Myasthenia gravis disease is an autoimmune disease

1. What’s New in
Myasthenia
Gravis
1

2. 2
Introduction to MG
• MG is an autoimmune disease of the the neuromuscular junction. It is characterized by variable
weakness in skeletal muscle (ocular, bulbar, limb and respiratory):
o Fatigable Weakness
• Muscle weakness that fluctuates with rest and activity
o Selective Vulnerability
• Muscle weakness in eyes, eyelids, shoulder, hip, breathing muscles (diaphragm), neck,
chewing/swallowing muscles
• Muscle weakness results in double vision, obstruction of vision, trouble chewing/swallowing,
trouble talking, trouble breathing, and dysfunction of arms/legs
• Incidence of 8-10 cases/million/year1
• Prevalence of 200 cases/million1,2
o Est: 70,000 people with MG in US
• Age of onset: Women < 40 years; Men > 50 years
1. Gilhus, 2016 2. Phillips, 2003

3. Overview of MG subgroups
3
Subgroups influence therapeutic
decisions and prognosis.
1. Gilhus, 2016

4. MG clinical forms
4
• The two main clinical forms of MG are:
o Ocular myasthenia - weakness is limited to the eyelids and extraocular muscles.
o Generalized disease - weakness commonly affects ocular muscles, but it also
involves a variable combination of bulbar, limb, and respiratory muscles.
• Additional forms of MG are:
o Neonatal MG - a transient form in neonates that results from transplacental
passage of maternal antibodies that interfere with function of the neuromuscular
junction.
o Congenital MG - nonimmune-mediated forms that
may result from mutations that adversely affect
neuromuscular transmission.
1. Grob, et al., 2008
Image courtesy of Michael Hehir, MD

5. MG antibody status
• Seropositive MG - Patients have detectable
antibodies to AChR, MuSK, or LRP4
o ~50% of patients with ocular
myasthenia are seropositive
o ~90% of patients with generalized
disease are seropositive
• Seronegative MG – Patients lack AChR,
MuSK, or LRP4 antibodies on standard
assays
5
1. Gilhus, 2015
Figure adapted from reference #1. Re-created with BioRender.com
5

6. Worst MGFA Status
• 89% MGFA 3-5
• (Moderate Weakness or
worse)
• 44% MGFA Grade 4/5
• (Severe Weakness or
worse)
• 28% Respiratory Crisis
• Many Progress Rapidly
within 2 – 3 weeks
1. Pasnoor, et al., 2010
Anti-MuSK MG is a severe form of MG
Anti-MuSK (Muscle Specific Kinase):
• 1/3 Seronegative MG (7% total)
• 4000 - 5000 patients in US
Age of onset
• Females - 36.7 ± 18.7 years
• Males - 44.1 ± 17.0 years
In 64% of patients, onset was before 40
years of age.
6

7. MG Disease Progression
1. Peeler, et al., 2015
• Ptosis and diplopia are common initial symptoms, but disease remains restricted to ocular
muscles in a minority of patients
• In 15% of patients with MG, symptoms and signs are confined to ocular muscles.
o In most patients with purely ocular MG 2 years after the start of symptoms, disease will
persist as a focal eye-muscle weakness
o In patients with ocular MG, presence of AChR-binding antibodies slightly increases the
risk of subsequent generalized disease1
• 90% of patients with MG experience the maximal amount of weakness within the first 2
symptomatic years
o Patients with anti-MuSK antibody+ MG often experience maximal weakness in the first
symptomatic year
7

8. MG thymic status
The thymus has a key role in inducing anti-AChR antibody
production in patients with MG.
~10-15% of patients with MG have an underlying thymoma,
and the prevalence increases with increasing age.
In patients with ocular MG, presence of thymoma increases the
risk of subsequent generalized disease1
Imaging of the thymus with a CT or chest MRI is recommended
for patients with AChR and Seronegative MG
2/3 of patients with MG have generalized early- or late-onset
disease and no thymoma.
1. Li, et al., 2018 2. Gilhus, et al., 2015
8

