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Monitoring MS with clinical and MRI data
1. Monitoring the MS patient
Dr Pramod Krishnan
Consultant Neurologist and Epileptologist
Manipal Institute of Neurological Disorders
Manipal Hospital
2. Confidential and Proprietary
2
• DMT=disease-modifying therapy.
• Giovannoni G et al. Mult Scler Relat Disord. 2016;9(Suppl 1):S5-S48.
Purpose of Monitoring
Safety and
Tolerability
Efficacy
Disease
activity
3. Monitoring in Multiple Sclerosis
• Regular clinical and radiological monitoring of disease activity and
recording this information formally need to become routine.
• All parameters that predict future relapses and disability
progression should be included in the definition of disease activity.
• This permits early identification of suboptimal disease control and
inform treatment decisions.
4. Confidential and Proprietary
Monitoring is crucial to
identifying treatment failure and
enabling timely switching to a
different DMT
Giovannoni G et al. Multiple Sclerosis and Related
Disorders 2016. 9, S5-S48
5. Apo, apolipoprotein; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; OCB, oligoclonal band.
1. Tintore M et al. Brain. 2015;138:1863–1874. 2. Miller D et al. Lancet Neurol. 2005;4:281–288.
3. Alroughani R et al. BMC Neurol. 2016;16:240. 4. Leray E et al. Brain. 2010;133:1900–1913.
5. Kulhe J et al. AAN April 22–28, 2017; Boston, USA. Oral Presentation: 005.
Good prognosis Poor prognosis
Young1
Female sex1
“Unifocal” onset2
Isolated sensory symptom (optic neuritis, sensory)2
Full recovery from attack2
Long interval to second relapse2
No disability after 5 years2
MRI: Low lesion load2
No posterior fossa lesions2
No brain atrophy3
CSF negative for OCBs2
Older age of onset1
Male sex1
“Multifocal” onset2
Efferent system affected (motor, cerebellar, bladder)2
Partial or no recovery from a relapse4
High relapse rate in the first 2 years2
Disability after 5 years2
MRI: Large lesion load2
Posterior fossa lesions2
Brain atrophy3
CSF positive for OCBs2
Neurofilament light chain (NfL)5
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Individual prognostic factors
7. Clinical:
1. Relapses
2. Disability progression
Radiological:
1. White matter lesions
2. Brain atrophy
3. Grey matter changes
Patient reported
outcomes:
1. Fatigue
2. Activity limitations
3. Cognitive impairment
Laboratory:
1. Neurofilament light
chain (Nfl)
2. Neurofilament (pNF-H)
3. OCB
Monitoring
Disease Activity
Monitoring can also improve adherence to prescribed DMTs (which is associated
with fewer relapses and lower medical costs).
8. Disease monitoring
• Historically, the treatment target for MS was to prevent or reduce
clinical disease activity: relapses and, disability progression.
Fox, E.J. Rhoades, R.W. Curr. Opin. Neurol. 2012; 25: s11–s19
Stangel, M. et al. Ther. Adv. Neurol. Disord. 2015; 8: 3–13
• This is based on evidence from large international databases that
the EDSS score 5 years after the MS onset predicts disability
progression, and that once disability has progressed, it worsens
more rapidly from EDSS score 4.0 onwards than from EDSS score
2.0 onwards.
Hughes, S. et al. J. Neurol. Neurosurg. Psychiatry. 2012; 83: 305–310
9. • However, neurological
reserve is affected by damage
to the CNS even when it does
not lead directly or
immediately lead to disability
progression or a relapse.
• Therefore, consider all
indicators of disease activity,
not just the clinical
symptoms at the ‘tip of the
iceberg’.
Giovannoni G. Biomarkers in
MS. EFNS/ENS Joint Congress of
Neurology, Istanbul. 31 May–3 June 2014.
10. Why is it important to monitor
Relapses and Disability
progression?
11. Relapses indicate disease activity and predict
disability progression
• Studies consistently show a correlation between relapses in the
first few years of the disease and later levels of disability.
Stangel, M. et al. Ther. Adv. Neurol. Disord. 2015; 8: 3–13
• A short time gap from the first to the second relapse appears to be
a particularly strong predictor of disability progression.
Scalfari et al. J. Neurol. Neurosurg. Psychiatry. 2014; 85: 67–75
• Meta-analyses and real-world evidence indicate that correlations
exist between the effects of DMT on relapses and disability
progression, and that relapses predict disability progression.
