“Outcome measures in
Autoimmune NMJ Diseases”
Renato Mantegazza
Dept. Neuroimmunology and Neuromuscular
Diseases
Fondazione Istituto Neurologico C. Besta
Milan (I)
MG Clinical Symptoms
•Muscle weakness
•Muscle fatigability
•
•
•
•
Ocular MG
Generalized MG
Bulbar MG
Respiratory MG
Myasthenia Gravis classifications
Antibody-based
Clinico-biological
AchR-Ab
highly specific for MG,
IgG1, bind C’
85% generalized MG
Early onset MG with AChR-Ab
Onset < 50 years
Follicular hyperplasia of the thymus
Female > Males
Musk-Ab
IgG4, do not bind C’
interference w Musk
«Oculobulbar MG»
respiratory insufficiency
Late onset MG with AChR-Ab
Onset > 50 years
Follicular hyperplasia
LRP4-Ab
IgG1
receptor for nerve agrin
loss of agrin-LRP4
interaction
altered AChR clustering
Other antibodies
agrin,
cortactin,
titin & RyR
Thymoma-associated MG
AChR+, 10-20 % of MG patients
Thymoma associated disorders
MuSK-associated MG
Thymoma not reported
Cranial and bulbar muscles
Respiratory crises
LRP4-associated MG
2-30% of AChR/MuSK DN MG
Females
ocular/generalized MG
Ocular MG
No symptoms/signs of gen. MG
Seronegative MG - Triple neg?
 No differential clinical features
(Jaretzki A et al Neurology 2000)
2000, MGFA
« A task force of the Medical Scientific Advisory
Board of the MGFA emphasized that changes in
the MGFA Clinical Classification should not be
used to measure change in severity, but rather
that a quantitative severity score should be used
for this purpose»
Jaretzki III, A et al Neurology 2000; 55;16-23
MG Scoring Systems
Scoring System
Scores
Measurements significance
MGS/QMG *
x/39
3-point change significant (I or W)
MMS*
x/100
20 points for a treatment response
MG-MMT *
x/72
 2 points clinically meaningful
MG-Composite*#
x/50
INCB-MG Score§
x/500,000
 3-point improvement clinically
significant and meaningful to most
patients
CSR/PR, > 90% MI, > 60% I,
< 60% W
OBFR
x/21
Not defined
* Ordinal values to evaluate severity; # Includes both physician & patient referred scores
§ Values
weighted for severity
MG Scoring Systems
which include patient-reported assessment
of the disease
Scoring System
Scores
Measurements significance
MG-ADL
x/24
Weak correlation with MMT & QMG
F-MG scale
x/35
 1-point for clinical improvement
MG-Q
x/50
Correlation with Osserman
MGII
X/69
Correlation with MG-ADL, MGC
and QMG
QMG Score (MGFA, Neurology 2000)
MG Composite (Burns et al. Neurology 2010)
Carlo Besta Neurological Institute – Myasthenia Gravis
Scale (INCB-MG)
Ocular level
Score
0 Normal
1 Diplopia in 1 or 2 cardinal directions, unilateral
ptosis
2 Diplopia in primary position or diplopia in bilateral
direction
3Ophthalmoplegia
Generalized level
Facial muscles
0 Normal
10 Orbicularis oculi and/or oris weak but can overcome
outside resistance and/or snarl smile
20 Orbicularis oculi and/or oris weak and cannot
overcome outside resistance
30 Lagophthalmos and/or orbicularis oculi/oris plegia
Anterior head/neck flexor muscles
0 Normal
10 Weak against resistance
20 Weak without resistance
30 Unable to lift the head
Abdominal muscles
0 Trunk flexion with hands clasped behind the head
10 Trunk flexion with forearms extended forward
20 Raises shoulder with limbs outstretched
30 Inability to curl trunk
Deltoid muscles
0 Normal
10 Weak against resistance
20 Weak without resistance
30 Unable to abduct upper limbs
Lower extremity muscles
