Thursday, 20 July 2017

BrainHealth

Today in the News you may hear about brain health to help protect against Dementia from Alzheimer's. However, these are all relevant to MS too
There are 9 things mentioned that may help 

The nine risk factors include:
  • Less childhood education
  • Hearing loss
  • Hypertension
  • Obesity
  • Smoking
  • Diabetes
  • Depression
  • Physical inactivity
  • Social isolation
Potential risk factors:

  • Pollution
  • Visual loss
We all know that an active body and and active brain, helps protect against ill-health, 

If I asked you to think of things that promote brain health, you could write this on the bad of a fag-packet, which you should throw away as you shouldn't be smoking.

The interesting ones to me are hearing loss but this makes sense because hearing and vision are essential part of sensory input that is going to keep your brain active making new connections.

However, if you look at the list above, many of them are all inter-connected e.g. physical activity, obesity, diabetes.

Please note you can do all the unhealthy things and not get dementia and you can be as healthy as possible and get dementia, the list above are risk factors that are modifiable by life style, adopt them they reduce your risk but do not prevent risk.

MS Blog of Year 2017

We received notice that we were one of the Healthline's 
Best MS Blogs of the Year

Here is the list (CLICK). Be warned this site contains adverts and this has nothing to do with us.

psychiatric disorders in children

Psychiatric disorders in children with demyelinating diseases of the central nervous system.Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Waubant E, Goldacre MJ.
Mult Scler. 2017 Jul 1:1352458517719150. doi: 10.1177/1352458517719150. [Epub ahead of print]

INTRODUCTION:

The profile of psychiatric disorders associated with multiple sclerosis (MS) may differ in children. We aimed to assess the risk of psychiatric disorders in children with MS and other demyelinating diseases, and vice versa.

PATIENTS AND METHODS:

We analyzed linked English Hospital Episode Statistics, and mortality data, 1999-2011. Cohorts were constructed of children admitted with MS and other central nervous system (CNS) demyelinating diseases. We searched for any subsequent episode of care with psychiatric disorders in these cohorts and compared to a reference cohort.

RESULTS:

Children with CNS demyelinating diseases had an increased rate of psychotic disorders (rate ratio (RR) = 5.77 (95% confidence interval (CI) = 2.48-11.41)); anxiety, stress-related, and somatoform disorders (RR = 2.38 (1.39-3.81)); intellectual disability (RR = 6.56 (3.66-10.84)); and other behavioral disorders (RR = 8.99 (5.13-14.62)). In analysis of the paediatric MS cohort as the exposure, there were elevated rates of psychotic disorders (RR = 10.76 (2.93-27.63)), mood disorders (RR = 2.57 (1.03-5.31)), and intellectual disability (RR = 6.08 (1.25-17.80)). In reverse analyses, there were elevated rates of a recorded hospital episode with CNS demyelinating disease after a previous recorded episode with anxiety, stress-related, and somatoform disorders; attention-deficit hyperactivity disorder (ADHD); autism; intellectual disability; and other behavioral disorders.

CONCLUSION:

This analysis of a national diagnostic database provides strong evidence for an association between pediatric CNS demyelinating diseases and psychiatric disorders, and highlights a need for early involvement of mental health professionals.

Children who get MS are at a 6 times risk of getting psychiatric issues,

Wednesday, 19 July 2017

#TeachSpeak: our belief in small numbers

Why do we have so many cognitive frailties; e.g. our belief in small numbers? #TeachSpeak

I want to restate what I said yesterday in a comment that the mistake I made, and many others are making, when considering the cancer risk with ocrelizumab is that we are over interpreting data based on very small numbers. To understand this phenomenon I suggest you read the classic, and probably one of the most influential, papers in psychology by Tversky and Kahneman on the 'belief in the law of small numbers'. The problem with the human brain is that we believe in small numbers. What we really need is slow thinking and large numbers, for that we will have to wait some time for more safety data to emerge regarding rare adverse events. 

One of  the reasons for keeping the survey below open so long is that I want a large sample; I need several hundred respondents for the results to have face validity and, obviously, to move away from small numbers.  


TVERSKY & KAHNEMAN. BELIEF IN THE LAW OF SMALL NUMBERS. Psychological Bulletin, 1971, Vol. 76, No. 2. 105-110. 

People have erroneous intuitions about the laws of chance. In particular, they regard a sample randomly drawn from a population as highly representative, that is, similar to the population in all essential characteristics. The prevalence of the belief and its unfortunate consequences for psvchological research are illustrated by the responses of professional psychologists to a questionnaire conceming research decisions.


CoI: multiple

Neutrophil loss after alemtuzumab

Gaitán MI, Ysrraelit MC, Correale J. Neutropenia in Patients With Multiple Sclerosis Treated With Alemtuzumab. JAMA Neurol. 2017 Jul 17. doi: 10.1001/jamaneurol.2017.1456


We all know that alemtuzumab depletes lymphocytes and if you don’t, you should have read our recent papers. 

Both cladribine and alemtuzumab may effect MS via B-cell depletion.Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, Schmierer K. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 5;4(4):e360.


Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab.Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. JAMA Neurol. 2017 Jun 12. doi: 10.1001/jamaneurol.2017.0676. [Epub ahead of print]

However, CD52 is expressed on a number of other cells like monocytes, which get transiently depleted. It is also found on sperm. 

It is also expressed on by polymorphonuclear cells. These form about 70% of your white blood cells. These are part of your first line of defense from infection. This is the main reason why you are taken out of circulation for 20-30 days after HSCT, as you have to wait for your neutrophils to be repopulated. They only live for about 5 days and then die to be replaced by new ones.

This report talks about polymorphonuclear neutrophils and says to their surprise that alemtuzumab causes loss of neutrophils in some people with MS and this hasn’t been reported before. 

Smith A, Couvillion R, Zhang R, Killackey M, Buell J, Lee B, Saggi BH, Paramesh AS.Incidence and management of leukopenia/neutropenia in 233 kidney transplant patients following single dose alemtuzumab induction. Transplant Proc. 2014 Dec;46(10):3400-4.

