Prediction is a risky business in any. Predicting and preventing the future: actively managing multiple sclerosis Michael Hutchinson REVIEW

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1 133 REVIEW Pract euro 2009; 9: Predicting and preventing the future: activey managing mutipe scerosis Michae Hutchinson Reapsing-remitting mutipe scerosis (MS) has a highy variabe cinica course but a number of demographic, cinica and MRI features can guide the cinician in the assessment of disease activity and ikey disabiity outcome. It is aso cear that the infammatory activity in the first five years of reapsingremitting MS resuts in the neurodegenerative changes seen in secondary progressive MS years ater. Whie conventiona first-ine disease modifying therapy has an effect on reapses, about one third of patients have a suboptima response to treatment. With the advent of highy active secondine therapies with their evident marked suppression of infammation, the cinician now has the toos to manage the course of reapsing-remitting MS more effectivey. The deveopment of treatment optimisation recommendations based on the cinica response to first-ine therapies can guide the neuroogist in more active management of the eary course of reapsingremitting MS, with the aim of preventing both acute infammatory axona injury and the neurodegenerative process which eads to secondary progressive MS. Prediction is a risky business in any wak of ife. Whie natura history studies of cohorts of mutipe scerosis (MS) patients have outined a number of factors associated with a good (benign) prognosis, or a more aggressive course, it is often difficut to appy them to the individua patient in the cinic. The course of the disease is highy variabe between patients; even after 10 years of iness it M Hutchinson Consutant euroogist Department of euroogy, St Vincent s University Hospita, Em Park, Dubin 4, Ireand; mhutchin@io.ie

2 134 Practica euroogy varies from asymptomatic to severe disabiity and even, occasionay, death. The assessment of disease severity has however been made easier by the increasing use of brain and spina MRI for observing markers of infammatory activity. These days, the management of reapsing-remitting MS by anti-infammatory, immunomoduatory or immunosuppressant therapy is driven by the orthodoxy that MS is initiay a potentiay treatabe infammatory demyeinating disorder, and that adequate suppression of the infammatory phase shoud prevent the severe axona injury which causes the as yet untreatabe secondary neurodegenerative process. The aim of this review is to use the avaiabe evidence of the importance of the eary cinica course of reapsing-remitting MS to guide the neuroogist deaing with the eary reapsing-remitting patient in optimising treatment using disease modifying treatment. I wi not address the equay important issue of symptomatic therapy, nor wi I dea with the probem of the 15% of patients with primary progressive MS. The need for better assessment of MS prognosis has been accentuated by the range of therapies now avaiabe to the neuroogist. Indeed it seems ikey that the phase 3 studies of a number of ora therapies wi expand the TABLE 1 Demographic, cinica and MRI features in the first five years of disease course suggesting a better and poorer ong-term outcome in 1 6, 9, 11, 21 patients with reapsing-remitting MS Factor Better prognosis Worse prognosis Age at onset Younger Oder Gender Femae Mae Onset reapse type Optic neuritis Sensory symptoms Motor Sphincter invovement Mutifoca onset Reapse frequency 1 2 reapses in 5 years 3 or more in first five years Residua disabiity after Fu recovery Incompete recovery reapse First remission Greater than 2 years Less than 2 years Time to EDSS 4 Greater than 5 years Less than 5 years Lesions on first MR brain 1 3 esions 10+ esions scan Increase in T2 esion voume in first 5 years,1.0 cm 3 /year Approx 3 cm 3 /year therapeutic repertoire even more in the next few years. Therefore, assessing the ikey disease course in patients on disease-modifying treatment wi become increasingy important. Apart from the cinica measures of reapse history and disabiity, neuroogists have ony one adequate marker of disease activity, the MR scan, the prognostic utiity of which has been expored in a number of studies. CLIICAL AD DEMOGRAPHIC PREDICTORS What do cohorts of MS patients te us about prediction? The arge natura history studies from Lyon, Ontario and Sweden are usefu sources of information about the outcome of cohorts of MS patients foowed at mutipe time points. 1 6 They have identified factors associated with a better outcome, at east in the initia years of a ife-ong iness (tabe 1). The cinica features of the eary phase in the iness which suggest a mider disease course incude: femae sex younger age at onset optic neuritis at onset a onger interva between the first and second reapse compete recovery from the first reapse and fewer reapses in the first five years of iness. Features at inception which suggest a poorer outcome incude: mae sex oder age at onset mutifoca onset (eg, simutaneous optic neuritis and cord symptoms) motor symptoms and signs. One very important message is that once a Kurtzke expanded disabiity status scae (EDSS) of 4 is reached (that is, fuy ambuatory without aid, sef-sufficient, up and about some 12 hours a day despite reativey severe disabiity; abe to wak without aid or rest some 500 m) there is an inexorabe progression of disabiity. Confavreux in Lyon has demonstrated ceary that prognostic factors associated with a mider or more severe course (as above) ony affect the time to reach EDSS 4. 1, 2 Once that /jnnp