0 15 squats
10 <15 squats
20 Able to rise from a normal chair
30 Unable to rise from a normal chair
Bulbar level
Chewing
0
Normal strength of masseter muscle
1,000 Weakness of masseters against resistance
2,000 Jaw drop
Tongue
0
Normal
1,000 Inability to press the tip against the cheek
and/or inability to curl the tongue and reach the
upper lip frenulum
2,000 Inability to protrude the tongue
Phonation
0
Normal
1,000 Slight nasal voice
2,000 Severe nasal voice, speech still intelligible
3,000 Speech difficult to understand
Swallowing
0
Normal
1,000 Dysphagia and/or necessity for soft foods
20,000 Impossible, tube feeding
INCB-MG abnormal
values:
O-MG
1-3
G-MG
10 - 150
B-MG
1,000 – 20,000
Respiratory Level
0
200,000
300,000
400,000
Normal
Shortness of breath on exertion
Shortness of breath at rest
Mechanical ventilation
R-MG 200,000 – 400,000
Total INCB MG score
Fatigability 0 - 240”
Fatigability
Upper limbs (seconds)
Lower limbs (seconds)
_____
_____
Total fatigability
____
Antozzi et al., Muscle Nerve 2016
FDA
Guidance for Industry
Patient-Reported Outcome Measures (PROM): Use in Medical
Product Development to Support Labeling Claims,
December 2009
Evaluation of MG patients’ life complexity
Aspects evaluated
 Physical status
 Psychological well-being
 Social functioning
 Occupational functioning
Scoring System
Scores
Measurements
INQoL
---
Under assessment, valid also for
muscle diseases other than MG
MG-QOL15
x/60
Correlation with MG-ADL, MMT
ICF
---
HRQoL & disability correlated
MG-DIS
x/100
Include MG-specific items (n. 20),
correlates w MG-C and other
physician scoring systems
MG-DIS a new PROM for MG
 MG-DIS includes items representing ocular, generalized, bulbar and respiratory
symptoms
 MG-DIS has good metric properties, is stable and well correlated with MG-C
Raggi A et al. J Neurol 2016
MG-DIS a new PROM for MG
 Able to sense group differences and to detected longitudinal changes
Table 1: Sensitivity to change analysis
Worsened (N=11).
FU duration: 271 days.
MG duration: 12.9 years
MG-DIS
Generalized impairmentrelated problems
Bulbar function-related
problems.
Mental health and fatiguerelated problems
Vision-related problems
Unchanged (N=40).
FU duration: 250 days.
MG duration: 11.0 years
MG-DIS
Generalized impairmentrelated problems
Bulbar function-related
problems.
Mental health and fatiguerelated problems
Vision-related problems
Improved (N=24).
FU duration: 212 days.
MG duration: 5.2 years.
MG-DIS
Generalized impairmentrelated problems
Bulbar function-related
problems.
Mental health and fatiguerelated problems
Vision-related problems
Mean (95%CI)
Baseline
Follow-up
18.8
35.4
(9.9-27.7)
(26.7-44.0)
13.6
27.9
(5.6-21.9)
(15.5-40.3)
18.2
41.8
(2.1-34.2)
(25.9-57.7)
28.2
40.5
(14.9-41.5)
(32.3-48.6)
15.9
33.3
(3.3-28.5)
(23.0-43.6)
16.1
16.9
(11.8-20.4)
(12.2-21.6)
12.2
13.5
(6.8-17.5)
(7.9-19.1)
8.9
9.6
(4.8-13.0)
(4.3-15.0)
25.5
26.4
(19.7-31.3)
(20.3-32.4)
21.5
21.2
(14.4-28.5)
(15.0-27.5)
29.6
11.8
(21.5-37.6)
(8.8-14.9)
23.7
9.4
(14.0-33.4)
(6.2-12.6)
24.2
7.3
(13.8-24.5)
(4.3-10.3)
39.6
20.2
(30.8-48.4)
(14.8-25.6)
35.4
11.1
(22.5-48.4)
(8.1-14.2)
P
ES
.005
1.25
.006
1.16
.032
0.99
.005
0.62
.003
0.93
.994
0.06
.518
0.08
.954
0.05
.260
0.05
.987
0.01
<.001
0.94
.003
0.62
.006
0.69
<.001
0.93
.001
0.79
Notes. MG-DIS, MG-specific Disability Assessment.
