What is epidemiology?
Epidemiology is essentially the study of disease in people. Epidemiology can answer seemingly straightforward questions, such as 'are men and women at a similar risk of developing MS?' The answer appears to be 'no'; women appear to be at a greater risk, with around 75% of people with MS being female. More complex questions might include 'what is the prognosis in MS?' or 'how will MS progress over time?' We need information from long-term natural history studies to answer these questions.
What do natural history studies tell us?
Natural history studies can tell us how MS progresses 'naturally' or 'normally' over a period of time, independent of any drugs that might modify the disease. These studies are designed to examine the natural course of the disease over many years and often try and identify characteristics that might be associated with the clinical course. Interestingly, despite the relatively high prevalence of MS, and the need for these studies, there are surprisingly few large, long-term studies investigating the natural course of MS.
How do these studies apply to me?
MS is a very variable disease and it is often said that no two people are the same. So it is always important to remember that the findings from most natural history studies are based on averages from large MS populations. Findings are often reported as the median time to a disability milestone, such as using a stick or wheelchair. The median time, by definition, is the estimated time taken for 50% of the MS population to reach that milestone. While useful, it is currently not possible to accurately predict an individual's course or prognosis.
Key findings (and myth busters) from the natural history studies in British Columbia
The study design
The study included 2837 people with MS followed for an average 20.1 years from across British Columbia on the west coast of Canada. We typically looked at the time it took for people to reach a score of 6 on the Expanded Disability Status Scale (EDSS), which ranges from 0 to 10 with a higher score indicating a higher level of disability. A score of 6 essentially means that a person requires a stick to walk 100m. There are many other factors which can be important in MS but are not well captured by EDSS. These might include quality of life, employment issues, fatigue, bladder problems, memory and so on.
Traditionally, MS natural history studies report disease progression from the first recognized symptoms of MS onwards. However, we also investigated the age at which people reached a certain disability milestone. This provided us with some interesting findings and allowed us to challenge the following myths:
Myth buster #1: Men do worse than women
A commonly held perception in MS has been that men fair worse than women, at least in terms of their disease progression. Our study showed that this is not necessarily true. We found that on average men and women with MS required a stick to walk at around the same age: 59 years old for men and 60 for women.
Myth buster #2: An older age at onset is worse than a younger age
Another commonly held belief was that the outcome for those older at MS onset was gloomy. We challenged this and found that it was not always true. We found that those who were older at onset of MS were on average still older when they required a stick to walk compared to their younger counterparts. When you combine this with the fact that these people have enjoyed a longer disease free period, then it seems that an older age at MS onset is not so bad after all.
Myth buster #3: Relapses drive the long-term disability progression
It has often been thought (or assumed) that relapses drive the long-term irreversible disability progression. So much so that many of the disease modifying drugs for MS primarily work by reducing relapses rates with the belief that this will automatically result in a beneficial effect on long-term disability outcomes. However, a number of different studies are showing that relapses might not be the main factor influencing long-term progression in MS.
In our study, we were able to look at over 11,700 relapses that occurred in 2,477 people with relapsing-onset MS (ie relapsing remitting or secondary progressive MS) over a mean follow-up of 20.6 years from onset of MS. It was quite challenging to analyze so much information spanning such a long period of time. However, by teaming up with some talented statisticians, we found that relapses tended to pose a transitory short-term risk rather than having substantial longterm consequences. However we did find that relapses occurring in the first five years from disease onset or in people under 25 seemed to have more of an impact than those occurring ten or more years after onset or in people over 35 years at MS onset.
We also looked separately at secondary progressive MS and found that relapses occurring during the progressive phase had little impact on future disease progression.
In summary, we found that relapses occurring later were likely to have a lesser impact than a relapse occurring earlier in the disease course. Age was also relevant, such that younger people might have a longer window during which relapses exhibit an elevated impact on disease progression. Our study was also novel because unlike other studies, we were able to look at the impact of relapses whenever they occurred. Other studies have typically only considered the very first few relapses a person ever experiences - right around the time of MS onset.
It is important to note that our study did not look at the impact or effect of the current disease modifying drugs. Consequently, our findings cannot be used to evaluate whether these drugs will have the much hoped for positive impact on long-term disease progression. That is a separate important question and a separate study altogether. However, our study does add to the body of literature which calls for drugs to be developed which move beyond just targeting inflammation and relapses in MS and focus more on factors thought to be associated with longterm disease progression, such as axonal degeneration.
All that said, it should also not be forgotten that the impact of a relapse can be devastating to the individual and that the unpredictable nature of relapses can cause much anxiety and anger.
Unexpected finding: disease progression appeared to be slower than in previous studies
We found that after 15 years from onset of MS, 21% of people had reached an EDSS of 6 or more, this increased to 69% after 40 years from onset. Also, 40 years after onset 22% were full-time wheelchair users. These findings appeared to indicate that disease progression was slower than in some previous natural history studies, but similar to other contemporary studies from places such as Olmsted County, USA and Lyon, France.
While these findings may give some comfort in that rapid disability progression is not inevitable, MS still remains a very variable disease. Some people will fair a lot better and some people will fair a lot worse. Why this is the case is unclear; research is ongoing by our group to try and uncover what drives these differences.
Written by Professor Helen Tremlett, University of British Columbia, for Open Door - May 2012