1. Alina Webber Neurology R3
Treatment of MS
Alina Webber Neurology R3

2. Outline Overview of MS Acute treatment (relapse) Long term management
MS and Lifestyle

3. MS (A brief overvveiw)
Figure. A: RRMS is characterized by acute attacks with full recovery or with partial recovery. B: SPMS starts with a RR course followed by a progressive phase. C: PPMS is characterized by progression from onset of disease without acute relapses. D: PRMS is characterized by progression from onset of disease with acute relapses. Data from Lublin F, et al.[2]

4. Pathogenesis of MS Lawrence Steinman & Scott Zamvil. Nature 2003
T cells, B cells and antigen-presenting cells (APCs), including macrophages, enter the central nervous system (CNS), where they secrete certain chemicals known as cytokines that damage the oligodendroglial cells. Lymphocytes diapedese into the CNS through use of a surface receptor known as alpha4-integrin. This step is impeded by antibodies specific for alpha4-integrin or by interferon-beta (IFN-beta). Once the blood–brain barrier is breached, other inflammatory cells accumulate in the white matter. Inside the brain, T cells and accompanying macrophages and microglial cells release osteopontin (OPN), interleukin-23 (IL-23), IFN-gamma and tumour-necrosis factor (TNF), all of which damage the myelin sheath. Also, the presence of OPN might lead to the attraction of T helper 1 (TH1) cells. T-cell activation can be blocked by altered peptide ligands (APLs), such as copaxone, or by statins. Concomitantly, B cells (plasma cells) produce myelin-specific antibodies, which interact with the terminal complex in the complement cascade to produce membrane-attack complexes that further damage oligodendroglial cells. DNA vaccination can be used to tolerize T- and B-cell responses to myelin.
Lawrence Steinman & Scott Zamvil. Nature 2003

5. Good to know when talking about MS trials…
EDSS
McDonald Criteria
Poser Criteria
Dinner tomorrow?

6. EDSS (Expanded Disability Status Scale)
EDSS steps 1.0 to 4.5 refer to people with MS who are fully ambulatory. EDSS steps 5.0 to 9.5 are defined by the impairment to ambulation. (FS = functional systems: cerebellar, bladder, brainstem, sensory, motor… )
0.0: Normal Neurological Exam
1.0: No disability, minimal signs on 1 FS
2.0: Minimal disability in 1 of 7 FS
3.0: Moderate disability in 1 FS; or mild disability in FS, though fully ambulatory
4.0: Fully ambulatory without aid, up and about 12hrs a day despite relatively severe disability. Able to walk without aid 500 meters
5.0: Ambulatory without aid for about 200 meters. Disability impairs full daily activities
6.0: Intermittent or unilateral constant assistance (cane, crutch or brace) required to walk 100 meters with or without resting7.0: Unable to walk beyond 5 meters even with aid, essentially restricted to wheelchair, wheels self, transfers alone; active in wheelchair about 12 hours a day
8.0: Essentially restricted to bed, chair, or wheelchair, but may be out of bed much of day; retains self care functions, generally effective use of arms
9.0: Helpless bed patient, can communicate and eat
10.0: Death due to MS
Kurtzke JF. Neurology. 1983; 33:

7. McDonald Criteria Origianlly devised in 2001 by Dr. Ian McDonald.
They made use of MRI, and were intended to replace old Poser and Schumacher criteria.
Recent update and change to criteria in 2010 (out of criticism that non-caucasion pts did not fit the origincal criteria

