Thursday, 25 May 2017

A reason for thyroid problems

Greer JM, Broadley S, Pender MP. Reactivity to Novel Autoantigens in Patients with Coexisting Central Nervous System Demyelinating Disease and Autoimmune Thyroid Disease. Front Immunol. 2017 May 8;8:514.

Several lines of evidence suggest a definite and unique link between CNS demyelinating diseases and autoimmune thyroid disease (AITD). The aim of the current study was to systematically compare the clinical and laboratory features of patients with co-existent AITD and CNS demyelinating disease with those of patients with just CNS demyelinating disease. Forty-four patients with co-existing CNS demyelinating disease and AITD were identified and their clinical and radiological features were recorded. Blood and DNA were collected and tested for HLA type and for the response of T cells and antibodies to a variety of antigens. Patients with multiple sclerosis (MS) without AITD and healthy individuals were included as controls. Patients with co-existing AITD and CNS demyelinating disease were almost exclusively female (43/44) and had prominent spinal cord involvement as the main neurological finding. The HLA molecules carried by individuals with CNS demyelinating disease and AITD differed from both other MS patients and healthy individuals. Furthermore, patients with both CNS disease and AITD showed less T cell reactivity than patients with MS alone to myelin proteolipid protein, but, compared to other groups, showed elevated levels of T cell reactivity to the calcitonin gene-related peptide, which is present in both the CNS and the thyroid, and elevated levels of T cell and antibody to the leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4), a molecule that is expressed in the brainstem and spinal cord, and which is a homolog of the thyroid-stimulating hormone receptor. We suggest that reactivity of autoreactive immune cells in these patients against antigens present in both the thyroid and the spinal cord is a potential mechanism underlying the pattern of lesion development in the CNS in patients with coexisting AITD and MS and might indicate a novel mechanism of disease pathogenesis in these patients.

Thyroid disease occurs in people with MS. is a comon occurance in people with MS, notably in those treated with alemtuzumab. In this study they suggest there is a common target in both tissues to explain the finding that MS and thyroid disease can co-exist and maybe this is why the thyroid problems occur. Reactivity to  Calcitonin gene-related peptide occurred which is a nerve transmitter found in nerves all over the body. Leucine-rich repeat-containing G-protein coupled receptor 4 is found in a number of organs. So it can be a cross-reactivity, but there are other explanations

Wednesday, 24 May 2017

Targeting the “virus factory” to stop MS activity

This is a #PlainEnglish version of this post.
We are trying out 'translating' some of the posts on the blog so they're accessible and understandable to a wider audience.

Memory B cells and MS
We have been saying that the MS drugs which seem to work the best, appear to deplete memory B cells the most.

Memory B cells are cells that have helped your body to fight infection. A number of them stay dormant in the body and remember the infection. They can fight it off when the infection returns to the body. The problem is that they can sometimes attack the body, instead of attacking infections. They can create cytokines, “baddies” that can help other cells to create MS, or stimulate T cells to do the business.

In the past Prof G has called this idea the ‘Black Swan Theory’ (here, here and here). It’s when something unusual or highly improbable occurs, and has the potential to have an enormous impact. For MS, that means that instead of MS treatments targeting T-cells, they should instead target Memory B cells. It’s a game-changer, because it suggests MS may be caused by a virus that hides in the memory B cells. Although some treatments currently do deplete Memory B cells, MS is still primarily thought of as a T-cell disease.

Is MS caused by a virus?
Epstein Barr Virus (EBV) hides in Memory B cells. It shows itself every so often, when the T cells can kick its butt.

We’ve suggested that ocrelizumab - in targeting B cells, may actually be destroying a "virus factory". Indeed we’ve said that all active MS drugs may be doing this. Is there evidence for this?

In a study done on treating EBV with rituximab patients in a DIFFERENT disease, those with the highest level of EBV showed the best response to therapy, compared to people who were so-called EBV negative.

But the results didn’t show 100% response to the drug. Why? And why is it that some B-cell-targeting drugs don’t stop MS activity fully? The treatment failure may be because the cells causing the failure are already in the brain and it is too late. In the study, the bone marrow was also not emptied by rituximab. Other studies show rituximab does not effectively deplete EBV in the lymph glands.

What does this mean for MS treatments?

