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From Unità dipartimentale: Centro Riferimento Regionale Sclerosi Multipla (CReSM) and Neurobiologia Clinica (Drs. Bertolotto, Gilli, Sala, Capobianco, Malucchi, Milano, Melis, Marnetto, Bottero, Di Sapio, and Giordana), Ospedale Universitario S. Luigi Gonzaga, Orbassano (Torino), Italy; and Departments of Research and Neurology (Dr. Lindberg), University Hospitals, Basel, Switzerland.
Address correspondence and reprint requests to Dr. Antonio Bertolotto, Centro Riferimento Regionale Sclerosi Multipla (CReSM) & Neurobiologia Clinica, Azienda Ospedaliera S. Luigi di Orbassano, Regione Gonzole 10, 10043 Orbassano, Italy; e-mail: NSGLB{at}tin.it
Background: MxA is an antiviral protein exclusively induced by type I interferons (IFN) and some viruses, and MxA gene expression is one of the most appropriate markers for measuring the biologic activity of exogenous IFNß.
Methods: A new quantitative-competitive PCR method was used to quantify MxA mRNA in peripheral blood mononuclear cells of 99 treatment-naïve and 92 IFNß-treated patients with MS (22 Avonex, 17 Betaferon, and 53 Rebif-22). Every 3 months, IFNß-induced neutralizing antibodies (NAb) were evaluated in sera using a cytopathic effect assay. Three categories of patients were identified: NAb negative (NAb-), persistent NAb positive (NAb+, 
2 consecutive positive samples), and isolated NAb+ (one positive sample).
Results: Treatment-naïve patients expressed detectable MxA mRNA levels (mean = 36 ± 32 fg MxA/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH); range 1 to 160) and an upper normal threshold was established (mean + 3 SD = 132 fg MxA/pg GAPDH). IFNß-treated patients exhibited more than 11-fold higher levels (mean = 412 ± 282 fg MxA/pg GAPDH; range 16 to 1,172). However, 17 patients did not exhibit an increase in MxA mRNA level; 15 of these 17 patients showed a concurrent Nab+ titer. Moreover, 13 were persistent NAb+. Isolated NAb+ patients did not show a decrease in bioavailability of IFNß (n = 9; mean = 567 ± 366 fg MxA/pg GAPDH; range 83 to 1,120). In NAb- patients, bioavailability was comparable among the three different IFNß preparations 12 hours after injection.
Conclusion: During IFNß therapy, the presence of NAb reduced or abolished bioavailability in a relevant percentage of patients. These data could be important for the early detection of patients with MS who are not responsive to IFNß therapy.
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