Title: Improving the long-term outcomes for people with multiple sclerosis by studying real-world data.
Funder: Department of Health and Social Care

Abstract: Research QuestionCan real-world data inform the optimal use of current disease-modifying treatments (DMTs) to reduce disability accumulation in relapsing-remitting multiple sclerosis (RRMS)?Background125,000 people live with MS in the UK. As the disease typically starts in the 20s, any disability has long-term detrimental effects, both personal and societal. There are 13 licensed DMTs in MS, of varying toxicity and efficacy. However, their optimal use is not established because clinical trials do not address many key issues (e.g. how to respond to subclinical disease activity, shown by clinically silent MRI lesions (CSLs), occurring on treatment) and their duration is usually too short to determine long-term impact.Real-world data benefits from long follow-up duration from large numbers of people with MS (pwMS). Although the UK has a rich potential source of data on pwMS, our national registries contain few detailed records and data from only 1,000 pwMS data is submitted to the largest international registry, MSBase. Aims and ObjectivesProject 1. To establish the prognosis and optimal management of pwMS who have on-treatment CSLs, to generate evidence-based clinical guidelines. Pilot data (comparing 3,566 pwMS from MSBase) found that on-treatment CSL predicted a significantly greater risk of relapses, irrespective of DMT, lesion location and type.Project 2. To compare the outcomes of immediate versus later DMT initiation in people with a first clinical episode of MS.Project 3. To design a system to improve access to data on the treatment of pwMS, to improve clinical care and provide more data to existing national/international MS registries. Key questions raised by our pwMS steering group could then be answered: how should DMTs be most effectively sequenced? And how should DMTs be personalised to individual pwMS? MethodsProjects 1 and 2 will use existing registries (MSBase, Swedish MS Register and University Hospital Wales) to compare long-term disability outcomes in pwMS: [1] with and without CSL on treatment (stratified by CSL number and site, and whether treatment was switched); and [2] with a first clinical episode of MS whose DMTs are initiated immediately or delayed (stratified by MRI disease activity and DMT potency).Project 3. Development and introduction of an automated system to extract data on consented pwMS to send to existing national and international MS registries, piloted in all twelve NHS hospitals using one international electronic healthcare record (EHR) then incorporated into two others. Dissemination and outputsPresent and publish each aim including evidence-based management guidelines on CSL and timing of treatment initiation. Anticipated impact Projects 1 & 2 will identify treatment strategies to reduce long-term disability accrual, reducing the costs of MS to the person, the health service and society.Project 3 will provide ongoing detailed clinical data from 10,000-21,300 pwMS to MS registries (from the UK pilot alone) without additional clinician time. The automated extraction methodological framework will be published and applied to other EHRs, further increasing depth and breadth within registries. FeedbackOur patient steering group and the neurology lead for NHS Getting It Right First Time strongly support this project.

Lay abstract: Multiple sclerosis (MS) is amongst the most common causes of disability in the young. Over half of working-age people with MS (pwMS) are no longer employed, and over 40% require daily help. My research aims to reduce disability in MS by improving how existing drug treatments are used. Instead of trials, I use registries of 'real-world' routine data collected from MS clinics around the world. I recently used the largest international MS registry, MSBase, to show that using more potent drugs within 5 years of MS onset gave the biggest reduction in conversion to the fatal and largely untreatable secondary progressive MS phase. Now, I want to see if starting treatment even earlier, after the very first attack of MS, leads to better outcomes. MSBase contains data on over 27,000 pwMS collected from the first attack; 3,492 were treated straight away. I will compare the long-term disability levels between patients who were treated immediately versus those treated later. Next, I will examine whether it matters if you use the more powerful drugs (for example natalizumab) compared to modestly-effective ones (for example beta-interferon). The second project examines pwMS receiving MS treatments - we know that escalating treatment leads to better outcomes in those with new MS symptoms. But we need to understand the significance of developing new changes on MRI scans in pwMS receiving treatments in the absence of new symptoms (termed 'silent lesions'). Are they worse off compared to treated pwMS without silent lesions? Previous studies examined the short-term effects of developing silent lesions in pwMS receiving one infrequently used drug. I will examine the effect of silent MRI lesions that occur while on a range of treatments, over much longer time periods; and answer whether subsequently switching the treatment in response to silent lesions improves long-term outcomes. I will then produce guidance for pwMS and their doctors on how often pwMS should have MRI scans and what to do if silent MRI lesions occur. For both projects I will extract data from MSBase and the Swedish MS Registry, as the UK MS register has insufficient numbers of patients (fewer than 1% of UK pwMS). But even these registries cannot answer other crucial questions due to inadequate numbers and detail. The third fellowship project builds a system within hospital electronic healthcare record systems - used throughout the UK and internationally -h; to: Improve collection of relevant data for each pwMS and display it for clinicians and pwMS to study in clinic (for example graphs showing how particular parameters have changed over time (e.g. disability scores, MRI/blood results, patient-completed questionnaires, treatments). This will improve efficiency in clinic and ensure that treatment decisions are made with more complete information; Increase research awareness and uptake by tracking whether each pwMS has consented to take part in research (and sending automated trial eligibility alerts/contact information if so) Substantially increasing the numbers of detailed and updated clinical records in UK and international MS registries without any extra clinician time, by automatically sending fully-anonymised detailed information to MS registries from pwMS who consent. This is projected to increase the numbers of UK pwMS in registries more than 10 times, enabling other vital questions to be answered in the future (for example personalised drug choices or how to order treatments for maximal benefit and least side effects in MS). Our Steering Group of pwMS reviewed, improved and unanimously supported the application and this summary. One member said:'Investigating whether early treatmentis more effective would be extremely valuable. The findings could lead to improvements in quality of life for pwMS, while cutting healthcare costs and keeping [them] employed.'

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL