Tuesday, 22 August 2017

A bygone era: AZA, MTX, CYC increase cancer risk in MS

BMC Neurol. 2017 Aug 8;17(1):155. doi: 10.1186/s12883-017-0932-0.

Association between multiple sclerosis, cancer risk, and immunosuppressant treatment: a cohort study.

Ragonese P, Aridon P, Vazzoler G, Mazzola MA, Lo Re V, Lo Re M, Realmuto S, Alessi S, D'Amelio M, Savettieri G, Salemi G.

Abstract

BACKGROUND:

The association between multiple sclerosis (MS) and cancer has long been investigated with conflicting results. Several reports suggest an increased cancer risk among MS patients treated with immunosuppressant (IS) drugs.

METHODS:

We performed a cohort study including MS patients recruited at the Neurological Department of the University of Palermo. Mean follow-up period was ten years for the whole cohort. We calculated cancer incidence among patients treated with IS. Incidence rates were compared in the cohort by calculating the relative risk according to length and dose of exposure to IS. Cancer incidence among MS patients was compared to cancer incidence in the general population of Sicily in similar age groups.

RESULTS:

On an overall cohort of 531 MS patients (346 women and 185 men) exposed to IS, we estimated a crude incidence rate for cancer of 2.26% (2.02% in women, 2.7% in men). Cancer risk was higher compared to rates observed among an equal number of patients not exposed to IS, and to the risk in the general population in Sicily at similar age groups (adjusted HR: 11.05; CI 1.67-73.3; p = 0.013).

CONCLUSION:

The present study showed a higher cancer risk in MS patients associated only to previous IS exposure. Studies on long-term outcomes are essential to evaluate the possibility that treatment options that need to be considered for a long time-period may modify risk for life threatening diseases.


The association between MS therapies and cancer risk is neither simple nor clear cut. However, context is all, and cancer is undoubtedly the single most important thing in a person's life - not too banal to be buried under some statistic or to exercise tolerance over...And yet our understanding of it has not improved. A work in progress.

Here, Ragonese et al., report that simply having MS does not increase your cancer risk. Although, other epidemiological research have alluded to a link based on the type of cancer. The authors, however did note an increase cancer risk in those who took the older immunosuppressant drugs - azathioprine (AZA), mitoxantrone (MTX) and cyclophosphamide (CYC); compared to age-adjusted controls (hazard ratio 11.05; 95% CI 1.67-73.3). This risk appears to be largely driven by AZA and MTX, rather than CYC where no cancers were observed (although the group receiving CYC was small and the follow up was not as long as for the other drugs). The average treatment period was 5y for AZA and 1y for MTX, but this alone led to a 4-fold increase in cancer. With MTX, the association was with leukaemia, which is a known risk of the drug. We no longer use AZA/MTX in MS, but continue to do so in neuromyelitis optica, sarcoidosis, for example, and as such should be more cautious over their long-term use. Improved surveillance programmes may be the answer.

Unfortunatly, this work does not look at the newer agents (Copaxone, Interferons, and monoclonal antibody therapies). Again, the data on this from other studies are conflicting, and it's not certain whether these drugs are exposing an intrinsic cancer susceptibility in MS.

In summary, cancer risk from immunosuppressant use is a realistic one. It is a debate worth having. Make it your agenda for this year and the next.

Monday, 21 August 2017

In Top 50 MS blogs


Got Email to say we are in top 50 MS blogs.....Ta.....However no links to their website even from the picture..So you'll have to guess who ;-)

Gene expression is controlled in MS the effect of Carbon and hydrogen

Pinto-Medel MJ, Oliver-Martos B, Urbaneja-Romero P, Hurtado-Guerrero I, Ortega-Pinazo J, Serrano-Castro P, Fernández Ó, Leyva L.Global methylation correlates with clinical status in multiple sclerosis patients in the first year of IFNbeta treatment.
Sci Rep. 2017;7(1):8727.


The alteration of DNA methylation patterns are a key component of disease onset and/or progression. Our objective was to evaluate the differences in Long Interspersed Nuclear Element-1 (LINE-1) methylation levels, as a surrogate marker of global DNA methylation, between multiple sclerosis (MS) patients and healthy controls. In addition, we assessed the association of LINE-1 methylation with clinical disease activity in patients treated with IFNbeta (IFNβ). We found that individuals with high levels of LINE-1 methylation showed 6-fold increased risk of suffering MS. Additionally, treated MS patients who bear high LINE-1 methylation levels had an 11-fold increased risk of clinical activity. Moreover, a negative correlation between treatment duration and percentage of LINE-1 methylation, that was statistically significant exclusively in the group of patients without clinical activity, was observed. Our data suggest that in MS patients, a slight global DNA hypermethylation occurs that may be related to the pathophysiology of the disease. In addition, global DNA methylation levels could play a role as a biomarker for the differential clinical response to IFNβ.

So in this study it implicates hypermethylation as a problemChomyk AM, Volsko C, Tripathi A, Deckard SA, Trapp BD, Fox RJ, Dutta R.DNA methylation in demyelinated multiple sclerosis hippocampus.Sci Rep. 2017 ;7(1):8696

Multiple Sclerosis (MS) is an immune-mediated demyelinating disease of the human central nervous system (CNS). Memory impairments and hippocampal demyelination are common features in MS patients. Our previous data have shown that demyelination alters neuronal gene expression in the hippocampus. DNA methylation is a common epigenetic modifier of gene expression. In this study, we investigated whether DNA methylation is altered in MS hippocampus following demyelination. Our results show that mRNA levels of DNA methyltransferase were increased in demyelinated MS hippocampus, while de-methylation enzymes were decreased. Comparative methylation profiling identify hypo-methylation within upstream sequences of 6 genes and hyper-methylation of 10 genes in demyelinated MS hippocampus. Genes identified in the current study were also validated in an independent microarray dataset generated from MS hippocampus. Independent validation using RT-PCR revealed that DNA methylation inversely correlated with mRNA levels of the candidate genes. Queries across cell-specific databases revealed that a majority of the candidate genes are expressed by astrocytes and neurons in mouse and human CNS. Taken together, our results expands the list of genes previously identified in MS hippocampus and establish DNA methylation as a mechanism of altered gene expression in MS hippocampus.


