Resilience Despite Relapse

Frequent flare-ups in the first few years of relapsing-remitting multiple sclerosis (RRMS) have long been thought to predict more rapid disability and a quicker onset of secondary progression (SP). Now a new study casts doubt on the widespread belief that cumulative damage from those early relapses actually causes SP. In a long-term follow-up of 158 untreated patients who experienced more than three relapses in the first 2 years following diagnosis, only two-thirds converted to SP in a median of just 5 years. For unknown reasons, one-third of people seemed resilient to the numerous early setbacks (Scalfari et al., 2013).

This is "an important study that needs confirmation," writes Gavin Giovannoni, a neurologist at the London School of Medicine and Dentistry in the United Kingdom (and MSDF scientific adviser), on his blog, Multiple Sclerosis Research. The observational study raises questions about how well relapses mirror the underlying disease process, he writes.

The paper comes at a time of growing concern about the limited effectiveness of treatments for RRMS. Some drugs reduce relapses in many people but may not slow disease progression, and drugs for the more severe progressive forms of MS are lacking (Ropper, 2012; Fox et al., 2012). For 20 years, an expanding arsenal of disease-modifying therapies (DMTs) has transformed the treatment of RRMS by targeting the immunological underpinnings of relapses and inflammatory lesions in the brain and spinal cord (Greenberg et al., 2013). But if the early flare-ups are not causally linked to SP, treating those exacerbations may not delay or prevent SP, at least for some people.

"The field is changing," said Helen Tremlett, an epidemiologist at the University of British Columbia in Vancouver, Canada, in an interview with MSDF. Clinicians and scientists believed that relapses drove disability, she says. "Now, it seems more likely that this is not the case [and that] neurodegeneration ultimately puts someone in a wheelchair and alters their long-term outcome."

Inflammatory attacks on the central nervous system can exert their destructive effects in the earliest stages of the disease, precipitating relapses. A separate neurodegenerative process seems to begin early in the disease, which may be more important to the advancement of disability than relapses. This process is not yet well served by MS therapies, say a vocal and growing number of scientists and doctors, including the authors of the new paper.

"Some people can have lots of attacks, and 25 years later they are happy as clams," says George Ebers, a neurologist at the University of Oxford in the U.K. and the corresponding author of the new study, published in the February 2013 JAMA Neurology (formerly the Archives of Neurology).

"Something seems to divide people who do exceptionally well and worrisomely badly," Ebers says. He speculates that the inflammatory events that occur during relapses may have different effects on myelin and axons. The effects may depend on how vulnerable different parts of neurons are to degeneration, possibly as a result of underlying genetic factors. Such factors are probably more directly tied to a more aggressive or more benign disease course than is the inflammation itself, he says.

The new paper taps into data from a population-based cohort in southwestern Ontario, Canada. From 1972 to 1984, Ebers and his colleagues at a clinic in London, Ontario, recruited 1000 people with MS from within a 100-mile (160 km) radius into a natural history study. All of the subjects were followed for a minimum of 16 years. By the time Ebers left in 1999, the London MS clinic was one of the largest in the world, with more than 5000 patients, including those in the study.

In their 28-year study, the investigators examined study participants once or twice a year. In many cases, they used the patient's recall as well as records from other medical providers to determine the date of the first relapse (which defines the onset of MS) and to help verify subsequent exacerbations and disability that occurred before enrollment in the study or between study examinations. They defined relapses as acute development of new symptoms or the worsening of existing systems for more than 24 hours. They scored functional status, such as needing a cane to walk or requiring a wheelchair for mobility, with the original Disability Status Scale (DSS), an early version of the current standard, the Expanded Disability Status Scale (EDSS). No patients in the study received disease-modifying therapy, even after interferon β (IFN-β; see interferon beta-1a and interferon beta-1b), the first DMT, received U.S. approval in 1993 and was licensed 2 years later in Canada.

Three years ago, Ebers and his colleagues reported that the apparent cumulative impact of relapses on disability during the secondary progressive phase boiled down to the frequency and interval of relapses in the first 2 years, at least among the 800 people with RRMS in their cohort (Scalfari et al., 2010). After the second year, relapses had no apparent deleterious effect on the time course of the disease or disability endpoints.

