Association Between Retinal Layer Atrophy With Clinical and Radiologic Progression in People With Relapsing Multiple Sclerosis.

Progression independent of relapse activity (PIRA) is the main driver of disability accumulation in relapsing multiple sclerosis (RMS). Retinal layer atrophy measured by optical coherence tomography (OCT) reflects neuroaxonal damage and is associated with PIRA. However, it remains unclear whether this association is driven by subclinical inflammatory activity or reflects true progression independent of acute inflammation. Here, we aimed to investigate the relationship between retinal layer atrophy and progression independent of relapse and MRI activity (PIRMA) to clarify the impact of subclinical inflammatory activity. From an ongoing prospective observational study, patients with RMS meeting the following criteria were included: an OCT scan conducted 3-6 months after disease-modifying treatment (DMT) initiation (rebaseline) and at least one follow-up OCT after ≥12 months. Disability accrual was defined as a composite measure comprising worsening in either Expanded Disability Status, Timed 25-Foot Walk Test, 9-Hole Peg Test, or Symbol Digit Modalities Test using a roving baseline with a 6-month confirmation interval. PIRA was defined as disability accrual without relapse between roving baseline and confirmation. PIRMA was defined as PIRA that remained radiologically silent. We evaluated associations between PIRMA and thinning of the peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell plus inner plexiform layer (GCIPL) using multivariable mixed-effects linear regression models adjusted for relevant covariables (age, sex, disease duration, GCIPL/pRNFL at rebaseline, and moderate vs high-efficacy DMT). A total of 210 patients with RMS (mean age 30.5 years, SD 7.9; 74.1% female) were analyzed over a median observation period of 2.3 years (range 1-5.9 years). PIRMA was observed in 28 (13.3% overall, 41.8% of all disability accruals, 54.1% of PIRA) patients, while PIRA was encountered in 50 (23.8% overall, 77.2% of all disability accruals). Multivariable models revealed that PIRMA (vs no PIRMA) was associated with significantly more pronounced thinning of both GCIPL (0.72% per year, 95% CI 0.50-0.82, p < 0.001) and pRNFL (1.05% per year, 95% CI 0.89-1.18, p < 0.001). Our findings indicate that retinal atrophy is significantly linked with PIRMA, reinforcing its potential as a biomarker of MS-related neuroaxonal degeneration that occurs independently of acute focal inflammation.