Wednesday, 22 February 2017

HSCT activity in Progressive MS

Paolo A. Muraro, et al.Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol 2017

Question:  What are the long-term outcomes after autologous hematopoietic stem cell transplantation for the treatment of multiple sclerosis?

Findings:  In this multicenter cohort study of 281 patients with predominantly progressive forms of multiple sclerosis who underwent autologous hematopoietic stem cell transplant between 1995 and 2006, transplant-related mortality was 2.8% within 100 days of transplant, and neurological progression-free survival was 46% at 5 years. Younger age, relapsing form of multiple sclerosis, fewer prior immunotherapies, and lower neurological disability score were significantly associated with better outcomes.

Meaning:  The results support the rationale for further randomized clinical trials of autologous hematopoietic stem cell transplantation for the treatment of multiple sclerosis.


Importance:  Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.

Objective:  To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.

Design, Setting, and Participants:  Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.

Exposures:  Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.

Main Outcomes and Measures:  The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.

Results:  Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).

Conclusions and Relevance:  In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

If you cared to read the paper by ProfG and others members of TeamG on length dependent axonopathy (we hope that it will be open access soon) it suggests that it is not too late to benefit people with progressive MS, even with immunosupression. 

Therfore just as well wee havn't given in progressive MS.

This study offers some support when analysis of people with MS undertaking HSCT was done. In this 80% of people had progressive MS and disability progression was stoped in about 50% of 5 people up to 5 years of analysis. It will take longer follow-up to see if this is sustained but based on the data below people continue to fail so at 10 years the progression free cohort only makes up about 30 percent. As you can see if you were relapsing verses progressive you were about two-three times as likely to see benefit.

So it says 50% of people progressed and tells me we need more than peripheral immunosuppression. I suspect you need to deal with inflammation in the brain. It also says that nearly 3% of people didnt make it, so it is not something you should do with your eyes closed. However in more recent studies this risk of mortality has reduced. 

You need to be clear what the risks are and the competence and success of centres where you may undergo this . The types of HSCT was not all the same and (17.4% [49 of 281] low intensity, 63.7% [179 of 281] intermediate intensity, and 18.9% [53 of 281] high intensity treatment regimes. 

The data raise the possibility that AHSCT may have reduced the risk of disease progression in the treated patients, yet demonstration is lacking in the absence of a control group. 

The incidence of new autoimmune disease was 5.0% (14 of 281), but considerably lower than after lymphocyte-depleting treatment with alemtuzumab, which approaches a risk of 50%.,

It is open access so have a read.

#NeuroSpeak & #ClinicSpeak: treating PML-related IRIS

A new treatment for PML-related IRIS based on hard science and anecdote #NeuroSpeak #ClinicSpeak #MSBlog

Substituting one disease for another. A large number of you argue that by treating MS, a disabling disease, with immunosuppressive therapies we simply create another ticking time bomb and swap one disease, MS, for another disease, immunosuppression. The difference between these two diseases is that MS-related disability is in general irreversible and associated with loss of quality of life. Immunosuppression on the other hand can be derisked to some extent and its consequences, in particular the opportunistic infections, treated.

The poster-child for derisking opportunistic infections must be natalizumab-associated PML. We now know that pwMS who are JCV-seropositive need to come off natalizumab because of the risk of PML. In high-risk subjects who decide to stay on natalizumab, against our advice, we offer them 3-monthly MRI studies to look for asymptomatic PML, which has a better prognosis than symptomatic PML. The problem with PML is that you need immune reconstitution to clear the virus from the brain and herein lies the problem. When you wash out natalizumab with either plasma exchange, or by waiting for it to wash-out spontaneously, when your immune cells start re-trafficking into the brain you develop and encephalitis. This is called IRIS (immune reconstitution inflammatory syndrome). IRIS in itself is very dangerous. Therefore in patients with a large PML burden, or PML in strategic brain areas such as the brainstem, we tend to give steroids to try and dampen down the damage associated with IRIS. Anecdotal experience suggests steroids work. Is there another strategy we can try?

Two case reports below describe the anti-HIV drug, maviroc, which blocks a particular chemokine receptor CCR5 on lymphocytes, may help prevent or dampen down IRIS. T-cells, including cytotoxic CD8+ T-cells, use CCR5 to cross the blood-brain-barrier. Blocking CCR5 dampens down IRIS and appeared to prevent IRIS-related damage in these two cases. Clearly maviroc as a monotherapy is not enough to stop the immune system clearing the JC virus from the CNS. The question that arises is whether or not maviroc is better than steroids in achieving this? The latter will require a clinical trial. 

In reality I hope the number of cases of natalizumab-associated PML drops to become a very rare complication of this treatment. Now that we have derisking strategies, and other highly-effective DMTs which are safer do we really need to continue to put pwMS at such a high risk of PML? 

Please note that until we get a drug  that clears JCV from the body we will never derisk the PML problem completely. As you are aware PML is a complication of immunosuppression and therefore it will remain a very rare complication of our MS treatments. 

Steiner & Benninger. Maraviroc in PML-IRIS: A separate ball game under HIV infection and natalizumab? Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e331. doi: 10.1212/NXI.0000000000000331. 

Progressive multifocal leukoencephalpathy (PML) is a severe, often fatal, opportunistic infection of the CNS. First reported in 1958 as a white matter disorder in 3 patients with lymphoproliferative disorders, subsequent studies revealed a polyomavirus, named John Cunningham (JC) virus from the initials of the patient from whose brain it was initially isolated, as the causative agent.

The pathogen is a ubiquitous DNA virus that infects only humans. Subclinical infection often takes place within the first decade of life. 

PML became strikingly prevalent, observed in 4%–5% of all patients with HIV prior to the availability of highly active anti-retroviral therapy (HAART). 

The era of monoclonal antibodies for immune-mediated conditions such as natalizumab (Tysabri) for MS and Crohns disease and efalizumab (Raptiva) for psoriasis heralded another context for PML. 

As of November 30, 2016, there have been 698 reported cases of PML under natalizumab.

While HAART has a significant beneficial impact on the prognosis of PML in patients with HIV, it remains one of the 4 most common CNS opportunistic infections affecting patients with AIDS.

