MRI

MRI

ASN MS Update 2015 Annual Meeting Carefree, AZ Guy Buckle, MD, MPH Director of Neuroimaging Research Andrew C. Carlos MS Institute at Shepherd Center Atlanta, GA Learning Objectives Discuss how new information on the immunopathology of MS affects understanding of the disease process Employ current information on the use of MRI to improve diagnosis, treatment, and monitoring of patients with MS Overview MS History and Epidemiology MS Presentation and Diagnostic Criteria Emerging Prognostic Tools

St. Lidwina of Schiedam (1380-1433) St Lidwinas disease began soon after a fall while skating, at the age of 16. From that time onwards, she developed walking difficulties, headaches and violent pains in her teeth. By the age of 19, both her legs were paralyzed and her vision was disturbed. Over the next 34 years, Lidwina's condition slowly deteriorated, although with apparent periods of remission, until eventually she died at the age of 53. Robert Carswell (1793-1857) "a peculiar diseased state of the chord and pons Varolii, accompanied with atrophy of the discoloured portions"

Jean Cruveilhier (1791 1874) "had been ill six years without cause she noticed that the left leg resisted her will to such a degree that she fell in the street" DR. JEAN MARTIN CHARCOT (1825-1893) Nikola Tesla (1856-1943) The operators body, in this experiment, is charged to a high potential by means of a coil responsive to the waves transmitted to it from a distant oscillator. Electrical

Review, March 29,1899 First MRI in MS Ian R Young "[MRI] scanning promises to be of value in patients presenting with symptoms and signs referable to the brain and ... spinal cord ." Reproduced with permission from Nuclear magnetic resonance imaging of the brain in Multiple Sclerosis, IR Young et al., The Lancet, Nov 14, 1981, p1063-5 Copyright The Lancet Ltd, 1981 Gadolinium (Gd) enhancement Robert Grossman Introduction of Gd

as a contrast agent. Robert Grossman, a radiologist working in Philadelphia, found that when using the enhancing agent gadolinium-DPTA, some MRI lesions enhance while others do not. Grossman recognized that the Gd enhancement identified breakdown of the blood-brain barrier, indicating areas of active inflammation. Epidemiology of MS The most common chronic disabling disease affecting the CNS in young adults

MS strikes individuals between the ages 20-50 ~400,000 cases in the US (1:1000) ~2 million cases worldwide Risk factors First degree relative with MS (25% with identical twin) Distance from the equator Caucasian Women (~ 2.5:1) HLA-DR*1501 (OR = 3.2) http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-getsms/index.aspx. Accessed October, 2013. Pathogenesis of MS Infectious Agent Genetic Predisposition Abnormal Immunologic Response

O'Gorman C, et al. Int J Mol Sci. 2012;13(9):11718-11752. Environmental Factors MS Immune Pathways Linker RA, et al. Trends Pharmacol Sci. 2008;29(11):558-565. Claussen MC, Korn T. Clin Immunol. 2012;142(1):49-56. Davila L, et al. Nat Rev Rheumatol. 2011;7(9):537-550. MS: Prevalence Average World UV Index http://www.temis.nl/uvradiation/UVindex.html. Accessed October 2013. Vitamin D Status is Associated With New Brain MRI Activity

Mowry EM, et al. Ann Neurol. 2012;72(2):234-240. Natural History of MS Measures of brain volume Relapses and impairment MRI burden of disease MRI activity Preclinical (RIS) CIS Secondary-Progressive RRMS Time Comi. Opin Neurol. 2000;13:235; Munschauer. Clin Ther. 1997;19:868; Weinshenker. Brain. 1989;112:1422. Multiple Sclerosis: Diagnosis and Monitoring

RIS: Definition and natural history CIS: Early Findings and predictive value CDMS and RRMS: Diagnostic Criteria Effect of DMTs on MRI RIS Criteria Okuda D T et al. Neurology 2009;72:800-805 RIS: Typical Findings Figure 1 Cross-sectional and longitudinal MR images from select RIS cases (A) Axial 3.0 T proton density image demonstrating a juxtacortical and multiple, ovoid, periventricular foci of T2 prolongation (arrows). Okuda D T et al. Neurology 2009;72:800-805 2013 American Academy of Neurology

