Optimizing treatment success in multiple sclerosis

Abstract

Despite important advances in the treatment of multiple sclerosis (MS) over recent years, the introduction of several disease-modifying therapies (DMTs), the burden of progressive disability and premature mortality associated with the condition remains substantial. This burden, together with the high healthcare and societal costs associated with MS, creates a compelling case for early treatment optimization with highly efficacious therapies. Often, patients receive several first-line therapies, while more recent and in part more effective treatments are still being introduced only after these have failed. However, with the availability of highly efficacious therapies, a novel treatment strategy has emerged, where the aim is to achieve no evidence of disease activity (NEDA). Achieving NEDA necessitates regular monitoring of relapses, disability and functionality. However, there is only a poor correlation between conventional magnetic resonance imaging measures like T2 hyperintense lesion burden and the level of clinical disability. Hence, MRI-based measures of brain atrophy have emerged in recent years potentially reflecting the magnitude of MS-related neuroaxonal damage. Currently available DMTs differ markedly in their effects on brain atrophy: some, such as fingolimod, have been shown to significantly slow brain volume loss, compared to placebo, whereas others have shown either no, inconsistent, or delayed effects. In addition to regular monitoring, treatment optimization also requires early intervention with efficacious therapies, because accumulating evidence shows that effective intervention during a limited period early in the course of MS is critical for maintaining neurological function and preventing subsequent disability. Together, the advent of new MS therapies and evolving management strategies offer exciting new opportunities to optimize treatment outcomes.

Keywords: Brain atrophy; Disability evaluation; Drug therapy; Multiple sclerosis.

Fig. 1

The ‘windows of opportunity’ for treatment optimization in MS. Early initiation of treatment, and prompt intervention if disease activity persists despite initial treatment, are both critical to optimizing treatment outcomes. In both cases, there is only a limited period during which intervention will be effective. Adapted with permission from Tintoré [22]

Fig. 2

Associations between inflammatory and degenerative processes in MS and the clinical and MRI features of the disease

Fig. 3

The relationship between relapses, inflammation and disability in MS. The disease process in MS is characterized by both inflammation and progressive neuroaxonal damage. Importantly, such damage may be present in the early stages of MS, but may be masked by compensatory mechanisms; hence, progressive damage may go unrecognized until it is too late for intervention to be beneficial. As the disease progresses, the balance between degenerative and reparative processes shifts, resulting in progressive neuroaxonal degeneration and increasing disability

Fig. 4

Potential treatment strategies in MS. In patients with little evidence of disease activity at baseline, treatment can be started with conventional first-line therapies such as IFN-β, glatiramer acetate, DMF or teriflunomide. Treatment should be monitored every 6–12-months. For patients with highly active disease at baseline or rapidly evolving severe disease (≥2 disabling relapses in 1 year, with at least one Gd+ lesion on T1-weighted MRI or a significant increase in lesion load on T2-weighted MRI), newer agents can be used as first-line therapy. The main differences between these two strategies are the higher responder rate and the earlier onset of action with the latter, which has to be evaluated for each individual patient

Fig. 5

Assessment of patients at risk of disease progression or treatment failure will require attention to both traditional outcome measures, such as relapses and disability, and to newer measures such as MRI assessments of brain atrophy and patient-reported outcomes (PROs). This in turn will require benchmarking to establish baseline levels of disability, allowing longitudinal assessments of disability over time, and standardized MRI protocols to monitor treatment effects on brain atrophy