Over the next few months I will blog about a series of MS articles that I consider very important; important enough to shift or even change the paradigm*.
Orton et al. Lancet Neurol. 2006 Nov;5(11):932-6.
This study showed that the female to male sex ratio by year of birth has been increasing for at least 50 years and now exceeds 3.2:1 in Canada.
“The incidence of MS is increasing; particularly in woman. Why?”
* Paradigm: a worldview underlying the theories and methodology of a particular scientific subject.
What do you think? Why?Could it be linked to things like earlier menarche, later childbirth, fewer children?
"MS articles that I consider very important; important enough to shift or even change the paradigm"Can I ask a simple question – what is the current paradigm which may shift or change? The articles I red refer to MS as 'an auto-immune disease', 'an inflammatory de-myelinating ideases' 'a disease of the white matter diease. Is this the current paradigm/s? If so how might this shift / change? What might it mean for treatment?With regard to woman possible reasons for increase in MS are: having children later, not having children, smoking, contraceptive pill, lack of Vit D.This is good news for researchers – lots of subjects to research. But, Vit D might not be the issue. Growth of overseas holidays since mind-1970s (lots of skin cancer cases as a result). Womens clothes provide much more exposure that 60-70 years ago. Not sure smoking is such a risk factor – smoking as huge in the 1930s + I know 3 women with MS who have never smoked. There must be 30 women smokers outside my office every coffee break, none appear to have MS. Perhaps having children earlier would be protective (and has been in the past). Read today that girls are starting periods much earlier (9-11 years old). Cases of early MS should provide best clues. Is suspect more women are getting glandular fever in mid-teens (from kissing boyfriends etc). Worse time to get it for MS risk. Perhaps 70 years ago they got it a children or later. So I think it's something to do with age of EBV infection – more getting it in mid-teens which increase chances of getting MS. Roll on your EBV trial!
The autoimmune hypothesis is based largely on experimental models of MS and the pathology. In my opinion the autoimmune hypothesis does not explain the epidemiology of MS; i.e. the pattern of disease in the world. It is clear that the MS animal models are not MS; they are more similar to a condition we call ADEM (acute disseminated encephalomyelitis). Regards the pathology, it is a mess. There is no consensus in the field; what is clear is that the inflammatory response may be secondary. More in this later.
The increase in of MS in females is partially explained by smoking! Apart from this there is little evidence pointing to other factors although vD needs further exploration. The cause to MS needs to explain the increase in incidence of MS in woman.
RE: "what is clear is that the inflammatory response may be secondary"Prof G, Would this possibly explain why interferons, which generally act on inflammation, only produce an up to 38% or so reduction in relapse rate – i.e. it's like treating a "symptom" rather than a cause? Or have I understood this wrong? (Sorry, I know you said there would be more on this later but I wanted to ask while it's in my head!)
Any theory to explain the increased rates of MS should also explain why more children are getting it.
Prof G,Thanks for your honesty about the mouse model. In my view this model has been the reason for the slow progress. It has provided researchers with a lazy option where cn keep tackling inflammation (and measuring the results) yet when the treatments developed from the mosue model are transferred to humans they only have minimal effect. "what is clear is that the inflammatory response may be secondary". Isn't this true with all inflamamtion i.e. it's a response to damage e.g. cutting my skin? Until the trigger for the inflammatory response is identified, we'll never get to a cure. Saying that, some of the anti-inflammatories such as Alemtuzumab do appear to have a massive impact on the disease by eradicating the inflamatory response. Perhaps they also impact on the underlying issue? B cells infected with EBV?
Re Why? I don't know, but I spend a lot of time thinking about it. Some of it is due to smoking and some due to vD; more in-door activity and use of make-up containing UV blockers.
Re: "Would this possibly explain why interferons, which generally act on inflammation, only produce an up to 38% ….": We don't really know how interferon works; it may work by being anti-viral. The modest reduction hides the observation that some patients respond better than others; in my opinion 20% are responders, 40% partial responders and 40% non-responders.
RE "in my opinion 20% are responders, 40% partial responders and 40% non-responders."How would someone on interferons know which one they are? (apart from having a relapse, of course).
Re "How would someone on interferons know which one they are? (apart from having a relapse, of course)."MRI monitoring! Over 4 years ~20% of PwMS on IFN-beta remain disease-activity free (no MRI-activity, relapses or disease-progression).
Surely it would make sense for all MS patients on interferons to be routinely given serial MRI scans then? Or is this too simplistic a view?
Re serial MRIs: yes, we have started to that more often. More on this later.
Can be not ban rmforall permanently?
Prof G – I thought I had read a report that there was a test to see if you would respond or not to interferon….http://f1000.com/1103645Or was I imaginging it? Does such a predictive test exist?
Re: "… I thought I had read a report that there was a test to see if you would respond or not to interferon…. http://f1000.com/1103645"Yes, we run this assay in our lab. It is a good screen for NABs! The data on using it as a predictive response marker needs validation, but I agree appears promising.
Anonymous(e)"Thanks for your honesty about the mouse model. In my view this model has been the reason for the slow progress. It has provided researchers with a lazy option where cn keep tackling inflammation (and measuring the results) yet when the treatments developed from the mosue model are transferred to humans they only have minimal effect."Point taken but there are maore than one EAE models. The one we work on certainly does seem to model what goes on in MS pretty convincingly, particularly in respect to pathology/symptoms and neurodegeneration which is now the main focus of our research to find treatments to slow degeneration/progression. This work has directly resulted in cannabis being licensed to treat spasticity in MSers for example.Also Tysabri and Gilenya to give a couple of examples arose as a result of MS animal models so we shouldn't throw the baby out with the bathwater just yet!What we need are better more realistic models and experimental design, many people who do EAE merely pay MS lip service and are only really interested in looking at immune mechanisms. We aren't and we don't.