Happy New Year Q&A Jan 2018

Happy New Year!

For those who want to say something unrelated to the posts this the place for you.

So whilst ProfG prepares a year that was, it is a two-way street 




This is a message I came across this Christmas from Lucy Woods,  she was 5 years old when she was diagnosed with MS. So as the year turns a message to us.

Texting and walking: don't forget to self monitor

For soft science of the week, we have texting whilst walking. We know this can be bad for your health, particularly when crossing roads.

There were many similarities between pwMS and those that didn't have MS, but there were some differences in gait too and these may involve CNS issues.

Pau M, Corona F, Pilloni G, Porta M, Coghe G, Cocco E.Texting while walking differently alters gait patterns in people with multiple sclerosis and healthy individuals.Mult Scler Relat Disord. 2017 Dec 2;19:129-133.

BACKGROUND:In recent times, increasing safety concerns have been associated with the use of mobile phones by pedestrians. In particular, texting has been shown to significantly alter gait patterns. However, no specific investigations have been performed on people with Multiple Sclerosis (pwMS), who are already characterized by gait dysfunctions caused by the disease.
OBJECTIVE:To assess the existence of possible alterations in spatio-temporal parameters of gait in pwMS when simultaneously texting on a smartphone and walking.
METHODS:Fifty-four pwMS (mean age 40.5 ± 10.5) and 40 age-matched unaffected individuals were tested in two conditions: walking, and walking while texting on a smartphone. Spatio-temporal parameters of gait were assessed using a wearable accelerometer located on the lower back.
RESULTS:Texting induces reduction of gait speed, stride length and cadence in both groups, but such changes were smaller in magnitude in pwMS. An increase of stance and double support and reduction of swing phase were observed in pwMS only.
CONCLUSIONS:Texting alters gait patterns of pwMS differently from unaffected individuals, probably due to a different prioritization of the task, which appears to take into account the motor and  sensory impairments associated with the disease by favoring the motor task.

Is this time to change the 25 metre walk to walk with a phone? 

I think not, because it adds complexity, but don't forget to get a 9 Hole Peg test and a piece of string so you can monitor your output yourself.

Hopefully ProfG is back from his Hols refreshed and has done Highlights of the year

End of Year Revision

As the year draws to a close, it has been a productive year for papers and ideas. 

I predict that during 2018, we will get even more clarity on the story.

But do you believe the academic minnow or the whale?

As we have said many times before, people do not all agree on the driving force of MS.

Most people are still in the T cell camp or midway into the T cell camp. Even those in the B cell camp are not convinced and so do not provide any clarity into what is going on. 

Is it Chewbacca Science, like the chewbacca defence...you throw a load of facts in the air and it simply confuses every one, so every one agrees with you but non-one knows what's really going on. 

You are never wrong because you suggest every possibility. Everyone is happy.

However, it allows you to lack focus and so waste time by not doing the important things.

 Chewbacca Science-Lovely and Cuddly

Greenfield AL, Hauser SL.B Cell Therapy for Multiple Sclerosis: Entering an Era. Ann Neurol. 2017. doi: 10.1002/ana.25119.

Monoclonal antibodies that target CD20 expressing B cells represent an important new treatment option for patients with multiple sclerosis (MS). B cell depleting therapy is highly effective against relapsing forms of the disease and is also the first treatment approach proven to protect against disability worsening in primary progressive MS. Moreover, evolving clinical experience with B cell therapy, combined with a more sophisticated understanding of humoral immunity in preclinical models and in patients with MS, have led to major progress in deciphering the immune pathogenesis of MS. Here, we review the nuanced roles of B cells in MS autoimmunity, the clinical data supporting the use of ocrelizumab and other anti-CD20 therapies in the treatment of MS, as well as safety and practical considerations for prescribing. Lastly, we summarize remaining unanswered questions regarding the proper role of anti-CD20 therapy in MS, its limitations, and the future landscape of B cell-based approaches to treatment. 

