Wednesday, 26 July 2017

More on the safety of MRI contrast agents

A recent post on the safety of Gadolinium based contrast agents used in MRI caused some concern, so I thought we should follow up with yet more expertise and analysis. I therefore asked Dr Tom Campion to summarise his thoughts on a recent guidance statement by the International Society for Magnetic Resonance in Medicine (ISMRM) on this important topic.

Tom Campion is a senior radiology registrar at Barts Health NHS Trust, where he is currently undergoing neuroradiology training. He has an MSc in Neuroimaging for Research, and a research interest in imaging in multiple sclerosis. He is the trainee representative for the British Society of Neuroradiologists and runs a blog at www.bsnrtrainees.com. Tom has recently published a well received paper on a new method to improve the diagnosis of MS (free for download here). He has no conflicts of interest.


"Gadolinium-based contrast agents (GBCAs) are safe medications widely used in medical imaging, but have come under scrutiny due to the finding over the last few years that residual gadolinium is left in specific areas of the brain following their usage. The ISMRM published a recent guidance statement summarizing the evidence available so far, so here’s what we know [1]:

- In multiple studies, gadolinium has been found deposited in the brain, by imaging and by autopsy, long after GBCA administration
- This deposition appears more pronounced when people have had repeated doses of GBCA.
- Of the two types of GBCA, ‘linear’ and ‘macrocyclic’ (for a detailed explanation of the difference, see [2]), deposition is significantly more pronounced with linear compared to macrocyclic agents but has been demonstrated in both.
- The mechanism for the deposition is not yet understood.
- This has not been shown to cause any harm in human or animal models.

So what do we, as doctors and patients, do with this information? It is important to realize that we don’t give GBCAs for every MRI scan – each case is evaluated on an individual basis taking into account the potential benefits and risks. The benefits of GBCAs, simply put, are that they give us better images of abnormalities in the brain; the reason for this is that they penetrate the barrier between the blood vessels and the brain if there is a problem with the barrier, which is what we see in many people with neurological disease. Our ability to detect these problems is reduced by not using GBCAs. In the setting of multiple sclerosis, this is particularly important to evaluate the activity of the disease at a given time, as well as to exclude other potential causes for symptoms. 

Clearly, the benefit/risk consideration is now slightly different due to the introduction of a theoretical risk from gadolinium deposition, and should continue to be assessed on an individual case basis. But the multiple studies performed thus far, including large-scale population studies [3], have not shown any functional deficit related to the areas affected by the gadolinium deposition (the dentate nucleus and globus pallidus, which are primarily involved in the initiation and control of movement), or indeed any evidence of harm that can be directly linked to the deposition. 

My interpretation of the current evidence as a radiologist, particularly the ISMRM guidance [1] and the FDA safety statement [4], is this:
1. In the vast majority of contexts in which we give GBCAs, the benefits will outweigh these theoretical risks. Important treatment decisions are made based on these MRI scans, and these decisions are significantly better informed by our use of GBCAs, and thus more likely to lead to better outcomes for people with neurological disease.
2. This doesn’t mean we should dismiss these potential risks. On the contrary, we should seek further evidence on long term outcomes, find out the mechanism of gadolinium deposition, and design and use newer agents to prevent it if proved to be harmful.
3. We should also always be looking for other ways to image safely – researchers are already investigating other imaging techniques which could be used in future to avoid contrast administration [5].

Of course these findings are anxiety-provoking for people undergoing MRI scans, and it is important not to offer false reassurance; however, we should also not allow people to come to more harm as a result of avoiding a test that may be of significant benefit.

For those interested in further information, I recommend reading the recent ISMRM guidance statement [1] and the US Food & Drug Administration Drug Safety Communication [5], both of which are available for free online."