8. A Historical note: Poser Criteria
Replaced Shumaker criteria for diagnosis of MS.
Clinically definite MS
2 attacks and clinical evidence of 2 separate lesions
2 attacks, clinical evidence of one and paraclinical evidence of another separate lesion
Laboratory supported Definite MS
2 attacks, either clinical or paraclinical evidence of 1 lesion, and cerebrospinal fluid (CSF) immunologic abnormalities
1 attack, clinical evidence of 2 separate lesions & CSF abnormalities
1 attack, clinical evidence of 1 and paraclinical evidence of another separate lesion, and CSF abnormalities
Clinically probable MS
2 attacks and clinical evidence of 1 lesion
1 attack and clinical evidence of 2 separate lesions
1 attack, clinical evidence of 1 lesion, and paraclinical evidence of another separate lesion
Laboratory supported probable MS
2 attacks and CSF abnormalities
SCHUMACKER et al. Ann N Y Acad Sci Mar 31;122:552–568
Poser CM, Paty DW, Scheinberg L, et al. (March 1983). Annals of Neurology 13 (3): 227–31

9. Steroids, and acute MS

10. Treatment of the acute attack
History:
First RCT in 1970’s: adrenocorticotropic hormone (ACTH) was given IM. (Rose et al, 1970)
n~200
Shortened recovery time, but 4 weeks post treatment there was no clinical difference.
Prominent SE’s (Na retention, hyperglycemia, Psych disorders) was what prompted trials of synthetic corticosteroids with a short half life.
1992: Several RCTs emerged with methylprednisolone (but the duration and dose of treatment varied from 500mg IV QD x 3days to 1000mg IV QD x 10 days. Some trials showed benefit of PO methylprednisolone (500mg PO QD x 5d) (Meyers 1992, medlink)

11. Current Protocol?
MOST COMMON CURRENT PROTOCOL: 3-7day course of IV methylprednisolone ( mg IV QD) with OR without a short taper
Methyprednisolone reduced the risk of worsening or not improving within 5 weeks. No long term benefits, however, just a quicker recovery.
Why not PO glucocorticoids?
Barnes, Lancet 1997: RCT, n~80 acute MS relapses:
Methlprednisolone 48 mg PO x 7d, then 24mg PO x 7d, then 12mg PO x 7d.
Vs. 1000mg IV methylpred x 3days.
No statistical difference in EDSS at 4 weeks.
The authors concluded that oral steroids was a better regime in terms of cost, pt preference….

12. So, why not PO steroids? The Optic Neuritis Treatment Trial (ONTT)
314 patients. Random assignment to:
PO prednisone 1mg/kg/d x 14 days, with a 4 day taper
IV methyprednisolone 250 QID x 3days, PO pred 1mg/kg/d x 11 days, four day taper.
PO placebo x 14 days
Primary outcome: visual acuity, contrast sensitivity
IV methylpred accelerated recovery, but 1 year outcomes were the same.
IV methypred reduced the risk of conversion to MS (7.5% vs and 16.7%
Oral pred arm had a significantly higher 2 year risk of recurrent optic neuritis in both eyes (30% vs 13 and 16%). At 10 years this risk remained.
Beck et al. Am J Ophthalmol. 2004

13. Steroids continued
Oral regimes are often used for MS exacerbations without optic neuritis.
No good theoretical evidence as to why PO glucocorticoids would do this.
SE’s of short term IV methyprednisolone:
Relatively few
Mental status changes
Unmasking of infection
GI disturbances
Decreased bone density if repeated Tx: yearly bone density scans recommended in pts with repeated treatments.

14. Other options for acute MS?
PLEX: plasma exchange vs. plasmapheresis? The difference?
Plasma exchange: removal of plasma and replacement with fluids
Plasmapheresis: the removal of plasma (aphaeresis is removal in greek)
The two are often used synonymously in medical literature.
Up to date uses them synonymously: (“Complications of therapeutic plasma exchange” article)
Buskard, Can Med Assoc J. 1978

15. PLEX
May be beneficial in acute severe MS attacks that do not respond to glucocorticoids.
One trial: 22 pts with CNS demyelinating disease (12 MS pts total) assigned to PLEX vs sham.
Moderate to greater improvements (42% PLEX, 6% sham).
A later trial: 116 MS pts: results were that PLEX led to faster improvement in exacerbations that sham. (Note: no long term benefits)
This let the AAN to include PLEX into the guidelines for a possible adjunctive treatment of relapsing MS.
Weiner, Neurology. 1989

