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Disease-activity free status talk - Cleveland Clinic 20 Sept 2012
 

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    Disease-activity free status talk - Cleveland Clinic 20 Sept 2012 Disease-activity free status talk - Cleveland Clinic 20 Sept 2012 Presentation Transcript

    • What would disease free status look like in MSand what is the evidence that we can achieve it? Gavin Giovannoni Barts and The London School of Medicine and Dentistry
    • What would disease free status look like in MS and what is theevidence that we can achieve it?
    • What would disease free status look like in MS and what is theevidence that we can achieve it?
    • What is a disease?
    • What is a disease/what is MS?A. Conventional definition • E.g. “hepatitis is inflammation of the liver”B. Pre-theoretical definition Ludwig Wittgenstein • “SLE is characterised by the ARA criteria” 1889-1951 • Indirect definition • Usually “polythetic” • Inclusive definition using multiple characteristics • According to Wittgensteins model of a "long rope twisted together out of many shorter fibres.“*C. Theoretical definition • E.g. “Down’s syndrome is trisomy 21”. • Usually “monothetic”. *Ludwig Wittgenstein a controversial 20th-century analytical philosopher (1889-1951).
    • What is multiple sclerosis?
    • Multiple sclerosis definitionPathological Definition: Inflammatory disease of the CNS characterised by demyelination and variable degrees of axonal loss and gliosis.Clinical Definition: Objective CNS dysfunction, i.e. involvement of two or more white matter structures (space) separated by time, with no other aetiology.
    • What constitutes a useful set of diagnostic criteria? TARGET DISORDER PRESENT ABSENT DIAGNOSTIC TEST + a b a+b RESULT - c d c+d a+c b+d a+b+c+dFrom these we determine the sensitivity and specificity as follows:SENSITIVITY = a/(a+c) > 80%SPECIFICITY = d/(b+d) > 80% Neurobiol Aging 1998; 19:109-116.
    • A clinico-pathoanatomical study of MS diagnosis SPECIFICITY = True-ve /(True-ve + False+ve) ?25% of cases diagnosed with MS on post-mortem are undiagnosed in life – asymptomatic – benign cases Engell T. Acta Neurol Scand. 1989 May;79(5):428-30.
    • The evolving clinical definition of MS is changing the natural history of MS1. Schumacker, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68.2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31.3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58:840-6.5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.
    • Will Rogers phenomenon in MS 1879 - 1935“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”
    • MS diagnosed according the old Poser Criteria RRMSInactive CIS Active CIS
    • MS diagnosed according the old Poser Criteria RRMS Inactive CIS Active CIS Less active MoreInactive CIS RRMS Active RRMS MS diagnosed according the New McDonald Criteria
    • Will Rogers Phenomenon in Multiple Sclerosis Poser McDonald Sormani et al. Ann Neurol 2008;64:428–433.
    • static protective factors dynamic protective factors Favourable disease-modifying factors protective HLA haplotypes Low risk Very low risk At risk High Risk RIS CIS MS static risk factors dynamic risk factors Unfavourable disease-modifying factors age family history place of residence genetics outdoor activity / sun exposure / sun screen sex month of birth diet / vitamin D supplements place of birth age of exposure to EBV smoking 1 Peripheral immunological changes T-regs (), NK cells, CD8 () 2 CNS changes 1. Declining Physiology – “peripheral immunological endophenotype” (OCBs and microscopic pathology) 2. Biological disease threshold – “CNS endophenotype” 3. Asymptomatic disease – RIS (abnormal MRI and/or evoked potentials) 3 4. Clinical disease a. Clinically isolated syndrome (CIS) MRI / evoked potentials changes b. Relapsing MS c. Relapsing secondary progressive MS 2 4a d. Non-relapsing secondary progressive MS 2 4b Clinical disease 2 4c 2 4dIn utero childhood Adolescence / early adulthood adulthood “THE MS ENDOPHENOTYPE” - Giovannoni et al. Lancet Neurol. 2010 Jul;9(7):727-39.
    • The evolving clinical definition of MS1. Schumacker, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68.2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31.3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58:840-6.5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.6. Polman, et al. ……………2016? RIS or asymptomatic/presymptomatic MS
    • What would disease free status look like in MS and what is theevidence that we can achieve it?What do you want to measure?
