Wednesday, 24 August 2016

ClinicSpeak: risk benefit, risk harm analyses

Do we need a new way to communicate benefits and risks? #ClinicSpeak #MSBlog #MSResearch
'Lies, damned lies, and statistics', Mark Twain

"The analysis below looks at the benefit and risk of DMTs from a different statistical perspective, i.e. how many patients do you need to treat with DMT to benefit, or harm, one patient? 

NNTB = number-needed-to-treat to benefit
NNTH = number-needed-to-treat to harm
LHH = likelihood to be helped-or-harmed
AAR = annualized relapse rate
PPR-F = proportion of relapse-free patients
PP-F-CDPS3M = proportion of disability progression free patients confirmed or sustained at 3 months

When analysed like this it is remarkable how well subcutaneous interferon-beta-1a (Rebif) does compared to the newer DMTs. Of the newer agents Natalizumab fares the best. Is this a compelling way to present data to people with MS? If I presented data in this way I suspect many of my patients may select interferon-beta as their agent of choice. The problem with this analysis is that it classifies harm very broadly and not all 'harmful events' are necessarily serious or life threatening. For example, raised liver enzyme that are asymptomatic and reversible is very different to PML or a life-threatening infusion reaction. In addition, this type of analysis does not take into account individual patient characteristics (prognostic profile and baseline disease activity) nor does it take into account lifestyle issues (family planning, cosmetic issues, etc.). I may be wrong but I am not sure it will be easy to present the relative risks and benefits of each of these DMTs to patients in this way without getting bogged down in the small print about rare adverse events. However, I may be wrong. What do you think?"

Mendes et al. Benefit-Risk of Therapies for Relapsing-Remitting Multiple Sclerosis: Testing the Number Needed to Treat to Benefit (NNTB), Number Needed to Treat to Harm (NNTH) and the Likelihood to be Helped or Harmed (LHH): A Systematic Review and Meta-Analysis. CNS Drugs. 2016 Aug 18. [Epub]

OBJECTIVE: This study aimed to test the number needed to treat to benefit (NNTB) and to harm (NNTH), and the likelihood to be helped or harmed (LHH) when assessing benefits, risks, and benefit-risk ratios of disease-modifying treatments (DMTs) approved for relapsing-remitting multiple sclerosis (RRMS).

METHODS: In May 2016, we conducted a systematic review using the PubMed and Cochrane Central Register of Controlled Trials databases to identify phase III, randomized controlled trials with a duration of ≥2 years that assessed first-line (dimethyl fumarate [DMF], glatiramer acetate [GA], β-interferons [IFN], and teriflunomide) or second-line (alemtuzumab, fingolimod, and natalizumab) DMTs in patients with RRMS. Meta-analyses were performed to estimate relative risks (RRs) on annualized relapse rate (ARR), proportion of relapse-free patients (PPR-F), disability progression (PP-F-CDPS3M), and safety outcomes. NNTB and NNTH values were calculated applying RRs to control event rates. LHH was calculated as NNTH/NNTB ratio.

RESULTS: The lowest NNTBs on ARR, PPR-F, and PP-F-CDPS3M were found with IFN-β-1a-SC (NNTB 3, 95 % CI 2-4; NNTB 7, 95 % CI 4-18; NNTB 4, 95 % CI 3-7, respectively) and natalizumab (NNTB 2, 95 % CI 2-3; NNTB 4, 95 % CI 3-6; NNTB 9, 95 % CI 6-19, respectively). The lowest NNTH on adverse events leading to treatment discontinuation was found with IFN-β-1b (NNTH 14, 95 % 2-426) versus placebo; a protective effect was noted with alemtuzumab versus IFN-β-1a-SC (NNTB 22, 95 % 17-41). LHHs >1 were more frequent with IFN-β-1a-SC and natalizumab.

