Clinical Advances in Multiple Sclerosis

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Clinical Advances in Multiple Sclerosis

Disclosures

Bruce A. Cohen, MD

Although no pivotal trial released results that would revolutionize

the treatment of multiple sclerosis (MS), a number of studies of

interest to the MS clinician were presented at this year's American

Academy of Neurology (AAN) Meeting.

Pathologic Variability and Response to Plasma Exchange

The impact of pathologic variability on treatment outcome was

highlighted in a study by Keegan and colleagues.[1] In this trial,

patients who had previously undergone diagnostic brain biopsy received

therapeutic plasma exchange after failing high-dose steroid therapy.

The investigators correlated the histopathologic lesion pattern and

response to plasma exchange and found that 10/10 responders had

complement/antibody-mediated disease (type II ), whereas 3 with type 1

(T-cell mediated) and 3 with type III (oligodendrogliopathy)

histopathology failed to respond.

Interferon Treatment

Early vs Delayed Treatment

Kinkel and colleagues[2] presented 5-year results on the impact of

treating patients with clinically isolated syndromes from the

CHAMPIONS study. Approximately 70% of the participants from the

preceding CHAMPIONS trial, and additional recruited subjects were

categorized by whether they started interferon-beta therapy

immediately at presentation of their clinically isolated syndrome or

delayed treatment (mean, 30 months) until entering the extension

trial. Results at 5 years demonstrated a significant benefit in favor

of early therapy on progression to clinically definite MS (35%

relative risk reduction) and on annual relapse rate, including a 42%

reduction between years 3 and 5 when all subjects were receiving

active therapy. Little disability developed in either group with only

13% reaching an Expanded Disability Status Scale (EDSS) score of 3 or

above. A significant reduction in new or enlarging T2 lesions on MRI

at 5 years was noted, but without significant differences in

contrast-enhancing lesions or T2-volume changes. The investigators

concluded that their results support the early initiation of therapy

in patients with clinically isolated syndromes and MRI abnormalities

suggestive of MS.

PRISMS MRI Burden of Disease

Li and Abdalla[3] presented an 8-year follow-up of MRI results from

the Prevention of Relapses and disability by Interferon-beta-1a

Subcutaneously in Multiple Sclerosis (PRISMS) trial demonstrating a

persistent reduction in the T2 burden of disease. This finding was

most pronounced in the group randomized to the higher-dose

interferon-beta treatment arm, with a 5% burden of disease in the

44-mcg three times weekly arm vs 17.4% in the group receiving 22 mcg

three times weekly.

8-Year EDSS Outcomes

An 8-year follow-up of individuals from the European study of

interferon-beta-1b for secondary progressive MS by Kuhle and

colleagues[4] demonstrated a prolonged benefit of treatment on

disability as measured by EDSS; however, the study was limited by a

reduction in the number of subjects participating in the open-label

extension.

Glatiramer for Relapsing-Remitting Disease

and colleagues[5] presented 10-year, follow-up results on

individuals participating in the extension of the glatiramer acetate

study for relapsing-remitting MS. They compared the disability

progression of 108 subjects on continuous therapy and 47 subjects who

initially entered the extension trial but withdrew after an average of

4 years of participation. An additional 77 subjects withdrew but were

lost to follow-up. Reasons for withdrawal included worsening (26%),

pregnancy (12%), inability to continue for logistic reasons (32%), and

a change to interferon or other therapy (29%). Individuals continuing

glatiramer therapy were less likely to reach an EDSS of 6, less likely

to have an EDSS worse than baseline, and more likely to achieve an

EDSS better than baseline. The researchers concluded that the results

demonstrate continued safety and efficacy of glatiramer therapy over

10 years.

Mitoxantrone Complications

Two presentations addressed the safety of mitoxantrone in MS therapy.