The institution of screening patients with MS for seropositivity for JC virus has decreased the prevalence of PML in natalizumab-treated patients with MS. The termination of this therapy and using plasma exchange to remove the monoclonal antibody from the circulation when PML is diagnosed has a beneficial effect on prognosis.

However, the introduction of HAART and the discontinuation of natalizumab led to the recognition of the immune reconstitution inflammatory syndrome (IRIS), an entity that is not unique to PML and has been observed also with mycobacterial diseases, leprosy, fungal infections, and herpes viruses. 

IRIS is the consequence of rapid entry of immune cells into the brain at the time of immune restoration. IRIS has occurred in the majority of patients with natalizumab-associated PML following withdrawal of natalizumab and plasma exchange. The diagnosis of CNS-IRIS in patients with MS with natalizumab-associated PML can be challenging because the deterioration might be attributed to PML, MS, or some other opportunistic infection.

Thus, diagnosis of PML in an immune-compromised patient is associated with a 2-edge challenge and risk: clearing the JC virus from the brain, which requires normalisation of the immune state, and reconstitution of immune surveillance while minimising infiltration of the brain with activated T cells that attempt to control an underlying CNS opportunistic infection.

Maraviroc is drug developed to protect against HIV. HIV infects human T cells via recognition of the CD4 and notably the chemokine receptor CCR5. Maraviroc blocks CCR5.

It has been reported that the CD8 T cells that target the JC-virus infected cells express CCR5, and maraviroc can inhibit the accumulation of CD8 T cells. 

It is also evident that maraviroc use can have serious side effects, including liver problems.

There are two case reports concerning the treatment of IRIS.

Hodecker et al. Maraviroc as possible treatment for PML-IRIS in natalizumab-treated patients with MS. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e325. doi: 10.1212/NXI.0000000000000325.

Serial axial postcontrast T1-weighted magnetic resonance images of the brain of case 1 (A–C) and case 2 (D–F). (A) In February 2015, a T1-weighted image showed right subcortical occipital lesion (hyperintense in T2-weighted images) with subtle contrast enhancement suggestive of progressive multifocal leukoencephalopathy (PML) in a clinically asymptomatic patient. (B) Four months later, MRI showed progression of the contrast-enhancing occipital lesion, and maraviroc treatment was initiated. (C) Six months after start of maraviroc, MRI shows regression of PML–immune reconstitution inflammatory syndrome (IRIS) with no detectable contrast enhancement. (D) A routine MRI in February 2015 showed disseminated contrast-enhancing lesions in the cerebellum suggestive of PML in a clinically asymptomatic patient. (E) In May 2015, a T1-weighted image showed extensive IRIS after discontinuation of maraviroc. (F) Eleven months after the initial diagnosis of PML and after 8 months of maraviroc treatment, multiple disseminated contrast-enhancing lesions in the cerebellum are still detectable.

Bsteh et al. Severe early natalizumab-associated PML in MS: Effective control of PML-IRIS with maraviroc. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e323.

(A, B) MRIs at admission show a lesion in the right central region without Gadolinium (Gd)-enhancement suspect of progressive multifocal leukoencephalopathy (PML). (C, D) MRIs after plasmapheresis show a markedly increased PML lesion size on T2 sequences but no Gd-enhancement. (E, F) Eight days after maraviroc initiation, MRIs reveal stable PML lesion size with inhomogenous spotty Gd-enhancement, consistent with moderate localized immune reconstitution inflammatory syndrome. (G, H) MRIs obtained 6 months after maraviroc initiation showed regression of PML lesion size in T2 without Gd-enhancement but a demarcated substance defect in T1 sequences.
CoI: multiple

Tuesday, 21 February 2017

Guest Post MSBaseGold: Comparisons of DMT

Today we are delighted to have another Guest post from Tomas Kalincik from University of Melbourne, Australia, please see his Biography on his previous post.

Kalincik et al. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol. 2017 Feb 10. pii: S1474-4422(17)30007-8.

BACKGROUND: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years.

METHODS: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models.

FINDINGS: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006).

INTERPRETATION: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles.

FUNDING: National Health and Medical Research Council, and the University of Melbourne.

Tomas Kalincik

"This large collaborative study brought together investigators from MSBase and clinicians from six academic MS centres in Cambridge, Cardiff, Swansea, Bristol, Dublin and Dresden. We have used propensity score matching, pairwise censoring and weighting in order to create a composite cohort of sufficient size to enable conclusive comparisons of alemtuzumab (a monoclonal antibody depleting circulating B and T lymphocytes, which was approved in multiple countries for use in relapsing-remitting MS in 2015) and three other commonly used therapies - interferon beta, fingolimod and natalizumab.

The comparison of alemtuzumab with interferon beta allowed us to replicate the results of the pivotal phase 3 trials of alemtuzumab (CARE-MS 1 and CARE-MS 2), anchoring our study in the existing evidence. It showed that the effect of alemtuzumab on suppressing relapses was superior to that of interferon beta. In patients with previously highly active disease, alemtuzumab was also more likely to prevent worsening of disability and even lead to some disability reversal. We have used this replication of the previous studies as a validation of our methodology before applying it to a new scenario - the comparison with fingolimod and natalizumab.

Alemtuzumab was superior to fingolimod in decreasing relapse incidence. However, its effect on disability (whether disability accrual or its resolution) was similar to that of fingolimod. On the other hand, alemtuzumab and natalizumab had very similar effects on suppressing MS relapses and worsening of disability. However, natalizumab was more often associated with improvement in disability early after patients commenced therapy. This difference in treatment effect was mostly seen during the first year of treatment.

Our study focused on comparing clinical efficacy of alemtuzumab and the three therapies. It did not compare the effect of the therapies on brain MRI, neither did it answer the question of its relative treatment safety."

CoITK reports grants from National Health and Medical Research Council (Australia), and Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne; grants, personal fees, and non-financial support from Biogen; personal fees from Roche, Teva, and BioCSL; and personal fees and non-financial support from Sanofi Genzyme, Merck, Novartis; and personal fees from WebMD Global.

