Tuesday, 31 March 2015

Another growth factor for oligodendrocytes

Hammond E, Lang J, Maeda Y, Pleasure D, Angus-Hill M, Xu J, Horiuchi M, Deng W, Guo F. The Wnt Effector Transcription Factor 7-Like 2 Positively Regulates Oligodendrocyte Differentiation in a Manner Independent of Wnt/β-Catenin Signaling.J Neurosci. 2015;35:5007-22.

Genetic or pharmacological activation of canonical Wnt/β-catenin signaling inhibits oligodendrocyte differentiation. Transcription factor 7-like 2 (TCF7l2), also known as TCF4, is a Wnt effector induced transiently in the oligodendroglial lineage. A well accepted dogma is that TCF7l2 inhibits oligodendrocyte differentiation through activation of Wnt/β-catenin signaling. We report that TCF7l2 is upregulated transiently in newly differentiated oligodendrocytes. Using in vivo gene conditional ablation, we found surprisingly that TCF7l2 positively regulates neonatal (Before birth) and postnatal (after birth) mouse oligodendrocyte differentiation during developmental myelination and remyelination in a manner independent of the Wnt/β-catenin signaling pathway. We also reveal a novel role of TCF7l2 in repressing a bone morphogenetic protein signaling pathway that is known to inhibit oligodendrocyte differentiation. Thus, our study provides novel data justifying therapeutic attempts to enhance, rather than inhibit, TCF7l2 signaling to overcome arrested oligodendroglial differentiation in multiple sclerosis and other
demyelinating diseases.

The Wnt signaling pathways are a group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. All three Wnt signaling pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the protein Dishevelled inside the cell. The canonical Wnt pathway leads to regulation of gene transcription, the noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell, and the noncanonical Wnt/calcium pathway regulates calcium inside the cell. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across many species of animal from fruit flies to humans.

Wnt signaling was first identified for its role in carcinogenesis, but has since been recognized for its function in embryonic development. The embryonic processes it controls include body axis patterning, cell fate specification, cell proliferation, and cell migration. These processes are necessary for proper formation of important tissues including bone, heart, and muscle. Its role in embryonic development was discovered when genetic mutations in proteins in the Wnt pathway produced abnormal fruit fly embryos. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice.

The clinical importance of this pathway has been demonstrated by mutations that lead to a variety of diseases, including breast and prostate cancer, glioblastoma, type II diabetes, and others.

This study finds yet another pro-myelination factor

Spinal fluid neurofilament levels: effective DMTs stops nerve damage

Spinal neurofilament levels are ready for prime time. #MSBlog #MSResearch

"The following study supports spinal fluid neurofilament levels as surrogate marker of neuroaxonal damage and loss in MS. Levels were raised at baseline and decreased during the study, but it was only significant in MSers on fingolimod. Why did levels drop in MSers on placebo? We call this regression to the mean. When we recruit for clinical trials we select MSers with active MS; this is usually based on relapses in  the last 12-24 months. MSers with recent relapses are more likely to have raised spinal fluid neurofilament levels as their disease has been recently active. These types of MSers are more likely to go into remission hence the slight drop in levels in the placebo arm. However this drop is nowhere near that which occurs with fingolimod; this indicates that fingolimod is reducing ongoing inflammation and damage and is hence protecting the surviving neurones and nerve processes (axons) from ongoing damage. Please note this is a trial in RRMSers. If this was a study in progressive MSers the levels are likely to go down, but are unlikely to be normalised. The latter has been elegantly shown in two studies of natalizumab treatment in SPMS and PPMS. This is why we think that in progressive MS we need to add a neuroprotective drug on top of an anti-inflammatory drug. The latter is what we are attempting to do in the PROXIMUS trial."

"What is not presented in the abstract is the observation that in individual MSers failing fingolimod or placebo, i.e with relapses and/or disease progression, that the spinal fluid neurofilament levels increase. This indicates that spinal fluid neurofilament levels may be a useful marker in individual MSers to ascertain what is happening to their disease and to sort out 'true relapses' from a 'pseudorelapses'. In other words subtle symptoms, without new neurological signs, in the absence of raised spinal neurofilament levels would indicate that the symptoms were  unlikely to be due to a significant new MS lesion. I think we should study the latter in a formal prospective study. What do you think?"  

Blue=Paranodal loops, Orange=microtubules, Green=neurofilaments, Magenta=mitochondria, Red=cross bridges and Yellow=septate junctions.

Epub: Kuhle et al, Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis. Neurology. 2015. pii: 10.1212/WNL.0000000000001491. 

OBJECTIVE: We assessed CSF levels of the light chain subunit of neurofilaments (NfL) at baseline and after fingolimod therapy or placebo in MSers with relapsing-remitting multiple sclerosis (RRMS). Changes in NfL levels were also correlated with relapse and MRI outcomes.

METHODS: CSF samples were available, at baseline and 12 months after treatment initiation, from a subset of 36 MSers with RRMS (fingolimod 0.5 mg: n = 9; fingolimod 1.25 mg: n = 15; placebo: n = 12) participating in the 2-year, phase 3 Fingolimod (FTY720) Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study. NfL levels were determined in a blinded fashion using a commercial ELISA kit.

RESULTS: Median NfL levels did not differ between treatment groups at baseline (0.5 mg: 644 pg/mL; 1.25 mg: 659 pg/mL; pooled 0.5/1.25 mg: 652 pg/mL, placebo: 886 pg/mL; p value [fingolimod vs placebo] = 0.619, 0.495, and 0.481, respectively). Following 12 months of treatment, median changes from baseline in NfL levels were lower than zero in the fingolimod groups (0.5 mg: -346 pg/mL, p = 0.039; 1.25 mg: -313 pg/mL, p = 0.035) and pooled 0.5/1.25 mg fingolimod group (-326 pg/mL, 83.3% with reduction, p = 0.002) but not in the placebo group (-214 pg/mL, 66.7% with reduction, p = 0.388). Reductions in NfL levels at month 12 correlated with an improvement in relapse and MRI outcomes.

CONCLUSIONS: Our results suggest a beneficial effect of fingolimod on this marker of axonal injury and support the utility of NfL as a quantitative biomarker in multiple sclerosis.

CoI: This work was done when Jens Kuhle who spent 2 years in London, in the Barts-MS team, on an ECTRIMS fellowship

Cognition in Progressive MS - a hard nut to crack!

