Slides - Projects In Knowledge

Report
Overview of
MS and Strategies for
Personalized Treatment
Douglas S. Goodin, MD
Professor of Neurology
Medical Director
Multiple Sclerosis Center
University of California, San Francisco
San Francisco, California
Multiple Sclerosis
Epidemiology
•
Prevalence
–
1.0–1.5 per 1,000 population in the United States
–
~2.5 million cases worldwide
•
Age at onset: 15–45 years
•
70%–75% of cases are women
•
Increasing worldwide prevalence (especially in women)
•
Ethnic origin: predominantly white, but does occur in
other ethnicities as well
Goodin DS. Epidemiology of MS. In: Handbook of Clinical Neurology. Philadelphia, PA: Elsevier; 2012.
Compston A, et al. McAlpine’s Multiple Sclerosis. 4th ed. London, England: Churchill Livingstone; 2006.
Goodin DS. Epidemiology of MS. In: Handbook of Clinical Neurology. Philadelphia, PA: Elsevier; 2012.
Etiology of MS
•
•
Genetics
–
Increased risk in persons who have relatives with MS1-3
–
50–200 susceptibility alleles2,3
–
Strongest association with HLA DRB1*15011-3
Environmental factors, current hypotheses
–
History of Epstein-Barr virus infection1,2,4,5
–
Vitamin D deficiency1,2,6
–
Smoking2 (active7 or passive8)
1. Goodin DS. PLoS One. 2009;4:e4565. 2. Goodin DS. Epidemiology of MS. In: Handbook of Clinical Neurology.
Philadelphia, Pa: Elsevier; 2012. 3. Goodin DS. BMC Neurology. 2010;10:101. 4. Santon A, et al. Mult Scler.
2011;17:1295-1300. 5. Lucas RM, et al. Neurology. 2011;77:371-379. 6. Munger KL, et al. Neurology. 2004;62:6065. 7. Handel AE, et al. PLoS One. 2011;6(1):e16149. 8. Hedström AK, et al. Mult Scler J. 2011;17:788-793.
Pathophysiology of MS
•
Acute inflammation  demyelination/relapses
– Blood-derived lymphocytes and monocytes
– Breakdown of blood-brain barrier
– Edema
– White and grey matter lesions

•
Myelin injury, axonal transection
Neurodegeneration  irreversible disability
– Neuronal loss
– Brain atrophy
Trapp BD, et al. Annu Rev Neurosci. 2008;31:247-269.
Subtypes of MS
•
•
•
•
Relapsing-remitting MS (RRMS)
– Episodes of acute neurologic dysfunction (attacks) ± recovery
– Stable disease between attacks
– Initial diagnosis in ~85% of patients
Primary-progressive MS (PPMS)
– Steady functional decline from onset without attacks
– ~10% of cases
Secondary-progressive MS (SPMS)
– Steady functional decline ± attacks; always follows RRMS
– 50%–80% develop SPMS
Progressive-relapsing MS (PRMS)
– Steady functional decline from onset with occasional attacks
– ~5% of cases
Lublin FD, Reingold SC. Neurology. 1996;46:907-911. Compston A, et al. McAlpine’s Multiple Sclerosis. 4th ed.
London, England: Churchill Livingstone; 2006.
MS Symptoms
Common
Less Common
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Vision disturbances
Fatigue
Numbness
Incoordination
Gait impairment
Bladder/bowel
dysfunction
Dizziness and vertigo
Pain
Cognitive dysfunction
Depression
Spasticity
Speech dysfunction
Swallowing difficulties
Hearing loss
Seizures
Respiratory impairment
Hauser SL, Goodin DS. Multiple sclerosis. In: Harrison’s Principles of Internal Medicine. New York, NY:
McGraw-Hill; 2008:2611-2621.
Revised Diagnostic Criteria
Multiple Sclerosis
• Dissemination of lesions in space (DIS)
– ≥1 T2 lesion in ≥2 of 4 CNS areas: periventricular,
juxtacortical, infratentorial, spinal cord*
• Dissemination of lesions in time (DIT)
– ≥2 clinical attacks, or 1 of the following MRI criteria

≥1 new T2 or gadolinium(Gd)-enhancing lesions
not found on baseline scan, irrespective of timing of
baseline scan

Simultaneous presence of asymptomatic
Gd-enhancing and nonenhancing lesions
*If brain stem or spinal cord syndrome, the symptomatic lesions are excluded from criteria and do not
count toward lesion count.
Polman CH, et al. Ann Neurol. 2011;69:292-302.
