Pauline Anderson

June 05, 2013

ORLANDO, Florida — Patients with multiple sclerosis (MS) die about 6 years earlier than those in the general population; they don't get cancer as often, although this could be due to "diagnostic neglect"; and they don't seem to gain significant benefit from therapy in terms of disability progression.

These are some of the long-term outcome data presented by Helen Tremlett, PhD, associate professor, Canada Research Chair in Neuroepidemiology & Multiple Sclerosis, University of British Columbia (BC), Vancouver, Canada, at the 5th Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS).

A new observational study at her center showed no strong association over time between exposure to β-interferon (β-IFN) and disability progression. Linking extensive data sources from April 1, 1985, to December 31, 2008, researchers looked at the association in patients with relapsing-remitting MS.

Such a study is needed, explained Dr. Tremlett, because although clinical trials measure efficacy of a particular agent, they include well-selected homogenous populations and exclude patients with comorbid conditions and those who can't adhere to the medication. There's a "gap" between these results and those seen in clinical practice with a more varied population, she said.

The analysis had 3 cohorts: those taking β-IFN (n = 868) and 2 untreated groups — a contemporary group of patients who were eligible for interferon but for some reason didn't take it (n = 829) and an historical group who would have been eligible for this treatment had it been available at the time in Canada (n = 959).

The main outcome was time to an Expanded Disability Status Scale (EDSS) score of 6. The study compared the treatment group with both control groups.

No Strong Association

After adjusting for age, sex, baseline EDSS score, socioeconomic status, disease duration, and presence of comorbid conditions, the study found no strong association between β-IFN exposure and disability progression (hazard ratio [HR] for the historical approach, 0.77 [95% confidence interval (CI), 0.58 - 1.02]; HR for contemporary approach, 1.30 [95% CI, 0.92 - 1.83]).

The HRs were "slightly different," but both crossed 1, "so we can't say they show an effect," said Dr. Tremlett.

In addressing a question from the audience, Dr. Tremlett acknowledged that medication indication bias was "absolutely a problem" in the contemporary cohort because patients who do badly are more likely to be prescribed the drug. "It's difficult to adjust for that in any model, to get rid of that indication bias, and we saw that in the contemporary analysis. But when we included the historical group, it didn't seem to be too much of an issue."

The findings don't necessarily mean that the drug is ineffective for all patients with MS, or that "all hope is lost," said Dr. Tremlett. "We might be able to modulate long-term outcomes in MS, but we weren't able to find this on a population level. I think the data does hint that some patients may respond to drug treatment, and we definitely need more accurate selection of potential treatment responders."

But the findings are "unfortunately consistent" with long-term follow-up of clinical trials, including a 16-year follow-up (Ebers, JNNP, 2010) and the CIS Benefit study (Kappos, Lancet Neurol, 2009).

"I think the study allows patients to have more realistic expectations on the potential benefits of some of these medications," said Dr. Tremblett.

Life Expectancy

Other recent BC research showed that patients with MS are living longer, but so, too, is the general population. "Patients with MS are living to a good old age," but their life expectancy is still about 6 years less than that of the general population: 78.6 years for women and 74.3 years for men, said Dr. Tremlett.

Women with MS live with the disease for 49.8 years compared with men, who live with it for 41.3 years.

The analysis also found that age at MS onset affected mortality; younger patients lived longer from the onset of symptoms compared with older patients, but they typically died younger. Patients with primary progressive MS had a higher relative mortality risk.

Although this analysis didn't capture cause of death in patients with MS, "that's our next project," said Dr. Tremlett.

Another BC research project collected information on 4 of the most common cancers: breast, prostate, lung, and colorectal. It showed that the overall cancer risk was lower in patients with MS (standardized incidence ratio for all cancers, 0.86; 95% CI, 0.78 - 0.94) but found a trend for patients with MS to be more likely to turn up with the largest tumour.

 
At the end of the day, it is suggestive of some diagnostic neglect there. Dr. Helen Tremlett
 

The findings, said Dr. Tremlett, are "a bit sobering" and could suggest that cancers are being overlooked in patients with MS. Perhaps a patient without MS who reports fatigue is sent for tests, whereas the same symptom in a patient with MS is chalked up to part of the disease.

"At the end of the day, it is suggestive of some diagnostic neglect there. We don't think it accounts for the entire reduced risk of cancer that we're seeing, but I think it could have major health implications in MS, particularly with these patients living longer."

Cause of Death in MS

The cause of death in patients with MS was recently studied by researchers led by Michael Corwin, MD, a principal at Care-Safe, associate professor of pediatrics and epidemiology at the Boston University Schools of Medicine and Public Health, and senior epidemiologist at the Slone Epidemiology Center at Boston University, Massachusetts, and presented at the recent American Academy of Neurology 65th Annual Meeting.

Generally, the cause of death on death certificates is listed as cardiorespiratory arrest, which is not really instructive because it's the "final common pathway" leading to death in "virtually everyone," Dr. Corwin told attendees at that meeting. MS is usually listed as an underlying cause but is very rarely the direct cause of death, he said. Instead, they looked at other contributing factors, listed after MS and before cardiorespiratory arrest on death certificates.

They used the Optimum Insight Research Database, a repository of billing claims on more than 39 million individuals insured by United Healthcare in the United States. Patients with MS and controls were matched for sex, age, residence region, and for their "first opportunity to die," to control for any time bias.

Their analysis showed that "the number 1 cause of excess death in our patients was sepsis, followed by pulmonary infection, pulmonary aspiration, and ischemic heart disease interestingly was significantly increased in the MS population compared to controls, along with stroke, embolic disease, genitourinary infections. Oddly — and I don't have a good explanation for this — accidental poisoning was significantly increased in the MS population, but not cancer," Dr. Corwin reported.

He concluded that their results show mortality in MS is driven by many conditions, "but most importantly, by infections, cardiovascular disease, and pulmonary disease. Sepsis and pulmonary infections were the primary contributors to most of these MS deaths," he said, and late-stage patients seemed prone to death from those causes related to their disability status, such as deep-vein thrombosis, cardiac disease, and infections.

"Physicians treating these patients should be advised or aware that MS patients have these risks and should aggressively treat infections and optimally manage cardiovascular and pulmonary disease," he said.

The research was funded by the National Multiple Sclerosis Society, Michael Smith Foundation for Health Research, MS Society of Canada.

5th Cooperative Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS): Symposium, Long-term Outcomes in MS: Presented May 30, 2013.

American Academy of Neurology (AAN) 65th Annual Meeting. Abstract S30.007. Presented March 20, 2013.

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