For each subset of patients, significance was set at P<.01 after Bonferroni correction. Effect size >0.80
indicate large differences.
Raggi A et al. J Neurol 2016
When evaluating MG patients:
In normal clinical practice
or
In the context of an experimental setting
Should MG outcomes be different ?
Should we use different scoring
systems ?
MG Outcome definitions
Complete stable remission (CSR)
Pharmacological Remission (PR)
Minimal Manifestation S. (MMS)
International consensus
guidance for management of
myasthenia gravis
Sanders DB et al Neurology 2016
Definition of Improved, Unchanged, Worsened is
still a gray area:
Outcome may depend on how it is evaluated
Clinically relevant changes need to be defined
Is the minimal change of a specific score
meaningful to truly describe patients’
improvement? (PROM)
Need of further comparative studies
Comparative analysis of known
MG outcome measures
 524 visits from 131 MG patients were compared
on different scoring systems, Physician, INCBMG, MGFA-PIS, QMG, MG-C, MG-ADL
 Weighted Cohen K coefficient was used:
0 = no concordance, 1= complete concordance
 Values are given as 1-k: the higher 1-k value,
the higher the discordance
Graphical comparison of different outcome
evaluations
Physician
INCB-MG
DB
Physician
0.8
PIS
0.8
QMG_3
0.6
0.4
ADL_4
QMG_2
PIS
ADL_4
0.2
0
QMG_4
ADL_3
COMP_3
COMP_4
COMP_2
ADL_4
Physician
0.8
0.4
DB
QMG_2
0.2
0
ADL_2
ADL_3
COMP_4
0.4
QMG_2
0
ADL_2
QMG_4
ADL_3
COMP_3
COMP_4
Physician
1
ADL_4 0.8
0.6
ADL_2
0.4
0.2
0
ADL_3
QMG_4
COMP_3
COMP_2
ADL_3
COMP_4
QMG_3
QMG_2
QMG_4
COMP_2
COMP_2
Physician
1.2
PIS
1
0.8
0.6
ADL_4
0.4
0.2
0
ADL_2
DB
COMP_4
MG-COMP_3
QMG_3
0.6
QMG_3
0.2
ADL_2
PIS
0.6
MGFA-PIS
COMP_3
MG-ADL_3
PIS
DB
QMG_3
QMG_2
QMG_4
COMP_2
Distance from center corresponds to 1-k (weighted Cohen K): discordant values are
ADL_4
Physician
1
0.8
0.6
0.4
0.2
0
DB
QMG_3
ADL_2
QMG_2
COMP_4
COMP_2
QMG_4
COMP_3
Other MG Outcomes
1. Steroids-sparing effects of immunosuppressive drugs:
How this effect should be quantified?
 Steroid dose at a particular time point
 Area under the dose-time curve (AUDTC) *MGFA recommended
 Proportion of subjects achieving a desired response at a target
dosage
Handling of dropouts, alternate days regimen, steroid delayed
protocols!
 MMF Trial failed because 5 mg prednisone was still effective and
the follow-up was too short!

2. Biomarkers:
Specific AutoAb dosing
SFEMG
Immunological biomarkers
Pharmacogenomic
miRNA
not useful
useful, but technical expertise
further studies
further studies; TPMT
under investigation
 SN-MG definition may change
from Double to Triple
Negative
Conclusions
• Outcomes measures in MG should
reflect the intrinsic features of the
disease
• Be useful both for clinical practice and
experimental settings
• Have a good concordance between
patients and physicians
• Need of further studies aimed at
homogeneity, relevant for international
studies