img.medscape.comimg.medscape.com/images/828/240/828240_slide.pdf · multiple sclerosis (ms) 101 •...

Balancing the Risks and

Benefits of Therapy

Scott Newsome, DO

Assistant Professor of Neurology

Director, Neurology Outpatient Services

Johns Hopkins University School of Medicine

Outline

• Multiple Sclerosis (MS) 101

• Clinically Isolated Syndrome (CIS)

• Disease-modifying Therapy Efficacy

• Disease-modifying Therapy Adverse Effects

and Monitoring

Multiple Sclerosis (MS) 101

• Immune-mediated disease of the central nervous

system that is associated with inflammation,

demyelination, axonal loss, and neurodegeneration

• Primary etiology unknown, but likely multifactoral

• Most common cause of nontraumatic disability in

18- to 60-year-old population

• Female predominance with peak incidence between

20 and 40 years old

• Risk factors: low vitamin D, viruses, genetics, smoking,

overweight/obesity, environmental exposures, etc.Calabresi PA, Newsome SD. Multiple Sclerosis; Neurology for the Non-Neurologist. 6th ed.

Lippincott Williams & Wilkins, 2010; 192-221.

Ascherio, A. Expert Rev. Neurother. 2013;13(12 Suppl):3-9.

Relapsing-Remitting

Secondary Progressive

Preclinical

Time

Measures of brain volume

Relapses and impairment

MRI burden of disease

MRI activity

Axonal loss

Natural History of MS: Summary

Adapted from Goodkin DE. UCSF MS Curriculum. 1999.

Clinically Isolated Syndrome (CIS)

• CIS is an individual’s initial neurological episode that

occurs due to CNS inflammation/demyelination

• CIS can be:

– A first attack of MS

– An isolated idiopathic episode

– Secondary to another condition (eg, lupus)

• Usually monosymptomatic (eg, optic neuritis), but can

be polysymptomatic

• Can diagnose MS after a single attack with 2010

McDonald criteriaMarcus J, Waubant E. Neurohospitalist. 2013; 3(2): 65–80.

Frohman EM, et al. Arch Neurol. 2006;63(4):614-619.

Polman CH, et al. Ann Neurol. 2011;69(2):292-302.

Low-risk and High-risk CIS

Brain MRI with suspicious lesions?

Low-risk CIS- Watchful waiting

- Recommend close

monitoring with serial MRIs

High-risk CIS- Strongly consider initiation

of MS disease-modifying

treatment

NO YES

Marcus J, Waubant E. Neurohospitalist. 2013; 3(2): 65–80.

Frohman EM, et al. Arch Neurol. 2006;63(4):614-619.

Risk of MS After CIS

1Beck, et al. N Eng J Med. 1993;329:1764-1769. 2Optic Neuritis Study Group. Arch Ophthalmol 1997;115:1545-1552. 3Beck, et al. Arch

Ophthalmol. 2003;12:944-949. 4Optic Neuritis Study Group. Arch Neurol. 2008;65:747-732. 5Morrisey, et al. Brain. 1993;116:135-146. 6O’Riordan, et al. Brain. 1998;121:495-503. 7Brex, et al. NEJM. 2002;346:158-164. 8Fisniku, et al. Brain. 2008;131:808-817. 9Perumal, et al. J

Neurol. 2008;255:89–93. 10Bourre, et al. Arch Neurol. 2012;69(3):357-362. 11Sellner, et al. Eur J Neurol. 2008;15(4):398-405.

Study MS risk with normal

brain MRI

MS risk with abnormal brain MRI

Optic Neuritis

Treatment Trial1-4

• 16% at 5 years

• 22% at 10 years

• 25% at 15 years

1 or more lesions:

• 42% at 5 years

• 56% at 10 years

• 72% at 15 years (60% with 1 lesion, 68%

with 2 lesions, 78% with >3 lesions)

Any CIS, London

cohort5-8

• 3% at 5 years

• 11% at 10 years

• 19% at 14 years

• 21% at 20 years

3 or more lesions:

• 65% at 5 years (54% with 1 to 3 lesions,

85% with 5 or more lesions)

