Wednesday, 24 May 2017

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.

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% ( 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 

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 

Be A Hero Ocrevus

Drugs. 2017 May 18. doi: 10.1007/s40265-017-0757-6. [Epub ahead of print]

Ocrelizumab: First Global Approval.

Frampton JE.


Ocrelizumab (Ocrevus™) is a humanised anti-CD20 monoclonal antibody that has been developed by Genentech, Inc. (a subsidiary of Roche) for the treatment of multiple sclerosis (MS). The drug is designed to deplete B cells, which play an important role in the pathogenesis of MS. In March 2017, ocrelizumab was approved in the USA for the treatment of patients with relapsing or primary progressive forms of MS; currently, it is awaiting approval in the EU for the same indications. This article summarizes the milestones in the development of ocrelizumab leading to its first global approval for the treatment of MS.

Figure: Key milestones in the development of Ocrevus in multiple sclerosis

We live in hubristic times. By spending time in an elevated position, we come to think of ourselves as gods among men. Wrongfully, or rightfully we misjudge any attack on this inflated self-perception as mere jealousy. And then comes the downfall, because real life isn't rad like jazz or sweet like cinnamon, it is painful in the lessons it teaches the wilful, and the stupid...

Ocrelizumab (Ocrevus) is a humanised anti-CD20 monoclonal antibody that targets B cells, developed by Genentech, Inc. (subsidiary of Roche Pharma) and Biogen Idec Pharma. Genentech, however, is responsible for development of Ocrevus in MS taking on 100% of the costs, while Biogen Idec will receive tiered, double digit royalties on US sales that will approximate its current 30% interest in Ocrevus. Development of Ocrevus in rheumatoid arthritis was halted in May 2010, quoting safety reasons:

"In March, Roche and Biogen Idec announced the suspension of treatment in the ocrelizumab RA program. This decision followed a recommendation from the independent ocrelizumab RA & Lupus Data and Safety Monitoring Board (DSMB). The DSMB concluded that the safety risk outweighed the benefits observed in these specific patient populations at that time based on an infection related safety signal which included serious infections, some of which were fatal, and opportunistic infections. Subsequently, the U.S. Food and Drug Administration (FDA) placed the RA studies on clinical hold".

Results from the pooled analysis of the Phase III programme are open access and available on the internet from Emery et al. 2014 in PlosOne. The authors noted a greater number of serious infections were observed in the high dose group OCR500 + methotrexate (MTX) vs. placebo + MTX. In their own words:

"The conclusion that the two doses of OCR, in combination with MTX tested in the RA clinical trials did not demonstrate a superior benefit-risk profile compared with available treatments led to the termination of the clinical development program of OCR in RA. OCR500+MTX demonstrated clinical benefit by improving signs and symptoms of RA and radiographic outcomes [10][13]; however this dose was associated with an increased incidence of SIEs. OCR200+MTX did not show superior efficacy compared with existing therapies, but was safe and well-tolerated. The clinical development of OCR is continuing in multiple sclerosis, for which there remains an unmet need for more effective therapies and background immunosuppressant therapy is not used".

Eyes wide open...

Monday, 22 May 2017

What is your Choice?

Grant Idea of the Month

As you know we give away our ideas on this blog so this month this is for the Mousers or maybe a clinical study.

When you make choices of treatments there are sites such as the MS trust Decisions web site. This needs abit of updating.

I expect they will be adding Ocrelizimab soon.

However there are a number of things that you have to think about when making a choice.   Depending on where you live, cost will come into play and whether your government/insurance will cover the cost. Many people in Low and Middle Income Countries make less in a year than the cheapest of the cheap and so get no access. 

One would think that the International MS Federation would be pushing for access for "Treatment for All", but where are we on that one?

But there are others to consider and this is how to do transition off a drug, in case it doesn't work for you.

This can occur because they simply aren't potent enough or maybe because you start to make neutralizing antibodies, which can stop protein drugs from working.

We have the problem of rebound for the anti-migration drugs. This is a well known problem with Natalizumab. It stops the cells from getting into the brain, but is not stopping what is driving their production. They are their waiting to get into the brain as the drug wears off . It is like having sprinters under starters orders ready to race into to your brain once the started gun goes off, there all arrive in the brain at once and this is a rebound (worse than just a relapse) 
You switch after 24 months if you are JC positive.