Earlier in the week we suggested alemtuzumab may fail in many people after switching from fingolimod, this is because it traps white blood cells in the lymph glands and bone marrow and because alemtuzumab does not clear out the bone marrow (this is based on an animal study). Is the level of purging of the bone marrow and lymph glands by ocrelizumab going to be enough so it doesn't to suffer the same fate as alemtuzumab after fingolimod treatment?

CD20 antibodies deplete EBV

If you haven’t been living under a rock for the past few months :-),
you will have noticed that we have been saying that MS drugs that work the best, seem to deplete the memory B cells the most.

What! You are a ground hog and have just come out of hibernation.

Ok… go on have a read. Its free (Click Here). Let’s get that altmetric up:-0

Centre stage is the memory B cells. According to the Immunologist they can turn into antibody making machines to help create MS, they can make goodies (cytokines) or should I say baddies that can help other cells to create MS and for the die-hards stuck in the mud, they can stimulate T cells to do the business. 


However, we can see ProfG’s Black swan perched on a Roche-inspired B cell. Don’t understand have a read of past posts.


http://multiple-sclerosis-research.blogspot.com/2014/03/ebv-re-activation-in-relapses.html

Search on "Black Swan"

But ProfG’s swan may be laying a big egg. The dots may not be CD20 the target for Ocrelizumab as Roche intended, 
but seeds of discontent for alternative thought and the blobs of budding virus.


my favorite


Epstein Bar Virus infects via a B cell marker and hides in memory B cells. This shows itself every so often, when the T cells can kick it's butt.

So we suggested rather than depleting B cells to treat MS, ocrelizumab may be destroying a virus factory. Indeed we said that all active MS drugs may be doing this.
Is there evidence for this? 

Do we do some work or just a bit of reading?

The following was not done in MS (I have removed the disease)

Magnusson M et al. Epstein–Barr virus in bone marrow of patients predicts response to rituximab treatment.
Objectives. Viruses may contribute to disease. This prompted us to monitor viral load and response to anti-CD20 therapy in patients.

Methods. Blood and bone marrow from 35 patients were analysed for CMV, EBV, HSV-1, HSV-2,parvovirus B19 and polyomavirus using real-time PCR before and 3 months after rituximab (RTX) treatment and related to the levels of autoantibodies and B-cell depletion. Clinical response to RTX was defined as decrease in the disease activity score (DAS) >1.3 at 6 months.

Results. Before RTX treatment, EBV was identified in 15 out of 35 patients (EBV-positive group), of which 4 expressed parvovirus. Parvovirus was further detected in eight patients (parvo-positive group). Twelve patients were negative for the analysed viruses. Following RTX, EBV was cleared, whereas parvovirus was unaffected. Eighteen patients were responders, of which 12 were EBV positive. The decrease in the DAS was significantly higher in EBV-positive group compared with parvo-positive group (P = 0.002) and virus-negative patients (P = 0.04). Most of EBV-negative patients that responded to RTX (75%) required retreatment within the following 11 months compared with only 8% of responding EBV-positive patients. A decrease of  Ig-producing cells and CD19+ B cells was observed following RTX but did not distinguish between viral infections. However, EBV-infected patients had significantly higher levels of Fas (Suicide molecule) -expressing B cells at baseline as compared with EBV-negative groups.
Conclusions. EBV and parvovirus genomes are frequently found in bone marrow of patients. The presence of EBV genome was associated with a better clinical response to RTX. Thus, presence of EBV genome may predict clinical response to RTX.

So what does this study show. You can have a look at a few graphs from the paper.
EBV was eliminated from by the treatment of rituximab. This would be consistent with the B cells being infected by EBV being depleted. 

Those with the highest level of EBV showed the best response to therapy, compared to people who were so-called EBV negative (This proportion is too low compared to what we know of the normal population). 

Anyway, I have suggested that looking at memory B cells may be able to predict response to therapy, but this shows a hole in the argument because you can see that rituximab emptied the blood of B cells and as memory B cells make up about 30% of the CD19 population they are emptied from the blood too, and in this case there was not a 100% response to therapy.


However, if we drive from London (Bone Marrow/Lymph gland) to Leeds (Brain) along the M1 motorway (blood) and we can see a car (B cell) if we have a look for a minute from a bridge over the motorway (blood test). If I drive my car (Pathogenic B cell) to York (Centre of Gods own Country about 200miles north) to cause the problem (MS), if you look at 3 in the afternoon you might see loads of cars but do it at 3 in the morning and you might not see any although the problem is indeed a car driving to York (a few miles from Leeds) along the M1 motorway. 