In my opinion, this paper seems to be little more than an advert for ocrelizumab, particularly as it states the manufactures provide "writing assistance for CD20-related presentations"

Anyway, it says:

"Although most disease-modifying therapies for MS have traditionally been conceptualized as functioning via T cell-based mechanisms, a growing body of data indicates that all have demonstrable effects on B cells as well".

"Common themes include 

• Promoting naive rather than memory or plasmablast (alemtuzumab); 
• Shifting B cell cytokines towards an anti-inflammatory tone (beta interferon, glatiramer acetate, fingolimod);
• Increasing B-regs (beta interferon, glateriamer acetate, fingolimod and dimethyl fumarate); 
• Decreasing class II MHC and constimulatory molecules on B cells required for antigen presentation (beta interferon and dimethyl fumarate); 
• Sequestering B cells in lymphoid organs (fingolimod); 
• Blocking VLA-4 mediated B cell trafficking to the CNS (natalizumab); or
• Direct cytolysis of B cells (alemtuzumab, teriflunomide, mitoxantrone)" 

As for ocrelizumab

• Potentially pathogenic memory B cells remain at reduced levels
• Fewer GM-CSF producing B cells and higher levels of IL-10
• Fewer pro-inflammatory Th1 & Th17 cells
• Large number of CD25+FOXP3 regulatory T cells

So as the year draws to a close, 

I ask you to remember what you have learnt this year and ask you to consider this ....

Do you want to believe the Jumble of Conflicting and Inconsistent Ideas? as all the above are possible. It means the MS treatment landscape is difficult to comprehend and navigate or

Is it simpler that MS treatments all physically or functionally deplete memory B cells (maybe to stop them becoming plasmablasts) to prevent them entering the CNS.

This gives a unifying idea on aetiology, pathology and response to treatment?

It makes treatment choices easier.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50.

Which fits the MS reality?

Let's put it to the test and see what happens in 2018.

I predict that more people will fall off the fence

Or maybe I'll eat humble pie.

Reduce your price or else seems to be the message

To follow on from NDG story

Multiple sclerosis - interferon beta, glatiramer acetate (review TA32) [ID809]: Appraisal consultation: 1

The key dates for this appraisal are:
Closing date for comments: 24/01/2018
Fourth appraisal committee meeting: 6 March 2018
Extavia (interferon beta 1b) is recommended as an option for treating multiple sclerosis, only if:

• the person has relapsing–remitting multiple sclerosis or 
• the person has secondary progressive multiple sclerosis with continued relapses and 
• the company provides it with the discount agreed in the patient access scheme. 

Glatiramer acetate and the other beta interferons (Avonex, Betaferon, Plegridy and Rebif) are more expensive than Extavia, and the most likely cost-effectiveness estimates for these treatments compared with best supportive care are higher than what NICE normally considers acceptable. So, these treatments are not recommended for multiple sclerosis because they would not be a good use of limited NHS resources at their current prices.

By Dec 20 NICE had confirmed 

A discount to the price (above) of this drug now means it can be recommended as a cost effective option for adults with relapsing- remitting multiple sclerosis (MS) or secondary progressive MS with continued relapses

So this would suggest that Merck, Biogen, Bayer and Teva have until March 2018 to reduce their price or its curtains.


2018 is shaping to be a year of a shake up in the UK, 

What happens when generics small molecules arrive?  

The end of the biologicals?

Remyelination studies: Publishing the data after pharma has dumped the idea

Positive data for a target for remyelination.

I suspect you are hearing about it after clinical development has been stopped.

Chen Y, Zhen W, Guo T, Zhao Y, Liu A, Rubio JP, Krull D, Richardson JC, Lu H, Wang R. Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination.PLoS One. 2017 Dec 18;12(12):e0189380.

