MxA mRNA quantification and disability progression in interferon beta-treated multiple sclerosis patients

PLoS One. 2014 Apr 14;9(4):e94794. doi: 10.1371/journal.pone.0094794. eCollection 2014.

Abstract

Even though anti-interferon beta (IFNβ) antibodies are the main determinants of IFNβ bioactivity loss and Myxovirus-resistance protein A (MxA) is the most established marker of IFNβ biological activity in IFNβ-treated multiple sclerosis patients, their usefulness in the routine clinical practice is still debated. Therefore, 118 multiple sclerosis patients naïve for treatment were enrolled for a 3-year longitudinal observational study mimicking the conditions of a real-world setting. In order to evaluate the kinetics of bioactivity loss in blood samples obtained every 6 months after therapy initiation, MxA and interferon receptor isoform/subunit mRNA were quantified by real-time PCR, anti-IFNβ binding antibodies were detected by radioimmunoprecipitation, and neutralizing antibodies by cytopathic effect inhibition assay. Clinical measures of disease activity and disability progression were also obtained at all time points. We found that, at the individual-patient level, the response to IFNβ therapy was extremely heterogeneous, including patients with stable or transitory, early or late loss of IFNβ bioactivity, and patients with samples lacking MxA mRNA induction in spite of absence of antibodies. No interferon receptor isoform alterations that could explain these findings were found. At the group level, none of these biological features correlated with the measures of clinical disease activity or progression. However, when MxA mRNA was evaluated not at the single time point as a dichotomic marker (induced vs. non-induced), but as the mean of its values measured over the 6-to-24 month period, the increasing average MxA predicted a decreasing risk of short-term disability progression, independently from the presence of relapses. Therefore, a more bioactive treatment, even if unable to suppress relapses, reduces their severity by an amount that is proportional to MxA levels. Together with its feasibility in the routine laboratory setting, these data warrant the quantification of MxA mRNA as a primary tool for a routine monitoring of IFNβ therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Neutralizing
  • Biomarkers / metabolism
  • Disability Evaluation*
  • Disease Progression*
  • Female
  • Humans
  • Interferon-beta / therapeutic use*
  • Kinetics
  • Male
  • Middle Aged
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / genetics*
  • Myxovirus Resistance Proteins / genetics*
  • Myxovirus Resistance Proteins / metabolism
  • Patient Dropouts
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Interferon alpha-beta / metabolism
  • Young Adult

Substances

  • Antibodies, Neutralizing
  • Biomarkers
  • Myxovirus Resistance Proteins
  • Protein Isoforms
  • Protein Subunits
  • RNA, Messenger
  • Receptor, Interferon alpha-beta
  • Interferon-beta

Grant support

Biogen Idec sponsored and funded this study. The funders were not responsible for the study design, but monitored clinical data collection; however, they had no role in data analysis and preparation of the manuscript, but provided a critical review before approval for submission.