    • Current Dogma“autoimmune endophenotype” immune activationinnate and adaptive responses BBB breakdown focal inflammationaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology delayed neuroaxonal loss and gliosis - clinical outcomes - biomarkers
    • Current Dogma“autoimmune endophenotype” immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology delayed neuroaxonal loss and gliosis - clinical outcomes - biomarkers Disease Progression
    • Current Dogma“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology delayed neuroaxonal loss and gliosis - clinical outcomes - biomarkers Disease Progression
    • Current Dogma“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology release of soluble markers delayed neuroaxonal loss and gliosis e.g. neurofilaments - clinical outcomes - biomarkers Disease Progression brain & spinal cord atrophy
    • Current Dogma“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activation innate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology release of soluble markers delayed neuroaxonal loss and gliosis e.g. neurofilaments - clinical outcomes - biomarkers Disease Progression brain & spinal cord atrophy
    • Current Dogma“autoimmune endophenotype”  T2 & T1 lesions   Gd-enhancement immune activation innate and adaptive responses BBB breakdown focal inflammation Clinical Attack Clinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology - clinical outcomes release of soluble markers e.g. neurofilaments ? delayed neuroaxonal loss and gliosis - biomarkers Disease Progression brain & spinal cord atrophy
    • Current Dogma“autoimmune endophenotype”   T2 & T1 lesions   Gd-enhancement immune activation  innate and adaptive responses BBB breakdown  focal inflammation Clinical Attack Clinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology - clinical outcomes release of soluble markers e.g. neurofilaments ? delayed neuroaxonal loss and gliosis - biomarkers brain & spinal cord atrophy Disease Progression 
    • Effect of natalizumab on clinical and radiological disease activity in MS: a retrospectiveanalysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study Gd R 35% vs. 64% T2 Δ = 29% CU DP Gd R T2 14% vs. 58% DP Δ = 44% CU Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.
    • Effect of natalizumab on clinical and radiological disease activity in MS: a retrospectiveanalysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study Gd R T2 DP CU 15% vs 47% 13% vs 68% 6% vs 37% Δ 32% Δ 55% Δ 31% Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.
    • A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple SclerosisGd RT2CU DP Polman et al. N Engl J Med 2006;354:899-910.
    • Clinical implications
    • Breakthrough disease after treatment initiationPatients with breakthrough disease can be identified with:• Clinical measures • Relapses • EDSS progression• MRI measures • T2 and Gd+ lesions• Biological markers • IFNb neutralizing antibodies (NAbs)/lack of MxA induction • Anti-natalizumab Abs
    • Relapse on IFNβ therapy increases risk of sustained disability progression • Risk is not much greater for 2 relapses or more • Sensitivity is only 50%33 Bosca et al. Mult Scler 2008;14:636-39.
    • MRI to monitor treatment response to IFN-beta: a systematic review One new T2 lesion 2 or more new T2 lesionsMeasurement sensitivity? Dobson et al. Submitted 2012.
    • MRI to monitor treatment response to IFN-beta: a systematic review One new Gd+ lesion 2 or more Gd+ lesions35 Dobson et al. Submitted 2012.
    • Strongest predictor of disability progression on IFNβ therapy is progression itself • Disease activity during 2 years of treatment and prediction of disability progression* at 6 years Sensitivity (%) Specificity (%) Group (CI) (CI) A. An increase of at least one EDSS step confirmed at 6 months 85 (64-95) 93 (86-97) B. Occurrence of any relapse 80 (58-92) 51 (41-61) C. Occurrence of two or more relapses 45 (26-66) 81 (72-82) D. A decrease in relapse rate less than 30% compared with 2 years before therapy 40 (22-61) 86 (77-91) E. A decrease in relapse rate less than 50% compared with 2 years before therapy 40 (22-61) 81 (72-88) F. No decrease or identical relapse rate compared with 2 years before therapy 35 (18-57) 88 (79-93) G. Definition A or B 90 (70-97) 48 (38-58) H. Definition A or E 85 (64-95) 76 (66-83) I. Definition A and B 75 (53-89) 97 (91-99) J. Definition A and E 40 (22-61) 99 (94-99)* EDSS ≥6.0 or increase in at least 3 EDSS steps. Rio et al. Ann Neurol. 2006;59:344.
