Thursday, 17 August 2017

Are MS drugs a waste of time

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

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

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

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

Where?..........yep you got National Parks in the USA. 

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

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

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

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

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

ProfG will be sitting on a beach somewhere in the USA pondering what this means for his therapeutic lag idea but more importantly what it would mean if hand function was the main outcome. More reason not to use DMT in SPMS

I really would like to see if you look at the effect of highly effective DMT/HSCT use and subsequent course of MS. Progression will occur because this has already been seen with alemtuzumab and but will the rate of decline change?

Wednesday, 16 August 2017

Older people do less well

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

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

Tuesday, 15 August 2017

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

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

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

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


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

 Plasma exchange

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

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

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

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

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

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

Monday, 14 August 2017

Seeing is B-lieving

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

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

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

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

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

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

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




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

Materials and methods

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


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


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

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

Sequencing of DMTs will become increasingly complex. #NeuroSpeak

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

I have had three patients like this already.

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

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

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

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


Experimental Brains in A Dish

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

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

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

#GuestPost & #ClinicSpeak: An MSer's perspective

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

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

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

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

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

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

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

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

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

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

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

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

Sunday, 13 August 2017

Good to see our animal work repeated in humans

Klistorner A, Graham EC, Yiannikas C, Barnett M, Parratt J, Garrick R, Wang C, You Y, Graham SL.
Progression retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations. Eur J Neurol. 2017 Aug 10. doi: 10.1111/ene.13404. [Epub ahead of print]

BACKGROUND: The mechanism of retinal ganglion cell (RGC) and retinal nerve fibre layer (RNFL) loss in multiple sclerosis (MS) remains unknown. This study aims to investigate the association between temporal RNFL (tRNFL) thinning and disease activity in the brain determined by T2 lesions on MRI.

METHODS: 55 consecutive relapsing-remitting MS (RRMS) patients and 25 controls were enrolled. All patients underwent annual optical coherence tomography (OCT) and high-resolution MRI scans for tRNFL thickness and brain lesion volume analysis, respectively.

RESULTS: Significant tRNFL thickness reduction was observed over the 3-year follow-up period at a relatively constant rate (1.02 μm per year). Thinning of tRNFL fibers was more prominent in younger patients (p = 0.01). The tRNFL loss was associated with new MRI lesions in the optic radiations (OR). There was significantly greater tRNFL thinning in patients with new lesional activity in OR compared to patients with new lesions outside of OR (p = 0.009).

CONCLUSIONS: This study supports the notion that retrograde transneuronal degeneration caused by optic radiation lesions might play a role in progressive RNFL loss.

The visual system is the most accessible, it is often used in MS to assess the effects of MS. Most recently it is being studied with optical coherence tomography (OCT). You shine a light beam in the eye and it reflects light back and it gives a picture of the eye. It's like an ultrasound of the eye but using light rather than sound.

A few years ago we made some mice that had retinal cells that glowed in the dark and the mice also got inflammation of the optic nerve.

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis Katie Lidster, Samuel J. Jackson, Zubair Ahmed, Peter Munro, Pete Coffey, Gavin Giovannoni, Mark D. Baker, David Baker PLoS One. 2013; 8(11): e79188.

It showed us that damage to the optic pathway resulted in die-back of the nerve and the retinal ganglion cell died and disappeared a few days later.

This causes thinning of the retina, and a loss in retinal nerve thickness layer, so I'm not sure why this abstract starts the way it does as there are hundreds of animal studies showing retrograde loss of retinal nerves after damage nerves between the eye and the brain. So good to see when they look in humans they find the same thing happens.

Saturday, 12 August 2017

#ClinicSpeak: managing unrealistic expectations in relation to HSCT

We need a national debate about the use of HSCT to treat MS and we need to educate MSers about what to expect. #ClinicSpeak

I received an email from a colleague this week that stated:

"I saw a patient last week that I thought might be worth discussing on the blog. The patient had a self-funded AHSCT in Russia last year after doing badly on an injectable. She went into the transplant with the expectation she would be cured. A year after the transplant she has now developed a spinal cord relapse confirmed on MRI. To complicate matters her lymphocyte count is still around 0.8x10^9/L. She was absolutely devastated when I gave her the MRI results that the HSCT had not worked. It was worse for her than receiving the initial diagnosis of MS. I started my training initially in medical oncology. It reminded me of giving the news to young woman with breast cancer who had just finished six months of adjuvant chemo and at the end of treatment her scan showed new metastatic disease. This is not a situation I've encountered before but makes the point that although HSCT is a highly effective DMT, it is not a cure for MS as it is often sold to people travelling abroad to be treated."

