Key risk factors for progression independent of relapse activity in relapsing-remitting MS include age and longer disease duration.
During the 2023 Fall Conference of The American Academy of Neurology, Augusto Miravalle, MD, FAAN, gave an update on MS and neuroimmunology, with a review of current diagnostic standards for MS, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. In discussing the results with Physician’s Weekly, Dr. Miravalle highlighted the “critical” role of progression independent of relapse activity (PIRA) in MS.
A study published in JAMA Neurology by Jannis Müller, MD, Cristina Granziera, MD, PhD, Ludwig Kappos, MD, and several other researchers examined the available evidence on PIRA through a systematic review. The researchers also studied terminology used in the context of PIRA and suggested a “harmonized definition” of PIRA for use in clinical practice and clinical trials.
“Relapsing-remitting MS (RRMS) is typically characterized by relapses—for example, neurologic dysfunctions occurring within days—followed by more or less complete recovery,” Dr. Müller, Dr. Granziera, and Dr. Kappos tell PW. “The conventional belief was that, in the time between relapses, the disease is dormant, and no clinical deterioration occurs. However, systematic long-term studies and the use of increasingly effective drugs to prevent relapses have revealed continuous progression in these seemingly quiescent phases among patients with a typical relapsing course. This newly uncovered phenomenon, termed ‘PIRA,’ has been repeatedly documented in various patient groups in recent years.”
Age & Disease Duration Influence PIRA
The research team included 48 studies in their analysis and found that PIRA occurred in approximately 5% of all patients with RRMS per annum, causing at least 50% of all disability accrual events in typical RRMS.
“We pinpointed PIRA as the most frequent form of disability accrual in RRMS,” Dr. Müller and colleagues note. “Identified key risk factors included age, longer disease duration, and, despite a lower number of absolute events, potent suppression of relapses by highly effective disease-modifying therapies. However, the comparability of the studies was hampered by a variety of PIRA definitions that were used.”
To address that, the investigators identified relevant factors that constitute a PIRA event, such as timing, dynamics and severity of clinical deterioration, and the duration of the absence of relapses. “We combined these elements with established descriptors related to progression in MS used in protocols of prospective controlled clinical trials and observational cohorts,” they explain. “Further, we refined these descriptors in several iterative rounds to optimally describe the clinical phenomenon of PIRA, incorporating clinical trial, imaging, body-fluid biomarker, and biostatistical expertise.”
Incorporating PIRA in Clinical Practice
The detailed description of the factors that encapsulate PIRA will provide clinicians and researchers with “clear diagnostic criteria” that can lay the groundwork for earlier, more reliable detection of PIRA, Dr. Müller, Dr. Granziera, and Dr. Kappos explain.
“Our proposed harmonized definition balances the sensitivity and specificity and improves the comparability of results in current and future cohorts and data sets,” they say. “Ultimately, it serves as a valuable tool to quantify treatment response in studies that aim at the prevention of long-term disability accumulation using targeted, individually tailored therapies.”
Future research should assess PIRA in the context of comprehensive digital measures, such as active tasks, passive monitoring, and patient-reported outcomes, to gather “a more nuanced understanding of the phenomenon of PIRA,” Dr. Müller and colleagues say. “Also, the relationship between PIRA and MRI activity should be further elucidated using conventional and advanced brain and spinal cord imaging techniques to extend our understanding of the relation of subclinical (focal) inflammation and clinical PIRA.”
Such research can “capitalize on the advantages offered by real-world evidence while incorporating elements of randomized prospective trial design,” they note.
Further, including the concept of PIRA in standard definitions of MS, as well as more advanced concepts that are based on multimodal characterization, offers the chance for “a more accurate prediction of both the natural disease course and the response to targeted therapeutic options,” according to Dr. Müller and colleagues.
