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Off-label Discussion Disclosure
This educational activity may contain discussion of published
and/or investigational uses of agents that are not indicated
by the Food and Drug Administration. PCME does not
recommend the use of any agent outside of the labeled
indications. Please refer to the official prescribing information
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Educational Objectives
At the conclusion of this activity, participants should be
able to demonstrate the ability to:
• Select the most appropriate DMD therapies that can be
used to initiate treatment earlier in the disease course
• Develop individualized treatment plans to optimize
adherence and improve outcomes in patients with MS
• Describe how emerging biomarkers and newer MRI
measures to improve the accuracy of diagnosis and
monitoring of MS disease activity
Multiple Sclerosis: An Immuno-genetic Disease
Genetic Predisposition
Environmental Factors
-Twins studies
Demographics/Epidemics
-HLA-DR2 (DRß1*1501)
(antigen presentation)
Microbial Agents
EBV
-IL-2Ra
(regulatory T-cells)
Vitamin D
Smoking
-IL-7Ra
(memory T-cells)
GWAS (>100 alleles)
Dhib-Jalbut S. 2013.
Salt
Immune Dysregulation
MS
Immunopathogenesis of MS
Inflammatory Processes Occurring Early in MS Lead
to Demyelination and Axonal Loss
Inflammation
Regeneration
Onset of
Disease
Time
Inflammation
Compston A et al. Lancet. 2008;372:1502-1517.
Paolillo A et al. J Neurol. 2004;251:432-439.
Demyelination
Axonal loss
Kuhlmann T et al. Brain. 2002;125:2202-2212.
Trapp BD et al. Curr Opin Neurol. 1999;12:295-302.
Dublin Revision 2011
• For DIS: At least one T2 lesion in two of the following
locations:
– Periventricular
– Juxtacortical
– Infratentorial
– Spinal cord
• For DIT: Any new lesion on any follow-up scan after a
baseline scan done anytime after onset of CIS
DIS=Dissemination in space; DIT=Dissemination in time; CIS= Clinically isolated syndrome
Polman et al. Ann Neurol. 2011;69:292-302. McHugh et al. Mult Scler. 2008;14:81-85.
Single Early MRI
• In CIS, a single MRI, even in first 3 months, with Gad
enhancing lesion(s) and T2H has high specificity for
development of CDMS
CDMS = clinically definite MS
Polman et al. Ann Neurol. 2011;69:292-302.
Radiologically Isolated Syndrome
5-year Risk for an Initial Clinical Event from a
Multinational Cohort (RISC)
• Retrospective analysis of 20 databases from 5 countries
• >430 patients (largest cohort examined to date)
• 5-year observed conversion rate to first clinical event: 34%
• In multivariate model, several factors significantly associated
with conversion:
– Age (younger > older)
– Gender (M > F)
– Presence of spinal cord lesions
RISC = Radiologically Isolated Syndrome Consortium
Okuda D et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract PL01.002.
RIS: Management Implications
• Potential for misdiagnosis
• High probability of benign MS
• “Wait and watch” approach may be best
• Future challenges:
– How to identify high-risk RIS group
– Standardized MRI
– Combining MRI with other predictors
– Population-based prospective study
RIS = Radiologically Isolated Syndrome
Okuda D et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract PL01.002.
“I look to the future because that’s where
I’m going to spend the rest of my life.”
—
George Burns
Predicting the Course of MS
• Clinical features of onset bout
– Motor worse than sensory
– Polyregional worse than monosymptomatic
– Early bladder involvement poor prognosis
• Incomplete recovery from initial attack
• Short interval between attacks
MRI and MS Prognosis
• Initial MRI
EDSS > 3
70
– T2 lesion numbers
– 3 or 4 Barkhof criteria
moderate correlation
with EDSS at 5 years
60
% patients
– Median EDSS at 20
years = 6 for ≥10 T2
lesions
EDSS ≥ 6
50
40
30
20
10
0
0
1-3
4-9
# of brain lesions
Fisniku LK. Brain. 2008;131:808-817.
