Myasthenia gravis risk factors

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2]

Risk Factors

Myasthenia gravis (MG) is a complex autoimmune disease of the neuromuscular junction in which disease risk reflects interaction between genetic susceptibility, demographic factors, thymic disease, immune dysregulation, environmental exposures, and drug-related triggers. Genetic susceptibility, including HLA associations and other inherited risk loci, is discussed in the genetics microchapter. This section focuses on clinically relevant risk factors for MG onset, drug-induced MG, and factors that may precipitate MG exacerbation or myasthenic crisis.

Summary of clinically relevant risk factors

Risk factor category Examples Clinical relevance
Demographic risk factors Female sex in early-onset MG; male sex in late-onset MG; older age MG has a characteristic age-sex distribution. Early-onset MG is more common in women, whereas late-onset and very-late-onset MG are more common in men.[1][2]
Lifestyle and environmental factors Cigarette smoking; nicotine exposure, including smokeless tobacco; infections; stress-related disease activity Smoking and nicotine exposure have been associated with increased risk of early-onset MG, particularly AChR-antibody-positive early-onset disease. Infection and physiologic stress may precipitate worsening in established MG.[3][4]
Coexisting autoimmune disease Autoimmune thyroid disease, Graves disease, systemic lupus erythematosus, pernicious anemia, rheumatoid arthritis, neuromyelitis optica Autoimmune comorbidity is more common in MG than in the general population and is most frequent in early-onset MG and thymic hyperplasia.[5][6]
Thymic disease Thymoma; thymic hyperplasia Thymoma is present in approximately 10-20% of patients with MG and approximately 30% of patients with thymoma develop MG.[7][8]
Drug-induced MG Immune checkpoint inhibitors; D-penicillamine; interferons; selected tyrosine kinase inhibitors These agents may induce de novo MG or MG-like syndromes. Immune checkpoint inhibitor-associated MG is often severe and may overlap with myositis and myocarditis.[9][10]
Exacerbating drugs Fluoroquinolones, macrolides, telithromycin, aminoglycosides, beta-blockers, magnesium, neuromuscular blockers, botulinum toxin, high-dose corticosteroid initiation These drugs may worsen neuromuscular transmission or precipitate clinical deterioration in susceptible patients. Telithromycin is contraindicated in MG, and fluoroquinolones carry an FDA boxed warning for MG exacerbation.[11][12][13]

Demographic risk factors

Sex

MG demonstrates a characteristic sex-dependent distribution that varies by age of onset. Early-onset MG, usually defined as onset before age 50 years, is more common in women. Late-onset MG is slightly more common in men, and very-late-onset MG demonstrates a clearer male predominance.[1][2] This age-sex pattern is clinically important because late-onset MG in older men is increasingly recognized and may be underdiagnosed when fatigable weakness is attributed to frailty, stroke, pulmonary disease, or medication adverse effects.

Age

Age at onset is both a classification feature and a risk modifier. Contemporary epidemiologic studies suggest that the incidence and prevalence of MG have increased over recent decades, particularly among older adults, likely because of improved recognition, better diagnostic testing, population aging, and longer survival.[1] A large contemporary cohort reported peak incidence in older age groups, including patients aged 70-74 years.[2]

Lifestyle and environmental factors

Nicotine exposure

In the Swedish nationwide GEMG study, smoking at disease onset was associated with increased risk of early-onset MG, with a stronger association in AChR-antibody-positive early-onset MG.[3] Use of Swedish snuff, a high-nicotine smokeless tobacco product, was also associated with increased early-onset MG risk.[3] These findings suggest that nicotine exposure may be a subtype-specific risk factor rather than a uniform risk factor across all MG phenotypes.

Alcohol consumption

The Swedish nationwide GEMG study reported an inverse association between alcohol consumption and MG risk, particularly in late-onset MG.[3] This finding is observational, may be affected by residual confounding or reverse causality, and should not be interpreted as a recommendation to consume alcohol for MG prevention.

