Monday, 27 December 2010

Placebo vs. interferon-beta in combination with mycophenolate

24 treatment-naïve RRMS patients participated in a 1 year prospective safety study. There were no differences were identified between the two treatment groups with respect to patient-reported adverse events or laboratory abnormalities. The combination treatment regimen of interferon beta-1a and mycophenolate was well tolerated.

The investigators conclude: "Despite the small sample size, therapeutic trends were observed in favor of combination therapy. An adequately powered controlled trial of mycophenolate in MS appears warranted."

Remington et al. Ther Adv Neurol Disord. 2010 Jan;3(1):3-13.

I couldn't agree more with the investigators; given the current dogma concerning the autoimmune pathogenesis of MS, mycophenolate should be given a chance. The problem is that with the imminent launch of several oral therapies, will it be possible to design an affordable trial to test mycophenolate in RRMS? I suspect not!

Mycophenolate vs. Interferon-beta: an underpowered study

Mycophenolate is an anti-rejection agent widely used in transplantation. This was a randomised, 6-monthly, study to compare the effectiveness of mycophenolate to interferon beta in 35 untreated patients with RRMS. Not surprisingly there was no difference between mycophenolate and interferon beta therapy treatment groups. The mycophenolate group showed a trend toward a lower accumulation of lesions on MRI, but this was not significant. This study was simply too small to draw any conclusions (underpowered). It should have been appropriately powered to give a definitive answer; the worrying consequence of this study is will anybody be brave enough now to do a definitive trial? Has this study killed a potentially promising oral agent?

Frohman et al. Ther Adv Neurol Disord. 2010 Jan;3(1):15-28.

Is it ethical to do under-powered studies? NO!

Should people with MS who volunteer to participate in treatment trials expect the studies to be appropriately powered? YES!

Wednesday, 22 December 2010

If you can; get your walking shoes on!

Walking impairment in patients with multiple sclerosis: exercise training as a treatment option; "exercise training and physical activity might hold significant potential for the management of progressive mobility disability in MS."

Motl et al. Neuropsychiatr Dis Treat. 2010 Nov 16;6:767-74.

Monday, 20 December 2010

At last the published results of the anti-IL12 & anti-IL23 trial

Until recently the cytokines* interleukins 12 and 23 were believed to be very important in driving inflammation in MS. A drug that neutralises these cytokines has failed to have the desired effect on the disease thus questioning the current dogma. As a result of this study most immunologists have changed their thinking about the disease. Although this trial was negative the people with MS who volunteered to participate in this study have made a very valuable contribution to the field. Negative trial results can be as important as positive ones; in this case the results have changed the way we think about the disease.

Vollmer et al. Mult Scler. 2010 Dec 6.


* cytokines is a term immunologists use to describe the protein messages that cell send to each other to communicate; not too dissimilar to the role of hormones!

Statins for MS?

This review confirms our advice that there is insufficient evidence to support statins (cholesterol lowering drugs) as a treatment for MS.

Wang et al. Cochrane Database Syst Rev. 2010 Dec 8;12:CD008386.

A good vitamin D update

THE AUTHORS' CONCLUSIONS ARE SELF-EXPLANATORY: "The current level of evidence for the effectiveness of vitamin D supplementation in the management of people with MS is based on a single randomised control trial with potential high risk of bias, which does not at present allow confident decision-making about the use of Vitamin D in MS. Therefore, until further high quality evidence is available, clinicians may wish to consider relevant MS guidelines on vitamin D supplementation when making decisions about the care of people with multiple sclerosis. Adequately powered, multi-centred RCTs with a focus on clinical as well as immunological and MRI outcomes that are meaningful to people with MS, and are able to provide insight into the benefits of Vitamin D in people with MS, are still required."

Jagannath et al. Cochrane Database Syst Rev. 2010 Dec 8;12:CD008422

New evidence that natalizumab reduces axonal damage

Natalizumab treatment markedly reduces the release of neurofilament into the spinal fluid of people with MS. Neurofilaments are the main structural protein of neurons and axons. This is further evidence that natalizumab treatment reduces the accumulation of nerve injury in MS. Hopefully, this will stimulate pharmaceutical companies to include spinal fluid neurofilament analysis in all of their clinical trials.

Gunnarsson et al. Ann Neurol 2010

Pregnancy and foetal outcomes after interferon-β exposure in multiple sclerosis

A report on 88 pregnancies in Italian woman that were exposed to interferon-beta (average exposure 4 to 5 weeks) has demonstrated that exposure to interferon-beta was not associated with an increased risk of spontaneous abortion. However, it was associated with both a lower baby weight and length. No significant fetal complications, malformations, or developmental abnormalities were noted with a follow-up of 2 years. These findings point to the relative safety of IFNβ foetal exposure of up to 4 weeks during pregnancy. These data will assist woman with MS on interferon beta with difficult decisions with regard to pregnancy.

Amato et al. Neurology 2010;75:1794-802.

Monday, 6 December 2010

Friday, 3 December 2010

How much vitamin D is too much?

If you interested please read the Institute of Medicine's 2010 report on vitamin D and calcium intake.

Click here for on-line access to the report

The committee of scientists, convened by the National Academies' Institute of Medicine, doubled the upper level of vitamin D that people that people between the ages of 9 and 50 can safely take in any given day from 2,000 to 4,000 IU.

Please click here to read a commentary in Science News

Wednesday, 1 December 2010

MS Endophenotype Study

HELP!

