Advancements in Treatment Options, MS Relapses, and

Adherence

Apri l 27, 2013Orlando, FL

S c o t t L . G o l d , M . D .M e d i c a l D i r e c t o r

M S C e n t e r o f B r e v a r dH e a l t h F i r s t M e d i c a l G r o u p

M e l b o u r n e a n d V i e r a

Disclosures

Present at seminars sponsored by the following pharmaceutical companies: Biogen-Idec EMD-Serono QuestCor Teva Neurosciences

Engage in research for the following companies: Biogen-Idec Elan EMD-Serono Janssen Pfizer Roche Teva Neurosciences

A disorder or group of disorders affecting the CNS -

central nervous system (brain, spinal cord)

An autoimmune process causing inflammation in the

CNS in genetically susceptible individuals after one or

more triggers

Inflammation involves myelin, causing demyelination

in the CNS, which leads to slower nerve conduction

and reduced nerve signals controlling function

Axonal injury and destruction occur early and are

associated with permanent neurological dysfunction

What is MS?

Auto-immune Diseases¨ Joints: Rheumatoid Arthritis, Lupus, Psoriatic arthritis

¨ Muscles: Polymyositis; Neuromuscular junction: Myasthenia Gravis

¨ Peripheral Nerves: Guillain Barré, CIDP

¨ Skin: Psoriasis, Dermatomyositis, Lupus

¨ Blood Vessels: Lupus, Polyarteritis Nodosa, Temporal Arteritis

¨ Blood: TTP (platelet disorder)

¨ Sinuses: Allergic Rhinitis

¨ Thyroid: Thyroiditis

¨ Lungs: Asthma

¨ Gastrointestinal: Crohn’s Disease, Autoimmune Hepatitis, UC

¨ Kidney: Glomerulonephritis

¨ Pancreas: Juvenile Diabetes

How Does MS Affect the CNS?

Diagnoses That Mimic MS Infection

Lyme disease Neurosyphilis PML, HIV, HTLV-1

Inflammatory SLE Sjögren’s Other CNS vasculitis Sarcoidosis Behçet’s disease Guillain Barré Myasthenia Gravis

NPH Trauma (chronic SDH) Vascular

Multi-infarct state

Metabolic Vitamin B12 and E

deficiencies Thyroid disorders

CADASIL - rare/familial Cancer

CNS lymphoma Paraneoplastic syndrome

Congenital Chiari malformation

Syringomyelia

Degenerative Cervical spondylosis

Motor neuron disease (ALS and SMA)

Clinical Courses of MS

1. Relapsing-remitting 2. Primary-progressive

3. Secondary-progressive 4. Progressive-relapsing

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Adapted from: Lublin FD, Reingold SC. Neurology. 1996;46:907-911.

5-10%

66% of RRMS

5-10%

80-85%

Relapses

Focal disturbances of function >24 hours

Follows stability of at least 30 days

In absence of environmental, metabolic, or infectious

processes

Occur on average once a year in untreated patients (highly

variable)

Over time, frequency of relapses typically drops, even w/o

treatment (so any treatment looks favorable if not

compared with placebo or other standard DMT’s)

Acute MS Relapses

Prevent Relapses

Treat Relapses

Learn to recognize mimics / pseudoexacerbations

Manage symptoms – acutely during relapses and

chronically if they persist

Delay progression to disability (DMT)

Stabilizing or improving the MRI

Goals of Treatment

Non-Medical Management: Rest in a cool environment Symptomatic - treatment of individual symptoms:

Cognition Fatigue Muscle spasms / stiffness Nerve pain / neuralgia Ataxia Bladder difficulties Seizures

Acute MS Relapses

Medical Management: IV Therapy:

- methylprednisolone, 500-2000 mg IV for 3-5 days, sometimes followed by a short course of prednisone over 1-3 weeks; MOA = cortisol effect on inflammation, stabilizing the BBB

- Acthar gel, IM/SC, 80-120 units daily for 5-21 days (when IV steroids are poorly tolerated or ineffective or if the patient has poor IV access) – comparable in benefit and side effects, but different MOA = cortisol + melanocortin effects (may have

advantages over steroids, with loss cortisol effects and more immune cell effects in the brain and throughout the body)

