A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting

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1 European Journal of Neurology 2006, 13: A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting D. Karussis a, L. D. Biermann b, S. Bohlega c, A. Boiko d, M. Chofflon e, F. Fazekas f, M. Freedman g, S. Gebeily h, R. Gouider i, E. Havrdova j, G. Jakab k, R. Karabudak l and A. Miller m for the International Working Group for Treatment Optimization in MS a Department of Neurology, Hadassah Hebrew University Hospital, Ein-Karem, Jerusalem, Israel; b Queenswood, South Africa; c King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; d Department of Neurology and Neurosurgery, Russian State Medical University, Moscow, Russia; e Service de Neurologie, Hoˆpital Cantonal de Gene`ve, Rue Micheli-du-Crest, Geneva, Switzerland; f Universita tsklinik fu r Neurologie, Graz, Austria; g Multiple Sclerosis Research Clinic, Ottawa Hospital General Campus, University of Ottawa, Ottawa, ON, Canada; h Neuroscience Department, Lebanese Hospital Geitawi, Archrafieh, Beirut, Lebanon; i Neurological Department, Razi Hospital, Manouba, Tunis, Tunisia; j Department of Neurology, University Hospital, Praha, Czech Republic; k Neurology Department, Uzsoki St Hospital, Budapest, Hungary; l Department of Neurology, Hacettepe University Hospitals, Neuroimmunology Unit, Ankara, Turkey; and m Division of Neuroimmunology and Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel Keywords: consensus, diseasemodifying drug, glatiramer acetate, interferon beta, mitoxantrone, multiple sclerosis Received 26 August 2004 Accepted 18 January 2005 An International Working Group for Treatment Optimization in MS met to recommend evidence-based therapeutic options for the management of suboptimal responses or intolerable side-effects in patients treated with disease-modifying drugs (DMDs) for multiple sclerosis (MS). Several DMDs are now available for the treatment of MS that have been shown to alter the clinical course of the disease by decreasing disease activity and delaying the progression of disability. Nevertheless, many patients continue to experience disease activity whilst on treatment, and recommendations have been made on how the success of therapy in an individual patient can be assessed. However, even after having identified criteria for a suboptimal response to current treatments, clinicians require guidance on how to improve the outcomes. This report summarizes the conclusions from a workshop at which this issue was addressed. We suggest treatment pathways for optimizing therapy for those patients with suboptimal responses to DMDs, and therapeutic options for patients with unacceptable sideeffects on their current therapy. Introduction Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS), which is frequently progressive and eventually results in permanent CNS damage and chronic neurological disability [1]. The onset of the disease is often gradual, and patients present with a wide variety of symptoms that may overlap with those of other neurological disorders. Establishing a definite diagnosis of MS is challenging, and criteria for the diagnosis of MS, recently revised, classify patients into one of three categories: MS, possible MS and not MS [2]. Whilst there is no cure for MS, a number of diseasemodifying drugs (DMDs) are now available that alter the clinical course of the disease by decreasing disease activity and delaying the progression of disability (for reviews see [3,4]). Despite DMD therapy, however, some patients continue to experience progression of the Correspondence: International MS Group, 63A Pitts Road, Headington, Oxford, OX3 8BA, UK. (tel./fax: ; disease. The neurologist may therefore need to determine whether the response to a DMD treatment in an individual patient is optimal. Elaboration of an evidence-based medicine approach would be of help. In order to identify patients with suboptimal responses, an Analog Model has been developed to facilitate visualization of overall change in MS [5 7]. The model consists of three gauges that assess changes in relapses, disability progression and magnetic resonance imaging (MRI) activity. Each gauge ranges from no changes (no concern) to notable, then worrisome and, finally, actionable (high level of concern). By performing regular and standardized examinations, the treating neurologist can alter each gauge to provide a measure of the progress of an individual patient. If all three dials read ÔnotableÕ, any two read ÔworrisomeÕ or any one is ÔactionableÕ, treatment response may be suboptimal and the choice of therapy might have to be reconsidered [5]. Slight modifications to the assessments and weightings given to changes in the three key criteria have been suggested [6,7]. Nevertheless, this model provides a useful framework for assessing response to therapy. Ó 2006 EFNS 61

2 62 D. Karussis et al. Having ascertained that a patient has a suboptimal response to their current treatment, clinicians lack guidance on how to improve treatment outcomes. The objective of this consensus meeting was to develop evidence-based recommendations on the subsequent therapeutic options that could be considered for a patient with MS who has a suboptimal response or unacceptable side-effects on their current DMD therapy. Methods The development process for this treatment algorithm was initiated by an MS expert panel that prepared a number of statements focusing on specific issues in the medical management of MS. Thirteen neurologists from different countries around the world, experienced in the management of MS, were then invited to a workshop to discuss the statements. They were asked to indicate their support for each statement, according to the ranking in Table 1, and to comment on the rationale behind their decisions. In the light of their suggestions, the wording of the statements was modified, if necessary, until the group reached a