MouseDoctor says:

As we are looking at MS drugs in the Real World today, we would like to thank Tomas for discussing his recent work. If you can spare a minute and can understand Australian:-). 

You can have a view of  Dr.Kalincik in the News (Click here)

Drug companies generally only do head to head studies when they know their product will win. Therefore it is great that registries exist, to allow comparisons of effects to be undertaken. This study confirms what we suspect in terms of drug hierarchies. 

Real world data on efficacy or #alternativefact

Neurol Ther. 2017 Feb 16. doi: 10.1007/s40120-017-0064-x. [Epub ahead of print]

Comparative Effectiveness Research of Disease-Modifying Therapies for the Management of Multiple Sclerosis: Analysis of a Large Health Insurance Claims Database.

Boster A, Nicholas J, Wu N, Yeh WS, Fay M, Edwards M, Huang MY, Lee A.



Limited data are available on the real-world effectiveness of newer oral disease-modifying therapies (DMTs) in multiple sclerosis. The purpose of this study was to retrospectively compare the real-world effectiveness of dimethyl fumarate (DMF), fingolimod, teriflunomide, and injectable DMTs in routine clinical practice based on US claims data.


Patients newly-initiating DMF, interferon beta (IFNβ), glatiramer acetate (GA), teriflunomide, or fingolimod in 2013 were identified in the Truven MarketScan Commercial Claims Databases (N = 6372). Relapse episodes were identified based on a published claim-based algorithm and used to determine the annualized relapse rate (ARR) for the year before and after initiating therapy. Poisson and negative binomial regression was used to determine the adjusted incidence rate ratio (IRR) for each therapy relative to DMF.


Significant ARR reductions in the year after initiating therapy were reported for DMF and fingolimod (P < 0.0001). Compared with DMF, the adjusted IRR (95% CI) for relapse in the year after initiating therapy was 1.27 (1.10-1.46) for IFNβ, 1.34 (1.17-1.53) for GA, 1.23 (1.05-1.45) for teriflunomide, and 1.03 (0.88-1.21) for fingolimod. Results were consistent across subgroup and sensitivity analyses.


These real-world data suggest DMF and fingolimod have similar effectiveness and demonstrate superior effectiveness to IFNβ, GA, and teriflunomide.


Biogen, Cambridge, MA, USA.

In the way that social media has changed the face of news distribution once and for all, open access journals are steadfastly changing the face of science - for better or worse is a matter open to debate. Their 'free at point of access' policy means that their readership naturally increases with time compared to traditional paid journals. Open access journals may therefore become the modern-day equivalent of the unwitting accomplice for here-sayers and nay-sayers.

In MS therapeutics, as we have no head to head studies against the different disease-modifying therapies in MS, we are left with retrospective analysis of recorded data. In the case of the US, this would be the 'Commercial claims' insurance databases. Boster et al. (in a study funded by Biogen) claim that DMF (tecfidera) has similar effectiveness to fingolimod, but is SUPERIOR to the other first-line therapies (alemtuzumab and natalizumab were not included) (see Figure below). They justifiably point out that this can be explained by the non-compliance to therapy on injectables, but even controlling for this it would appear that DMF still comes out on top. The accuracy of data keeping and truthfulness of accounts is barely just touched upon.

The market size of DMF is sizable and that is food for thought. The fact that I have posted on this today will increase the altametrics of this article (Multiple Sclerosis BlogSpot averages on ~5000 page views/day). The alternative oral drug, Novartis's fingolimod (gilenya) is it's main competitor.

The authors conclude: "These data should assist in treatment decisions regarding the choice of DMT and enable clinicians to consider both real-world effectiveness and route of administration in consultations with their patients". In an attempt to be equally provocative I might add that biosimilars demonstrating equivalent efficacy are the poor man's alternative! It would be therefore reasonable to assume that in the current day #alternativefact, that almost nobody is flush with aces.

Figure: Unadjusted annualized relapse rates for 1 year before and 1 year after DMT initiation. DMT disease-modifying therapy

Monday, 20 February 2017

#OffLabel & #ClinicSpeak: nabilone instead of street cannabis

Off label Nabilone is a treatment option for MS-related spasticity #OffLabel #ClinicSpeak #MSBlog

I grew up in apartheid South Africa and recall the sweet smell of 'dagga' (SA street lingo for cannabis), that wafted from the workers, or gardeners, quarters at my primary school. The workers, who were all black at that time, generally used cannabis in large amounts to survive the drudgery of their apartheid existence. They were all migrant workers with families who tragically lived far away. They barely survived on a minimum wage, doing menial unskilled labour. Their bloodshot eyes, clouded awareness and sweet bodily aroma made me aware  at a very young age, that the torpor due to their excessive cannabis use could not be good for either their physical or mental health. Apartheid has many wrongs to answer for; the mental and physical health of the majority comes close to the top of the list.  

It would be decades later as a MS researcher that I would discover, from the MouseDoctors, that cannabis could have real benefits for pwMS. Our research led to the development of THC as a symptomatic treatment for pwMS and should also have led to the development of THC as an add-on neuroprotective drug for people with more advanced MS. Unfortunately, the phase 2 neuroprotective trial we were involved in was done at a time when we did not have the insights we now have about the EDSS (not fit for purpose), asynchronous progressive MS, nor that MS is a length-dependent axonopathy. I am confident that if we had the opportunity to do a trial of THC as an add-on neuroprotective agent in more advanced MS we would design the trial very differently and have more than a fighting chance of getting a positive result. 

Although we do have a licensed cannabinoid for the treatment of MS-related spasticity we can't prescribe it under the NHS. Sativex, which contains the active ingredients of cannabis (THC and CBD), cannot be prescribed as it has not been 'NICEd'. Sativex has not bee shown to be cost-effective. This is very frustrating as so many of our patients would benefit from this drug. This very unfortunate situation forces many pwMS in the UK to buy street cannabis. As a neurologist I can't sanction this; cannabis is illegal in the UK and I would be putting myself at risk if I prescribed, or even recommended, street cannabis. I am aware that in other parts of the world, where cannabis has been legalised for medicinal use, neurologists can prescribe cannabis. 