• 83% at 10 years

• 88% at 14 years

• 82% at 20 years

Acute transverse

myelitis9-11

• 26% at 3 years

• 29% at 5 years

At least 1 brain lesion:

• 54% at 3 years

• 92% at 8 years (if OCBs present)

Typical MRI in High-risk CIS

Brain MRI Cervical Spine MRI

Factors Associated with

More Aggressive MS

Clinical factors

• Male gender

• Older age at onset

• African American*

• Motor involvement

• Cerebellar involvement

• Sphincter involvement

• Frequent relapses

• Poor recovery from

relapses

• Multifocal involvement at

onset

Paraclinical factors

• MRI high lesion burden at

presentation

• Two gadolinium-

enhancing/new T2 lesions

or more than two T1

hypointense lesions*

• Two spinal cord lesions*

• Brain atrophy*

• Low vitamin D

*Freedman, et al. Can J Neurol Sci. 2013;40:307-323.

Non-selective Selective

Antigen-specificBroad-spectrum

Immunosuppression

Toxicity Antigens unknown

or multiple ones!

Strategies to Block the

Immune System’s Attack

Slide courtesy of P. Calabresi

Currently Approved MS Disease-modifying Therapies

Generic Name (Brand Name) Approval

Year

Route Known Main Mechanism(s) of Action

IFNβ-1b (Betaseron) 1993 SC QODReduce T-cell activation/proliferation, reduce

secretion of MMPs, inhibit interferon gamma

release, and reduce expression of HLA

IFNβ-1a (Avonex) 1996 IM QW Same as above

Glatiramer acetate (Copaxone) 1996 SC QD Th1 to Th2 shift & blocking MHC peptide antigen

Mitoxantrone (Novantrone) 2000IV every 3

months

DNA topoisomerase II inhibitor; suppresses

proliferation of T cells, B cells, and macrophages

IFNβ-1a (Rebif) 2002 SC TIW Same as other interferon agents

Natalizumab (Tysabri) 2004IV

monthly

Targets alpha-4 integrin on immune cells which

prevents cell interaction with vascular endothelium

and transmigration into CNS

IFNβ-1b (Extavia) 2009 SC QOD Same as other interferon agents

Fingolimod (Gilenya) 2010 PO QD

Sphingosine 1-phosphate receptor modulator;

prevents activated lymphocytes egress out from

secondary lymphoid organs to peripheral

circulation

Teriflunomide (Aubagio) 2012 PO QDInhibits dihydro-orotate dehydrogenase; decreases

proliferation of activated immune cells

Dimethyl fumarate (Tecfidera) 2013 PO BIDTh1 to Th2 shift & activates Nrf2 transcriptional

pathway

Glatiramer acetate (Copaxone) 2014 SC TIW Same as Glatiramer acetate above

See prescribing information for each agent; O'Connor PW, Oh J. Handb Clin Neurol. 2014;122:465-501.

Disease-modifying Treatment in High-risk CIS

Agent Study Name Entry Criteria Results

IM IFNβ-1a 30 mcg

weekly (Avonex)

CHAMPS/CHAMPIONS(NEJM. 2000;343:898-904;

Neurology. 2006;66: 678-684)

2 or more MRI

lesions

Lower rate of MS dx at

3 years (35% vs. 50%)

SC IFNβ-1a 22 mcg

weekly (low-dose

Rebif)

ETOMS(Lancet. 2001;357:1576-1582)

4 or more MRI

lesions or 3

lesions if one

enhancing or

infratentorial


2 years (34% vs. 45%)

SC IFNβ-1a 44 mcg

TIW (Rebif)

REFLEX(Lancet. 2012;11:33-41)

2 or more MRI

lesions


2 years (21% vs. 38%)

SC IFNβ-1b 250 mcg

qod (Betaseron)

BENEFIT (Neurology. 2006;67: 1242-

1249; Lancet. 2007;370:389-

397)

2 or more MRI

lesions


2 years (28% vs. 45%);

decreased disability

development

Glatiramer acetate

20 mg SC daily

(Copaxone)

PreCISe(Lancet. 2009;374:1503-1511)

2 or more lesions Lower rate of MS

diagnosis

(45% reduction at 36

months)

Disease-modifying Therapy Efficacy

Agent Relapse MRI

12-week

Disability

Progression

Initial Pivotal

Clinical Trials

(Placebo Controlled)

IFNβ-1a (low dose) ARR: ↓ 18%Gd+ lesions: ↓50%

T2 lesions: no effect↓ 37%

Multiple Sclerosis Collabrative

Research Group. Ann Neurol.