consensus. Amendments generally involved rewording or rephrasing of individual statements, rather than major changes in the content. Each of the resulting statements was accepted completely, or with minor reservations, by all of those present. Finally, the evidence presented and decisions made were translated into clinical strategy by the Working Group, with the development of proposed decision pathways for the management of patients with definite or possible MS. The report is therefore presented in two sections: first, the statements, which address key issues in the management of MS and a summary of the major points raised during discussion at the consensus meeting; and, secondly, the treatment algorithms, with associated commentary and opinion. Results The statements 1. Candidates for initiation of DMD therapy should ideally meet the McDonald criteria for the diagnosis of MS. Table 1 Levels of support used in voting in the development of the statements Accept completely Accept with minor reservation Accept with major reservation Reject partially Reject completely The McDonald criteria [2] were developed to increase the sensitivity and specificity of diagnosis of MS, and there was concern amongst the Working Group that the criteria should not be used as the sole guideline for treatment decisions. Whilst it was accepted that the majority of patients recommended for initiation of DMD therapy should have MS (as described by the McDonald criteria; Table 2), the Working Group agreed that some patients who fall short of fulfilling the McDonald criteria still warrant consideration for treatment. The example raised at the workshop was that of a patient with a clinically isolated syndrome (CIS, i.e. one attack but either mono- or polysymptomatic presentation) compatible with demyelination, and evidence of lesions typical of MS on MRI (i.e. dissemination of lesions in ÔspaceÕ). In order to fulfil the McDonald criteria for MS, there is a need to demonstrate evidence of dissemination of lesions in time, as seen either by the appearance of new lesions on MRI or the development of a second clinical attack [2]. This requirement was regarded as being too restrictive, and participants agreed that other patients with a CIS who are at high risk of developing MS (based on MRI and clinical criteria, as defined by available evidence from treatment trials in this stage of the disease) could still be considered for DMD therapy. There is evidence that early DMD therapy in patients with a first acute clinical demyelinating event may provide long-term benefit in delaying the progression of the disease and conversion to clinically definite MS [8]. However, in order to avoid the inconvenience of a patient receiving unnecessary treatment, the group recommended that in the case of Ôpossible MSÕ [2], special care must be taken before any treatment decisions are made and advice should be sought from a neurologist who is experienced in managing patients with MS. The majority of patients with possible MS and abnormal brain MRI will eventually progress to MS [9], and it is the management of patients with MS that is the main focus of this publication. It should be noted that the major clinical trials with DMDs that were conducted before the publication of the McDonald criteria used the earlier Poser criteria for the diagnosis of MS, which defined patients as having clinically ÔdefiniteÕ or ÔprobableÕ MS [10]. 2. Some factors are known to be associated with a poor long-term prognosis, but the absence of such factors does not guarantee a mild disease course. The course of MS is unpredictable and determination of a ÔbenignÕ disease course is usually retrospective. There are a number of clinical and demographic factors that have been reported to adversely affect the prognosis of MS. These include: an older age

3 Treatment algorithm in relapsing MS 63 Table 2 Diagnosis of MS according to the McDonald criteria [2] Clinical presentation Additional data needed for MS diagnosis Two or more attacks; objective clinical evidence of 2 or more lesions Two or more attacks; objective clinical evidence of 1 lesion One attack; objective clinical evidence of 2 or more lesions One attack; objective clinical evidence of 1 lesion (monosymptomatic presentation; clinically isolated syndrome) Insidious neurological progressions suggestive of MS None a Dissemination in space, demonstrated by MRI b or 2 or more MRI-detected lesions consistent with MS plus CSF c or await further clinical attack implicating a different site Dissemination in time, demonstrated by MRI or second clinical attack. Dissemination in space, demonstrated by MRI b or two or more MRI-detected lesions consistent with MS plus positive CSF c and dissemination in time, demonstrated by MRI or second clinical attack Positive CSF c and dissemination in space, demonstrated by (i) nine or more T2 lesions in brain or (ii) two or more lesions in spinal cord, or (iii) four to eight brain plus one spinal cord lesion or abnormal visual-evoked potential d associated with four to eight brain lesions plus one spinal cord lesion demonstrated by MRI and dissemination in time, demonstrated by MRI or continued progression for 1 year Table reproduced with permission of WI McDonald, and John Wiley & Sons, Inc., from McDonald et al. [2]. If criteria indicated are fulfilled, the diagnosis is multiple sclerosis (MS); if the criteria are not completely met, the diagnosis is Ôpossible MSÕ; ifthe criteria are fully explored and not met, the diagnosis is Ônot MSÕ. a No additional tests are required; however, if tests [MRI, cerebral spinal fluid (CSF)] are undertaken and are ÔnegativeÕ, extreme caution should be taken before making a diagnosis of MS. Alternative diagnoses must be considered. There must be no better explanation for the clinical procedure. b MRI demonstration of space dissemination must fulfil the criteria derived from Barkhof et al. [54] and Tintore et al. [55]. c Positive CSF determined