Does Progression Without Relapse Warrant Reclassification of MS?

Randy Dotinga

February 22, 2023

Progression independent of relapse activity (PIRA) is fairly common among patients with multiple sclerosis (MS) and is linked to poorer outcomes in new findings that investigators say should prompt reconsideration of how patients with relapsing-remitting MS are classified.

"We believe that these patients should be considered to be patients with progressive MS, with or without MRI inflammatory activity, independent of their disability score or their disease duration," lead author Carmen Tur, MD, PhD, Autonomous University of Barcelona, Spain, and colleagues write.

"This may have therapeutic implications," they add.

The findings were published in the February issue of JAMA Neurology.

"Silent Progression"

Tur told Medscape Medical News his team conducted the study to gain more insight into the effect of PIRA.

"Over the last 2 to 3 years, it has been proposed that PIRA is the main mechanism responsible for the accumulation of disability in multiple sclerosis," she said.

"This has also been called 'silent progression' and can occur at any time during the disease course, even before a formal diagnosis of secondary progressive MS. We aimed to assess the PIRA phenomenon and its long-term consequences in patients with a first demyelinating attack," Tur added.

The investigators tracked 1128 patients (69.2% women; mean age, 32.1 years) who had a first demyelinating attack from MS from 1994–2020 and who were treated at a study center in Spain.

Of the participants, 277 (25%) developed one or more PIRA events at a median follow-up time of 7.2 years.

"Presenting with at least one PIRA event at any time during the disease course is strongly associated with an unfavorable long-term prognosis, especially if such first PIRA event occurs within the first 5 years of the disease," Tur noted.

If that happened, risk for reaching a marked level of disability (defined as a score of 6 on the Expanded Disability Status Scale [EDSS]) "was 26 times higher than that of patients who present with PIRA at later stages of the disease," she said. The hazard ratio (HR) was 26.21 (95% CI, 2.26 – 303.95; P = .009).

Risk for reaching an EDSS of 6 was eightfold higher overall among those with PIRA vs those without PIRA (HR, 7.93; 95% CI, 2.25 – 27.96; P = .001)

PIRA in the presence of previous inflammatory activity was not clearly associated with a worse prognosis compared with nonactive PIRA.

Underlying Process?

Tura noted that the researchers also observed that PIRA was the main factor responsible for the accumulation of disability in patients with relapse-onset MS as opposed to relapse-associated worsening, as shown in previous studies.

Unfortunately, "we found that prediction of PIRA is extremely challenging. In our cohort, only an older age at symptom onset predicted higher risk of PIRA," Tura said.

PIRA is such a good indicator of poor outcomes, said Tura, because it may reflect "an underlying neurodegenerative process, which may be present from symptom onset in some patients.

"Thus, the fact that a patient presents with PIRA may suggest...there is a relatively strong or perceptible neurodegenerative process that will most likely determine their long-term prognosis," she added.

She noted that the study highlights the importance of detecting PIRA early since it "may have important prognostic implications."

She added that the findings may contradict the idea that "relapsing-remitting MS is characterized by relapses, with a variable degree of recovery after them and no clear progression between relapses.

"Do we need to change the current clinical classification of MS?" Tura asked.

"Robust Results"

Neurologist Cristina Granziera, MD, PhD, University of Basel, Switzerland, co-wrote an accompanying editorial. Commenting for Medscape Medical News, she said the study appears valid, and "the size of the cohort gives confidence that the results are robust."

In addition, Granziera said the findings jibe with her observations of patients in the clinic ― and she agrees that it is time to reclassify types of MS.

"The disease is extremely complex," she said. "We need to find other ways of defining our patients, and this cannot be done solely using clinical parameters."

Granziera added that MRI scans, biomarkers, and spinal fluid tests can provide other helpful information.

The study was funded by La Caixa Foundation, the Spanish Ministry of Science and Innovation, and Fundación Merck Salud. Tur has received speaker honoraria from Roche and Novartis and nonfinancial support from Biogen. Granziera has received grants from the Swiss National Science Foundation, Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung, Horizon 2020, Siemens, GeNeuro, and Roche as well as institutional fees from Actelion, Genzyme-Sanofi, Novartis, GeNuero, and Roche. Disclosures for the other investigators and editorialists are listed in the original articles.

JAMA Neurol. Published online December 19, 2022. Abstract, Editorial

Randy Dotinga is a freelance journalist and board member of the Association of Health Care Journalists.

For more Medscape Neurology news, join us on Facebook and Twitter.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.