November 20, 2017

PARIS — Several new studies investigating the controversial issue of "benign" multiple sclerosis (MS) have come to different estimates of its prevalence and provoked conflicting opinions on therapeutic implications.

Benign MS — when a patient has been diagnosed with MS for many years but accumulates very little disability — was the subject of four new studies presented at the recent 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting.

All four studies suggested that there is a subset of patients who appear to progress very slowly and have near-normal lives even several decades after initial diagnosis. But the estimates of exactly how many patients actually follow such a benign course ranged from less than 4% to more than 30%, and the problem of how to identify these patients early on remains.  

One of the issues with the concept of benign MS is that definitions vary. One common contemporary definition is having an Expanded Disability Status Scale (EDSS) score of 3 or less after 15 years since diagnosis, but some studies have used slightly higher or lower EDSS cutoffs and durations of time varying from 10 to 30 years. And some groups include other measures of probable symptoms, thereby reducing the number of patients who would fit the definition.

Three studies presented at the conference examined various cohorts of patients with MS and estimated the prevalence of benign MS based on EDSS scores at 15 to 30 years at about 25% to 30%.

The authors of these studies suggested that perhaps aggressive early treatment was not the right option for all patients and that waiting to see how active the disease course was before rushing in with treatment may be justified in some cases.

Russian Roulette?

But commenting on these studies for Medscape Medical News, John Corboy, MD, Rocky Mountain Multiple Sclerosis Center, University of Colorado, Westminster, strongly disagreed with this interpretation.

"Every study on the planet shows that whatever happens in the first 5 years is going to have an impact on you as you age," he said. "If you dawdle in those first 5 years, you are simply disabling people unnecessarily. You are playing Russian roulette with someone's life."

And a fourth study suggested that truly benign MS was actually much less common than thought.  In this study, researchers looked more closely at patients fulfilling the EDSS definition of benign MS and found that most of these patients did have symptoms that affected their lives and therefore the disease really should not be considered benign. 

"Some physicians have a philosophical view that we may be able to avoid treatment in certain patients as they seem to have a benign course, but I think we are moving away from that view and our data supports that," lead author of this study, Emma Tallantyre, MD, University Hospital of Wales, Cardiff, United Kingdom, commented to Medscape Medical News.

Commenting on the studies in a round-up of the meeting's clinical highlights, Alasdair Coles, MD, Cambridge University Hospitals, United Kingdom, said, "There is a group of people with benign MS who go on to acquire less physical and cognitive disability, but unfortunately that isn't sufficient for us to advise individual patients for whom we may have made that diagnosis initially because they can turn at any time into a more conventional disease disability trajectory."

Study Details

The three studies assessing benign MS based on EDSS scores came from Sweden, the United Kingdom, and the United States and showed similar results. 

The largest study, with data on more than 11,000 patients with relapsing-remitting MS (RRMS) from the national Swedish MS database, was presented by Ali Manouchehrinia, MD, Karolinska Institute, Stockholm, Sweden.    

He reported that 22% of patients had a benign course according to the definition of an EDSS score of 3 or less 15 years from the first clinical symptom. Similar estimates were found with other definitions, such as an EDSS score of 2 or less at 10 years.

The researchers linked these data to national information on sick days and disability benefits, and they confirmed that patients fulfilling the EDSS definitions of benign MS also had fewer sick days and disability benefit claims than did other patients with MS.

Results also showed that patients following a more benign course were more often female (75% vs 69%), had a younger onset age (28.4 vs 33.7 years), and were less likely to have been exposed to first- and second-line disease-modifying treatments (53% vs 65% and 14% vs 42%, respectively).

However, by 25 years, only 6% to 7% of patients still had an EDSS score of 3 or less. "So they were progressing, but slowly," Dr Manouchehrinia concluded. 

"There does seem to be a group with slow or very slow progression who might not benefit from treatment as much as others," he commented to Medscape Medical News. "These patients can live long and productive lives without treatment, and drug therapy would just give them the discomfort of adverse effects."

