Friday, 22 September 2017

#NeuroSpeak: do you know what an IRT is?

We are already beyond ECTRIMS and planning for the ECF 2017 meeting in Baveno. #ECF2017 #NeuroSpeak

I am trying to communicate the new treatment concept of using a new class of treatments called the immune reconstitution therapies, or IRTs. If you are an HCP and are attending the European Charcot Foundation meeting in Baveno, Italy (30th November - 2nd December 2017), you may want to consider extending your stay to attend the following satellite symposium. I will be speaking on the topic of IRTs. To attend you need to pre-register online via this URL

CoI: multiple

#ChariotMS & #ThinkHand: therapeutic lag explains why we don't have treatments for progressive MS

We need to do longer studies in progressive MS #ChariotMS #ThinkHand

Summary: This post explains therapeutic lag and why people with more advanced MS don't see an immediate response to DMTs.

I have been invited to give a grand round talk at Imperial College this morning. I have chosen the topic: "Is progressive MS (more advanced MS) modifiable?".  This is an extension of our #ThinkHand campaign to get the wider neurological community to accept that MS is potentially modifiable throughout its course. Despite us posting and reposting about reserve capacity, therapeutic lag, MS being a length-dependent axonopathy and the asynchronous progressive MS hypothesis we still get questions such as: "Why don't pwPPMS, or pwMS with an EDSS >6.0 respond, to HSCT and other DMTs?"

It is the same issue in relation to responders vs. non-responders to ocrelizumab in the PPMS trial. It is very difficult to know who is a responder and non-responder based on the current data from the ocrelizumab PPMS, or ORATORIO, trial. Why? Simply because clinical trials are designed, or powered, to get a significant read-out in a reasonable period of time. It doesn't mean that if someone with PPMS does not stabilise, on a high-efficacy therapy, in say a period of 2 years is a non-responder. Because of therapeutic lag, it may take much longer to see a response to treatment, particularly in pwMS who are older and have less reserve capacity in the particular pathway (usually the legs) being assessed.

I often refer to the study below which showed that interferon-beta treatment, a moderate efficacy DMT, would probably work in PPMS provided the follow-up is long enough; in this case 7 years. In this study PwPPMS who had only been treated with IFNbeta for 2-years clearly did better at 7-years than those people treated on placebo over the same period of time. There was a lag in the impact of interferon-beta on the outcome.

Why a lag? One interpretation is that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression in someone with PPMS over the next 2 years was primed by inflammation from years ago. Suppressing inflammation today will have no impact over the next 2-years as the damage priming progression over the next 2 years has already occurred. All anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.

Does this make sense?

To illustrate this concept I drew the picture below, which has now been published in our length-dependent axonopathy paper. Importantly in this study, the actively-treated subjects (INF-beta) only did better than placebo-treated subjects in terms of upper limb function (9HPT), cognition and brain volume loss. There was no difference in terms of the EDSS and T25FW, which assess lower limb. The reason why there was no difference in lower limb function is almost certainly due to loss of reserve, i.e. too many nerve fibres supplying the limbs had been damaged already for an anti-inflammatory to make a difference. The other issue is that in this study the treatment period was too short. Please note this study is only one of many studies showing the same effect, a greater impact of anti-inflammatory therapies on upper limb, compared to lower limb, function and is one of the reasons we are running our #ThinkHand campaign and trying to get support for our CHARIOT-MS study.

In the ocrelizumab PPMS, ORATORIO, trial the treatment effect was almost double in the arms compared to the legs. This is why I have little doubt that ocrelizumab is effective in PPMS. If the trial was extended for longer the treatment effect on lower limb function will have gotten greater simply because of lag; survival or Kaplan-Meier curves diverge further with time.

I am convinced we are correct about 'therapeutic lag' and the MS community is beginning to take this it into account when designing progressive MS trials. This means being clever about our studies and getting the regulators to accept the 9HPT as a primary outcome measure. The MS community has made it clear that they value arm and hand function more than leg function, we now need the wider community to help get this message across. There is also an economic argument for taking DMTs into wheelchair users to protect upper limb function; once people lose their arm function they lose their independence and the costs, both medical and social, for looking after these become very high. 