MS is a common, complex neurological disease. Although the precise aetiology of MS is not yet known numerous studies indicate that both genetic and environmental factors are important. It now appears that the environment acts long before MS becomes clinically evident and suggests the existence of a prodromal phase for the disease. The possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring "endophenotypes" that result from associated risk factors. Identifying and studying individuals, for example family members of people with MS, with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.

We are therefore recruiting people with MS who have brothers and/or sisters without MS, and people with MS who are twins (identical and non-identical) to explore the possible cause of MS. Twins will help us understand the cause of disease and the influence of early environmental exposures; identical twins have the same genetic background and twins in general share the same early environment, which can be different when looking at non twins and unrelated individuals.

If you can help please click here for more details

Saturday, 16 October 2010

ECTRIMS 2010 Update: Phase 2 Ocrelizumab Results in RRMS

Ocrelizumab (anti-CD20) that targets B-cells was given as two treatment cycles, 6 months apart, in a phase 2 study in relapsing-remitting MS. It reduced MRI activity by ~90% (median T1 Gd-lesions at wk 24: placebo 1.6, 600mg 0.0, 2000mg 0.0, Avonex 1.0; p<0.0001 vs placebo) and annualised relapse rate by up to 80% (ARR: placebo 0.61, 600mg 0.18 (RRR 80%), 2000mg 0.2 (RRR 72%), Avo 0.4). Importantly the overall adverse event profile looks good (AEs: placebo 70%, 600mg 61%, 2000mg 65%, Avonex 55%). Infusion reactions typically disappeared at the day 15 infusion and there were no opportunistic infections. Worryingly there was one death in the high dose Ocrelizumab group at 14 weeks, from "systemic inflammatory response syndrome". These very impressive results need to be tempered against the death that we must assume is due to Ocrelizumab. Nevertheless this study demonstrates the importance of B cells in the pathogenesis of MS; the latter needs further exploration and may ultimately lead to a safer and even more effective therapy.

Monday, 4 October 2010

Improvement in MS disability after Alemtuzumab

Treatment of early RRMS with Alemtuzumab reduces relapses and the accumulation of disability compared to interferon β. Remarkably PwMS treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained for at least 3 years in comparison to those treated with interferon β.

Critics have poopooed this observation as the study was single-blinded and liable to unblinding; i.e. only the evaluating neurologist is blinded to what the study subject received in the study. Due to infusion reactions from Alemtuzumab it is not possible to do double-blinded studies with the agent; i.e. studies in which the evaluating neurologist and study subjects do no know what they have received.

In an additional analysis of the phase 2 trial data it appears that the participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity during the study trial, were noted to improve after Alemtuzumab but not following interferon β treatment. This would suggest that disability improvement after Alemtuzumab may not simply be due to its anti-inflammatory effects.

This statement is subject to the same criticisms levelled at the whole study; but despite these criticisms this would be the first treatment in MS to offer such a benefit. No wonder PwMS are so excited about the prospect of receiving this therapy.

Preliminary experiments hint that Alemtuzumab stimulates white blood cells to produce growth factors that promote survival of nerve cells and enhanced oligodendrocyte (cells that produce myelin) function. This data will need to be replicated and shown to be relevant in patients treated with Alemtuzumab.

The implications of this research for PwMS cannot be overemphasised; at last a possible treatment with the potential to promote recovery.

Jones et al Brain. 2010 Aug;133(Pt 8):2232-47. Epub 2010 Jul 21.

Friday, 24 September 2010

Oral Cladribine turned down by the European Medicines Agency

Despite evidence that oral cladribine is effective in relapsing-remitting MS the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a negative opinion regarding the marketing authorization for Cladribine Tablets. The CHMP have concerns about the long-term safety of Cladribine.

In my opinion, long-term safety data can only be obtained from post-marketing surveillance studies and the extension study of the pivotal clinical trial. Unfortunately, there are probably not enough patients in the latter study to answer this question. It is a good thing that the drug is licensed in Russia and Australia.

Click here for press release from Merck-Serono

Click here for Bloomberg's press release

Click here for the abstract of the CLARITY study

Wednesday, 22 September 2010

Fingolimod - first oral drug for MS in the United States

The FDA has licensed Fingolimod as a first-line therapy for people with relapsing-remitting MS. Let's hope it passes through the European Medicine Agency (EMA) with the same ease as the FDA and NICE gives it the thumbs up in the UK; the pessimist in me expects not. I predict that its use will be handcuffed in Europe for patients with highly-active disease (similar to Natalizumab) and for patients intolerant of first-line injectable therapies. I also suspect NICE will make it second-line; however this will depend on how much Novartis charge for the drug.

Click here for Bloomberg's Statement

To see how the drug works please see the following YouTube video:

Click here for YouTube video on Fingolimod's mechanism of action

Wednesday, 8 September 2010

Vince Cable's "Science, Research and Innovation" Speech

Apologies about politicising this blog, but what happens to investment in science in the UK will eventually impact on the lives of people with MS and their families. The only way to limit the impact of this devastating disease is through scientific research. The unmet need in MS is massive:

1. We have yet to optimise disease-modifying therapies. Is expecting a cure too much?
2. What about restorative therapies?
3. Symptomatic MS therapies are dismal; too many side effects and limited or suboptimal efficacy.
4. What about prevention? Preventative strategies are just beginning to emerge as potential option.

Without investment in research how are we going to address these needs?

You may find Vince Cable's speech interesting.