When the depleting drugs fail the damaging cells will trickle out of the bone marrow/lymph glands into the blood, so the attack is not as intense as with a rebound atttack.

However, after some of the depleting drugs you don't replete, how long do you wait before you start treatment again?

However, this rebound can be a problem for fingolimod, if this really is, an anti-migration drug. The cells are trapped in the lymph glands, (according to Dogma), but I would put money on the Bone Marrow (Site where immune cells are made) being equally if not more important, ready to get into the blood and ready to get into your brain.

If it is true that fingolimod can stops (in about 25% of people) alemtuzumab from working because it traps the white blood cells into places where the antibody does not deplete very well, then is this problem also going to happen with ocrelizumab too. Alemtuzumab and ocrelizumab both target the MS-causing cells and both deplete via the same mechanism (antibody-dependent cellular cytotoxicity). This means the antibody binds to the B memory cells (MS causing cell...if you are still a T cell fan read T cell here) and natural killer cells and neutrophils bind to the antibody and relate their contents, which puts holes in the B cells and kills the memory B cell. 

Can the killer cells get into the bone marrow and lymph glands to do this killing?  Not as well as it gets in the blood. 

I don't know the ocreliziumb data, but we do know about rituximab.
We need to see the data in the humanised CD20 mouse and see if they use complement (A set of proteins that punch holes in cells, abit like the Killer cells) to kill, which Alemtuzumab didn't. 

To do this you use Cobra Venom and that depletes complement. simples, we could block ADCC.

Alemtuzumab kills natural killer cells (~40%), so it could be different from ocrelizumab in this respect but we need to be be vigilant and monitor for this.

So will fingolimod interfere how CD20 depleting drugs work?
We know there are people who have done this with rituximab

P.S. Happy to do this study, if you are interested.

CoI. None.

Sunday, 21 May 2017

#NeuroSpeak: DMF as a second-line agent or not

Did you know that dimethyl fumarate is not as effective when used 2nd- or 3rd-line? #NeuroSpeak #MSBlog

The Mouse Doctor did a good deed this weekend; he kindly agreed to speak about MS treatments at a meeting the allied HCPs hosted at Queen Square our former Institution. At the meeting he was asked about why dimethyl fumarate (DMF) had not being recommended by NICE as a second-line therapy for patients with highly-active or rapidly-evolving severe MS? He wasn't sure so he dropped me an email.  The reason is that DMF is a much more effective treatment in pwMS who are naive to treatment. When DMF is used 2nd-line it has an impact on relapses, but in the post-hoc analysis it had no impact on disability progression. All the NICE cost-effective models are driven by disability progression and hence in this subgroup of patients it was not considered cost-effective.

This data was presented at ECTRIMS in 2013, but has not subsequently been published. I have uploaded the poster for you so that you can see the data for yourself. The answer to your question is in Figure 4 in relation to disability progression. Please note that the data on DMF in newly diagnosed patients, which is very good has been published. I have suggested to Biogen that they should also publish the 2nd-line data, but my request seems to have fallen on deaf ears. I wonder why?

Based on the post-hoc analysis below I don't recommend DMF second-line unless the reason for switching treatments is due to a tolerance issue or there are specific reasons for someone requesting DMF. The latter is usually linked to fingolimod or teriflunomide being contraindicated. Whilst we are the topic of 1st-line vs. 2nd-line efficacy some of you may be remember a post I did on Terifluomide being more effective as a 2nd- or 3rd-line DMT compared to when it is used 1st-line. It the only DMT to be more effective when used later than earlier. The finding was consistent across both phase 3 trials and therefore must be linked to real biology. If you can work out why Teriflunomide is an outlier in this regard you may be able to explain something important about the biology of MS. We have some ideas, but I will keep you in suspense. We are trying to get a grant from Genzyme-Sanofi to explore our hypothesis in more detail and will keep you posted. 

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials.

OBJECTIVE: To evaluate delayed-release DMF in newly diagnosed relapsing-remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM.

METHODS: Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy.

RESULTS: The newly diagnosed population comprised 678 patients treated with placebo (n = 223) or delayed-release DMF 240 mg BID (n = 221) or TID (n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% (p < 0.0001) and 47% (p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF.

CONCLUSION: Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.