FDA-Approved Disease-Modifying
Therapies
Drug
Recommended Dose
Indication
IFN beta-1b
(2 brands)1,2
250 mcg SC q2d
Relapsing MS, CIS
IFN beta-1a3
22 or 44 mcg SC TIW
Relapsing MS
IFN beta-1a4
30 mcg IM weekly
Relapsing MS, CIS
20 mg SC qd
RRMS, CIS
0.5 mg orally qd
Relapsing MS
Natalizumab7
300 mg IV over 1 h
q4wk
Relapsing MS
(nonresponders/intolerant to
alternate therapy)
Mitoxantrone8
12 mg/m2 over 5–15 min
IV q3mo
SPMS, PRMS, worsening
RRMS
GA5
Fingolimod6
Abbreviations: CIS, clinically isolated syndrome; GA, glatiramer acetate; IFN, interferon; IM, intramuscular;
IV, intravenous; SC, subcutaneous.
1. Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals; 2010. 2. Extavia [PI]. East Hanover, NJ: Novartis
Pharmaceuticals Corp; 2012. 3. Rebif [PI]. Rockland, MD: EMD Serono; 2011. 4. Avonex [PI]. Cambridge, MA: Biogen
Idec; 2012. 5. Copaxone [PI]. Kansas City, MO: Teva Neuroscience; 2009. 6. Gilenya [PI]. East Hanover, NJ: Novartis
Pharmaceuticals Corp; 2012. 7. Tysabri [PI]. Cambridge, MA: Biogen Idec; 2012. 8. Novantrone [PI]. Rockland, MD:
EMD Serono; 2010.
Comparisons of Therapies
Short-Term Outcomes in MS
Establishing Efficacy in MS
• Outcome measures: disease activity
1. Clinical assessment
(eg, attack rate or attack-free status)
2. Radiologic (MRI) assessment
(eg, new T2, Gd+, or combined unique lesions)
• Outcome measures: disease severity
1. Clinical assessment
(eg, confirmed EDSS progression or MSFC)
2. Radiologic (MRI) assessment
(eg, T2 burden, T1 black holes, or atrophy)
Abbreviations: EDSS, Expanded Disability Status Scale; MSFC, Multiple Sclerosis Functional Composite.
Outcome Assessment
Relative Risk
Relative risk =
Risk of illness (exposed or treated)
Risk of illness (unexposed or untreated)
RRate =
Rate of illness (exposed or treated)
Rate of illness (unexposed or untreated)
Odds ratio =
Odds of illness (exposed or treated)
Odds of illness (unexposed or untreated)
Bewick V, et al. Critical Care. 2004;8:287-291. Courtesy of Douglas S. Goodin, MD.
Outcome Assessment
Absolute Risk—NNT/NNH
1
NNT/NNH =
| Risk controls – Risk treated |
=
1/ARR
1
NNT/NNH =
(Events/Patient)
=
Patients/Events
Abbreviations: ARR, absolute risk reduction; NNH, number needed to harm; NNT, number needed to treat.
Courtesy of Douglas S. Goodin, MD.
Prospective Randomized Trial
Trial Design
Total
population
Sample from
total population
Time
Study
sample
Randomization
A
Outcome
assessment
Courtesy of Douglas S. Goodin, MD.
B
RR = (1/6)/(4/6) = 0.25
ARR = (4/6) – (1/6) = 0.5; NNT = 2
The Need for Head-to-Head Trials
Relative Efficacy (RR)
GA
20 mg
qd
IFN beta-1a IFN beta-1b,
30 mcg
250 mcg
IM qwk
SC q2d
IFN beta-1a
44 mcg
TIW
Natalizuma
b
300 mg/mo
Annualized
relapse rate
-29%
-18%
-34%
-32%
-68%
Relapse-free
(2 years)
+42%
+36%
+100%
+36%
+57%
3-month
sustained
progression
(≥1 EDSS point)
-12%
-37%
-29%
-30%
-42%
New T2
lesions
-38%
-36%
-83%
-78%
-83%
Gd+ or CU
lesions
-33%
-42%
-
-88%
-92%
Goodin DS, et al. Neurology. 2008;71:766-773. Courtesy of Douglas S. Goodin, MD.
The Need for Head-to-Head Trials
Absolute Efficacy (NNT and NNH)
GA
20 mg
qd
IFN beta-1a IFN beta-1b, IFN beta-1a
Natalizumab
30 mcg IM 250 mcg SC
44 mcg
300 mg/mo
qwk
q2d
TIW
Annualized
relapse rate
4
7
2
2
2
Relapse-free
(2 years)
15
9
7
6
4
Progressionfree (%)
33
8
13
9
8
New T2
lesions
0.17
1.3
0.34
0.3
0.11
Annualized
rate of Gd+
lesions
0.09
1.4
-
0.11
0.91
Goodin DS, et al. Neurology. 2008;71:766-773. Courtesy of Douglas S. Goodin, MD.