References
1. Gulani et al. (2017) Gadolinium Deposition in the Brain: Summary of Evidence and Recommendations. Lancet Neurol 16:564-70. Available at: http://www.ismrm.org/ismrm-position-paper-on-gd-deposition/
2. Kanal et al. (2014) Gadolinium contrast agents for CNS imaging: current concepts and clinical evidence. AJNR 35:2215-26.
3. Welk et al. (2016) Association Between Gadolinium Contrast Exposure and the Risk of Parkinsonism. JAMA 316:96-9.
4. FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm559007.htm
5. Gupta et al. (2017) The Use of Noncontrast Quantitative MRI to Detect Gadolinium-Enhancing Multiple Sclerosis Brain Lesions: A Systematic Review and Meta-Analysis. AJNR 38:1317-22.

Tuesday, 25 July 2017

Seizures in MS - what we don't know

Brain Behav. 2017 May 24;7(7):e00726. doi: 10.1002/brb3.726. eCollection 2017 Jul.

Unprovoked seizures in multiple sclerosis: Why are they rare?

Kavčič A, Hofmann WE.


Abstract

INTRODUCTION:

The frequency of seizures in patients with multiple sclerosis (MS) ranges from 1.5% to 7.8% and is considerably more common than chance events. The etiopathogenesis of seizures in MS is still poorly understood.

METHOD:

A review of the literature on seizures and MS using PubMed.

RESULTS:

Cortical gray matter involvement appears to be an all-too-common pathological finding in MS to play a primary role in the pathogenesis of seizures in MS patients. There is no clear relationship between seizures and the severity of MS. In approximately 10% of cases, a seizure is actually an initial neurological symptom of MS.

CONCLUSION:

Searching for coherence in the occurrence of unprovoked seizures in MS directs attention to the dichotomy in MS pathology characterized by a complex intertwining of neuroinflammatory and neurodegenerative processes. The appearance (or nonappearance) of seizures in MS in relation to disease activity and disease progression indicates a distinct clinical phenotype of MS that opens up new perspectives in MS research.


Despite our vast knowledge and understanding of MS, there are vexingly the unknown knowns about the simplest things in MS. We can only know that we know nothing about something; and sadly this is the only thing we know anything about! The occurrence and cause of seizures in MS is one such example.

From a logical perspective, seizures in MS should either be a reflection of more severe disease (like in other neurological disorders, such as brain tumours and Alzheimer's disease) or an indication of an above threshold occurrence of cortical involvement (the potion of the brain that houses the nerve center and a focal point of seizure onset). This is neither the case. 

Here Kavčič and Kofmann, after reviewing a series of publications on seizures in MS report exactly this. They note that despite the rarity of incidence of MS, the frequency of seizure presentations varies between 1.5-7.8%, a number which is more than what would be expected by chance alone (the background rate of seizure occurrence in the general population is 3%). However, in overall terms the frequency is still rarer than the degree of involvement of the cortex of the brain by MS. Moreover, in the most severe cases of MS, you're not guaranteed to have seizures, and conversely, seizures are not a sign of severe MS. Whilst in around 10% of early MS cases, seizures are sometimes the presenting feature!

So, the aetiology of seizures in MS is something of a mystery. Is it because in MS there is significant reserve in the brain which is playing a contributory role? Or, is it that the neurodegenerative process paradoxically diminishes the neural network hyper-excitability in MS and hence, seizure occurrence?

Monday, 24 July 2017

#GuestPost: taking the MS Society to task

Has the MS Society been caught navel gazing? #GuestPost 

I have in the past criticised the MS Society over various issues. It was therefore surprising when one of our patients complained to me about them as well. I think the issue he has raised is important enough to be discussed in public and I therefore asked him to prepare a guest post.  


MS Society. Together we walk

On 24th September 2017 the MS Society is organising a sponsored walk. On their website they state ‘This September hundreds of MS Superstars, our friends and families, will join forces in London to take in the sights and raise funds to stop MS. Will you join us?’

There will be walks of 3 different lengths, 6km, 10 km and 20 km. The two shorter walks are fully accessible

In October 2016 the MS Society published the following:

Exercise is known to have a positive impact in MS. As well as promoting general health, research has found that exercise can help manage fatigue and improve quality of life for people with MS. It can also improve particular MS symptoms, including cognitive changes, balance and walking.

So we are all agreed that exercise can help people with MS. The MS Society is organising a walk and they would like people to be sponsored and raise money for the MS Society.