1996;39(3):285-294.

IFNβ-1a (high dose) ARR: ↓ 33% Gd+ lesions: ↓84%

T2 lesions: ↓78%↓ 30%

PRISMS. Lancet. 1998;352:

1498–1504.

IFNβ-1b ARR: ↓ 34% Gd+ lesions: ↓83%

T2 lesions: ↓75%

Barely

significant

IFNB Multiple Sclerosis Study

Group. Neurology. 1993;43(4):

655-661.

Glatiramer acetate ARR: ↓ 29%Not adequately

assessedNot significant

Copolymer 1 Multiple Sclerosis

Study Group. Neurology

1995;45:1268-1276.

Natalizumab ARR: ↓ 68%Gd+ lesions: ↓92%

T2 lesions: ↓83%↓42%

AFFIRM. N Engl J Med.

2006;354(9):899-910.

Mitoxantrone

(12 mg/m2)ARR: ↓ 68%

Gd+ lesions: + trend

T2 lesions: ↓85%↓43%

MIMS Trial. Lancet. 2002;360:

2018–2025.

Fingolimod ARR: ↓ 54%Gd+ lesions: ↓82%

T2 lesions: ↓74%↓ 32%

FREEDOMS. N Engl J Med.

2010;362:387-401.

Teriflunomide

(14 mg)ARR: ↓ 32%

Gd+ lesions: ↓80%

Lesion volume: ↓67%↓ 30%

TEMSO. N Engl J Med.

2011;365:1293-1303.

Dimethyl fumarate ARR: ↓ 53%Gd+ lesions: ↓90%

T2 lesions: ↓85%↓ 38%

DEFINE. N Engl J Med.

2012;367:1098-1107.

Disease-modifying Therapy Adverse Effects/Monitoring

Agent Minor Adverse Effects Major Adverse EffectsPregnancy

CategoryMonitoring

IFNβ-1a

(low dose)

Flu-like symptoms,

headache, transaminitis,

depression

Suicidal ideation, anaphylaxis,

hepatic injury, blood dyscrasias,

seizures, autoimmune hepatitis

C

CBC with differential, LFTs, TFTs,

interferon neutralizing antibodies

(if clinically warranted)

IFNβ-1a

(high dose)

Same as above and

injection-site reactions

Same as above and skin necrosisC

Same as above

IFNβ-1b Same as above Same as above C

Same as above

Glatiramer

acetate

Injection-site reactions and

post-injection vasodilatory

reaction

Lipoatrophy, skin necrosis,

anaphylaxis B

None required

Natalizumab Headaches, joint pain,

fatigue, wearing off

phenomenon

Progressive multifocal

leukoencephalopathy, infusion

reaction, herpes zoster, other

infections

C

CBC with differential, LFT’s,

serum JCV antibody (Q6 months),

MRI, Tysabri antibodies

(if clinically warranted)

Mitoxantrone Nausea, vomiting, hair

thinning, menstrual

irregularities

Cardiac toxicity, acute

myelogenous leukemia, infections,

infertility, liver dysfunctionC

CBC with differential, LFT’s, ECG,

Echo/MUGA scan (even after

therapy completed), lifetime dose

140 mg/m2

Fingolimod Lymphopenia (absolute

lymphocyte count >200),

transaminitis

Bradycardia, heart block,

hypertension, risk of infections

(herpetic), lymphopenia (absolute

lymphocyte count <200),

transaminitis, macular edema, skin

cancer, reactive airway, PRES

C

1st dose cardiac monitoring, eye and

skin exams, CBC with differential,

LFTs, VZV IgG prior to starting

medication, PFTs

(if clinically indicated)

Teriflunomide Diarrhea, nausea, hair

thinning

Transaminitis, lymphopenia,

teratogenic, latent tuberculosis,

neuropathy, hypertension

X

CBC with differential, LFTs (monthly

for first 6 months), PPD prior to

starting, wash out (if needed)

Dimethyl

fumarate

Flushing, gastrointestinal

distress

Transaminitis, leukopeniaC

CBC with differential, LFTs

See prescribing information for each agent; O'Connor PW, Oh J. Handb Clin Neurol. 2014;122:465-501.