CoI: multiple

Blast from the Past...Memory B cells depleted by HSCT

Storek J, Zhao Z, Lin E, Berger T, McSweeney PA, Nash RA, Akatsuka Y, Metcalf MD, Lu H, Kalina T, Reindl M, Storb R, Hansen JA, Sullivan KM, Kraft GH, Furst DE, Maloney DG. Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases).
Clin Immunol. 2004;113:285-98.
To ascertain the consequences of severe leukopenia and the tempo of recovery, we studied the immunity of 56 adult patients treated for multiple sclerosis or systemic sclerosis with autologous CD34 cell transplantation using extremely lymphoablative conditioning. NK cell, monocyte, and neutrophil counts recovered to normal by 1 month; dendritic cell and B cell counts by 6 months; and T cell counts by 2 years post-transplant, although CD4 T cell counts remained borderline low. Initial peripheral expansion was robust for CD8 T cells but only moderate for CD4 T cells. Subsequent thymopoiesis was slow, especially in older patients. Importantly, levels of antibodies, including autoantibodies, did not drop substantially. Infections were frequent during the first 6 months, when all immune cells were deficient, and surprisingly rare (0.21 per patient year) at 7-24 months pos-transplant, when only T cells (particularly CD4 T cells) were deficient. In conclusion, peripheral expansion of CD8 but not CD4 T cells is highly efficient. Prolonged CD4 lymphopenia is associated with relatively few infections, possibly due to antibodies produced by persisting pre-transplant plasma cells.

I didn't have the MS HSCT data one our B cell paper, So thanks to Luis for finding this one. 

This is paper on HSCT, using cyclophosphamide and anti-Thymocyte globulin. Many people had MS. 

The repopulation kinetics are here.

What can you see?

Massive overshoot of B cells, due to mature B cell over population, that masks a major deletion of memory B cells. CD4 T cells disappear for over 2 years , CD8 are down for  8 months. Black bars 5th and 95th percentile of health and dotted line is the medium of health. No reports of autoimmunity in the report. Does this say anything, but the memory B cells were down

What does it look like?

Saturday, 20 May 2017

#ThinkSpeak: social medicine and meat

How much red and processed meat are you consuming? #ThinkSpeak #SocialMedicine

Unless I am travelling a typical Friday night is a take-away pizza, a bottle of good quality wine, watching 'Have I got news for You' and an early night with the latest issue of the Economist. Last night was no different except we ditched the pizza and went for a vegetarian curry. We are trying to reduce our red, and processed, meat intake based on the latest data that was published in the BMJ a few week's ago. I am also currently reading 'Homo Deus: A Brief History of Tomorrow' by Yuval Noah Harari and the section on how we are treating our domesticated farm animals is enough to make anyone vegetarian. If you have the time to read I would highly recommend this book; it is a wake-up call for Homo sapiens to get their act together. 

Last night, however, I had difficult unwinding due to the germ of an idea occupying my thoughts. I had just finished running one of our Barts-MS 2-day teaching courses, or MS Preceptorships, and it struck me how important the social interactions were for patients who are on natalizumab. As you know if you are on natalizumab you have to come up for monthly infusions, which typically happen in an infusion suite in which several patients are receiving their natalizumab at the same time. This allows fellow patients to speak to each other, form friendships, engage in each other problems and help each other with the management of their MS. I am aware of several patients forming deep and lasting friendships that extend beyond the infusion unit. Some arrange to socialise outside the hospital, have dinner together and invite each other to weddings and special events. I am not aware of any marriages yet, but I suspect there may be several natalizumab-weddings in the world.  It is not uncommon that if one patient delays their infusion by week the others in the group want to do so as well. Occasionally when one person in the group comes off natalizumab the others in the group go into mourning. Thankfully we have not had a case of PML yet, within our unit, but I could imagine the devastating effect a death might have on the group. What is clear is that people with MS on natalizumab value these relationships and the support and help they receive from their fellow MSers. 

These observations are a reminder that we are social animals and we like to be part of a group and to belong. Most of our healthcare is based on keeping people with diseases apart. If we can make medicine, and in this context MS care, more social we will almost certainly improve outcomes. The most used Apps on the web are social Apps. Can we learn from the tech industry and create a social app that will allow people with MS to interact with each other and their healthcare professionals to improve outcomes? This is the challenge I have set myself. The blog is not the platform for this; the blogger software is not designed to be social in the way it would need to be. Could we use Google+, Facebook or WhatsApp to do this? The problem is the curation of the content and allowing new users to navigate the platform and to find friends and to interact with each other in private or in the open. 

