Rational basis for early treatment in MS. Bonaventura Casanova Estruch Unitat d Esclerosi Múltiple Hospital Universitari la Fe València

Transcription

1 Rational basis for early treatment in MS Bonaventura Casanova Estruch Unitat d Esclerosi Múltiple Hospital Universitari la Fe València

2 Bonaventura Casanova Department of Neurology University Hospital La Fe Valencia, Spain In compliance with the Continuing Medical Education (CME) guidelines of the European Accreditation Council for Continuing Medical Education (EACCME), I declare to be a member of the following companies advisory board, board of directors or other similar groups: Merck-Serono, TEVA, Sanofi Aventis.

3 Multiple sclerosis disease progression hypothesis Initially, very little structural damage causes a strong response in functional reorganization and hyperactivation in the brain, resulting in low disability and cognitive preservation in phase 1. After functional reorganization reaches its peak in phase 2 and decreases thereafter, cognitive impairment and disability progressively develop throughout phase 3 Schoonheim MM. NEUROLOGY 2010;74:

4 GOALS To treat Relapsing-Remitting MS patients To modify the natural course of MS To treat with the best treatment

5 Rational basis for early treatment in MS 1. Pathology of early MS 2. Early Clinical and MRI predictors of disability 3. Immunomodulatory therapy effects over predictors of disability 4. Can we select patients for early treatment?

6 Early pathologic phenomena in MS Inflammation Axonal degeneration Frischer JA. Brain (2009): 132;

7 Early pathologic phenomena in MS Khulmann T. Brain (2002): 125;

8 Disability is related to axonal degeneration Tallantyre CA. Mult Scl 2010: 16; 406 Healthy control SPMS patient

9 Axonal destruction begins very early in the course of MS Disability is related to axonal degeneration EARLY DIAGNOSIS EARLY TREATMENT

10 Diagnosis of early MS? A Clinically Isolated Syndrome MS clinically probable (C3-Poser) MS probable (McDonald) A CIS with DIS MRI criteria A CIS with OCGB MS probable (McDonald) MS probable (McDonald) MS laboratory supported (B3-Poser) Definitive MS (McDonald)? A definitive MS by DIS and DIT MRI criteria (Montabán X. Neurology 2010) Definitive MS (McDonald) A clinically definitive MS (2 relapses) Clinically definitive MS (A1-Poser)

11 Early MS A suggestive syndrome and OCGB+ DLS-MS (B3) OCGB Sensitivity 91 (82-100) Specificity 94 (82-100) PPV 96 (91-100) NPV 84 (67-100) DIS and DIT Sensitivity Specificty PPV McDonald (36-58) 91 (85-95) 78 (65-89) McDonald (49-70) 87 (81-93) 77 (65-87) Swanton (61-81) 87 (80-92) 79 (68-88) Rovira (31-60) 86 (80-90) 43 (29-55) A suggestive syndrome and a MRI diagnostic (Neurology 2010) 3 months MRI

12 Early MS RRMS: A CIS plus OCGB (95%) RRMS according McDonald citeria (77%)

13 Early clinical prognostic factors Multifocal presentation Cerebellar, pyramidal or sphinteric involvement at presentation Severity of the first attack Persistent disability after the first attack Interval between first and second attack Relapse rate during the first years Disability accumulated after the first years Martinelli V. Neurol Sci Suppl 4

14 Early clinical prognostic factors No. of patients Time to reach an EDSS of Median 95% IC p Initial symtoms Isolated ON Reference Isolated BSS Isolated dysfunction of long tracts <0.001 Combination of symptoms <0.001 Recovery from the first relapse Complete Incomplete 274 1? <0.0001

15 Early clinical prognostic factors No. of patients Time to reach an EDSS of Median 95% IC p Time to a 2 sd relapses <2 y y Reference 2-5 y y <0.001 >5 y y <0.001 <0.001 Number of relapses during 5 y y Reference y < y <0.001 <0.001