Lower-Risk

Therapies• Interferon-beta

• Glatiramer

acetate

Moderate-Risk Therapies• Fingolimod

• Natalizumab <24

months if JC

virus Ab positive

(high index)

Higher-Risk

Therapies• Mitoxantrone

• Natalizumab >24

months if JC

virus Ab positive

(high index)

Natalizumab; JCV Ab -

Natalizumab; JCV Ab + (low index)

Dimethyl fumarate

Teriflunomide

Pipeline agents

?

Disease-modifying Therapy Risk

“Baskets”

Conclusions

• MS therapeutics is dynamic and becoming

more complicated (↑ efficacy = ↑ risks)

• Low-risk CIS needs close monitoring while

high-risk CIS should be treated

• Clinical and MRI data are critical for

assessing treatment success or failure

• Ongoing need to balance efficacy and

safety of therapeutic interventions

CASE: 32-year-old Woman

• A 32-year-old woman with migraine headaches and

a brain MRI suggestive of CNS demyelination

• Referred for an abnormal brain MRI

• She has had occasional migraine headaches since

adolescence but recently developed more frequent

headaches several times a month prompting an

MRI by her primary physician to rule out a tumor or

vascular anomaly

CASE: Continued

• Probing questioning elicits no history of

prior neurologic symptoms other than the

headaches and some associated visual

scintillations

• She is otherwise healthy

• Neurological exam is normal

CASE: Continued

• Brain MRI shows ten T2 lesions in the periventricular,

and central hemispheric white matter

– Three lesions are ovoid and have the appearance of

“Dawson’s fingers”

– One lesion is juxta-cortical

– None of the lesions enhance following contrast infusion

• MRI of the cervical spinal cord obtained and is normal

• Serologic and metabolic testing for conditions

associated with white matter lesions reveals no

abnormalities

Your diagnosis would be:

1. Multiple sclerosis

2. Clinically isolated syndrome

3. Radiologically isolated syndrome

4. Other

If this patient had a silent partial segmental lesion in

the cervical spinal cord, but still had a normal

neurological examination, your next step be:

1. Spinal fluid exam

2. Start treatment with a disease modifying

agent

3. Repeat the brain MRI in 6 months

CASE: Continued

• The patient is not treated with a DMT

• Treated with a beta blocker and a change in birth

control pills results in reduction in the frequency of her

migraine headaches

• Six months later, a follow-up MRI of the brain shows a

new T2 hyper-intensity in the left central white matter

which does not enhance following contrast infusion

– She has had no new neurological symptoms

– Her neurological exam still normal

– She has no spinal cord lesion

Your next step would be:

1. Spinal fluid exam

2. Start treatment with a disease modifying

agent

3. Repeat the brain MRI in another 6 months

CASE: For the Panel

• Do you ever treat patients with DMTs on their first presentation

with RIS?

• What factors influence your decision to treat patients with RIS?

• Do you treat patients with RIS on appearance of a new lesion

on follow-up brain MRI regardless of clinical symptoms or

findings?

• Do you believe the natural history of patients with RIS as a

cohort is different from patients presenting with CIS, or is RIS

simply the accidental discovery of a group of patients of whom

most will become symptomatic in the future?