Edan and colleagues[6] pooled data from 802 patients treated in 12

centers in France. Most patients received monthly infusions of

mitoxantrone for 6 months. Congestive heart failure occurred in 1

individual (0.1%); 33 patients (4%) experienced asymptomatic reduction

in the left ventricular ejection fraction (LVEF), which persisted in 8

patients (1%). Two cases (.25%) of acute myelogenous leukemia

developed within 2 years of the onset of therapy. Prolonged amenorrhea

occurred in 48 women (10.7%), 14% of those over 35 years of age and 7%

of women younger than 35.

and associates[7] presented the results to date from the

Registry to Evaluate Novantrone Effects in Worsening Multiple

Sclerosis (RENEW) study of 500 patients receiving mitoxantrone at 12

mg/m2 every 3 months. Congestive heart failure occurred in 3 patients

and reductions in LVEF in 6, with another 28 demonstrating

asymptomatic diminished LVEF > 10% from baseline. Three deaths

occurred (meningitis, septic shock, and pneumonia). The investigators

concluded that the results to date indicate a favorable risk-benefit

profile.

Treatment for Primary Progressive MS

Two studies presented the results of therapeutic trials for primary

progressive MS. Kita and colleagues[8] randomized patients to receive

treatment with 12 mg/m2 of mitoxantrone or placebo every 3 months for

2 years and found no benefit of treatment on time to sustained

disability progression, as measured by EDSS and a composite 25-foot

walk and 9-hole peg test. The results were affected by low-outcome

events in both study arms.

Wolinsky and coworkers[9] presented a new analysis of the PROMISE

trial of glatiramer acetate for primary progressive MS. The trial was

stopped by the sponsor after a planned interim analysis indicated that

the primary outcome measure of confirmed time to EDSS progression

would not be met. However, post hoc analyses suggested a trend in

favor of a treatment effect, particularly in participants who were men

and those with the most rapid progression as well as evidence of

reductions in new contrast-enhancing and T2 lesions seen on MRI in an

ondrug cohort analysis. The low-outcome-event rate and the premature

discontinuation of the study limit the strength of the analyses.

Steroids to Prevent Exacerbations

De Seze and colleagues[10] evaluated pulse methylprednisolone therapy

to prevent postpartum exacerbations. They treated a series of 20 women

with monthly 1000-mg steroid pulses and found a significantly reduced

relapse rate in the first trimester post partum as compared with an

historical control population from the 3 years preceding the study

intervention. Although the use of historical controls is a concern,

the study suggests possible efficacy of steroid pulses in this

setting.

Zivadinov and coworkers[11] found less confluence and enlargement of

T2 lesions in a cohort of patients treated with steroid pulses every 4

months as compared with those given steroids only for exacerbations.

Previous reports of this cohort indicated a benefit in the

pulse-treatment group on clinical disability progression.

Special Populations

Optic Neuritis and Risk for MS

Sandberg-Wollheim and colleagues[12] presented the results of a

30-year natural history study of 86 patients with optic neuritis as a

clinically isolated syndrome. The risk of clinically definite MS at 15

years was 40%; of these, 60% converted within 3 years. Risk was

increased by inflammatory cerebrospinal fluid young age, or onset of

symptoms during winter. HLA-DR-2 positivity did not increase the risk

of MS. Of the 42 subjects without other symptoms, 30 consented to

undergo MRI; 20 of these 30 scans revealed >/= 2 lesions after 19-31

years.

Treatment of Optic Neuritis

Two studies addressed the treatment of optic neuritis with intravenous

immunoglobulin (IVIG). Roed and coworkers[13] randomized 68 patients

with optic neuritis to receive either IVIG 400 mg/kg for 3 days and

then at 30 and 60 days or placebo. They found no benefit from therapy

on measures of contrast sensitivity, visual acuity, or color vision.

Khan and colleagues[14] treated 47 patients within 3 months of onset

of severe optic neuritis resulting in visual acuity < 20/200. After

administering open-label IV methylprednisolone, patients received

either IVIG 400 mg/kg for 5 days and then monthly for 5 additional

months or placebo. In all, 21/23 IVIG-treated patients recovered to a

visual acuity of 20/30 or better, whereas only 3/24 placebo-treated

patients improved to 20/70 or better. These investigators concluded

that early use of IVIG can improve visual outcome of optic neuritis in

this setting.

Pediatric Treatment

Two studies reported treatment of pediatric MS patients with immune

modulating therapy. Ghezzi and associates[15] and Tenembaum and

Segura[16] found both interferon-beta and glatiramer to be effective

in reducing the relapse rate and disability progression in this

population. Typical side effects of these agents were well tolerated

by most of the patients reported.

Combination Therapy

A number of reports evaluated combination therapy for MS. Calabrese

and colleagues[17] treated 15 patients with breakthrough relapses with

interferon-beta-1b plus azathioprine and demonstrated a 63% reduction

in enhancing lesions, as demonstrated by serial MRI scans and compared

with their precombination therapy level.

Massachesi and coworkers[18] compared azathioprine at 3 mg/kg/d with

interferon-beta-1a 22 mcg 3 times weekly in patients with relapsing MS

and found the reductions in contrast-enhancing lesions on 6 monthly

MRIs to be similar. In an open-label study, Preiningerova and

colleagues[19] administered mitoxantrone 12 mg/m2 every 3 months to 22

patients with relapsing-remitting or secondary progressive MS who were

taking interferon-beta or glatiramer acetate and found the combination

to be well tolerated. At 1 year, the researchers found no significant

difference between the effects of the 2 combinations on EDSS, MS

functional composite, or atrophy measured by the brain parenchymal

fraction. Vermersch and associates[20] added mycophenolate mofetil 2

g/d to interferon-beta in an open-label study of 30

relapsing-remitting patients with breakthrough disease and found the

combination to be well tolerated.

Preliminary Trials of New Agents

A number of preliminary trials of novel agents were presented. Barkhof

and coworkers[21] gave 0.1 or 0.3 mg/d of laquinimod or placebo orally

to 209 patients with relapsing MS and demonstrated a significant

reduction in new active lesions in the higher-dose treatment arm. Rose

and colleagues[22] administered daclizumab, a monoclonal antibody

directed against the interleukin-2 receptor alpha chain, to 20

patients with suboptimal responses to standard disease-modifying

agents and observed improvements in disability by EDSS and reductions

in new active lesions seen on MRI over a 24-month period.

Cree and coworkers[23] gave rituximab, a monoclonal antibody directed

at CD20 on B lymphocytes, to 4 patients who had neuromyelitis optica

and 4 who had worsening MS. Treatment resulted in significant

improvement in ambulation for 6 of the patients. Yadav and

colleagues[24] administered alpha-lipoic acid, an inhibitor of matrix

metalloproteinase-9 (MMP-9) in doses of 600 mg twice daily, 1200 mg

once daily, 1200 mg twice daily, or placebo to 37 MS patients, and

found reductions in serum MMP-9 levels in inverse proportion to the

alpha-lipoic acid dosage.

Chen and colleagues[25] used quantified magnetic transfer ratio

measurements and reported reductions of both demyelination and

remyelination in 5 patients after 1 year following intense

immunosuppression with autologous hematopoietic stem-cell rescue. In

an autopsy of a patient from the same study who died 2 months

following transplantation, however, Kuhlman and associates[26]

reported the persistence of macrophages and CD8 T cells in

inflammatory lesions, suggesting that the intense intervention failed

to eliminate the formation of new inflammatory infiltrates.

Krupp and colleagues[27] treated MS patients who had evidence of mild

cognitive impairment with donepezil 10 mg/d or placebo and

demonstrated benefit on verbal learning and memory. Wilken and

coworkers[28] gave modafinil 200 mg/d to patients taking

interferon-beta who had demonstrated attention problems on a screening

battery. They found significant improvements on a number of cognitive

tests in those receiving modafinil as compared with those on

interferon-beta alone.

References

1. Keegan M, Konig F, Bitsch A, et al. Multiple sclerosis subtype

predicts response to therapeutic plasma exchange. Program and

abstracts of the 56th Annual Meeting of the American Academy of

Neurology; April 24-May 1, 2004; San Francisco, California. Abstract

S29.002.

2. Kinkel RP, Kollman C, Glassman A, et al. Inferferon beta-1a

(Avonex) delays the onset of clinically definite MS over 5 years of

treatment: results from CHAMPIONS study. Program and abstracts of the

56th Annual Meeting of the American Academy of Neurology; April 24-May

1, 2004; San Francisco, California. Abstract S29.006.

3. Li D, Abdalla JA. Long-term observational follow-up of the

PRISMS cohort: analyses of MRI bod shows benefit of high dose, high

frequency IFN beta-1a (Rebif). Program and abstracts of the 56th

Annual Meeting of the American Academy of Neurology; April 24-May 1,

2004; San Francisco, California. Abstract PO2.118.