≥10
“The future ain’t what it used to be.”
Lawrence Peter “Yogi” Berra
Assessing Risk
• Patients need to be informed and involved in decisionmaking process
• Need to steer patients to a limited number of options based
upon disease severity
• Patient risk tolerance to adverse events
• Patient disease tolerance to neurologic dysfunction
Defining Breakthrough Disease
• 1 moderate/severe clinical relapse over 1 year
• 2 mild clinical relapses over 2 years
• 1-2 Gd enhancing brain lesions over 1 year
• 2 T2 lesions over 2 years
• A functionally significant worsening in cognition, ambulation,
upper extremity function
• Need to account for time for medication to work optimally
• Follow-up MRI 6-12 months after treatment initiation
Existing and Emerging MS Therapies
Ofatumumab
Ocrelizumab
Daclizumab
Ampyra®
(4-amino pyradine)
Mastinib
Betaseron®
Nuedexta®
Tysabri®
(IFNβ-1b)
(dextromethorphan/
quinidine)
(natalizumab)
Avonex®
Laquinimod
Plegridy®
Extavia®
(IFNβ-1a)
(IFNβ-1b)
(IFNβ-1a)
Cladribine*
Lemtrada®
Copaxone®
(alemtuzumab)
(glatiramer acetate)
Gilenya®
Aubagio®
(fingolimod)
Novantrone®
(teriflunomide)
(mitoxantrone)
Tecfidera®
(dimethyl fumarate)
Rebif ®
(IFNβ-1a)
1995
2000
2005
Approved therapies
2009
Approval date
2010
2011
Phase III completed
*In March 2011, the FDA did not approve cladribine and requested Merck KGaA provide an
improved understanding of its safety risks and overall benefit-risk profile
2012
2013
2014
Estimated launch date
In Phase III
ADVANCE
Phase III Trial of PEGylated IFNb-1a in RRMS
• PegIFN has longer t1/2 and results in prolonged exposure (AUC, Cmax) than standard
formulations
• Pts (n=1512) randomized to placebo, pegIFNb-1a 125 mcg q2wk, or q4wk
PEGIFNB-1A
Q2WK
PEGIFNB-1A
Q4WK
35.6%*
27.5%*
Accrual of disability
38%*
38%*
T2 lesions
67%*
28%*
Gd-enhancing T1 lesions
86%*
36%*
ENDPOINT (reduction compared with placebo at 1 year)
ARR
• Neutralizing Abs seen in <1% of patients in both IFN groups
• Adverse events similar to known IFN profile (ISRs, pyrexia, flu-like symptoms,
hepatic enzyme elevations)
• ATTAIN: long-term extension study from ADVANCE ongoing
* Statistically significant finding
PEG=polyethylene glycol; AUC=area under the curve; ARR=annualized relapse rate; IFN=interferon; Abs=antibodies; ISRs=injection site reactions
Calabresi P et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S31.006.
Glatiramer Acetate Low-frequency
Administration (GALA): Phase III Study
Primary Endpoint: ARR
34.4% reduction, P < 0.0001
ARR ± SEM
0.5
0.4
0.3
0.505
0.2
0.331
0.1
7
Enlarging T2 Lesions (n)
0.6
Secondary Endpoint: Cum. No. of
New/Enlarging T2 Lesions
34.7% reduction, P < 0.0001
6
5
4
3
5.592
2
3.65
1
0
0
Placebo
(n = 461)
GA 40 mg tiw
(n = 943)
Placebo
(n = 441)
ARR = annualized relapse rate; SEM = standard error of mean
Khan O et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S01.005.
GA 40 mg tiw
(n = 884)
Lymphocyte Trafficking Inhibition
Implications for Multiple Sclerosis Therapy
Leukocyte
Chemoattractant signal
a4b1 (VLA-4)
Blood Vessel Lumen
Leukocyte infiltration
and brain
inflammation
Endothelial Cells
Tissue
VCAM-1
Leukocyte
Chemoattractant Signal
a4b1 (VLA-4)
Blood Vessel Lumen
Endothelial Cells
Tissue
VCAM-1
O’Connor P. Expert Opin Biol Ther. 2007;7:123-136.
