Myasthenia gravis

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Myasthenia gravis
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• prevalence - 20 per 100,000
• population-between 53,000 and 60,000 cases /USA

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Pathophysiology of Myasthenia Gravis
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Pathophysiology of Myasthenia Gravis

• 85 of patients with MG have detectable serum
  antibodies against AChRs
• 20 to 40 of the remaining patients are positive
  for anti-MuSK antibodies
• about 10 of patients are double-seronegative MG
  
• anti-LRP4 autoantibodies exist in serum samples
  of patients with double-seronegative MG.

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Autoantibodies in Myasthenia Gravis
Antigen MG Control
Anti-AChR Human 85-90 TE671 80 0
Anti-Musk 2-5 of all MG, gt20 of AChR-SNMG 0
Anti-striated muscle 40 4
Anti-thyroid 44 14
Anti-nuclear 14-39 4
Anti-titin (MGT30) 85 (MGthymoma) 0
Anti-ryanodine receptor 50 (MGthymoma) 0
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Evidence that MG is autoimmune disease

• MG Patients have increased incidence of other
  immune-mediated diseases, such as rheumatoid
  arthritis
• A transitory neonatal form of the disease occurs
  in MG.
• Immunosuppressive treatment, including plasma
  exchange, produces improvement in most patients
• An animal model of MG can be produced by
  immunization with purified AChR
• Antibodies against human AChR are found in the
  serum of most patients

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Evidence that MG is autoimmune disease

• Myasthenic serum or IgG produces abnormal
  neuromuscular transmission when injected into
  animals
• IgG and complement components are attached to the
  postsynaptic endplate membrane in myasthenic

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Antibody-Mediated Mechanisms

• Accelerated degradation of AChRs
• Complement-Mediated AChR-loss
• Blockade of AChRs

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Possible Origin of Autoimmunity in MG

• Cross reacting epitope
• Idiotypic dysregulation
• Abnormal antigen
• Drug related antigen
• Helper T-cell defect
• Regulatory T-cell defect

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AChR Seronegative Myasthenia Gravis

• 10-15 of MG patients
• Clinical presentation similar to seropositive
  generalized MG
• Thymus usually normal
• Reduced-AChRs probably due to antibodies, to
  another NMJ antigen, or signal transduction
  effect on AChR function

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Autoimmune disorders applied to seropositive and
seronegative MG
Seropositive MG Seronegative MG
AChR antibodies Yes No
Improvement after plasma exchange Yes Yes
Defect transferable to mice by Ig Yes Yes
Transfer features
NMT defect Yes Yes
AChR reduction Yes No
Antibody attached to AChR Yes No
Immunization against antigen(s) Produces disease Not yet clear
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• AChR-positive MG (85-90)
• AChR-negative MG
• MuSK positive (around 20-40)
• MuSK negative (double negative)

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Clinical Presentation

• Ptosis or diplopia was the initial symptom in two
  thirds
• Almost all have both within 2 years of disease
  onset
• Difficulty chewing, swallowing, or talking is the
  initial symptom in one sixth of patients and limb
  weakness in one tenth.
• Weakness typically fluctuates during the day .

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Clinical Presentation
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Disease course

• MG is variable but usually progressive
• Restricted to the ocular muscles in 10-40 of
  patients
• Maximum weakness occurs during the first year in
  two thirds of patients.
• Before corticosteroids were used for treatment,
  approximately one third of patients had
  spontaneous improvement, one third had
  progressive disease, and one third died of the
  disease.

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Factors that worsen myasthenic symptoms

• Emotional upset,
• Systemic illness (especially viral respiratory
  infections).
• Hypothyroidism / hyperthyroidism.
• Pregnancy, the menstrual cycle,
• Drugs affecting neuromuscular transmission
• Fever.

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Physical Findings

• Ocular Muscles -Asymmetrical weakness of several
  muscles in both eyes is typical.
• Ptosis is usually asymmetrical and varies during
  sustained activity
• Oropharyngeal Muscles changes in the voice,
  difficulty chewing and swallowing
• Limb Muscles Neck flexors are usually weaker than
  neck extensors, deltoids, triceps, and
  wrist/fingers extensors are often weaker than
  other muscles.

