Treatment of Multiple Sclerosis - Essay Example

? Treatment of Multiple Sclerosis Multiple sclerosis is a degenerative disease involving the central nervous system of the human body. The cause of multiple sclerosis is still not clear. However, multiple sclerosis is believed to be linked to an abnormal immune response to CNS antigens, break down of the blood-brain barrier, and transendothelial migration from the peripheral circulation to the CNS by activated leukocytes, chemokines, and cytokines. There is growing acceptance to multiple sclerosis not being a unified disease entity, but instead a complex mix of several clinical syndromes that have varied underlying neuropathology and dissimilar therapeutic response to the currently available therapeutics. The significant heterogeneity of multiple sclerosis and the unpredictable course of the disease are key factors that make the treatment of multiple sclerosis challenging. Traditionally immunosupressants in the form of cyclophosphamide and azathoprine were the main therapeutic agents used to treat multiple sclerosis. The limited effectiveness of this class of drugs has led to the emergence of two new classes of drugs in the treatment of multiple sclerosis. These new classes of drugs in the treatment of multiple sclerosis are Immunomodulatory drugs, like Interferon, Glatiramer Acetate, and Mitoxantrone, and monoclonal antibodies like Natalizumab, Daclizumab, Alemtuzumab, and Rituximab. Oral therapeutic agents used in the treatment of multiple sclerosis include Fingolimod, Fumaric Acid and its Esters, and Cladribine. Introduction Borazanci et al, 2009, p.229, define multiple sclerosis (MS) as “an inflammatory demyelinating and degenerative disease of the human central nervous system (CNS)”. In the U.S.A about 500,000 individuals are affected by this disease, which targets young individuals, and is a significant reason for neurological deficits among the young adult population of the nation. In spite of several and continuous efforts to remove the enigma in the etiology of MS, its cause remains elusive, and so too a cure for the disease. Till about two decades back no MS specific treatments were available, but currently several MS specific treatments are available (Borazanci et al, 2009). Etiology Though the exact cause of MS is still clouded in mystery, its pathogenesis is linked to an abnormal immune response to CNS antigens, break down of the blood-brain barrier, and transendothelial migration from the peripheral circulation to the CNS by activated leukocytes, chemokines, and cytokines. In the active form of the disease apparently there is continuing inflammatory and neurodegenerative processes occurring in the environment of the CNS. The trigger for the preliminary attack of MS still remains to be uncovered, but it is hypothesized that genetic and environmental factors are involved in the development of the disease (Borazanci et al, 2009). Experimental studies on mice have led to the surmise that autoreactive T cells are activated in the peripheral immune system against the CNS antigens like myelin basic protein and proteolipid protein, and then cross the blood-brain barrier to enter the CNS. It is also presumed that prior to this disruption of the blood-brain barrier and the migration of the T-cells, disintegration of the occluding and VE-cadherin molecules of the cerebral endothelial cells occurs. Monocytes and T-lymphocytes also migrate into the CNS. T-Lymphocytes are responsible for the inflammatory response in MS. Experimental studies in mice have also linked cytokines with the pathogenesis of MS and the inflammatory response. In addition, Th1 cytokines and cytotoxic CD8 T cells are believed to promote macrophagial activity, which leads to the loss of the oligodendrocyte/myelin complex observed in MS. The final participants believed to be involved in the pathogenesis of MS are the B cells. In the CNS the B cells are believed to be activated by a T-cell-dependent-mechanism to generate antibodies against myelin antigens (Borazanci et al, 2009). There is growing acceptance to MS not being a unified disease entity, but instead a complex mix of several clinical syndromes that have varied underlying neuropathology and dissimilar therapeutic response to the currently available therapeutics. MS is currently classified into four major types of relapsing-remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), and progressive relapsing MS (PRMS). RRMS is the largest component in MS, making up nearly 85% of all MS cases, and also having a gender bias towards the female gender (Borazanci et al, 2009). In the light of the complexity of MS and the development of therapeutic agents being a comparably recent development, this paper attempts to evaluate the therapeutic agents available for the treatment of MS in relation to their efficacy in the treatment of the disease, and the safety profile in their use. Treatment of MS The