In MS maybe not but anyway, they report on two cases of people with MS that have severely depleted their neutrophils. This is means the people were susceptible to infection and in this paper they treat the neutrophil deficiency with granulocyte (neutrophils are a type of granulocyte as they have neutral granules compared to those with alkali granules in a basophil or acid granules in an eosinophil important as neutrophils) growth factor. So if this is interesting as a safety perspective…then surely it is interesting to know how common this event it is following use in MS.

So yesterday when I saw the paper, I trawled through the unpublished phase III trial alemtuzumab data set supplied by the European Medicines agency, wrote and submitted the paper for review and publication. So thanks for that.

So you and your neuros are aware, Neutrophils are not depleted to a great extent by alemtuzumab in most people, transient minor depletion is common in 20-25% of people, but about 3% of people develop severe neutropenia (loss of neutrophils) and this is transient in most people. You could check for this by monitoring your blood counts after alemtuzumab.

Tuesday, 18 July 2017

#NewsSpeak: an eagle has just landed in Oz

People living with PPMS in Australia have something to cheer about. #NewsSpeak #MSBlog

I just received an email from a pwMS about the good news down-under (see press release below). Let's hope the EMA & NICE have provide similar cheer for people living with PPMS in Europe and England, respectively. I wonder if other HTAs accepting the results of the ocrelizumab in PPMS trial (ORATORIO) and licensing ocrelizumab for PPMS, puts pressure on the EMA? I suspect not. To help, please have your say and complete the survey below. Thank you. 



CoI: multiple

Is contrast use in MRI safe?

Radiology. 2014 Mar;270(3):834-41. doi: 10.1148/radiol.13131669. Epub 2013 Dec 7.

High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material.

Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D.

Abstract
PURPOSE:

To explore any correlation between the number of previous gadolinium-based contrast material administrations and high signal intensity (SI) in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance (MR) images.

MATERIALS AND METHODS:

The institutional review board approved this study, waiving the requirement to obtain written informed consent. A group of 381 consecutive patients who had undergone brain MR imaging was identified for cross-sectional analysis. For longitudinal analysis, 19 patients who had undergone at least six contrast-enhanced examinations were compared with 16 patients who had undergone at least six unenhanced examinations. The mean SIs of the dentate nucleus, pons, globus pallidus, and thalamus were measured on unenhanced T1-weighted images. The dentate nucleus-to-pons SI ratio was calculated by dividing the SI in the dentate nucleus by that in the pons, and the globus pallidus-to-thalamus SI ratio was calculated by dividing the SI in the globus pallidus by that in the thalamus. Stepwise regression analysis was undertaken in the consecutive patient group to detect any relationship between the dentate nucleus-to-pons or globus pallidus-to-thalamus SI ratio and previous gadolinium-based contrast material administration or other factors. A random coefficient model was used to evaluate for longitudinal analysis.

RESULTS:

The dentate nucleus-to-pons SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P < .001; regression coefficient, 0.010; 95% confidence interval [CI]: 0.009, 0.011; standardized regression coefficient, 0.695). The globus pallidus-to-thalamus SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P < .001; regression coefficient, 0.004; 95% CI: 0.002, 0.006; standardized regression coefficient, 0.288), radiation therapy (P = .009; regression coefficient, -0.014; 95% CI: -0.025, -0.004; standardized regression coefficient, -0.151), and liver function (P = .031; regression coefficient, 0.023; 95% CI: 0.002, 0.044; standardized regression coefficient, 0.107). The dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios in patients who had undergone contrast-enhanced examinations were significantly greater than those of patients who had undergone unenhanced examinations (P < .001 for both).

CONCLUSION:

High SI in the dentate nucleus and globus pallidus on unenhanced T1-weighted images may be a consequence of the number of previous gadolinium-based contrast material administrations.


J Neurol Neurosurg Psychiatry. 2017 Jul 14. pii: jnnp-2017-316102. doi: 10.1136/jnnp-2017-316102. [Epub ahead of print]

Lack of T1 hyperintensity in the dentate nucleus after 15 administrations of a macrocyclic contrast agent in multiple sclerosis. 

Eisele P, Szabo K, Alonso A, Ong M, Platten M, Schoenberg SO, Gass A

Figure: Increased signal intensity particularly in the dentate nucleus (picture to the left) is observed with linear gadolinium-based contrast agents.

For all the advantage an MRI scan provides in terms of diagnosis and disease monitoring, it is also probably the safest and most non-invasive investigation we have available to us in the 21st century. But, like all developments, what is considered superior at the time will at some point be considered inferior. Since its discovery 40 years ago, the first major problem with MRIs becomes apparent, striking at its main functionality, which is its ease of repetition. It is yet not known what the long-term effects of the high signal intensity seen in the brain (specifically the dentate nucleus and the globus pallidus) of those repeatedly receiving gadolinium, but it cannot be ignored.

It has emerged that linear gadolinium-based contrast agents (GBCAs) may be to blame (see figure above), even in the absence of kidney impairment (most things are got rid of from the body by the kidneys). Based on these findings, on the 10th March 2017m the EMAs Parmacovigilance and Risk Assessment Committee (PRAC) recommended suspension of the marketing authorisations for four gadolinium contrast agents. There is insufficient evidence to suggest whether exposure to macrocyclic GBCAs leads to deposition of gadolinium in the brain. The letter to JNNP (see above for the reference) suggests that this may be a safe alternative. They sampled 22 PwMS who had had 15-26 (average 17) contrast scans with a follow-up period of 3-7 years (average 4.5 years), and found no increase in signal intensity in the MRI examinations using the macrocylic contrast agents gadoterate meglumine and gadobutrol. 

I'm not certain, that this sufficiently placates my concern over gadolinium use. Overall, this new development is likely to impact significantly on clinical decision making. One recommendation, maybe, is to use surveillance MRIs less frequently (this will impact on clinicians practicing 'no evidence of disease activity'), or to rely more on non-contrast scans. Another, maybe, to use alternative modes of monitoring, such as clinical or blood/CSF biomarkers.

Monday, 17 July 2017

#TeachSpeak: reverse causation

Are you a knee-jerker or a deep-thinker? #TeachSpeak #MSBlog

Yesterday's post on B-cells and breast cancer has generated a lot of debate, some justified and some not. Before joining the debate you need to know how the mind works. There is a rapid, or fast, intuitive decision making system called system 1 and a slow more rational decision making system called system 2. If you are interested in reading about the way we think I would suggest you read 'Thinking, Fast and Slow', the best-selling book by Nobel laureate Daniel Kahneman. Just reading the introductory chapter of the book will be enough to give you the gist of system 1 and system 2 thinking. 