16. Disease Modifying Treatment
Avonex (interferon beta 1a)
Betaseron (interferon beta 1b)
Extavia (Interferon beta-1b)
Rebif (interferon beta 1a)
Copaxone (Glatiramer acetate)
Tysabri (natalizumab)
Mitoxantrone

17. Interferons
Pharmacology: Cytokines that mediate antiviral, antiproliferative and immunomodulatory activities in response to viral infections and other biological inducers.
Interferon beta binds to human cells, leads to ifn gene product production… exact mechanism not understood, but there are some ideas:
Modulates plasma cell IgG synthesis
Decreases antigen presentation in microglia
Anti inflammatory effects via T cells (regulates migration, downregulates adhesion molecules…

18. The Interferons History
Landmark paper in the 1980’s (Jacobs et al, 1986) showed for the first time that interferon beta, when intrathecally administered, could improve MS exacerbations.
In 1987 a trial of IV interferon gamma was performed (n=18). (Panitch et al).
The results? A dramatic increase in the relapse rate of patients treated with interferon gamma!
Yet the important discovery that activating the peripheral immune system with peripheral drug administration can change the course of a CNS disease.

19. History continued
The first approved med by the FDA was interferon beta 1b in 1993.
In double blind placebo studies, interferon beta 1b:
Decreases relapses by 34% at 2 years
Decreased T2 lesion burden at 5 years
Slowed disease progression
The IFNB Multiple Sclerosis Study Group. Neurology. Apr 1993;43(4):655-61

20. Interferon beta-1a Interferon beta 1a had similar efficacy:
301 patients initially
Exacerbation rate decreased 29%
Disease progression was slowed (progression in 29% of patients on interferon vs 34% in the placebo group).
Decrease in the mean MRI lesion volume and number of enhancing lesions.
The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. Mar 1996;39(3):285-94
Dosing? Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial
Relapses occurs less frequently with higher doses, and MRI lesions were reduced with higher doses
Neutralizing antibodies occurred more with higher doses, and this did affect the outcome in pts with neutralizing Abs.

21. Options for interferons:
Brand (Generic Name)
Frequency
Route of Delivery
Usual Dose
Avonex
(interferon beta-1a)
Once a week
Intramuscular (into the muscle) injection
30 mcg
Betaseron
(interferon beta-1b)
Every other day
Subcutaneous (under the skin) injection
250 mcg
Extavia (interferon beta-1b)
Rebif (interferon beta-1a)
Three times a week
44 mcg

22. Side Effects of InterferonsSE
Beta-1b every other day
Once weekly beta-1a
3x/week beta 1a
management
tolerability
Local Skin reactions
85%
15%
46%
Transient 50% dose reduction, or improve injection technique
Good
Fever
49%
23%
35%
Tylenol, NSAIDS, pentoxyphilline
Flulike Sx.
52%
61%
56%
Leuko or thrombocytopenia
40% 8%
20%
Transient 50% dose reduction
Increased liver enzymes
19%
10%
Good (disappear within months.

23. Interferon Beta SE’s continued…
Beta-1b every other day
Once weekly beta-1a
3x/week beta 1a
management
tolerability
Depression
16%
10%
24%
Anti-depressants
Poor
Skin Necrosis 5% 0% 2%
Improve injection technique, stop treatment
Thyroid
alterations
1-2%
Transient 50% dose reduction
Good

24. Other SE’s worth mentioning (that didn’t fit neatly into my table):
Neutralizing antibodies to interferon beta (NAbs)
May effect clinical and MRI efficacy.
Whether or not NAbs are detrimental to initial treatment response is unclear (studies yield mixed results)
NAbs have been more consistantly shown to have a detrimental effect in the long term (3-4 years)
NAbs occur with a lower frequency in IM interferon 1A (2-6%).
SubQ interferon beta 1a (12-25%)
Interferon beta 1b (22-38%)

25. Monitoring guidelines:
CBC, Chem7, LFTS at 1,3, and 6 months. TSH should be checked every 6 months if Hx. Thyroid dysfunction
Psych sx (depression, SI)
Pregnancy test
CXR
EKG

26. Glatiramer acetate
Copaxone is a random polymer of four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine. The mixture is antigenically similar to myelin basic protein, a component of the myelin sheath of nerves

27. Glatiramer acetate (copolymer 1)
Mechanism of action – unclear of the exact mechanism, but:
Experimental models: binds to MCH molecules and competes with myelin antigens for their presentation to T cells.
Induces T helper 2 type suppressor cells to the CNS, these cells express anti-inflammatory granules.