9. 9
Risk factors
Thymic status and HLA pattern help to distinguish MG subgroups.
Early-onset MG
• Often characterized by thymic hyperplasia
• Associated with HLA-DR3, HLA-B8, and non-HLA genes that influence immune
system
• 3 times as likely to be diagnosed in females as it is in males
• Coexisting autoimmune disorders are common
Late-onset disease
• Often characterized by thymic atrophy
• Associated with HLA-DR2, HLA-B7, and HLA-DRB1 15.01
• Males slightly outnumber females in the late-onset group
Patients with MG commonly have coexisting conditions related to their disease.
• Autoimmune thyroid disease, systemic lupus erythematosus, rheumatoid arthritis,
neuromyelitis optica
1. Gilhus, 2016

10. Risk factors (continued)
10
Checkpoint inhibition in cancer patients
• Reports of MG caused by checkpoint inhibition therapy in cancer
patients are rare but growing
• 50-60% of these cases are AChR and MuSK Negative
• It takes a mean time of 2 – 4 cycles (up to 14 weeks) of
checkpoint inhibition therapy to develop neurological
complications
• Concurrent myositis is common
• Treatment for MG caused by checkpoint inhibition may be
different than other MG subgroups
1. Dubey, et al., 2020 2. Kolb, et al., 2018
Immune checkpoint inhibitors
prevent tumor cells from binding
to inhibitory receptors on T
cells, enabling the T cells to
remain active.

11. Mechanism of disease
11
1. Howard, 2018
2. Berrih-Aknin, 2014
3. Conti-Fine, 2006
Pathophysiology of anti-AChR+ MG
Autoreactive Th2 T-cell stimulated B-cell
response produces high affinity anti-AChR
IgG Ab, which results in:
• Ab crosslinking and complement
activation  ending in MAC formation
• Internalization/degradation of surface
AChR
• Direct blocking of Ach binding to
receptor
Pathophysiology of anti-MuSK+ MG
Presence of anti-MuSK IgG4 Ab causes:
• Decrease in AChR clustering Figure adapted from reference #1.
11

12. Signs and symptoms
MG can produce weakness in any skeletal muscle group, but certain presentations are characteristic
of MG:
• >50% of patients present with ocular symptoms of ptosis and/or diplopia
• Many patients without ocular manifestations develop ptosis or diplopia at some point in the
disease course
• ~15% of patients present with bulbar symptoms -- dysarthria, dysphagia, and fatigable chewing
• Patients with anti-MuSK MG are more likely to present with early bulbar and respiratory muscle
weakness1
• <5% present with proximal limb weakness alone
• Less common presentations include:
o Isolated neck weakness
o Isolated respiratory muscle weakness
o Distal limb weakness
Clinical Presentation:
Location:
Ocular MG
Generalized MG
Refractory MG
Thymus Pathology
Age Onset
1. Pasnoor, et al., 2010 2. Gilhus, 2016
12

13. Diagnostic algorithm for MG
13
1. Wang, et al., 2007 2. Mercuri, et al., 2018
1. Hehir and Ciafaloni, 2011

14. Antibody Diagnostic Utility
Thymus
Pathology
Additional
Considerations
AChR-Binding
Gen MG: Sens: 70-95%
Spec: 90+%
Ocular MG: Sens: 30-75%
Spec: 90+%
Rare False Positive:
SLE, RA, Autoimmune
hepatitis, thymoma w/o
MG
AchR-
Modulating
Positive in 3-4% of patients
with normal AChR-Binding
May be predictive of
Thymoma
False positive in
hemolysis
AChR-Blocking
Positive in fewer than 1%
patients with normal AChR-
Binding
Striated Muscle Gen MG: Sens: 30%
Predictive
Thymoma
• >80% MG with
thymoma
• 24% thymoma
w/o MG
• More common in
elderly patients.
• False positive in: RA,
LEMS, Graft vs. Host
1. Meriggioli and Sanders, 2005 2. Benatar, 2006
• Testing for AChR
antibodies is sensitive
and specific in
generalized MG.
• Testing for AChR
antibodies is less
sensitive in ocular
MG.
Diagnostic testing for anti-AChR antibodies
14