I have one significant issue with ‘Together we walk’; I really enjoy taking exercise but I will be unable to participate. I suffer from secondary progressive multiple sclerosis and one of the problems of my MS is that I have serious foot drop. I cannot walk unaided. It takes me about 45 minutes to walk 1km which is my limit and I must use a rollator.

There are plenty of people with progressive MS who suffer from mobility issues and would love to take part in the walk. As well as participating they would like to achieve a goal. The sense of satisfaction in achieving a goal cannot be underestimated.

Surely it cannot be too difficult to organise walks of say 1km and 500m. This would allow people like me who suffer from progressive MS and have serious mobility issues to participate. We can raise money for the MS Society and achieve a goal. This is a win-win for everyone.

Yes I could go on my mobility scooter and complete a distance of between 6 and 20 km but that is not a challenge. Where is the sense of achievement?

Why has the MS Society taken it upon itself to discriminate against people who would like to raise money for the MS Society but are physically unable to walk more than a short distance? Why can’t I join in with the walk, be sponsored for walking an agreed distance?



I am Patrick Burke, I was diagnosed with RRMS in 1995 but I believe the symptoms started in 1972.The disease turned into SPMS in about 1999/2000. I took medical retirement in 2012 and setup the website Aid4Disabled in the same year. The website is the story of my MS since retirement and it also identifies a wide range of objects that are readily available and can improve quality of life. I am also a member of the Barts MS Advisory Group.


CoI: None

Sunday, 23 July 2017

EBV and Vitamin D..reducing antibodies

Rolf L, Muris AH, Mathias A, Du Pasquier R, Koneczny I, Disanto G, Kuhle J, Ramagopalan S, Damoiseaux J, Smolders J, Hupperts R. Exploring the effect of vitamin D3 supplementation on the anti-EBV antibody response in relapsing-remitting multiple sclerosis. Mult Scler. 2017:1352458517722646. 

BACKGROUND:Epstein-Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis(MS).
OBJECTIVES:To investigate the effect of high-dose vitamin D3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti-EBNA-1 antibody levels.
METHODS:This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D3 (14,000 IU/day; n = 30) or placebo ( n = 23) over 48 weeks. Circulating levels of 25-hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti-cytomegalovirus (CMV) antibodies were measured. EBV load in leukocytes, EBV-specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored.
RESULTS:The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D3 group (526 (368-1683) to 455 (380-1148) U/mL) compared to the placebo group (432 (351-1280) to 429 (297-1290) U/mL; p = 0.023). EBV load and cytotoxic T-cell responses were unaffected. Anti-EBNA-1 antibody levels remained below detection limits in B-cell cultures.
CONCLUSION:High-dose vitamin D3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.
As ProfG sits on a beach pondering the "meaning of MS", does this study hit the jackpot,?

It has vitamin D and EBV as two things close to his heart as the centre of MS susceptibility. 

What does this study  say? 

It is a trial of vitamin D supplementation and they look at EBV antibody levels and find that if you supplement with vitamin D the levels of of antibodies against parts of the EBV virus go down. 

However, this has no impact on viral load. They then conclude this result does not implicate a promoted immune response against EBV.

Whilst ProfG contemplates whats this means, I ask what is the relevant biology here?

The implication is that vitamin D has an impact in utero (in the womb) and perhaps shapes the immune response in early life. This is what is implicated from studies in type 1 diabetes. EBV is a trigger factor when it infects someone years later. 

Now I can go with the flow that studying the effect of vitamin D supplementation,decades after birth, has impact. This idea has caused a myriad of clinical studies in all sorts of conditions, many outside MS. The charities are shelling out loads of cash investigating this, in response to the interest whipped up by the Docs doing the trials. However,  this study highlights one of the problems I have with the vitamin D brigade and the clinical fraternity.

This is a trial involving 53 people. 

What is this really going to tell us about vitamin D?

It is hopelessly underpowered to tell us much and certainly can't tell us whether vitamin D impacts on MS. A P value = 0.023 so about a 1 in fifty chance that this occurs by chance. It will need repeating...another unpowered trial:-(

It is just like the omega oils...lots of useless small trials giving no answers.