I think it is important to realise that until we know the cause of MS and how it drives MS disease activity we won't be able to declare a victory over MS, i.e. say to someone that you have been cured. This is why I am always careful to use the term 'potential cure', simply because I am not 100% sure I know what causes MS. 

I get very upset when I hear stories such the one above. AHSCT is not a cure and a significant number of pwMS will relapse after having HSCT. NEDA rates at 3 years are about 75% and this figure will drop with time.

Please note there are a lot of Charlatans out there who promise pwMS a cure, take their money and are not around, or disappear, when the shit-hits-the-fan. To protect yourself you need to be careful. The following is a sensible information sheet that has been prepared by the MS Group in Bristol that explains what you need to do when exploring HSCT abroad.

I actively discourage my patients from going abroad for HSCT, because it is risky, expensive and you need follow-up post-HSCT. This is one of the reasons why Barts-MS have started offering it to our patients in London, but we have strict guidelines governing its use. Please note that the NHS does cover the costs of HSCT and MS is specifically mentioned in the NICE guidelines for bone marrow transplantation. In addition NICE is in the process of generating MS-specific guidelines to cover HSCT for RRMS. In short there is no reason for you to travel abroad. 

CoI: multiple

Friday, 11 August 2017

Taking out the rubbish: proteasome inhibitor for NMO

Neuromyelitis Optica (NMO) is an autoimmune inflammatory disease of the CNS in which antibodies directed against nerve cells - usually against a water channel called aquaporin-4 - lead to inflammatory lesions affecting mainly the optic nerves and the spinal cord.  Around 1/2 to 1/4 of people with NMO don't respond to aggressive immunomodulating drugs like azathioprine and rituximab. 

A drug that has been suggested as a possible option in NMO is bortezomib (Velcade). Bortezomib is a relatively new anti-cancer drug which is most often used in multiple myeloma, a disease caused by uncontrolled production of antibody by abnormal B cells. Interestingly it is also being trialled in Lupus, another B-cell-driven autoimmune disorder, We don't really understand how bortezomib works. On a subcellular level, it binds to and inhibits the function of the proteasome - the cellular machinery responsible for degrading proteins. So bortezomib prevents waste disposal.

How does this killl B cells? Bortezomib kills cells most effectively when they are producing lots of immunoglobulin. This suggests that cells making lots of protein are especially dependent on effective waste disposal via the proteasome, and that inhibiting the proteasome allows waste products to accumulate and kill the cell.

A study published last month in JAMA neurology found 5 people with refractory NMO despite full medical therapy. They gave these people 4 cycles of bortezomib. Each cycle consisted of 4 days of injections spaced out over about a fortnight. The cycles were 10 days apart. People were allowed to continue using steroids or azathioprine alongside. 

4 out of the 5 people in the study were relapse-free for one year despite previously having very active disease. There was an overall reduction in mean EDSS scores at 1 year - a measure of disability from 5.5 to 4. Bortezomib was associated with a drop in the serum antibody levels and serum total and plasma B cell counts. 

Obviously this study is too small to support routine use of bortezomib for people with NMO. But it certainly supports designing a phase 2 trial to test whether this drug is more effective than standard therapy for highly-active NMO.

What does this mean for MS? Well, we think that B cells are incredibly important in MS: it is not entirely clear which subsets are involved and this may differ from person to person. We think plasma cells probably play a role, but they don't seem to be the main driver of the disease as they are in NMO, myeloma, and Lupus. Once we understand more about the role of plasma cells in MS, it may be appropriate to trial bortezomib in selected people with plasma cell-driven disease. Until then, I don't think bortezomib will add much to our current arsenal of DMTs in MS, but it will teach us a lot about basic B cell biology in autoimmune disease and cancer. 