CASE: Summary

• RIS represents the incidental discovery of patients with imaging

characteristics typical of CNS demyelination in whom no clinical

history of symptoms compatible with CNS demyelination is

present, or has occurred in the past

• The long term natural history of such patients is currently

unknown and may differ from the newly identified symptomatic

MS patient, potentially including a group of patients destined to

have clinically benign MS who would not require treatment

• The presence of silent spinal cord disease is known to increase

the likelihood of a future symptomatic demyelinating event in a

patient with RIS

MS Therapeutic Strategies:

What to Use, In Whom, and

When to Switch

Robert Bermel, MD

Staff Neurologist and Medical Director

Mellen Center for Multiple Sclerosis

Cleveland Clinic

Cleveland, OH

The Clinical Situation in RRMS

• We are well-equipped to treat and monitor the

inflammatory component of RRMS

– 10 (11) approved therapies

– Widespread availability of MRI for monitoring

• Early treatment is emphasized

• DMTs are variably effective in individuals

• No biomarker to prospectively predict efficacy of specific

treatments in individual patients

• Choosing and monitoring a therapy (clinically and with

MRI) is common, though there are no standards or

defined targets in the clinic

• Symptomatic treatment and wellness play a large role

Therapeutic Options: 2014

Monitoring off therapy

Injectables:

Interferon beta-1b

Interferon beta-1a IM

Interferon beta-1a SC

Glatiramer acetate qd

Glatiramer acetate tiw

Orals:

Fingolimod

Teriflunimide

Dimethyl fumarate

Infusions/MAbs:

Natalizumab (JCV Ab +)

Natalizumab (JCV Ab -)

Therapeutic Options:

2014 Overly Simplifying Efficacy


Injectables:

Interferon beta-1b





Orals:

Fingolimod

Teriflunimide

Dimethyl fumarate

Infusions/MAbs:




2014 Overly Simplifying Safety


Injectables:

Interferon beta-1b





Orals:

Fingolimod

Teriflunimide

Dimethyl fumarate

Infusions/MAbs:



Key Considerations

• Disease severity/burden/prognosis

– Recovery from prior relapses, MRI lesion burden

• Disease activity

– Relapse frequency, MRI activity

• What have they been on in the past?

• JCV Ab status

• Pregnancy plans?

• Patient and physician preference and risk tolerance


2014 More Realistic

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Inte

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Inte

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Gla

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Abs:

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)

Nata

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Patient

Monitoring off

therapyOrals:

Fingolimod

Teriflunimide

Dimethyl fumarate

How can we evaluate an individualized

treatment plan for success?

Treating to Target in MS

• What do we expect of our current

therapies?

• Do we discuss it with our patients?

• How do we know if we are achieving the

desired result?

• Model from rheumatoid arthritis and

diabetes

One Possible Treatment Target

• No new or enlarging T2 lesions

• No new Gad+ lesions

• No relapses

• No confirmed EDSS worsening

No Evidence of Disease Activity• Previously defined in analysis of clinical trials

• Can it be applied to the MS clinic?

When to Switch?

• Common situations:– Noncompliance

– Symptoms or “Global Impression”

– Definite relapses

– Exam changes/disability progression

– Neutralizing antibodies

– Gad lesions

– New/enlarging T2 lesions

Does subclinical disease activity on treatment matter?

Early MRI Activity on IFN Predicts

Poor Long-term Outcome

Reprinted with Permission from Bermel RA, et al. Ann Neurol. 2013;73(1):95-103.

MRI activity and relapses predicted future disability in patients treated with IFNβ

ASSURANCE Study (15-year f/u of IM IFN beta1a) ─ Results:

Modified Rio Score

• Based on PRISMS-4 data (IFN)

• Composite score integrating

new T2 lesions and relapses

• Disease activity over first year to

predicts disability progression in

subsequent 3 years

Reprinted with Permission from Sormani M, et al. Mult Scler. 2013;19(9):1246-1247.

Probability of disability progression

MRI Activity on IFN: The Dominant

Factor Predicting EDSS Worsening

Reprinted with Permission from Prosperini L, et al. Eur J Neurol. 2009;16(11):1202-1209.

