Tuesday, 11 October 2016

Avonex and spinal cord atrophy

BMC Med Imaging. 2016 Oct 5;16(1):56.

The effect of intramuscular interferon beta-1a on spinal cord volume in relapsing-remitting multiple sclerosis.

Dupuy SL, Khalid F, Healy BC, Bakshi S, Neema M, Tauhid S, Bakshi R.

Abstract

BACKGROUND:

Spinal cord atrophy occurs early in multiple sclerosis (MS) and impacts disability. The therapeutic effect of interferon beta-1a (IFNβ-1a) on spinal cord atrophy in patients with relapsing-remitting (RR) MS has not been explored.

METHODS:

We retrospectively identified 16 consecutive patients receiving weekly intramuscular IFNβ-1a for 2 years [baseline age (mean ± SD) 47.7 ± 7.5 years, Expanded Disability Status Scale score median (range) 1.5 (0-2.5), timed 25-foot walk 4.6 ± 0.7 seconds; time on treatment 68.3 ± 59.9 months] and 11 sex- and age-matched normal controls (NC). The spinal cord was imaged at baseline, 1 and 2 years later with 3T MRI. C1-C5 spinal cord volume was measured by an active surface method, from which normalized spinal cord area (SCA) was calculated.

RESULTS:

SCA showed no change in the MS or NC group over 2 years [mean annualized difference (95 % CI) MS: -0.604 mm2 (-1.352, 0.144), p = 0.106; NC: -0.360 mm2 (-1.576, 0.855), p = 0.524]. Between group analysis indicated no differences in on-study SCA change [MS vs. NC; year 1 vs. baseline, mean annualized difference (95 % CI) 0.400 mm2 (-3.350, 2.549), p = 0.780; year 2 vs. year 1: -1.196 mm2 (-0.875, 3.266), p = 0.245; year 2 vs. baseline -0.243 mm2 (-1.120, 1.607), p = 0.712].

CONCLUSION:

Established IFNβ-1a therapy was not associated with ongoing spinal cord atrophy or any difference in the rate of spinal cord volume change in RRMS compared to NC over 2 years. These results may reflect a treatment effect. However, due to sample size and study design, these results should be considered preliminary and await confirmation.

 Fig: Quantification of spinal cord area

Spinal cord volume loss over the disease course has been linked to disability progression in PwMS, whether it be relapsing-remitting MS or progressive forms of MS. The volume loss in spinal cord is thought to occur not only as a direct result of lesions but as an indirect loss due to dying back axons from a lesion elsewhere in the cord or brain (a process termed Wallerian degeneration). This is probably why spinal cord volume loss is an important indicator of disability progression. Along these lines measurements of spinal cord volume loss can be used to study the efficacy of disease modifying treatments, particularly in primary progressive MS.

Here Dupuy et al. study the neuroprotective effect of Avonex (IFNbeta-1a, Biogen) on spinal cord volume loss. At this stage I must point out that this is a small study (a pilot) and measurements are only done over a two year period and therefore the study is unable to tell you about whether Avonex can slow the rate of volume loss, since there is often a lag in treatment effect by several years. Moreover, there is no direct comparison with PwMS not on treatment, but this study simply looks at spinal cord volume loss in those without MS (I don't think including PwMS not on treatment over two years is ethical considering the current availability of treatments that work).

The study found that there was no difference in the rate of volume loss in the spinal cord of those on Avonex compared to those without MS over a two year period. They allude to a treatment effect by Avonex based on the lack of difference between the two groups.

Traditionally, the effect of disease-modifying treatments in MS are not studied owing to methodological difficulties of measuring the cross-sectional area of what is a small structure and it's variability over time. However, previously another group had studied the effect of Rebif (IFNbeta-1a, Biogen) over a four year period in untreated and treated PwMS, and found no difference in the rate of spinal cord volume loss (Lin X et al. Spinal cord atrophy and disability in multiple sclerosis over four years: application of a reproducible automated technique in monitoring disease progression in a cohort of the interferon B-1a (Rebif) treatment trial. JNNP 2003; 73: 1090-4). In the latter study, they found no difference between baseline spinal cord volumes in the RRMS and those without MS, hinting that spinal cord volume loss may not be significant in early MS and may explain the lack of difference in the Avonex treatment group and those without MS! Clearly, this study needs repeating and preferably in a larger group.

8 comments:

  1. So, not to be too jaded, this study was under powered i.e. too small sample size and too short in duration yet it was performed with the financial backing of Biogen. I also see it was performed at the Harvard Medical Corporation. edu...that explains it.

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    1. I agree with under powering of studies, this should be factored into the study design from the beginning. Pharmaceutical funding of university research is on the other hand nothing new and we're likely to see more of this over time. Why I say this is that research funding from research councils (i.e. government funded research) is steadily shrinking and as you see from the amount of MS related research we post, very few of them are in fact funded by them. There is at least in the UK an apparent disconnect in the work which we want to know about and what is funded by the government. But there are also reasons for pharmaceutical industries funding a particular piece of research...

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    2. It just seems that if Pharma is funding a study then there is a bias introduced, i.e. they design the study to succeed, or am I mistaken?

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    3. Why would you plan a study to fail? :-)

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    4. Looks like Biogen's ASCEND study on Tysabri and SPMS was designed to fail, at least in Dr. G's opinion.

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    5. Things are never black and white. What happens is that you design the ideal study based on the knowledge available to you at the time, you then realise half way though the trial that x, y, z is wrong or more commonly haven't been factored in. By which point it's all too late.

      My ethos is that if the evidence base is sound to begin with and you've just managed royally screw it up, accept the error, change it and then repeat it. This is what the Ocrelizumab trial in PPMS was all about. Although, pathophysiologically speaking it was a large risk on Roche's part to go with PPMS rather than SPMS. But then Teva had the idea of taking their drug into PPMS well before the Ocrelizumab study - so maybe the same set of people advising??

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  2. I would really appreciate an answer to this. In 2011 I had an MRI which showed lesions and mild atrophy on my spinal cord. It was seen again in 2012. This year in Feb the MRI appeared normal with no lesions or atrophy. The scan was repeated again a few weeks ago on an even more detailed scan (3T) and again no atrophy or lesions were seen. I still have the foot drop and spasticity from the cord lesion. What could this mean?

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    1. Lesions shrink in size over time and may not be apparent on imagining. Spinal cord MRI in particular gives grainy views with poor resolution on axial views (see image above) making it difficult to visualise lesions in some cases. Volume measurements also are prone to errors, from the person reading it to how much water the person has drunk. It is also not comparable between different scanners. With the clinical symptoms such as foot drop this may be the result of involvement of the motor pathways from the brain to the spinal cord and a number of different lesions may be contributory, the same applies for spasticity which is the result of delay or inability of inhibitory responses getting down the spinal cord from the brain and lack of this inhibition on local spinal reflexes and cannot be attributed to a single or specifically to a lesion in one position. The use of MRI in the clinical setting is when there are new lesions or enhancing lesions.

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