Myasthenia gravis (MG) treatment has been transformed in the past decade by the development of targeted biologics — terminal complement inhibitors, anti-FcRn agents, and others — that have moved beyond symptomatic acetylcholinesterase inhibition and broad immunosuppression to mechanistically targeted disease modification. The neurologist treating MG must navigate symptomatic management, immunosuppressive selection, crisis management, and the new biologic options. This page covers the complete pharmacotherapy landscape for myasthenia gravis.

Pathophysiology Relevant to Therapy

  • Autoimmune disease against acetylcholine receptor (AChR) at neuromuscular junction.
  • ~80% AChR antibody-positive; ~10% MuSK antibody-positive; ~10% seronegative (some LRP4 or other).
  • Antibodies cause: receptor degradation, complement activation, blockade of ACh binding.
  • Treatments target: symptomatic ACh enhancement, antibody production (B cells), antibody clearance (FcRn), and complement activation.

Symptomatic Treatment: Pyridostigmine

  • Mechanism: AChE inhibitor; prolongs ACh effect at NMJ.
  • Dosing: 30-60 mg PO q4-6h initially; titrate to symptom control; max 120-360 mg/day typically.
  • Effect onset: 30-60 min; duration 3-4 hours.
  • Side effects: SLUDGE (salivation, lacrimation, urination, defecation, GI, emesis); muscle cramps, fasciculations; bradycardia.
  • Cholinergic crisis: pyridostigmine overdose → SLUDGE + paradoxical muscle weakness; differentiate from myasthenic crisis.
  • Extended-release: pyridostigmine ER 180 mg; bedtime for nocturnal/morning weakness.

Corticosteroids

  • Prednisone: most commonly used; 60-100 mg daily for induction.
  • Watch initial deterioration in first 1-2 weeks (paradoxical weakening); consider tapering with another immunosuppressive cover or IVIG pre-treatment.
  • Gradual taper: 5-10 mg every 2-4 weeks to lowest effective maintenance.
  • Long-term: maintenance 5-15 mg most patients.
  • Side effects: weight gain, diabetes, hypertension, osteoporosis, cataracts, mood changes, infection risk.
  • Bone protection: bisphosphonate, vitamin D, calcium.

Steroid-Sparing Immunosuppressants

Azathioprine

  • 50-200 mg/day; takes 6-12 months for full effect.
  • Check TPMT genotype before initiation (poor metabolizers at risk of toxicity).
  • Side effects: GI, hepatotoxicity, leukopenia, malignancy risk (long-term).
  • Monitor CBC, LFTs.

Mycophenolate Mofetil

  • 500-1500 mg BID; takes 6-12 months.
  • Better tolerated than azathioprine; less hepatotoxicity.
  • Side effects: GI, leukopenia, malignancy risk.
  • Teratogenic; contraindicated in pregnancy.

Methotrexate

  • Once-weekly oral or SC.
  • Folate supplementation.
  • Useful in patients who fail or cannot tolerate azathioprine/mycophenolate.
  • Hepatotoxic.

Cyclosporine

  • Calcineurin inhibitor.
  • Nephrotoxicity.
  • Used less commonly now with alternatives available.

Tacrolimus

  • Calcineurin inhibitor; alternative to cyclosporine.
  • Useful in MuSK-positive MG.
  • Nephrotoxicity; monitor levels.

Cyclophosphamide

  • Aggressive immunosuppression; oral or IV.
  • Reserved for severe refractory disease.
  • Significant toxicity: hemorrhagic cystitis, infertility, malignancy.

Newer Biologic Therapies

Complement Inhibitors

Eculizumab (Soliris)

  • Anti-C5 monoclonal antibody.
  • IV every 2 weeks.
  • FDA-approved for refractory AChR-positive generalized MG.
  • Meningococcal vaccination required: significant Neisseria risk.
  • Cost: very high.

Ravulizumab (Ultomiris)

  • Anti-C5; longer half-life than eculizumab.
  • IV every 8 weeks.
  • FDA-approved for AChR-positive generalized MG.
  • Same meningococcal precautions.

Zilucoplan (Zilbrysq)

  • Small-molecule C5 inhibitor.
  • Daily SC injection.
  • FDA-approved 2023 for AChR-positive generalized MG.
  • Same meningococcal precautions.

