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Early MS Treatment
Early MS Treatment M Tintoré Clinical Neuroimmunology Unit, Vall d’Hebron University Hospital, Barcelona, Spain
Summary Evidence from research suggests that many patients with
are likely to impact on the long-term evolution of the
clinically isolated syndromes or early MS should be
disease. The decision to start treatment should be
treated with disease-modifying drugs at an early stage.
made jointly by the patient and the physician after
Certainly, when continuing disease activity has been
reviewing the existing evidence. While MRI can be
demonstrated clinically or by magnetic resonance
used to determine who will benefit most from treatment,
imaging (MRI), the need to initiate treatment is clear.
the use of other biological markers needs to be
Studies supporting early treatment rely on evidence
confirmed in different settings before they can be used
which shows that the experiences of the first few years
in clinical practice.
KEY WORDS: CLINICALLY
ISOLATED SYNDROMES;
DISEASE-MODIFYING
AGENTS;
MULTIPLE SCLEROSIS; MAGNETIC
RESONANCE IMAGING;
EARLY
TREATMENT
Introduction Early Treatment
Multiple sclerosis is a chronic, unpredictable disease that varies clinically from patient to patient. The choice of and time to start treatment with diseasemodifying agents (DMA) still remains quite controversial, particularly in patients presenting with clinically isolated syndromes (CIS). However, there is growing evidence to suggest that early treatment is beneficial, given the recent European licence changes for Betaferon®/Betaseron® and Rebif ®. The McDonald diagnostic criteria allow for the anticipated diagnosis of MS in patients presenting with a first episode suggestive of demyelination when certain
Histopathological Studies Histopathological studies have demonstrated that axonal integrity is already compromised during the early stages of MS and that the extent of axon damage correlates with the severity of inflammation during active demyelination.3 Pathology has also shown that oligodendrocytes are typically lost in chronic MS lesions, although a variable degree of preservation is seen in active lesions.4 Remyelination is also present and extensive in the early phases of the disease. Apart from the inflammatory component,
magnetic resonance imaging (MRI) conditions are fulfilled.1,2 Although this so-called ’early diagnosis’ has fostered debate both for and against ’early treatment’, the final decision about when to start treatment should be taken jointly by the patient and the physician after reviewing the existing evidence. Studies supporting early treatment rely on evidence which shows that the
an important degenerative process appears mainly during the chronic phases.5 Authors have suggested that, hypothetically, the tissue injury, penumbra, is modified by early treatment. Histopathological studies have shown that the acute MS lesion is highly oedematous with an extensive loss of myelin and axons; however, there may be considerable sparing
experiences of the first few years of the disease will impact on its long-term evolution. This review summarizes current opinions on the early diagnosis and treatment of MS and CIS based on the results of recent research.
of oligodendrocytes and remyelination. Antiinflammatory therapy reduces oedema and produces a downregulation of pro-inflammatory molecules that may contribute, according to this hypothesis, to the reversal of ongoing injury of axons and prevention of
The International MS Journal 2007; 14: 5–10
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criteria at baseline had a low risk of a relapse, patients
efficacy of interferon beta-1a (Avonex®) in delaying the development to CDMS in patients with a single demyelinating event that presented on MRI with at least two T2 lesions suggestive of MS. A total of 383 patients were randomized into CHAMPS to receive either Avonex® 30 µg (n=193) or placebo (n=190) by intramuscular injection once weekly. At 2 and 3 years, the risk of developing CDMS was 21% and 35% in the Avonex® group and 39% and 50% in the placebo
magnetization transfer ratio is already reduced in patients with CIS,6 and spectroscopic studies in
with 1 and 2 Barkhof criteria had an intermediate risk
group, respectively; the relapse rate ratio was 0.56,
and patients with 3 or 4 Barkhof criteria had a very
these patients have shown a reduction of N-acetylaspartate, a marker for axonal integrity.7
high risk of developing a new attack, within a very
showing an overall treatment effect of 44% (Figure 1).23 An extension study with a 5-year follow-up
short time period. EDSS at year 5 correlated with the
(CHAMPIONS) appears to confirm the significant
