  Background: Recent systematic reviews of randomised controlled trials (RCTs)
in relapsing multiple sclerosis (RMS) revealed a decrease in placebo annualized
relapse rates (ARR) over the past two decades. Furthermore, regression to the
mean effects were observed in ARR and MRI lesion counts. It is unclear whether
disease progression measured by the expanded disability status scale (EDSS)
exhibits similar features.
  Methods: A systematic review of RCTs in RMS was conducted extracting data on
EDSS and baseline characteristics. The logarithmic odds of disease progression
were modelled to investigate time trends. Random-effects models were used to
account for between-study variability; all investigated models included trial
duration as a predictor to correct for unequal study durations.
Meta-regressions were conducted to assess the prognostic value of a number of
baseline variables.
  Results: The systematic literature search identified 39 studies, including a
total of 19,714 patients. The proportion of patients in placebo controls
experiencing a disease progression decreased over the years (p<0.001). Meta
regression identified associated covariates including the size of the study and
its duration that in part explained the time trend. Progression probabilities
tended to be lower in the second year compared to the first year with a
reduction of 24% in progression probability from year 1 to year 2 (p=0.014).
  Conclusion: EDSS disease progression exhibits similar behaviour over time as
the ARR and point to changes in trial characteristics over the years,
questioning comparisons between historical and recent trials.