How to get around this problem in the UK? I have recently started prescribing nabilone, a licensed small molecule drug that works on the CB1 receptor. CB1 is the cannabinoid receptor responsible for THC's anti-spastic effects. Nabilone is licensed in the UK for the control of nausea and vomiting, caused by chemotherapeutic agents and used in the treatment of cancer. I have recently had two patients who were using excessive street cannabis to control their spasticity and nocturnal leg spasms. Nabilone at a dose of 2 mg twice of day has allowed both these patients to stop smoking street cannabis and both have noted improved control of their spasticity. On the plus side both these patients have stopped smoking cannabis, which in itself has health benefits in that they are not exposing their lungs to smoke. 

Please be aware that the use of off-label nabilone is not ideal and in a perfect world we would have unfettered access to Sativex. What is galling is that Sativex was developed, and made, in the UK by a small start-up Pharma company. If the NHS does not support its own, UK-based, Pharma industry what hope is there for Pharma UK? This is in distinct contrast to France and Germany, where the politicians go out of their way to make sure their national healthcare systems support their own, home-grown, Pharma Companies. Is this nepotism? Is this the reason Trumpster's want to the UK to shutdown NICE?  

Please note that some patients are prescribed Sativex in the UK under the IFR (individual funding request) system, via patient access schemes paid for by individual NHS Trust's and not NHS England, or via the private prescription route. 

CoI: multiple

Sunday, 19 February 2017

The SPMS trial that never was.

Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis.Brochet B, Deloire MS, Perez P, Loock T, Baschet L, Debouverie M, Pittion S, Ouallet JC, Clavelou P, de Sèze J, Collongues N, Vermersch P, Zéphir H, Castelnovo G, Labauge P, Lebrun C, Cohen M, Ruet A; PROMESS study investigators..
PLoS One. 2017 Jan 3;12(1):e0168834. doi: 10.1371/journal.pone.0168834.

BACKGROUND:Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far.
OBJECTIVE:To compare CPM to methylprednisolone (MP) in SPMS.
METHODS:Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model.
RESULTS:Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31-1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14-4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected.
CONCLUSION:Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability.
TRIAL NCT00241254.

So more not good news for SPMS, here is another trial that has failed. Cyclophophamide forms an metabolite that is active and entrers the CNS and can kill B cells as well as any other cell that is dividing including hairs in the follicles. There was a hint of activity but the trial was terminated because there were not enough volunteers.

Saturday, 18 February 2017

#ResearchSpeak: when best practice clinical guidelines our out of date

Is your neurologist a sheep or a wolf, a herder or an independent thinker? #ResearchSpeak #MSBlog

The following study looks at decision-making by neurologists in relation to a simple case scenario. The researchers come to the conclusion that neurologists display herd behaviour, i.e. they follow the crowd rather deciding independently. The study is based on a simple case scenario of a 40-year-old woman with MS who has been stable for 3 years on subcutaneous interferon and developed a self-limited neurological event. I assume this was a relapse. There were no new magnetic resonance imaging (MRI) lesions. Her neurological examination and disability scores were unchanged. She was advised by her MS neurologist to switch from interferon to fingolimod against best practice guidelines

What this scenario doesn't explore is that we all know the EDSS is not fit for purpose and the fact that it was unchanged is neither here nor there. You can still have a relapse despite an unchanged EDSS. Similarly, the there were no new lesions on the MRI. The scenario doesn't mention whether or not a spinal cord MRI was done. May her relapse due to a spinal cord lesion. The researchers assume that if the MRI shows no new lesions then this person has not had a relapse. A significant number of relapses occur without new MRI lesions. The MRI only detects lesions that are ~4mm in size or larger. A small lesion in a critical area can cause a relapse without being detected on MRI.  They also assume that the MRI and EDSS are the disease, when in fact they are not the disease. The disease is biological and hence needs to be thought of as a biological process. They also assume the 'best practice clinical guidelines' are set in stone and to be obeyed at all costs and are current and up-to-date.  Most guidelines take so long to produce and get consensus that when the come out they are usually out-of-date. Guidelines are usually reached by consensus and hence are typically behind the adoption curve and not at the vanguard of new treatment paradigms.  

I assume that the neurologist who read this scenario interpreted the 'self-limited neurological event' as a relapse and advised the patient be switched to a more effective treatment. Unless these investigators can provide evidence that this was not a relapse how can the expect the neurologists they surveyed not to switch treatments? In an era of treat-2-target of NEDA it is clear that the 'best practice clinical guidelines' our out of date. In my opinion this study shows that the neurologists who applied the 'best practice clinical guidelines' were the herders, blindly following guidelines and the ones that elected to switch treatment were the independent thinkers, acting in their patient's best interests. My conclusion on reading this paper is the exact opposite to the researchers' conclusions. 

What do you think? 

Saposnik et al. Herding: a new phenomenon affecting medical decision-making in multiple sclerosis care? Lessons learned from DIScUTIR MS. Patient Prefer Adherence. 2017 Jan 31;11:175-180. doi: 10.2147/PPA.S124192. eCollection 2017.

PURPOSE: Herding is a phenomenon by which individuals follow the behavior of others rather than deciding independently on the basis of their own private information. A herding-like phenomenon can occur in multiple sclerosis (MS) when a neurologist follows a therapeutic recommendation by a colleague even though it is not supported by best practice clinical guidelines. Limited information is currently available on the role of herding in medical care. The objective of this study was to determine the prevalence (and its associated factors) of herding in the management of MS.

METHODS: We conducted a study among neurologists with expertise in MS care throughout Spain. Participants answered questions regarding the management of 20 case scenarios commonly encountered in clinical practice and completed 3 surveys and 4 experimental paradigms based on behavioral economics. The herding experiment consisted of a case scenario of a 40-year-old woman who has been stable for 3 years on subcutaneous interferon and developed a self-limited neurological event. There were no new magnetic resonance imaging (MRI) lesions. Her neurological examination and disability scores were unchanged. She was advised by an MS neurologist to switch from interferon to fingolimod against best practice guidelines. Multivariable logistic regression analysis was conducted to evaluate factors associated with herding.