So we may have to look outside of the blood to get the answer

The other problem is the treatment failure may be because the cells causing the failure are already in the brain and it is too late. In the ocrelizumab trials they re-baselined their results to allow 3 months
for the drug to work. A sensible thing to do if you are looking for efficacy.

However, you can also see that the bone marrow was not emptied by rituximab. If we look at other posts of rituximab, we can see that the lymph glands are not effectively depleted.

Subcutaneous versus Intravenous Administration of Rituximab: Pharmacokinetics, CD20 Target Coverage and B-Cell Depletion in Cynomolgus Monkeys Cheng-Ping Mao, Martin R. Brovarney, Karim Dabbagh, Herbert F. Birnböck, Wolfgang F. Richter, Christopher J. Del Nagro PLoS One. 2013; 8(11): e80533

Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing.  B-cell levels were decreased by 57% (subcutaneous) and 42% (intravenous...so not that great) respectively. Yes this is in monkies but I could be bothered to go through 4000 references to pick a relevant human one.

Looks like ocrelizumab does something similar

http://multiple-sclerosis-research.blogspot.com/2017/05/what-is-your-choice.html 

where it was suggested that alemtuzumab may fail in many people after switching from fingolimod 


This is because it traps white blood cells in the lymph glands and bone marrow and because alemtuzumab does not clear out the bone marrow (at least in animals expresing human CD52). Is the level of purging of the bone marrow and lymph glands by ocrelizumab going to be enough so it doesn't to suffer the same fate as alemtuzumab after fingolimod treatment?

#ResearchSpeak: MS is one disease

How can we change the dogma surrounding PPMS? #MSBlog #ResearchSpeak #1-disease-not-2-or-3-diseases

Certain dogmas about PPMS have crept into the field and have become entrenched as facts that need challenging; in particular that (1) PPMS in non-inflammatory, (2) that pwPPMS don't have relapses and (3) PPMS is a different disease to relapse-onset MS.

Dogma 1: PPMS in non-inflammatory - WRONG!


The following pathology study done at the Institute of Neurology (Queen Square) when I was doing my PhD clearly showed that PPMS is inflammatory, albeit at a slightly lower level than SPMS. The dogma has crept in because we tend to view MS through the spectacles of an MRI; pwPPMS have fewer focal lesions on MRI. This however does not mean that there is no inflammation; focal inflammation is simply occurring at a level below the detection level of the MRI. What MRI sees in relation to focal lesions is simply the tip of the iceberg. The PPMS iceberg simply looks different with less above the surface. In addition, pwMS have oligoclonal IgG in their CSF. If they were no inflammatory you would expect these OCBs to be absent or disappear. 

Revesz et al. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain. 1994 Aug;117 ( Pt 4):759-65.

Background: The dynamics of primary progressive multiple sclerosis differ from those of the more common secondary progressive form. The observation by MRI that the frequency of enhancement with gadolinium-DTPA, a marker for blood-brain barrier dysfunction, is significantly less in the primary progressive form, has led to the hypothesis that inflammation is less intense in this group.

Aims: To test this, we have studied postmortem material from 9 cases judged from a retrospective analysis of case notes to show clear clinical evidence of either primary progressive or secondary progressive disease.

Methods: 578 lesions were analysed.

Results: There was significantly more inflammation in secondary progressive multiple sclerosis (as judged by the frequency of perivascular cuffing and cellularity of the parenchyma) than in primary progressive disease.

Conclusions: These observations have implications for therapeutic strategies in progressive multiple sclerosis.

Dogma 2: pwPPMS don't have relapses - WRONG!

In almost all PPMS trials done to date a proportion, albeit a small proportion, of pwPPMS who go onto have relapses. For example in the Rituximab trial in PPMS (Olympus Trial), 11 out of 439 (2.5%) of study subjects had a relapse during the 96 weeks of the trial. In the Ocrelizumab (ORATORIO) study protocol-defined relapses were reported for 11% of subjects in the placebo group and 5% subjects in the ocrelizumab group.


Similarly, about 5% of study subjects in the glatiramer acetate PPMS, or PROMISE, trial had relapses. Unfortunately, the exact number of relapses is not reported in the main manuscript. What is reported is MRI activity; 14% of 938 study subjects had Gd-enhancing lesions on MRI during the study. The latter is the MRI equivalent of relapses. 


