BACKGROUND: Clinical intuition suggests that a sharp increase in the
number of enhancing lesions should signal an increased risk of relapse.
The ‘rule of five’ recommends that subjects exhibiting at least five
lesions over the baseline level be referred for closer monitoring. This
rule has been used as an informal safety criterion with limited formal
OBJECTIVE: The purpose of this study was to determine the
best threshold for the rule and to demonstrate its predictive validity
for risk of subsequent relapses for multiple sclerosis (MS) trials.
We used logistic regression modeling to apply the rule to patient data
from a phase II clinical trial. Predictive validity was ascertained
using rate ratios and receiver operating characteristic (ROC) curves.
We found that, for these data, a threshold of five lesions over the
baseline constituted the best definition of a threshold. Overall, 35% of
subjects broke the rule at least once. Breaking the rule increased the
odds of imminent relapse by a factor of 3.2 (95% confidence interval
CONCLUSION: Breaking the rule of five was found to be
a significant predictor of an imminent relapse. Length of follow-up and
the number of lesions discovered via magnetic resonance imaging (MRI)
were also significant predictors of relapse.