In this study some genes are methylated others are not

Methylation is the addition of a methyl group which is one carbon atom and three hydrogen atoms




DNA contains combinations of four nucleotides which include cytosine, guanine, thymine and adenine. DNA methylation refers to the addition of a methyl (CH3) group to the DNA strand itself, often to the fifth carbon atom of a cytosine ring. This conversion of cytosine bases to 5-methylcytosine is catalysed by DNA methyltransferases (DNMTs). These modified cytosine residues usually lie next to a guanine base (CpG methylation) and the result is two methylated cytosines positioned diagonally to each other on opposite strands of DNA.

Different DNMTs work together either as nw DNMTs, establishing the methyl group pattern on a sequence of DNA or as maintenance DNMTs that copy the methylation pattern on an existing strand of DNA to its new partner following replication. Methylation is sparse but global in mammals, found in CpG sequences across the entire genome, aside from certain stretches (of around one kilobase) where the content of CpG is high (CpG islands). When those sequences are methylated, the result can be silencing of gene.
This also enables the expression of retroviral genes to be suppressed, 

What does it all mean, i don't know at present but this is a way that gene function can be altered.





Sunday, 20 August 2017

Do Marmosets hold the answer to understanding the role of EBV virus

't Hart BA, Jagessar SA, Haanstra K, Verschoor E, Laman JD, Kap YS. The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple Sclerosis. Front Immunol. 2013 Jun 13;4:145

The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the role of CD20+ B cells in a unique experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. We will also discuss the relevance of these data for MS. Different from rodent EAE models, but similar to MS, disease progression in marmosets can develop independent of autoantibodies. Progressive disease is mediated by MHC class Ib (Caja-E) restricted cytotoxic T cells, which are activated by γ-herpesvirus-infected B cells and cause widespread demyelination of cortical gray matter. B-cell directed monoclonal antibody therapies (anti-CD20 versus anti-BLyS and anti-APRIL) have a variable effect on EAE progression, which we found associated with variable depletion of the Epstein Barr virus (EBV)-like γ-herpesvirus CalHV3 from lymphoid organs. These findings support an important pathogenic role of CD20+ B cell in MS, especially of the subset infected with EBV.


MS is a uniquely human disease, but we have been modeling it in animals for years. Anti-CD20 antibodies made people stop and think. We have reported that anti-CD20 and all effective agents deplete memory B cells. This could be depleting the viral reservoir of MS as EBV infects CD21 expressing B cells and this virus drives then down the memory cell lineage.

EBV is largely unique to humans but there are some non-human primates that have a similar herpes virus, one such animal is the marmoset, which I first encountered when it was being used in Burkitt's Lymphoma-related research. Indeed marmosets have their own EBV-like virus. 

What does it do in the marmosets? Is it pathogenic or is co-evolved.
Do marmosets get spontaneous MS?

I don't think they do, but  stand to be corrected, but they do get EAE.

For many, many years the TH1/Th17 CD4 brigade had ruled the roost, shaping ideas on MS pathology and treatment. However, looking at MS and the response to therapy did not support this view. Both rodent relapsing EAE and the Marmoset treated late questioned the importance of IL12/IL23, but the T cell brigade ploughed on did the trial in MS which failed. In our hands CD20 in rodents doesn't do too much, in marmosets it is much more effective  and dropped the Marmoset-EBV virus. Blocking APRIL (B cell growth factor) increased the virus but also blocked EAE, however in MS blocking APRIL, made MS worse. Was this because it made more virus or memory cells?

To date it suggested that EBV-infected B cells present antigen to T cells and CD8 drive progressive disease. Will this drive a trial of CD8 depletion?  Will this work or will it make MS worse, as Prof Pender has shown anti-viral CD8 T cells are being used to treat MS.

Dental Bacteria suppressing EAE still not the right info for microbiome transplants..Keep brushing your teeth.

Mangalam A, Shahi SK, Luckey D, Karau M, Marietta E, Luo N, Choung RS, Ju J, Sompallae R, Gibson-Corley K, Patel R, Rodriguez M, David C, Taneja V, Murray J. Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease. Cell Rep. 2017 Aug 8;20(6):1269-1277. doi: 10.1016/j.celrep.2017.07.031.

The human gut is colonized by a large number of microorganisms (∼100 million, million bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4+FoxP3+ regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS.

Prevotella histicola are Gram-negative bacilli that are obligately anaerobic, vary in pigmentation and are non-motile. Prevotella histicola is found in the mucosal tissues of the human oral cavity and is considered a normal flora of the human oral microbiota.

Prevotella histicola is found living in the dental plaque of the mouth. Dental plaque is simply the colonization of a microbial community on the teeth in the form of a biofilm. Dental plaque is thought to be beneficial to the host as it may aid in fighting off pathogens. It also may contribute to pathogenesis.


But before you give up getting your teeth cleans, remember this is a mouse study and the same group did a study in mouse arthritis last year and came to the same conclusion. We would need to know what this bacteria does in other species importantly in humans.



