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More MS news articles for May 2003

In Search of Better Therapies for MS

http://www.medscape.com/viewarticle/453292

April, 2003
Rohit Bakshi, MD

In recent years, patients have benefited from numerous important advances in the diagnosis and treatment of multiple sclerosis (MS). These developments have wielded a partial but significant impact on the devastating effects of MS. Continuing research pertaining to the immunomodulatory treatment of MS was presented at this year's AAN meeting.

New Treatment Strategies in MS

Do We Need Better Therapies for MS?

Five immunotherapies -- intramuscular interferon-beta-1a,[1] subcutaneous interferon-beta-1a,[2] subcutaneous interferon-beta-1b,[2] subcutaneous glatiramer acetate,[3] and intravenous mitoxantrone[4] -- are FDA-approved for the treatment of MS. These medications are clearly beneficial in limiting the natural history of the disease, but they are not curative. Some patients with MS continue to suffer relapses or disease progression despite the best available therapies. These include patients with relapsing-remitting MS who experience relapses or accumulation of disability, those with progressive MS in whom physical disability worsens, and patients with conditions related to MS for which proven therapies do not exist. Thus, the search continues for additional treatments to supplement those that are already available.

Statins

Statins are a group of cholesterol-lowering agents with anti-inflammatory properties. Studies in a mouse model of MS indicate that statin drugs such as lovastatin and simvastatin can favorably modulate T-cell function and inhibit the expression of deleterious inflammatory markers in brain tissue.[5] There are several potential advantages of statins over the 5 most commonly used MS drugs:
 

Vollmer, from Barrow Neurological Institute, Phoenix, Arizona, and colleagues[6] from Medical University of South Carolina, Charleston, South Carolina; University of Colorado Health Sciences Center, Denver, Colorado; and Yale University School of Medicine, New Haven, Connecticut, presented data from a 6-month, open-label, single-arm pilot study of simvastatin, 80 mg daily, given orally to 27 patients with relapsing-remitting MS. Patients included in the study had at least 1 gadolinium (Gd)-enhancing lesion among 3 pretreatment monthly brain MRI scans. All patients were then treated with simvastatin for 6 months, with MRI obtained at months 4, 5, and 6. The primary outcome was the change in number of enhancing lesions compared with baseline. Secondary outcomes included safety and other MRI measures, such as volumes of Gd-lesions and number of new Gd-lesions, and change from baseline in neurologic assessments.

Analysis of pre- and posttreatment brain MRI showed a 43% reduction in the mean number of enhancing lesions (P < .0001); the mean volume of enhancing lesions was also less with treatment (P = .0016). The annualized relapse rates during pre- and posttreatment were 0.43 and 0.32. The study was also designed to test safety of the drug. The patients tolerated the medication well and no patient stopped because of side affects. Two patients had mildly elevated liver function tests, which resolved after stopping the drug.

This study suggests that daily treatment with 80 mg of simvastatin may be safe and effective for the treatment of relapsing-remitting MS. However, because of study design and sample size, no firm conclusions can be drawn. Larger randomized, controlled studies are warranted to definitively ascertain the effectiveness of this treatment.

Bone Marrow Transplantation

There are various targets for immunotherapy in MS: T-cells, macrophages/microglia, natural killer cells, and B-cells. Aggressive immunosuppressive therapies such as total-body irradiation, cyclophosphamide, and mitoxantrone are limited by their toxicities and inability to induce complete remission. Because autoimmune processes are thought to play an important role in the pathogenesis of MS and because the immune system arises from hematopoietic cells in the bone marrow, there is rationale for the use of immunoablation followed by hematopoietic stem cell therapy (HSCT). Before performing HSCT, stem cells must be harvested from the patient's bone marrow or peripheral blood. The peripheral blood collection may be necessary to enrich the cells that are obtained from bone marrow. The infusion of the stem cells is preceded by high-dose chemotherapy and/or radiation therapy to maximally suppress the patient's immune cells. If complete immunoablation can be accomplished with minimal morbidity, it might produce a long-lasting remission of disease activity. Experimental MS in animals (eg, autoimmune encephalomyelitis) can be cured by HSCT if the treatment is started early in the disease process.

Freedman and colleagues[7] from the Canadian MS/BMT Study Group in Ottawa, Toronto, and Montreal, Canada, presented results of a multicenter phase 2 nonrandomized trial of complete immunoablation followed by autologous HSCT in 32 patients with early aggressive MS; 24 received full therapy and 8 were given best medical therapy only. Autologous bone marrow harvesting was followed by stem-cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). Leukophoresed stem cells were depleted of T cells using Miltenyii immunomagnetic CD34-positive selection. Immunoablation was accomplished using cyclophosphamide, busulfan, and rabbit anti-thymocyte globulin.