Jokubaitis et al. Ann. Clin. Transl. Neurol. 2015; 2: 479–491
12. Definitions:
• Clinical relapse: Occurrence of symptoms that occur over a
minimum of 24 hours and separated from the previous attack by
atleast 30 days.
• Radiological relapse: Occurrence of new T2W lesions, or
enlargement of prior T2W lesions or T1 gadolinium enhancement
of lesions in the brain, spinal cord or both.
• Sustained disability progression: Increase in EDSS of ≥1 over a
period of 6 months.
13.
14. • The risk of entering SPMS phase increased proportionally with disease duration
(OR=1.07 for each additional year; p<0.001).
• Shorter latency to SPMS was associated with shorter times to severe disability.
• Time to DSS 8 from onset of progression were significantly shorter among those with
high early relapse frequency (≥3 attacks), and among those presenting with cerebellar
and brainstem symptoms.
15. Factors associated with earlier progression to SPMS
Male, onset after 30 years age and “frequent early relapsers” are associated with 5–10 years of earlier
progression to SPMS
Survival analysis from disease onset
Kaplan–Meier analysis
n (%) Mean years to onset of
SPMS (95% CI) P-value
Total population 769 (33.8) 21.4 (19.5–23.1)
Gender
Male 240 (24.6) 15.9 (13.4–17.1) <0.001
Female* 529 (38.0) 22.4 (21.4–26.1)
Age at onset
≤20 145 (41.1) 25.8 (21.7–29.9) <0.001
21–30 371 (38.1) 20.2 (18.2–21.7) <0.001
>30* 285 (24.6) 15.3 (13.3–17.3)
Relapses during Years 1–2
1 380 (28.7) 19.9 (18.3–21.5) 0.01
2 179 (30.2) 16.7 (14.6–18.9) 0.38
≥3* 149 (34.2) 15.1 (12.8–17.4)
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18. Within 5 years from MS onset >5–10 years from MS onset
>10 years
from MS
onset
Early relapses impact long-term prognosis
Tremlett H et al. Neurology. 2009;73:1616–1623.
Early relapse is a predictor of poorer long-term prognosis
−10
0
10
20
30
40
50
60
0–5 years >5–10 years >10 years >5–10 years >10 years >10 years
Follow-up (ie, disease duration from onset of MS)
%Changeinthehazardof
reachingEDSS6.0(95%CI)Impact of a relapse on the hazard of reaching EDSS 6.0 at different time points
Risk if relapse occurred
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19. Change in EDSS according to number of relapses experienced per phenotype
Relapse phenotypes impact long-term prognosis
Pyramidal, cerebellar, and bowel/bladder relapses are predictors of poorer long-term
prognosis.
4.0
3.0
2.0
1.0
0
−1.0
0 1–2 3–4 5+ 0 1–2 3–4 5+ 0 1–2 3–4 5+ 0 1–2 3–4 5+ 0 1–2 3–4 5+ 0 1–2 3–4 5+ 0 1–2 3–4
CerebralVisualBrainstemCerebellarBowel/bladderSensoryPyramidal
Number of relapses per phenotype
ChangeinEDSS
Markers indicate the mean change in EDSS
for patients who experienced 0, 1–2, 3–4, or
more than 5 relapses of each phenotype
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20. Recovery from the first relapse impacts
long-term prognosis
DSS, Disability Status Scale; HR, hazard ratio.
Leray E et al. Brain. 2010;133:1900–1913.
Poor recovery from the first relapse is a predictor of poorer long-term prognosis
Variable
Time from MS onset
to DSS 3 (n=1609)
HR
(95% CI) P-value
Residual deficit from the first relapse
No
Yes
1
2.44 (2.07–2.88)
0.0001
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22. Why is it important to monitor MRI lesions in patients
with MS?
*Confirmed disability worsening was defined as a ≥1.0-point increase in EDSS score confirmed at 6 months. Mean follow-up was 4.8 years.
Adapted from Prosperini L, et al. Eur J Neurol. 2009;16:1202–1209; Marcus JF, et al. Neurohospitalist. 2013;3:65–80.