BACKGROUND: Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo.
METHODS: A high-content screening assay with differentiation of primary rat oligodendrocyte precursor cells was used to screen GSK-proprietary annotated libraries for remyelination-promoting compounds. Compounds were further validated in vitro and in vivo models; clinical relevance of target was confirmed in human post-mortem brain sections from patients with MS.
RESULTS: Of ~1000 compounds screened, 36 promoted oligodendrocyte precursor cell differentiation in a concentration-dependent manner; seven were histamine receptor-3 (H3R) antagonists. Inverse agonists (deliver a negative signal) of H3R but not neutral antagonists (receptor blockers) promoted oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed throughout OPC differentiation; H3R expression was transiently upregulated on Days 3-5 and subsequently downregulated. H3R gene knockdown in OPCs increased the expression of differentiation markers and the number of mature oligodendrocytes. Overexpression of full-length H3R reduced differentiation marker expression and the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and Hes-5 were identified as key downstream targets of H3R during OPC differentiation. In the mouse cuprizone/rapamycin model of demyelination, systemic administration of brain-penetrable GSK247246 enhanced remyelination and subsequently protected axons. Finally, we detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS, and validated a genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to multiple sclerosis.
CONCLUSIONS: From phenotypic screening to human genetics, we provide evidence for H3R as a novel therapeutic target to promote remyelination in patients with multiple sclerosis

               Hrh3 histamine 3 receptor expression from BrainSeq

We have heard of anti-cholingeric/muscarinic receptor drugs (acetyl choline (nerve transmitter) receptor) promoting remyelination. These include clemastine. However this is also an anti-histamine drug and blocks the Histamine 1 receptor. 

In this study they find that Histamine receptor 3 inhibiting drugs promote remyelination. 

Oligodendrocyte differentiation is regulated through the cAMP/CREB/HDAC1/Hes-5 pathway. Constitutively active H3R inhibits cAMP increase, which would otherwise activate PKA phosphorylation of CREB leading to oligodendrocyte differentiation through HDAC1 and Hes-5. AC, adenyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate, CREB, cAMP response elements; H3R, histamine receptor 3; HDAC, Histone deacetylase. MBP, myelin basic protein; OL, oligodendrocyte; OPC, oligodendrocyte precursor cell; P, phosphate; PKA, protein kinase A.

Now before you get too excited, I have reported on this before when it was presented at ECTRIMS:

http://multiple-sclerosis-research.blogspot.com/2014/09/news-from-actrimsectrims-2014-pharma-in.html

If you read that post you can see that the clinical trial with the clinical candidate drug GSK239512 was already underway 3 years ago. 

The logic of the approach is that, histamine H3 receptor antagonism has been proposed to increase cholinergic signaling.

Between 2007 and 2014, GSK conducted six clinical trials on this compound, three in Alzheimer's, two in multiple sclerosis, and one in schizophrenia.

The antagonist improved episodic memory but not other cognitive domains or clinical measures in Alzheimers. 

The results in MS were published:

Schwartzbach CJ, Grove RA, Brown R, Tompson D, Then Bergh F, Arnold DL.Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study. J Neurol. 2017 Feb;264(2):304-315.

Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.

http://multiple-sclerosis-research.blogspot.com/2016/12/researchspeak-remyelination-study.html

So a positive effect great.....so what is happening?

So we look to the side effects it caused predominantly headaches, dizziness, and problems sleeping (Grove et al., 2014). As of November 2015, this compound was no longer listed in GSK’s development pipeline. So it was dumped.

I think this will be the problem for most of the remyelinating drugs, as the targets people are finding e.g. RXR are all used in other important bodily functions and so blocking or activating them will have side-effects. This does not surprise me as the body uses the same signalling molecules to do many things, because this is not where the specificity of the activity is located. However, will probably hamper long-term use of such agents. 

Importantly, we have yet to answer the question. Do you need long-term treatment to remyelinate or will a pulse of treatment get the differentiation/maturation arrested oligodendrocyte precursor cells the kick they need to become myelinating cells?

The animal models used can't answer this question as they naturally remyelinate anyway, but it is an essential question that needs answering.