J Neurol Sci. 2015 Mar 3. pii: S0022-510X(15)00124-0. doi: 10.1016/j.jns.2015.02.044. [Epub ahead of print]

Orienting network dysfunction in progressive multiple sclerosis.

Ayache SS, Palm U, Chalah MA, Nguyen R, Farhat WH, Créange A, Lefaucheur JP.

Among patients with multiple sclerosis (MS), cognitive impairment affects up to 70% of the population . The most frequently impaired domains are memory, processing speed and attention. Three main attentional networks were described: the alerting network responsible for controlling vigilance and performance during tasks, the orienting network in charge of orientation to external stimuli, and the executive control network that deals with solving conflicts, detecting targets, and focal attention. The evaluation of these networks is possible by the means of the Attention Network Test (ANT). To our knowledge, this test has been studied in patients with relapsing–remitting MS (RRMS) but not in MS patients with progressive subtypes. We postulated that the increase in lesion load and cerebral atrophy throughout disease progression might have more impact on the attentional capacities in progressive MS.

Regarding ANT performance, MS patients were found slower (MRT: 816.84 ± 142.8 vs 683.5 ± 93.1; p = 0.0006), and less accurate (MA 94.2 ± 9.4 vs 97.7 ± 5.8; p = 0.002) than their healthy counterparts. Looking at the network effect, MS patients had a significant deficit in the orienting network (54.2 ± 55.5 vs. 24.9 ± 29.4; p = 0.047), but not in the alerting (24.0 ± 32.1 vs. 27.3 ± 26.5; p = 0.53) or the executive control (159.1 ± 74.9 vs. 134.5 ± 37.7; p = 0.23) networks.

You might ask what the heck is the orienting network?!! It would appear from this study that there is exclusive dysfunction of this domain in progressive MSers.

Orienting network, is the network that directs attention to a target stimulus - an example of this is having your attention drawn to someone new entering into the room (you may have wandered what triggers this, now you know!). 

This is not easy to achieve, and is the product of a distributed neural network - involving the frontal eye fields (located in the frontal lobe), superior parietal lobe and temporal-parietal junction (where knowledge and intelligence originate from), superior colliculus (helps to orient the head and eyes to all types of sensory stimuli) and the pulvinar (virtually non-existent in the rat) of the thalamus (important in visual attention and eye movements).

The key is the amount of invested effort in terms of brain power which is required to maintain this network, with a constant recruitment of mental resources for post-production executive monitoring (i.e. what the heck am I seeing?) and preparatory processes for on-going monitoring (i.e. for continued ogling!). Impaired memory, and in particular, processing speed probably has a significant impact on high-load tasks such as this.

Monday, 30 March 2015

Comorbidities: MS and cancer risk

MSers may have a higher incidence of developing bladder cancer. #MSBlog #MSResearch

"The following meta-analysis is the next in a recently published series of papers by Ruth-Ann Marrie and colleagues. It suggests MSers have a higher incidence of urinary tract cancers and meningiomas than the general population. The higher incidence of meningiomas is likely to be explained by ascertainment bias; MSers are more likely to have MRI scans and hence small incidental meningiomas are more likely to be detected. Why would urinary tract and in particular bladder cancers be higher? This is probably due to the high incidence of bladder problems in MS and the resultant recurrent or chronic urinary tract infections. Bacterial metabolism and inflammation in the bladder drive genetic mutations in the cells lining the bladder, which increases the risk of getting bladder cancers. In addition, at one time cyclophosphamide, a chemotherapeutic drug, was commonly used to treat MS. One of the active breakdown products or metabolites of cyclophosphamide is concentrated and excreted in the urine. This metabolite is carcinogenic and may explain some of the historical risk of bladder cancer at a population level."
"In my slide presentation below I make a suggestion that MSers treated with interferon-beta who develop long-lasting neutralizing antibodies to IFN-beta may also be at increased risk of developing cancers. IFN-beta is know to have anticancer effects and if NABs neutralises your own IFNbeta this may increase your risks of developing some cancers. Several years ago I asked all the three companies manufacturing IFN-beta as a treatment for MS to set-up a surveillance study to look at this question and other in relation to the potential long term effects of NABs. Unfortunately, none of the companies were interested doing this and by inference none were interested in knowing about the longterm impact of NABs. At the time I was surprised by this, but as I have gotten older and more cynical I am not surprised. IFNbeta is a multi-billion dollar a year franchise; any focus on long term safety would jeopardise that franchise. The good news is the Danish MS Registry is addressing this question and we should get an answer from them soon. The one caveat is there may be too few MSers in Denmark with NABs and too few cancers to give a definitive answer. In my presentation I also highlight the possible risk of NABs to bone health, that is in MSers and children born to mother with NABs, and on the risk of infections." 

"In summary, we need new and larger studies to assess whether or not MSers are at increased risk of getting cancer. The meta-analysis of published studies does not provide sufficient information."

Marrie et al. A systematic review of the incidence and prevalence of cancer in multiple sclerosis. Mult Scler. 2015 Mar;21(3):294-304. Epub 2014 Dec 22.

BACKGROUND: Studies of cancer incidence and prevalence in MS have produced conflicting results.

OBJECTIVE: To estimate the incidence and prevalence of cancer in MSers and review the quality of included studies.

METHODS: We searched the PUBMED, SCOPUS, Web of Knowledge, and EMBASE databases, conference proceedings, and reference lists of all articles retrieved. Abstracts were screened for relevance by two reviewers. Data from included articles were captured using a standardized form, and the abstraction was verified by a second reviewer. We assessed quality of the included studies. We quantitatively assessed studies using the I 2 statistic, and conducted meta-analyses for population-based studies.

RESULTS: We identified 38 studies. Estimates for incidence and prevalence varied substantially for most cancers. In population-based studies, cervical, breast, and digestive cancers had the highest incidence. The risk of meningiomas and urinary system cancers appeared higher than expected, while the risks of pancreatic, ovarian, prostate and testicular cancer were lower than expected.

Conclusion: The complexity of understanding cancer risk in MS is augmented by inconsistencies in study design, and the relative paucity of age, sex and ethnicity-specific risk estimates from which the strong impact of age on the incidence of cancers can be assessed.

"The following are my slides from the recent NMSS-ECTRIMS comorbidity meeting in Toronto."

"The following is the programme from last week's NMSS-ECTRIMS comorbidity meeting in Toronto; you may need to see the programme to put my talk into the correct context."

