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To the Editor: Sormani et al.1 attempt to validate multiple sclerosis (MS) relapse frequencies as surrogates for estimating the prevention of disability progression expected from relapse reduction. In pooled data on relapsing-remitting MS (RRMS), a strong association (R2 = 0.71; p < 0.001) was observed between treatment effects on relapses and on defined Expanded Disability Status Scale (EDSS) “worsening” defined in these trials.
However, neither Sormani et al. nor the editorialists2 acknowledge that the measures of disability used in these trials could not be validated themselves.3 Trial-defined worsening was no more likely than improvement, identically defined, in placebo arms. The results of Sormani et al., limited to 2-year periods, conflict with natural history analysis of times to cane, bed, and death from MS at 28 years,4 information perhaps not available then.3 Low (1–2), intermediate (3–4), and high (greater than or equal to 5) attack frequencies during RRMS did not differ in times to hard disability endpoints.
Frequent relapses from year 3 after onset to conversion to secondary progressive MS (SPMS) are associated with better outcomes, invalidating these relapses as outcomes predicting late disability.3 This epoch characterizes the data in the analysis by Sormani et al. Patients in trials and ethics committees considering their appropriateness should be aware that this measure cannot be validated. Potential benefit of relapse suppression on short-term neurologic dysfunction and possibly on lower, often asymptomatic, levels of the disability scale is conceded.
In an untreated natural history cohort, we cannot support conclusions recently endorsed by Rudick and Kappos.2 Clinical trials usually observed for 2 years after randomization need the context of times to hard DSS endpoints as long as 2 …
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