Tuesday, 26 September 2017

Should RIS (radiologically isolated syndrome) be treated?

Mult Scler. 2017 Sep 1:1352458517729462. doi: 10.1177/1352458517729462. [Epub ahead of print]

Radiologically isolated syndrome should be treated with disease-modifying therapy-Yes.

Okuda DT


Radiologically isolated syndrome should be treated with disease-modifying therapy – No

Andrés Labiano-Fontcuberta, Julián Benito-León First Published September 14, 2017


MS treatments are a caveat emptor. Global consumerism has hit the MS market succeeding in banishing moderation, thereby legitimising price hikes in the name of competition. It, therefore, falls to the responsible clinician to take the moral and ethical high ground. So, if science gives us the opportunity to treat early, regardless of cost, wouldn't it be wrong not to follow its instruction? Is, there an alternative viable option - realistically speaking? A transformative approach to early treatment in MS should therefore not be swept under the table. A pragmatic approach that demands an unequivocal demonstration of efficacy is not an approach to take in the path to a cure.

Okuda, above argues that MRI lesions in radiologically isolated syndromes (RISs) are very typical to those seen in MS in terms of appearance, frequency and distribution in the brain. Of those scanned 24% demonstrate contrast enhancing lesions on their baseline scan - it is well know that this cohort has further increased risk for future contrast enhancing lesions on subsequent head scans (Hazard ratio=3.4). Early DMT use, therefore, is a sound strategy for preventing further disease evolution.

"An estimated 11,000 axons are transected per cubic centimeter of contrast enhanced tissue".

Okuda, however, concludes with the realities of DMT use in MS: "Relating radiological features specific to in situ demyelination may be challenging at times. However, how truly accurate are clinical descriptions of experiences by patients that we routinely use to fulfill the clinical component of the diagnostic criteria in those with established MS? Would our concerns for treatment in RIS subjects be different if the costs of DMT were not so exorbitant or if the treatments provided were substantially safer than our current offerings?"

The counter argument for not treating RIS is provided by Labino-Fontcuberta and Benito-Leon. They argue on the point that the current risk-benefit ratio of DMTs is unfavorable for treating early. The current evidence is that ~ 7/10 RIS cases may not go onto develop MS in the next 5 years. In this case, a greater number would need to be treated to avoid developing MS, than is necessary. The authors appeal to a greater understanding of the nature of the disease at the RIS stage before we as a community offer treatments for it. 

"Emerging data suggest that in RIS, the clinical and pathological damage of magnetic resonance imaging (MRI) lesions might be compensated by more efficient reparative mechanisms".
 
I leave it to you to draw your own conclusions - are you for or against early treatment in RIS?

Monday, 25 September 2017

#ThinkSpeak & #NewsSpeak: social medicine the great disruptor

We are in the process of 'professionalising' the Barts-MS blog, by reducing the number of posts and improving the quality and relevance of each post for pwMS. As part of this transition, I will be moving all of my #ThinkSpeak posts, which are not directly relevant to MS onto Medium, a relatively new and evolving social media platform. Although the #ThinkSpeak post '#SocialMedicine the great disruptor' that I posted on Medium is underpinned by many ideas that I have developed on this blog I don't think its content is appropriate for this site.


#NeuroSpeak: treating MS in patients with PML

Teriflunomide is the drug of choice for treating MS in patients recovering from PML. #NeuroSpeak #CharcotProject

Summary: This post summarises the scientific principles for treating multiple sclerosis in patients who have PML as a complication of natalizumab treatment. I make the case for using DMTs that are not immunosuppressive and highlight the antiviral effects of Teriflunomide that make it the DMT of choice. 

At the grand round at Imperial College on Friday, a case of natalizumab-associated PML was presented. The patient had developed IRIS and was deteriorating. The question was posed about MS rebound contributing to some of the later deterioration in functioning and how to treat MS in this situation. 

It is clear that you cannot use an MS DMT that causes immunosuppression, particularly one that targets T-cells, in this situation. Patients with PML need their CD8+ cytotoxic T-cell to recover from PML. In my opinion, this only leaves 4 drugs that have a suitable profile:

(1) Interferon-beta: IFNbeta is not immunosuppressive and has many activities that are anti-viral. However, a lot of people who are on natalizumab may have failed IFNbeta in the past. IFNbeta has also been shown not to be that effective in preventing MS rebound post-natalizumab. 

