“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)

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

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+, 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  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

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 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 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 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 ____ 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

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 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, 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

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

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

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