Monday, 31 October 2016

#ClinicSpeak & #NeuroSpeak: alemtuzumab and opportunistic infections

Calling all alemtuzumabers please be extra-vigilant about infections when your lymphocyte counts are low. #ClinicSpeak #NeuroSpeak #MSBlog

I was at a meeting on Friday and heard about a patient who had died of Listeria meningitis after receiving alemtuzumab. Listeria is an opportunistic infection and tends to occur more often in people who are immuno-compromised. Nocardia is another opportunistic infection that has been described post-alemtuzumab (see below). These cases are likely to be at the vanguard and are not 'unexpected'; a case of Listeria meningitis was described in the clinical trial programme and we know from basic principles that immunosuppressive therapies are associated with opportunistic infections. Importantly, you need to know that you can de-risk Listeria to some extent by being on a 'pregnancy diet' post-treatment for the first 3-4 months until your lymphocyte counts have recovered. We recommend that all our patients follow the pregnancy diet for 3 months, which can be found on the NHS Preventing Listeria web-page

Preventing Listeriosis (adapted from the NHS website) 

The best way to prevent getting listeriosis is to always ensure that you follow good basic food hygiene. This includes:

  • Peeling raw vegetables, salads or fruit, or washing them thoroughly before eating.
  • Washing your hands before preparing food, before eating and after going to the toilet.
  • Washing kitchen surfaces and utensils regularly, particularly after preparing raw meat, poultry and eggs.
  • Always separating raw foods from ready-to-eat foods. Don't store raw meat above ready-to-eat foods, because there's a risk that juice containing harmful bacteria may leak from the raw meat.
  • Always cooking food thoroughly and checking cooking instructions carefully, including the cooking time.
For foods that are "ready to eat", the most important ways of reducing the risk of listeriosis are to:
  • not use food after its "use by" date
  • make sure that the temperature of your fridge is 0-5C
  • follow storage instructions on food labels
As an alemtuzumabers' are high-risk group for catching listeriosis, you should avoid eating foods known to be at risk of listeria contamination. Foods to avoid include:
  • soft mould-ripened cheese – such as Brie, Camembert and chèvre (a type of goat's cheese)
  • soft blue-veined cheese – such as Danish blue and gorgonzola 
  • all types of pâté – including vegetable pâté
  • unpasteurised milk
  • undercooked food
It's safe to eat hard blue-veined cheese , such as Stilton, as well as other types of hard cheese, including Cheddar and Parmesan – even if these are made from unpasteurised milk.

Read more about foods to avoid after alemtuzumab and during pregnancy.

Farm animals: Alemtuzumabers should avoid close contact with farm animals that are giving birth or have recently given birth. This is to avoid the small, but serious, risk of an infection.

Read more about the potential risks of close contact with farm animals on GOV.UK.

Please note that alemtuzumab is an induction therapy and is irreversible. Based on its mode of action there will be complications. The only way to de-risk the opportunistic infections is to be vigilant and to take symptoms of infection seriously. If in doubt seek advice. Please note that once your immune systems have reconstituted the risk of opportunistic infections is very low. 

Rau et al. Listeria Meningitis Complicating Alemtuzumab Treatment in Multiple Sclerosis--Report of Two Cases. Int J Mol Sci. 2015 Jun 29;16(7):14669-76.

Alemtuzumab, a humanized monoclonal antibody targeting the surface molecule CD52, leads to a rapid depletion of immune cells in the innate and adaptive immune system. In phase 2 and 3 trials in multiple sclerosis (MS), infections have been reported more frequently inalemtuzumab than in interferon beta treated patients. Here we report two patients treated with alemtuzumab for MS developing Listeriameningitis few days after the first infusion cycle. Both patients recovered completely after prompt diagnosis and adequate treatment. Physicians and patients should be aware of this serious, but treatable complication.

#GuestPost & #MSChampion: exercise as driver of recovery

Exercise is not only important for Brain Health, it helps recovery of function. #BrainHealth #MSChampion #MSBlog

I met Olga Bobrovnikva, at an MS event, almost 10 years years ago and we have been in contact ever since. She is a MS Champion and an inspiration to many. If you get a chance please read her book 'Playing the Pathways of My Brain'; I have a signed copy if anyone wants to borrow it. 