(2) Glatiramer acetate: GA is not immunosuppressive, is only moderately effective in treating MS, is not effective in preventing MS rebound post-natalizumab and has a delayed onset of action. Therefore, it would not be the ideal agent to prevent MS rebound post-alemtuzumab in a patient with PML.

(3) Teriflunomide: Teri is not immunosuppressive as defined by the regulators, it has a complex mode of action that includes general anti-viral activity. Interestingly, leflunomide, a prodrug that is converted into teriflunomide, has been shown to have antiviral effects against BK virus (see below), that is very closely related to JCV, the cause of PML. In addition, there is some emerging evidence that Teri may cross the blood-brain barrier and hence may be able to inhibit JCV with the CNS. At the last AAN there was a poster of a switch study showing that Teri, post-natalizumab, was able to hold back rebound MS disease activity in the majority of patients and overall these patients did well.

(4) Daclizumab: Dac is not immunosuppressive, as defined by regulators, and only drops CD8 cell numbers by ~10%. Therefore, antiviral responses, for example against JCV should be intact. Dac also expands the NK, or natural killer, cell population that have anti-viral effects. We are in the process of doing a switch study to assess the effectiveness of Dac post-natalizumab to see how effective it is in preventing post-natalizumab rebound. Daclizumab also has a rapid-onset of action making which makes it an ideal agent post-natalizumab. However, as Dac reduces IL2 signalling in activated T-cells it may blunt effector T cell responses, i.e. reduce their reactivity, which makes me concerned about using it in patients with active JCV infection and PML. 

My recommendation, therefore, to the team looking after this patient particular patient was to use high dose Leflunomide (40mg per day) until JCV was not detectable in her CSF and then to switch her to Teriflunomide 14mg per day. The choice of Leflunomide dose is based on that used to treat BK-virus associated nephropathy. In my opinion, the team looking after this patient have little to lose; her JCV viral load in the spinal fluid was dropping so the IRIS (immune reconstitution syndrome) was at least taking care of the JC virus. However, she needs something to take care of MS without impacting on her immune system and at the same time assisting with the treatment of her PML.


With regard to Teriflunomide, there is an increasing number of reports of how well pwMS are doing on teriflunomide long-term. Teriflunomide is the only DMT that works significantly better second, or third, line than it does as a first-line treatment (see figure below). I have hypothesised that these observations may be due to teriflunomide's mode of action as an anti-viral agent. Professor Julian Gold and I are in the process of exploring this hypothesis under the umbrella of the Charcot Project. We will let you know as soon as we have data available.  




Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006 Mar 15;81(5):704-10.



BACKGROUND: Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals.

METHODS: We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy.

RESULTS: In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added.

CONCLUSIONS: Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Morita et al. Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review. J Clin Virol. 2016 Sep;82:133-8. doi: 10.1016/j.jcv.2016.07.015.

Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomidetreatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains.


CoI: multiple

Delayed Repopulation white cell population after stopping DMF

Bhupendra O. Khatri, Sergey S. Tarima, Benjamin Essig, Jean Sesing, Tayo Olapo. Delayed lymphocyte re-population following discontinuation of dimethyl fumarate and after switching to other disease modifying drug therapies MSARDS DOI: http://dx.doi.org/10.1016/j.msard.2017.09.014

