Worsening Disability Independent of Relapse Linked to Brain Atrophy in Relapsing MS

Disability progression independent of relapse activity (PIRA) was associated with accelerated brain tissue loss in patients with relapsing multiple sclerosis (RMS), a longitudinal cohort study found.

Brain volume atrophy, driven by gray matter loss in cerebral cortex, was increased in patients with PIRA compared with clinically stable RMS patients (mean difference in annual percentage change −0.36, 95% CI −0.60 to −0.12, P=0.02), reported Cristina Granziera, MD, PhD, of the University of Basel, Switzerland, and co-authors in JAMA Neurology.

Brain volume loss of both deep and cortical gray matter also was seen in RMS patients who had relapses (mean difference in annual percentage change −0.18, 95% CI −0.34 to −0.02, P=0.04) compared with clinically stable patients. After propensity-score matching, the rate of brain atrophy did not differ for PIRA and relapsing groups, Granziera and colleagues observed.

PIRA has recently emerged as a crucial clinical feature in RMS, Granziera and co-authors noted. "Our results showing an association between PIRA and diffuse neurodegeneration provide strong evidence of the need to promptly recognize PIRA, to prevent the accrual of irreversible central nervous system tissue damage," they wrote.

"Recognizing silent progression when it occurs could prompt clinicians to consider changing treatments to therapies known to have beneficial effects in patients with progressive forms of MS (such as siponimod or ocrelizumab) or refer such patients to clinical trials in progressive forms of MS," Bruce Cree, MD, PhD, of the University of California, San Francisco (UCSF), who was not involved with the study, told BreakingMED.

The term "silent progression" was first described in the UCSF longitudinal EPIC cohort, Cree noted. In that cohort, "some participants with relapsing multiple sclerosis were found to experience worsening disability as measured by increases in the EDSS [Expanded Disability Status Scale] that was independent from relapsing disease activity," he said.

"This worsening of neurologic disability occurred so insidiously that its occurrence was largely unrecognized by clinicians or their patients who were considered to still have relapsing MS," Cree continued. "This phenomenon was surprisingly common and was termed ’silent progression’ to signify progressive worsening of disability that occurred silently, meaning without being recognized by the patient or the clinician. The radiographic features of those with silent progression were similar to patients with secondary progressive MS."

In 2020, an international group of researchers assessed the contribution of relapse-independent progression to disability accumulation in an analysis of pooled phase III trial data of ocrelizumab versus interferon β-1a and concluded that "most overall disability accumulation in RMS is attributable to an underlying progressive disease course independent of relapse activity, challenging the current phenotypical distinction of relapsing and progressive forms of MS."

In their study, Granziera and colleagues evaluated 516 patients ages 18-80 with RMS (mean baseline age 41.4, 67.4% female) seen at MS centers and referral hospitals in the Swiss Multiple Sclerosis Cohort, an observational multicenter study. Data were obtained between January 2012 and September 2019, with a median follow-up of 3.2 years. The analysis was propensity-score matched for variables including age, sex, disease duration, and treatment with disease-modifying therapies.

All participants had two or more brain MRIs available for volumetric analysis (median number of scans was four). Measurements included total brain volume, total and deep gray matter, total white matter, cerebral cortex, thalamus, cerebellum, and ventricular system. Mean cortical thicknesses for whole and regional areas were determined, and total intracranial volume was used to adjust for head-size differences.

Expanded Disability Status Scale (EDSS) scores were assessed by certified raters every 6 or 12 months. The median study entry score was 2.0. Confirmed disability progression was defined as an EDSS increase—confirmed 6 months after the first decline—of 0.5 to 1.5 points on the scale, depending on baseline disability level.

PIRA was defined as an episode meeting criteria for confirmed disability progression with no relapse during 90 days before the EDSS increase, or during the 6-months between initial EDSS increase and confirmation.

The researchers identified four groups of patients: those with at least one relapse but no PIRA during follow-up (relapse-only, n=122); at least one episode of PIRA but no relapse during follow-up (PIRA-only, n=46); at least one episode of relapse and one of PIRA (mixed, n=14); and no relapse and no PIRA (clinical stability, n=334).

Annualized median rates of change in EDSS points for the groups were 0 for the relapse-only group, 0.20 for the PIRA-only group, 0.19 for the mixed group, and 0 for the clinically stable reference group. Radiological inflammatory activity was linked with increased atrophy rates in several brain compartments, while a higher annualized relapse rate was linked to accelerated deep gray matter volume loss.

"Approved disease modifying therapies may differ in the ability to prevent disability accumulation due to PIRA, and escalation/induction strategies have not yet been assessed in patients with PIRA," the researchers wrote. "Future clinical trials should therefore aim at identifying the best therapeutic strategy for these patients, both those with and those without relapses."

Limitations of the study include PIRA determined by EDSS scores which may have missed small or subtle worsening, and MRI data acquired with different protocols.

In addition, the analysis did not include measurement of spinal cord atrophy or cortical lesions. "Both may help further characterize the mechanisms underlying PIRA, as they have been previously shown to predict physical disability and disease progression, silent progression, and conversion to secondary progressive MS," Granziera and colleagues acknowledged.

The Swiss Multiple Sclerosis Cohort study received funding from the Swiss MS Society and unrestricted grant funding from Biogen, Celgene, Merck, Novartis, Roche, and Sanofi.

Granziera reported that her institution received research support and other fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro, Roche, and Siemens.

Cree has received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, EMD Serono, Gossamer Bio, Horizon, Neuron23, Novartis, Sanofi, TG Therapeutics, and Therini and received research support from Genentech.

Cagol A, et al "Association of brain atrophy with disease progression independent of relapse activity in patients with relapsing multiple sclerosis" JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2022.1025.