When I was preparing our teaching course for ECTRIMS on #BrainHealth she sent me the following email. She subsequently given me permission to share the email with you as a guest post. It is a personal story of how exercise and determination can help improve physical disability. It is clear that recovery of function occurs more commonly than we previously thought in MS, but for this to occur it needs rehabilitation, i.e re-training old, or training new, pathways to do a specific task. The need for physical rehabilitation in driving recovery in spinal cord injury, stroke and head injury has been known for decades; it is no different in MS. What Olga's short story tells us that physical exercise is not only important for Brain Health, but for recovery of lost function.

Dear Gavin,

Three years ago four falls within the space of a few weeks prompted me to seek help from my neurologist.

Two years later, after assessment , review, advice and physiotherapy with a succession of “clinical specialists” and big efforts at my health club and yoga, I was suffering from increasing gait and fatigue problems even though I was managing my balance a little better and was physically in good shape.

Due to my national health care system, I was paying a significant proportion of the bi weekly physio costs and I finally gave up in total despair.

Then my partner and collaborator on my book “Playing the Pathways” took as he said “an aviation attitude” to my problems. “Balance is about your interface with the ground” he said, and immediately looked at my feet and their ability to mange the interface.

He discovered four toes on my right foot had no sensory or motor capability, something all my previous assessments and therapy had failed to reveal.

As he had, “ done time” in Headley Court in 1963 to learn to walk again after DVT damage, he set about resistive flexions on each “dead” toe. Within a few short sessions some resistance was being generated and sensation returned. Now 8 months later we still do 2 sessions a day and the performance of right and left toes is identical.

But the toes were just the starting point for a new regime, as it was evident that the rest of my right leg functions were not optimum. We set out to check and repair, with massage and resisting flexion, each joint in a sequence from toes, feet, ankle, knee, thigh, hips and back. The sequence being necessary, while also eliminating other exercises, to ensure elimination of compensatory pathways and muscle usage.

It is now quite evident to us that my MS damaged a neural pathway, maybe to one muscle and that over the last 25 years my body has gradually compensated for this and the compensation created collateral degradation which finally met my normal age degradation which resulted in my falling over problems.

My main successes after 8 months are:
  • Restoration of motor and sensory functions in the 4 right toes
  • Reduction almost elimination of paresthesia in the sole of the foot
  • Matched R/L flexions and power in toes ankles and knees
  • Ability to flex right leg rearwards
  • Ability to perform cycling movements while laying on back
  • Ability to describe circles in the air with right ankle and toes 
  • Ability to describe circles in the air with right leg, ankle and toes
  • Ability to run with springy ankles and elevated knees
  • Ability to put on sock and knickers in standing and sitting positions
  • Ability to vary pace length and speed
  • Improvement of upward knee flexion and power
  • Improved right leg balance
  • Overall reduction in spasticity and knowledge of how to provoke huge spacticity to order!
  • Intermittent gait improvement (fatigue related)
  • At best fully limbic gait control to automatically step over obstacles
My Immediate Targets are:
  • Further correction to toe position on walking
  • Improve power of upward knee flexion
  • Improve ability to hitch hips (hula hoop)
  • Increase the bulk and response of the Right leg medial thigh muscles (Pectineus and Gracilis)
I do not know if my experience is typical, regarding failure of conventional rehab or success by home rehab. The need for two or three 10 minute sessions daily makes this difficult to achieve with the conventional rehab systems.
I have hope again, as I have halted my “progression”. I want to get this “episode” to as many people with MS and clinicians as possible, to find out if others can use and replicate this. So I would love to ask all my PwMS fellows - please check your toes ! 

If you think this has value would you please help me to do this?

Looking forward to hearing from you,

I remain, sincerely

Olga Bobrovnikova
Mu-Sic Foundation Association for Global Awareness of MS & the Brain

Short Biography: Olga Bobrovnikova is a concert pianist with MS. Olga trained in the Moscow Conservatory and Gnessin Institute in Chamber Piano Performance and Therapy for Music. Since her diagnosis of MS in Brussels fourteen years after her first symptoms, she has for 15 years dedicated to raising awareness and funds for MS Charities and Organisations. As Ambassador for the Year of the Brain she reviewed the research abstracts and literature on Music and the Brain to unravel the mysteries of music and piano performance, which she describes in her book “Playing the Pathways of My Brain”. Her concept of a balanced performance triangle, comprising physical, mental and emotional functions, is based on separate rewards from limbic, motor and associative pathways. Employing these ideas, her new, progressive method for early teaching of music, uses children’s instinctive mirror learning responses, to establish the physical and mental functional pathways, essential for cognitive learning.