number of Barkhof criteria at baseline, and patients with 3 or 4 Barkhof criteria at baseline MRI had a higher risk for reaching disability.16 In the Optic Neuritis Treatment Trial study group, however, the disability level after 10 years appeared to be unrelated to the number of baseline lesions.17 Optic neuritis patients have a lower risk of converting to definite MS compared with other CIS presentations, though interestingly 50% had a normal baseline MRI. For patients with optic neuritis with an abnormal baseline MRI, their risk of a second attack seemed to be the same as that for other topographies, again pointing to the critical role of MRI in detecting patients with a higher risk for converting to MS and developing disability.18 The use of biological markers to detect patients with a high risk of developing MS has also been proposed. Berger and co-workers found patients with CIS with serum antibodies against myelin oligodendrocyte glycoprotein and myelin basic protein present had an adjusted hazard ratio of 76.6 for the development of clinically definite MS (CDMS).19 These data have not been confirmed in other CIS cohorts and remain controversial.20 The use of biological markers for identifying patients at high risk for conversion to MS and the development of disability remains a matter for further investigation; this is difficult to translate into a clinical setting at present.21,22
benefit conferred by early treatment in terms of relapses and MRI activity measures, though no difference in mean EDSS was seen.27 In the ETOMS (Early Treatment Of MS Study) trial, with a similar primary end-point, patients presenting with a first neurological event were randomized to receive weekly subcutaneous interferon beta-1a at 22 µg or placebo for 2 years (this dose and
Non-Conventional Magnetic Resonance Studies Non-conventional magnetic resonance studies have also shown that irreversible tissue damage can be detected in patients with a first attack. The
Natural History Studies Natural history studies have shown that 25 years after diagnosis, about 90% of patients will have moderateto-severe disability.8 However, a recent study has pointed to a milder disease course and found that 17% of all patients with MS will remain fully ambulatory after 20 years of the disease.9 The Lyon cohort from natural history studies has also shown that the number of relapses occurring during the first few years of the disease is related to the time to accrued disability. It shows that patients presenting with three or more relapses during the first 5 years reach expanded disability status scale (EDSS) 4.0 after a median time of 9.5 years. Conversely, the reference group with only one relapse in this period developed this level of disability after a median time of 15.1 years.10 These data also seem to suggest that early treatment prevents accumulation of irreversible deficits. Prospective Clinically Isolated Syndrome Cohorts The use of MRI in prospective cohort studies has provided a means to identify patients at high risk of presenting new relapses and developing disability. The group from the National Hospital for Neurology and Neurosurgery, at Queen Square, London, UK, reported the findings from patients with CIS studied with MRI and followed for 5, 10 and 14 years.11–13 They clearly demonstrated that the presence of even a very small number of baseline MRI lesions is associated with an increased risk of developing MS and, more importantly, that the increase in volume of the lesions seen in the first 5 years correlates with the degree of disability in the longer term. 6
In the Barcelona CIS cohort, patients were classified according to the Barkhof criteria, which are used to determine a positive MRI. The criteria are one gadolinium (Gd)-enhancing lesion, or nine T2 hyperintense lesions if no Gd-enhancing lesions are present; one or more infratentorial lesions; one or more juxtacortical lesions; and three or more periventricular lesions.14,15 In this cohort, patients with 0 Barkhof
Clinical Trials Three Phase III clinical trials (CHAMPS, ETOMS and BENEFIT) in patients with CIS and abnormal brain MRI have shown the significant benefit of initiating early therapy with DMA.23–26 The CHAMPS study (Controlled High Risk Avonex® Multiple Sclerosis) demonstrated the The International MS Journal 2007; 14: 5–10
Key Points • Current treatments for patients with MS and, particularly, patients with CIS are limited • The experiences during the first few years of MS may impact on the long-term evolution of the disease • MRI can be used to determine who will benefit most from treatment • The CHAMPS, ETOMS and BENEFIT trials have investigated early therapy • CIS or early MS patients may benefit from early treatment with immunomodulatory drugs
brain tissue at 2 years compared with patients on placebo. Such treatment reduces the accumulation of brain atrophy by about 30% within 2 years.28 The BENEFIT (Betaseron® in Newly Emerging multiple sclerosis For Initial Treatment) trial data have been presented at several international meetings and recently published.25,26 In this multicentre, double-blind, placebo-controlled, randomized trial, patients with a first clinical demyelinating event and at least two clinically silent brain MRI lesions were randomized in a 5:3 ratio to receive 250 µg of interferon beta-1b (n=292) or placebo (n=176) every other day.
