Presentazione sul tema: "La Clinica e la terapia della SM"— Transcript della presentazione:
1La Clinica e la terapia della SM G.L MancardiClinica Neurologica II, Università di Genova e Centro di Eccellenza per la Ricerca Biomedica
2La Sclerosi multiplaLa SM e’ una malattia infiammatoria cronica del SNC, caratterizzata da distruzione mielinica focale, lesione e perdita assonale di vario grado e progressiva disfunzione neurologica.La malattia e’ verosimilmente dovuta a una risposta immunomediata linfocitaria T e anticorpale diretta contro antigeni del SNC. Non sono ancora completamente chiari gli eventi che scatenano tale risposta autoimmune e i meccanismi di cronicizzazione della risposta entro il SNC
12MS. Fibrillary gliosis of NAWM From Prineas and McDonald, 1997
13Interpretazione dei patterns di IgG Bande oligoclonali presenti solo nel CSFSingola banda nel CSFMirror patternBande addizionali presenti nel CSFNormalePattern Monoclonale IgG nel CSF e nel siero
14Decorso della sclerosi multipla Compston and Coles, Lancet 2002
15I sintomi della Sclerosi Multipla Nell’80% circa dei casi il decorso e’ inizialmente a ricadute e remissioni.La frequenza di ricadute e’ di circa 1.5 all’anno, e tendono a diminuire col passare del tempo.L’esordio e’ intorno ai anni e verso i anni la malattia diventa progressiva.
16I sintomi della Sclerosi Multipla Sintomi di esordioIpostenia in uno o più arti 40%Neurite ottica 22%Parestesie 21%Diplopia 12%Vertigine 5%Turbe urinarie 5%Altre < 5%
17I sintomi della Sclerosi Multipla Sintomi motoriIposteniaSpasticitàFaticaSintomi cerebellariDisturbi della motilità oculareParalisi internucleareNistagmo
18I sintomi della Sclerosi Multipla Disturbi sensitiviDoloreSegno di LhermitteDisturbi parossisticiNeurite otticaAltri nervi cranici
19I sintomi della Sclerosi Multipla Disturbi sfintericiDisturbi cognitivi
20Terapia della sclerosi multipla Terapia di prima lineaInterferon beta 1a 1bCopolimero 1Azatioprina*Terapia di seconda lineaMitoxantroneCiclofosfamide*Natalizumab*Non approvate per la terapia della SM
21Frequenza di ricadute 68% Riduzione vs. placebo Placebo n=315TYSABRI n=6270.00.10.20.188.8.131.52.184.108.40.206Annualized Relapse Rate (95% CI)P<0.00010.730.23Anni 0-268%70%0.780.670.270.20Anno 0-1Anno 1-266%The pre-specified primary endpoint at 1 year was the rate of clinical relapses. Annualized relapse rate for the TYSABRI and placebo groups over the 2-year study period and over the first and second years of the AFFIRM trial are shown in this slide.Over the 2-year study, TYSABRI reduced annualized relapse rate by 68% compared with placebo (P<0.0001). During this 2-year period, the annualized relapse rate was 0.23 in the TYSABRI group and 0.73 in the placebo group. From baseline to Year 1, the annualized relapse rate was 0.27 in the TYSABRI group and 0.78 in the placebo group (P<0.0001), representing a reduction of 66%. From Year 1 to Year 2, TYSABRI reduced the annualized relapse rate by 70% compared with placebo (0.20 in the TYSABRI group and 0.67 in the placebo group; P<0.0001).When annualized relapse rate was calculated using the same methods used by the FDA for the 1-year AFFIRM data (the per-subject mean), the relapse rate at 2 years was 0.22 in the TYSABRI group and 0.67 in the placebo group (67% reduction).Polman C, et al. Presented at the 57th Annual Meeting of the American Academy of Neurology, April 12, 2005.AFFIRM Study