Sunday, 30 October 2016

#BrainHealth: on how-not to do it

Are you a Brain Health yo-yoer? Brain Health should be about consistency. #BrainHealth #MSBlog

I taught on the 2nd annual specialist-neurology-registrar (SpR) master course on Friday. One topic I covered was brain health and the holistic management of MS. We go onto the subject of MSer-activation and making them responsible for their own care. One topic of discussion was exercise and how to prescribe it. Should we not be giving away gym memberships or a subscription to a personal fitness trainer? This is happening in some areas of the country. The problem with an exercise prescription is that very few MSers adhere to the prescription. Why and how can we change things? One thing for certain is not to do it the way I do.

The aim of the Barts-MS Brain Health Challenge was to make HCPs (healthcare professionals) take-up exercise and a healthy lifestyle so  that when we prescribe these things to our patients we have the moral high-ground. I have lost the moral high-ground; over the last 3 months I had gone from exercising 4-5x per week down 1-2x per week and as a result I am feeling awful. I am not sleeping as well (early morning wakening), I have put on weight and my mood has sagged. So when I got home on Friday evening, after the course, I went for a 10 km run in the dark. I have now put in 4 training sessions this weekend (3 runs and 1 session on the rowing machine) and I am now stiff and sore. I am feeling better for it; it is amazing how exercise makes you feel great. The message should be consistency and not stop-start, or yo-yoing. I aim determined to get back on track this week with my own Brain Health Challenge. What about you? 

B cells as antigen presenting cells.

Fraussen J, Claes N, Van Wijmeersch B, van Horssen J, Stinissen P, Hupperts R, Somers V. B cells of multiple sclerosis patients induce autoreactive proinflammatory T cell responses. Clin Immunol. 2016 . pii: S1521-6616(16)30163-2

Antibody-independent B cell functions play an important role in multiple sclerosis (MS) pathogenesis. In this study, B cell antigen presentation and costimulation in MS were studied. Peripheral blood B cells of MS patients showed increased expression of co-stimulatory CD86 and CD80 molecules compared with healthy controls (HC). In MS cerebrospinal fluid (CSF), 12-fold and 2-fold increases in CD86+ and CD80+ B cells, respectively, were evidenced compared with peripheral blood. Further, B cells from MS patients induced pro-inflammatory T cells in response to myelin basic protein (MBP), in contrast to B cells of HC. Immunomodulatory treatment restored B cell co-stimulatory molecule expression and caused significantly reduced B cell induced T cell responses. Together, these results demonstrate the potential of B cells from MS patients to induce autoreactive proinflammatory T cell responses. Immunomodulatory therapy abrogated this effect, emphasizing the importance of B cell antigen presentation and costimulation in MS pathology.

How do B cells influence MS?

They must because MS is responding to B cell depletion. 

This study says that B cells are antigen presenting cells...however there other ideas, ProfG thinks you are getting rid of EBV.

Saturday, 29 October 2016

#PoliticalSpeak & #OffLabel: stand-up and shout

Why are neurologist's so reluctant to prescribe off-label DMTs? #PoliticalSpeak #OffLabel #MSBlog

It is wonderful to see some momentum behind the off-label use of DMTs for treating MS. Since the Swedish experience with rituximab was published a few weeks ago the position paper on reducing the cost of MS treatments below came to my attention with an accompanying blog post, 'Stand-up for Rituximab'. 

On this blog we have been actively promoting off-label prescribing for over two year. The motivation for doing started on my sabbatical in 2014 when I visited South Africa and saw first-hand how pwMS were not being treated with DMTs because of their high price. My position on this only got stronger when I visited other resource poor countries, in particular India. We have now generated a list of 9 off-label treatments; 5 of which are on the WHO list of essential medicines. The latter is important in that this ensures they are available in almost all resource poor countries. 
  1. Azathioprine*
  2. Cladribine
  3. Cyclophosphamide*
  4. Fludarabine*
  5. Leflunomide
  6. Methotrexate*
  7. Mitoxantrone
  8. Rituximab*
  9. HSCT/BMT 