frequency is not available for treatment). Treatment with interferon beta-1a resulted in fewer patients converting to CDMS (34% versus 45%, Figure 2).24 Additional data on brain volume have been published recently.28 Patients treated with interferon beta-1a showed a significant slowing in the loss of
50 Clinically definite MS (%)
the development of astroglial scars. Furthermore, treatment may contribute to the preservation of oligodendrocytes and oligodendrocyte progenitors, which again may induce myelin repair.
Early MS Treatment
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From Jacobs LD et al.23 Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in mutiple sclerosis. N Engl J Med 2000; 343: 898–904. Copyright © 2000 Massachusetts Medical Society
Early MS Treatment
Interferon beta-1a Placebo
40 30 20 10 0 1
4
7
10 13
16 19 22 25
28 31 34 37
Months Interferon beta-1a group No. at risk Clinically definite MS Early withdrawal from study Followed until end of study
193 177 164 151 143 139 112 112 9 6 7 5 3 4 0 2 7 7 6 3 1 4 0 1 19 0 36
73 4 0 0
69 3 0 2
41 3 0 2
36 0 1 1
Placebo group No. at risk Clinically definite MS Early withdrawal from study Followed until end of study
190 165 146 139 131 124 18 13 7 4 6 8 7 6 0 4 1 1 17
58 1 0 3
54 6 2 20
26 0 0 1
25 1 0 0
98 6 1 1
90 3 5 24
Figure 1. Results from the Controlled High Risk Avonex® Multiple Sclerosis (CHAMPS) study.21 Kaplan–Meier estimates of the cumulative probability of the development of clinically definite MS according to treatment group. A total of 383 patients were randomized to receive either interferon beta-1a 30 µg (n=193) or placebo (n=190) by intramuscular injection once weekly
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Interferon beta-1a
0.9
Placebo
0.8 0.7 0.6 0.5 0.4 0.3 0.2 Log rank P = 0.034
0.1 0
0
100
200
300
400
500
600
700
Time since randomization (days) Number of patients at risk 154 Interferon beta-1a 154 Placebo
129 115
115 96
105 86
99 81
Figure 2. Kaplan–Meier survival curve of probability of no conversion to clinically definite multiple sclerosis over 2 years. In the ETOMS (Early Treatment Of MS Study) trial, patients presenting with a first neurological event were randomized to receive weekly subcutaneous injections of interferon beta-1a at 22 µg or placebo for 2 years24
Interferon beta-1b significantly delayed the progression from the first clinical event to CDMS and McDonald MS. According to proportional hazards regression analysis adjusted for standard baseline covariates, the risk of progression to CDMS in the interferon beta-1b group was reduced by 50% and for McDonald MS by 46% (Figure 3). Interferon beta1b prolonged the time to CDMS by 1 year based on the 25th percentiles. The post-hoc subgroup analysis of CHAMPS and ETOMS showed that patients with more inflammatory disease activity at baseline defined by MRI had a higher treatment effect. Nevertheless, the subgroup analysis of BENEFIT has shown a stronger treatment effect in patients with a monofocal clinical presentation, fewer than nine T2 lesions and absence of Gd enhancement. This apparent discrepancy is currently being analysed and publications of treatment effect in different subgroups of the BENEFIT population are in progress. The different patient populations included in these clinical trials may provide a partial explanation. CHAMPS exclusively enrolled patients with monofocal presentations, while BENEFIT and ETOMS also enrolled patients with multifocal manifestations at onset. A Phase III trial of glatiramer acetate versus placebo in patients with CIS and abnormal MRI is currently underway. 8
50
Interferon beta-1a Placebo
Clinically definitive MS (%)
1.0
40 30 20 10 Log rank P < 0.0001 0
Day 0
Day 90
Day 180
292 176
267 156
249 139
Day 270
Day 360
Day 450
Day 540
Day 630
Day 720
205 101
200 96
47 24
Patients at risk Interferon beta-1b n = Placebo n =
237 125
223 115
210 111
