MxA protein – an interferon beta biomarker in primary progressive multiple sclerosis patients A. Millonig a , A. Dressel b , D. Bahner b , A. Bitsch b , T. Bogumil b , E. Elitok b , B. Kitze b , H. Tumani b , F. Weber b , C. Gneiss a and F. Deisenhammer a a Department of Neurology, Innsbruck Medical University, Innsbruck, Austria and b Department of Neurology, Georg-August-University, Go ¨ttingen, Germany Keywords: biomarker, clinical trial, Interferon beta, Multiple sclerosis, MxA, neutraliz- ing antibodies, Primary progressive multiple sclerosis Received 28 February 2008 Accepted 30 April 2008 Background and purpose: Interferon beta (IFNb) preparations have some effect on the progressive phase of multiple sclerosis (MS). This limited effect might be partially because of a certain number of IFNb non-responders. Myxovirus resistance protein A (MxA) – a marker of IFNb bioactivity – was correlated with the clinical response during an uncontrolled trial, investigating the safety of IFNb-1b in primary pro- gressive (PPMS) patients. Methods: Twenty PPMS were treated with IFNb-1b (s.c.) for 1 year. Blood samples were taken before and 1, 2, 3, 6, 9, 12, and 15 months after treatment initiation and MxA protein levels were measured. Patients were clinically evaluated by EDSS and the more sensitive Incapacity Status Scale (ISS) and stratified in a stable and a progressing group. Results: Using ISS criteria, 11 patients remained stable and nine patients progressed during treatment. The mean area under the curve of log MxA levels during treatment were significantly higher in stable than in pro- gressing patients (10.87 vs. 5.99; P = 0.002). Conclusion: A good biological response to IFNb might be associated with a better clinical effect of this drug and could be helpful in future clinical studies for early identification of treatment responders. Introduction Primary progressive multiple sclerosis (PPMS) is a subtype of multiple sclerosis (MS) characterized by a progressive course from the onset of disease without superimposed relapses and remissions. Approximately 10% of patients with MS show this clinical phenotype that differs from relapsing–remitting MS (RRMS) by an older age of onset, a more balanced sex ratio, and a poorer prognosis [1,2]. As yet no drugs have been approved for therapy of PPMS and only few clinical trials specifically addressing PPMS patients have been conducted, partly because of relatively small patient numbers and lack of validated outcome measures [3]. However, two randomized pla- cebo-controlled trials showed some beneficial effects of interferon beta (IFNb) in PPMS patients [4,5]. The bioactivity of IFNb can be measured by several biomarkers e.g., neopterin, tumor necrosis factor-related apoptosis inducing ligand, matrix metalloproteinase 9, signal transducers and activator of transcription 1 (STAT-1), and myxovirus resistance protein A and B (MxA, MxB) [6–9]. The most specific and sensitive of these biomarkers is MxA [10]. This antiviral protein is probably not involved in the therapeutic action of IFNb but has been shown to be specifically and in a dose- dependent manner, upregulated by type I interferons. Also, there is some evidence that MxA correlates with the clinical response to IFNb [10–17]. Methods Patients and study protocol We prospectively investigated blood samples for neu- tralizing antibodies (NAB) and MxA in a single arm, open-label clinical trial that was conducted at the Department of Neurology, University of Go¨ttingen, Germany. In this trial, 20 PPMS patients were treated with IFNb-1b for 1 year [18–22]. Thirteen of the pa- tients were men and seven were women. Age ranged from 18 to 60 years (mean 46) and disease duration ranged from 2 to 18 years (median 9). EDSS scores [23] Correspondence: Florian Deisenhammer MD, MSc, Professor of Neurology, Department of Neurology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria (tel.: +43 512 504 24264; fax: +43 512 504 24266; e-mail: florian.deisenhammer@i-med.ac.at). Addresses: A. Dressel (Department of Neurology, University of Greifswald, Ellernholzstrabe 1/2, 17847 Greifswald, Germany); D. Bahner (Klinik fu¨r Neurologie, Klinikum Bad Hersfeld, Seilerweg 29,36251 Bad Hersfeld, Germany); A. Bitsch (Ruppiner Kliniken GmbH, Fehrbelliner Strabe 38, 16816 Neuruppin, Germany); T. Bogumil (Bayer HealthCare Pharmaceuticals Inc., PO Box 1000, Montville, NJ 07045, USA); H. Tumani (University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany); F. Weber (Section of Neurology, Max-Planck Institute of Psychiatry, Kraepelinstrabe 2-10, 80804 Munich, Germany); and Dr. Ercan Elitok (Nihon Kohden Europe Gmbh, Raiffeisenstraße 10, 61191 Rosbach v.d.H., Germany). 822 Ó 2008 The Author(s) Journal compilation Ó 2008 EFNS European Journal of Neurology 2008, 15: 822–826 doi:10.1111/j.1468-1331.2008.02190.x