The paper:
In neuromyelitis optica spectrum disorder (NMOSD), enhanced plasma cell activity contributes to antiaquaporin-4 autoantibody (AQP4-ab) production.1 Longitudinal data indicate that 25% to 66% of patients with NMOSD who are treated with azathioprine, rituximab, and other immune-modifying therapies still experience relapses.2 Here we assess the safety and efficacy of bortezomib, a selective inhibitor of the 26S proteasome subunit, among patients with highly relapsing NMOSD.
This is a registered longitudinal study from the National Institutes of Health (NCT02893111) that was conducted from December 2015 to January 2017. Five Chinese female patients who satisfied the 2015 diagnostic criteria of NMOSD were enrolled.3 The study protocol and supporting documentation were approved by the ethical committee of Tianjin Medical University General Hospital. Written informed consent was obtained from each patient or a legally acceptable surrogate. The characteristics of patients and their responsiveness to prior therapies were collected and illustrated in the Table. Study patients received 4 cycles of subcutaneous bortezomib at a dosage of 1 mg/m2 of body surface area on days 1, 4, 8, and 11 per cycle followed by a 10-day treatment-free interval. This intervention was concurrent with an oral corticosteroid or azathioprine regimen.
Relapses, Expanded Disability Status Scale scores, and pain levels (visual analog scale) were assessed by 2 experienced neurologists who were blinded to the study. Serum AQP4-ab titers were tested by a green fluorescent protein–AQP4 fluorescence immunoprecipitation assay. Peripheral B cells and plasma cell counts were measured by flow cytometry with anticluster of differentiation (CD) 19 (allophycocyanin; Biolegend) and anti-CD138 (fluorescein isothiocyanate; Biolegend), respectively. Descriptive values are given as medians (interquartile range [IQR]) for continuous variables.
Despite undergoing vigorous therapies (Table), all the patients experienced at least 2 relapses in the previous 6 months or 3 relapses throughout the years (Figure, A). After initiating bortezomib treatment, 4 of the 5 patients, including patient 2, were relapse-free during the 1-year follow-up. A myelitis relapse was only observed in patient 1 when the patient experienced slight paraplegia 10 months following the onset of bortezomib. Magnetic resonance imaging with gadolinium enhancement showed a new lesion in the 12th thoracic–first lumbar segment of the spinal cord. Prompt treatment with intravenous methylprednisolone (500 mg/d) for 5 days ameliorated her symptoms.
None of the 5 patients experienced further neurological deterioration at the conclusion of the study. The median Expanded Disability Status Scale scores reduced from a median (IQR) of 5.50 (3.75-6.25) at baseline to 3.50 (0.75-4.25) after 1-year follow-up (Figure, B). Their visual analog scale scores also declined from a median (IQR) of 6.0 (5.0-6.75) on study entry to 3.0 (2.25-3.75) after 12 months. Compared with the baseline, serum AQP4-ab titers reduced from a median (IQR) of 66.4nM (35.7-147.3) to 27.1nM (18.7-34.9) after 1 year (median reduction, 59.2%) (Figure, C). Peripheral CD19+ B cell counts declined from a median (IQR) of 230/μL (175-390) to 41/μL (21-158) and CD138+ plasma cell counts decreased from 7/μL (6-13) to 2/μL (1-3) after 1 year. Finally, the observed adverse effects related to bortezomib were mild and transient (Table).

The reason that a proportion of patients with NMOSD treated with rituximab still experience attacks may be derived from resistance to CD20 devoid of long-lived plasma cells that are resistant to depletion.4,5 Bortezomib can deplete long-lived plasma cells.6Our results support this notion and suggest that bortezomib could serve as a promising escalation therapy for highly active NMOSD that does not respond well to or does not tolerate current immunosuppressive treatments. In addition, clinical improvements among the 5 patients were closely associated with the reduction of autoimmune activity, reflected by a decrease in serum AQP4-ab titers, peripheral plasma cell count, and precursor B cells with proteasome inhibition. However, this study is limited by a small and heterogeneous sample size of Asian women. Large-scale randomized clinical trials are further required to generate definitive evidence.