Figure 3. Time to clinically definite multiple sclerosis (CDMS) in the BENEFIT trial. Patients with a first clinical demyelinating event and at least two clinically silent brain MRI lesions were randomized in a 5:3 ratio to receive 250 µg interferon beta-1b every other day (n=292) or placebo (n=176)25,26
From Kappos L et al.25,26 Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006 [Epub ahead of print]. © 2006 Lippincott Williams & Wilkins
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From Comi G et al.24 Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study. Reprinted from The Lancet 2001; 357: 1576–1582, with permission from Elsevier
Proportion without confirmed CDMS
Early MS Treatment
About 50% of the patients treated at these very early stages continue to present clinical and/or MRI activity, demonstrating the incomplete therapeutic effect of early immunomodulatory treatment. These current drugs for treating early MS are well tolerated and do not appear to have long-term serious adverse effects.29 However, the appearance of a flu-like syndrome, the need for injection and the chronic nature of the therapy reduce the willingness of patients to engage in the treatment. Realistic expectations and individual counselling are crucial to improving adherence to treatment.30 The use of the autoinjector, dose–titration scheme and medication to counter the side-effects, however, are believed to contribute to good adherence The high cost of these medications also needs to be considered when selecting patients as candidates for treatment. Different points of view exist regarding the best time and strategy for initiating treatment.31–33 The majority of patients with CIS and abnormal MRI will develop MRI activity very rapidly. All patients with CIS or early MS should probably be treated with DMA when it is clear that continuing disease activity, demonstrated either clinically or by MRI, is present. It might be wise to adopt a more conservative approach in those few patients in whom no activity is seen from clinical and MRI monitoring. However, in the BENEFIT study, a stronger effect of interferon The International MS Journal 2007; 14: 5–10
beta-1b treatment has been shown when the disease is less active. This, and future data, may suggest that treatment should be initiated in patients with less active disease. Obviously, the final decision as to when to initiate treatment must be agreed by the patient and family after reviewing all the available evidence. The negative aspects of these treatments, such as partial effectiveness in the short term and the fact that long-term prevention of disability remains
3.
4.
5.
6.
unproven, must also be addressed.
Conclusions Current treatments for patients with MS and, particularly, patients with CIS are limited, though new approaches are being evaluated in clinical trials. Immunomodulatory treatment should be proposed and discussed with the patients as soon as ongoing disease activity, shown by clinical or MRI monitoring, is confirmed. MRI remains the best tool for classifying patients according to their risk of conversion to MS or development of disability, and therefore for selecting candidates for treatment. However, future data may suggest considering initiating treatment in patients with less active disease. Other biological markers need to be confirmed in different settings before they can be used in the clinical practice.
7.
Conflicts of Interest
11.
The MS unit of Vall d’Hebron Hospital has received research grants from drug companies named in the present study. M Tintoré has received honoraria and travel expenses from Biogen Idec, Schering AG, Serono and Pfizer Inc.
8.
9.
10.
12.
Address for Correspondence M Tintoré, Clinical Neuroimmunology Unit, Vall d’Hebron University Hospital, 08035 Barcelona, Spain E-mail:
[email protected]
13.
Received: 11 July 2006 Accepted: 30 August 2006
14.