60–70% of brain lesions and 30% of spinal cord
lesions develop without corresponding clinical
attacks
Measuring subclinical activity
100
0 1 2 ≥3
Number of new T2w-hyperintense lesions
after 1 year of therapy
0
20
40
60
80
Patientswithconfirmed
disabilityworsening*(%)
New T2w-hyperintense lesions after 1 year
of IFNβ treatment predict confirmed
disability worsening
Predicting poor outcomes
New silent lesions appear 5 to 10 times more
frequently than lesions associated with clinical
relapses
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23. Every 3 to 6 months for high-risk PML patients (JC virus, NAT treatment duration over 18 months)
At the start/ discontinuation of any treatment for patients with high risk of PML who switch treatments.
Regular MRIs are needed to enable earlier and informed decision-making, allowing us to
improve long-term clinical outcomes in patients with MS
Monitoring a patient with MRI
1. Wattjes, MP et al. Nat Rev Neurol. 2015;11:597–606;
2. Traboulsee A, et al. AJNR Am J Neuroradiol. 2016;37:394–401.
Baseline scans and
then at least yearly while on
treatment (more frequently if there
are safety concerns)1
Pretreatment, rebaseline at
6 months of treatment, then scan
every 1–2 years on treatment2
Pretreatment, rebaseline at
6 months of treatment, then scan
every 12 months, adjusting
frequency as needed
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24. MRI
• Although MRI is crucial in the diagnosis of MS and the decision
to initiate DMT, many people with MS are switched to a different
DMT only if they experience new clinical symptoms, and not
solely on the basis of MRI evidence of new lesions.
• A 2014 survey of 108 UK neurologists with an interest in MS
revealed that although 59% of respondents used MRI to monitor
treatment response, only 9% did so routinely.
Schmierer, K., et al. J. Neurol. Neurosurg. Psychiatry 2018: 89; 844-850.
25. 0 1 2 5
0.8 (0.2–2.7)
1.9 (0.6–5.6)
2.9 (1.5–5.6)
2.1 (1.1–4.0)
1.2 (0.4–3.3)
1 new T2 lesion#
2 new T2 lesions#
≥3 new T2 lesions#
>1 Gd+#
1 Gd+#
1-year predictors:
Early MRI activity
MRI cohort (n=233)
Mean follow-up of
6.75 years
aHR‡ (95% CI)
Baseline
variablesDecreased risk Increased risk
Single-center cohort (n=516) identifies levels of on-treatment disease activity to predict poor long-term
treatment outcome to IFNβ in patients with RRMS
9.4 (4.0–22.5)
9.6 (4.1–22.6)
10.2 (5.7–18.6)
2.7 (1.3–5.8)
3.5 (1.2–10.3)
2.9 (1.4–6.0)
2.9 (1.1–8.2)
aHR* (95% CI)
0 1 10 20
SPMS
EDSS 7.5
≥5 EDSS steps
SPMS
EDSS 7.5
≥5 EDSS steps
SPMS
≥1 EDSS point
1 relapse†
Clinical cohort (n=283)
Mean follow-up of
11.5 years
Baseline
variablesDecreased risk Increased risk
2-year predictors:
Early clinical activity
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• *Odds ratio for SPMS; †no relapses as the reference category; ‡adjusted for age, gender, and baseline EDSS;
§no new T2 or Gd lesions as the reference category.
Adapted from: Río J et al. Mult Scler J. 2018;24:322-330.
Early MRI and clinical disease activity predict poor long-term outcomes
26. Brain atrophy
• Brain atrophy occurs as a result of damage that takes place via a
number of different mechanisms.
• Brain volume should be monitored in addition to active and total
numbers of lesions, which represent only one kind of damage.
• In addition, brain volume is a measurable indicator of brain
reserve, and rates of brain atrophy higher than those in the general
population indicate MS disease activity.
• However, the MRI technology required to measure brain atrophy
is not yet widely available in clinical practice.
27.
28. Rio Score: Combining clinical and MRI disease markers
CI, confidence interval; Gd+, gadolinium-enhancing; MRI, magnetic resonance imaging.
Río J, et al. Mult Scler. 2009;15:848–853.