significant heterogeneity of MS and the unpredictable course of the disease are key factors that make the treatment of MS challenging. From the traditional standpoint, immunosupressants that include cyclophosphamide and azathioprine have been prime contenders in the treatment of MS, with a variable degree of benefits to the patient. Two factors have driven these immunosuppresants to the background. These factors are the high risk for serious infections as a component of the side effects experienced with them, and the emergence of a new class of drugs for the treatment of MS, in the form of the immunomodulatory drugs. Immunomodulatory drugs emerged in the early 1990s with the promise of preventing relapse, minimizing disability, and reduction in disability progression, without major immunosuppressive side effects. Interferon (IFN) and glatiramer acetate have since become the first-line therapy for the treatment of MS. A second class of drugs called monoclonal antibodies like natalizumab has become the second line therapy in the treatment of more severe MS. Recent developments in the drugs available for the treatment of MS are the newer monoclonal antibodies and oral agents for the treatment of relapsing and progressive forms of MS. The oral agents hold out the additional benefits of better patient compliance and absence of infusion side effects (Lim & Constantinescu, 2010). Immonosupressants Interferon Therapies for RRMS For more than a decade Interferon (IFN) therapies are a first line option in the treatment of RRMS. There are three IFN formulations that are approved for use in RRMS. They are the subcutaneously administered IFN-1b, the intramuscularly administered IFN-1a, and the subcutaneously administered IFN-1a. Irrespective of their mode of administration, all three have demonstrated efficacy in respect of relapse related measures. Eleven comparative studies have been undertaken. Evaluation of the comparative studies shows that the comparative studies have not thrown up any conclusive evidence on the potential efficacies among these IFN therapies, with some studies showing no significant variation in the efficacy of these drugs in MS and others pointing to varied efficacies in these drugs. Since MS is a chronic disease, safety and tolerability of the therapies are important. Evaluation of studies on IFN therapies safety and tolerability have shown that there is reasonably good tolerance with IFN preparations. Flu-like symptoms and injection site reactions are the most commonly reported side effects. Other adverse events found with the use of IFN therapies in the treatment of MS include asthenia, headache, hypertonia, and visual disturbances (Limmroth, Putzki & Kachuck, 2011). Treatment of MS with IFN preparations suffers from a drawback in the form of the development of differing levels of antibodies to neutralize the effects of IFN. In vivo studies have demonstrated that the effect of these antibodies is reduction in the bioavailability of drug and reduction in the therapeutic effect (Grossberg et al, 2011). Grossberg et al, 2011, comparing the development of antibodies and its effect in the IFN therapies have found that the frequency for development of antibodies was highest in IFN-1a at 35%, moderate with IFN-1b at 22%, and least with intramuscular IFN-1a at 7.5%, suggesting that intramuscular IFN-1a offers the best option to avoid reduction in the efficacy of IFN in the treatment of MS. Glatiramer Acetate Glatiramer Acetate (GA) has demonstrated the ability to suppress the disease activity of MS. Immunological responses of patients stable on GA therapy show variances, and evidence from studies is not consistent. In an attempt for better clarity Sellebjerg et al, 2012, studied the immunological response to GA and its influence on disease activity. The study found that the effect of long term treatment was the reduction of T helper type 1 and 17 cytokines and transcription factors, which had no relationship to the expression of cytokines and transcription factors and anti –GA antibodies. In addition, treatment of MS with GA contributed to the development of IgG and IgG4 anti-GA antibodies during the initial period of treatment, which persisted during long-term treatment. The development of anti-GA bodies in the use of GA however, had no relation to the measures of cellular immunity, clinical, or MRI disease activity (Sellebjerg et al, 2012). The beneficial effects of GA were further demonstrated by Mair et al, 2006, in their comparative study of IFN-1b and GA using rat models. The study findings show that although in early treatment both IFN-1b and GA demonstrate beneficial effects, protective effects of retinal ganglion cells were only seen with GA. In addition the study found that neuroprotection that resulted from GA treatment was not exclusively dependent on the reduction of the inflammatory infiltrates within the optic nerve. The findings of the study