Wednesday, 1 April 2015

PML on Tecfidera - the MHRA response

Following the death due to PML last year of a German MSer who had been taking Tecfidera for over 4 years, and been lymphopenic for over 3, the MHRA has now issued a new "Drug safety update".

Your chances of developing an opportunistic infectious disease (such as PML in people who are JCV+) will increase if you have chronic lymphopenia.

The Barts-MS Guideline for people on Tecfidera is as follows:

Harking the cytokines

Balasa R, Maier S, Voidazan S, Hutanu A, Bajko Z, Motataianu A.
An Intricate Mechanism of Action of Avonex in Relapsing Remitting Multiple Sclerosis Patients: Variation of Serum Titre of Interleukin-17A, Interleukin-10 and Transforming Growth Factor-β.CNS Neurol Disord Drug Targets. 2015 Mar. [Epub ahead of print]

INTRODUCTION: The immunopathogenesis of multiple sclerosis (MS) is a main field of research, together with the mechanism of action of most immune therapies in this disease, such as interferon beta. Interleukin (IL)-17 is considered to play a central part in the initial immune cascade in MS, though there are numerous interactions between other cytokines that might explain the heterogeneity of disease evolution and treatment response.
MATERIAL AND METHODS: We tested the serum levels of IL-17A, IL-10 and transforming growth factor (TGF-β) using the enzyme-linked immunosorbent assay method in three small groups of relapsing-remitting MS patients: 10 being naïve without treatment, 10 patients receiving Avonex treatment early in the MS evolution (≤ one year from the MS onset) and 12 MS patients who received Avonex later in the disease evolution. The values were compared with those obtained from 32 healthy subjects using statistical analysis.
RESULTS: In the naïve multiple sclerosis group: IL-17A values were statistically higher than among healthy subjects; IL-17A inversely correlated with MS duration; serum IL-17A negatively correlated with TGF-β. A direct correlation was found between the serum titre of IL-17A and IL-10 in the early treated multiple sclerosis group; the titre of IL-17A was significantly reduced compared with that from the late treated multiple sclerosis group.
CONCLUSIONS: The role in MS pathology of IL-17A, IL-10 and TGF-β is only partially elucidated. IL-17 plays an important role in the inflammatory phase of relapsing-remitting MS and is diminished by Avonex mainly if this disease modifying treatment is administered early in the evolution of MS.

IL-17 is considered to be a pro-inflammatory T cell growth factor and blocking it is a thought to be a good thing. IL-10 and transforming growth factor are thought to be ant-inflammatory actors but are also pro-B cell factors. IL-17 dropped with treatment and IL-17 levels correlated with IL-10 levels. Maybe not quite what was envisioned.

Although I am not saying this happened here Harking is a science term used to described changing the hypothesis after you have the results.

Thank you for Nominating Us

Thanks you so much, we were not expecting this but we are so happy that one of you (?) nominated us for the MS Society's “Researchers of the Year 2015”.

What an Honour! 

This is extra special after some of you, said that you wouldn’t do it if we didn't spill the beans.  Just goes to show that most of you aren't trolls:-)

We are looking forward to meeting you at the the Awards, as we assume that you will get an invite for doing the nomination. Hope they pay the train fare down from Leicester!.  

Yep, we do know who you are, as the MS Society informed us about how supportive you were on Twitter:-(. We've been following you for some time now and we even bought ProfG, one of your records after that nice Newsletter that you wrote about us:-(.

We got the citation yesterday thanking us for our service to MS and our research excellence for finding new treatments .  

MD2 was so excited that she ran out an bought a new posh frock for the party, as she is looking forward to meeting the celebs

 Yep MD2 is not really a  Guy
called Gareth. She and we have been 
spinning the myth for some time.
MD2 is called ********

We'll be posting Pics of the Bash

Is the genetic susceptibility to MS in African-Americans different to Europeans?

Why are African-Americans susceptible to MS? #MSBlog #MSResearch

"The following study looked to see if the genetic risk of MS in African Americans was different to that of people of European descent. As you are aware man migrated out of Africa about 60,000 years ago and in that time a lot of genetic variation / selection took place to give rise to modern Europeans. There is genetic, linguistic (language) and archeological evidence that there were at least 3 and possibly 4 waves of migration of modern man into Europe. During this time European man interbred with Neanderthals and was exposed to a very different  environment that resulted in natural selection. The result is there are genetic differences between Africans and Europeans. The question then are different genes, or genetic variants, responsible for MS risk different between Americans of European or African descent? The study below suggest not. The majority of the susceptibility variants are shared between African-Americans and European-Americans. Interestingly, variability around some of these variants suggest they are not due genetic admixture (interbreeding) and reassuringly imply that these variants must be relevant to the biology of MS."

"Some susceptibility variants found appear to be unique to African-Americans, but need to be confirmed. These results indicate that although the genetic susceptibility to MS is complex there is a common set of pathways that dictate risk across populations. It is therefore important to examine these biological pathways to see how they interact with known environmental factors so that we can pin-down the cause of MS. For example, some of the pathways identified are involved in B cell biology supporting this cell as being important, and possibly pivotal, in MS."

Map of the migration of modern humans out of Africa, based on mitochondrial DNA. Colored rings indicate thousand years before present. From Wikipedia.

"You may be interested to know that I have been searching the literature intermittently for over 15 years looking for a case report, or reports, of  MS occurring in people with rare hereditary causes of B cell deficiencies. As of yet I have not found a report. Is this telling us something? If you know of someone with an hereditary defect in B cell function and a diagnosis of MS please let me know. Thanks."

Epub: Isobe et al. An ImmunoChip study of multiple sclerosis risk in African Americans. Brain. 2015. pii: awv078.

Background: The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. 

Methods: Using the ImmunoChip custom array we genotyped 803 African American cases with MS and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. 

Results: Of the 110 non-major histocompatibility complex MS-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate MS variants (P < 10-4), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10-5). 

Conclusion: Our data demonstrate substantial overlap between African American and European MS variants, indicating common genetic contributions to multiple sclerosis risk. 

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