(Barcelona, Spain, Wednesday, 24, September 2025) Novel research presented today at the 41st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2025) provides the first evidence of specific cerebrospinal fluid (CSF) protein signatures that distinguish patients with progression independent of relapse activity (PIRA) from those with stable disease [1].
PIRA, defined as disability progression occurring outside of relapses and confirmed by sustained worsening on the Expanded Disability Status Scale (EDSS), is increasingly recognised as a major driver of disability in relapsing multiple sclerosis (RMS), yet its biological mechanisms remain poorly understood.
Researchers analysed CSF samples from 122 RMS patients across treatment groups (treatment-naïve, alemtuzumab, natalizumab, and fingolimod) and matched them with detailed longitudinal clinical data. Patients were also categorised into three states (stable [no evidence of disease activity], PIRA, relapse-associated worsening [RAW]), with the current analysis focusing on comparisons between stable patients and those with PIRA.
Using a high-throughput proteomic platform (Olink Explore 3072), investigators screened more than 2,800 proteins and applied advanced machine learning (LASSO regression) to identify discriminatory markers. The analysis revealed 13 proteins that distinguished stable patients from those with PIRA with ~86% accuracy, suggesting that distinct biological pathways drive progression independently of relapses.
“These findings indicate that PIRA involves a complex interplay of immune dysregulation, altered growth factor pathways, and changes in cellular homeostasis,” explained presenting author Andrea Landwehr. “Importantly, we found these signatures not only in treatment-naïve patients but also in those receiving disease-modifying therapies, underlining why current treatments targeting relapses do not fully prevent disability progression.”
The study marks a step forward in MS biomarker research by demonstrating that a small subset of proteins could serve as a robust biomarker panel for identifying and monitoring PIRA. Next steps include validation in independent cohorts and prospective clinical studies, as well as targeted research into the functional roles of these proteins in MS pathophysiology.
“Ultimately, this research may provide tools for earlier detection and patient-specific monitoring of PIRA,” said Landwehr. “It also opens the door to novel therapeutic strategies focused specifically on progression pathways, which could significantly improve long-term outcomes and quality of life for people with MS.”
ENDS
About ECTRIMS 2025:
ECTRIMS 2025 – held on 24-26 September at the CCIB Barcelona International Convention Center in Barcelona, Spain – is the premier meeting place for researchers, clinicians and healthcare providers to collaborate on life-changing research and treatment options for people with MS and related diseases. This year’s programme offers top-tier scientific sessions, education, networking, and more.
Discover more: https://ectrims.eu/ectrims2025
About the study author:
Andrea Landwehr is a researcher at the Department of Neurology, University Hospital Münster, Germany. She is an emerging expert in neuroimmunology, working within the research group led by Prof. Dr Luisa Klotz. Her work focuses on MS and related neuroinflammatory disorders, including biomarker discovery for disease progression, cognitive impairments in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and real-world evaluations of immunotherapies for neuromyelitis optica spectrum disorder (NMOSD) and MOGAD.
References:
- Landwehr A., et al. Proteomic Signatures of PIRA: Distinct proteins in cerebrospinal fluid are associated with progression independent of relapse activity in multiple sclerosis. Presented at ECTRIMS 2025, Barcelona, Spain.