Please note that Rituximab is not a cheap drug. It will come off patent soon and hopefully the biosimilars will reduce its price. However, as rituximab is a biological, biosimilars will only have a modest impact on its price. Then there is brand loyalty. In India they already have a rituximab bio-similar, Reditux. Despite it costing a third of the price of the innovator compound, MabThera, its is not as commonly used as you would think. When I visited NIMHANS, the large neurology centre in Bangalore, I was told that Reditux was not as good as MabThera. However, when I look at the B-cell depletion data, and B-cell re-population kinetics, of Reditux there was no indication that it was inferior to MabThera. What we are seeing play out here is the power of the brand. Indian neurologists trust and feel more comfortable prescribing something they know. They simply believe that Reditux is inferior and they want the best for their patients. Please note they were not using rituximab to treat MS at NIMHANS, but were using it for other neurological conditions. 

The MS community needs to understand that off-label prescribing is unlikely to take-off without political support. The latter is not going to happen any time soon, trust me we have tried to get British politicians behind our campaign. Politicians have to take a macro-economic view of the world and tend to have little interest in single-issue diseases. It is clear that our politicians have struck a deal with Pharma and have put in place rafts of legislation to protect Pharma's intellectual property and business models on the condition that Pharma continue to spend money on R&D, create and support local jobs and more importantly generate large sums of money for the tax coffers and pension funds. However, Pharma must not assume that their cosy and rather 'special' relationship with government is going to stay the same if they don't deliver on their obligations. A few bad apples have been giving Pharma a very bad name and it is up to Pharma to clean-up their act. For example, Gilead's share-buy back programme to boost their share-price, and maximise staff bonuses and short-term shareholder value, over spending their profits on R&D is simply outrageous. This is why Gilead are in the cross-wires of US politicians; they have renegaded on the deal. 

We all agree that at the moment Pharma are the only show in town, but they need to act responsibly and not abuse their privileged position. If they don't society will turn against them. The high-cost of MS drugs is one of many factors that is contributing to their bad public image. This is something that Pharma can do something about. I sincerely hope that Roche assesses the situation carefully, with a big and responsible worldview, and that they make ocrelizumab affordable. Ocrelizumab does have advantages over rituximab, but if ocrelizumab is too expensive the community will find ways to disrupt the market and use rituximab. 

At our Barts-MS strategy day we decided to hand-over the baton for our #OffLabel campaign to the MS International Federation. We only have so much time in a day and we also failed to get our health policy unit at Barts and The London to engage with this campaign. We need people who understand policy and have the necessary resources to run a political campaign. One of the priorities of the MSIF are increasing drug access for pwMS living in resource-poor environments and off-label prescribing is one way to achieve this. We will continue to help and support the #OffLabel campaign, for example by posting about it on this blog, but it will not be a major priority of our group this year. Please note we will continue to make available our protocols for off-label prescribing. 

Annette M. Langer-Gould. Stand up for Rituximab. NEUROLOGY E D I T O R' S B L O G, O C T O B E R 1, 2 0 1 6.


...... The unaffordability of MS medications is driven by the outrageous prices that are in no way tied to the benefits these medications provide....

...... The experiences they share include a few simple strategies to lower costs without diminishing quality of care. The one with the most impact is the use of rituximab.... 

...... The biggest barriers to implementing rituximab use are: 1) most insurance carriers deny coverage because it is not FDA approved for MS; 2) neurologists are afraid of legal action if they prescribe a non-FDA approved product and 3) the drug companies are incredibly good at marketing their products with glossy ads to promote brand bonding, enticing many prominent neurologists with speaker fees, dinners, first-authorship on New England Journal articles for studies they didn’t design, conduct, analyze and so on....... 

...... Biogen and Roche are already busy creating false distinctions between ocrelizumab and rituximab as they did for Lucentis and Avastin and frightening neurologists into believing they would be harming their patients or at risk of litigation if they use rituximab......

...... Off-label prescribing is what neurologists do all the time, the only legal risk is if ocrelizumab had been proven to be superior or safer than rituximab, data that do not exist and a study Roche and Biogen would be afraid to conduct......

....... The Swedish and Kaiser Permanente neurologists negotiated with their medical centers to allow the use of rituximab in their highly active patients when natalizumab was not an option. Use of rituximab has increased dramatically in Sweden and Kaiser Permanente as the highly favorable efficacy/safety profile and high patient satisfaction becomes clearer......

