Early MS Progression Independent of Relapse Activity Suggests an Ominous Prognosis

Patients with multiple sclerosis (MS) who present with progression independent of relapse activity (PIRA) after a first demyelinating event were more likely to experience unfavorable long-term disability outcomes, especially if PIRA occurred early in the course of disease, a longitudinal cohort study showed.

Among over 1,100 patients, those with PIRA had higher Expanded Disability Status Scale (EDSS) annual increase rates (0.18 vs 0.04; P<0.001) and an eightfold greater risk of reaching EDSS 6.0 (HR 7.93, 95% CI 2.25-27.96, P=0.001) compared with those without PIRA, reported Carmen Tur, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona, Spain, and co-authors.

Moreover, those with early PIRA had higher EDSS annual increase rates than those with late PIRA (0.31 vs 0.13; P<0.001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR 26.21, 95% CI 2.26-303.95, P=0.009), they noted in JAMA Neurology.

Of all patients with PIRA, 31% developed early PIRA (within 5 years of the disease), and 51% developed active PIRA, i.e., presence of new T2 lesions in the previous 2 years.

“Identifying all who will develop PIRA as soon as possible after the first demyelinating event, especially early PIRA, may lead to better treatment choices, and subsequently, better long-term outcomes,” Tur and team concluded.

Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Of note, older age at the first attack was the only predictor of PIRA (HR 1.43, 95% CI 1.23-1.65, P<0.001 for each older decade).

In an accompanying editorial, Ludwig Kappos, MD, of University Hospital Basel in Switzerland, and colleagues noted that the study’s findings expand on recent “unequivocal evidence … that PIRA is by far the most frequent manifestation of confirmed disability accumulation in RRMS [relapsing-remitting MS] in the era of immunomodulatory and immune-targeting therapeutics,” by extending the findings “to people with MS presenting with a very first demyelinating event.”

They pointed out that PIRA contributed to 66% of all confirmed disability worsening events, while relapse-associated worsening contributed to 34% — “figures [that] are nearly identical to those recently reported from the Italian MS Registry.”

“While both studies are concordant in showing that approximately 1 of 4 patients develops confirmed disability worsening during the early stages of the disease, both probably underestimate the real incidence of confirmed disability accumulation,” Kappos and team wrote.

“In fact, in these studies, the quantification of disability exclusively relies on a change in EDSS score, a measure that is notoriously coarse and that is heavily influenced by deficits in motor function,” they continued. “Combining EDSS score with measures of cognitive function, walking speed, upper limb function, and — more importantly — digital measures allowing more continuous, granular, and comprehensive monitoring of disability worsening should provide more precise estimates of the proportion of patients with RRMS experiencing relapse-independent confirmed progression.”

For this study, Tur and colleagues included 1,128 patients with MS assessed at a single center within 3 months of a first demyelinating attack from January 1994 through July 2021. Mean age was 32.1 years, and 69.2% were women.

Of the included patients, 25% developed one or more PIRA events at a median follow-up time of 7.2 years.

Those with early PIRA versus late PIRA were older (median age 34.8 vs 32.1) and had more spinal cord lesions (≥4 lesions in 8.8% vs 7.2%). Patients with active PIRA were younger (median age 31.1 vs 35.2) and more likely to have cerebrospinal fluid oligoclonal bands (81.0% vs 58.3%) compared with those with nonactive PIRA and had more brain T2 lesions (≥9 lesions in 68.1% vs 37.7%). However, no significant differences in outcomes were observed between the active and nonactive subgroups.

Tur and colleagues noted that the long follow-up of their cohort could be a study limitation, since patients were exposed to various diagnostic procedures and treatments.