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Numerous trials have established that immunomodulatory therapy reduces short-term relapse risk after a high-risk clinically isolated syndrome (CIS) — a first clinical demyelinating attack that is typical of multiple sclerosis (MS). The long-term consequences of delaying treatment are less clear. To address this question, researchers conducted an industry-sponsored follow-up of the CHAMPS (Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study) study, a randomized, placebo-controlled trial that demonstrated reduction in relapse risk with once-weekly interferon beta-1a in CIS. When CHAMPS ended, participants were allowed to continue with interferon beta-1a as part of an open-label follow-up cohort without being informed of their original treatment assignment. Those originally randomized to interferon beta-1a were designated the “immediate treatment” group, and those originally randomized to placebo were designated the “delayed treatment” group (median time to interferon beta-1a initiation, 30 months). Five-year follow-up demonstrated a reduction in the risk for conversion to clinically definite MS with immediate treatment (Neurology 2006; 66:678). The authors now report 10-year findings.
At 10 years, 68 (35%) of the 193 participants in the immediate-treatment arm remained in the cohort, as did 59 (31%) of the 190 participants in the delayed-treatment arm. The cumulative probability of conversion to clinically definite MS at 10 years was lower in the immediate-treatment group (58%) than in the delayed-treatment group (69%). Few patients overall developed secondary progression or sustained disability.
Kinkel RP et al. Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: A 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance. Arch Neurol 2011 Oct 10; [e-pub ahead of print]. (http://dx.doi.org/10.1001/archneurol.2011.1426)
Comment
The main threat to validity in this kind of long-term follow-up analysis is selection bias: Were the patients who remained at 10 years truly representative of the original study population, or were those with more active disease disproportionately lost to follow-up? Therefore, the main finding from this study — that a short delay in treatment initiation is associated with long-lasting effects on conversion to clinically definite MS — must be considered cautiously. Nonetheless, these results are consistent with findings from the BENEFIT study (Lancet Neurol 2009; 8:987).
Arguably, disability is a more important outcome than relapse risk in assessing treatment delay. In a large observational analysis, treatment of relapsing-remitting MS with any formulation of interferon beta delayed time to secondary progression and accumulation of ambulatory disability compared with no treatment (JW Neurol Aug 28 2007), and earlier initiation of therapy (within 1 year of disease onset) delayed time to disability accumulation (Ann Neurol 2009; 66:513). These data add weight to the idea that earlier initiation of immunomodulatory therapy has long-term benefits, but more-rigorous efforts to record disease activity in participants who left the cohort would have been helpful to allay concern about potential bias.