Infections

Respiratory infections are common triggers of MG exacerbation and myasthenic crisis.[4] Specific infectious agents have been investigated as possible triggers for MG onset, including Epstein-Barr virus, human papillomavirus, and poliovirus; however, a systematic review concluded that evidence for a causal relationship between specific pathogens and MG onset remains limited.[14] During the COVID-19 pandemic, MG worsening was reported in a substantial proportion of infected patients, supporting the clinical importance of respiratory infection prevention and early management in established MG.[15]

Stress

Stress-related disorders are associated with increased risk of autoimmune diseases broadly, but MG-specific evidence for stress as an independent cause of MG onset is limited.[16] In established MG, chronic stress, depression, and personality-related stress vulnerability have been associated with relapse risk and symptom burden in observational studies.[17][18]

Autoimmune comorbidities

Approximately 15% of patients with MG have another autoimmune disease, most often in early-onset MG and thymic hyperplasia.[5] A Danish nationwide case-control study found that patients with MG were more likely than matched controls to have another autoimmune disease before or after MG diagnosis.[6]

Commonly associated autoimmune diseases include:

The presence of one autoimmune disease should increase clinical suspicion for additional autoimmune disease when symptoms are compatible. Thyroid disease is particularly relevant because ocular thyroid disease may mimic ocular MG and because thyroid dysfunction may worsen fatigue or weakness.

Thymoma and thymic disease

Thymoma is present in approximately 10-20% of patients with MG, and approximately 30% of patients with thymoma develop MG.[7][8] Thymoma-associated MG is typically AChR-antibody-positive, generalized, and clinically more severe than purely ocular MG.[7] WHO type B1 and B2 thymomas have been associated with higher likelihood of MG association.[19]

A small proportion of patients with thymoma may develop new-onset MG after thymectomy. Preoperative AChR antibody positivity or higher AChR antibody titers may identify patients at increased risk for post-thymectomy MG.[8]

Drug-induced myasthenia gravis

Drug-induced MG should be distinguished from medication-triggered worsening of established MG. Drug-induced MG refers to de novo autoimmune MG or MG-like disease occurring after exposure to a medication, whereas medication-triggered worsening reflects impaired neuromuscular transmission or immune activation in a patient with known or subclinical MG.[9]

Immune checkpoint inhibitors

Immune checkpoint inhibitors may cause de novo MG or unmask preexisting MG. The estimated frequency of MG among patients treated with PD-1 inhibitors is 0.12-0.2%, with median onset approximately 4 weeks after ICI initiation.[20] ICI-associated MG is clinically important because of its severity: bulbar involvement occurs in approximately 75%, respiratory failure in approximately 45-65%, concurrent myositis in approximately 37-51%, and concurrent myocarditis in approximately 8-16%. Mortality ranges from approximately 28% to 38% across systematic reviews, with respiratory failure as the most common cause of death. AChR antibodies are elevated in approximately 58-66% of tested patients; MuSK antibodies have not been detected in ICI-induced MG.[10][21]

Patients with suspected ICI-associated MG should be evaluated for overlap with myositis and myocarditis, including creatine kinase, aldolase, troponin, and electrocardiogram when clinically appropriate.[22]

D-penicillamine

D-penicillamine, used historically for rheumatoid arthritis and Wilson disease, can induce MG, usually with AChR antibodies and rarely with concurrent MuSK antibodies.[23] D-penicillamine-induced MG is often reversible after drug discontinuation, although immunotherapy may be required in some patients.[24][25]

Other reported drug-induced causes

Interferons and selected tyrosine kinase inhibitors have been reported to induce or unmask MG, but the evidence is less robust than for immune checkpoint inhibitors and D-penicillamine.[9]

Medications that may worsen established MG

Medication review is essential in all patients with known or suspected MG. The following medications may worsen MG or precipitate exacerbation. Risk varies by drug, dose, route, baseline MG severity, respiratory reserve, and availability of alternatives.

