Article In Brief
“We have to consider treating more people aggressively up front, prior to them showing evidence of brain atrophy or disability as measured by an exam.”
—DR. SCOTT NEWSOME
Long-term disease progression in patients with relapsing-remitting multiple sclerosis (RRMS) occurs independently of relapse activity and is associated with accelerated brain atrophy, researchers reported. They proposed using the term, silent progression, to describe the accumulating disability in patients with RRMS.
A new 10-year study of patients with relapsing-remitting multiple sclerosis (RRMS) found that while relapses were associated with disability progression over the course of a year, relapses did not contribute to long-term disability progression. Most markedly, the results found that no evidence of disease activity (NEDA) at two years did not predict long-term stability.
Instead, the researchers said, disability progression was associated more with brain atrophy, leading them to recommend more aggressive treatment for atrophy much earlier to address this “silent progression” aspect of the disease timeline.
In the report, published in the March 9 online edition of Annals of Neurology, investigators noted, however, that earlier, more aggressive treatment could lead to increased long-term side effects for patients, some of which are severe, and some patients might not want to take that risk.
Lead researcher Bruce A. C. Cree, MD, PhD, FAAN, clinical research director at the University of California, San Francisco Multiple Sclerosis Center, said the general assumption with MS is that the disease is a two-stage process in which the number of relapses and increased disease activity, seen as brain lesions on an MRI, directly impact the secondary progression of the disease.
The researchers aimed to determine if they could find evidence of that process being clearly delineated, and the results were unexpected.
“I was definitely surprised,” said Dr. Cree. “I thought that what we'd see was that more severe relapses resulted in long-term disability driven by cumulative injury.
“But in our dataset, we did not find that link. Instead, many disability events seemed to occur completely independently of relapses... and even if the patient was showing signs of increased disability, they often had no change of disease activity on the MRI.”
Study Design, Findings
Researchers measured disability progression in 407 patients over five years, and 372 patients over a decade from the University of California, San Francisco MS EPIC (expression/genomics, proteomics, imaging, and clinical) dataset. They assessed the effect of new brain lesions on silent progression and on brain atrophy in treated and untreated patients in four groups: treated participants without new lesions, treated participants with new lesions, untreated participants without new lesions, and untreated participants with new lesions.
Progression was determined by an increase of 1.5, 1.0, or 0.5 points from the baseline scores on the Expanded Disability Status Scale (EDSS), as well as tests of walking speed, the nine-hole peg test, and other cognitive measures. The researchers assessed disability progression from baseline to year five and sustained until year 10. Age at baseline, disease duration at baseline, male sex, and years of follow-up were all associated with a decline in relative brain volume loss.
Examples of relapses included vision loss, double vision, weakness in one or more limbs, sensory disturbances including paresthesias, and loss of coordination. The investigators found that the occurrence of relapses was associated with clinically meaningful EDSS worsening at the next annual exam: 29.7 percent of yearly intervals in which participants experienced relapses were associated with disability worsening at the next visit, compared with 22.7 percent of yearly intervals during which participants did not relapse (p = 0.012).
However, the relapses had no impact on confirmed disability worsening, defined as disability worsening at the visit following the relapse and confirmed at the subsequent year: 12.9 percent of yearly intervals with relapse, and 14.4 percent without relapse, were associated with confirmed worsening. Similarly, there was no association between relapses during the first six study years and long-term disability worsening.
MS specialists, who were not involved with the study, said the trial was important and intriguing. They wondered if improved treatments had simply reduced the number of lesions overall and pointed out that lesions on the spinal cord would have a significant impact on disability. Some questioned if the progression was truly “silent” or simply something that clinicians did not or could not currently measure.
“My clinical experience is that patients often perceive worsening even when our exam does not demonstrate it,” said Myla D. Goldman, MD, MSc, FAAN, associate professor of neurology at the University of Virginia and director of the school's MS clinic. She said the term “subclinical progression” might be more appropriate.
“They may often notice cognitive difficulties, which can be hard to measure at the bedside, but which I suspect is an expression of disease progress, so-called ‘silent progression.’ Although, I would ask silent how? By exam, by MRI, by patient report, by neuropsychological testing?”
Dr. Cree noted that some neurologists do not measure disability progression in a systematic way. He said a lot of patients are aware of small changes in function that a neurologist may not be able to see, and that it is important for patients to know they need to communicate even small deviations.
“Many disability events seemed to occur completely independently of relapses.. and even if the patient was showing signs of increased disability, they often had no change of disease activity on the MRI.”
—DR. BRUCE A. CREE
Robert J. Fox, MD, FAAN, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic, agreed with Dr. Cree that even experienced clinicians may not notice small changes in patients they see regularly and the “revolutionary” study should give notice that doctors often wait too long to start proactive treatments.
