Large Study Uncovers How Patients With Multiple Sclerosis Acquire Disability Over Time

Findings were published in Brain in February 2022. Fred D. Lublin, MD, the Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai and a world- recognized authority on multiple sclerosis (MS), was first author. Dr. Lublin is Director of Mount Sinai’s Corinne Goldsmith Dickinson (CGD) Center for Multiple Sclerosis.

Significantly, the team examined not only relapse-associated worsening (RAW), but a clinical area that has received little attention in the past—progression independent of relapse activity (PIRA). Says Dr. Lublin: “Our study found that PIRA plays a significant role in disease worsening in adult relapsing-remitting multiple sclerosis (RRMS), the most common form of MS, and we further learned that PIRA gradually becomes the principal way by which patients with MS acquire disability in progressive disease.”

Providing an ideal tool for researchers to investigate the mechanisms of disability acquisition was the Novartis-Oxford multiple sclerosis (NO.MS) dataset. It is currently the largest and most comprehensive clinical trial dataset for MS, spanning all phenotypes and containing data from approximately 27,000 patients who received up to 15 years of follow-up. This resource enabled the team to analyze the relative importance of RAW and PIRA, the role of relapse on all-cause disability worsening, and the impact of the mechanisms of worsening and disease-modifying therapies (DMTs) on the length of time to reach milestone disability levels.

The study revealed the following:

• Relapses are a significant and clinically meaningful contributor to all-cause disability worsening.

• Preexisting disability and older age are the principal risk factors for further disability accumulation, suggesting that patients developing residual disability after a relapse are more likely to do so on subsequent relapses, perhaps due to the body’s lack of adequate repair capacity or neuronal plasticity.

• Pediatric MS is almost exclusively of the relapsing sub-type, with relapse rates higher in pediatric-onset than adult-onset MS.

• PIRA starts early in MS, occurs across all phenotypes (pediatric, relapsing-remitting MS, secondary progressive MS, and primary progressive), and becomes the primary driver of disability accumulation in the progressive phase of the disease.

Among the most important findings were those relating to the impact of DMTs, many of which Dr. Lublin and his colleagues at Mount Sinai have been involved in developing over the past 30 years. For placebo-treated patients with minimal disability (EDSS 1), it took 8.95 years to reach increased limitation in walking disability (EDSS 4) and 18.48 years to require walking assistance. Treating patients with DMTs significantly delayed those times by 3.51 years and 3.09 years, respectively. In cases of relapsing-remitting MS, patients who worsened exclusively due to RAW events took a similar time to reach milestone EDSS values compared to those with PIRA events, with the fastest transitions observed in patients with PIRA and superimposed relapses.

“Current MS therapies primarily target focal inflammation and therefore their relative effect is strongest and most promising in young patients where inflammation is most prominent,” explains Dr. Lublin. “The extent to which disease-modifying therapies impact long-term outcomes has not been fully answered, but by elucidating the mechanisms of disability accrual and their contribution to impairment, our work is opening important new doors to research in this critical area for MS patients.”