Background:Dimethyl fumarate (DMF) reduces absolute lymphocyte counts, CD4, and CD8 counts, without significantly affecting total white blood cell counts. However, the recovery rate of these cells after discontinuation of DMF is unknown. The effect of subsequent disease modifying therapies (DMTs) on re-population rate is also unknown.
Objectives:To study the re-population rate of absolute lymphocytes, CD4, and CD8 counts back to baseline after discontinuation of DMF. 2. To measure the effect of subsequent DMTs on the re-population rate of these cells after DMF therapy. 3. To study the effect of the duration of exposure to DMF on repopulation of these cells.
Methods:A retrospective chart review of subjects who had discontinued DMF and in whom, CBC with differential, CD4 and CD8 counts were available at baseline, discontinuation and at follow-up (n=113).
Results: DMF causes a significant drop in absolute lymphocyte, CD4, and CD8 counts. Re-population of these cells after discontinuation of DMF is significantly delayed, irrespective of whether or not a subsequent DMT is used, although there is a difference in re-population rate among DMTs. The re-population rate is also dependent on the duration of time patients have been exposed to DMF; longer exposure was associated with more delayed recovery.
Conclusion:During this 30 month study period, re-population rates were significantly delayed post-DMF, irrespective of what subsequent DMT the patients received. Furthermore, no recovery of lymphocyte counts occurred in patients who were started on fingolimod or alemtuzumab after DMF was discontinued; in fact there was a continued decline in all of the cell populations studied.



As I have been saying for some time, when you start a DMT you have to think of what next after the DMT, as many will fail particularly the lower efficacy agents. DMT is higher efficacy agent. It is an immune depleting agent, which is pretty good at getting rid of CD8 T cells. It is moderate at removing memory B cells so that affects its ranking in my mind. But what else does it do. It is evident that some people who take DMF, deplete their cells and they do not functionally recover for some time, suggesting that DMF must hit the baby T cells so that there is little to repopulate with.
This offers a conundrum of when is best to start, because you don't want to wait too long before starting the next treatment so rebound does not occur, but if you are adding a lymphopenia inducing drug when you are lymphopenic are you going to be more susceptible to infections?
Worth knowing and discussing with your neuro before the switch.  ProfG maybe can expand on the DMF switch when he wakes up in Trumpland.

Sunday, 24 September 2017

Up in Smoke

Palacios N, Munger KL, Fitzgerald KC, Hart JE, Chitnis T, Ascherio A, Laden F. Exposure to particulate matter air pollution and risk of multiple sclerosis in two large cohorts of US nurses. Environ Int. 2017 Sep 19;109:64-72.

BACKGROUND:Air pollution is thought to raise the risk of neurological disease by promoting neuroinflammation, oxidative stress, glial activation and cerebrovascular damage. Multiple Sclerosis is a common auto-immune disorder, primarily affecting young women. We conducted, to a large prospective study of particulate matter (PM) exposure and multiple sclerosis (MS) risk in two prospective cohorts of women: the Nurses Health Study (NHS) and the Nurses Health Study II (NHS II).
METHODS: Cumulative average exposure to different size fractions of PM up to the onset of MS was estimated using spatio-temporal models. Participants were followed from 1998 through 2004 in NHS and from 1988 through 2007 for NHS II. We conducted additional sensitivity analyses stratified by smoking, region of the US, and age, as well as analyses restricted to women who did not move during the study. Analyses were adjusted for age, ancestry, smoking, body mass index at age 18, region, tract level population density, latitude at age 15, and UV index.
RESULTS: We did not observe significant associations between air pollution and MS risk in our cohorts. Among women in the NHS II, the HRs comparing the top vs. bottom quintiles of PM was 1.11 (95% Confidence Intervals (CI): 0.74, 1.66), 1.04 (95% CI: 0.73, 1.50) and 1.09 (95% CI: 0.73, 1.62) for PM10 (≤10μm in diameter), PM2.5 (≤2.5μm in diameter), and PM2.5-10 (2.5 to 10μm in diameter) respectively, and tests for linear trends were not statistically significant. No association between exposure to PM and risk of MS was observed in the NHS.
CONCLUSIONS: In this study, exposure to PM air pollution was not related to MS risk.

Phew pollution is not a risk factorof MS,...an makes a change from finding risks...what next?

Can we find something else that doesn't link with MS:-)

But wait like buses, no sooner than one paper on pollution we have two.

Amy M. Lavery, Amy T. Waldman, T Charles Casper, Shelly Roalstad, Meghan Candee, John Rose, Anita Belman, Bianca Weinstock-Guttman, Examining the Contributions of Environmental Quality to Pediatric Multiple Sclerosis

Background Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade.
Objective:To examine potential environmental factors in pediatric MS using geographic information systems (GIS).
Methods:Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects’ geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence <20 or ≥20 miles from the recruiting center), using logistic regression.
Results Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p=0.90 <20 miles from center; p=0.43 ≥20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR=2.83; 95%CI 1.5, 5.4) and those who reside ≥20 miles from a referral center (OR=1.61; 95%CI 1.2, 2.3).
Conclusion: Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures.