Based on Kahnerman's theory a system 1 (knee-jerk) response to my post is that B-cells prevent breast cancer hence ocrelizumab causes breast cancer. A system 2 response, the slower more rational response, would lead to a more nuanced interpretation. Firstly, you need to be aware that greater than 50% of oncology research findings can't be reproduced. In other words this paper's finding are likely to be a false positive based on pure statistics. 


Then there is 'reverse causation', which is likely to be the best explanation. In other words benign breast lesions that don't recruit B-cells are different biologically to those that do and are more likely to become malignant. The B-cells may simply be innocent bystanders and their presence or absence makes no difference in the long-term. Despite this there is the possibility that the findings are causal, i.e. B-cells are involved in preventing breast cancer. 

So what needs to be done? Other groups need to try and replicate the Mayo clinic study's findings and additional studies need to be done to explore the role of B-cells in breast cancer pathogenesis. We also need to set-up and monitor breast cancer incidence in relation to B-cell depletion therapies to assess whether or not the signal in the ocrelizumab trial programme is real or not. As with most DMTs the trial programme is too small and too short to give a definitive answer. All I would suggest is that pwMS considering ocrelizumab are made aware of the uncertainty and let them make up their own mind about the potential risk. You also have to remember that breast cancer can be detected early with increased vigilance and that the prognosis of breast cancer in 2017 is very good most patients with breast cancer are cured. All pwMS, women and men, need to be made aware about the possibility of secondary malignancies on immunosuppressive  therapies and taught how to monitor for possible malignancies. This message is not unique to ocrelizumab and applies to all most all of the DMTs. 

Another example of reverse causation in MS is low vitamin D levels in pwMS that have been linked to MS disease activity. Because of this observation everyone has interpreted the results that vD supplementation is essential to control MS disease activity. In reality almost every inflammatory disease studied has shown low vD levels that are linked to the degree of inflammation. The most likely explanation is a consumptive hypovitaminosis  D; i.e. inflammatory cells consume vD as part of their biology. Giving vD is unlikely to make any difference to their functioning or the outcome of the diseases concerned. We did a meta-analysis of the trials of vD supplementation that had been done to date and found no indication of vD being a DMT. Please note this comment does not apply to vD supplementation and MS prevention. Based on the literature and epidemiological studies vD plays a role in MS risk and there is an overwhelming case for doing vD prevention studies. 

Baker & Dolgin. Cancer reproducibility project releases first results. Nature 18 January 2017.

Excerpts

..... The Reproducibility Project: Cancer Biology launched in 2013 as an ambitious effort to scrutinize key findings in 50 cancer papers published in Nature, Science, Cell and other high-impact journals. It aims to determine what fraction of influential cancer biology studies are probably sound — a pressing question for the field. In 2012, researchers at the biotechnology firm Amgen in Thousand Oaks, California, announced that they had failed to replicate 47 of 53 landmark cancer papers. That was widely reported, but Amgen has not identified the studies involved.

..... The reproducibility project, by contrast, makes all its findings open — hence Ruoslahti’s discomfort. Two years in, the project downsized to 29 papers, citing budget constraints among other factors: the Laura and John Arnold Foundation in Houston, Texas, which funds the ­project, has committed close to US$2 million for it. Full results should appear by the end of the year. But seven of the replication studies are now complete, and eLife is publishing five fully analysed efforts on 19 January.

...... These five paint a muddy picture (see ‘Muddy waters’). Although the attempt to replicate Ruoslahti’s results failed, two of the other attempts “substantially reproduced” research findings — although not all experiments met thresholds of statistical significance, says Sean Morrison, a senior editor at eLife. The remaining two yielded “uninterpretable results”, he says: because of problems with these efforts, no clear comparison can be made with the original work.

CoI: multiple

Sunday, 16 July 2017

#ResearchSpeak: B-cells and breast cancer

Is there a biological reason for anti-CD20 therapy to increase your risk of developing breast cancer? #ResearchSpeak

There is nothing like a 'dirty little fact' to unseat a entrenched dogma. I was at a meeting yesterday and we were discussing cancer risks and DMTs. At some point I stated that the breast cancer signal in the ocrelizumab trials may turn out to be a false positive signal. I said this as I knew of no biological reason of how ocrelizumab could cause breast cancer within a 24-36 month period. I also thought that carcinogenesis (the biological process that leads to cancer) in relation to the breast took much longer than 3 years to occur. Similarly, I made the statement based on 'immunological dogma'  that I didn't think it could be due to peripheral immune surveillance because that job is done by T-cells and NK-cells and I was not aware of B-cells playing a role. 


A very good colleague of mine from Switzerland then shot me down and quoted the paper below. In this study from the Mayo Clinic, women having biopsies for benign breast disease were followed up to see who developed breast cancer. Women with reduced B-cells in their breast tissue had an almost 6-times higher risk of developing breast cancer in the future. This data suggests that B-cells may be critical in preventing disease progression from benign to malignant breast disease. If this study can be replicated it could explain the breast cancer risk with anti-CD20 therapies and suggests a new role for B cells in peripheral tumour immuno-surveillance. The other explanation is reverse causation and that benign breast lesions that don't recruit B-cells are different biologically to those that do and the B-cells are innocent bystanders.  

I am now prepared to change my position on this topic and admit the breast cancer signal with ocrelizumab may prove to be real. However, if this is the case why should it be limited to ocrelizumab? If B-cells are necessary to keep breast cancer at bay then all B-cell depleting agents should increase the risk. 

All I can say is that we can speculate until the cows' come home; so let's wait and see what happens in the post-marketing surveillance studies. 


Degnim et al.  Alterations in the Immune Cell Composition in Premalignant Breast Tissue that Precede Breast Cancer Development. Clin Cancer Res. 2017 Jan 26. doi: 10.1158/1078-0432.CCR-16-2026.

Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD).


Experimental Design: A breast tissue matched case-control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells).

Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4-23.1) for subsequent breast cancer risk.

Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk.

