MS Relapse Affects Short-Term Prognosis but Has Minimal Long-Term Effect on Disability

Janis C. Kelly

November 06, 2009

November 6, 2009 — Multiple sclerosis (MS) relapses within the first 5 years of disease are associated with a nearly 50% increased risk of needing a cane in the first 5 years after onset but have little effect on long-term risk for disability, according to a new study published in the November 4 issue of Neurology.

In addition, the effect of the early relapse lessened over time. Those with early relapse who did not need a cane after 5 years were at only a 10% higher hazard of needing one 10 years after disease onset than those without early relapses.

The effect of relapses that occurred later — either at 5 to 10 or at more than 10 years after the start of the disease — also waned over time and became insignificant after long-term follow-up. Relapses in people younger than 25 years had a greater effect on disability compared with those older than 35 years.

"Our study suggests that later use of immunomodulatory drugs [IMDs] might be less valuable in terms of subsequent disease progression," lead author Helen Tremlett, PhD, told Medscape Neurology. "This is because relapses later in the disease course had a lesser impact on disease progression. The diminishing impact of relapses over time is really interesting and is something that others have not been able to look at."

Dr. Tremlett is assistant professor of neurology and MS Society of Canada and Michael Smith Foundation for Health Research Scholar at the University of British Columbia's Brain Research Centre in Vancouver, Canada.

Time-to-Cane

Dr. Tremlett and colleagues reviewed the medical records of 2477 people with MS who experienced relapses. They assessed the effect of relapses at different time periods on time-to-cane, or a score of 6 on the Expanded Disability Status Scale (EDSS) and secondary progressive MS (SPMS). Mean follow-up was 20.6 years, during which the subjects had 11,722 relapses.

MS patients who had a relapse within 5 years of disease onset were at a 48% higher hazard of reaching EDSS 6 within 5 years postonset than those who did not have an early relapse (95% confidence interval [CI], 37% – 60%) and a 29% hazard for SPMS (95% CI, 20% – 38%).

This risk was reduced substantially after 10 years postonset, to 10% for EDSS 6 (95% CI, 4% – 16%) and 2% for SPMS (95% CI, 2% – 7%).

"Our findings may represent an important message to people diagnosed with MS today. Those who have a history of relapses could potentially be offered reassurance that as time goes on, these relapses will have a diminishing effect on their everyday lives," Dr. Tremlett said. "In addition, our study calls upon the need for new medications that target axonal degeneration, which is suspected of causing permanent disability, especially for people who have had MS for many years or who are older at diagnosis."

Dr. Tremlett said that the age data raise the question of whether younger patients have a longer "window of opportunity" or "window of risk."

"By this, I mean they may have a longer period of time over which relapses place the individual at an elevated hazard of disease progression (window of risk), but we also might have a longer 'window of opportunity' to treat these patients with a drug which reduces their relapse rate — the assumption being that reducing their relapse rate with an IMD might actually favorably alter their long-term disease progression," Dr. Tremlett said.

However, Dr. Tremlett warned that decisions regarding IMD treatment should not be made solely based on these findings, which she described as "an additional piece of information for the treating physician (and the person with MS) that must be placed into context along with other studies. Remember that in our study we specifically looked at patients not treated with an IMD," she said.

Dr. Tremlett said that the effect of age on drug response should be considered in the design of MS clinical trials. "Studies investigating the efficacy of IMDs in early MS might wish to consider examining, a priori, the impact of IMDs according to the patients' age, rather than just adjusting for age, which assumes that treatment impact is uniform across all ages. Specific groups of younger patients may derive benefit not readily apparent in the entire cohort," she said.

Do Not Forget Other Effects of Relapse

In an accompanying editorial, Ruth Ann Marrie, PhD, from the University of Manitoba, Winnipeg, Canada, and Gary Cutter, PhD, from the University of Alabama, Birmingham, comment that teasing out the role of relapses is important because disease-modifying drugs that are approved to treat MS clearly reduce relapse frequency but have shown only moderate effects on disability progression in the limited duration of most clinical trials.

Dr. Marrie and Dr. Cutter also caution against underestimating the role of relapses, despite the fact that Dr. Tremlett's team found a diminishing effect of relapses on disability progression over time.

"Tremlett et al suggest relapses have a small impact on physical disability, but the other effects of relapses should not be forgotten," they write. "The financial cost of a single severe relapse is estimated at more than $10,000. The emotional costs — including anxiety and anger — and social costs are also high."

Although moderate or severe gait dysfunction is inherently important and more easily measured than other domains, they write, domains such as vision, cognition, and hand function are also important. "Relapses might produce measurable changes in these domains without influencing gait dysfunction, but this issue was not addressed in either this or prior studies," they note.

"Although the long-term relationship between relapses and disability progression is still incompletely understood, relapses are important," Dr. Marrie and Dr. Cutter conclude.

The study was supported by the US National MS Society. Dr. Tremlett has received speaker honoraria from the Swiss Multiple Sclerosis Society and the University of British Columbia Multiple Sclerosis Research Program and has received research support from the Canadian Institutes of Health Research, the US National Multiple Sclerosis Society, and the Multiple Sclerosis Society of Canada.

Neurology. 2009;73:1616–1623, 1612–1613.

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