What is meant by progression?
Doctors will often refer to disease progression when they talk to you about the course of multiple sclerosis and the impact of treatment. But progression can mean different things – which can cause a bit of confusion.
Most people are diagnosed with the relapsing-remitting form of MS (RRMS), which is characterized by relapses and periods of remission. At some point, many will go on to develop secondary-progressive MS (SPMS). During this phase, relapses become less frequent but there is an accumulation of disability. What this means is that the disease is now less inflammatory (so fewer relapses), but neurodegeneration – irreversible damage to nerve fibres – becomes more prominent.
SPMS is the beginning of the progressive period of MS. During RRMS, relapses can cause some disability – a worsening of symptoms resulting in impairment. But this impairment may improve as you recover from the relapse so that your level of function returns to what it was before. Progression means that there isn’t the same degree of recovery. A loss of function becomes “the new normal”. Additional losses will further subtract from that. These impairments can occur even if you aren’t having relapses because of ongoing neurodegeneration – a process that’s more subtle than inflammation but ultimately more devastating.
The start of SPMS roughly corresponds to a sustained EDSS score of 4.0. “Sustained” means that against the backdrop of good and bad days, you maintain a certain amount of disability over a period of 6-12 months. Up to EDSS 4.0, disability doesn’t relate to walking ability (that becomes more important after EDSS 4.0). Instead, disability is a matter of the severity of signs and symptoms in the eight “functional systems” that doctors assess. These signs and symptoms are such things as tingling or numbness, vision problems, bowel/bladder problems, and so on. For example, if you have minimal disability in one of these areas, you would be scored as EDSS 2.0. If this disability was somewhat worse, or if there was mild disability in three or four areas, you would be scored as EDSS 3.0. Once the disability is significant, you would be scored as EDSS 4.0.
Long-term studies of the untreated MS population have found that the median time to EDSS 4.0 is about 10-15 years (Confavreux and colleagues. N Engl J Med 2000;343:1430-1438; Scalfari and colleagues. Brain 2010;133:1914-1929). “Median” means that half of the people were above EDSS 4.0 and half were below. So it put it another way, there’s a 50-50 chance that SPMS will begin 10-15 years after diagnosis. But you may not realize it at the time. SPMS is a retrospective diagnosis, meaning that it’s only 6-12 months after it starts that your doctor can say with any certainty that you now have progressive MS.
The periodic worsening seen during relapses may seem like progression. But it’s actually “early progression” or “EDSS progression”. What these terms mean is that you have progressed (i.e. gotten worse) on your EDSS score. However, much or all of this loss may be regained as your body heals – which can take months (or years in some cases).
Progression has become a hot topic in drug trials, in part because reducing relapses (the most common measure of the effectiveness of a drug) may do little for the outcome that people care about the most – becoming disabled. Ideally, a trial would evaluate whether a drug slowed disease progression, but this isn’t feasible in a short-term study. During a two-year trial, some people will get worse – but this is largely the effect of relapses. It isn’t necessarily true progression. So investigators came up with the idea of “sustained disability progression” as something to evaluate in drug studies as an approximation of how treatment will impact disease progression. We’ll look at this concept of sustained progression in Part 2.
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