for postgraduate students

1. Progressive MS
By Mohamed A. Tarek
Assistant lecturer of Neurology
FEBN

2. Definition
Pathogenesis
Markers for progression
Treatment approach
Lublin classification
Home message

3. IS PMS is a separate entity
from RRMS?

6. So Progressive and relapsing MS should be considered to occur on a spectrum rather than as different diseases,
and the understanding that these two forms share several common features in biology, clinical evolution, and
imaging findings is growing.

7. Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity,
and is associated with accelerated brain atrophy. We propose the term silent progression to describe
the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–
remitting MS.

9. Pathogensesis:

12. Definitions:

13. Lublin Classification:

15. Active RRMS

16. ACTIVE RRMS

17. Highly Active RRMS

18. Highly Active RRMS

19. Aggressive RRMS
• One or more of the following :
>>>EDSS > or = 6 within 5 years of MS onset.
>>>EDSS > or = 6 by age 40
>>> SPMS within 3 years of a relapsing onset course,
Menon et al ., 2013

20. Aggressive RRMS

21. Aggressive RRMS

22. Aggressive RRMS

23. Aggressive RRMS Rush et al.,2015 option 1

24. Aggressive RRMS Rush et al.,2015 option 2,3

25. Aggressive RRMS Freedman et al.,2016 option 1

26. Aggressive RRMS Freedman et al.,2014 option 2,3

28. Criteria for Diagnosis PPMS
• The 2017 revised McDonald diagnostic criteria for MS include specific criteria for primary
progressive MS:
including 1 year of disability progression (retrospectively or prospectively determined)
independent of relapses plus at least two of the following: one or more T2 lesions in
characteristic regions on brain MRI, two or more spinal cord MRI lesions, or the presence
of OCB.
Over 1 year + 2/3
1 MRI brain lesion
2 spinal cord lesions
OCB

29. Criteria for Diagnosis SPMS
• 3-6-month sustained worsening of at least 1 point.
• The magnitude of EDSS sustained worsening many times is defined on the baseline level of disability. Definitions have
included
>>> 1.5 points for baseline EDSS score of 0,
>>> 1 point sustained change for those with a baseline EDSS score of less than 6.0,
>>> 0.5 point for baseline EDSS score greater than 6.0.
- Pyramidal score > or =2
- No recent relapse
- EDSS > or = 4
• A 2015 study showed that requiring demonstration of sustained worsening for longer periods (12 to 24 months)
Remember
2-3-4-5-6

32. EDSS PLUS
EDSS +
-(timed 25-foot walk)
-(9-hole peg test): upper extremity function
[a test of manual dexterity in which the time to place nine pegs into a
3 x 3 array is recorded]

33. Multiple Sclerosis Functional
Composite (MSFC)
-(timed 25-foot walk)
-(9-peg hole test): upper extremity function
[a test of manual dexterity in which the time to place nine pegs into a
3 x 3 array is recorded]
-Cognitive function (Paced Auditory serial addition test)

34. T25FWT

35. 9PHT

36. PASAT

37. Interpretation :
• a 20% change in the timed 25-foot walk
• a 20% change in the 9-hole peg test,
• a 4-point (10%) change in the Symbol Digit Modalities Test.
>>>>>>> indicates progession

38. CASE
A 38-year-old man presented for a second neurologic opinion with a 2-year
history of progressive left lower extremity weakness and difficulty controlling his
right hand. Worsening over the past 12 months was confirmed by his prior
neurologist.
Examination revealed left lower extremity weakness, with long tract signs, spasticity, and moderate right arm
dysmetria. MRI of his brain showed several T2 lesions, and two of the lesions demonstrated contrast
enhancement. MRI of his cervical spine showed nonenhancing discrete lesions at C4 and T1. CSF studies
showed positive oligoclonal bands with normal glucose, protein, and cell count.

39. What’s Your diagnosis ?

40. • This patient meets diagnostic criteria for primary progressive multiple sclerosis
and would be an ideal candidate for ocrelizumab. In addition, he is male and
young and has enhancing lesions and positive oligoclonal bands, all suggesting
that he may respond favorably to treatment. Infectious complications, although
possible, are relatively less likely than in older patients with more advanced
disability given that he is otherwise healthy.

41. Markers for Progression
• 1- NFL in serum and CSF

42. Markers for Progression:
•2-OCT
Retina mirrors brain

43. Markers for progression :
3- Conventional and advanced spinal cord MRI diffusion tensor imaging and
spectroscopy measures hold promise as potential biomarkers for progressive
multiple sclerosis.
● Brain lesions in progressive multiple sclerosis are indistinguishable from
those seen in relapsing multiple sclerosis; however, on average, patients with
primary progressive multiple sclerosis tend to have fewer brain T2 lesions
and fewer lesions with gadolinium enhancement.