Reduced leukocyte
infiltration and brain
inflammation
Natalizumab v Placebo
Affirm Study
0.81
Annualized Relapse Rate (95% CI)
1.0
P<0.0001
0.9
0.8
0.7
0.6
68%
0.5
0.4
0.26
0.3
0.2
0.1
0.0
Placebo
n=315
Polman C et al. N Engl J Med. 2006;354:899-910.
Natalizumab
n=627
Natalizumab
Use in the Post-marketing Setting and PML Risk
Overall
Exposure
≥ 18 Months
≥ 24 Months
≥ 30 Months
≥ 36 Months
≥ 42 Months
≥ 48 Months
72,400
60,300
3
50,300
2.95
41,400
2.5
33,500
2.33
2
26,100
19,600
1.5
Patients
Incidence per 1,000 patients
≥ 12 Months
104,300
224,718 patient-years of
natalizumab exposure
2.79
2.63
2.63
2.23
2.32
1.94
1.90
1.76
1.54
1.38
1
0.82
0.5
0.11
0.02
0
Post Marketing
0.61
0.45
0.05
1–12
13–24
25–36
37–48
49–60
Number of infusions
*As of October 22, 2012: 298 cases of natalizumab-associated PML have been reported; of these, 62 patients have died (22%)
Vermersch P et al. Presented at ECTRIMS 2012; October 9-13, 2012; Lyon, France. [Abstract 173].
Estimated Incidence of Natalizumabassociated PML Stratified by Risk Factors
Anti-JCV Antibody Status
Negative
Positive
0.1/1000
95% CI: 0.1-0.35
Prior IS Use?
Sorenson P et al. Mult Scler. 2012;18:143-152.
No
Yes
Natalizumab
exposure
No Prior IS Use
Prior IS Use
1–24 months
0.7/1,000 patients
1.8/1,000 patients
25–48 months
5.3/1,000 patients
11.2/1,000 patients
49–72 months
6.1/1,000 patients
Insufficient data
Anti-JCV Antibody Index Distribution in Anti-JCV Ab+
non-PML and pre-PML Patients with No Prior IS Use
Plavina T et al. Use of anti-JC virus antibody index to further define risk of PML in anti-JCV antibody-positive
TYSABRI-treated patients with MS. Platform presentation presented at 23rd Annual Meeting of European
Neurological Society, June 9, 2013; Barcelona, Spain.
PML Risk Estimates by Index Threshold in
Anti-JCV Ab+ Patients with No Prior IS Use
Plavina T et al. Anti-JCV antibody index further defines PML risk in TYSABRI-treated MS patients.
Poster presented at CMSC 27th Annual Meeting, May 29-June 1 2013; Orlando, FL.
Fingolimod (FTY720): Mode of Action
S1P receptor
T cell
Prevents T cell
invasion of CNS
FTY720-P
FTY720 results in internalization
of the S1P1 receptor
This blocks lymphocyte egress
from lymph nodes while sparing
immune surveillance by circulating
memory T cells
Cohen JA, Chun J. Ann Neurol .2011;69:759-777.
LN
FTY720 traps
circulating
lymphocytes in
peripheral lymph
nodes
Fingolimod Efficacy
FREEDOMS
TRANSFORMS
0.6
P< 0.001
Adjusted
Annualized
Adjusted Annualized
Relapse
RelapseRate
Rate
0.5
P<0 .001
P= 0.16
0.4
0.33
0.3
0.20
0.2
0.16
0.1
0.0
Interferon
(N=4 31)
Kappos L et al. N Engl J Med. 2010;362:387-401.
Cohen JA, et al. N Engl J Med. 2010;362:402-415.