15. Newer assays for diagnosis of MG
1. Clustered AChR Cell Based Antibody Assay
2. Anti-LRP4 (Low Density Lipoprotein 4) Ab
1. Howard, 2018
2. Zisimopoulou, et al., 2014
3. Rodriguez Cruz, et al., 2015
4. Vincent, et al., 2018
Figure adapted from reference #1.
Table adapted from reference #4.
MG Antibody Assays
a-AChR RIA
a-MuSK RIA, ELISA, CBA
a-Titin RIA, ELISA
a-Clustered AChR CBA
a-LRP4 CBA, ELISA
a-Agrin CBA
a-Cortactin CBA
a-Kv1.4 CBA
RIA - radioimmunoassay
ELISA - enzyme-linked immunosorbent assay
CBA - cell-based assay
15

16. Recommended management guidelines
16
Current treatment options for MG include:
Symptomatic Treatment:
1. Acetylcholinesterase inhibitors
Disease Modifying Treatments:
1. Corticosteroids (e.g. prednisone)
2. Non-steroid Immune Suppressants
(e.g. mycophenolate mofetil and azathioprine)
3. Intravenous immunoglobulin (IVIG)
4. Plasma Exchange/Therapeutic Apheresis
5. Complement Inhibitors (e.g. eculizumab)
1. Howard, 2018
Figure adapted from reference #1.

17. 1. Sieb, 2014
MG Treatment Landscape (2020)
Symptomatic:
Acetylcholinesterase Inhibitors
• Pyridostigmine (Mestinon)
Immune-based treatment:
Corticosteroids: Retrospective Data
Azathioprine: RCT and Retrospective
Cyclosporine: RCT and Retrospective
Mycophenolate: RCT Neg
Retrospective Positive
Tacrolimus: Retrospective
Rituximab: Retrospective, RCT expected
IVIG/PLEX: RCT Impending Crisis
Eculizumab: RCT
SC IG: Retrospective, RCT ongoing
17

18. Cholinesterase Inhibitors
Slow breakdown of acetylcholine
Improves strength by increasing competition for limited receptors
Symptomatic treatment only
Goal:
• Improvement in strength (e.g. elimination of double vision)
• Benefit: 4 – 6 hours
Side Effects:
• GI upset
• Salivation
If medication is successful, can consider treating
side effects (e.g. glycopyrrolate)
1. Simon, et al. 2015
Figure adapted from reference #1. Re-created using BioRender.com
18

19. Corticosteroids
1. Pascuzzi, et al., 1984
Dose:
60-100mg daily (1.5-2 mg/kg/day)
Begin taper after strength improved (4-6 weeks)
Initial exacerbation (5 days post treatment
initiation)
Results:
• 80% marked improvement (53%) or remission
(27%)
• Onset benefit 3 weeks (85%)
• Max benefit 2 weeks - 6 years
Problem = Side Effects!
66.7% patients side effects
Include:
• Cushing
• Weight gain
• Diabetes
• Osteoporosis
19

20. Immunosuppressants
1. Hehir, et al., 2010 2. Palace, et al., 1998
Azathioprine
Block T cell production
Onset: 12 – 18 months
Typical Dose:
1.5 – 2.5 mg/kg/day (150-250mg)
Goals Therapy:
Improve Strength
• Increase relapse free period
Reduce or Eliminate Steroids
• 63% off prednisone 3 years
Mycophenolate (CellCept/Myfortic)
Reduce production of T and B Cells
Onset: 12 – 18 months
Typical Dose:
1000 – 1500mg twice per day
Goals Therapy:
Improve Strength
Reduce or Eliminate Steroids
• 50% off prednisone 2 years
• 70% on low dose prednisone 2 years
Monitor: CBC, hepatic
Side Effects:
• Nausea/Diarrhea
• Infection
• Red/White Blood Cell
• Suppression
Monitor: CBC
20

