Sunday, 31 March 2013

BG12 will cost $54,900 annually

Robert Weisman. Biogen Idec’s new pill to treat MS will cost about $54,900 per patient annually.

Biogen Idec Inc. said Friday it will price Tecfidera, its newly approved pill to treat multiple sclerosis, at $54,900 a year per patient in the United States.

Officials at the Weston-based biotechnology company said the figure represents a “solid value” for MS patients, who will take the capsule twice a day. Most MS treatments now on the market have to be injected or taken through intravenous infustion.

“We think it’s appropriate price,” said Tony Kingsley, executive vice president for commercial operations at Biogen Idec. “The clinical benefit of the product is very meaningful. We look at it in comparison to the alternatives on the market and the investment we’ve made.”

Biogen Idec, the largest Massachusetts-based biotechnology company, won Food and Drug Administration approval Wednesday to sell the oral therapy. Company officials said Tecfidera will distributed, stocked, and available topatients “on or around” Monday.

MS is a chronic autoimmune disease that affects the central nervous systems of about 400,000 people in the US and about 2.5 million worldwide, disrupting communication between the brain and other parts of the body. Over time, patients can suffer from muscle weakness, loss of balance, and a progressive decline in function.

Most current treatments for MS are priced between $45,000 and $60,000 annually.

The cost of Tecfidera represents a slight premium over the the $51,000 projected by investment fund managers polled by New York research firm ISI Group. But it is less expensive than the first MS pill, Gilenya, sold by Swiss drug maker Novartis AG, which costs $60,000.

A more recent market entry, the Aubagio pill marketed by the Cambridge-based Genzyme division of French drug maker Sanofi SA, has been priced at $45,000 a year. Analysts said Tecfidera has demonstrated greater safety and effectiveness than competing pills.

Click here to read full article

"Is the US Healthcare system sustainable?"

On-line disease monitoring

#MSBlog: Has the era of on-line disease monitoring finally arrived? Not if you are a MSer under the care of the NHS.

Epub: Bove et al. Evaluation of an Online Platform for Multiple Sclerosis Research: Patient Description, Validation of Severity Scale, and Exploration of BMI Effects on Disease Course. PLoS One. 2013;8(3):e59707. doi: 10.1371/journal.pone.0059707.

OBJECTIVES: To assess the potential of an online platform, (PLM), for research in multiple sclerosis (MS). An investigation of the role of body mass index (BMI) on MS disease course was conducted to illustrate the utility of the platform.

METHODS: First, we compared the demographic characteristics of subjects from PLM and from a regional MS center. Second, we validated PLM's patient-reported outcome measure (MS Rating Scale, MSRS) against standard physician-rated tools. Finally, we analyzed the relation of BMI to the MSRS measure.

RESULTS: Compared with 4,039 MS Center MSers, the 10,255 PLM members were younger, more educated, and less often male and white. Disease course was more often relapsing remitting, with younger symptom onset and shorter disease duration. Differences were significant because of large sample sizes but small in absolute terms. MSRS scores for 121 MS Center MSers revealed acceptable agreement between patient-derived and physician-derived composite scores (weighted kappa = 0.46). The Walking domain showed the highest weighted kappa (0.73) and correlation (rs = 0.86) between MSer and physician scores. Additionally, there were good correlations between the MSer-reported MSRS composite and walking scores and physician-derived measures: Expanded Disability Status Scale (composite rs = 0.61, walking rs = 0.74), Timed 25 Foot Walk (composite rs = 0.70, walking rs = 0.69), and Ambulation Index (composite rs = 0.81, walking rs = 0.84). Finally, using PLM data, we found a modest correlation between BMI and cross-sectional MSRS (rho = 0.17) and no association between BMI and disease course.

CONCLUSIONS: The PLM population is comparable to a clinic population, and its MSer-reported MSRS is correlated with existing clinical instruments. Thus, this online platform may provide a venue for MS investigations with unique strengths (frequent data collection, large sample sizes). To illustrate its applicability, we assessed the role of BMI in MS disease course but did not find a clinically meaningful role for BMI in this setting.

"This is a very important proof-of-principle study showing that online tools can be used to monintor the clinical course of MS. This is definitely the way forward. Can we manage MS using online tools and can we do studies using this technology? Watch this space!"

Research: North South Gradients in Oz assessed by Drug use

Hollingworth S, Walker K, Page A, Eadie M. and the Australian regional prevalence of multiple sclerosis. Mult Scler. 2013. [Epub ahead of print]

BACKGROUND: Over some 50 years, field surveys have shown that the prevalence of multiple sclerosis (MS) increases with increasing distance from the equator in both the northern and the southern hemispheres. Such a latitudinal gradient has been found in field surveys of MS prevalence carried out at different times in various local regions of Australia.
OBJECTIVE: The objective of this paper is to use a pharmacoepidemiological approach to obtain whole of population estimates of the prevalence of MS in the various Australian states and territories from the use of MS disease-modifying drugs used to treat relapsing-remitting MS (RRMS).
METHODS: We analysed the dispensed use of subsidised RRMS drugs by jurisdiction.
RESULTS: In the 2005-2008 period, the calculated mean treated RRMS prevalence in Australia ranged from 7.5 per 100,000 in the far north to 53.2 per 100,000 in the extreme south and was linearly related to increasing southerly latitude. Public domain Australian data suggested that multiplying this prevalence by a factor of 2.2 (to account for untreated RRMS and other types of MS) may provide a measure of the prevalence of all varieties of the disease.
CONCLUSION: These findings provide contemporary and more comprehensive evidence for the gradient of MS prevalence with latitude in Australia than has previously been available.
The results say it all. Maybe be of interest particularly to our friends Down Under and the Vitamin D brigade.

