Saving Brain: early highly-effective treatment

Saving Brain: early highly-effective treatment! #MSBlog #MSResearch

Alemtuzumab 3-year brain atrophy data is simply stunning. #MSBlog #MSResearch

Will the FDA be convinced by the 3-year Alemtuzumab brain atrophy data? #MSBlog #MSResearch

"I have just returned from the AAN 2014 in Philadelphia. It was a very busy week so apologies for not posting more often. On reflection the issue that came up most at the meeting in relation to MS was that MS was a two component disease; i.e. an inflammatory (relapses and focal MRI activity) and degenerative (disease progression and brain atrophy) disease. It is clear that although many licensed DMTs are very good at suppressing inflammatory disease activity they are not that good at stopping brain atrophy. A study by Figueira and colleagues from Brazil below, showed despite many MSers being free of disease activity on platform or injectable therapies (inteferon-beta and GA) 50% of them showed a progressive brain atrophy that was comparable with those MSers who were suboptimal responders, i.e. had relapses or MRI activity."

"In comparison highly effective therapies seem to be able to suppress both inflammatory and neurodegenerative components of the disease. In a Spanish study Costa-Arpin and colleagues showed that the majority of MSers on natalizumab did not have a change in the volume of their corpus callosum and structure that is being increasinlgt used as an integrator for brain volume change in MSers. Even more impressive was the late-breaking results from the 3-year follow-up of the Alemtuzumab phase 3 studies showing that alemtuzumab has a profound impact on slowing, or even normalizing, brain volume loss in MSers. The following is the brain volume changes in the 3-years of the study. As you can see there is some pseudo-atrophy in year 1 when alemtuzumab switches-off the inflammation and then in year 2 and 3 the brain volume loss slows dramatically. You need to remember that brain atrophy is a normal phenomenon and occurs at a rate of between 0.1% and 0.4% in normal people. Therefore brain atrophy rates of 0.19% and 0.1% are well withing what is expected in normal people. 


Time PeriodCARE-MS ICARE-MS II
Year 0 to 1
−0.59%
−0.48%
Year 1 to 2
−0.25%
−0.22%
Year 2 to 3
−0.19%
−0.10%

These results are in line with what has been reported from the Canadian cohort of MSers who have been treated with bone marrow transplantation."

"After seeing and interpreting these results it is hard not to come to the conclusion that if  you want to get on top of both the inflammatory and neurodegenerative components of MS you want to be treated early with the most effective therapies. I suspect many of you will disagree with my interpretation of this data."

"'Saving Brain: early highly-effective treatment' is my new slogan!"

Arnold et al. Alemtuzumab Improves Brain MRI Outcomes in Patients With Active Relapsing-Remitting Multiple Sclerosis: Three-Year Follow-up of the CARE-MS Studies. AAN 2014; S65-008.

Addendum:

"On my Sunday run I was thinking about this data and realised it may be too good to be true (I do my best thinking when running). What may be happening is that in the subgroup of MSers who have reactivation of their disease the recurrence of inflammation may be reversing pseudo-atrophy. Therefore some of the reduction in volume loss may be rebound of disease activity. To look into this we would need to analyse brain atrophy rates in those with NEDA in year 3 vs. those without EDA (evident disease activity ) in year 3. Please note that about 1 in 5 MSers had EDA and required re-treatment with alemtuzumab in year 3." 


Normal (L) vs. MS (R): Can we save brain? 

Figueira et al. Sub-optimal Response to Therapy in Disease-free MS Patients: A Paradox? AAN 2014; P6.113 Thursday, May 1, 2014 7:30 AM

Objective: Axonal loss is an early finding in multiple sclerosis (MS) and relates to disability. So we propose its use as a marker for treatment optimization.

Background: Current MS therapies target inflammatory activity of disease, defined by clinical relapses and EDSS progression, besides with absent T1W contrast enhancing lesions as well as no new or enlarging T2W lesions on MRI, in a way to impact disability development. So, the absence of clinical and MRI activity are accepted paradigms of disease free status in treated patients. Nevertheless, axonal loss seems to be a major determinant of disability, and may occur with lacking clinical expression and sophisticated MRI requirements. In this paper, we discuss current concept of disease free applied in real world, and propose that measures of atrophy be used in daily practice as a tool for optimal therapy.


Design/Methods: Our group studied 206 consecutive non-selected patients with relapsing-remitting MS diagnosed according to 2001 McDonald criteria, on regular immunomodulatory treatment. They were submitted to serial clinical examinations and conventional MRI evaluation focus on relapses, EDSS progression and the presence of T1W Gd enhancing or T2W new/enlarging lesions. On conventional MRI sequences, we studied brain parenchymal fraction (BPF) and corpus callosum index (CCI), annually comparing results with data from a control group, composed by non-inflammatory diseases.


Results: After 5 year, 56.7% patients presented with some evidence of disease activity: all but two patients showed worsening scores in BPF and CCI. On the other hand, 43.2% fulfilled accepted criteria for free of disease status, despite 48.3% of them showed a progressive reduction on BPF and CCI, comparable with those stratified as suboptimal responders.


Conclusions: Our data demonstrates that axonal loss can be detected using corpus callosum index on routine follow up conventional MRI sequences, even among apparently stable patients. We propose axonal loss to be included as a requirement to consider a patient "disease free", during MS therapy.


Costa-Arpin et al. Evolution of Corpus Callosum Index in Patients with Relapsing Remiting Multiple Sclerosis Treated with Natalizumab. AAN 2014; P6.116 Thursday, May 1, 2014 7:30 AM

OBJECTIVE: Our main objective was analyze the evolution of cerebral atrophy in Multiple Sclerosis (MS) patients on treatment with Natalizumab.

BACKGROUND: Axonal damage has been shown in MS patients, even in early phase, conditioning cerebral atrophy and disability. An accesible form of quantify cerebral atrophy is the Corpus Callosum Index (CCI), which has been shown a low interobserver variability and a good correlation with other atrophy indices. In patients with MS, an anual average decline in CCI of 0,01+0,02 has been demonstrated.

DESIGN/METHODS: All patients on treatment with Natalizumab during one year or more were included in the study. The CCI was calculed in a basal MRI (made before treatment starting) and was compared with the CCI obtained in the last annual control MRI.

RESULTS: 22 patients were included in the study (54% women) with a middle age of 41+10 years. The median EDSS was 3,5 + 1,5. The average time between MRI was 36,9+11,15 months. The mean CCI was 0,374+0,037 on basal MRI and 0,364+0,036 in last control MRI. The annual CCI decrease was 0,006+0,01 and there were no changes in 59% (n=13).

CONCLUSIONS: More than a half of our patients with MS on treatment with Natalizumab have not been experienced changes in CCI over an average of three years. These data could reflect a possible neuroprotective effect of Natalizumab. 

CoI: multiple

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