1. “Outcome measures in Autoimmune NMJ Diseases” Renato Mantegazza Dept
“Outcome measures in Autoimmune NMJ Diseases” Renato Mantegazza Dept. Neuroimmunology and Neuromuscular Diseases Fondazione Istituto Neurologico C. Besta Milan (I)

2. MG Clinical Symptoms Ocular MG Severity Gradient Generalized MG
Bulbar MG
Respiratory MG
Muscle weakness
Muscle fatigability
Severity Gradient

3. Myasthenia Gravis classifications
Antibody-based
AchR-Ab
highly specific for MG,
IgG1, bind C’
85% generalized MG
Musk-Ab
IgG4, do not bind C’
interference w Musk
«Oculobulbar MG»
respiratory insufficiency
LRP4-Ab
IgG1
receptor for nerve agrin
loss of agrin-LRP4 interaction
altered AChR clustering
Other antibodies
agrin,
cortactin,
titin & RyR
Clinico-biological
Early onset MG with AChR-Ab
Onset < 50 years
Follicular hyperplasia of the thymus
Female > Males
Late onset MG with AChR-Ab
Onset > 50 years
Follicular hyperplasia
Thymoma-associated MG
AChR+, % 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)

4. 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

5. MG Scoring Systems Scoring System Scores Measurements significance
MGS/QMG * x/39 3-point change significant (I or W)
MMS* x/ points for a treatment response
MG-MMT * x/72  2 points clinically meaningful
MG-Composite*# x/50  3-point improvement clinically significant and meaningful to most patients
INCB-MG Score§ x/500,000 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

6. 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

7. QMG Score (MGFA, Neurology 2000)
MG Composite (Burns et al. Neurology 2010)

8. 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
Ophthalmoplegia
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
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
30 Unable to abduct upper limbs
Lower extremity muscles
squats
10 <15 squats
20 Able to rise from a normal chair
30 Unable to rise from a normal chair
Bulbar level
Chewing
Normal strength of masseter muscle
1,000 Weakness of masseters against resistance
2,000 Jaw drop
Tongue
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
Normal
1,000 Slight nasal voice
2,000 Severe nasal voice, speech still intelligible
3,000 Speech difficult to understand
Swallowing
1,000 Dysphagia and/or necessity for soft foods
20,000 Impossible, tube feeding
Respiratory Level
Normal
200,000 Shortness of breath on exertion
300,000 Shortness of breath at rest
400,000 Mechanical ventilation
Total INCB MG score
Fatigability
Upper limbs (seconds) _____
Lower limbs (seconds) _____
Total fatigability ____
Carlo Besta Neurological Institute – Myasthenia Gravis Scale (INCB-MG)
INCB-MG abnormal values:
O-MG
G-MG
B-MG ,000 – 20,000
R-MG ,000 – 400,000
Fatigability ”
Antozzi et al., Muscle Nerve 2016

9. FDA Guidance for Industry Patient-Reported Outcome Measures (PROM): Use in Medical Product Development to Support Labeling Claims, December 2009

10. 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/ Include MG-specific items (n. 20), correlates w MG-C and other physician scoring systems

11. 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

12. MG-DIS a new PROM for MG
Able to sense group differences and to detected longitudinal changes
Raggi A et al. J Neurol 2016

13. 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 ?

15. 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

16. Comparative analysis of known MG outcome measures
524 visits from 131 MG patients were compared on different scoring systems, Physician, INCB-MG, 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

17. Graphical comparison of different outcome evaluations
Distance from center corresponds to 1-k (weighted Cohen K): discordant values are

18. 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 not useful
SFEMG useful, but technical expertise
Immunological biomarkers further studies
Pharmacogenomic further studies; TPMT
miRNA under investigation

19. SN-MG definition may change from Double to Triple Negative

20. 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