Click here for his speech

Sunday, 5 September 2010

No association between allergies and multiple sclerosis

Different types of inflammation are defined by immunologists by the type of cells and the mediators used by these cells.

The current dogma: inflammation in MS is mediated by either T-helper one (Th1) or T-helper 17 (Th17) cells. In comparison, allergies are due to a T-helper two (Th2) immune response, which may be protective in MS.

A large analysis of all published studies on allergic disease and MS provides no evidence of a positive or negative association between the allergic diseases asthma , allergic rhinitis and eczema.

Implications: this analysis challenges the current dogma and also raises questions about the treatment strategy of trying to stimulate Th2 immunity in PwMS; e.g. by promoting parasitic infections of the gut.

Click here for abstract: Monteiro et al. Acta Neurol Scand. 2010 Apr 29 (Epub ahead of print)

Thursday, 2 September 2010

Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis

Does low does naltrexone (LDN) improve quality of life in PwMS?

A study in 80 PwMS was performed to evaluate the effect of 8 weeks of treatment with LDN (4.5mg taken at night). Although LDN was associated with significant improvement in some mental health quality of life measures, the trial was too small to draw definitive conclusions.

Interpretation: this study was too small to be definitive. However, it provides further support for a large definitive study of LDN in MS. Unfortunately, the current "Big Pharma" business model does not support investigating drugs that are off patent. May be "Big Pharma" will now try and develop a follow-on me-to drug to test in PwMS.

Cree et al. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010 Aug;68(2):145-50.

In memory of her mother; J K Rowling's £10m for MS

Good news for MS Research in the UK. The Edinburgh team are leading the field on neuro-restorative therapies in MS.

Click here to read article

A personal account of living with MS: further motivation to prevent this disease.

Cathy John: My diagnosis with MS has taught me the wisdom of 'gathering ye rosebuds while ye may'

Click here to read article

Tuesday, 24 August 2010

Vitamin D and the genome

New research shows the effect of vitamin D on the genome is widespread and localises to genes and areas of the genome associated with increased susceptibility to MS and other autoimmune diseases. This paper is very important in that it provides a clue to why the effects of vitamin D are so widespread and potentially why vitamin D deficiency is associated with so many different diseases.

Click here for article

Please see the following press releases on the significance of this work:

1. The Guardian
2. The Metro

Sunday, 15 August 2010

MS and Twins

Twin studies were first proposed over a century ago to separate the relative contributions of nature (genes) and nurture (the environment) in determining a trait/disease. Higher concordance (where both twin pairs are affected) rates between genetically identical (monozygotic, MZ) twins versus non identical (dizygotic, DZ) twins provides evidence for genetic factors determining a disease. In MS, about 30% of MZ twins are concordant as compared to about 5% of DZ twins. More MZ twins being concordant as compared to DZ, suggests that genes are involved in MS, but the fact that MZ twins are not 100% concordant means that the environment also plays a role in the cause of MS.

However, given that the average adult has billions of cells and that when DNA is copied between these cells errors can arise, differences in the DNA sequence of MZ twins have been reported. Furthermore, a relatively new field of genetics, called epigenetics, which refers to modifications of DNA that regulate the function of the genome, has also been shown to differ between MZ twins. MZ twins discordant for a disease could actually therefore be explained by genetic or epigenetic differences between twins, but until recently this has not been examined in detail.

Baranzini and colleagues sequenced the genome and epigenome from one pair of MZ twins discordant for MS (http://www.nature.com/nature/journal/v464/n7293/full/nature08990.html). Given that the sequence of the first human genome that was released in 2000 represented 15 years of work and $3 billion. This work represents the future of genetic research as technology has vastly improved meaning that a whole genome can be sequenced in 1 week for $10,000.

So what was found? Comparison of the entire genome and some regions of the epigenome did not find any reproducible difference in DNA sequence between twins, suggesting that as previously thought, the environment plays the most significant role in determining twin concordance for MS.

However, genetic and epigenetic differences between twins are not completely ruled out by this study. Whilst the paper represents a huge effort, there are a number of limitations including the fact that only 3% of the epigenome was investigated. The epidemiology of MS (e.g. more females being affected) implies that epigenetics will be important in the cause of the disease and more work is needed to work out which factors are involved.

Watch this space.

Tuesday, 10 August 2010

The Genetics of CCSVI

A recent study published in BMC Medical Genetics (http://www.biomedcentral.com/1471-2350/11/64) has attempted to study genetic risk factors for CCSVI. The authors investigated
copy number variations (CNVs, segments of DNA that differ between people in terms of number of copies) in the HLA region (the region that confers the biggest MS genetic risk) of 15 patients with CCSVI. The authors found that the number of CNVs correlated with the number of venous malformations a patient had.

This is an interesting study, but needs to be validated in a much larger cohort of patients and healthy controls. Furthermore, it is not yet clear how CNVs in different parts of the HLA region can lead to the same CCSVI phenotype.

Monday, 9 August 2010

Following the sunshine vitamin

This BBC radio show is a great listen. It’s discusses the virtues of Vitamin D, particularly where Britain’s health is concerned. The presenter interviews many leading experts in vitamin D such as Prof. Reinhold Vieth (University of Toronto), Dr. Doug Brown (MS Society) plus many others. It’s a succinct story about the ins and outs of the vitamin and why our low levels of vitamin D are becoming a concern. The benefits of a higher vitamin D status are said to span some 30 diseases (including MS), pregnancy and even sports performance.