RESULTS: Out of 161 neurologists who were invited to participate, 96 completed the study (response rate: 60%). Herding was present in 75 (78.1%), having a similar prevalence in MS experts and general neurologists (68.8% vs 82.8%; P=0.12). In multivariate analyses, the number of MS patients seen per week was positively associated with herding (odds ratio [OR] 1.08, 95% CI 1.01-1.14). Conversely, physician's age, gender, years of practice, setting of practice, or risk preferences were not associated with herding.

CONCLUSION: Herding was a common phenomenon affecting nearly 8 out of 10 neurologists caring for MS patients. Herding may affect medical decisions and lead to poorer outcomes in the management of MS.

CoI: multiple

Meta analysis points a finger at a virus.

Morandi E, Tanasescu R, Tarlinton RE, Constantinescu CS, Zhang W, Tench C, Gran B.The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis. PLoS One. 2017 ;12(2):e0172415.

BACKGROUND:The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS.
OBJECTIVE: To perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients.
METHODS:Medline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS. Meta-analysis was performed on the HERV-W family. Odds Ratio (OR) and 95% confidence interval (CI) were calculated for association.
RESULTS: 43 reports were extracted (25 related to HERV-W, 13 to HERV-H, 9 to HERV-K, 5 to HRES-1 and 1 to HER-15 family). The analysis showed an association between expression of all HERV families and MS. For HERV-W, adequate data was available for meta-analysis. Results from meta-analyses of HERV-W were OR = 22.66 (95%CI 6.32 to 81.20) from 4 studies investigating MSRV/HERV-W (MS-associated retrovirus) envelope mRNA in peripheral blood mononuclear cells, OR = 44.11 (95%CI 12.95 to 150.30) from 6 studies of MSRV/HERV-W polymerase mRNA in serum/plasma and OR = 6.00 (95%CI 3.35 to 10.74) from 4 studies of MSRV/HERV-W polymerase mRNA in CSF.
CONCLUSIONS:This systematic review and meta-analysis shows an association between expression of HERVs, and in particular the HERV-W family, and MS.

We all have endogenous retroviruses in our genome, it makes up about 5% of our genome. There is a suggestion that these can be reactivated to be a target in MS. This study does a meta analysis of data out there and concludes that HERV-W is associated with MS. However, how many papers are related to the fact that there is commercial development of an anti-HERV-W antibody.

The problem with meta analysis is publication bias, as there is bias towards positive data being published, and if you don't understand the biology then you can't sort out the "wheat from the chaff".

This is why meta analysis of EAE data is largely futile, there is a dearth of negative studies and there is such over-interpretation of results to make them look interesting. 

The number of studies where drug X or compound Y is reported to save nerves, cause remyelination, when the drug never gets into the CNS. So if you see that there is an immunosuppressive action, it will be neuroprotective and stop demyelination and even allow remyelination because inflammation is stopped. You claim your drug to be neuroprotective and pro-remyelination and the person doing the meta analysis buys it. 

Therefore, be careful all sorts stuff can be believed of as fact.

If we did a meta analysis on whether T or B cells are the important target in MS, I bet T cells will win hands down.

Fingolimod works by trapping white blood subsets in lymph glands...if you did a meta analysis on that, we would all agree  that this is so. Are there any decenting ideas or data...I think there is.

Therefore careful understanding of the facts, probably gives us greater insight. We need more thinkers than herders

Friday, 17 February 2017

#ResearchSpeak: are polyunsaturated fatty acids intake a preventable risk factor for MS?

PUFAs supplements may reduce your risk of getting MS. #RsearchSpeak #MSBlog

The study below shows that high intake of polyunsaturated fatty acids (PUFA) reduces your risk of getting MS. This observation is independent of other identifiable risk factors. Is this association or causation; chicken or egg? The only way to do this is by doing a randomised controlled population study to see if PUFA supplementation reduces the risk of getting MS, compared to a suitable control substance (placebo or another fatty acid). Another strategy would be to confirm this finding in another cohort of people, which may be difficult, or to try and test the hypothesis using a genomic approach, i.e. Mendelian randomisation. The problem with the latter is that we will need to know a lot about the biology of PUFAs and how subtle genetic variants affect the metabolism and levels of PUFAs. 

What it does suggest that if you are 'at risk' of getting MS, i.e. are a first, second or even a third degree relative of someone with MS it may be a good idea to look at your diet to make sure you are getting enough PUFAs. If not you can easily supplement your diet. In addition to this you need to make sure you are vitamin D replete, you don't smoke and you keep your weight down. 

As with all dietary interventions PUFAs have an up and a down side. Omega-3 PUFAs can increase your risk of bleeding and may interact with other medications.

Bjørnevik et al. Polyunsaturated fatty acids and the risk of multiple sclerosis. Mult Scler. 2017 Jan 1:1352458517691150.

BACKGROUND: Results from previous studies on polyunsaturated fatty acid (PUFA) intake and multiple sclerosis (MS) risk are conflicting.

OBJECTIVE: To prospectively investigate the association between dietary intake of PUFA and MS risk.

METHODS: We followed 80,920 women from Nurses' Health Study (1984-2004) and 94,511 women from Nurses' Health Study II (1991-2009) who reported on diet using a validated food frequency questionnaire every 4 years and identified 479 incident MS cases during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), for the effect of PUFA intake on MS risk adjusting for age, latitude of residence at age 15, ancestry, cigarette smoking, supplemental vitamin D intake, body mass index, and total energy intake.

RESULTS: Higher intake of total PUFA at baseline was associated with a lower risk of MS (HR top vs bottom quintile: 0.67, 95% CI: 0.49-0.90, p trend = 0.01). Among the specific types of PUFA, only α-linolenic acid (ALA) was inversely associated with MS risk (HR top vs bottom quintile: 0.61, 95% CI: 0.45-0.83, p trend = 0.001). The long-chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not associated with MS risk.

CONCLUSION: Low dietary PUFA intake may be another modifiable risk factor for MS.