But he said the study was limited by the fact that it did not look at spinal cord lesions on brain MRI.
“If you have a lesion in the temporal or parietal lobe, it may not have an impact, but if you have the same size lesion in the brainstem or spinal cord, that's a big problem,” Dr. Fox said. “A brain MRI isn't enough, and the study falls short on suggesting what else we should be following. It notes the atrophy, but brain injury is a general litmus test.”
Dr. Fox and others pointed out that the study may not have addressed current relapse treatments that reduce new lesions, and that may account for some of the lack of lesion-to-disability correlation.
“If lesions are not associated with long-term disability, then should we stop treating lesions and relapses? Probably not,” he said.
Although the study recommended more aggressive and earlier treatment with drugs that address brain atrophy, Dr. Fox said that some patients simply refuse treatment. Dr. Fox was the lead author of a study, published online in Neurology March 13, which found that patients were most resistant to drugs with a possible risk of progressive multifocal leukoencephalopathy and kidney injury, both of which are associated with MS drugs.
In the Neurology study, 24.6 percent of patients were not actively being treated and 14.2 percent had never been treated, a number that seemed quite large to some of the doctors Neurology Today interviewed.
“The problem is that once you see atrophy on the imaging, or once you have someone with fixed disability, it's already too late—the horse is out of the barn in terms of deriving maximum treatment effect,” said Scott Newsome, DO, MSCS, FAAN, associate professor of neurology at Johns Hopkins Hospital and co-director of the Multiple Sclerosis Experimental Therapeutics Program.
“We have to consider treating more people aggressively up front, prior to them showing evidence of brain atrophy or disability as measured by an exam. It's very humbling to realize that even with these best measures, we do a poor job of identifying early on who will ultimately develop into the secondary progression of the disease.”
“My clinical experience is that patients often perceive worsening even when our exam does not demonstrate it.”
—DR. MYLA D. GOLDMAN
“I tell patients that this is a marathon disease, not a 50-yard dash, and what we do now will impact what happens tot them down the road.”
—DR. SCOTT NEWSOME
Dr. Newsome pointed out the challenges clinicians face with some patients who are not enthusiastic about being proactive in their own treatment. He recently saw a patient who was reluctant to start a disease-modifying medication after a relapse because right then in clinic, she felt fine.
Dr. Cree, the study author, agreed that working with patients to approach the disease proactively could be a challenge.
“There are definitely some downsides to the medications, and a number of patients hold off on pursuing therapy; one observation in the study was that is not a good strategy over the long-term,” said Dr. Cree. “We have to consider that one of the most critical goals of therapy is preserving brain volume, because once the brain is shrunk, it's irreversible.”
Dr. Newsome said more research needs to be done focusing on identifying better biomarkers of future disability and treatment response— whether it is a blood test or MRI measure—so that clinicians have a better idea of what the best treatment strategy is for an individual now and over time.
“I tell patients that this is a marathon disease, not a 50-yard dash, and what we do now will impact what happens to them down the road,” he said.
Dr. Goldman, of the University of Virginia, said it will be important to identify clinical correlates to brain atrophy in a way that could be used as an indicator, as brain atrophy as an outcome in clinical practice has several limitations.
“A brain MRI isn't enough, and the study falls short on suggesting what else we should be following. It notes the atrophy, but brain injury is a general litmus test.”
—DR. ROBERT J. FOX
“Our clinical tools, for example, EDSS, may be insensitive to detect change so we call it ‘silent,’ but if we used the right tools or patient-report measures, perhaps it is indeed ‘visible,’” she said. “We also need to better understand how our current therapies impact brain atrophy over time in a way that could guide therapeutic decision making.”
Dr. Cree has received consultant fees from Biogen Idec, EMD Serono, and Novartis. Dr. Fox has received consultant fees from Biogen Idec, GlaxoSmithKline, Novartis, Mallinckrodt, Actelion, EMD Serono, Genentech, Teva, Xenoport, and Apitope, as well as grant and research support from Novartis. Dr. Newsome has received consulting fees from Biogen, Celgene, EMD Serono, Genentech, and Syntimmune. Dr. Goldman serves on the scientific advisory boards of Novartis Pharmaceuticals (institutional contract), Biogen, IDEC (institutional contract), Acorda (institutional contract, and has received consulting fees from Questcor, Genzyme, Novartis Pharmaceuticals, and EMD Serono. Dr. Fox has received personal consulting fees from Actelion, Biogen, EMD Serono, Genentech, Novartis, and Teva. He has served on advisory committees for Actelion, Biogen, and Novartis, and received clinical trial contract and research grant funding from Biogen and Novartis.