Multiple Sclerosis. News and Views in. Supplement commissioned by Merck Serono who have reviewed the content solely for factual accuracy

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1 SUPPLEMENT TO ACNR VOLUME 12 ISSUE 2 MAY/JUNE 2012 ACNRISSN ADVANCES IN CLINICAL NEUROSCIENCE & REHABILITATION News and Views in Multiple Sclerosis ACNR VOLUME 4 NUMBER 4 SEPTEMBER/OCTOBER Supplement commissioned by Merck Serono who have reviewed the content solely for factual accuracy

2 Access to treatments and services for people with MS in the UK Simon Gillespie Simon Gillespie joined the Multiple Sclerosis (MS) Society as Chief Executive in July Simon has overseen the introduction of the Society's new strategy based on an extensive consultation with people affected by MS, new approaches to research and support for people with MS, and new governance arrangements. Simon has extensive experience of charity and non-profit governance, and as a non-executive director/trustee. He is currently the nonexecutive chair of Neurological Commissioning Support (NCS), a joint venture between the MS Society, the MND Association and Parkinson s UK. He is a Trustee and Treasurer of the Neurological Alliance, a trustee of the Institute for Security and Resilience Studies at University College London, and a lay member of the General Medical Council's Fitness to Practice panels. He is also chair of the Care and Support Alliance, which comprises over 50 major organisations representing older and disabled people. . sgillespie@mssociety.org.uk The MS Society was established in The Society has over 38,000 members and around 300 branches. It is the UK s largest charity for people affected by multiple sclerosis (MS) and the largest not-for-profit dedicated funder of MS research in the UK. Our staff and volunteers are committed to ensuring that everyone with MS in the UK has access to high quality health and social care. There are around 100,000 people in the UK with MS; it remains an incurable condition but we have some cause for increasing optimism. In the past two decades treatments have become available and these treatments have delivered benefits to many people with relapsing-remitting MS. We are now seeing the range of treatment options increase, and there are signs of potential development of safe and effective treatments for people with progressive MS. However, these positive signs in the development of new therapies are in stark contrast with the UK s low prescribing rates for current MS therapies. In 2009 Kobelt and Kasteng produced a report on Access to Innovative Treatments in Multiple Sclerosis in Europe. 1 In this report, the UK was placed at 26 out of 28 European countries in terms of access to treatments for MS. The report found that a similar level of access as Germany in the UK would mean that 33-40,000 patients in the UK would currently be receiving treatment rather than an estimated (Kobelt & Kasteng, 2009). This depiction of low treatment rates in the UK was supported by a later report by Professor Sir Mike Richards (2010), Extent and causes of international variations in drug use; 2 in this report the UK was ranked 13 out of 14 countries in terms of access to treatments for MS. These two reports highlight the urgent need for MS treatment and service provision in the UK to be addressed. The issue of poor service provision has also recently been highlighted by the National Audit Office (NAO). 3 So what are the barriers to people with MS in the UK achieving access to the therapies they need? Processes and costs delay treatments. The 18 week target recommended by NICE from GP referral to diagnostic tests to treatment is achieved by 87% of MS centres in the UK (MS Forum report, ). Many centres report that the length of time taken to see a consultant is relatively short, but the time taken to access treatment varies considerably. Whilst 90% of MS specialist centres prescribe treatments, only 11% of people with MS are currently taking disease modifying drugs (MS Forum report, 2011). The timescale is frequently determined by the type of treatment required and its cost. In addition, the Risk Sharing Scheme set up a decade ago to ensure access to therapies is no longer fit for purpose, acting as a barrier to access to first generation therapies, and providing inadequate data against which to compare new therapies. There are significant variations in service provision. The number of neurology consultants in the UK has risen from 1 per 200,000 people in 1998 to 1 per 115,000 in However, this remains less than a third of the European average (Royal College of Physicians, 2011). Such a shortage of neurologists is likely to have an impact on treatment rates for people with MS in the UK. No figures are available for the number of MS specialists in the UK. 40% of MS Constitution of MS specialist neurological teams (MS Forum report, 2011) 02