Not in My Name. Time to Stop -. Stem cells

Papers are getting assessed on altmetrics and one of the outputs are blog posts, so anyone who has clicked on the altmetric link to get here you are in for a on

Jiang H et al. Amelioration of experimental autoimmune encephalomyelitis through transplantation of placental derived mesenchymal stem cells.Sci Rep 2017 Feb 10;7:41837. doi: 10.1038/srep41837.

Placental derived mesenchymal stem cells (PMSCs) have been suggested as a possible source of cells to treat multiple sclerosis (MS) due to their immunomodulatory functions, lack of ethical concerns, and potential to differentiate into neurons and oligodendrocytes. To investigate whether PMSCs share similar characteristics with embryonic mesenchymal stem cells (EMSCs), and if transplanted PMSCs have the ability to integrate and replace degenerated neural cells, we transplanted rat PMSCs and EMSCs into the central nervous system (CNS) of Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our findings demonstrated that transplanted PMSCs, similar to EMSCs, were effective in decreasing infiltrating inflammatory cells, preserving axons, and ameliorating demyelination, thereby improving the neurological functions of animals. Moreover, both PMSCs and EMSCs had the ability to migrate into inflamed tissues and express neural-glial lineage markers. These findings suggest that PMSCs may replace EMSCs as a source of cells in MS stem cell therapy.

The blog is a site that allows us to talk about research, and some of it is good news and some is bad news. We hope some of the readers are scientists and neurologists as we feel it has educational content for all..but also we need to educate the public about the type of things scientists do.

We can do the rose-coloured tinted glasses approach, which you get in most Science websites where every thing is great. But if every thing was great, we would have cured something by now.

As a card carrying vivisectionist,  we have to take the flank from parts of Society that do not like or want animal experiments. However, the UK Government want us to be open about working with animals, and this is why we post on animal studies.

I have decided against doing "cure of the week" which happens every week as I realize many animal studies are years away from offering something of use. 

Anyway back to the post

If you poll pwMS about where we should be putting their research resources?. I bet high on the list will be people wanting stem cell trials. 

This is because science has promised that we can reverse the effects of time, and the media and public have bought into this view, so you rightly say trials, trials, trials!

Indeed the MS Societies listen and put their resource behind their members wishes. Trials have been initiated and everybody's hopes are high. The hope you are being sold is that the stems cells turn into myelinating cells and new nerves and then we can turn back time.

Mesenchymal stem cells, or MSCs, are multipotent stromal cells that can differentiate into a variety of cell types. Mesenchyme is embryonic connective tissue that is derived from the mesoderm and that differentiates into haematopoietic and connective tissue, whereas MSCs do not differentiate into haematopoietic cells.

Everyone gets on the band wagon, and even we dipped our toe in the stem-cell waters. 

I know you like to hear about this stuff, but I need to put this into perspective, because if the stem cells trials don't work you will be blaming the animals.....Don't!

So to describe the paper in this study creates mesencyhmal stem cells from embryos and placenta and show that they inhibit EAE and stop demyelination and nerve loss when transplanted into the brain.

Yeah we say.

However, how many more of these studies are we going to see? 

MSC made from this or that cell. 

I wonder whether we should call time? 

Are we going to want to use stem cells from embryos or someone else's placenta, when one can make stem cells from yourself.  
Technology has moved on

There have been endless studies of mesenchymal stem cells and EAE. The results are remarkedly consistent (As seen below, from this study).

The effects are pretty uninspiring.

The benefit is a small diminution, and sometimes a delay, due to a small inhibitory effect. Perhaps much of the benefit of demyelination and nerve loss reported can be then be downstream of this, because the damaging inflammatory response has not arrived in the CNS to cause damage. 

It is often impossible to work out if it was in fact a diminution of the severity of disease or was it because a few animals in the experiment didn't get disease. 

I maintain that we need to see this data. 

However, this minor effect in the most optimum of conditions can easily be bettered by most current DMT. 

If this is good as it gets, then the chances of this being useful in MS is really rather dubious. 

If all they really do is have an immunosuppressive action then is this the way to go?. 

I'm yet to be convinced.

However, do we need these types of study? Mesenchymal trials in humans are well underway. 

Therefore, do we need more animal experiments for the  time being? Perhaps the time for these types of animal experiments has passed.

The success or failure of trials in humans will determine whether this approach is developed or not. 

It will probably be safe, but will it work?....I suspect something towards a failure or something wishy-washy as the trials are based on data made of quick-sand.

Remember this is an opinion and I could be wrong.

Trials in humans are done due to opportunity and public pressure, where we are running before we can walk. How do we guide the mesencymal cells to become oligodedrocytes etc, can they do anything when given systemically? Do they really convert into useful cells? (answer in animals is generally no), there are so many unknowns. This means that the chance of success are slim.

I am there to be proved wrong and then I will eat humble pie when I am.. I don't mean to dash hopes. Stem cells do have potentials 

Am I wrong to be a cynic? and burst some bubbles or should I have a rant and say "Not in my name"

I have to justify what I do, but I am not going to defend all the work of others and this paper happened to come into my firing line.

Am I sorry for doing this in public...No. 

The 3Rs of animal use is supposed to a core principle of working with animals in Europe.

In the experiment above, there is a group where experiment healthy animals are followed and show nothing. They,
 are sometimes injected with adjuvants that serve essentially no useful function excepts it wastes animals. It is no longer an experiment, we know it is not going to induce neurological signs...stop it!

Next up, For anyone reading this study, the method of disease induction and method of killing are no longer allowed in the UK. 

To kill animals they chop their heads off. 

This is not worse thing...a Japanese person once said they throw rats into liquid nitrogen to freeze the brain quickly....non-sense it would not be the quickest way of doing it!- This was stupidity and animal abuse

Anyway "This technique should only be used in rare circumstances and where there is exceptional scientific justification" The animals must be dead before being decapitated. (

However, if you call people on things does it make them hide the truth.

In the study they only state they inject the adjuvant subcutaneoulsly, but where is this? 

I guessed they have been rejected for saying where, so they don't say it. However, they give a reference  which says the same thing and gives a reference from the yesteryear and it states that the adjuvant is put subcutaneous in the feet.