INCOMIN Trial
24 Months
IFN beta-1a
30 mcg IM
qwk
IFN
beta-1b
250 mcg SC
q2d
% change
P value
Relapse-free
36%
51%
+42%
.036
T2 lesion-free
26%
55%
+112%
<.003
EDSS progression
30%
13%
-44%
.005
Gd+ lesion-free
49%
76%
+55%
.001
+11.7%
-2.8%
-14.5%
.0001
Burden of disease
Red indicates primary endpoint.
Durelli L, et al. Lancet. 2002;359:1453-1460.
EVIDENCE Trial
Final Results
Relative Improvement with
IFN beta-1a 44 mcq TIW SC
vs 30 mcq IM qwk
P value
Relapse rate
17%
.033
Odds ratio–relapsing
33%
.023
Hazard ratio, time to relapse
30%
.002
Steroid use
32%
.009
T2 lesions
36%
<.001
T2 active scans
38%
<.001
T2 inactive patients
55%
<.001
Disability progression
6%
ns
Red indicates primary endpoint.
Panitch H, et al. Neurology. 2002;59:1496-1506. Courtesy of Douglas S. Goodin, MD.
REGARD Trial
Final Results
IFN beta-1a 44 mcg
SC TIW (n = 386)
GA 20 mg/d
(n = 378)
P value
Time to first relapse (30th percentile)
495 d
432 d
ns
Patients free from relapse
62%
62%
ns
Annualized relapse rate
0.30
0.29
ns
T2 active lesions
0.67
0.82
ns
Gd-enhancing lesions
0.24
0.41
.0002
CU lesions
0.91
1.22
.010
New T1 hypointense lesions
0.23
0.24
ns
-1.240
-1.073
.018
Brain volume change
MRI measures reported as lesions per patient per scan. Red indicates primary endpoint.
ns = not significant
Mikol DD, et al. Lancet Neurol. 2008;7:903-914.
BEYOND Trial
Final Results
Endpoint
BEYOND
IFN beta-1b
250 mcg
(n = 897)
P Values
GA
(n = 448)
Relapse risk
ns
Relapse rate
0.36
0.34
ns
Progression-free
89%
80%
ns
New/Enlarging T2 Lesions
3.3
4.6
0.011
Gd+ Enhancing
0.9
1.2
ns
-0.65%
-0.61%
ns
Change in Brain Volume
Red indicates primary endpoint.
O’Connor P, et al. Lancet Neurol. 2009;8:889-897.
Oral Fingolimod
0.5 mg/d
Endpoint
TRANSFORMS
(Month 12)
P Values
Fingolimod
(n = 429)
IFN beta-1a
IM
(n = 431)
Relapse rate
0.16
0.33
<0.001
Relapse-free
82.6%
69.3%
<0.001
Progression-free
94.1%
92.1%
ns
1.7
2.6
0.004
Gd+ Lesion Free
90.1%
80.8%
<0.001
Gd+ Enhancing
0.23
0.51
<0.001
New/Enlarging T2 Lesions
Comparisons all P <.05, except for TRANSFORMS progression-free, P = .25.
Abbreviations: TRANSFORMS, Trial Assessing Injectable Interferon vs FTY720 Oral in RRMS.
1. Kappos L, et al. N Engl J Med. 2010;362:387-401. 2. Cohen JA, et al. N Engl J Med. 2010;362:402-415.
Natalizumab
300 mg/m + weekly IFN beta-1a
SENTINAL
(Month 24)
Endpoint
P Values
Natalizumab
(n = 589)
IFN beta-1a IM
(n = 582)
Relapse rate
0.34
0.75
<0.001
Progression-free
77%
71%
0.02
New T2 Lesions
0.9
5.4
0.001
Gd+ Lesion Free
96%
75%
0.001
Rudick RA, et al. N Engl J Med. 2006;354:911-923.
Red indicates primary endpoint
The Value of Early Treatment
Disease-Modifying MS Therapies
Disease Stage and Therapeutic Effects
Therapeutic Benefit
Potential therapeutic
benefit of DMTs
Monosymptomatic
MS
RR to SP
Axonal loss
RRMS
Natalizumab
Fingolimod
Disability threshold
IFN beta-1a
GA
Disease stage
IFN beta-1b
IFN beta-1a
SPMS
RRMS
SPMS
NA-SPMS
IFN beta-1b
time
Abbreviation: NA-SPMS, North American Secondary-Progressive MS Trial. Courtesy of Douglas S. Goodin, MD.
Early Treatment of MS with DMTs
IFN beta1a
IFN beta1a
IFN beta1b
22 mcg SC
qwk
30 mcg IM
qwk
250 mcg
SC q2d
0%1
-18%2
-34%2
-29%2
-33%3
-44%4
-50%5
-45%6
RRMS
(reduction in
relapse rate vs
placebo)
CIS
(reduction in rate
of conversion to
CDMS vs
placebo)
GA
20 mg SC
qd
1. OWIMS Study Group. Neurology. 1999;53:679-686. 2. Goodin DS, et al. Neurology. 2008;71:766-773. 3. Comi
G, et al. Lancet. 2001;357:1576-1582. 4. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 5. Kappos L, et al.
Neurology. 2006;67:1242-1249. 6. Comi G, et al. Lancet. 2009;374:1503-1511.
Courtesy of Douglas S. Goodin, MD.
Long-Term Treatment Outcomes
Propensity-Adjusted Cox PH Model
% Risk Relative to Low Exposure
High Exposure to IFN beta-1b
100
80
60
40
20
0
Any Negative
Goodin DS, et al. PLoS One. 2011;6:e22444.
EDSS = 6
SPMS
Wheelchair
IFN beta-1b 21-Year Long-Term Follow-Up
Study Design
Vital status of 366 (98.4%) of
372 original RCT participants
was identified after 21 years
Randomized trial
(N = 372)
Placebo
IFN beta-1b
50 mcg q2d
IFN beta-1b
250 mcg q2d
1988
Regular medical care
1993
2005
2006
RCT complete
Abbreviations: LTF, long-term follow-up; RCT, randomized controlled trial.
Goodin DS, et al. Neurology. 2012;78:1315-1322. Courtesy of Douglas S. Goodin, MD.
2009
2010
21-year
LTF
IFN beta-1b 21-Year Long-Term Follow-Up
Results
• More deaths were observed among patients originally randomized
to placebo than to IFN
• 78.3% of deaths were from MS-related causes
HR of
Death
Reduction
in HR
95% CI
P value
IFN beta-1b 250 mcg SC
q2d vs placebo
0.532
46.8%
0.314–0.902
.0173
IFN beta-1b 50 mcg SC
q2d vs placebo
0.540
46.0%
0.318–0.915
.0202
Abbreviations: CI, confidence interval; HR, hazard ratio.
Goodin DS, et al. Neurology. 2012;78:1315-1322.
Long-Term Follow-Up in RRMS
Glatiramer Acetate
•
•
15-year open-label extension of 2-year phase III trial1
−
Relapses reduced to ~1 every 4 years compared with
1.12 every year at open-label entry
−
57% had improved or stable EDSS scores
−
65% had not progressed to SPMS
Mean 5.8-year follow-up of open-label extension of
18-month trial2
−
Patients taking glatiramer acetate at study onset less
likely to need walking aids vs those starting active
treatment at extension entry (P = .034)
1. Ford C, et al. Mult Scler. 2010;16:342-350. 2. Rovaris M, et al. Mult Scler. 2007;13:502-508.
Impact of DMTs on
Cognitive Impairment
•
Likelihood of cognitive impairment was reduced with
–
Early vs delayed IFN beta-1b SC initiation in CIS1
–
Higher-dose IFN beta-1a SC in RRMS2
•
IFN beta-1a IM in relapsing MS improved information
processing and learning/recent memory3
•
Cognitive function was preserved in most patients
taking glatiramer acetate during 10-year open-label
follow-up4
1. Kappos L, et al. Lancet. 2007;370:389-397. 2. Patti F, et al. Mult Scler. 2010;16:68-77. 3. Fischer JS, et al.
Ann Neurol. 2000;48:885-892. 4. Schwid SR, et al. J Neurol Sci. 2007;255:57-63.
Safety and Tolerability
Safety of Interferons
•
Side effects: Flu-like symptoms, injection-site
reactions, hepatotoxicity (hepatic enzyme elevations),
leukopenia, depression (?), headache, thyroid
dysfunction
•
Pregnancy: Category C
•
Laboratory tests: Periodic CBC with differential,
liver function tests, thyroid function tests
Abbreviation: CBC, complete blood count.
Betaseron [PI]. Montville, NJ: Bayer HealthCare Pharmaceuticals; 2010. Extavia [PI]. East Hanover, NJ: Novartis
Pharmaceuticals Corp; 2012. Rebif [PI]. Rockland, MD: EMD Serono; 2011. Avonex [PI]. Cambridge, MA: Biogen
Idec; 2012.
Safety of Glatiramer Acetate
•
Side effects
–
Injection-site reactions, lipoatrophy
–
Immediate postinjection reaction (flushing, chest
pain, palpitations, anxiety, shortness of breath)

Self-limited; usually nonrecurrent; no treatment
required
•
Pregnancy: Category B
•
Laboratory tests: None required
Copaxone [PI]. Kansas City, MO: Teva Neuroscience; 2009.