4. Kuhle J, Hardmeier M, Hooghe MD, et al. 8 year follow-up of the

European study of interferon beta-1b (EUSPMS) in secondary progressive

MS. Program and abstracts of the 56th Annual Meeting of the American

Academy of Neurology; April 24-May 1, 2004; San Francisco, California.

Abstract PO6.084.

5. KP, Panitch HS, Ford C, k RP. Long term slowing of

disability progression in patients receiving continuous glatiramer

acetate compared with those withdrawing from therapy: 10 year results

from an ongoing trial. Program and abstracts of the 56th Annual

Meeting of the American Academy of Neurology; April 24-May 1, 2004;

San Francisco, California. Abstract S20.004.

6. Edan G, Brochet B, Clanet M, et al. Safety profile of

mitoxantrone in a cohort of 802 multiple sclerosis patients: a 4 year

mean follow-up study. Program and abstracts of the 56th Annual Meeting

of the American Academy of Neurology; April 24-May 1, 2004; San

Francisco, California. Abstract PO6.093.

7. C, -Bresnahan MV, Beagan J. Safety and tolerability

of Novantrone (mitoxantrone) in clinical practice: status report from

the registry to evaluate Novantrone effects in worsening MS (RENEW)

study. Program and abstracts of the 56th Annual Meeting of the

American Academy of Neurology; April 24-May 1, 2004; San Francisco,

California. Abstract PO6.083.

8. Kita M, Cohen JA, Fox RJ, et al. A phase II trial of

mitoxantrone in patients with primary progressive multiple sclerosis.

Program and abstracts of the 56th Annual Meeting of the American

Academy of Neurology; April 24-May 1, 2004; San Francisco, California.

Abstract S12.004.

9. Wolinsky JS, Pardo L, Stark Y, et al. Effect of glatiramer

acetate on primary progressive multiple sclerosis: initial analysis of

the completed PROMISE trial. Program and abstracts of the 56th Annual

Meeting of the American Academy of Neurology; April 24-May 1, 2004;

San Francisco, California. Abstract S12.001.

10. De Seze J, Chapelotte M, Dufour-Delalande S, et al.

Pregnancy-related relapse in multiple sclerosis: interest of monthly

intravenous corticosteroids during post partum period. Program and

abstracts of the 56th Annual Meeting of the American Academy of

Neurology; April 24-May 1, 2004; San Francisco, California. Abstract

S20.005.

11. Zivadinov R, Zorzon M, De Masi R, et al. Evolution of confluent

T2 lesions in relapsing-remitting multiple sclerosis. Long term

results of a phase II clinical trial with pulsed IVMP. Program and

abstracts of the 56th Annual Meeting of the American Academy of

Neurology; April 24-May 1, 2004; San Francisco, California. Abstract

PO4.035.

12. Sandberg-Wollheim M, Nilsson P, Larsson E-M, et al. The outcome

of optic neuritis after 30 years of follow-up. Program and abstracts

of the 56th Annual Meeting of the American Academy of Neurology; April

24-May 1, 2004; San Francisco, California. Abstract S40.003.

13. Roed HG, Langkilde A, Sellebjerg FT, et al. The effect of IVIG

treatment on visual outcome after acute optic neuritis (ON): a

double-blind, randomized, placebo-controlled trial. Program and

abstracts of the 56th Annual Meeting of the American Academy of

Neurology; April 24-May 1, 2004; San Francisco, California. Abstract

S29.005.

14. Khan O, Din M, Caon C, et al. Treatment of severe refractory

optic neuritis in MS patients with intravenous immunoglobulin. Program

and abstracts of the 56th Annual Meeting of the American Academy of

Neurology; April 24-May 1, 2004; San Francisco, California. Abstract

PO2.121.

15. Ghezzi A, Gallo P, Marrosu G, et al. Effectiveness and

tolerability of immunomodulatory drugs in multiple sclerosis during

childhood or adolescence. Program and abstracts of the 56th Annual

Meeting of the American Academy of Neurology; April 24-May 1, 2004;

San Francisco, California. Abstract PO6.078.

