Whats-New-in-Myasthenia-Gravis.pptx

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): Fatigable Weakness Muscle weakness that fluctuates with rest and activity 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/year 1 Prevalence of 200 cases/million 1,2 Est: 70,000 people with MG in US Age of onset: Women < 40 years; Men > 50 years Gilhus , 2016 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: Ocular myasthenia - weakness is limited to the eyelids and extraocular muscles. 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: Neonatal MG - a transient form in neonates that results from transplacental passage of maternal antibodies that interfere with function of the neuromuscular junction. Congenital MG - nonimmune-mediated forms that may result from mutations that adversely affect neuromuscular transmission. 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 ~50% of patients with ocular myasthenia are seropositive ~90% of patients with generalized disease are seropositive Seronegative MG – Patients lack AChR , MuSK , or LRP4 antibodies on standard assays 5 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 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 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. In most patients with purely ocular MG 2 years after the start of symptoms, disease will persist as a focal eye-muscle weakness In patients with ocular MG, presence of AChR -binding antibodies slightly increases the risk of subsequent generalized disease 1 90% of patients with MG experience the maximal amount of weakness within the first 2 symptomatic years 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 disease 1 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. Li, et al., 2018 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 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 Dubey , et al., 2020 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 Howard, 2018 Berrih-Aknin , 2014 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 weakness 1 <5% present with proximal limb weakness alone Less common presentations include: Isolated neck weakness Isolated respiratory muscle weakness Distal limb weakness Clinical Presentation : Location: Ocular MG Generalized MG Refractory MG Thymus Pathology Age Onset Pasnoor , et al., 2010 Gilhus , 2016 12

13. Diagnostic algorithm for MG 13 Wang, et al., 2007 Mercuri, et al., 2018 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 Meriggioli and Sanders, 2005 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 Clustered AChR Cell Based Antibody Assay Anti-LRP4 (Low Density Lipoprotein 4) Ab Howard, 2018 Zisimopoulou , et al., 2014 Rodriguez Cruz , et al., 2015 Vincent, et al., 2018 Figure adapted from reference #1. Table adapted from reference #4. 15

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

17. 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) Acetylcholinesterase Simon, et al. 2015 Figure adapted from reference #1. Re- created using BioRender.com 18

19. Corticosteroids 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 Hehir , et al., 2010 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 Wolfe , et al., 2017 Gilhus , 2016 Clifford, et al., 2019 21

22. Suh , et al., 2013 Sanders, et al., 2016 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 Howard, et al., 2017 Eculizumab 23 Responder analyses conducted at 26 weeks follow-up. Figures adapted from reference #1.

24. Tandan , et al., 2017 Table adapted from reference #1. 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. Tandan , et al., 2017 Hehir , et al., 2017 Marino, et al., 2020 Table adapted from reference #2. Table adapted from reference #1. 25

26. 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 Counting in 1 Breath (inability count 20 can indicate severe weakness) Neck Flexion Strength while Supine Forced Vital Capacity (FVC) Mean Inspiratory Pressure (MIP) 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 Elsheikh , et al., 2016 Chevrolet and DeleAmont , 1991 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 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: Quinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin) Aminoglycosides (e.g. gentamycin, neomycin) 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 Sieb , 2014 Barth, et al., 2011 30

31. Sanders, et al., 2016 Hobson-Webb , et al., 2015 Gupta , et al., 2016 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. Taper medications after period of stability 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 Relevant Meaningful Reliable Ease of Use Ease of Interpretation Logistical In the Public Domain Burns, 2016 33

34. MG Metrics - Composite Scale Burns, 2012 Table adapted from reference #1. 34

35. MG Metrics - MG-QOL15  Figure adapted from reference #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 Farmakidis, 2020 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