CoI: multiple

Breast feeding and MS

Ragnedda G, Leoni S, Parpinel M, Casetta I, Riise T, Myhr KM, Wolfson C, Pugliatti M. Reduced duration of breastfeeding is associated with a higher risk of multiple sclerosis in both Italian and Norwegian adult males: the EnvIMS study.J Neurol. 2015. [Epub ahead of print]

Breastfeeding for at least 4 months has been found to be associated with a reduced risk of immune-mediated diseases including multiple sclerosis (MS). Using data from a large multinational case-control study (EnvIMS), the association between MS and breastfeeding was investigated in two distinct populations. A questionnaire (EnvIMS-Q) which included a section on feeding during the first year of life was administered to MS cases and to age and sex frequency-matched controls from Italy and Norway. Logistic regression was used to estimate the odds ratio (ORs) and 95 % confidence intervals (95 % CIs) as a measure of the association between MS and exposure to prolonged breastfeeding (4 months or more, used as the reference category), vs. no breastfeeding or breastfeeding for less than 4 months (reduced exposure). Education, smoking habits, smoking in mother's pregnancy, and other types of milk used in infant feeding were included as covariates. A total of 547 cases and 1039 controls in Italy, and 737 cases and 1335 controls in Norway were studied. The distribution of prolonged (reference) breastfeeding differed between the Norwegian (65.4 %) and the Italian (48.9 %) study participants. A significant association between MS and reduced/no exposure to breastfeeding was found overall for Italy (ORadj = 1.37; 95 % CI 1.09, 1.73), but not for Norway (ORadj = 1.14; 95 % CI 0.92, 1.40). However, only in men, significant associations were observed for both populations (ORItaly = 2.33; 95 % CI 1.50, 3.65, ORNorway = 2.13; 95 % CI 1.37, 3.30). Reduced exposure to breastfeeding in males was found to be associated with increased risk of MS in Italy and in Norway.

This is one of those MS Risk papers and we have had a fair few, with vitamin D, smoking, high salt, cats and now breast feeding. Shorter duration of breast feeding was associated with a higher risk of developing MS notably in Males in Italay and Norway. Obviously this will need repeating and many people with MS will have been breast fed.
Breast feeding has many benefits for the newborne 

Cortical; Relapses

Puthenparampil M, Poggiali D, Causin F, Rolma G, Rinaldi F, Perini P, Gallo P.Cortical relapses in multiple sclerosis.
Mult Scler. 2015. pii: 1352458514564483. [Epub ahead of print]

BACKGROUND:Multiple sclerosis (MS) is a white and grey matter disease of the central nervous system (CNS). It is recognized that cortical damage (i.e. focal lesions and atrophy) plays a role in determining the accumulation of physical and cognitive disability that is observed in patients with progressive MS. To date, an association of cortical lesions with clinical relapses has not been described.
RESULTS: We report clinical and magnetic resonance imaging (MRI) findings of five relapsing-remitting MS (RRMS) patients who had clinical relapses characterized by the acute appearance of cortical symptoms, due to the development of large, snake-like, cortical inflammatory lesions. Symptoms were: acute Wernicke's aphasia mimicking stroke; agraphia with acalculia, not associated to a motor deficit nor linguistic disturbance; hyposthenia (weakness/lack of strength) of the left arm, followed by muscle twitching of the hand, spreading to arm and face; acute onset of left lower limb paroxysmal hypertonia (spasms/spasticity/contraction) ; and temporal lobe status epilepticus (epilepsy) , with psychotic symptoms.
CONCLUSIONS:Cortical relapses may occur in MS. MRI examination in MS should include sequences, aimed at visualizing cortical lesions, especially in the presence of symptoms of cortical dysfunction.

Receptive aphasia, also known as Wernicke’s aphasia, fluent aphasia, or sensory aphasia, is a type of aphasia traditionally associated with neurological damage to Wernicke’s area in the brain,Brodmann area 22, in the posterior part of the superior temporal gyrus of the dominant hemisphere). However, the key deficits of receptive aphasia do not come from damage to Wernicke's area; instead, most of the core difficulties are proposed to come from damage to the medial temporal lobe and underlying white matter. Wernicke's aphasia results from damage in the posterior one-third of the superior gyrus of the temporal lobe of the left hemisphere. Damage in this area not only destroys local language regions but also cuts off most of the occipital, temporal, and parietal regions from the core language region.

People with receptive aphasia are unable to understand language in its written or spoken form, and even though they can speak with normal grammar, syntax, rate, and intonation, they cannot express themselves meaningfully using language. People with Wernicke's aphasia are typically unaware of how they are speaking and do not realize it may lack meaning.

Agraphia is an acquired neurological disorder causing a loss in the ability to communicate through writing, either due to some form of motor dysfunction or an inability to spell. The loss of writing ability may present with other language or neurological disorders; disorders appearing commonly with agraphia are alexia, aphasia, dysarthria,agnosia, and apraxia.

Acalculia is an acquired impairment in which patients have difficulty performing simple mathematical tasks, such as adding, subtracting, multiplying and even simply stating which of two numbers is larger.

This study demonstrates that cognitive dysfunction may also be a relapse in MS and it is not just movement problems 

Sunday, 29 March 2015

Progressive MS trials are like buses you wait ages for one and then two come at the same time

Whilst  I appreciate that maybe our car-loving readers may not get the concept of two buses coming at the same time when you have been waiting ages for one, it is funny that this is just what is happening in progressive MS. 

We have to take the 55 bus or the 205 bus each day or walk 2-3 miles (~4-5km) to see the beasties, some times multiple times a day

The idea of MS-SMART trials was started many years ago and the drug candidates were selected based on evidence in MS, some evidence in EAE (Which was all largely irrelevant because EAE studies are not done in a way that they are very informative about protection) and evidence from other conditions. We even tested some candidates in EAE for this approach. They were not found to be very good. This was all done systematically.

One candidate was Ibudilast and this was selected but it turns out that a study is doing this in the USA. (Two studies on the same drug, well it was not possible for technical reasons and so next they come up with Fluoxetine (commonly known as Prozac), which is a selective serotonin re-uptake inhibitor. So it is of interesting that FLUOX-PMS is now ongoing in primary and secondary progressive MS in the homes of people in Netherland and Belgium

Serotonin is removed from the space around cells by a transporter system that sucks it up into cells. So it can bind to serotonin (5-HT) receptors. This can reduce depression. How does increasing serotonin affect progression, well I'm not sure there is some EAE data showing an immunomodulating effect, but as I think that such an effect is irrelevant to control of progression we need some more ideas. Some people think that SSRI may affect astrocyte function,that may affect sodium-dependent glutamate uptake by astrocytes, and the release of lactate, which serves as energy source for axons Fluoxetine also stimulates the release of the neuroprotective brain-derived neurotrophic factor (BDNF) from astrocytes, and may improve cerebral blood flow by dilating cerebral arterioles independent of the endothelium.

