Natalizumab Induces Changes of Cerebrospinal Fluid Measures in Multiple Sclerosis

Abstract

Background: There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. Aim: We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. Methods: Together, 411 patients were screened for eligibility and 93 subjects with ≥2 CSF examinations ≤6 months before and ≥12 months after natalizumab initiation were recruited. The effect of natalizumab on CSF as well as clinical and paraclinical measures was analyzed using adjusted mixed models. Results: Natalizumab induced a decrease in CSF leukocytes (p < 1 × 10−15), CSF protein (p = 0.00007), the albumin quotient (p = 0.007), the IgG quotient (p = 6 × 10−15), the IgM quotient (p = 0.0002), the IgG index (p = 0.0004), the IgM index (p = 0.003) and the number of CSF-restricted oligoclonal bands (OCBs) (p = 0.0005). CSF-restricted OCBs positivity dropped from 94.6% to 86% but 26 patients (28%) had an increased number of OCBs at the follow-up. The baseline to follow-up EDSS and T2-LV were stable; a decrease in the relapse rate was consistent with a decrease in the CSF inflammatory markers and previous knowledge about the effectiveness of natalizumab. The average annualized brain volume loss during the follow-up was −0.50% (IQR = −0.96, −0.16) and was predicted by the baseline IgM index (B = −0.37; p = 0.003). Conclusions: Natalizumab is associated with a reduction of basic CSF inflammatory measures supporting its strong anti-inflammatory properties. The IgM index at the baseline predicted future brain volume loss during the course of natalizumab treatment.

A single-cell analysis framework allows for characterization of CSF leukocytes and their tissue of origin in multiple sclerosis

“…Although we could identify subclusters within B cells isolated from the CSF of patients with MS and were able to detect some B cells in tumefactive MS lesions, the virtual absence of these cells in CSF from controls and natalizumab-treated patients suggests that B cells represent a mostly infiltrating cell type in relapsing-remitting MS. B cells represented a very small fraction of leukocytes in immune cell enriched control brain snRNAseq datasets (0.06%), and these displayed a rather naive phenotype. However, because there are reports of resident plasma cells in secondary progressive MS lesions ( 14 ) and the presence of oligoclonal bands is hardly reduced by treatment with natalizumab ( 62 ), infiltrating B cells may differentiate into resident plasma cells over the disease course.…”

Editorial of Special Issue “Multiple Sclerosis: From Diagnostic Biomarkers to Imaging and Clinical Predictors”

“…In order to treat the neuroinflammatory pathology in MS, multiple anti-inflammatory disease-modifying therapies (DMTs) have been developed with various levels of efficacy and safety properties [ 11 ]. The manuscript by Subramaian et al explores the effect of natalizumab (antibody against α4-integrin that blocks the leukocyte adhesion and their migration through the blood–brain barrier) on CSF-based and MRI-based inflammatory markers [ 12 ]. In the 93 MS patients that had data before and after natalizumab initiation, natalizumab resulted with a significant decrease in CSF leukocytes, protein level, albumin quotients and CSF-based oligoclonal bands [ 12 ].…”

“…The manuscript by Subramaian et al explores the effect of natalizumab (antibody against α4-integrin that blocks the leukocyte adhesion and their migration through the blood–brain barrier) on CSF-based and MRI-based inflammatory markers [ 12 ]. In the 93 MS patients that had data before and after natalizumab initiation, natalizumab resulted with a significant decrease in CSF leukocytes, protein level, albumin quotients and CSF-based oligoclonal bands [ 12 ]. In nine patients, the oligoclonal bands disappeared completely after natalizumab treatment [ 12 ].…”

“…In the 93 MS patients that had data before and after natalizumab initiation, natalizumab resulted with a significant decrease in CSF leukocytes, protein level, albumin quotients and CSF-based oligoclonal bands [ 12 ]. In nine patients, the oligoclonal bands disappeared completely after natalizumab treatment [ 12 ]. The strong natalizumab-induced changes in CSF inflammatory metrics were concurrently occurring with the reduction in relapse activity and stabilizing the disability worsening, T2 lesion volume accrual and the rate of brain atrophy [ 12 ].…”

“…In nine patients, the oligoclonal bands disappeared completely after natalizumab treatment [ 12 ]. The strong natalizumab-induced changes in CSF inflammatory metrics were concurrently occurring with the reduction in relapse activity and stabilizing the disability worsening, T2 lesion volume accrual and the rate of brain atrophy [ 12 ].…”