3 135 eve of disabiity has been reached there is a uniform progression of disabiity; initiay good prognostic factors no onger operate. The time to reach EDSS 6 from EDSS 4 is amost aways about six years, and is not infuenced by the earier cinica course. Sustained disabiity at EDSS 4 is the herad of the onset of secondary-progressive MS and refects the burden of axona injury inficted during the period of recurrent reapses. The message from the natura history studies is if we are going to ater the natura history of MS with the therapeutic agents avaiabe, then they need to be used eary in the course of reapsing-remitting MS, we before the onset of sustained disabiity progression to EDSS 4. Quantifying risk for the future compicated measures A number of studies have attempted to summarise, using mutivariate anaysis, baseine data into an equation which can be used to construct a mathematica mode of prognostic vaue. This approach was used initiay in the London, Ontario inception cohort 5 and others have subsequenty appied the same technique. 7, 8 The equations are compicated and in reaity of itte use to the practising neuroogist with ow sensitivity for predicting a poorer or better outcome. For exampe, the Bayesian Risk Estimate for MS (BREMS) score has been proposed as a mode for determining outcome in MS patients, based on the cinica characteristics of the first year of iness. 7 It differs significanty between those patients who, when foowed for a further nine years, remain reapsing-remitting from those who enter the secondary progressive phase. However, the range of scores at one year overap consideraby; patients who deveop eary secondary progressive MS have a median BREMS score of 0.82 (interquartie range 0.11 to 1.51), those who remain in the reapsing-remitting phase have a median score of 0.28 (IQR to 0.93). 7 The poor predictabiity of a benign course, even at 10 years after MS onset Athough some cinica features are indicative of possibe future outcome, the evidence from a number of ong-term foow-up cohorts indicates that even assessing a patient as ikey to have a benign course at 10 years of iness is a weak indicator of outcome a further 20 years ater. In the foow-up of the 1985 Gamorgan cohort of 379 MS patients ony 19% of those considered benign (Kurtzke (4) after 10 years of disease remained benign a further 20 years ater. 9 Simiar findings have been reported in other cohorts in Ireand 10, 11 but not in orth America where 12, % of patients remained benign. Recenty Amato and her coeagues have emphasised that a subgroup (one quarter) of apparenty benign MS patients after 15 years of iness have cognitive impairment associated with higher esion oads on brain MRI than patients who were cognitivey intact; 14 therefore, cassifying patients as benign purey on their Kurtzke scae may be inappropriate. The evidence is that cassifying an MS patient as benign after 10 years of iness does not necessariy mean that the onger term outcome is necessariy good. These patients must sti be carefuy foowed up; a high esion oad on brain MRI or new cinica reapse activity shoud aert the cinician to the need to consider first-ine disease modifying therapy. Are reapses important in reation to future cinica course? The evidence from short duration randomised controed trias (RCTs) is that the accumuation of disabiity in the eary phase of reapsing-remitting MS is due to incompete recovery from reapses. Certainy the Lyon database indicates that frequent reapses in the first five years, incompete reapse recovery, and a shorter interva between the first and second reapse a predict a shorter period to EDSS 4. Surprisingy, there is itte information on the effect on residua disabiity foowing reapses but two studies have examined this important subject. Lubin and coeagues anaysed pacebo treated reapsing-remitting MS patients in a number of RCTs; 42% had an increase in EDSS score post reapse, 28% increasing by at east one point, 38% had no change in disabiity, and 19% experienced EDSS improvement. 15 In a study of a UK hospita popuation of reapsingremitting MS patients, 279 reapses were Even assessing a patient as ikey to have a benign course at 10 years of iness is a weak indicator of outcome a further 20 years ater

4 136 Practica euroogy Disease burden in white matter is matched by that occurring in the cortex /jnnp studied; 49% patients had an increase in their EDSS score, 33% by one point, 35% were unchanged, and 16% experienced an improved EDSS score. 16 The study from the RCTs was probaby more accurate (athough RCT popuations may not be a true refection of what happens in the genera popuation of MS patients) because the more systematic approach in an RCT shoud have captured a reapses, incuding reativey mid ones, whereas in the hospita study patients with mid reapses may not have come to medica attention. evertheess both studies indicate that for just under haf of a reapses there is an increase in residua disabiity. Thus reapses are important both in reation to the short-term accumuation of disabiity and in reation to onger-term impications for increased risk of deveoping secondary progressive MS. Residua disabiity accumuation foowing reapses impies axona injury due to both acute transection of axons and subsequent ong-term degeneration of chronicay demyeinated axons because of oss of the protective effects of their myeination. 17 CSF AALYSIS: THE IMPORTACE OF OLIGOCLOAL BADS Using isoeectric focusing, CSF oigocona banding is found in about 95% of patients with estabished MS. The frequency is much ess in patients with a first episode and in eary MS, but sti has some prognostic vaue. 18 The Barceona group found, in a arge study of 415 patients with a first episode, that 61% had oigocona bands. The presence of bands independent of MRI abnormaities somewhat increased the risk of a second reapse with a hazard ratio (HR) of 1.7 (95% CI 1.1 to 2.7). However, brain MRI at baseine had greater prognostic utiity than the CSF findings, depending on the number of esions; for an MR brain scan with 1 9 esions the HR was 3.4 (1.7 to 6.9) and for 10 or more esions it was 9.2 (4.6 to 18.7). However, there is sti a reason to examine the CSF in patients with a cinicay isoated first episode and a norma MR brain scan; 23% of those with bands had another reapse in four years, but ony 4% of those without. 16 Furthermore, a Scandinavian first episode study showed that, in patients presenting with optic neuritis, the probabiity of deveoping cinicay definite MS at three years with 3+ MR brain esions and oigocona bands was 66% (42 80%), with no abnormaity in the CSF or on MRI the probabiity was ony 9% (2 32%) 19 Patients with estabished MS and negative CSF oigocona bands are of course a very sma group in any cinic, and certainy the absence of bands shoud aways ead one to question the diagnosis. In a arge combined study from Bristo and Cardiff, 100 patients, 3% of the MS popuation, were oigocona band negative. 20 Their cinica course was more benign than matched band-positive patients; median time to reach EDSS 6 was 11 years for the band-positive patients and 19 years for the band-negative patients. MRI: OK FOR DIAGOSIS, BUT WHAT ABOUT PROGOSIS? We know that the cinica features of MS, in particuar reapse history, are weak predictors of short-term disabiity. This is mainy due to the iceberg nature of cinica reapses; for every reapse recorded there are 8 10 more infammatory events detectabe by brain MRI in non-eoquent white matter tracts. However, as a biomarker, routine brain MRI is ikey to be equay imited because the commony used sequences do not detect cortica MS paques. europathoogy studies have demonstrated that the disease burden in white matter is matched by that occurring in the cortex. Athough some measure of cortica pathoogy can be visuaised by doube inversion recovery techniques, this is not widey avaiabe and in any event may not measure a the cortica disease that is actuay present. Using the MR scan to predict the future Since the mid 1980s a number of academic centres, in both ongitudina and cross-sectiona studies, have deineated the natura history of MS as reveaed by MR scanning. A series of papers on cinicay isoated syndromes and the ong-term outcome from the Institute of euroogy in London have important essons. In the most recent 20 year foow-up, the number of MR esions at baseine was a marker both of the ikeihood of deveoping cinicay definite MS (Poser criteria) and the degree of disabiity at 20 year foow-up. 21 A

5 137 patient with a cinicay isoated syndrome and no esions on the MR brain scan had a 21% risk of deveoping cinicay definite MS at 20 years (10% at 10 years) whereas any white matter esions (compatibe with demyeination) increased the risk to approximatey 80% at 20 years. The number of esions at baseine was aso predictive of disabiity at 20 years; patients with 1 3 esions had an 18% risk of significant disabiity (EDSS >6.0) at 20 years, whereas those with 10 or more had a 45% risk. One other important point from this study was the observation that the rate of MRI esion voume deveopment in the first five years of foow-up was a significant predictor of the deveopment of secondary progressive MS (fig 1). Thus an increased esion oad on MR brain scanning of patients within the first five years of iness is a predictor of MS severity 15 years ater. This is of singuar importance; it is consistent with the ong-term natura history studies from Lyon that the frequency of reapses in the first five years, and a short period between the first and second reapse, are predictors of a worse ong-term outcome. One of the difficuties in other studies of MRI parameters and disabiity progression is that they were reativey short in duration, often ony two years, and in such a setting correations between T2 esion oad, T1 back hoes and disabiity deveopment, athough statisticay significant, have been weak Atrophy measured by percentage brain voume change is a measure commony used in phase three RCTs and by academic MRI centres; whie there is evidence that this occurs eary in the course of reapsingremitting MS and correates with cinica measures of disabiity progression, it is not readiy avaiabe to the neuroogist deaing with MS on a daiy basis. 22 The importance of measures of cerebra atrophy in reapsingremitting MS is that grey matter atrophy is a very important part of the neurodegenerative process caused by infammatory cortica esions which are not reveaed by conventiona MRI techniques. 25 EARLY DISEASE MODIFYIG THERAPY? THE WIDOW OF OPPORTUITY COCEPT The thrust of my approach to treatment is based on the evidence that the ony way to prevent, or at east deay, secondary progressive MS must be to activey manage the reapsing-remitting phase of the iness so as to suppress infammatory disease. To do this one must cosey monitor reapsing-remitting patients at east every six months. I fuy subscribe to the window of opportunity concept put forward by Aasdair Coes and coeagues patients receiving effective anti-infammatory treatment before the cascade of events eading to uncontroed destruction of the axon-gia unit is irretrievaby estabished wi not subsequenty accumuate disabiity deveop cerebra atrophy or enter the secondary progressive phase of the iness. 26 When to start disease modifying therapy? Whether to start patients with a presumed first episode of MS on a first-ine disease-modifying drug (that is, beta interferon or gatiramer acetate) depends on a number of factors. If the MR brain scan is norma then no-one woud recommend therapy. On the other hand, if the brain and spina MRI satisfy the McDonad criteria 27 for dissemination in space, and the CSF is oigocona band positive, many (outside the UK) woud initiate disease modifying therapy after discussion with the patient, particuary if there is a high esion oad (.10 T2 esions) on the initia brain MRI. The Association of British euroogists (AB) guideines (2001) recommend starting with first-ine disease-modifying therapy in reapsing-remitting MS patients who are waking independenty and who have had two cinicay significant (whatever that means) reapses in the ast two years. 28 Figure 1 Increasing T2 esion oad during the 20- year foow-up of a cohort of cinicay isoated syndrome (CIS) patients. Patients are subdivided by outcome: remaining reapse free, reapsingremitting (RR) MS, and secondary progressive (SP) MS. ote the patients who deveoped SPMS experienced a marked increase in the T2 voume in the first five years of iness. With permission from Fisniku et a, IQR: interquartie range. Median T 2 esion voume (T 2 LV) (cm 3 ) over time for patient groups. Bars show IQR; numbers of patients shown. (Reproduced with permission from Oxford University Press. 21 )

6 138 Practica euroogy Patients must be assessed at east six-monthy, asked about possibe reapses and have their disabiity assessed with the EDSS /jnnp These guideines woud incude a patients who had demonstrated cinica evidence of dissemination in time within two years of onset but not patients who had a second reapse at three years, even if their repeat MRI brain showed a marked increase in T2 esion oad. An aternative strategy woud to be to observe the patient and repeat the MR brain scan in 3 6 months; if there is further disease activity, even if subcinica (judged by new T2 esions or gadoinium enhancement), satisfying the McDonad criteria for dissemination in time, then first-ine disease-modifying therapy shoud be started. Other than their use in reducing the ength of reapses, there is no evidence for steroid therapy as a ong-term disease-modifying therapy. Intravenous immunogobuin (IVIg) has been examined in a number of trias; the data are contradictory and IVIg probaby shoud not be used outside of an RCT. The counter argument: no evidence of effect of diseasemodifying therapies on disabiity progression Because most phase 3 RCTs in reapsingremitting MS ony asted 2 3 years we cannot and do not have the ong-term evidence that eary initiation of disease-modifying therapy has any significant effect on disabiity progression after 10 or 20 years of iness. This is often used by sceptics to argue against the enthusiastic use of expensive first-ine diseasemodifying therapies. However, eegant ongterm RCTs are impractica in reapsing-remitting MS and my argument adduced from the evidence I have presented, incuding the use of the newer more effective therapies (see beow), is that suppression of infammation in reapsing-remitting MS wi prevent disabiity progression by preventing destruction of axons. With the newer second-ine disease-modifying therapies, we now have the toos to effect change in the natura history of MS. MAAGIG RELAPSIG- REMITTIG MS PATIETS O FIRST-LIE DISEASE-MODIFYIG THERAPY Having initiated therapy, patients must be assessed at east six monthy, asked about possibe reapses and have their disabiity assessed with the EDSS. The cinician coud aso ask the patient to compete the Mutipe Scerosis Impact Scae-29 (MSIS-29) whie waiting to be seen; this does not add significanty to cinic time. 29 The MSIS-29 score can aert the neuroogist to significant changes from baseine. 