28. History:
Benefits of Glatiramer acetate first established in a double blind trial of RRMS pts (n=251) (Johnson et al 1995)
At two years, significantly lower relapse rate (29%)
Slowed EDSS progression
No MRI outcome in initial trial.
Other studies, including a 2007 trial which showed similar results and a reduction of MRI activity –
two doses were tested as well (20 and 40mg). The higher dose was more effective
(Cohen et al, 2007)

29. SE’s of Copaxone: Frequency Management Tolerability
Local skin reactions
90%
Transient, no treatment
Good
Pain
64%
Erythema
57%
Pruritis
38%
Necrosis 0%
Lipoatrophy
45%
Systemic reactions
15%
Dyspnea
13%
Flushing 8%
Chest Pain
10%
Palpitations 5%

30. Side effects Generally well tolerated
Short lived skin reactions are most common
Localized lipoatrophy has been reported in up to 45% of pts in some studies, mainly women.
May occur within months of therapy.
Disfiguring, permanent

31. Monitoring:
No routine tests recommended

32. Fingolimod

33. Before I talk about Fingolimod, the following was stolen shamelessly from Medscape’s latest CME quiz on Oral MS treatment (An okay video, but sponsored by Novartis):

34. What factor(s) go into selecting the optimal therapy, both injectable and oral, for patients with RRMS?
Efficacy, cost, convenience, monitoring, tolerability, and safety
Burden of therapy
Safety and efficacy
Cost, convenience, monitoring, tolerability, and safety

35. Answer:
Efficacy, cost, convenience, monitoring, tolerability, and safety

36. Which of the following treatment approaches is best supported by a currently available evidence base in a patient with highly active RRMS who shows breakthrough disease after taking interferon-beta for 6 months?
Switching to natalizumab
Switching to fingolimod
Continuing with interferon-beta for another 6 months and then switching to fingolimod
Continuing with interferon-beta until steroids can no longer control motor symptoms and then switching to either fingolimod or natalizumab

37. Answer: A wide body of evidence supports an early switch in RRMS to fingolimod in pt’s with highly active disease and show signs of disease progression while on interferon beta therapy. Little data is available on the benefits of switching to tysabri

38. For patients with no history of cardiovascular disease and who are considering starting fingolimod, guidelines from the European Medicines Agency (EMA) recommend that they should have their heart activity monitored:
Before the first dose of fingolimod and continuously overnight after the first dose
Periodically during the first 6 weeks of therapy
Never, only patients with a history of cardiovascular disease are at risk of cardiac side effects
Before the first dose and continuously for at least the first 6 hours thereafter

39. Answer: The EMA (European Medicines Agency) recommends all patients starting fingolimod should have their heart activity monitored BEFORE the 1st dose, and continuously for 6 hours. EXTEND monitoring by 2 hours in pts whose HR is lowest 6h post first dose, or overnight if cardiac problems are clinically significant.

40. Fingolimod
An Sphingosine 1-Phosphate (S1P)-receptor modulator, derived from a fungal metabolite
Reduces circulating WBCs by sequestering lymphocytes in lymph nodes, preventing them from becoming active.
Originally developed as an antirejection drug, not marketed for this. Now under investigation as a potential CHF/antiarrythmic med.