Just imagine what happens to your self-esteem and quality of life when you can't transfer your self from your wheelchair to the toilet and need a carer to help you go the toilet? When we asked people with MS what hand and arm function they valued most many pwMS stated being able to go the toilet without help.

As you can see we will continue to make the case for doing trials in more advanced MS. This is why we need your help getting the CHARIOT-MS trial funded.  The CHARIOT-MS study will compare subcutaneous cladribine to placebo in subjects with more advanced MS (EDSS 6.0 to 8.0), using the 9-hole peg test as the primary outcome measure.

If you are a wealthy philanthropist reading this post? DrK (@KlausSchmierer) is looking for a large donation of ~£2M to support his application to the NIHR for the CHARIOT-MS study. He needs to bring the costs of the study for NIHR down to under £2.5M to have any chance of getting this trial funded and to help people with more advanced MS.

Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.

OBJECTIVES: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of PPMS.

MAIN OUTCOME MEASURES: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 MSers, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 MSers, respectively.

EDSS = Expanded Disability Status Scale

MSFC = MS Functional Composite ( a composite 3 tests the PASAT, 9-hole peg test and the timed 25-ft walk)

9-Hole Peg Test = test of upper limb function

Word List Generation Test = cognitive task

RESULTS: After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (p=0.02) and Word List Generation Test (p<0.001) scores, and MRI measures in the normal-appearing white matter were significantly better. During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain volume (p=0.004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (p =0.004).

CONCLUSIONS: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.


Thursday, 21 September 2017

#ChariotMS & #ThinkHand: is it ever too late to treat MS?

It is never too early, nor too late, to treat MS. #Never2EarlyNor2Late #ChariotMS #ThinkHand

Summary: This post makes a case for a new treatment philosophy at Barts-MS based on the principle that “It’s never too early, nor too late, to treat MS”. The post also describes the influence of the London Underground, or tube, on our thinking about MS. This post is longer than usual and no summary can do it justice so please take the time to read it in full. Thank you.

What has the tube, or London Underground, have to do with MS? My rendition of London Underground map to explain the MS journey should come to mind. I was recently told that my published, earlier, version has achieved iconic status as it is frequently used by other people in their presentations. It is a pity because things have moved on since I created the published version. Firstly, it depicts MS as a one-way journey that starts in the at-risk period and terminates in death valley. Another negative is that it is an all or nothing picture; it is not layered, it is not subtle. You may have noticed that I often show the MS tube map with a cut onion; if you peel an onion too fast it is going to make you cry. My ultimate aim is to produce a fold-out MS tube map that will allow you to unfold the journey one segment at a time. In this way, you can look at one part of the MS journey at a time. Secondly, my latest version of the map has become very dense with many additional lines and one line that is still under construction. This under construction line, or the dotted grey line, is the one that leads to long-term remission, a cure and normal ageing. It is under construction because the data is yet to emerge showing we can cure MS. I added this line to give people with MS hope and to make the point that the journey is not necessarily a one-way journey. Other add-ons to the map that I am particularly proud of include the co-morbidity, lifestyle and wellness lines. These illustrate the importance of managing MS holistically. Despite its limitations and criticisms, I maintain that the MS tube map creates a framework for laying out what MS is for people with the disease. Healthcare professionals can also use the map as a reference point to help them pigeonhole their knowledge and for explaining MS to their patients.

What about the criticisms? The cynics, and trolls, never miss an opportunity to take a punt at me and say that I created the MS tube map on behalf of Pharma to promote the prescribing of DMTs. The truth is that Pharma has never had a say in its content. The only reasons DMTs are a large part of the map is because there has been an explosion in the number of DMTs available to treat MS and with this, the complexity of treating MS has increased.

