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


Allizond V, Scutera S, Rossi S, Musso T, CrocillĂ  C, Cavalla P, Trebini C, Marra ES, Cuffini AM, Banche G.
Polymorphonuclear Cell Functional Impairment in Relapsing Remitting Multiple Sclerosis Patients: Preliminary Data.
PLoS One. 2015;10(6):e0131557. Multiple Sclerosis patients run an increased risk of microbial infections, which leads to high rates of hospitalization and infection-related mortality. Although immunotherapy may increase infection risk in some cases, data as to the relationship among microbial factors, immunotherapy and alterations in the innate immunity of these patients are still scanty. On these grounds, this interdisciplinary study aims at investigating the role the functional activity of polymorphonuclear cells (PMNs) play in relapsing remitting multiple sclerosis at different stages. The in vitro ability of PMNs from patients, either untreated or treated with immunosuppressant or immunomodulatory drugs to kill Klebsiella pneumonia or Candida albicans, were investigated and compared to PMNs from healthy subjects. The release of various cytokines was also assessed, as was the production of reactive oxygen species and their ability to regulate apoptosis after microbial stimulation. Our results indicate that although patients have a normal number of PMNs, they have a statistically significant (p<0.05) reduction in intracellular killing activity. Although variations are strongly related to the therapeutic management of patients, they are independent from their disease stage. As no statistically significant differences were observed between patients and controls in cytokine release values, reactive oxygen species production or apoptosis, we came to the conclusion that other factors may be involved. Supportive validation of these results from further studies might well help in identifying a subset of patients at high risk of infection who could benefit from a closer follow-up and/or antibiotic prophylaxis.

Polymorphonuclear cells (PMNs) are a type of white blood cell that is involve in killing infections. For many years they have not bben considered to be important in MS, then people studying mouse EAE have found lots of them in some mouse lesions in EAE and so now they are looking in MS again. Although there are no less cells their activity seems to be less in MSers.. Is this relevant to disease, I think more work is needed.

Neuroimaging cant really predict movement problems

Daams M, Steenwijk MD, Wattjes MP, Geurts JJ, Uitdehaag BM, Tewarie PK, Balk LJ, Pouwels PJ, Killestein J, Barkhof F.
Unraveling the neuroimaging predictors for motor dysfunction in long-standing multiple sclerosis.Neurology. 2015 . pii: 10.1212/WNL.0000000000001756. [Epub ahead of print]
PMID: 26115736

OBJECTIVE:To find the strongest neuroimaging predictors for motor dysfunction using conventional and quantitative imaging measures focusing on the corticospinal tract (CST) in a large cohort of patients with long-standing multiple sclerosis (MS).
METHODS:In this cross-sectional study, a wide spectrum of neuroimaging measures at the whole-brain, cervical, and CST level were analyzed in 195 patients with MS and 54 healthy controls. Motor function was assessed using the Expanded Disability Status Scale (EDSS), 9-Hole Peg Test, Timed 25-Foot Walk Test, and Multiple Sclerosis Walking Scale. Associations between damage in different parts of the motor system and motor functioning were assessed using stepwise linear regression.
RESULTS:Patients had an average disease duration of 19.98 (±6.99) years and a median EDSS score of 4 (range: 1.0-8.0). EDSS score was associated with number of infratentorial and cervical cord lesions, lesion volume in the CST, and mean upper cervical cord area (adjusted R2 = 0.403). Timed 25-Foot Walk Test score was associated with number of infratentorial lesions and cerebellar volume (adjusted R2 = 0.150), 9-Hole Peg Test score with number of infratentorial lesions and thickness of the cortex connected to the CST (adjusted R2 = 0.245), and Multiple SclerosisWalking Scale with number of infratentorial and cervical lesions, thickness of the cortex connected to the CST, and mean upper cervical cord area (adjusted R2 = 0.354).
CONCLUSIONS:Motor dysfunction in MS has a complex substrate that cannot be ascribed to a single neuroimaging finding, but is the consequence of infratentorial and spinal cord damage, as well as damage in the CST

The corticospinal tract is tract in the spinal cord where nerves run to the brain that controls movement. In this study they looked at a number of behavioural outcomes  and at imaging outcomes in the CST an the cord in the neck and the brain. Not a single imaging outcome could be linked to the movement problems, so begs he question of what these imaging outcomes really mean