As it is difficult to get enough vitamin D from diet alone, many are recommending vitamin D supplementation (vitamin D3), and some are pushing for the fortification of foods.

It’s a half-hour show and good food for thought, so have a listen here: http://www.bbc.co.uk/iplayer/episode/b00t66nr/Food_Programme_01_08_2010/

Monday, 26 July 2010

The Zamboni myth: why “CCSVI” is surreal

Some further reflection on CCSVI: click here

Cord blood banking; what to advise regarding stem cell therapies

My response to a question about banking cord blood from a newborn baby to treat a family member with severe MS.

"The potential of stem cell therapies for neurological conditions has been over-hyped by both the basic scientists involved and the media. This is great pity as it raises false expectations of a breakthrough for vulnerable people with disabling conditions.

At present the research is a long way from reaching the clinic with some early exploratory safety studies underway in the UK and elsewhere. The science suggests that mesenchymal stem cells, i.e. those derived from skin, and bone-marrow derived stem cells may work as immunomodulatory therapies rather than as a neuro-restorative therapies; this means that they will be of benefit early in the course of the disease to modify the clinical course. They will not help people who are already disabled.

Embryonic stem cells, which are derived from foetal tissue, are unlikely to be used in humans as they have a propensity to cause primitive tumours because of their ability to differentiate in numerous cell types; there are several reports of this occurring already. In my opinion, routine storage of cord blood cells should therefore be done for altruistic reasons to support research. To do it specifically for an unproven therapy or a potential therapy in the future cannot be recommended at this stage."

Genes determine low levels of vitamin D: implications for MS

Vitamin D is crucial for maintenance of the immune system and vD deficiency has been implicated in the causal pathway of MS. In this study genetic variants at three places in the genome were associated with vD levels. Subjects with a score that combined all three variants were at increased risk of having low vD concentrations. These variants in the genome are near genes involved in cholesterol metabolism and vD transport. It will be very important to see if these areas are associated with MS. This study tells us that the story behind vD and MS will be very complex; it will take a lot of hard work to pin down how vD deficiency contributes to the pathogenesis of MS.

Wang et al. Lancet. 2010 Jul 17;376(9736):148-9.

CCSVI Alliance

The proponents of CCSVI launch an alliance: http://www.ccsvi.org/

Tuesday, 22 June 2010

More news on CCSVI

Using virtually identical ultrasound techniques to try and reproduce the results by Dr Zamboni, Florian Doepp and colleagues in Berlin have not been able to reproduce the results that put CCSVI on the map. Their results seriously challenge the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS.

What are the implications of these findings for people with MS?

Clearly we need to wait for other studies in this area to clarify the discrepency in the results of these studies. From a clinical perspective we continue to advise against undergoing any interventional therapy until there is clarity on whether or not CCSVI is a real entity or not.

Please click here for an abstract on the study

Sativex for MS-related spasticity

It has been a long haul, but finally another option for people with MS-related spasticity.

Click here for press release

The signficance of this license cannot be under estimated; particularly as the registration study will probably set a precedent for how spasticity studies are done in the future. The Ashworth Scale has had its day and is seriously flawed as an outcome measure. This result can also be viewed as a victory for patient-related outcome measures or PROMS.

Friday, 30 April 2010

Reduced maternal UV exposure contributes to MS risk in later life

A study reported in today’s BMJ confirms that multiple sclerosis is probably an epigenetic disease with in utero exposure to low vitamin D levels determining disease susceptibility in later life. Judith Staples and colleagues show that low maternal exposure to ultraviolet radiation in the first trimester of pregnancy is independently associated with subsequent risk of MS in their offspring in Australia. The adjusted incidence rate ratio for MS is 1.32 (95% confidence interval 1.10 to 1.58, P<0.01) for those subjects born in November or December compared with those born in May or June. As expected the inverse is observed in the Northern hemisphere. How exposure to low vitamin D levels in utero determines disease susceptibility is unknown but is clearly an area of major scientific interest and is being actively pursued by our group. The public health implications of these observations are profound and support the need for high-dose vitamin D supplementation in early pregnancy. In a collaborative study between Queen Mary University of London and Oxford University we are exploring this phenomenon further and would urge anyone with MS to complete our online survey. click here to complete online survey.

Staples et al. Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis. BMJ 2010;340:c1640.

Sunday, 18 April 2010

Some MS-related News from the AAN in Toronto

[P02.155] The Cellular Immune Response Against Epstein-Barr Virus in Multiple Sclerosis and Cross-Reactivity with Brain Antigens
J. William Lindsey, Landon M. Hatfield, Houston, TX

The cellular immune response against EBV is similar in PwMS and controls; with no evidence of cross-reactivity between EBV and brain antigens.

[S31.003] Evaluation of the Incidence of Anti-JCV Antibodies in a Cohort of Natalizumab-Treated MS Patients
Leonid Gorelik, Sarah Bixler, Michaela Lerner, Ewa Wilson, Anne Cheung, Ling Ling Chen, Melissa Berman, Mary Crossman, Ken Simon, Brian Schlain, Susan Goelz, Meena Subramanyam, Cambridge, MA

Classification of MS patients as sero-negative or sero-positive with respect to previous JC virus exposure is possible with a new assay. Thirteen out of 13 patients who developed PML all had evidence of prior infection with JCV, as measured by the presence of anti-JCV antibodies. This assay will help stratify patients into high and low risk groups and modify the risk for individual subjects; those with positive antibodies will have double the risk of getting PML (this is based on the observation that ~54% of subjects in the original natalizumab trial were sero-positive. The corollary to this is that subjects seronegative have a very low risk of getting the disease.