A combination of MRI and clinical monitoring, as used in the Rio Score, may enhance
the ability to predict future disease activity
Relapses Progression MRI activity
Risk of relapse Risk of progression
Odds ratio (CI) P-value Odds ratio (CI) P-value
‒ + ‒ 1.2 (0.3–4.3) 0.8 0.3 (1.0–2.1) 0.3
+ ‒ ‒ 1.1 (0.4–3.2) 0.8 0.5 (0.1–2.2) 0.4
‒ ‒ + 1.5 (0.7–3.4) 0.3 2.3 (0.9–4.4) 0.07
‒ ‒ ‒ 1 (reference category) 1 (reference category)
+ + + 9.8 (2.6–53.4) 0.0005 6.5 (1.9–23.4) 0.004
+ ‒ + 8.3 (2.9–28.9) <0.0001 4.4 (1.6–12.5) 0.004
‒ + + 3.3 (0.8–15.6) 0.1 7.1 (1.6–33.9) 0.011
+ + ‒ 1.8 (0.3–9.9) 0.5 3.9 (0.6–21.6) 0.1
Single
measures
Combined
measures
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29. Other candidate parameters
• Neurofilaments in CSF, serum
• Grey matter involvement.
• Patient reported outcomes: cognition, fatigue, depression.
• CSF levels of CHI3L1 predicts conversion of CIS to RRMS.
• CSF OCB also predicts conversion of CIS to RRMS.
• Optical Coherance tomography
• Multi modal evoked potentials.
31. NEPAD:
• No evidence of progression or active disease.
• It has been used for progressive MS and is defined as:
1. No evidence of progression (NEP) using a composite endpoint:
• No 12-week confirmed progression of ≥1 point/≥0.5 point on the
EDSS if baseline EDSS ≤5.5/>5.5 points.
• No 12-week confirmed progression of ≥20% on the timed 25-foot
walk test and on the 9-hole peg test.
2. NEDA 3
MEDA: Minimal evidence of disease activity.
32. Vitamin D and smoking
Time, y
Probability of CDMS after year 1 in
≥50 nmol/L vs <50 nmol/L: P=0.05 (log-rank test)
<50 nmol/L (n=150)
≥50 nmol/L (n=127)
1 2 3 4 5
0.0
0.1
0.2
0.4
0.3
ProbabilityofconvertingtoCDMSafter1y
Lower vitamin D levels increase risk of
converting to CDMS1
1.00
0.75
0.50
0.25
0.00
0 20 40 60 80
P<0.001
Age, y
ProportionbelowEDSS4.0
Current smoker†
1–15 smoke-free years†
>15 smoke-free years†
Smoking reduces age of progression to EDSS 4.02
1. Ascherio A et al. JAMA Neurol. 2014;71:306–314; 2. Tanasescu R et al. Nicotine Tob Res. 2017.
Age at EDSS 4.0 Age (y) 95%CI
Current smokers: 41 36-43
1-15 y smoke-free: 43 40-46
>15 y smoke-free: 52 48-56
34. The definition of a treatment non-responder has evolved
to include assessments of both clinical and MRI activity
1. Miller DH, et al. NeuroRx. 2004;1:284–294;
2. Meyer-Moock S, et al. BMC Neurology. 2014;14:58;
Clinically relevant, but subjective, with high inter-rater
variability
Acute relapses1 Clinical disease
progression1,2
Focal lesions
on MRI1
0
10
2.0
4.0
6.0
7.0
9.0
EDSS
T2w FLAIR
Objective and sensitive
Captures subclinical activity
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36. Early identification of treatment non-response may help to prevent disability at 4
years (Modified Rio Score)
Sormani M, et al. Mult Scler. 2013;19:605–612.
Score=0
Score=1
Score=2–3
100
80
60
40
20
0
Disabilityprogressionprobability,(%)
Years
0 1 2 3 4
High risk
Medium risk
Low risk
After 12 months of IFNβ treatment, MRI scans help us to identify
those patients with a higher risk of future disability
IFNβ-treated patients (n=222)
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37. Treatment failure: Is there any consensus?
*In the 1st year; †>2 EDSS points increase in 6 months or 2 EDSS points increase in 12 months; ‡In the first 2 years.
