In addition, use of blood biomarkers such as NABs and MxA could improve the sensitivity and accuracy of early recognition of responders and nonresponders to IFNB. and PE859 nonresponders to interferon beta. However, since the presence of neutralizing antibodies can only partially explain the nonresponse to interferon beta, biomarkers of interferon beta activity possibly related to the pathogenesis of the disease could represent a future step toward a tailored, long-lasting effective treatment against multiple sclerosis. ? 2009 EFNS. Abbreviations: IFNB, interferon beta; MRI, magnetic resonance imaging; HR, hazard ratio. Composite scores to identify response and nonresponse to IFNB Some investigators still consider that isolated MRI activity is not sufficient to determine IFNB failure, and have proposed composite scores based on PE859 integration of different parameters of disease activity to identify response and nonresponse to IFNB treatment.24,53C55 This PE859 latter suggestion is based on evidence that the effect of treatment around the combination of MRI activity and relapses in the first year accounts for almost 100% of the effect of treatment on progression of disability at 2 years.56 The Canadian MS Working Group has updated its recommendations to neurologists for optimal use of disease-modifying agents.57 While these consensus recommendations were based on a qualitative analogic model that takes into account relapses, disability, and MRI features during treatment, other groups have designed quantitative scoring systems based on combinations of clinical and radiological disease activity.53,54 The seminal paper suggested that only the concomitant presence of at least two parameters (relapses, progression of disability, activity on MRI) in the first year of treatment with IFNB has significant value for identifying nonresponders in the subsequent 2 years.53 This scoring system was recently refined on the basis of a reanalysis of the active arms of the PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study,7 and was then validated in a separate group of patients from the post-marketing Barcelona cohort.53 This new scoring system, known as the modified Rio score,54 classified patients into three risk groups for disability progression based on first-year treatment events: low risk, ie, 4 new T2-hyperintense lesions and no relapses; medium risk, ie, 4 new T2-hyperintense lesions and one relapse or .4 new T2-hyperintense lesions and no relapses; and high risk, ie, 4 new T2-hyperintense lesions and 2 relapses or 4 new T2-hyperintense lesions and one relapse.54 However, despite its excellent specificity (97%), this score demonstrated very low sensitivity (24%), implying a significant risk of misdiagnosing poor responders to IFNB. The modified Rio score has recently been refined further, with the suggestion that a second MRI scan 6 months on from the 1-year MRI scan enables better classification of the medium-risk group.24,55 The authors suggest that patients who relapse or accumulate two or more new T2 lesions during months 12C18 of treatment with IFNB can be classified as nonresponders.24,55 Blood-derived biomarkers of response and nonresponse to IFNB Biological markers of responsiveness to treatment, with IFNB in particular, are landmarks of research in multiple sclerosis. According to the National Institutes of Health Biomarkers Definitions Working Group,58 a biomarker is usually a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Biological activity can be defined as the pharmacological, physiological, and biochemical effects resulting from the interaction of a drug with its target receptor, and is a necessary but not sufficient condition for effectiveness. Development of neutralizing antibodies (NABs) is one of the main reasons for reduction or loss of PPP1R49 biological activity of IFNB.59C61 NABs develop in 2%C40% of treated patients according to the manufacturers of the product, and the majority of NAB-positive patients are identified within the PE859 first 2 years of treatment.62 The immunogenicity of IFNB is mainly influenced by the manufacturing process and the formulation, frequency of injection, route of administration (the subcutaneous route being more immunogenic than the intramuscular route) and dose used.63 Several studies have shown that the outcome for NAB-positive patients, in terms.