 spontaneous abortion, and 1 elective abortion.