Dr. Freedman presented results of the first 6 patients, including 1-year follow-up of the first 3. Flow cytometry and immune assays indicated that grafts were devoid of T cells and immunoablation was complete. Several transient minor early toxicities occurred in the first month (eg, stomatitis, GI disturbance), and longer-term toxicities included gonadal failure. Early mild infections and late herpes zoster (shingles) infection occurred after HSCT. Clinical stabilization or improvement was seen in the majority of patients. MRI showed a lack of enhancing lesions, a reduction in hyperintense T2 lesion load, and stabilization of pretreatment progressive brain atrophy. Repeat cerebrospinal fluid testing 12 months after HSCT demonstrated an unchanged, stable pattern of oligoclonal bands.

This pilot study shows that immunoablation followed by autologous HSCT is associated with minimal but predictive toxicity in patients with progressive MS. Preliminary data on efficacy suggest both clinical and MRI stabilization of disease in patients who had been actively and rapidly progressing. These results are preliminary but very encouraging. Dr. Freedman indicated that this study is ongoing and that follow-up data will be forthcoming.

Two additional studies presented data on the effect of autologous HSCT in MS. Burt and colleagues[8] from Northwestern University, Chicago, Illinois, and Medical College of Wisconsin, Milwaukee, performed HSCT on 28 patients with MS, 18 of whom had advanced physical disability, defined as secondary progressive disease course[9] and loss of independent ability to ambulate. During follow-up of an average of 2 years (range, 6 months to 6 years), the transplants were relatively uncomplicated. Of the 18 advanced patients, 10 continued to progress, were lost to follow-up in nursing homes, or subsequently died from complications of progressive MS. Of 10 patients who could ambulate independently at study entry, no patient progressed; 1 patient experienced a regression of disability. This study shows that HSCT does not prevent further disability progression in patients with progressive disease and high disability. Thus, HSCT studies should focus on patients who are earlier in the disease course.

Samijn and colleagues[10] from Erasmus University, Rotterdam, The Netherlands, reported results of HSCT in 12 patients with MS. During the follow-up period (ranging from 3-48 months), most patients experienced some degree of general malaise, elevated liver enzymes, mucositis, and moderate-to-severe toxicodermia, but no serious bacterial infections. Five patients developed a self-limited Epstein-Barr virus reactivation several months after HSCT. Eight patients were followed for more than 1 year; disability improved in 2, was stable in 1, and worsened in 5. Active inflammatory activity, defined by brain MRI gadolinium enhancement, was completely absent in the brain and spinal cord in all patients after HSCT, but noncontrast lesions continued to progress in those with increasing disability.

These 3 studies indicate that further studies are warranted to fully characterize the safety and efficacy of HSCT in larger cohorts of patients with MS. Such studies also need to better determine which subgroups of MS patients are the most likely to respond to this aggressive treatment, in which side effects are not trivial.

Treatment of Primary Progressive MS

The 4 recognized clinical subtypes of MS include: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). A panel of experts has developed consensus guidelines for defining these clinical categories.[9] RR-MS includes acute relapses that are followed by some degree of recovery; the patient's disability does not worsen between relapses. SP-MS is sustained progression of physical disability occurring separately from relapses, and develops in patients who previously had RR-MS; patients with SP-MS may or may not continue to experience superimposed relapses. PP-MS is defined as progression of disability from onset without superimposed relapses. When patients with PP-MS develop acute relapses well after the disease onset, they are classified as having PR-MS.

As recently reviewed,[11,12] PP-MS appears to represent an especially challenging form of MS, including a more aggressive disease course and unique MRI features. Whereas there are several proven therapies for RR-MS, no clearly successful treatments have been developed for PP-MS. Coustans and colleagues[13] from Hôpital de Pontchaillou, Rennes, France, evaluated mitoxantrone (MITOX) 20 mg IV either monthly for 6 months (n = 34) or every 3 months for up to 24 months (n = 30) to treat 64 patients with PP-MS. In the year before receiving MITOX, 44% of the cohort had suffered increasing physical disability, which is consistent with natural history data. During treatment, mean disability score remained stable in the group at both years 1 and 2. During the 2 years of the trial, one third of patients deteriorated and one fourth improved. Among the 29 patients who were independently ambulatory at study entry, no patients deteriorated in the monthly MITOX-treated group, compared with one fourth of patients in the 3-monthly treated group (P < .05). Thus, MITOX appeared to favorably alter the natural history of the disease.