FcRn Inhibitors

Efgartigimod (Vyvgart / Vyvgart Hytrulo)

  • Anti-FcRn; reduces total IgG (including pathogenic anti-AChR / anti-MuSK antibodies).
  • IV (Vyvgart) or SC with hyaluronidase (Vyvgart Hytrulo).
  • Cyclic dosing: weekly for 4 weeks, then a treatment-free interval.
  • Originally FDA-approved 2021 for AChR-antibody-positive generalized MG; the indication was expanded in 2026 to include adult generalized MG broadly, including AChR-antibody-seronegative adults.
  • Side effects: infections (less than complement inhibitors), headache.

Rozanolixizumab (Rystiggo)

  • Anti-FcRn; reduces IgG.
  • SC weekly cycles.
  • FDA-approved 2023 for AChR-antibody-positive AND anti-MuSK-antibody-positive generalized MG.

Nipocalimab (IMAAVY)

  • Anti-FcRn; reduces pathogenic IgG.
  • IV weekly maintenance dosing (after initial loading).
  • FDA-approved 2025 for generalized myasthenia gravis in patients age 12 and older who are anti-AChR or anti-MuSK antibody positive.
  • First FcRn inhibitor approved down to age 12, expanding the biologic options for adolescent gMG.

B-Cell Depleters

Rituximab (off-label for MG)

  • Anti-CD20; depletes B cells.
  • Particularly effective in MuSK-positive MG.
  • Various dosing regimens (e.g., 375 mg/m² weekly × 4; or 1000 mg × 2 doses).
  • Repeat at 6-12 months as needed.
  • Side effects: infusion reactions, hypogammaglobulinemia (long-term), PML (rare).

Treatment Algorithm

Step 1: Symptomatic

  • Pyridostigmine: titrate to symptoms.
  • Most patients need additional therapy.

Step 2: Add Steroids

  • Prednisone for moderate-severe disease.
  • Initial deterioration possible (consider IVIG bridge).
  • Cover with steroid-sparing agent.

Step 3: Steroid-Sparing

  • Azathioprine or mycophenolate for chronic immunosuppression.
  • Methotrexate, tacrolimus as alternatives.

Step 4: Refractory Disease

  • Newer biologics:
    • Anti-complement: eculizumab, ravulizumab, zilucoplan.
    • FcRn inhibitors: efgartigimod, rozanolixizumab.
    • Rituximab (especially MuSK-positive).
  • Cyclophosphamide for severe.
  • Thymectomy in selected (thymoma, generalized MG without thymoma in younger patients).

Myasthenic Crisis

Recognition

  • Respiratory failure: bulbar weakness, diaphragmatic weakness.
  • FVC <15-20 mL/kg or NIF less negative than -20: consider intubation.
  • ABG monitoring.
  • Differentiate from cholinergic crisis (SLUDGE + paradoxical weakness from over-pyridostigmine).

Treatment

  • Plasmapheresis: 5 sessions over 1-2 weeks; rapid.
  • IVIG: 2 g/kg over 2-5 days; similar efficacy to plasmapheresis.
  • Hold pyridostigmine (or continue depending on situation; some specialists hold during crisis).
  • Start or increase immunosuppression.
  • Avoid drugs that worsen MG.
  • Intubation if respiratory failure.

Drugs to Avoid in MG

  • Aminoglycosides: severe neuromuscular blockade.
  • Fluoroquinolones: can worsen.
  • Macrolides: can worsen.
  • β-blockers: caution.
  • Magnesium: severe blockade (avoid in pregnancy if possible).
  • Succinylcholine: use with caution; modified dosing.
  • Calcium channel blockers: cautious.
  • D-penicillamine: can induce MG.
  • Iodine contrast: rare worsening.
  • Some antipsychotics: tardive worsening.
  • Telithromycin: contraindicated.

Thymectomy

  • Thymoma: surgical removal.
  • Generalized MG (no thymoma): controversial; MGTX trial showed benefit at 5 years.
  • Younger patients (<50 yr) with generalized MG: often recommended.
  • Robotic-assisted thymectomy increasingly common.

MuSK-Positive MG

  • Distinct phenotype: prominent bulbar, neck, respiratory weakness.
  • Pyridostigmine often less effective; some patients worsen on pyridostigmine.
  • Steroids effective.
  • Rituximab particularly effective.
  • Rozanolixizumab now FDA-approved for MuSK MG.
  • Thymectomy NOT helpful in MuSK MG.