3 centres do not class themselves as multidisciplinary teams, thereby restricting the services and specialists that people are able to access. 15% of MS centres do not have a neurologist specialising in MS and 38% of centres do not have a specialist MS neurophysiotherapist (MS Forum report, 2011). These variations are illustrated in the graph on the previous page on the constitution of MS specialist neurological teams. The recent NAO report highlights the disparities and variations in service provision, and the impact on people with MS, that result from the current piecemeal approach. Guidelines for treating MS are woefully out-ofdate. The NICE MS Clinical Guidelines have not been revised since 2003 and an updated version may be published in The revised Clinical Guidelines and the forthcoming Quality Standard for MS will eventually help to establish an up-to-date guidance and benchmark for clinicians and commissioners - but the guidelines are more than two years from publication and the date for the publication of the Quality Standard is unknown. This leaves people with MS struggling for access to new and more effective treatments and equipment. Looking ahead, we hope for better investment in therapies for people with MS to improve their quality of life, and enable them to live life to the full. There is a requirement for clear national leadership, for example by a neurology tsar. The NAO report supports the creation of a targeted national strategy for neurological conditions. Such a strategy would assist in addressing the variations in service provision for people with MS. The changes in health structures have also added to concerns that the range of services for people with neurological conditions will not always be provided. Right across the UK, health budgets are under severe pressure. This means that people with MS may fall victim to short-term cost savings rather than benefiting from investment in their health and quality of life for the longer-term. The MS Society is working to tackle these issues, by raising awareness of the condition and by lobbying politicians and national decision-makers to ensure people with MS get access to effective treatments when they need them, now and in the future. References 1. EKobelt G and Kasteng F. (2009) Access to Innovative Treatments in Multiple Sclerosis. A report prepared for the European Federation of Pharmaceutical Industry Associations. Accessed 09/12/11: Access%20to%20MS%20treatments%20%20October % pdf 2. Richards M. (2010) Extent and causes of international variations in drug use: A report for the Secretary of State for Health. Accessed 09/12/2011: Publicationsandstatistics/Publications/Publications PolicyAndGuidance/DH_ National Audit Office (2011) Services for people with neurological conditions. MS 2015 Vision: A Report by the MS Forum 4. Accessed 09/12/11: ms-resources/ms-2015-vision-report-ms-forum The second revision of McDonald criteria for the diagnosis of MS Klaus Schmierer Klaus Schmierer is a Clinical Senior Lecturer at Barts and The London School of Medicine & Dentistry, and a Consultant Neurologist at Barts Health NHS Trust. He has a special interest in the pathogenesis, disease monitoring and treatment of multiple sclerosis. He is a PI on trials sponsored by Novartis and Roche. He has received speaking honoraria from, and served on advisory boards for, Novartis and Merck-Serono. He is in receipt of a Higher Education Funding Council for England (HEFCE) Clinical Senior Lectureship, and grant support from Barts and The London Charity and from Novartis. . k.schmierer@qmul.ac.uk Ben Turner Dr Ben Turner is Consultant Neurologist and Honorary Senior Lecturer at Barts Health NHS Trust. He is CI and PI in Clinical trials for Biogen, Sanofi-Aventis, Genzyme, Roche and received Travel Grants from these companies. The McDonald criteria have been very useful for those of us in research, providing a uniform approach to what had been a rather vague diagnostic process. But they had less impact on real-life practice, particularly in the UK where the case for hyper-early treatment of multiple sclerosis has never really been accepted. Most neurologists just have not been bothered with the rather complicated protocol for repeat imaging and determining a positive scan. But the 2010 revisions were intended to make life simpler. Should we pay more attention to these? Two war-horses of the multiple sclerosis world give their views. Alasdair Coles The striking sensitivity of magnetic resonance imaging (MRI) to depict lesions in the CNS of people with multiple sclerosis (pwms) was recognised soon after MRI became available for clinical studies. 