Drug class Examples Clinical concern Practical approach
Fluoroquinolones Ciprofloxacin, levofloxacin, moxifloxacin Can worsen MG; fluoroquinolones carry an FDA boxed warning for exacerbation of muscle weakness in MG, with postmarketing reports of deaths and requirement for ventilatory support. The FDA label advises avoiding fluoroquinolones in patients with a known history of MG. Avoid when reasonable alternatives exist; monitor closely if no alternative is appropriate.[11][9][13]
Macrolides and ketolides Azithromycin, clarithromycin, telithromycin May worsen weakness. Telithromycin is contraindicated in MG; it directly inhibits nicotinic acetylcholine receptors and has caused life-threatening exacerbation within hours of first dose, including respiratory failure and cardiac arrest. Telithromycin is no longer commercially available in the United States. Telithromycin must not be given to patients with MG. Use other macrolides cautiously when necessary.[7][26][27]
Aminoglycosides Gentamicin, tobramycin, amikacin, neomycin May impair presynaptic acetylcholine release and worsen neuromuscular transmission. Avoid if possible, especially in generalized MG or respiratory weakness.[9]
Beta-blockers Propranolol, metoprolol, atenolol and other agents May worsen fatigable weakness in susceptible patients. Individualize use; monitor after initiation or dose escalation.[28]
Magnesium Intravenous magnesium sulfate May impair neuromuscular transmission and precipitate respiratory weakness; especially important in pregnancy and preeclampsia. Avoid or use only with extreme caution and close monitoring in MG.[4][29]
Neuromuscular blocking agents Succinylcholine; rocuronium; vecuronium; other nondepolarizing agents May cause prolonged paralysis or unpredictable neuromuscular blockade. Require anesthesiology awareness, dose adjustment, monitoring, and perioperative MG optimization.
Botulinum toxin Botulinum toxin preparations Blocks presynaptic acetylcholine release and may worsen weakness. Avoid or use only with careful specialist assessment.[9]
Calcium channel blockers Verapamil, diltiazem and other agents Reported to worsen weakness in some patients. Use cautiously if clinically necessary; monitor symptoms after initiation.
Statins Atorvastatin, simvastatin, rosuvastatin and other agents Rarely reported to unmask or worsen MG; myopathy may mimic MG worsening. Not absolutely contraindicated when cardiovascular benefit is strong; monitor for new or worsening weakness.[5]
Corticosteroids High-dose prednisone or prednisolone initiation Transient early worsening occurs in up to 50% of patients starting high-dose prednisone, typically within the first several days after initiation. Risk is higher with higher initial doses, older age, bulbar symptoms, severe generalized MG, thymoma, and prior thymectomy. Start carefully and consider inpatient monitoring or bridging therapy in high-risk patients.[4][30][31][32]

Triggers for exacerbation and myasthenic crisis

Myasthenic crisis is respiratory failure caused by MG-related weakness. Approximately 15-20% of patients with MG experience crisis at least once.[4][33][34]

Common triggers include:

  • Infection, especially upper respiratory infection, bronchitis, pneumonia, and sepsis
  • Exposure to drugs that impair neuromuscular transmission
  • Recent surgery, trauma, or perioperative exposure to neuromuscular blocking agents
  • Pregnancy or the postpartum period
    • Exacerbation of MG occurs in approximately 19-50% of pregnancies, most commonly in the first trimester, with postpartum exacerbations in approximately 27%. Myasthenic crisis occurs in approximately 6.4% of women with MG during pregnancy and approximately 8.2% in the postpartum period.[29][35]
    • A Swedish nationwide cohort study found no increased risk of MG hospitalization during pregnancy itself, but the postpartum period was associated with increased risk of prolonged MG admissions.[36]
  • Intravenous magnesium exposure in pregnant patients with MG
  • Rapid tapering, discontinuation, or inadequate dosing of immunotherapy
  • High-dose corticosteroid initiation in high-risk patients
  • Vaccination, rarely reported as a temporal trigger; in most patients with MG, the benefits of recommended vaccination generally outweigh the risk of disease worsening[4]
  • No identifiable trigger, which occurs in approximately 30-40% of crises[4]

Risk factors for crisis include prior crisis, prominent oropharyngeal weakness, severe generalized symptoms, MuSK antibody positivity, thymoma, and reduced respiratory reserve.[4]

Clinical pitfalls

  • Do not assume MG is primarily a disease of young women. Late-onset MG is increasingly common and often affects older men.[2]
  • Do not prescribe fluoroquinolones, macrolides, aminoglycosides, magnesium, or neuromuscular blocking agents without checking for MG history and assessing respiratory reserve.[9]
  • Do not give telithromycin to patients with MG. Telithromycin is contraindicated in MG and is no longer commercially available in the United States.[7][26]
  • Do not overlook ICI-associated MG in patients receiving cancer immunotherapy who develop ptosis, diplopia, dysphagia, dysarthria, dyspnea, or proximal weakness.[10]
  • Do not treat suspected ICI-associated MG as an isolated neurologic adverse event without evaluating for concurrent myositis and myocarditis.[22]
  • Do not start high-dose corticosteroids in severe generalized or bulbar MG without a monitoring plan, because early transient worsening may precipitate crisis.[4]
  • Do not rely on stress as a stand-alone explanation for MG onset; the evidence is stronger for stress as a disease activity modifier than as an independent causal risk factor.

