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
land A. Miller
mfor the
International Working Group for Treatment Optimization in MS
aDepartment of Neurology, Hadassah Hebrew University Hospital, Ein-Karem, Jerusalem, Israel;bQueenswood, South Africa;cKing Faisal
Specialist Hospital and Research Centre, Riyadh, Saudi Arabia;dDepartment of Neurology and Neurosurgery, Russian State Medical
University, Moscow, Russia;eService de Neurologie, Hoˆpital Cantonal de Gene`ve, Rue Micheli-du-Crest, Geneva, Switzerland;
fUniversita¨tsklinik fu¨r Neurologie, Graz, Austria;gMultiple Sclerosis Research Clinic, Ottawa Hospital General Campus, University of
Ottawa, Ottawa, ON, Canada;hNeuroscience Department, Lebanese Hospital Geitawi, Archrafieh, Beirut, Lebanon;iNeurological
Department, Razi Hospital, Manouba, Tunis, Tunisia;jDepartment of Neurology, University Hospital, Praha, Czech Republic;kNeurology
Department, Uzsoki St Hospital, Budapest, Hungary;lDepartment of Neurology, Hacettepe University Hospitals, Neuroimmunology Unit,
Ankara, Turkey; andmDivision of Neuroimmunology and Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel
Keywords:
consensus, disease-modifying drug, glatir-amer 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 recom-mend 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 con-tinue 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 side-effects 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 pre-sent 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 pa-tients into one of three categories: MS, possible MS and not MS [2].
Whilst there is no cure for MS, a number of disease-modifying 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
disease. The neurologist may therefore need to deter-mine whether the response to a DMD treatment in an individual patient is optimal. Elaboration of an evi-dence-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 reson-ance 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.
Correspondence: International MS Group, 63A Pitts Road, Headington, Oxford, OX3 8BA, UK. (tel./fax: +44 1865 744773; e-mail: [email protected]) .
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 evi-dence-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 modi-fied, 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.
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 presenta-tion) 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 cri-teria 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 consid-ered 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 man-aging 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 conduc-ted 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
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
(>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 progres-sive MS from onset (for reviews see [11,12]). In addi-tion, 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 can-not be predicted during the early stages of the disease and is determined retrospectively. Moreover, the defi-nition 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 des-cribed as having Ôinactive MSÕ and that initiation of treatment with DMDs in such patients is not warran-ted. 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 Ôoff-labelÕ treatments or combinations cannot be recommen-ded as first-line therapies.
Three DMDs, interferon (IFN) beta-1a (Avonex, Rebif), IFN beta-1b (Betaseron/Betaferon) and glatiramer acetate (Copaxone), 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 well-designed 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 accord-ing 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 signifi-cant especially in patients with superimposed relapses [21,22].
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
Nonea
Two or more attacks; objective clinical evidence of 1 lesion Dissemination in space, demonstrated by MRIbor2 or more MRI-detected
lesions consistent with MS plus CSFcorawait further clinical attack implicating a different site
One attack; objective clinical evidence of 2 or more lesions Dissemination in time, demonstrated by MRI or second clinical attack. One attack; objective clinical evidence of 1 lesion
(monosymptomatic presentation; clinically isolated syndrome)
Dissemination in space, demonstrated by MRIbortwo or more MRI-detected
lesions consistent with MS plus positive CSFcanddissemination in time,
demonstrated by MRI or second clinical attack
Insidious neurological progressions suggestive of MS Positive CSFcand 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 potentialdassociated 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; if the criteria are fully explored and not met, the diagnosis is Ônot MSÕ.
aNo 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].
cPositive 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].
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 (Novant-rone) has also been shown in a phase III clinical trial to reduce relapse rates and relapse-related MRI out-comes in relapsing MS, and may have a beneficial effect on disease progression in patients with worsening con-ditions [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 ther-apy 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 evidence-based.
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 demye-linating 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 treat-ment [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 recom-mendations 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 dis-ability. 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
suboptimal clinical response, although in some cases this will become apparent much earlier.
8. A change in therapy is warranted if there are tol-erability issues that obviate the use of the proven effective regimen of a given DMD.