Etemadi et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ. 2017 May 9;357:j1957. doi: 10.1136/bmj.j1957.

Objective:  To determine the association of different types of meat intake and meat associated compounds with overall and cause specific mortality.

Design: Population based cohort study.Setting Baseline dietary data of the NIH-AARP Diet and Health Study (prospective cohort of the general population from six states and two metropolitan areas in the US) and 16 year follow-up data until 31 December 2011.Participants 536 969 AARP members aged 50-71 at baseline.Exposures Intake of total meat, processed and unprocessed red meat (beef, lamb, and pork) and white meat (poultry and fish), heme iron, and nitrate/nitrite from processed meat based on dietary questionnaire. Adjusted Cox proportional hazards regression models were used with the lowest fifth of calorie adjusted intakes as reference categories.

Main outcome measure: Mortality from any cause during follow-up.

Results: An increased risk of all cause mortality (hazard ratio for highest versus lowest fifth 1.26, 95% confidence interval 1.23 to 1.29) and death due to nine different causes associated with red meat intake was observed. Both processed and unprocessed red meat intakes were associated with all cause and cause specific mortality. Heme iron and processed meat nitrate/nitrite were independently associated with increased risk of all cause and cause specific mortality. Mediation models estimated that the increased mortality associated with processed red meat was influenced by nitrate intake (37.0-72.0%) and to a lesser degree by heme iron (20.9-24.1%). When the total meat intake was constant, the highest fifth of white meat intake was associated with a 25% reduction in risk of all cause mortality compared with the lowest intake level. Almost all causes of death showed an inverse association with white meat intake.

Conclusions: The results show increased risks of all cause mortality and death due to nine different causes associated with both processed and unprocessed red meat, accounted for, in part, by heme iron and nitrate/nitrite from processed meat. They also show reduced risks associated with substituting white meat, particularly unprocessed white meat.
Strijbis EMM, Kooi EJ, van der Valk P, Geurts JJG.
Cortical Remyelination Is Heterogeneous in Multiple Sclerosis.
J Neuropathol Exp Neurol. 2017 May 1;76(5):390-401.

Cortical lesions (CLs) are an important component of multiple sclerosis (MS) pathology; they correlate better with physical disability and cognitive impairment than white matter lesions (WMLs). Because remyelination can be extensive in CLs, we quantified remyelination in gray matter (GM) and white matter (WM), addressing oligodendrocyte (OGD) maturation state and clinical relevance of remyelination. Brain tissue samples from 21 chronic MS patients were immunohistochemically stained for myelin proteolipid protein, Olig2, which is strongly expressed in OGD precursor cells (OPCs), but weakly expressed in mature OGDs and other OGD markers. Sections were scored for the presence of normal-appearing WM and GM, de- and remyelination, and OPC and OGD cell counts. Remyelination was significantly more extensive in CLs than in WMLs with a trend toward more GM remyelination in primary progressive MS (PPMS) vs relapse-onset MS patients. More OPCs were found in remyelinated and nonremyelinated CLs vs remyelinated WMLs and nonremyelinated WMLs. Thus, there is more remyelination in the GM than in the WM in MS patient brains, with a trend toward more remyelination in those with PPMS. There does not seem to be a significant OPC recruitment failure in the GM, which casts new light on the process of remyelination failure.

Grey mater is less sensitive to demyelination

So Grey matter can remyelinate better than white matter, this supports what has been said before.

Friday, 19 May 2017

#ClinicSpeak: what is CMV reactivation disease?

If you are being treated with alemtuzumab or HSCT you need to know about CMV #ClinicSpeak #MSBlog

In response to a question yesterday about 'what does CMV infection mean?'. Yes, in the small print of the AAN poster I mentioned yesterday the estimated incidence of cytomegalovirus infection on alemtuzumab treated patients is 0.13%. CMV infection has only been identified with alemtuzumab and HSCT and is not, to the best of my knowledge, associated with other DMTs. CMV reactivation typically occurs with quite marked immunosuppression that hits both innate (neutrophils and monocytes) and adaptive (T-cells) immunity. We have only had one patient at our centre with this complication and this patient did not have MS, but a condition called CNS vasculitis. He presented with a pyrexia and a pneumonia, about a week after have alemtuzumab treatment. He responded rapidly to ganciclovir treatment and made a full recovery.