Saturday, 19 August 2017

Prognosis Spinal attacks from onset

Tiftikcioglu BI, Ilgezdi I, Zorlu Y, Sener U, Tokucoglu F. Long-term disability and progression in spinal onset multiple sclerosis. Acta Neurol Belg. 2017 Aug 10. doi: 10.1007/s13760-017-0828-1. [Epub ahead of print]

The aim of this study is to investigate the long-term effects of the initial spinal cord (SC) involvement in MS patients. In this retrospective, single-center study, 824 patients with definite MS were screened. A total of 348 patients were excluded for ambiguous documentation of the initial relapse, pediatric onset, diagnosis of primary progressive disease, irregular assessments or visits causing doubt on the onset of progression time, and clinical follow-up duration less than 12 months. Eventually, 476 MS patients were included. Data regarding the demographics, initial symptoms, the degree of recovery from the initial relapse, neuroimaging, cerebrospinal fluid analysis, long-term disability, and progression were collected from the medical registry. The mean duration of follow-up was 7.49 ± 5.30 years. The percentage of patients entering the progressive disease course was 23.3 in the whole group. A total of 157 patients (33.0%) had SC involvement during the first clinical relapse. These patients were significantly older at disease onset (31.69 ± 10.18 vs. 29.55 ± 9.49; p = 0.028), had higher rates of progression (32.5 vs. 18.8%; p = 0.001), and had higher disability scores in long-term follow-up (3.41 ± 2.19 vs. 2.62 ± 1.81; p < 0.001). Mean age at the transition of progressive phase was 41.4 ± 11.2 years. The degree of recovery from the initial relapse significantly affected the long-term disability. The poor recovery from the initial relapse was associated with older onset age and higher EDSS scores. Being older than 40 years during MS onset and poor recovery from the initial relapse exerted an increased risk for progression. The initial SC involvement was related to a more severe relapse with less chance of complete recovery and higher risk for progression.


You can read this so I don't think I need to interpret, but it is not surprising that if the lesions are concentrated in the spinal cord then they will impact on disability which is a product of lower limb mobility.

Friday, 18 August 2017

Quality of life is better on effective DMT

Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis.
Dayo Afolabi, Christo Albor, Lukasz Zalewski, Dan R Altmann, David Baker
and Klaus Schmierer. Mult Scler J, August 17, 2017

Abstract
Background: A number of elements of the pivotal ‘cladribine tablets treating multiple sclerosis orally’ (CLARITY) trial have remained unpublished.
Objective: To report the impact of cladribine on health-related quality of life (QoL) in people with relapsing multiple sclerosis (pwRMS).
Methods: QoL data from the phase III trial of two different doses (3.5 and 5.25 mg/kg) of oral cladribine in pwRMS were acquired from the European Medicines Agency through Freedom of Information. Spearman’s rank correlation was used to analyse the relationship between baseline QoL scores and baseline
Expanded Disability Status Scale (EDSS) scores. Responses of the Euro Quality of Life 5 Dimensions (EQ-5D) and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaires were compared between treatment and control groups using univariate analyses of covariance.
Results: In total, n = 5148 EQ-5D responses and n = 894 MSQOL-54 physical, mental health and dimension scores were extracted. Baseline EQ-5D indices correlated with EDSS scores. After 2 years, pwRMS taking 3.5 (p = .001) and 5.25 mg/kg (p = .022) reported significantly improved EQ-5D index scores compared with placebo. Positive, yet non-significant, differences were detected in MSQOL-54 scores between cladribine and placebo.
Conclusion: Analysis of the CLARITY dataset suggests that, over and above its established clinical efficacy, cladribine leads to improved QoL over 96 weeks. ClinicalTrials.gov identifier: NCT00213135.

We maintained our interest in cladribine even after it had been rejected by the EMA in 2011, because its efficacy was impressive, and its adverse effects comparatively minor. We revealed important pathophysiological insights from the cell count data collected during CLARITY, confirmed that the cancer risk of cladribine in pwMS is no different when compared to licensed DMT, and subsequently started using the drug in a select group of pwMS.

Here's further output from our work on cladribine, an analysis of the quality of life data collected during the largest ever trial of the compound in pwMS. Though the data was available since 2010 nobody cared to analyse and publish them, so we did it after receiving the CLARITY dataset from the EMA through freedom of information, and with zero industry support.

Congratulations to Dayo Afolabi BSc, medical student at Cambridge University and Christo Albor PhD, epidemiologist and currently junior doctor at Barts Health NHS Trust for their excellent work, supported by QMUL IT (Lukasz Zalewski) and Dan Altmann, statistician at QMUL, UCL and The London School for Hygiene & Tropical Medicine.

The abstract summarises the results well, however reading the paper you will learn more about various aspects of this project and the potential of the drug. 

Available open access shortly.


CoI: Multiple, however none related to this paper.

The mechanism is more important than the ethics. EAE experiments

Arima Y, Ohki T, Nishikawa N, Higuchi K, Ota M, Tanaka Y, Nio-Kobayashi J, Elfeky M, Sakai R, Mori Y, Kawamoto T, Stofkova A, Sakashita Y, Morimoto Y, Kuwatani M, Iwanaga T, Yoshioka Y, Sakamoto N, Yoshimura A, Takiguchi M, Sakoda S, Prinz M, Kamimura D, Murakami M.Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit.Elife. 2017 Aug 15;6. pii: e25517. doi: 10.7554/eLife.25517

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.



This is the type of post ,where I get called arrogant because I dare to say something not good about science.

However I have to say "not in my name" in public.

As part of public engagement in science, we need to talk about animal experiments. 


I have signed up to this and the UK Government want scientists to be more open about animal studies. 

We can be fluffy and say every thing is amazing but in reality some of it isn't. You know this.