CONCLUSIONS: These metrics may be valuable for benefit-risk assessments, as they reflect baseline risks and are easily interpreted. Before making treatment decisions, clinicians must acknowledge that a higher RR reduction with drug A as compared with drug B (versus a common comparator in trial A and trial B, respectively) does not necessarily mean that the number of patients needed to be treated for one patient to encounter one additional outcome of interest over a defined period of time is lower with drug A than with drug B. Overall, IFN-β-1a-SC and natalizumab seem to have the most favourable benefit-risk ratios among first- and second-line DMTs, respectively.

CoI: multiple

Tuesday, 23 August 2016

The 3Rs of Animal research

If you work with animals in the European Union you have to think about and apply the 3Rs (reduction refinement and replacement) principles to animal research. 

MS research in animals is considered to be one of the more "severe" procedures that nasty researchers do to animals. Therefore the regulators watch out for things that may make the EAE procedure less severe.

Many years ago, the way to induce disease in beasties was to inject animals in the feet with nerve proteins mixed with an immune stimulator. This used to make an immune response in the feet of the animals and so it became swollen, and sensitive to pressure and so the poor animals could not walk properly, because it was painful.  I hear you say Uck!. I say Uck too!

So not surprisingly this procedure was banned.

This occurred in the UK many, many years ago. The EU was a bit slower when it came to banning this and some countries don't really give a stuff about ethics of use of animals and still do this practice.

I never accept any paper that does this, as it is unethical, and have urged other people to do the same. I was lambasted by some person for saying this. However, my retort was that there are ways to achieve sensitization without causing the pain to the animals, so time to change rather that doing nothing.

Some groups have been looking in how to avoid the injection reactions and one approach is 

Saul L, Besusso D, Mellanby RJ.LPS-matured CD11c+ bone marrow-derived dendritic cells can initiate autoimmune pathology with minimal injection site inflammation.Lab Anim. 2016 Aug 3. pii: 0023677216663584. [Epub ahead of print]

The pathogenesis of human autoimmune disorders is incompletely understood. This has led to the development of numerous mouse models in which the pathogenesis of autoimmunity can be probed and the efficacy of novel therapies can be tested. One of the most widely-used mouse models of autoimmunity is experimental autoimmune encephalomyelitis (EAE). To induce autoimmune pathology, mice are often immunized with an autoantigen alongside an adjuvant, typically complete Freund's adjuvant (CFA). Unfortunately, CFA causes significant inflammation at the site of administration. Despite the well-recognized complication of injection site inflammation, CFA with autoantigen immunization is widely used to induce central nervous system autoimmunity. We performed a literature review which allowed us to estimate that over 10,000 mice were immunized with CFA in published EAE studies in 2013. In this study, we demonstrated that subcutaneously administered myelin basic protein (MBP)-pulsed CD11c+ bone marrow-derived dendritic cells (BMDC) were as effective at inducing EAE as subcutaneously administered MBP plus CFA. Importantly, we also discovered that the CD11c+ BMDC caused significantly less injection site inflammation than MBP plus CFA immunization. This study demonstrated that the use of CD11c+ BMDC can enable the development of autopathogenic T-cells to be studied in vivo without the unwanted side-effects of long-lasting injection site inflammation. This model represents a significant refinement to existing EAE models and may lead to the improvement of the welfare of experimental mice used to study the development of autoimmunity in vivo.

So in this study they look at C57BL/10.PLx C57BL/6 mice which are not that susceptible to EAE and show that if you transfer dendritic cells (an immune stimulator immune cell) that have been bound to myelin basic protein that you can induce disease that is as good as the EAE induced by injecting mice with a nasty immune stimulating adjuvant. 

The Home Office in the UK, waters its lips and sees a way to reduce the severity of animal research because the study is published in an animal care rag.  

However, the problem is that most animal strains do not respond to myelin basic protein and there are no transgenic animals for alll antigens and for all strains and species, to do all the background work

Importnantly, you can also induce disease using myelin specific T cells, rather than doing the procedures done in the current study.