RIS: Natural History Figure 2 Kaplan-Meier curves for clinical and radiologic endpoints KaplanMeier curves for patients with endpoints including (A) tie to first clinical event and (B) time to first new T2-weighted focus on subsequent brain MRI studies. Okuda D T et al. Neurology 2009;72:800-805 2013 American Academy of Neurology RIS: Predictive Value of Spinal Cord Imaging Asymptomatic cervical spinal cord lesion in a subject with radiologically isolated syndrome (A) Sagittal T2-weighted MRI of the cervical spine demonstrating a focus of high signal abnormality at C2. Okuda D et al. Neurology 2011;76:686-692

2013 American Academy of Neurology 3 Cases 26 y/o Woman w/ numbness, tingling and HA: Neurologic Exam, LP, EPs, S.C. imaging all WNL Clinically Isolated Syndrome: Optic Neuritis 26 year-old woman with acute onset of monocular visual loss O.S. with pain on eye movement. Examination: Mild papilledema; Acuity of 20/200 w/ red desat. central scotoma and RAPD. Remainder of exam is normal.

Clinically Isolated Syndrome 2: Initial Findings on FLAIR MRI FLAIR = fluid-attenuated inversion recovery Clinically Isolated Syndrome 2: Transverse Myelitis 23-year-old woman with gradual onset of tingling and numbness in her feet that ascends to the umbilicus over the next 4 days. Exam shows a T8 sensory level to LT and temp. and reduced vibratory sensation with hyperreflexia in the LEs. The remainder of the neurological examination is normal.

T2 T1 + Gd Clinically Isolated Syndrome 2: Initial Findings on Proton Density MRI Proton Density T1 w/Gd Medical History Patient is active and appears to be in good health. No personal history of previous neurological disease. There is no family history of neurological or autoimmune disease. Patient does not report any other symptoms. Basic Differential

Diagnosis TM Metabolic B12 Copper deficiency Infectious Lyme, syphilis, HIV, HTLV-1 Vascular arteriovenous malformation (AVM) Malignancy intramedullary or extrinsic tumor Inflammatory/autoimmune SLE, Sjgren's, sarcoidosis, APLS, NMO Structural cervical spondylosis Clinically Isolated Syndrome: Discussion Points Which patient has multiple sclerosis (MS)? Would you recommend treatment for this patient? If yes, what type of treatment should be offered? If no, how should this patient be followed? Clinically Isolated

Syndrome (CIS) Patients who present with clinically isolated syndrome (CIS) should be managed based on their risk of progression to MS: In the Optic Neuritis Trial, risk at 10 years was: 56% for patients with 1 lesion 22% for patients with no lesions In patients with CIS and no lesions, risk of MS at 14 years was: 19% for clinically definite (CD) MS Brex et al. N Engl J Med. 2002;346:158-164. Optic Neuritis Study Group. Arch Ophthalmol. 2003;121:944-949. Median EDSS Score at Year 14 Number and Volume of T2 Lesions at Presentation Predict Disability 7 6

6 5 4 4 3 2 1.75 2 0 (0 cm3) 1 to 3 (0.6 cm3) 1 0

4 to 10 (0.9 cm3) >10 (5.6 cm3) Number (Median Volume) of T2 Weighted Lesions at Presentation Brex. N Engl J Med. 2002;346:158. Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:808-817. Multiple Sclerosis: Evolution of Diagnostic Criteria Poser Criteria Define MS as Clinically Definite or Probable

8 Clinically definite MS A1: 2 attacks + 2 lesions A2: 2 attacks + 1 lesion + 1 paraclinical lesion Laboratory-supported definite MS B1: 2 attacks + 1 lesion or 1 paraclinical lesion + abnormal CSF B2: 1 attack + 2 lesions + abnormal CSF B3: 1 attack + 1 lesion + 1 paraclinical lesion + abnormal CSF Poser criteria also includes 2 additional categories Clinically probable MS Laboratory-supported probable MS

Poser CM et al. Ann Neurol. 1983;13(3):227-231. Diagnosis of Multiple Sclerosis: McDonald Criteria Objective evidence of dissemination in space (DIS) and dissemination in time (DIT) is essential. Alternative diagnostic considerations must be excluded (no better explanation). Clinical evidence must be based on objective clinical signs (not solely on pts provided history). MRI, CSF, and visual evoked potentials may be helpful for diagnosis when clinical presentation is not diagnostic (SSEPs and BAERs discarded). Following evaluation, diagnosis will be: MS, not MS, or possible MS (no laboratory-supported, clinically probable MS, etc.).

