The effects of MS treatments on atrophy have been investigated in several clinical trials, including those for IFNP-1a (Avonex) (Rudick et al., 1999), Campath 1H (Paolillo et al., 1999), cladribine (Filippi et al., 2000), linomide (Wolinsky et al., 2000), glatiramer acetate (Copaxone) (Rovaris et al.,
2001a; Ge et al., 2000a), IFNP-1b (Betaseron) (Molyneux et al., 2000), pulsed intravenous methylprednisolone (IVMP) (Zivadinov et al., 2001), and IFNP-1a (Rebif) (Wolinsky et al., 2001) (Table 3). Many of these drugs have been shown to be effective in reducing the number of gadolinium-enhancing lesions, but their effects on atrophy are not well understood. A 2-year Phase III trial of IFNP-1a in RR-MS (Rudick et al., 1999) demonstrated a significant treatment effect on atrophy in the second year of the trial. Similar rates of atrophy were observed in the European dose comparison study of IFNP-1a in RR-MS (Freitag et al., 2001), where the brain atrophy rate in the second and third years was about half of that of the first year. The delay in effectiveness may be due to a continuation of destructive processes initiated by pretrial inflammatory activity. A treatment effect on brain volume change was also observed in a subset of 27 patients from the 2-year Phase III trial of glatiramer acetate in RR-MS (Ge et al., 2000a), but not in the larger, but shorter term European trial of glatiramer acetate (Rovaris et al., 2001b). A 5-year study of pulse IVMP in RR-MS (Zivadinov et al., 2001) resulted in a significantly reduced rate of atrophy in the treated group compared to a group who received steroids only for relapses. In a 3-year European trial of IFNP-1b in SP-MS (Molyneux et al., 2000), there was no treatment effect for the group overall, but stratification by the presence of gadolinium-enhancing lesions at baseline revealed that in the subgroup without enhancing lesions, the treated group had significantly less atrophy than the placebo group. Other trials (Filippi et al,. 2000; Wolinsky et al., 2001; Jones et al., 2001) have found no treatment effects on atrophy. Results are not easy to compare across trials because each used a different type of atrophy measure and studied patients with different baseline characteristics. The durations of the controlled trials also varied considerably from 9 months to 5 years, and time may be an important factor to consider in studies of brain tissue loss resulting from MS. Atrophy measurement is attractive as an outcome measure for MS treatment trials because it may provide a means to test the ability of a particular therapy to halt tissue destruction.
Results have been more encouraging with RR-MS trials, where some but not all trials show therapeutic benefits on the rate of atrophy progression. To date, no studies in progressive MS have shown a therapeutic effect of anti-inflammatory therapy on atrophy progression. These results are consistent with the view that inflammation drives atrophy during early stages of MS to a greater degree than later in the disease (Fig. 3).
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