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.