CoI: multiple

Sunday Challenge.. Literature Review. Does rituximab cause Breast Cancer?

If ocrelizumab, which depletes CD20 B cells, really causes breast cancer (there were non in the the placebo groups in the trials), then based on biology any long-term depletion of CD20 B cells should cause breast cancer if this is true. 

Was the ocrelizumab a fluke result as we suggests the the result in the cladribine trial was, after looking at the data from other trials with cladribine and the occurrence of cancer in trials with other MS drugs.

Therefore, is it a random fact that is a bit of mud, that can stick do to perceptions, which is supported by another random fact.

So the question is, 

Is there an increased risk of Breast Cancer after Rituximab?.

A quick search on pubmed gives 198 papers. 

If you look... a lot will be using rituximab to treat B lymphoma in the breast. So it needs some detective work. 

I have a date with the DIY paint brush so don't have the time to do a search but maybe you can just post a list of the papers of what you find in the comments box and we can do a follow-on post with an answer.

I'll start you off


Fleury I, Chevret S, Pfreundschuh M, Salles G, Coiffier B, van Oers MH, Gisselbrecht C, Zucca E, Herold M, Ghielmini M, Thieblemont C. Rituximab and risk of second primary malignancies in patients with non-Hodgkin lymphoma: a systematic review and meta-analysis.
Ann Oncol. 2016 Mar;27(3):390-7.

Among the 241 solid SPM subtypes reported, 125 occurred in patients randomized to R and 116 in patients not randomized to R. High-grade SPM subtypes of solid cancers reported were (in the order of frequency): lung (R = 18, No R = 16), prostate (R = 16, No R = 13), colorectal (R = 12, No R = 15), breast (R = 8, No R = 10), pancreas (R = 7, No R = 5), urothelium (R = 5, No R = 6), melanoma (R = 8, no R = 3), basal cell carcinoma (R = 7, no R = 3), stomach (R = 3, No R = 6), head and neck (R = 4, No R = 5), skin cancer not melanoma or basal cell carcinoma (R = 5, no R = 3), squamous cell (R = 5, No R = 1), biliary tract (R = 2, No R = 2), esophagus (R = 3, No R = 1), liver (R = 1, No R = 3), kidney (R = 1, No R = 3), neuroendocrine (R = 2, No R = 1), endometrium (R = 2, No R = 1), ovary (R = 0, No R = 2), sarcoma (R = 2, No R = 0), adenocarcinoma of unknown primary site (R = 2, No R = 0), carcinoma of unknown primary site (R = 2, No R = 1), thyroid (R = 1, No R = 1), peritoneal carcinomatosis of unspecified origin (R = 1, No R = 1), relapsed prostate (R = 0, No R = 1), relapsed breast (R = 0, No R = 1), adrenal metastasis of unspecified origin (R = 0, No R = 1), anal (R = 0, No R = 1), pleura (R = 1, No R = 0), brain (R = 0, No R = 1), GIST (R = 0, No R = 1). Low-grade SPM subtypes consisted of in situ skin cancer or dysplastic naevus (R = 3, No R = 6), liver adenoma (R = 1, No R = 1), lipoma (R = 1, No R = 0), meningioma (R = 1, No R = 0), prostate nodule (R = 1, No R = 0) and chondroma (R = 0, No R = 1)

So there were 8 in the rituximab group and 10 in the non-rituximab group...this could mean neither cause cancer and this is part of life or the both cause breast cancer.

Rituximab trials in other autoimmune diseases would be good place to search.




Saturday, 15 July 2017

#ClinicSpeak & #ThinkHand: therapeutic lag

At times I feel like I am trapped in an echo chamber shouting therapeutic lag. #ClinicSpeak #ThinkHand


The Wheelchair Kamikaze raised the issue of responders vs. non-responders to ocrelizumab in the PPMS trial. I am partly to blame for this issue, but it is very difficult to know who is a responder and non-responder based on the current data from the ocrelizumab PPMS , or ORATORIO, trial. Why? Simply because clinical trials are designed, or powered, to get a significant read-out in a reasonbale period of time, for example 2-3 years. Does this mean that pwPPMS who don't read-out in that period are non-responders? No it doesn't, because it takes much longer to see a response to treatment in pwMS who are older and have less reserve capacity in the particular pathway (usually the legs) being assessed.

The study below showed that interferon-beta treatment would probably work in PPMS provided the follow-up is long enough; in this case 7 years. In this study PwPPMS who had only been treated with IFNbeta for 2-years clearly do better at 7-years than those people treated on placebo over the same period of time. There was a lag in the onset of action of interferon-beta

Why a lag? One interpretation is that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression in someone with PPMS over the next 2 years was primed by inflammation two years ago. Suppressing inflammation today will have no impact over the next 2-years as the damage priming progression over the next 2 years has already occurred. All anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.

I hope this concept makes sense.

To illustrate this concept I drew this picture, which has now been published in our length-dependent axonopathy paper. I hope you can understand it. Interestingly, the actively-treated subjects only did better than placebo-treated subjects on terms of upper limb function (9HPT), cognition and brain volume loss. There was no difference in terms of the EDSS (and T25FW), which in more advanced MS is essentially a walking scale. The reason why there was no difference in lower limb function is almost certainly due to loss of reserve, i.e. too many nerve fibres supplying the limbs had been damaged already for an anti-inflammatory to make a difference. The other issue is that in this study the treatment period was too short. Please note this study is only one of many studies showing the same effect, a greater impact of anti-inflammatory therapies on upper limb than lower limb function and is one of the reasons that is underpinning our #ThinkHand campaign. 

In the ocrelizumab PPMS, ORATORIO, trial the treatment effect was almost double in the arms compared to the legs. This is why I have little doubt that ocrelizumab is effective in PPMS. If the trial was extended for longer the treatment effect on lower limb function will have gotten greater simply because of lag. 


I am convinced we are correct about 'therapeutic lag' and the MS community is starting to take it into account when designing progressive MS trials. This means being clever about our studies and getting the regulators to accept the 9HPT as a primary outcome measure. The MS community have made it clear that they value arm and hand function more than leg function, we now need the wider community to help get this message across. There is also an economic argument for taking DMTs into wheelchair users to protect upper limb function; once people lose their arm function they lose their independence and the costs, both medical and social, for looking after these people is very high.

