Multiple Sclerosis: Update and management FOM Nov 2015

Transcription

1 Multiple Sclerosis: Update and management FOM Nov 2015

2 disease prevalence per 100,000 population Stroke 1000 Alzheimer's 690 Epilepsy 650 Multiple Sclerosis 150 ( )* Parkinson s Disease 130 ( ) *Cost 1,000,000 per patient

3 McDonald 2010 criteria for diagnosis of MS Clinical Presentation 2 attacks with objective clinical evidence of 2 lesions, or objective clinical evidence of 1 lesion and reasonable historical evidence for a prior attack 2 attacks with objective clinical evidence of one lesion 1 attack with objective clinical evidence of 2 lesions 1 attack with objective clinical evidence of 1 lesion Insidious onset suggestive of primary progressive MS Additional data needed to diagnose MS None Dissemination in space on MRI criteria a Dissemination in time on MRI criteria b Dissemination in space a and time b on MRI criteria 1 year of progression, with 2 of: Evidence for dissemination in space in the brain on MRI a Evidence for dissemination in space in the spinal cord on MRI a Positive oligoclonal bands on CSF a Dissemination in space is demonstrated by lesions in 2 of the following characteristic areas: periventricular, juxtacortical, infratentorial and spinal cord b Dissemination in time is demonstrated either by simultaneous presence of gadolinium-enhancing and non-enhancing lesions, or by new T2 lesions or gadolinium-enhancing lesions on a followup scan after an interval of at least a month CH Polman, SC Reingold, B Banwell et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol, 69(2): , Feb 2011

4 Frequency Multiple sclerosis: Age at onset Paediatric 5% Adult onset 90% Late onset 5% Age at onset of paediatric cases Male Female Total Years 0 Harding et al. JNNP 2015

5 Presenting symptom Multiple Sclerosis: Presentation OT MT PS ON CB BB VE OM FS FM SX SP SS UE LE UK % Willis et al Eur J Neurology 2014

6 patient No Prevalence/100,000 Epidemiology of MS: S Wales Prevalence from diagnosis/100,000 Prevalence from disese onset/100, New diagnosis Inward migration Outward migration Death Change of diagnosis

7 Changing sex ratios Male F emale All Sex ratio 1.8 : : 1

8 MS Long term disability outcomes Prognostic markers Early motor/sphincter involvement Disease course Relapse rate Social class Age Sex MRI OCBs

9 Employment

10 Precipitants for change in employment status

11 Infrastructure and facilities Cardiff Neuroinflammatory Unit (3800 patients, 3000 prevalent, active case load circa 2000) Outpatient specialist clinic(s) Acute/relapse clinic Inpt beds Infusion facility Specialist Physio Consultant Specialist Clinical Neuro- Occupational Nurses Staff Trainees Research Psychologist Therapist fellow Specialist tertiary services Research Institute facilities (MRC Centre)

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13 Patient contacts per month

14 Inflammation vs degeneration (therapeutic window of opportunity)

15 Genetic risk and a primary role for cellmediated immune mechanisms in multiple sclerosis 102 SNPs 95 Regions - 6 secondary - 1 tertiary IMSGC & WTCCC2 Nature (2011) 476; 214-9

16 Pathological mechanism of disease T cell mediated inflammation and demyelination B cell cortical inflammation and demyelination Axonal degeneration Gliosis Complement mediated inflammation

17 Personalised biology driven therapeutic approach Alemtuzumab Anti CD52 T Cell driven pathology Eculizamab Anti-C5 Rituximab anti-cd19 Ocrelizumab Anti-CD20 Complement driven pathology B cell driven pathology

18 Hypothetical MS Treatment Paradigms Stepwise escalation 1 1 st line 2 nd line 3 rd line 4 th line (incl. rescue) 2 Personalised treatment Disease activity BASE THERAPY Efficacy ESCALATION THERAPY High Biologics High Cytotoxic agents /experimental therapies Moderate Oral DMTs Biologics Low Platform DMTs (ABCRE) Moderate None None Low/none Oral DMTs 3 Induction and maintenance Induction Maintenance DMTs, disease-modifying treatments.