Oral steroids: - prednisone, methylprednisolone, or dexamethasone

- high doses are more effective and reasonably well tolerated

- used for people with poor IV access or can’t tolerate IV steroids

Other Therapy: plasmaphoresis, IVIg, cyclophosphamide

Acute MS Relapses

Treatment of MS Diet: NMSS website. Also: The Zone Diet, by Dr. Barry Sears, hunter-gatherer variation

by Dr. Terry Wahls: http://www.youtube.com/watch?v=KLjgBLwH3Wc&feature=youtube_gdata_player

Vitamin D3 supplementation Exercise: stretching, weight training, aerobic conditioning; keep in the best shape

possible to be able to fight against any future challenges / attacks

Sleep: quality and quantity

Rest: planned rest periods for energy conservation

Others: relaxation exercises, biofeedback, meditation, tai chi, yoga

Foreign Substances:

eliminate tobacco use

alcohol (ok in small amounts - 1-2 beverages per day)

marijuana (probably ok in small amounts)

medications, especially sedatives, in combination with the above

Be aware of conditions or factors that may mimic or aggravate MS symptoms

stress, depression, sleep deprivation, medical conditions (UTI, bronchitis/lung

disorders, thyroid disorders, heart disease), and effects of medications

Educate yourself on all available treatments Adjust the intensity of treatment to the severity of disease (risk

vs. benefit) Be realistic about what treatments can offer – they don’t cure

MS and may only keep you from declining Treat early, stay positive, and stay committed to your chosen

therapy. Don’t be afraid to change therapies if the current one isn’t right

for you (intolerable side effects or not providing benefit); on the other hand, think twice about going off a therapy that is working

Be open and honest with your family, physician, and most of all, yourself

“MS is a marathon, not a sprint. It’s not how you start, but how you finish that’s important.”

- Dr. Randall Schapiro

Goals of Treatment

Timing of Therapy

Natural course of disease

Theoretical Model

Later intervention

Latertreatment

Treatmentat diagnosis

Intervention at diagnosis

Time Disease onset

Dis

ab

ility

The Changing Treatment Landscape

Currently not submitted FDA-approved therapies

1995 2000 2005 2009 2010 2011

AlemtuzumabExtavia®

(IFNβ-1b)

Gilenya™(fingolimod)

Tysabri® (natalizumab)

Betaseron®

(IFNβ-1b)

COPAXONE®

(glatiramer acetate injection)

Avonex® (IFNβ-1a)

Rebif ® (IFNβ-1a)

Novantrone® (mitoxantrone)

Laquinimod

Approval date

2012 2013

Aubagio(teriflunomide)

Daclizumab

Tecfidera

(DMF/BG12)

18

Impact on the Immune System in MS: Expanding our view beyond the CNS1-5

Lymph node

Bloodstream

Naïve T cells

Anti-inflammatory Th2 cells (MS-specific)

• Multiple sclerosis is a debilitating autoimmune disease characterized by both inflammation and axonal degeneration1

• In order to regulate CNS damage, treatment of MS is focused on restoring immune system balance2-5

• It is important to expand our view to consider treatment impact on the overall immune response

1. Kasper LH, et al. Neurology. 2010;74(Suppl1):S2-S8. 2. Ziemssen T. J Neurol. 2005;252(Suppl 5):V/38-V/45. 3. Yong VW, et al. Neurology. 2007;68(22 Suppl 3):S32-S37. 4. Dhib-Jalbut S. Neurology. 2007;68(22 Suppl 3):S13-S21. 5. Tzartos JS, et al. Am J Pathol. 2008;172(1):146-155.

Proinflammatory Th1 cells (MS-specific)

19

Multiple Sclerosis: Looking at the key players in the CNS1-4

MS-specific proinflammatory immune cells cross from the bloodstream into the central nervous system (CNS), secrete proinflammatory cytokines, and eventually destroy myelin and facilitate neuronal death.

1. Ziemssen T. J Neurol. 2005;252(Suppl 5):V/38-V/45. 2. Yong VW, et al. Neurology. 2007;68(22 Suppl 3):S32-S37. 3. Dhib-Jalbut S. Neurology. 2007;68(22 Suppl 3):S13-S21. 4. Tzartos JS, et al. Am J Pathol. 2008;172(1):146-155.