by oligoclonal bands detected by established methods (preferably isoelectric focusing) different from any such bands in serum or by a raised IgG index [56,57]. d Abnormal visual-evoked potential of the type seen in MS (delay with a well-preserved wave form) [58]. (>40 years) at onset, presence of motor, cerebellar, sphincter or polyregional symptoms at onset; frequent attacks during the early years of the disease; a short interval between the first two attacks; incomplete remissions; rapid progression of disability or progressive MS from onset (for reviews see [11,12]). In addition, MRI findings may be of prognostic value in patients with MS [9,13 16]. However, the nature and timescale of disease progression varies dramatically between individual patients. Whilst there are patients with benign MS who experience little or no progression of disability over a prolonged period of time, this cannot be predicted during the early stages of the disease and is determined retrospectively. Moreover, the definition of ÔbenignÕ in itself is controversial. 3. To date, benign MS cannot be predicted. Although the term ÔbenignÕ MS is frequently used by neurologists to describe the subgroup of patients who may have a long history of clinical or MRI inactivity, this disease course cannot be determined prospectively. Participants agreed that such patients should be described as having Ôinactive MSÕ and that initiation of treatment with DMDs in such patients is not warranted. However, as MS is unpredictable, patients should be monitored at regular intervals in order to detect any evidence of disease activity and start DMD therapy in appropriate time. Such follow-ups could make use of the Analog Model described in the introduction [5 7]. On this model, patients with inactive MS would have no activity on the gauges, and any sign of change during regular follow-up would warrant closer monitoring in order to take action and begin treatment if necessary. 4. Recommendations related to the treatment paradigm should be based on approved agents with proven efficacy in large, phase III trials in MS; experimental or Ôofflabel Õ treatments or combinations cannot be recommended as first-line therapies. Three DMDs, interferon (IFN) beta-1a (Avonex Ò, Rebif Ò ), IFN beta-1b (Betaseron Ò /Betaferon Ò ) and glatiramer acetate (Copaxone Ò ), have been shown to reduce disease activity during large, phase III clinical trials in patients with relapsing remitting (RR)MS who had experienced at least two attacks in the 2 3 years prior to study entry [17 20] and will be included in the treatment paradigm. The efficacy of these DMDs in RRMS is supported by Class I evidence from welldesigned prospective, randomized, controlled clinical trials [3]. In addition, IFN beta-1a, at the low dose of 30 mcg once weekly, has been shown to delay the development of clinically definite MS (defined according to the Poser criteria; [10]) and changes in MRI findings in patients with a first demyelinating event [8], and there is some effect of IFN beta on disability in secondary-progressive (SP)MS, which appears significant especially in patients with superimposed relapses [21,22].

4 64 D. Karussis et al. The beneficial effects of IFN beta in RRMS appear to be related to both dose and dosing frequency, with higher and more frequent doses of the drug having greater clinical efficacy. Yet the interaction of dosage and dosing frequency appears to be quite complex. With once-weekly IFN beta-1a, increasing the dose from 30 to 60 mcg provided no significant clinical benefit over 4 years [23,24]. Similarly, no improvement in clinical efficacy was observed over 48 weeks if the dose of IFN beta-1a was doubled to from 22 to 44 mcg, although there was a significant improvement in MRI measures [25]. However, the PRISMS (Prevention of Relapses and disability by IFN beta-1a Subcutaneously in Multiple Sclerosis) study provides evidence of greater long-term benefit in RRMS if IFN beta-1a is given at a dose of 44 mcg three times weekly, compared with 22 mcg three times weekly [26]. In addition, the EVI- DENCE study [27] provides Class I evidence [3] that IFN beta-1a, 44 mcg three times weekly, is significantly more effective on both clinical and MRI outcome measures in RRMS over 48 months compared with IFN beta-1a, 30 mcg once weekly. Moreover, in a 2-year study, IFN beta-1b, 250 mcg every other day, has been shown to have a greater benefit in RRMS compared with IFN beta-1a, 30 mcg once weekly [28], based on Class I evidence on MRI endpoints but Class III evidence for clinical observations [3]. The immunosuppressant mitoxantrone (Novantrone Ò ) has also been shown in a phase III clinical trial to reduce relapse rates and relapse-related MRI outcomes in relapsing MS, and may have a beneficial effect on disease progression in patients with worsening conditions [29]. The American Academy of Neurology (AAN) has, however, stated that the potential toxicity of mitoxantrone considerably limits its use in patients with relapsing forms of MS, and recommends that this agent be reserved for patients with rapidly advancing disease who have failed other therapies [30]. In the development of the MS treatment algorithms, the four DMD products will therefore be considered as first-line therapies and mitoxantrone as second line. In addition, it may be appropriate to consider other, unapproved therapies (as defined in Statement 15) for a patient in whom all else has failed. 