Safety of Fingolimod
•
Side effects: Headache, liver enzyme elevations, bradycardia,
atrioventricular block, severe lymphopenia, macular edema
•
Pregnancy: Category C
•
Drug interactions: QT prolonging drugs, beta-blockers
•
Laboratory tests: CBC with differential, liver enzymes
–
At least 6 hours of cardiovascular observation after
1st dose, with hourly pulse and blood pressure
measurement for all patients
–
EKG obtained prior to 1st dose and at end of
observation period
–
Cardiovascular monitoring should be extended past
6 hours in patients at higher risk of bradycardia and
should include continuous overnight EKG monitoring
FDA Drug Safety Communication. May 14, 2012. Accessed 5/14/12 at:
http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm.
Safety of Natalizumab
•
Side effects: Hypersensitivity reactions, fatigue,
diarrhea, infections
–
PML/IRIS
•
Pregnancy: Category C
•
Lab tests: JC virus antibody testing prior to/during
treatment; antibody testing if persistent antibodies
suspected
Abbreviations: IRIS, immune reconstitution inflammatory syndrome; PML, progressive multifocal leukoencephalopathy.
Tysabri [PI]. Cambridge, MA: Biogen Idec; 2012.
Natalizumab
PML Risk Factors
•
Duration of use1
−
−
−
−
•
JC virus antibodies (JCV Ab) present in ~55%1
–
–
–
–
•
•
1–12 months: 0.04 cases/1000 patients
13–24 months: 0.56 cases/1000 patients
25–36 months: 1.93 cases/1000 patients
37–48 months: 1.99 cases/1000 patients
FDA-approved screening test now available2
54 cases with samples all JCV Ab positive prior to PML1
3.80–3.87 cases per 1000 patients if JCV Ab positive1
≤0.09 cases per 1000 patients if JCV Ab negative1
Prior immunosuppressive therapy1
− 34.5% in PML vs 20.3%–23.5% in all natalizumab users)
Risk is further increased if multiple risk factors1
1. Bloomgren G, et al. N Engl J Med. 2012;366:1870-1880. 2. Stratify JCV [PI]. Cypress, CA: Focus Diagnostics; 2011.
Natalizumab & IRIS
•
IRIS follows PML; in most cases after PE1
–
Due to rapid restoration of immune function after NTZ
clearance2
•
Typical  PML Sx; days to weeks after PE; may require ICU care3
•
Corticosteroids: Strike balance between adequate
immunosuppression while maintaining effective immune response
against JC virus4
–
Methylprednisolone 1 g/d IV for 5 days followed by oral steroids;
repeated courses may be necessary3
–
In case studies, corticosteroids reduced IRIS and improved
EDSS scores in most patients, compared with several deaths3
and worse EDSS scores in patients whose IRIS was untreated5
1. Tysabri [PI]. Cambridge, MA: Biogen Idec; 2012. 2. Carson KR, et al. Lancet Oncol. 2009;10:816-824. 3. Clifford DB, et
al. Lancet Neurol. 2010;9:438-446. 4. Berger JR. Neurology. 2009;72:1454-1455. 5. Tan IL, et al. Neurology.
2011;77:1061-1067.
Emerging Disease-Modifying
Therapies
Emerging Disease-Modifying
Therapies
Small Molecules
Monoclonal Antibodies
•
BAF312
•
Alemtuzumab
•
Dimethyl fumarate (BG-12)
•
Daclizumab
•
Laquinimod
•
•
ONO-4641
Ocrelizumab and
ofatumumab
•
Teriflunomide
Conclusions
•
•
Early treatment more effective than late
–
Reduction in relapses, disability progression, MRI
–
Better long-term outcome (physical and cognitive)
Recent studies of long-term follow-up show
–
Improved survival/reduced MS-related mortality
–
Good safety track record (GA, IFN)
•
Natalizumab has serious adverse events and requires
careful monitoring
•
Fingolimod is probably safe but requires careful monitoring
•
Mitoxantrone
–
•
Rarely used due to serious adverse events
More options expected in the near future
Partnering with Patients to Improve
Adherence in MS
Amy Perrin Ross, MSN
Neuroscience Program Coordinator
Department of Neurosciences
Loyola University Chicago
Maywood, Illinois
Goals of Treatment with
Disease-Modifying Therapy
•
•
•
•
•
Reduce frequency and severity of relapses
Reduce new/enhancing lesions on MRI
Delay disability progression
Increase overall quality of life and function
Provide therapy that is well tolerated and safe
– Acceptable benefit vs risk
A wellness philosophy is the focal point of
comprehensive care
The Multiple Sclerosis Team
Neurologist
NMSS/MSAA/MSF
Nurse
Support Staff
Ancillary Services
Physical Therapist
Patient/Family
OUTPUTS
Quality of life
Adherence
Adjustments/
adaptation
Urologist
Neuropsychologist
Social
Work/
Occupational
Counselors
Therapist
Speech Therapist
Recreational Therapist
Abbreviations: MSAA, Multiple Sclerosis Association of America; MSF, Multiple Sclerosis Foundation;
NMSS, National Multiple Sclerosis Society.