Yes animal experiments are unpleasant, but they can lead to new understanding. 

However, the question at what cost to the animals?

These days virtually all animal experiments have to go through ethical review panels, but sometimes what they support horrifies me. Maybe in the UK, we care too much about our furry friends or maybe people elsewhere don't care enough!

This is a good example. I comment on it so when people click on the altmetrics to this paper, you will come to this blog post. 

This research is being done for people with MS. 
However, do you feel it is relevant to your disease? 

The opening statement says "To examine the impact of stress conditions in a transfer EAE model, we first employed a sleep disorder model, in which continuous stress is imposed on mice on a free rotation wheel for 2 days by the perpetual avoidance of water". They do this by filling the cage with water and make they run on a wheel.

Surely this is torture. Which ethical review panel would think this is OK. What is worse, is when when they transfer cells into the animals it causes death. 

Is it OK to kill animals, when there can be endpoints before this. 

I would have to say no, this does not have 3Rs merit.

The animals were dying and they had bloody stools which surely could have been used as an endpoint at the very least.

The authors say that changes in the circulation in the brain affect intestinal activity and further say vagal nerve activation is involved in the development of the severe gastrointestinal failure triggered by brain micro-inflammation.

However, there is no mention that vagal nerve stimulation in humans has been reported to inhibit autoimmunity so in complete contrast to the human potential reality 

The ARRIVE guidelines by the NC3Rs  asks for the translational value of the study. 

Is there any?

First thing. In the study they applied parametric statistics to non-parametric data and so the explanation of the data in the experiment maybe fatally flawed. It is underpowered as there are not enough animals in a group (such as n = 3) to give any real statistical meaning, using the proper statistrics. 

No wonder the three referees remained anonymous.

Thursday, 17 August 2017

Are MS drugs a waste of time......for progressive MS

Lorscheider J, Jokubaitis VG, Spelman T, Izquierdo G, Lugaresi A, Havrdova E, Horakova D, Trojano M, Duquette P, Girard M, Prat A, Grand'Maison F, Grammond P, Pucci E, Boz C, Sola P, Ferraro D, Spitaleri D, Lechner-Scott J, Terzi M, Van Pesch V, Iuliano G, Bergamaschi R, Ramo-Tello C, Granella F, Oreja-Guevara C, Butzkueven H, Kalincik T; MSBase Study Group. Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS. Neurology. 2017 Aug 9. pii: 10.1212/WNL.0000000000004330. doi: 10.1212/WNL.0000000000004330. [Epub ahead of print]

OBJECTIVE: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).
METHODS: Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.
RESULTS: Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7-1.1, p = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4-1.1, p = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, p = 0.79), or change in disability burden (area under the EDSS-time curve, β = -0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results.
CONCLUSIONS: Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.

I'm back....(What! you didn't notice that I've not been around and that there were slow responses).

I been in the Third World.....................of internet access, with zero email and essentially no access to the web...with even the paid-for "high speed" (yeah right) net.


Where?..........yep you got it........in the USA. 

In a number of National Parks the internet access has been woeful

Who would have thought that a gas (petrol) station in the middle of nowhere, would turn out to be a cyber oasis compared to the dearth for International Travellers.


However, I saw an amazing example of "thinkhand" and why giving access to people in wheelchairs access to treatment to save upper limb function is something we really must do. 


If you look at the picture above you can see on the right of the top of the waterfall there is a platform, which is full of people watching the waterfall. This waterfall is 308 feet (94 metres), where the top is some 600 feet down the canyon.  


I was passed on the way up the canyon, by a hand-driven wheelchair, OK with some help from their partner and encouragement by the kids. They were at the top looking down by the time I got there. Why shouldn't we stop deterioration of loss of hand function.


Anyway more news from the MSBase people and they haven't done a post on this one but it is something the Pharmaceutical nihilists will be shouting out loud about why it is OK to do nothing. This study suggests that use of DMT does not influence the course of secondary progressive MS if used after onset.


ProfG will be sitting on a beach somewhere in the USA pondering what this means for his therapeutic lag idea, but more importantly what it could mean if hand function was the main outcome. 


The take home message of this story is more reason not to use DMT in SPMS. Which is not what we have been saying.

There were about 25% in the untreated ground that had MRI lesions and about 20% in the treated group (so not effectively treated)

However, you can see the (median) follow up was for only two years although it was longer for many people, and when the ASCEND trial of natalizumab looked  and there was no change in EDSS over two years. However if the trial was followed for 3 years then they was an influence. So the follow up in this study may not have been long-enough for the therapeutic lag effect to show itself, (if it existed, which it didn't when it was looked for).

Likewise, I really would like to see if you look at the effect of only highly-effective DMT/HSCT use and subsequent course of MS. Yes, I know that use of CRAB drugs is the real life situation, but the picture is going to be muddied if you include use of CRAB drugs. 

We know progression will often occur because this has already been seen with alemtuzumab and HSCT, but will the rate of decline change? 

H. Pylori: good, bad, ugly, or not quite sure?

Many people think that MS is triggered by exposure to infectious agents in our environment. The most well-known putative trigger is EBV, but there has also been debate surrounding the role of H. Pylori, an enteric pathogen better known for its role in causing peptic ulcers. Epidemiological evidence has been conflicting on whether H. Pylori infection protects against MS, increases the risk of MS, or has no association at all.

A nice new study systematically examined the amounts of anti-H. Pylori antibody in a big cohort of 139 pwMS, 39 pwParkinson's Disease, 21 pwAlzheimer's Disease, and 68 controls without any neurological diseases. The key advantage of this study is that they looked at antibodies against a wide range of H. Pylori antigens, the fragments of the bug exposed to the immune system.