5. All approved first-line DMD treatments can be considered for use after the first demyelinating event in patients at high risk of conversion to MS. Patients with a first attack and with dissemination of MRI lesions in space and time have MS according to McDonald criteria [2] and are therefore eligible for DMD therapy, as defined in Statement 1. DMD therapy can also be considered for some high-risk patients with possible MS [9,13 16,31]. Whilst participants agreed that all approved first-line treatments (IFN beta-1a, IFN beta-1b and glatiramer acetate, as defined in Statement 4) should also work in patients with CIS and thus may be considered for use in such patients, they accepted that this recommendation is not evidencebased. There are no data with IFN beta-1b or glatiramer acetate in patients with a CIS suggestive of MS, although studies are ongoing. Phase III clinical trials have shown that IFN beta-1a, 30 mcg once weekly, delays conversion to clinically definite MS [10] and changes in MRI criteria in patients with a first demyelinating event [8]. However, it appears that once-weekly dosing with IFN beta-1a in RRMS is less effective than a higher, more frequent dose (44 mcg three times weekly) in maintaining patients relapse-free and in reducing MRI activity after 24 and 48 weeks of treatment [27]. The Working Group wondered whether a higher dose of IFN beta-1a would also be more effective in patients with a CIS. They concluded that, as IFN beta-1a, IFN beta-1b and glatiramer acetate have all been shown to be effective in RRMS, and a patient with a CIS is highly likely to progress to MS, it is reasonable to propose early treatment with these DMDs at the doses approved for MS, even though there is not yet evidence to support this approach. 6. Treatment should be aimed at reducing, or ideally stopping, the disease activity that ultimately leads to progression. Either a change or escalation in therapy should be considered for patients with continued disease activity despite therapy. Treatment optimization recommendations could be used to assess whether patients may warrant a change in therapy. The aim of treatment in MS is to stop the disease activity that leads to progression and increasing disability. However, no current treatment can achieve this outcome and the realistic aim, for the present, is to reduce disease activity with a DMD. Thus, many patients continue to experience disease activity despite treatment. In an individual patient with MS it is therefore important to monitor the results being achieved with a chosen DMD. The Analog Model described earlier [5 7] was recommended as a useful tool to help the treating neurologist decide when it may be necessary to modify or escalate treatment in order to optimize the outcome. 7. The minimum length of time to assess an agent before determining that it is yielding a suboptimal clinical response is 6 12 months. The majority of patients will respond to DMD therapy within 1 year. With high-dose IFN beta, a measurable effect is achieved by 3 months [27], whereas an effect with glatiramer acetate may take 6 months [32]. It is therefore reasonable to try an agent for 6 12 months before determining that it is yielding a

5 Treatment algorithm in relapsing MS 65 suboptimal clinical response, although in some cases this will become apparent much earlier. 8. A change in therapy is warranted if there are tolerability issues that obviate the use of the proven effective regimen of a given DMD. Relatively few patients treated with DMDs experience major side-effects that are likely to warrant a change of therapy. In the pivotal phase III clinical trials in RRMS, <5% of patients treated with IFN beta-1a withdrew because of adverse events during the 2-year period [19,20] compared with 8.1% of those taking IFN beta-1b [17]. With glatiramer acetate, the package insert reports a discontinuation rate because of adverse events of approximately 8% [33]. Where tolerability is a problem, the treating neurologist should initially try to address the issues if possible. The majority of side-effects of DMD therapy are mild, occur early during therapy and later disappear. Influenza-like symptoms (headache, fever, fatigue, chills, pain and myalgia), for example, occur in 50 60% of patients taking IFN beta [34 36]. They are more common at the initiation of therapy, tend to decline with time, and can usually be managed with over-the-counter remedies such as acetominophen, or by injecting the drug at night so that the patient sleeps through many of the symptoms [37]. With glatiramer acetate, approximately 10% of patients experience a systemic reaction immediately after injection that includes flushing, chest pain, palpitations and anxiety [33]. In general, these symptoms are transient and self-limited, and do not require specific treatment. Injection-site reactions are also a common adverse event in patients treated with subcutaneous IFN beta or glatiramer acetate, although their incidence can be reduced by educating patients on correct injection technique. More serious events such as injection-site necrosis are infrequent [27]. Injection-site necrosis rarely occurs more than once in the same patient and should not necessarily warrant a change in therapy. Lipoatrophy from injections of glatiramer acetate is not uncommon, but is an irreversible side-effect warranting a change in injection site location or cessation of therapy. More rarely, allergic-type reactions such as localized itching or hives have been noted with glatiramer acetate. Other side-effects of DMD therapy should be managed as advised in the manufacturer s package insert. In addition, there are a number of ways of initiating therapy in an individual patient. With high-dose IFN beta, for example, it is recommended that the dose be increased gradually over a 1-month period in order to allow tachyphylaxis to develop, thus reducing adverse events. If there are initial tolerability problems, these can frequently be addressed by reducing the dose in the short-term and then retitrating to the higher dose. Workshop participants concluded that it is reasonable to spend up to 3 months titrating the therapy. If, after this period of time, the patient is still unable to cope with high-dose IFN beta because of unacceptable sideeffects, a change of therapy to a lower approved dose of IFN beta should be considered. If tolerability problems persist, a switch to glatiramer acetate might be