Friday, 18 August 2017

Quality of life is better on effective DMT

Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis.
Dayo Afolabi, Christo Albor, Lukasz Zalewski, Dan R Altmann, David Baker
and Klaus Schmierer. Mult Scler J, August 17, 2017

Abstract
Background: A number of elements of the pivotal ‘cladribine tablets treating multiple sclerosis orally’ (CLARITY) trial have remained unpublished.
Objective: To report the impact of cladribine on health-related quality of life (QoL) in people with relapsing multiple sclerosis (pwRMS).
Methods: QoL data from the phase III trial of two different doses (3.5 and 5.25 mg/kg) of oral cladribine in pwRMS were acquired from the European Medicines Agency through Freedom of Information. Spearman’s rank correlation was used to analyse the relationship between baseline QoL scores and baseline
Expanded Disability Status Scale (EDSS) scores. Responses of the Euro Quality of Life 5 Dimensions (EQ-5D) and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaires were compared between treatment and control groups using univariate analyses of covariance.
Results: In total, n = 5148 EQ-5D responses and n = 894 MSQOL-54 physical, mental health and dimension scores were extracted. Baseline EQ-5D indices correlated with EDSS scores. After 2 years, pwRMS taking 3.5 (p = .001) and 5.25 mg/kg (p = .022) reported significantly improved EQ-5D index scores compared with placebo. Positive, yet non-significant, differences were detected in MSQOL-54 scores between cladribine and placebo.
Conclusion: Analysis of the CLARITY dataset suggests that, over and above its established clinical efficacy, cladribine leads to improved QoL over 96 weeks. ClinicalTrials.gov identifier: NCT00213135.

We maintained our interest in cladribine even after it had been rejected by the EMA in 2011, because its efficacy was impressive, and its adverse effects comparatively minor. We confirmed that the cancer risk of cladribine in pwMS is no different when compared to licensed DMT, and subsequently started using the drug in a select group of pwMS.

Here's further output from our work on cladribine, an analysis of the quality of life data collected during the largest ever trial of the compound in pwMS. Though the data was available since 2010 nobody cared to analyse and publish them, so we did it after receiving the CLARITY dataset from the EMA through freedom of information, and with zero industry support.

Congratulations to Dayo Afolabi BSc, medical student at Cambridge University and Christo Albor PhD, epidemiologist and currently junior doctor at Barts Health NHS Trust for their excellent work, supported by QMUL IT (Lukasz Zalewski) and Dan Altmann, statistician at QMUL, UCL and The London School for Hygiene & Tropical Medicine.

The abstract summarises the results well, however reading the paper you will learn more about various aspects of this project and the potential of the drug. 

Available open access shortly.


CoI: Multiple, however none related to this paper.

The mechanism is more important than the ethics. EAE experiments

Arima Y, Ohki T, Nishikawa N, Higuchi K, Ota M, Tanaka Y, Nio-Kobayashi J, Elfeky M, Sakai R, Mori Y, Kawamoto T, Stofkova A, Sakashita Y, Morimoto Y, Kuwatani M, Iwanaga T, Yoshioka Y, Sakamoto N, Yoshimura A, Takiguchi M, Sakoda S, Prinz M, Kamimura D, Murakami M.Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit.Elife. 2017 Aug 15;6. pii: e25517. doi: 10.7554/eLife.25517

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.


This is the type of post ,where I get called arrogant because I dare to say something not good about science.

However I have to say "not in my name" in public.

As part of public engagement in science, we need to talk about animal experiments. 

I have signed up to this and the UK Government want scientists to be more open about animal studies. 

We can be fluffy and say every thing is amazing but in reality some of it isn't. You know this.

Yes animal experiments are unpleasant, but they can lead to new understanding. 

However, the question at what cost to the animals?

These days virtually all animal experiments have to go through ethical review panels, but sometimes what they support horrifies me. Maybe in the UK, we care too much about our furry friends or maybe people elsewhere don't care enough!

This is a good example. I comment on it so when people click on the altmetrics to this paper, you will come to this blog post. 

This research is being done for people with MS. 
However, do you feel it is relevant to your disease? 

The opening statement says "To examine the impact of stress conditions in a transfer EAE model, we first employed a sleep disorder model, in which continuous stress is imposed on mice on a free rotation wheel for 2 days by the perpetual avoidance of water". They do this by filling the cage with water and make they run on a wheel.

Surely this is torture. Which ethical review panel would think this is OK. What is worse, is when when they transfer cells into the animals it causes death. 

Is it OK to kill animals, when there can be endpoints before this. 

I would have to say no, this does not have 3Rs merit.

The animals were dying and they had bloody stools which surely could have been used as an endpoint at the very least.