21. Thymectomy
In patients with a thymoma and MG, thymectomy should be performed to
remove the tumor.
Importantly, a benefit of total thymectomy has been reported for patients with
early-onset MG without a thymoma.
• Guidelines and consensus statements recommend early thymectomy for:
• Early-onset MG
• MG in children
• Patients with generalized MG who have anti-AChR antibodies and
whose symptoms developed at the age of 50-65 years
• Current evidence does not support thymectomy in patients with:
• MG and anti-MuSK or anti-LRP4 antibodies
• Ocular MG
1. Wolfe, et al., 2017 2. Gilhus, 2016 3. Clifford, et al., 2019
21

22. 1. Suh, et al., 2013 2. Sanders, et al., 2016 3. Silvestri and Wolfe, 2014
Refractory Myasthenia Gravis
Approximately 10-15% of patients do not respond adequately to
currently available therapies for MG, or they experience intolerable
side effects on IST, so are considered to have refractory MG.
Some options exist for individuals with refractory disease:
• Eculizumab
• Rituximab
• Chronic IVIG
• Chronic plasma exchange/apheresis

23. Approved by the FDA in Oct. 2017 for adult patients
with generalized MG who are anti-AchR+.
Typical Treatment
• Induction:
• 900mg IV weekly x 4 weeks
Maintenance:
• 1200mg IV weekly
Annual Cost
• $650,000/year cost to infusion center/hospital
1. Howard, et al., 2017
Eculizumab
23
Responder analyses conducted at 26 weeks follow-up. Figures adapted from reference #1.

24. 1. Tandan, et al., 2017
Table adapted from reference #1.
Treatment effect All MG (n=169) AChR MG (n=99) MuSK MG (n=57) P-value (AChR vs. MuSK)
Minimal manifestations or better
(PIS-m scale)
75 of 169 (44%) 30 of 99 (30%) 41 of 57 (72%) <0.001
Chronic stable/pharmacologic
remission (PIS-m scale)
45 of 169 (27%) 16 of 99 (16%) 27 of 57 (47%) <0.001
Any relapse after rituximab 26 of 101 (26%) 21 of 63 (33%) 4 of 29 (14%) 0.05
Relapses after rituximab 0.4 +/- 0.9 (n=100) 05. +/- 1.0 (n=62) 0.2 +/- 0.6 (n=29) 0.04
Rituximab treatment effect in MG
Rituximab
There is no consensus on the role of rituximab in management of AChR antibody and
seronegative MG.
Typical Treatment:
• 375 mg/m2 IV weekly x 4 weeks
Repeat infusions every 6-12 months
(suppresses B-cells)
Monitor CD19/20
Cost to Insurance/Patient:
• $80 - $120 K/year
• (Assume 2-3 cycles per year)
24

25. Rituximab use for MuSK MG
Rituximab is emerging as an extremely successful treatment for patients with the IgG4 mediated anti-
MuSK MG.
1. Tandan, et al., 2017 2. Hehir, et al., 2017 3. Marino, et al., 2020
Table adapted from reference #2.
Table adapted from reference #1.
Treatment effect All MG (n=169) AChR MG (n=99) MuSK MG (n=57) P-value (AChR vs. MuSK)
Minimal manifestations or better
(PIS-m scale)
75 of 169 (44%) 30 of 99 (30%) 41 of 57 (72%) <0.001
Chronic stable/pharmacologic
remission (PIS-m scale)
45 of 169 (27%) 16 of 99 (16%) 27 of 57 (47%) <0.001
Any relapse after rituximab 26 of 101 (26%) 21 of 63 (33%) 4 of 29 (14%) 0.05
Relapses after rituximab 0.4 +/- 0.9 (n=100) 05. +/- 1.0 (n=62) 0.2 +/- 0.6 (n=29) 0.04
Rituximab treatment effect in MG
Rituximab-treated (n=24) Control (n=31) P-value
Level 2 or better (MGSTI scale) 14 of 24 (58%) 5 of 31 (16%) 0.002
Level 1 or better (MGSTI scale) 13 of 24 (54%) 2 of 31 (6.45%) <0.001
Minimal manifestations or better (PIS-m scale) 16 of 24 (67%) 8 of 31 (26%) 0.003
Outcome at time of last visit of patients with MuSK MG
25