The key findings were:
- Anti-flagellin antibodies were less common in MS than controls. 
- Anti-VacA antibodies were more common in SPMS than controls.
- Anti-p54, anti-p29-UreA and anti-p26 correlated with EDSS.
- Anti-p41, p54-flagellin, p29-UreA, p67-FSH, and p120-CagA were less common in RRMS than control.
- Anti-p26 and anti-p17 correlated with number of relapses.

This is big news - it demonstrates that the antibody response to H. Pylori infection differs between pwMS and controls, between pwRRMS and pwSPMS, and is correlated with disease activity.

How do we interpret this?

There are a few possible explanations. My initial thoughts:
- Exposure to H. Pylori is protective against MS
- Exposure to VacA (a secreted bacterial protein) increases the risk of SPMS
- An underlying problem with immune regulation in people who are at-risk of developing MS affects the immune response to H. Pylori (this could be genetic e.g. MHC polymorphisms, environmental e.g. a consequence of EBV infection, etc...)
- DMTs affect the immune response to H. Pylori
- A combination of some/all of the above!

These don't explain why higher titres of certain anti-H. Pylori antibodies would correlate with disability and relapses. 

In short I'm not quite sure what these data mean but they are certainly interesting. If anti-H. pylori antibodies are protective then vaccination might even be on the cards as a preventative strategy.

Abstract
To assess whether Helicobacter pylori (Hp) antibody (ab) reactivity against individual Hp antigens is pathogenetically relevant to multiple sclerosis (MS), we systematically investigated prevalence and clinical significance of abs against 14 immunodominant and subdominant Hp antigens by ELISA and immunoblotting in 139 consecutive MS patients with relapsing-remitting (RRMS, n = 102) or secondary progressive (SPMS, n = 37). Sera from 39 patients with Parkinson’s disease (PD), 21 with Alzheimer’s disease (ALZ) and 68 healthy controls (HCs), were also tested. Anti-flagellin (18.3%) and anti-p41 (25.0%) abs in MS were less frequent than in HCs (39.4%, 48.5%, respectively). Abs against 5 of the 14 antigens were less frequent in RRMS than HCs, including p41, p54-flagellin, p29-UreA, p67-FSH, and p120-CagA. Anti-VacA abs were more frequent in SPMS than in HCs (42.1 vs 12.1%, p = 0.019). Anti-p54, anti-p29-UreA and anti-p26 correlated with extended disability status scale (EDSS) (p = 0.017, p = 0.005, p = 0.002, respectively). Anti-p26 and anti-p17 correlated with the number of relapses (p = 0.037 and p = 0.047, respectively). This is the first comprehensive analysis of ab reactivities against most Hp antigens in MS patients. Ab responses differ between MS and HCs and between RRMS and SPMS, being more prevalent in SPMS than RRMS, thus suggesting an association between anti-Hp and the former type of MS.

Wednesday, 16 August 2017

Older people do less well



Guillemin F, Baumann C, Epstein J, Kerschen P, Garot T, Mathey G, Debouverie M; LORSEP Group.Older Age at Multiple Sclerosis Onset Is an Independent Factor of Poor Prognosis: A Population-Based Cohort Study.Neuroepidemiology. 2017 Aug 10;48(3-4):179-187.
BACKGROUND:Late-onset multiple sclerosis (LOMS) frequently features a primary progressive (PP) course, strongly predicting severe disability. In this population-based cohort, we estimated the prognostic role of age at multiple sclerosis (MS) onset, independent of PP course, on disability progression.
METHODS:The association of age at disease onset (adult, <50 years [AOMS], vs. late, ≥50 years [LOMS]) and time to Expanded Disability Status Scale (EDSS) score 4 and 6 was estimated by Cox regression modelling.
RESULTS:Among 3,597 patients, 245 had LOMS. Relapsing-remitting (RR) disease was less frequent with LOMS than AOMS (51.8 vs. 90.8%, p < 0.0001). PP course, LOMS and male gender predicted short time to EDSS 4 and 6. Worse outcome with LOMS (time to EDSS 4 and 6, HR 2.0 [95% CI 1.7-2.4] and 2.3 [1.9-2.9]) was independent of PP course or male gender. LOMS had greater impact on RR than PP disease (time to EDSS 4 and 6, HR 3.1 [2.3-4.0] and 4.0 [2.9-5.6]). Only LOMS predicted time from EDSS 4 to 6 (p < 0.0001).
CONCLUSIONS:Late onset MS was strongly associated with poor prognosis, independent of initial disease course, in predicting the disability progression along time.


ProfG has often said that "Age Matters" especially when it relates to brain health. As we age our repair and protective capabilities wane. This study supports this view and the the older you are there less well you do. However this is at a population level and there will be older people who do very well and younger people who do very badly.

Tuesday, 15 August 2017

Alternative solutions - treatment of acute relapse in steroid-unresponsive MS

Int J Mol Sci. 2017 Aug 11;18(8). pii: E1749. doi: 10.3390/ijms18081749.

Treatment of the First Acute Relapse Following Therapeutic Plasma Exchange in Formerly Glucocorticosteroid-Unresponsive Multiple Sclerosis Patients-A Multicenter Study to Evaluate Glucocorticosteroid Responsiveness.

Ehler J, Blechinger S, Rommer PS, Koball S, Mitzner S, Hartung HP, Leutmezer F, Sauer M, Zettl UK.