Graphic courtesy of June Halper.
Choosing the Right Treatment for the
Individual Patient with MS
Initiation of treatment
• Which disease-modifying therapy will fit an
individual patient?
• 1st-line medications vs 2nd-line
• Ability to self-inject – SQ/IM vs oral/IV
• Lifestyle issues
• Career/family roles
• Planning pregnancy
• Planning trip? Vaccines
Decision Making
•
•
•
•
•
•
•
•
Discussion of pros and cons with patients
Partnership with patients and families
Possible use of consent form/contract
Future plans and therapies
Long-term effects of certain medications
Combination of therapies
Safety of medications
Pregnancy
Adherence vs Compliance
•
Compliance implies giving in to a request, wish, or
demand; it implies a subordinate position to healthcare
professionals
Versus
•
Adherence is voluntary, active collaborative involvement
of the patient in a mutually acceptable course of behavior
leading to a desired outcome
Adherence to Therapy
Although it is felt to be important
•
Adherence is difficult
–
•
Nonadherence estimates are about 50%–70%; this is true
for many chronic diseases
Many reasons offered as to why
–
Perception that drug is not working
–
Continued MS symptoms
–
Side effects
–
Insurance coverage
Barriers to Adherence
•
Lifestyle issues
•
Cultural considerations and healthcare literacy
•
Fear of injections
•
Concerns about adverse effects, including injection
site reactions that can affect lifestyles
•
Perceived benefits
•
Lack of an effective support system
•
Depression
•
Cost
Barriers to Adherence
•
•
•
•
Progression of disease – hopelessness
Physical impairments – visual disturbances, tremor,
weakness
Absence of symptoms
Fatigue – too tired to inject
Uncover Injection Barriers
•
What is your schedule for injections?
•
How many injection sites/areas do you use in
1 week?
•
How many injections did you miss in the past month?
•
What were your reasons for missing these injections? Was it
because of site reactions, etc?
•
Can you show me the last 3 sites you injected?
•
If needed, would you ask for help with your injections?
Uncover Oral/IV Barriers
• What is your schedule for taking pills?
• How many pills did you miss in the past month?
• Have you had your follow-up monitoring done?
• Do you have trouble with IV access?
• Do you have storage/transportation issues?
Promoting Adherence
•
•
•
•
•
Educate
Identify and address barriers
Develop individualized strategies
Encourage realistic expectations
Advocate
–
Assist with reimbursement
–
Identify resources
–
Involve family and support system
Fostering Realistic Expectations
•
For MS patients, realistic expectations are critical
to the success of long-term disease management
•
Inform patients that disease-modifying therapies
are not curative but that they can:
–
Reduce the rate and frequency of relapses
–
Slow the progression of the disease

–
Having relapses while on treatment does not mean
therapy is ineffective; conversely, the lack of
relapses when not on treatment does not mean
disease is not progressing
Improve quality of life
Fostering Realistic Expectations
Risk of Not Treating/Delaying Treatment
•
Compared with no treatment, treatment with diseasemodifying therapy (IFN B-1a, IFN B-1b, or glatiramer
acetate)
–
Significantly delays the onset of clinically definite MS1,2,3,4
–
Significantly reduces annualized relapse rates4
–
Significantly reduces loss of brain volume1
–
Significantly reduces the number of new or enlarging lesions
and gadolinium-enhancing lesions1,4
1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Kappos L, et al. Lancet. 2007;370:389-397. 3.Comi G, et al. Lancet.
2009;374:1503-1511. 4. Comi G, et al. Lancet. 2001;357:1576-1582.
Fostering Realistic Expectations
Risk of Not Treating/Delaying Treatment
Early vs delayed treatment
–
Patients receiving early treatment had a significantly
reduced risk of progression of disability
–
Patients receiving early treatment performed significantly
better on tests of cognitive function than those receiving
delayed treatment
Kappos L, et al. Lancet. 2007;370:389-397.