They give a whiff of something but are never big enough to give a useful answer about the benefit or lack of it, and we will be supplementing forever so H& B (vitamin Shop) are happy. 

How many individual trials are being funded on vitamin D?.

I suspect that in MSm vitamin D will not be a very good immune modulator, if it was great you would have all sorts of side effects....you don't... so don't expect the earth. Can it be of benefit, sure it can and you need to ensure good bone health.


Saturday, 22 July 2017

#ResearchSpeak: are you a drinker?

What is the evidence that alcohol is good for you? #ResearchSpeak #MSBlog

The following study implies that moderate alcohol consumption is associated with lower disability and suggest red wine is good for you. However, moderate red wine consumption (1-3 glasses per week) was associated with a faster increased in MRI T2 lesion volume, i.e. focal MRI activity. How do we square this circle? We don't the results are not that convincing and suggest an association. In other words alcohol drinking may be associated with other factors that are actually responsible for the lower levels of disability. The association with red wine drinking looks like a false positive and the positive spin in this article could be due a framing effect based on the marketing of red wine as an anti-ageing agent. A framing effect is the interpretation of results in a particular way based on a bias (frame) that has been established by past experiences or prior knowledge. 


There has been work done on resveratrol, an anti-oxidant, in red wine as an anti-ageing, and neuroprotective, compound. The problem is that the amount of resveratrol you get from drinking red wine is too low to have much biological impact. Despite this the French wine industry has managed to get the message across that red wine is good for you.

This paper must be balanced against the literature showing how bad excessive alcohol intake is for your health overall. More recently excessive, and even moderate, alcohol consumption has also been shown to reduce cognition. 

I must point out that the levels of consumption of alcohol studied in this paper are quite low. This study in not going to alter my practice and I will continue to recommend that if you choose to drink please do so in moderation and if you choose to be teetotal that is also fine. The evidence that alcohol is neuroprotective is very weak. We need well designed and larger studies to control for con-founders before making any unrealistic claims about the benefits of alcohol to pwMS. 

Diaz-Cruza et al. The effect of alcohol and red wine consumption on clinical and MRI outcomes in multiple sclerosis. Multiple Sclerosis and Related Disorders. Volume 17, October 2017, Pages 47-53.

Background: Alcohol and in particular red wine have both immunomodulatory and neuroprotective properties, and may exert an effect on the disease course of multiple sclerosis (MS).

Objective: To assess the association between alcohol and red wine consumption and MS course.

Methods: MS patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) who completed a self-administered questionnaire about their past year drinking habits at a single time point were included in the study. Alcohol and red wine consumption were measured as servings/week. The primary outcome was the Expanded Disability Status Scale (EDSS) at the time of the questionnaire. Secondary clinical outcomes were the Multiple Sclerosis Severity Score (MSSS) and number of relapses in the year before the questionnaire. Secondary MRI outcomes included brain parenchymal fraction and T2 hyperintense lesion volume (T2LV). Appropriate regression models were used to test the association of alcohol and red wine intake on clinical and MRI outcomes. All analyses were controlled for sex, age, body mass index, disease phenotype (relapsing vs. progressive), the proportion of time on disease modifying therapy during the previous year, smoking exposure, and disease duration. In the models for the MRI outcomes, analyses were also adjusted for acquisition protocol.

Results: 923 patients (74% females, mean age 47 ± 11 years, mean disease duration 14 ± 9 years) were included in the analysis. Compared to abstainers, patients drinking more than 4 drinks per week had a higher likelihood of a lower EDSS score (OR, 0.41; p = 0.0001) and lower MSSS (mean difference, − 1.753; p = 0.002) at the time of the questionnaire. Similarly, patients drinking more than 3 glasses of red wine per week had greater odds of a lower EDSS (OR, 0.49; p = 0.0005) and lower MSSS (mean difference, − 0.705; p = 0.0007) compared to nondrinkers. However, a faster increase in T2LV was observed in patients consuming 1–3 glasses of red wine per week compared to nondrinkers.