This practice was likewise outlawed in the UK over twenty-25 years ago as being inhumane, as putting the adjuvant into the feet you get swelling and so pain and the animal has problems walking. This can be put under lose skin and this does not seem to cause the animals the same problem. Therefore, the foot pad injection has no place in science, at least in EAE science. Maybe they did not do this, they selected the wrong references

I personally refuse to accept this work if they do use injection in feet, it is bad science.This is the way to make people change practise..maybe not they just hide things:-). 

It is obvious there are some people that do not care about this and they are based in prominent countries that should know better! 

This is perhaps what happens when you move your research to places, where they do not give a stuff about the beasties they work with. Remember this,  as UK science based on animals closes down

Perhaps it is about time that Journals state producing a list of procedures that they will not accept on ethical grounds.

Yes, EAE will eventually end up there, but if we continue to undertake bad practices then we will hasten this process and so a good reason to speak out...the animals can't 

However, killing off animal work in the UK is going to mean that you get more of this guff.

Some people out there will be saying shut you whining minnie, 
"This is why we move out of the UK you are too Regulated"

Thursday, 16 February 2017

#DigitalHealth: Using VR headset to self-monitor vision

First of all, a bit about myself, my name is Nicolas Dubuisson. I completed my medical training in Belgium and so far I am 3 years through my Neurology training, so well on the way to becoming a Neurologist. I joined BartsMS as an ECTRIMS Clinical Training Fellow to ProfG four months ago. I plan to stay with Barts team until October 2017.

Currently, I’m working with Alison and the team in order to develop new self-monitoring tools for people with MS. One of these projects involves working with a team of designers to develop two smartphone applications that will be able to evaluate visual field and colour vision. The ultimate aim is to embed these into the web-EDSS calculator to improve it as an outcome measure. At the moment people with MS have to rely on their neurologist to tell them if there eyes are affected by MS, or not.

The first function of the APP will be to develop the Humphrey test, currently conducted by a optometrist, into an engaging resource for people to use. Its first objective is mainly to evaluate deficits in the visual fields, which could occur following a lesion along the visual pathway.
This function of the APP is not specifically for people with MS, but rather we hope the resource can be used to help diagnose and monitor other ophthalmological problems as well.
In the existing humphrey test, the optometrist asks the patient to look at a white dot with one eye at a time. Other bright dots will appear on the screen in different places and the patient must press a button each time the signal is caught by their eye.

Existing Humphrey Test in ophtalmology clinic.

The final result is displayed as two circles (one for each eye) with different shades of grey. The light grey represents a perfect vision and the black an absence of vision.

Humphrey result showing a right superior quadrantanopia (black zone).

The application we are developing takes exactly the same principle but the machine is replaced by the virtual headset and a smartphone.

We are developing software to conduct the same test from the phone and a headset.

The second function of the APP will be to test the colour vision. In clinical practice, the current test is called the Ishihara test. We are working to develop an APP in the form of a 3D game. The first prototype that we have shows a wall with 16 coloured squares in front of you. You then have to point out (moving your head) which box is a different colour. Once the correct box has been identified, the wall rises and the player move towards the next wall.

The first step in our project (which will start next week) will be to invite patients from neuro-ophthalmology clinic to compare our tests with those used in routine practice (Humphrey and Ishihara). Once validated (we know that our tests work the same as the current tests), we will look into making these test more engaging and ultimately enable these tests to be made available for others to use at home.

We plan to share updates on this project on the blog. We’d be interested to hear about your experiences of eye tests in relation to your MS. Have you completed any of these tests or have you tried any eye testing APPs?

NB: This will not replace your appointments with the ophthalmologist but on the contrary will be complementary to it and hopefully empower you and other people with MS to monitor their own disease.

Compound in cannabis does not look Dope

van Amerongen et al. Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. Clin Ther. 2017 Feb 9. pii: S0149-2918(17)30054-1

PURPOSE: The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS).

METHODS: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements.

FINDINGS: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.

This study looks at oral THC in spasticity and pain and the simple answer is it failed?

Why because the outcomes will have been self-assessed; the sativex study says that it did not work on the scientific outcomes, but on how people were feeling. 

In this study people were obviously not feeling good enough.

They say it is of value..... because it is well tolerated, so is a glass of water, but is that going to treat your pain and spasticity? 

The only thing it worked on was when the people were in clinic.

Was the study big enough to be of value, I suspect not.

CoI: I'm a competitor

Wednesday, 15 February 2017

#ClinicSpeak & #NeuroSpeak: alternative facts and PML

Pharma vs. the EMA: whose PML figures are more reliable? #ClinicSpeak #NeuroSpeak #MSBlog

A person with MS from Spain emailed me last week asking for advice. I assume he is on natalizumab and is JCV seropositive and is at risk of developing PML (progressive multifocal leukoencephalopathy) as a complication of his treatment. His neurologist has offered him a choice of dimethyl fumarate (DMF, Tecfidera) or fingolimod (Gilenya). He is however very concerned about the risk of PML on both of these options; the PML figures his neurologist gave him in relation to the number of cases of PML on both of these DMTs are very different to figures he found when searching online. He emailed me to find out which figures are correct. 

Biogen informed me a few weeks ago that a 5th case of PML had been reported on Tecfidera and that last case had had lymphopaenia with only one total lymphocyte count below 500/mm3 (0.5x109/L). Similarly, in December Novartis informed the MS community of the 9th case of PML on Gilenya unrelated to previous natalizumab exposure. I was therefore surprised when this patient referred me to the European database of suspected adverse drug reaction reports.

It is clear that in this database, as at 31st January 2017, there are at least 19 cases of PML reported on Tecfidera and at least 56 cases of PML on Gilenya. Which figures do we believe? I have asked both Biogen and Novartis to clarify, which figures are correct, i.e. their official figures of 5 and 9 cases of PML, respectively, or the EudraVigilance figures of 19 or 56 cases of PML, respectively. 