point to better and longer lasting effects of neuroprotection from treatment of MS with GA than with IFN-1 (Mair et al, 2006). Mitoxantrone Martinelli et al, 2005, reviewed the available results of studies on the effect and safety of mitoxantrone (MA) in the treatment of MS, as it has shown moderate efficiency in the treatment of MS. The review of the studies show that MX has a moderate efficiency in retardation of the progression of the disease in patients with RRMS, PRMS, and SPMS over a short term period of study of two years. The studies do not report any significant neoplastic or cardiotoxicity effects of MX. However, the review recommends that more studies are required to confirm the efficiency of MX in the treatment of MS, and long-term risks in connection with leukemias and cardiotoxicity (Martinelli et al, 2005). The cardiotoxicity warning of Martinelli et al, 2005, finds substance in the subsequent Kingwell et al, 2010 study, which evaluated the incidence of adverse events in the use of MX in the treatment of MS, in 163 patients, over a period of eight years. Though MA was well tolerated by the patients, cardiotoxicity was clearly present in the patients, even at dosages that were kept well below the maximum levels currently recommended for the treatment of MS. The findings of this study clearly demonstrate the potential cardiotoxicity in the use of MX for treatment of MS, and in case it is used as a long-term treatment modality for MS it is vital that monitoring of cardiotoxicity is put in place (Kingwell et al, 2010). Monoclonal Antibodies Natalizumab Natalizumab is among the new monoclonal antibodies treatment agents available for MS. Natalizumab binds to the protein, which is known as alpha-4 integrin. By binding to alpha-4 integrin, Natalizumab hinders or alters abnormal cellular responses (US Food and Drug Administration, 2004). In phase III studies it has shown good efficacy in the treatment of RRMS, with the added benefit of being well tolerated by the patients. Yet, there is evidence of safety risks associated with the use of Natalizumab. The safety risk pertains to the possible development of progressive multifocal leucoencephalopathy (PML). The potential for PML with Natalizumab necessitates safeguards in its use. The safeguards include using clinical MRI, and laboratory assessments to uncover any potential for the development of PML in MS patients under treatment with Natalizumab. Maintenance of such a vigil results in early termination of treatment with Natalizumab in patients, whereby the potential for immune reconstruction is enhanced, leading to better prognosis in the event of PML being confirmed (Kappos et al, 2007).These observations of efficiency and potential risk for PML and assessment vigil of MS patients using Natalizumab finds strong support from Fox and Rudick, 2012. Three risk factors associated with the Natalizumab-related PML have been found. These factors are cumulative use of Natalizumab, with the associated risk enhancing up to three years, subsequent to which the risk potential remains the same; earlier use of cytotoxic drugs or immunosuppresants; and any prior history of JCV infection, which is indicated by the presence of JCV antibodies. Using these parameters, risk stratification is essential in the use of Natalizumab to treat MS (Fox & Rudick, 2012). Daclizumab According to Kaufman 2004, p.276, “Daclizumab is a recombinant monoclonal immunoglobulin of the human IgG1 isotype.” Daclizumab acts by binding to IL-2Ra, which is expressed on activated T cells, and vital to their clonal expansion. The action of daclizumab is the inhibition of the binding of IL-2 to IL-2Ra, which interferes with the signaling system for activation of T cells (Kaufman, 2004). Daclizumab is used in the treatment of MS on the rationale that the disease is a T-cell-mediated autoimmune disease, and that targeting lymphocytes may prove useful in the treatment of the disease. In phase II trials Daclizumab has proved to be useful in providing positive clinical outcomes for MS and decreasing relapse rates. However, several adverse events ranging from urinary tract infections and respiratory tract infections to lymphadenopathy and thrombocytopenia are associated with its use. More studies are necessary to confirm the efficacy and safety of Daclizumab in the treatment of MS (Kim, 2009). Adding on Daclimuzab to INFB treatment has shown that the there is enhanced reduction of the disease activity and reduction of relapse cases associated with treatment using INFB only. This paves the way for evaluating combination of monoclonal antibodies with immunosuppressants to increase the efficiency in the treatment of MS and reduce relapse rates (Wynn et al, 2010). Alemtuzumab In comparison to treatment of MS with INFB agents and Alemtuzumab, Alemtuzumab demonstrated far greater efficiency, by reducing the risk for sustained disability and relapse by 71% and 74%, even when