considered, even though there is no evidence to support this last step. IFN beta might be considered for patients not able to tolerate glatiramer acetate. Tolerability issues may also develop later during treatment. In particular, an elevation of liver enzymes to grade 2 (>2.5 to 5 times the upper limit of normal) or grade 3 (>5 to 5 times the upper limit of normal) requires a dose reduction followed by a gradual re-escalation of dose when the enzyme levels have normalized [38]. Although slight liver enzyme elevations are common during IFN beta therapy, they are generally asymptomatic and remit spontaneously whilst on therapy. Francis et al. [38] reported that only 0.4% of patients discontinued treatment with IFN beta-1a because of hepatic adverse events. Where a change in therapy is required because of problems related to tolerability, participants recommended a switch to an alternative regimen or therapy with proven efficacy rather than to a suboptimal dose of the current therapy. 9. DMDs should be used as first-line treatment in relapsing MS because of their more favourable benefit: risk profile compared with immunosuppressant agents. Due to cumulative cardiotoxicity, the possibility of infertility and special requirements for administration, mitoxantrone is better used for escalating therapy in patients with continued severe disease activity and progression despite DMD treatment. The view that the potential toxicity of mitoxantrone may outweigh the clinical benefits early in the course of MS and should be reserved for patients with rapidly advancing disease who have failed other therapies is in line with the recommendations of the AAN [3,30]. 10. It may be possible to show clear evidence of benefit for a given therapy using clinical parameters (such as the percentage of relapse- or progression-free patients). As there is no randomized study that provides a direct comparison of all the available DMDs, there is no way to perform an absolute ranking of the existing treatments. Head-to-head trials are rare in most therapeutic areas, and the relative effect of treatment has to be assessed by the comparison of key endpoints, whilst bearing in mind that differences in the study populations and designs may contribute to the observed apparent differences in efficacy.

6 66 D. Karussis et al. Using published data from clinical trials in MS, the AAN has evaluated the relative effectiveness of the different therapies [3,30]. In addition, efficacy of the DMDs can be assessed based on the statistical significance of the findings on relapses, MRI and disease progression endpoints from the pivotal clinical trials (Table 3; [17 20,29,32,39 45]). These comparisons can provide at least some rationale for treatment escalation amongst DMDs. When a decision to escalate treatment because of suboptimal response is to be made in individual cases, the strong indication of a dose and dosing frequency response with IFN beta [26 28] should be taken into account. If a patient fails on low-dose IFN beta, it would be logical to increase the dose and dosing frequency. Whilst results of head-to-head studies with glatiramer acetate are not yet available, this agent fails to achieve statistical significance on many of the parameters that are impacted significantly by therapy with IFN beta-1a or IFN beta-1b (Table 3; 18]). Thus, in the pivotal clinical trial with glatiramer acetate, the change in disease progression during the first 2 years of the study was not significant [18], although a secondary analysis of data from the extension phase of this study reported a reduction in progression rate over 3 years in treated patients compared with control subjects using survival analysis [44]. The AAN conclude that this observation is of uncertain validity and that glatiramer acetate may only possibly slow sustained disability progression, whereas IFN beta therapy probably achieves this aim [3]. Head-to-head trials that are currently under way should provide clearer information about the relative efficacies of glatiramer acetate compared with IFN beta. However, on the basis of current evidence, patients who fail on glatiramer acetate should be recommended therapy with IFN beta. There was some discussion about whether the appearance of consistent neutralizing antibodies (NAb) against the existing DMD should influence the decision to change treatment. There is some evidence that the development of persistent NAb may be associated with a reduction in clinical response to IFN beta [46 48]. Therefore, in a patient with treatment failure, the detection of high levels of NAb may provide additional information. However, overall clinical significance of measuring NAb in an individual on IFN beta therapy is uncertain [3]. Furthermore, the availability of tests for NAb is restricted to very few specialized MS centres. It was therefore felt that this topic was outside the scope of the meeting and that the key factor influencing treatment decisions should be whether or not a particular patient continues to have a good clinical response to their current DMD therapy. 11. Before considering escalation therapy with immunosuppressants, treatment with high-dose IFN should be considered. This follows on from the previous two statements, and concerns about the adverse side-effects associated with immunosuppressant therapy. 