Saturday, 28 February 2015

CrowdSpeak: we need a new name for the Charcot 2 trial

How are your creative skills? Can you come up with a better name than HEART? #CrowdSpeak #MSBlog #MSResearch

"Since launching our crowdsourcing project and proposing the anti-EBV/HAART study we have a few complaints about the acronym HEART. Can you come-up with something better? Something more catchy?"

"Our survey remains open and we have expanded the number of questions to include a suggestion for a new name."

"This remains a community project so please feel free to comment. Thank you."

CoI: multiple

ClinicSpeak: risk of stopping natalizumab

How to prevent getting worse when stopping natalizumab. #ClinicSpeak #MSResearch #MSBlog

"A critical issue in MS with regard to risk:benefit assessment of DMTs (disease-modifying therapies) is the short-change we give to the risk of MS. This real-life data study below shows that when we de-risk PML by taking MSers off natalizumab, we increase their risk of becoming more disabled. If you are on natalizumab and stop the drug your have two-fold higher risk of getting worse compared to MSers who stay on natalizumab. More importantly if you stop natalizumab you are likelihood of having an improvement in disability plummets and is 68% lower than MSers who stay on natalizumab."

"This study is telling us several things:

  1. How are expectations have shifted since we have licensed high-efficacy DMTs; we are not only expecting MSers to flatline (no increase in disability), but expect a significant proportion of MSers to have a sustained improvement in disability.
  2. Your baseline disability level predicts worsening. In other words if you have lost time, or brain, you are more likely to progress when coming off natalizumab. This makes sense biologically. What protects from developing progressive MS is reserve capacity; if your nervous system has not lost too many neurons and axons the surviving cells have the ability to compensate.
  3. Natalizumab is not an induction therapy; it is a maintenance therapy. In other words when you stop natalizumab MS comes back with a vengeance. Some observations suggest the rebound with natalizumab is much worse than you would expect from natural history studies. Natalizumab is an interesting observation.
Should we accept these results? No. I think there are now several strategies that we can adopt to prevent rebound and worsening post natalizumab. This study was done in the era when we did wash-outs and allowed rebound to occur post-natalizumab. I think most of us will not simply stop natalizumab without transitioning MSers onto other high-efficacy therapies. I have posted on this before."

Previous posts of interest:

  1. Switching therapies: considerations around alemtuzumab20 Aug 2014
  2. Multiple Sclerosis Research: Effects of switching to fingolimod06 Aug 2014
  3. Clinic Speak: switching from natalizumab to alemtuzumab05 May 2014
  4. Clinic Speak: switching from fingolimod to alemtuzumab07 May 2014

OBJECTIVE: The objective of this paper is to estimate the risk of reaching well-established disability milestones after withdrawal of natalizumab (NTZ) due to concern about the risk of progressive multifocal leukoencephalopathy in MSers.

METHODS: Data from 415 MSers followed-up for six years after starting NTZ were collected from seven tertiary MS centres. The risk of disability worsening, i.e. reaching Expanded Disability Status Scale (EDSS) scores of 4.0 or 6.0, and the likelihood of experiencing a disability reduction of one EDSS point (or more), were assessed by propensity score-adjusted analyses in MSers who discontinued and in those still on treatment at the end of follow-up.

RESULTS: A total of 318 MSers who received standard NTZ treatment without experiencing evidence of disability worsening in the first two years were included in the six-year follow-up analysis, with 196 (61.6%) still on treatment and 122 (38.4%) discontinuing after a median time of 3.5 years. MSers in the discontinuing group had a more than two-fold increased risk of disability worsening (p = 0.007), and a 68% decreased likelihood of experiencing disability reduction (p = 0.009) compared with the continuing group.

CONCLUSION: While discussing the overall risk/benefit profile of NTZ, MSers should be advised that, in case of treatment discontinuation, the risk of disability worsening is one in three, and increases to one in two if the EDSS score at NTZ start is above 3.0.

CoI: multiple

Genetics of thin brains give ideas to control progression

Matsushita T, Madireddy L, Sprenger T, Khankhanian P, Magon S, Naegelin Y, Caverzasi E, Lindberg RL, Kappos L, Hauser SL, Oksenberg JR, Henry R, Pelletier D, Baranzini SE. Genetic associations with brain cortical thickness in multiple sclerosis.
Genes Brain Behav. 2015. doi: 10.1111/gbb.12190. [Epub ahead of print]

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of grey matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by MRI. The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified 9 areas showing different thickness between cases and controls (regions of interest, ROI) (8 of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for sub networks enriched with nominally associated genes and searched for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signalling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS.

We are a product of our genes and Genome Wide Association Studies (GWAS) have so far found about 150 MS Susceptibility  genes or gene products. In this study they looked for pathology and notably MRI-detected Grey matter thickness as a marker of cognitive disability and found no associate with any single gene. It has been said that unless you examine thousands of samples you get nothing that is reproducible. This what was found.

However if you look at networks of gene  they found associates that influenced calcium levels (we know if you have too much calcium it triggers cell suicide). Excessive glutamate levels trigger calcium excessive calcium concentrations within the cell that can lead to cell death. These will all need to verified in additional studies, but already we have been thinking about blocking glutamate signalling. 

In animals, blocking excessive glutamate signalling can slow progressive nerve loss however this is associated with significant side-effects and also the system is rapidly de-sensitized, so drugs don't work. So far in MS this approach has not worked..I won't say I told you so, but I could have told you so.