Confavreux et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000 Nov 16;343(20):1430-8.
METHODS: In 1844 MSers who were followed for a mean (+/- SD) of 11 +/- 10 years, they determined the time of the clinical onset of the disease, the initial course (relapsing-remitting or progressive) and the subsequent course (relapsing-remitting, secondary progressive, or primary progressive), the times of relapses, the time to the onset of irreversible disability, and the time course of progressive, irreversible disability. They used three scores on the Kurtzke Disability Status Scale (range, 0 to 10, with higher scores indicating more severe disability) as measures of the severity and progression of disability: a score of 4 (limited walking ability but able to walk for more than 500 m without aid or rest), a score of 6 (ability to walk with unilateral support no more than 100 m without rest), and a score of 7 (ability to walk no more than 10 m without rest while leaning against a wall or holding onto furniture for support). They used Kaplan-Meier analyses to determine the influence of relapses on the time to the onset of irreversible disability.
RESULTS: The median times from the onset of MS to the assignment of a score of 4, a score of 6, and a score of 7 on the disability scale were longer among the 1562 MSers with a relapsing-remitting onset of disease (11.4, 23.1, and 33.1 years, respectively) than among the 282 MSers who had progressive disease from the onset (0.0, 7.1, and 13.4 years, respectively; P<0.001 for all comparisons). In contrast, the times from the assignment of a score of 4 to a score of 6 were similar in the two groups (5.7 and 5.4 years, P=0.74). The time course of progressive, irreversible disease among patients with the primary progressive type of multiple sclerosis was not affected by the presence or absence of superimposed relapses.
BACKGROUND: The influence of the patterns of onset of MS and relapses of the disease on the time course of irreversible disability is controversial.
METHODS: In 1844 MSers who were followed for a mean (+/- SD) of 11 +/- 10 years, they determined the time of the clinical onset of the disease, the initial course (relapsing-remitting or progressive) and the subsequent course (relapsing-remitting, secondary progressive, or primary progressive), the times of relapses, the time to the onset of irreversible disability, and the time course of progressive, irreversible disability. They used three scores on the Kurtzke Disability Status Scale (range, 0 to 10, with higher scores indicating more severe disability) as measures of the severity and progression of disability: a score of 4 (limited walking ability but able to walk for more than 500 m without aid or rest), a score of 6 (ability to walk with unilateral support no more than 100 m without rest), and a score of 7 (ability to walk no more than 10 m without rest while leaning against a wall or holding onto furniture for support). They used Kaplan-Meier analyses to determine the influence of relapses on the time to the onset of irreversible disability.
RESULTS: The median times from the onset of MS to the assignment of a score of 4, a score of 6, and a score of 7 on the disability scale were longer among the 1562 MSers with a relapsing-remitting onset of disease (11.4, 23.1, and 33.1 years, respectively) than among the 282 MSers who had progressive disease from the onset (0.0, 7.1, and 13.4 years, respectively; P<0.001 for all comparisons). In contrast, the times from the assignment of a score of 4 to a score of 6 were similar in the two groups (5.7 and 5.4 years, P=0.74). The time course of progressive, irreversible disease among patients with the primary progressive type of multiple sclerosis was not affected by the presence or absence of superimposed relapses.
CONCLUSIONS: Among MSers, relapses do not significantly influence the progression of irreversible disability.
“The graphs show that the rate of progression in MSers with and without relapses occurs at the same rate. The graph on the left is from EDSS 4 and the right from EDSS 6. Importantly, the presence of absence of supreimposed relapses did not affect the course of progressive disease. Therefore will switching off relapses at these stages of MS affect the progressive course? Unlikely! What is needed once progression starts are drugs that are neuroprotective; i.e. the protect nerves and axons from dying.”
Other articles of interest on this blog: This series of articles highlights landmark discoveries in the field of MS; in scientific jargon citation classics!
Prof G,Thanks for your post."What is needed once progression starts are drugs that are neuroprotective; i.e. the protect nerves and axons from dying."I thought I read somewhere that progression starts early in the disease, so I'm guessing that neuro-protective drugs should be started ASAP after diagnosis.A couple fo questions:I thought B cell depleting therapies had shown some promise in progressive MS. Does this suggest that they are neuro-protective?When are we likely to star seeing the results of some of the neuro-protectve trial? The paper you quote is 12 years old, so it's frustratignt aht neuro-protective trials have only relatively recently begun (and no agents have been approved).The responsess to your earlier post got pretty animated. I hope you can appreciate the basis of the frustration (which I thnk was directed at the MS research world in general). It's all about timing – limteing disability what all MSers want and to do this we need neuro-protective drugs ASAP. We've been disappointed with Lamotrigine and the cannaboid trials and really need something available soon.
I thought I read somewhere that progression starts early in the disease, so I'm guessing that neuro-protective drugs should be started ASAP after diagnosis.Yes. In one of our trials we are starting neuroprotection on first reported symptom i.e CIS. This is what a number of other trials are doing also. The problem will be getting people to recruit because there may be a time window of oppertunity for maximal benefit and by the time people do their homework that window may be shut."I thought B cell depleting therapies had shown some promise in progressive MS. Does this suggest that they are neuro-protective?"They appeared to affect the relapsing (Gadolinium-enhancing MSers) aspects of PPMS. If that can get rid of the B cells in the CNS maybe we would see greater efficacy, the gadolinium-enhancing MSers would get more antibody into their brains.We've been disappointed with Lamotrigine and the cannaboid trials and really need something available soon. However if you talk to both PIs of these trials they will probably tell you that both drugs worked. However, the trial design and application was the problem. In the Lamotrigine trial the MRI outcome was not fit for purpose and the trial was too short to show an affect. In the cannabis trial people did not progress so its hard to show a drug stopping progression if your placebo does not get worse. In subgroup of EDSS less than 5.5 there was a significant affect, but we need to wait until the data is published. However, it shows these drugs do not work miracles and they can only slow the rate of progression and not stop it. One needs combinations or cocktails of drugs, Prof G wasted more than 5 years of his life trying to get pharma on board with this idea, essentially none were interested.