Coma Bella 2014

www.thelancet.com/neurology Vol 13 January 2014 113 Review Body fluid biomarkers in multiple sclerosis Manuel Comabella, Xavier Montalban Biomarkers can be thought of as multifaceted indicators of healthy status or of pathological disorders. The study of multiple sclerosis can benefit from the use of biomarkers because of the disease’s inherent heterogeneity. Biomarkers in multiple sclerosis might assist with diagnosis, prediction of disease course, or identification of response outcome to treatments. Despite the need for biomarkers and extensive research to identify them, validation and clinical application of biomarkers is still an unmet need in multiple sclerosis, and large gaps remain between exploratory biomarkers proposed in many studies, validated biomarkers, and biomarkers that are integrated into routine clinical practice. Introduction Biomarkers can be defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic inter- vention”. 1 Multiple sclerosis (MS) is a complex disease that is characterised by a high degree of heterogeneity in clinical, radiological, and pathological features and therapeutic response. 2–5 Therefore, biomarkers that reliably capture the different aspects of disease hetero geneity are needed, and might help to better understand MS disease aetiopathogenesis, diagnosis, and prognosis; to predict response outcome to treatments; and to develop new treatments. The biomarker research field is very active in MS. However, despite the large numbers of candidate molecular biomarkers proposed, very few biomarkers have been rigorously validated and used in clinical practice. In this Review, we discuss the strength of evidence for predictive, diagnostic, disease activity, and treatment- response body fluid biomarkers in MS, with a focus on biomarkers that might affect clinical decision making (ie, antibodies against natalizumab, neutralising antibodies to interferon beta, anti-aquaporin-4 antibodies, and antibodies against varicella zoster and JC viruses); comment on factors that might disrupt the path from biomarker discovery to clinical application; and discuss the desired properties of a biomarker and the right tests to measure it. Types of molecular biomarkers in MS Categorisation Molecular biomarkers in MS can be categorised into four groups: predictive, diagnostic, disease activity, and treatment-response biomarkers (figure 1). Use of prognostic biomarkers as a separate group has been avoided, since all biomarkers in the four groups have prognostic implications. Some biomarkers can be included in several groups—eg, the light subunit of neurofilaments (NEFL) could be regarded as a diagnostic biomarker based on increased concentrations in CSF in patients with clinically isolated syndrome who have later converted to clinically definite MS; 6 or as a disease activity biomarker based on its association with the number of gadolinium-enhancing lesions; 6 and potentially as a response biomarker to natalizumab based on the significant reduction in CSF NEFL concentrations in patients with MS who have been given the drug. 7 Predictive and diagnostic biomarkers Predictive biomarkers could be used to identify individuals at risk of developing MS. Predictive biomarkers would be measured in neurologically asymptomatic individuals, mainly first-degree relatives of patients with MS. Diagnostic biomarkers can be used to distinguish patients who have MS from patients with other neurological or autoimmune disorders, or from healthy individuals. Diagnostic biomarkers are measured in patients with neurological symptoms suggestive of a demyelinating disorder, those with clinically isolated syndromes, 8 and those with radiologically isolated syndromes. 9 Ideally, these biomarkers can be helpful in combination with clinical and radiological disease diagnostic criteria to improve the sensitivity and specificity of diagnosis. The use of d iagnostic biomarkers might be particularly relevant in patients with clinically isolated syndromes or for patients in the early phases of the disease who do not yet fulfil consensus diagnostic criteria in order to identify individuals in whom the first neurological event is due to MS and not other neurological disorders. Disease activity biomarkers Disease activity biomarkers can be measured in patients with relapsing-remitting and progressive disease courses. In patients with MS, these biomarkers can be more or less associated with the different pathophysiological processes of the disease. 10 Biomarkers of inflammation, demyelination, and oxidative stress are expected to have more important roles in the relapsing- remitting phases of the disease than are biomarkers of glial dysfunction, remyelination, and axonal damage, which will be related to the progressive and, hence, neurodegenerative phases of MS. This type of biomarker can help to distinguish between patients with benign MS and those with aggressive disease courses, on the basis of the presence of clinical activity (relapses and accumulation of disability), radiological inflammatory activity (changes in T2-weighted and gadolinium- enhancing lesions on MRI), and development of brain atrophy. Disease activity biomarkers can be used in Lancet Neurol 2014; 13: 113–26 Department of Neurology and Neuroimmunol ogy, Centre d’Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d´Hebron, Barcelona, Spain (M Comabella MD, Prof X Montalban MD) Correspondence to: Dr Manuel Comabella, Centre d’Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d´Hebron, Barcelona 08035, Spain [email protected]

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Coma Bella 2014