41. History: FREEDOMS trial N-1272, RRMS patients (0.5 or 1.25 mg PO QD)
24 months:
The annual relapse rate was 0.18, 0.16, and 0.4 (0.4 was placebo).
Incidence of serious infections was similar.
Macular edema occurred in 7 pts on the high dose group.
TRANSFORMS trial
N = 1200, RRMS pts (0.5mg or 1.25mg PO QD vs interferon beta-1a
Relapse rate lower in fingolimod group ( 0.2, 0.16 and 0.33)
MRI favored fingolimod
No change in disease progression
More serious adverse effects in fingolimod groups: (2 serious disseminated infection: 1 herpes, 1 VSV. 12 patients developed skin or breast ca, 19 developed bradycardia or AV block)

42. SE’s Risk of Herpes virus infections Macular edema
Fatal tumor development
Headache (25%)
Diarrhea (12%)
Elevated LFTs (14%)
Flu like sx (13%)
Cardio: HTN, bradycardia
Heme: Lymphopenia, leukopenia

43. Monitoring: Before initiation: CBC, LFTs, EKG Optho exam
Varicella serology and vaccination Hx. (Fingolimod should not be started one month after vaccination
Derm exam – r/o precancerous lesions

44. Monitoring: First dose; During Tx:
BP, cardiac monitor x 6hr (exxtend for 2 more hours if lowest HR at 6hr post dose), and overnight if cardiac sx.
During Tx:
Avoid live vaccines
Optho exam at 3 mo, and routinely if diabetic or hx uveitis
LFT follow up
Pulmonary Function tests if clinically indicated

45. Tysabri (Natalizumab)
Tysabri is a monoclonal antibody directed against alpha 4 integrins, specifically the very late antigen 4 (VLA-4) and vascular-cell adhesion molecule 1 (VCAM-1) and lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) interactions, respectively
Alpha-4 integrin is expressed on the surface of inflammatory lymphocytes and monocytes and may play a critical role in adhesion to the vascular endothelium.

46. Mechanism of action and significance?
Rituximab, Natalizumab, and Efalizamab all inhibit the lyphocytes from binding to the endothelium in a similar manner, and all three are associated with rare cases of PML.

47. Tysabri:
Two key trials: AFFIRM and SENTINEL – results pooled in a 2011 review:
Significantly reduced the risk of having a relapse during two years of Tx (57%)
Reduced the risk of progression of sx (RR = 0.74)
NNT to prevents one exacerbation in 2 years was 4.
83% reduction in MRI plaques
Increased proportion of relapse free patients (32%)

49. Side effects: Tysabri AFFIRM study ENTINEL study Flu-like syndrome 22%
24%
Infections
13%
15%
Allergic reactions 7% --
GI disorders 8%
12%
Menstrual disorders 5%
18%
Chest discomfort
4.5%
<1%
Vertigo 6%
Anxiety
Tremor 1%
Depression
19%
21%
Local Bleeding 3%
Insomnia
17%
PML

50. Clinical use
AAN guidelines recommend Tysabri be reserved for selected RRMS pts who have failed therapies because of:
Continued disease activity
Medication intolerance (should try both interferons AND copaxone before determining treatment failure/intolerance)
Aggressive initial disease course (debatable*)
Not to be used with beta interferon or other immunosuppresants b/c of PML risk.
Drug Holiday?
NOT recommended (gr 2C evidence), but a reasonable option for pts who are more concerned about PML.

51. Monitoring on Tysabri
Before initiating: Leukocyte counts, initial brain MRI, JC serology for risk stratification
Clinical evaluations every 6 months
Monitor for:
hepatotoxicity
hypersensitivity reactions 1hr post infusion
Consider antibody testing to tysabri if drug holiday (higher risk of allergic rxn)
US: tysabri can only be given in select centers. Manditory patient registry (US) with checklist that asks about PML symptoms.

52. Mitoxantrone
An antineoplastic drug with long lasting immunosuppressive effects.
Approved for both RRMS and progressive forms of MS (Note: in progressive MS other meds are otherwise used off label)
AAN 2003 Guidelines: because of cardiac toxicity, and limited benefits in small trials, mitoxantrone should be limited to patients who have failed other therapies.

