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Natural history of multiple sclerosis and a US view of treatment

 

Clinical bottom line

Multiple sclerosis is a complex chronic disease. Patients, carers and professionals want to be able to do something, but treatment is really difficult for all sorts of reasons. An understanding of the natural history can inform trial outcomes and clinical practice.


References

  1. GC Ebers. Natural history of multiple sclerosis. J Neurol Neurosurg Psychiatry 2001 71 Suppl II: ii16-ii19.
  2. DS Goodin et al. Disease modifying therapies in multiple sclerosis. Report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology and MS Council for Clinical Practice Guidelines. Neurology 2002 58: 169-178.

Both of these are important papers, both are required reading, and for neither can Bandolier provide more than a flavour of their content and impact. At first glance they are as different as chalk and cheese, yet both take hard-headed looks at evidence tempered with clinical experience.

Natural history of MS

Ebers [1] uses information derived from the London, Ontario, cohort of 1000 patients with MS followed up for 25 years. Some of the observations await full publication. The main comments were:

Table 1: Median time to disability (EDSS 3 and 6) according to first two year attack rate

  Years to reach

First two year attack rate

EDSS 3

EDSS 6

1

13

20

2

8

17

3

9

18

4

8

14

5 or more

3

7

Table 2: Relative risks for walking 100 metres only with aids, to a wheelchair and death

Indicator

Relative risk

Progressive course

6

Relapse rate year 1/year 2

3

Time between first and second attack

2

Polysymptomatic onset

2

Time from onset to EDSS 3

2

 

One of the most telling conclusions from studies on the natural history of MS was that neither the total number of attacks, nor the frequency before onset progression were related to the hard outcomes of time to cane, bed, or grave. Once the disease begins to develop a progressive phase, perhaps before clinical symptoms arise, the course of deterioration seems to be the same irrespective of the presence of prior or subsequent exacerbations or their frequency. This has implications for the likelihood that relapse suppression therapies will be effective when progression has begun.

Disease modifying therapies

The US practice guidelines [2] are detailed. They review (either in the paper or in additional Internet materia) all the relevant trials in great detail and try to put these into perspective, and there are some really sensible words about the relevance (or, rather, lack of relevance) of the level of statistical significance of 0.05, and they rather suggest that true significance is found only at the level of 0.01.

The trouble, as always, is outcomes. Some therapies, over a few years, appear to reduce attacks (exacerbations). Some reduce the burden of damage to the brain as seen by magnetic resonance imaging. Some therapies have no real evidence at all.

Comment

This is tough territory for most of us. But it's tough territory for the experts, too, who may not always agree on what works, or even if we could tell if something that truly was working was working (as opposed to those things that didn't work mistakenly showing up as if they did work).

There are real issues raised by Ebers about the conduct of future trials. Exacerbations may be helpful for prognosis, but not as surrogate markers of treatment efficacy. What about other markers, like MRI imaging? Where a disease like MS takes many years to run its course, in the absence of surrogate markers each trial will have to take 10-25 years. That's not practical. Therefore the absolute requirement for a reliable surrogate marker for efficacy trials.

These two papers will probably make your brain ache, but for those interested in understanding more, they are compelling reading.