Monday, 6 July 2015

EBV and natalizumab

What can we learn from natalizumab treatment in MS? #MSBlog #MSResearch

"These results are similar to our earlier results, which we have presented in abstract form but not submitted for publication. Unlike interferon-beta, natalizumab seems to have little effect on EBV serology. I was secretly hoping to see a massive rise in antibody titres on natalizumab indicating reactivation of lytic virus within the CNS and release of EBV antigen into  the periphery to stimulate a B cell antibody response. This is what happens to JCV antibody levels prior to the development of PML. This was the hypothesis we were testing in relation to EBV. The slight increase in anti-VCA (viral capsid antigen) and not EBNA-1 levels in this study, suggest there may be an increase in EBV lytic infection within the body. However, their data is not compelling nor definitive."

"You may be aware by now that a significant proportion of MSers on natalizumab lose the oligoclonal IgG bands (OCBs) in the spinal fluid. This is fascinating and is telling us that you need trafficking of cells, presumably T-cells, into the brain and spinal cord to maintain the so called B-cell like follicles and plasma cells that are responsible for producing these antibodies. There is also an hypothesis, supported by data, that OCBs and the B cell follicles may be driving progressive MS. This is one of the reasons why natalizumab has a small chance, and I mean a small chance, of being successful in SPMS. What about ocrelizumab? The latter is currently being tested in PPMS and also targets B cells. However, it recognises the surface antigen CD20 that is not expressed on the surface of plasma cells. We also know that rituximab reduce the levels of antibody in the spinal fluid but does not clear the OCBs. Therefore on balance natalizumab may have a better chance of being positive in progressive MS than ocrelizumab. The problem with the natalizumab SPMS trial (ASCEND Trial) is that it is short (2 years), too short in my opinion, for SPMS. Let's hope I am wrong."

"I recently found out that plasma cells need to live in a niche, or local micro-environment, to survive. The molecular velcro that keeps plasma cells healthy in this niche relies on a VCAM-1-VLA-4 interaction. This is one of the adhesion molecule pairings that is disrupted by natalizumab and may explain why OCBs disappear from the spinal fluid in natalizumab-treated MSers. Plasma cells are meant to be long-lived; however, if you disrupt their microenvironment, for example with natalizumab, they may die sooner than we realise."


Epub: Castellazzi et al. Epstein-Barr Virus Specific Antibody Response in Multiple Sclerosis Patients during 21 Months of Natalizumab Treatment.Dis Markers. 2015;2015:901312. doi: 10.1155/2015/901312. Epub 2015 May 26.

Background: MS is a chronic inflammatory autoimmune disease of the central nervous system. Natalizumab, a humanized anti-α4 integrin monoclonal antibody, is a highly effective treatment approved for MS. An association between MS and an exposure to Epstein-Barr Virus (EBV) sustained by the levels of antiviral capsid antigen (VCA) and anti-Epstein-Barr nuclear antigen-1 (EBNA-1) IgG has been described. 

Aim: Our goal was to verify the utility of EBV-specific IgG as a marker in Natalizumab treated MS. Twenty patients (17 female and 3 male) in treatment with Natalizumab were enrolled. 

Methods: Serum levels of anti-VCA and anti-EBNA-1 IgG were determined and expressed as arbitrary units (AU) before treatment and every three months for 21 months of therapy. 

Results: Anti-VCA IgG levels were increased at the 15th month (235410 ± 196712 AU) comparing with the 3rd (98146 ± 47145 AU) and the 6th (109866 ± 52270 AU) months of therapy (p < 0.05). No significant differences were found for serum anti-EBNA-1 IgG levels. 

Conclusion: Our data indicate that a transient, self-limited, EBV reactivation can occur in MS during Natalizumab therapy but our results do not support the use of serum EBV-specific antibody levels as biomarkers for monitoring therapeutic response to Natalizumab in the course of MS.

CoI: multiple

8 comments:

  1. Replies
    1. No.
      http://www.academia.edu/2393374/Long_term_lymphocyte_reconstitution_after_alemtuzumab_treatment_of_multiple_sclerosis

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    2. Based on daclizumab's MOA, will it impact this?

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    3. No effect of daclizumab on OCBs. In fact the only one of the mabs I've seen that decreases OCBs is natiluzumab (Tysabri).

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  2. Prof G,

    Not sure what all this means. Is getting rid of OCBs a good thing? How does this relate to Natalizumab normalising neurofilament levels? Why is Alem not having the same effect on OCBs if it depletes B cells. There's something important here, I think. I'm less convinced Charcot will be a success?

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  3. The complexity of the MS/EBV connection is hurting my brain....:-)

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  4. If Tysabri clears OCBs, and then you stop taking it... Do they come back?

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