#ClinicSpeak & #PoliticalSpeak: ageing the other elephant in the room

Do you think payers, or even regulators, would dare to be ageist in relation to MS treatments? #ClinicSpeak #PoliticalSpeak

Age, in particular old age (> 50 years of age), is a poor prognostic factor for MS and for most other neurological disorders. The aged brain does not deal with insults very well. Why? Age chews up brain and cognitive reserve and hence the capacity for the brain to recover from attacks is limited. I am convinced that a large part of the treatment response in DMT trials is driven by recovery of function, which may explain why in almost all studies the older you are the less effective the DMT. This is particularly evident in progressive MS trials, for example in the rituximab, ocrelizumab and siponimod trials. The implications of this is that when one these drugs get to market will NICE, and other payers, dare look at the cost-effectiveness of these treatments in older pwMS and decide that it is simply not worth paying for DMTs if you are above a certain age. 

Guillemin et al. Older Age at Multiple Sclerosis Onset Is an Independent Factor of Poor Prognosis: A Population-Based Cohort Study. Neuroepidemiology. 2017 Aug 10;48(3-4):179-187.

BACKGROUND: Late-onset multiple sclerosis (LOMS) frequently features a primary progressive (PP) course, strongly predicting severe disability. In this population-based cohort, we estimated the prognostic role of age at multiple sclerosis (MS) onset, independent of PP course, on disability progression.

METHODS: The association of age at disease onset (adult, <50 years [AOMS], vs. late, ≥50 years [LOMS]) and time to Expanded Disability Status Scale (EDSS) score 4 and 6 was estimated by Cox regression modelling.

RESULTS: Among 3,597 patients, 245 had LOMS. Relapsing-remitting (RR) disease was less frequent with LOMS than AOMS (51.8 vs. 90.8%, p < 0.0001). PP course, LOMS and male gender predicted short time to EDSS 4 and 6. Worse outcome with LOMS (time to EDSS 4 and 6, HR 2.0 [95% CI 1.7-2.4] and 2.3 [1.9-2.9]) was independent of PP course or male gender. LOMS had greater impact on RR than PP disease (time to EDSS 4 and 6, HR 3.1 [2.3-4.0] and 4.0 [2.9-5.6]). Only LOMS predicted time from EDSS 4 to 6 (p < 0.0001).

CONCLUSIONS: Late onset MS was strongly associated with poor prognosis, independent of initial disease course, in predicting the disability progression along time.

CoI: multiple

EBV making Memory B cell

Styles CT, Bazot Q, Parker GA, White RE, Paschos K, Allday MJ. EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency. PLoS Biol. 2017 Aug;15(8):e2001992.

Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, and proliferate. If the cells are infected ex vivo, they are transformed into continuously proliferating lymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes, express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activated B-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), in which EBV persistence is established. 

Three related latency-associated viral proteins EBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellular genes. EBNA3B is not necessary to establish Lymphoblastoid lines, but EBNA3A and EBNA3C are required to sustain proliferation, in part, by repressing the expression of tumour suppressor genes. 

Here we show, using EBV-recombinants in which both EBNA3A and EBNA3C can be conditionally inactivated or using virus completely lacking the EBNA3 gene locus, that-after a phase of rapid proliferation-infected primary B cells express elevated levels of factors associated with plasma cell (PC) differentiation. 

These include the cyclin-dependent kinase inhibitor (CDKI) p18INK4c, the master transcriptional regulator of plasma cell differentiation B lymphocyte-induced maturation protein-1 (BLIMP-1), and the cell surface antigens CD38 and CD138/Syndecan-1. Chromatin immunoprecipitation sequencing (ChIP-seq) and chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) indicate that in lymphoblastoid cell lines inhibition of CDKN2C (p18INK4c) and PRDM1 (BLIMP-1) transcription results from direct binding of EBNA3A and EBNA3C to regulatory elements at these loci, producing stable reprogramming. Consistent with the binding of EBNA3A and/or EBNA3C, cells become committed to a B-blast fate in less than 12 days post-infection and are unable to de-repress p18INK4c or BLIMP-1-in either newly infected cells or lymphoblastoid cells by inactivating EBNA3A and EBNA3C. 