It is quite common for Pharma to not publish their data until after they have lost interest in a project. This keeps it secret so their competitors don't get an advantage.

So back to the drawing board.

Guest post: Digesting Science makes it to Scotland

We've been trying to get Digesting Science up to Scotland since we started the project. Scotland has one of the highest rates of MS in the world; 11,000 people according to some estimates.


MS Specialist Nurse Mhairi Coutts and her team led a Digesting Science event at Revive MS Support - a therapy centre based in Glasgow. Here's her account of the event:

On Saturday 9th December we held our first Digesting Science event here at Revive. Delivering the course along with myself, there was Rachel Morrison – MS Specialist Nurse, Western Isles, Chris Batchelor – Research Nurse, Anne Rowling Centre, Dr Niall MacDougall – Consultant Neurologist and Dr Paul Gallagher – Neurology Registrar.

The families that attended all gave very positive feedback and found the event really helpful. We were able to spend more time with the families and answer any queries. The children had a lot of fun and also felt that they had learned lots about MS. Since our post about the course on our Facebook page I have had several enquiries from other families keen to attend this event. The team that delivered the course on Saturday are definitely committed to delivering another course and we hope to get another date in diary for early in the new year.

Revive MS Support is a charity dedicated to helping those living with MS. Our aim is to enable people to maintain and improve their quality of life and live life to the full. We respect each individuals’s physical, psychological and emotional needs in everything we do. Our services are provided by a specialist team of staff dedicated to making a real difference. Our centre is a welcoming, friendly environment and we work closely with our colleagues in the NHS/ local healthcare and social services.
***********************************************

If you would like to run a Digesting Science event, contact us or go to our Facebook, Twitter or website for more information.

What you had to say about coffee and MS

Thank you for completing our recent survey on coffee consumption amongst pwMS and the reasons for drinking coffee. The results are quite interesting. What do you think? 

The following are the results of the coffee survey in pwMS. Is clear that you find coffee helpful. 

ProfG    

Education: What are B cell follicles?

The lymphatic system is part of the circulatory system and a very important part of the immune system, comprising a network of lymphatic vessels that carry a clear fluid called lymph (from Latin (lympha meaning "water") 

Want to learn more?

The human circulatory system processes an average of 20 litres of blood per day through capillary filtration, which removes plasma while leaving the blood cells in the blood. 

Roughly 17 litres of the filtered plasma are reabsorbed directly into the blood vessels, while the remaining three litres remain in the interstitial fluid. One of the main functions of the lymph system is to provide a return route to the blood for the surplus three litres.

The lymph in the tissues is moved along the lymphatic vessel network by either intrinsic contractions of the lymphatic passages or by extrinsic compression of the lymphatic vessels via external tissue forces (e.g. the contractions of skeletal muscles). 

The organization of lymph glands and drainage follows the organization of the body into external and internal regions; therefore, the lymphatic drainage of the head, limbs, and body cavity walls follows an external route, and the lymphatic drainage of the thorax, abdomen, and pelvic cavities follows an internal route. Eventually, the lymph vessels empty into the lymphatic ducts (thoraic duct), which drain into one of the two subclavian veins, near their junction with the internal jugular veins.

The other main function is that of defence in the immune system. Lymph is very similar to blood plasma: and also contains waste products and cellular debris together with bacteria and proteins from the tissues in the body. The lymph passes through lymph glands on its way back to the blood:

Lymph glands are where lymphocyte-mediated immune reactions are started

Cells laden with antigens (Something recognized by the immune system) that pickup from their surroundings, or perhaps free-floating antigen flows down the lymphatics into the lymph glands. In the skin these cells are called Langerhans cells (named after a German Scientist Paul Langerhans in 1868) and there are 700 cells for every square mm of skin. These present the antigens to T cells but by the time they arrive in the lymph node they have a new name called interdigitating cells as they have long processes that can inter weave with T cells. They are also known as dendritic cells. When a T cell is activated for the first time they proliferate.