Fingolimod,
0.5 mg
(N=4 29)
Fingolimod,
1.25 mg
(N=4 20)
Managing Fingolimod Patients
• Prior to Treatment Initiation
– Baseline CBC and hepatic panel
– Ophthalmological examination
– Cardiac status
– Varicella immune status
• Rx Initiation: 6-hour observation b/o bradycardia
• On Treatment
– CBC, hepatic panel
– Ophthalmological exam at 3-4 months
– Check BP
Recent Additions to Fingolimod
Prescribing Information
First Dosing Monitoring
Observe signs and symptoms of bradycardia for at least 6 hrs after first dose
with hourly pulse and blood pressure measurement
Obtain ECG prior to dosing and at the end of the observation period
Monitor AV block until resolution if heart rate <45 bpm, or a new onset 2nd-degree or higher
Pts at lowest post-dose heart rate at the end of observation period should be monitored until heart rate
increases
If symptomatic bradycardia, begin continuous ECG monitoring until symptoms have resolved
• If pharmacological intervention required for bradycardia, continue ECG monitoring overnight in a
medical facility, and repeat 1st-dose monitoring procedures for 2nd dose
Patients who may be less tolerant of fingolimod-induced bradycardia are at higher risk of serious rhythm
disturbance, or with prolonged QTc interval at baseline, or at any time during the observation period,
should be observed overnight with continuous ECG monitoring
Patients who have stopped taking fingolimod for more than 14 days and re-initialize treatment are
advised to again follow these updated recommendations
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo.
http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1309.
Teriflunomide
A Selective Dihydro-orotate Dehydrogenase Inhibitor
• A newly approved oral diseasemodifier for relapsing forms of MS
(RMS)
• Blocks de novo pyrimidine synthesis,
reducing T- and B-cell proliferation
and function in response to
autoantigens
• Preserves replication
and function of cells
(e.g. haemopoietic cells,
memory T-cells) living on the
existing pyrimidine pool (salvage
pathway)
Resting lymphocyte
Blasting lymphocyte
De novo pathway
Nonlymphoid
cells
DHO-DH
Teriflunomide
Pyrimidine pools
Salvage
pathway
CTP-, UTP-sugars
Nucleotides
CDP lipids
Glycoproteins, Glycolipids
RNA, DNA
Phospholipids
Cell-cell contact
Adhesion and
diapedesis
Proliferation
Ig
secretion
Cell membranes
Second
messengers
DHO-DH, dihydro-orotate dehydrogenase;
Miller A et al. Clinical and MRI outcomes from a Phase III trial (TEMSO) of oral teriflunomide in multiple sclerosis with relapses.
Presented at AAN Annual Meeting, April 9-16, 2011, Honolulu, HI.
Teriflunomide for RRMS (Phase III TEMSO Study)
Key Clinical Outcomes
Annualized Relapse Rate
0.6
0.5
RRR: 31.2%
P=0.0002
RRR: 31.5%
P=0.0005
0.539
EDSS 12 Week Sustained Change
30.0
25.0
0.4
23.7%
P=0.0835
27.3
20.0
0.369
0.370
0.3
0.2
29.8%
P=0.0279
21.7
21.7
20.2
7 mg (n = 365)
14 mg (n = 358)
15.0
10.0
0.1
5.0
0.0
Placebo (n = 363)
7 mg (n = 365)
14 mg (n = 358)
Teriflunomide
RRR = relative risk reduction
O’Connor P et all. N Engl J Med. 2011;365:1293-1303.
0.0
Placebo (n = 363)
Teriflunomide
Teriflunomide
Phase III TOWER Study
Efficacy Outcome
ARR (primary endpoint)
Reduction vs placebo
Placebo
0.501
12-week confirmed disability progression
HR vs placebo
Mean EDSS change (baseline to week 48)
0.089
*Statistically significant vs placebo.
Miller A et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S01.004.