If you agree with therapeutic lag then you have to support our petition to the regulators and payers about the significance of the ocrelizumab PPMS results.



Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.

OBJECTIVES: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of PPMS.

MAIN OUTCOME MEASURES: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 MSers, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 MSers, respectively.

EDSS = Expanded Disability Status Scale
MSFC = MS Functional Composite ( a composite 3 tests the PASAT, 9-hole peg test and the timed 25-ft walk)
9-Hole Peg Test = test of upper limb function
Word List Generation Test = cognitive task

RESULTS: After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (p=0.02) and Word List Generation Test (p<0.001) scores, and MRI measures in the normal-appearing white matter were significantly better. During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain volume (p=0.004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (p =0.004).

CONCLUSIONS: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.

CoI: multiple

Breast Feeding is Better


Breastfeeding, ovulatory years, and risk of multiple sclerosis.
Langer-Gould A, Smith JB, Hellwig K, Gonzales E, Haraszti S, Koebnick C, Xiang A. Neurology. 2017 Jul 12. pii: 10.1212/WNL.0000000000004207. doi: 10.1212/WNL.0000000000004207. [Epub ahead of print]

OBJECTIVE:
To determine whether women who breastfeed their infants longer or have fewer ovulatory years are at lower risk of developing multiple sclerosis (MS).
METHODS:We recruited women with newly diagnosed MS or its precursor, clinically isolated syndrome (CIS) (n = 397), and matched controls (n = 433) into the MS Sunshine Study from the membership of Kaiser Permanente Southern California. A structured in-person questionnaire was administered to collect the behavioral (pregnancies, breastfeeding, hormonal contraceptive use) and biological (age at menarche (onset of 
menstruation)  and menopause (Ending of menstruation), amenorrhea (absence of menstruation)) factors to make up ovulatory years.
RESULTS: Among women who had live births, a cumulative duration of breastfeeding for ≥15 months was associated with a reduced risk of MS/CIS (adjusted odds ratio [OR] 0.47, 95% confidence interval [CI] 0.28-0.77; p = 0.003 compared to 0-4 months of breastfeeding). Being ≥15 years of age at menarche was also associated with a lower risk of MS/CIS (adjusted OR 0.56, 95% CI 0.33-0.96; p = 0.035). Total ovulatory years and the remaining factors that determine it, including gravidity, parity, episodes of amenorrhea, and hormonal contraceptive use, as well as age at first birth, showed no significant association with the risk of MS/CIS.
CONCLUSIONS: Mothers who breastfeed longer may be at lower subsequent risk of developing multiple sclerosis. This is consistent with the other known maternal health benefits of breastfeeding and with our previous observation that women with MS who breastfeed exclusively are at lower risk of postpartum relapses.
You can read this one but this may be of interest

Friday, 14 July 2017

#ClinicSpeak & #PoliticalSpeak: indication-based pricing is one-way to get ocrelizumab to PPMSers

Before we short-changed PPMSers can we think for creative solutions to the pricing of ocrelizumab? # ClinicSpeak #PoliticalSpeak

I am rather disappointed with the survey response I have had in relation to the results of the ocrelizumab PPMS study and whether or not the results are clinically meaningful. I am deeply concerned that pwPPMS in the UK will not have access to ocrelizumab because it will be priced to treat relapsing-forms of MS and this will make it too expensive to pass cost-effectiveness thresholds for PPMS. In PPMS the cost will be compared to best supportive care and it is highly likely that NICE will say ocrelizumab is too expensive. This means those who can afford to pay for ocrelizumab privately will do say. Life sucks if you poor you won't be able to access ocrelizumab. 

I have argued many times for differential pricing of ocrelizumab, i.e. a lower price for treating PPMS will make it cost-effective. Is the NHS and Roche ready for differential pricing? There is an interesting perspective piece in this week's NEJM covering indication-based pricing, which is another term for differential pricing. It is a very good read and makes a strong argument for differential pricing. 

If you have not done so already can you please complete the survey below? I plan to publish it online and send it the EMA and NICE at the appropriate time.

Thank you.

Effects of Uniform Pricing versus Indication-Based Pricing. In scenario 1, the value of the treatment is relatively retained across indications; in scenario 2, the value is low for indication C, which affects a relatively large population.

Chandra & Garthwaite. The Economics of Indication-Based Drug Pricing. N Engl J Med 2017; 377:103-106.

Excerpts:

...... Pharmaceutical treatments and medical devices often have varying effectiveness depending on the indication for which they’re used: in oncology, for instance, response to a treatment varies with the type of tumor and stage of disease. The advent and proliferation of precision medicine in which biomarkers — whether genomic, proteomic, or structural — identify patients likely to receive greater treatment benefits only increase the range of variability in the effectiveness of the same product.

...... Yet manufacturers traditionally charge the same price for all indications. Recently, there have been calls for “indication-based” pricing systems, in which manufacturers are paid more when treatments are used for indications for which they have higher value (“high-value indications”) and less for indications for which they confer less benefit (“low-value indications”). Supporters hope that such a system will reduce prices for low-value indications but that prices for high-value indications will not increase. This expectation arises from a belief that manufacturers currently set uniform prices according to the value generated for high-benefit indications and somehow get patients who receive lower value to pay the same price.


CoI: multiple

Cost effectiveness of Ocrelizumab

Yang H, Duchesneau E, Foster R, Guerin A, Ma E, Thomas NP. Cost-effectiveness analysis of ocrelizumab versus subcutaneous interferon beta-1a for the treatment of relapsing multiple sclerosis. J Med Econ. 2017 Jul 13:1-23. doi: 10.1080/13696998.2017.1355310. [Epub ahead of print]