Background: Human cytomegalovirus, or CMV, is a member of the herpes virus family. CMV infection is typically asymptomatic in healthy people, but can be life-threatening in immunocompromised people. After infection, CMV remains latent within the body throughout life and like other herpes viruses can be reactivated at any time. CMV is strongly associated with mucoepidermoid carcinoma and possibly other malignancies. CMV is found throughout the world and all socioeconomic groups, and infects between 60% and 70% of adults in developed countries and almost 100% in emerging countries.

As with all herpes viruses CMV has genes dedicated to altering and/or evading innate (hard-wired) and adaptive (memory) immunity. The immune system has a lifelong battle with CMV and as we get older a large number of your peripheral T-cells, or T-cell repertoire, becomes dedicated to keeping CMV in check. CMV is the virus most frequently transmitted to the developing foetus and can cause congenital CMV infection, which is one of the leading causes of deafness, learning disabilities, and intellectual disability in children.

Clinical features of CMV reactivation: CMV infection post-alemtuzumab is usually due to reactivation of latent virus and not new infection. Reactivated CMV infection can affect different parts of the body:

  1. Retina: CMV retinitis affects the eyes and can cause blindness. 
  2. Lungs: CMV pneumonia caused by CMV can be life threatening. 
  3. GIT: CMV can affect any part of the gastrointestinal tract, including the esophagus, stomach, liver, gall bladder, pancreas and colon, causing ulcers, liver inflammation, intestinal obstruction and colitis. Symptoms can include painful and difficult swallowing, nausea, vomiting, abdominal pain, yellow skin (jaundice) and watery or bloody diarrhoea. 
  4. Brain: CMV can infect the brain and other parts of the nervous system, causing symptoms like headache, confusion, and leg weakness. 
CMV pneumonia
Diagnosis: The diagnosis of CMV usually requires a detailed physical and targeted tests depending on which part of the body is infected. Typically the virus is detected in the blood, urine and/or stools. Occasionally, a biopsy of the affected organ, such as the lung or colon, is needed to confirm the diagnosis. Retinal involvement is usually typical and most ophthalmologists suggest the diagnosis based on the retinal examination.

CMV retinitis displaying frosted branch angiitis

Treatment: CMV reactivation is usually treated with anti-viral agents including ganciclovir, valganciclovir, cidofovir and foscarnet. Ganciclovir can be given intravenously, orally or as a pellet implanted in the eye to treat an infection in the retina. Valganciclovir has better oral absorption than ganciclovir but the two medications are otherwise very similar. Cidofovir is approved from treatment of CMV retinitis. Foscarnet must be given intravenously and is usually reserved for those who have virus that is resistant to ganciclovir or those who have serious side effects from ganciclovir. Side effects of ganciclovir and valganciclovir include the suppression of white blood cells, red blood cells and platelets. Because cidofovir and foscarnet can cause renal toxicity, kidney function needs to be monitored carefully.

The following are guidelines for alemtuzumab associated CMV reactivation. Please note that the severity of CMV reactivation in pwMS treated with alemtuzumab is likely to be less severe than that which occurs alemtuzumab-treated cancer patients and those undergoing HSCT.

CoI: multiple

Steroids and relapse route does not matter

Lattanzi S, Cagnetti C, Danni M, Provinciali L, Silvestrini M.Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017 . doi: 10.1007/s00415-017-8505-0.

Glucocorticoids are the standard of care for multiple sclerosis (MS) relapses, but the most desirable route of administration is still matter of debate. The aim of the study was to compare the efficacy and safety of oral versus intravenous steroids for treatment of acute relapses in patients with MS. Randomized or quasi-randomized, parallel group trials with direct comparison between oral and intravenous steroid treatment in MS patients with acute relapse were identified through a systematic literature search. Six trials were included involving 419 participants, 210 for oral, and 209 for intravenous groups, respectively. The weighted mean differences (WMDs) in the Kurtzke's Expanded Disability Status Scale (EDSS) score reduction between the oral and intravenous groups were 0.32 [(-0.09 to 0.73); p = 0.129] and 0.11 [(-0.12 to 0.33); p = 0.355] at 1 and 4 weeks after treatment, respectively. The risk ratios (RRs) for improvement by at least one EDSS point were 0.79 [(0.37-1.68); p = 0.539] at week 1 and 0.92 (0.76-1.12); p = 0.400] at week 4. There were no differences in the relapse rate and relapse freedom at 6 months between groups. The WMDs in the mean percentage reduction of Gadolinium-enhancing lesions between oral and intravenous arms were 0.14 (-0.02, 0.29); p = 0.083] and 0.04 (-0.19, 0.28); p = 0.705] at 1 and 4 weeks from treatment. Among the adverse events, insomnia was significantly associated with the oral route of steroid administration [RR 1.25 (1.07-1.46); p = 0.005]. In adult patients with acute MS relapse, there were no clear-cut differences in the efficacy and overall tolerability between oral and intravenous steroids