[P05.047] The Kinetics of CSF Lymphocyte Recovery after Cessation of Natalizumab in Patients with Multiple Sclerosis
Adil Javed, Chicago, IL, Howard Rossman, Farmington Hills, MI, Anthony Reder, Chicago, IL

After stopping natalizumab treatment CSF lymphocytes counts may recover within 3 months. This implies that immune surveillance is restored shortly after cessation of natalizumab therapy and coincides with observation that IRIS in the setting of natalizumab-associated PML also occurs at this time-point unless hastened by plasma exchange.

[S31.002] Effects of Natalizumab Treatment on the Presence of JC Virus DNA in Blood or Urine in Multiple Sclerosis Patients
Richard Rudick, Solon, OH, Paul O'Connor, Toronto, ON, Canada, Chris Polman, Amsterdam, The Netherlands, Andrew Goodman, Rochester, NY, Soma S. Ray, Stephanie Jurgensen, Cambridge, MA, Susan Goelz, Portland, OR, Fiona Forrestal, Maidenhead, Berkshire, United Kingdom, Leonid Gorelik, Alfred Sandrock, Cambridge, MA

Cross-sectional and longitudinal testing in a large cohort of MS patients demonstrates that there is no substantial change in the presence of JCV DNA in the plasma, whole blood or urine with natalizumab treatment. Less than 1% (4 out of 1397) patients had JCV DNA in their blood, which did not predict the occurrence of PML. In addition, in cases that developed PML plasma samples were negative prior to diagnosis. This study and other recent studies seriously calls into question the validity of the results of other smaller studies suggesting that natalizumab increases peripheral blood and urine JCV detection rates. From a practical perspective we cannot use plasma, peripheral blood or urine JCV DNA detection to predict PML risk in natalizumab-treated patients. Will this study end the debate? Please watch this space.

[P05.036] Long-Term Follow-Up of Immune Thrombocytopenia after Treatment of Multiple Sclerosis Patients with Alemtuzumab in CAMMS223
Edward Fox, Round Rock, TX, N. A. on Behalf of the CAMMS223 Study Group

Cutaneous symptoms of ITP went unrecognized in the 1st case until onset of a fatal cerebral haemorrhage. Five other cases were subsequently diagnosed with ITP with onset between 1.5 and 16 months after alemtuzumab. In one case ITP resolved without treatment. In 2 cases, remission was achieved with corticosteroid treatment alone and in the other 2 patients following treatment with rituximab cycle. On balance these results suggest that ITP is a manageable side effect of alemtuzumab provided it is detected and treated early.

[P04.213] Alemtuzumab Reduces Disease Progression in RRMS: Long-Term Results of the CAMMS223 Trial
Omar Khan, Detroit, MI, N. A. on Behalf of the CAMMS223 Study Group

At year 4: (1) 77% of alemtuzumab-treated patients were relapse–free compared to 49% of IFNB-1a-treated patients; (2) 91% of alemtuzumab-treated patients were disease progression free vs. 68% of IFNB-1a patients (p<0.001); (3) 71% of alemtuzumab patients were clinically disease-free v. 35% for IFNB-1a at year 4 (p<0.001). A treatment effect at year 4 in patients who only completed 2 annual cycles of alemtuzumab during the first 12 months supports the strategy of aggressive induction therapy in early MS. No wonder PwMS want this drug.

Wednesday, 14 April 2010

Strains of Epstein-Barr virus infecting multiple sclerosis patients.

Of all the viruses EBV is the clear leader of the pack as being the most likely cause of MS. Could a specific strain of EBV cause MS? A superficial look at has not revealed obvious difference between EBV strains in people with MS and control subjects.

Brennan R, et al. Strains of Epstein-Barr virus infecting multiple sclerosis patients. Mult Scler. 2010 Mar 29. [Epub ahead of print]

Opinion: a deeper look is required before abandoning the possibility that a specific strain may cause the disease. The million dollar question is how and where to look?

Sunday, 11 April 2010

How do you prove something is the cause of MS?

Causation theory is a complex science and involves philosophy and the social sciences. Causation is rarely, if ever, a black-or-white issue. The first to appreciate this was Robert Koch who discovered the cause of TB; in fact he had to formulate his postulates to convince his peer-group that he had found the cause of TB. Even then it took Robert Koch more than a decade to convince the scientific community of the significance of his findings.

The issue of causation theory has come up recently in relation to our posts on CCSVI. If you are interested in reading more about causation and causation theory, specifically in relation to MS, I would recommend the following articles as a starter:

Giovannoni G, et al. Infectious causes of multiple sclerosis. Lancet Neurol. 2006 Oct;5(10):887-94.

Giovannoni G, Ebers G. Multiple sclerosis: the environment and causation. Curr Opin Neurol. 2007 Jun;20(3):261-8.

Saturday, 10 April 2010

Chronic cerebrospinal venous insufficiency and MS

Neurologists speak-out about CCSVI!

Click here for: Khan et al. Ann Neurol. 2010 Mar;67(3):286-90.

Progressive loss of nerve fibres in the eye in MS

Using a very cool technology called optical coherence tomography (OCT) a new study has demonstrated progressive thinning of the retinal nerve fibre layer as a function of time in some patients with MS. Importantly, this thinning occurred in either the presence or absence of previous optic neuritis (focal inflammation in the optic nerve) and was associated with clinically significant visual loss.

