Saturday, 25 June 2016

ClinicSpeak: PML without immunosuppression

PML is a complex disease with many variables to consider when assessing risk. #ClinicSpeak #MSBlog 

"The single case report on a 55-year old man with PML and no underlying risk factors highlights the the issue that PML can occur in immuno-competent individuals. This has implications for assessing risk in pwMS on DMTs and in general. Firstly, it makes it impossible to say that drug x, or drug y, is not associated with some PML risk, albeit a very small risk, of developing PML. I have often been taken to task by certain Pharma reps because of this position; they obviously want to control the messaging around their drug and I want to be honest. In short no DMT has zero risk of PML. In my career as a neurologist, I have seen three patients with PML with no apparent underlying immune disorder. All three of these patients were old, in fact they were all over 70 years of age. Presumably immuno-senescence, or an aged immune system, is a risk factor for PML. This is playing out in the MS space as well, where age is emerging as a risk factor as well. This is why we need to be wary about relatively low levels of lymphopaenia in pwMS who are over the age of 60, i.e. between 500 and 800 per mm3."

Grewal et al. Progressive multifocal leukoencephalopathy in a patient without apparent immunosuppression. Journal of NeuroVirology First online: 06 June 2016

Progressive multifocal leukoencephalopathy (PML) is a viral demyelinating disease due to the reactivation of the JC virus (JCV), which usually occurs in the context of immunosuppression in HIV infection, malignancy, or in patients on disease modifying therapy for autoimmune diseases, such as multiple sclerosis (MS) and Crohn's disease. Notably, there is growing recognition that PML can occur in patients with transient immune dysfunction. Here, we present a case of a 55-year-old man without history of immunosuppression or evidence of ICL who was diagnosed with PML on brain biopsy. We will discuss the potential etiologies of mild and transient immunosuppression that can lead to PML with non-apparent immunosuppression.

CD8 Cells after Immunological Stem Cell Reconstitutions

Arruda LC, de Azevedo JT, de Oliveira GL, Scortegagna GT, Rodrigues ES, Palma PV, Brum DG, Guerreiro CT, Marques VD, Barreira AA, Covas DT, Simões BP, Voltarelli JC, Oliveira MC, Malmegrim KC.Immunological correlates of favourable long-term clinical outcome in multiple sclerosis patients after autologous haematopoietic stem cell transplantation. Clin Immunol. 2016 pii: S1521-6616(16)30098-5.

High dose immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT) induces prolonged clinical remission inmultiple sclerosis (MS) patients. However, how patient immune profiles are associated with clinical outcomes has not yet been completely elucidated. In this study, 37 MS patients were assessed for neurological outcomes, thymic function and long-term immune reconstitution after AHSCT. Patients were followed for a mean (SD) of 68.5 (13.9) months post-transplantation and were retrospectively clustered into progression- and non-progression groups, based on Expanded Disease Status Scale (EDSS) outcomes at last visit. After AHSCT, both patient groups presented increased regulatory T-cell subset counts, early expansion of central- and effector-memory CD8+T-cells and late thymic reactivation. However, the non-progression group presented early expansion of PD-1-expressing CD8+T-cells. Here, we suggest that along with increased numbers of regulatory T-cell subsets, PD-1 inhibitory signaling is one possible immunoregulatory mechanism by which AHSCT restores immune tolerance in MS patients.

What drives MS, what controls MS?. One thing that is increasingly clear is that myoablative haematopeoitic stem cell therapy is very effective at controlling relapsing MS and it is clear that relapsing MS is a product of the immune system enetering the CNS. 

This week, I saw the data from the HALT-MS study presented (BEAM myoablation  followed by HSCT) and is high efficacy, and the way the immune system reconstituted was reported to. The authors said they would do a "guest post" on this.

However this is another study looking at immune reconstitution after the transplant. The first wave of reconstitution is the innate system and the neutrophil which has to get you some protection from infection, but which lmymphocytes appear and how does this relate to disease activity. With Alemtuzmab long-term depletion of CD4 and CD8 depletion and transient CD19 B cell depletion is associated with a good outcome for MS, not secondary B cell autoimmunities:-( 

In this study CD8 and T regulatory subsets rapidly appear, is this due to regulation or in response to viruses that lurk in our environments?, However there was a population of CD8 cells enriched in those that didnot reactivate their disease and the expressed PD-1. Programmed cell death protein 1, also known as CD279 is a cell surface receptor that binds two molecules, PD-L1 and PD-L2.

PD-1, plays an important role in down regulating the immune system 
by preventing the activation of T-cells, which in turn reduces autoimmuity and promotes self-tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen antigen specific T-cells, while simultaneously reducing death in regulatory T cells. 

Friday, 24 June 2016

#Cladribine4MS - effective disease modification for all, even (or particularly?) after Brexit

After oral Cladribine was dropped by Merck Serono in 2011, we identified other sources of Cladribine and developed a UK network of over 30 MS neurologists willing to try and do a head to head study with Alemtuzumb, with a view of licensing generic Cladribine.

This was not funded in 2014/15 partly on the basis of considered lack of need and the cost of the trial: Though £32,000,000 would have been saved for the NHS by doing the study our request was £2,000,000 above the ring-fenced budget that British Science (NIHR) would fund.

Since that time, with the failure of the repurposing bill, UK Government ministers have asserted that generic Cladribine can be prescribed off-label.


Based on published data, Cladribine is as effective or more effective than current MS DMTs.

It is just as safe (or safer) than current highly effective agents and not known for the development of PML or autoimmunities characteristic of other MS drugs.

It is as convenient (or more convenient) than any agent, requiring only a few cycles of administration a year, and after just over one year you monitor and wait & see whether you remain NEDA or re-dose, compared to monthly monitoring for drugs such as teriflunomide or alemtuzumab.