30 Other toos incude a timed 25 ft wak and a 9 hoe peg test, but these are unikey to be used outside a research setting. The minimum information needed comes from the cinica assessment (has there been a reapse?) and the EDSS (has there been disabiity progression?). Disabiity progression refers not just to the recovering disabiity in the wake of a reapse, but confirmed worsening of the EDSS score at repeat examination three or six months ater. Intoerance to first-ine therapy About 10 15% of patients do not toerate the adverse effects of beta inteferon; 31 most of these shoud be switched to gatiramer acetate or enroed in one of the phase 3 ora therapy RCTs if that option is avaiabe. Stopping disease-modifying therapy Given that disease-modifying therapies are used to suppress infammation, they shoud be stopped when the inexorabe process of secondary progressive MS with observed increase in disabiity over at east six months without reapses has been estabished. The AB guideines are cear and indicate that oss of the abiity to wak with or without aids persisting over six months is a marker for the need to stop first-ine disease-modifying therapies. 28 In practice, an emai po of internationa experts that I conducted yieded a wide variation of poicies, athough most agreed with the AB guideines. Other stopping criteria incude a contempated pregnancy, usuay stopping at east two months before conception. Patients who have had two disabing reapses in one year are another group in whom first-ine disease-modifying therapies shoud be stopped they need to go on more effective second-ine therapy. Suboptima responders to firstine disease modifying therapy Approximatey one third of reapsing-remitting MS patients deveop sustained disabiity increase, even on therapy. This refects the

7 139 inadequacy of first-ine therapies, or in some patients may be due to the deveopment of neutraising antibodies (Abs) to beta interferon. Because it is so important to detect inadequate response in the cinic, any neuroogist treating these patients shoud be using EDSS assessments at each six monthy visit. Furthermore, reapses occurring on treatment aso indicate inadequate disease contro. Patients with reapses in the first two years of therapy are at greater risk of disabiity progression Athough disabiity progression in the first two years of therapy in one study had high sensitivity, specificity and accuracy to predict marked disabiity after six years of therapy, 35 any reapses combined with eary disabiity progression had the highest sensitivity (90%) but ess specificity. Thus the occurrence of a reapse and/or disabiity worsening is an indicator of inadequate therapy. Reapses which eave residua disabiity, indicated by a persisting increase in the EDSS, which affect the motor or cerebear systems or which require treatment with corticosteroids are often used in guideines as an indicator that a change of therapy is indicated, whereas reapses which are purey sensory, with compete recovery and not requiring steroids are given ess weight. To my mind any reapse indicates disease activity and shoud aert the neuroogist to suboptima treatment response. A posterior coumn reapse in the mid cervica region may ony produce sensory symptoms and few signs, but the cumsy hand can sti be very disabing, whie a simiar esion but in the mid-thoracic cord posterior coumns may have reativey minima effects. Using the absence of disabiity from a reapse as an indicator that everything is fine is being unduy optimistic. Treatment optimisation Various groups have deveoped treatment optimisation recommendations. 37 Perhaps the most practica come from Canada 38 and these incude two cinica measures; reapse assessment and disabiity progression to define eves of disease activity in terms of being of ow, medium or high concern with regard to the future risk for disabiity. MRI is used for suppementary information but not in isoation to determine the eve of concern. The It is the accumuating infammatory T2 esion voume in the first five years of the iness which determines entry into the secondary progressive MS stage practicaity and vaidity of this approach has been addressed by examining the outcome of patients who were treated in two of the beta interferon trias. 39 When foowed through years 2 4, the patients estimated to have had high and medium activity in year 1 had a subsequent annuaised reapse rate of 1.12 compared to 0.48 for those patients who had been cassified as having no or ow risk on the basis of their reapse activity in year one. 40 Simiary, athough ess sensitive and specific, 18% of patients assigned to high or medium concern and 8% of patients with no or ow concern on the basis of disabiity progression in the first year of treatment, were more ikey to progress through years 2 4. It shoud be emphasised that disabiity progression in the short term does not strongy correate with reapse occurrence, the important point in detecting suboptima contro eary in the initia years of first-ine therapy is that one is attempting to prevent axona injury which wi ony become manifest years ater. I make no apoogy in repeating the esson from the ong-term MRI study of David Mier and his coeagues 21 that it is the accumuating infammatory T2 esion voume in the first five years of the iness which determines entry into the secondary progressive MS stage, and progressive disabiity a further years on. The practicaities of treatment optimisation After the first year of disease-modifying therapy, the patient shoud be assessed in reation to the occurrence of reapses or disabiity progression. Any reapse is graded as being of ow, medium or high concern. Simiary, any disabiity progression is graded using the same degrees of concern (tabe 2). 38 Patients with high and medium concern at review shoud be regarded as having suboptima contro and be considered for a change of therapy, most often to a secondine therapy. Patients with ow or no concern shoud continue on their present therapy