26. 1. Sanders, et al., 2016
MG Crisis
What is Impending Crisis?
• Severe worsening of muscle weakness due to MG that could lead to crisis in short team (days to weeks)
Signs/Symptoms:
• Shortness of breath at rest. With activity.
• Shortness of breath when lying on back
• Use of accessory muscles to breathe
• Slurred speech
• Trouble swallowing secretions
• Trouble holding up head
• Trouble lifting head up off a bed
• Trouble walking or sitting independently
What is Myasthenic Crisis?
• Severe muscle weakness due to MG which leads to respiratory failure
• Need for mechanical ventilation or non-invasive ventilation (BIPAP)
26

27. Tests of Patients with Shortness of Breath
1. Counting in 1 Breath (inability count 20 can indicate severe weakness)
2. Neck Flexion Strength while Supine
3. Forced Vital Capacity (FVC)
4. Mean Inspiratory Pressure (MIP)
5. Mean Expiratory Pressure (MEP)
Warning:
Pulse oximetry is NOT a reliable indicator of
respiratory status in a patient with MG
• Good O2 saturation does not mean there
is no respiratory compromise in MG
• Hypoxia often seen only after life-threatening respiratory
failure has already developed
1. Elsheikh, et al., 2016
2. Chevrolet and DeleAmont, 1991
3. Thieben, et al., 2005
27

28. Triggers of MG Crisis
• Illness
• Infection
• Surgery
• Reduced Dosage of MG Medications
• Exposed to medication which may worsen MG
• Pregnancy
• Stress
• Heat
• No identified trigger
1. Gummi, et al., 2019 28

29. Medications that May Worsen MG
Some medications may worsen MG symptoms and should be avoided or used with caution:
• Magnesium
• IV steroids
• Cardiac drugs: beta-blockers, calcium channel blockers, procainamide
• Common antibiotics:
o Quinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin)
o Aminoglycosides (e.g. gentamycin, neomycin)
o Macrolides (e.g. azithromycin “Z-pack”, clarithromycin, erythromycin, telithromycin)
• Neuromuscular blocking agents: especially non-depolarizing agents such as cisatracurium and
rocuronium
• Immune system checkpoint inhibitors (e.g. pembrolizumab)
The Myasthenia Gravis Foundation of America (MGFA) website provides a list a of drugs that
may worsen disease:
• https://myasthenia.org/MG-Community/MyMG-App
• https://myasthenia.org/What-is-MG/Drugs-and-MG
29

30. Medical Management MG Crisis
Plasma Exchange/Apheresis:
5 – 6 Exchanges (Every other day)
Intravenous Immunoglobuin (IVIG):
2 gm/kg over 2 - 5 days
Ineffective in anti-MuSK
Corticosteroids:
Avoid as initial therapy
• Expect worsening in MG for 5 – 7 days
1. Sieb, 2014 2. Barth, et al., 2011
30

31. 1. Sanders, et al., 2016
2. Hobson-Webb, et al., 2015
3. Gupta, et al., 2016
4. Oskarsson, et al., 2016
Tapering of Immunosuppressant Therapy
• Guidelines for MG therapy recommend the tapering of
corticosteroids and immunosuppressants to prevent risk of long-
term side effects.
• Tapering of therapies has been associated with some risk of
relapse.
• Current evidence with CellCept and Azathioprine suggests that
tapering of these medications is safe.
o Taper medications after period of stability
o Slow tapering is best
31