Based on this data can we say that PPMS is non-relapsing?

Dogma 3: PPMS is a different disease to SPMS - WRONG!

Did you know that it not uncommon in siblings pairs with MS for one to have relapse-onset disease and the other to have PPMS? The figure from the UK sibling study is in fact 23% (please see article and table below). This indicates to me that relapse onset and PPMS are the same disease.


Chataway et al. Multiple sclerosis in sibling pairs: an analysis of 250 families. J Neurol Neurosurg Psychiatry. 2001 Dec;71(6):757-61.



(33.7+27) / (84+68.3+33.7+39.3+27+9.7) x 100 = 23%


Other arguments in favour of PPMS and SPMS being the same disease relates to genetic and natural history studies. People with PPMS and relapse-onset MSers have the same genetic background. Once people with relapse-onset MS enter the so-called clinical phase of SPMS they progress at exactly the same rate as pwPPMS. 

Kremenchutzky et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006 Mar;129(Pt 3):584-94.



It is for the reasons above that there is a strong argument for doing trials on combined populations of progressive MS. In other words we should combine PPMS and SPMS populations into one study. I am aware that this is a controversial topic, particularly in the eyes of the regulators, but it needs serious and prolonged debate. If we don't do this then treatments will continue to be licensed for one subtype of progressive MS, and not the other clinical subtype, until additional trials are done. This is not in the interests of pwMS. Additional trials cost money and time. Time is not a something people with progressive MS have on their side. 5-years in the life of someone with progressive MS may be the difference between using a walking-stick and being bed-ridden.

CoI: multiple

Tuesday, 23 May 2017

#ThinkSpeak & #ClinicSpeak: do PPMSers need a DMT?

If you have PPMS how would you want it treated? #ClinicSpeak #ThinkSpeak #MSBlog

I have had another email from a US colleague who is worried about the risk-benefit ration of ocrelizumab in PPMS. He/she is worried about the risk of secondary malignancy with ocrelizumab and is therefore going to 'continue prescribing off-label Rituximab instead'. I pointed out to him/her that the safety data on Rituximab-treated PPMSers in real life is too small to assume it is safe in PPMS and that he/she is prescribing a therapy that has been shown to be ineffective in PPMS. Because Rituximab is effective in RRMS does not mean we can extrapolate the RRMS rituximab data to PPMS and assume it will be effective in PPMS as well. 



It is interesting to see how the mind works and that someone is prepared to extrapolate efficacy data from RRMS to PPMS, despite the rituximab PPMS trial being negative and ignoring the fact that the ocrelizumab PPMS trial is positive. 

Could there be an efficacy difference between rituximab and ocrelizumab that explains the results? I have recently learnt that ocrelizumab is a much more potent B-cell depleter than Rituximab, i.e. ~10x as potent. Could this explain its therapeutic effect in PPMS? A 600mg dose of ocrelizumab is therefore ~6x more potent than 1,000mg dose of rituximab. The large punch provided by ocrelizumab may explain and efficacy difference particularly if we are targeting the hard to get to meningeal and intrathecal B cells? Let's hope an ocrelizumab CSF biomarker study is done to explore this possibility. Another way of looking at this is to see what impact ocrelizumab has on cortical gray matter atrophy and B cell follicles using imaging. We think some of the gray matter atrophy that occurs in MS is due to the meningeal B-cell infiltrates. 

I also pointed out to my colleague that to assume that ocrelizumab increases his/her patient's risk of secondary malignancy may be premature; the ocrelizumab malignancy signal at the moment could be a false positive signal. We really need to wait for more data to emerge through post-marketing surveillance to clarify this issue. We have the same issue with oral cladribine; the only way to assess secondary malignancy risks with DMTs is with long-term follow-up studies. 

It is interesting to see the spectrum of opinions about ocrelizumab treatment of PPMS. On the one hand some neurologists are saying it is not effective and hence they are not going to prescribe it for their patients, on the other hand some are saying they don't think it is safe and therefore they will prefer to prescribe a treatment that has not been shown to be effective in PPMS and yet others accepting the results and agreeing that their patients should receive ocrelizumab. In reality all these options are right and it simply reflects the complexities of clinical decision making that lead to variable adoption rates of new innovations. 

CoI: multiple