Long-term use of disease-modifying therapies (DMTs) in people with relapsing-remitting multiple sclerosis (RRMS) has a beneficial cumulative effect compared to shorter treatments, delaying the development of irreversible disability and conversion to secondary progressive MS (SPMS), a recent study shows.
The study, “Cumulative effects of therapies on disability in relapsing multiple sclerosis,” was published in the Multiple Sclerosis Journal.
The short-term efficacy of DMTs in MS has been demonstrated in clinical trials; yet their long-term impact is less well-established.
Extension trials are a common strategy for long-term analysis, but are limited by selection bias because most clinical trial participants who respond to treatment are more likely to enter an extension trial, thus leading to an overestimation of effectiveness.
Recently, statistical methods have been developed to control some of these biases. However, most studies used conventional statistical approaches and overlooked the cumulative impact of DMT exposure over time on current disability.
This led to the development of a statistical model to assess current risk, regardless of treatment or combination of treatments in the past. The model includes DMT exposure, dose, and timing of past exposure to generate a value called a weighted cumulative exposure (WCE) metric.
Researchers in France now used the WCE metric to analyze the medical records of 2,285 adult patients with RRMS to estimate associations between exposure to DMT over time, and the current risk of irreversible disability and conversion to SPMS. Notably, most people with RRMS eventually develop SPMS.
Participants’ mean age was 33.4, including 75% women with a median follow-up of 14.9 years. Most patients (78.6%) were exposed to at least one DMT during follow-up, while 57.5% received two or more DMTs, and 40.2% three or more DMTs.
The analysis focused on DMTs received three to 20 years before.
Results showed that past DMT use longer than five years was associated with a cumulative protective effect over time. The effect was most prominent between five and 10 years prior.
If a patient started DMTs 15 years ago, 10 years of treatment led to a 36% decrease in the current risk of developing an irreversible disability, as defined by an expanded disability status scale (EDSS) of four (i.e., significant disability, able to walk without aid or rest for 500 meters, or 546 yards), compared to two years of treatment started at the same time.
The results suggested that “long-term DMT is, therefore, more beneficial than DMT prescribed at the same time for a short period,” the researchers wrote.
Also, the risk of irreversible disability decreased by 26% for continuous DMT use of 15 years starting 20 years ago compared to five-years beginning 10 years ago, and 38% lower than those who had two years of continuous exposure starting seven years ago.
Thus, “the earlier and the longer the use of DMT, the lower the risk of reaching an irreversible EDSS 4,” the researchers wrote.
Also, compared to untreated patients, there was a 24% decrease in the current risk of permanent disability for those who were treated continuously for five years, starting 10 years ago.
A statistical analysis found the risk factors significantly associated with irreversible disability were sex, current age, irreversible EDSS score at the beginning of the study, inclusion period of treatment, and the cumulative number of relapses during follow-up.
For every one-year increase of age, the risk of irreversible EDSS 4 also increased in patients who experienced relapses.
Regarding progressing to SPMS, past DMT use over five years before had a significant protective and cumulative effect on risk.
Here, the risk of developing SPMS was 45% lower for participants who were treated continuously for 10 years starting 15 years ago compared to those treated for two years, starting at the same time. Again, “longer duration of DMT had a beneficial cumulative effect on the current risk,” the scientists wrote.
When the team combined early treatment data with treatment duration, there was a 34% reduction in SPMS risk for those treated for 15 years starting 20 years ago, than it was for five years beginning 10 years ago.
Compared to untreated patients, later or long-term DMT treatment also significantly affected the current risk with a 31% decrease in those given DMTs for five years starting 10 years ago, and 54% lower risk for treatment beginning 15 years ago.
“In conclusion, the results stress that a long-term use of DMT is associated with a stronger beneficial cumulative impact over time than only early use on the current risk of disability or occurrence of secondary progression in RRMS,” the team wrote.
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