....... Pharma tried to pressure the Swedish government to halt this use of rituximab, which was met by outrage from their neurologists. Swedish health care authorities reviewed the extensive use of rituximab in MS and deemed it scientifically sound and legal.....

....... I urge all neurologists to stand up for their patients as the Swedish neurologists have done and help your patients get access to rituximab.......

Kister & Corboy. Reducing costs while enhancing quality of care in MS. Neurology October 11, 2016 vol. 87 no. 15 1617-1622

The rapid escalation in prices of disease-modifying therapies (DMTs) for multiple sclerosis (MS) over the past decade has resulted in a dramatic overall increase in the costs of MS-related care. In this article, we outline various approaches whereby neurologists can contribute to responsible cost containment while maintaining, and even enhancing, the quality of MS care. The premise of the article is that clinicians are uniquely positioned to introduce innovative management strategies that are both medically sound and cost-efficient. We describe our “top 5” recommendations, including strategies for customizing relapse treatment; developing alternative dosing schedules for Food and Drug Administration–approved MS DMTs; using off-label therapies for relapse suppression; and limiting the use of DMTs to those who clearly fulfill diagnostic criteria, and who might benefit from continued use over time. These suggestions are well-grounded in the literature and our personal experience, but are not always supported with rigorous Class I evidence as yet. We advocate for neurologists to take a greater role in shaping clinical research agendas and helping to establish cost-effective approaches on a firm empiric basis.

Some other blog posts of interest on off-label prescribing

Oct 18, 2014 ... "In response to some of the comments yesterday I have to stand up for people living with MS in South Africa and defend their right to treatment.
4 days ago ... The study below summarises the off-label experience of using rituximab to treat both relapsing and progressive forms of MS in Sweden.
Sep 5, 2016 ... HSCT-BMT had been added to our essential unlicensed treatments list # PoliticalSpeak #MSBlog #OffLabel. An important issue we, and others, ...
Jun 18, 2015 ... Therefore we are in a Catch-22 situation at present with regard to the use ofofflabel rituximab for treating MS in the NHS. This is great pity as it ...
Oct 18, 2016 ... #ClinicSpeak & #OffLabel: alemtuzumab between a rock and a hard place ... that 3rd, and subsequent courses, of alemtuzumab are off-label?
Jan 14, 2016 ... BartsMS Off-label Cladribine use Information Sheet. For those Health Care professionals and People with MS who may be interested. We have ...
Apr 15, 2015 ... "After last week's post on off-label prescribing, I contacted our health policy unit about formally addressing this issue in the UK with the aim of ...
Dec 30, 2015 ... "A part of the solution we have been promoting the use of off-label, cheaper, alternative DMTs to treat MS. The following is our Barts-MS ...
Dec 16, 2014 ... Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when ...
Apr 15, 2016 ... The use of off-label drugs to treat MS in resource-rich environments remains a hot potato. Despite been given the green-light to do so by our ...
Jul 26, 2016 ... "Let's hope the rituximab data is good enough for NHS England to adopt off-label prescribing in MS; at present they won't. At last, we will know ...
Jan 27, 2016 ... The issues in the disease areas discussed in this piece dovetail to some extent with our off-label prescribing initiative and the Barts-MS ...

CoI: multiple

Do nothing Lose teeth....Do Nothing Lose Brain..I can get falsies

Neurology is an odd subject because there are lots of conditions and not many treatments. 

Therefore you can have a bright bod that can diagnose you…but then they can say “sorry we can’t do anything about it”

In the bad old days this is what happened. 

But this should not be the case with MS. This is because there are an increasing number of treatments that may offer least if you have RRMS. 

So here’s a story.

Whats the diference between me and Brian Cox...We have the same Birthday Arghhhhhhhh!

He is a famous Scientist & I’m an infamous Scientist.

I have the worst teeth in the UK,   
He has all the teeth in the UK!   :-)

Anyway too many fizzy drinks as a kid, and not enough fluoride and the seeds were sown and has left me with a mouth full of metal (mainly mercury, the gold came from a bike accident) and more crowns than the Queen. 

Having resisted the temptation to do private dentistry, I have had NHS dental giving me a filling after filling and crown on filling and crown on crown something different each time. 