Teri
7 mg
Teri
14 mg
0.389*
22.3%
0.319*
36.3%
0.955
0.685*
0.042
-0.05*
TOWER: Treatment-Emergent AEs
Preferred term, %
Headache
Leading to discontinuation
Placebo
(n = 385)
10.9
0.3
Teriflunomide
7 mg (n = 409)
14.7
0
Teriflunomide
14 mg (n = 371)
12.4
0
Increased ALT
Leading to discontinuation
8.3
1.6
11.2
2.9
14.0
2.4
Alopecia (hair thinning)
Leading to discontinuation
4.4
0.3
10.3
0
13.5
1.6
Diarrhea
Leading to discontinuation
7.3
0.3
12.0
1.0
11.1
0.8
Nausea
Leading to discontinuation
8.8
0
8.3
0
10.2
0.8
Neutropenia
Leading to discontinuation
2.9
0
7.1
1.0
9.4
2.2
ALT = alanine aminotransferase
Miller A et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S01.004.
Teriflunomide Counseling and Start-up
• Pregnancy Category X
• At Baseline: CBC with diff, LFTs, TB testing
• Monthly x 6 months: AST/ALT
• Every 6 months: CBC with diff, LFTs
Proposed Mechanisms: Dimethyl Fumarate
• An oral formulation of dimethyl fumarate
• Inhibits the expression of adhesion molecules and
proinflammatory cytokines
• Induces a Th1 to Th2 shift
• Decreases circulating T cells
• Activates the Nrf2 pathway
• >30 years of use of fumaric acids in the treatment of
psoriasis (both topical and oral)
Kappos L et al. Lancet. 2008;372:1463-1472.
Gold R et al. N Engl J Med. 2012;367:1098-107.
Gasperini C et al. Expert Opin Emerg Drugs. 2008;13:465-477.
DMF: Integrated Efficacy Analysis
of DEFINE and CONFIRM
Endpoint (at 2 years)
Annualized relapse rate (ARR)
Reduction vs placebo
Proportion of patients relapsed
HR vs placebo
Time to 12-week confirmed disability progression
HR vs placebo
Time to 24-week confirmed disability progression
HR vs placebo
*Statistically significant vs placebo
Fox RJ et al. Presented at AAN; March 16-23, 2013; San Diego, CA. Abstract P07.097.
Placebo
(n = 771)
DMF BID
(n = 769)
0.37
0.19*
49%
0.57*
0.68*
0.71*
Alemtuzumab MOA
• Targets CD52 antigen expressed on B and T lymphocytes
• FDA approved for leukemia
• Phase II study comparing Campath vs Rebif in 334
patients
– 12 mg/day for 5 days at month 0, 12, 24
– 24 mg/day for 5 days at month 0, 12, 24
• Three-year observation period with interim analyses
Alemtuzumab vs Interferon-B1a:
Care-MS Phase III Studies
CARE – MS1
CARE – MS2
IFN-B1a
Alemtuzumab
(12mg)
IFN-B1a
Alemtuzumab
(12mg)
0.39
0.18
0.52
0.26
Ann. relapse rate
54.9% (P<0.0001)
Risk reduction
Sustained disability (% pts)
11
Net EDSS change
Cohen JA et al. Lancet. 2012;380:1819-1828.
Coles AJ et al. Lancet. 2012;380: 1829-1839.
21.1
30% (P=0.22)
Risk reduction
Δ EDSS from baseline
8
49.4% (P<0.0001)
- 0.14
- 0.14
12.7
42% (P=0.0084)
0.24
- 0.17
0.41 (P<0.0001)
Extension Analysis of Care-MS
Phase III Studies
CARE-MS I
CARE-MS II
ARR
0.24
0.25
EDSS improvement
40%
45%
Received alemtuzumab re-tx*
18%
20%
*Criterion for re-treatment was 1 relapse or ≥ 2 new lesions on MRI
Fox E et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S41.001.