Please note the MS tube map will never be complete. It needs to evolve and improve. So if you have any ideas about improving it please drop me an email (

The real reason for penning this post is that DrK and I had a discussion on the tube last night about MS (yes, DrK and I are typical Londoners - we commute to and from work on the underground). Our discussion revolved around the observation that we as a group at Barts-MS are pushing two messages that may seem incongruent. (1) To treat early to prevent damage from occurring in the first place, but also (2) to treat late as there is always some neurological function to preserve. This led us to come up with a new slogan:

“It’s never too early, nor too late, to treat MS!” 

or in eSpeak 


What do we mean by this? It is clear that people with active MS do better with early access to treatment compared to delayed access to treatment. Similarly, people with MS treated with highly-effective treatments early (rapid-escalation or flipping the pyramid) do better than those who are started on less effective treatments first and escalated if necessary to highly effective therapies later (slow stepwise approach). However, even the former approach may not be early enough. We know that a significant number of people presenting with clinically isolated syndromes (CIS) already have substantial damage. Therefore we really need to define early, as being even earlier, and try and identify people in the asymptomatic phase of the disease, or in the at-risk period of MS, and treat them to prevent them getting MS in the first place. I am also very keen that we expand the diagnostic criteria of MS to include RIS (radiologically isolated syndrome) as part of the treatable MS spectrum. Approximately, 25% of RIS patients already have significant cognitive impairment. Why would we not want to treat these patients and prevent further damage?

It is never too late. At the moment all the trials that have led to licensed DMTs have excluded patients who are wheelchair users. The consequences of this are that many international guidelines, including NHS England guidelines, require us to stop DMTs once a patient reaches EDSS 7.0. We know this is wrong. We have emerging evidence that treatments still work in more advanced MS and slow down the progression of the disease in neuronal systems that still have reserve capacity, for example, the arms, speech and swallowing. Our #ThinkHand campaign’s main aim is to raise awareness about this issue and to get the MS community to take the preservation of upper limb function seriously. What we need is class 1 evidence (randomised-controlled trials) of the effect of DMTs on upper limb function in people with more advanced MS. This is why we are trying to get funding in place for our CHARIOT-MS study. The CHARIOT-MS study will tell us if subcutaneous cladribine, given to patients with more advanced MS (EDSS 6.0 to 8.0), will delay the inevitable loss of function of the upper limbs. Please note that Pharma has no interest in funding this trial; the liquid formulation of cladribine is generic and hence there is no financial incentive in place for them to do this trial. You may ask what about Mavenclad, the licensed oral formulation of cladribine? Unfortunately, the patent life on the oral formulation is too short; by the time a study in more advanced MS is done Mavenclad is likely to be generic.

In parallel to the CHARIOT-MS trial, we will continue to lobby Pharma. In my opinion, the four best agents, apart from Mavenclad, to test in more advanced MS are natalizumab, alemtuzumab, ocrelizumab and ofatumumab. Please note these are all high efficacy therapies. Insights that have led us to design the CHARIOT-MS study come from the ASCEND (natalizumab in SPMS) and ORATORIO (ocrelizumab in PPMS) trials. These studies indicate that we probably need a high efficacy therapy to make a difference in advanced MS. We are aware that Genzyme is developing a follow-on anti-CD52 monoclonal to replace alemtuzumab and Novartis have ofatumumab in phase 3 trials in RRMS. Therefore, which of the big guns, Genzyme, Biogen, Roche or Novartis are prepared to be bold and take-up the challenge of testing their drugs in more advanced MS? If anyone from one of these companies is reading this post can you please forward our message to the decision-makers in your companies?

Life tends to reward the bold, the risk-takers, and people who care. Which one of you cares enough about MS to take-up the challenge? The rewards of doing a study of this nature go way beyond economics. Can you imagine what the MS community will say about you as a company if you challenge the current dogma that ‘advanced MS is not modifiable’? One of the reasons for inviting so many company people as co-authors on our length-dependent axonopathy paper was to try and catalyse a change of thinking within your companies. We sincerely hope this is happening.

A softer and possibly easier option is to dig deep into your pockets and to make a large donation to DrK’s (@KlausSchmierer) CHARIOT-MS project. DrK is looking for a large donation to support his application to the NIHR for the CHARIOT study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded.

DrK with a smile

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

CoI: multiple

The case for NEDA

I have been asked to look at the paper below, perhaps with a subtext to say how rubbish MS drugs are and how great HSCT is.

Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015 Feb;72(2):152-8

IMPORTANCE: With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown.
OBJECTIVE: To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI).
DESIGN, SETTING, AND PARTICIPANTS: Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset).
MAIN OUTCOMES AND MEASURES: NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes.
RESULTS: A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ≤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years.
CONCLUSIONS AND RELEVANCE:NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.