The authors say that changes in the circulation in the brain affect intestinal activity and further say vagal nerve activation is involved in the development of the severe gastrointestinal failure triggered by brain micro-inflammation.

However, there is no mention that vagal nerve stimulation in humans has been reported to inhibit autoimmunity so in complete contrast to the human potential reality 

The ARRIVE guidelines by the NC3Rs  asks for the translational value of the study. 

Is there any?

First thing. In the study they applied parametric statistics to non-parametric data and so the experiment is fatally flawed. It is underpowered as there are not enough animals in a group (such as n = 3) to give any real statistical meaning. 

No wonder the three referees remained anonymous.

Thursday, 17 August 2017

Are MS drugs a waste of time......for progressive MS

Lorscheider J, Jokubaitis VG, Spelman T, Izquierdo G, Lugaresi A, Havrdova E, Horakova D, Trojano M, Duquette P, Girard M, Prat A, Grand'Maison F, Grammond P, Pucci E, Boz C, Sola P, Ferraro D, Spitaleri D, Lechner-Scott J, Terzi M, Van Pesch V, Iuliano G, Bergamaschi R, Ramo-Tello C, Granella F, Oreja-Guevara C, Butzkueven H, Kalincik T; MSBase Study Group. Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS. Neurology. 2017 Aug 9. pii: 10.1212/WNL.0000000000004330. doi: 10.1212/WNL.0000000000004330. [Epub ahead of print]

OBJECTIVE: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).
METHODS: Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.
RESULTS: Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7-1.1, p = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4-1.1, p = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, p = 0.79), or change in disability burden (area under the EDSS-time curve, β = -0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results.
CONCLUSIONS: Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.

I'm back....(What! you didn't notice that I've not been around and that there were slow responses).

I been in the Third World.....................of internet access, with zero email and essentially no access to the web...with even the paid-for "high speed" (yeah right) net.


Where?..........yep you got it........in the USA. 

In a number of National Parks the internet access has been woeful

Who would have thought that a gas (petrol) station in the middle of nowhere, would turn out to be a cyber oasis compared to the dearth for International Travellers.


However, I saw an amazing example of "thinkhand" and why giving access to people in wheelchairs access to treatment to save upper limb function is something we really must do. 


If you look at the picture above you can see on the right of the top of the waterfall there is a platform, which is full of people watching the waterfall. This waterfall is 308 feet (94 metres), where the top is some 600 feet down the canyon.  


I was passed on the way up the canyon, by a hand-driven wheelchair, OK with some help from their partner and encouragement by the kids. They were at the top looking down by the time I got there. Why shouldn't we stop deterioration of loss of hand function.


Anyway more news from the MSBase people and they haven't done a post on this one but it is something the Pharmaceutical nihilists will be shouting out loud about why it is OK to do nothing. This study suggests that use of DMT does not influence the course of secondary progressive MS if used after onset.


ProfG will be sitting on a beach somewhere in the USA pondering what this means for his therapeutic lag idea, but more importantly what it could mean if hand function was the main outcome. 


The take home message of this story is more reason not to use DMT in SPMS. Which is not what we have been saying.

There were about 25% in the untreated ground that had MRI lesions and about 20% in the treated group (so not effectively treated)

However, you can see the (median) follow up was for only two years although it was longer for many people, and when the ASCEND trial of natalizumab looked  and there was no change in EDSS over two years. However if the trial was followed for 3 years then they was an influence. So the follow up in this study may not have been long-enough for the therapeutic lag effect to show itself, (if it existed, which it didn't when it was looked for).

Likewise, I really would like to see if you look at the effect of only highly-effective DMT/HSCT use and subsequent course of MS. Yes, I know that use of CRAB drugs is the real life situation, but the picture is going to be muddied if you include use of CRAB drugs. 

We know progression will often occur because this has already been seen with alemtuzumab and HSCT, but will the rate of decline change? 

H. Pylori: good, bad, ugly, or not quite sure?

Many people think that MS is triggered by exposure to infectious agents in our environment. The most well-known putative trigger is EBV, but there has also been debate surrounding the role of H. Pylori, an enteric pathogen better known for its role in causing peptic ulcers. Epidemiological evidence has been conflicting on whether H. Pylori infection protects against MS, increases the risk of MS, or has no association at all.

A nice new study systematically examined the amounts of anti-H. Pylori antibody in a big cohort of 139 pwMS, 39 pwParkinson's Disease, 21 pwAlzheimer's Disease, and 68 controls without any neurological diseases. The key advantage of this study is that they looked at antibodies against a wide range of H. Pylori antigens, the fragments of the bug exposed to the immune system.