1 Lesions detected on MRI were thus incorporated as paraclinical evidence of dissemination in time (DIT) and space (DIS) in the 1982 review of the diagnostic criteria for MS, alongside other paraclinical tests such as computerised tomography, evoked potentials, urodynamic studies and the hot bath test. 2 It was not until the next review in 2000 by the International Panel (which Ian McDonald chaired) that MRI became firmly integrated in the diagnostic scheme of MS. 3 The major advantage of the McDonald criteria over previous diagnostic criteria is that MRI can help to establish a fundamental pattern of MS lesion development (DIS and DIT) in the absence of clinical symptoms or signs, allowing an earlier diagnosis of MS with high accuracy. The second review of the McDonald criteria published last year 4 acknowledged that even following a first update in the criteria remained complex, at times confusing, for the neurologist and even the MS specialist in clinical practice. 6,7 Three significant amendments in the 2010/11 update of the McDonald criteria addressed the need for simplification. Firstly, the Barkhof/Tintore criteria, 8,9 incorporated in previous editions of the McDonald criteria 03

4 to demonstrate DIS, were all but abandoned. To demonstrate DIS it is now sufficient to identify using T2 weighted (T2w) MRI any number of lesions typical of demyelination in at least two of four anatomic locations: periventricular, juxtacortical, infratentorial, spinal cord. Secondly, provided the criterion for DIS is fulfilled, it is now possible to diagnose MS following a single bout of demyelination (Clinically Isolated Syndrome, CIS) if contrast enhanced T1 weighted (T1w) scans reveal a minimum of one asymptomatic enhancing (Gd+) lesion, thus demonstrating DIT. Thirdly, DIT may now be demonstrated by a new lesion on T2w MRI and/or a Gd+ lesion on contrast enhanced T1w MRI at any time point after a baseline scan. Previously, lesions had to be assessed on scans separated by at least 30 days to qualify for demonstration of DIT. 5 However, based on recent evidence, this restriction was lifted. 10 Whereas the above largely applies to people with relapsing-remitting, and thus the majority of pwms, the criteria for primary progressive (PP) MS have also been revised to now incorporate the new DIS criteria and altogether dropping visual evoked potentials from the diagnostic criteria for PPMS. What are the benefits of this second update of the McDonald criteria, and are there any caveats? Firstly, MS can still be diagnosed on clinical grounds alone, with historical and physical evidence of DIS and DIT, which is reassuring. Secondly, the possibility to diagnose MS after a single demyelinating event may reduce the necessity for early repeat scanning. Whilst an early diagnosis is desirable (according to the International Panel without compromising sensitivity or specificity compared to earlier editions of the McDonald criteria) prospective studies will need to evaluate for how many patients this really applies in clinical practice. Thirdly, one should bear in mind the specificity of a diagnosis based on McDonald MRI criteria for clinically definite MS is 91% at best, and in the seminal paper underpinning the new MRI criteria, only 41% of the original cohort of 208 patients with CIS had actually developed CDMS within the observation period of three years. 11 Fourthly, the optimum time lapse between baseline and follow up MRI in patients with CIS with no evidence of DIT at presentation remains unclear. How long should one wait before referral for the next MRI in an asymptomatic patient? Whilst MRI continues to play a major role in the McDonald criteria it cannot be overemphasised that MS should only be diagnosed in somebody with a history and findings on examination suggestive of demyelination, and with differential diagnoses excluded that may better explain a patient s syndrome. To this end we strongly feel investigation of the cerebro-spinal fluid should still be encouraged, to rule out other causes as much as to underpin the diagnosis of MS. 12,13 The need to exclude other causes applies in particular to patient cohorts traditionally not in the bull s eye of MS criteria development, such as paediatric MS and MS in Latin American and Asian populations. Recent evidence suggests the new criteria work well for children suspected to have MS, 14 however more research is needed to establish their value in non-caucasians. Will the new criteria be useful in