In Search of Better Therapies for MS

In Search of Better Therapies for MS

This activity has been designed to meet the educational needs of physicians and other health care professionals who wish to learn more about adult immunizations, including those for influenza, pneumococcal disease, pertussis, and herpes zoster. In the first study, Dr. Bone turnover markers are an exciting new tool to aid clinicians in treating osteoporosis. 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. Ghezzi noted in his presentation. Treatment-Naïve Patients with Pulmonary Arterial Hypertension – What Do We Know and What Choices Do We Have? Online, choose the best answer to each test question.

Participants should consider that clinical evidence for use of other therapies discussed in this activity is in an unlabeled or experimental capacity and fully review all prescribing information, indications, drug-drug interactions, and adverse events for therapies in use. MMF is widely used by people with an organ transplant because it is very effective in preventing rejection of the transplanted organ. The current drugs are given by injection, compared with oral administration of simvastatin. The subcutaneous and intramuscular injectable drugs may be associated with undesirable side effects, such as pain and swelling at the site of injection and flu-like symptoms. In addition, you must complete the Activity Evaluation to provide feedback for future programming. Patients were randomized (2:1) to receive rituximab or placebo (on days 1, 15, 168, and 182) as well as their standard medications; also, all patients received protocol-defined corticosteroid tapering. 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. Patients had a mean of 5.8 gadolinium-enhancing lesions at 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. Certain educational activities may require additional software to view multimedia, presentation or printable versions of their content. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. Chen and colleagues[1] reported the results of a large study evaluating the role of MMF. 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. Secondary BILAG endpoints, which were physician-assessed flare, patient-reported outcomes, anti-dsDNA antibodies, and safety measures, were also similar between groups. Larger randomized, controlled studies are warranted to definitively ascertain the effectiveness of this treatment. There are various targets for immunotherapy in MS: T-cells, macrophages/microglia, natural killer cells, and B-cells. Of the 4 patients positive for antibodies who stopped treatment, as well as 2 other patients who stopped for other reasons, 3 were treated with interferon or with glatiramer acetate. 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. CME Scholar designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit TM . Rituximab is an antibody that destroys specific immune cells that are thought to underlie the development of IMN. 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. The primary outcome measure was the incidence of mortality and end-stage renal failure, which were both significantly lower in the MMF group (RR 0.33, P < .001 and RR 0.41, P = .059, respectively). 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. Studying pediatric cases of MS also provides an opportunity to study risk factors for the disease much closer to disease onset, perhaps mitigating the confounding factors that might mask these relationships. 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. Systemic lupus erythematosus (SLE) is a systemic disease in which the body's immune system reacts against specific organs. 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. On the basis of a descriptive analysis of 7 patients who received 4 short-term infliximab (5 mg/kg) infusions, 5 had rapid response with more than 80% reduction in proteinuria. 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. TEVA Pharmaceutical Industries Ltd, sanofi-aventis, Serono Symposia International Foundation, Biogen-Dompè, and Bayer-Schering have given 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. One patient developed significant worsening of disease, and 6 patients discontinued MMF -- 3 because of side effects (infection, anemia, and GI intolerance), 2 due to a desire to have a planned pregnancy (MMF use is contraindicated during pregnancy), and 1 for unknown reasons. 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. At the University of Miami, children with proliferative lupus nephritis who had WHO class III, IV, or V+ lupus nephritis and who had been treated with IV cyclophosphamide in the past had only an approximately 28% chance of having still-functioning kidneys 5 years after their initial diagnosis. 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. In Search of Better Therapies for MS

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. Daniel Cattran, MD,[8] an international expert in the treatment of glomerulonephritis, reviewed the world’s literature on the use of MMF to treat glomerulonephritis. 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 randomized control study of mycophenolate mofetil treatment in severe IgA nephropathy. References 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. 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. 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. J Am Soc Nephrol. 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. 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]. Vollmer T, Durkalski V, Tyor W, et al. An open-label, single arm study of simvastatin as a therapy for multiple sclerosis (MS). 2002;13:670A. Abstract S11.004. 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. 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. Lublin FD, Reingold SC, for the National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Cattran DC. Neurology. 1996;46:907-911. 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. 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. McDonnell GV, Hawkins SA. Primary progressive multiple sclerosis: increasing clarity but many unanswered questions. J Neurol Sci. 2002;199:1-15. 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. 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. 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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