Provide Balanced Information
•
Present balanced information about disease-modifying
therapies; include pivotal trial data, mechanism of
action, potential adverse effects
•
Refer to:
–
National Multiple Sclerosis Society
–
Multiple Sclerosis Association of America
–
Multiple Sclerosis Foundation
–
Consortium of Multiple Sclerosis Centers
•
Direct patients to appropriate websites and provide
information kits if available
•
Teach patients to critically evaluate MS educational
materials
Strategies to Address Barriers
•
•
Medication specifics
–
Develop realistic expectations
–
Discuss dosing and consistent administration
–
Provide tips to minimize side effects, including injection
site reactions (eg, medications prior
to injection, site rotation, lifestyle, and site
of injection)
–
Address side effects
Patient/caregiver issues
–
Identify information gaps, provide education
–
Assess patient’s financial status and support wherever
possible with resources
Management of Injectable
Side Effects
•
Warm mixed medications to room or body temperature
•
Warm or ice site for 30–60 seconds before injection
•
Inject immediately after a shower
•
Use aerosolized ethyl chloride
•
Apply local anesthetics (lidocaine, benzocaine, etc)
•
For flu-like symptoms, ibuprofen and acetaminophen can be
recommended
Injection Mechanics
•
Consider autoinjectors
•
Modify needle length for body mass index
•
Avoid medication on needle tip
•
Fully penetrate the skin to avoid intradermal infiltration
•
Ensure complete vertical needle penetration into
skin surface
Management of Injection
Site Reactions
•
•
Use topical steroids for postinjection erythema
Avoid topical steroids at sites of infection or apparent
abscess or necrosis
Graphics courtesy of Colleen Harris.
To Be Successful, a Patient…
• Must be ready to begin therapy
• Must believe that therapies can make
a difference
• Must be willing to make a commitment
• Must be well educated
–
Regarding MS
–
Regarding therapies for MS
Who Can Help?
•
•
•
•
Neurologists
Nursing staff
Company-sponsored support
Multiple Sclerosis Association of America (MSAA)
– www.msassociation.org
•
National Multiple Sclerosis Society (NMSS)
– www.nationalmssociety.org
•
Multiple Sclerosis Foundation (MSF)
– www.msfocus.org
•
Consortium of Multiple Sclerosis Centers
– www.mscare.org
General Advice for
Motivating Patients
•
MS is lifelong; therapy is a lifelong commitment
•
Take good care of yourself: a wellness approach
–
Rest
–
Eat well
–
Exercise
–
Reduce stress
•
Find a strong support network that includes other
people with MS
•
Find and develop a positive relationship with a
healthcare provider whom you trust and respect
Dimensions of Wellness
Intellectual
Environmental
Learning
Growth
New challenges
Healthy setting
Self-protection
Physical
Spiritual
Nutrition
Fitness
Lifestyle
habits
Life meaning
Purpose
Values
Social
Emotional
Stress management
Acceptance
Expression of
feelings
Respect
Relationships
Intimacy
Tolerance
Anspaugh D, et al. Wellness: Concepts and Applications. New York: McGraw-Hill; 2008.
The Ultimate Goals in
MS Treatment
•
•
•
•
•
•
Prevent accumulation of disability
Prevent relapses
Improve quality of life—short- and long-term
Develop convenient, effective, safe and tolerable treatments
Repair damage and restore function
Promote realistic
hope
Translating Science into
Practice: Case Studies
Patricia K. Coyle, MD
Acting Chair, Department of Neurology
Director, MS Comprehensive Care Center
Stony Brook University
Stony Brook, New York
Case 1
18-Year-Old White Female
History
•
•
•
•
•
Patient presented with monocular vision loss over 2
days, with right eye pain
She has no prior medical history
Exam showed diminished right eye vision (20/70), red
color desaturation, central scotoma, and afferent pupil
Brain/orbit MRI showed enhancement of the right optic
nerve only
Diagnosis is retrobulbar optic neuritis
Decision Point 1
Which best describes your diagnostic assessment?
a.
Clinically isolated syndrome (CIS) at low risk for
multiple sclerosis (MS)
b. CIS at high risk for MS
c.
Definite MS
Decision Point 2
Would you encourage this patient to start diseasemodifying therapy for MS?
a. Yes
b. No
Additional Nonenhancing Lesions
Suppose the brain MRI, in addition to enhancement of
the optic nerve, showed 2 nonenhancing lesions: a 5mm juxtacortical lesion and a 4-mm periventricular
lesion?
Decision Point 3
What is your diagnostic assessment now?
a.
CIS at low risk for MS
b. CIS at high risk for MS
c.
Definite MS
Decision Point 4
Would you encourage the patient to start diseasemodifying therapy?
a.
Yes
b. No
Additional Enhancing Lesions
Suppose the brain MRI, in addition to enhancement of
the optic nerve, showed 2 lesions, 1 of which enhanced:
a 5-mm enhancing juxtacortical lesion and a 4-mm
periventricular lesion?
Decision Point 5
What is your diagnostic assessment?
a.
CIS at low risk for MS
b. CIS at high risk for MS
c.
Definite MS
Decision Point 6
What would be your choice of treatment?
a.
IFN beta-1a
b. IFN beta-1b
c.