These areas are organised to activate T and B cells. As mentioned they are structured to aid function.

In the B cell areas there are CD4 T helper cells to help the B cells to produce antibodies. These are known as follicular helper cells.

How do T cells help B cells as they relate to the lymphatic system?
Follicular B helper T cells (also known as just follicular helper T cells or TFH), are antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. 

Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, TFH cells trigger the formation and maintenance of germinal centres through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate into these seeded germinal centres, predominantly composed of rapidly dividing and mutating B cells. 

Within germinal centres, TFH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into special plasma cells capable of producing high affinity antibodies against foreign antigen, or memory B cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered. 

Memory B cells and plasma cells (antibody making cells) forming in the germinal centres

Then we have been talking about memory B cells and whilst we have been saying that memory B cells and antibody forming cells are formed in the germinal centres (GC), looking at that the  expression of CD27 (CD27+), there are a few in the germinal centres. They accumulate in the marginal zone surrounded by the T cells, so they shuttle out of the germinal centre.

This can be see in histology. CD20 binds B cells but not plasma cells so you can see most of the cells in the germinal centre have CD20 so they are not plasma cells. CD27 is on the memory B cells but can be found on activated T cells. CD1c  is a molecule associated with a form of antigen presentation.IgD is immunoglobulin D which is on B cells and is lost once memory cells class switch to produce IgA, IgG and IgE. So you can see the memory B cells are largely outside the follicle.

Where are the plasma cells?
Based on the fancy diagrams and all the hoo hah about ectopic follicles in the brain of MS, I was also under the assumption that the plasma cells would be located inside the follicle. 

These cells stain with CD138. 

When I had a look at the distribution of CD138 in lymphoid tissue I got a shock. The plasma cells are a few cells scattered outside the follicles and B cell areas.

Like the memory cells the plasma cells must rapidly leave the follicles where they are formed and the plasma cells then are found outside the follicles!

Here they are in the spleen, so you can see they are not really in the follicles. This is a revelation to me, because we are probably wasting our time looking for follicles, the plasma cells may be the odd cell next to a macrophage/microglia pumping out antibodies.

So maybe those pesky pathologists have done it again:-)....We are looking for the wrong thing.

I'll have to do some more reading. It's good that we learn together.
Some of you can hopefully spot my mistakes and misunderstandings.

NICE and not so nice

Bah, humbug! 

The cynic in me would say would say that NICE (The National Institute for Health Care & Excellence) timed the release of this consultation document in the UK exactly right. Dare I say, an overused political strategy this year has been to shoe it under the door before anyone is the wiser (I won't mention any specifics). And again they will be correct in assuming that over the yuletide, key opinion leaders in MS would either be inebriated, or staving off the first signs of a diabetic coma to take much notice. I don't mind people exercising a bit of stealth when it is required. However, it is the calculated nature by which the process is undertaken that I take umbrage to. It would be a mistake to assume, just simply because their is acquiescence, their is also acceptance.

On the 20th December 2017, NICE published an appraisal document on the use 1st line DMTs (disease-modifying treatments), specifically the interferon's and glatiramer acetate (see below for the full report).

The summary points are:

• Extavia (IFNB 1b) is recommended as a treatment for people with relapsing remitting MS or secondary progressive MS with continued relapses.
  
• Copaxone, Avonex (IFNB 1a), Betaferon (IFNB 1b), Plegridy (pegylated IFNB 1b) and Rebif (IFNB 1a) are not recommended.
• Anyone already taking one of these drugs will not be affected by this guidance and can continue without change until they and their neurologist consider it appropriate to stop.

This consultation only applies to those resident in the UK (excluding Scotland).



Historically, NICE performed an assessment of all 1st line DMTs and in accordance with the submitted evidence concluded that they were more clinically effective than best supportive care, but not cost effective for the NHS (National Health Service). In response, the Department of Health (DoH) and various stakeholders got together and established the Risk Sharing Scheme (RSS). RSS allowed clinicians to prescribe 1st line DMTs in the NHS at a deduct price, and as part of the agreement, data on efficacy was also collected. This ran for 10 years and has now come to an end; which is the reason for the reappraisal.