19 E f f I c a c y MS: Therapeutic interventions Licensed and approved for use in UK Drug Mechanism Admin Relapse rate reduction Interferon-β (1a/1b) Immune system modulation, mechanism not clear S/c IM Glatiramer acetate Cross reactivity with and suppression of immune response against myelin basic protein S/c 20% (vs placebo) 29% (vs placebo) Teriflunomide Reversible inhibition of mitochondrial enzymes Oral 31.5% (vs placebo) Fingolimod Sphingosine-1-phosphate receptor antagonist, which prevents egress of T cells from lymph nodes, sequestering autoactive T cells in lymph tissue BG-12 Natalizumab Activation of cellular defence mechanisms against oxidative stress Blocks migration of lymphocytes into the CSF by binding to cell surface receptors, thereby preventing their binding to endothelial cell receptors and crossing the blood brain barrier Alemtuzumab Monoclonal antibody targeted at CD52, resulting in prolonged T cell depletion and modulation of the lymphocyte repertoire In development Anti-LINGO-1 (RENEW) RBN Phase 2 Inhibition of LINGO-1 oligodendrocyte precursor cell differentiation Ocrelizumab Ant CD20 IV 46% (vs IFN-β) IV Oral Oral IV IV 45% (vs placebo) 47% (vs placebo) 59% (vs placebo) 74% (vs IFN-β) 34% improvement in VEP latencies (vs placebo)

20 Therapeutic risk MS DMTs and side effects Bone marrow transplantation Plasma exchange Tysabri Campath Rituximab IVIG Fingolimod BG12 Laquinimod Beta Interferons Glatirimer acetate Steroids Disease aggression

21 Clinical deterioration of NMO following Natalizumab Author Yr N= AqP4 Outcome Jacob A Increased disability, Increased T2 and Gd+ Jurynczyk M Increased disability, Increased T2 and Gd+ + Increased disability, Increased T2 and Gd+ + Increased disability Kitley J _ Increased disability, Increased T2 and Gd+ De-Hyung L Increased disability, Increased T2 and Gd+

22 Neurology PMC Defining the Clinical Course of Multiple Sclerosis: the 2013 revisions Lublin F et al Neurology 2014 Jul 15; 83(3): Clinically isolated syndrome (CIS) Active Inactive Indeterminate Relapsing remitting disease (RRMS) Active Inactive Indeterminate Progressive disease (PPMS, SPMS) Active and with progression Active but without progression Not active but with progression Not active and without progression (stable disease) Active: Clinical: Radiological: Progressive disease Relapses GD+ T1 or new or unequivocally enlarging T2 lesions Clinical steadily increasing documented neurological dysfunction/disability

23 2 months after presentation

24 Thresholds for change Relative vs absolute MRI (brain +/- spinal cord) T2 new or enlarging Gd+ Atrophy T1 holes Clinical Relapses Disability progression Stopping criteria

25 New prescriptions per year Cardiff longitudinal prescribing patterns

26 SE Wales Cohort: DMT compliance and time on treatment

27 MS and long term disability outcomes Figure 3. Observed EDSS within the UoWMS cohort and the predicted EDSS using both the UoWMS and the BCMS models Lawton M

28 A Window of therapeutic opportunity? Disability Time in years Disease course milestones Time in years

29 Mean EDSS Survival analyses to disability milestones in a real life cohort 8 Basel 6 4 Monoclonal Induction 2 0 Pre ARR (SD) Post ARR (SD) Monoclonal Induction 2.28 (± 1.93) 0.28 (± 0.42 ) Injectable Induction 1.08 (± 0.97 ) 0.40 (± 1.03) Escalation 1.72 (± 2.04 ) 0.64 (± 0.54 ) % Reduction

30 Second line (mab) treatment failure Alemtuzumab Anti CD52 Clinical trials new drugs (Commonly excluded) Natalizumab Anti alpha4 integrin (Ocrelizumab) Anti CD20 Repurposed drugs/techniques AZP Statins Amiloride Rituximab CycloP Mitoxantrone BMT PEx IVIg Anti C : Eculizamab Tier 1 DMTs INF, GA, DMF, Teriflunomide, Fingolimod

31 MS Clinical and Research Group Cardiff Research Fellows Gillian Ingram Claire Hirst Mark Cossburn Katherine Harding Mark Wardle Seb Luppe James Hjrastjl Mark Willis Emma Tallantrye Sarah Healy Clinical Nurse Specialists Gail Weaver Gaynor Williams Rhiannon Jones Emma Horton Sarah Thomas Belinda Gunning Anne Guishard Sian Locke Physiotherapy Rhian Goodfellow Annabelle Price Occupational therapy Paula Cornelius Clinical Neuropsychology Phil Moore Paul Bradley Consultant staff Neil Robertson Trevor Pickersgill Fady Joseph Owen Pearson Valentina Tomassini Biostatistics/Epidemiology Yoav Ben-Shlomo Biochemistry and Laboratory support WMSBB Sam Loveless Sara Butterworth Bethan Dancy L Hakobyan Paul Morgan Administrative support Lucy Coates Sue Butler Alisa Jones Karen Blatchford