clinical practice? The latest updates, particularly of the DIS criteria, are likely to render the new McDonald criteria more applicable in the clinical setting, ie outside the recruitment for clinical trials, and may thus become more widely accepted than the previous editions had already been. 7 Some neurologists will remain uncomfortable to diagnose and/or even treat patients at first presentation given the significant albeit limited number of patients fulfilling MRI criteria for MS without ever developing CDMS. 15 And the lack of convincing evidence that treatment with current DMD s after a first demyelinating event affects long term disability suggests a more conservative approach may not necessarily be detrimental to patients with a single clinical episode of demyelination. 16,17 MRI has undoubtedly transformed the diagnostic approach to MS. Further studies should be pursued to validate the 2010/11 criteria, particularly in non- Caucasian populations, and to underpin their benefit for patients. References 1. Young IR, Hall AS, Pallis CA, Legg NJ, Bydder GM, Steiner RE. Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet 1981;14: Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13: McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. Recommended Diagnostic Criteria for Multiple Sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001;50: Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria. Ann Neurol 2011;69: Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O Connor PW, Sandberg- Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the McDonald Criteria. Ann Neurol 2005;58: Montalban X, Tintoré M, Swanton J, Barkhof F, Fazekas F, Filippi M, Frederiksen J, Kappos L, Palace J, Polman C, Rovaris M, de Stefano N, Thompson A, Yousry T, Rovira A, Miller DH. MRI criteria for MS in patients with clinically isolated syndromes. Neurology 2010;74: Hawkes CH, Giovannoni G. The McDonald Criteria for Multiple Sclerosis: time for clarification. Multiple sclerosis 2010;16: Barkhof F, Filippi M, Miller DH, Scheltens P, Campi A, Polman CH, Comi G, Adèr HJ, Losseff N, Valk J. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain. 1997;120: Tintoré M, Rovira A, Martínez MJ, Rio J, Díaz-Villoslada P, Brieva L, Borrás C, Grivé E, Capellades J, Montalban X. Isolated demyelinating syndromes: comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis. AJNR Am J Neuroradiol 2000;21: Tur C, Tintoré M, Rovira A, Nos C, Río J, Téllez N, Galán I, Perkal H, Comabella M, Sastre-Garriga J, Montalban X.Very early scans for demonstrating dissemination in time in multiple sclerosis. Mult Scler 2008;14: Swanton JK, Rovira A, Tintore M, Altmann DR, Barkhof F, Filippi M, Huerga E, Miszkiel KA, Plant GT, Polman C, Rovaris M, Thompson AJ, Montalban X, Miller DH. MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study. Lancet Neurol 2007;6: Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, Galetta SL, Hutchinson M, Johnson RT, Kappos L, Kira J, Lublin FD, McFarland HF, Montalban X, Panitch H, Richert JR, Reingold SC, Polman CH. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008;14: Tumani H, Deisenhammer F, Giovannoni G, Gold R, Hartung HP, Hemmer B, Hohlfeld R, Otto M, Stangel M, Wildemann B, Zettl UK. Revised McDonald criteria: the persisting importance of cerebrospinal fluid analysis. Ann Neurol 2011;70: Sedani S, Lim M, Hemingway C, Wassmer E, Absoud M. Paediatric multiple sclerosis: examining utility of the McDonald 2010 criteria. Mult Scler Oct Fisniku LK, Brex PA, Altmann DR, Miszkiel KA, Benton CE, Lanyon R, Thompson AJ, Miller DH. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008;131: Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Radü EW, Bauer L, Dahms S, Lanius V, Pohl C, Sandbrink R; BENEFIT Study Group. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3- year follow-up analysis of the BENEFIT study. Lancet 2007;370: Pittock SJ. Interferon beta in multiple sclerosis: how much BEN- EFIT? Lancet 2007;370:

5 Healthcare for people with MS in England and Wales: how does NHS provision compare to NICE Clinical Guidelines? Carolyn Young is an experienced neurologist and rehabilitationist. She has taken part in many clinical trials as well as running one of the most innovative and effective multiple sclerosis clinical services in the country. She has also been on both sides of NICE: coping in her hospital with the impact (or otherwise) of its guidelines as well as seeking to influence its decisions from the outset. She is well placed to comment on the aspirations and realities of NICE guidelines and healthcare in the UK. Alasdair Coles Carolyn Young Professor Carolyn Young is Consultant Neurologist at the Walton Centre for Neurology & Neurosurgery, Liverpool, UK and Honorary Professor of Neurology at University of Liverpool. Prof Young started the MS service in Liverpool, having dual trained in neurology and rehabilitation, in She has participated in numerous treatment trials and has a major research interest in outcome measurement and service delivery. She has contributed to ABN MS guidelines, NICE guideline development groups, NICE technology assessments and the RCP/MS Trust audits. . carolyn.young@ thewaltoncentre.nhs.uk The National Institute for Health and Clinical Excellence (NICE) produces clinical guidelines on specific diseases, which are evidenced-based recommendations for care. These guidelines are written by health professionals and representatives of patient groups, with input from technical experts. Health professionals and organisations can register as stakeholders and will be involved throughout the process, including being able to participate in one or more consultation periods. Previously an independent Guideline Review Panel ensured stakeholder comments were reflected in the final recommendations of the Guideline Development Group, but from 2012 the guidelines committee manager and associate director will do this. The collaborating centre produces the final guideline. Guidelines are periodically revised to reflect changes in practice and emerging evidence. NICE Clinical Guidelines on MS The clinical guidelines on MS (CG8) were issued in 2003, and covered all aspects of diagnosis and management in primary and secondary care which could be evidenced from the literature. 1 It would not be anticipated that any locality would have available every intervention or service that had been described. However CG8 described six key recommendations which should be considered fundamental, advocating specialised, seamless services offering rapid diagnosis and thorough assessment, which allow people with MS to be involved in clinical decisions and to reaccess services as needed. National audits on guideline compliance There can be little dissent from such recommendations but, bearing in mind that it is not mandatory that the NHS provides funding for the treatments and services described in NICE clinical guidelines, how widespread are these high quality specialised neurology and neurological rehabilitation services for MS? NICE clinical guidelines can be readily used to develop standards to assess clinical practice. Several audits have been published. In the Royal College of Physicians of London and MS Trust found poor adherence to the 2003 NICE guidelines. 2 They conducted a full national audit in England and Wales in and found significant concerns. 3 In 2011 they conducted a third national audit to assess the NHS s performance in providing healthcare services to people with MS against the NICE guidance and also against relevant quality requirements from the National Service Framework for Long Term Conditions. 4 This most recent audit is the most extensive, seeking information from a wide range of sources. These included people with MS (service users), acute NHS Trusts (secondary care providers), GPs (primary care), community services (primary secondary interface), PCTs and LHBs (service commissioners), and SHAs (service performance managers). Analysable data were received from 704 people with MS, who completed a web or paper-based audit tool after sign posting by charities, websites, MS healthcare professionals, and the national press. No check on their diagnosis was made. The findings reported by people with MS were in keeping with the data provided by professionals about service provision. Key findings of 2011 audit The 2011 national audit showed no major improvement since 2006 in the six key recommendations from CG8:- 1 Access to specialised neurology and neurological rehabilitation services 73% of people with MS thought they could access a specialist neurology service but only 36% a specialist neurological rehabilitation service. Specialised neurological rehabilitation services were described as providing an integrated programme from a multidisciplinary team. 05