    • Post-hoc analysis, disease-activity free: Patients with no relapse, no sustained disability progression and no new MRI lesion activity Weeks 0–24 Weeks 0–48 Weeks 0–96 OR (95% CI): OR (95% CI): OR (95% CI): 3.68 (2.73, 4.97) 4.13 (3.02, 5.66) 4.58 (3.26, 6.43) OR (95% CI): 80 3.31 (2.46, 4.46)Patients disease activity-free (%) OR (95% CI): 3.80 (2.77, 5.22) OR (95% CI): 4.26 (3.03, 5.99) 69.7 67.3 60 56.1 54.2 44.2 45.7 40 38.9 20 23.9 p<0.001 p<0.001 p<0.001 15.8 0 Placebo 3.5 mg/kg 5.25 mg/kg Placebo 3.5 mg/kg 5.25 mg/kg Placebo 3.5 mg/kg 5.25 mg/kg (n=373*) (n=395*) (n=406*) (n=360*) (n=384*) (n=396*) (n=379*) (n=403*) (n=411*)Gd R Cladribine tablets Cladribine tablets Cladribine tabletsT2CU DP OR = odds ratio *Based on observed data; no imputation used
    • Fingolimod treatment increases the proportion of patients who are free from diseaseactivity in multiple sclerosis; results from a phase 3, placebo-controlled study (FREEDOMS)Gd RT2CU DP Kappos et al., AAN 2011
    • BG-12 Increases the Proportion of Patients Free of Clinical and Radiologic Disease Activity in Relapsing–Remitting Multiple Sclerosis: Findings from a DEFINE Post Hoc AnalysisGd RT2CU DP Giovannoni et al., AAN 2012
    • Fingolimod Treatment Increases the Proportion of Patients who are Free from Disease Activity in Multiple Sclerosis Compared to Interferon beta-1a: Results from a Phase 3 Active-Controlled Study (TRANSFORMS)Gd RT2CU DP Khatri et al. AAN 2012.
    • Disease Activity-Free Status in Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I (CARE-MS I) - Phase 3 Study p<0.0001 p=0.0388 p=0.0064 CDA-Free MRI Activity–Free MS Disease Activity-Free Odds of experiencing MS disease activity for SC IFNB-1a patients was 1.75 times higherGd than alemtuzumab patients; odds ratio=1.75 (95% CI: 1.17, 2.61), p=0.0064 RT2CU DP Giovannoni et al. ENS 2012 41
    • Power calculations from CLARITY study Absolute difference 90% power treatment rate - placebo rate 10% 20% 30% Placebo 1 group 1 group 1 group rate 15% 354 108 54 +10% 389 118 59 30% 496 134 63 +10% 546 147 69Gd RT2CU DP Giovannoni et al. Unpublished observations
    •  Current Dogma“autoimmune endophenotype” T2 & T1 lesions   Gd-enhancement immune activation innate and adaptive responses BBB breakdown focal inflammation Clinical Attack Clinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss ? ? - biology release of soluble markers delayed neuroaxonal loss and gliosis e.g. neurofilaments - clinical outcomes - biomarkers ? ? ? Disease Progression brain & spinal cord atrophy
    • Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108..
    • Axonal Damage in Relapsing Multiple Sclerosis is Markedly Reduced by Natalizumab Gunnarsson et al. Ann Neurol 2010.
    • Conclusions / Questions• What would disease free-status look like? • Absence of any clinical and biomarker evidence of disease activity • Current definition = relapse, disease-progression, Gd-enhancing lesions and new T2 lesions • What about brain atrophy and CSF neurofilament levels?• Should the definition be stage specific? • CIS/RRMS vs. R-SPMS vs. NR-SP/PPMS• What do we do about post-inflammatory neurodegeneraton?• What about the potential effects of superimposed accelerated or premature aging?• How do we define an appropriate baseline for comparison? • We need to optimise the time fore re-base lining MRI when looking for a change; this may need to be agent specific.• How do we deal with the difference between maintenance and induction therapies? • Maintenance - absence of DAF status indicated non-response • Induction – absence of DAF status indicates a time to retreat.• How do we standardise (or improve) on the metrics?
    • Do we need to challenge the dogma?“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology release of soluble markers delayed neuroaxonal loss and gliosis e.g. neurofilaments - clinical outcomes - biomarkers Disease Progression brain & spinal cord atrophy
    • Do we need to challenge the dogma?“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss release of soluble markersViral infection delayed neuroaxonal loss and gliosis e.g. neurofilaments brain & spinal cord atrophy Disease Progression
    • What will a cure in MS look like?
    • www.ms-res.org