16. Tenembaum SN, Segura MJ. Clinical effects of disease-modifying

therapies in early-onset multiple sclerosis. Program and abstracts of

the 56th Annual Meeting of the American Academy of Neurology; April

24-May 1, 2004; San Francisco, California. Abstract PO6.080.

17. Calabrese PA, Bash CN, Costello K, et al. Optimization of the

safety and efficacy of interferon beta1b and azathioprine combination

therapy in multiple sclerosis. Program and abstracts of the 56th

Annual Meeting of the American Academy of Neurology; April 24-May 1,

2004; San Francisco, California. Abstract PO6.089.

18. Massachesi L, Barilaro A, Repice A, et al. Comparison of

azathioprine and interferon beta1a efficacy on prevention of new brain

lesions in relapsing remitting multiple sclerosis. Program and

abstracts of the 56th Annual Meeting of the American Academy of

Neurology; April 24-May 1, 2004; San Francisco, California. Abstract

PO4.036.

19. Preiningerova J, N, Conway K,et al. An open label safety

and tolerability study of mitoxantrone combination therapy with either

interferon or glatiramer acetate. Program and abstracts of the 56th

Annual Meeting of the American Academy of Neurology; April 24-May 1,

2004; San Francisco, California. Abstract S12.006.

20. Vermersch P, Waucquier N, Bourteel H, et al. Treatment of

multiple sclerosis with a combination of interferon beta-1a (Avonex)

and mycophenylate mofetil (Cellcept): results of a phase II clinical

trial. Program and abstracts of the 56th Annual Meeting of the

American Academy of Neurology; April 24-May 1, 2004; San Francisco,

California. Abstract S29.001.

21. Barkhof F, Polman CH, Sandberg-Wollheim M, et al. Oral treatment

with laquinimod reduces development of active MRI lesions in relapsing

MS. Program and abstracts of the 56th Annual Meeting of the American

Academy of Neurology; April 24-May 1, 2004; San Francisco, California.

Abstract S12.005.

22. Rose JW, Watt HE, White A, R. Treatment of multiple

sclerosis with daclizumab. Program and abstracts of the 56th Annual

Meeting of the American Academy of Neurology; April 24-May 1, 2004;

San Francisco, California. Abstract S12.002.

23. Cree B, Lamb S, Chin A, et al. Tolerability and effects of

rituximab (anti-CD20 antibody) in neuromyelitis optica (NMO) and

rapidly worsening multiple sclerosis (MS). Program and abstracts of

the 56th Annual Meeting of the American Academy of Neurology; April

24-May 1, 2004; San Francisco, California. Abstract PO6.090.

24. Yadav V, Lovera J, Marracci G, et al. Randomized, double-blind,

placebo-controlled pilot trial of alpha lipoic acid in multiple

sclerosis: pharmacokinetics, safety, and effects on matrix

metalloproteinase-9. Program and abstracts of the 56th Annual Meeting

of the American Academy of Neurology; April 24-May 1, 2004; San

Francisco, California. Abstract S29.003.

25. Chen JT, Arnold DL, Freedman MS. The impact of immunoablation

with autologous stem cell transplant on lesion remyelination and

demyelination in aggressive multiple sclerosis. Program and abstracts

of the 56th Annual Meeting of the American Academy of Neurology; April

24-May 1, 2004; San Francisco, California. Abstract S40.005.

26. Kuhlmann T, Metz I, Bruck W, et al. A case report:

histopathology of MS lkesions after high-dose chemotherapy and

haematopoietic stem cell rescue. Program and abstracts of the 56th

Annual Meeting of the American Academy of Neurology; April 24-May 1,

2004; San Francisco, California. Abstract PO2.120.

27. Krupp LB, Christodoulou C, Melville P, et al. Effects of

donepezil on memory and cognition in multiple sclerosis: comprehesive

analysis of the AIMS study. Program and abstracts of the 56th Annual

Meeting of the American Academy of Neurology; April 24-May 1, 2004;

San Francisco, California. Abstract S20.003.

28. Wilken JA, Wallin MT, Sullivan CL, et al. Combination therapy

(Provigil + Avonex) in the treatment of attention problems in patients

with relapsing remitting MS. Program and abstracts of the 56th Annual

Meeting of the American Academy of Neurology; April 24-May 1, 2004;

San Francisco, California. Abstract PO2.123.