6 2 Rapid diagnosis the NICE standard is 12 weeks between initial referral and final diagnosis. The median time was longer in the limited number of respondents who had been diagnosed in the last 12 months. 3 Seamless service CG8 recommends organisations agree and publish protocols for sharing information and care. While people with MS felt information sharing was good between health organisations, less than a third felt it was adequate from health to social services, a worsening from Involvement in clinical decisions about half felt they were as involved in decisions as they wished, a proportion similar to Sensitive but thorough assessment CG8 advocates systematic assessment including fatigue, depression, cognitive impairment and impaired bladder or sexual function. 69% respondents felt they had a sensitive and thorough assessment. 6 Self referral people with MS should be aware how and when to make contact with specialist services if they are not under regular review. 72% felt able to refer back to neurology and 30% to neurological rehabilitation. With regard to the NSF guidance, services were very sparse for vocational rehabilitation, respite care, support to carers and families, and assessment by MS specialists if admitted to a non-neurology ward. About half of respondents reported access to equipment, including mobility aids, and adaptations. Disease Modifying Drugs for MS improve Quality of Life and reduce disease progression Helen Ford Helen Ford is a Consultant Neurologist at Leeds Teaching Hospitals NHS Trust. She leads the West Yorkshire MS Treatment Programme. . Helen.ford@leedsth.nhs.uk Future directions It has recently been agreed that the NICE MS clinical guidelines will be revised. 5 The review process has acknowledged there is a need to cover additional topics such as the revised McDonald criteria, fatigue management, exercise interventions, functional electrical stimulation, cognitive retraining and medicines like donepezil. This revision reflects a welcomed expansion of the evidence base for care of people with MS. The Royal College of Physicians of London and the MS Trust have refined their audit methodology and plan a fourth audit in about three years. However, repeated audit cycles do not show significant progress with meeting the key recommendations of the 2003 guidelines. It is evident that a third strand of development is vital. As well as care guidelines, and national audits of care, steps to ensure the widespread translation of care guidelines into clinical practice are necessary. Clinical staff, NHS organisations and the Department of Health all need to review their practices to bridge the gap between the standards described in the NICE clinical guidelines and the services provided to people with MS. References 1. National Institute of Health and Clinical Excellence, Multiple sclerosis: management of multiple sclerosis in primary and secondary care (CG8). 2003, NICE: London. 2. Wade, D., NHS services for people with multiple sclerosis: a national survey. 2006, Royal College of Physicians and Multiple Sclerosis Trust: London. 3. Royal College of Physicians and Multiple Sclerosis Trust, National audit of services for people with multiple sclerosis. 2008, Royal College of Physicians and Multiple Sclerosis Trust: London. 4. Royal College of Physicians and Multiple Sclerosis Trust, The national audit of services for people with multiple sclerosis. 2011, Royal College of Physicians and Multiple Sclerosis Trust: London. 5. National Institute for Health and Clinical Excellence, Review of Clinical Guideline (CG8) Multiple sclerosis: national clinical guideline for diagnosis and management in primary and secondary care Physicians are not terribly interested in the quality of life of their patients. Or, at least, that might be your conclusion from the very low currency given to quality of life outcomes in multiple sclerosis trials. So it is very helpful to have Helen Ford, who pioneered work in this area, remind us of the evidence for improved quality of life on disease-modifying therapy in multiple sclerosis. She also tackles the question of disease progression on these therapies. Nowhere else in the world would this even be an issue; but British neurologists still think the disease-modifying therapies may not influence the accumulation of disability in patients. I think this reflects the natural scepticism and sobriety of those UK key opinion leaders in the 1990s who gave interferon-beta (rightly) such a hard time. However, there is no doubt that these, and all the other disease-modifying therapies, reduce disability over 2-3 years compared to placebo, provided patients are still in the relapsing-remitting phase. The key questions now are: are these beneficial effects maintained in the long-term and do they delay the start of the secondary progressive phase. Helen, sensibly, avoids these issues, because there is no data to speak to them. But we must recognise that the long-term natural history data from Lyons, and even from London Ontario, may be interpreted to show that the onset of secondary progression is completely, or mainly, divorced from early relapse and disability history. It is possible worryingly that all our hard work suppressing relapses in the first years of the disease may be for nothing, and patients will progress nonetheless years later. In the next few years we should begin to get a feel for this, as the patients started on interferon in 1993 in the US are coming up to the time when most will by natural history have started to progress. We will see Alasdair Coles 06

