title: MxA mRNA quantification and disability progression in interferon beta-treated multiple sclerosis patients.
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.
authors.affiliation: CREA, Diagnostics Department, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Serana
authors.affiliation: CREA, Diagnostics Department, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Imberti
authors.affiliation: Department NEUROFARBA, Neuroscience Section, University of Florence, Florence, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Amato
authors.affiliation: Department of Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Multiple Sclerosis Center, S. Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gasperini
authors.affiliation: Multiple Sclerosis Center, Gallarate Hospital, Gallarate, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ghezzi
authors.affiliation: Department of Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Neurological Clinic, Ospedali Riuniti of Ancona, Ancona, Italy.
authors.forename: Leandro
authors.initials: L
authors.lastname: Provinciali
authors.affiliation: Multiple Sclerosis Center, Papa Giovanni XXIII Hospital, Bergamo, Italy.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Rottoli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Sotgiu
authors.affiliation: UOSI Riabilitazione Sclerosi Multipla, IRCCS Istituto delle Scienze Neurologiche of Bologna, Bologna, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Stecchi
authors.affiliation: Multiple Sclerosis Center, St. Elia Hospital, Caltanissetta, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Vecchio
authors.affiliation: Multiple Sclerosis Center, Gallarate Hospital, Gallarate, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Zaffaroni
authors.affiliation: Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cordioli
authors.affiliation: Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: Capra
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing; D015415:Biomarkers / Q000378:metabolism; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics*; D064547:Myxovirus Resistance Proteins / Q000235:genetics* / Q000378:metabolism; D010352:Patient Dropouts; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; D064547:Myxovirus Resistance Proteins; D020033:Protein Isoforms; D021122:Protein Subunits; D012333:RNA, Messenger; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta
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