Progressive Multiple Sclerosis Definitions, Clinical Course and Emerging Therapies M. Mateo Paz Soldán, MD, PhD Neurology Service, VA Salt Lake City HCS Assistant Professor of Neurology, University of Utah 8 th PVA Healthcare Summit Dallas, Texas 28-August-2018
Disclosures Presenter has no financial or non-financial interest to disclose. PESG staff, PVA staff, and planning/review committee members have no financial or non-financial interest to disclose. This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with Paralyzed Veterans of America. PESG, PVA, and all accrediting organization do not support or endorse any product or service mentioned in this activity.
Objectives At the conclusion of this activity, the participant will be able to: Describe the clinical and radiological characteristics of progressive versus relapsing MS. Describe the impact of relapses and DMT on the course of progressive MS. Discuss emerging treatments for progressive MS.
Progressive MS What is progressive MS?
Progressive MS: definitions Progression process of moving gradually towards a more advanced state Progressive disease disease that is spreading or whose course is worsening Stedman's Medical Dictionary
Progressive MS: definitions Schumacher 1965 slow or step-wise progression of signs and symptoms, over a period of at least 6 months Poser 1983 steady progression has taken place for at least 6 months, and evidence for [other CNS] involvement should not have been present at the time paraparesis first appeared McDonald 2001 insidious neurological progression suggestive of MS dissemination in space (MRI +/- VEP) continued progression for 1 year positive CSF Schumacher et al, Ann NY Acad Sci 1965 Poser et al, Ann Neurol 1983 McDonald et al, Ann Neurol 2001
Progressive MS: definitions McDonald 2005 insidious neurological progression suggestive of MS 1 year of disease progression two of the following + brain MRI, + spinal cord MRI, + CSF McDonald 2010 insidious neurological progression suggestive of MS same as 2005, with less strict MRI criteria McDonald 2017 1 year of disability progression independent of clinical relapse two of the following (same as 2010) Polman et al, Ann Neurol 2005 Polman et al, Ann Neurol 2011 Thompson et al, Lancet Neurol 2018
Progressive MS: definitions Progressive disease course insidious accumulation of neurologic deficits independent of relapses and MRI activity Progression of disability insidious accumulation independent of relapses stepwise accumulation from relapses Weinshenker et al, Brain 1989; Trojano et al, JNNP 1995 Kantarci et al, Neurology 1998; Confavreux et al, Brain 2006 Tutuncu et al, MSJ 2012
Progressive MS: disease course Two clinical patterns of MS symptoms MS subtypes based on presence/timing Disability Relapsing Progressive RR SP PP PR Lublin FD Reingold SC, Neurology 1996
Progressive MS: disease course Is primary progressive MS a distinct disease? Miller DH Leary SM, Lancet Neurol 2007
Progressive MS: disease course Multiple sclerosis PPMS vs RRMS/SPMS Tutuncu et al. MSJ 2012 Confavreux et al. NEJM 2000
Progressive MS: disease course Two clinical patterns of MS symptoms MS subtypes based on presence/timing Disability Relapsing Progressive RR SP PP PR Lublin FD Reingold SC, Neurology 1996
Progressive MS: disease course Two clinical patterns of MS symptoms MS subtypes based on presence/timing CIS RIS Marcus et al, Neurohospitalist 2013 Okuda et al, PLoS One 2014
Progressive MS: disease course Kantarci et al, Ann Neurol 2016
Progressive MS: disease course Two clinical patterns of MS symptoms MS subtypes based on presence/timing CIS RRMS CIS SPMS RIS RRMS RIS PPMS Marcus et al, Neurohospitalist 2013 Okuda et al, PLoS One 2014
Progressive MS: disease course Multiple sclerosis PPMS vs RRMS/SPMS Tutuncu et al. MSJ 2012 Confavreux et al. NEJM 2000
Progressive MS: disease course Multiple sclerosis PPMS vs RRMS/SPMS Tutuncu et al. MSJ 2012 Kremenchutzky et al. Brain 2006
Progressive MS: definitions Progressive disease course insidious accumulation of neurologic deficits independent of relapses and MRI activity strongest determinant of disability progression Progression of disability insidious accumulation independent of relapses stepwise accumulation from relapses small % of patients reach EDSS 6 before progression Weinshenker et al, Brain 1989; Trojano et al, JNNP 1995 Kantarci et al, Neurology 1998; Confavreux et al, Brain 2006 Tutuncu et al, MSJ 2012
Progressive MS: impact of relapses Progressive MS onset to EDSS6 (yrs) HR: 2.20 (1.80-2.69) HR: 1.48 (1.27-1.78) pre-progression relapses post-progression relapses Paz Soldan et al, Neurology 2015