Complexities: Monitoring

• Monitoring disease activity is complex

– Reestablishing the baseline for MRI monitoring

– How to appropriately analyze MRI

– No easy way to track the components of NEDA in most

electronic medical records

– Threshold to act (and what to do) is unclear

• Implementing in the clinic may be facilitated by

enlisting radiology colleagues, and using

technology

NEDA=No Evident Disease Activity

A Consistent Strategy

• There is no “one size fits all” treatment

• Choice of initial therapy depends on multiple factors

• Regardless of choice, monitoring for tolerability,

adherence and efficacy is important

• A “treat-to-target” approach may be reasonable, though

more research guiding this strategy is needed

• If breakthrough disease, switching mechanisms of

action makes sense, though largely based on data from

interferon long-term follow-up

• Do not forget symptomatic therapy and wellness

CASE: 27-year-old Woman

• A 27-year-old woman has been taking glatiramer

acetate for the past four and a half years

• Her symptoms began with an episode of optic neuritis

5 years ago

• Her brain MRI showed five T2 hyper-intense lesions

including periventricular lesions with the appearance of

“Dawson’s fingers”

• She was started on interferon beta but did not tolerate

the flu-like symptoms and was switched to glatiramer

acetate

CASE: Continued

• Surveillance brain MRI reveals 2 new lesions compared

to her last image about a year prior

• Prior monitoring MRIs have been stable

• Neurologic exam reveals left optic disc pallor with visual

acuity of 20/25 corrected, and mild vibratory loss in her

left foot, unchanged from her initial exam 6 years ago

• EDSS is 1.5

• No new symptoms since presentation

• No comorbid medical conditions

• Previous imaging of her cervical spinal cord was normal

In counselling this patient, what

would you recommend next?

1. Change in DMT therapy

2. Continuation of current therapy and repeat

brain MRI in 6 months

3. Continuation of current therapy and repeat

brain MRI in a year

4. Repeat cervical MRI

CASE: Continued

• A year goes by and she has another small

new lesion in the right hemispheric white

matter on a follow-up surveillance MRI

• Her exam is unchanged

• She has had no new neurologic symptoms

• She has now been on glatiramer acetate for

5.5 years

At this time what would you advise?

1. Continue glatiramer acetate unless she

has a new clinical event

2. Switch to an alternate DMT

3. Continue to monitor MRIs to see if she

develops more lesions

4. Switch DMTs if a new silent lesion

develops in the brainstem or spinal cord

In a clinically stable mildly affected MS patient,

how many new MRI lesions would prompt you

to switch DMTs?

1. 1

2. 2

3. 3

4. 4

5. 5 or more

6. I would not change treatment based only on new MRI lesions

CASE: For the Panel

• How often do you obtain surveillance MRIs?

• How many lesions are sufficient to prompt you to change DMTs

in a clinically stable patient?

• Does the timing of new lesions in relation to the duration of MS

and the current DMT treatment affect your decision making?

• Does the severity of the patient’s existing (stable) clinical

condition affect your decision making when a new lesion

appears?

• Does any new relapse warrant a switch in DMTs, or does the

duration of stability prior to the event affect your decision?

Adherence: Monitoring,

Achieving, and Optimizing

Kathleen Costello, ANP-BC, MSCN, MSCS

National Multiple Sclerosis Society

Johns Hopkins Medicine

New Information About Adherence

Really?

Adherence

“The extent to which a person’s behavior –

taking medication, following a diet, and/or

executing lifestyle changes – corresponds

with agreed recommendations from a health

care provider.”1

1World Health Organization. (2003). Adherence to Long-term Therapies: Evidence for Action. Geneva: WHO.

What Do We Know

About Nonadherence?

• The number of patients who are nonadherenthas reached epidemic proportions.1

• 3.8 billion prescriptions written/year yet >50% are taken incorrectly or not at all.2

• A survey of 1000 patients, nearly 75%, admitted to partial or nonadherence.3

• Among the chronically ill, who regularly fill their prescriptions, only 1/2 of the doses are taken.4

1Chesanow N, Medscape. 2014; 2Osterberg L and Blaschke T. NEJM. 2005;353:487-489.3National Council on Patient Information and Education 2007; 4Fischer M, et al. J Gen Intern Med. 2010;25(4):284–90.

