Advanced Multiple Sclerosis: Progressive MS Epidemiology

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1 Advanced Multiple Sclerosis: Progressive MS Epidemiology CMSC 2007-Washington, DC Mitchell T. Wallin, MD, MPH Associate Director-Clinical Care VA MS Center of Excellence-East East Associate Professor of Neurology Georgetown University Medical School

2 Progressive MS: Epidemiologic Features I.. Definitions & Measures of Morbidity II. Risk Factors for Progression III. Treatment Issues in Progressive MS

3 Multiple Sclerosis Subtypes (Coyle P, 2002 and Lublin F, et al Neurology 1996)

4 Prevalence of Subtypes of MS Primaryprogressive (PP) 10% Progressiverelapsing (PR) 5% (N = 3019) Secondary-progressive (SP) 30% Relapsing-remitting (RR) 55% Jacobs et al. Mult Scler. 1999;5:

5 Progressive MS Definitions The RR-SP MS Transition Onset of progressive disability x 6 mo Fewer attacks and less recovery during attacks > 50% make transition by 10 yrs from MS onset Up to 90% by 25 yrs from MS onset Benign MS and Progression EDSS < 2-33 at 10 years from onset Progression (>( EDSS 3) at 20 years from onset from baseline EDSS < 2 at 10 yrs 30 % in Canadian Population (Sayao, 2007) 7% in Olmsted County Population (Pittock, 2004)

6 McDonald Diagnostic Criteria Primary Progressive MS Polman C, Ann Neurol, 2005 Insidious course with one year of steady progression of clinical deficits + two of the following: Positive Positive Brain MRI (9 T2 lesions or 4 or more T2 lesions with positive VEP) Positive Positive spinal cord MRI (2 focal T2 lesions) Positive Positive CSF (OCB, or increased IgG index)

7 Secondary Progressive MS vs. Primary Progressive MS RR-SP MS PP MS Age at onset (mean) 30 yrs 40 yrs Sex ratio (M:F) 2:1 1:1 Race Onset symptoms Sensory, visual Paraparesis

8 Multiple Sclerosis Morbidity Scales Kurtzke Expanded Disability Status Score Scale is a central clinical measure in most longitudinal studies ranges from: 0 = normal 4 = walks unaided for greater than 500 meters 5 = walks unaided for greater than 100 meters 6 = needs a cane to walk 100 meters 7 = restricted to wheelchair, walks less than 20 meters with aid 8 = confined to bed/wheelchair, use of arms 10 = death Cognitive problems, fatigue, sexual function, job capabilities, and social factors do not weigh heavily in EDSS Similar Scales: EDMUS-GS (Grimaud, 1999), Disease Steps (Hohol, 1999), PDDS (Schwartz, 1999)

9 Multiple Sclerosis Morbidity Scales Multiple Sclerosis Functional Composite measure measure of motor function of legs (25 timed walk) motor function of arms (9-Hole Peg) cognition (PASAT) adds adds information to the Kurtzke EDSS first first used in a phase 3 clinical trial of intramuscular interferon-beta 1a (Cohen, et al 2001)

10 Measures of Morbidity for MS Progression Clinical Relapses Global Neurological Disability: EDSS, MSFC Other morbidity scales Imaging: T2, T1, & Gd enhancing lesions, atrophy DT MRI, MRS, fmri

11 Brain Atrophy as a Measure of Morbidity Bermel, 2006 Clinical-imaging imaging paradox of MS Brain atrophy begins early in RR MS RR MS %/yr SP MS %/yr 0.8%/yr PP MS %/yr Whole brain gray matter volume & disability EDSS r = -0.46, p= timed walk: r = -0.52, p= 0.002

12 Atrophy of Caudate Nuclei in MS (Bermel, 2006) Box plot of normalized caudate volumes; MS (N=24) and age-matched healthy control s (N=10) Caudate nucleus of 50 yr old male with MS (green) and normal control (pink)

13 Cervical Cord Atrophy SP & PP MT ratio cervical cord histograms overlap Cervical cord atrophy separates PP vs. RR MS (Bieniek, 2006): PP MS: 67.8mm 2 RR MS: 72.7mm 2 in Progressive MS Healthy ctls: 73.4mm 2 (p=0.007) Rovaris, 2001

14 Progressive MS: Epidemiologic Features I.. Definitions & Measures of Morbidity II. Risk Factors for Progression III. Treatment Issues in Progressive MS

15 Clinical & Demographic Predictors of Progressive Disability in MS Favorable Risk Factors Young age at onset Female Sex Race: White Onset sx: optic neuritis, sensory RR disease onset Unfavorable Risk Factors Older age at onset Male sex Race: African American Onset sxs: motor, cerebellar, sphincter Severe disability after first attack Short interval between first-second attack High frequency of attacks in first 5 yrs Progressive disease from onset

16 Predictors of Long-term Disability in RR MS (Langer-Gould, 2007) Sphincter symptoms at onset Systematic review of the literature Strongest predictors Sphincter sxs : HR Incomplete recovery first attack: HR Short interval between 1 st - 2 nd attack: HR Incomplete recovery after first attack