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OCCULAR SYMPTOMES

• Weakness usually involves one or more ocular
  muscles without overt pupillary abnormality
• Weakness is typically variable, fluctuating, and
  fatigable
• After down gaze, upgaze produces lid overshoot
  ("lid twitch").
• Pseudo-internuclear ophthalmoplegia-limited
  adduction is present, with nystagmoid jerks in
  abducting eye.
• In asymmetrical ptosis, covering the eye with
  the ptotic lid may relieve contraction of the
  opposite frontalis.
• Passively lifting a ptotic lid may cause the
  opposite lid to fall.
• Cold applied to the eye may improve lid ptosis.

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• myasthenic crisis
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Clinical association of MuSK abs

• Distinct population
• Age at onset around third decade
• More women than men
• More bulbar patients
• Response to plasma exchange
• Incidence 20-40 of AChR negative MG
• (Possible additional plasma factor involved ?)

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The Thymus in Myasthenia Gravis

• Breakdown in immune tolerance toward
  self-antigens in the thymus.
• 10 of patients with MG have a thymic tumor most
  are benign.
• 70 have hyperplastic changes (germinal centers)
  that indicate an active immune response
• Virtually all patients with MG and thymoma have
  elevated concentrations of AChR-binding
  antibodies

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Diagnostic Procedures-1

• Edrophonium Chloride (Tensilon) Test
• positive in more than 90 of patients with MG
• Tensilon Test is not unique to MG
• A dose of 2 mg is injected intravenously, and the
  response is monitored for 60 seconds. Then 3 and
  5 mg.

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Diagnostic Procedures-2

• Electromyography
• 10 decrement in amplitude when the first
  stimulus is compared to the fourth or fifth
• SFEMG is the most sensitive clinical test of
  neuromuscular transmission and shows increased
  jitter .

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Diagnostic Procedures-2
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Treatment

• Cholinesterase Inhibitors- Mestinon 30-60
  mg/4-8/day
• Corticosteroids 75 of patients markdly
  improved ! Prednisone 1.5-2.0 mg/kg per day
• Immunosuppressant Drugs-
• Plasma Exchange ,IVIG
• Thymectomy

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Treatment-2

• Azathioprine
• Onset action 4-8  
• side effects allergic reaction,hepatic
  toxicity, leukopenia
• Cyclosporin  Onset action 2-3 renal toxicity,
  hypertension, multiple potential drug
  interactions
• Cyclophosphamide  Onset action variabl  
• side effects leukopenia, hair loss, cystitis

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Efficacy of PE in myasthenia gravis Hadassah
experience

• 86 myasthenic patients were treated with repeated
  courses of PE (ranging from 6-126 exchanges
  during a period of 3 years)
• The follow up period was 3 years
• During this period the efficacy of PE was
  evaluated the response rate was over 85 of
  patients (improved).

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Myasthenia gravis Myasthenic crisis
Before Plasmapheresis
After Plasmapheresis
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Current therapy of myasthenia gravis

• What do we treat patients with MG when the
  conventional therapy fails?

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mAb therapy for neuro-inflammatory diseases

• Monoclonal antibodies (mAbs) represent an
  emerging and rapidly growing field of therapy in
  neuro-inflammatory diseases .
• Most of them have been developed in systemic
  autoimmune diseases and Oncology.
• There are currently more the 240 mAbs in clinical
  development

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mAb therapy for neuro-inflammatory diseases

• Monoclonal antibodies mode of action
• Depletion of specific cells
• Blocking specific molecules expressed on the cell
  membrane
• Neutralizing soluble serum factors

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Monoclonal Abs directed at specific immunologic
aspects of MG

• Abnormal B cells activation
• Complement activation
• BAFF disregulation
• Helper and Regulatory T-cell defect