Research Biomarker for Progression

Gnanapavan S, Ho P, Heywood W, Jackson S, Grant D, Rantell K, Keir G, Mills K, Steinman L, Giovannoni G.Progression in multiple sclerosis is associated with low endogenous NCAM. J Neurochem. 2013 Mar 15. doi: 10.1111/jnc.12236. [Epub ahead of print]

Multiple sclerosis (MS) is a central nervous system (CNS) disorder characterised by demyelination and neurodegeneration. Although hallmarks of recovery (remyelination and repair) have been documented in early MS, the regenerative capacity of the adult CNS per se remains uncertain with the wide held belief that it is either limited or non-existent. The neural cell adhesion molecule (NCAM) is a cell adhesion molecule that has been widely implicated in axonal outgrowth, guidance and fasciculation. Here, we used in vitro and in vivo studies in MS to investigate the role of NCAM in disease progression. We show that in health NCAM levels decrease over time, but this occurs acutely after demyelination and remains reduced in chronic disease. Our findings suggest that depletion of NCAM is one of the factors associated with or possibly responsible for disease progression in MS.

This study  shows that following demyelination in a test tube in animals and progressive MS there is a loss of neural cell adhesion molecule in culture, the CNS tissues or CSF in MS. There is noticeable a loss of this molecule when RRMSers develop SPMS. This molecule is associated with nerve outgrowth as nerves are lost the levels of NCAM drop. Is this causal to the disease process or part of the consequence of the disease process but the less NCAM there is in the CSF the more likely the MSer is to have more disability. We will have to wait until further studies are reported.

CoI: This is work from Team G and was part of the Promise2010 initative

Saturday, 30 March 2013

CCSVI March 2013

Valdueza JM, Doepp F, Schreiber SJ, van Oosten BW, Schmierer K, Paul F, Wattjes MP. What went wrong? The flawed concept of cerebrospinal venous insufficiency. J Cereb Blood Flow Metab. 2013 Feb 27. doi: 10.1038/jcbfm.2013.31. [Epub ahead of print]

In 2006, Zamboni reintroduced the concept that chronic impaired venous outflow of the central nervous system is associated with multiple sclerosis(MS), coining the term of chronic cerebrospinal venous insufficiency ('CCSVI'). The diagnosis of 'CCSVI' is based on sonographic criteria, which he found exclusively fulfilled in MS. The concept proposes that chronic venous outflow failure is associated with venous reflux and congestion and leads to iron deposition, thereby inducing neuroinflammation and degeneration. The revival of this concept has generated major interest in media and patient groups, mainly driven by the hope that endovascular treatment of 'CCSVI' could alleviate MS. Many investigators tried to replicate Zamboni's results with duplex sonography, magnetic resonance imaging, and catheter angiography. The data obtained here do generally not support the 'CCSVI' concept. Moreover, there are no methodologically adequate studies to prove or disprove beneficial effects of endovascular treatment in MS. This review not only gives a comprehensive overview of the methodological flaws and pathophysiologic implausibility of the 'CCSVI' concept, but also summarizes the multimodality diagnostic validation studies and open-label trials of endovascular treatment. In our view, there is currently no basis to diagnose or treat 'CCSVI' in the care of MS patients, outside of the setting of scientific research.

This is open access so you can read and debate it yourself  but this study indicates that the concept of CCSVI may be based on thin ice
and this paper calls for a "complete halt to therapy".
"With the ‘old’ ‘CCSVI’ criteria being refuted, the ‘new’ criteria seem to call for new confirmatory studies to confirm or refuse the new results. However, the scientific quality appears unaltered low, as the core statements of our critical discussion also apply to the new modified criteria"

I see the hate campaign will be on its way again however coupled with hints of the blinded trial not being positive then it is going to be increasingly difficult to argue against this view.

CoI: One of the authors works at the Blizard Institute (Neuroscience) & Barts Health

But if a group were going to try to refuse it it may be this next group

Zivadinov R, Magnano C, Galeotti R, Schirda C, Menegatti E, Weinstock-Guttman B, Marr K, Bartolomei I, Hagemeier J, Maria Malagoni A, Hojnacki D, Kennedy C, Carl E, Beggs C, Salvi F, Zamboni P. Changes of Cine Cerebrospinal Fluid Dynamics in Patients with Multiple Sclerosis Treated with Percutaneous Transluminal Angioplasty: Case-control Study. J Vasc Interv Radiol. 2013 Mar 20. doi:pii: S1051-0443(13)00531-9. 10.1016/j.jvir.2013.01.490. [Epub ahead of print
PURPOSE:To investigate characteristics of cine phase contrast-calculated cerebrospinal fluid (CSF) flow and velocity measures in patients with relapsing-remitting (RR) multiple sclerosis (MS) receiving standard medical treatment who had been diagnosed with chronic cerebrospinal venous insufficiency (CCSVI) and underwent percutaneous transluminal angioplasty (PTA).
MATERIALS AND METHODS: This case-controlled, magnetic resonance (MR) imaging-blinded study included 15 patients with RR MS who presented with significant stenoses (≥50% lumen reduction on catheter venography) in the azygous or internal jugular veins. Eight patients underwent PTA in addition to medical therapy immediately following baseline assessments (case group) and seven had delayed PTA after 6 months of medical therapy alone (control group). CSF flow and velocity measures were quantified over 32 phases of the cardiac cycle by a semiautomated method. Outcomes were compared between groups at baseline and at 6 and 12 months of the study by mixed-effect model analysis.
RESULTS: At baseline, no significant differences in CSF flow or velocity measures were detected between groups. At month 6, significant improvement in flow (P<.001) and velocity (P = .013) outcomes were detected in the immediate versus the delayed group, and persisted to month 12 (P = .001 and P = .021, respectively). Within-group flow comparisons from baseline to follow-up showed a significant increase in the immediate group (P = .033) but a decrease in the delayed group (P = .024). Altered CSF flow and velocity measures were associated with worsening of clinical and MR outcomes in the delayed group.
CONCLUSIONS: PTA in patients with MS with CCSVI increased CSF flow and decreased CSF velocity, which are indicative of improved venous parenchyma drainage.
If you have angioplasty on stenosed veins then you get increased blood flow. 