8 140 Practica euroogy TABLE 2 Canadian treatment optimisation recommendations for determining the eve of concern on the basis of the occurrence of reapses and disabiity progression 38, 40 in the first year of treatment with standard disease modifying treatment Leve of concern Reapse High 1 severe or 2 moderate attacks Medium 1 moderate or 2 mid attacks Low 1 mid Disease progression Baseine EDSS,3.5 Baseine EDSS 4+ Leve of concern on combined reapse and disabiity measures.2 points.1 point 1 high or 2 medium = overa high concern 2 points 1 point 1 medium or 2 ow = overa medium concern point 1 ow = overa attack points ow concern one o attacks 0 point 0 point o active disease = overa no concern Cinica action Change treatment Change treatment o change o change These coud equay appy to any subsequent year. Patients with overa high or medium concern shoud be considered for a change of treatment; those with ow or no concern shoud continue present treatment. A mid reapse is defined as not requiring corticosteroids, no motor/cerebear invovement, no effect on function and compete recovery. A moderate reapse: requires steroids, invoves motor/cerebear systems, affects activities of daiy iving (ADL) and has incompete recovery at 3 months. A severe reapse requires steroids and hospitaisation, invoves motor/cerebear systems with a severe effect on ADL with incompete recovery at 6 months /jnnp (fig 2). Patients with any degree of concern from the second year onward shoud have their neutraising antibodies (Abs) to beta interferon checked; if significanty eevated and if there is cinica evidence of concern then they shoud be switched from beta interferon to gatiramer acetate. Athough the AB guideines suggest that Abs shoud be checked on two occasions, if there is evidence of disease activity with one eevated Ab titre, I woud act on the principe that an eevated titre indicates oss of pharmacoogica effectiveness of the beta interferon. MRI activity shoud aso be checked in patients with any medium or high concern, both to act as a new baseine scan and aso to assess the patient s suitabiity for second-ine therapy according to ICE (the UK ationa Institute for Heath and Cinica Exceence) guideines for nataizumab. 41 The cinica criteria for concern are pre-eminent because a number of authorities have recognised the weak predictive vaue of MRI aone on future short-term disabiity. 24 Suboptima response to beta interferon therapy what next? Patients who are truy suboptima responders on the basis of the above criteria shoud be offered nataizumab, 42 aemtuzumab, 43 mitoxantrone 44 or rituximab. 45 In particuar, if on firstine therapy, there is convergence of the three criteria for concern reapse activity, disabiity progression, and new T2 or gadoinium enhancing esions on brain MR it is imperative that more active therapy is empoyed. The patient may not have much disabiity now, say EDSS 3.0, but the aim is to suppress, as far as possibe, infammation which wi cause disease progression in 10 years time.

9 141 Which second-ine therapy? More effective drugs but more risk Short-term RCTs ceary indicate marked suppression of infammatory disease activity and reduction in disabiity progression with nataizumab, mitoxantrone and aemtuzumab. The evidence for rituximab 45 is ess secure. But a the second-ine therapies are accompanied by the risk of ife-threatening compications which are beyond the scope of this review. The cinica evidence to date suggests that nataizumab is the first choice for suboptima responders to beta interferon. Patients who deveop an aergic reaction to nataizumab (1 in 25) shoud be treated with aemtuzumab or mitoxantrone. The ICE guideine for nataizumab recommends it as an option for the treatment ony of rapidy evoving severe reapsing-remitting MS defined by two or more disabing reapses in one year, and one or more gadoinium-enhancing esions on brain MRI or a significant increase in T2 esion oad compared with a previous MRI. 41 The European Medicines Agency (EMEA) guideines for nataizumab incude: Patients who have faied to respond to a fu and adequate course of a betainterferon; they shoud have had at east one reapse in the previous year whie on therapy, and at east nine T2-hyperintense esions on brain MRI or at east one gadoinium-enhancing esion Patients with rapidy evoving severe reapsing-remitting MS, defined by two or more disabing reapses in one year, and with one or more gadoinium enhancing esions on brain MRI or a significant increase in T2 esion oad as compared to a