Maybe if you are not depressed then you are less stressed and this slows things down.

If you have SPMS and live in the UK, please seriously consider signing up to MS SMART (CLICK), not all sites may be active yet, but it is coming.

Will it work? I have my thoughts, but I don't really know. P.S. please do not ask for my thoughts as a penny or a few pounds is not going to let me part with them

But as DrK reminded me, after a trying week, about a note from the London Underground.

"Anyone who says failure is not an option has also ruled out innovation"

Innovation is the future and we have to be prepared to fail otherwise change will never happen.

CoI: This is nothing to do with me...but I would be very happy if you volunteer to take a drug that may (I won't guarantee it) do you some good.

My biomarker wishlist for the MS-SMART study

Those of you I met and talked to at the 'MS Research Day' on the 21.3.2015 would already know that my field of work is on biomarkers - specifically biological markers found in bodily fluids.

A biomarker is "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention" (NIH Biomarkers Definitions Working Group definition). For example, blood pressure is a marker of a biological process, cholesterol is a marker of a pathogenic process i.e. heart disease, and CA-125 (as Angelina Jolie-Pitt is in the news for having this measured!) is a marker of ovarian cancer treatment response.

It is apparent that in the time-frame of a progressive MS trial two years is too short to see a true clinical benefit. Why is this you might ask? Well...realistically speaking if you look back at how long it took for you to develop the disability, you're probably looking at a treatment strategy which targets long-term stabilisation, with no apparent physically/clinically evident changes in the short-term.

This is, however, not to say that changes are not taking place in your body, they are....and this is at the level of your brain cells. Changes in this can be visualised by MRI brain atrophy measures but can also sampled in the spinal fluid; which is my area of interest. My plan is to devise a biomarker strategy for MS-SMART that looks at the changes that are modulated by the trial drugs (fluoxetine, riluzole, amiloride) in the body, as well as those which are suggestive of a good clinical outcome i.e. a positive treatment effect (see Figure below).

Figure: Diagrammatic representation of my biomarker strategy. Therapeutics 1-5 all have different modes of action and the stem biomarkers are representative of this, whilst the biomarker at the trunk is more representative of the desired clinical outcome (in this case reducing disability).

I plan to look at the following (biomarkers listed):
I am interested to know what you think? Have you heard of a biological marker which would be interesting to look at, or are interested in finding out more on a specific process in progressive MS? 

Please write in the comments section below.

MSers participating in the MS-SMART trial are participating in this study on a voluntary basis, and so far 13 MSers have consented. Thank you.

MS Comorbidities Toronto 2015

My comorbidity talk from the NMSS-ECTRIMS meeting in Toronto. #MSBlog #MSResearch

"As promised the following is my presentation from the NMSS-ECTRIMS comorbidities meeting in Toronto. I found preparing this presentation very difficult. I am sure I delivered on the brief. Overall the meeting made me think a lot of about how we treat MS and I will now need to update my comorbidities line on my tube map. The meeting also made we realise that if we want to optimise outcomes for MSers we need to actively and aggressively target comorbidities and health. Poor health behaviour is not only a general problem, but is a big issue in MSers as it contributes to poorer outcomes and is exacerbated by reduced activity and psychiatric problems (depression and anxiety) that impact on motivation."

"When I was on my recent trip to Australia several MS clinical nurse specialists asked me why we don't post more on diet and MS. The reason is there is not much research in this field and this is not really our area of expertise. After attending this comorbidity meeting I now realise that I have to get up to speed on diet as this is a large component of any health initiative. I also realise I better walk the talk and sort out my own lifestyle; how can I tell MSers how to live if I don't swallow my own medicine?"

"The following is the programme from the meeting; you may need to see it to put my talk into the correct context."

CoI: multiple

Saturday, 28 March 2015

How do like your pills?

Wicks P, Brandes D, Park J, Liakhovitski D, Koudinova T, Sasane R.Preferred features of oral treatments and predictors of non-adherence: two web-based choice experiments in multiple sclerosis patients. Interact J Med Res. 2015;4(1):e6. doi: 10.2196/ijmr.3776.

BACKGROUND:Oral disease modifying therapies (DMTs) for multiple sclerosis (MS) differ in efficacy, tolerability, and safety.
OBJECTIVE: We sought to understand how these attributes impact patient preference and predicted DMT non-adherence among oral-naïve MS patients.
METHODS:Adult MS patients from the "PatientsLikeMe" Web-based health data-sharing platform completed a discrete choice exercise where they were asked to express their preference for one of three hypothetical oral DMTs, each with a certain combination of levels of tested attributes. Another Web-based exercise tested a number of possible drivers of non-adherence, mainly side effects. Data from an MS clinic were used to adjust for sample bias. Respondents' preferences were analyzed using Hierarchical Bayesian estimation.
RESULTS:A total of 319 patients completed all questions. Most respondents were female (77.7%, 248/319) with mean age 48 years (SD 10). Liver toxicity was the attribute that emerged as the most important driver of patient preference (25.8%, relative importance out of 100%), followed by severe side effects (15.3%), delay to disability progression (10.7%), and common side effects (10.4%). The most important drivers of predicted non-adherence were frequency of daily dosing (17.4% out of 100%), hair thinning (14.8%), use during pregnancy (14.1%), severe side effects (13.8%), and diarrhea (13.0%).
CONCLUSIONS:Understanding the important concerns expressed by patients may help health care providers to understand and educate their patients more completely about these concerns. This knowledge may therefore improve both choices of appropriate therapy and adherence to therapy over time.
This is a survey on what you want from your pills. So if you look at which pills you prefer obviously you want them to work and then there is an issue of side effects. It they have nasty side effects you won't want them, So if its hair thinning we know which pill you are worried about (Aubagio), pregnancy, you may not want some (Aubagio) because of birth defect potential, gut problems (Tecfidera) don't want to take it too often (Tecfidera). I guess it's not rocket science but Pharma do spend alot on Marketing so your choice...is their profit.