Are they saving my problems up so they get paid more on each visit rather than doing it all at once?  

Having not had an injected anaesthetic until I was eighteen and plenty of fillings…I know what it’s like when some German Dentist says “Is it Safe?” (Never seen" Marathon man with Dustbin Hoffman..get it and Squeal).

However, the old school of NHS dentists..doing good for society are dying off to be replaced by the “we haven’t got the time allocated. If it ain’t easy and quick…..just pull it out!”. 
So do I "pull-it" for a few quid or "pull-it" and go implant for a few thousand, cos the NHS does not do Implant. Should I go private and find someone to save the tooth? Privatisation by neglect.

This is fine it you can afford the privitisation many can't

Is this the way NHS medicine has gone and is going, and in cash strapped Britain are those expensive drugs going to get more and more rationed and appointments cut to nothing as we get Privatisation by neglect. We are already getting privatisation by the back door.

I wonder how many people get MS, and go to private medicine to get a diagnosis and maybe treatment?  

If you go private you can certainly jump the queue to see a doctor, but does it give you better treatment?

Simple answer depends on what you do and who you see!
Just cause its private don't mean its better advice, 
It is the same in the NHS...oh because its the same doctors!

P.S. ProfG doesn't do private before you start moaning.

So do your homework. 
Is the person an MS specialist? 
Do they treat softly softly? or 
Do they hit hard and early?
What is their treatment philosophy?

It would be interesting to see what hospitals prescribe. 
This could give us a feel to that answer by the number of CRAB drugs, Big gun drugs compared to their MS population...
Freedom of Information? Someone's been checking up on us. Wonder who?
I think at Barts Health, the Neuro team are in the Hard and Early mind set.

Do you and your neuro want to save your cognitive and neural reserve...because do nothing and it is tick, tick, ticking away.

Is your private neuro a great Guy or Gal with a nice personality that is going to tell you what you want to hear? 

You are doing alright now, so we can wait before we start those treatments because you are doing all right. See you in a few more months so I can line my pocket and do very little. 

Tick tock, Tick Tock

Oh damn.... I have done nothing and now my reserve has gone, 
I'm not doing alright...Do something! Do something!

Time to refer you on to some that treats and has to look after you
The big guns are out but the damage is done. 

Did I listen when I was told " you should brush your teeth properly and eat less sugar".

You should listen when I say "Don't waste that reserve by doing nothing" 

The Scandinavian data is very, very clear. Get on treatment and you do better, I hope that the day will emerge when you all get on a highly effective treatment ASAP and you do better still.

At least I can get falsies….if I do nothing and if I could do some private work, can maybe afford implants but saddly you can’t get a new brain......not yet at least

Read MSBrainHealth, if you are a practioner or a pwMS (Click here)

Better reported trials

Rikos D, Dardiotis E, Tsivgoulis G, Zintzaras E, Hadjigeorgiou GM.Reporting quality of randomized-controlled trials in multiple sclerosis from 2000 to 2015, based on CONSORT statement.
Mult Scler Relat Disord. 2016 Sep;9:135-139.BACKGROUND:

Randomized controlled trials (RCTs) are the best tool to evaluate the effectiveness of clinical interventions. The CONSORT (Consolidated Standards of Reporting Trials) statement is an evidence-based approach to improve the quality of RCTs reporting.
OBJECTIVE:To evaluate the reporting quality of published RCTs concerning multiple sclerosis from 2000 to 2015 according to a checklist based on the CONSORT statement.
METHODS:Electronic databases were searched for English-language RCTs involving patients with multiple sclerosis (MS). Trials were considered eligible when participants were randomly assigned to at least two medicinal treatment arms and included patients with MS. Quality of reporting was assessed using a 39-item questionnaire based on the CONSORT checklist. Articles were grouped in three 5-year periods and comparisons were made using descriptive statistics.
RESULTS AND CONCLUSION:The search identified 102 eligible articles for analysis. 20 of the 38 items of the checklist (52.6%) were addressed in 75% or more of the studies. Reporting of more than 75% of CONSORT items (>75% CONSORT compliance) was increased during the three five-year time periods from 2000 to 2015 (p<0.05).
CONCLUSIONS:Quality of reporting in RCTs focusing on multiple sclerosis is showing improvement over time, but still remains unsatisfactory. Further improvement of reporting is necessary to assess the validity of clinical research.