Importantly, nobody in Europe injects into the legs and feet anymore or nobody should be injecting into feet, so the revelation is so much not a revelation but a misnoma. 

However this is never mentioned in the manuscript. The nasty adjuvant is injected under the skin in the flank and so does not cause the distress that this manuscript aims to suggest.

Most people now inject the immune stimulator under loose skin in the flank. It is certainly less painful there and one may ask if it is painful at all? Certainly the injections site do not appear painful to touch in mice, based on pain faces and the lack of appreciable responses to the injection sites being touched.

In this study they first inject normal animals with T cells that respond to the myelin antigen and then they inject the animals with antigen on dendritic cells.

They get good disease, but the injection site reaction is better compared to the nasty adjuvant, which is never now used in the way reported.

Now I am waiting for the Home office Inspector to come and say why not use this 3Rs approach, and we will spend weeks and thousands investigating this.

Stop beating around the bush in aggressive MS!

Neuropsychiatr Dis Treat. 2016 Aug 1;12:1907-12. doi: 10.2147/NDT.S111885. eCollection 2016.

A study of patients with aggressive multiple sclerosis at disease onset.

Kaunzner UW, Kumar G, Askin G, Gauthier SA, Nealon NN, Vartanian T, Perumal JS.



Identify aggressive onset multiple sclerosis (AOMS) and describe its clinical course.


AOMS patients were identified from a multiple sclerosis (MS) database based on a set of criteria. The subsequent clinical course of AOMS patients was then reviewed with the goal of potentially identifying the best approaches to manage these patients.


Fifty-eight of 783 (7.4%) patients in the MS database met the criteria for AOMS, and 43 patients who had complete data for the duration of their follow-up were included in the subsequent analysis. The mean duration of the follow-up was 54 months. Thirty-five patients (81%) were started on a conventional first-line agent (injectable therapies for MS). Only two of these 35 patients (5.7%) had no evidence of disease activity. Twenty-two of 35 patients suffering from refractory disease were switched to a more aggressive treatment (natalizumab, rituximab, alemtuzumab, cyclophosphamide). Eight patients were started on aggressive treatment as their initial therapy, and seven of these eight (87.5%) patients showed no evidence of disease activity.


With recognition of the crucial significance of early optimal treatment during the potential window of opportunity for best long-term outcomes, we describe AOMS within 1 year of disease onset and discuss possible treatment considerations for these patients.

In general terms it's difficult to predict the course of MS at onset, it's retrospectively made, but at the same time disastrous if you get it wrong.

Evidence points to roughly 9% of MS being of the aggressive variety and can progress to requiring a walking stick within 5 years of first symptom onset (Gholipour T et al. Demographic and clinical characteristics of malignant multiple sclerosis. Neurology. 2011;76(23):1996–2001). There is then only a small window of opportunity to modify the course of the disease.

Work by Kaunzer et al. just adds to what we already know from previous database studies. They demonstrate that only 6% of those with aggressive disease started on first line treatment (i.e. injectables such as the interferons or glatiramer acetate) have no evidence of disease activity (NEDA). This is compared to 88% who are put on second line treatment (i.e. natalizumab, rituximab, alemtuzumab, cyclophosphamide). Therefore, we are potentially losing valuable time by doing escalation therapy in those with aggressive MS!

So, how do we pick out those who would have a poor long-term outcome? Answer - neurofilament analysis; and how do you prevent poor outcome in aggressive disease? Answer - don't put them on first-line treatment, but move directly to second line treatment.