Mistry N, Dixon J, Tallantyre E, Tench C, Abdel-Fahim R, Jaspan T, Morgan PS, Morris P, Evangelou N.Central Veins in Brain Lesions Visualized With High-Field Magnetic Resonance Imaging: A Pathologically Specific Diagnostic Biomarker for Inflammatory Demyelination in the Brain. JAMA Neurol. 2013 Mar:1-6. doi: 10.1001/jamaneurol.2013.1405. [Epub ahead of print]

IMPORTANCE There is no single test that is diagnostic for multiple sclerosis (MS), and existing diagnostic criteria are imperfect. This can lead to diagnostic delay. Some patients require multiple (sometimes invasive) investigations, and extensive clinical follow-up to confirm or exclude a diagnosis of MS. A diagnostic biomarker that is pathologically specific for the inflammatory demyelination in MS could overhaul current diagnostic algorithms. OBJECTIVE To prospectively assess the diagnostic value of visualizing central veins in brain lesions with magnetic resonance imaging (MRI) for patients with possible MS for whom the diagnosis is uncertain. DESIGN Prospective longitudinal cohort study. The reference standard is a clinical diagnosis that is arrived at (after a mean follow-up of 26 months) by the treating neurologist with a specialist interest in MS. The 7-T MRI scans were analyzed at baseline, by physicians blinded to the clinical data, for the presence of visible central veins. 
PARTICIPANTS A consecutive sample of 29 patients referred with possible MS who had brain lesions detected on clinical MRI scans but whose condition remained undiagnosed despite expert clinical and radiological assessments. 
EXPOSURE Seven-Tesla MRI using a T2*-weighted sequence. MAIN OUTCOMES AND MEASURES The proportion of patients whose condition was correctly diagnosed as MS or as not MS, using 7-T MRI at study onset, compared with the eventual diagnosis reached by treating physicians blinded to the result of the MRI scan. 
RESULTS Of the 29 patients enrolled and scanned using 7-T MRI, so far 22 have received a clinical diagnosis. All 13 patients whose condition was eventually diagnosed as MS had central veins visible in the majority of brain lesions at baseline. All 9 patients whose condition was eventually not diagnosed as MS had central veins visible in a minority of lesions. 
CONCLUSIONS AND RELEVANCE In our study, T2*-weighted 7-T MRI had 100% positive and negative predictive value for the diagnosis of MS. Clinical application of this technique could improve existing diagnostic algorithms.

This is not really CCSVI, but it just says that veins are at the centre of lesions in those that get diagnosed with MS.

Brain atrophy helps predict the development of disability

#MSBlog: Brain atrophy is more important than you realise.

Epub: Popescu et al. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 Mar 23.

OBJECTIVE: To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS).

DESIGN: From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MSers with MR imaging at baseline and after 1-2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. MSers were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing-remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset MSers were classified as minimally impaired (EDSS=0-3.5, n=111) or moderately impaired (EDSS=4-6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores.

RESULTS: In the whole MSer group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R2=0.74 in the whole group and R2=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R2=0.68), lesion volumes in moderately impaired relapse onset patients (R2=0.21) and whole brain atrophy in primary progressive MS (R2=0.34).

CONCLUSIONS: This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.

"Are you surprised? If your brain has already shrunk, or is shrinking, you have a worse prognosis than someone who has no brain shrinkage or atrophy. What is remarkable about this study is the so called R2 or R-squared values; these range from 0.68 to 0.74. In other words the model that includes both atrophy and lesions explains 74% of the variance in relation to disability progression at 10 years. The implications of  this are very profound; if these factors are linked causally then preventing lesion formation and brain atrophy should prevent most MS-related disability."

"It is becoming increasingly important to include a brain atrophy metric into our definition of NEDA (no evidence of disease activity)." 

"Clearly these results will need to be replicated by others before we get too excited!"

"It is interesting that the survey results below from a few months ago tell us how important the issue of brain atrophy is to you. You therefore need to raise this issue with your consultant."

Other posts on brain atrophy:

31 Jan 2013
The first problem is that our neuroradiologists don't routinely report brain atrophy, unless it is gross atrophy, i.e. easy to see with the naked eye. Although we know that brain atrophy occurs early in the disease course it is often ...
15 Feb 2013
"This study confirms what we already know from several other studies that MS is associated with progressive brain atrophy that begins early in the disease and is associated with disability progression. This is why it is important ...
26 Nov 2012
Poll results: outcome measures and brain atrophy. "The headline result is that MSers rate a delay in disease progression the most important outcome measures in relation to DMTs." "The problem with disability progression in ...
17 Nov 2012
"Data from several emerging DMTs now supports the natural history studies and the observation that there is a disconnect between relapses and disease progression and importantly an impact on brain atrophy. We have ...

01 Feb 2013
Atrophy: a picture tells a 1000 words. "As a follow-up to yesterday's post on brain atrophy; please study the MRIs above. These MRIs are from two MSers I met when I did my PhD from 1993 to 1996; they were participating in a ...
20 Oct 2012
Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis: a prospective, non-randomized pilot study. Eur J Neurol. 2012 Oct 11. doi: 10.1111/j.1468-1331.2012.03882.x.
31 May 2012
METHODOLOGY/PRINCIPAL FINDINGS: Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, ...
29 Nov 2011
RESULTS: The mean (SD) annualized brain atrophy rate in MS'ers with benign MS (-0.16% [0.51%]) was lower than that in patients with early MS (-0.46% [0.72%]) (P = .02). The difference remained significant after controlling ...

20 Mar 2012
Research: Brain Shrinkage. Riccitelli et al. Mapping regional grey and white matter atrophy in relapsing-remitting multiple sclerosis.Mult Scler. 2012 Mar 15. [Epub ahead of print] Objective: We aimed to investigate the regional ...
06 Feb 2013
Measures of retinal atrophy are associated with the brain parenchymal fraction (BPF) assessed by magnetic resonance imaging (MRI). However, in MS, data on the relation of OCT measures and grey and white matter ...
21 Nov 2012
More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy. CONCLUSIONS: Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory ...
23 Nov 2012
BACKGROUND: Brain size, white matter hyperintensity, and the development of brain atrophy are known to be highly heritable. The decrease of brain volume starts from the very onset of MS and is 10-fold compared with ...