References

  1. ↑ 1.0 1.1 1.2 Punga AR, Maddison P, Heckmann JM, Guptill JT, Evoli A (2022). "Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders". Lancet Neurology. 21 (2): 176–188. doi:10.1016/S1474-4422(21)00297-0.
  2. ↑ 2.0 2.1 2.2 2.3 Huang X, Yu ZH, Cui Y; et al. (2025). "Outcomes in relation to the age at onset in patients with myasthenia gravis". Neurology. 105 (12): e214428. doi:10.1212/WNL.0000000000214428.
  3. ↑ 3.0 3.1 3.2 3.3 Petersson M, Jons D, Feresiadou A; et al. (2025). "Nicotine, alcohol consumption, and risk of myasthenia gravis: Results from the Swedish nationwide GEMG study". Neurology. 105 (1): e213771. doi:10.1212/WNL.0000000000213771.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Claytor B, Cho SM, Li Y (2023). "Myasthenic crisis". Muscle & Nerve. 68 (1): 8–19. doi:10.1002/mus.27832.
  5. ↑ 5.0 5.1 5.2 Gilhus NE (2016). "Myasthenia gravis". New England Journal of Medicine. 375 (26): 2570–2581. doi:10.1056/NEJMra1602678.
  6. ↑ 6.0 6.1 Nielsen JJJ, Levison LS, Andersen H (2026). "Associated autoimmunity in myasthenia gravis in Denmark: A nationwide case-control study". European Journal of Neurology. 33 (2): e70498. doi:10.1111/ene.70498.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Gilhus NE, Verschuuren JJ (2015). "Myasthenia gravis: Subgroup classification and therapeutic strategies". Lancet Neurology. 14 (10): 1023–1036. doi:10.1016/S1474-4422(15)00145-3.
  8. ↑ 8.0 8.1 8.2 Kim A, Choi SJ, Kang CH; et al. (2021). "Risk factors for developing post-thymectomy myasthenia gravis in patients with thymoma". Muscle & Nerve. 63 (4): 531–537. doi:10.1002/mus.27169.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Sheikh S, Alvi U, Soliven B, Rezania K (2021). "Drugs that induce or cause deterioration of myasthenia gravis: An update". Journal of Clinical Medicine. 10 (7): 1537. doi:10.3390/jcm10071537.
  10. ↑ 10.0 10.1 10.2 Marini A, Bernardini A, Gigli GL; et al. (2021). "Neurologic adverse events of immune checkpoint inhibitors: A systematic review". Neurology. 96 (16): 754–766. doi:10.1212/WNL.0000000000011795.
  11. ↑ 11.0 11.1 Uysal SP, Li Y, Thompson NR, Li Y (2025). "Frequency and severity of myasthenia gravis exacerbations associated with the use of ciprofloxacin, levofloxacin, and azithromycin". Muscle & Nerve. 71 (6): 1063–1071. doi:10.1002/mus.28410.
  12. ↑ Marriott M, Schwery A, VandenBerg A (2023). "Myasthenia gravis: What does a pharmacist need to know?". American Journal of Health-System Pharmacy. 80 (5): 249–257. doi:10.1093/ajhp/zxac343.
  13. ↑ 13.0 13.1 Food and Drug Administration (2024). "Levofloxacin prescribing information". Missing or empty |url= (help)
  14. ↑ Leopardi V, Chang YM, Pham A, Luo J, Garden OA (2021). "A systematic review of the potential implication of infectious agents in myasthenia gravis". Frontiers in Neurology. 12: 618021. doi:10.3389/fneur.2021.618021.
  15. ↑ Verschuuren JJ, Palace J, Murai H; et al. (2022). "Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders". Lancet Neurology. 21 (2): 189–202. doi:10.1016/S1474-4422(21)00463-4.