Monday, 22 August 2016

ClinicSpeak: social networking for MSers

What are your thoughts on using socially media for interacting with other MSers? #ClinicSpeak #MSBlog

"Do you use social networking sites to manage your MS? There is an interesting news piece in last week's BMJ looking into some of the issues around social networking and the use of social media to self-manage medical conditions (please read the article). In era of when knowledge has been democratised this comes as no surprise to me. What is worrying is that some of these social media groups have a 'them-and-us' philosophy and have been deliberately set-up in competition to the medical profession. Some of these sites support 'unproven therapies' and 'pseudoscience' and tend to be unmoderated. Clearly a balance needs to be maintained between you the person with MS and the medical profession and the best patient-run social networking sites partner with the medical profession. At the end of the day the aims and ambitions of patient groups and the medical profession should be aligned. Surely we have the same objectives"

"Do you belong to a social networking sites dedicated to MS? What do you think of them? Would you recommend them to other people with MS? Do you think healthcare professionals should join? Do you think they should be open or closed networks? What about advertising on these sites; is it overt or covert? Are there ways to vet members to make sure they are real people rather than some avatar to push an agenda? How do you deal with bullying? What happens if someone, or a small group, dominate the site and  take it over to push one issue?"

"You could argue that our Blog is a social networking site, but we took the decision to remove the membership app and simply leave it as open resource. May be we need to change that policy?"

Stephen Armstrong. Social networking for patients. BMJ 2016;354:i4201


..... Is social media saving lives? Or is it spreading poor information and damaging private confidentiality?....

..... Patient groups began as small gatherings for people with the same condition in the same area to meet each other. They then evolved into highly professional operations, with often national or international organisations doing everything from connecting patients to raising public awareness of conditions and lobbying governments on behalf of their members.....

...... Today social media have become invaluable for many patients, especially those with unusual or rare conditions.....

...... Facebook, the world’s leading social media network, with some 1.09 billion daily active users radically changed the structure and content of online support groups by enabling anyone to set up a group, usually without expert moderators......

..... The BMJ contacted Facebook to ask how many patient groups the company hosted, what sort of oversight there was for patient groups, and whether Facebook worked with drug companies on advertising or data gathering. A company spokesperson refused to comment, offering only a link to the general Facebook groups information page, which contains no data.....

...... When setting up a Facebook group, founders have three privacy options—public, closed, and secret. Anyone can see or join a public group, whereas they have to ask to join or be invited to join a closed group. People can only join a secret group if they are invited by an existing member.....

..... As a result of information exchanges between members of the group and physicians at the Jefferson Headache Center in Philadelphia, the centre has begun trials of ketamine infusion therapy for cluster headaches with members of the support group......

..... he set out a series of rules for participation in the private group, “including a ban on pseudoscience, reliance on trustworthy advice backed by medical science, and intolerance for bullying.” .....

..... Some US patients disagree with a ban on treatment suggestions that aren’t recommended by healthcare professionals. “If you are seriously ill, you cannot assume that your doctor is an expert who keeps up with current research,” argues Liz Logan, from New York, whose husband was diagnosed with Parkinson’s disease two years ago. “You have to do your own research. You probably will have to change doctors more than once, and social media is where you get information from people most invested in getting better: other patients. I know far more about Parkinson’s at this point than the first idiot neurologist who dismissed the possibility of my husband having Parkinson’s, resulting in two miserable years before diagnosis by a movement disorders specialist, which I wouldn’t have known was the right kind of neurologist without social media.”......

...... The risk of social media being used for promotion of dangerous or unsuitable remedies is a big concern for healthcare professionals.....

..... “Peer support between patients can be hugely beneficial for their wellbeing during an illness, or when in recovery, and social media can provide a convenient, accessible platform for this,” explains Maureen Baker, chair of the Royal College of GPs. “However, while we encourage patients to take an active interest in their health, using online support groups, and other tools to share medical ‘tips’ could result in them receiving misleading, superfluous, or incorrect information, so these forums should not be seen as a replacement for proper medical care.”......

...... “there is no guarantee that a closed Facebook group is actually 100% private.....

...... This lack of control coupled with Europe-wide regulations codified in the United Kingdom under the Association of the British Pharmaceutical Industry’s code of practice mean that drug companies outside the US and New Zealand are steering clear of all Facebook support groups.....