7 In considering this topic it is worth reflecting on the introduction of the first of the disease modifying treatments (DMTs) for multiple sclerosis (MS) in 1995 and how much has changed since then. At the time neurologists were concerned about the potential impact of injectable treatments and their side effects, including possible suicide risk, on the quality of life of people with MS. The first pivotal trials of DMTs didn t include quality of life as a primary or secondary outcome measure. 1,2,3 The PRISMS study included measures of depression and the General Health Questionnaire and reported no difference between treated and placebo groups. 4 In the West Yorkshire MS Treatment Programme we assessed quality of life using a disease-specific measure, the self-report Leeds MS Quality of Life scale (LMSQoL), 5 in a population of 210 MS patients before and after starting on disease modifying drugs. 6 There was a significant and sustained increase in quality of life associated with disease modifying treatment. An increase in the LMSQoL score did not correlate with baseline age, disease duration, disability or number of prior relapses. However, patients with a poor quality of life at baseline showed the most benefit from treatment. Those who had their treatment stopped due to progression, side effects or lack of effect had significantly lower LMSQoL scores on treatment. The improvement in quality of life in relapsing patients treated with DMTs has been confirmed in more recent studies. 7 The role of DMTs in disease progression is more controversial. It is well accepted that first line DMTs reduce relapses by about a third. There is no evidence that interferons or glatiramer acetate have an impact on disease progression in established secondary progressive MS. In short trials (two years) of disease modifying treatments the development of progressive disability is likely to be due to stepwise worsening from relapses rather than the development of secondary progressive disease. 49% of relapsing-remitting patients have been shown to have a residual increase in disability postrelapse. 8 Disease modifying treatments by reducing relapse rates reduce the accrual of fixed disability in relapsing MS. In relation to long term disease progression there is an association of early relapses in year one and two and later progression of disability to disability endpoints DSS 6,8, and DMTs used early in the disease course may potentially influence long term disability although confirmation of this would require much longer term follow-up studies. 10 In summary there is evidence that DMTs have no deleterious effect on quality of life contrary to early concerns and further evidence of improved quality of life on treatment. Reduction in disability is likely to be due to the impact of DMTs in relapse reduction and postrelapse accrual of disability. References 1. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43: Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45: Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996;39: PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998;352: Ford HL, Gerry E, Tennant A,Whalley D, Haigh R,Johnson MH. Developing a disease-specific quality of life measure for people with multiple sclerosis. Clin Rehabil 2001; 15: Lily O, McFadden E, Hensor E, Johnson M, Ford H. Disease-specific quality of life in multiple sclerosis: the effect of disease modifying treatment. Multiple Sclerosis 2006;12: Putzki N, Fischer J, Gottwald K, Reifschneider G, Ries S, Siever A, Hoffmann F, Käfferlein W, Kausch U, Liedtke M, Kirchmeier J, Gmünd S, Richter A, Schicklmaier P, Niemczyk G, Wernsdörfer C, Hartung HP; "Mensch im Mittelpunkt" Study Group. Quality of life in 1000 patients with early relapsing-remitting multiple sclerosis. J Neurol 2009;16: Hirst C, Ingram G, Pearson O, Pickersgill T, Scolding N and Robertson N. Contribution of relapses to disability in multiple sclerosis. J Neurol 2008; 255: Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M et al. The natural history of multiple sclerosis: A geographically based study 10. Relapses and long-term disability. Brain 2010;133: Freedman MS. Improving long-term follow-up studies of immunomodulatory therapies. Neurology 2011 Jan 4;76(1 Suppl 1):S

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