AIM: To conduct a cost-effectiveness analysis to compare ocrelizumab versus subcutaneous (SC) interferon beta-1a for the treatment of relapsing multiple sclerosis (RMS).
METHODS:A Markov cohort model with a 20-year horizon was developed to compare ocrelizumab with SC interferon beta-1a from a US payer perspective. A cohort of patients with relapsing-remitting MS (RRMS) and Expanded Disability Status Scale (EDSS) scores of 0-6, who initiated treatment with ocrelizumab or SC interferon beta-1a, were entered into the model. The model considered 21 health states: EDSS 0-9 in RRMS, EDSS 0-9 in secondary-progressive multiple sclerosis (SPMS), and death. Patients with RRMS could transition across EDSS scores, progress to SPMS, experience relapses, or die. Transition probabilities within RRMS while patients received ocrelizumab or SC interferon beta-1a were based on data from the two SC interferon beta-1a-controlled Phase III OPERA I and OPERA II trials of ocrelizumab in RMS. Transitions within RRMS when off-treatment, RRMS-to-SPMS transitions, transitions within SPMS, and transitions to death were based on the literature. Utilities of health states, disutilities of relapses, costs of therapies, and medical costs associated with health states, relapse, and adverse events were from the literature and publicly available data sources. The model estimated per-patient total costs, incremental cost per life year (LY) gained and incremental cost per quality-adjusted LY (QALY) gained. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analysis (PSA) were conducted to evaluate the robustness of the model results.
RESULTS: Ocrelizumab was associated with a cost savings of $63,822 and longer LYs (Δ=0.046) and QALYs (Δ=0.556) over a 20-year time horizon. The results of the model were robust in the DSA and PSA.
LIMITATIONS:The model did not consider subsequent treatments and their impact on disease progression.
CONCLUSIONS:The results suggest that ocrelizumab is more cost-effective than SC interferon beta-1a for the treatment of RMS.


The case for Relapsing QALY but what about PPMS

Thursday, 13 July 2017

#PoliticalSpeak: pharma in the naughty corner

Pharma vampires will finally have to stop gouging. #PoliticalSpeak 

Legislation to stop pharmaceutical companies price gouging has been on the cards for years and it has finally happened in the US. Gouging occurs because companies selling certain off-patent generics find themselves in a position were there is no competition. This tends to happen with low volume speciality drugs. Although gouging is not illegal it is considered unethical by most people. Imagine being poor and you need a medication, that is life saving, and you find you can't afford it because the price has been increase by over 600%? 

Let's hope the anti-gouging legislation will allow the pharma industry as a whole to regain some credibility. The issue of high-cost drugs and the emergence of cartel-like market behaviour still needs to be addressed. I also suspect there will be tweaks to the patent legislation, in relation to pharmaceuticals, to rebalance the risks and rewards associated with drug development. The patent system has been designed by society to reward Pharma for innovation, but not to reward them for too long so as to incentivise them to spend on R&D. The abuse of this system by some Pharma companies, particularly in relation to differential pricing between countries has created a global imbalance. Why should the US market subsidise drug development costs and drugs costs in other countries? I suspect the latter issue may trigger US legislation to try and rebalance the global system. This means European countries, in particular the UK, will have to be prepared to pay more for innovative pharmaceuticals. It will be interesting to see how British politicians deal with this issue when they have to start negotiating trade deals with the US post-Brexit? Pharmaceutical pricing will be high on the agenda. 


Greene & Padula. Targeting Unconscionable Prescription-Drug Prices — Maryland’s Anti–Price-Gouging Law.  N Engl J Med 2017; 377:101-103

Excerpts:

..... Why, in the early 21st century, are so many drugs that were cheaply available in the 20th century becoming prohibitively expensive? The past few years have seen a series of dramatic price hikes on essential off-patent medications, from albendazole to albuterol, digoxin to naloxone, Daraprim to EpiPen. In the storm of allegations and indignation that has followed each of these revelations, one explanation has remained consistent. 

...... To paraphrase Senators Susan Collins (R-ME) and Claire McCaskill (D-MO), who were the chair and the ranking member of the Senate Special Committee on Aging, firms that corner the market on off-patent medications and raise prices wildly often do so simply because they can. When the committee issued a 130-page report last December documenting the parallel strategies used by firms to engage in monopolistic price gouging on older essential drugs, the senators pointed out that these actions, though arguably unethical, have so far not been found to be illegal.

..... Until now. In April, the Maryland General Assembly voted by substantial, bipartisan majorities to pass legislation prohibiting price gouging on essential off-patent or generic drugs; by the end of May, this bill had passed into law. The law authorizes Maryland’s attorney general to prosecute firms that engage in price increases in noncompetitive off-patent–drug markets that are dramatic enough to “shock the conscience” of any reasonable consumer. 

...... Manufacturers of innovative drugs will not be affected, nor will the majority of generic drug manufacturers, who collectively generated $1.7 trillion in cost savings over the past decade by participating in competitive markets to bring drug prices down. Rather, the law specifically targets companies that intentionally pursue a strategy of hiking prices on noncompetitive off-patent drugs.

...... Rather than inhibiting competition, it will deter manufacturers who would take a page from the playbook of Amedra (which raised prices on albendazole), Turing (pyrimethamine), or Valeant (penicillamine and isoproterenol) by exploiting noncompetitive drug markets for short-term profit through unconscionable behavior that imperils public health and individual welfare.

CoI: multiple

B Cells Story getting better if you know where to look

Gelfand JM, Cree BAC, Hauser SL. Ocrelizumab and Other CD20 B-Cell-Depleting Therapies in Multiple Sclerosis. Neurotherapeutics. 2017. doi: 10.1007/s13311-017-0557-4. [Epub ahead of print]

Selective depletion of CD20+ B cells by anti-CD20 monoclonal antibodies as monotherapy in multiple sclerosis (MS) profoundly suppresses acute inflammatory disease activity and signifies an important advance in the treatment of relapsing-remitting MS. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, is also the first proven therapy to lessen disability progression in primary progressive MS-a breakthrough for patients with a disease that had no proven therapy. Ocrelizumab is generally well tolerated, with the most common adverse events experienced being infusion reactions and infections. In ocrelizumab trials in MS a numerical imbalance in the risk of malignancies was observed. In this article, we review advances in anti-CD20 B-cell-depleting biological therapies for MS, including ocrelizumab, rituximab, and ofatumumab.
Prof Hauser is part of the "Rumble in the Jungle" which is the "burning debate" at ECTRIMS 2017. This puts two heavy weight immunologists/neurologists against other hopefully we can stream this live from Paris. 

In the Blue corner we have Prof David Hafler from Yale, USA leading the charge of "MS is a T cell disease". In the Red corner we will have Prof Stephen Hauser from San Francisco USA leading the "MS is a B cell condition". The ring master is Prof David Wraith from Birmingham, UK. 