Glatiramer acetate
d. Natalizumab
e.
Fingolimod
Case 2
28-Year-Old Lawyer
History
•
•
•
•
•
Patient was diagnosed with relapsing-remitting MS
following 2 attacks over 14 months
Her exam is normal
She feels well, believes she has benign disease, and is
ambivalent about going on anything that can harm her
body
You counsel her about MS, the damage process, and the
benefits of disease-modifying therapy
You then discuss individual agents
Interferon Beta Counseling
•
•
•
•
Adverse reactions include flu-like symptoms, injection
reactions, headache/depression
Monitoring includes liver function tests, thyroid, complete
blood count and differential
Therapy initiation involves dose escalation, premedication, and possible early evening dosing
Blood tests are required every 3 months for
1 year, then every 6 months for higher-dosed interferon
beta
Glatiramer Acetate Counseling
•
•
Adverse reactions involve injection site reactions,
systemic immediate postinjection reaction
No routine blood testing is required
Natalizumab Counseling
•
Associated with the risk of a potentially fatal adverse
event (ie, progressive multifocal leukoencephalopathy)
–
•
Risk stratification (JC virus antibodies, duration of therapy,
prior immunosuppression)
Monitoring includes liver function test, neutralizing
antibodies at 6 months
Fingolimod Counseling
•
•
•
Prescreen patients for exclusion criteria, macular edema,
complete blood count and differential, liver function tests
(LFTs), IgG/M to VZV, electrocardiogram (EKG)
6-hour initiation dose monitoring with EKG
pre and post
Repeat ophthalmologic screen, liver function tests at 4
months
Decision Point
What would be your treatment choice for this
patient?
a. IFN beta-1a
b. IFN beta-1b
c. Glatiramir acetate
d. Natalizumab
e. Fingolimod
Follow-Up Strategy
•
•
Regular visits
–
Every 3–4 months on initiation or change in diseasemodifying therapy (for 1 year)
–
Every 6–12 months when stable
Surveillance brain MRI with contrast
–
At 12 months (6 months if high concern)
–
Annually for the early course, then at the discretion of
patient/physician
Suspected Relapse
•
•
•
•
•
•
•
Clarify symptoms and time course
Assess adherence
Document objective changes
Rule out pseudorelapse
Consider whether you want MRI
Discuss acute management
Consider disease-modifying thrapy implications
General Counseling
•
•
•
Stress adherence
Continue close follow-up and reassessments (clinical,
MRI)
Advise patients to notify of any significant changes
–
•
Patients often bring up changes months after they occur
Let patients know that current expected attack rate 1
every 3–5+ years
Case 3
42-Year-Old Female
History
•
This 42-year-old relapsing-remitting patient has been on
therapy with glatiramer acetate for 8 years
•
She has now had her 1st relapse on therapy
•
The relapse involved right leg hypesthesia, with complete
recovery
Decision Point 1
Would you change disease-modifying therapy?
a. Yes
b. No
Paraparesis with Incomplete Recovery
Suppose the relapse involved paraparesis with gait
ataxia, with incomplete recovery?
Decision Point 2
Would you change disease-modifying therapy?
a. Yes
b. No
Hypesthesia and New Lesions
•
Suppose the relapse involved hypesthesia with complete
recovery?
•
Brain MRI showed 4 contrast lesions, and 10 new lesions
from her last MRI a year ago
Decision Point 3
Would you change disease-modifying therapy?
a.
Yes
b. No
Paraparesis and Stable MRI
Suppose the relapse involved paraparesis with gait ataxia,
with incomplete recovery, and stable MRI?
Decision Point 4
Would you change disease-modifying therapy?
a.
Yes
b. No
Switching Disease-Modifying Therapy
Suppose the patient was JC virus antibody negative?
Decision Point 5
What would you recommend?
a.
Maintain current therapy
b. Switch to interferon beta
c.
Switch to fingolimod
d. Switch to natalizumab
e.
Other
Patient Outcomes
•
•
•
•
•
Patient was started on IV natalizumab
She does well, feels stronger, and experiences
no relapses
Brain MRI is completely stable, with no
enhancing lesions
JC virus antibody is tested every 6 months
She continues to do well at 3 years on therapy
JC Virus Antibody Positive
Suppose the patient was JC virus antibody positive?
Decision Point 6
What therapy would you recommend?
a.
Interferon beta
b.
Fingolimod
c.
Natalizumab
d. Other
Patient Outcomes
•
•
•
•
•
•
Patient was started on fingolimod
Total lymphocyte level is below normal limits
Since there is no infection issue, she remains
on therapy
There is no evidence of macular edema at 4 months
Brain MRI is stable at 6 and 12 months
She continues to do well on fingolimod at 24 months on
therapy

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