Sclerosi multipla: definizione Malattia infiammatoria cronica del sistema nervoso centrale caratterizzata patologicamente da perdita di mielina, in modo plurifocale, interessante prevalentemente la sostanza bianca cerebrale Sclerosi Multipla -Farmacoterapia- Fase precoce – dissoluzione della mielina (macrofagi) con risparmio delle cellule nervose e fibre, infiltrati perivascolari linfocitari, riduzione oligodentrociti 10.10.08 C. Gobbi Fase tardiva – Gliosi, sclerosi, perdita assonale La guaina mielinica SM epidemiologia Sclerosi multipla: sintomi precoci Scala dello Stato di Disabilità Espansa (EDSS) Disturbi sensitivi Stanchezza Neurite ottica Diplopia Paresi Vertigine Urgenze minzionali 20-50% 20% 16% 15% 10% 5% 3% Handicap dopo 5 anni = 1/3 di quello che sarà dopo 15 anni Page Sclerosi multipla: decorso Remittente recidivante Primaria progessiva Primaria recidivante 80% 10% <5% Secondaria progressiva 90% Farmacoterapia Sclerosi multipla: terapia acuta Sclerosi multipla: terapia RR Methylprednisolone altodosato IFNIFN-beta 1b (Betaferon® (Betaferon®) 8 MI 1x/2 g s.c. IFN1x/Se. 30µ 30µg i.m. IFN-beta 1a (Avonex® (Avonex®) IFN3x/22 o 44µ 44µg/Se. IFN-beta 1a (Rebif® (Rebif®) s.c Glatirameracetat (Copaxone® (Copaxone®) 20 mg/g s.c. Natalizumab (Tysabri® 300 mg/1mese (Tysabri®) Mithoxantrone (Novantron® (Novantron®) 12mg/Kg – 1gr/d i.v. per 3 g opp. 0.5 gr/d per 5g con ev.coda Prednisone p.o 3g – Controversia sulla via di sommistrazione Tapering – Ca, Vit D3, protezione gastrica Riposo Trattamento precoce sul decorso della SM Studi nel CIS Betaferon, e.o.d. IFNB IFNB-1a, onceonce-weekly CHAMPS finestra terapeutica % of patients with CDMS at 2 years Handicap Trattamento piu’ tardivo Evoluzione spontanea della malattia 50 Trattamento piu’ tardivo trattamento al momento della diagnosi tempo Selon: Trapp BD, et al. Curr Opin Neurol. 1999;12:295; Trapp BD, et al. Neuroscientist. 1999;5:48; Trapp BD, et al. N Engl J Med. 1998;338:278; Jeffery D. J Neurol Sci. 2002;197:1-8; Cohen JA, et al. J Neuroimmunol. 1999;98:29-36. % of patients with CDMS at 2 years % of patients with CDMS at 2 years 50 50 P = 0.047 40 30 30 30 20 20 20 10 10 10 0 0 P = 0.002 Placebo IFNB-1a Placebo IFNB-1a P < 0.0001 40 40 Trattamento precoce Inizio della malattia BENEFIT ETOMS 0 Placebo Betaferon Jacobs LD et al., NEJM 2000; Comi G et al., Lancet 2001; Kappos et al., Neurology 2006 Page Slide 12 Anticorpi Efalizum ab * monoclonali Selective Adhesion Molecule Inhibition: Implications for Multiple Sclerosis Therapy Proposed Rituximab MOA Rituximab Macrophage, monocyte, or natural killer cell ADCC 1. Leukocyte migration from blood to tissue CD20 FcγRII, FcγRIII Cell lysis CDC Complement activation (C1qC1rC1s) Natalizumab B cell 2. Leukocyte priming and activation 3. Modulation of leukocyte apoptosis MAC CD20 Cell lysis Apoptosis Natalizumab ADCC = antibody-dependent cellular cytotoxicity. CDC = complement-dependent cytotoxicity. Golay J et al. Blood 2000;95:3900; Reff et al. Blood 1994;83:435; Byrd JC et al. Blood 2002;99:1038 Alemtuzumab Immunosoppressione Page Cladribine Synthetic purine nucleoside analogue 2-chlorochloro-2’-deoxyadenosine (2(2-CdA) Prodrug, activated by intracellular phosphorylation First synthesized at the Scripps Research Institute in the late 1970s for treatment of lymphoid malignancies NH2 N N N CI HO Licensed since 1993 as Leustatin® injection for HCL, and in some countries for CLL N O OH C10H12CIN5O3 MWt = 285.69 CLL, chronic lymphocytic leukaemia; HCL, hairy cell leukaemia Leist T, Vermersch P. CMRO 2007;23;2667–76 Page
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