Predictors of Progression Independent of Relapse Activity in Relapsing Remitting Multiple Sclerosis

The goal of this prospective observational cohort study is to determine the frequency of progression independent of relapse activity (PIRA) and identify its clinical, radiological, neuroaxonal, and functional predictors in patients with early relapsing-remitting multiple sclerosis (RRMS) attending the Multiple Sclerosis Unit at Assiut University Hospital. Although relapses have traditionally been considered the primary driver of disability accumulation in RRMS, growing evidence indicates that disability may also progress independently of clinical relapses. This phenomenon, known as PIRA, has emerged as a major contributor to long-term disability and an early manifestation of the progressive disease process. Early identification of patients at risk for PIRA may facilitate timely initiation of high-efficacy disease-modifying therapies (DMTs), improve individualized treatment strategies, and reduce long-term neurological disability.

PIRA is defined as confirmed disability accumulation (CDA) occurring during a relapse-free period and is increasingly recognized as a reflection of chronic neurodegenerative processes and compartmentalized inflammation within the central nervous system. Recent studies suggest that PIRA may occur even during the earliest stages of RRMS and is associated with accelerated brain atrophy, greater gray matter loss, increased risk of conversion to secondary progressive multiple sclerosis (SPMS), and poorer long-term functional outcomes. Despite its clinical importance, reliable predictors of PIRA remain insufficiently established, particularly in patients with early RRMS. This study seeks to address this knowledge gap by integrating clinical assessments with advanced imaging, laboratory biomarkers, optical coherence tomography (OCT), and validated functional outcome measures.

The main questions this study aims to answer are:

What is the frequency of PIRA among patients with early RRMS during the study follow-up period? Which demographic and clinical characteristics are associated with the development of PIRA? Which MRI characteristics, including lesion burden, lesion location, spinal cord involvement, brain atrophy, and chronic inflammatory imaging biomarkers, are associated with subsequent PIRA? Can retinal neuroaxonal measurements obtained by OCT, including peripapillary retinal nerve fiber layer (pRNFL) thickness and macular ganglion cell-inner plexiform layer (mGCIPL) thickness, predict future disability progression independent of relapses? Are circulating biomarkers of neuroaxonal injury and astroglial activation, including serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), associated with the occurrence of PIRA? Which baseline variables independently predict disability progression after adjustment for potential confounding factors? Does combining clinical, radiological, OCT, and laboratory biomarkers improve prediction of PIRA compared with individual markers alone?

Participants diagnosed with early RRMS according to the 2024 McDonald diagnostic criteria and meeting the study eligibility criteria will be prospectively enrolled and followed according to the study protocol.

Each participant will undergo standardized baseline and follow-up evaluations including:

Collection of demographic data, disease duration, clinical presentation, relapse history, disease-modifying therapy exposure, vascular risk factors, and other relevant medical history.

Comprehensive neurological examination with disability assessment using the Expanded Disability Status Scale (EDSS) to determine baseline disability and detect confirmed disability accumulation during follow-up.

Brain and spinal cord magnetic resonance imaging (MRI) using standardized imaging protocols to evaluate T2 lesion burden, gadolinium-enhancing lesions (when clinically indicated), lesion distribution, brain atrophy measures, spinal cord lesions, and, where available, advanced imaging biomarkers such as chronic active lesions or paramagnetic rim lesions.

Optical coherence tomography (OCT) assessment of retinal neuroaxonal integrity through measurement of pRNFL and mGCIPL thickness.

Laboratory assessment of serum biomarkers including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), where available, to evaluate neuroaxonal injury and chronic astroglial activation.

Administration of validated functional and patient-reported outcome measures evaluating cognition, fatigue, depression, quality of life, and physical function, according to the study protocol.

Prospective follow-up to identify confirmed disability accumulation, classify disability progression as PIRA or relapse-associated worsening (RAW), and evaluate disability persistence throughout the observation period.

The primary outcome is the frequency of PIRA, defined as confirmed disability accumulation occurring independently of clinical relapses according to established international criteria.

Secondary outcomes include identification of independent clinical, MRI, OCT, laboratory, and functional predictors of PIRA; determination of factors associated with persistent disability progression; evaluation of the relationship between imaging biomarkers and disability accumulation; and development of a predictive model for early identification of patients at increased risk of PIRA.

The findings of this study are expected to improve understanding of the mechanisms underlying disability progression in early RRMS and provide evidence for integrating multimodal biomarkers into routine clinical practice. Early identification of patients at increased risk of PIRA may facilitate individualized treatment decisions, support earlier use of high-efficacy disease-modifying therapies, and ultimately improve long-term neurological outcomes.

Inclusion criteria

• RRMS diagnosis per 2024 McDonald Criteria Disease duration ≤ 5 years from disease onset At least 1 year on disease-modifying therapy (DMT) Age 18-55 years (both sexes) Written informed consent obtained

Exclusion criteria

• • Alternative diagnosis confirmed (e.g., NMOSD, vasculitis)

• Confirmed RAW
• SPMS or progressive onset at baseline
• Any systemic or neurological disorders affecting either mobility or cognition
• Psychoactive drug use
• Recent optic neuritis within the previous six months.
• Any ophthalmological condition known to affect retinal nerve fiber layer (RNFL) or ganglion cell-inner plexiform layer (GCIPL) thickness.

Glaucoma. Diabetic retinopathy. Retinal vascular disease. High myopia (>6 diopters). Previous ocular trauma or intraocular surgery (except uncomplicated cataract surgery >6 months).

Media opacity preventing reliable OCT acquisition.

• Incomplete follow up or poor compliance