Pharma behaving badly in San Diego

Miller JE. Bioethical accreditation or rating needed to restore trust in pharma Nature Medicine 19, 261 (2013) doi:10.1038/nm0313-261.

"After years of decline in the public eye, drug companies should implment a bioethics accreditation or rating program to help appropriately restore the industry's good name and improve its effectiveness in advancing global health and new treatments.

The pharmaceutical industry was once among the most admired industries on the planet. Today, it is heavily criticized and distrusted, with only 12% of people in the US believing that drug companies are generally honest and ethical, according to a Harris poll published late last year. Countless experts have raised this problem before, and drug companies have attempted numerous remedial strategies to address bioethical concerns and repair trust deficits. Nonetheless, the mistrust persists, arguably weakening the effectiveness of these important institutions. Is there something new that companies can do to demonstrate the quality of their processes and genuinely earn back our trust? I believe there is.............."

"This article is very timely and couldn't have popped into my consciousness at a more opportune time. At the AAN, in San Diego, I boycotted the exhibition hall; I simply find the waste of money on very expensive glitzy marketing stands distressing. I have posted on the issue of the exhibitionism by the marketing arm of Pharma before, using the Red Queen Effect as the analogy."

"Unfortunately, the marketeers took things to a new level in San Diego; you couldn't walk around San Diego without being reminded that MS Pharma was in town. They were determined to get their subliminal messages across. The pedicabs or pedal taxis were branded with a particular MS drug throughout the meeting. My colleagues and I were horrified that a Pharmaceutical company would treat a MS Drug like a consumer product and advertise it on taxis. Do they think we, neurologists, are morons and respond to billboard advertising as if MS DMTs were the equivalent to Coca Cola? It is time the Pharma industry took their marketing seriously and displayed some social responsibility. MS is a serious disease and MS DMTs are simply overpriced, particularly in the USA. Neurologists are not muppets and we should not be treated as such. Pharma should use their marketing budgets wisely; their marketing needs to be innovative and more importantly add value to the field. The MS market is not a consumer market and should not be treated as such. The marketing and advertising executives who came up with the idea of advertising a very expensive MS drug on taxis should find jobs in another sector!"

Essential additional reading on this blog: Red Queen Effect

Friday, 29 March 2013

Don't Crucify the Messenger!

Sometimes we are the bringers of bad news; we don't necessarily make the bad news. 

So there is no point in venting your ire our way.

Happy Holidays!

Apologies if you think the image is in poor taste; it is Good Friday after all. 

Virally Affected B cells are the Centre of EAE

Epub: Anwar Jagessar et al. The Different Clinical Effects of Anti-BLyS, Anti-APRIL and Anti-CD20 Antibodies Point at a Critical Pathogenic Role of γ-Herpesvirus Infected B Cells in the Marmoset EAE Model. J Neuroimmune Pharmacol. 2013 Mar 19.

Background: The robust and rapid clinical effect of depleting anti-CD20 monoclonal antibodies (mAb) in multiple sclerosis (MS) demonstrates a critical pathogenic contribution of B cells. The clinical effect of anti-CD20 mAb has been replicated in a relevant preclinical MS model, experimental autoimmune encephalomyelitis (EAE) in marmoset monkeys (Callithrix jacchus). By contrast, treatment with mAbs against two essential cytokines in B cell activation growth and survival, i.e. BlyS/BAFF and APRIL, was only partially effective. All three mAbs induced depletion of CD20+ B cells from the circulation, albeit with different kinetics and based on distinct mechanisms of action.

Objective: In the current study we analyzed whether the different clinical effect of anti-CD20 mAb or the anti-BLyS and anti-APRIL mAbs is due to different depletion of B cells infected with the EBV of marmosets, CalHV3. 

Methods & results: Employing a novel PCR-based assay, half of the colony of group-housed marmosets was tested positive for CalHV3 DNA in secondary lymphoid organs (Lymph glands). The same prevalence was observed in placebo-treated monkeys. In marmosets treated with anti-CD20 mAb the load of CalHV3 DNA in lymphoid organs was substantially reduced, while this was not observed in the monkeys treated with anti-BLyS or anti-APRIL mAbs. To examine the pathogenic role of virus-transformed B cells, we infused EBV-transformed B lymphoblastic cell (BLC) lines presenting the immunodominant MOG34-56 peptide. We observed in the recipients of MOG34-56 pulsed BLC, but not in their fraternal siblings infused with non-pulsed BLC, activation of anti-MOG34-56 T cells and meningeal inflammation. 

Conclusions: Collectively, the data show that among CD20+ B cells, the herpesvirus-transformed subset has a particularly important pathogenic role in the marmoset EAE model.

B cell activating factor (BAFF) is critical for B cell survival factor it is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. It is expressed as transmembrane protein on various cell types. The transmembrane form can be cleaved from the membrane, generating a soluble protein fragment. BAFF is the natural ligand of three unusual tumor necrosis factor receptors named BAFF-R, TACI, and BCMA. These receptors are expressed mainly on mature B lymphocytes and BCMA on plasma cells-antibody producing cells). TACI binds worst since its affinity is higher for a protein similar to BAFF, called a proliferation-inducing ligand (APRIL), which does a similar thing to BAFF.

As Prof G puts it "BAFF and APRIL are immunological fertilizer for B cells. In the presence of BAFF and APRIL B cells are more likely to survive, proliferate and make antibodies." In MS, anti-CD20 and ati-CD19 inhibit relapses but BAFF-inhibitors did not appear to work belimumab a BAFF inhibitor failed in trials. Atacicept is a recombinant fusion protein that combined the binding site for two cytokines that regulate maturation, function, and survival of B cells, B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), with the constant region of immunoglobin. This made MS worse.

As shown previously Anti-BLys and Anti-APPRIL antibodies ameliorated but did not stop EAE developing, so not quite the same as in MS. This relative lack of efficacy of ant-BAFF treatment compared to anti-CD20 was related in this study to the relative lack of effect of removing B cells infected with a virus. This study implicates virally infected B cells as important mediators in the development of autoimmunity. Should this not mean that half the marmosets in the colony not get EAE if this is the case? Could this be the same in multiple sclerosis and maybe treatments that inhibit viruses may be beneficial in MS? The hypothesis is being tested in the Charcot Project.