ClinicSpeak: psychiatric comorbidity

Do you suffer from anxiety, depression or substance misuse? #ClinicSpeak #MSBlog #MSResearch

"The meta-analysis below confirms what we know; MSers are likely to have a high rate of psychiatric co-morbidity. This includes depression, anxiety and alcohol and substance abuse. Psychiatric comorbidity is the hidden, often ignored, underbelly of MS. Anxiety and fatigue are so common that they are virtually ubiquitous foes of the MSer. It is very important that anxiety is recognised and managed early. I suspect that alcohol and substance misuse is due to MSers self-medicating. Alcohol is anxiolytic and is almost certainly the most widely used anxiolytic on the planet."

"MSers have reason to be anxious and depressed. The uncertainty that goes with being diagnosed with MS cannot be underestimated. I have recently discovered mindfulness, through the recommendations of some of my patients. Mindfulness is a technique of self-meditation that teaches you to focus on the here and now and not the future; you can't control the future so why worry about it. The NHS and NICE recommends mindfulness training as part of a holistic approach to the management of anxiety. Mindfulness is a useful adjunct to CBT (cognitive behavioural therapy) and exercise to help anxiety. Finally, if anxiety cannot be managed using these, and other, techniques there is also the option of medication, for example the SSRIs. I typically try to avoid SSRIs because of weight gain as a side effect and the increasing recognition of a withdrawal syndrome on stopping them.The latter is called the anti-depressant withdrawal syndrome and occurs in ~30-40% of people who stop SSRIs."

"If you suffer from anxiety, depression, fatigue, alcohol and substance misuse don't ignore the problem please raise it with your GP, neurologist or MS specialist nurse."

Marrie et al. The incidence and prevalence of psychiatric disorders in multiple sclerosis: A systematic review. Mult Scler. 2015 Mar;21(3):305-317.

BACKGROUND: Psychiatric comorbidity is associated with lower quality of life, more fatigue, and reduced adherence to disease-modifying therapy MS.

OBJECTIVES: The objectives of this review are to estimate the incidence and prevalence of selected comorbid psychiatric disorders in MS and evaluate the quality of included studies.

METHODS: We searched the PubMed, PsychInfo, SCOPUS, and Web of Knowledge databases and reference lists of retrieved articles. Abstracts were screened for relevance by two independent reviewers, followed by full-text review. Data were abstracted by one reviewer, and verified by a second reviewer. Study quality was evaluated using a standardized tool. For population-based studies we assessed heterogeneity quantitatively using the I 2 statistic, and conducted meta-analyses.

RESULTS: We included 118 studies in this review. Among population-based studies, the prevalence of anxiety was 21.9% (95% CI: 8.76%-35.0%), while it was 14.8% for alcohol abuse, 5.83% for bipolar disorder, 23.7% (95% CI: 17.4%-30.0%) for depression, 2.5% for substance abuse, and 4.3% (95% CI: 0%-10.3%) for psychosis.

CONCLUSION: This review confirms that psychiatric comorbidity, particularly depression and anxiety, is common in MS. However, the incidence of psychiatric comorbidity remains understudied. Future comparisons across studies would be enhanced by developing a consistent approach to measuring psychiatric comorbidity, and reporting of age-, sex-, and ethnicity-specific estimates.

Treatment inhibits the formation of cortical lesions

Rinaldi F, Perini P, Atzori M, Favaretto A, Seppi D, Gallo P. Disease-modifying drugs reduce cortical lesion accumulation and atrophy progression in relapsing-remitting multiple sclerosis: results from a 48-month extension study. Mult Scler Int. 2015;2015:369348. doi: 10.1155/2015/369348. Epub 2015 Feb 23.
Cortical lesions (CLs) and atrophy are pivotal in multiple sclerosis (MS) pathology. This study determined the effect of disease modifying drugs (DMDs) on CL development and cortical atrophy progression in patients with relapsing-remitting MS (RRMS) over 48 months. Patients (n = 165) were randomized to sc IFN β-1a 44 μg (rebif), im IFN β-1a 30 μg (Avonex) , or glatiramer acetate 20 mg. The reference population comprised 50 DMD-untreated patients with RRMS. After 24 months, 43 of the untreated patients switched to DMDs. The four groups of patients were followed up for an additional 24 months. At 48 months the mean standard deviation number of new CLs was significantly lower in patients treated with sc IFN β-1a (1.4 ± 1.0, range 0-5) compared with im IFN β-1a (2.3 ± 1.3, range 0-6, P = 0.004) and glatiramer acetate (2.2 ± 1.5, range 0-7, P = 0.03). Significant reductions in CL accumulation and new white matter and gadolinium-enhancing lesions were also observed in the 43 patients who switched to DMDs after 24 months, compared with the 24 months of no treatment. Concluding, this study confirms that DMDs significantly reduce CL development and cortical atrophy progression compared with no treatment.

Cortical lesions (grey matter) lesions are difficult to spot and yet this study again shows that it is better to be treated than not treated to be treated. In this study rebif came up trumps but in other things it doesn't so it is swings and roundabouts, but it would also suggest that with a more active DMD the chance for improvement is even better because no cortical lesions are going to be better than .

Friday, 27 March 2015

The chronicles get a new story

Now that some of you know what this is all about........
No Comments Needed..Thanks.

You had to be at the Research Day to Find out.
What happened at the Research Day...Stays at the Research Day:-(
All will be revealed soon I suspect.

ClinicSpeak: MS comorbidities

A focus on MS comorbidities; at least it is something we can target in progressive MS. #ClinicSpeak #MSBlog #MSResearch

"I  have just arrived in Toronto to attend, and speak at, the NMSS-ECTRIMS Comorbidities meeting. The programme below may be of interest to you. What is a comorbidity?  The following is a reasonable working definition:

'In medicine, comorbidity is the presence of one or more additional disorders (or diseases) co-occurring with a primary disease or disorder; or the effect of such additional disorders or diseases. The additional disorder may also be a behavioral or mental disorder.' Source Wikipedia