16 Early clinical prognostic factors No. of patients Time to reach an EDSS of Median 95% IC p Time to a 2 sd relapses <2 y y Reference 2-5 y y <0.001 >5 y y <0.001 <0.001 Number of relapses during 5 y y Reference y < y <0.001 < Time to reach an EDSS of 4.0 according the time to a 2 relapses Time to reach an EDSS of 4.0 according the number of relases in 5 years <2 y 2-5 y >5 y. 0 1 relapses 2 relapses 3 relapses

17 MRI prognostic factors Number of T2 lesions and Total T2 lesion load Brex PA. New Engl J Med Number of Barkhof-Tintoré criteria Tintoré M. Neurology (0 cm 3 ) Nº and median Volumen T2 lesions 1-3 (0.6 cm 3 ) 4-10 (0.9 cm 3 ) >10 (5.6 cm 3 ) N CIS-n (%) 16 (76) 1 (6) 0 1 (6) CDMS-n(%) 4 (19) 16 (89) 13 (87) 15 (88) EDSS> Median EDDS Increases in T2 lesion load. Fisniku LK. Brain 2008 Brain atrophy. Fisher E. Neurology 2002 Di Filippo. JNNP 2010

18 IMM activity over Early prognostic factors Interval between first and second attack Relapse rate during the first years Accumulated disability after the first years Number of T2 lesions and Total T2 lesion load Number of Barkhof-Tintoré criteria Increases in T2 lesion load. Brain atrophy.

19 Interval between first and second attack Analysis of the primary end point in CIS trials CHAMPS Avonex ETOMS Rebif BENEFIT Betaferon PreCISe Copaxone N Arm PLB IMM PLB IMM PLB IMM PLB IMM % converted to CDMS Delayed in CDMS conversion n.a Ref: 1. Jacobs LD et al, New England Journal of Medicine 2000, 343,13, Comi g et al, Lancet 2001, Vol 357, Kappos L et al. Neurology 2006: 67; , 4. Comi, G. Presented at AAN 2008, April 16, 2008 Chicago IL.LBS.003

20 Relapse rate during the first years 3,5 3 2,5 2 1, ,56 0, 8 1,82 1,73 1,4 1,2 1 0,8 0,6 1,2 1,2 0,8 0,6 1 0,4 0,5 0,2 0 PLB Ifnβ-1a 22 Ifnβ-1a 44 0 PLB INFB1a 24 months previous On study 12months previous On study INFβ-1a subcutaneous trial INFβ-1a once a week trial 4 3,5 3,6 3,3 3,4 3,5 3 2,9 2,9 3 2,5 2 2,5 2 1,68 1,5 1 1,27 1,17 0,84 1,5 1 1,19 0,5 0,5 0 0 PLB INFB 1,6 INFB 8 PLB GA 24 months previous On study INFβ-1b trial 24 months previous On study Glatiramer acetate trial

21 % of change from the basal study (median) Increases in T2 lesion load % of the change in the T2LV (median) 44 mcg vs Placebo p = mcg vs Placebo p = Months Placebo Ifnβ-1a sc 22 mcg Ifnβ-1a sc 44 mcg SPECTRIMS study group Neurology 2001;56;

22 Disability accumulated after the first years Kappos L. Lancet Neurology 2009; 8:987-97

23 Surrogate markers of axonal damage 1- Sarchielli P. 1H-MRS in patients with multiple sclerosis undergoing treatment with interferon beta-1a: results of a preliminary study. J Neurol Neurosurg Psychiatry. 1998; 64: patients 2- Narayanan S. Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta -1b. J Neurol. 2001;248: patients 3- Schubert F. Serial 1H-MRS in relapsing-remitting multiple sclerosis: effects of interferon-beta therapy on absolute metabolite concentrations. Magma. 2002;14: Merge between lesioned and non-lesioned areas 4- Parry A. Beta-Interferon treatment does not always slow the progression of axonal injury in multiple sclerosis. J Neurol. 2003;250: patients