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diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127. 2. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L et al. Diagnostic criteria for multiple sclerosis: 2005 revisions
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Early MS Treatment
to the ‘McDonald Criteria’. Ann Neurol 2005; 58: 840–846. Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–399. Bruck W, Schmied M, Suchanek G, Bruck Y, Breitschopf H, Poser S et al. Oligodendrocytes in the early course of multiple sclerosis. Ann Neurol 1994; 35: 65–73. Bruck W, Stadelmann C. The spectrum of multiple sclerosis: new lessons from pathology. Curr Opin Neurol 2005; 18: 221–224. Iannucci G, Tortorella C, Rovaris M, Sormani MP, Comi G, Filippi M. Prognostic value of MR and magnetization transfer imaging findings in patients with clinically isolated syndromes suggestive of multiple sclerosis at presentation. Am J Neuroradiol 2000; 21: 1034–1038. Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A et al. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 2003; 126: 433–437. Weinshenker BG, Bass GP, Rice J, Noseworthy J, Carriere W, Baskerville J et al. The natural history of multiple sclerosis: a geographically based study. I Clinical course and disability. Brain 1989; 112: 133–146 Pittock SJ, Mayr WT, McClelland RL, Jorgensen NW, Wegand SD, Noseworthy JH et al. Change in MS-related disability in a population-based cohort: a 10year follow-up study. Neurology 2004; 62: 51–59. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126: 770–782. Morrissey SP, Miller DH, Kendall BE, Kingsley DP, Kelly MA, Francis DA et al. The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study. Brain 1993; 116: 135–146. O’Riordan JI, Thompson AJ, Kingsley DPE, MacManus DG, Kendall BE, Rudge P et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS: a 10 year follow-up. Brain 1998; 121: 495–503. Brex PA, Ciccarelli O, Jonathon I, Sailer M, Thompson AJ, Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002; 346: 158–164. Barkhof F, Filippi M, Miller DH, Scheltens P, Campi A, Polman CH et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120: 2059–2069. Tintore M, Rovira A, Martinez MJ, Rio J, Diaz-Villoslada P, Brieva L et al. Isolated demyelinating syndromes: comparison of different MRI criteria to predict conversion to
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clinically definite multiple sclerosis. Am J Neuroradiol 2000; 21: 702–706. Tintore M, Rovira A, Rio J, et al. Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 2006; 67: 968–972. Beck RW, Smith CH, Gal RL, Xing D, Bhatti MT, Brodsky MC et al. Optic Neuritis Study Group. Neurological impairment 10 years after optic neuritis. Arch Neurol 2004; 61: 1386–1389. Tintore M, Rovira A, Rio J, Nos C, Grive E, Tellez N et al. Is optic neuritis more benign than other first attacks in multiple sclerosis? Ann Neurol 2005; 57: 210–215. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003; 349: 139–145. Lim ET, Berger T, Reindl M, Dalton CM, Fernando K, Keir G et al. Anti-myelin antibodies do not allow earlier diagnosis of multiple sclerosis. Mult Scl 2005; 11: 492–494. Pelayo R, Tintore M, Montalban X, Rovira A, Espejo C, Reindl M et al. Antimyelin antibodies with no progression to multiple sclerosis. N Engl J Med 2007; 356: 426–428. Kuhle J, Pohl C, Mehling M, Edan G, Freedman MS, Hartung HP et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 2007; 356: 371–378. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ et al. Intramuscular interferon-beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000; 343: 898–904. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study. Lancet 2001; 357: 1576–1582. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67: 1242–1249. Polman CH, Kappos L, Freedman MS et al. for the BENEFIT Study Group. Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): Subgroup Analyses. Neurology 2006; 66 (Suppl 2): A61. Kinkel RP, Kollman C, O’Connor P, Murray TJ, Simon J, Arnold D et al. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006; 66: 678–684. Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, Comi G et al. Interferon beta-
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1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, doubleblind, placebo-controlled trial. Lancet 2004; 364: 1463–1464. 29. Río J, Tintore M, Nos C, Tellez N, Galan I, Montalban X. Interferon beta in relapsingremitting multiple sclerosis. An eight years experience in a
specialist multiple sclerosis centre. J Neurol 2005; 252: 795–800. 30. Rio J, Porcel J, Tellez N, Sanchez-Betancourt A, Tintore M, Arevalo MJ et al. Factors related with treatment adherence to IFNbeta and glatiramer acetate therapy in multiple sclerosis. Mult Scler 2005; 11: 1–4. 31. Roach ES. Early multiple
Meeting Report
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sclerosis: to treat or not to treat? Arch Neurol 2006; 63: 619. 32. Frohman EM, Havrdova E, Lublin F, Barkhof F, Achiron A, Sharief MK et al. Most patients with multiple sclerosis or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol 2006; 63: 614–619. 33. Pittock SJ, Weinshenker BG,
Noseworthy JH, Lucchinetti CF, Keegan M, Wingerchuk DM et al. Not every patient with multiple sclerosis should be treated at time of diagnosis. Arch Neurol 2006; 63: 611–614.