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Monoclonal Abs directed at specific immunologic
aspects of MG.
Dalakas , Ann N Y Acad Sci, 2012
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Examples of Therapeutic Monoclonal Antibodies
Name Antigenic target Clinical use
Muromomab CD3 Transplant rejection
Daclizumab CD25 Transplant rejection,adult T-cell leukemia
Rituximab CD20 B-cell lymphoma, AUTOIMMUNITY
Infliximab TNF Crohns disease, RA
Alemtuzumab CD52 CLL,MS
Adalimumab TNF RA
Efalizumab CD11a Psoriasis
Natalizumab ABT-874 a-4 integrin Anti IL-12 MS, Crohns disease Not yet identified
Toralizuma CD40L, CD154 ineffective in SLE
No candidate Non Fc-binding Not yet identified
Eculizumab Anti-C5 paroxysmal nocturnal hemoglobinuria and atypical hemolytic-uremic syndrome
Abatacept Anti-CTLA4 ineffective in SLE
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Targeting B-cells

• AChR MG is the prototypic antibody mediated
  disease with clear evidence that AChR antibodies
  induce the disease in animal models and in
  humans.
• Both AChR and MuSK antibody positive patients
  respond to plasma exchange.
• Anti-MuSK patients do not appear to respond to
  IVIg.
• Anti-MuSK antibodies are IgG4 which do not
  activate complement.
• Anti-AChR are IgG1 and IgG3 that activate
  complement.

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Targeting B-cells

• B-cell targeting therapies
• Rituximab
• Ocrelizumab
• Ofatumumab

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Rituximab Anti-CD20
Target CD-20 receptor
Other names Mabthera Rituxan, and Zytux
Rationale B cells involvement in autoimmune diseases antibody mediated , B cells role as APCs and cytokines production
Mode of action The antibody binds to CD20 expressed on B cells, from early pre-B cells to later in differentiation, but absent on terminally differentiated plasma cells. eliminates nearly all CD20-expressing B cells by CDC and ADCC as well as induction of apoptosis
Safety and tolerability Severe infusion reaction, cardiac arrest, Infections PML. Resistance development, most likely due to less efficient antibody-dependent cytotoxicity or to generation of human antichimeric antibodies (HACA).
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The role of B-cell activating factor (BAFF) in
myasthenia gravis

• B-cell activating factor (BAFF) is important in
  the differentiation and maturation of B cells and
  plasma cells.
• Although the mechanism(s) by which BAFF and its
  receptors help regulate B-cell function and
  tolerance is not known, it may play a significant
  role in the immune process involved in myasthenia
  gravis.
• Serum BAFF levels were found to be significantly
  higher in MG patients compared to controls
  including those with MS There was no correlation
  to disease severity but a trend for levels to be
  higher in AChR patients.
• There is also evidence that BAFF is upregulated
  in germinal follicle like structures in
  myasthenic thymuses.

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Belimumab Anti-BAFF
Target BAFF
Other names Anti-BAFF
Rationale BAFF- is important in the differentiation and maturation of B cells and plasma cells
Mode of action inhibits BAFF action via binding circulating BAFF and reducing the number of circulating B-cells but not to the extent as rituximab
Safety and tolerability approved in the US, Canada and Europe for the treatment of systemic lupus erythematosis A phase II trial in rheumatoid arthritis was encouraging but no phase III trial is underway. A phase II trial in MG has been announced
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Therapy that targets complement

• Complement mediated damage to the post-synaptic
  junction has been demonstrated to bind to the
  AChR-antibody complex inducing membrane-attack-com
  plex damage to the membrane reducing
  post-synaptic folds, widening the synaptic cleft
  and reducing the numbers of receptors.

