In Secondary-Progressive Multiple Sclerosis, Questions Abound, But So Do Breakthroughs

In setting out to define secondary-progressive multiple sclerosis (SPMS or MS), Bruce Bebo, Ph.D., the executive vice president for research at the National Multiple Sclerosis Society, immediately runs into a problem.

“There’s a little bit of debate in the community about whether MS is a distinct disease, or whether it’s a phase of a continuum of disease,” he tells Managed Healthcare Executive.®

MS is a disease in which the body’s immune system turns against its central nervous system, resulting in damage to myelin-the “insulation” that protects nerve fibers. The results look different from patient to patient, but patients generally experience physical pain and impairment as the disease progresses.

Only about one in 10 people who are diagnosed with the demyelinating disease are initially diagnosed the form that steadily gets worse, called primary progressive MS (PPMS).

The majority of people who are diagnosed with the relapsing-remitting form (RRMS), a form in which patients experience temporary flare-ups (lasting a few days or weeks) that then abate for a period of time. 

Eventually, most patients with RRMS will transition to what’s called secondary-progressive MS (SPMS), in which the back-and-forth of RRMS gives way to a steady progression similar to PPMS. 

The question for Bebo and others in the MS research community is this: Is it all a single continuum, in which some patients aren’t diagnosed until the disease is already in its progressive phase, or are there two separate diseases: one that starts with relapsing/remitting and one that starts with progressive MS. 

If such a question appears academic, it’s become more intriguing in recent years as scientists have begun to make major breakthroughs, with drug developers winning approval from the US Food and Drug Administration (FDA) for more than a dozen disease-modifying therapies. Some of these drugs, such as clabridine, siponimod, and diroximel fumarate, have now been approved to treat both RRMS and active SPMS.

The new class of drugs has shown impressive results, Bebo says. “The evidence is clear that they can significantly reduce the frequency of relapses, and certainly part of the disability that occurs in MS is due to the accumulation of damage that is a consequence of those relapses,” he said. 

What’s less well-known, however, is the extent to which the lessening of damage related to relapses translates into a total cessation of disease progression, or whether there is a parallel underlying progressive pathology that continues unabated, Bebo said. If so, there might eventually need to be a two-part strategy, he said, with one part dealing with the acute inflammatory facet of the disease, and another part tackling the underlying pathology.

“You could imagine a one-two punch where you have an anti-inflammatory approach... and then a neuroprotective approach,” he says.

Other recent advancements have focused on how best to detect and measure MS. Typically, MRI is the primary method by which neurologists measure disease activity and mark the progress of therapies. Bebo said on a population-wide level, lesion volume measured via MRI correlates fairly well with disease severity. However, Bebo said MRI is not a reliable measure of disease severity in an individual patient.

However, new research suggests new biomarkers might help solve the puzzle. Among the first was a 2019 study suggesting sodium accumulation in cortical grey matter is a meaningful indicator of underlying neuronal metabolic abnormalities and therefore could help physicians better understand the disease course and severity in an individual patient.

Another study published in the journal Neurology last year, suggested that blood neurofilament light chain (NfL) might be a meaningful biomarker for disease severity and evolution. 

These advancements might allow physicians a better ability to understand how an individual patient’s disease is progressing and responding to therapy. 

In September, a study in JAMA Neurology, found serum NfL was elevated in patients 6 years before the onset of clinical MS. Bebo said suggests that if MS is a continuum, the continuum begins well before the patient shows up for his first MRI.

“There’s stuff going on well before clinical symptoms,” he says.