Todays Talk: What We Know About MG, and What We Wish We Knew

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Todays Talk What We Know About MG, and What We
Wish We Knew

• Some History
• Clinical features
• How MG works the Nerve-muscle junction
• Autoimmunity
• Origin, and Genetics (GWAS)
• Treatment Strategies

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1672 103 yrs before Mozart
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Physostigmine N-M Jct
M. Walker. Lancet 11200-1, 1934
Sir Henry Dale
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Clinical Features of MG

• Muscle weakness.
• Fatigue on repeated contraction.
• Double vision, droopy lids, weakness Crisis
  Respiration, Swallowing
• No changes in sensation or autonomic function.

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A Little Background

• The Neuromuscular Junction Site of the
  abnormality in MG A Receptor problem
• The Immune Systems Job The bodys police
  department Must recognize a Trillion
  items Distinguish good from bad LAPD

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Current Concepts of MG

• Receptor disorder AChRs at NM junctions
• Autoimmune Antibody mediated (T Cell
  dependent)
• Ab Mechanisms Accelerated degradation Blockad
  e Comp.-mediated damage
• Antigen AChR Sequenced Cloned
  MuSK
• Origin Thymus Contains AChR
• Immune cells Genetic Factors
  (GWAS)
• Treatment Current Effective Future
  Specific ?

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Unsolved Problems in MG

• What triggers the autoimmune response?
• What keeps it going?
• What can cure it?

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Circa 1970
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Bungarus Multicinctus
C.Y.Lee 1970
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Motor Point Biopsies
Nl
AChRs / jct Control 3.8 x 107 Myasthenic
0.7 x 107
Nl
MG
AChE
MG
Fambrough, Drachman, Satyamurti Science 1973
Labeled with 125I-?BuTx
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Autoimmune Pathogenesis of MGEarly Evidence

• Association with other autoimmune diseases. (Ian
  Simpson1960)
• Thymic abnormalities Hyperplasia Thymoma
  
• Improvement of MG with steroid treatment.
• EAMG Immunization with AChR produces model of
  MG.

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EAMG
Patrick Lindstrom Science 1972
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EAMG

• Rabbits, Lewis rats, mice, frogs, monkeys
• Immunize with AChR from electric organs of
  electric eels or fish.
• Clinical weakness Cellular responses
  Antibody responses

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Neonatal MG Clue to Ab-mediated pathogenesis

• Note decremental response at 5 Hz

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MG is Antibody-mediated
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Antibody Mediated Mechanisms in MG

• Accelerated degradation of AChRs.
• Blockade of AChRs.
• Damage to AChRs (Complement).

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MG Antibody Accelerates AChR Degradation
Kao Drachman Science 1977
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Endocytosis of Clustered AChRs
Clusters
Freeze-Fracture EM
Pumplin Drachman J. Neurosci 1983
Pit
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Diagnosis in MG

• AChR antibody MuSK antibody
• Tensilon test
• Repetitive nerve stimulation Jolly test
• SFEMG
• CLINICAL FEATURES!

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AChR Antibody Titer

• Positive in 85 of MG patients.
  50 with ocular MG
• In different patients absolute titer does not
  correlate with severity.
• In a given patient, change in titer corresponds
  to change in severity.

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Antibody Negative MG

• 40 to 50 percent of patients with ocular MG
  have no detectable anti-AChR Ab.
• 10 to 20 percent of patients with generalized MG
  have no detectable anti-AChR Ab
• 40 of these have antibodies to MuSK (Muscle
  Specific Kinase) at NM Jct.

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There are Antibodies in "AChR Ab-Negative" MG

• Patients have reduced AChRs at NM junctions (7/7
  cases).
• Passive transfer to mice AChRs and mepps (6/7
  cases).
• 70 of Ab Neg sera bind to mammalian muscle in
  culture.
• 40 have anti MuSK antibodies. (What are the
  rest?)

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Origin of M.G.

• Role of Thymus.
• Abnormal immune regulation.
• "Molecular Mimicry" (Virus?).
• Genetic Predisposition! GWAS

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Thymus and the origin of MG

• Thymus is abnormal in 75 of pts 85 of these
  have Hyperplasia. 15 have Thymoma.
• Thymectomy is beneficial in up to 80 of pts.
• Myoid (muscle-like) cells express AChRs, in midst
  of immunocompetent cells.
• BUT- What triggers immune attack? Abnormal AChR?
  (No evidence) Novel fragment cleaved by
  Granzyme B? ?Viral infection Searching for
  viral DNA- (Vogelstein lab)

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Features of Thymus in MG

• Thymus is abnormal in 75 of patients
• 85 Hyperplasia 15 Thymoma

Hyperplasia (Germinal centers)
Myoid cells
Kao Drachman Science 1977
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What Happens in the Thymus?

• ACh Receptor is cut by the immune cells
  surrounding it (Granzyme B).
• The new fragments look dangerous.
• The immune cells attack, and make antibodies.
• But what triggers the immune cells to cut AChR
  ? A viral infection?
• We are looking!

Casciola-Rosen et al 2008J. Neuroimm. 201-233
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Do Genes Predispose to MG?

• MG features in family membersFamilial MG up to
  4 of family members Identical twins AChR
  antibodies.
• Association with other autoimmune diseases
  Thyroid, LE, RA, etc.
• Immune systemsome special features.
• GWASGenome wide association study

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GWAS Genome-wide association

• Multiple genes predispose to MG.
• Better telescopes more stars (SNP Chips like
  Hubble)
• 600,000 SNPs per chip (genes).
• 15 MG Centers in North America 1,000 MG
  patients (and 4,000 normals).