Thursday, 28 March 2013

Research: Measuring Nerve Damage

Epub: Kuhle et al. A comparative study of CSF neurofilament light and heavy chain protein in MS. Mult Scler. 2013 Mar 25. 

BACKGROUNDThere is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)).

METHODS: We evaluated the analytical and clinical performance of the UmanDiagnostics NF-light® enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of a group of 148 patients with clinically isolated syndrome (CIS) or multiple sclerosis (MS), and 72 controls. We compared our results with referring levels of our previously-developed CSF NfHSMI35 assay.

RESULTS: Exposure to room temperature (up to 8 days) or repetitive thawing (up to 4 thaws) did not influence measurement of NfL concentrations. Values of NfL were higher in all disease stages of CIS/MS, in comparison to controls (p ≤ 0.001). NfL levels correlated with the Expanded Disability Status Scale (EDSS) score in patients with relapsing disease (rs = 0.31; p = 0.002), spinal cord relapses and with CSF markers of acute inflammation. The ability of NfL to distinguish patients from controls was greater than that of NfHSMI35 in both CIS patients (p = 0.001) and all MS stages grouped together (p = 0.035).

NfL proved to be a stable protein, an important prerequisite for a reliable biomarker, and the NF-light® ELISA performed better in discriminating patients from controls, compared with the ECL-NfHSMI35 immunoassay. We confirmed and expanded upon previous findings regarding neurofilaments as quantitative markers of neurodegeneration. Our results further support the role of neurofilaments as a potential surrogate measure for neuroprotective treatment in MS studies.

This study looked for the presence of neurofilaments, which are the scaffolding of nerves, see Annie's talk on PROXIMUS trial at the Research Day. There are different sizes of this molecule one is called heavy and another light, because it is smaller. To get a handle of what is going on, notably in relation to nerve damage and loss, spinal taps were done and the presence or absence of neurofilaments within the cerebrospinal fluid were examined. This study found that measuring the light version gave more robust results than the heavy version. This is why this light version will be measured in the the PROXIMUS trial.

CoI: Members of Team G did this work

Research Vitamin D in India

Epub: Pandit et al. Association of vitamin D and multiple sclerosis in India. Mult Scler. 2013 Mar.

Vitamin D deficiency is widely prevalent in India. The association between vitamin D status and multiple sclerosis (MS) has not been previously studied in Indians.

OBJECTIVE: The objective of this paper is to determine whether vitamin D status is associated with MS in India.

METHODS: In this study 110 MS patients and 108 matched controls were included. Serum 25-hydroxyvitamin D (25(OH)D) was measured in 63 patients in relapse, 77 patients in remission and all controls. Quantity of sun exposure in childhood and body mass index (BMI) were calculated. Patients and controls were genotyped for HLA-DRB1*1501.

RESULTS: Patients had significantly lower 25(OH)D levels than matched controls (p = 0.003), and patients in relapse had a significantly lower vitamin D level as compared to those in remission (p = 0.001). Vitamin D deficiency (< 50 nmol/l) was seen in a higher proportion of cases (71.8%) than controls (53.7%) (p = 0.01). Higher quartiles of vitamin D (> 58 nmol/l) showed an inverse relationship with MS (OR = 0.28, CI = 0.11-0.68, p= 0.005). This effect persisted after adjusting for sun exposure.

The results of our study indicated that serum 25(OH)D shows an inverse relationship with MS in the Indian population. Reverse causality cannot be excluded.

Therefore MSers have less vitamin D in India also, so need to make sure MSers and the rest of the population are vitamin D replete. This is especially the case when people that are ethnic Indians live in places like the UK where there is no sun and dark skin means less vitamin D is obtained from sunlight. 

CoI: Work was from members of Team G

AusD study: Vitamin D and sun xpsore in Australia

#MSBlog: Is there a difference between vD from tablets and vD from sunshine? We will have to wait to find out.

Epub: Brodie AM, Lucas RM, Harrison SL, van der Mei IA, Armstrong B, Kricker A, Mason RS, McMichael AJ, Nowak M, Whiteman DC, Kimlin MG.The AusD Study: A Population-based Study of the Determinants of Serum 25-Hydroxyvitamin D Concentration Across a Broad Latitude Range. Am J Epidemiol. 2013 Mar 22.

Background: Observational studies suggest that people with a high serum 25-hydroxyvitamin D (25(OH)D) concentration may have reduced risk of chronic diseases such as osteoporosis, multiple sclerosis, type 1 diabetes, cardiovascular disease, and some cancers. 

Objective: The AusD Study (A Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults) was conducted to clarify the relationships between ultraviolet (UV) radiation exposure, dietary intake of vitamin D, and serum 25(OH)D concentration among Australian adults residing in Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S), and Hobart (42.8°S). 

Methods: Participants aged 18-75 years were recruited from the Australian Electoral Roll between 2009 and 2010. Measurements were made of height, weight, waist:hip ratio, skin, hair, and eye color, blood pressure, and grip strength. Participants completed a questionnaire on sun exposure and vitamin D intake, together with 10 days of personal UV dosimetry and an associated sun-exposure and physical-activity diary that was temporally linked to a blood test for measurement of 25(OH)D concentration. Ambient solar UV radiation was also monitored at all study sites. The investigators' collected comprehensive, high-quality data from 1,002 participants (459 males, 543 females) assessed simultaneously across a range of latitudes and through all seasons. 

Conclusion: The investigators' describe the scientific and methodological issues considered in designing the AusD Study.

"When this study reports it should get to the bottom of whether or not there is a difference between vD from sunlight and vD from dietary supplements. As you know already sunlight exposure may have affects on immune function independently of vD levels."

"At a personal level I find sun exposure very rewarding; it makes you  feel healthy. For those of us living in the UK this is becoming increasingly uncommon."

