ResearchSpeak: natalizumab and brain atrophy

Will brain atrophy sort the men out from the boys? Almost surely! #MSResearch #MSBlog #ResearchSpeak

"There is one commentator who keeps saying natalizumab has no effect on brain atrophy; in fact he/she states it has zero effect. This is simply incorrect."

"In the STRATA, or extension study of the pivotal natalizumab trials, about 70% of MSers had brain atrophy rates of -0.4% or lower (slides 4 & 5). This is the unofficial cut-off for 'normalisation'. If you ask me this is pretty impressive data and is congruent with the clinical impact of natalizumab."

"Natalizumab has complex effects on brain atrophy. In year-1 it causes an increase in atrophy rate; we think this is due to the fact that it so effective as an anti-inflammatory that it reduces the swelling of the brain associated with inflammation. We call this effect pseudoatrophy as we don't think the brain atrophy in year-1 is only due to loss of neurones and axons. In year 2 on natalizumab the story is very different, here the atrophy rates are much lower in the order of 0.24% in the pivotal phase 3 or AFFIRM study (slide 1), well within the published 'normal range' (see slides 1-3 below). When you follow MSers up into year 3 the atrophy rates slow even further; the study below from Barcelona shows this very elegantly (slides 6 & 7)."

"Please note that until we follow-up age- and sex-matched normal controls in our phase 3 studies we can't claim brain atrophy rates are normalised. All we can do is compare them to published data sets on normal people."

"It is becoming increasingly clear that brain atrophy occurring now is driven by inflammation in the past. Inflammation doesn't only transect and destroy axons now, it damages other axons that then take months to years to degenerate, which is the pathological substrate for brain atrophy in the future. I have referred to the disconnect between the starting of an anti-inflammatory and its impact on brain atrophy years down the line as 'therapeutic lag'. The latter is not a very good term, but simply tries to capture the disconnect between switching off inflammation and the impact on brain atrophy as a therapeutic marker (see slides 6 & 7)."

"MSers with no inflammation, or Gd-enhancing lesions at baseline, have very little if any pseudoatrophy and much lower brain atrophy rates in years 2 & 3. In comparison, MSers with inflammation, or Gd-enhancing lesions, at baseline have much more prominent pseudoatrophy in year-1 and their brain atrophy rates are greater in year 2 & 3 (slides 6 & 7)."

"Please note pseudoatrophy and therapeutic lag with regard to natalizumab is also observed with other high efficacy therapies, i.e. alemtuzumab and HSCT. The impact of fingolimod is similar, but complicated by an impact of fingolimod on brain volumes very early on. We don't really know what the latter observation means; I suspect the early effect on brain volume changes is due to fingolimod-induced effects on other cell types (glial cells)."

"In conclusion, natalizumab does have an impact on brain atrophy; you simply have to look in the right time window."



Sastre-Garriga et al. Brain atrophy in natalizumab-treated patients: A 3-year follow-up. Mult Scler. 2015 May;21(6):749-56.

BACKGROUND: A pseudoatrophy effect has been held responsible for the lack of net impact of natalizumab on brain volume outcomes in 2-year trials, but no data are available beyond 24 months.

OBJECTIVE: We aimed to investigate brain volume dynamics in natalizumab-treated patients in up to 3 years after therapy initiation with clinical correlations.

METHODS: Patients on natalizumab for at least 3 years were clinically assessed 3-monthly. Magnetic resonance imaging scans were performed at baseline and yearly. Brain volume changes were obtained with SIENA. Multivariate models were used to investigate the association between baseline inflammation and changes in brain volume and disability.

RESULTS: Sixty-two patients with multiple sclerosis were analysed. Mean age and disease duration were 34.7 (SD: 8.3) and 10.4 (SD: 6.6) years. Presence of gadolinium enhancement at baseline was not associated with Expanded Disability Status Scale changes (p=0.468), but was associated with larger brain volume decreases (p=0.005) in the first (p=0.024) and second year (p=0.019) but not in the third year (p=0.863). Brain volume changes at 12 and 36 months were marginally associated with disability status at month 12 (p=0.094) and 36 (p=0.084), respectively.

CONCLUSIONS: Baseline inflammation affects brain volume measures up to 24 months after natalizumab initiation. A marginal association of brainvolume changes with disability is present.

CoI: multiple

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