These findings indicate that asymptomatic or sub-clinical nerve fibre (or axonal loss) occurs in the visual pathways in MS.

Opinion:

1. If these findings can be confirmed it will add credence to the claims that MS is a primary neurodegenerative disease. "I hope not."

2. This study supports the use of OCT as a method to evaluate the effectiveness of neuroprotective agents in MS; we will need to show that drugs or combinations of drugs stop or at least slow down this loss of nerve fibres to accept that they are "neuroprotective".

Click here: Talman et al. Longitudinal study of vision and retinal nerve fiber layer thickness in MS. Ann Neurol 2010; in press.

Thursday, 8 April 2010

Early life factors in MS

We need your help with a survey investigating early life factors in MS. If you have MS and are willing to help please complete the following survey:

Click here

Thank you.

Saturday, 27 March 2010

Sativex in MS-related spasticity

Click here

Treating spasticity in MS is a big problem; it is very common and the current drugs we use are too sedating and tend to have a negative impact on cognition, which limits their use early on in the course of the disease.

This study compares Sativex (the active ingredient in cannabis) with placebo in a 15-week study. The design of this study is interesting for two reasons: (1) it used an enrichment phase to select responders before randomising them to blinded active comparator stage of the trial; and (2) it used a numeric rating scale (NRS) as the primary outcome rather than the Ashworth scale (the traditional outcome measure in spasticity trials). In summary the change in NRS score and responder-status (defined as a greater than or equal to 30% improvement from baseline) were both significantly superior for Sativex, compared with placebo. Importantly, Sativex appears to be well tolerated in this group of patients with quite advanced MS.

It will be interesting to see if Sativex gets a license based on the results of this trial. The availability of Sativex will allow us to "spread the hope" and offer something to patients in whom our current medications are not enough to control their spasticity.

Tuesday, 23 March 2010

Vitamin D status is associated with relapse rate in pediatric-onset MS

Click here

Among 110 North American paediatric CIS/MS subjects, every 10 ng/mL increase in the adjusted 25 hydroxyvitamin D3 level was associated with a 34% decrease in the rate of subsequent relapses.
This study adds compelling evidence in support of a role for vitamin D in reducing MS relapse rates as initially seen in smaller studies in adult MS cohorts (Wingerchuk et al, JNNP 2005; Soilu-Hänninen et al, JNNP, 2008). As vitamin D deficiency/insufficiency is endemic worldwide (Holick, NEJM, 2007), further studies of vitamin D as a treatment measure in MS are warranted.

Sreeram Ramagopalan

43 confirmed post-marketing Natalizumab-related cases of PML

The news of 43 confirmed cases of post-marketing Natalizumab-related PML coincides with the timely publication of the description of the first 28 such cases and a review on the topic:

Clifford DB, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010 Apr;9(4):438-446.

Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010 Apr;9(4):425-437.

These developments underpin the urgent efforts to implement an appropriate risk-stratification strategy to lower the risks of developing PML for people with MS receiving Natalizumab.

Please watch this space for an update.

Human leukocyte antigen-DR15, low infant sibling exposure and multiple sclerosis: Gene-environment interaction

Click here!

The cause of multiple sclerosis (MS) is not yet conclusively known but both genes and the environment are important. A region on chromosome 6, the HLA class II, exerts the single strongest genetic effect but the involvement of the environment is also inescapable and is no better illustrated than by the geographical distribution of the disease. The identity of the environmental factors involved in MS is not known unequivocally but there are a few leading candidates, namely, Epstein-Barr virus, vitamin D and smoking. It has been suggested that low sibling infant exposure (classed as having no older siblings and any younger siblings having an age difference of at least 5 years) increases MS risk (Ponsonby et al, JAMA, 2005). Genetic and environmental factors are not independent. In an intriguing study, van der Mei and colleagues observed that HLA-DRB1*15 (a form of the gene involved in MS on chromosome 6) interacted with low sibling infant exposure to increase MS risk. This result could thus be of importance in disease aetiology but requires replication. Other groups have been unable to support an effect of low infant sibling exposure on the risk of MS (Sadovnick et al, Lancet Neurol, 2005; Bager et al, Am J Epidemiol, 2006) so the gene-environment interaction uncovered by van der Mei and others may be specific to Australia; this will require confirmation.

Dr Sreeram Ramagopalan

Tuesday, 16 March 2010

2010 Annual Evidence Update on Multiple Sclerosis

You may find the following NHS resource useful:

Click here

Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis

Another blank. Sargsyan and colleagues failed to find evidence of persistent infection in the cells that produce antibodies (plasma and B cells) within the brains of people with MS. Only in active MS plaques was EBV-encoded RNA (EBER)-1 rarely detected.

Click here

Conclusion: My take on this is that we need to focus on active and preactive MS lesions; I suspect that is where the action will be. Although the score at the moment is strongly against overt CNS EBV infection being a direct factor in MS pathogenesis we need to keep an open mind to the contrary. Post-mortem tissue studies are not necessarily the best means of investigating the link between active EBV infection within the central nervous system and MS.

Thursday, 4 March 2010

EBV specific killer cells in early MS

A new study looking into the immune response to EBV in people with MS has shown that a group of white blood cells responsible for killing EBV, the so called CD8+ cytotoxic lymphocytes or CTLs, are increased in theblood of people with early MS as compared to controls and other patients. Importantly these cells were shown to be increased in the spinal fluid of subjects with MS compared to subjects with other diseases. This data further strengthens the association between EBV and MS, in particular early disease.