McDonald WI, et al. Ann Neurol. 2001;50:121-127. McDonald Criteria 2001 CLINICAL (ATTACKS) OBJECTIVE LESIONS 2 or more 2 or more 2 or more 1 1 2 or more

1 mono- symptomatic 0 (progression from onset) ADDITIONAL REQUIREMENTS TO MAKE DIAGNOSIS None; clinical evidence will suffice (additional evidence desirable but must be consistent with MS) Dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with MS or further clinical attack involving different site Dissemination in time by MRI or second clinical attack 1 Dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with MS

AND Dissemination in time by MRI or second clinical attack 1 Positive CSF AND Dissemination in space by MRI evidence of 9 or more T2 brain lesions or 2 or more cord lesions or 4 48 brain and 1 cord lesion or positive VEP with 4 48 MRI lesions or positive VEP with less than 4 brain lesions plus 1 cord lesion AND Dissemination in time by MRI or continued progression for 1 year McDonald Criteria: Dissemination in Space MRI evidence of dissemination in space Three of the following: One Gd-enhancing lesion or 9 T2-hyperintense lesions

At least 1 infratentorial lesion At least 1 juxtacortical lesion At least 3 periventricular lesions Note: 1 spinal cord lesion can be substituted for 1 brain lesion. McDonald WI, et al. Ann Neurol. 2001;50:121-127. 2005 Criteria for Demonstration of Dissemination in Space (DIS) ORIGINAL MCDONALD Three out of four of the following: 1. One Gd-enhancing lesion or nine T2 hyperintense lesions if there is no Gdenhancing lesion 2. At least one infratentorial lesion 3. At least one juxtacortical lesion 4. At least three periventricular lesions NOTE: One spinal cord lesion can substitute for one brain lesion THE 2005 REVISIONS Three out of four of the following:

1. One Gd-enhancing lesion or nine T2 hyperintense lesions if there is no Gd-enhancing lesion 2. At least one infratentorial lesion 3. At least one juxtacortical lesion 4. At least three periventricular lesions NOTE: A spinal cord lesion can be considered equivalent to a brain infratentorial lesion: an enhancing spinal cord lesion is considered to be equivalent to an enhancing brain lesion, and individual spinal cord lesions can contribute along with individual brain lesions to reach the required number of T2 lesions.

Table 1 - MRI Criteria for Dissemination of Lesions in Time (DIT) ORIGINAL 2001 MCDONALD CRITERION 1. If a first scan occurs 3 months or more after the onset of the clinical event, the presence of a Gd-enhancing lesion is sufficient to demonstrate dissemination in time, provided that it is not at the site implicated in the original clinical event. If there is no enhancing lesion at this time, a follow-up scan is required. The timing of this follow-up scan is not crucial but 3 months is recommended. A new T2- or Gdenhancing lesion at this time then fulfills the criterion for dissemination in time. 1. If the first scan is performed less than 3 months after the onset of the

clinical event, a second scan done 3 months or more after the clinical event showing a new Gd-enhancing lesion provides sufficient evidence for dissemination in time. However, if no enhancing lesion is seen at this second scan, a further scan not less than 3 months after the first scan that shows a new T2 lesion or an enhancing lesion will suffice. MRI Criteria for Dissemination of Lesions in Time (DIT) THE 2005 REVISIONS 1. Detecting Gd enhancement at least 3 months after the onset of the initial

clinical event, if not at the site corresponding to the initial event. 2. Detecting a NEW T2 lesion if it appears at any time compared to a reference scan done at least 30 days after the onset of the initial clinical event. McDonald 20011,2 3 of: Dissemin ation in Space (on Either

