Advancements In Treatment Options MS Relapses & Adherence. Presented by Scott Gold, MD April 27, 2013

2.  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

3.  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

4. 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

7.  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)

8. 1. Relapsing-remitting 2. Primary-progressive
3. Secondary-progressive 4. Progressive-relapsing
Time Time
Time Time
Increasingdisability
Increasingdisability
Increasingdisability
Increasingdisability
Adapted from: Lublin FD, Reingold SC. Neurology. 1996;46:907-911.
5-10%
66%
of
RRMS
5-10%
80-85%

9.  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)

10.  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

11.  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

12.  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

13.  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

14.  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

15. Natural course of disease
Theoretical Model
Later intervention
Later
treatment
Treatment
at diagnosis
Intervention at diagnosis
Time
Disease onset
Disability

17. Currently not submittedFDA-approved therapies
1995 2000 2005 2009 2010 2011
Alemtuzumab
Extavia®
(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. 1
8
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. 1
9
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 cells
release destructive cytokines
and neurotoxic agents
Blood-brain barrier
Th1 cell crossing
blood-brain barrier

20. Normal MS
Inflammatory
IFN-
IL-12
TNF
Inflammatory
IFN-
IL-12
TNF
Anti-inflammatory
IL-4
IL-10
TGF-
Anti-inflammatory
IL-4
IL-10
TGF-

21. 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

22. Other 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

23. 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

24. The New Yorker www.cartoonbank.com

25.  The ability to follow the treatment plan
that you and your health care
provider agreed upon (a contract)
 Average adherence = 50%

26.  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”

27.  Patients who stopped DMTs had:
 more severe disability, including SPMS
 more relapses
 poor to fair health
 depressed mood

28.  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

29.  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

30.  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…

31. Thank You
for
Your Attention!