32. Multidisciplinary Care
32
A multidisciplinary approach has shown utility in the management of several
neuromuscular diseases.
A multidisciplinary clinic for patients with MG is likely to include the following
practitioners:
• Neurologist
• Nurse
• Pharmacist
• Research Coordinator
Quality of care for patients with MG depends on navigating complicated
treatment options.
32

33. Outcome Metrics in Clinical Practice
1. Relevant
2. Meaningful
3. Reliable
4. Ease of Use
5. Ease of Interpretation
6. Logistical
7. In the Public Domain
1. Burns, 2016
33

34. MG Metrics - Composite Scale
1. Burns, 2012
Clinical feature Scale range Baseline = 0 Severe presentation
Ptosis, upward ease 0-3 >45 seconds Immediate = 3
Double vision on lateral gaze, left or right 0-4 >45 seconds Immediate = 4
Eye closure 0-2 normal Severe weakness (unable to keep eyes closed) = 2
Talking 0-6 normal Difficult to understand speech = 6
Chewing 0-6 normal Gastric tube = 6
Swallowing 0-6 normal Gastric tube = 6
Breathing 0-9 normal Ventilator depenence = 9
Nexk flexion or extension 0-4 normal Severe weakness = 4
Shoulder abduction 0-5 normal Severe weakness = 5
Hip flexion 0-5 normal Severe weakness = 5
Overview of MG composite scale
Table adapted from reference #1.
34

35. MG Metrics - MG-QOL15
Please indicate how true each statement has been (over the past few weeks). Not at all Somewhat Very much
0 1 2
1. I am frustrated by my condition
2. I have trouble using my eyes because of my condition
3. I have trouble eating
4. I have limited my social activity because of my condition
5. My condition limits my ability to enjoy hobbies and fun activities
6. Because of my physical condition, I have trouble meeting the needs of my family
7. I have to make plans around my condition
8. My occupational skills and/or job status has been negatively affected by physical condition
9. I have difficulty speaking
10. I have trouble driving
11. I am depressed about my condition
12. I have trouble walking
13. I have trouble getting around public places
14. I feel overwhelmed by my condition
15. I have trouble performing my personal grooming needs
Figure adapted from reference #1.
1. Burns, et al., 2008 35

36. Practical Use of MG Metrics – EMR Data
IVIG
IVIG
2gm/kg
Lost to
Follow-up
IVIG
IVIG
IVIG
It is important to follow MG metrics over time.
In this example, use of MG composite from EMR
data demonstrates response to therapy.
79 year old Dairy Farmer w/ Generalized AChR
MG
• Bulbar, Respiratory, Limb Weakness
Treatments:
• Prednisone = Severe Depression
• CellCept = Insomnia
• Imuran = Severe Oral Ulcers
Now on standing IVIG for disease management
MG Composite Score used for Insurance
36

37. Experimental Therapies On the Horizon
37
1. Farmakidis, 2020
Drugs in development for generalized myasthenia gravis
Category Route of Administration Study Status
Efgartigimod Neonatal Fc receptor inhibitor Intravenous Phase 2 complete; phase 3 underway
Rozanolixizumab Neonatal Fc receptor inhibitor Intravenous Phase 2 complete; phase 3 ongoing
M281 Neonatal Fc receptor inhibitor Intravenous Phase 2 ongoing
Ravulizumab Terminal complement inhibitor Intravenous Phase 2 complete; phase 3 underway
Zilucoplan Terminal complement inhibitor Subcutaneous Phase 2 complete; phase 3 in planning stage
Table adapted from reference #1.

38. 38
Future directions
• Awaiting results of multiple phase 2 and 3 studies for drug
candidates
• Trial of weaning immunosuppressants in stable patients
• Epigenetics, metabolomics
Information about active clinical trials can be found at:
• https://myasthenia.org/Research/Clinical-Trials
• https://www.clinicaltrials.gov

39. 39
Thank You