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In MS, progression independent of relapse activity is associated with neurodegenerative processes in the spinal cord and the presence of chronic active lesions.

Progression independent of relapse activity (PIRA), a feature of progressive MS (PMS), contributes greatly to accumulated disability in relapsing-remitting MS (RRMS), yet researchers do not fully understand its underlying mechanisms. Accelerated brain atrophy has been found with PIRA, but other neurodegenerative processes may be involved.

“Progression happens in all patients with MS, regardless of disease subtype,” Tirisham Gyang, MD, who was not involved in the current study, explains.

“Predicting whether a patient we diagnose with MS on day one rapidly progresses or develops a steadier progression over 10, 20, or 30 years is difficult,” Dr. Gyang continues. “The EDSS [Expanded Disability Status Scale] scale can miss very subtle changes in, for example, a patient who is progressing but has not yet crossed the threshold from one EDSS score to the next.”

To investigate whether PIRA is linked with the rate of spinal cord atrophy and the burden of brain paramagnetic rim lesions (PRLs), Alessandro Cagol, MD, and colleagues conducted an observational, longitudinal multicentric study of patients with MS who participated in the Swiss Multiple Sclerosis Cohort between January 2012 and March 2022.

The study included patients aged 18-80 with an MRI scan that included 3-dimensional echo planar imaging (3D-EPI) and a regular clinical and conventional MRI follow-up during the 4 years prior to the 3D-EPI scan. Participants also underwent standardized neurologic tests, including EDSS scores, at least once a year. The mean baseline age of the 445 participants was 45; 64.9% were female, and 11.2% had PMS.

The researchers compared spinal cord atrophy rates using linear mixed-effect models and PRL count using negative binomial regression models between 1.) relapsing-remitting MS (RRMS) and PMS phenotypes and 2.) patients with PIRA and patients without confirmed disability accumulation (CDA) during follow-up. Using multivariable Cox regression analyses, they investigated links between baseline MRI volumetric measurements and time to PIRA. 

The findings were published in Neurology. 

PIRA Tied to Increased Structural Damage

Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; 95% CI -2.36 to -0.47; P=0.004). The PMS group also had higher PRL load (incidence rate ratio [IRR] 1.93; 95% CI 1.25-3.12; P=0.005).

Increased spinal cord atrophy (MD-APC -1.39; 95% CI -2.18 to -0.59; P<0.001) and PRL burden (IRR 1.95; 95% CI 1.34-2.92; P=0.0008) were found in patients with PIRA compared with those without confirmed disability accumulation. Such differences also held when analysis was restricted to patients with RRMS (Figure).

Baseline volumetric measurements of the cervical spinal cord, whole brain, and cerebral cortex significantly predicted the length of time to PIRA (all P≤0.002).

PIRA “is associated with neurodegenerative processes in the spinal cord and with the presence of brain chronic active lesions,” the study team reported. “Our results, together with previous evidence showing increased CNS structural damage in PIRA, stress the need for early recognition of PIRA in clinical practice to prevent irreversible tissue loss.” 

Findings May Lead to Validated MS Markers

The results from Dr. Cagol and colleagues “have clinical relevance and may lead to the development and validation of future predictive markers,” Dr. Gyang says.

The authors acknowledged the limitations of their study, including that the one-time assessment of PRL burden for each patient precluded studying the relationships between PRLs and PIRA over time. In addition, the 4-year follow-up period, chosen a priori, may have biased the results; subclinical cervical cord focal inflammation may have partially influenced the observed rates of spinal cord atrophy, and the EDSS did not detect subtle neurologic worsening.

Importantly, though, Dr. Gyang says the study shows that patients with relapsing forms of MS have progression independent of relapse. “We need more studies like this and more metrics that capture and predict MS progression over time, which is usually slow and difficult to assess. “

Further, in clinical trials of MS, “we can measure only what our validated tools allow us to measure,” she says. “This study highlights our need for more validated markers that can become clinical and research tools to help us understand progress over time.”