Two additional studies examined other treatments for PP-MS. Zephir from University Hospital of Lille and colleagues[14] from several centers in France, retrospectively analyzed data from 128 patients with PP-MS who had been treated for at least 1 year by monthly pulses of cyclophosphamide. After 12 months of cyclophosphamide therapy, physical disability had stabilized or improved in 73.5% of the patients. Approximately one fifth developed noticeable side effects, 1 of whom withdrew due to intolerance.

Montalban and colleagues[15] from Hospital Universitari Vall d'Hebron, Barcelona, Spain, presented results of a randomized, placebo-controlled exploratory phase 2 study of interferon-beta-1b for 73 patients with MS, 49 of whom had PP-MS. Patients had moderate-to-severe physical disability and received either interferon-beta-1b (8 million IU) or placebo every other day, subcutaneously for 2 years. Side effects significantly associated with interferon included injection-site skin reactions, flu-like symptoms, and leukopenia. The proportion of patients with confirmed progression of physical disability at 3 months was 27.8% for those receiving interferon and 37.8% for placebo (P = .3135). A statistically significant treatment effect was found for a composite measure of neurologic function (P = .03) and for MRI measures of disease activity, including T2 (P = .006), T1 (P = .001), and enhancing lesions (P = .005).

These findings are encouraging regarding the efficacy of various agents in PP-MS and suggest that larger randomized, controlled studies are warranted.

References

  1. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39:285-294.
  2. Paty DW, Li DKB, UBC MS/MRI Study Group, IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Neurology. 1993;43:662-667.
  3. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing remitting multiple sclerosis - results of a Phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995;45:1268-1276.
  4. Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360:2018-2025.
  5. Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 2003; Mar 5 [epub ahead of print].
  6. Vollmer T, Durkalski V, Tyor W, et al. An open-label, single arm study of simvastatin as a therapy for multiple sclerosis (MS). Program and abstracts of the 55th Annual Meeting of the American Academy of Neurology; March 29-April 5, 2003; Honolulu, Hawaii. Abstract S11.004.
  7. Freedman MS, Atkins HL, Arnold D, et al. Treatment of aggressive MS using immunoablative treatment with autologous stem cell rescue: one year clinical and laboratory follow-up of the first six treated patients. Program and abstracts of the 55th Annual Meeting of the American Academy of Neurology; March 29-April 5, 2003; Honolulu, Hawaii. Abstract S11.006.
  8. Burt RK, Cohen BA, Lobeck L, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome. Program and abstracts of the 55th Annual Meeting of the American Academy of Neurology; March 29-April 5, 2003; Honolulu, Hawaii. Abstract P02.137.
  9. Lublin FD, Reingold SC, for the National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911.
  10. Samijn JP, te Boekhorst PA, Flach ZH, et al. Bone marrow transplantation after maximum T-cell depletion in rapidly progressive multiple sclerosis. Program and abstracts of the 55th Annual Meeting of the American Academy of Neurology; March 29-April 5, 2003; Honolulu, Hawaii. Abstract P02.136.
  11. Bakshi R. Medscape Neurology Ask The Experts: How often should MRI be performed on a patient with primary progressive multiple sclerosis? Medscape Neurology & Neurosurgery. 2001. Available at: http://www.medscape.com/viewarticle/413716 Accessed April 15, 2003.
  12. McDonnell GV, Hawkins SA. Primary progressive multiple sclerosis: increasing clarity but many unanswered questions. J Neurol Sci. 2002;199:1-15.
  13. Coustans M, Le Page E, Leray E, et al. Clinical impact of mitoxantrone in 64 primary progressive multiple sclerosis. Program and abstracts of the 55th Annual Meeting of the American Academy of Neurology; March 29-April 5, 2003; Honolulu, Hawaii. Abstract S31.002.
  14. Zephir H, de Seze J, Duhamel A, et al. Treatment of progressive forms of multiple sclerosis by cyclophosphamide. A cohort study of 490 patients. Program and abstracts of the 55th Annual Meeting of the American Academy of Neurology; March 29-April 5, 2003; Honolulu, Hawaii. Abstract P02.131.
  15. Montalban X, Brieva L, Tintore M, et al. Single centre, DBPC, randomised trial of interferon 1b in primary progressive and transitional progressive multiple sclerosis: an exploratory phase II study. Program and abstracts of the 55th Annual Meeting of the American Academy of Neurology; March 29-April 5, 2003; Honolulu, Hawaii. Abstract P06.113.


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