22Proportion With Sustained Progression Progressione della disabilità 42% Riduzione della disabilità verso placeboNumber of Patients at RiskPlaceboTYSABRI315296283264248240229216208200627601582567546525517503490478Placebo 29%TYSABRI 17%0.00.10.20.30.4Weeks1224364860728496108120199473P=0.0002Hazard ratio (HR)=0.58Proportion With Sustained ProgressionThe effect of TYSABRI on disability was assessed using multiple measures.The pre-specified primary endpoint at 2 years was the time to onset of sustained disability progression as measured by the EDSS. Sustained disability progression was defined as either a 1.0-point increase in EDSS score from baseline EDSS score of 1.0 sustained for 12 weeks, or a 1.5-point increase in EDSS score from baseline EDSS score of 0.0 sustained for 12 weeks; progression could not be confirmed during a relapse.Time to sustained disability progression was analyzed using a Cox proportional hazards model. The predefined statistical model included baseline EDSS score, and additional baseline factors were tested for inclusion in the model: EDSS score (3.5 or >3.5), Gd+ lesions (present or absent), number of T2-hyperintense lesions (<9 or 9), and age (<40 or 40 years). Each covariate was tested in the model for statistical significance using a backward selection procedure, and only statistically significant covariates were included. Only age was included in the final model for disability progression.This slide shows Kaplan-Meier plots of time to sustained disability progression in the TYSABRI and placebo groups over 2 years in the AFFIRM trial. TYSABRI reduced the risk of sustained disability progression over 2 years by 42% compared with placebo (Hazard ratio = 0.58; 95% confidence interval [CI]: 0.43, 0.77; P=0.0002). Kaplan-Meier estimates of the cumulative probability of progression over 2 years were 17% in the TYSABRI group and 29% in the placebo group.Polman C, et al. Presented at the 57th Annual Meeting of the American Academy of Neurology, April 12, 2005.AFFIRM Study
23Lesioni Gd+ 92% Riduzione vs. Placebo 92% reductionP<0.0001Mean Number of Gd+ Lesions0.00.20.40.60.81.01.21.4At Year 20.1Placebo n=315TYSABRI n=627Gd+ lesions are a marker of BBB breakdown and acute inflammation. This MRI outcome was selected to evaluate the potential of TYSABRI to reduce the formation of the acute areas of demyelination, which often correlate with acute clinical attacks.This slide shows the mean number of Gd+ lesions at 2 years in the AFFIRM trial. TYSABRI significantly reduced the mean number of Gd+ lesions by 92% compared with placebo (P<0.0001).The robust effect of TYSABRI on the number of Gd+ lesions in AFFIRM indicates that TYSABRI reduces the formation of acute areas of demyelination, which have been shown to correlate with acute clinical relapses.1-3 The effect of TYSABRI on Gd+ lesions is important because of the established association between Gd+ lesions and the evolution of more chronic pathology as measured by T1-hypointense lesions, which reflect permanent demyelination and axonal damage.4 Given the mechanism of action of TYSABRI (inhibition of leukocyte migration across the BBB), the current results validate the importance of interfering with this component of the disease process in reducing inflammation and subsequent neuropathology.1Kappos L, et al. Lancet. 1999;353: ; 2Koudriavtseva T, et al. J Neurol Neurosurg Psychiatry. 1997;62: ; 3Miller DH, et al. Ann Neurol. 1996;39:6-16; 4Simon JH, et al. Neurology. 2000;55:Miller DH, et al. Presented at the 57th Annual Meeting of the American Academy of Neurology, April 12, 2005.AFFIRM Study
24IMMUNOSOPPRESSION IN MULTIPLE SCLEROSIS AzathioprineCyclophosphamideMethotrexateMitoxantrone*CyclosporineCladribineCAMPATH-1HTBI/TLIASCT*The only immunosuppressive therapy approved for SPMS, PRMS and RRMS.
25La terapia della SM Non solo terapia etiopatogenetica Terapia sintomaticaAccettazione della disabilitàConservazione del ruolo lavorativo, sociale, familiare.