Impact on Health

• Increasing the effectiveness of adherence,

interventions may have a greater impact on

long-term health benefits than

improvements in specific medical

treatments.

World Health Organization. (2003). Adherence to Long-term Therapies: Evidence for Action. Geneva: WHO.

Adherence to MS Medications

• A substantial affect (N=2446) on the clinical

and economic impact of adherence to

DMTs

– Less likelihood of hospitalization

– Less likelihood of relapse, particularly severe

relapse

– Less medical costs overall

Tan H, et al. Adv Ther. 2011;28:51-61.

Nonadherence to DMTs

• Several large DMT adherence studies in MS

1. Treadaway K, et al. J Neurol. 2009: N=798

Nonadherence over 3 questionnaire periods or waves:

39%, 37%, and 36%

2. Devonshire V, et al. Eur J Neurol. 2011: N=2648

(4 weeks)

Overall nonadherence: 25%

3. Arroyo E, et al. Eur J Neurol. 2011: N=254 (2 years)

Overall nonadherence: 18%

Reasons Cited for

DMT Nonadherence

1. Forgetting to take the medication

2. Injection related reasons

3. Did not feel like it

4. Lack of perceived benefit

Treadaway K, et al. J Neurol 2009;256:568-576; Devonshire V, et al. Eur J Neurol. 2011;18:69-77;

Arroyo E, et al. Eur J Neurol. 2011;65:59-67.

Adherence to DMTs

• A study of 55 multiple sclerosis patients that looked at

various neuropsychological factors and adherence to

DMTs over an 8-week time frame

• Results indicated that

– MS patients with current mood or anxiety disorders were

nearly 5 times as likely as MS patients with no psychiatric

diagnosis to exhibit problems adhering to treatment.

– Poor adherence was also associated with memory

difficulties, anxiety, depression, neuroticism, and low

conscientiousness.

Bruce J, et al. J Behav Med. 2010;33:219–227.

Adherence to DMTs

• A UK study of 2390 patients, conducted for several years, assessed factors that influence persistence with IFN β-1a SC treatment

• Overall 24% of patients discontinued treatment

• Associated with discontinuation:– Feeling unwell on treatment (adverse effects)

– Feeling poorly informed at the start of treatment

Bruce J, et al. J Behav Med. 2010;33:219–227.

What is Being Done

to Improve Adherence?

• >40,000 peer-reviewed papers on the

subject – yet the estimated rate of poor

adherence has not changed over the past

several decades.

Honigberg R, et al. Utilization Review Accreditation Commission. 2011.

Steps in Initiation and Adherence

1. Prescription written/explained

2. Prescription filled

– The first 6 months are the most critical time for adherence

3. Individual factors for nonadherence

– Forgetfulness (25%)

– Insurance/Cost (17%)

– Adverse events (20%)

– Perception of need (14%)

4. Consider that the patient spends a few hours with the provider

each year – but 5000 hours living without us

– A lot can happen to influence adherence!

HCP Role in Adherence

• Education/re-education

– Purpose

– Expectations

– Adverse effects/management

• Insurance pre-authorization/appeals

• Followup

– Several studies indicate improved adherence with nurse

phone f/u1

• Assess/address individual factors affecting adherence

1Caon C, et al. Journal of Neuroscience Nursing. 2010;42(5 suppl):S5-S9.

Addressing Individual Factors

• Forgetfulness

– Simplified dosing regimen

– Frequent followup

– Maximize support network

– Telephone counseling

• Adverse effects

– Assess ISR

– Aggressively assess and treat

– Change treatment if

interventions exhausted

– Frequent followup

• Treatment fatigue

– Discuss with patient

– Enlist family/other support

– Change treatment if needed

– Motivational interviewing

• Cost

– Assist with resource

identification

– Appeals to insurance

Remington G, et al. International Journal of MS Care. 2013;15:36-45.

Summary

• Adherence continues to be a problem despite our

best efforts

• The MS adherence literature suggests that from

20% to 40% of patients are nonadherent

• Numerous contributing factors have been identified

• Adherence plans that address individual

nonadherence factors, with attention to close

followup may improve adherence to DMTs

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