Baselines or FollowUp Magnetic Resonan ce Imaging [MRI]) McDonald 20051,3 3 of: McDonald 2010 1 lesion in each of 2 characteristic locations 9 T2 lesions or 1 gadolinium-enhancing lesion 9 T2 lesions or 1 gadoliniumenhancing lesion

Periventricular 3 periventricular lesions 3 periventricular lesions Juxtacortical 1 juxtacortical lesion 1 juxtacortical lesion Posterior fossa 1 posterior fossa lesion 1 posterior fossa lesion Spinal cord

1 cord lesion can replace 1 brain lesion Any number of lesions can be included in lesion count All lesions in symptomatic regions excluded in brain stem and spinal cord syndromes 1) 1 gadolinium-enhancing lesion 3 months after CIS onset (if not related to CIS) 2)

A new T2 lesion with reference to a prior scan obtained 3 months after CIS 1) 1 gadoliniumenhancing lesion 3 months after CIS onset (if not related to CIS) 2) A new T2 lesion with reference to a prior scan obtained 30 days after CIS Dissemination in

Time 1) Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time 2) A new T2 and/or gadolinium-enhancing lesion on follow-up MRI irrespective of timing of baseline scan A 32-year-old woman with left heminumbness and left leg weakness. No prior Patient Meets

Criteria for MS Using thesensation MAGNIMS medical history. Examination demonstrates diminished in the 2010 left upper and lower extremities; mild weakness Criteriaof the left leg with extensor plantar response and asymmetrically hyperreflexic. Brain MRI shows: Posterior fossa lesion Juxtacortical lesion Asymptomatic gadoliniumenhancing lesion

Periventricular lesion Asymptomatic T2 lesion Images courtesy of Omar Khan, MD. Predicting Conversion From CIS to CDMS Specificity (95% CI) Sensitivity (95% CI) Positive Predictive Value (95% CI) McDonald (2001) 91.1% (85-95)

47.1% (36-58) 78.4% (65-89) McDonald (2005) 87.8% (81-93) 60.0% (49-70) 77.3% (65-87) MAGNIMS 2010 87.0% (80-92) 71.8% (61-81) 79.2% (68-88) Criteria

CDMS: clinically defined MS Montalban X, et al. Neurology. 2010;74:427-434. Importance of New MAGNIMS/ McDonald MRI Criteria User-friendly Clinically oriented Lead to earlier diagnosis Sensitivity and specificity are comparable to existing diagnostic criteria May reduce repeat MRI scans Caution: consider other possibilities in the differential diagnosis. Careful interpretation of the MRI scans will be critical

Why Treat Early? Relapses and impairment parallel the MRI burden of disease.1-3 Axonal damage occurs early and may cause permanent neurological dysfunction.4 Number of MRI lesions are predictive of future disability.5 Preventing development of lesions may prevent progression of disability in patients.6 Preventing early relapses may prevent long-term disability in patients.3 1. Comi. Curr Opin Neurol. 2000;13:235; 2. Munschauer. Clin Ther. 1997;19:868; 3. Weinshenker. Brain. 1989;112:1422; 4. Trapp. N Engl J Med. 1998;338:278; 5. Brex. N Engl J Med. 2002;346:158; 6. ORiordan. Brain. 1998;121:495. Early Relapses Affect LongTerm Disability 100 Low (01 attacks in 2 years) Intermediate (24 attacks in 2 years) High (>5 in 2 years)

Patients (%) 80 60 40 20 0 0 10 20 30 40 50 Time From Onset of MS (years) Actuarial analysis of disability: percentage of patients not having reached EDSS 6:

difference between the groups significant (P<0.0001). Weinshenker. Brain.. 1989;112:1422. Axons Are Transected in MS Plaques and in NAWM SMI-32 (non-phosphorylated neurofilament) Trapp. N Engl J Med. 1998;338:278. Number of Transected Axons Increases with Level of Activity in MS Lesions 12,000 11,236 10,000 8,000 6,000 3,138

4,000 875 2,000 0 Active Chronic active edge (NAWM: normal-appearing white matter) Trapp BD, et al. N Engl J Med. 1998;338:278-285. Chronic active core 17 0.7

