Part 1 of 2
January 9, 2004
Amit Bar-Or, M.D.
This Viewpoint series will examine whether treating MS patients with medications that decrease the number of relapses is likely to translate into less long-term disability. It would seem obvious that decreasing the frequency of relapses would be a good thing for patients with MS. For one, relapses can be very disruptive and, so - the fewer the better. However, an issue that has been controversial for some time relates to the relationship between relapses and subsequent disability. Does the presence of more relapses early in the course of MS translate into more disability in the future? It is well appreciated that over time patients can develop progressive neurological disability without relapses (for example, individuals with primary progressive, or secondary progressive MS). This points to a more complex relationship between relapses and disability. Will a medication that decreases relapse rate automatically also result in less disability progression in the long run? These are important questions to consider since the available therapies are not perfect and have a certain burden of side effects and costs. It has been suggested by some experts that the focus of new therapies should be on their ability to prevent progressive disability, regardless of how well they decrease relapse rate.
In this two-part series, we will consider two important publications that have contributed to our growing understanding of the relationship between relapses and disability in MS. The first, by Prof. Confavreux and colleagues is titled ‘Relapses and progression of disability in multiple sclerosis’ will be the subject of this Viewpoint and suggests that at some point during the course of MS, the presence of few or many relapses does not appear to make a difference to subsequent progression of disability (ref 1). In the recent publication by Prof. Lublin and colleagues, titled ‘Effect of relapses on development of residual deficit in multiple sclerosis’, evidence suggests that relapses can directly contribute to disability (ref 2). The paper by Lublin et al will be the subject of the next Viewpoint, in which we will also consider why these two reports - that initially seem to contradict one another - may actually both make sense.
The complexity of the relationship between clinical relapses of MS and progressive disability has been recognized for some time. As noted above, worsening neurological condition in patients with secondary-progressive MS (SPMS) can continue to occur for many years after clinical relapses have stopped completely. At the same time it makes intuitive sense that decreasing relapses should translate into less damage and less disability. For many years, researchers have thought that assessing the impact of MS therapies on the frequency of clinical exacerbations would be an important measure of the efficacy (benefit) of the drug in question. Indeed, the approval of the currently available immune modulators was based, in part, on showing in clinical trials that these medications can decrease the MS relapse rate. Such thinking was based, in large part, on earlier studies, for example by Prof. Weinshenker and colleagues (ref 3), reporting that patients who had many relapses (5 or more) in the first two years of their MS diagnosis, progressed more quickly than patients who had a small number of relapses (less than 2) in the first two years.
In a large French study (ref 1), Confavreux and colleagues set out to examine this relationship. They used a large patient database that was established in Lyons, France, in 1976. By reviewing the records, they identified 1562 patients who met the formal diagnostic criteria for having MS that started as relapsing remitting (RR) MS. At the time of publication (2000), 1066 of those patients continued with a RRMS course, and 496 had developed the SPMS form. Of those patients with SPMS, 299 continued to have occasional relapses, whereas 197 had SPMS with no superimposed relapses. They then compared the SPMS patients with relapses, to the SPMS patients with no further relapses, and asked whether the presence or absence of relapses during the SPMS phase had an effect of subsequent progression of disability. Somewhat surprisingly, they discovered that patients with SPMS who reached a certain level of disability, experienced subsequent progression of disability at the same rate, regardless of whether they did or did not have superimposed relapses.
The authors point out that ‘relapses’ and ‘progression’ are the two basic clinical features of MS. Based on their study, they conclude that the apparent absence of a relationship between super-imposed relapses and progressive disability points to differences in the biological processes that underlie these two clinical features. They suggest that ‘relapses’ reflect recurrent waves of inflammation that attack the central nervous system, whereas ‘progression’ reflects the consequences of myelin loss, axonal damage and scarring. Based on their results, the authors suggest that medications that are able to decrease the rate of MS relapses, may not necessarily delay the progression of disability.
The ‘Confavreux’ study therefore raised important questions about the relation between MS relapses and progression, and about the rational for the use of approved therapies and development of future therapies in MS. In the next Viewpoint, we will discuss the recent publication by Lublin et al (ref 2), which demonstrates an important relationship between relapses and disability. We will reconcile the apparent discrepancies between the two papers and conclude that early treatments that are able to decrease relapse rate in MS probably do have a benefit on disability progression.
1. Confavreux, Christian et al. Relapses and progression of disability in multiple sclerosis. New England Journal of Medicine. 2000:343(20):1430-1438.
2. Lublin, Fred et al. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003:61:1528-1532.
3. Weinshenker, Brian et al. The natural history of multiple sclerosis:
a geographically based study. I. Clinical course and disability. Brain.
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