Abstract


Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS) as first-line and therapeutic plasma exchange (TPE) as second-line treatments in GCS-unresponsive patients. No guidelines exist for the treatment of another relapse following TPE. We retrospectively analyzed the responsiveness to GCS in a subsequent relapse following TPE in previously GCS-unresponsive MS patients. Thirty-seven patients with GCS-unresponsive MS relapses received TPE (relapse A). All patients developed another relapse after the completion of TPE and received GCS again (relapse B). The primary study endpoint was the clinical response to GCS and TPE. Marked improvement was defined as clinically significant improvement in function, moderate improvement as a definite change of symptoms without significant impact on function, no effect comprised unchanged symptoms, and deterioration a worsening of symptoms or new deficits. The secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. All patients were GCS-unresponsive during relapse A and received TPE. During GCS treatment of relapse B, marked improvement was observed in 10, moderate improvement in 24, and no effect in three patients. The EDSS decreased in 15 patients. GCS might remain the first-line relapse treatment following TPE in formerly GCS-unresponsive MS patients.

 Plasma exchange

Like you reading my post today, I too suffer from a little known, but commonplace condition called epistemophilia - meaning to have an insatiable thirst for knowledge. Google, Facebook, Twitter all present facts piecemeal as conclusive statements, but in academia, broadly speaking, the truth of knowledge is based on the strength of evidence.

Many of you know that steroids are used for the treatment of acute relapses, but how many of you knew that there were additional treatment options? Is there a plan B if you do not respond to steroids after a relapse? The answer is a 'yes'. Steroids remain the panacea for a variety of neurological conditions, but at the same time, particularly in inflammatory conditions, doctors have investigated other avenues; including intravenous immunoglobulins and plasma exchange. The latter, is the process of removal of the substrate of the blood, cleansing it of everything floating in it; circulating cytokines, antibodies, complement and immune complexes. Plasma exchange is a second-line option for those who don't respond to steroids. The optimal time period in which to see the peak effect of steroids is 7-10 days after a course, and deemed sub-optimal after 2 weeks. 

In this study, the authors evaluated responsiveness to steroids before and after plasma exchange to see whether subjects remain unresponsive to steroids after plasma exchange in a subsequent relapse or become steroid responsive again. They included 37 steroid-unresponsive subjects. For the first relapse they all received steroids. Only 5 subjects showed moderate improvement after steroids, remainder none. Whilst, follow up plasma exchange for the first relapse showed marked improvement in 12 (32.4%), moderate improvement in 18 (48.7%), and no effect in 7 (18.9%). All 37 subjects experienced a second relapse ~150 days later (range 31-2588 days). Steroids were given to 35/37 subjects, and achieved marked improvement in 10 (27%), moderate improvement in 24 (64.9%), and no effect in 3 (8.1%).

In summary, there is improved steroid responsiveness to the second relapse compared to the first, an interesting statistical difference from a clinical study. This is in part secondary to the use of plasma exchange in the initial relapse (see second set of bars in figure below). 

Mechanistically, steroids induce T cell apoptosis, whereas plasma exchange removes factors that are the paraphernalia of immune response (antibodies, cytokines, immune complexes etc.). This resetting may explain some of the regain in response to steroids at the second relapse. Unfortunately, the investigators didn't measure any biomarkers, so we don't know what changes were taking place at a biological level, which is disappointing. However, it's a study to be done for the future.

Figure: Different response to glucocorticosteroid (GCS) treatment before and after therapeutic plasma exchange (TPE) in 37 clinically isolated syndrome (CIS) and multiple sclerosis (MS) patients. Deterioration was defined as worsened target neurologic deficit or new neurologic symptoms, marked improvement as clinically significant improvement in function, moderate improvement as a definite change of the neurologic deficit without significant impact on function within the functional score, and no effect as unchanged symptoms.

Monday, 14 August 2017

Seeing is B-lieving

The success of B-cell-depleting therapies tells us that B cells play an important role in driving MS. We don't really understand how - they may be producing antibodies targeted against 'self', they may be recruiting other immune players like T lymphocytes and monocytes, or they may be doing both. 

There are many different types of B cell, each of which has a different set of roles in the immune system. 

So a sensible question to ask is whether the numbers and types of B cell present in the CSF - the spinal fluid - can predict the course of the disease.

A new study asked this question by looking at 128 pwMS and 40 people with other neurological disorders as their control group. They took samples of CSF - spinal fluid - and analysed the different subsets of B cells present. They then correlated this information with clinical details such as disease course and MRI findings.  

The numbers of mature B cells and plasmablasts (the precursors to long-lived antibody-secreting plasma cells) were raised in the group of people with bout-onset forms of MS (CIS, RRMS, SPMS) compared to PPMS and the control group. There was no difference in T cell numbers between the groups. 

CSF lymphocyte counts were not predictive of disability progression, conversion from CIS to RRMS.

This is very interesting. It implies that the CSF B cell profile is 'diagnostic' but not 'prognostic'. CSF B cells may be involved in driving relapses or may be a consequence of a 'leaky' blood-brain barrier in relapse-onset disease. What is odd and intriguing is that CSF B cells were not raised in PPMS. Given the success of ocrelizumab - a B cell depleter - in PPMS it is a bit counter-intuitive that this group did not show any evidence of having high CSF B counts. This may be because only two types of B cells, mature and plasmablasts, were examined here. In fact, the number of B lymphocytes in the CSF of the pwPPMS was slightly raised (although not statistically significant) compared to the control group. Given that the control group were also people with neurologic disorders, many of whom would be expected to have a degree of CNS inflammation, we may be missing a genuine difference here. Further studies are needed to examine the CSF of pwPPMS to determine whether there is a selective increase in specific B cell populations, such as the memory B's.


***

Abstract

Background

There is evidence that B cells play an important role in disease pathology of multiple sclerosis (MS). The aim of this prospective observational study was to determine the predictive value of cerebrospinal fluid (CSF) B cell subtypes in disease evolution of patients with MS.