previous recent MRI. 46 In our practice in a University hospita setting, most (90%) of our 70 reapsingremitting MS patients on nataizumab have started therapy because of suboptima response to first-ine therapy and many woud not have fufied the ICE guideine, which to my mind, is too conservative. We now ony use mitoxantrone for patients who are aergic to nataizumab, or who deveop breakthrough reapses on nataizumab with or without Abs to nataizumab. Aemtuzumab or rituximab might be aternatives in patients unwiing to consider being treated with mitoxantrone. Conservative neuroogists and anxious patients wi argue that the potentia risks of second-ine therapies are too great for the patient with ony mid disabiity. The patient seeks reassurance and the neuroogist in a busy cinic may opt to continue with first-ine disease-modifying therapy and to intensify symptomatic therapy. But neuroogists must take the ead in aerting patients to the risks of this approach when there is evidence of incompete disease contro, and advise the patients of the dangers of therapeutic compacency. One of the advantages of being Figure 2 A fow diagram summarising cinica events and treatment decisions when foowing a reapsing-remitting MS patient during the first two years on first-ine disease modifying treatment using treatment optimisation recommendations. ot a the decisions have a strong evidence base. DMT, disease-modifying treatment; Abs, neutraising antibodies; GA, gatiramer acetate; RRMS, reapsing remitting MS; IFB, beta interferon; GAD, gadoinium)

10 142 Practica euroogy PRACTICE POITS Predicting the course of MS is difficut; a number of prognostic factors incuding baseine demographics, reapse activity in the first few years, initia MRI esion oad and its increment in the first few years, are a important. Reapses indicate ongoing infammatory disease activity which needs contro, about 50% of reapses resut in increased disabiity after recovery, for every cinica reapse there are 8 10 sient esions in the brain, and reapses cause axona destruction. Disabiity after years of MS is due to disease activity measured by reapses and increase in MRI brain esion oad during the first 5 years of iness. The natura history of MS can ony be atered by therapy in the initia infammatory phase; once a sustained disabiity score of EDSS 4 is reached current therapies have itte effect. One third of reapsing-remitting MS patients have a suboptima response to first-ine disease-modifying treatments Treatment optimisation protocos measuring reapse activity and disabiity shoud be activey empoyed in assessing patients on first-ine diseasemodifying treatments. Despite their higher risks, the more effective treatments, usuay nataizumab or mitoxantrone but aso consider aemtuzumab or rituximab, shoud be used eary in reapsing-remitting MS patients with suboptima response to first-ine disease-modifying treatments. an oder (edery?) neuroogist as I am, is that I have treated patients from the onset of their iness for up to 35 years and observed the consequences of the inadequacy of the present first-ine therapies in 30 40% of reapsing-remitting MS patients. ACKOWLEDGEMETS This artice was reviewed by Richard Hughes, London, UK. Competing interests: I have received research grants and honoria from Schering AG and Merck- Serono, for ectures and fees for acting on the medica advisory boards of the AFFIRM (nataizumab) and COFIRM (BG12) studies for Biogen-Idec. REFERECES 1. Confavreux C, Vukusic S, Moreau T, et a. Reapses and progression of disabiity in mutipe scerosis. Eng J Med 2000;343: Confavreux C, Vukusic S, Adeeine P. Eary cinica predictors and progression of irreversibe disabiity in mutipe scerosis: an amnesic process. Brain 2003;126: Weinshenker BG, Bass B, Rice GP, et a. The natura history of mutipe scerosis: a geographicay based study: I. Cinica course and disabiity. Brain 1989;112: Weinshenker BG, Bass B, Rice GPA, et a. The natura history of mutipe scerosis: a geographicay based study: II. Predictive vaue of the eary cinica course. Brain 1989;112: Weinshenker BG, Rice GPA, oseworthy JH, et a. The natura history of mutipe scerosis: a geographicay based study: III. Mutivariate anaysis of predictive factors and modes of outcome. Brain 1991;114: Runmarker B, Andersen O. Prognostic factors in a mutipe scerosis incidence cohort with 25 years of foow up. Brain 1993;116: Bergamaschi R, Quagini S, Trojano M, et a. Eary prediction of the ong term evoution of mutipe scerosis: the Bayesian risk estimate for mutipe scerosis (BREMS) score. J euro eurosurg Psychiatry 2007;78: Sormani MP, Rovaris M, Comi G, et a. A composite score to predict short-term disease activity in patients with reapsing-remitting MS. euroogy 2007;69: Hirst C, Ingram G, Swinger R, et a. Change in disabiity in patients with mutipe scerosis: a 20- year prospective popuation-based anaysis. J euro eurosurg Psychiatry 2008;79: Hawkins SA, McDonne GV. Benign mutipe scerosis? Cinica course, ong term foow up, and assessment of prognostic factors. J euro eurosurg Psychiatry 1999;67: Costeoe L, Thompson A, Wash C, et a. Long term cinica reevance of criteria for designating mutipe scerosis as benign after ten years of disease. J euro eurosurg