Home, Search, Index, Links, Pathology, Molecules, Syndromes, Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

Myasthenia Gravis: Treatments ¹⁸

• Genetics
  • Poor treatment response in AChR Ab+ MG: MG risk TERT lead variant rs2736099 ¹⁹
• Pyridostigmine (Mestinon) is the usual first line treatment for MG.
  • Cost/Year: $400
• Prednisone: Used for long-term immunosuppression when
  • Relatively rapid onset of benefit is desired (Weeks to Months)
  • Most effective treatment for ocular MG
  • May be used during pregnancy
  • Cost/Year: $250 - $1,000
• Cyclosporine A
  • Relatively rapid onset of benefit is desired (Months)
• Tacrolimus
  • Substitute for cyclosporine or prednisone
  • Shorter latency to benefit
  • Limiting features
    • Drug interactions
    • Blood-level monitoring needed
  • Cost/Year: $2,300
• Azathioprine
  • Provides: Long-term immunosuppression
  • Dose: Use ≥ 2.2 mg/kg
  • May be used during pregnancy
  • Limiting features
    • Long latency before benefit begins: Up to 1-2 years
    • Some patients: No improvement
    • Side effects
      • "Flu-like" syndrome: 20% to 30% need to stop drug
      • Neoplasm risk: Increased
  • Cost/Year: $500
• Mycophenolate mofetil
  • Substitute for azathioprine: Fewer side effects & Shorter latency of action
  • Some studies show no benefit in MG
  • Cost/Year: $1,000
• Rituximab
  • Uses
    • AChR Ab+ MG, Steroid refractory
    • MuSK MG
  • Cost/Year: $50,000
• Plasma exchange (PE) or Human immune globulin (IVIg)
  • Are used when
    • MG patients have life-threatening signs: Respiratory insufficiency or Dysphagia
    • A very rapid response to treatment is desired
  • PE is preferred for exacerbations
  • No benefit from > 5 PE during crisis ⁸
  • IVIg Chronic treatment
    • Indications: ?
    • Cost/Year: $75,000 to $150,000
• Thymectomy is performed for
  • Long-term benefit
  • In patients aged 8 to 55
  • Generalized MG
  • Thymoma
• C5 inhibitors: Eculizumab
  • Indication: Uncertain; Possibly AChR Ab+ MG refractory to other treatments
  • Cost/Year: $450,000 ⁹
  • Complement inhibitors, Other ¹¹
• Fc Receptor antagonists
  • Indications
    • Reduce AChR antibody titers
    • Possibly AChR Ab+ MG refractory to other treatments
  • Efgartigimod
    • Cost/Year: $450,000 ⁹
  • Nipocalimab
    • Cost/Year: $350,000
• Drug discontinuation

• Safe Medications
  • Pyridostigmine
  • Corticosteroids: Moderate doses
  • IVIg or SQIg
  • Plasma exchange
• When strict need for severe disease
  • Azathioprine
  • Eculizumab
  • Efgartigimod
• Contraindicated
  • Rituximab
  • Mycophenolate mofetil
  • Methotrexate
  • Cyclophosphamide
  • Cyclosporine A
  • Tacrolimus

Pyridostigmine (Mestinon) 7 Usual doses Adults Pills 60 mg tid to 120 mg q3h Higher does Virtually never effective Often have side effects Timespan pills 90 to 180 mg qhs Use only at bedtime Many cholinergic side effects if used more often than qhs Liquid: 60 mg pyridostigmine bromide per teaspoonful (5 mL) Childhood: Anti-AChE drugs Indications Autoimmune MG Most AChR Ab+ patients: First line treatment MuSK Ab+ patients: Often less helpful Congenital MG: Some syndromes Fatigue syndromes without MG: 30 mg 2x to 3x per day Orthostatic hypotension: With spared peripheral noradrenergic axons 6 Advantages Rapid onset of benefit Few serious side effects Inexpensive May be discontinued when immunomodulation becomes effective Disadvantages Side effects: Rarely serious Cholinergic symptoms & crisis: Especially with timespan tablets Muscle cramps Diarrhea Effective for ADL only subset of MG patients Less complete benefit: Severe MG; Ocular MG Comparison to corticosteroids or other immunomodulating agent treatment Often less effective over long term More likelihood of MG relapse when given alone Other Management: Do not use tensilon to gauge pyridostigmine dosing External link: 1935 Anti-AChE Rx (YouTube)

By Unknown (wellcomeimages.org) Mary Broadfoot Walker

• Usual doses
  • Inpatient: starting
    Begin at 20 mg qd
    • Increase by 5 mg every 2 to 3 days
    • Maximum: 50 mg qd
  • Outpatient: Starting
    Begin at 5 mg qd
    • Increase by 5 mg every week
    • Maximum: Significant clinical improvement, or 50 mg qd
  • Maintenance
    
    • Start taper after: 3 to 6 months; or clinical improvement begins
    • Taper slowly
      1. Initially by 5 mg on alternate days q2 to 4 weeks until 50 mg and 10 mg
         
