Box 1 | Multiple sclerosis biomarkers and immunological staging

As a result of its complex clinical and pathogenic heterogeneity, predicting the natural history and treatment response of individual patients with multiple sclerosis (MS) often poses a significant challenge to the clinician. The identification of reliable biological surrogate markers of clinical, prognostic and therapeutic end points is therefore of great interest, not only in daily clinical practice but also as a means to validate new specific treatments. The inability to accurately prognosticate and manage progressive MS is particularly frustrating for clinicians and patients alike.

It is thought that the irreversible accumulation of disability in patients with MS relates to ongoing diffuse neuroaxonal degeneration that is independent, at least in part, from central nervous system (CNS) inflammation. Magnetic resonance imaging (MRI) metrics such as CNS atrophy, T1 hypointense lesion load, N-acetyl-aspartate levels or magnetization transfer ratios of normal-appearing brain matter have been used as surrogate markers of neurodegeneration^{253, 254, 255, 256, 257, 258, 259, 260, 261}. However, their validity to predict disease progression and disability remains to be determined. This uncertainty is illustrated by the clinical and MRI dissociation that is often present in patients with progressive MS, which raises the question of what other additional biological events may contribute to the process. In this respect, as increasing evidence implicates peripheral immunity changes in disease staging^{262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274}, a new notion that adaptive immunity may be involved in relapsing–remitting disease, while specific innate immunity dysfunction may relate to disease progression, is arising. Along this line, we propose that immunological staging, by which patients may be grouped based on their phenotypic and functional-immune profile, could be a novel conceptual tool that, in addition to clinical and imaging staging, may positively affect our understanding and optimize the management of MS on an individual basis, which would be targeted to the specific immune dysfunctions identified.

Owing to the multilevel variability of this disease, it would be impractical to expect that a single biomarker could serve as a true surrogate end point of MS. It should be noted that a large proportion of candidate markers under investigation relate to active inflammation, but other important in vivo processes that contribute to patient clinical outcome such as neurodegeneration and repair, myelination, excitotoxicity and oxidative stress, among others, should also be included in this quest^{275, 276, 277, 278, 279}. Excellent reviews on biomarker classification and their use in MS have been presented elsewhere^{280, 281}.

We performed an antigen microarray analysis to characterize patterns of low-affinity antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Using computational analysis for validation, we found unique autoantibody signatures that distinguished relapsing–remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS), from healthy controls and other neurological or autoimmune diseases³¹⁸. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS and PPMS were characterized by unique patterns of reactivity to CNS antigens.We also examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy⁴ and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to type I and type II patterns. The demonstration of unique serum immune signatures linked to different stages and pathological processes in MS provides a new avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.

As the understanding of the pathophysiology of MS increases, a new era in disease management is envisioned, in which the development of comprehensive immune and non-immune biomarker profiles allow for the stratification of patients with MS who share common clinical, prognostic and/or therapeutic patterns, towards which combination therapies specifically targeted to some or, ideally, all of these processes, can be rationally and individually tailored.