Conclusions: Higher total alcohol and red wine intake were associated with a lower cross-sectional level of neurologic disability in MS patients but increased T2LV accumulation. Further studies should explore a potential cause-effect neuroprotective relationship, as well as the underlying biological mechanisms.


CoI: I am wine lover.

Mouse Flu is it really informative about Man Flu

Blackmore S, Hernandez J, Juda M, Ryder E, Freund GG, Johnson RW, Steelman AJ. Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2017. pii: 201620415

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.


So here we have a mouse stuffed full of T cells waiting to attack the spinal cord and optic nerve and you do nothing and 5% get disease, you stimulate their T cells with the toxin from whooping cough and 100% get disease and here you give a live virus and about 30% get disease. They give a normal mice the flu and they find changes in the genes in the brain suggestive some cellular activation and say a cytokine is involved.. However if they had done anything to stimulate the T cells they would get disease and so the inference in that the paper that flu is a trigger of MS fails down. 

Friday, 21 July 2017

Sorry I messed up

I have to apologise but I was immersed in the World Para Athletics 2017 and the Last Leg and was supposed to launch your comments but deleted them by pressing the wrong button by mistake, so if you have the comments please submit again.

Autoimmunity in MS: Neurofilament light

Puentes F, van der Star BJ, Boomkamp SD, Kipp M, Boon L, Bosca I, Raffel J, Gnanapavan S, van der Valk P, Stephenson J, Barnett SC, Baker D, Amor S. Neurofilament Light as an Immune Target for Pathogenic Antibodies. Immunology. 2017. doi: 10.1111/imm.12797. [Epub ahead of print]

Antibodies to neuronal antigens are associated with many neurological diseases including paraneoplastic neurological disorders, epilepsy, amyotrophic lateral sclerosis and multiple sclerosis. Immunisation with neuronal antigens such as neurofilament light NF-L, a neuronal intermediate filament in axons, has been shown to induce neurological disease and spasticity in mice. Also, while antibodies to NF-L are widely used as surrogate biomarkers of axonal injury in amyotrophic lateral sclerosis and multiple sclerosis, it remains to be elucidated if antibodies to NF-L contribute to neurodegeneration and neurological disease. To address this, we examined the pathogenic role of antibodies directed to NF-L in vitro using spinal cord co-cultures and in vivo in experimental autoimmune encephalomyelitis (EAE) and optic neuritis animal models of multiple sclerosis. Here we show that peripheral injections of antibodies to NF-L augmented clinical signs of neurological disease in acute EAE, increased retinal ganglion cell loss in experimental optic neuritis and induced neurological signs following intracerebral injection into control mice. The pathogenicity of antibodies to NF-L was also observed in spinal cord co-cultures where axonal loss was induced. Taken together, our results reveal that as well as acting as reliable biomarkers of neuronal damage, antibodies to NF-L exacerbate neurological disease, suggesting that antibodies to NF-L generated during disease may also be pathogenic and play a role in the progression of neurodegeneration.

When nerves are damaged they breakdown and release their contents and these products are measured as a marker of disease activity. However, it is clear that neurofilament directed antibodies are generated to clear up these breakdown products. 

We have shown that if you cause the antibodies to be produced in mice that they can cause neurological problems. 

This study shows that these antibodies, however can be potentially damaging and so clearly shows there is autoimmunity occurring in MS. In this study neurofilament specific antibodies were injected into animals and it made EAE worst, once T cells had opened the blood brain barrier to allow the antibody to enter the brain. This was not surprising as this has been shown with a number of antibodies. More surprisingly when injected directly into the brain these antibodies caused signs of disease. It was surprising because neurofilament is inside a nerve and so would not be easily assessable.  The signs occurring were very different to the signs occurring when antibodies targeting basal ganglia from a person with a tic disease was injected into the brain. 

These neurofilment directed antibodies can kill nerves and so could contribute to damage in MS.

