Although disease-modifying therapies help reduce the frequency of multiple sclerosis (MS) relapses, they do not cure MS. Not every patient progresses, however, and the factors that promote progression are unclear.

Progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) are not entirely unique, and there is some overlap between the 2. The more stringently a relapse is defined, the more likely it is that the worsening is attributed to PIRA. Conversely, the more loosely a relapse is defined, the more likely it is that the worsening is attributed to RAW. In addition, if the duration between relapse and worsening is short, the worsening is more likely to be attributed to RAW. The frequency of MS worsening attributed to RAW really depends on how hard one looks for it, but at least 50% of MS attacks leave some measurable residual impairment. PIRA also affects many patients, but it is not predetermined that it will occur.

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PIRA may occur at any time, and, in some patients with MS, it can start very early in the disease course. It often goes unrecognized because clinicians are concentrating on stopping patients’ relapses. This is not surprising because, therapeutically, we are much better at controlling relapses than we are at controlling progression. Hopefully, as better therapies become available to control MS progression, we can employ them earlier in the disease course.

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All of our current therapies are essentially aimed at reducing the relapse rate and, to some degree, the disability that occurs in patients with relapsing MS. The effect of the currently available agents on PIRA is still being investigated. While several drugs seem to have some effect on PIRA, it appears to be of a much lower magnitude than their effects on relapse activity. So, there is a major unmet need for more effective therapies. In the phase 3 ORATORIO trial, for example, ocrelizumab showed only a very modest benefit in patients with primary progressive MS. The phase 3 HERCULES study evaluating the investigational agent tolebrutinib in patients with nonrelapsing secondary progressive MS has also reported benefit. Tolebrutinib is not yet US Food and Drug Administration (FDA) approved or available on the market, but it is the first drug to impact the nonrelapsing secondary progressive MS group.

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It is unclear if nonpharmacologic approaches can prevent or reduce the effects of PIRA in patients with MS. We try to emphasize a healthy lifestyle for all of our patients with MS—not just those with PIRA—through the promotion of a well-balanced diet such as the Mediterranean diet, exercise, maintaining vitamin D levels, and not smoking.