....... Few physicians are currently using social media to talk to patients—a practice that the General Medical Council suggests be treated cautiously......

...... For some patients, the idea of any healthcare professionals taking part in patient groups is an anathema; many see them as private patient spaces where people can vent frustrations about treatment.....

Sunday, 21 August 2016

ClinicSpeak: how fragile is your optimism?

Do you think we need a simple course to teach parents about MS? #MSBlog #MSResearch #ClinicSpeak

"Is the term 'fragile optimism'  something we should be proud of using? The study below looks at the uncertainty that exists around childhood MS and how parents deal with it. The coping strategies parents use to deal with are variable including 'denial' or 'selective attention', i.e. avoid sources of information and support that threatens 'fragile optimism'. With the emergence of more effective DMTs the prognosis of MS is so much better, at least in the short and intermediate term, than it was two decades ago. In addition, the innovation machine rolls on and we have to assume things will get even better in the future. For example, the emergence of DMTs for progressive MS. Therefore it is important for healthcare professionals (HCPs) to spread hope, but to do it in a way that is realistic and not in away that creates unrealistic expectations. I personally don't believe in pulling punches, which is why we try and tell it how it is. At the same time it is important to try and layer the information and allow pwMS. and their parents, to receive information when they are ready to receive it. When I develop the next version of our tube map it is going to fold out, so when you initially see the map, the later stages of MS will be hidden away. I like to use the peeling onion analogy to describe the layering of information; if you peel an onion too quickly you are going to cry."

"Although this study refers to children with MS, parents never stop worrying, taking responsibility and caring for their children even when they are adults. As a parent myself I totally understand this; it is part of the unconditional love you have for your children. The other day a very concerned mother phoned me for advice about her 30 year daughter; she was concerned that her daughter was not being managed proactively enough and wanted advice. The daughter was not interested in reading about MS or the latest developments in the field, but the mother was. The mother was an active reader of our blog and wanted advice about her daughters treatment and in particular family planning. As I was not responsible for her daughter all I could do was give generic advice. It was clear the mother was very anxious about her daughter and wanted the best outcome."

"What about the other way round? What about the anxieties children have for a parent with MS? This is one of the reasons we launched our 'Digesting Science' programme to teach young children about MS. The course targets children between 6-12 years of age. I think we may need to extend this programme for teenagers. What do you think? I have so many stories to tell about teenage carers, i.e. children who have taken on the role of looking after and caring for a disabled parent with MS. This post may be all over the place, but it does highlight a problem in the field in relation to education and how we should be providing information."

Hinton & Kirk. Living with uncertainty and hope: A qualitative study exploring parents' experiences of living with childhood multiple sclerosis. Chronic Illn. 2016 Aug 17. pii: 1742395316664959. [Epub]

BACKGROUND: There is growing recognition that multiple sclerosis is a possible, albeit uncommon, diagnosis in childhood. However, very little is known about the experiences of families living with childhood multiple sclerosis and this is the first study to explore this in depth.

OBJECTIVE: Our objective was to explore the experiences of parents of children with multiple sclerosis.

METHODS: Qualitative in-depth interviews with 31 parents using a grounded theory approach were conducted. Parents were sampled and recruited via health service and voluntary sector organisations in the United Kingdom.

RESULTS: Parents' accounts of life with childhood multiple sclerosis were dominated by feelings of uncertainty associated with four sources; diagnostic uncertainty, daily uncertainty, interaction uncertainty and future uncertainty. Parents attempted to manage these uncertainties using specific strategies, which could in turn create further uncertainties about their child's illness. However, over time, ongoing uncertainty appeared to give parents hope for their child's future with multiple sclerosis.

CONCLUSION: Illness-related uncertainties appear to play a role in generating hope among parents of a child with multiple sclerosis. However, this may lead parents to avoid sources of information and support that threatens their fragile optimism. Professionals need to be sensitive to the role hope plays in supporting parental coping with childhood multiple sclerosis.