Materials and methods

128 patients were included between 2004 and 2012. Median follow up time was 7.9 years (range 3.3–10.8 years). 10 patients were lost to follow-up. 32 clinically isolated syndrome- (CIS), 25 relapsing remitting MS- (RRMS), 2 secondary progressive MS- (SPMS) and 9 primary progressive MS- (PPMS) patients were included. The control group consisted of 40 patients with other neurological diseases (OND). CSF samples were analyzed for routine diagnostic parameters. B cell phenotypes were characterized by flow cytometry using CD19 and CD138 specific antibodies. Standardized baseline brain MRI was conducted at the time of diagnostic lumbar puncture. Main outcome variables were likelihood of progressive disease course, EDSS progression, conversion to clinical definite MS (CDMS) and relapse rate.

Results

CSF mature B cells (CD19+CD138-) were increased in bout-onset MS compared to PPMS (p<0.05) and OND (p<0.001), whereas plasma blasts (CD19+CD138+) were increased in bout-onset MS (p<0.001) and PPMS (p<0.05) compared to OND. CSF B cells did not predict a progressive disease course, EDSS progression, an increased relapse rate or the conversion to CDMS. Likelihood of progressive disease course (p<0.05) and EDSS (p<0.01) was predicted by higher age at baseline, whereas conversion to CDMS was predicted by a lower age at onset (p<0.01) and the presence of ≥9 MRI T2 lesions (p<0.05).

Conclusion

We detected significant differences in the CSF B cell subsets between different clinical MS subtypes and OND patients. CSF B cells were neither predictive for disease and EDSS progression nor conversion to CDMS after a CIS.

#NeuroSpeak: what do when you have failed a IRT?

Sequencing of DMTs will become increasingly complex. #NeuroSpeak

Somebody asked over the weekend what I would do if someone failed alemtuzumab and had a persistent lymphopaenia. In short it depends on individual factors. 



I have had three patients like this already.

#1: One patient had 5 courses of alemtuzumab and had developed anti-alemtuzumab antibodies and had very little depletion after her last round of treatment. Her disease remained active on MRI (multiple enhancing lesions). Her lymphocyte counts were around 0.9. I recommended rituximab, but as she was hoping to start a family she opted for de-escalation therapy and chose glatiramer acetate. Her neurologist tells me she is doing well on GA. This case illustrates that you don't always have to go upwards in terms of efficacy, you can de-escalate and use a platform therapy after an IRT (immune reconstitution therapy).

#2: The second case failed alemtuzumab therapy at month 17 into her two years of treatment. Interestingly she repopulated rapidly after her second course, i.e. her lymphocyte counts were 0.8 at month 1 and were 0.9 the week before she started her second course of alemtuzumab. I suspect she may be another case of anti-alemtuzumab antibodies. She had previously failed glatiramer acetate. As she was JCV-seronegative she elected to be treated with natalizumab. This patient was offered HSCT, but turned it down when she realised there would be a good chance of her not being able to have children. The haematologist had given her 45-50% chance of going into the premature menopause. She had the option of egg banking, but as her MS active she was not prepared to wait 2 months and go through the relatively stressful, and invasive procedures, of ovarian stimulation and egg harvesting. Then there is the cost of storage.

#3: The third case who I saw last week with her second relapse after her second course of alemtuzumab (month 19). Interestingly, despite having just started natalizumab she still had a relapse. Her lymphocyte count was 0.8. when she started natalizumab. This last relapse came on just 2 weeks after her first infusion of natalizumab. This shows you that almost all DMTs take time to start working and that a relapse takes weeks to evolve. In other words, if you are destined to have a relapse in the next week or two natalizumab will not prevent it from occurring. This patient was also offered daclizumab, but after the recent death due to fulminant hepatotoxicity on daclizumab, she decided to go with natalizumab. Interestingly, this patient has also just developed Graves disease (thyrotoxicosis) so she was hit with a secondary autoimmune complication of alemtuzumab without deriving the long-term benefit of its efficacy. This particular patient would have chosen ocrelizumab, over natalizumab, if it was available. The option of rituximab is not on the table as in the first case as NHS England have stopped us using rituximab to treat MS.

I am hoping to create a ClinicSpeak App that deals with all the issues raised about the sequencing of treatments. The purpose of the App is to help people understand issues such as the ones raised in these case vignettes.


CoI:multiple

Experimental Brains in A Dish

Tan GA, Furber KL, Thangaraj MP, Sobchishin L, Doucette JR, Nazarali AJ. Organotypic Cultures from the Adult CNS: A Novel Model to Study Demyelination and Remyelination Ex Vivo. Cell Mol Neurobiol. 2017 Aug 9. doi: 10.1007/s10571-017-0529-6. [Epub ahead of print]

Experimental models of multiple sclerosis (MS) have significantly advanced our understanding of pathophysiology and therapeutic interventions. Although in vivo rodent models are considered to most closely represent the complex cellular and molecular disease states of the human central nervous system (CNS), these can be costly to maintain and require long timelines. Organotypic slice cultures maintain the cytotypic organization observed in the intact CNS, yet provide many of the experimental advantages of in vitro cell culture models. Cerebellar organotypic cultures have proven useful for studying myelination and remyelination, but this model has only been established using early postnatal tissue. This young brain tissue allows for neuro development ex vivo to mimic the 'mature' CNS; however, there are many differences between postnatal and adult organotypic cultures. This may be particularly relevant to MS, as a major barrier to myelin regeneration is age. This paper describes a modified protocol to study demyelination and remyelination in adult cerebellar tissue, which has been used to demonstrate neuroprotection with omega-3 fatty acids. Thus, adult cerebellar organotypic cultures provide a novel ex vivo platform for screening potential therapies in myelin degeneration and repair.