This current paper is by Prof Hauser and is a review article on B cells. I wondered, if was going to be the basis for a strategy of the approach to be used in the debate?...

Hope not, as this is zzzzzzzzzzzzzzzzzzzzzzzzzing. 


The paper is a simple review on the observations around the clinical trials, which has been written loads of times before.

There is not much data supporting any idea of  how the therapies are actually working, but we get the standard sitting on the fence


It's an anti-T cell agent killing a miniscule population of T cells....really:-( 

It then states that following B-cell therapy, "repopulating B cells consist of larger numbers of naïve B cells and fewer antigen-educated memory B cells and plasmablasts, possibly explaining the continuing suppression of MS disease activity noted even after B-cell reconstitution has occurred".

So not a lot to tell you what is going on.

Clearly our view that memory B cells are important targets has not yet gained traction.

Maybe people can't be bothered to read it......What you haven't read it yet. It's here and free.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.
Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50
So maybe it sounds like we need to shout a bit louder, so that people start to try and disprove the idea...However, so far this year it was not been difficult to build on the idea.

However, when I was presenting the data a couple of weeks ago, someone asked how does it fit into the idea that oligodendrocytes are the major target in MS.

I waffled a rubbish answer and good point I thought.

If CD4  T cells are the cause of  problem one also has to struggle to answer the question too. Why? Because oligodendrocytes do not express MHC class II (a restriction element for CD4 T cells. See the education posts) in vivo and so are not going to be targeted by CD4 T cells directly so its effect would have to be indirect.

Whilst those bothered that CD4 TH17 cells are the problem can ponder this question, it is evident that B cells make factors that can kill oligodendrocytes and nerves.

Lisak RP, Nedelkoska L, Benjamins JA, Schalk D, Bealmear B, Touil H, Li R, Muirhead G, Bar-Or A. B cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro.J Neuroimmunol. 2017 Aug 15;309:88-99.

B cells mediate multiple sclerosis (MS) pathogenesis by mechanisms unrelated to immunoglobulin (Ig). We reported that supernatants from cultured B cells from blood of relapsing remitting MS (RRMS) patients, but not normal controls (NC), were cytotoxic to rat oligodendrocytes (OL). We now show that RRMS blood B cells, not stimulated in vitro, secrete factor/s toxic to rat and human neurons. Cytotoxicity is independent of Ig and multiple cytokines, not complement-mediated, and involves apoptosis. The factor/s have an apparent mw of >300kDa. B cells (twice the size of an IgG antibody molecule and much bigger than typical cytokines) could contribute to damage within the central nervous system by secreting molecules toxic to OL and neurons.

The previous paper I had forgotten about  Lisak RP, Benjamins JA, Nedelkoska L, Barger JL, Ragheb S, Fan B, Ouamara N, Johnson TA, Rajasekharan S, Bar-Or A.Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J Neuroimmunol. 2012; 246(1-2):85-95. B cells are important in the pathogenesis of multiple sclerosis (MS) and some of the effects are not dependent on maturation of B cells into immunoglobulin (Ig) producing plasmablasts and plasma cells. B cells present antigen, activate T cells, and are involved in immunoregulation and cytokine secretion. To determine if B cells from MS patients secrete products that have deleterious effects on glial cells not mediated by Ig, and to compare effects with secretory products of normal controls (NC), we isolated B cells from 7 patients with relapsing remitting MS (RRMS) and 4 NC. B cells were cultured alone or after stimulation with CD40 ligand (CD40L), CD40L+cross-linking of the B cell antigen receptor (xBCR) and CD40L+xBCR+stimulation of toll like receptor 9 (TLR9). Supernatants were harvested and incubated with mixed central nervous system (CNS) neonatal rat glial cells. Supernatants from unstimulated NC B cells induced on average death of 7% (range 0-24%) of differentiated oligodendrocytes (OL); in contrast, supernatants from unstimulated B cells from RRMS patients induced death of 57% (range 35-74%) of OL. Supernatants of stimulated B cells from NC did not increase the minimal OL death whereas stimulation of B cells from RRMS had variable results compared to unstimulated B cells. Supernatants from both NC and RRMS induced microglial enlargement and loss of normal resting bipolar morphology. OL death did not correlate with levels of tumor necrosis alpha (TNF-α), lymphotoxin alpha (LT-α), interleukin 6 (IL-6), IL-10, transforming growth factor beta 1 (TGF-β1) or any combination or ratio of these cytokines. Analysis of 26 supernatants from NC and RRMS patients failed to detect IgM. There were very low levels of IgG in 8 of the 26 supernatants, and no correlation between of OL death and presence or absence of IgG. Sera used in both the B cell and glial cell cultures were heated, which inactivates complement. The effects of B cell supernatants on OL could be direct and/or indirect involving either microglia and/or astrocytes. The identity of the toxic factor(s) is as yet unknown. Thus we have demonstrated that B cells from patients with RRMS but not NC secrete one or more factors toxic to OL. It is possible that such factors produced by peripheral blood B cells when within the CNS could contribute to demyelination in MS patients.

Whats is the factor? I don't know but more of a focus for B cells




Wednesday, 12 July 2017

#MSPrevention & #NewsSpeak: will Pharma develop an EBV vaccine?

Why don't the Courts' consider the wider implications of their decisions? The anti-vaccine lobby is smiling. #MSPrevention #NewsSpeak

The story about hepatitis B vaccination causing MS seems to resurface every few years and the source is usually from France. The news piece below, in last week's Science, raises major concerns for the vaccine industry. The epidemiology is pretty clear; hepatitis B vaccination does not cause MS, so why did they rule to the contrary? 

Hepatitis B vaccination is common, MS is uncommon, and by pure chance a small number of  people will develop their first attack of MS soon after vaccination. The epidemiological studies have confirmed that the number of people developing MS in relation to hepatitis B vaccination is no higher than what you would expect by chance. It appears that the European court does not necessarily agree with the scientific data. The court's ruling potentially sets a dangerous precedent for vaccine manufacturers. 