CoI. This is work bt TeamG

#GuestPost & #NewsSpeak: feedback from the MS-Chariot meeting

An MSer's perspective the MS-Chariot meeting. #GuestPost #ThinkHand #MSChariot

Last week, I attended the first MS Chariot meeting at St Barts. Around the table were about twenty of us - mostly neurologists from the UK and abroad, health researchers, an MS Society  representative and a few of us MSers - all there to discuss the possibilities, funding, treatments and yes - frustrations - of those with advanced MS who have traditionally been overlooked in the quest for disease modifying drugs.

This was made all the more apparent at the start of the day when Craig Milverton sat down at a piano and began playing a handful of songs by George Gershwin, Cole Porter and other jazz greats.

Playing is the key word here.

You see in 2010, the very year Milverton was named Jazz Pianist of the Year, he was diagnosed with PPMS. With each passing month, his symptoms got worse. His walking deteriorated, his fingers became more and more numb and he began missing notes on the piano. His career as a pianist was over, he thought.


Then in 2012 he was able to get on ocrelizumab - an experimental drug currently being assessed for drug licensing by the EMA for RRMS and PPMS. Almost immediately after his first infusion he started to feel better. Since then, his symptoms have stabilised and he has been able to continue playing across the country.

Craig is one of the lucky ones. Until very recently, it was thought that a person with advanced  MS - with an EDSS score above 5.5 and requiring a walking aid - would not benefit from a disease modifying treatment (DMT). It was not quite “Diagnosis and Adios,” but pretty close.

Why? Selective interpretation of trial data, too much focus on EDSS scores as a key outcome, a belief immunotherapy did not work “beyond the wheelchair,” regulatory process, cost and numbers. Advanced MS is uncommon. Only 10-15% of MSers are initially diagnosed with it.

Such a belief also meant that for those with advanced MS preserving upper limb function was not seen as a priority. But if you think about it, what keeps pwMS independent is their arms and hands. When you lose the ability to walk - that is bad enough. But at least with your hands, you are able to get into your wheelchair, dress yourself, clean your teeth, feed yourself, make a telephone call, use a keyboard, self-catheterize, work a remote control… Lose that and your quality of life plummets.

Thankfully this mindset is starting to change. “At the moment, there are no established options for advanced MS, but emerging therapies are offering hope,” said Cris Constantinescu, a neurologist from Nottingham University, to the group.

For Dr. Klaus Schmierer, a neurologist at St Barts who organised the forum, real promise lies in cladribine, a drug traditionally used for the past 25 years to treat hairy cell leukemia, but which has also proved to be highly effective in treating RRMS. As an MS drug, it has many advantages. It is safe, easy to use, convenient - it is an injectable but also comes in tablet form -  and cheap as it is a generic drug.

Intriguingly, there is also evidence, dating from the early 1990’s, that cladribine may also slow advanced MS. At the moment, about one hundred patients at the Royal London Hospital with advanced MS - who have failed other therapies - are using it and finding it effective. “It meets the needs of some patients for whom we have little to offer,” says Schmierer. But definitive trials are lacking, a source of frustration for Schmierer, who is currently looking for funding.

Another MS drug which offers hope is rituximab, an injectable, which works in a similar fashion to ocrelizumab.  Though the NHS has declined to fund rituximab for the treatment of MS in the UK - citing insufficient trial results - Swedish neurologists have been using the drug for RRMS and advanced MS for more than a decade. “It fulfilled an unmet need and there were fewer options available for advanced MS,” said Frederik Piehl, a neurologist from the Karolinska Institute. In Sweden, he said rituximab has been found to have been highly effective and well tolerated. However in the UK, neurologists are not allowed to prescribe it for their patients.

By the end of the day, it had become apparent that there were no one-off easy answers regarding treatment options for those with advanced MS. The challenging nature of treating MS, plus wrangles over drug licensing, potential funding and drug company priorities ensures this However there was a feeling that, at least, attention is finally being focused on those with advanced MS who might have been previously ignored. Studies have shown - and as Craig Milverton apply demonstrated - advanced MS is modifiable. Now it is key to get the rest of the community on board.

As Aisling McMahon, head of clinical research at the MS Society, said: “We are very aware that progressive MS is the greatest area of unmet need.”

RMH

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