LRP4 / Seronegative MG

  • Similar approach to AChR MG.
  • Some respond to standard treatments; some refractory.

Pregnancy in MG

  • Disease course variable (~1/3 each: improve, stable, worsen).
  • Pyridostigmine, prednisone, azathioprine: relatively safe.
  • Mycophenolate: TERATOGENIC; switch before conception.
  • Methotrexate: contraindicated.
  • Magnesium AVOID (worsens MG).
  • Neonatal myasthenia: transplacental antibody transfer; supportive care.

Pediatric MG

  • Juvenile MG: similar approach; growth considerations.
  • Neonatal MG: temporary; supportive.
  • Congenital myasthenic syndromes: different pathophysiology; some respond to AChE inhibitors, β-agonists, or specific molecular treatments.

Outcome Measures

  • MGFA classification (I-V).
  • QMG (Quantitative MG).
  • MG-ADL (Activities of Daily Living).
  • MG-QOL (Quality of Life).
  • Track for treatment response and adjustments.

🔍 Did You Know?

The introduction of FcRn inhibitors (efgartigimod, rozanolixizumab) and complement inhibitors (eculizumab, ravulizumab, zilucoplan) has fundamentally transformed treatment of refractory myasthenia gravis, providing the first targeted disease-modifying biologic options. The mechanisms are mechanistically distinct: FcRn inhibitors reduce total IgG levels (including pathogenic anti-AChR antibodies) by accelerating IgG catabolism — efgartigimod’s cyclic 4-week dosing produces dramatic IgG reduction with rapid clinical effect; complement inhibitors prevent terminal complement activation at the neuromuscular junction, blocking the membrane attack complex that destroys AChRs. The clinical impact: patients previously requiring chronic high-dose steroids and broad immunosuppression now have targeted options with often dramatic clinical responses. Particularly important: rozanolixizumab is FDA-approved for both AChR-positive AND MuSK-positive MG — the first such approval for MuSK MG. The lesson generalizes: autoimmune neurology has entered a biologic era, and the same mechanistic targeting principles are being applied across NMJ disorders, CIDP, NMOSD, and other conditions. For practicing neurologists, the take-home: refractory MG patients should be referred to specialty centers offering biologics, and the conversation about MG treatment now includes the specific mechanisms relevant to each patient (complement-mediated vs antibody-mediated dominance). The cost barriers remain, but coverage is improving as the standard of care evolves.

Pitfalls and Pearls

  • Pyridostigmine: AChE inhibitor; symptomatic mainstay; SLUDGE side effects.
  • Cholinergic crisis: pyridostigmine excess → paradoxical weakness.
  • Prednisone: induction; initial worsening possible.
  • Azathioprine, mycophenolate: steroid-sparing; 6-12 months for effect.
  • Eculizumab, ravulizumab, zilucoplan: complement inhibitors; meningococcal vaccination.
  • FcRn inhibitors: efgartigimod (Vyvgart / Vyvgart Hytrulo — adult gMG including seronegative since 2026 expansion), rozanolixizumab (Rystiggo — AChR+ or MuSK+), nipocalimab (IMAAVY — 2025, age 12+, AChR+ or MuSK+).
  • Rituximab: especially for MuSK-positive MG.
  • Thymectomy: thymoma; consider in younger generalized MG patients.
  • Myasthenic crisis: plasmapheresis or IVIG.
  • AVOID in MG: aminoglycosides, fluoroquinolones, magnesium, telithromycin.
  • Pyridostigmine ER bedtime: for morning weakness.
  • Mycophenolate teratogenic: switch before conception.
  • MuSK MG: rituximab effective; pyridostigmine less effective.
  • Bridge therapy with IVIG or plasmapheresis: prior to surgery, during steroid initiation.
  • Lambert-Eaton: presynaptic Ca²⁺ channel; 3,4-DAP (amifampridine).
  • Monitor with QMG, MG-ADL: standardized outcome measures.

References

  1. Howard JF Jr, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT). Lancet Neurol. 2021;20(7):526-536.
  2. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis (MGTX). N Engl J Med. 2016;375(6):511-522.
  3. Howard JF Jr, Utsugisawa K, Benatar M, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN). Lancet Neurol. 2017;16(12):976-986.
  4. Diaz-Manera J, Martinez-Hernandez E, Querol L, et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology. 2012;78(3):189-193.
  5. Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87(4):419-425.