In vitro, about 20 days after infection with EBV lacking functional EBNA3A and EBNA3C, cells develop a plasma cell-like phenotype. Together, these data suggest that EBNA3A and EBNA3C have evolved to prevent differentiation to plasma cells after infection by EBV, thus favouring long-term latency in Memory B Cells and asymptomatic persistence.

EBNA3A and EBNA3C inhibit the differentiation of Epstein-Barr virus (EBV)-activated B cells to plasma cells.

Upon EBV infection, mature human B cells become activated, grow and proliferate. In vivo, in the presence of T cells or T cell–derived factors, infected cells can enter the germinal centre and differentiate into memory B cells, the site of long-term EBV latency and persistence. However, it has not been established what happens if T cell help is unavailable (Th-ve). Usually in the absence of T cell help, antigen-activated B cells can enter the default plasma cell differentiation pathway, resulting in antibody-producing plasma cells. We suggest EBV has evolved to prevent default plasma cell differentiation, thus favouring latency in memory B cells, through specific repression of the plasma cell differentiation factors p18INK4c and B lymphocyte-induced maturation protein-1 (BLIMP-1), by the viral transcription factors EBNA3A and EBNA3C that act in vitro to support the activated B-blast population in establishing continuously proliferating lymphoblastoid cell lines (LCLs). Since the repression of the p18INK4c and BLIMP-1 genes utilizes the polycomb system (PRC2) and is stable and heritable, continuous expression of functional EBNA3A and EBNA3C is unnecessary to favour memory cell rather than plasma cell differentiation.

We have been arguing that drugs that target memory B cells are important for control of MS. One potential reason is because they are removing Epstein Bar Virus. This study looks to see what happens when B cells are infected with the virus. It appears that some viral gene elements stop the B cells differentiating into antibody producing plasma cells and instead makes them form memory B cells where the virus can become latent and avoid immune destruction, but at the same time this will help virus and importantly memory B cells persist. Therefore does this cause immune memory to persist and so create an advantage to most infected humans.

So would a vaccine to kill EBV be a good thing.

Thursday, 10 August 2017

#ThinkSpeak & #BrainHealth: treating your microbiome as a pet

It is that time of year when I seem to have time for rumination and reflection. #ThinkSpeak #BrainHealth

Last night I was at dinner with nine of my trainees who have recently left, or are about to, to continue with their career progression (please note progression as it is being used here denotes improvement).

We had some interesting discussion about the changes that are occurring to the practice of medicine and inevitably the conversation came down to AI (artificial intelligence) and algorithmic medicine. One of the other issues we touched on was the stress medics are under and despite knowing about bad behaviours a lot of us still self medicate to reduce stress. Too many medics smoke, drink too much, sleep and exercise too little, have poor diets, etc. If we can't take control over our own lives how can we expect to give advice to our patients and expect them to take the advice seriously? This conundrum has been pinging around in my head for several years and is one of the motivations behind our #BrainHealth campaign. In response to this problem we are planning to launch a #BrainHealth competition at ECTRIMS in Paris where we will be asking MS centres, Pharma companies and other MS stakeholders to put forward teams of at least 7 people to compete over 100 days to see who which team can collect the most activity points. We hope by making this competitive we will get greater participation and at the same time they will be living examples to pwMS that it can be done. We are also proposing that the teams include pwMS. What do you think? At present we are proposing to use the Virgin Pulse platform to run the competition. Wouldn't it be nice to see Barts-MS being beaten by a team from Australia?

I don't think this competition will include diet. So what about diet? What can we do to improve the nation's and our patients diets? 

I was looking at our dog this morning and thought about how much value he brings to our lives. Because we look after our dog by feeding him well and making sure his comfortable why we wouldn't we do the same to pets living inside our body? This is when I thought of starting a relationship with my gut microbiome and to start treating it as a pet. If we did this we may be more disciplined about how we feed  it and look after it. After all we are what we eat and our gut microbiome sits at the interface. If we treat our microbiome well, by eating well, it will treat us well.  

Education- Epstein Bar Virus

ProfG has been banging on about EBV as a cause of MS, but what do we know about EBV. 

