The importance of early intervention clinician perspective Øivind Grytten Torkildsen
«You can never diagnose MS too late» Neuroradiologist from Norway, early 1990s
Prognosis in untreated MS
Early diagnosis RIS CIS RRMS SPMS Cerebral Volume Relapses and Disability MRI Lesion Load MRI Activity Trapp BD et al. Neuroscientist. 1999;5:48-57.
Probability Employment in untreated MS Probability of Remaining in Active Employment After Onset of MS 1.0 Control Persons MS Patients 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 Time (years) Pfleger CC et al. Mult Scler. 2010;16:121-126.
Proportion of Patients 65 Years Old Working (%) Employment Change with EDSS Score Increase 90 80 70 60 50 40 30 Austria Belgium Germany Italy Netherlands Spain Sweden Switzerland United Kingdom 20 10 0 0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0 EDSS Score Adapted from Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926. 6
Utility (EQ-5D: 0=Death; 1=Full Health) Quality of life decreases with increasing EDSS-score 1.0 0.9 0.82 0.8 0.70 0.7 0.65 0.6 0.61 0.58 0.57 0.5 0.46 0.37 0.4 0.3 0.2 0.1 0.05 0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0 9.0 EDSS Score 1.00 Best Possible Health Status 0.00 Worst Possible Health Status 0.85 mean utility of normal population 1 0.82 mean utility of aging patients with osteoporosis, no fracture 2 0.72 mean utility of patients with rheumatoid arthritis at stage 1 3 0.58 mean utility of patients with Parkinson s disease 4 0.55 mean utility of patients with MS 1 0.48 mean utility of severe hemophilia patients with inhibitors 5
Survival in untreated MS 8 years decreased survival
In other words 1977
After 10 years: 1/4 of MS-patients have died from the disease 1/4 are still employed 1/2 are not employed, with different degrees of disability
What happens in MS Acute damages
Normal White Matter Animasjon basert fra Trapp BD et al. N Engl J Med. 1998;338:278
Active Lesion Animasjon basert fra Trapp BD et al. N Engl J Med. 1998;338:278
Chronic Active Lesion Animasjon basert fra Trapp BD et al. N Engl J Med. 1998;338:278
Chronic Inactive Lesion Animasjon basert fra Trapp BD et al. N Engl J Med. 1998;338:278
Trapp BD et al. N Engl J Med. 1998;338:278
Trapp BD et al. N Engl J Med. 1998;338:278
Transected axons in different MSlesions 12000 11236 Number of Transected Axons Per Mm 3 10000 8000 6000 4000 2000 0 Active 3138 Chronic Active Edge 875 Chronic Active Core 17 NAWM 0.7 Control Trapp BD et al. N Engl J Med. 1998;338:278
Number of damaged axons by disease duration Number of APP-Positive Axons per mm 2 500 400 300 200 100 0 <1 Year 1 5 Years 5 10 Years >10 Years Disease Duration Increasing acute axonal damage Kuhlmann T et al. Brain. 2002;125(Pt 10):2202-2212.
What happens in progressive MS?
Ann Neurol. 2012 Feb;71(2):227-44
Ann Neurol. 2012 Feb;71(2):227-44
Ann Neurol. 2012 Feb;71(2):227-44
Mitochondrial damage? Lassmann, 2013
Prognosis with treated MS
Early treatment significantly reduced the risk of EDSS-progression Ann Neurol. 2009 Oct;66(4):513-20
Goodin DS, et al. 2012 Neurology;78(17):1315-22
Ann Neurol. 2013 Jan;73(1):95-103
New MRI-lesions during MS-treatment 100 predict disability progression 80 60 40 20 0 None 1 2 3 No. of New T2-Hyperintense Lesions After 1 Year of Therapy *Sustained disability progression was defined as a 1.0-point increase in EDSS score confirmed at 6 months. Mean follow-up was 4.8 years. Prosperini L et al. Eur J Neurol. 2009;16:1202-1209.
J Neurol. 2006 Jan;253(1):98-108
Summary Early treatment most effective Disease activity during treatment poorer prognosis
Introduction of RRMS Therapies in the EU Outcome Measures Goals of Therapy Address Symptoms Slow Disease Progression Stop Disease Progression Repair No Evidence of Disease Activity (NEDA) 6 2009 Sustained improvement 7 2011 1983 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 SC IFNβ-1b 1995 IM IFNβ-1a 1997 SC IFNβ-1a 1998 GA Natalizumab 2006 2001 Fingolimod 2010 Mitoxantrone 2000 DMF Peginterferon Beta-1a 2014 Alemtuzumab Teriflunomide 2013?
No Evidence of Disease Activity (NEDA) No relapses Relapses EDSS-progression No EDSS progression MRI activity No new T2-lesions No new Gd+-lesions + + 35 Imitola J, Racke MK. JAMA Neurol. 2015;72:145-147; Stangel M et al. Ther Adv Neurol Disord. 2015;8:3-13.
Disability Early Treatment vs Later Treatment Late treatment Disease onset Time Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11. 36
Disability Early Treatment vs Later Treatment Window of opportunity Late treatment Effective treatment at diagnosis Disease onset Time Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11. 37
Summary MS is a serious disease, if untreated. Early and effective treatment can alter the prognosis.
"When you change the way you look at things, the things you look at change. Max Planck