12. Response to the DMD therapies approved for use in MS has been shown to be sustained. There are no long-term placebo-controlled studies with any of the DMDs that have continued for longer than 5 years. However, follow-up data from patients who have been on immunomodulatory therapy for many years indicate that DMDs do have long-term benefit on disease progression [49 51]. By contrast, mitoxantrone cannot be used for more than 2 3 years, Table 3 Ranking of data on DMD in RRMS based on the significance level of the findings on attack rate, confirmed progression and changes on MRI Number of patients Class of study e Reduction of clinical attack Reduction of MRI attack rate Reduction of MRI severity Reduction in confirmed progression IFN beta-1a (Rebif Ò ) a 560 I h h h n IFN beta-1a (Avonex Ò ) a 301 I n n ns n IFN beta-1b a 372 I h h h ns Glatiramer acetate a 251 I h nr nr ns Glatiramer acetate b 249 I n h h ns Mitoxantrone c 42 II/III n h nr n Mitoxantrone d 51 II/III h n nr n Mitoxantrone a 188 I/III h n nr n IFNB Multiple Sclerosis Study Group [17]; Paty and Li [39]; IFNB Multiple Sclerosis Study Group and The University of British Colombia MS/MRI Analysis Group [40]; Johnson et al. [18]; Jacobs et al. [19]; Simon et al. [41]; Edan et al. [42]; Millefiorini et al. [43]; Rudick et al. [44]; PRISMS Study Group [20]; Li and Paty [45]; Comi et al. [32]; Hartung et al. [29]. Table reproduced with permission of D.S. Goodin. h, significantly improved ( P < 0.01); n, marginally improved ( P ¼ ); ns, not improved; nr, not recorded. Duration of study: a 2 years; b 9 months; c 6 months; d 1 year. e Data from clinical trials are classified according to a ratings scheme, in which ÔIÕ is the highest rating (exceptionally well-designed trial prospective, blinded, randomized, controlled trial) and IV is the lowest (uncontrolled studies, case series, case reports or expert opinion).

7 Treatment algorithm in relapsing MS 67 because the toxicity of the product limits the total cumulative dose that can be given to a patient [30]. 13. RRMS and SPMS should be considered as a continuum of the same disease process, and the decision to escalate or change treatment should be made on the basis of disease progression and presence of relapses, and not on the ÔtypeÕ of disease. There are few data on the efficacy of DMD therapy in SPMS, but the available evidence appears to suggest that efficacy is probably dependent on ongoing inflammation. Thus, the efficacy of IFN beta in SPMS appears to be significant, particularly in patients with superimposed relapses [21,22] and, in such patients, suboptimal responses to DMD therapy would perhaps warrant an escalation of therapy. However, a time will be reached in SPMS when it is appropriate to stop DMD therapy. 14. Suboptimal response (determined using the treatment optimization model described in the Introduction) in terms of progression with immunosuppressive therapy warrants discontinuation of that therapy. If escalation therapy with approved DMDs and immunosuppressants fails, it may be appropriate to consider experimental approaches, as described below. 15. Unapproved therapies, including combination therapies, should be considered as experimental. There are a number of therapies that may possibly be effective in MS but for which only Class II or III evidence exists, including chronic steroid treatment, azathioprine, cyclophosphamide, plasmapheresis and IVIg [3], as well as experimental modalities and combination therapies. These therapies are, as yet, formally unproven and should be considered only when all firstline treatments have failed. Translation of the statements into clinical strategy Based on the earlier discussions and the statements developed above, the workshop participants discussed how their conclusions could be translated into clinical strategy. The algorithms they developed suggest changes in treatment that may be considered for patients with suboptimal responses to current therapy (identified using the Analog Model described earlier), or patients who develop side-effects that render their current therapy intolerable (Fig. 1). Management of a suboptimal response in a patient with MS initiating DMD therapy In naïve patients with MS, the choice of initial therapy made by the treating neurologist should be based primarily on the medication s efficacy/safety profile [52]. In several countries, treatment has frequently been withheld from some patients because they do not Glatiramer acetate Patient naïve Intolerable to glatiramer side-effects acetate does not wish to go on immunosuppressives Patient with contraindication to mitoxantrone* Sub-optimal response Unapproved therapies * Mitoxantrone Naïve patient with definite MS Try: 1. Symptom management 2. Dose modification * Sub-optimal response Sub-optimal response Intolerable side-effects Persistent intolerable side-effects High-dose IFN beta Sub-optimal response Sub-optimal response Intolerable side-effects Try: 1. Symptom treatment 2. Dose titration 3. Dose modification Persistent intolerable side-effects Glatiramer acetate Low-dose IFN beta Intolerable side-effects meet the clinical trial inclusion criteria. It is important to remember that the pivotal clinical trials required patients to have active MS on entry in order to detect a response to DMD therapy in the shortest possible time. There is no justification for limiting access or duration of treatment on the basis, for example, of the patient s age or the number of clinical relapses over a specific period, provided there is evidence of recent or continued disease activity [53]. However, each case must be judged individually, and decisions about when and whether to begin therapy with a DMD should only be made after discussion with the patient about the options available. Similarly, the patient should be involved in any decision about a change of therapy. The treatment algorithm begins with the assumption that the patient will receive treatment with either lowdose IFN beta, high-dose IFN beta or glatiramer acetate. Patients who have suboptimal responses to low-dose IFN beta after 6 12 months of treatment (see statement 7) should be switched to high-dose IFN beta. Patients who have suboptimal responses to glatiramer acetate should be switched to IFN beta therapy. If there * Unapproved therapies * Refer to MS centre. There is evidence available to indicate that the efficacy of IFN beta is dose-related (see Statement 4). As defined in Statement 15. Figure 1 Pathway for the management of a suboptimal response or side-effects in a patient taking DMD therapy.