Steroids are a standard treatment for relapses. They may aid in a quicker recovery and their value has been rehearsed by prof G a number of times. The basis of the study was to suggest that it was not clear if oral verses intravenous is better and a meta analysis is done. The answer in their analysis is their is no difference. 
So perhaps rather than a meta analysis, perhaps a quick trip to pharmacokinetics should be done. You can work out how quick 
and how much a drug gets on board via the oral and intravenous route. DrK below found the difference was amount given to amount gets in the blood, oral and cladribine you get 40% on board and intravenously and subcutaneously you get 100% on board, so no particular advantage except you can use half the amount of drug verses oral. For my own drug if it goes oral to a mouse the maximum amount is their in 15minutes after oral compared to instant with intravenous. You save a few minutes is this important?

coI None:-

Thursday, 18 May 2017

Beating the drum for drug C yet again...

Alvarez-Gonzalez CAdams A, Mathews J, Turner BP, Giovannoni G, Baker D, Schmierer K. 
Ann Clin Transl Neurol 17 May 2017


Rebound disease following cessation of disease modifying treatment (DMT) has been reported in people with both relapsing and progressive multiple sclerosis (pwRMS, pwPMS) questioning strict separation between these two phenotypes. While licensed DMT is available for pwRMS to counter rebound disease, no such option exists for pwPMS. We report on a pwPMS who developed rebound disease, with 45 Gadolinium-enhancing lesions on T1 weighted MRI brain, within 6 months after fingolimod 0.5 mg/day was stopped. Treatment with a short course of subcutaneous cladribine 60 mg led to effective suppression of inflammatory activity and partial recovery with no short-term safety issues or adverse events.

We have been accused of beating the drum for cladribine a little too often. However, please read this case of one of my patients, consider the alternatives, and you may agree there aren't many with a comparable risk:benefit profile. The arguments are detailed in the discussion.

There are a few lessons beyond the effect of the drug used such as:

(i) Even in somebody with the clinical phenotype "primary progressive" MS, the principal mode of disability accrual may be through inflammatory lesions that look no different on MRI from relapsing MS.

(ii) Based on this and previous reports one should be very careful stopping a DMT known to be effective in relapsing MS, even when efficacy in the trial (INFORMS) was not significant *on the cohort level*. In our case, my impression would certainly be that fingolimod did work.

Unfortunately, our acknowledgement appears to have been lost in the course of proof editing the paper: We would like to thank Novartis for letting us use the clinical data of this participant, and for providing the lymphocyte counts, acquired during INFORMS.

CoI: multiple

#ThinkSpeak & #PolitcalSpeak: a balancing act

Safety vs. rare, but life threatening adverse events. #ThinkSpeak #PoliticalSpeak

My oldest daughter recommended I watch the BBC Panorama programme about the HIV contamination of blood products in the 1980s. She is horrified by the Government's response to the crisis and has no doubts about who is to blame. 

It tells a harrowing story of people with haemophilia being saved but a technological advance (plasma Factor VIII concentrate) on the one hand and being exposed to, and infected by, HIV on the other hand. The story is not a simple one. It involves doctors trying to save lives, and improve the quality of life, of their patients with the latest innovations and the perceived slowness of public health officials and politicians to act on an emerging risk of HIV, and hepatitis C, from high risk blood donation practices in the USA. The documentary alludes to the dark arm of the Pharmaceutical industry who were processing, manufacturing, marketing and distributing the Factor VIII concentrate to be responsible, despite no evidence being presented to support the claim. Blaming Pharma seems to be the default position of Panorama. 

The programme raises very important issues about at what point in an emerging epidemic, AIDS in  people with haemophilia in the USA, do public health officials and doctors act? Scotland responded quicker than England and hence the rate of HIV infection in people with haemophilia in Scotland was half that of England. England is larger than Scotland and it was suggested that they couldn't respond as quickly because of a much greater demand and relatively lower supply of plasma donors in England. 