      2. Then by 2.5 mg on alternate days q2 weeks to 50 mg and 0 mg
         
      3. Then taper high day dose by 2.5 mg q 4 weeks
         
      4. Minimum dosage is qod, or twice weekly, if possible.
    • Discontinuation without other immunosuppression
      • MG will recur in most MG patients if Prednisone is stopped

  Indications Significant disability due to disease symptoms Effective long term immunosuppression in pyridostigmine resistant patient Relatively rapid effect desired Refractory ocular MG Monitor: Weight; Blood pressure; Blood glucose & electrolytes; Ocular exam Advantages Short onset of action (1 to 3 months) Effective in most patients Can be used in pregnancy Best disease outcome Most likely complete remission or minimal disease manifestations Disadvantages Transient initial severe exacerbation Time: Usually after 1 to 3 weeks (2% to 5%) Associations: High initial steroid dose; No previous plasma exchange Many long-term side effects Fewer with twice weekly dosing

  Glucocorticoid Side Effects Cushingoid features Weight gain Bone: Avascular necrosis; Osteoporosis Myopathy: Myosin-loss; Type II atrophy Diabetes Skin: Acne; Striae Hypertension Psychosis & Mood change Pseudotumor cerebri Glaucoma Infection

• Usual doses
  Initial: 2.5 to 3 mg/kg qd
  • Maintenance: 1.5 to 2.5 mg/kg qd
• Indications
  • Long-term immunosuppression when rapid onset is not necessary
  • Steroid sparing
  • Minimize side effects
• Monitor: Hct, WBC & platelets; Liver function
• Advantages
  • Few subjective side effects
• Disadvantages
  • Serious side effects
    • Increased risk of malignancy: Not demonstrated in MG patients
    • Reduced RBC, WBC, Platelets: dose related or idiosyncratic
    • Liver dysfunction
    • Flu-like reaction: 20% to 30% of patients
      • Azathioprine cannot be restarted
    • Teratogenic
    • Never give with allopurinol: Myelotoxic
  • Long onset of action (6 to 24 months)
  • Moderate to high cost

• Usual doses
  Initial: 2.5 mg/kg bid
  Maintenance: Lowest effective dose
  • May be effective below "therapeutic range" in serum
• Indications
  • Long-term immunosuppression
  • Especially when prednisone cannot be used or is ineffective
  • When relatively rapid response (months) is desired
• Monitor
  • Renal function; Blood pressure
  • Blood level: Drawn exactly 12 hours after previous dose
• Advantages: Short onset of action (1 to 3 months)
• Disadvantages:
  • Serious side effects: Most are dose related
    • Nephrotoxicity
    • ?Increased risk of malignancy
    • Teratogenic
  • Many drug interactions
    • Especially avoid: NSAIDs; Amphotericin B and nephrotoxic drugs
  • High cost
  • Needs serum level monitoring
    • Trough levels: Obtain 12 hours after last dose

• Dose
  • Usual
    • Starting: 3 mg/day (Single dose) oral
    • Often reduced to 2 mg/day
  • Other: 0.05 to 0.1 mg/kg/day; 0.035 mg/kg bid
  • Take on empty stomach
  • 50% of dose in transplant medicine
  • Intravenous dose: 25% to 33% of oral dose
  • Trough plasma level
    • 4.8 to 10 ng/ml
    • MG response: May be better with ≥ 4.8 ng/mL
    • Testing frequency: Trough levels
      • Weekly for the first month
      • Every 2 to 3 months thereafter
      • Serum level drawn at exactly 12 hours after dose
• Effects
  • Latency of action: 2 to 8 weeks
  • May be associated with progressive MG improvement over years
  • AChR antibody titers: Often reduced by 50% to 90%
• May be used
  • Myasthenia gravis
    • Primary MG treatment drug
    • As a steroid sparing agent in MG
    • To reduce relapses
  • Immune myopathies ³
• Laboratory
  • Associated with gradual reductions in anti-AChR antibody titers
  • Hyperglycemia: Less than corticosteroids
  • Hypomagnesemia
• Side effects
  • Tremor
  • Possible neoplasms
  • Diarrhea: Idiosyncratic
  • Dermatitis: Idiosyncratic
  • Hepatotoxicity: Idiosyncratic
  • Nephrotoxicity: Concentration dependent
  • Serum creatinine: Increased

• Usual dose: 1 g twice daily
• Indications
  • Long-term immunosuppression
  • Especially when prednisone cannot be used or is ineffective
• Advantages
  • Moderate onset of action (1 to 12 months)
  • Few side effects: Low risk for late malignancies; No major organ toxicity
• Disadvantages
  • High Cost
  • Onset of action may be delayed 6 to 12 months
  • Limited experience of utilization for MG