Wednesday, 27 March 2013

Inhibition of Microglia protects Axons

Morsali D, Bechtold D, Lee W, Chauhdry S, Palchaudhuri U, Hassoon P, Snell DM, Malpass K, Piers T, Pocock J, Roach A, Smith KJ. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain. 2013 Mar 20. [Epub ahead of print]

Axonal degeneration is a major cause of permanent disability in the inflammatory demyelinating disease multiple sclerosis, but no therapies are known to be effective in axonal protection. Sodium channel blocking agents can provide effective protection of axons in the white matter in experimental models of multiple sclerosis, but the mechanism of action (directly on axons or indirectly via immune modulation) remains uncertain. Here we have examined the efficacy of two sodium channel blocking agents to protect white matter axons in two forms of experimental autoimmune encephalomyelitis, a common model of multiple sclerosis. Safinamide is currently in phase III development for use in Parkinson's disease based on its inhibition of monoamine oxidase B, but the drug is also a potent state-dependent inhibitor of sodium channels. Safinamide provided significant protection against neurological deficit and axonal degeneration in experimental autoimmune encephalomyelitis, even when administration was delayed until after the onset of neurological deficit. Protection of axons was associated with a significant reduction in the activation of microglia/macrophages within the central nervous system. To clarify which property of safinamide was likely to be involved in the suppression of the innate immune cells, the action of safinamide on microglia/macrophages was compared with that of the classical sodium channel blocking agent, flecainide, which has no recognized monoamine oxidase B activity, and which has previously been shown to protect the white matter in experimental autoimmune encephalomyelitis. Flecainide was also potent in suppressing microglial activation in experimental autoimmune encephalomyelitis. To distinguish whether the suppression of microglia was an indirect consequence of the reduction in axonal damage, or possibly instrumental in the axonal protection, the action of safinamide was examined in separate experiments in vitro. In cultured primary rat microglial cells activated by lipopolysaccharide, safinamide potently suppressed microglial superoxide production and enhanced the production of the anti-oxidant glutathione. The findings show that safinamide is effective in protecting axons from degeneration in experimental autoimmune encephalomyelitis, and that this effect is likely to involve a direct effect on microglia that can result in a less activated phenotype. Together, this work highlights the potential of safinamide as an effective neuroprotective agent in multiple sclerosis, and implicates microglia in the protective mechanism.

Although the original hypothesis used to suggest that sodium channel blockers will be useful in MS was because they block the effects of sodium overload in demyelinated nerves, it was obvious from the very first experiments in 2002 using sodium channel blockers in EAE, that they also had some immunomodulatory effects in mice, that did not have a demyelinated nerve in sight when the drugs were working. It has been shown previously that sodium channel blockers can affect immune function, notably via actions on macrophage/microglia and this study further highlights this. This is good news because we have been searching for inhibitors of microglial function as they could be useful for progressive MS. This study highlights Safinamide, which is a drug used in Parkinsons Disease. It is however a dirty drug as it has many activities on in sodium channel blockage, another is calcium channel blockage, which is also neuroprotective and another is monoamine oxidase . We could add a few more to the list. The question will be how to we show that they work in MS.

We have two trials planned one has started and is investigating effects in optic neuritis and the other is the PROXIMUS trial of sodium channel blockers and the data in this study further suggest our design is a valid approach and that we should treat during the "immunological/inflammatory penumbra". Maybe we will see safinamide on the agenda for MS.

Childhood MS

#MSBlog: Childhood MS in the spotlight.

"This report is timely can confirms the MS communities commitment to children with MS and the need to get DMTs approved for treating childhood MS. Hopefully, parents of children with MS will find this initiative a move in the right direction."

Chitnis et al. International Pediatric MS Study Group Clinical Trials Summit: Meeting report. Neurology. 2013 Mar;80(12):1161-1168.

OBJECTIVE: Paediatric studies for new biological agents are mandated by recent legislation, necessitating careful thought to evaluation of emerging multiple sclerosis (MS) therapies in children with MS. Challenges include a small patient population, the lack of prior randomized clinical trials, and ethical concerns. The goal of this meeting was to assess areas of consensus regarding clinical trial design and outcome measures among academic experts involved in pediatric MS care and research.

METHODS: The Steering Committee of the International Pediatric MS Study Group identified key focus areas for discussion. A total of 69 meeting attendees were assembled, including 35 academic experts. Regulatory and pharmaceutical representatives also attended, and provided input, which informed academic expert consensus decisions.

RESULTS: The academic experts agreed that clinical trials were necessary in pediatric MS to obtain pharmacokinetic, safety and efficacy data, and regulatory approval allowing for greater medication access. The academic experts agreed that relapse was an appropriate primary outcome measure for phase III pediatric trials. An international standardized cognitive battery was identified. The pros and cons of various trial designs were discussed. Guidelines surrounding MRI studies, pharmacokinetics, pharmacodynamics, and registries were developed. The academic experts agreed that given the limited subject pool, a stepwise approach to the launch of clinical trials for the most promising medications is necessary in order to ensure study completion. Alternative approaches could result in unethical exposure of patients to trial conditions without gaining knowledge.

CONCLUSION: Consensus points for conduct of clinical trials in the rare disease paediatric MS were identified amongst a panel of academic experts, informed by regulatory and industry stakeholders.

Tuesday, 26 March 2013

Doctor Ruth Week

Last week saw three papers published by Doctor Ruth, one was a review. Some of the Ram-Magic is clearly rubbing off.

Dobson R, Leddy SG, Gangadharan S, Giovannoni G. Assessing fracture risk in people with MS: a service development study comparing three fracture risk scoring systems. BMJ Open. 2013 Mar 11;3(3). doi:pii: e002508. 10.1136/bmjopen-2012-002508. Print 2013.

BACKGROUND: Suboptimal bone health is increasingly recognised as an important cause of morbidity. Multiple sclerosis (MS) has been consistently associated with an increased risk of osteoporosis and fracture. Various fracture risk screening tools have been developed, two of which are in routine use and a further one is MS-specific. We set out to compare the results obtained by these in the MS clinic population.