So  what does it say at 7 Years only about 8% have not had some form of disease activity, so MS is difficult to treat. If that disease activity in a clinically eloquent place, you may suffer the consequences of that activity for the rest of your life as in some cases damage done is not repaired. So do not do nothing , think of your brain health and do something and positively manage your condition.

"Most pwMS used first-line injectable agents because they were enrolled in 2000 through 2005 before oral disease-modifying therapies and natalizumab became available. Although comparing drug performance on NEDA is of great potential interest, such comparisons may be of limited value in an observational setting because of patient selection into specific treatment groups based on antecedent disease severity. Due to the small number of patients in each treatment group at each time point, we were underpowered to determine how specific therapies affect the predictive value of NEDA". 

This what we want to know. How good is each drug

Based on this natalizumab is best at 47%, followed by cladribine at 46% and the CRABS are 13-33%. 

As you know I am not a fan of CRABS, I never have been and never will yes I am biased, but yes I accept that some people can do well on them...many don't. 

I think data generated from them simply muddy the water, because until the studies are done with the highly active agents we won't know the real answer

COI: I do not get support from any Pharma companies and mine is an opinion..others will disagree. 

Alemtuzumab is not very good, I was told once that it was our fault:-(.. as too many different people did the EDSS assessments and they did not tie up. Maybe, but I think you asked about this because of the NEDA data in the 5 year extension studies 

Havrdova E et al. Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy.
Neurology. 2017;89(11):1107-1116. 

How can a 33% NEDA over two years (see above) become 61.7% NEDA at year 3 60.2% NEDA at year 4 and 62.4% NEDA at year 5. It is a fudge of course and presenting the results this way hides the reality. 

It says in any given year only about 40% had evidence of activity but it does not say that 60% of people were disease free of 5 years which is what we want to know. 

Based on that presented previously as I don't have the paper result to hand but seem to remember it was only about 30% were disease free over this time, so if we look at the failures in the first two years the NEDA rate is much lower. In fact in the extension study the NEDA rate for the trial part was well over 60% how can that be? 

Well there are a significant number of people who did not go into the extension study, so I suspect a number of these were failures in the original study, remove them and efficacy goes up.  

It is simply bad refereeing that the authors get away with not reporting important aspects.
However, you say...HSCT is miles better

Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, Mancardi GL. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology. 2017; 88:2115-2122.

The pooled proportion of NEDA patients at 2 years was 83% (range 70%-92%) and at 5 years was 67% (range 59%-70%).

Yes it is or yes it appears to be that way.  The pooled estimate of mortality due to the procedure was 2.1% (95% confidence interval [CI] 1.3%-3.4%).

If you have activity early on it is a poor prognostic sign of where you may end up.

The problem with NEDA. Which is no evidence of Disease control.

NEDA is only as good as you look for it.

(a) No MRI  Gadolium lesion

(b) No clinical Relapses

(c) No clinical progression....This is a problem as this is the outcome you desire, however if you have say PPMS and are progressing the NEDA rate for the treatment may be irrelevant because it depends on the course of the individual.

(d) Then we have NEDA-4..brain atrophy....If your brain is shrinking something is happening but is may not be nerve loss, because if you get rid of inflammation and oedema goes the brain shrinks, so the outcome is not fit for purpose.

Measure spinal cord atrophy and you can miss spinal cords that have lost 60% of their nerves but have not shrunk, so its not fit for purpose.

Maybe imaging grey matter volume is better.

(e) NEDA-5 and neurofilament. Having minimal neurofilament is an indicator of less nerve loss but you loose nerves due to inflammation of relapses and you loose nerves because of advancing disease. So there can be noise isn the system 

But the problem is if you use CSF the simple answer is if you don't live in Sweden, then no-one wants to have a lumbar puncture, so you have to rely on blood, the blood is not a direct correlate of the CSF.

(f) What about NEDA-6, 7, 8 could it be peripheral blood B memory cells  as a marker of disease activity. 

Do memory B cells have any correlate with disease activity in MS. In other conditions where anti CD20 antibodies work like arthritis, lupus, graft verses host disease, M.gravis, nephritis of the kidney, NMO etc etc..  

Why is HSCT so good compared to the DMT....well it is the ultimate DMT with the total immune clear out (Maybe missing the stuff in the CNS) and a complete reboot. 