Psychiatry 2008;79: Pittock SJ, McCeand RL, Mayr WT. Cinica impications of benign mutipe scerosis: A 20-year popuation based foow-up study. Ann euro 2004;56: Sayao AL, Devonshire V, Tremett H. Longitudina foow-up of benign mutipe scerosis at 20 years. euroogy 2007;68: Amato MP, Portaccio E, Stromio ML, et a. Cognitive impairment and quantitative magnetic resonance metrics can hep to identify benign mutipe scerosis. euroogy 2008;71: Lubin FD, Baier M, Cutter GR. Effect of reapses on deveopment of residua deficit in mutipe scerosis. euroogy 2003;61: Hirst C, Ingram G, Pearson O, et a. Contribution of reapses to disabiity in mutipe scerosis. J euro 2008;255: Wikins A, Scoding. Protecting axons in mutipe scerosis. Mut Scer 2008;14: Tintoré M, Rovira A, Río J, et a. Do oigocona bands add information to MRI in first attacks of mutipe scerosis? euroogy 2008;70: Jin YP, de Pedro-Cuesta J, Huang YH, et a. Predicting mutipe scerosis at optic neuritis onset. Mut Scer 2003;9: Joseph FG, Hirst CL, Pickersgi T, et a. CSF oigocona band status informs prognosis in MS: a case contro study of 100 patients. J euro eurosurg Psychiatry 2008;80: Fisniku LK, Brex PA, Atmann DR, et a. Disabiity and T2 MRI esions: a 20-year foow-up of patients with reapse onset of mutipe scerosis. Brain 2008;131: Minneboo A, Jasperse B, Barkhof F, et a. Predicting short-term disabiity progression in eary mutipe scerosis: added vaue of MRI parameters. J euro eurosurg Psychiatry 2008;79: /jnnp

11 Mesaros S, Rocca MA, Sormani MP, et a. Cinica and conventiona MRI predictors of disabiity and brain atrophy accumuation in RRMS. A arge-scae, short-term foow up study. J euro 2008;255: McFarand HF, Barkhof F, Ante J, et a. The roe of MRI as a surrogate outcome measure in mutipe scerosis. Mut Scer 2002;8: Fisniku LK, Chard DT, Jackson JS, et a. Gray matter atrophy is reated to ong-term disabiity in mutipe scerosis. Ann euro 2008;64: Coes AJ, Cox A, Le Page E, et a. The window of therapeutic opportunity in mutipe scerosis: evidence from monocona antibody therapy. J euro 2006;253: Poman CH, Reingod SC, Edan G, et a. Diagnostic criteria for mutipe scerosis: 2005 revisions to the McDonad Criteria. Ann euro 2005;58: Association of British euroogists. Guideines for the use of betainterferons and gatiramer acetate in mutipe scerosis Avaiabe at org/documents/msdoc.pdf (accessed 3 Dec 2008). 29. Riazi A, Hobart JC, Lamping DL, et a. Mutipe Scerosis Impact Scae (MSIS-29): reiabiity and vaidity in hospita based sampes. J euro eurosurg Psychiatry 2002;73: Costeoe L, O Rourke K, Kearney H, et a. The patient knows best: significant change in the physica component of the Mutipe Scerosis Impact Scae (MSIS-29 physica). J euro eurosurg Psychiatry 2007;78: O Rourke KE, Hutchinson M. Stopping betainterferon therapy in mutipe scerosis: an anaysis of stopping patterns. Mut Scer 2005;11: Rudick RA, Lee JC, Simon J, et a. Defining interferon beta response status in mutipe scerosis patients. Ann euro 2004;56: Waubant E, Vukusic S, Gignoux L, et a. Cinica characteristics of responders to interferon therapy for reapsing MS. euroogy 2003;61: O Rourke K, Wash C, Antonei G, et a. Predicting beta-interferon faiure in reapsing-remitting mutipe scerosis. Mut Scer 2007;13: Rio J, os C, Tintore M, et a. Assessment of different treatment faiure criteria in a cohort of reapsing mutipe scerosis patients treated with interferon beta: impications for cinica trias. Ann euro 2002;52: Bosca I, Coret F, Vaero C, et a. Effect of reapses over eary progression of disabiity in mutipe scerosis patients treated with beta-interferon. Mut Scer 2008;14: Jeffery D, Bashir K, Buchwad L, et a. Optimizing immunomoduatory therapy for MS patients: an integrated management mode. J euro Sci 2002;201: Freedman MS, Patry DG, Grand Maison F, et a. Treatment optimization in mutipe scerosis. Can J euro Sci 2004;31: PRISMS (Prevention of reapses and disabiity by interferon beta-1a subcutaneousy in mutipe scerosis) Study Group. Randomized doube-bind pacebo controed study of interferon beta-1a in reapsing/remitting mutipe scerosis. Lancet 1998;352: Freedman MS, Forresta FG. Canadian treatment optimization recommendations (TOR) as a predictor of disease breakthrough in patients treated with interferon B-1a: anaysis of the PRIMS study. Mut Scer 2008;14: ICE technoogy appraisa guidance 127. ataizumab for the treatment of aduts with highy active reapsing remitting mutipe scerosis. Avaiabe at (accessed 3 Dec 2008). 42. Poman CH, O Connor PW, Havrdova E, et a. for the AFFIRM Investigators. A randomized, pacebo-controed tria of nataizumab for reapsing mutipe scerosis. Eng J Med 2006;354: The CAMMS223 Tria Investigators. Aemtuzumab vs. interferon beta-1a in eary mutipe scerosis. Eng J Med 2008;359: Hartung HP, Gonsette R, Konig, et a, for the Mitoxantrone im Mutipe Scerosis Study Group (MIMS). Mitoxantrone in progressive mutipe scerosis: a pacebo-controed, doube-bind, randomised, muticentre tria. Lancet 2002;360: Hauser SL, Waubant E, Arnod DL, et a,, for the HERMES Tria Group. B-ce depetion with rituximab in reapsing remitting mutipe scerosis. Eng J Med 2008;358: EMEA guideines. Avaiabe at europa.eu/humandocs/pdfs/epar/tysabri/h-603- en6.pdf (accessed 30 Oct 2008).