So in this study in childhood MS, risk was not associated with environmental (air, water etc) quality per say..so I thought replication within a day of the above and hopefully the need for no more studies on this:-), but then we had the air quality bit and it says in children living in poor air quality are affected so I spoke too soon. 

You were 3 times more likely to have MS if you live near to the MS hospital in a poor quality area the risk and was one and half times if living more than 20 miles (32km) away. 

So I'm not sure what to make out of this.....numerous other studies on air pollution on the way....:-( 

Do parents with kids with MS move to be nearer treatment centres?

or is it god forbid cars and all the air pollution they cause. 

We have been demonising the hubble ciggie for along time, but should we be ditching the motor...as driving kills!

Will new car adverts have to feature the pictures of car accidents and ill children as a health warning.

Should America start to use public transport for the sake of their children or...Maybe too much heresy for one day:-). 

Saturday, 23 September 2017

#ClinicSpeak: hospice care the underbelly of MS

Why is death and dying with MS such a taboo amongst MS stakeholders? #ClinicSpeak 

Summary: As multiple sclerosis advances people may enter a phase when the complications of MS become life-threatening. This phase is referred to as the terminal phase of MS. This post discusses a hotline service provided by the German MS Society to help German MSers with advice about palliative care and hospice.


Just over a year ago I bought a pair of rose-tinted glasses to improve my outlook on the world. Several commentators on the blog thought some of our posts were too morbid and not positive enough. I responded that we don't pull our punches and tell things as they are. If people don't want to know the truth they can go somewhere else; there are plenty of sights on the web dedicated to alternative facts. 

The following study addresses the underbelly of MS, its terminal phase. It describes the experience of a German MS hotline dedicated to palliative care and hospice care. The hotline received 222 calls over a 27 month period; i.e. ~8.2 calls per month. Germany is a large country with a population of ~83 million, therefore this is probably the tip of the MS iceberg. What this study shows is that there is a need for information and advice about terminal care. 

Just yesterday I was asked to comment about a person with MS who was locked-in and was being managed in an intensive care unit as a result of severe brainstem disease. This person was in her late 50's and had MS for ~20 years. The patient was conscious and was actually not quite locked in as she could still twitch one of her fingers. She was using this finger twitch to communicate. I made the point that this is the exact situation when having an advanced directive or living will in place is helpful.  It provides clear instructions to your family and medical team years before they need it to guide their treatment decisions in the future. I would recommend you all address this issue in advance. The NHS Choices has very good advice on end-of-life issues and advanced directives. 

End-of-life issues that are highlighted on our MS Tube map that possibly need consideration are:


  1. Palliative care
  2. Legal aid
  3. Social services
  4. Hospice
  5. Respite care
  6. Dignitas
  7. Assisted suicide
  8. Funeral planning
  9. Dignified dying
  10. Mortality (cause of death)
  11. Living will



Did you know that one of the MS Society's asked me permission to use my tube map, but wanted to remove the terminal line? They felt it would not be appropriate to inform or remind pwMS that MS has a terminal phase. On principle I said no; if they wanted to use the map they needed to take it as is, warts and all. Was I wrong? I feel the days of the patronising HCP, deciding what information to give pwMS, are over. To be honest, life has a terminal phase and the issues being discussed here are not unique to MS and apply to everyone so I am not sure we need to be overly sensitive about these issues.

The following is an example of an advanced directive to refuse treatment at the end-of-life. This can be adapted for MS. 


Strupp et al. Evaluation of a palliative and hospice care telephone hotline for severely affected Multiple Sclerosis patients and their caregivers. Eur J Neurol. 2017 Sep 19. doi: 10.1111/ene.13462.

BACKGROUND: Palliative and hospice care (PHC) still highly focus on cancer patients.


OBJECTIVES: To connect severely affected Multiple Sclerosis (MS) patients and caregivers to PHC, a nationwide hotline was implemented facilitating access to PHC.