It's been a tough year! Make no mistake, this consultation is all about money. NHS has limited resources and increasingly finds its funding squeezed on all fronts. High-cost drugs, firstly in cancer, then Rheumatology & Respiratory, and now MS are under heavy scrutiny. 

The incremental cost-effectiveness ratio (ICER) for Extavia is less than £30,000 per QALY (quality adjusted life year) gained. For the others (glatiramer acetate, Avonex, Betaferon, Plegridy and Rebif) who also boast similar clinical effectiveness (~30% annualized relapse rate reduction) the calculations exceed that of £30,000. The DoH and Novartis (proprietor of Extavia) have agreed that Extavia will be made available to the NHS through a patient access scheme for an unknown amount.

As we're living in a democratic society, the closing date for comments on this consultation is the 24th January 2018 (tighter than some of my grant deadlines!). The MS Trust is compiling view points in a survey, so please take a moment to complete: www.surveymonkey.co.uk/r/MTApwMS.

Can Jesus's Christmas Present stop MS

So a bit of festive research for today

Frankincense is an aromatic resin used in incense and perfumes, obtained from trees of the genus Boswellia. 

If you believe this stuff, it was brought by the Three Kings to Jesus's birth place, a long time ago.

But can it affect MS?

Stürner KH, Stellmann JP, Dörr J, Paul F, Friede T, Schammler S, Reinhardt S, Gellissen S, Weissflog G, Faizy TD, Werz O, Fleischer S, Vaas LAI, Herrmann F, Pless O, Martin R, Heesen C. A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial).

J Neurol Neurosurg Psychiatry. 2017 Dec 16. pii: jnnp-2017-317101. doi: 10.1136/jnnp-2017-317101. [Epub ahead of print]

OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period.
RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections.  Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug.

INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial.

The study looks at the effect of Frankincense in a bicentric trial. Whilst this means it occurred in two places on first sight, I thought it was eccentric.

Anyway the logic is Frankensence contains Boswellic acids that are anti-inflammatory. Incensole acetate and its derivatives, which are major components of Boswellia resin, to be nuclear factor-kappaB inhibitors so they will block cytokine responses. The number of MRI lesions dropped by a half (P<0.001). Brain atrophy slowed.

When they looked T regs were up (Yippie if you follow the fashion or Yawn if you are me) and a decrease in IL-17 (Yawn....only joking but it is funny that dogma has dictated which studies were done...next year they will be looking for memory B cells....Yeah who am I kidding:-).

So it looks interesting and there were more infections which you might expect for an anti-inflammatory. Will they be doing a phase II /III in Germany where this study was done or Oman where the trees grow?

 However, this was a before and after trial. The problem here is that you tend to get recruited to these types of trials when you have been active as you see a neuro and then you get "regression to the mean" meaning that by chance you will get better.  Also to put it in perspective beta interferon reduces MRI lesions against placebo by about 70%, so a 50% drop is not that great compared to over 90% with the highly active agents.

Happy Christmas

Happy Holidays to all our Readers

Best Wishes from TeamG

Unusual cases may hold key to understanding

Case reports can off insight into MS, 

B cells at the forefront but does this end of year case report burst the B memory bubble?

Rinaldi F, Federle L, Puthenparampil M, Perini P, Grassivaro F, Gallo P.Evidence of B-cell dysregulation in severe CNS inflammation after alemtuzumab therapy.

Neurol Neuroimmunol Neuroinflamm. 2017, 13;5(1):e420.

This is another case report about disease activation within a few months of alemtuzumab. This person was doing very well on natalizumab but stopped to have a baby. 

Post-partum the person had a relapse and decided to switch to alemtuzumab. 

