Residual inflammation in the cerebrospinal fluid after short- and long-term natalizumab treatment in relapsing-remitting multiple sclerosis

Background and objectives Natalizumab (NTZ) is a high-efficacy therapy for relapsing-remitting multiple sclerosis (RRMS) that blocks peripheral immune cell migration into the central nervous system. While short-term NTZ treatment reduces cerebrospinal fluid (CSF) inflammation, the extent of residual intrathecal inflammation after long-term NTZ treatment and its association with oligoclonal band (OCB) status remains unclear. In this study, we examined associations between NTZ treatment duration, OCB status and CSF inflammatory and tissue biomarkers as well as presence of residual intrathecal inflammation after more than five years of NTZ treatment. Methods In this cross-sectional observational study, fifteen inflammatory and tissue biomarkers were reliably measured in CSF using validated immunoassays or extracted from clinical records of 88 NTZ-treated RRMS and 104 untreated RRMS patients as well as 94 controls. Results Compared to untreated RRMS patients, most CSF biomarkers were significantly lower in NTZ-treated and controls (Bonferroni-adjusted p (adj-p) < 0.05). However, soluble B cell maturation antigen (sBCMA), soluble CD27 (sCD27), chitotriosidase-1 (CHIT1), IgG index and interleukin-10 (IL-10) were higher in NTZ-treated compared to controls (adj-p < 0.05). NTZ treatment duration was inversely associated with sCD27 levels, and a positive OCB status was associated with higher sCD27 and IgG index (adj-p < 0.05). In patients treated with NTZ for more than five years (n = 41), levels of sCD27, IgG index and sBCMA were higher in OCB-positive patients (adj-p < 0.05), but not in OCB-negative, compared to age-matched controls. Discussion Natalizumab treatment reduces CSF inflammation biomarkers, but after more than five years of treatment levels of sCD27, sBCMA and IgG index remain significantly above control levels in OCB-positive NTZ-treated patients. This indicates residual intrathecal adaptive immune activation in OCB-positive NTZ-treated RRMS patients, suggesting that compartmentalized adaptive inflammation in RRMS is incompletely suppressed by NTZ.