For me the answer is not a lot. So I thought I would try and educate myself a bit.

The Epstein–Barr virus (EBV), also called human herpesvirus 4 (HHV-4), is one of eight known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. 

Never thought I'ld be saying "I've got Herpes". Now most of us will have to say this as EBV infects 90-95% of the population. Are the other 5% just lucky? or Do they have a defect? 

Epstein–Barr virus infection is spread via saliva, and has an incubation period of four to seven weeks.The virus replicates first within epithelial cells in the pharynx (which causes pharyngitis, or sore throat), and later primarily within B cells (which are invaded via their CD21  receptor. The host immune response involves cytotoxic (CD8-positive) T cells against infected B lymphocytes, resulting in enlarged, atypical lymphocytes (Downey cells).

EBV is best known as the cause of infectious mononucleosis (glandular fever).  T
here may be the presence of an enlarged spleen, and swollen posterior cervical, axillary, and inguinal lymph nodes

Mono most commonly affects those between the ages of 15 to 24 years in the developed World. In the developing World, people are more often infected in early childhood when the symptoms are less. In those between 16 and 20 it is the cause of about 8% of sore throats.  About 45 out of 100,000 people develop mono each year in the United States. Nearly 95% of people have been infected by the time they are adults. The disease is known as "the kissing disease"

It is often treated with anti-biotics, which is useless for an viral disease. 

I suspect glandular fever is causing a "sickness behaviour" because the lymphocytes are expanding and releasing cytokines and causing more B cells to be produced. Then T cells expand to come to kill the virally infected B cells. 

However EBV is also associated with particular forms of cancer such as: 

  • Hodgkin's lymphoma, In the United States, 0.2% of people are affected at some point in their life. The most common age of diagnosis is between 20 and 40 years old.common symptom of Hodgkin's is the painless enlargement of one or more lymph nodes, or lymphadenopathy. The nodes may also feel swollen when examined. The nodes of the neck and shoulders are most frequently involved (80–90% of the time, on average). The lymph nodes of the chest are often affected.There are two major types of Hodgkin lymphoma: classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma )NLPHL).Diagnosis is by finding Hodgkin's cells such as multinucleated Reed–Sternberg cells (RS cells) in lymph nodes. The Reed-Sterberg Cell has its origins in B cells as does NLPHL. 
So it is a B cell that is hyper-proliferating and cell growth is not checked.
  • Burkitt's lymphoma, is another B cell cancer and is associated with EBV infection in some developing countries.
So again a B cell hyper-proliferation and cell growth is not checked.

Most people become infected with EBV and gain adaptive immunity. In the United States, about half of all five-year-old children and about 90 percent of adults have evidence of previous infection. Infants become susceptible to EBV as soon as maternal antibody protection disappears. Many children become infected with EBV, and these infections usually cause no symptoms or are indistinguishable from the other mild, brief illnesses of childhood. In the United States and other developed countries, many people are not infected with EBV in their childhood years. When infection with EBV occurs during adolescence, it causes infectious mononucleosis 35 to 50 percent of the time.

EBV infects B cells of the immune system and epithelial cells. Once EBV's initial lytic infection is brought under control, EBV latency persists in the individual's B cells for the rest of the individual's life

BV is a relatively uniquely human virus that I guess has co-evolved with human. It has learnt to evade the human immune response for most of the time and infects most humans. However, is it like the papillomavirus and a warty pain in the bum or does it have any useful function? 

My guess it is in fact a bit of both.

My guess it has co-evolved such that it creates long-lived B memory cell responses and so gives survival advantage to the human race, so we tolerate it rather than kill it. We know that EBV can immortalise B cells as we use this technique to make B cell lines and so maybe it helps B cells to live longer and keep immunity. However as a down side it causes a few cancers where B cells do not stop proliferating, it causes glandular fever, which is a consequence of non-cancerous B cells proliferating and it causes MS and a number of other autoimmune diseases, which seem to be a problem of memory B cell. As autoimmunities occur later than when reproduction historically occurred, it is not much consequence to the human population and from an evolutionary prospective the enhanced protective autoimmunity may help the human race more than the influence of  a bit of autoimmunity.