Relatively few patients treated with DMDs experi-ence 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 neurol-ogist 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. Influ-enza-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 com-mon at the initiation of therapy, tend to decline with time, and can usually be managed with over-the-coun-ter 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, approxi-mately 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 ther-apy. More rarely, allergic-type reactions such as localized itching or hives have been noted with glatir-amer 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 side-effects, 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 con-sidered, 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 gener-ally 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 recom-mended 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 pro-gression despite DMD treatment.
The view that the potential toxicity of mitoxant-rone 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 thera-peutic 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 popula-tions and designs may contribute to the observed apparent differences in efficacy.
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 signifi-cance 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 fre-quency. 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 cur-rently under way should provide clearer information about the relative efficacies of glatiramer acetate com-pared 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 partic-ular patient continues to have a good clinical response to their current DMD therapy.
11. Before considering escalation therapy with immu-nosuppressants, 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 studye Reduction of clinical attack Reduction of MRI attack rate
Reduction of MRI severity
Reduction in confirmed progression
IFN beta-1a (Rebif)a 560 I h h h n
IFN beta-1a (Avonex)a 301 I n n ns n
IFN beta-1ba 372 I h h h ns Glatiramer acetatea 251 I h nr nr ns Glatiramer acetateb 249 I n h h ns Mitoxantronec 42 II/III n h nr n Mitoxantroned 51 II/III h n nr n Mitoxantronea 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 ( P¼ 0.01–0.05); ns, not improved; nr, not recorded. Duration of study:a2 years;b9 months;c6 months;d1 year.
eData from clinical trials are classified according to a ratings scheme, in which ÔIÕ is the highest rating (exceptionally well-designed trial –
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 theÔtypeÕ 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 treat-ment 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 evi-dence exists, including chronic steroid treatment, azathioprine, cyclophosphamide, plasmapheresis and IVIg [3], as well as experimental modalities and com-bination therapies. These therapies are, as yet, formally unproven and should be considered only when all first-line 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 chan-ges 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 ther-apy intolerable (Fig. 1).
Management of a suboptimal response in a patient with MS initiating DMD therapy
In naı¨ve patients with MS, the choice of initial ther-apy 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
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 low-dose IFN beta, high-low-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
Naïve patient with definite MS Glatiramer acetate High-dose IFN beta† Low-dose IFN beta Persistent intolerable side-effects Glatiramer acetate Mitoxantrone
Try: 1. Symptom management 2. Dose modification
Try: 1. Symptom treatment 2. Dose titration 3. Dose modification Patient naïve
to glatiramer acetate does not wish to go on immunosuppressives * 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. Sub-optimal response Sub-optimal response Sub-optimal response Sub-optimal response Unapproved therapies‡ Sub-optimal response * Patient with contraindication to mitoxantrone* Intolerable side-effects Intolerable side-effects Intolerable side-effects Persistent intolerable side-effects Intolerable side-effects
Figure 1 Pathway for the management of a suboptimal response or side-effects in a patient taking DMD therapy.
is a suboptimal response to high-dose IFN, the logical escalation would be to move towards an immunosup-pressant, such as mitoxantrone. However, because of the possible side-effects associated with immunosup-pression, treatment with glatiramer acetate might be considered as an alternative for patients who are naı¨ve 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 mitoxant-rone 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 subse-quent 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/m2 is not recommended for the treatment of MS. At a dose of 12 mg/m2administered 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 recommen-ded that patients should be informed about the com-mon 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 dur-ing which to try and manage side-effects before con-sidering 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 glatir-amer acetate should be switched to IFN beta. Toler-ability 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 appro-priate for patients with persistent intolerable systemic effects with low-dose IFN beta therapy. If side-effects 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 mitox-antrone. 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, discon-tinuation 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 pre-scriptive. 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 pro-gression, 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, prog-nosis 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
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 Ser-ono; EH has participated in clinical trials sponsored by Bayer, Biogen, Elan, Octapharma, Schering and Ser-ono; GJ has participated in clinical trials involving Avonex and Copaxone, 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 parti-cipated 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).
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