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More MS news articles for May 2004

Clinical Advances in Multiple Sclerosis

http://www.medscape.com/viewarticle/477720

May 2004
Bruce A. Cohen, MD
Medscape

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

Johnson 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.

Smith 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. Johnson KP, Panitch HS, Ford C, Lisak 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. Smith C, Lopez-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, Allen 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, Martin 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.


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