Natalizumab and changes in normal appearing white matter

Epub: Mellergård et al. Association between Change in Normal Appearing White Matter Metabolites and Intrathecal Inflammation in Natalizumab-Treated Multiple Sclerosis. PLoS One. 2012;7(9):e44739. Epub 2012 Sep 17

BACKGROUND: MS is associated not only with focal inflammatory lesions but also diffuse pathology in the CNS. Since there is no firm association between the amount of focal inflammatory lesions and disease severity, diffuse pathology in normal appearing white matter (NAWM) may be crucial for disease progression. Immunomodulating treatments for MS reduce the number of focal lesions, but possible effects on diffuse white matter pathology are less studied. Furthermore, it is not known whether intrathecal levels of inflammatory or neurodegenerative markers are associated with development of pathology in NAWM.

METHODS: Quantitative proton magnetic resonance spectroscopy ((1)H-MRS)* was used to investigate NAWM in 27 MSers with relapsing MS before and after one year of treatment with natalizumab as well as NAWM in 20 healthy controls at baseline. Changes in (1)H-MRS metabolite concentrations during treatment were also correlated with a panel of intrathecal markers of inflammation and neurodegeneration in 24 of these 27 MSers.

* Proton magnetic resonance spectroscopy ((1)H-MRS) – this is a MRI technique that is used to quantify nerve cells and axonal numbers.

RESULTS: The group levels of (1)H-MRS metabolite concentrations were unchanged pre-to post-treatment but a pattern of high magnitude correlation coefficients (r = 0.43-0.67, p<0.0005-0.03) were found between changes in individual metabolite concentrations (total creatine and total choline) and levels of pro-inflammatory markers (IL-1β and CXCL8).

CONCLUSIONS: Despite a clinical improvement and a global decrease in levels of inflammatory markers in cerebrospinal fluid during treatment, high levels of pro-inflammatory CXCL8 and IL-1β were associated with an increase in (1)H-MRS metabolites indicative of continued gliosis development and membrane turnover in NAWM.

“Is  this good or bad news for MSers on Natalizumab? I am not sure. You could interpret this as something else going in the NAWM despite the absence of inflammation; this could be the primary pathological process that drives MS. In other words inflammation is secondary to what is causing MS. If this is the case Natallizumab won’t stop MSers developing SPMS. The jury is out on this and we will get an answer sometime soon.”

“This study is relevant to our recent grand challenge on peripheral stem cell migration into the CNS.”