NAWM Control white Prognosis Summary High volume and high number of T2 brain lesions at presentation predicts a worse future course Early relapse rate and disability accumulation is correlated with a worse future disease course Serum and CSF biomarkers may refine disease course prediction, but to date none have been validated other than presence of OCBs in CSF. MRI is our Biomarker in MS. MRI Lesions at 12 Month F/U Scan Indicate Treatment Failure MRI Lesions at 12 Months 394 patients

Mean follow-up 4.8 years 30.4% poor responders Responders Poor responders (sustained progression 1 point on EDSS) Prosperini L, et al. Eur J Neurol. 2009;16:1202-1209. Multiple Sclerosis: Effects of DMTs on MRI MRI Defined Burden of Disease Traditionally defined as total volume of hyperintense lesion on T2-weighted images. Also defined as sum of T2 hyperintense and T1 hypointense lesion volume. Number of new gad-enhancing lesions Number of new T2 or enlarging and/or gadenhancing lesions (Combined unique lesions) Brain volume (atrophy)

Personal communication from Dr. Bakshi. IFN Beta-1b SC (Betaseron): T2 Burden of Disease Median % Change from Baseline p=0.0363 p=0.0002 p=0.0055 p=0.0015 p=0.0012 n=75 n=72 n=62 n=77 n=72 n=61 n=73 aTreatment administered every other day

IFNB=interferon beta; MIU=million international units; SC=subcutaneous IFNB MS Study Group et al. Neurology 1995;45:1277-85. n=70 n=59 n=73 n=72 n=61 n=14 n=16 n=19 91.4% reduction p<0.0001 IFNB-1b 8 MIU sq QOD Pretreatment (n=27) 160 Total Contrast-enhancing Lesions Mean New Contrast-enhancing Lesion Frequency

Interferon Beta-1b (Betaseron): Gd-enhancing Lesions 140 120 100 80 60 40 20 0 1 2 3 4 5

6 7 Month Stone LA et al. Neurology 1997;49:862-69. 8 9 10 11 12 European/Canadian MRI Trial Median % Change in T2

Lesion Volume (Baseline to 9 Months) Glatiramer Acetate (CopaxoneTM): T2 Burden of Disease Comi G et al. Ann Neurol 2001;49:290-97. 40.3% reduction p=0.001 n=120 n=119 European/Canadian Trial Glatiramer Acetate (Copaxone): Gd-enhancing Lesions Over 9 months Cumulative Median Enhancing Lesion Volume (mL)

Cumulative monthly change from baseline in Gd-enhancing lesion volume showed a significant treatment effect in favor of glatiramer acetate compared with placebo 3.0 Placebo (n=120) Glatiramer acetate (n=119) 2.5 2.0 p<0.05 1.5 p<0.05 1.0 0.5 0

0 1 2 3 4 5 Month Comi G et al. Ann Neurol 2001;49:290-97. 6 7 8

9 AFFIRM Trial Natalizumab (Tysabri): T2 Lesion Counts over 2 Years Median No. of New or Enlarging T2 Lesions Placebo (n=315) Miller DH et al. Neurology 2007;68:1390-401. Natalizumab (n=627) 83% reduction p<0.001 AFFIRM Trial

Natalizumab (Tysabri): T2 Lesion Load over 2 Years Placebo (n=315) Mean Change in T2 Hyperintense Lesion Volume (mm3) Natalizumab (n=627) Miller DH et al. Neurology 2007;68:1390-401. p<0.001 AFFIRM Trial Mean No. of Gd-enhancing Lesions Natalizumab (Tysabri): Gd-enhancing Lesions

Miller DH et al. Neurology 2007;68:1390-401. 92.3% reduction (p<0.001) 91.6% reduction (p<0.001) Natalizumab: Mechanism of Action Prescribing information for natalizumab (Tysabri). Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Tysabri clinical efficacy 67% relative reduction in relapses at 2 yrs (P <0.001) Natalizumab: Risk Management Infusion-related reactions

Neutralizing antibodies Hepatotoxicity Opportunistic infections Progressive Multifocal Leukoencephalopathy (PML) Polman CH, et al. N Eng J Med. 2006;354(9):899-910. Factors that Increase PML Risk JCV exposure indicated by anti-JCV antibody positive status Receiving an immunosuppressant prior to receiving natalizumab Natalizumab treatment duration (especially >2 years) JCV = John Cunningham virus Prescribing information for natalizumab (Tysabri ). Available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Soelberg Sorensen P, et al. Mult Scler. 2012;18(2):143-152. Fox RJ. Rudick RA. Neurology. 2012;78(6):436-437.