Please note that European database of suspected adverse drug reaction reports is an official website. All the data displayed in the web reports is taken from EudraVigilance, a system designed for collecting reports of suspected side effects, used for evaluating the benefits and risks of medicines during their development and monitoring their safety following their authorisation in the European Economic Area (EEA).

The following is a list of important facts about the source of the data you can view on this website for each web report:
  1. Each individual case in EudraVigilance refers generally to a single patient; an individual case is composed of at least one report, called the initial report, which might be complemented by follow-up reports.
  2. A web report shows serious spontaneous cases held in EudraVigilance since the medicine or active substance was authorised for use in the EEA. A case is classified as 'serious' by the reporter when a side effect is one that (i) results in death, (ii) is life-threatening, (iii) requires hospitalisation or prolongation of existing hospitalisation, (iv) results in persistent or significant disability/incapacity (as per reporter's opinion), (v) is a congenital anomaly/birth defect, or (vi) results in some other medically important conditions.
  3. A web report shows serious spontaneous cases where an authorised medicine or active substance is suspected by the reporter to have caused or contributed (e.g. by interacting with one or more other medicines) to a serious side effect. Reports where an authorised medicine or active substance is reported as a concomitant medicine are excluded. 
  4. The figure displayed is always the running total of serious spontaneous cases reported up to the end of the previous month. The figures are updated online on the 15th of the current month.
  5. Pharmaceutical companies that hold the marketing authorisation of a medicine, as well as national medicines regulatory authorities, are legally required to submit reports of suspected side effects that occurred in the EEA to EudraVigilance. This includes reports received from healthcare professionals and patients.
  6. Pharmaceutical companies that hold the marketing authorisation for a medicine in the EEA are also legally required to submit to EudraVigilance all reports of suspected unexpected adverse reactions that are serious and that occurred in a third country (non-EEA) where they hold a marketing authorisation.
  7. The web report does not include reports from studies (e.g. clinical trial, non-interventional study) or other types of reports (i.e. only spontaneous reports).
I was as confused as this Spanish person with MS who simply wanted to know the risk of PML on DMF and/or Fingolimod. The clarifications below are very helpful. The EudraVigilance figures are a crude indicator of an adverse event on a particular drug, but the numbers cannot be used to calculate incidences. 

Addendum Added 16h20, GMT, 15-Feb-2017:

I have now had a formal response from Novartis. The EMA, or EudraVigilance, figures are essentially from two sources. One from EU members states and the other from Novartis. The Novartis figures are global figures. The numbers in the 
EudraVigilance database are both suspected, and confirmed, cases of PML and as expected some of them will turn-out not to have PML and some will be duplicate entries. Novartis provide the EMA with information about whether or not the cases are associated with, or without, the previous use of natalizumab. 

The following are Novartis’ official and latest figures:

The overall rate of PML under fingolimod therapy not attributed to previous natalizumab treatment is very rare and estimated to be less than 1:10,000 patients.

10 PML cases in ~184,000 fingolimod treated patients (~397,000 patient-years) as of November 2016.

(Estimated risk (95% CI) is 0.054 (0.026, 0.1)/1,000 patients and incidence rate (95% CI) is 2.52 (1.21, 4.63)/100,000 patient-years exposure.)

Two cases presented with confounding factors, 1 case had previous natalizumab exposure for 10 months (3 years 9 months before PML diagnosis).

One additional case, PML occurred during 3-month natalizumab exposure, after 4.5 years fingolimod treatment, history of recent exposure to steroids.

Nine patients were within the age range of 49 to 63 years, while one patient was 32 years old.

In nine cases, fingolimod exposure ranged between 30 and 54 months, while one received fingolimod for 18 months.

None of the patients had sustained grade 4 lymphopenia.

Addendum Added 16h36, GMT, 15-Feb-2017:

The Biogen figures are 5 confirmed PML cases in ~230,000 dimethylfumarate treated patients (~330,000 patient-years of exposure) as of October 2016. 

CoI: multiple

Metabolomics in MS

Metabolomic signatures associated with disease severity in multiple sclerosis.Villoslada P, Alonso C, Agirrezabal I, Kotelnikova E, Zubizarreta I, Pulido-Valdeolivas I, Saiz A, Comabella M, Montalban X, Villar L, Alvarez-Cermeño JC, Fernández O, Alvarez-Lafuente R, Arroyo R, Castro A. Neurol Neuroimmunol Neuroinflamm. 2017 Jan 27;4(2):e321.

OBJECTIVE:To identify differences in the metabolomic profile in the serum of patients with multiple sclerosis (MS) compared to controls and to identify biomarkers of disease severity.
METHODS:We studied 2 cohorts of patients with MS: a retrospective longitudinal cohort of 238 patients and 74 controls and a prospective cohort of 61 patients and 41 controls with serial serum samples. Patients were stratified into active or stable disease based on 2 years of prospective assessment accounting for presence of clinical relapses or changes in disability measured with the Expanded Disability Status Scale (EDSS). Metabolomic profiling (lipids and amino acids) was performed by ultra-high-performance liquid chromatography coupled to mass spectrometry in serum samples. Data analysis was performed using parametric methods, principal component analysis, and partial least square discriminant analysis for assessing the differences between cases and controls and for subgroups based on disease severity.
RESULTS:We identified metabolomics signatures with high accuracy for classifying patients vs controls as well as for classifying patients with medium to high disability (EDSS >3.0). Among them, sphingomyelin and lysophosphatidylethanolamine were the metabolites that showed a more robust pattern in the time series analysis for discriminating between patients and controls. Moreover, levels of hydrocortisone, glutamic acid, tryptophan, eicosapentaenoic acid, 13S-hydroxyoctadecadienoic acid, lysophosphatidylcholines, and lysophosphatidylethanolamines were associated with more severe disease (non-relapse-free or increase in EDSS).
CONCLUSIONS:We identified metabolomic signatures composed of hormones, lipids, and amino acids associated with MS and with a more severe course.

Last week we had metabolomics telling us what type of MS you were getting so it is interesting that a look-see study reported a week later did not get excited about the trypophan metabolomics but they did report that tryptophan is associated with EDSS not sure if it increased or decreased like the study from Australia