“In response to my post yesterday on ‘Brain atrophy: the ultimate outcome in MS‘ I thought it would be worthwhile revisiting the pivotal IFNbeta-1b (Betaseron/Betaferon) long-term follow-up data. In the 16-year follow-up baseline 3rd ventricular width, a crude measure of brain atrophy, correlated with disability progression and cognitive impairment at 16 years. Please note that the abstract states it does not correlate with physical disability progression; however in the table in the paper the p-value is significant albeit it with a low R-squared value. For those of you who are not statisticians this means that brain atrophy at baseline is not a very good predictor of EDSS progression but does explain a small component of it.”
“Unfortunately, the on-study changes in the MRI variables did not explain much change at 16 years; why not? Firstly, IFN-beta-1b subsequently was not been shown to affect brain atrophy, the drug is only a moderately effective DMT and the placebo-controlled part of the trial was relatively short. I therefore would not put too much weight on this studies conclusions. With the more effective DMTs on study changes are predictive of long-term outcomes; despite the follow-up being shorter than 16 years at present. What is also important to note is that the average disease duration of the MSers in this IFN-beta-1b study, when it started, was over 8 years, which is far too far along the disease course to have a major impact. We need to hit this disease earlier before too much reserve capacity is lost to have an impact. This study supports the concept of brain atrophy being the integrator of end-organ damage in MS; those who came into the study with end-organ damage did worst.”
“Who wouldn’t want to protect their brain from shrinking?”
|Note the enlargement of the 3rd ventricle between the two scans. This is a crude index of brain atrophy that can be seen in serial scans done as part of routine clinical care.|
BACKGROUND: Evaluating the long term benefit of therapy in MS is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established.
METHODS: In a MSer cohort from the pivotal interferon β-1b trial, the value of clinical and MRI measures were analysed, both at baseline and during the RCT, for predicting long term physical and cognitive outcome.
RESULTS: Baseline disability correlated with both physical (R(2)=0.22; p<0.0001) and cognitive (R(2)=0.12; p<0.0001) outcome after 16 years. Accrual of disability during the RCT (R(2)=0.12; p<0.0001) and annualised relapse rates during the trial correlated with physical outcome (R(2)=0.12; p<0.0001) but not with cognition. In contrast, baseline MRI measures of atrophy and lesion burden correlated with cognitive (R(2)=0.21; p<0.0001), but not with physical, outcome. Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome. Multivariate regression analysis using stepwise elimination demonstrated that baseline variables contributed independently to predicting long term outcomes while trial outcome variables contributed little. Overall, and considerably dependent on baseline measures, the models developed by this method accounted for approximately half of the variance in long term cognitive and disability outcome.
CONCLUSIONS: Although on-trial change in some short term clinical measures correlated with long term physical and disability outcomes, the proportion of the variance explained by single commonly employed on-study variables was often small or undetectable. Better correlations were observed for several baseline measures, suggesting that long term outcome in MS may be largely determined early in the disease course. Trial registration number http://Clinical Trials.gov, study registration NCT00206635.