METHODS: The hotline was designed in cooperation with the German Multiple Sclerosis Society. Self-disclosed information given by callers was documented using case report forms supplemented by personal notes. Data was analysed descriptively.

RESULTS: 222 calls were documented in 27 months. Patients' (mean age 51.12; range 27-84) mean illness duration was 18 years (range 1 month to 50 years). Inquiries included information on PHC (28.8%), and access to PHC (due to previous refusal of PHC, 5.4%), general care for MS (36.1%), adequate housing (9.0%), emotional support in crisis (4.5%). 31.1% of callers reported "typical" palliative symptoms (e.g., pain 88.4%), 50.5% symptoms evolving from MS, and 35.6% psychosocial problems. For 67 callers (30.2%), PHC services were recommended as indicated.

CONCLUSIONS: The hotline provides insight into needs and problems of patients severely affected by MS and their caregivers, some of which may be met by PHC. Future follow-up calls will demonstrate if the hotline helps improve access to PHC beyond providing information. Overall, our hotline seems to be easily accessible for severely affected MS patients whose mobility is limited.

Addendum: Results of blog surveys done in the past related to this topic.

How does Daclizumab work? Can animal studies tell us

Bhopale MK, Hilliard B, Constantinescu CS, Phillips SM, Rostami A. DAB389IL-2 recombinant fusion toxin effect on lymphocyte- and macrophage-producing cytokine subpopulation cells in experimentally induced demyelinating disease in mice. Immunopharmacol Immunotoxicol. 2017 :1-12

CONTEXT: We have reported previously that DAB389IL-2 recombinant fusion toxin targets IL-2R bearing CD4+ cells, and suppresses demyelinating disease in acute (A) - and chronic (C) - experimental autoimmune encephalomyelitis (EAE) animal models of multiple sclerosis.
OBJECTIVES: The present study was undertaken to investigate the effect of DAB389IL-2 treatment on various cytokine-secreting cell populations in A-EAE and C-EAE mice.
MATERIALS AND METHODS:The effects of DAB389IL-2 at doses of 200-, 800-, or 1600 kU administered i.v. on days 11-13 and 15 on the clinical score and cytokine-secreting cell populations were examined using flow cytometry.
RESULTS:C-EAE mice treated with 1600kU DAB389IL-2, but not A-EAE mice treated with 800 kU had significantly reduced disease. The CD3+CD25+ sub-population in spleens and spinal cords of A-EAE mice treated with 800 kU DAB389IL-2 a was increased, whereas in C-EAE mice treated with 1600 kU this population was increased. DAB389IL-2 treatment reduced CD3+CD4+, CD3+CD8+, CD4+CD8+, CD3+IL-2+, CD3+IFN-γ+ and CD3+TNF-α+ T cell subpopulations in the spinal cord in A-EAE, and C-EAE mice on day 16. CD11b+ macrophages that were IL-2-, IFN-γ-, and TNF-α- positive were reduced in A-EAE mice. DAB389IL-2 treatment reduced CD19+ B-cells positive for IL-2 or CD11b+ in the spinal cord in acute and chronic disease. DAB389IL-2 treatment also reduced lymph node CD3+CD8+, CD4+CD8+, CD3+CD25+ populations on day 16, and lymph node CD3+IL-10+ and peripheral blood CD3+CD25+ populations on day 24.
DISCUSSION AND CONCLUSIONS: Our study demonstrates that DAB389IL-2 fusion toxin suppresses EAE in a dose-dependent manner, and alters inflammatory cell sub-populations during disease development



One of the flavors of the decade in terms of disease mechanisms has been the identification of Fox3P, CD25+, CD4 T regulatory cells. You can't see a paper these days where this is not the mechanism of action of EAE inhibition.

This is all well and dandy, but in terms of MS there is one nasty fact. 

People ignore from their world view. 

This is daclizumab. 

This antibody blocks CD25 which is the high affinity interleukin2 (T cell growth factor) receptor. Block this and natural killer subsets increase and MS goes away, but a problem is so do the T reg cells as these are depleted.