8 68 D. Karussis et al. is a suboptimal response to high-dose IFN, the logical escalation would be to move towards an immunosuppressant, such as mitoxantrone. However, because of the possible side-effects associated with immunosuppression, treatment with glatiramer acetate might be considered as an alternative for patients who are naïve to this agent. Immunosuppressive therapy should only be considered under the supervision of an MS specialist, ideally at an MS centre. Patients with suboptimal responses to IFN beta and subsequently to mitoxantrone should be referred to an MS centre as soon as possible, where they could be considered for treatment with unapproved therapies. There was some concern about the lack of subsequent options for patients treated with mitoxantrone. It is unknown how long mitoxantrone will stabilize the disease and, because of potential cardiac toxicity, a cumulative dose of more than 140 mg/m 2 is not recommended for the treatment of MS. At a dose of 12 mg/m 2 administered every 3 months, this limitation translates to a maximum duration of therapy of only 2 3 years [30]. At the end of this period, or even earlier, there may be an option to return to DMD therapy, although there are currently no data to support such an approach. Management of side-effects Many patients suffer side-effects at the start of therapy that later disappear. The Working Group recommended that patients should be informed about the common possible side-effects associated with their therapy and how they can be minimized or managed, thus enhancing adherence to therapy. They concluded that a period of 3 months is a reasonable length of time during which to try and manage side-effects before considering a change of therapy, although an earlier switch may be necessary for a patient who requests that their treatment be changed. Patients who suffer intolerable side-effects on glatiramer acetate should be switched to IFN beta. Tolerability issues in patients taking IFN beta can frequently be managed by symptom treatment, dose titration or dose modification. Thus, a patient who initially cannot tolerate high-dose IFN beta may be able to do so if the dose is reduced and gradually retitrated to the high dose. Alternatively, patients can be prescribed a lower dose of IFN beta, which may be better tolerated. A switch from IFN beta to glatiramer acetate is appropriate for patients with persistent intolerable systemic side-effects with low-dose IFN beta therapy. If sideeffects persist after a switch to glatiramer acetate, referral to a specialist MS centre for possible treatment with an unapproved therapy would be an appropriate next step. Workshop participants would not recommend switching a patient who has intolerable side-effects on IFN beta or glatiramer acetate to mitoxantrone because of the known toxicity problems associated with mitoxantrone. However, a patient who was switched to mitoxantrone after a suboptimal response to glatiramer acetate or IFN beta, and who persists with side-effects on this agent despite symptom management and dose modification, should be referred to an MS centre for possible treatment with unapproved therapies. At any point in the treatment algorithm, discontinuation of therapy is always an option. Discussion The aim of the workshop was to address the problem of suboptimal response and tolerability issues in some patients taking DMD therapy for MS and to provide recommendations for treatment optimization. During the initial discussions about which patients should receive DMD therapy, it became apparent that the McDonald criteria for the diagnosis of MS [2] should not be regarded as guidelines that drive treatment decisions. The options suggested in the algorithms developed at the workshop are recommendations based on the available evidence and are not intended to be prescriptive. Workshop participants stressed the need for patients to be informed about the therapeutic options available, and to be involved in the decisions about their initial therapy and subsequent changes. It has to be recognized that some patients may choose not to be treated and this view must be respected. A patient with a CIS suggestive of MS, for example, who is perceived by the neurologist to be at high risk of disease progression, may prefer to wait for a second attack before beginning treatment. Others may reject treatment with IFN beta or glatiramer acetate because they do not wish to have injections. Participants recognized that the options for action may sometimes be limited. They highlighted the need for new drugs and further studies on the possible benefits of combination therapies, as well as for the identification of biomarkers of disease activity, prognosis and response to therapy in MS, which may assist clinical decision-making in the future. An additional route that should be open to all patients at any stage is therefore referral to an MS centre for inclusion in a clinical trial of an unapproved therapy. Conflict of interest All the participants received sponsorship for travel and, all but RG, an honorarium from Serono IBO. AB has participated in clinical trials supported by several