They had a substantial relapse 4 months after dosing and there were only 0.8 lymphocytes x 10*9 /L in the blood.  

There were 0.18 x 10*9 CD19+ B/L and 0.14 x 10*9 CD3 T cells in the blood. 

In the CSF, CD19+ were 12% of the lymphocytes of which 40% where CD20- so they were most likely plasmablasts (plasma cells would be CD20-, and largely CD19-), there were extra oligioclonal bands in the CSF. 

The inference was that the problem was B cell dysfunction. 

Does this tell us the problem is in the plasmablasts and memory are not the problem? 

Maybe

It is cases like this that can teach us stuff. It is open access so you can all read and we need to try explain them whether it is a problem of T or B or both.

Antibody in the blood was not the problem as removal of antibody made no effect. 

However, this would not remove antibodies being produced in the CSF, so maybe those in the brain were the problem.

There was no EBV detected.

Is this an issue. Only if you think they are the cause of the problem?

Maybe the relapse was destined before the alemtuzumab was started. 

However, the questions are what were the other 0.4 x 10*9 lymphocytes that were not CD19+ T cells and CD3+ T cells?

Also in the CSF what were the 60% CD19 B cells that were CD20+. 

Were they plasmablasts but these would be CD38+ as would mature and immature B cells so there is about 60%% CD38-ve, CD20+, CD19- . Probably would be memory B cells. But we dont know. 

Remember they can become plasma blasts.

So the idea is not quite dead yet.

This person was destined for HSCT. and probably myoablative (replace the immunsystem) at that.

If you don't do myoablative HSCT it may not be that good.

Nothing quite like HSCT to get the comments flooding in. 

However, I will be tucking into my Christmas Pud rather than answering the comments I'm afraid.

The study below, suggests that relapses after 7 months can occur with non-ablative HSCT. So this appears no better than using DMT.

This also shows that HSCT is not immune to the risk of PML. 

The high intensity treatment failed after ten years.

There is no question that HSCT can be very effective.

Frau J, Carai M, Coghe G, Fenu G, Lorefice L, La Nasa G, Mamusa E, Vacca A, Marrosu MG, Cocco E.Long-term follow-up more than 10 years after HSCT: a monocentric experience. J Neurol. 2017. doi: 10.1007/s00415-017-8718-2. [Epub ahead of print]

BACKGROUND:Autologous hematopoietic stem cell transplantation (aHSCT) is used in aggressive relapsing and progressive multiple sclerosis (MS). The multicentre studies and case series reported have relatively short follow-up.
AIM:To evaluate long-term effect and safety of HSCT in MS.
MATERIALS AND METHODS: Patients referred to the MS centre of Cagliari and undergoing HSCT were included. Variations in relapses and EDSS before and after HSCT were evaluated by Wilcoxon test. A descriptive analysis was made for other clinical data.

RESULTS:Nine patients (female 6, males 3; 5 relapsing-remitting, 2 secondary progressive, 1 primary progressive, and 1 progressive relapsing) performed HSCT (1999-2006). The median follow-up was 11 years (11-18). Eight patients underwent aHSCT, seven using a low intensity conditioning regimen, and one an intermediate intensity. The primary progressive underwent allogeneic HSCT, due to onco haematological disease. The relapses number decreased in the 2 years following the procedure compared to the two preceding years (p = 0.041). New relapses or disease progressions were observed after a range of 7 (low intensity regimen)-118 (intermediate intensity) months. At last follow-up, the EDSS was stable in two patients, improved in two, and worse in five (maximum 2 EDSS in one patient). Six patients showed new lesions, and seven gadolinium-enhancing on brain MRI after a mean of 23.3 and 19.8 months, respectively. Two serious adverse events were reported: melanoma, and progressive multifocal leukoencephalopathy.
CONCLUSIONS AND DISCUSSION: Our results confirm in a long follow-up the efficacy of HSCT in reducing relapses and disability progression. The risk/benefit profile is better for intermediate intensity regimens.