Wednesday, 20 August 2014

Imperial College MS Study Day 26th September 2014

Invitation to attend the Imperial College MS Study Day 26th September 2014. #MSBlog #MSResearch

"The following is an invitation to attend the Imperial College MS Study Day on the 26th September 2014. You need to register online if you want to attend."

Switching therapies: considerations around alemtuzumab

Are you a switcher? There are several issues that need to be resolved regarding safety. #MSBlog #MSResearch

"The following are my slides from a talk I gave last night at the SINS meeting in Santiago, Chile. The focus of the talk was an informal discussion of the issues and considerations in relation to switching MSers from one DMT to alemtuzumab. As you are aware from previous posts on the blog that there are many issues that still need to be resolved by doing studies to assess the safety and timing of starting alemtuzumab. My biggest concerns relate to switching patients at high-risk of PML from natalizumab to alemtuzumab and switching patients who have been on fingolimod for a long period of time to alemtuzumab."




CoI: multiple

Back to the Stone Age

Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, Waubant E, Polman CH.Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014. pii: 10.1212/WNL.0000000000000560. [Epub ahead of print] 

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression.

The original MS clinical descriptions were published in 1996, and provided the 4 MS clinical courses which we currently use -
  • Relapsing- remitting (RRMS)
  • Secondary progressive (SPMS)
  • Primary progressive (PPMS)
  • Progressive relapsing (PRMS)
The new recommendations now suggest that modify this to active or not active based on MRI disease activity -
  • Clinically isolated syndrome - Active/Not active
  • RRMS - Active/Not active
  • Progressive disease - Active and with progression/Active but without progression/Not active but with progression/Not active and without progression

Not only is this a mouthful - consultations littered with active but lets see if it's progressive...reading the recommendations was somewhat of an anti-climax (imagine yourself going to the Miss World contest but discovering at the last minute that its the Miss Essex contest!). 

In the words of the authors: "When proposed [back in 1996], it was noted that these clinical course descriptors were based on subjective views of MS experts and lacked objective biological support... [But] We recognise that there (may) be other markers of disease activity, but there is insufficient evidence for including them at this time". 

If truth be known, we now know so much about MS that it's the clinical descriptors that are superfluous! MS is an autoimmune disease affecting the nervous system - there I've said it.

Proponents who lost out in this revision were:
  • MRI (atrophy, MTR, DTI etc)
  • All body fluid biomarkers
  • Optical coherence tomography (OCT)
  • Patient-reported outcomes
Imagine what precedent would be set if these had been included ???

Although, in a bizarre way there may be light at the end of the tunnel/loophole, which is by deciding to use disease activity as a descriptor more patients maybe eligible for treatment! - take that NICE!!

Low Testicular functionincreases your risk of MS

Pakpoor J, Goldacre R, Schmierer K, Giovannoni G, Goldacre MJ.
Testicular hypofunction and multiple sclerosis risk: A record-linkage study. Ann Neurol. 2014. doi: 10.1002/ana.24250. [Epub ahead of print]

The influence of gonadal hormones on multiple sclerosis is not well characterised and has thus far been investigated primarily in animal models or as a proposed therapeutic approach. We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and multiple sclerosis risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011. We report a strong positive association between testicular hypofunction and subsequent multiple sclerosis, rate ratio 4.62 (95% confidence interval 2.3-8.24, p<0.0001). Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females.

It has been shown in EAE that sex hormones can influence susceptibility to autoimmunity and it is very clear that sex is a risk factor for MS,with a ratio of about 2:1-5:1 females to males affected. The ProfG put on his mining hat and went off to Oxford to search health records...or should I say Julia did the slog and looked at the relationship between low testis function, which probably means low sperm count, that may relate to lower balance of female to male sex hormones.  It was found that you were about 4-5 times more likely to get MS if you had low testicular function. It does not mean that if you are a male with MS that you have a low sperm count. 
 
Does this equate to actual testosterone levels. Seems like a new project....surely the US military measure testosterone of their boys so should be simple to do. However even simplery stick "testosterone and multiple sclerosis" and pubmed.


OBJECTIVE: To assess the prevalence and clinical associations of hypogonadism in men with MS.
METHODS: Male patients, aged 18-65 years, with relapsing-remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually.
RESULTS:
Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone. Their low testosterone levels and testosterone:estradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012).
CONCLUSIONS: Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes. 

See ProfGs comments on this one. Proving cause and effect is an issue


CoI: Study performed by TeamG

Testosterone protects you from getting MS

How does low testosterone increase your risk of getting MS? #MSBlog #MSResearch

"There are many reasons why MS may be more common in females than males. The following epidemiological study suggests high testosterone levels in males may protect you from getting MS. How? To be honest I haven't a clue. What this study shows that men with testicular hypofunction have a much greater risk of developing MS than normal males. This observation will need to be explained when we finally pin down the cause of MS. I sincerely hope that countries such as Sweden and Denmark, with national databases, try and reproduce this observation; it may be a lot more important than we realise."


Epub: Pakpoor et al. Testicular hypofunction and multiple sclerosis risk: A record-linkage study. Ann Neurol. 2014 Aug 18. doi: 10.1002/ana.24250.

Background: The influence of gonadal hormones on multiple sclerosis is not well characterised and has thus far been investigated primarily in animal models or as a proposed therapeutic approach.

Methods: We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and multiple sclerosis risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011. 

Results: We report a strong positive association between testicular hypofunction and subsequent multiple sclerosis, rate ratio 4.62 (95% confidence interval 2.3-8.24, p<0.0001). 

Conclusion: Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females. 

CoI: Julia Pakpoor is part of our group