Jaquiéry E, et al. Intrathecal immune responses to EBV in early MS. Eur J Immunol. 2009 Dec 16;40(3):878-887. [Click here]

Tuesday, 23 February 2010

Progressive Thinking

"Gross National Happiness (GNH)" vs. "Gross Domestic Product (GDP)"

Please see Nature Editorial, "Progressive Thinking".

What do you think?

Friday, 12 February 2010

Multiple sclerosis 'blood blockage theory'

http://news.bbc.co.uk/1/hi/health/8374980.stm

We remain sceptical about this theory; venous outflow obstruction does not explain the epidemiology of MS and falls down short on many other observations.

The interventions required to relieve venous obstruction are not without risks. The 'blood blockage theory' remains a theory and any involvement with the theory should be via ethically approved research studies.

Wednesday, 10 February 2010

Ethical or unethical advertising?

Is direct-to-patient on-line advertising ethical or not? Please see following news piece for a debate on the issue:

Meredith Wadman. Drug ads move online, creating a web of regulatory challenges. Nat Med 2010;16:22. or http://www.nature.com/nm/journal/v16/n1/full/nm0110-22.html

The earlier use of natalizumab!

Biogen-Idec and Elan have announced the eminent start of a clinical trial, called Surpass, to assess the effectiveness of switching to natalizumab (Tysabri) in patients that have experienced disease breakthrough with either glatiramer acetate or interferon beta.

I interpret this as a show of confidence by the companies that we can overcome the PML problem; there are now 31 confirmed cases of post-marketing PML in patients with MS receiving natalizumab.

Sunday, 7 February 2010

End of Life Issues

We need your help. Please copy and past this link into your browser's address field to participate in a survey on end of life issues in relation to multiple sclerosis:

https://www.surveymonkey.com/s/end-of-life-ms-survey

Please send this link to as many people with multiple sclerosis that you know.

Thank you

What dose of vitamin D?

After our MS Research Day on the 30th January we have been asked by several people about the correct dose of vitamin D to take to try and prevent MS and related disorders. Unfortunately we don't know. Until we do the appropriate clinical trials any recommendations will not be evidence-based. At present we defer to the Vitamin D Council's recommendations (www.vitamindcouncil.org):

".... if you have little UVB exposure, my advice is as follows: healthy children under the age of 1 years should take 1,000 IU per day—over the age of 1, 1,000 IU per every 25 pounds of body weight per day. Well adults and adolescents should take 5,000 IU per day....."

Before starting vD supplementation at this level we would urge you to see your doctor to discuss things formally; ideally this should be done in conjunction with blood monitoring.

Saturday, 6 February 2010

Do you think placebo-controlled trials are ethical?

I received a strongly worded email criticising our site for participating in placebo-controlled MS clinical trials; in the opinion of the critic as there are licensed disease-modifying therapies for people with MS, placebo-controlled trials are unethical.

What do you think?

I responded as follows:

“Yes, there are several ethical considerations that need to be taken into account in relation to placebo-controlled MS trials; this issue has been extensively debated and discussed in the literature and there are International guidelines on the conduct of placebo-controlled trials.

In the UK, ethics committees make us insert a statement in the patient information sheet stating that there are licensed therapies and that by participating in a particular study people with MS could be denying themselves active treatment. In addition, we have to reconsent study participants after each relapse and/or confirmed disease progression. In addition, contemporary placebo-controlled trials have rescue arms, which allow study subjects active treatment within a study if their disease becomes active.

It is important to recognise that despite there being licensed therapies some patients don’t want to go onto them because they are injectables; if we did all trials with an active comparator, i.e. an injectable, we would exclude these patients from participating. People with needle phobia and those that have failed injectables because of side effects make up the majority of patients volunteering for placebo-controlled trials. I suspect, however, that once oral therapies are licensed for MS it will become very difficult to recruit subjects for placebo-controlled trials.

The issue of placebo-controlled trials should also be viewed on the background of the limited efficacy of the current injectables and the fact that we still don’t have data on whether or not they impact on the long-term prognosis of the disease.

In summary, I don’t think it is unethical to do placebo-controlled trials. However, you have to do them with carefully designed trials and informed consent. People with MS are perfectly capable of making an informed decision about not taking up the option of going on to a moderately effective first-line therapy and volunteering for a placebo-controlled trial of a new agent. At the end of the day we need to be pragmatic; without clinical trials we won’t advance the field and people living with MS are very aware of this. “


Please have your say if you agree or disagree with this stance!

Monday, 1 February 2010

FDA approves dalfampridine

On the 22nd January the FDA approved dalfampridine (Ampyra, Elan/Acorda Therapeutics) extended-release tablets to improve walking in people with MS. Dalfampridine is a potassium channel blocker, that has been shown to improve walking speeds vs placebo. The drug was previously known as fampridine sustained release. Given at doses greater than the recommended 10 mg twice a day, dalfampridine can cause seizures. The most common adverse events reported in clinical trials were urinary tract infection, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling in the nose or throat, constipation, diarrhoea, indigestion, throat pain, and burning, tingling, or itching of skin. Dalfampridine, should not be used in patients with moderate or severe kidney disease. In these patients, blood levels with the drug approach those associated with the occurrence of seizures.

