Modifying disability in progressive multiple sclerosis

www.thelancet.com Vol 383 June 28, 2014 2189 Multiple sclerosis is the most common cause of chronic neurological disability in young adults in developed countries and seems to be increasing in frequency. Disease presentation in 80–90% of patients follows an initial phase characterised by bouts of relapsingremitting neurological dysfunction. These relapses are thought to represent focal areas of infl ammation in the CNS, and arise with unpredictable frequency and variable recovery. However, after an inconsistent interval, most patients then develop a progressive disease course, with a gradual development of disability in the absence of relapses. The later disease phase accounts for most of the permanent disability and is thought to be mediated by neurodegenerative processes including axonal degeneration. Although some controversy remains regarding the rate at which conversion to secondary progressive multiple sclerosis takes place, a fi gure of 2–3% per year with age-related infl uences is widely accepted. The overall eff ect, in a disorder whose duration exceeds 30 years, is that most patients will, at some stage, develop secondary progressive multiple sclerosis, and at any one time most prevalent patients are in a disease phase for which there is no eff ective treatment. Initial therapeutic advances targeted the early infl ammatory disease phase, with several licensed immunomodulatory treatments emerging. Treatments available to clinicians for management of relapsingremitting multiple sclerosis are now substantial. Available drugs all have an eff ect on relapse frequency, reduction of brain MRI lesion formation, and can reduce permanent disability when defi ned as worsening with no reversal in 3–6 months. However, the pattern of rising severity and frequency of serious adverse events with increasing drug effi cacy needs careful patient selection, clinical management, and surveillance. Despite these limitations, early and eff ective intervention for relapsing-remitting multiple sclerosis is hoped to have the long-te rm outcome of delaying or abolishing the progressive phase. Nevertheless, evidence for the long-term outcome of early intervention has so far been elusive and, although a much debated treatment strategy, a reluctance to administer powerful immunomodulators at onset, in a disease which can have a highly variable outcome, has made quantifi cation of the eff ect of early aggressive immunomodulatory treatment on long-term outcome diffi cult. No licensed drugs have shown a convincing eff ect on long-term disability, or specifi cally on progressive disease. Although identifi cation of interventions that have a signifi cant eff ect in modifi cation of physical disability in progressive disease is a main aspiration of clinical trials of multiple sclerosis, an obstacle will be the large numbers of patients needed to achieve adequate power when conventional measures of disability are used. Indeed, this challenge might have contributed to negative results in trials of progressive disease to date, and more accurate contemporary power calculations are needed to inform future studies that aim to report disability as the primary outcome measure. As a result, eff ective alternative measures to identify promising drugs in phase 2 studies are needed before large-scale investments in larger trials are considered. In multiple sclerosis, measurement of brain atrophy has been recognised as a plausible surrogate outcome for disability, and some studies of immunomodulatory drugs have shown an eff ect on reducing this outcome. Further support for the use of change in brain volume in this context has also emerged in an analysis of treatment in relapsing multiple sclerosis that showed a correlation of treatment eff ect on brain atrophy with the eff ect on disability (r2=0·48). However, the association with eff ect on disability was greater with use of MRI lesion activity (r2=0·61) and greater still when both MRI outcomes were combined (r2=0·75). Modifying disability in progressive multiple sclerosis 11 The European Parliament and the Council of the European Union. Directive 2011/36/EU of the European Parliament and of the Council of 5 April 2011 on preventing and combating traffi cking in human beings and protecting its victims. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:20 11:101:0001:0011:EN:PDF (accessed May 7, 2014). 12 Council of Europe. Convention on Human Rights and Biomedicine. April 4, 1997. http://conventions.coe.int/Treaty/en/Treaties/Html/164.htm (accessed May 7, 2014). 13 Joint Council of Europe/United Nations Study. Traffi cking in Organs, Tissues and Cells and Traffi cking in Human Beings for the Purpose of the Removal of Organs (2009). http://www.edqm.eu/site/Report-1-TO-en-569-1.html (accessed May 7, 2014).