Outcome Measures in Autoimmune NMJ Diseases

1. “Outcome measures in Autoimmune NMJ Diseases”Renato MantegazzaDept. Neuroimmunology and Neuromuscular DiseasesFondazione Istituto Neurologico C. BestaMilan (I)

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

3. Myasthenia Gravis classifications • 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+, 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 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 (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 scoreshould 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/100 20 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 Systemswhich 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) INCB-MG abnormal values: O-MG 1 - 3 G-MG 10 - 150 B-MG 1,000 – 20,000 R-MG 200,000 – 400,000 Fatigability 0 - 240” Antozzi et al., Muscle Nerve 2016 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 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 Respiratory Level 0 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 ____

9. FDAGuidance for IndustryPatient-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/100 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. Should MG outcomes be different ?Should we use different scoring systems ? When evaluating MG patients: In normal clinical practice or In the context of an experimental setting

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