Monday, 2 February 2015

ClinicSpeak: brain atrophy predicts disability

End-organ damage; can we prevent it? #ClinicSpeak #MSBlog #MSResearch

"Moving beyond NEDA and focusing on end-organ damage is my mantra for 2015. In rheumatoid arthritis the rheumatologists look for subchondral erosions; subchondral simply means beneath the cartilage of the joint. When they see these little cystic like structures they know from long-term studies that joint is damaged beyond protection and will probably end-up needing to be replaced in the future. We think accelerated brain atrophy is the MS equivalent of subchondral erosions. The meta-analysis of all the fingolimod trial MSers shows that accelerated brain volume loss predicts disability progression. Are we surprised? No. I personally think that brain volume loss over a relatively long period of time is a good integrator of end-organ damage; in other words it sums all the damage that MS causes."

"There are problems measuring brain volume loss and interpreting it over the short-term, i.e. up to 12 months. But over a 2-4 year period it seems to be a reliable biomarker that is increasingly being incorporated into clinical trials and clinical practice. If you have an inflammed brain with active Gd-enhancing lesions on your scan and you go onto a DMT your brain will shrink quite rapidly; we call this pseudoatrophy. Pseudoatrophy is what happens when the swelling associated with inflammation resolves. To get rid of pseudoatrophy we have to rebaseline the scans at say 12 months and then measure brain atrophy that occurs after the first 12 months. When we do that it is a very good predictor of disability progression."

"What is remarkable in the study below is that brain atrophy correlated so well with inflammatory markers on MRI (focal lesions as represented by T2 and T1 lesions). This would indicate that brain atrophy is being driven by inflammation. The corollary of this is that if you switch off inflammation you should slow down brain volume loss, protect the brain and prevent end-organ damage. There is now a push to start including brain atrophy measurements into clinical practice to guide clinical decision making. Some of us want to include it as fourth metric in NEDA; NEDA-4. There are large number of hurdles to get over before being able to do this, but unless we start using brain volume loss we won't think about preventing end-organ damage. Once we start getting brain volume measurements in clinic it will make us think about preventing its loss."

"When you line up the different DMTs it is only really the most effective DMTs that prevent end-organ damage on average. That is why I push for monitoring and a rapid escalation to more effective therapies if you are not responding to less effective DMTs. The rapid escalation policy needs MRI monitoring to implement it."

"The following is a short slide show to illustrate some of the points I have made above:
  1. End-organ damage means that an MSer will lose about 30-40% of their brain volume by the time they die.
  2. Brain volume loss occurs throughout the course of the disease.
  3. MS disease activity is like an iceberg; most of the damage is occurring without you being aware of it hence the need to be monitored using MRI.
  4. In a meta-analysis of trials inflammation (focal MRI activity) and neurodegeneration (brain volume loss) predicted 75% of disability over 2 years. Therefore to prevent disability progression we need to stop both these processes from occurring.
  5. A picture is worth a 1000 words; two examples of brain loss over 18 months in two RRMSers.
  6. A summary of how the different DMTs affect brain volume loss.
  7. The Barts-MS treat-2-target algorithm; at present it does not include brain volume loss.
  8. End-organ damage in a RA joint.
  9. A treatment algorithm stolen the gastroenterologists who treat inflammatory bowel disease; we have adopted the accelerated step-care (rapid-escalation) or the early-top-down approach (induction therapy) in MS."

Epub: Radue et al. Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis. Neurology. 2015 Jan .

OBJECTIVE: We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among RRMSers from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS.

METHODS: Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 MSers from the trials and their extensions. The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models. The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years.

RESULTS: Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume (p < 0.001, all). The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume (p < 0.01, all). During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count (p < 0.001, both), and number of confirmed on-study relapses (p < 0.01). Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in MSers with greatest BVL.

CONCLUSIONS: Rate of BVL in RRMSers during the fingolimod trials correlated with disease severity at baseline and new disease activity on study, and was associated with worsening disability.

CoI: multiple

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