The key findings were:
- Anti-flagellin antibodies were less common in MS than controls. 
- Anti-VacA antibodies were more common in SPMS than controls.
- Anti-p54, anti-p29-UreA and anti-p26 correlated with EDSS.
- Anti-p41, p54-flagellin, p29-UreA, p67-FSH, and p120-CagA were less common in RRMS than control.
- Anti-p26 and anti-p17 correlated with number of relapses.

This is big news - it demonstrates that the antibody response to H. Pylori infection differs between pwMS and controls, between pwRRMS and pwSPMS, and is correlated with disease activity.

How do we interpret this?

There are a few possible explanations. My initial thoughts:
- Exposure to H. Pylori is protective against MS
- Exposure to VacA (a secreted bacterial protein) increases the risk of SPMS
- An underlying problem with immune regulation in people who are at-risk of developing MS affects the immune response to H. Pylori (this could be genetic e.g. MHC polymorphisms, environmental e.g. a consequence of EBV infection, etc...)
- DMTs affect the immune response to H. Pylori
- A combination of some/all of the above!

These don't explain why higher titres of certain anti-H. Pylori antibodies would correlate with disability and relapses. 

In short I'm not quite sure what these data mean but they are certainly interesting. If anti-H. pylori antibodies are protective then vaccination might even be on the cards as a preventative strategy.

Abstract
To assess whether Helicobacter pylori (Hp) antibody (ab) reactivity against individual Hp antigens is pathogenetically relevant to multiple sclerosis (MS), we systematically investigated prevalence and clinical significance of abs against 14 immunodominant and subdominant Hp antigens by ELISA and immunoblotting in 139 consecutive MS patients with relapsing-remitting (RRMS, n = 102) or secondary progressive (SPMS, n = 37). Sera from 39 patients with Parkinson’s disease (PD), 21 with Alzheimer’s disease (ALZ) and 68 healthy controls (HCs), were also tested. Anti-flagellin (18.3%) and anti-p41 (25.0%) abs in MS were less frequent than in HCs (39.4%, 48.5%, respectively). Abs against 5 of the 14 antigens were less frequent in RRMS than HCs, including p41, p54-flagellin, p29-UreA, p67-FSH, and p120-CagA. Anti-VacA abs were more frequent in SPMS than in HCs (42.1 vs 12.1%, p = 0.019). Anti-p54, anti-p29-UreA and anti-p26 correlated with extended disability status scale (EDSS) (p = 0.017, p = 0.005, p = 0.002, respectively). Anti-p26 and anti-p17 correlated with the number of relapses (p = 0.037 and p = 0.047, respectively). This is the first comprehensive analysis of ab reactivities against most Hp antigens in MS patients. Ab responses differ between MS and HCs and between RRMS and SPMS, being more prevalent in SPMS than RRMS, thus suggesting an association between anti-Hp and the former type of MS.

Wednesday, 16 August 2017

Older people do less well



Guillemin F, Baumann C, Epstein J, Kerschen P, Garot T, Mathey G, Debouverie M; LORSEP Group.Older Age at Multiple Sclerosis Onset Is an Independent Factor of Poor Prognosis: A Population-Based Cohort Study.Neuroepidemiology. 2017 Aug 10;48(3-4):179-187.
BACKGROUND:Late-onset multiple sclerosis (LOMS) frequently features a primary progressive (PP) course, strongly predicting severe disability. In this population-based cohort, we estimated the prognostic role of age at multiple sclerosis (MS) onset, independent of PP course, on disability progression.
METHODS:The association of age at disease onset (adult, <50 years [AOMS], vs. late, ≥50 years [LOMS]) and time to Expanded Disability Status Scale (EDSS) score 4 and 6 was estimated by Cox regression modelling.
RESULTS:Among 3,597 patients, 245 had LOMS. Relapsing-remitting (RR) disease was less frequent with LOMS than AOMS (51.8 vs. 90.8%, p < 0.0001). PP course, LOMS and male gender predicted short time to EDSS 4 and 6. Worse outcome with LOMS (time to EDSS 4 and 6, HR 2.0 [95% CI 1.7-2.4] and 2.3 [1.9-2.9]) was independent of PP course or male gender. LOMS had greater impact on RR than PP disease (time to EDSS 4 and 6, HR 3.1 [2.3-4.0] and 4.0 [2.9-5.6]). Only LOMS predicted time from EDSS 4 to 6 (p < 0.0001).
CONCLUSIONS:Late onset MS was strongly associated with poor prognosis, independent of initial disease course, in predicting the disability progression along time.


ProfG has often said that "Age Matters" especially when it relates to brain health. As we age our repair and protective capabilities wane. This study supports this view and the the older you are there less well you do. However this is at a population level and there will be older people who do very well and younger people who do very badly.