Bloomgren G, et al. New Eng J Med. 2012;366:1870-1880. Natalizumab-Associated PML: Updated Incidence by Treatment Epoch As of 12/31/12, ~112,200 patients have received natalizumab in the post-marketing setting worldwide As of 5/13/13, there have been 347 confirmed cases of PML worldwide Biogen Idec. Data on file. List of PML diseases under Tysabri. Available at: http://chefarztfrau.de/?page_id=716. Current Stratification of Natalizumab-Associated PML Risk Anti-JCV Antibody Status Positive

Negative Prior IS Use NTZ Exposure 0.07/1,000 95% CI 00.38 NO YES 124 months 0.6/1,000 patients (95% CI 0.40.9) 1.8/1,000 patients (95% CI 1.12.8)

> 24 months 5.2/1,000 patients 95% CI 4.36.2) 10.6/1,000 patients (95% CI 8.113.8) JCV = John Cunningham virus; IS = immunosuppressant. Dong-Si T, et al. Presented at AAN; March 1623, 2013; San Diego, CA. Abstract P04.271. Foley J. Presented at AAN; March 1623, 2013; San Diego, CA. Abstract S30.002. Newer Therapies for MS Oral Medications fingolimod (Gilenya) teriflunimide (Aubagio) dimethyl fumarate (Tecfidera) Monoclonal Antibodies alemtuzumab (Lemtrada) Fingolimod: Mechanism of Action

Activation S1P Proliferation and differentiation Afferent lymphatic vessel Lymphatic sinus Activated T cells S1P1 receptor Nave T cell Sinus-lining endothelium Efferent lymphatic vessel

Lymph node S1P1 downregulation Fingolimod S1P = sphingosine-1 phosphate Horga A, Montalban X. Expert Rev Neurother. 2008;8:699-714. Sinus-lining endothelial cell barrier enhancement Reduced T cell egress FREEDOMS Trial Mean No. of New or Enlarging T2 Lesions Fingolimod (Gilenya): T2 Lesions at 24 Months

Kappos L et al. N Engl J Med 2010;362:387-401. -74% p<0.001 -74% p<0.001 FREEDOMS Trial Mean No. of Gd-enhancing Lesions Fingolimod (Gilenya): Gd-enhancing Lesions over 24 Months Kappos L et al. N Engl J Med 2010;362:387-401. 82% reduction (p<0.001)

Teriflunomide (Aubagio) Phase 2 Study: Primary Efficacy Endpoint Teriflunomide (7 or 14 mg/day) was generally well tolerated and reduced MRI activity vs. placebo1 These findings led to the initiation of the phase 3 program Patients completing this study were eligible for entry into a long-term open-label extension; 8-year follow-up available2,3 Mean No. of Unique Active Lesions per Scan Significant reduction in number of combined unique active lesions RR: 61.3% RR: 61.1%

* Teriflunomide *p<0.03 placebo vs. 7 mg p<0.01 placebo vs. 14 mg RR=relative reduction 1. O'Connor PW et al. Neurology 2006;66(6):894-900; 2. Li D et al. ECTRIMS 2010; 3. Confavreux C et al. Mult Scler 2012;18(9):1278-89. TEMSO Trial Teriflunomide (Aubagio): Gd-enhancing Lesions Mean No. of T1 Gd-enhancing Lesions per Scan

Proportion of Patients Free from T1 Gd-enhancing Lesions (%) 1.4 1.2 1.0 RRR: 57.2%a (p<0.001) 1.33 (n=363) 0.8 0.6 0.57 (n=365) 0.4 0.2 0 p<0.001

0.26 (n=358) Placebo (n=363) 7 mg (n=365) 14 mg (n=358) Teriflunomide Proportion of Patients (%) Mean No. of Lesions Per Scan RRR: 80.4%a (p<0.001) 70 60

p<0.001 64.1 (n=358) 50 40 30 39 (n=363) 51.4 (n=365) 20 10 0 Placebo (n=363)