I was always of a mind-set that that the inhibitory effect is not surprising because the action of daclizumab is because it is simply killing or blocking activated T cells and have more recently switched to thinking it is because it kills activated memory B cells. The NK story is a smoke screen. ProfG disagrees he thinks that this creates and better anti-viral response, due to more NK cells.

However T regs are dogma. They are there to stop autoimmunity developing, which I totally understand. However, one question I have always posed is why would we want to spend a lot of effort to generate an immune response, outside the control of T reg control to give you life long protection, only to have it reeled back in by T regs. 

Since T regs were discovered, most studies give the interleukin 2 blocker before disease induction and low and behold it blocks T reg function and autoimmunity gets worse.....Hurrah for dogma.

What happens when this is done after disease has become established?

I have often thought of doing this for a student project, we could by the antibody with their lab expenses and see what happens I predicted nothing or it makes EAE better because EAE is driven by T cells and the blocker blocks activated T cells. 

Now I have found a few examples where people block the CD25 molecule after disease has developed and disease gets worse...so hoorah for dogma again. 

However I have also seen studies where cladribine stops mouse EAE, however someone forgot to tell the authors that cladribine does not work properly on rodents (don't believe me ask Merck..I did and they should know) and is not T cell immunosuppressive. This could be deduced by reading the early cladribine studies that showed that rodent metabolise cladribine in a different way to humans. We knew this years ago (experiments done in 2004). 

So on first read of the manuscript I thought has this had been done
and it didn't block the early acute phase but blocked the chronic phase, but on re-read whilst writing this....I must say uuurgh,

In this study they used a toxin linked to interleukin2 so when it binds to the the CD25 it kills the target. Do this and Eh.....the number of T reg cells increases but T cells decrease and EAE is reduced so hooray dogma persists.  

Should I do that study project?

Friday, 22 September 2017

#NeuroSpeak: do you know what an IRT is?

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

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





CoI: multiple

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

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


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

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


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

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

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

Does this make sense?

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

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



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

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

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

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

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

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

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

EDSS = Expanded Disability Status Scale

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

9-Hole Peg Test = test of upper limb function

Word List Generation Test = cognitive task

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

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

CoImultiple

Thursday, 21 September 2017

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

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

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

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

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

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



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


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

or in eSpeak 

#Never2EarlyNor2Late

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

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

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

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

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

DrK with a smile

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

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

CoI: multiple

The case for NEDA

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

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

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


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

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

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




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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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


NEDA is only as good as you look for it.


(a) No MRI  Gadolium lesion


(b) No clinical Relapses


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


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


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


Maybe imaging grey matter volume is better.


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


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


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


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


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


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


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


So is there a fudge?


Is the efficacy artificially good?


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


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


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


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


Burman J et al.Autologous haematopoietic stem cell transplantation for neurological diseases JNNP http://dx.doi.org/10.1136/jnnp-2017-316271Neuroinflammatory diseases such as multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis are leading causes of physical disability in people of working age. In the last decades significant therapeutic advances have been made that can ameliorate the disease course. Nevertheless, many affected will continue to deteriorate despite treatment, and the costs associated with disease-modifying drugs constitute a significant fiscal burden on healthcare in developed countries. Autologous haematopoietic stem cell transplantation is a treatment approach that aims to ameliorate and to terminate disease activity. The erroneous immune system is eradicated using cytotoxic drugs, and with the aid of haematopoietic stem cells a new immune system is rebuilt. As of today, more than 1000 patients with multiple sclerosis have been treated with this procedure. Available data suggest that autologous haematopoietic stem cell transplantation is superior to conventional treatment in terms of efficacy with an acceptable safety profile. A smaller number of patients with other neuroinflammatory conditions have been treated with promising results. Herein, current data on clinical effect and safety of autologous haematopoietic stem cell transplantation for neurological disease are reviewed.

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

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

Isn't this what you wanted me to say?