People getting the HSCT tend to be more active people who have failed treatment, but when you look at the demographics they are different from other trials. 

People tend to have a higher EDSS and longer into their disease, which is a demographic you would associate with fewer relapses and a slow rate of deterioration.

So is there a fudge?

Is the efficacy artificially good?

Probably this is relevant and just as Prof G was taken to task for loading the ocrelizumab trials with people with active PPMS that respond to DMT, should we be saying that the HSCT trials are fudged too.

Of course I wouldn't say that before "BearMS" and the rest get on their high horse

A new review from Sweden looks at the same data and argues that whilst the data looks impressive, it is not without its faults.

It s open access so you can read it, if interested

Burman J et al.Autologous haematopoietic stem cell transplantation for neurological diseases JNNP diseases such as multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis are leading causes of physical disability in people of working age. In the last decades significant therapeutic advances have been made that can ameliorate the disease course. Nevertheless, many affected will continue to deteriorate despite treatment, and the costs associated with disease-modifying drugs constitute a significant fiscal burden on healthcare in developed countries. Autologous haematopoietic stem cell transplantation is a treatment approach that aims to ameliorate and to terminate disease activity. The erroneous immune system is eradicated using cytotoxic drugs, and with the aid of haematopoietic stem cells a new immune system is rebuilt. As of today, more than 1000 patients with multiple sclerosis have been treated with this procedure. Available data suggest that autologous haematopoietic stem cell transplantation is superior to conventional treatment in terms of efficacy with an acceptable safety profile. A smaller number of patients with other neuroinflammatory conditions have been treated with promising results. Herein, current data on clinical effect and safety of autologous haematopoietic stem cell transplantation for neurological disease are reviewed.

If a randomised trial is done will it convince neuros to refer people to the procedure. 

Probably not, as they a a bunch of risk averse people, but it will stave off competition against current DMT for a while and by the time we get a definitive answer, drug patents will have run out:-). 

Isn't this what you wanted me to say?

Myelin autoimmunity..the delusion complex

Jae-Won Hyun et al. JNNP 2017
Background We evaluated the seroprevalence of myelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG) and associated clinical features of patients from a large adult-dominant unselected cohort with mainly relapsing central nervous system (CNS) inflammatory diseases. We also investigate the clinical relevance of MOG-IgG through a longitudinal analysis of serological status over a 2-year follow-up period.
Methods Serum samples from 505 patients with CNS inflammatory diseases at the National Cancer Center were analysed using cell-based assays for MOG-IgG and aquaporin-4 immunoglobulin G (AQP4-IgG). MOG-IgG serostatus was longitudinally assessed in seropositive patients with available serum samples and at least 2 years follow-up.
Results Twenty-two of 505 (4.4%) patients with CNS inflammatory diseases were positive for MOG-IgG. Patients with MOG-IgG had neuromyelitis optica spectrum disorder (NMOSD, n=10), idiopathic AQP4-IgG-negative myelitis (n=4), idiopathic AQP4-IgG-negative optic neuritis (n=4), other demyelinating syndromes (n=3) and multiple sclerosis (n=1). No relapses were seen in patients when they became MOG-IgG seronegative, whereas a persistent positive serological status was observed in patients with clinical relapses despite immunotherapy.
Conclusions In a large adult-predominant unselected cohort of mainly relapsing CNS inflammatory diseases, we confirmed that NMOSD phenotype was most commonly observed in patients with MOG-IgG. A longitudinal analysis with 2-year follow-up suggested that persistence of MOG-IgG is associated with relapses.Myelin oligodendrocyte glycoprotein (MOG) is the main antigen to induce EAE, and if you ask an EAEer or c linical immunologists, what is the antigen targeted in MS, they will say myelin basic protein or MOG. But what is the evidence....there is essentially none that is not circumstantial.

MBP is a terrible candidate as it is not CNS restricted and so much work was done with this myelin protein because it was easy to purify and was water soluble. MBP is about 30% of the myelin protein but MOG is less than 1%.   MoG-specific transgenic animals get optic neuritis and spinal cord lesions but do they get MS. 

Well no..animals don't get MS. But do people with MS have autoimmunity to MOG. The answer is no they don't and in a group of  people with neuroinflammatory disease few had anti-MOG antibodies and very few of these had MS. Are we deluding ourselves .