Please note the definition defines it as the presence or additional disorders or diseases. Implicit in this definition is that it affects health; i.e. comorbidities makes you less healthy or unhealthy. This then brings up a debate about what is health. In preparation for this meeting I did a lot of background reading on what constitutes health or poor health and again there is no agreement. For example the World Health Organisation (WHO) defines health 'as a state of complete physical, mental and social well-being, and not merely the absence of disease or infirmity'. As a clinician this definition is unworkable. As part of preparation for my talk, which I am finding impossible to prepare, I read a very good series of article in a the latest issue (#7) of the NewPhilosopher; the whole issue is dedicated to the philosophy of health. For example, the best debate was on whether or not we should classify ageing as a disease and whether or not getting old causes you to become unhealthy. A quote from the issue that I plan to use in my talk later today is from David Seedhouse (New Philosopher 2015;7:97-99): 'Health is more than the opposite of disease'. This worldview and some of the other intellectual meanderings in the NewPhilosopher make me realise that health is more a state of mind that something that can be defined by the medical profession. Why can't you have MS and be healthy? A medicalised worldview is that disease and poor health or synonymous; this is clearly not the case. You can attend any one of my large MS follow-up clinics and you will see that a significant number of MSers are healthy or at least describe themselves as being healthy. " 

"I have also come to realise that the medical profession, clinicians and scientists, have a lot to learn from the philosophers. How to define illness, sickness, disease and health is a starting point. If we understand the impact of labelling people as ill, sick, diseased or unhealthy we may think twice about what our objectives are as neurologists treating MSers. Is it to simply relieve suffering? Do we have a responsibility to maximise health? Are we responsible for trying to help MSers age healthily? These are the sorts of questions that have been percolating in my mind. What is clear that I doubt I will be able to answer them at this meeting. What is clear we can't shirk our responsibilities when it comes to comorbidities; if want to treat MSers we need to approach MS holistically."

"I only give my talk late morning so any suggestions would be welcomed. As usual once I have given my talk I will share the slides with you on SlideShare." 

CoI: multiple

Education: Don't believe every thing you read.

#MS Research. Animal studies trend to go more trial-like.

I was asked this week what sources of information do you trust. I said definitely not the media.....and the best judgement is to learn the science and read the papers yourself. However, this is not easy especially if you learn bad practises.

There has been a trend to make animal studies more like clinical studies. Whilst the intention is to improve the rigour of experimental design and reporting, unfortunately it can go the other way. Once having a statistical value of P>0.05 (means is you did experiment twenty times, by chance this result would happen) was considered a failure experimentally. 

However, in clinical studies, which are often small in nature, there has been a tendency for people to say that when P<0.1 there is a trend rather than say there was no statistically significant difference. So being positive when it really is negative.

OK you can reject a null hypothesis when there is in fact a real biological difference or accept a null hypothesis that there is no difference between observations when there is a biological difference these are called Type I and Type II errors.

Null hypothesis (H0) is
Judgement of Null Hypothesis (H0)RejectType I error
False Positive
Correct inference
True Positive
Accept (fail to reject)Correct inference
True Negative
Type II error
False negative
Now more human trial-like animal studies arrives in Nature Journals, leading us into more bad science:-).

So in a recent paper it states about statistical analysis

"Unless stated otherwise, non-paired Student’s t-tests were performed for statistical analysis. P values <0.05 are indicated by *P values <0.005 by **P values <0.1 were considered as a trend".
Maybe the referee is a clinician, who else would accept this?, and now failure becomes a trend:-(

Maybe power the study to get the answer, but we know Nature Journals have not been good at this

Two years later: journals are not yet enforcing the ARRIVE guidelines on reporting standards for pre-clinical animal studies. Baker D, Lidster K, Sottomayor A, Amor S. PLoS Biol. 2014 Jan;12(1):e1001756. There is growing concern that poor experimental design and lack of transparent reporting contribute to the frequent failure of pre-clinical animal studies to translate into treatments for human disease. In 2010, the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were introduced to help improve reporting standards. They were published in PLOS Biology and endorsed by funding agencies and publishers and their journals, including PLOS, Nature research journals, and other top-tier journals. Yet our analysis of papers published in PLOS and Nature journals indicates that there has been very little improvement in reporting standards since then. This suggests that authors, referees, and editors generally are ignoring guidelines, and the editorial endorsement is yet to be effectively implemented.

When analysed, less than 5% of animal studies do a power calculation. This is because animal studies that are published are invariably positive as there is a publication bias of positive results.

In that paper we asked whether the data was analysed incorrectly. 

EAE scoring is an scale of limp tail, limp legs and a random score is given to these features this type of data is not continuous this is called non parametric data and you should use non parametric statistics to analyse. Other data like height are continuous such as there are measures between 1m and to 2m say such as 1.5m, 1.24m, 1.23m. EAE data on the whole should not be analysed with parametric (e.g. T tests) but should use non-parametric data. We looked in the literature and found that in many cases parametric statistics are wrongly used. This occurred in the top journal (These have a high impact factor)
Overall it was about half the time in Journals, but in the Nature/ Science Journals it was wrong in about 95% of cases. So they are setting the bad example 

Baker D, Lidster K, Sottomayor A, Amor S. Reproducibility: Research-reporting standards fall short. Nature. 2012 Dec 6;492(7427):41. doi: 10.1038/492041a

After we called them on this, they introduced reporting standards. Did they and their referees learn about the statistics?

So recently we got this figure in a Nature Journal and the work was splashed across the media..........The great new hope.

So we looked as the data
Figure legend. Clinical scores of two independent EAE experiments at d23 post disease induction. Individual scores as well as the mean score of two independent experiments are shown. Control: n=10, vehicle: n=13, xxxxx-345: n=11. Control versus vehicle: P=0.620, control versus xxxxx-345: P=0.017, vehicle versus xxxxx-345 P=0.029.  * indicate P values <0.05 and ** indicate P values <0.005 based on a non-paired Student’s t test. Error bars are s.e.m.

There is a thought in clinical trial studies that you should supply
the primary data so it can be re-analysed. Many companies now willingly do this. This probably will occur or science papers too.

So in the figure above they provide primary data. In the drug-treated animals the scores appear to be: 0, 0 ,0, 0.5, 0.5, 2, 2.5, 3, 3.5, 3.5, 3.5 n=11 in vehicle scores appear to be: 0.5, 2.5, 2.5, 2.5, 2,75, 2.75, 3, 3.5, 3.5, 3.5, 3.5, 3.5, 3.5 n=13. 

Do a t test drug verses vehicle and you get p=0.029 (as in the legend to the figure above) so all is fine and drug is great. The media go mad.....an its the next best thing since sliced bread:-) 

However, you should not do a t test on this type of data. The assumptions of a t test as that the data is (a) normally distributed. You test this and it passes the test p=0.152, 

However, it also assumes that (b) data groups have equal variances (the square of standard deviation). Test for that and it fails P<0.05. So it is not valid to do a t test on this data but importantly it is not valid to do a t test on this data, because the data is not parametric, it is non-parametric.