9 Treatment algorithm in relapsing MS 69 companies, including Biogen, Schering, Serono and Teva; FF has participated in treatment trials of MS and in related meetings and teaching activities sponsored by the various companies producing drugs for MS (e.g. Bayer, Baxter, Biogen, Schering, Serono, Novartis, Teva). He has also served as medical adviser to these companies and received unrestricted research funding; MF receives honoraria from Bayer, Berlex, Pfizer, Schering, Serono and Teva; RG is participating in clinical trials sponsored by Sanofi-synthe labo and Serono; EH has participated in clinical trials sponsored by Bayer, Biogen, Elan, Octapharma, Schering and Serono; GJ has participated in clinical trials involving Avonex Ò and Copaxone Ò, and has given lectures at symposia sponsored by Biogen, Schering, Serono and Teva; RK has participated in clinical trials supported by Biogen, Schering, Serono and Teva; DK has participated in clinical trials sponsored by Biogen, Schering, Serono and Teva, and has given lectures in symposia supported by all four above-mentioned companies; AM has participated in clinical therapeutic trials sponsored by Biogen, Schering, Serono and Teva. Acknowledgements The participants would like to thank Dr Hansjo rg Schlegel for his assistance in organizing the workshop meeting and Dr Ann McIlhinney for her help in the preparation of the manuscript. The consensus meeting was supported by a grant from Serono IBO (Zug, Switzerland). References 1. Weinshenker BG. The natural history of multiple sclerosis. Neurologic Clinics 1995; 13: McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of Neurology 2001; 50: Goodin D, Frohman E, Garmany G, et al. Diseasemodifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58: O Connor P on behalf of The Canadian Multiple Sclerosis Working Group. Key issues in the diagnosis and treatment of multiple sclerosis. 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10 70 D. Karussis et al. ised trial of interferon b-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352: Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS. Neurology 2001; 56: Clanet M, Radue EW, Kappos L, et al. A randomized, double-blind dose-comparison of weekly interferon b-1a in relapsing MS. Neurology 2002; 59: Clanet M, Kappos L, Hartung HP, Hohlfeld R. Interferon beta-1a in relapsing multiple sclerosis: four-year extension of the European IFN beta-1a Dose-Comparison Study. Multiple Sclerosis 2004; 10: The Once Weekly Interferon for MS Study Group Evidence of interferon beta-1a dose response in relapsingremitting MS: the OWIMS Study. Neurology 1999; 53: PRISMS Study Group, University of British Columbia MS/MRI Analysis Group PRISMS-4: long-term efficacy of interferon-b-1a in relapsing MS. Neurology 2001; 56: Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 2002; 59: Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). INdependent COmparison of INterferon (INCOMIN) Trial Study Group. Lancet 2002; 359: Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360: Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003; 61: Berger T, Rubner P, Schautzer F, et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. New England Journal of Medicine 2003; 349: Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Annals of Neurology 2001; 49: Copaxone Ò. Glatiramer acetate injection, package insert. Teva Neuroscience Inc., 01/ Avonex Ò. Interferon beta-1a, package insert. Biogen Inc., 02/ Betaseron Ò. Interferon beta-1b, package insert. Berlex Laboratories, 04/ Rebif Ò. Interferon beta-1a, package insert. Serono Inc., June Bayas A, Rieckmann P. Managing the adverse effects of interferon-beta therapy in multiple sclerosis. Drug Safety 2000; 22: Francis GS, Grumser Y, Alteri E, et al. Hepatic reactions during treatment of multiple sclerosis with interferonbeta-1a: incidence and clinical significance. Drug Safety 2004; 2003; 26: Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 1993; 43: IFNB Multiple Sclerosis Study Group and The University of British Colombia MS/MRI Analysis Group. Interferon beta-1b in the treatment of MS: final outcome of the randomised controlled trial. Neurology 1995; 45: Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies of intramuscular interferon b-1a for relapsing multiple sclerosis. Annals of Neurology 1996; 43: Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. Journal of Neurology, Neurosurgery and Psychiatry 1997; 62: Millefiorini E, Gasperini C, Pozzilli C, et al. Randomized placebo-controlled trial of mitoxantrone in relapsingremitting multiple sclerosis: 24-month clinical and MRI outcome. Journal of Neurology 1997; 244: Rudick RA, Goodkin DE, Jacobs LD, et al. Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 1997; 49: Li DK, Paty DW. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebocontrolled study of interferon beta 1a in relapsing-remitting multiple sclerosis. Prevention of relapses and disability by interferon beta-1a subcutaneously in multiple sclerosis. 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11 Treatment algorithm in relapsing MS Francis GS. Benefit risk assessment of interferon-b therapy for relapsing multiple sclerosis. Expert Opinion on Drug Safety 2004; 3: Freedman MS, Blumhardt LD, Brochet B, et al. International consensus statement on the use of diseasemodifying agents in multiple sclerosis. Multiple Sclerosis 2002; 8: Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120: Tintore M, Rovira A, Martinez MJ, et al. Isolated demyelinating syndromes: comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis. AJNR. American Journal of Neuroradiology 2000; 21: Link H, Tibbling G. Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. Scandinavian Journal of Clinical and Laboratory Investigation 1977; 37: Andersson M, Alvarez-Cermeno J, Bernardi G, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. Journal of Neurology, Neurosurgery and Psychiatry 1994; 57: Halliday AM. (eds) Evoked Potentials in Clinical Testing, 2nd edn. London, UK: Churchill Livingstone, 1993.

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