Please see previous posting below discussing the concerns with dalfampridine.

Sunday, 24 January 2010

Primary EBV infection and MS

A NEW STUDY ON INITIAL EBV INFECTION AND MS

Ascherio et al. Primary EBV infection and MS. Ann Neurol 2010; in press.

"In this study all EBV-negative subjects (10 out of 10) who developed MS became EBV positive before MS onset. In contrast, only 36% (10 of the 28) controls subjects who were EBV-negative became EBV-positive with follow-up. Ascherio and colleagues conclude that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection."

Interpretation: This study is very important with regard to pinning down whether or not EBV causes MS. It ticks one of the criteria for causation; i.e. the correct temporal sequence. You need to get infected with EBV prior to MS onset.

Prof G

Which oral?

I am often asked which oral would you prescribe? There is no simple answer to this question. The answer will depend on several factors some of which are still to emerge; to mention a few:

1. If and when these agents get licensed and the conditions of licensing; i.e. a first- or second-line indication.
2. The price and more importantly the cost-effectiveness of the agents; NICE will dictate the conditions of use in the UK.
3. Level of disease activity; inactive vs. active vs. highly-active disease.
4. Perceived long-term risk; infections and possible risk of malignancy.
5. Local infrastructure to start the orals.
6. Requirements and intensity of monitoring whilst on medication.
7. Fertility issues.
8. Previous use of other disease-modifying agents.
9. Underlying medical problems.
10. Etc, etc.

It is clear from the above that the decisions about which agent to use will be personalised and will depend largely on patient choice. It is important to ensure that patients have choice and that the choice is an informed one.

Prof G

Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis

In patients with relapsing–remitting multiple sclerosis, oral fingolimod was more effective than intramuscular interferon beta-1a in reducing relapse rates. Adverse events associated with fingolimod included herpes virus infections, atrioventricular block, macular edema, skin cancer, and liver-enzyme elevation.

http://content.nejm.org/cgi/content/full/NEJMoa0907839

A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis

In patients with relapsing–remitting multiple sclerosis, oral fingolimod reduced the rates of relapse and disability progression, as compared with placebo. Adverse events included bradycardia, atrioventricular conduction block, macular edema, elevations in liver-enzyme levels, and mild hypertension.

http://content.nejm.org/cgi/content/full/NEJMoa0909494

A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis

Oral cladribine reduced relapse rates and lowered the risk of sustained disability in patients with relapsing–remitting multiple sclerosis. Patients who were treated with cladribine had large reductions in lymphocyte counts and more infections, including one death from reactivation of tuberculosis.

http://content.nejm.org/cgi/content/full/NEJMoa0902533

SAFETY WARNING FOR NATALIZUMAB

EU RECOMMENDS MORE SAFETY WARNINGS FOR ELAN, BIOGEN'S TYSABRI
2010-01-21 18:28:09.776 GMT

21 January 2010; EMA/37607/2010: Press Office

European Medicines Agency recommends additional measures to better manage risk of progressive multifocal leukoencephalopathy (PML) with Tysabri. The risk of PML increases after two years, but benefits of Tysabri continue to outweigh risks for patients with highly active relapsing-remitting multiple sclerosis.

The European Medicines Agency has finalised a review of Tysabri (natalizumab) and the risk of progressive multifocal leukoencephalopathy (PML), a rare brain infection caused by the JC virus. The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the risk of developing PML increases after two years of use of Tysabri although this risk remains low. However, the benefits of the medicine continue to outweigh its risks for patients with highly active relapsing-remitting multiple sclerosis, for whom there are few treatment options available.

Because it is important that PML is detected early, the Committee recommended that a number of measures be put in place to ensure that patients and doctors are fully aware of the risks of PML. These include:

* an update of the product information to add information about the increase in the risk of PML after two years of treatment and additional advice on how to manage patients who show signs of PML;
* forms to be signed by patients at the beginning of treatment with Tysabri, and again after two years of treatment, after in-depth discussions about the risk of PML with their doctor.

Measures to minimise the risk of PML were part of the initial marketing authorisation for Tysabri, issued in June 2006. Since then, they have been continuously updated and strengthened to increase awareness of the risk of PML.

The new measures are designed to complement the existing recommendations that patients, and their carers, partners and families should be made aware of the symptoms of PML and that patients should be closely monitored throughout treatment.


Notes

1. Tysabri, from Elan Pharma International Ltd, is used to treat relapsing-remitting multiple sclerosis in patients with high disease activity despite treatment with a beta-interferon or whose disease is severe and progressing rapidly.

2. More information about the review of Tysabri is available in a
question-and-answer document. http://www.ema.europa.eu/humandocs/PDFs/EPAR/tysabri/Tysabri_A20-29_Q&A.pdf

3. More information about Tysabri is available in the European Public Assessment Report: http://www.ema.europa.eu/humandocs/Humans/EPAR/tysabri/tysabri.htm

4. This press release, together with other information on the work of the European Medicines Agency, can be found on the Agency's website: www.ema.europa.eu

Tuesday, 5 January 2010

1st Barts and The London MS Research Day - 30th Jan 2010

We are holding an MS Research Day for people with MS and their families on the 30th January 2010. If you want to attend please RSVP to Maria Espasandin (M.Espasandin@qmul.ac.uk).

You can download an invitation and preliminary programme from the following link:

https://download.yousendit.com/TzY3c0w1Qk5tNEpMWEE9PQ

We look forward to seeing you on the 30th.

Prof G