• Dose
  • Usual: 0.75 g/m² IV q 4 weeks x 6 doses; Maximum 1.5 g/ dose
  • Renal impairment (< 30% of normal): 0.75 g/m²
  • Anti-emetics with each dose
  • Pneumocystis jirovecii pneumonia prophylaxis: Cotrimoxazole
  • Post Rx: Maintenance with Methotrexate, Azathioprine or Mycophenolate
• Indication
  • MG, AChR Ab+: Treatment refractory or Severe Generalized
• Advantages
• Outcome MG score of 0: 40%
• Improvement in MG score: 87%
• Steroid dose reduction: 80% or more
• Lower cyclophosphamide dose: Reduced neoplasm risk
• Disadvantages
  • No response: 13%
  • Cytopenias: Mild; Monitor 2 weeks after dose
  • Nausea
  • Fertility loss

• Dose: 5 exchanges over 9 to 10 days
• Indications
  • Acutely ill MG patient
  • Pre-thymectomy in patient with respiratory or bulbar involvement
  • NOT for long-term treatment
• Advantages
  • Very short onset of action (3 to 10 days)
  • Probably more effective in crisis than human immune globulin
• Disadvantages
  • Requires specialized equipment & personnel
  • Complications more frequent in elderly
  • High cost
  • Benefit only short-term (weeks)
  • More side effects than human immune globulin

• Dose: 2 grams/kg (over 2 to 5 days)
• Indication
  • Acutely ill MG patient
  • NOT for long-term treatment
• Advantages
  • Easily administered: Widely available; Dosage over 2 days
  • Serious side effects rare
  • Short onset of action
  • Fewer side effects than plasma exchange
• Disadvantages
  • Benefits not well demonstrated
  • High cost
  • Benefit only short-term
  • Probably less effective in crisis than

• Indications
  • Generalized MG in patients aged ~8 to 55
  • Thymoma
  • Only indicated as an elective procedure
• Approaches
  • Transsternal
    • Standard method
    • Thymoma removal
  • Transcervical
    • Only when performed with direct visualization of thymus
• Advantages
  • Low short-term & minimal long-term morbidity
• Disadvantages of thymectomy
  • Benefits poorly documented
  • Only very-long term benefit likely
  • Experienced surgeon necessary
• Course: Risk factors for myasthenic crisis in years after thymectomy ²
  • Older age
  • Bulbar involvement
  • Preoperative crises

• Mechanism
  • C5 Complement inhibition
  • Binds to epitope on C5
• Indications in MG
  • Generalized, Refractory, AChR antibody positive
  • Possibly useful for acute MG exacerbations
• Treatment
  • Route: Intravenous
  • Induction: 900 mg weekly x 4
  • Maintenance: 1,200 mg every other week
• Other requirement
  • Vaccination vs Neisseria meningitides with both quadrivalent & B-serotype vaccines
• Time course of benefit
  • Onset: Days to Weeks
  • Maximum: 12 weeks
• Marker: CH50 loss
• Mutation (Arg885His) in C5 ¹⁶
  • May interfere with drug binding & efficacy
  • Zilucoplan, which binds to a different C5 epitope, may be more effective
• Disadvantages
  • Cost
    • Western countries: Very expensive
    • Other regions: Comparable to Plasma exchange or IVIg
  • Side effects: Headache; Nasopharyngitis
• Other Complement Inhibiting drugs ¹¹
  • Zilucoplan, subcutaneous
  • Ravulizumab, IV
• Complement Inhibiting drugs in trials
  • Pozelimab
  • Cemdisiran
  • Gefurulimab
  • Danicopan
  • Iptacopan

• Indications
  • MuSK MG
  • MG: Generalized, Refractory, AChR antibody positive
  • General AChR Ab+ MG: Reduces relapses requiring rescue therapy
  • Not useful: Reduction of corticosteroid doses
• Other B-cell drugs: In clinical trials

• Status
  • In clinical trials or Approved
  • No useful evaluation of relative efficacy vs other immunomodulating medications
• Drugs
  • Rozanolixizumab ¹⁴
    • Dose: 7 to 10 mg/kg subcutaneous q 6 weeks
  • Efgartigimod ¹²
    • Dose: 10 mg/kg IV q 1 week x4
  • Nipocalimab ¹³
    • Dose: 30 mg/kg IV loading; Then 15 mg/kg q 2w eeks
• Mechanism: Reduces total IgG & AChR Ab levels
• Clinical
  • Benefit course: Over days to weeks
  • More benefit with
    • Generalized MG
    • Short disease duration
    • Bulbar dysfunction
  • Less benefit ¹⁵
    • Thymoma & Other neoplasms
    • Thyroid disease
    • Additional autoimmune disorders
• Disadvantages
  • Very expensive
  • No oral formulation

Myasthenia Gravis: Drug discontinuation ¹⁷

• General relapse rate: 55%
• Time to relapse: 6 months to 2 years
• Risk factors
  • Shorter treatment time: More relapse risk
  • Rituximab: Reduced relapse risk
  • Acetylcholinesterase inhibitor monotherapy: Increased relapse risk
  • Higher maximum steroid dose: Increased relapse risk