Cladribine is the only MS DMT that is CNS penetrant and has a mechanism of action that can work inside the CNS. It targets dividing (like beta interferon, teriflunomide, DMF) and non-dividing lymphocytes and may kill plasma cells (antibody producing cells). We know that targeting lymphocytes is beneficial in MS, because HSCT can be very effective.

This sounds like good news for Merck (Serono no more), who claim they are going back to the regulators to get their oral version licensed for relapsing MS, yet we have heard that for about 18 months now with submission still being "imminent", confirmed as recently as yesterday...

I am also told Merck might try hard to keep the price at a reasonable level should a license come their way, but is this likely I wonder?  More likely this will be priced in the region of current MS DMT, i.e. 20-30 times the cost of generic subcutaneous Cladribine, of which all gets into the body (100% bioavailability) compared to only 42% of what is ingested with the Cladribine pro-drug pill, which is converted to Cladribine after digestion.

Cladribine could be cost effective alternative for resource strapped healthcare settings, such as the UK.  Current MS drugs cost about $50,000, multiplied by 5 years thats $250,000 for most MS drugs, for some it is more. If you are NEDA after only 1 course of Cladribine that could be $350 - $1000 depending on the source. In the UK one course costs about £1600.

How about creating access to an effective DMT for the 300,000 or so pwMS on the planet whose annual income is lower than the annual cost for a DMT (and that is for the least efficacious brands)?  ECTRIMS, ACTRIMS, PACTRIMS, MSIF, MS Societies of the World - anybody interested?

That aside, Cladribine may still be a useful approach for people with progressive MS, who have slipped through the current DMT net, and this is where we can focus our energy in the UK to give people with nothing an alternative to nothing.

Please tweet the Video:

I’ve tweeted the link earlier today, so you could just retweet that if you prefer (

+++ Latest Brexit News +++ Withdrawal of video considered as according to LEAVE campaign leaders now £350 Million/week extra for NHS available +++ Apparently, The Palace considers overuling referendum due to concerns over new Scottish exit vote +++ As a result video remains available on Youtube until further notice +++

Thursday, 23 June 2016

NurseSpeak: continuing professional development or CPD

Should we run accredited CPD via the blog? Have your say. #NurseSpeak #MSBlog

"I received a very touching letter from a MS Clinical Nurse Specialist who works in the North of England stating that his/her main source of MS education is the Barts-MS Blog with an appeal for us not to close it down. They valued our 'independent interpretation' and frank discussion. 

Two things: 

(1) We may be independent, but we have conflicts of interest as declared. Conflicts may affect the way we present results and interpret them; please be aware of this. 
(2) This blog is not really being run for CPD. We have therefore shared your letter with Amy Bowen from the MS Trust who has kindly agreed to do a guest post on MS Clinical Nurse specialist CPD. May be we should run formal CPD posts with and interactive feedback via the blog. We could potentially get these accredited. We want the blog to evolve so any suggestions would be helpful on the format, frequency, etc., of CPD sessions."

BrainHealth & ClinicSpeak: Six ways to lead a brain-healthy lifestyle

The next phase of of Brain Health: Time Matters in MS! #BrainHealth #MSBlog #ClinicSpeak

"In addition to MS-specific treatments and minimising time delays we are now promoting a Brain Healthy Lifestyle for MSers."


"The simple descriptive study below shows that obesity in pwMS comes with a price; in short obesity is associated with reduced and slower mobility. The study does not address cause or effect. Does reduced mobility cause the obesity rather than the obesity being the cause of the reduced mobility. Regardless of causation, or reverse causation, if you have MS you should try an maintain a normal body weight. This is common sense and applies to the general population as well. including healthcare professionals working in the field of MS."

Kalron. Relationship of Obesity With Gait and Balance in People With Multiple Sclerosis. Am J Phys Med Rehabil. 2016 Jun 17.

OBJECTIVE: The aim of this study was to examine the relationship of obesity with walking and balance in people with multiple sclerosis.

DESIGN: This was a cross-sectional study performed at the Multiple Sclerosis Center, Sheba Medical Center, Israel. Four hundred thirty-six people with multiple sclerosis were divided into obese (n = 178) and normal-weight (n = 258) groups. Spatiotemporal parameters of gait, 2-Minute Walk test, 6-Minute Walk test, Timed Up and Go test, Timed 25-Foot Walk test, Multiple Sclerosis Walking Scale self-reported questionnaire, and posturography measures were determined.

RESULTS: Compared with normal-weight patients, obese subjects walked significantly slower [98.7 (SD, 29.2) m/s vs. 106.4 (SD, 29.2) m/s; P = 0.01], with shorter step lengths [54.8 (SD, 11.6) cm vs. 58.1 (SD, 10.7) cm; P = 0.003] and a wider step width [12.1 (SD, 3.7) cm vs. 10.9 (SD, 4.6) cm; P = 0.01]. Furthermore, the obese group walked a shorter distance on the 6-Minute Walk test [378.2 (SD, 145.5) m vs. 426.1 (SD, 129.8) m; P ≤ 0.001] and slower on the Timed 25-Foot Walk test [9.0 (SD, 8.0) seconds vs. 7.2 (SD, 2.4) seconds; P = 0.006] and the Timed Up and Go test [9.2 (SD, 6.3) seconds vs. 10.0 (SD, 6.1) seconds; P = 0.002]. No significant differences between groups were noted in the Multiple Sclerosis Walking Scale self-reported questionnaire and postural control measures.

CONCLUSION: Obesity affects walking but not postural control in people with multiple sclerosis despite the level of neurological disability.