Proinflammatory cytokinesProinflammatory Th1 cells (MS-specific)

Proinflammatory cellsrelease destructive cytokines and neurotoxic agents

Blood-brain barrier

Th1 cell crossing blood-brain barrier

Cytokine Imbalance in MS

Normal MS

InflammatoryIFN-IL-12TNF

InflammatoryIFN- IL-12TNF

Anti-inflammatoryIL-4IL-10TGF-

Anti-inflammatoryIL-4IL-10TGF-

Th1 Th2

Th1

Th2

Step Therapy in MS** proposed by Dr. William Stuart of the MS Center of Atlanta

Step 1: Main (Platform) medications Interferon beta (Avonex, Rebif, Betaseron, Extavia)

Glatiramer acetate (Copaxone)

Natalizumab (Tysabri)

Fingolimod (Gilenya) Teriflunomide (Aubagio) Dimethyl Fumarate (Tecfidera)

Step 2: Switch between the platform agents if an agent is

ineffective (based on several factors) or poorly tolerated

Step 3: Add IV methylprednisolone or IM/SC ACTHAR (short

course vs. pulses); pulse therapy is not permitted in combination

with Tysabri

Step 4: Switch to or add (except Tysabri) immunosuppressants Imuran, CellCept -> methotrexate -> cyclophosphamide or mitoxanthrone

Other Therapies in MSOther alternatives: Experimental agents prior to release onto

the market; some protocols contain a placebo arm; relapsing

and progressive MS (Melbourne, Vero Beach, Orlando,

Maitland)

Future oral agents (daily) - laquinimod (2013/2014)

Infusions – alemtuzumab (IV yearly), rituxumab / ocrelizumab

(IV every 6 months)

Injections: daclizumab (IM every 2 weeks)

Stem cells – currently limited to RRMS

Bone marrow transplantation

Implanting stem cell and other immature cells, such as

oligodendrocyte progenitor cells in brain / spinal fluid

Closely monitor disease activity and response to therapy Careful history of relapses, progression, and side effects of medications

Neurological examination

MSFC (Multiple Sclerosis Functional Composite: Timed 25ft Walk, 9-

hole peg test, PASAT)

EDSS (Expanded Disability Status Score): cognitive, visual, brainstem,

motor, cerebellar, sensory, bowel/bladder

Neuropsychological testing (Cognitive/Emotional)

MRI’s of the brain and upper (C-/T-) spine

Evoked potentials

OCT / V.A. (especially with varying contrasts) / Visual Field testing

Blood work (25-hydroxy-vitamin D levels, CBC/LFT’s)

Quality of Life

Management

Barriers to Treatment

The New Yorker www.cartoonbank.com

Adherence

The ability to follow the treatment plan that you and your

health care provider agreed upon (a contract)

Average adherence = 50%

Adherence Factors interfering with adherence:

treatment (especially needle) fatigue loss of motivation / complacency financial challenges lack of curative benefit unrealistic expectations (of cure, reversal of

disability, resolution of current symptoms)

adverse effects of medications pregnancy doctor recommended against it treatment was “a hassle”

Adherence Patients who stopped DMTs had:

more severe disability, including SPMS

more relapses

poor to fair health

depressed mood

Adherence Reasons for never using DMT:

my MS was not severe enough doctor didn’t recommend it or advised against it fear of DMT making things worse of causing

adverse effects cost used other therapies fear of needles didn’t know about the DMTs

Adherence Improving adherence:

encouragement education, especially importance of treatment manage medication side effects injection technique and follow-up work with emotional issues (anxiety and

depression) recognize and work around cognitive deficits integrate a treatment schedule into the patient’s

lifestyle encourage a team approach – patient, family,

friends, nurses, clinicians, self-help groups, and pharmaceutical support programs

Determine what’s most important in your life - prioritize

based on your limitations at any given time

Keep active with family and friends

Be active in your church, synagogue, and community

Improve your lifestyle - exercise regularly, do yoga and tai

chi, eat a balanced diet, with small amounts through

the day, avoid tobacco, avoid excessive alcohol

Look at the “big picture” – don’t sweat the small stuff

Don’t dwell on the things you can’t change; focus on what’s

truly important…

Summary

Thank Youfor

Your Attention!