7 mg (n=365) 14 mg (n=358) Teriflunomide Derived from a Poisson regression model with robust error variance; the model included treatment, EDSS strata, region, and baseline number of unique active lesions as covariates and log-transformed number of scans as an offset variable. Data presented for the modified intent-to-treat population. OConnor P et al. N Engl J Med 2011;365:1293-303. a Dimethyl Fumarate (BG-12/Tecfidera): T2 Lesions at 2 Years 20 16 17

85% p<0.001 74% p<0.001 12 8 4 4.4 2.6 0 Placebo n=165 BG-12 240 mg BID

BG-12 240 mg TID n=152 n=152 Adjusted Mean No. of New/Newly Enlarging T2 Lesions Adjusted Mean No. of New/Newly Enlarging T2 Lesions DEFINE1 (Secondary efficacy endpoint) CONFIRM2 (Secondary efficacy endpoint) 20 15

17.4 71% p<0.001 73% p<0.001 54% p<0.001 10 8.0 5 0 1. Gold R et al. N Engl J Med 2012;367:1098-107; 2. Fox RJ et al. N Engl J Med 2012;367:1087-97. 5.1

4.7 BG-12 Glatiramer Placebo BG-12 240 mg BID 240 mg TID acetate n=139 n=140 n=140 n=153 Dimethyl Fumarate (BG-12/Tecfidera): Gd-enhancing Lesions at 2 Years DEFINE1 (Secondary efficacy endpoint) CONFIRM2

(Tertiary efficacy endpoint) 90% p<0.001 73% p<0.001 Mean No. of Gd+ Lesions Mean No. of Gd+ Lesions 2.0 2 74% p<0.001 65% p<0.001

61% p=0.002 1.5 1.0 0.7 0.5 0.5 0.4 0.0 Placebo BG-12 240 BG-12 240 Glatiramer mg BID mg TID acetate n=165

n=152 n=152 n=139 n=140 n=140 Compared with placebo, BG-12 BID and TID significantly reduced the mean number of new Gd+ lesions at 2 years in both DEFINE and CONFIRM trials 1. Gold R et al. N Engl J Med 20y12;367:1098-107; 2. Fox RJ et al. N Engl J Med 2012;367:1087-97. n=153 Median % Change in T2 Lesion Load Alemtuzumab (Lemtrada): Phase 2

CAMMS223: T2 Burden of Disease Over 36 Months Coles J et al. N Engl J Med 2008;359:1786-801. p=0.03 p=0.01 Alemtuzumab (Lemtrada): Gd-enhancing Lesions CARE-MS II2 CARE-MS I1 p=0.17 p=0.77 p=0.51

p=0.009 52% reduction p=0.02 SC IFNB-1a (n=187) Alemtuzumab 12 mg (n=376) 1. Arnold DL et al. AAN 2012, S11.006; 2. Arnold DL et al. ECTRIMS 2012, P877. SC IFNB-1a (n=202) Alemtuzumab 12 mg (n=426) Alemtuzumab CAMMS223 Study: Safety Principal AEs associated with alemtuzumab included: Infusion reactions Mild-to-moderate infections Autoimmunity Immune thrombocytopenia (ITP approx. 1%)

Thyroid disorders (28% vs 3% for IFN-1a) Glomerulonephropathy (Goodpasture syndrome). Coles A. Presented at ECTRIMS, Dsseldorf, Germany, September 9-12, 2009. Poster # 890. p=0.5 p=0.2 p=0.2 OCR=ocrelizumab Kappos L et al. Lancet 2011;378;1779-87. Total number of new or enlarging T2 lesions

at Week 24 Mean change in volume of T2 lesions from baseline to Week 24 Ocrelizumab: T2 Hyperintense Lesions at 24 Weeks p=0.3 p<0.0001 p<0.0001 Ocrelizumab: Gd-enhancing lesions over 24 weeks Mean (SD) Gd-enhancing Lesions 25

Median *p<0.0001 vs. placebo 20 15 10 5 0 89% reduction vs. placebo 96% reduction vs. placebo 5.5 * 0.6