Myelin autoimmunity..the delusion complex



Jae-Won Hyun et al. JNNP 2017 http://dx.doi.org/10.1136/jnnp-2017-315998
Background We evaluated the seroprevalence of myelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG) and associated clinical features of patients from a large adult-dominant unselected cohort with mainly relapsing central nervous system (CNS) inflammatory diseases. We also investigate the clinical relevance of MOG-IgG through a longitudinal analysis of serological status over a 2-year follow-up period.
Methods Serum samples from 505 patients with CNS inflammatory diseases at the National Cancer Center were analysed using cell-based assays for MOG-IgG and aquaporin-4 immunoglobulin G (AQP4-IgG). MOG-IgG serostatus was longitudinally assessed in seropositive patients with available serum samples and at least 2 years follow-up.
Results Twenty-two of 505 (4.4%) patients with CNS inflammatory diseases were positive for MOG-IgG. Patients with MOG-IgG had neuromyelitis optica spectrum disorder (NMOSD, n=10), idiopathic AQP4-IgG-negative myelitis (n=4), idiopathic AQP4-IgG-negative optic neuritis (n=4), other demyelinating syndromes (n=3) and multiple sclerosis (n=1). No relapses were seen in patients when they became MOG-IgG seronegative, whereas a persistent positive serological status was observed in patients with clinical relapses despite immunotherapy.
Conclusions In a large adult-predominant unselected cohort of mainly relapsing CNS inflammatory diseases, we confirmed that NMOSD phenotype was most commonly observed in patients with MOG-IgG. A longitudinal analysis with 2-year follow-up suggested that persistence of MOG-IgG is associated with relapses.Myelin oligodendrocyte glycoprotein (MOG) is the main antigen to induce EAE, and if you ask an EAEer or c linical immunologists, what is the antigen targeted in MS, they will say myelin basic protein or MOG. But what is the evidence....there is essentially none that is not circumstantial.

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

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

Wednesday, 20 September 2017

#ChariotMS: what do we need to do to convince the community that more advanced MS is modifiable?

What needs to be done to tackle 'progressive' or more correctly 'advanced' MS? #ClinicSpeak #ThinkHand #ChariotMS

Summary: This post summarises what needs to be done to tackle more advanced MS including people with MS using wheelchairs. It makes the case for making several changes in the way we study advanced MS. What is needed now is a large injection of money to kick-start a trial in wheelchair users to delay loss of upper limb function. This post is an essential read for anyone who cares about people with more advanced MS. 


Earlier this week I had a debate with a colleague about therapeutic targets and whether or not they are achievable. He thought NEDA was a crap target as most of our patients who achieve NEDA still have residual problems. Therein lies the rub. NEDA, or no evident disease activity, refers to evidence of ongoing inflammation. NEDA does not refer to previous damage, nor does it refer to the ongoing consequences of previous damage. You can only do so much with an anti-inflammatory agent, i.e. switch-off inflammation, and even then most anti-inflammatory agents we use don't switch-off innate immunity within the CNS (hot microglia), nor do they purge the nervous system of plasma cells and oligoclonal immunoglobulins. In reality, we can only ask so much of our current DMTs. This is why we need combination therapy strategies. 

The following are some points about progressive MS that needs repeating: 


