Paramagnetic rim lesions (PRLs) are a subset of chronic active multiple sclerosis (MS) lesions, characterized by a rim of iron-laden macrophages and microglia encircling a demyelinated core. These lesions signify persistent inflammatory activity in the central nervous system (CNS), yet their responsiveness to B cell depletion therapy has not been well established. Ocrelizumab, a humanized monoclonal antibody that targets CD20+ B cells, is effective in suppressing acute MS activity; however, its impact on chronic CNS inflammation, particularly within PRLs, remains unclear. To address this question, we conducted a retrospective longitudinal imaging study of MS patients undergoing Ocrelizumab treatment. All participants had pre-treatment imaging with at least one PRL identified via quantitative susceptibility mapping (QSM). Using an R2*QSM source separation (SS) framework, we disentangled the contribution from iron sources with positive susceptibility (QSMp) and myelin sources with negative susceptibility (QSMn) to quantify iron and myelin changes within lesions. Lesions were individually segmented, and PRLs were classified through expert consensus. Modeling of QSMp and QSMn was performed using mixed effects and joint-point regression analysis to assess temporal changes in lesion properties. Across 29 patients, we identified 97 PRLs. Prior to treatment, PRLs exhibited significantly elevated QSMp compared to non-PRLs (p=0.001), consistent with iron enrichment at the lesion rim. Following Ocrelizumab initiation, PRLs showed a significantly greater reduction in QSMp than non-PRLs (p<0.001), with joint-point analysis revealing an accelerated decline beginning approximately four months after treatment for PRLs. PRLs demonstrated lower QSMn values than non-PRLs pre-treatment (p<0.001), but without significant post-treatment divergence (p=0.382). Joint-point analysis revealed a steep increase in QSMn beginning approximately three months after treatment for PRLs. These findings suggest that Ocrelizumab may influence the trajectory of chronic active MS lesions by attenuating iron-related inflammation. This work provides preliminary insight into the potential of B cell-targeting therapies to modulate slow-burning inflammatory processes in MS and underscores the value of advanced MRI techniques, such as R2*QSM SS, in capturing subtle treatment effects on chronic CNS pathology.

The authors have declared no competing interest.

This study was funded by Genentech (ML44547)

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IRB of Weill Cornell Medicine gave ethical approval for this (IRB #22-12025448)

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Raw data were generated at Weill Cornell Medicine. Derived data supporting the findings of this study are available from the corresponding author on request.