About the same time, Tremlett and her co-authors found that a higher relapse rate in the first 5 years was associated with a quicker pace toward the disability milestone of needing a cane or reaching SP. In their study, the impact of relapses diminished with time. Overall, cumulative relapses had only a minimal impact on long-term disease progression. Their findings came from a retrospective review of nearly 2500 patients in British Columbia with a median follow-up of about 20 years (Tremlett et al., 2009).

Authors of both papers speculate that disability accumulation and progression are tied to axonal degeneration that proceeds by mechanisms that are independent from those that cause the relapses.

In the new paper, Ebers; first author Antonio Scalfari, a neurologist at Imperial College London in the U.K.; and their co-authors took a closer look at the subset of 158 people in the London, Ontario, cohort who experienced more than three relapses in the first 2 years of disease. Individual disease courses varied greatly, but half of these patients had converted to the secondary progressive form of the disease 9 years after disease onset, a figure that increased to two-thirds by 24 years. The remaining patients in the group of 158 did not enter the progressive phase of the disease, and only half of them attained DSS 3 in an estimated median time of 16 years. DSS 3 is an indication of full mobility accompanied by moderate disability affecting daily living. "We've taken a factor associated with worse than average outcomes [frequent early relapses] and shown that association is driven by one population that does really badly," Ebers says.

These findings may not be generalizable. Doctors now typically prescribe DMTs for most people diagnosed with MS, perhaps altering the course of disease and the impact and significance of relapses. Also, older natural history studies define and measure relapses differently than modern clinical trials do, says Jerry Wolinsky, a neurologist at The University of Texas Health Science Center at Houston, who estimates he has been involved at some level in about 70% of the clinical trials of new drugs for MS in the last 20 years.

In recent clinical trials, patients are experiencing fewer relapses in both placebo and therapeutic trial arms than patients did in earlier studies. This could reflect earlier diagnosis, more restrictive definitions of relapses, and even the response of patients to diagnosis, such as losing weight or stopping smoking, says Timothy Coetzee, chief research officer of the National Multiple Sclerosis Society in New York City.

The paper has implications for research into the causes and therapeutics for MS, say Ebers and his co-authors. Ebers calls for the end of relapse rate as a primary endpoint in clinical trials. Also needed are studies to identify potential genetic factors that affect axonal vulnerability or resistance to degeneration.

"Nobody knows where the truth lies exactly," Wolinsky says. "We use attacks to define when the disease begins for the vast majority [of MS patients]. None of us know when neurodegeneration begins."

At this stage, the findings should not change patient-management decisions, with one possible exception. Physicians should be clear about the limited evidence for long-term benefits of DMTs, Ebers and others say. "Yes, [relapses] do matter," Ebers says, but "you cannot tell patients they'll be better off in the long term because you suppress those relapses. None of the therapies has been shown to make much of a difference in long-term disability. That doesn't say they won't, but none have so far."

"The current drugs we use for MS were developed with a belief that if you reduced relapse rates, you could have a positive impact on long-term disability progression," says Tremlett, who last summer reported no strong association between IFN-β treatment and progression of disability in a retrospective cohort of more than 800 people with RRMS who were treated with the drug (Shirani et al., 2012).

"Just because we find a disassociation between relapses and long-term outcome is not the same thing as saying, if we reduce relapses we will have zero impact," she says. "Relapses are unpredictable. They're not pleasant. They can put you in the hospital. While hope remains that some patients might benefit from the DMTs in terms of long-term disease progression, from the studies to date, we don't know who those patients are."

Key open questions

• What are the relative roles of inflammation and neurodegeneration in the course and outcomes of MS?
• Why do only early relapses seem to predict higher levels of disability and quicker pace toward progressive disease, and what makes some people resilient to the riskier early relapses?
• How meaningful are relapse rates as clinical trial outcomes?

Image credit

Thumbnail image on landing page. Detail from “The Fortune Teller” by Michelangelo Merisi da Caravaggio,  part of a collection of reproductions compiled by The Yorck Project and distributed by DIRECTMEDIA Publishing GmbH, via Wikimedia Commons. The work of art and the reproduction thereof are in the public domain.