  1. We all need to accept that ‘progressive MS’ is a misnomer. Progression means improvement. At Barts-MS prefer the term ‘advanced MS’ this captures the associated disability that comes with this phase of the disease.
  2. We need to accept that the pathology that drives neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘advanced MS’) as being there from the beginning. This means the neurodegenerative phase of MS is present from the beginning before pwMS become physically disabled.
  3. MS is 1-disease and not 2-3-or-4-diseases. As I have said before the false division of MS into several diseases is not backed up by science, nor by philosophical arguments. This false division of MS into many diseases has become counter-productive to the field of MS. The division of MS into relapsing and progressive forms was Pharma-led to get MS defined as an orphan disease, which allowed interferon-beta-1b to get a license based on the results of one pivotal phase 3 study. It also allowed the company concerned to charge rather a lot of money for its product. Overall this has been good for MS in that it has attracted a lot of Pharma interest and has supercharged drug development in MS, but it is now slowing down drug development and making it very expensive. We need cheaper drugs for advanced MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for advanced MS need to be priced lower than those for relapsing forms of MS.
  4. Following on the point above the division between SPMS and PPMS is false. There is no pathological, genetic, imaging or other data that suggests these are different entities. We, therefore, should be doing trials in both populations simultaneously.
  5. Slay the dogma that more advanced MS has reduced inflammation, or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a big part in driving advanced MS. Therefore not to target more advanced MS with an anti-inflammatory is folly.
  6. Accept that reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we refer to this as therapeutic-lag. These observations are explained by the length-dependent axonopathy hypothesis. This means that we will need to focus more on the arm-and-hand function as a primary outcome in pwMS who have lost too much function in their lower limbs (EDSS>=6.0). This is what we are proposing to do in our CHARIOT study (parenteral cladribine).
  7. Challenge the dogma that once someone has lost lower limb function and is a wheelchair user that the disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in advanced MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign.
  8. Accept that we will need to use combination therapies to make a real difference to more advanced MS. We are not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms - for example, laquinimod which targets hot microglia - with a classic anti-inflammatory against targeting adaptive immune mechanisms.
  9. We need to ditch the EDSS as the primary outcome in advanced MS trials. The whole community knows that the EDSS is not fit for purpose in more advanced MS. We need to get the regulators to accept this. We also need to work on a set of outcome measures that capture the whole impact of MS on someone with the disease. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more PROMS in the battery, in particular, a better hand-and-arm function PROM. We are aware that there are several out there and some are in development, including one from Barts-MS.
  10. We need to think creatively about our trial design. I am not an expert here, but some in the community are pushing for adaptive trials, i.e. a multi-arm phase 2 trial with a seamless design allowing it to be converted into a phase 3 study. Pharma doesn't like adaptive designs nor do the regulators. I do think we do need two phases to trials in more advanced MS, i.e. the standard head-to-head phase with a robust primary outcome, say a multi-outcome composite, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more advanced MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).
  11. Acceptance of more sensitive biomarkers to get proof-of-concept trials done more quickly. I know I am biased, but I really think neurofilament level monitoring in the CSF and blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past. We have fully recruited our PROXIMUS trial and we have learned a lot in the process. For those of you new to this blog the PROXIMUS trial was an add-on neuroprotective trial in which we add oxcarbazepine, a sodium channel blocker, on top of an existing DMT in subjects with ‘early SPMS’. Labelling eligible subjects as having early SPMS was a mistake. Nobody wants to be told they have SPMS, therefore their clinicians were reluctant to refer patients eligible for the study. My advice to anyone doing trials in this space is to avoid the term progressive.
  12. Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and have even written a paper on the so-called ‘Big Pharma Alternative’ to explain our thoughts on this.
  13. Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials. Some of my colleagues think this is a big issue; I don’t. If we do a trial and provide compelling data that drug x in combination with drug y delays, or stops, worsening disability in upper limb function in pwMS in wheelchairs they would be obliged to license the combination, provided it was safe. What we need from them, however, is to accept the need for combination therapies. MS is a complex disease and hence will need a complex solution to tackle it, i.e. combination therapies, this is not rocket science and happens all the time in other disease areas for example oncology.
  14. More detailed cost-effective models that focus on the loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the recent EU cost of MS study that costs soar as pwMS lose arm function.
  15. We also need to tackle ageing and its impact on worsening MS. The evidence that early, or premature, ageing from the reduced brain, and cognitive, reserve drives worsening of MS in older pwMS, is beyond doubt. What we need is some way of dissecting-out premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, in particular, smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. I sit on many trial steering committees and we deal with this problem by simply putting an age cap on the trial population. This is the main reason why trials in advanced MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.
  16. We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal, similar to my colleague's expectations. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for me to falsely raise their hopes. To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote axonal sprouting, synaptogenesis and plasticity mechanisms to restore function. This is not rocket science. If you are coming to ECTRIMS I will be giving a talk on this exaxt topic in a satellite symposium. 



As you can see we are passionate about tackling more advanced MS. I personally think we have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted in the points above. We need to start a serious debate about these issues and get on with the job of protecting arm and hand function in pwMS. 

If there are any wealthy philanthropists out there? DrK (@KlausSchmierer) is looking for a large donation to support his application to the NIHR for the CHARIOT study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded. 


DrK with a smile

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

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

CoI: multiple