The story is relevant to MS. When PML emerged as a risk factor for pwMS on natalizumab treatment, Biogen withdrew natalizumab from the market and did a risk assessment. Biogen then relaunched natalizumab with a 'black box' warning and regulators restricted natalizumab to a group of pwMS with very active disease (rapidly evolving severe). Despite the risks neurologists and pwMS continued to use natalizumab with a resulting epidemic of PML that as of the 1st December 2016 there have been 698 confirmed cases of PML (695 with MS and 3 with Chron's disease) with 161 deaths. Who is responsible for these deaths; Biogen for relaunching natalizumab, regulators for allowing natalizumab back on the market, neurologists for prescribing it or patients for choosing natalizumab over other, albeit limited, options? In my opinion no one is to blame. The relaunch of natalizumab allowed people with very active, and disabling MS, to be treated,  the risk of PML to be better defined and for natalizumab to be derisked. In 2017 there should be very few new cases of natalizumab-associated PML. From a public health perspective the above process saved natalizumab for future generations of pwMS. The sad side of the story is that over 160 people had to die for us to get to where we are today. In the case of the haemophilia-HIV story lessons were learnt and heat-inactivation was rapidly shown to destroy the HIV virus rendering the Factor VIII concentrate safe from HIV. Plasma derived Factor VIII has subsequently been superseded by the development of recombinant factor VIII. 

Are there lessons to be learnt? Yes, transparency and honesty is needed. The Government was not, and subsequently has not been, transparent in relation to haemophilia-HIV epidemic. May be someone in the Department of Health should study the natalizumab-PML story as a case study on how to manage an emerging healthcare crisis. 

We will almost certainly have other crises like this going forward. In the MS space we don't really know what the risk of secondary malignancies is from the various licensed, or to be licensed, MS DMTs. What will happen if in the future a well-defined cancer risk emerges with one of the MS DMTs? Who will be to blame? Sometimes risks only become clear with time and provided we all admit that the risk can't be defined at present and we make sure that all parties are aware of this and then we collect the data and act on it in a timely fashion no one will be blamed and everyone will benefit. 

I have been hypercritical of Genzyme and the emerging Listeriosis crisis with alemtuzumab for similar reasons. It is clear that Listeriosis is a problem with alemtuzumab. However, we have been kept in the dark about the number of cases and the mortality associated with Listeria infection in alemtuzumab-treated patients. The only reference to the number of cases is in the small print of a poster at the AAN that stated the incidence of Listeria to be 0.26%. What we don't know is how many cases have there been and what is the mortality of alemtuzumab-associated Listeriosis. How many cases had Listeria meningitis and how many systemic Listeriosis? If only Genzyme could learn from Biogen's experience we would all be in a better place. Genzyme have no idea how difficult they are making if for neurologists on the coalface. What do we tell our patients? Wouldn't it be better if we had hard facts? I would urge Genzyme executives to watch 'Contaminated Blood' and imagine themselves as a patient with MS trying to weigh-up the risks and benefits of the various treatments on offer. Genzyme should also be leading on derisking alemtuzumab. Listeria infection, like PML with natalizumab, is preventable. 

BBC Panorama. Contaminated Blood: The Search for the Truth. First shown: 10 May 2017

It has been called the worst treatment disaster in the history of the NHS. More than 2,000 people died and thousands more were infected with HIV and Hepatitis C after being treated with contaminated blood products. All the victims were infected over 25 years ago, but even now new cases are still being diagnosed. Survivors and their families are trying once more to persuade the government to hold a UK public inquiry.

Panorama examines recently released documents, and asks if the government could have done more to save lives. The film hears the heartbreaking testimony of some of the victims and their families and explores the dilemmas of doctors who had to carry on treating their patients through the unfolding crisis.

Active EBV cause Attacks?

Serafini B, Scorsi E, Rosicarelli B, Rigau V, Thouvenot E, Aloisi F. Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal.J Neuroimmunol. 2017 Jun 15;307:14-17

Rebound of disease activity in multiple sclerosis patients after natalizumab withdrawal is a potentially life-threatening event. To verify whether highly destructive inflammation after natalizumab withdrawal is associated with Epstein-Barr virus (EBV) reactivation in central nervous system infiltrating B-lineage cells and cytotoxic immunity, we analyzed post-mortem brain tissue from a patient who died during a fulminating MS relapse following natalizumab withdrawal. Numerous EBV infected B cells/plasma cells and CD8+ T cells infiltrated all white matter lesions; the highest frequency of EBV lytically infected cells and granzyme B+ CD8+ T cells was observed in actively demyelinating lesions. These results may encourage switching to B-cell depleting therapy after natalizumab discontinuation.