22nd ECTRIMS Congress, Madrid, Spain, 27–30 September 2006 Over 3500 physicians and scientists attended the 22nd
Immunology and Neurobiology
ECTRIMS congress to participate in a programme that
Norbert Goebels (Zurich, Switzerland) summarized CD8-related MS research, and Bernhard Hemmer (Düsseldorf, Germany) focused on the role of B-cells for persistent central nervous system (CNS) inflammation. The description of secondary meningeal lymphoid follicles in progressive MS by Francesca Aloisi’s group (Rome, Italy), abnormal BAFF expression in the cerebrospinal fluid (CSF), and the therapeutic efficacy of plasmapheresis in steroidresistant MS relapses all contributed to this notion. Hemmer presented flow cytometric data on persistent B-cell inflammation in CSF, and passive transfer of patients’ sera recognizing native myelin oligodendrocyte glycoprotein on mammalian cells. Thus, demyelinating experimental autoimmune encephalomyelitis (EAE) could be induced in rats, confirming the pathogenetic relevance of anti-myelin serum responses. The role of regulatory immune networks in MS was
included a stimulating mix of novel clinical studies, educational sessions and clinical science updates.
Treatment Decisions in MS Treatment decisions in specific manifestations of MS were addressed in the MS Forum symposium. Takahiko Saida (Kyoto, Japan) presented a case with contiguous spinal cord magnetic resonance imaging (MRI) lesions extending over three or more vertebral segments, proposing the designation ‘long cord lesion’ MS. This condition shares many features with neuromyelitis optica (NMO) – Devic’s disease. He suggested that treatment should focus on humoral factors such as removal of pathogenic autoantibodies. Barry Arnason (Chicago, USA) discussed patients with minimal symptoms not fulfilling current MS diagnostic criteria, and Xavier Montalban (Barcelona, Spain) analysed a patient with clinically isolated syndrome. All treatment options considered in these cases were reviewed by Ralf Gold (Bochum, Germany), with a focus on novel B-cell directed therapies such as plasmapheresis and anti-CD20. The satellite symposium of the Charcot Foundation re-analysed intravenous immunoglobulin (IVIg) in MS therapy. Judith Haas (Berlin, Germany) and Per Soelberg Sorensen (Copenhagen, Denmark) made strong points based on meta-analyses, confirming a reduction of relapse rate with IVIg treatment. Yet a failed secondary progressive MS trial and the lack of regeneration with IVIg therapy make it difficult to recommend IVIg in the era of evidence-based medicine and innovative therapeutics. 10
reviewed by David Hafler (Boston, USA) who had shown decreased suppressive Treg cell activity from MS patients. Another regulatory cellular element, the plasmacytoid dendritic cell (pDC) has been investigated: Antonios Bayas (Würzburg, Germany) showed that pDCs from MS patients have delayed maturation and altered response to stimulation of tolllike receptor (TLR) 9. This may link infections and clinical relapses in MS. The role of glutamate toxicity for oligodendrocyte death and experimental myelin injury was reviewed by Carlos Matute (Leioa, Spain). Ken Smith (London, UK) described the role of sodium channel blockade for protection from axonal damage. The International MS Journal 2007; 14: 10–11
Meeting Report
Poster Highlights
9 months in 90 patients selected on the basis of gadolinium (Gd) enhancement. The primary end-point of MRI activity was reduced by 38% in the 40 mg group compared with 20 mg, but failed to reach significance. The relapse rate was also diminished by 40% in the high-dose treatment arm. Ernst Radue (Basel, Switzerland) presented the MRI results of a Phase II study of fingolimod (FTY720). In accordance with the recently published clinical data,
Marco Prinz (Göttingen, Germany) used conditional