Much or what we have learned about myelination and nerve development comes from animal studies and using animals shortly  after or before birth when the nervous system is developing. However developmental myelination is not always the same as remyelination. So techniques to show how nerve function and myelination occurs in adults is welcome. Let.s hope this takes off and is useful. Many save on animal use.

#GuestPost & #ClinicSpeak: An MSer's perspective

What does an MS’er look for in their HCP team?

A few weeks ago I was speaking about living with MS to a group of healthcare professionals (HCPs), mostly trainee neurologists and MS nurses. It gave me the opportunity to speak to them about what I look for in an HCP, as a patient who is living with MS. ProfG was in attendance and he asked if I could turn what I said into a guest blog post. So here it is!
*Disclaimer: These are my personal views and I’m fully aware that everyone deals with their diagnosis differently so may look for different things from their HCPs*

Be approachable
It sounds obvious, but the worst thing is to feel that your HCP team aren’t approachable and you’re on your own. Small things like smiling, not clock watching, asking how someone is outside of their MS... they all go towards putting us at ease and building a good relationship. I don’t mind that my neurologist’s clinic often runs late because I know that once I’m in there, he gives me all the time that I need. What would really annoy me is being “pushed out of the door” when my 15 minutes is up regardless of whether I’ve discussed everything I need to discuss.
On the subject of time, remember to give patients time to ask questions. The last thing you need is someone to go home after an appointment and consult Dr. Google. I personally know someone who was given a likely diagnosis of MS, wasn’t told what it is, went home and googled it and managed to convince himself he was dying. Really not helpful for the patient or you!

Be available – keep lines of communication open in a “non-invasive” way
I want to be able to contact my neurology team if I have a concern, especially as I know they’re the experts and not my GP. However, I also know they’re very busy. Rather than taking up a valuable appointment, which might not be necessary, I like having an email contact or mobile number that I can use to speak to my neuro team. Sending an email, text or voicemail means I know I’ll get a response when it’s convenient for them, without feeling like I’m “bothering” a very busy team. Just please remember to respond!

Encourage the expert patient, don’t be afraid of them, especially with shared decision making
Gone are the days when the doctor sits there and tells the patient what to do and the patient just does it, no questions asked. Expert patients are on the increase. I’m one of them. Don’t be afraid of us! We’re not going anywhere and we could make your life easier. I’m able to tell pretty well when something might be my MS or not. That means I contact my neuro team directly, not my GP. That’s more efficient use of time and resources for everyone. Shared-decision making is also much better when a patient is informed. So I’d say encourage patients to be informed and help them to become informed. That way, you can have the confidence that they’re fully aware of the impact of decisions being made about their healthcare.

Be inclusive
An MS patient is often not just one person. It’s a network of people. So, encourage carers, family members and those who have a significant role in the patient’s life to engage with you if necessary. Make the patient aware that they can attend clinic appointments with these people if they’d like.

Mind your language!
Again, it sounds obvious, but I’ve had people contact me after coming out of appointments and ask me to “translate” what their neurologist has told them, especially when it comes to test results. Please use plain language, especially at the time of diagnosis.

Look to your peers – the ones who have patient support, the ones who are leading the way and being innovative.
In the interests of protecting my personal information, I won’t say who my neurologist is, however, when I mention him to other people who have MS their reaction is often “WOW! I wish he was my neurologist. You’re so lucky! That HCP team is fantastic!” These are the HCPs you can learn from. Ask yourself why do their patients like them so much? What are they doing that is setting them apart?

Signpost, signpost, signpost!
You don’t have to know everything and you don’t need to have the time to convey every single bit of information a patient might need to know. But make yourself aware of where they can go for further, reliable information if necessary. The MS Society, MS Trust and MS-UK websites are always good places to start. However, you’d be surprised the number of MS patients I talk to who tell me their neurologist has never mentioned any of these organisations to them. It takes some of the pressure off you so why wouldn’t you do it?!

It’s a consumer market.....
Be aware that as patients we talk to each other, especially with the rise in social media. It’s a consumer market out there. I’ll be honest, if someone isn’t happy with their healthcare team they’ll go onto social media and ask around as to who WILL give them the type of care they want. Then they’ll move to a team that they’re happier with. So if you have patients consistently asking for things that others are getting elsewhere, maybe explore why and how their requests can be fulfilled.

AND FINALLY... Don’t take it personally if you just don’t click with a patient
I want to know that my neurologist is on the same page as me and has the same approach to my healthcare that I do. We’re in this together for the foreseeable future so I want to feel like we’re headed in the same direction. Sometimes there’s just a clash. Don’t take it personally. Life would be boring if we all thought the same, right?


Trishna Bharadia is a multi-award winning advocate for people with multiple sclerosis and chronic illness. Diagnosed with RRMS in 2008, aged 28, she's used her experiences to raise awareness and improve support for people affected by MS and other chronic illnesses. A full-time Spanish-English translator, in her spare time she collaborates with organisations in the UK and abroad, including charities, pharmaceutical firms and nonprofits, to help improve patient experience and engagement. She’s a writer, blogger, vlogger and inspirational/expert patient speaker, as well as advising on projects, research proposals, and diversity strategies, and is a regular contributor in the media for issues relating to MS, chronic illness and disability. She’s a patron/ambassador for several MS/disability charities and is currently a member of “The Ozone” virtual round table for key opinion leaders across healthcare specialties. You can follow her on Twitter @TrishnaBharadia and Facebook www.facebook.com/trishnabharadia2015