Safety Analysis of Care-MS Phase III Studies
Autoimmune thyroid disorders
• 19.4% in extension; 29.9% total study
• Autoimmune thrombocytopenia (ITP):1.3%; nephropathy: 0.3% (n=3)
Infections
• More common with alemtuzumab compared with IFN (Incl. URI, UTI,
sinusitis, and mucocutaneous herpetic and fungal infections)
− Acyclovir prophylaxis seemed to reduce the risk of herpetic infection
− Infections highest in mos 1 and 13 (after each alem course),
− No evidence that neutrophil or lymphocyte counts before a treatment course predicted infection risk
Fox E et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract S41.001.
Wray S et al. Presented at AAN 2013; March 16-23, 2013; San Diego, CA. Abstract P01.172.
Trials in Progressive MS
• Secondary Progressive MS
– ASCEND: Natalizumab vs Placebo
– Siponimod vs Placebo
• Primary Progressive MS
– FREEDOMS: Fingolimod vs Placebo
– ORATORIO: Ocrelizumab vs Placebo
Choice of Therapy
Aggressive Disease?
Aggressive
Disease?
Yes
JCV AB
Positive?
NTZ
?
No
JCV AB
Negative
Fingo
DMF
Safest
NTZ
GA
IFN
Pregnancy?
Non-injection
GA
INSURANCE
Teri
?DMF
?Fingo
?NTZ
Immunopathogenesis of MS
Fampridine K+
CD8
CTL
Reg
GA
Olig
o
Glutamate
CD8p
IL-10
TGFb
B7 CD28
MCP-1
MIP-1a
IP-10
RANTES
Th1
DC
Th17
CCL20 IL-17
CCR6
Th17
Treg
CD40 CD40L
Foxp3
IL-6 Treg
Foxp3
Th17
S1Pr
IL-6 & IL1-ß
Th0
Dhib-Jalbut S. 2013.
Tr1
Th3
IFNB
GA
Treg
Foxp3
IFNB
BBB
IFNg
TNF
S1Pr
TGFß
Fingolimod
Rituximab
VCAM-1
MMP-2/9
CD20
Natalizumab
Th1
B
VLA-4
IL-12
Th0
TF
TCR
B7-CD28
GA
S1Pr
Astrocyte
ICAM-1
IL-23
EBV
B
IFNg
TNF
Neut
Ab+C9neo
PL
RNO
ROS
TNF
MMP
BG-12
S1Pr
CD8
FcR
Epitope
spreading
Tr1
Th3
IL-4
IL-5
IL-10
IL-13
TGF-b
GA
Th2
TLR
HLA
Th0
APC
Myelin Ag
Microbial Ag
BG-12
IL-4
IFN-ß BIOMARKERS
Defining Interferon ß Response Status in MS
• 15-year follow-up of pivotal MSCRG trial for weekly interferon
• 172 patients in placebo-controlled IFN-ß1a trial x 2 years
• In IFNb-1a group, disease activity predicted EDSS worsening:
– Gadolinium-enhancing lesions (OR, 8.96; P<0.001)
– Relapses (OR, 4.44; P=0.01)
– New T2 lesions (OR, 2.90; P=0.08)
• Conclusion: New MRI activity during IFN-ß1a treatment
correlates with suboptimal response
Rudick RA et al. Ann Neurol. 2004;56:546-555.
Bermel RA et al. Ann Neurol. 2013;73:95-103.
MRI as a Surrogate of Future Disease Activity
• 370 patients underwent MRI at baseline and 1 year after
beginning IFN
• Followed for relapse or disability progression in years 1-4
• At year 1: ≥1 Gd enhancing lesion or ≥2 T2 lesions had
same risk for worsening disease in years 1-4 and for a
clinical relapse within the first year
• MRI activity after starting IFN has similar implication as a
relapse
Prosperini L, Pozzilli C. Mult Scler J. 2013;2013:756564.
