Progressive forms of multiple sclerosis present a number of challenges for MS specialists, the biggest of which being whether or not disease-modifying therapy is required.
Managing disease for patients with progressive multiple sclerosis (MS) is currently an area of care that poses some difficulty for specialists. Many of the approaches are limited in the sense that they are only available for active disease, and few options exist to address the accumulation of disability experienced by many patients.
Occasionally, though, as Benjamin Segal, MD, chair, Department of Neurology, and director, Neuroscience Research Institute, The Ohio State University, told NeurologyLive and discussed in his lecture at the ACTRIMS Forum 2021, the conversation with patients who have progressive disease can center around the discontinuation of therapy altogether due to a lack of benefit from disease-modifying therapy (DMT) in inactive disease.
Although, a number of patients have active disease and do experience relapses that require treatment with DMT. Some of the therapies available for the treatment of progressive disease include siponimod (Mayzent; Novartis) for secondary progressive MS (SPMS), and ocrelizumab (Ocrevus; Genentech) for primary progressive MS (PPMS). A few others are indicated for active disease in SPMS, including cladribine (Mavenclad; EMD Serono) and a number of other DMTs that can be used for relapses.
In a recent NeurologyLive Peer Exchange, “Management of Progressive Multiple Sclerosis,” a group of MS specialists came together to discuss these challenges and the state of care for progressive MS. Led by Bruce Cree, MD, PhD, professor of clinical neurology, and George A. Zimmermann Endowed Professor in Multiple Sclerosis, Department of Neurology, University of California San Francisco, the panel covered what physicians should keep in mind when assessing their patients’ therapeutic needs.
“Up until the ORATORIO study, we didn’t have a treatment for progressive disease, be it PPMS or SPMS. The use of ocrelizumab in patients with PPMS was shown to have a modest effect: a 20% or 30% reduction in disability progression at 3 months in 20% to 30% of individuals,” Joseph R. Berger, MD, professor of neurology, and associate chief, Multiple Sclerosis Division, Hospital of the University of Pennsylvania, highlighted in episode 4 of the series. He added that anti-CD20 monoclonal antibodies have shown some effect in PPMS, and while no data are available to suggest that they’re as effective in SPMS as PPMS, “there’s no reason to think not.”
Additionally, Berger noted that sphingosine 1 receptor 1 (S1P1) modulators such as siponimod have shown modest reductions in the progression of the disease and on relapses, but thus far, none of the approved agents have delivered the “home run,” as Berger puts it, that MS specialists have been hoping for.
“But at least we’re seeing some effect,” he said. “In my mind and in reading the literature, where they seem to be most effective, at least in individuals with SPMS, are in those individuals who are in that transition phase where they still have superimposed relapses and active disease. These drugs are most effective in that context.”
Although the understanding of the driving forces behind progressive disease is still in its infancy, much is being done to gain that knowledge. This is some of what Segal pointed out in his lecture at ACTRIMS Forum 2021, noting that while the field is aware that there is a destructive response from the immune system which, in turn, transforms the clinical course of disease from a relapsing-remitting pattern to a more gradual and progressive accumulation of disability, "we don't really have a good grasp on that.” Segal told NeurologyLive that this lack of understanding speaks to the current approaches to these different phases of the disease, and their overall modest effects.
“There are some therapies—or classes of drugs—that were originally used in relapsing-remitting MS [RRMS] that have shown some efficacy in progressive MS, but they mainly work in younger patients with progressive MS, and patients who still have a vestige of the inflammatory activity that drives relapsing-remitting disease,” Segal said. When patients enter this state of progressive disease, the evidence of blood-brain barrier breakdown—which leads to enhancing lesions and clinical episodes—is not there, these drugs become less effective.
Additionally, Segal noted that the differences in disease phases might reflect the normal, age-related changes in the immune system intersecting with the autoimmune process that causes damage in progressive MS. One such difference is the breakdown of the blood-brain barrier, something observed in RRMS but not in progressive MS. Segal speculates that protective plasma cells, which accumulate in perivascular infiltrates in the meninges as we age, may play a role, though this is not well understood.
“As we age, there is a systemic, low-grade chronic inflammation and the release of a lot of pro-inflammatory molecules from macrophages throughout the body,” Segal said. “Some of these pro-inflammatory molecules may cross the blood-brain barrier and cause this widespread microglial activation that we see in progressive MS. It’s not as prevalent in RRMS. Those factors might also cause activation of the microglia at the rim of lesions.”
And while research is ongoing to grow this understanding of the underlying processes of progressive disease, patients still require regular care, and the decisions that must be made involving DMTs can be tricky. In the panel discussion, Kristen Krysko, MD, staff neurologist, Unity Health Toronto–St Michael's Hospital; and assistant professor, University of Toronto, noted the elements that she takes into account when assessing a patient’s needs. The first of those, of course, is whether or not to start a patient on a DMT, with the risk-benefit ratio being taken into careful consideration.
“First, I think age is an important factor because younger individuals in the trials have tended to show a better response to therapy. If we have someone presenting with PPMS or converting to SPMS at a young age, that would be a factor that leaves me more likely to recommend treatment,” Krysko said. “Younger individuals also have more activity. The patients who have gadolinium-enhancing lesions or relapses recently are more likely to benefit as well. That’s been shown in a number of the trials in progressive MS.”
In addition to younger patients, Krysko highlighted that recent onset of disease, evidence of new lesions, enhancing lesions, and/or relapses are all reasons to indicate that a patient with progressive MS would benefit from therapy. As well, comorbidities and the level of an individual’s disability are worth taking into account, as they can increase the risks of DMT, such as infection rates or issues with tolerability. For instance, a patient who is wheelchair-bound is likely at a higher risk for infection, making them an unlikely candidate for immunosuppressive treatment.
“The rate of progression is also something to consider. Even if someone’s not having activity, if you see them getting worse at each clinic visit, it’s hard not to recommend a therapy that may provide some benefit. Whereas if someone’s stable, it’s hard to know if you’re providing any benefit of the treatment,” she added.