Progressive MS: impact of relapses Time to EDSS 6 after progressive MS onset Pre-progression relapses SPMS SAPMS PPMS = 50% in 4 years = 50% in 7 years = 50% in 10 years Paz Soldan et al, Neurology 2015
Progressive MS: impact of relapses Relapsing onset = faster disability accrual Cottrell 1999, Kremenchutzky 1999 Confavreux 2006 Debouverie 2008 (trend) Tremlett 2009 Disability accrual not influenced by initial disease course Confavreux 2000 Trojano 2002 Kremenchutzky 2006, Scalfari 2011 Leray 2010 Methodological differences progression onset, EDSS milestones
Progressive MS: impact of relapses Time to EDSS 6 after progressive MS onset Pre-progression relapses SPMS SAPMS PPMS = 50% in 4 years = 50% in 7 years = 50% in 10 years Post-progression relapses 2 yrs. shorter with ongoing relapses Paz Soldan et al, Neurology 2015
Progressive MS: impact of relapses Presence of ongoing relapses after progressive MS onset SPMS = 29.5% SAPMS = 10.7% PPMS = 3.1% Timing of ongoing relapses after progressive MS onset 91.6% within 5 years 95.2% before age 55 Paz Soldan et al, Neurology 2015
Progressive MS: therapy FDA approved DMTs mitoxantrone for SPMS October 2000 Hartung et al, Lancet 2002
Progressive MS: therapy FDA approved DMTs mitoxantrone for SPMS October 2000 Hartung et al, Lancet 2002
Progressive MS: therapy FDA approved DMTs mitoxantrone for SPMS October 2000 ocrelizumab for PPMS March 2017
Progressive MS: therapy FDA approved DMTs ocrelizumab for PPMS March 2017 Montalban et al, NEJM 2017
Progressive MS: therapy FDA approved DMTs ocrelizumab for PPMS positive rituximab for PPMS negative Hawker et al, Ann Neurol 2009
Progressive MS: therapy FDA approved DMTs ocrelizumab for PPMS positive mean age 44.6 years disease activity at baseline gadolinium + lesions 26.5% rituximab for PPMS negative mean age 49.9 years disease activity at baseline gadolinium + lesions 24.5% Hawker et al, Ann Neurol 2009
Progressive MS: therapy FDA approved DMTs mitoxantrone for SPMS October 2000 ocrelizumab for PPMS March 2017 rituximab for PPMS negative Emerging DMTs siponimod for SPMS positive
Progressive MS: therapy Emerging DMTs siponimod for SPMS Randomized 2:1 to siponimod (1099) or placebo (546) 449 CDP events captured risk of 3-month CDP reduced 21% risk of 6-month CDP reduced 26% T25FW not significant Kappos et al, Lancet 2018
Progressive MS: therapy Emerging DMTs siponimod for SPMS positive fingolimod for PPMS negative Kappos et al, Lancet 2018 Lublin et al, Lancet 2016
Progressive MS: therapy Emerging DMTs siponimod for SPMS positive mean age 48 years disease activity in year prior gadolinium + lesions 21% clinical relapses 22% fingolimod for PPMS negative mean age 48.5 years disease activity in year prior gadolinium + lesions 13% clinical relapses ~8% Kappos et al, Lancet 2018 Lublin et al, Lancet 2016
Progressive MS: therapy Emerging DMTs siponimod for SPMS Randomized 2:1 to siponimod (1099) or placebo (546) 449 CDP events captured risk of 3-month CDP reduced 21% risk of 6-month CDP reduced 26% T25FW not significant Kappos et al, Lancet 2018
Progressive MS: therapy FDA approved DMTs mitoxantrone for SPMS October 2000 ocrelizumab for PPMS March 2017 rituximab for PPMS negative Emerging DMTs siponimod for SPMS positive fingolimod for PPMS negative
Progressive MS: therapy Pathologic mechanisms of progressive MS?
Progressive MS: therapy FDA approved DMTs mitoxantrone for SPMS October 2000 ocrelizumab for PPMS March 2017 rituximab for PPMS negative Emerging DMTs siponimod for SPMS positive fingolimod for PPMS negative high-dose biotin
Progressive MS: therapy Emerging DMTs high-dose biotin Tourbah et al, Mult Scler 2016
Progressive MS: therapy Emerging DMTs high-dose biotin Tourbah et al, Mult Scler 2016
Progressive MS: therapy FDA approved DMTs mitoxantrone for SPMS October 2000 ocrelizumab for PPMS March 2017 rituximab for PPMS negative Emerging DMTs siponimod for SPMS positive fingolimod for PPMS negative high-dose biotin positive lipoic acid
Progressive MS: therapy Emerging DMTs lipoic acid Spain et al, Neurology 2017
Progressive MS: therapy Emerging DMTs lipoic acid Spain et al, Neurology 2017
Progressive MS: therapy FDA approved DMTs mitoxantrone for SPMS October 2000 ocrelizumab for PPMS March 2017 rituximab for PPMS negative Emerging DMTs siponimod for SPMS positive fingolimod for PPMS negative high-dose biotin positive lipoic acid positive
Progressive MS: disease course Lublin et al, Neurology 2014
Progressive MS: disease course Lublin et al, Neurology 2014
Progressive MS: definitions Active clinical relapses and/or MRI activity Progressive insidious accumulation of neurologic deficits independent of relapses and/or MRI activity Lublin et al, Neurology 2014
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