So do a non-parametric test on the data like the Mann Whitney U test . This has less power to detect differences than a t test.

Do this on the data above and P=0.082.........Ooooops.

So now do drug verses untreated as well and this also fails P=0.121, so not even a trend:-)

There is no statistically significant effect. The drug has not worked! So you accept this or do more studies to show if this so called trend is real or not, harder to do in humans, much easier to do in animal studies.

Simple school-boy stuff. All the reviewers need to do is read:

Baker D, Amor S.Publication guidelines for refereeing and reporting on animal use in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2012 ;242(1-2):78-83.

Hopefully, this will get the altimetrics up on the old papers:-)

I suspect many of you won't be bothered by this post,but if you were pinning your hopes on drug xxxxx-345 then these hopes are being dashed. This type of detective work can not normally be done because we do not get to see the primary data.

This is not a rare example..but a new one to use in my teaching on experimental design 1O1. 

Death of the Cord lets hit RIP to get oligos to live

Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, Ye J, Zhang X, Chang A, Vakifahmetoglu-Norberg H, Geng J, Py B, Zhou W, Amin P, Lima JB, Qi C, Yu Q, Trapp B, Yuan J. Activation of Necroptosis in Multiple Sclerosis. Cell Rep. 2015 Mar 17. pii: S2211-1247(15)00209-0. doi: 10.1016/j.celrep.2015.02.051. [Epub ahead of print]

Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demye
lination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS

Necrosis is a form of cell injury that results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma that result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. Cells that die due to necrosis do not follow the apoptotic signal transduction pathway but rather various receptors are activated that result in the loss of cell membrane integrity and an uncontrolled release of products of cell death into the extracellular space. This initiates in the surrounding tissue an inflammatory response which prevents nearby phagocytes from locating and eliminating the dead cells by phagocytosis.
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis (programmed cell death), necrosis, and inflammation

Caspases are essential in cells have been termed "executioner" proteins for their roles in the cell. Failure of apoptosis is one of the main contributions to tumour development and autoimmune diseases; 

Initiator caspases (e.g., CASP2, CASP8, CASP9, and CASP10) cleave inactive forms of effector caspases, thereby activating them. Effector caspases (e.g., CASP3, CASP6, CASP7) in turn cleave other protein targets to trigger the cell death. The initiation of this cascade reaction is regulated by caspase inhibitors. 

Caspase8 is invovled in the control of white cell numbers but it also turns up in in inclusion bodies in neurodegenerative diseases. Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. One of the best known inclusion body is the Lewy Body in diseases such as Parkinsons disease. A Lewy body is composed of the protein alpha-synuclein associated with other proteins, such as ubiquitinneurofilament protein, and alpha B crystallin. Tau proteins may also be present, and Lewy bodies may occasionally be surrounded by neurofibrillary tangles, which occur in Alzheimers Disease. Some of the proteins which don't dissolve in water (insoluble) or the cytoplasm of a cell found in MS are also found in other neurodegenerative diseases. Are these a cause of nerve loss? or are these a consequence of cell stress and their attempt to stop nerve damage?. Probably a bit of both.

In this study they show that nerves in the cortex are probably dying, which is going to contribute to progressive MS. They show that

Receptor-interacting serine/threonine-protein kinase 1 RIPK1) is activated in MS lesions. RIPK1 is known to have function in a variety of cellular pathways including the NF-κB pathway which will promote cytokine release and programmed necrotic cell death (necroptosis).  RIPK3 is a component of the tumor necrosis factor (TNF) receptor-I signaling complex. It was found that RIPK1 stimulates Tumour necrosis factor mediated damage of the myelin forming oligodendrocytes. So if they knockout RIPK3 there was less oligodedrocyte damage and then block of RIPK1 with an inhibitor also limited oligodendrocyte damage.

It has been reported that brain cholesterol can stimulate RIPK1 I and cause nerve damage, I wonder, Is this how statins have a neuroprotective effects in secondary progressive MS?. It makes more sense that via an immunological effect. Is this why cholesterol pathways have been implicated in pathology of Alzheimers disease

Thursday, 26 March 2015

Neuroprotection and regeneration is this the new way forward

Targeting Repulsive Guidance Molecule A to Promote Regeneration and Neuroprotection inMultiple Sclerosis.
Demicheva E, Cui YF, Bardwell P, Barghorn S, Kron M, Meyer AH, Schmidt M, Gerlach B, Leddy M, Barlow E, O'Connor E, Choi CH, Huang L, Veldman GM, Rus H, Shabanzadeh AP, Tassew NG, Monnier PP, Müller T, Calabresi PA, Schoemaker H, Mueller BK. Cell Rep. 2015  pii: S2211-1247(15)00206-5. doi: 10.1016/j.celrep.2015.02.048. [Epub ahead of print]

Repulsive guidance molecule A (RGMa) is a potent inhibitor of neuronal regeneration and a regulator of cell death, and it plays a role in multiple sclerosis (MS). In autopsy material from progressive MS patients, RGMa was found in active and chronic lesions, as well as in normal-appearing gray and white matter, and was expressed by cellular meningeal infiltrates. Levels of soluble RGMa in the cerebrospinal fluid were decreased in progressive MS patients successfully treated with intrathecal corticosteroid triamcinolone acetonide (TCA), showing functional improvements. In vitro, RGMa monoclonal antibodies (mAbs) reversed RGMa-mediated neurite outgrowth inhibition and chemorepulsion. In animal models of CNS damage and MS, RGMa antibody stimulated regeneration and remyelination of damaged nerve fibres, accelerated functional recovery, and protected the retinal nerve fibre layer as measured by clinically relevant optic coherence tomography. These data suggest that targeting RGMa is a promising strategy to improve functional recovery in MS patients.

Repulsive Guidance Molecules (RGMs) are members of a three gene family (in vertebrates) composed of RGMa, RGMb, and RGMc (also called hemojuvelin). RGMa has been implicated to play an important role in the developing brain and in the scar tissue that forms after a brain injury. For example, RGMa helps guide Retinal Ganglion Cell(RGC) axons to the midbrain. It has also been demonstrated that after induced spinal cord injury RGMa accumulates in the scar tissue around the lesion. Further research has shown that RGMa is an inhibitor of axonal outgrowth. Taken together, these findings highlight the importance of RGMa in axonal guidance and outgrowth. In this study they made a blocker of RGMa and this facilitated recovery and may have stimulated nerve outgrowth.  It is open source so you can all read the paper.It will have the same problem as the anti-Lingo in that it has to get into the CNS (Biogen claim that it is the 0.1% that gets in that does the business.) However very encouraging

Dear Company, if you are reading this and you want to put this to the test contact us!.