17 Predictors of Long-term Disability in RR MS (Langer-Gould, 2007) Age at onset Age: Older age at onset associated with worse prognosis in 9/10 studies. Sex: Men have worse prognosis vs. women (5 studies) No significant sex difference (5 studies) Male sex

18 Longitudinal Follow-up of Benign MS at 10 years (Sayao, 2007) 200 MS pts with EDSS < 3 at 10 yrs from onset from British Columbia Database Conversion to SP MS in 23% 10 -year EDSS score was only significant predictor of progression

19 Initial Course of MS and Time to EDSS 4 and EDSS 6 (Confavreux, 2000) Median time to EDSS 4 RR Onset: 11.4 yrs Progressive Onset: 0 yrs Median time EDSS 4 to 6 RR Onset: 5.7 yrs Progressive Onset: 5.4 yrs EDSS 4 Threshold: once EDSS 4 is reached, progression in MS is not affected by relapses

20 Influence of Initial Course on Age to Reach EDSS End-Points (Confavreux, 2006 ) RR MS were older than PP MS to reach EDSS 4 (Graph A) & EDSS 6 (Graph B); 95% CI overlap Age to reach EDSS 7 between groups similar (Graph C) SP MS had younger age of assignment of EDSS 4, 6, and 7 vs. PP MS

21 Relapses and Progression in MS (Kremenchutzky, 2006) Three subgroups defined: PP MS (N=219) SP MS (N=146) Single attack before onset of progression (SAP; N=140) PP had the worse outcome vs. SP and SAP based on time from onset of MS No difference in time to reach DSS 6, 8 and 10 from onset of progression Progressive course independent of relapses

22 Relapse-induced MS Disability (Lublin, 2007) Placebo Arm of NMSS Clinical Trial Dataset (N=224) Mean EDSS scores plotted before, during and after relapses 42% pts had residual deficit EDSS 0.5 and 28% with lasting EDSS > 1 point Relapse associated stepwise worsening supported

23 Age and Disability Progression

24 African Americans and MS Progression (Cree, et al 2004) Large retrospective cohort of AA (N=375) vs. CA (N=427) Median time to EDSS 6 (16 yrs vs. 22 yrs p=0.0001) Median time to EDSS 7 (30 yrs vs. 38 yrs) Adjusted Cox Hazard Ratio: 1.67 for walking with cane (p < 0.001)

25 VA Longitudinal MS Study (VALOMS) Demographic & Clinical Data Overview Variable African Americans (N=41) White Americans (N=40) p- value Male:Female Ratio * Mean age at first symptom onset 32.6 ± ± * Mean MS disease duration (yrs) 12.1 ± ± Median time from onset to diagnosis (yrs) 3.0 ± ± Median time from diagnosis to treatment (mo) Median time to SP MS 7.2 ± ± Median time to EDSS ± ±

26 VA Longitudinal MS Study (VALOMS) MS Onset to EDSS 6: AA vs. CA Log Rank (Mantel-Cox)= 0.41

27 Progressive MS: Epidemiologic Features I.. Definitions & Measures of Morbidity II. Risk Factors for Progression III. Treatment Issues in Progressive MS

28 Does treatment impact disability in progressive MS? SP MS: Some short-term data affirmative: Interferonbeta and immunosuppressive therapy No evidence for long-term benefits of any disease modifying therapy PP MS: No therapy that impacts disability

29 Interferon-beta Clinical Trials (adapted from Goodkin D, Int MS J 2005) Interferon beta Trial Size Clinical Activity MRI Activity Clinical Severity Phase III Trial RR MS IFN beta 1b SC 372 NS Phase III Trial RR MS IFN beta 1a IM 301 Phase III Trial RR MS IFN beta 1a SC 560 EUSPMS (Interferon beta 1b SC) 718 NASPMS (Interferon beta 1b SC) 939 NS IMPACT (Interferon beta 1a IM) 436 NS SPECTRIMS (Interferon beta 1a SC) 506 NS significant p<0.05 significant p<

30 Interferon beta Trials in SP MS (Rovaris, 2006)

31 Immunosuppressive Options for SP MS Pulsed IV corticosteroids (Goodkin, 1998) Mitoxantrone (Hartung, 2002) Methotrexate (Gray, 2006) Cyclophosphamide (LaMantia, 2007; Drachman 2005) Azathioprine (Yudkin, 1991) Mycophenolate mofetil (Frohman, 2004) Autologous Stem Cell Transplant (Saccardia, 2006)

32 Treatment Options for Progressive MS Current therapies benefit SP with relapses/active MRI Failure of many immune modifying drugs used in RR MS Once the cascade of events leading to axonal loss is established, immunosuppressive treatments are inadequate in slowing disease course New treatment approaches needed Neuroprotection Neuroregeneration Neurorehabilitation

33 Progressive MS Epidemiology Conclusions EDSS 4 is a disability threshold Age at achieving disability landmarks is not related to the initial MS course Benign MS does progress Current Risk factors for progression inadequate: reliable biomarker for MS morbidity needed Concept of MS as a diffuse CNS disease with a major neurodegenerative component supported by population data

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