Photo Credit: iStock.com/Nathan Devery

Moogeh Baharnoori, MD, discusses findings that question the role of progression and worsening indices as markers of neurodegeneration in multiple sclerosis.

Progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) may not be the best measure to determine the clinical impact of neurodegeneration in relapsing-remitting multiple sclerosis (RRMS), according to study findings published in Neurology.

“PIRA and RAW in their current definitions do not reliably distinguish between disability worsening due to inflammatory disease activity and neurodegeneration in RRMS,” researchers wrote. “In addition, PIRA and RAW have similar and troubling issues of random variation and measurement error as currently used trial outcome measures.”

Drawing Data From AFFIRM & SENTINEL Trials

 The study team reanalyzed individual patient-level data from the phase III AFFIRM and SENTINEL randomized controlled trials. These investigations compared monoclonal antibody therapy with interferon beta or placebo for RRMS in 2,113 participants at sites in 11 countries. Patients were, on average, in their mid- to late-thirties, and most were women.

Using records from visits that took place every 3 months for 2 years, the researchers calculated 3-month confirmed disability worsening (3M-CDW), RAW, and PIRA events based on worsening scores on the Expanded Disability Status Scale (EDSS), 9-hole peg test (9-HPT), or timed 25-foot walk test. They related worsening and improvement events to MRI activity during follow-up and contrasted worsening of disability with improvement.

Among their findings:

• Within 3-month consecutive time windows over 2 years, EDSS-related PIRA events increased from 2.3% of patients at 12 weeks to 6.8% at 108 weeks.
• More than 40% of patients (42.6%) who had EDSS-based PIRA events developed MRI activity within the first follow-up year, and 36.3% developed MRI activity in the second year.
• Between baseline and year 1, 42.7% of all EDSS-related improvement independent of relapse activity (IIRA) events were linked to radiologic disease activity, compared with 22.1% between year 1 and year 2.
• During follow-up, the number of 3-month confirmed disability improvement and IIRA events surpassed the number of 3M-CDW and PIRA events at all visits; the maximum was 10.5% of patients with IIRA at week 108 compared with 6.8% with PIRA.
• Improvement events exceeded PIRA events through the follow-up period and occurred in all trial groups.
• Time-to-PIRA between participants with and without radiologic disease activity was similar.

An Outside Expert’s Perspective

Moogeh Baharnoori, MD, PhD, a neurologist who was not involved in the study, spoke with Physician’s Weekly (PW) about the study and its potential impact on future clinical research and patient care.

PW: Why was this data reanalysis necessary?

Dr. Baharnoori: There is an emerging interest in using PIRA as an outcome measure for gradual MS progression and neurodegeneration. This is particularly important as we face more clinical trials testing medications for progressive MS. This study raises important questions about the validity of using PIRA as a biomarker for neurodegeneration and non-inflammatory disease progression.  

 Did the results surprise you?

In MS, disability may accumulate at any stage due to two main mechanisms: PIRA and RAW. While RAW is mostly associated with ongoing neuroinflammation, it is believed that underlying neurodegeneration drives PIRA.

It was reassuring to see an overall low number of PIRA and RAW events in this cohort. I was not surprised by the low number of RAW events, given that study participants were treated with a strong immunosuppressant.

I was surprised to see that a high percentage of individuals with PIRA had underlying MRI activity. This finding suggests that some PIRA events captured using the current definition may be driven by subclinical radiologic disease activity rather than a purely neurodegenerative process. I was also surprised that while PIRA and IIRA events increased during the trial period, RAW and relapse-associated improvement events remained stable.

As the authors mentioned, both RAW and relapse-associated improvement events may possibly extend beyond 90 days, which is our current cut-off for defining relapse-related worsening or improvement.

How could the findings impact the care of patients with RRMS?

The important take-home message is the role of subclinical MRI activity—the presence of new or enlarging T2 lesions or contrast-enhancing lesions without clinical relapse—in disability accrual over time. After all, asymptomatic radiologic disease activity may not be as benign as one may think. Clinicians need to consider treatment escalation in patients with RRMS who have ongoing MRI activity without clinical relapse to ensure disease stability over time.

Are any strengths or limitations especially noteworthy?

The main strength of this study was using original clinical trial data, including a comprehensive battery of tests: EDSS, T25FW, and 9-HPT. The authors calculated both disability worsening and improvement associated with relapse activity and independent of relapse. This comprehensive approach led to robust data on the validity of using this measure in capturing disability progression.

One limitation was that MRI scans were done annually, while disability data were calculated based on clinical assessments performed every 3 months. The lack of spinal cord MRI data also limits this study. It is well known that spinal cord lesions and cord atrophy are important determinants of MS disability progression over time.

What questions remain unanswered for you?

To what extent subclinical MRI activity drives PIRA events in patients with primary or secondary progressive MS remains unknown. It will be informative to conduct such an analysis in a cohort of patients with progressive MS and to perform similar studies on the clinical trial data of other classes of MS medications, such as B-cell therapies.

The other unanswered question is the concept of cognitive PIRA. It is not clear whether cognitive impairment independent of relapse is also affected by underlying radiologic disease activity or if it can be potentially used as an independent disability outcome in relapsing and progressive MS clinical trials.

Is there anything else you’d like to mention?

PIRA is generally accepted as a proxy for the neurodegenerative process of MS. However, this study highlights that the pathologic substrates of PIRA are not yet well understood.

These data suggest that some parts of PIRA are driven by underlying radiologic disease activity. The term PIRMA (progression independent of relapse and MRI activity) was recently introduced to capture disability accumulation in the absence of clinical relapse and new brain and spinal cord lesions. PIRMA might be a more accurate measure to capture MS-related neurodegeneration in future studies. Another important avenue to explore is using fluid biomarkers such as Neurological Fatigue Index (NFI) and Glial Fibrillary Acidic Protein (GFAP) to capture PIRA and RAW events.

Ultimately, we need a disability outcome measure that can be easily applied in clinical practice, particularly when performing frequent MRI exams is prohibited by limited access and high cost and doing a comprehensive battery of tests such as EDSS, T25FW, and 9-HPT are limited by time constraints in real-world clinical practice.