1. Río J, et al. Mult Scler. 2009;15:848–853; 2. Sormani MP, et al. Mult Scler 2013;19:605–612
≥1 relapse*
1 relapse*
(1 point)
≥2 relapses*
(2 points)
≥1 relapse* >1 relapse* 2 relapses‡
>2 new T2 or Gd+
lesions
>4 new
T2 lesions
(1 point)
≥3 new
T2 lesions
≥3 new T2 or Gd+
lesions
≥2 Gd+ lesions
(Year 1/2) or
≥3 new T2 lesions
(Year 2 vs baseline)
≥1 EDSS point
increase
— —
>2 EDSS points
increase† —
Bermel Criteria5Canada Treatment
Optimization4MAGNIMS Score3Modified Rio
Score2Rio Score1
39. Any biochemical, clinical or genetic evaluations that could aid in
modulation of drug type, dosage or schedule of administration to
optimally benefit the patient and minimize the possibility of ADRs.
40.
41. IFN 1b
• Anti drug antibodies (ADA) may be ‘Binding’ (Bab) or
‘Neutralising’ (NAb). Only NAbs reduce efficacy by reducing the
levels of myxovirus resistance protein A (MxA).
• IFN-β-1b has the highest incidence of NAbs (31%) and IFN-β-1a
intramuscular has the lowest incidence (5%).
• Most patients become positive for NAbs during the first 18 months
of therapy and rarely later.
• NAbs are cross reactive against all types of IFNb
Polman CH, et al. Lancet Neurol. 2010;9:740–750.
42. Bertolotto A. Clin Chim Acta. 2015;449:31–36.
European recommendations suggest the combined evaluation of MxA mRNA and antidrug antibody (ADA) to
assess the continuing efficacy of IFNb therapy.
43. Natalizumab
• CD49d and sVCAM-1 levels are reduced after infusion and revert to
pretreatment levels in the presence of ADAs
• The incidence of persistent NAbs was 3.5 to 6% in three large
cohorts, with 1% of cases having transient NAbs.
• The combined measurements of ADA, NAT serum level, and
CD49d could be utilized to tailor a personalized infusion regimen.
• Treatment has to be changed if there is persistent ADAs.
Sørensen PS, et al. Mult. Scler. 17(9), 1074–1078 (2011).
47. Summary
• All MS patients should be monitored using clinical and MRI
parameters.
• Monitoring enables identification of suboptimal response and
treatment failure which can necessitate treatment changes and
predict progression.
• NEDA 3 is currently the accepted target of MS treatment. The
concept of NEDA is likely to evolve with time.
• DMT should be monitored for toxicity or loss of efficacy, as
instructed by the manufacturer.
Through various clinical and etiological studies, we now know that not all MS patients are equal, that some patients have worse prognosis than others.
For example, poor prognostic factors for MS include, older age of onset, male sex, (…), and a high titre of neurofilament light chain.
We should be more proactive for those patients with these poor prognostic factors as they may have a smaller window of opportunity for treatment.
In particular, we should be cautious when MS patients are of male sex, older than 30 years old at onset, and when they have more than 3 relapses in the first 2 years after diagnosis, which often described as frequent early relapsers.
A previous report suggested that the these factors are associated with 5 to 10 years shorter duration to secondary progressive phase.
Therefore, if we see MS patients with these factors, we should consider starting treatment as early as and as efficiently as possible.
Speaking of MS relapse, we should remember that the impact of relapse on the long-term prognosis rather decreases with the disease chronicity.
For example, when a relapse was occurred within 5 years from MS onset, the hazard of reaching EDSS=6 or the cane dependency may be increased up to 50%, however, when it occurred after 10 years from MS onset, the impact is less than 20%.
Therefore, we should treat MS patients so as to minimize early relapses, particularly within 5 years from MS diagnosis.
Not only the timing of relapse, but also the phenotype of relapse matters also.
A previous report suggested that relapses with symptoms in pyramidal tract, cerebellar systems or bowel and bladder systems had the highest impact on physical disability, compared to other types such as those with sensory symptoms.
Taken together, if a patient exhibit early relapse, particularly with symptoms in these systems, then we should take it very seriously as that is the sign of poor prognosis.
Another study also suggested that MS patients with early residual deficit reached EDSS of 3 in 5 years compared to 11 years in those patients without deficits, therefore poor recovery from the first relapse should also be considered as a predictor of poorer long-term prognosis.
More recently, it has been reported that 3 or more new T2 lesions, or 2 or more new Gd-enhancing lesions at 12 months after the initiation of treatment are suggestive of poorer long-term outcome
When you look for 24 months predictors, then an increase in physical disability or presence of relapse were also suggestive of poorer long-term outcome.
early identification of these patients is important to
optimize the benefit of treatment and to determine the
best course of therapy