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What may we do with the GWAS Information?

• Design treatments related to genetic factors.
• Predict course of MG.
• Evaluate treatments most liekly to work.
• Susceptibility in family members.

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Myasthenia Was Gravis

• Remission 13
• Improved 26
• Unchanged 21
• Worse 10
• Died 30
• Bad prognosis 61

Grob, Arch Int Med 1961
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The Disney World Test
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Treatment of M.G.

• Anti-Cholinesterase Drugs "Band Aid
• Thymectomy To improve MG Thymoma
• Immunosuppression Steroids Others
• Removal of Antibodies Plasmapheresis
• IV gamma globulin
• High Dose Cytoxan for refractory patients
• "Re-booting the immune system"
• FUTURE Specific Immunotherapy.

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"Time-Linked" Treatment Plan

• Short-term Severity, or need for quick
  result. Anti-ChE IVIg Plasmapheresis
• Intermediate-term Take over after short
  term. Steroids Cyclosporine, FK506
• Long-term To minimize side effects. Thymectom
  y Imuran CellCept

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Anticholinesterase therapy

• Pyridostigmine (Mestinon)
• Delays hydrolysis of ACh Prolongs
  stimulation.
• Effects only temporary, partial.
• "Band Aid"

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Physostigmine
M. Walker. Lancet 11200-1, 1934
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Thymectomy in Myasthenia Gravis

• Indications Thymoma or For clinical
  benefit
• Diagnosis CT or MRI for thymoma Clinical
  indications
• Pre-op Optimize Never emergency
• Surgery Trans-sternal ?cervical ? Robotic
• Post-op Pulmonary care Anti-ChE
• Results Late 30 remissions 50 improved

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Questions About Thymectomy

• DOES IT WORK?? Will new study tell?
• How early after diagnosis?
• Age How old? How young?
• Severity of MG Ocular? (Schumm et al 1985)
• Surgical approach?

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Immunotherapeutic Agents in Current Use

• Prednisone
• Imuran (Azathioprine)
• Cyclosporine A (Neoral) Inhibits Calcineurin
  blocks IL2 production. (FK506)
• CellCept (Mycophenolate mofetil)
• Cyclophosphamide (Low vs High dose)
• IVIg
• Plasmapheresis

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CellCept

• Mycophenolate Used in transplantation Now in
  autoimmune diseases (MG).
• Mechanism Prevents B and T cell proliferation
  Blocks purine synthesis.
• Slow action Autoimmune cells must die off.
  Does not kill cells.
• Advantages Safety. Few side effects. Watch
  CBC.
• Dose 1 1.5 gm bid.

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Newer Immunosuppressive Agents

• Tacrolimus (FK506) Like CsA Inhibits
  calcineurin IL2 production
• Rituximab Anti-CD20 on B cells (Not plasma
  cells)
• ?Leflunomide Inhibits pyrimidine synthesis
• ? Abatacept (CTLA4Ig) Inhibits
  costimulation (EAMG studies)
• Rapamycin Inhibits IL2 action.

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Refractory MG

• Failure of adequate treatment with conventional
  agents.
• Unacceptable side effects.
• Co-morbidities preclude conventional Rx.
• Requirement for repeated rescue with short term
  treatments.

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Clean Slate Therapy
HEMATOPOIETIC STEM CELLS CD34
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EAMG Clean Slate
Combined Rx Cytoxan Irrad. BMT (autologous)
Just like naïve rats.
Pestronk Drachman, 1983
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High Dose CytoxanRe-booting

• For refractory patients only, so far.
• Mature WBC eliminated by Cytoxan.
• Bone marrow Stem Cells not killed by
  Cytoxan. Their aldehyde dehydrogenase inactivate
  s Cytoxan.
• Rapid reconstitution of Immune system.
• Re-booted Immune system may be tolerant of AChR.

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Results in Hi Cy Myasthenic Patients

• 12 patients treated at JH so far. All severe. 6
  months to 9 year follow up.
• Results11- Dramatic improvement 5 mos. to 8
  yrs1- Treatment-free remission 9
  yrs.5- Response to immunosuppressives not
  previously effective.2- Retreatment after 3
  6 yr. relapses- spectacular responses
  Maintenance CellCept
• BUT All but one relapsed eventually.

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Effects of Re-Booting

• Reduces autoantibodies (AChR) and Tetanus and
  Diphtheria Ab Not eliminated
• T cells increase (TRECs) despite lack of thymus.
• Re-booting, not Re-formatting.
• Requires maintenance treatment.

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Ideal Therapy of MG

• Specifically delete autoimmune response to
  AChR.
• Leave Immune system otherwise intact.
• Non-toxic.
• Long-lasting, permanent, or repeatable.

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Conclusions

• We know more about MG than any other autoimmune
  disease.
• Properly treated, 95 of MG patients are restored
  to normal lives.
• Even refractory patients respond.
• BUT We need to know the genetic factors.
• We wish we knew what triggers MG.
• A specific cure is the Holy Grail.

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Colleagues

• D. Fambrough B. Yang
• A. Pestronk F. Guarnieri
• I. Kao T. August
• K. Toyka A. Miagkov
• E. Stanley M. Williams
• R. Adams R. Brodsky
• K. McIntosh Y. Lu
• B. Wu W. Sun
• J-M. Wu

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