When you select a drug, you may consider things like safety and side-effects, efficacy (which is often inversely related to safety), convenience (route and how often you take drugs but also what screening for problems), however you have to also think what next as we know no MS drug is infallible. Even relapses occur after HSCT.

One problem that is evident is the migration inhibition drugs (natalizumab and to some extent fingolimod). The damaging cells are not killed but kept out of the brain. They are there ready to go if the brakes are removed. This is removed when you stop the drug and then there is a time bomb waiting. 

Can you get them under control before the damaging cells pile into the brain to cause rebound damage.  

This is why you need to plan the exit before you start the entry. 

Following fingolimod much needs to be defined, how best to switch, as it is not just a migration blocker but a depleter too.
Do you wait until blood levels increase, but do you risk damaging cells surging out of the lymph glands and bone marrow to cause a rebound.

The transition from Natalizumab is more defined, but occassionally things go wrong, as in this case. 

However, in these cases we know disease has been held in check for some time and so when an attack occurs what ever is driving the attack is present. 

In this individual there were loads of B cells and these were EBV infected and the virus was not latent but lytic and CD8 T cells were there presumably killing the virus infected cell. Is the trigger for the attack viral reactivation or does the virus activate because the B cells are activated and dividing?

The study infers that a switch to a B cell depleting therapy is needed, but before you accuse me of giving ocrelizumab a plug. I will remind you that we have shown that all MS drugs are memory B cell depleters, some are better than others at this.

MS Genes why they may not always cause MS

Ooi JD, Petersen J, Tan YH, Huynh M, Willett ZJ, Ramarathinam SH, Eggenhuizen PJ, Loh KL, Watson KA, Gan PY, Alikhan MA, Dudek NL, Handel A, Hudson BG, Fugger L, Power DA, Holt SG, Coates PT, Gregersen JW, Purcell AW, Holdsworth SR, La Gruta NL, Reid HH, Rossjohn J, Kitching AR. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature. 2017;545(7653):243-247

Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell self-epitope derived from the α3 chain of type IV collagen (α3135-145). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective with HLA-DR15. We show that autoreactive α3135-145-specific T cells expand in patients with Goodpasture disease and, in α3135-145-immunized HLA-DR15 transgenic mice, α3135-145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3135-145 epitope in different binding registers.
HLA-DR15-α3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered α3135-145-specific T-cell antigen receptor usage, HLA-DR15-α3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-α3135-145tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes.  Moreover, patients with Goodpasture disease display a clonally expanded α3135-145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Treg cells that leads to protection or causation of autoimmunity.

We know that MS is associated with genetic susceptibility and this susceptibility is linked to the major histocompatibility complex and the human leucocyte antigen HLA-DR and there are variants associated with susceptibility and in this case it it the HLA-DR15 from the HLA-DRB1*1501 genetic variant that is common in Northern Europeans. Look in the education section to see what these are.

Goodpastures disease is one of the side-effects to alemtuzumab, which is caused by an antibody response to the basement membranes in the kidney. Antibodies need T cells to be produced and this is probably why the secondary autoimmunities after alemtuzumab take time to appear as CD4 T cells are depleted for years after alemtuzumab. 

This study is not about MS but makes a relevant point why having an MS gene does not mean you get MS. We get one gene from our mum and another from our dad. These can be genetically identical so we are called homozygous (two of the same genes) or we can be heterozygous (two different variants of the same gene). T cells recognise peptides (9-13 amino acids)

What this shows is you have HLA-DR15, it recognises a peptide in one way and you get a pathogenic response, but if the same pepide is presented by HLA-DR1 variant it is seen in a slightly different way and causes T regulatory cells to occur. If you have HLA-DR15 and HLA-DR1 in the same person the DR1 generated regulatory cells dominate and stop the DR15-generated pathogenic cells from occuring and disease is prevented.

This is one reason why you may not pass MS onto your children as your MS risk risk gene effect may be controlled in your next generation