Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis

Mult Scler. 2014 Jan;20(1):43-50. doi: 10.1177/1352458513490544. Epub 2013 May 23.

Abstract

Background: In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression.

Objective: The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13).

Methods: CSF was obtained from 35 patients with PMS before and after 12-24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays.

Results: The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline.

Conclusions: Our data imply that 12-24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.

Keywords: CXCL13; Multiple sclerosis; axonal damage; biomarkers; cerebrospinal fluid; glial fibrillary acidic protein; immunosuppressive therapy; mitoxantrone; neurofilament light protein; rituximab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal, Murine-Derived / therapeutic use
  • Axons / pathology
  • Biomarkers / cerebrospinal fluid*
  • Chemokine CXCL13 / cerebrospinal fluid
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Glial Fibrillary Acidic Protein / cerebrospinal fluid
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Male
  • Middle Aged
  • Mitoxantrone / therapeutic use
  • Multiple Sclerosis, Chronic Progressive / cerebrospinal fluid
  • Multiple Sclerosis, Chronic Progressive / drug therapy*
  • Multiple Sclerosis, Chronic Progressive / pathology
  • Neurofilament Proteins / cerebrospinal fluid
  • Rituximab
  • Young Adult

Substances

  • Antibodies, Monoclonal, Murine-Derived
  • Biomarkers
  • CXCL13 protein, human
  • Chemokine CXCL13
  • Glial Fibrillary Acidic Protein
  • Immunosuppressive Agents
  • Neurofilament Proteins
  • neurofilament protein L
  • Rituximab
  • Mitoxantrone