these effects were independent of dose used. However, there was greater incidence of adverse events with Alemtuzumab in comparison to INFB agents. This is with particular emphasis on autoimmunity in the case of thyroid disorders, immune thrombocytopenia, and infections, demonstrating that while Alemtuzumab is more effective than INFB agents, the high risk of autoimmune side effects call for caution in its use to treat MS (Coles, Compston & Selmaj, 2008). Cossburn et al, 2011, evaluating the risk for auto-immune disease (AID) after treatment of MS with Alemtuzumab, have confirmed risk for AID. The cumulative risk for AID through the treatment of MS with Alemtuzumab was 22.2%, occurring most often in the 12 month and 18 month time window, and extending up to five years of treatment. Individual risk for AID was heightened through smoking and a family history of AID (Cossburn et al, 2011). Rituximab Pathogenesis of MS has shown that B cells are implicated in it. Rituximab has demonstrated ability to deplete circulating B cells, laying the rationale for its use in the treatment of MS. Evaluation of the efficiency and safety of Rituximab in the treatment of MS has shown that gadolinium-enhancing (GdE) brain lesions decreased with Rituximab treatment, with post treatment MRI scans in 74% of the cases showing absence of GdE activity (Naismith et al, 2010). However this efficiency of Rituximab in depleting B cells is accompanied by the potential risk for leukoencephalopathy that has caused the FDA to issue an advisory note on this safety risk associated with Rituximab (Rituximab in Relapsing–Remitting Multiple Sclerosis, 2008). Oral Agents for the Treatment of MS Fingolimod The findings that Fingolimod, an orally active immunomodulatory agent in mouse models are useful for ameliorating synaptic dysfunction, by reversing modification of glutametergic transmission in the stratium, along with decrease in the severity of dendritic spine loss pointed to Fingolimod being useful in the treatment of MS, where inflammation and synaptic pathology are factors that are associated with the pathogenesis of the disease (Gillingwater, 2012). However, infectious complications associated with Fingolimod have led to the caution that it should not be used as a first line treatment of MS, and even in the case of second line treatment of MS necessary vaccinations assessment of patients and precautions in its use are to be followed (Winkelmann et al, 2012). Fumaric Acid and its Esters Fumaric acid esters (FAE) have been in use for more than five decades in the treatment of psoriasis. The immunomodulatory efficacy and safety in its oral use have been established for over a decade. In a search for more safety associated with treatment agents for MS, FAE has stood as a possible candidate, leading to its evaluation as a potential oral therapeutic agent for MS (Moharregh-Khiabiani, et al, 2009). Experiments with mouse models of the CNS demyelination using FAE has shown clear preservation of myelin and axonal density, which is based on the antioxidative action through induction of the transcription factor Nrf-2. Patients with RRMS were treated with dimethylfumarate in a phase II clinical trial, which demonstrated a significant reduction in the number of GdE lesions after a period of 24 weeks. These positive findings with FAE in the treatment of MS have led to phase III clinical trials (Linker & Stangel, 2012). Cladribine Cladribine is an oral therapeutic agent for MS that offers short-course dosing and useful for patient compliance. The immunosuppressant action of cladribine is long sustained regulation of the immune system, by the means of action that depletes lymphocytes. Yet, the warning in the use of cladribine in the treatment of MS lies in the possible revelation of side effects (Gasperini, Ruggieri & Pozzilli, 2010). MS Treatment Agents not covered in this Paper Oral teriflunomide, oral laquinimod, and oral vitamin D as therapeutic agents for the treatment of MS have not been taken up in this paper. The reason for this is the shortness of the paper to do a complete evaluation of the treatment of MS. Conclusion MS is a complex mix of several clinical syndromes. Furthermore, there is varied response to the different therapeutic agents in use for treating MS. The evaluation shows on one side safer therapeutic agents like the immunosuppressants, but with lesser efficiency in the treatment of the disease, leading to relapses. On the other hand the more effective therapeutic agents like the monoclonal antibodies demonstrate higher efficiency in the treatment of MS, but are associated with higher severity of side effects. The current thumb rule for treating MS pertains to patient selection after proper assessment, to decide on which therapeutic agent would be most suitable to deliver efficiency in treatment, but at the same time is lower in side effects for that particular patient. The search for more