He added, however, that "at present, we cannot identify these patients at the start of the disease, but we may be able to in future, and analyzing data from cohorts of patients with benign disease such as ours will help to identify factors associated with a benign course."  

The UK study was presented by Karen Chung, MD, Queen Square Multiple Sclerosis Centre, London. She reported data on 30-year follow-up of a unique cohort of 132 patients with clinically isolated syndrome, very few of whom have received any drug treatment.

Of the 132 patients, 80 were known to have MS, and of these, 31 had no or mild physical disability after 30 years. In addition, only 1 of 20 patients tested was classified as having cognitive impairment. 

"This suggests that it is not uncommon for people with RRMS to have only mild or no physical or cognitive dysfunction approximately three decades after clinical onset," Dr Chung concluded.

She noted that only 11 patients in the entire cohort were receiving some sort of treatment, and of the 32 with low-level disability, only 3 had ever been treated — mainly because they were recruited into this cohort before drug therapy was available.

"We will never get a cohort of patients like this again as most patients are automatically put on some sort of treatment at the time of diagnosis," she told Medscape Medical News.

"My take-home is that there are people who have very little disability over the long term," she said. "We estimate this group to be about 25% of all MS patients. You can never say never, but they have lived 30 years without any major problems," she noted.

"Our data suggest there is a case for not putting everyone on treatment straight away. Especially if we can find some predictors of who these patients may be, then we can be a little less aggressive and depending on personality, lifestyle, age, pregnancy wish, et cetera, we can come to a decision that is a bit better informed than we currently do."

For the US study, Andrew Bouley, MD, Brown University, Providence, Rhode Island, analyzed data from 166 patients who had been seen at the hospital's clinic for more than 20 years. Results showed 52 of these (31%) had a benign course, defined as having had MS for at least 20 years and having an EDSS score of 3 or less.   

"Even though MS is very disabling for some individuals, there are also some patients who do really well down the line and are able to work effectively. More than 80% of patients in our cohort have been on a disease-modifying drug, and these therapies might be helping transition to a more benign course," he said.   

"There is currently a movement towards starting aggressive treatment early, but our data suggest that this is not necessary in all patients," he added. "Maybe we should consider stopping and waiting and see if there is any progression before thinking about aggressive treatment."

However, the fourth study, from Cardiff, United Kingdom, had some very different conclusions.

Dr Tallantyre reported data from a cohort of 2000 patients with MS, of whom about 10% met a contemporary definition of benign MS: unlimited walking ability (EDSS score of 2.5 or less) after 15 or more years from onset. Patients who had taken any disease-modifying therapies were excluded.

However, when these patients were examined more thoroughly, with a detailed clinical assessment, cognitive testing, and questionnaires (about mood, fatigue, impact of MS on employment, and bladder function), fewer than a quarter were found to be truly benign (defined as normal function in all domains).

"Our bottom line is that when you look beneath the surface at patients who may appear to have benign MS from an EDSS score, actually most do have symptoms caused by the disease and the number of patients who follow a truly benign course are very few — I would say less than 4%," she concluded. "These patients represent a very interesting group to study to look at the biology."

Dr Corboy said the Cardiff paper was "incredibly important" and supports the idea that "benign MS is a myth that is used to justify not treating aggressively from the outset."

He disagrees with the common definitions used for benign MS. "I would certainly not call an EDSS of 3 at 15 years 'benign' because that means you have significant disability in at least one of seven outcome measures of the subscales and that means your employability at that level would be 70% at best. And then when you follow people for another 10 or 15 years a significant number of those patients go on to use a cane or a wheelchair. That is by no means benign."

"These patients are at high risk of being undertreated," he added. "We struggle to get patients on highly effective therapy from the outset. In 2017 the greatest opportunity we have is to treat people up front."

7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting. Abstracts 199, 200, 327, and 329.  Presented October 26 and 27, 2017.

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