Multipl Sklerozda Oral Tedavi Seçenekleri
Özet
Multipl Skleroz (MS), genç erişkinlerde özürlülüğe yol açan, merkezi sinir sistemini hedef alan kronik nörodejeneratif bir hastalıktır. Kesin etyolojisi bilinmemekle birlikte immünolojik, genetik ve çevresel faktörler etkilidir. Hastalık; klinik seyrine göre RRMS, SPMS, PRMS ve PPMS olarak dört gruba ayrılır. Son yıllarda enjeksiyon tedavilerine alternatif olarak geliştirilen oral ajanlar (Fingolimod, Teriflunamid, Dimetil Fumarat), hasta uyumunu artırmayı ve yan etkileri minimize etmeyi hedeflemektedir. S1P reseptör modülatörü olan Fingolimod, dolaşımdaki lenfositleri azaltarak inflamasyonu yavaşlatır; ancak bradikardi, karaciğer enzimlerinde yükselme ve maküla ödemi gibi yan etkilere yol açabilir. Dihidrooratat dehidrogenaz enzimini inhibe eden Teriflunamid, aktif lenfosit sayısını düşürür ve alopesi ile hepatotoksik etkiler gösterebilir. Antiinflamatuar ve nöroprotektif etkileri olan Dimetil Fumarat ise lenfosit sayılarını azaltıp Nrf2 ekspresyonunu artırırken, gastrointestinal problemler ve ateş basması gibi yan etkiler barındırır. Bu oral tedaviler, kronik bir süreç olan MS'in yönetiminde önemli alternatifler sunmaktadır.
Multiple Sclerosis (MS) is a chronic neurodegenerative disease targeting the central nervous system, which constitutes a major cause of disability in young adults. Although its exact etiology remains unknown, immunological, genetic, and environmental factors are influential in its development. The disease is classified into four groups based on its clinical course: RRMS, SPMS, PRMS, and PPMS. In recent years, oral agents (Fingolimod, Teriflunomide, Dimethyl Fumarate) developed as alternatives to injection therapies aim to enhance patient compliance and minimize adverse effects. Fingolimod, an S1P receptor modulator, slows down inflammation by reducing circulating lymphocytes, though it may cause side effects such as bradycardia, elevated liver enzymes, and macular edema. Teriflunomide, which inhibits the dihydroorotate dehydrogenase enzyme, decreases the number of active lymphocytes and can exhibit side effects like alopecia and hepatotoxicity. Dimethyl Fumarate, possessing anti-inflammatory and neuroprotective effects, reduces lymphocyte counts and increases Nrf2 expression, while carrying side effects such as gastrointestinal problems and flushing. These oral treatments provide significant alternatives in managing the chronic process of MS.
Referanslar
Noseworthy JH, Lucchinetti C, Rodriguez M et al. Multiple sclerosis. New England Journal of Medicine. 2000;343(13):938-952.
Lublin FD, Miller AE. Multipl Skleroz ve Santral Sinir Sisteminin Diğer Demiyelinizan Hastalıkları. Bradley WG, Daroff RB, Fenichel GM, Jankovic J (editors). Neurology in Clinical Practise. Kurne A. (çeviri editörü), 5. Baskı. İstanbul: Veri Medikal Yayıncılık; 2008: 1583-1605.
Koch-Henriksen N, Sorensen PS. The changing demographic pattern of multipl sclerosis epidemiology. Lancet Neurology. 2010; 9:520–532
Rosati, G. The prevalence of multiple sclerosis in the world: an update. Neurological Science. 2001; 22:117–139
Ropper AH, Brown RH. Multiple Skleroz ve İlişkili Demiyelinizan Hastalıklar. Adams and Victor’s Principles of Neurology. Demir GA. (Çev. Ed.) 8. Baskı. Ankara Güneş Kitabevi; 2006: 771- 790.
Çelik Y, Birgili Ö, Yılmaz H. ve ark. Prevalance of multiple sclerosis in the metropolitan area Edirne City, Turkey. Balkan Medical Journal 2011;28:193-196.
Eraksoy M.Multiple Skleroz. In: E Öge, B Baykan, B Bilgiç (Eds). Nöroloji.İstanbul.Nobel Kitabevi.2021.p.1112-1136
Olsson, T, Barcellos LF, Alfredsson, L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nature Reviews Neurology.2017;13:25–36.
Lassmann H, Brück W, Lucchinetti CF. The Immunopathology of Multiple Sclerosis: An Overview. Brain Pathology.2007;17:210-218
Sospedra M, Martin R. Immunology of multiple sclerosis. Annual Review of Immunology.2005;23:683-747
Efendi H, Kuşcu DY. Multipl Skleroz Tani ve Tedavi Kılavuzu. Galenos Yayınevi, İstanbul, 2018. https://www.noroloji.org.tr/TNDData/Up
Díaz, C, Zarco, LA, Rivera DM. Highly active multiple sclerosis: An update. Multiple Sclerosis Related Disorders.2019;30:215-224.