therapeutic agents that are more effective and more safe has to go on. A possible light in this dark path is to identify the cause of MS, which currently lies obscured. Works Cited Birazanci, A. P., Harns, M. K., Schwendimann, R. N., Gonzalez-Toledo, E., Maghsi, A. H., Etemadifar, M., Alekseeva, N., Pinkston, K., Kelley, R. E. & Minagar, A. 2009. Multiple Sclerosis: Clinical Features, Pathophysiology, Neuroimaging, and Future Therapies. Future Neurology 4(2): 229-246. Coles, A. J., Compston, D. A. S. & Selmaj, K. W. 2008. Experimental Medicines in Multiple Sclerosis and Compassionate Use. New England Journal of Medicine 359: 1786-1801. Cossburn M., Pace, A. A., Jones, J., Ali, R., Ingram, G., Baker, K., Hirst, C., Zajicek, J., Scolding, N., Boggild, M., Pickergill, T., Ben-Shlomo, Y., Coles, A. & Robertson, N. P. 2011. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 77(6): 573-579. Fox, R. J. & Rudick, R. A. 2012. Risk stratification and patient counseling for natalizumab in multiple sclerosis. Neurology 78(6), 436-437. Gasperini, C., Ruggieri, S. & Pozzilli, C. 2010. Emerging oral treatments in multiple sclerosis – clinical utility of cladribine tablets. Therapeutics and Clinical Risk Management 6: 391-399. Gillingwater, T. H. 2012. Targeting synaptic pathology in multiple sclerosis: fingolimod to the rescue? British Journal of Pharmacology 165(4): 858-860. Grossberg, S. E., Oger, J., Grossberg, L. D. Gelchan A. & Klein, J. P. 2011. Frequency and Magnitude of Interferon ? Neutralizing Antibodies in the Evaluation of Interferon ? Immunogenicity in Patients with Multiple Sclerosis. Journal of Interferon & Cytokine Research 31(3) 337-344. Kappos, L., Bates, D., Hartung, H., Havrdova, E., Miller, D., Polman, C. H., Ravnburg, M., Hauser, H. L., Tudick, R. A., Weiner, H. L., O’Connor, P. W., King, J., Radue, E. W., Yousry, T., Major, E. O. & Clifford, D. B. 2007. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. The Lancet Neurology 6(5): 431-441. Kaufman, D. B. 2004. Induction Therapy. In, Rainer W. G. Gruessner & David E. R. Sutherland (Eds.), Transplantation of the Pancreas (pp.267-300). New York: Springer Verlag. Kim, S. E. 2009. Daclizumab treatment for multiple sclerosis. Pharmacotherapy 29(2): 227-235. Kingwell, E., Koch, M., Leung, B., Isserow, S., Geddes, J., Rieckmann, P. & Tremlett, H. 2010. Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS. Neurology 74(22): 1822-1826. Limmroth, V., Putzki, N. & Kachuck, N. 2011. The Interferon Beta Therapies for Treatment of Relapsing—remitting Multiple Sclerosis: A Comparative Review of Open-Label Studies Evaluating the Efficacy, Safety, or Dosing of Different Interferon Beta Formulations Alone or in Combination. Therapeutic Advances in Neurological Disorders 4(5): 281-296. Lim, S. Y. & Constantinescu, C. S. 2010. Current and Future Disease-modifying Therapies in Multiple Sclerosis. International Journal of Clinical Practice 65(5): 637-650. Linker, G. R. & Stangel, R. A. 2012. Fumaric acid and its esters: an emerging treatment for multiple sclerosis with antioxidative mechanism of action. Clinical immunology 142(1): 44-48. Mair, K., Kuhnert, A. V., Taheri, N., Sattler, M. B., Storch, M. K., Williams, S. K., Bahr, M. & Diem, R. 2006. Effects of glatiramer acetate and interferon-beta on neurodegeneration in a model of multiple sclerosis: a comparative study. American journal of pathology 169(4): 1353-1364. Martinelli, B. F., Rovaris, M., Capra, R. & Comi, G. 2005. Mitoxantrone for multiple sclerosis. Cochrane Database Systematic Reviews 19(4), CD002127. Moharregh-Khiabiani, D., Linker, R. A., Gold, R. & Stangel. M. 2009. Fumaric Acid and its Esters: An Emerging Treatment for Multiple Sclerosis. Current Neuropharmacology 7(1): 60-64. Naismith, R. T., Piccio, L., Lyons, J. A., Lauber, J., Tutlam, N. T., Parks, B. J., Trinkaus, K., Song, S. K. & Cross, A. H. 2010. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: A 52-week phase II trial. Neurology 74(23): 1860-1867. Rituximab in Relapsing–Remitting Multiple Sclerosis. 2008. The New England Journal of Medicine 358, 2645-2647. Sellebjerg, F., Hedegaard, C. J., Krakauer, M., Hesse, D., Lund, H., Nielsen, C. H., Sondergaard, H. B.& Sorensen, P. S. 2012. Glatiramer acetate antibodies, gene expression and disease activity in multiple sclerosis. Multiple sclerosis journal 18(3): 305-313. US Food and Drug Administration. 2004. “Drugs”. 25 April 2012. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm107203.htm Winkelmann, A., Lobermann, M., Reisinger, E. C. & Zetti, U. K. 2012. Fingolimod treatment for multiple sclerosis patients. Infectiological aspects and recommendations for vaccinations. Der Nervenarzt 83(2): 236-242. Wynn, D., Kaufman, M., Montalban, X., Vollmer, T., Simon, J., Elkins, J., O’Neil, G., Never, L., Sheridan, J., Wang, C., Fong, A. & Rose, J. W. 2010. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. The Lancet Neurology 9(4): 381-390. Read More