Treatment strategies in multiple sclerosis : current and future practice considerations

This thesis focuses on clinically-relevant questions regarding the care of patients with relapsing remitting multiple sclerosis (RRMS), including appraisal of the current relevant literature regarding the disease itself and therapeutic approaches. An understanding of the nature of MS is detailed in a review of its characteristics and natural history in the pre-treatment era, to establish a baseline upon which the utility of disease modifying therapies (DMTs) in the modern era can be evaluated. A review of the history of therapeutics in MS leads into an appraisal of trials in the modern era, including potential and actual pitfalls in their design and interpretation. A comprehensive tabulation of the pivotal placebo-controlled and head-to-head DMT trials is included and allows an appreciation of the complexity in evaluating the evidence-base for the therapeutic options currently available. Inter-trial comparisons are often made despite differing patient populations, methods and outcome analyses and these are discussed. The potential for new therapeutic options is also considered in light of emerging evidence for novel treatment approaches. The original work in this thesis stems from practical clinical dilemmas in the management of patients with RRMS and uses real-world observational data to address them. The available evidence-base supports the early initiation of DMTs in RRMS on short-term efficacy grounds, but there remains controversy regarding the timing and aggressiveness of therapeutic intervention, particularly with higher risk treatments, and uncertainty regarding the impact on long-term outcomes. We have studied the safety and efficacy of the oral DMTs dimethyl fumarate and fingolimod in our own centre, and describe their safety and efficacy in real clinical practice. The availability of oral DMTs in MS therapeutics was a watershed event and our cohorts exemplify the desire of patients to switch from injectable therapies when alternatives became available. Whilst our data support the efficacy of these therapies, their side effects remain limiting for a proportion of patients, and this was higher than expected from previous trials. Additionally, we have been able to describe potential risk factors for lymphopaenia with dimethyl fumarate, and identify cases where this can persist despite drug discontinuation, which is relevant given its (post-licensing) association with progressive multifocal leukoencephalopathy (PML). In identifying RRMS patients with similar disease profiles within two centres in Scotland who were often treated differently, we have provided evidence of significant variation in practice in a close geographical area. Additionally, whilst outcome comparisons were hampered by methodological issues, there were significant reductions in some disease measures when DMTs were started sooner rather than later in statistically-matched cohorts. These cohorts now provide the opportunity for a prospective study to compare more detailed long-term outcomes in patients treated or not in the early stages of their disease. Lastly, a unique dataset is analysed to evaluate the safety and efficacy of switching from one powerful anti-inflammatory immune therapy to another, namely natalizumab to alemtuzumab, in highly active RRMS. This is an increasingly used strategy since the worldwide licensing of alemtuzumab, despite little evidence upon which to base the approach. The use of alemtuzumab in the UK and Ireland for many years before this licensing, as a result of its development in Cambridge, provided a multicentre cohort of patients with longitudinal follow-up unavailable elsewhere, and we have demonstrated that this sequencing appears safe and effective. Additionally, the management of the switch between these two treatments is a dilemma in itself and we present data to support a direct switch and avoiding prolonged delay beyond excluding the possibility of (subclinical) infections. The studies presented here are therefore of real utility to the practising clinician in MS therapeutics.