Late-onset MS linked to relapse-free disability progression: Study

People who develop multiple sclerosis (MS) at age 50 or later are more likely to accumulate disability through mechanisms that are not directly linked to relapses or MRI activity than those with earlier-onset disease, according to an Italian registry study.

“This suggests that the adverse prognostic effect of [late-onset MS] is driven predominantly by progression mechanisms that are not fully captured by overt inflammatory activity,” researchers wrote.

The study, “Late-onset multiple sclerosis is associated with relapse-independent disability accrual: a propensity score-weighted recurrent-event study,” was published in the Journal of Neurology.

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Late-onset MS associated with faster disability accumulation

MS usually begins in early or middle adulthood, but about 5% to 12% of patients have late-onset MS (LOMS), usually defined as onset at or after 50 years of age. Compared with adult-onset MS (AOMS), LOMS usually has less typical inflammatory features and is associated with faster disability accumulation.

Because differences in inflammation cannot fully explain the more severe disease course in these patients, researchers believe that aging-related mechanisms, including increased nerve cell vulnerability, reduced ability to repair nerve damage, and the natural deterioration of the immune system, may contribute to faster disease progression.

To validate this, researchers in Italy investigated whether age at onset influences how disability accrues in people with MS. The team analyzed data from 888 people with relapsing-remitting MS included in the Ravenna Multiple Sclerosis Registry. Among them, 759 had AOMS and 129 had LOMS.

The researchers focused on three disability outcomes: confirmed disability worsening (CDW), defined as a sustained increase in disability scores lasting at least six months; progression independent of relapse activity (PIRA), which refers to CDW occurring in the absence of a relapse; and progression independent of relapse and MRI activity (PIRMA), defined as CDW in the absence of relapses, new or enlarging lesions, or lesions with active inflammation.

These findings highlight the need to consider age at onset as a key prognostic factor and suggest that current monitoring strategies based predominantly on inflammatory activity may be insufficient in this subgroup.

Results showed that all three disability outcomes occurred in a greater proportion of people with LOMS. About 30.3% of patients with AOMS versus 39.8% with LOMS experienced CDW, while PIRA was observed in 20.2% with AOMS and 37% with LOMS. PIRMA was seen in 16.3% and 32.2% of people with AOMS and LOMS, respectively.

After adjusting for confounding variables such as sex, initial disability scores, and initial symptoms, rates of CDW became similar in the two groups. However, LOMS remained significantly associated with a higher risk of relapse-independent disability progression, with a 55% increased risk of PIRA and a 63% increased risk of PIRMA compared with AOMS.

When MRI and spinal fluid biomarkers were added to the models, the association with PIRA remained significant, while the link with PIRMA was weaker or lost significance.

Notably, the association between LOMS and worse disability outcomes remained evident even in patients taking high-efficacy disease-modifying therapies.

“This observation is consistent with recent evidence suggesting that anti-inflammatory treatments, although highly effective in reducing relapse activity and MRI inflammation, may have limited impact on progression independent of relapse activity,” the researchers wrote. “These findings highlight the need to consider age at onset as a key prognostic factor and suggest that current monitoring strategies based predominantly on inflammatory activity may be insufficient in this subgroup.”