46. Treatment approach of Progressive MS:
Immune
Modulation
Neuroprotection B-Cell
Therapies

47. Immunomodualtion:
-ve
-ve *
-ve
+ve
-ve
+ve

48. Immunomodulation:
Early trials focused on older immunosuppressant medications,
including azathioprine, cyclosporine, mycophenolate mofetil, And
cyclophosphamide >>> -ve

49. B-cell therapies:
• Rituximab, a chimeric anti-CD20 monoclonal antibody, was the first B-cell therapy
studied in progressive MS; a placebo-controlled study in primary progressive MS
showed no benefit on the primary outcome of EDSS .
• However, subsequent subgroup analysis demonstrated possible benefit for younger
patients (≤51 years) with gadolinium-enhancing MRI lesions.
• ocrelizumab, a humanized anti-CD20 monoclonal antibody had FDA approval of for
primary progressive MS. It is important to note that 27% of patients in ORATORIO
trial>>> ocrelizumab arm had enhancing lesions at baseline, leading to speculation
that the use of a powerful anti-inflammatory in an enriched patient population
explains the positive results.

50. Neuroprotection:
• Several studies have been conducted examining the effects of putative
neuroprotectant medications in progressive MS, but no medications
have yet been approved .
• Simvastatin 80 mg >>>showed a 43% reduction in brain volume loss
compared with placebo in SPMS. (phase 3 trial).
• Ibudilast >>> a phosphodiesterase 2 inhibitor, was studied in 255
participants with primary progressive MS and secondary progressive
MS followed over 2 years. (plans for phase 3 trial )

51. Neuroprotection:
• High-dose biotin modestly improved EDSS scores in a placebo-controlled phase 3 study.
• The MS-SMART (Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial) study
compared the effects of riluzole, amiloride, and fluoxetine against placebo in patients with secondary
progressive MS in a large phase 2 clinical trial >>> -ve for all therapies.
• Several trials using remyelinating agents and cell-based therapies are under development.
• Finally, the management of progressive MS should also include control of medical comorbidities,
including hypertension, hyperlipidemia, diabetes mellitus, and vascular disease, and address issues
such as weight control and smoking .
• Supplementation of vitamin D, although not demonstrated to have an effect in progressive MS clinical
trials to date, should be considered with suspected or demonstrated low vitamin D levels.

52. Ocrelizumab (Ocrevus)
Dose Baseline
Monitoring
On therapy
Monitoring
Special
consideartion
SE Potentially serious
SE
the first anti-CD20 monoclonal antibody FDA approved to treat relapsing forms of MS and the
first of any disease-modifying therapy to gain approval for primary progressive MS.

54. Siponimod (Mayzent)
Mechanism of Action:
siponimod binds the sphingosine-1-phosphate receptor, subtypes 1 and 5 .
It was approved by the FDA on March 27, 2019, for relapsing forms of MS, including clinically
isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. This
was based on the results of the EXPAND (Exploring the Efficacy and Safety of Siponimod in
Patients With Secondary Progressive Multiple Sclerosis) trial of patients with secondary
progressive MS.

55. Siponimod (mayzent)
Dose:
Patients with CYP2C9 genotypes *1/*1, *1/*2, or *2/*2(rapid
metabolizers)
Initiate with a 5-day titration
Maintenance dose (Day 6): 2 mg PO qDay
Use a starter pack for patients who will be titrated to the 2-
mg maintenance dosage
Do not use starter pack for patients who will be titrated to
the 1-mg maintenance dosage
Titration for the 2-mg/day maintenance dose
Day 1: 0.25 mg (1 x 0.25 mg) PO
Day 2: 0.25 mg (1 x 0.25 mg) PO
Day 3: 0.50 mg (2 x 0.25 mg) PO
Day 4: 0.75 mg (3 x 0.25 mg) PO
Day 5: 1.25 mg (5 x 0.25 mg) PO
Day 6 and thereafter: 2 mg (1 x 2 mg) PO qDay
• Patients with CYP2C9 genotypes *1/*3 or
*2/*3 (Slow metabolizers)
• Initiate with a 4-day titration
• Maintenance dose (Day 5): 1 mg PO qDay
• Do not use the starter pack for patients who
will be titrated to the 1-mg maintenance
dosage
• Titration for 1-mg/day maintenance dose
• Day 1: 0.25 mg (1 x 0.25 mg) PO
• Day 2: 0.25 mg (1 x 0.25 mg) PO
• Day 3 0.50 mg (2 x 0.25 mg) PO
• Day 4: 0.75 mg (3 x 0.25 mg) PO
• Day 5 and thereafter: 1 mg (4 x 0.25 mg) PO qDay