Potential IFN-β Serum Biomarkers
Responders
Non-responders
Increase in IL-10
IL-17F levels>200pg/ml
Reduction in Th1 cytokines
High baseline IFN-β levels
Increased in neurotrophic factors
Increased monocytes IFN-I
secretion in response to TLR
NAB
Increase PSTAT1 and IFNR1 on
monocytes at baseline
Dhib-Jalbut S et al. J Neuroimmunology. 2013;254:131-140.
Comabella M et al. Brain. 2009;132:3353-3365.
Clinical Response to IFN-β
Key Points
• Relapses are reduced by one-third
• Response is heterogeneous
• No validated laboratory biomarkers
• Persistent active MRI lesions at 6 mos predicts clinical
activity
• Persistent high titer neutralizing Ab could be a reason
to switch therapy
Killestein J, Polman CH. Nat Rev Neurol. 2011;7:221-228.
GA-BIOMARKERS
Glatiramer Acetate Binds to HLA Class II
on Antigen Presenting Cells and Induces
Type-2 APCs
IL-4
IL-10
TGFB
IL-12
TNF
APC/type-2
Dendritic cells
GA
Th0
Th2
Treg
Weber MS et al. Nat Med. 2007;13:935-943.
Response by Haplotype
Dhib-Jalbut S et al. MSARD. 2013;2:340-348.
DR and DQ Haplotypes Predictors of Clinical
Response to GA
PROGNOSTIC
PROFILE
HAPLOTYPES
NR / R (%R)
Poor prognostic profile
DR15 - DQ6 absent
DR17 - DQ2 present
10 / 2 (16.7%)
Neutral prognostic profile
Good prognostic profile
Dhib-Jalbut S et al. MSARD. 2013;2:340-348.
DR15 – DQ6 present &
DR17 – DQ2 present
DR15 – DQ6 absent &
DR17 – DQ2 absent
DR15 – DQ6 present
DR17 - DQ2 absent
17 / 11 (39.5%)
7 / 17 (70.8%)
Summary of Potential GA-Biomarkers
GA-RESPONDERS
IL4/IFNg
IL-17
IL-10
IL-18
BDNF
Caspase-1
FOXP3+
DR15
DQ6
Dhib-Jalbut S. Presented at: ECTRIMS 2010.
GA NONRESPONDERS
DQ2
DR17
Black Holes
NATALIZUMAB
BIOMARKERS
Defer G et al. J Neurol Sci. 2012;314:138-142.
BIOMARKERS OF Rx
COMPLICATIONS
L-Selectin and Risk of PML in
Natalizumab-treated MS Patients
Schwab N et al. Neurology. 2013;81:865-871.
Serum IL-21 and Autoimmunity
Jones JL et al. J Clin Invest. 2009;119:2052-2061.
Choosing Therapies—Biomarkers
• Antibodies to aquaporin-4
• Immune markers
– IL-17 and response to IFN
– Alemtuzumab autoimmunity: serum IL-21
– Daclizumab: CD56Bright
• Genetics/genomics (HLA): Response to GA
• Neutralizing antibodies (NAB) (IFN-B, natalizumab)
• JC virus exposure (natalizumab)
Future Issues
• Neuroprotection – how to recognize, measure, Rx
• Pathologic-based phenotyping will be increasingly
important for treating progressive disease, informed
(targeted) repair
• Biomarkers
• Measures of improvement
Patient Resource Tools
• The National Multiple Sclerosis Society
– www.nmss.org
– An online resource of patient information
• The American Academy of Neurology
− http://patients.aan.com/go/brochures
− Understanding Multiple Sclerosis (located mid-page)
− Available as a downloadable PDF or printed copies can
be ordered by contacting Missy Render
(mrender@aan.com)
Participant CME Evaluation
• Please remove the Post-activity Survey and Evaluation from the
back of your packet
• If you are not seeking credit, we ask that you fill out the information
pertaining to your degree and specialty, as well as the few questions
in the Post-activity Survey measuring the knowledge and
competence you have garnered from this program.
• In order to receive CME credit, please complete the Evaluation
Form, as well, and return to onsite staff. Your participation will help
shape future CME activities.
Thank You!