* 0.2 1.6 0.0 0.0 1.0 Placebo (n=54) OCR 600 mg (n=55) OCR 2000 mg (n=55)

IFNB-1a IM (n=54) At Weeks 12, 16, 20 and 24 (ITT): average imputation Van Elteren test is stratified by geographical region and baseline presence of Gd-enhancing lesions (absent or present) IFNB-1a arm was open-label; all efficacy comparisons were exploratory OCR=ocrelizumab Kappos L et al. Lancet 2011;378:1779-87. 6.9 Risk-Benefit Assessment Risk-Benefit assessments should include: The benefits of therapies The risks of those therapies The risks of not treating or under-treating the disease itself Quality of life

Long-term outcomes Patients history of disease and disease activity Costs Risk-Benefit information should be communicated to patients! One More Experimental Symptomatic Therapy Conclusions MRI is a powerful and sensitive tool for diagnosing MS but lacks pathological specificity. MRI is a valuable surrogate marker of biological disease activity and severity. The continuing worsening of MRI findings, even if clinically silent, significantly impacts on long term clinical outcomes. Conventional MRI measures (T2 lesions and Gad. Enhancement)

represent only the tip of the iceberg, in terms of disease activity. Newer techniques hold greater promise for following both inflammation and neurodegeneration throughout all stages of the disease process. Thank you for your attention Any Questions?

Recently Viewed Presentations

  • Structural Components of Teeth Enamel, Dentin, Cementum Dermal

    Structural Components of Teeth Enamel, Dentin, Cementum Dermal

    Structural Components of Teeth Enamel, Dentin, Cementum Dermal denticles of sharks * * * * * * * * * * * * * * * * * * Characteristics Protects root dentin Provides for attachment to alveolus via Sharpey's...
  • FACILITATE OUTGOING PHONE CALLS - Amazon S3

    FACILITATE OUTGOING PHONE CALLS - Amazon S3

    4.6 Cost guest call for posting to account. How are calls charged? Posting charges to a guest account. Automatic posting via PMS. Slide . Discuss how guests are charged for their calls - include surcharges. How to cost guests to...
  • LEUCOCYTES - prime.edu.pk

    LEUCOCYTES - prime.edu.pk

    kidney * Phagocytosis Recognition Attachment and binding Pseudopodia around Ingestion (Neutrophils 5-20 bacteria Macrophage upto100 bacteria) Phagocytic vesicle or phagosome Lysosomal digestion Leukocytes consume and destroy foreign invaders and dead cells Ejected as Pus Opsonins Most microorganisms will NOT be...
  • Chapter 1

    Chapter 1

    A rule that rewrites the symbol and moves right, and. A rule that leaves the tape unchanged and moves left. ... any of which may accept the input string when the thread halts. For every nondeterministic Turing machine, there is...
  • www.cs.columbia.edu

    www.cs.columbia.edu

    Jared Samet Nigel Schuster Ishaan Kolluri Kevin Ye. Introduction & Motivation. Inspired by limitations of spreadsheets as a language. Reusability vs. copy-pasting a block of cells. Declarative programming language. Cells can contain composite as well as primitive data types.
  • Glaucoma - PGBLASTER- A NEW DIMENSION FOR PG-ASPIRANTS

    Glaucoma - PGBLASTER- A NEW DIMENSION FOR PG-ASPIRANTS

    Glaucoma is a chronic, progressive optic neuropathy caused by a group of ocular conditions which ultimately lead to damage to the optic nerve and loss of visual function. Risk factor of Glaucoma The most common risk factor for development of...
  • Bovine trichomoniasis in beef cattle in Wyoming, USA

    Bovine trichomoniasis in beef cattle in Wyoming, USA

    Among the 863 valid respondants, 312 actually tested their bulls. 304 producers reported that their bulls were tested as negative, and 8 producers reported their bulls were tested as positive during the past three years, which is 2.56% of the...
  • Coppin State University

    Coppin State University

    Brick, stone, and metal panel façade. Spread footing foundation. Composite metal deck floor system. 2" 20 gauge deck with 3.25" LWC topping (typical) Wide flange framing members. Concentrically braced frames for lateral support. HSS members for diagonal bracing. Introduction. General...