The CONSORT guidelines are a set of guidelines for things to report when you report a trial

You do a diagram explaining who go what

They try to explain

People are reporting more stuff and it is a marker of quality to indicate if the study was rigourous.

However trials still fail to report stuff, and some more than others;-0

Friday, 28 October 2016

Needles, haystacks, and primary progressive MS: big data debunks big headlines

Our understanding of how genes influence disease is better than ever, and increasing at an incredible rate. While some diseases like Huntington’s disease are caused by mutations in a single gene, most diseases are influenced by a huge number of variants across the genome. Multiple sclerosis, diabetes, and cardiovascular disease are examples of conditions which are not caused by a single gene problem, but nonetheless are influenced by various genetic risk ‘hotspots’ (also called loci).

A recent study blew this paradigm to bits by suggesting that certain cases of MS might be attributable to mutations in a single gene. Wang et al found that a mutation in the NR1H3 gene was present in 7 people with primary progressive MS from two separate families with a significant family history of the disease. This variant was present in 1 out of a further 2053 people with MS who they studied. They concluded that this mutation might be a cause of primary progressive MS in certain people.

This finding was big news – it had massive implications for both our understanding of MS pathogenesis and for the care of people with MS. What role could this gene have? How could its dysfunction be sufficient to cause such a complex disease? Why would it only cause PPMS and not RRMS? Did this mean that these diseases were even more distinct than we thought? In terms of real-life implications, did this mean that people with lots of affected family members should be routinely offered genetic testing, and even assisted reproduction?

But while revolutionary discoveries do happen, they are rare. The big players in international MS genetics sought to replicate Wang et al’s findings in bigger cohorts to check that their incredible result was genuine. The exome aggregation consortium (ExAC) has a database of pooled genetic data from over 60,000 people. They found that the ostensibly disease-causing variant in NR1H3 detected by Wang et al was present in 21 of their healthy controls (0.031%). This frequency is very similar to the frequency of 0.049% reported by Wang et al in their cohort of people with MS. If this variant does cause MS, you would expect its frequency to be much higher in the MS cohort. The possible explanations for similar frequencies between people with MS and controls are:
-                       1. That there is no association between this variant and disease risk, or
-                       2. That there is an association between this variant and disease risk but…
o   Some people in the control group have MS, or
o   The variant has a low penetrance (i.e. it confers an increased risk of disease, but does not always cause disease), or
o   The sample sizes are too small to detect a statistically significant difference.

The International MS genetics consortium (IMSGC) has another huge database of genetic information. They looked at data from 32000 people with MS and 36500 controls. The ostensibly disease-causing variant in NR1H3 was present in 31 people in each cohort. There was no association with disease risk or with disease sub-type.

This disagreement highlights a few important issues surrounding the way MS genetics research is both done and reported. It emphasises that reporting of these kinds of discoveries should be circumspect, and should clearly distinguish between fact and hypothesis. Second, it highlights the merits and weakness of two very different approaches to discovering disease-associated gene variants: big data vs small data. Big, international consortia like ExAC and IMSGC have vast swathes of genetic data at their disposal and can work in a data-driven way to discover associations. Family-based case-control studies, on the other hand, try to work the other way up, in a hypothesis-driven way. The problem is that rare variants with a low penetrance are incredibly difficult to detect and validate using either of these approaches. Broadly speaking, small case-control studies are likely to yield false positive results, as people who are closely related will share rare genetic variants that may or may not be associated with disease risk. Using larger, international cohorts is more likely to yield false negatives, as it is impossible to have up-to-date clinical information on tens of thousands of people, and so lots of people in the apparently healthy control group may have various undiagnosed or undocumented medical problems. This makes it tricky to detect small associations between risk variants and disease.

So neither massive genome-wide association studies nor small case-control studies are perfect for elucidating the genetics of MS. In this case, the evidence seems to support a lack of association between NR1H3 mutations and MS. However, this does not mean that the Wang et al paper is dishonest in any way – it merely reflects how difficult it is to show associations between rare gene variants and disease. There is an outside chance that future studies with more multiply-affected families might put this issue to bed. For now though, I don’t think we can say that NR1H3 mutations are a monogenic cause of MS in anyone.

CoI: none
The Paper
Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study, we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.