53. Side Effects: Frequency Management Tolerability Nausea 76% Give always
Frequency
Management
Tolerability
Nausea
76%
Give always
intravenous antiemetics
before infusions
Good
Alopecia
61%
Transient, no treatment
Menstrual disorders
(secondary amenorrhea)
60%
(10%)
(hormonal replacement)
(may be irreversible)
Urinary tract infection
32%
Antibiotics (check white
blood cell count)
Leukopenia
(granulocytopenia)
19%
(6%)
White blood cell count 3
to 6 days before and
every 10 days after
infusions (50% dose
reduction in neutrophil
count less than 1500
mm3

54. SE
Frequency
Management
Tolerability
Increased liver enzymes
15%
Usually transient, 50%
dose reduction if
greater than 5-fold
baseline
Good
Cardiac toxicity 2%
Echocardiogram every
6 months or above 100
mg cumulative dose;
stop if left ventricular
ejection fraction drops
by 10% or below 50%
May progress even after stopping treatment
Acute leukemia
Exceptional
May occur even after stopping treatment

55. Multiple other trials for disease modifying drugs with no evidence, or further evidence needed:
Alemtuzumab
Azathioprine
CCSVI treatment
Cladribine
Cyclophosphamide
Daclizumab
Dalfampridine
Fumarate
Glucocorticoids in combination therapy
Intravenous immune globulin
Laquinimod
Ocrelizumab
Rituximab
Statins
Stem cell transplantation
Teriflunomide

56. Since the first disease modifying treatment came out in 1993, there are now 7 drugs that are FDA approved for use in MS
Brand (Generic Name)
Frequency
Route of Delivery
Usual Dose
Avonex® (interferon beta-1a)
Once a week
Intramuscular (into the muscle) injection
30 mcg
Betaseron® (interferon beta-1b)
Every other day
Subcutaneous (under the skin) injection
250 mcg
Copaxone® (glatiramer acetate)
Every day
20 mg (20,000 mcg)
Extavia® (interferon beta-1b)
Gilenya™ (fingolimod)
Capsule taken orally
0.5 mg
Rebif® (interferon beta-1a)
Three times a week
44 mcg
Tysabri® (natalizumab)
Every four weeks
IV infusion in a registered infusion facility
300 mg

57. Manufacturer/Distributor & Year of Health Canada Approval
Avonex® Biogen Idec Canada — 1998 Betaseron® Bayer HealthCare Pharmaceuticals, Inc. — 1995 Copaxone® Teva Neuroscience — 1997 Extavia® Novartis Pharmaceuticals Canada Inc. — 2009 Gilenya® Novartis Pharmaceuticals Canada Inc. — 2011 Rebif® EMD Serono Canada Inc. — 1998 Tysabri® Biogen Idec Canada Inc. — 2006

58. For interest’s sake: How much would you guess MS drug treatment costs per year, in Canada?

59. From MS Society Canada:
Cost of disease modifying therapy: $20,000-$40,000 (dependant on the drug, the pharmacy, etc)
The amount of reimbursement varies between provinces.

60. A few small points on complementary tx

61. MS and Lifestyle Diet – no recommendations Vitamin D: Exercise
? Linked to decreased incidence of MS
IU vitamin D/day for people who may be vit D deficient.
Exercise
Reduces fatigue, improved bladder and bowel function, strength and mood.
Acupuncture
Studies suggesting benefit, not cosidered to be a CAM to avoid
MS Society Canada (2012)

62. Controversy and new directions
Surgeons look over a balloon at the end of the wire, which is put through with a surgical catheter into the patient as part of MS treatment.
(JOHN LEHMANN/THE GLOBE AND MAIL)

63. Commonly use CAM methods to avoid:
Removal of amalgam fillings
Some suggestions that mercury in dental fillings can cause or trigger MS – No evidence
Bee sting therapy
24 week RCT showed no change in activity, disability or fatigue. No change in quality of life.
MS Society Canada (2012)

64. Thanks!