CoI This study was performed by a pharmaceutical company so it means they have the potential to develop this molecule.

CrowdSpeak: What has happened to the Charcot Project?

The Charcot Project is alive and kicking. #CrowdSpeak #MSBlog #MSResearch

"The first study done under the Charcot umbrella, the INSPIRE or raltegravir trial, finished last year. Our University or sponsor of the study will not allow us to analyse the results until the database is locked. Unfortunately, these are the rules that the MHRA (The Medicines and Healthcare Products Regulatory Agency) put in place. We are currently sitting on our hands waiting for the database lock. It takes about 6 months for the sponsors to check all  the data, resolve all the queries and double-enter the data into a database. We are as frustrated as you the wait, but we will let you know the results as soon as we can."

"For those who don't follow the blog regularly will have heard that we have been looking for a crowd funding partner to take on the task of raising funds for a second proof-of-concept trial that is Charcot 2. You the community suggested crowdfunding, voted on the project (Charcot project vs. ZEUS Trial), given it a name (ARTEMIS - Anti-Retroviral Treatment for Epstein-Barr Virus in MultIple Sclerosis) and you are now helping resolve questions about its design. The good news is we have found a Crowd Funding partner called CROWDACURE; or to be more correct they found us. We have been impressed by the level of professionalism and dedication of the CrowdaCure team and it will be a pleasure working with them. We don't think we can launch the crowd funding campaign until we have finished designing the protocol, costing the work and getting it peer-reviewed."

"The following is your feedback on some of the inclusion and exclusion criteria. You want the study to take place in allcomers, i.e. MSers with both relapsing-remitting and progressive MS, you are undecided on an age cut-off and whether or not it should be added onto existing DMTs. As this is a proof of concept study looking at the impact of antiviral therapies on viral loads it is not that relevant what type of MSers are studied. However, we will have to exclude MSers on DMTs with known antiviral activity, i.e. interferon-beta and MSers with low white cell counts (leukopaenia or lymphopaenia); we need white cells to do our HERV assay. The latter will probably exclude MSers on fingolimod, those treated with alemtuzumab and some others as well."

"We love the name ARTEMIS as it is the name of a Greek moon goddess often portrayed as a virgin huntress. The primary aim of the Charcot Project is to hunt down the viral cause of MS; so having a trial named after a huntress is appropriate."

"Please note that there will be some aspects of the trial that we will not be able to ask for your input; simply because of the way protocols and studies are designed. For example, the choice of HAART. Professor Gold has a rationale for choosing a particular combination of anti-retrovirals based on their efficacy and penetration into the central nervous system. As I write this he is trying to source a supply for the study. HAART is expensive and we are hoping to get one of the large Pharma companies who market anti-retrovirals to donate the drugs for this trial."

"Some may ask what is the rationale for doing this study? There is emerging evidence that EBV and HERVs (human endogenous retroviruses) are involved in MS. Some of us in the MS community are of the opinion that EBV causes MS and that if you can prevent people becoming infected with EBV you may prevent MS. We don't know how EBV causes MS. One of the theories that we are investigating is that EBV causes MS via its interaction with HERVs."

"HERVs are viruses that live in our genome; about 6-8% of the human genome is HERVs. Why do we have so many HERVs in our genome? Evolution has selected for them because they must give us, and other mammals, a survival advantage. For example, one HERV protein is critical for the development of the placenta. Mammals who don't have a placenta (marsupials) don't have this HERV. As HERVs are sort of 'foreign', the human body has developed intricate ways of detecting them and if they are found to be expressed in a cell the cells immune system flags that it is infected with a virus so that the immune system can eliminate the cell. This so called danger signal is often is what is needed to activate the immune system and if this happens to be an autoreactive immune cell it can trigger autoimmunity. Interestingly, there is a very rare disorder due to mutations in the systems that detect and suppress HERVs in cells. The children with these mutations present with multiple autoimmune diseases indicating that uncontrolled HERV expression can drive autoimmune disease. You may be aware by now that there is emerging data that MSers have evidence of increased HERV expression in the cells of the peripheral blood and possibly in their brains as well. At present we don't know if MS causes HERV expression or does HERV expression cause, or drive, MS? This is one of the reasons why we have launched the Charcot project."

"So how do EBV and HERVs relate to each other? It turns out that herpes viruses, in particular EBV, are potent transactivators of HERVs. In other words EBV does something to wake-up the sleeping HERVs  in our genome and increases their expression. This is the rationale for using drugs to reduce EBV activity in the hope they will suppress HERVs, or even better drugs that target both EBV and HERVs."

"Why HAART (highly-active antiretroviral therapy)? This is based on our anecdotal evidence that MSers who have become HIV positive and go onto HAART do well regarding their MS. We agree that one swallow doesn't make a summer, which is why we have done other studies to try and confirm these observations. What we have shown is that people who are HIV-positive and go onto HAART have a low risk of getting MS. The longer they are on HAART the lower their risk of getting MS is. We are not the only ones to observe this; the Danes have made a similar observation in their country. The big question is it the HIV virus or the HAART that is lowering the risk of MS? We don't know."

"However, once you make an observation like this you can't ignore it. This is why we have done the INSPIRE trial using raltegravir an antiretroviral drug that blocks the integration of retroviruses into the genome. Raltegravir is a relatively new anti-retroviral, and was only launched in 2009 and only becoming widely used in the UK to treat HIV-1 infection from 2011.  The latter is important because our observations of HAART lowering the risk of getting MS was from the pre-raltegravir period. Therefore, regardless of whether or not the INSPIRE trial is positive we need to test HAART as a potential treatment for MS."

"I am aware that what I am saying above is complex, but I hope it sets out the rationale and makes the case for using both and anti-EBV drug and HAART in MS and more importantly for using them in combination. The proposed ARTEMIS study below is simply and enabling study to provide us with necessary virological and safety data to make the case for doing a larger efficacy study in MS."

"As you can see there are still many questions that need answering and we would like your input to answer them. The purpose of this study is to explore whether or not our candidate drugs do what the meant to do to on the target viruses in MSers and to show that there are no major safety issues. Further thoughts please?"

"This remains a community project so please feel free to comment. Thank you."

CoI: multiple