CoI: multiple

Other posts on this blog in relation to Natalizumab:
27 Sep 2012
BACKGROUND: Antibodies against natalizumab have been found in 4.5-14.1% of natalizumab-treated multiple sclerosis (MS) patients. If antibodies persist, they are associated with an adverse effect on treatment response.
25 Aug 2012
August natalizumab PML update. As of the 3rd July 2012 there have been 264 confirmed cases of PML in MSers on natalizumab. The next 3 figures are an update of the latest the risks. “The following is the monthly slide deck 
03 Jul 2012
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15 Jul 2012
As of the 6th June 2012 there are 258 confirmed cases of natalizumab-associated cases of PML. The risks are beginning clearer with time, as noted by the decreasing size of the error bars in the figure above. The smaller the 
02 Jul 2012
These predictions were most sensitive to changes in the costs of natalizumab infusion. Changing these costs of €255 within a range from €165 to €364 per infusion, resulted in cost savings varying from €4,031 to €8,923 after 2 
19 May 2012
BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is associated with natalizumab treatment. Biogen-Idec quantified the risk of PML in MSers, according to the presence or absence of three risk factors: 
27 Sep 2012
METHODS: We prospectively collected clinical and magnetic resonance imaging (MRI) data of RRMS patients treated with natalizumab and followed-up for 24months. They were categorized according to different outcomes of 
27 Sep 2012
METHODS: We analyzed the effects of introducing an anti-inflammatory treatment, natalizumab, in MS, on factors related to work ability. This was done through a comprehensive questionnaire distributed to all patients in 
30 Mar 2012
Prediction of antibody persistency from antibody titres to natalizumab. Mult Scler. 2012 Mar 28. Background: In a subgroup of MSers natalizumab therapy causes generation of anti-natalizumab antibodies that may be transient 
27 Apr 2012
Natalizumab PML Safety Update. This data has been kindly provided by Biogen-Idec. Posted by Gavin Giovannoni at 14:55 · Email ThisBlogThis!Share to TwitterShare to Facebook. Labels: Natalizumab, PML, PML Risk 
11 Sep 2012
In the short-term it appears not to be as MSers do very well on natalizumab. But I am worried about the long term effects of natalizumab on bone-marrow derived stem cell and monocyte migration; do our brains and spinal cord 
10 Mar 2012
As of February 1, 2012, 51 natalizumab-treated MS’ers with PML had samples tested for anti-JCV antibodies that were collected at least 6 months prior to PML diagnosis (range 6-187 months), and all 51 patients tested 
30 Jan 2012
Natalizumab has demonstrated efficacy in multiple sclerosis (MS), but is associated with increased risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal brain infection caused by the JC virus. At the time 
04 Feb 2012
Another way of looking at the risk is to inverse the figures; for example 10.6/1000 = 1 person in 94, who is JCV seropositive, has received previous immunosuppression, and has had 25 to 48 infusions of natalizumab, will 
08 Feb 2012
New trial of Natalizumab in SPMS: the ASCEND study. A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With SPMS (ASCEND in SPMS). Eligibility 
14 Jan 2012
Please note that if you have been on Natalizumab longer than 24 months, have previously been treated with immunosuppressive drugs, for example mitoxantrone, and you are JC virus positive (blood tests shows you have 
19 Sep 2011
Methods: Natalizumab was administered by intravenous injection every other day at doses of 0, 3, 10, and 30 mg/kg. Males began treatment at least 28 days prior to mating until they were sacrificed for the study (approximately 
25 Aug 2011
Observed clinical trial rate in patients who received a mean of 17.9 monthly doses of natalizumab. The post-marketing rate is calculated as the number of PML cases since reintroduction in patients that have had at least 1 
29 Jul 2011
The incidence for each period is calculated as the number of PML cases divided by the number of patients exposed to natalizumab. For example for 25 to 36 infusions all PML cases diagnosed during this period is divided by 
21 Jun 2012
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31 May 2011
Of the women exposed to natalizumab during pregnancy, 29 women gave birth to 28 healthy children; one child was born with hexadactyly (an extra finger), 5 pregnancies ended in an early miscarriage and one woman 
24 Jul 2011
“The expectation of Natalizumab therapy is to prevent future attacks; it does little to repair previous damage. In MS’ers with early disease suppressing on-going disease activity allows endogenous repair to occur; this is why 
28 Nov 2011
Natalizumab in SPMS. In response to one of yesterday’s comments: A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With SPMS (ASCEND in SPMS). Eligibility. Ages Eligible for 
19 May 2011
“In summary, it is bad news if you develop PML on Natalizumab. If you are on Natalizumab please urge your neurologist to discuss the risk with you and to send your bloods off to see if you have previously been exposed to the 
10 May 2011
Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some neurologists interrupt treatment of patients with MS despite a lack of data regarding the safety of 
18 May 2012
Background: Multiple sclerosis (MS) patients discontinuing natalizumab treatment are at risk of disease reactivation. No clinical or surrogate parameters exist to identify patients at risk of post-natalizumab MS reactivation.
18 Apr 2011
Hoevenaren et al. Acta Neurol Scand. 2011 Jun;123(6):430-433. The authors describe the pregnancy and outcome in two women with MS using natalizumab. The first patient used it in the periconceptional period, and the 
29 Mar 2011
Natalizumab can lead to sustained improvements in disability. Why can’t patients improve on disease modifying therapies? Please see Phillips et al. Mult Scler. 2011 Mar 18. Posted by Gavin Giovannoni at 23:45 

4 thoughts on “Natalizumab and changes in normal appearing white matter”

  1. Dear Prof. G, if your conclusion is right ("Tysabri won't stop MSers from developing SPMS"), then the current clinical trial of Tysabri for SPMSers will be a total fail, right? I guess we will know the answer during the ECTRIMS congress next week

  2. At last, you agree that inflammation is secondary to the real cause of MS. The next step is to admit that it is totally healthy. The third, to get rid of EBV as the cause of MS. It has no place in the real world, only in diffuse statistics.

  3. No VV, inflammation in the brain is not healthy, which is why the normal brain goes out of its way to maintain homeostasis. If you can stop inflammatory relapses you should be able to at least slow down the rate of neurodegeneration but it isn't the whole story, which is why we are looking at neuroprotective agents as an additional therapy.

  4. Neuroprotection is meaningful only if you know what to protect neurons from. You seem to easily bypass this part and go straight to diminishing the secondary inflammatory response. Wrong succession of steps, ipso facto, unsuccessful so far in fundamentally treating MS.This study shows that the underlying MS process is unaffected by the reduction of relapses. Time to realise that relapses are just inflammatory signs of the damage. By reducing relapses you reduce the signs of damage but not the sustained damage itself.

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