there was an 80% reduction in new T2 lesion load in
interferon (IFN)-receptor knockout mice to show that
those receiving 1.25 mg daily. Phase III studies with
modulation of myeloid cells, macrophages and microglia is a key action of IFNβ therapy, which may help identify the relevant mechanisms for IFNβ efficacy in long-term MS therapy. Following a similar line, Tarik Touil (Nottingham, UK) used TLR3 activation by poly I:C to suppress EAE and identified release of endogenous IFNβ as key mechanism. Glatiramer therapy can induce regulatory CD4+CD25+ T-cells that ameliorate EAE, as reported by Youngheun Jee (Phoenix, USA). In
an even lower dosage are currently initiated.
These contributions gained increased importance in the light of histopathological studies after autologous stem cell transplantation; despite pronounced immunosuppression, disease progression was observed in the CNS. Imke Metz (Göttingen, Germany) concluded that further studies on stem cell transplantation in late MS should be discouraged.
addition, glatiramer may down-regulate innate recognition molecules of the TLR family as reported by Lloyd Kasper’s group (Lebanon, USA). Angelika Escher (Göttingen, Germany) showed that immunization of Lewis rats with a beta-synuclein peptide induced grey matter pathology and inflammation in the spinal cord. This was associated with increased axonal damage.
Update on Combination Trials The ECTRIMS lecture by Giancarlo Comi (Milan, Italy) addressed MS research from a European perspective. The subsequent sessions dealt with combination trials of established immunomodulatory agents, without identifying promising approaches. The cross-talk of cannabinoids on the immune system and the CNS was discussed critically. Published randomized Phase III trial data suggest that therapeutic likelihood is limited. Unfortunately, the original suggestion of a predictive role of antimyelin antibodies in early MS was not confirmed in the BENEFIT trial. For the novel MS therapeutics, natalizumab patient selection and management guidelines in relapsing MS were presented by Ludwig Kappos.
Late-breaking News The North American double-blind Phase II study of glatiramer 20 mg versus 40 mg was performed over The International MS Journal 2007; 14: 10–11
The CNS white matter glycoprotein neurofascin was identified as a target protein for autoantibodies via a proteomic approach. It has a paranodal expression, and was associated with axonal damage in a chronic EAE model. The oral agent BG12, a second-generation fumarate compound, was used for a double-blind, randomized Phase II study in 235 patients with relapsing MS. In the 24-week MS study, the highest dosage of 720 mg was well tolerated and led to a 69% reduction of Gd-enhancing lesions versus placebo. New T2 lesions were reduced by 48%. The additional end-point relapse rate also revealed a 35% reduction in the high-dose group. Treatment was well tolerated, and a Phase III study will soon be initiated. Aquaporin-4 has received attention as putative autoantigen in NMO. In perivascular lesions from NMO patients, aquaporin immunoreactivity disappeared from inflamed tissue. Larry Steinman’s lecture (Stanford, USA) used innovative technologies to characterize targets of the immune attack in MS. Osteopontin expression by astrocytes increases T-cell survival in inflamed CNS, and thus neutralization of osteopontin expression may have therapeutic relevance. αβ crystalline is upregulated in MS lesions, but lessons from knockout mice demonstrated that it obviously has a protective function. In a lipid array search, sphingomyelin was identified as a possible target of the dysregulated immune response. This report describes only the true ‘cutting edge’ presentations made at ECTRIMS, and does not allow mention of many other valuable sessions at the meeting. Ralf Gold Bochum, Germany 11