24 IMM activity over Early prognostic factors Interval between first and second attack Relapse rate during the first years Accumulated disability after the first years Increases in T2 lesion load Brain atrophy and surrogate markers of axon degeneration

25 Conclusion at first IMM is useful for early treatment For all patients since the beginning?. Risk to CDMS What treatment?. Select the best

26 LS-OCMB predicts conversion to CDMS in CIS patients The risk of relapse after a clinically isolated syndrome is related to the pattern of oligoclonal bands. Boscá I. J Neuroimmunol 2010 in press. Probability of remaining free of a 2nd. relapse Years of follow-up G+ML+ G+ML- G-ML-

27 LS-OCMB predicts conversion to CDMS in CIS patients Oligoclonal bands Characteristics Total G+ / ML+ G+ / ML- G- / ML- p value No. patients (female %) 192 (71.9%) 42 (61.9%) 101 (75.2%) 49 (73.5%) (χ 2 ) Mean age years (SD) 31.9 (9.59) (9.98) (8.79) (10.88) (ANOVA) Clinical syndrome (%) Optic neuritis Spinal cord Brainstem Polyregional 29.8% 21.3% 18.1% 30.9% 19.0% 19.0% 16.7% 45.2% 26.8% 22.7% 20.6% 29.9% 44.9% 20.4% 14.3% 20.4% (χ 2 ) BTC+ (%) 43.5% 73.8% 48.0% 8.2% <0.001 (χ 2 ) CDMS (%) 116 (60.4%) 41 (97.6%) 71 (70.3%) 4 (8.2%) <0.001 (χ 2 ) Boscá I. J Neuroimmunol In press

28 Can we identify patients for specific treatments?

29 Can we identified patients for specific treatments? N=26 Non responders=14 Responders=12 N=7 N=7

30 Can we identify patients for specific treatments? Boscá I. Mult Scl In press Total patients (n=102) Patients LS-OCMB+ (n=40) Patients LS-OCMB- (n=62) Relapse rate in the year before treatment 1.5 (0.9) 1.7 (1.1) 1.4 (0.8) ns Relapse rate in the first year after treatment 0.49 (0.7) 0.82 (1.0) 0.27 (0.4).001 Relapse rate reduction , % relapse-free patients after treatment EDSS at treatment initiation 1.5 (1.1) 1.7 (1.3) 1.4 (0.9) ns Current EDSS 1.9 (1.3) 2.4 (1.7) 1.5 (0.9).001 % patients with 1.0 point EDSS increase p

31 Can we identify patients for specific treatments? Mean time of follow up 48 months 1,8 1,6 1,4 52% 80% 3 2,5 2,4 P= ,2 1 0,8 2 1,5 1,7 1,4 1,5 0,6 1 0,4 0,2 0,5 0 ARR-bt ARR-1y ARR-bt ARR-1y 0 bedss fedss bedss fedss Patients LS-OCMB+ (n=40) Patients LS-OCMB- (n=62) Patients LS-OCMB+ (n=40) Patients LS-OCMB- (n=62) Boscá I. Mult Scl In press

32 Can wemúltiples identify patients Esclerosis for specific Múltiples treatments? OCMB Total Events % relapse free patients Median time SD Log-rank p Present Absent Global Boscá I. Mult Scler In press

33 Conclusions There are robust evidences to treat RRMS early in the course of the diseases 1. Helps to arrest T2LV increase 2. Decreases the number of relapses 3. Action over disability or neurodegeneration still controversial 4. Today we can select patients with high risk to a 2 nd relapse 5. We have new tools to decide the best treatment at first

34 Some of us José Carlos Álvarez-Cermeño Isabel Boscà Bonaventura Casanova Francisco Coret Matilde Escutia María José Magraner María Simó Luisa María Villar Thank you for your attention