56. Siponimod (Mayzent)
Side effects :
-Bradyarrhythmia and AV conduction delays
-Macular edema
-Elevated transaminases
-Incidence of hypertension reported in clinical
trials in -patients treated with siponimod was
slightly higher than those treated with placebo
-PRES
-a decline in pulmonary function
-increased risk of basal cell carcinoma (BCC) with
long term use.
-Lymphopenia.
-infections : Herpes virus inf , PML, fatal
cryptococcal meningitis (CM)

57. Ozanimod (zeposia 0.92mg)
Mechanism of action :
Sphingosine 1-phosphate (S1P) receptor
modulator.
Binds with high affinity selectively to S1P
subtypes 1 (S1P1) and 5.
Indications :
Indicated for relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome,
relapsing-remitting disease, and active secondary progressive disease.

58. Ozanimod (zeposia)
Dose :
• Days 1-4: 0.23 mg PO qDay
• Days 5-7: 0.46 mg PO qDay
• Day 8 and thereafter: 0.92 mg PO qDay
Side Effects:
• Adverse Effects
• Upper respiratory tract infection (26%)
• Elevated hepatic transaminases (10%)
• Orthostatic hypotension (4%)
• Urinary tract infection (4%)
• Back pain (4%)
• Hypertension (4%)
• Upper abdominal pain (2%)
• <1% >>> Macular edema
• Bradycardia

59. Cladribine (Mavenclad)
• Mechanism of Action:
a purine analogue, is metabolized to its active form and concentrated
in lymphocytes and monocytes but not in other cells. Single-stranded
DNA breaks cannot be repaired, eventually resulting in cell death
>>>It is approved for relapsing-remitting disease and active secondary
progressive disease in those who have had an inadequate response to
or are unable to tolerate an alternate drug.

60. Cladribine (Mavenclad)
• Dose: 1.75 mg/kg per year
>>>Taken as 10 mg/d to 20 mg/d for 4 to 5
days in week 1 and week 5.
>>>The dose is repeated 1 year later.
>>>No treatment is given in years 3 and 4.
Oral tablets are 10 mg.

61. Cladribine (Mavenclad)
Important Adverse Effects :
• Lymphopenia
• Neutropenia
• Infections :
Varicella-zoster
Progressive multifocal leukoencephalopathy
Hepatitis B and C reactivation
Tuberculosis reactivation Malignancies
• Rash
• Alopecia
• Because of the risk of teratogenicity, both males and females should use effective
contraception for 6 months after the last dose of treatment.
• Cases of acute cardiac failure with myocarditis have been reported with cladribine.

62. Cladribine (Mavenclad)
• Laboratory tests and follow-up evaluations required during therapy with cladribine tablets
I. Prior to treatment initiation (first cycle):
• 1. CBC with differential: lymphocytes counts must be normal ≥ 1,000 cells/mm 3
• 2. Serum transaminases, bilirubin, blood urea nitrogen, creatinine
• 3. Screening for latent infections, in particular hepatitis B and C and tuberculosis (T-spot test). Initiation of cladribine should be delayed until the
infection is fully controlled
• 4.Testing for anti-VZV antibodies in patients without a history of chickenpox or without varicella zoster virus (VZV) vaccine. VZV vaccination of antibody-
negative patients should be considered prior to treatment initiation.
II. During the first and up to 6 months after the last (second) treatment cycle:
• 1. Complete blood count with differential: a) at 2 and 6 months of treatment initiation in each year of treatment.
• b) Before initiating cladribine in year 2, the lymphocyte counts should be at least 800 cells/mm3 . If necessary, the year 2 treatment cycle can be delayed
for up to 6 months to allow recovery of lymphocytes.

63. Rituximab

64. Rituximab (Mabthera)
• Mechanism of action:
a chimeric antibody against CD20 similar to ocrelizumab.
It has less antibody-dependent and more complement-dependent
cytotoxicity than ocrelizumab and a different binding site on the CD20 molecule. It is more highly immunogenic than
ocrelizumab.
Dose :
500 mg or 1000 mg IV every 6 months.
Precautions / Monitoring common SE

65. FDA changes approval of other drugs ‫ور‬ ‫اللي‬ ‫الدوا‬
‫ا‬
‫اخد‬
approval

66. Home message
• Progressive MS is a heterogeneous disease both pathologically and clinically.
• Although distinguished as a separate entity, progressive MS likely occurs on a spectrum with relapsing disease.
• Clinical and imaging features vary between progressive and relapsing MS and may be used to classify the
disease based on the occurrence of progression and presence of clinical and MRI activity.
• The first approved disease-modifying therapy for primary progressive MS, ocrelizumab .
• a medication for active secondary progressive MS (siponimod) has also been approved
• the use of disease-modifying therapies will need to be individualized considering the expected benefits and
risks of each medication.