DESIGN: This was a service development study. The 10-year risk estimates of any fracture and hip fracture generated by each of the algorithms were compared.

PARTICIPANTS88 patients with a confirmed diagnosis of MS.

OUTCOME MEASURES: Mean 10-year overall fracture risk and hip fracture risk were calculated using each of the three fracture risk calculators. The number of interventions that would be required as a result of using each of these tools was also compared.

RESULTS: Mean 10-year fracture risk was 4.7%, 2.3% and 7.6% using FRAX, QFracture and the MS-specific calculator, respectively (p<0.0001 for difference). The agreement between risk scoring tools was poor at all levels of fracture risk.

CONCLUSIONSThe agreement between these three fracture risk scoring tools is poor in the MS population. Further work is required to develop and validate an accurate fracture risk scoring system for use in MS.

Dr Ruth has been investigating bone health and this study looks at tools to predict risks of fracture. As you can see they are not very similar and not very accurate, so something is wrong and time for a rethink.

Dobson R, Topping J, Davis A, Thompson E, Giovannoni G. Cerebrospinal fluid and urinary biomarkers in multiple sclerosis. Acta Neurol Scand. 2013 Mar 7. doi: 10.1111/ane.12119. [Epub ahead of print]

OBJECTIVES: Biomarkers with the potential for longitudinal measurements are needed in multiple sclerosis (MS). Urine is easy to collect, and repeated sampling is possible.

METHODS: 39 paired CSF and urine samples were taken. Oligoclonal bands (OCBs) were measured in CSF. Kappa and lambda free light chain (FLC), neopterin and ubiquitin C-terminal hydrolase-L1 (UCHL1) were measured in CSF and urine.

RESULTS: 16/39 samples had OCBs unique to the CSF. CSF FLC levels (P < 0.0001) were higher in OCB-positive subjects, with no difference in urinary FLC. CSF and urinary FLC did not correlate. There were a significant correlation between total CSF FLC and CSF neopterin in MS samples (correlation coefficient = 0.588, P = 0.016) and a strong correlation between CSF lambda FLC and CSF neopterin in MS samples (correlation coefficient = 0.875, P < 0.001). There was a correlation between urinary neopterin/creatinine levels and urinary total FLC/protein levels (correlation coefficient = 0.452, P = 0.004). Only three CSF samples (8%) had detectable levels of UCHL1. 18/38 (48%) (8/15 MS and 10/23 control) urine samples had detectable levels of UCLH1.

CONCLUSIONS: This study confirms the relationship between CSF OCBs and CSF FLCs, highlighting the importance of intrathecal B- and plasma-cell activation in MS. There is a relationship between CSF FLC and CSF neopterin in MS, highlighting the multifaceted immune activation seen in MS. Correlations in the OCB-positive group highlight the multifaceted immune activation seen in MS.

"Sire you look like the p**s boy"......and you look like a bucket of s**t
(History of the World part 1)

When I first met Prof G doing research, he was knee deep in p**s, and so he has enthused others to follow in this urinary habit and is still chasing the elusive biomarkers in urine. Wouldn't it be great if you could have a quick test of your pee to know how your MS was doing. Needs to keep searching!

CoI: Work done by members of Team G

Laquinimod inhibits dendritic cell function

Epub: Jolivel et al. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain. 2013 Mar 20. 

Laquinimod is an orally administered compound that is under investigation in relapsing-remitting multiple sclerosis. To understand the mechanism by which laquinimod exerts its clinical effects, we have performed human and murine (IT'S MOUSE!!!!) studies assessing its immunomodulatory properties. In experimental autoimmune encephalomyelitis, the therapeutic administration of laquinimod beginning during the recovery of SJL mice, prevented further relapses as expected and strongly reduced infiltration of CD4+ and CD8+ T cells in the central nervous system. We hypothesized that this beneficial effect was mediated by dendritic cells, since we and others found a modulation of different dendritic cell subsets under treatment. According to the findings on antigen-presenting cells in the murine system, we found a reduced capacity of human monocyte-derived dendritic cells treated with therapeutic concentrations of laquinimod, upon maturation with lipopolysaccharide, to induce CD4+ T cell proliferation and secretion of pro-inflammatory cytokines. Furthermore, laquinimod treatment of mature dendritic cells resulted in a decreased chemokine production by both murine and human dendritic cells, associated with a decreased monocyte chemo-attraction. In laquinimod-treated patients with multiple sclerosis we consistently found reduced chemokine and cytokine secretion by conventional CD1c+ dendritic cells upon lipopolysaccharide stimulation. Similarly to the animal model of relapsing-remitting multiple sclerosis, dendritic cell subsets were altered in patients upon laquinimod treatment, as the number of conventional CD1c+ and plasmacytoid CD303+ dendritic cells were decreased within peripheral blood mononuclear cells. Moreover, laquinimod treatment in patients with multiple sclerosis and mice modified the maturation of dendritic cells demonstrated by an upregulation of CD86 expression in vivo. Our data suggest that inhibition of the NF-κB pathway is responsible for the changes observed in dendritic cell maturation and functions. These findings indicate that laquinimod exhibits its disease-modulating activity in multiple sclerosis by downregulating immunogenicity of dendritic cell responses. We suggest that monitoring dendritic cell properties in multiple sclerosis should be implemented in future therapeutic trials.

It is always good to understand how a drug works. This study reports that laquinimod affects dendritic cell function. Dendritic cells are specialized immune cell that is very good at inducing immune responses in T cells. In this study laquinimod inhibited relapses and therefore it would stop accumulation of immune cells into the CNS and in mice and humans there was a reduction in dendritic cell function. However we have to remember that in trials laquinimod did worse than beta interferon at slowing relapses. So what is the significance of these observations? Could this be more important in progression and explain why laquinimod seemed to slow brain shrinkage, much better than it stopped relapses.

Cognitive impairment differs between PP and RR MSers

#MSBlog: Is MS shredding your brain?

Epub: Ruet et al. Cognitive impairment differs between primary progressive and relapsing-remitting MS. Neurology. 2013 Mar.

