Experiencing disability in the early stages of multiple sclerosis (MS), even without relapses, increases the risk of progression to secondary progressive MS (SPMS), a more severe form of the disease, a large study finds. Starting a disease-modifying therapy early on in the disease may decrease the SPMS risk, however, especially if disability worsened due to an incomplete recovery from a relapse. The study, “Risk of secondary progressive multiple sclerosis after early worsening of disability,” was published in the Journal of Neurology, Neurosurgery and Psychiatry. Most people with MS start off with relapsing-remitting MS (RRMS), which features periods when symptoms get worse, called relapses, interspersed with periods of remission when symptoms ease or go away completely. For many, the disease develops into a more severe form, called SPMS, where symptoms gradually worsen over time, regardless of relapses. Symptoms of MS vary and can be severe enough to cause disability, meaning they can keep a person from working and doing everyday tasks. This disability can accumulate either from an incomplete recovery from a relapse, called relapse-associated worsening (RAW), or from gradual progression independent of relapse activity (PIRA). Early disability and secondary progressive MS Early accumulation of disability is linked to worse disability later in life. It’s unclear if having PIRA or RAW early in the disease shortens the time that SPMS develops or speeds up the rate that disability accumulates, leading researchers to review data from 10,692 people with RRMS from across 146 centers and 39 countries who were registered in the MSBase registry (ACTRN12605000455662). The patients had a mean age of 32 at the onset of their disease and 3,125 were men. A total of 2,059 episodes contributing to disability were recorded within the first five years after a diagnosis of MS; 1,232 (60%) were PIRA and 827 (40%) were RAW. Of the 1,896 (18%) patients who had at least one early episode, 1,143 (60%) had only PIRA and 697 (37%) had only RAW events. Fifty-six (3%) had both. Most had only one episode of PIRA (97%) or RAW (91%). Over a mean follow-up of 9.72 years, 1,056 (10%) patients developed SPMS according to the Lorscheider criteria, which are based on increases in the Expanded Disability Status (EDSS) score, a scale where a higher score indicates worse disability. Early PIRA or RAW events were linked to a higher risk of SPMS. That risk increased by 50% for every episode of early PIRA and by 153% for every episode of early RAW. “Worsening of disability experienced within [five] years from disease onset confers a higher risk of developing SPMS,” the researchers wrote. Being a man or being older at the time of disease onset also increased the risk of SPMS. Using a moderate or high-efficacy DMT decreased that risk, reducing it by 5% for every 10% of time on a DMT. Patients with both early PIRA and RAW were 6.28 times more likely to develop SPMS over those without early disability. For those with early RAW, that risk was 3.06 times higher. For those with early PIRA, it was 1.4 times higher. Being on a DMT reduced the effect of early RAW on the risk of developing SPMS. This wasn't seen in the case of early PIRA. “The effect of RAW … is modifiable with timely and sustained disease-modifying therapy and therefore represents an early treatable target for the prevention of progressive disease,” the researchers wrote. There was no link between early PIRA or RAW and the rate that disability accumulated during SPMS. This means, while early disability may increase the risk of SPMS, it's not associated with a faster SPMS progression. “Early PIRA and early RAW are important risk factors and potential determinants of SPMS,” the researchers wrote. This suggests that treating these early episodes may delay or prevent progression to the more severe form of MS.