Vaccines are amongst the most important and impactful innovations we have. Unfortunately, most of us have not lived, or experienced, what life was like before we had effective vaccines. In the pre-vaccine era life was a lottery.  At a personal level when I was training in South Africa I managed several patients with a terminal condition called SSPE (subacute sclerosing panencephalitis), that occurs as a result of wild-type measles infection. The sad thing is that SSPE is 100% preventable; all you need is to vaccinate people against measles to prevent SSPE. The anti-vaccine lobby has been so effective in sowing doubt in the mind of some people that there are now a large numbers of children getting wild-type measles infections. The latter means that we will begin to see SSPE re-emerging is few years time. Sad, very sad.   

Vaccine development is a very expensive and a very risky endeavour. Anything that acts as a disincentive to the Pharmaceutical industry, such as the court decision below, is bad news for the world. I have a vested interest in vaccinology; it is my ambition to be part of an EBV vaccination trial to see if we can prevent MS.  For the latter to happen we need Pharma, public health officials, politicians and society at large to be supportive of vaccination. The legal decision below, which is contrary to the science, just feeds the public's scepticism about the benefits of vaccination. Could you imagine if EBV vaccine development was stalled because Pharma thought it too risky to take forward?  


For those of you who are interested the following is a report of workshop that was recently hosted by the Wolfson Institute of Preventive Medicine on EBV and MS Prevention. It is clear to prove EBV is the cause of MS we need to do a vaccine trial and show that we can prevent MS. Simple? The Court's decision on hepatitis B has just made our job harder. 

   
Gretchen Vogel. Decision by Europe’s top court alarms vaccine expert. Science Jun. 27, 2017.

Excerpts:

..... Did the European Union’s highest court just deal a blow to science? "Vaccines can be blamed for illness without scientific proof," read many headlines about the European Court of Justice’s (ECJ’s) ruling on the case of a French man who claimed that a hepatitis B vaccine caused his multiple sclerosis (MS). Alarmed experts pointed out that no link between the vaccine and MS has ever been established and fretted that the Luxembourg-based court had opened the floodgates to large numbers of spurious lawsuits.

...... The case involves a French man, called “W” in court documents, who received the three recommended doses of a hepatitis B vaccine between December 1998 and July 1999. In August 1999, W developed symptoms of MS, an autoimmune attack on the protective sheath covering nerves. In 2006, he and his family sued Sanofi Pasteur, the vaccinemaker, claiming that the vaccine had caused the illness. (W died of MS-related complications in 2011.) Other people have made similar claims, but large epidemiological studies have found no connection between the vaccine and MS.

.... W initially won his case. In 2009, the regional court in Nanterre ruled that, because he had no obvious previous health issues and no family history of MS, the appearance of symptoms shortly after the third vaccine dose was sufficient to conclude that the vaccine was the likely cause. In 2011 the Court of Appeal of Versailles overturned that decision, ruling that although W had made a convincing case that the vaccine caused his MS, he hadn’t shown that the vaccine was "defective," as required by liability law because for the population as a whole the vaccine's benefits outweighed its risks.

...... W and his family appealed to the Court of Cassation, France’s highest court, which evaluates whether lower courts have properly applied the law. It ruled that the appeals court decision on whether the vaccine was defective should have weighed the specific facts of W’s case, not the general risks and benefits of the vaccine, and handed the case to the Court of Appeal in Paris. (The French legal system assigns cases to a new court when a decision has been overturned.) The Paris court reached a different verdict: It found that W had not proved the vaccine had caused his MS. The court cited the lack of scientific evidence for a connection between the vaccine and MS, and the fact that the disease process is thought to begin years before symptoms appear—in other words, before W was vaccinated.

...... If you start to have a significant number of court decisions in Europe that regard products as defective because of rare side effects, this could change things significantly.Jean-Sébastien Borghetti, Panthéon-Assas University

Imaging B cells

James ML, Hoehne A, Mayer AT, Lechtenberg K, Moreno M, Gowrishankar G, Ilovich O, Natarajan A, Johnson EM, Nguyen J, Quach L, Han M, Buckwalter M, Chandra S, Gambhir SS. Imaging B cells in a mouse model of multiple sclerosis using 64Cu-Rituximab-PET. J Nucl Med. 2017 Jul 7. pii: jnumed.117.189597. doi: 10.2967/jnumed.117.189597. [Epub ahead of print]

B lymphocytes are a key pathological feature of multiple sclerosis (MS), and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to non-invasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here we evaluated 64Cu-Rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using positron emission tomography (PET). 
Methods: To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of Myelin Oligodendrocyte Glycoprotein fragment 1-125 (MOG1-125) emulsified in complete Freund's adjuvant. Control mice received complete Freund's adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19h following 64Cu- (Radioactive copper sixty four) Rituximab administration. Mice were perfused and sacrificed after final PET scan, and radioactivity in dissected tissues was measured with a gamma-counter. CNS tissues from these mice were immunostained to quantify B cells or further analyzed via digital autoradiography. Results: Lumbar spinal cord PET signal was significantly higher in EAE mice compared to controls at all evaluated time points (e.g., 1h post-injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 %ID/g, p<0.05). 64Cu-Rituximab-PET signal in brain regions ranged between 1.74 ± 0.11 and 2.93 ± 0.15 %ID/g for EAE mice compared to 1.25±0.08 and 2.24±0.11%ID/g for controls, p<0.05 for all regions except striatum and thalamus at 1h post-injection. Similarly, ex vivo bio-distribution results revealed notably higher 64Cu-Rituximab uptake in brain and spinal cord of huCD20tg EAE, and B220 immunostaining verified that increased 64Cu-Rituximab uptake in CNS tissues corresponded with elevated B cells. 
Conclusion: B cells can be detected in the CNS of EAE mice using 64Cu-Rituximab-PET. Results from these studies warrant further investigation of 64Cu-Rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell-targeted therapeutics en route to the clinic.
                         Note the red in the spinal cord (White Arrow)

As we enter the age of the B cells, we would like to assess the effects of treatments on B cells. This is a study in mice and uses a radioactive version of rituximab to do this. In EAE they can pick up B cells in mice with EAE. This was easy peasey, but can this approach be used in humans.

In the animals, they are giving their imaging agents at a time when they will get into the CNS. The question is what happens when there are no focal lesions one images the penetration of antibody will not be great. It's a start.