OBJECTIVES: To characterize the cognitive abilities of MSers with primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS) compared with healthy controls (HCs) matched for age, sex, and education level while considering the different characteristics of PPMS and RRMS and to compare the cognitive patterns of these types of multiple sclerosis.

METHODS: Forty-one MSers with PPMS, 60 MSers with RRMS, and 415 HCs were recruited in a cross-sectional study. Controls were divided into 20 groups according to age, sex, and education level. Participants were assessed with a large battery of neuropsychological (NP) tests

RESULTS: MSers with PPMS had worse NP scores and were more impaired in cognitive domains than patients with RRMS. After controlling for Expanded Disability Status Scale score, the results remained unchanged.

CONCLUSION: The MSers with PPMS presented with a wide range of cognitive deficits in information processing speed, attention, working memory, executive function, and verbal episodic memory, whereas the impairments in MSers with RRMS were limited to information processing speed and working memory compared with their matched HCs. Cognitive deficits were more severe in MSers with PPMS than in MSers with RRMS.

"If you have PPMS you may not want to know this. Unfortunately, this is the harsh reality of a unpleasant disease."

"I have been watching the TV series West Wing. President Bartlett (played by Martin Sheen), who has MS, refers to MS shredding his brain. I wonder what made Aaron Sorkin, the writer, come up with this analogy?"

"What is critical in the future is that these sorts of studies are done with MRI to determine the extent of cortical involvement. It is not surprising that cognitive dysfunction is not linked to EDSS; the EDSS is strongly biased towards walking or motor impairment." 

Epub: Benedict et al. Influence of Personality on the Relationship Between Gray Matter Volume and Neuropsychiatric Symptoms in Multiple Sclerosis. Psychosom Med. 2013 Mar.

Background: Research has revealed an association between personality traits and health outcomes, and in multiple sclerosis (MS), there are preliminary data showing a correlation between personality traits and brain volume.

Objective: This study examined the general hypothesis that personality influences the relationship between gray matter volume (GMV) and cognitive/neuropsychiatric MS features.

Methods: Participants were 98 MSers who underwent magnetic resonance imaging and were tested with the Symbol Digit Modalities Test and the Neuropsychiatric Inventory, the latter providing measures of depression and euphoria that can be characteristic of MS, that is, cheerful indifference and disinhibition. Personality traits were assessed with the NEO Five Factor Inventory. They then examined the correlation between personality traits and both GMV and symptoms, and then modeled mediation and moderation influences on the relationships between GMV and cognitive/neuropsychiatric features.

Results: Linear regression modeling revealed that GMV (r = 0.54, p < .001) and NEO Five Factor Inventory low conscientiousness (r = 0.36, p = .001) were associated with cognitive function, but no mediator or moderator effects were observed. However, conscientiousness mediated the relationship between GMV and symptoms of euphoria (p = .002). The moderator analysis revealed a significant influence of high neuroticism on the GMV-euphoria relationship (p = .029).

Conclusions: Low conscientiousness and high neuroticism are associated with neuropsychiatric complications in MS, and each influences the relationship between GMV and euphoria. The findings suggest that MSers with low conscientiousness are at higher risk for MS-associated cognitive dysfunction and neuropsychiatric symptoms, a conclusion that has implications for the emerging role of personality in clinical neuroscience.

"Not sure if you can extrapolate these results to individual MSers. Nevertheless they are interesting and suggest that personality may influence the neuropsychiatric complications of MS."

AAN 2013: more on the safety of oral cladribine

"The following is the safety profile of oral cladribine in the ORACLE or CIS study that was presented at the AAN."

"The most important bit of information buried in this poster is the section on neoplasms."

Neoplasms (malignant, benign, and unspecified) occurred in 1 patient (0.5%) in the cladribine 5.25 mg/kg group (uterine leiomyoma), 3 (1.5%) in the cladribine 3.5 mg/kg group (papillary thyroid cancer, skin papilloma, squamous cell carcinoma of skin), and 6 (2.9%) in the placebo group (thyroid neoplasm [n=3], uterine leiomyoma [n=2], benign tonsillar neoplasm [n=1]). As defined by the study protocol, all neoplasms were considered serious and related to the study treatment.

"In comparison to the CLARITY or RRMS study there is not signal in this study that cladribine causes cancer, at least in the short-term. The question is whether or not, considering the profile of cladribine, you would be prepared to take the yet to be defined risk of a possible increase in cancer risk for the convenience and efficacy of cladribine tablets?"

CoI: multiple

Monday, 25 March 2013

Endothelin-2 another new factor that promotes remyelination

Epub: Yuen et al. Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. Brain. 2013 Mar.

Background: The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem.

Objective: By 'mining' these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and remyelination. 

Methods and results: Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited remyelination, respectively. Antagonists of endothelin receptor type B also inhibited remyelination of experimentally-generated demyelination in vivo. 

Conclusion: Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration.

There are three isoforms/types of endothelin (identified as ET-1, ET-2, ET3-3) with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC. Recently we saw how endothelin-1 from astrocytes may be affecting the vasculature. In this study a different type of endothelin ET-2 was found to promote remyelination. They started in a model where they can induce myelination in eye nerves that are not normally myelinated, they looked for gene production associated with this effect and came up with some chemokines (factors that direct movement of cells e.g. CXCL13, CCL20, etc) and endothelin-2. This is now yet another factor that can maybe help get myelin back on nerves. If they block endothelin-2 working it stopped remyelination. This is however another instance where the myelinating factor has many other influences besides remyelination. Endothelin-2 can influence blood pressure and ovulation. It is also an attractant of macrophages and it is well known that you need macrophages to clear up the debris before you can get repair, is this the action of ET-2 or could it give you a double whammy.

However because of multiple actions there may be that long term treatments will have side-effects. However we may not need to treat for ever but maybe pulse therapy will be enough to kick start repair using the progenitors (Baby myelinating cells) that are in and around MS lesions. But if we don't try we won't know. At least having targets allows us to test this and in the past couple of years there has been a constant stream of targets. Let's hope some that some of these can make the difference. At least there is now a stream of things to try.