Mehling M, Brinkmann V, Antel J et al. FTY720 therapy esertse differential effects on T cell subsets in multiple sclerosis. Neurology.2008;71:1261-1267.
Altunrende B, Birday E, Kasap M et al. Relapsing Remitting Multipl Skleroz Tedavisinde Fingolimod Kullanımı. Turkish Journal of Neurology.2017; 23(4): 176-185
Kappos L, Antel J, Comi G. Oral fingolimod (FTY720) for relapsing multiple sclerosis. New England Journal of Medicine.2006;355(3):1124-1140.
Kim W, Zandoná ME, Kim SH et al. Oral Disease-Modifying Therapies for Multiple Sclerosis. Journal of Clinical Neurology.2015;11(1):9-19.
Hunter SF, Bowen JD, Reder AT. The direct effects of fingolimod in the central nervous system: Implications for relapsing multiple sclerosis. CNS Drugs.2016;30:135–147.
Faissner S, Gold R. Oral Therapies for Multiple Sclerosis. Cold Spring Harbor Perspectives in Medicine 2019;9(1):a032011. doi: 10.1101/cshperspect.a032011.
Noda H, Takeuchi H, Mizuno T et al.Fingolimod phosphate promotes the neuroprotective effects of microglia. Journal of Neuroimmunology. 2013;256: 13–18.
Kappos L, Radue EW, O’Connor P et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine.2010;362:387-401.
Calabresi PA, Radue EW, Goodin D et al.Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurology.2014;13: 545–556.
Cohen JA, Barkhof F, Comi G et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England Journal of Medicine.2010;362:402-415.
Öztürk S, Aytaç G, Kızılay F ve ark. Multipl Skleroz. Akdeniz Tıp Dergisi.2017;3: 137-147.
Mazurais D, Robert P, Gout B et al.Cell type-specific localization of human cardiac S1P receptors. Journal of Histochemistry and Cytochemistry.2002;50:661-670.
Limmroth V, Haverkamp W, Dechend R et al. Interim analysis of the START study-extensive electrocardiographic monitoring confirms the good cardiac safety profile of Fingolimod. ECTRIMS; Barcelona, Spain, 2015:7-10.
Bruneau JM, Yea CM, Spinella-Jaegle S et al. Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide. Biochemistry Journal.1998;336(2):299-303.
Herrmann ML, Schleyerbach R, Kirschbaum BJ. Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology.2000;47:273-289.
Merrill JE, Hanak S, Pu SF et al. Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis. Journal of Neurology.2009;256:89-103.
Zeyda M, Poglitsch M, Geyeregger R, et al. Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation. Arthritis Rheumatology.2005;52: 2730-2739.
O’Connor P, Comi G, Freedman MS, et al. Long-term safety and efficacy of teriflunomide: nine-year follow-up of the randomized TEMSO study.Neurology.2016;86:920-930.
Confavreux C, O’Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebocontrolled, phase 3 trial. Lancet Neurology.2014;13:247-256.
Miller AE, Wolinsky JS, Kappos L, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurology. 2014;13: 977-986.
Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Multiple Sclerosis.2014;20:705-716.
Gold R.Oral therapies for multiple sclerosis: a review of agents in phase III development or recently approved. CNS Drugs.2011;25(1):37-52. doi:10.2165/11539820-000000000-00000.
BG 12: BG 00012, BG 12/Oral Fumarate, FAG-201, second-generation fumarate derivative--Fumapharm/Biogen Idec. Drugs in research & development. 2005;6(4):229-230.
Schilling S, Goelz S, Linker R, Luehder F, Gold R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol 2006;145: 101-107.
Treumer F, Zhu K, Gläser R et al. Dimethylfumarate is a potent inducer of apoptosis in human T cells. Journal of Investigative Dermatology.2003;121: 1383-1388.
Kappos L, Gold R, Miller DH et al. Efficacy and safety of oral fumarate in patients with relapsing remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet.2008;372:1463-1472.
Pitarokoili K, Ambrosius B, Meyer D, Schrewe L, Gold R. Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection. PLoS One.2015;30:10(11):e0143416. doi: 10.1371/journal.pone.0143416.
Gold R, Kappos L, Arnold DL et al; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. The New England Journal of Medicine.2012 Sep 20;367(12):1098-107. doi: 10.1056/NEJMoa1114287.
Fox RJ, Miller DH, Phillips JT et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. The New England Journal of Medicine.2012;367: 1087–1097.
Jalkh G, Abi Nahed R, Macaron G et al.Safety of Newer Disease Modifying Therapies in Multiple Sclerosis. Vaccines (Basel).2020 Dec 26;9(1):12. doi: 10.3390/vaccines9010012.
