May 6, 2024 | News | Living with MS MS Research MS Treatments

3 reasons for hope during MS Awareness Month

May is MS Awareness Month in Canada and other countries – a chance to look at how our understanding of MS has changed in important ways in recent years. These shifts in thinking will prove critical to improving the lives of people with MS in the years ahead.

1. Rethinking the disease process. Relapses are the most obvious feature of MS and have been the main focus of attention for decades. The thinking was that relapses caused an accumulation of nerve damage in people with MS that ultimately led to disability. So treatments were developed to reduce the frequency and severity of relapses.

That narrow focus on relapses underwent a sea change a few years ago when researchers recognized that disability (i.e. disease progression) got worse even when there were no relapses (Kappos and colleagues. Mult Scler 2018;24:963-973). This phenomenon would become known as PIRA (for progression independent of relapse activity). Two years later, a study found that about 90% of progression events (when disability got worse and never improved) were in fact PIRA (Kappos and colleagues. JAMA Neurol 2020;77:1132-1140). For all intents and purposes, PIRA is neurological disability – which has had enormous implications for MS research and treatment (Tur & Rocca. Neurology 2024;102:e207936).

First, while relapse reduction certainly makes life better for people living with MS, it does not appear to be a very good measure of whether a treatment is working or not. Relapses are not the target. The true target is the neurodegeneration that results in disability. This has spurred researchers to look at the very complex mechanisms at work in the brain that contribute to disability, as well as the healing mechanisms that could repair nerve damage. Finding the right target(s) is challenging, but work is now underway to explore dozens of novel medications.

Secondly, there is a need to change how treatment success is evaluated. The old measure of success – reducing relapses – will no longer serve. This was seen in the recent trial of evobrutinib, a novel brain-active drug that used relapse reduction as an indicator of treatment success rather than a measure demonstrating an impact on neurodegeneration. The trial failed on this score and evobrutinib is no longer being developed. It remains to be seen if other drugs in this class are able to show that new efficacy measures translate to long-term benefits (Barboza A. Mult Scler Relat Disord 2024;82:105395).

2. Earlier treatment of MS. There have been many efforts to identify MS earlier in the disease course. First there was clinically isolated syndrome (CIS), in which a person had a relapse but did not meet criteria for an MS diagnosis; then radiologically isolated syndrome (RIS), where an MRI detected MS-like lesions in the brain but the person had no signs or symptoms of MS; and then the MS prodrome, a rather vague assortment of symptoms that people may develop before the onset of MS. CIS trials (and more controversially RIS trials) have supported the idea of early treatment to prevent relapses (a criterion for an MS diagnosis).

While this measure of success (preventing a relapse) is of questionable importance, more recent studies have shown the more meaningful benefits of early treatment. For example, a study found that people with CIS (‘early MS’) had a 45% lower risk of developing moderate disability if they received treatment within the first six months rather than later on (Cobo-Calvo and colleagues. Neurology 2023;101:e1280-e1292). That means that early treatment will prolong the time a person can live without disability.

The benefits of early treatment have also been shown in numerous clinical trials, most notably of higher-potency medications. For example, the ASCLEPIOS trial compared people starting treatment with Kesimpta (a higher-efficacy medication) or Aubagio (a moderate-efficacy drug). After 18 months or so, people on the higher-efficacy treatment were significantly less likely to have disability worsening (Hauser and colleagues. N Engl J Med 2020;383:546-557). For the Aubagio group, this higher risk of disability persisted even four years after people switched to Kesimpta (Wiendl and colleagues. American Academy of Neurology 2024;P9.010). The same was seen in the OPERA studies of Ocrevus: people who started with Rebif before switching to Ocrevus did not do as well as those who were treated from the outset with Ocrevus (Hauser and colleagues. AAN 2024;S31.005). These studies illustrate the ‘stitch in time’ idea behind early, effective treatment: it is easier to prevent a problem than to correct the consequences later on.

3. Improving access to care. There was a time not so long ago that MS was considered to be a disease that almost exclusively affected people of northern European descent. MS was thought to be so uncommon in African-Americans or Asians that it was often considered to be a different disease. Improvements in diagnosis and greater awareness of MS among people in non-Western countries has helped to change that view. In fact, the latest research suggests that MS is more severe in people with Black, Hispanic, Middle Eastern and North African ethnicity (Mallawaarachchi and colleagues. Mult Scler Relat Disord 2024;81:105153).

What is difficult to tease out is how much of these differences are due to the disease itself and how much to the so-called social determinants of health, such as access to health care, poverty, nutrition, employment and working conditions (Robers & Amezcua. Curr Opin Neurol 2024;37:245-251). If a person does not have insurance through their employer, it may be years before they are seen by a doctor, the doctor may misdiagnose because they do not expect to see MS in that person, and treatment may not be started until after disability has become advanced. All of these barriers to care may make MS seem worse in a disadvantaged population than it otherwise would be if it were treated promptly and effectively (Marrie and colleagues. Neurology 2006;66:1235-1240). That said, a recent study comparing Black and White Americans accounted for social determinants of health and found that Blacks with MS still suffered from greater impairments in walking ability and physical performance (Huynh and colleagues. Mult Scler Relat Disord 2024;83:105439). These findings show the urgency of addressing the specific needs of different populations living with MS.

The invisible nature of MS in non-White populations has created two important problems that researchers are now looking to correct. Underdiagnosed groups do not show up in health databases, which are essential tools for understanding the nature of MS. Everyone needs to be represented to get a more complete picture of the disease. Secondly, few non-White persons with MS have been enrolled in drug trials thus far, so there is still uncertainty about the effectiveness of medications in some groups of people. That is now starting to change. The first drug trial exclusively in Blacks and Hispanics (called CHIMES, for Characterization of ocrelizumab in minorities with multiple sclerosis), which enrolled people from the U.S., Puerto Rico and Kenya, found that ocrelizumab appeared to be highly effective in these groups. Hopefully, that will help to overcome any reluctance to treat.

MS poses many challenges that will not end anytime soon. It is a complex disease, the disease likely differs in different people, and the best approaches to control the disease and enhance healing have not been fully worked out. But there are many reasons for hope – and not just the three outlined here. We are now at the beginning of a renaissance, a time of reimaging MS, that one day soon will improve the lives of people living with MS.

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