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Eculizumab Anti-C5
Target complement protein C5
Other names Soliris
Rationale Complement mediated damage to the post-synaptic junction has been demonstrated to bind to the AChR-antibody complex inducing membrane-attack-complex damage to the membrane reducing post-synaptic folds, widening the synaptic cleft and reducing the numbers of receptors.
Mode of action a recombinant humanized monoclonal IgG 2/4 antibody that binds to complement protein C5 which prevents the generation of the terminal complement C5b-9 complex
Safety and tolerability nausea, back pain, nasopharyngitis, and headache vulnerable to infection with encapsulated organisms. meningococcal vaccination is recommended at least 2 weeks prior to receiving eculizumab
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Agents targeting T cell intracellular signaling
pathways, and costimulation

• IL-2 mediate cell proliferation and
  differentiation.
• Daclizumab binds to CD25 (IL-2 receptor
  antagonist) and inhibits T cell proliferation.
• Daclizumab is very well tolerated, has been
  approved for one form of leukemia, and has been
  very promising in patients with multiple
  sclerosis in at least two clinical trials.
• Daclizumab An excellent agent to consider for MG

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Daclizumab Anti-CD25
Target IL-2 receptor a chain (CD25)
Other names Anti-CD25, Zenapax
Rationale IL-2 mediate cell proliferation and differentiation.
Mode of action Prevents IL-2 binding without triggering of complement- or cell-mediated cell depletion, modulation of the IL-2 receptor complex or induction of intracellular signaling events a marked expansion of regulatory CD56bright NK cells
Safety and tolerability Gastrointestinal (e.g. nausea, diarrhoea), metabolic and nutritional disorders
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Association of Myasthenia Gravis with Other
Diseases

• Hyperthyroidism
• Rheumatoid arthritis. 2
• Seizures
• diabetes mellitus 7
• thyroid disease 6
• nonthymus neoplasm 3,

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Transitory Neonatal Myasthenia.

• 10-20 of newborns of MG mothers
• frequency and severity correlate with antibody
  level
• Hypotonia and poorly fed during the first 3 days.
  symptoms may be delayed for 1-2 days. Usually
  last less than 2 weeks but may continue for as
  long as 12 weeks.

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Genetic Myasthenic Syndromes

• not immune mediated
• 21 male predominance.
• ophthalmoparesis and ptosis during infancy. Limb
  weakness is usually mild compared with
  ophthalmoplegia.
• Respiratory distress is unusual.
• ChE inhibitors improve limb muscle weakness in
  many forms of congenital genetic myasthenia

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Lambert-Eaton Myasthenic Syndrome

• A pre-synaptic abnormality of ACh release
• In association with malignancy, usually small
  cell lung cancer (SCLC).
• Abs against the voltage-gated calcium channels
  (VGCCs) on nerve terminals
• reduced tendon reflexes and enhanced by repeated
  muscle contraction or repeated tapping of the
  tendon.
• autonomic dysfunction dry mouth, impotence and
  postural hypotension.
• Treatment with Guanidine hydrochloride increases
  the release of ACh

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Drug alert for patients with myasthenia gravis

• Interferon-a, botulinum toxin, and
  d-penicillamine should never be used in
  myasthenic patients.
• The following drugs produce worsening of
  myasthenic weakness in most patients who receive
  them. Use with caution and monitor patient for
  exacerbation of myasthenic symptoms.
• Succinylcholine, d-tubocurarine, or other
  neuromuscular-blocking agents
• Quinine, quinidine, and procainamide
• Aminoglycoside antibiotics, particularly
  gentamicin, kanamycin, neomycin, and streptomycin
  
• Beta blockers (systemic and ocular preparations)
  propranolol, timolol maleate eyedrops
• Calcium-channel blockers
• Magnesium salts (including laxatives and antacids
  with high Mg2 concentrations)
• Iodinated contrast agents
• Many other drugs are reported to exacerbate the
  weakness in some patients with MG. All patients
  with MG should be observed for increased weakness
  whenever a new medication is started.

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BOTULISM

• A toxin produced by the anaerobic bacterium,
  Clostridium botulinum,
• Blocks the release of ACh from the motor nerve
  terminal
• Intoxication usually follows ingestion of
  contaminated foods that were inadequately
  sterilized
• First Nausea and vomiting and then neuromuscular
  symptoms 12-36 hours after ingestion
• Clinical symptoms
• blurred vision, dysphagia, and dysarthria.
• Pupillary responses to light are impaired.
• tendon reflexes are variably reduced.
• Fatal respiratory paralysis may occur rapidly.
• Autonomic dysfunction, such as dry mouth,
  constipation, or urinary retention in most.