  16. ↑ Song H, Fang F, Tomasson G; et al. (2018). "Association of stress-related disorders with subsequent autoimmune disease". JAMA. 319 (23): 2388–2400. doi:10.1001/jama.2018.7028.
  17. ↑ Bogdan A, Barnett C, Ali A; et al. (2020). "Chronic stress, depression and personality type in patients with myasthenia gravis". European Journal of Neurology. 27 (1): 204–209. doi:10.1111/ene.14057.
  18. ↑ Bogdan A, Barnett C, Ali A; et al. (2020). "Prospective study of stress, depression and personality in myasthenia gravis relapses". BMC Neurology. 20 (1): 261. doi:10.1186/s12883-020-01802-4.
  19. ↑ Menon D, Katzberg H, Barnett C; et al. (2021). "Thymoma pathology and myasthenia gravis outcomes". Muscle & Nerve. 63 (6): 868–873. doi:10.1002/mus.27220.
  20. ↑ Narayanaswami P, Sanders DB, Wolfe G; et al. (2021). "International consensus guidance for management of myasthenia gravis: 2020 update". Neurology. 96 (3): 114–122. doi:10.1212/WNL.0000000000011124.
  21. ↑ Safa H, Johnson DH, Trinh VA; et al. (2019). "Immune checkpoint inhibitor related myasthenia gravis: Single center experience and systematic review of the literature". Journal for ImmunoTherapy of Cancer. 7 (1): 319. doi:10.1186/s40425-019-0774-y. PMID 31753014.
  22. ↑ 22.0 22.1 National Comprehensive Cancer Network (2026). "Management of immune checkpoint inhibitor-related toxicities". Missing or empty |url= (help)
  23. ↑ Poulas K, Koutsouraki E, Kordas G, Kokla A, Tzartos SJ (2012). "Anti-MuSK- and anti-AChR-positive myasthenia gravis induced by D-penicillamine". Journal of Neuroimmunology. 250 (1–2): 94–98. doi:10.1016/j.jneuroim.2012.05.011.
  24. ↑ Vincent A, Palace J, Hilton-Jones D (2001). "Myasthenia gravis". Lancet. 357 (9274): 2122–2128. doi:10.1016/S0140-6736(00)05186-2.
  25. ↑ Albers JW, Hodach RJ, Kimmel DW, Treacy WL (1980). "Penicillamine-associated myasthenia gravis". Neurology. 30 (11): 1246–1249. doi:10.1212/wnl.30.11.1246.
  26. ↑ 26.0 26.1 Perrot X, Bernard N, Vial C; et al. (2006). "Myasthenia gravis exacerbation or unmasking associated with telithromycin treatment". Neurology. 67 (12): 2256–2258. doi:10.1212/01.wnl.0000247741.72466.8c.
  27. ↑ Fernandes P, Pereira D, Watkins PB, Bertrand D (2020). "Differentiating the pharmacodynamics and toxicology of macrolide and ketolide antibiotics". Journal of Medicinal Chemistry. 63 (12): 6462–6473. doi:10.1021/acs.jmedchem.9b01159.
  28. ↑ Gummi RR, Kukulka NA, Deroche CB, Govindarajan R (2019). "Factors associated with acute exacerbations of myasthenia gravis". Muscle & Nerve. 60 (6): 693–699. doi:10.1002/mus.26689.
  29. ↑ 29.0 29.1 Grover KM, Sripathi N (2020). "Myasthenia gravis and pregnancy". Muscle & Nerve. 62 (6): 664–672. doi:10.1002/mus.27064.
  30. ↑ Farmakidis C, Dimachkie MM, Pasnoor M, Barohn RJ (2020). "Immunosuppressive and immunomodulatory therapies for neuromuscular diseases. Part I: Traditional agents". Muscle & Nerve. 61 (1): 5–16. doi:10.1002/mus.26708.
  31. ↑ Díez-Porras L, Homedes C, Alberti MA, Vélez-Santamaría V, Casasnovas C (2020). "Intravenous immunoglobulins may prevent prednisone-exacerbation in myasthenia gravis". Scientific Reports. 10 (1): 13497. doi:10.1038/s41598-020-70539-4.
  32. ↑ Kanai T, Uzawa A, Kawaguchi N; et al. (2019). "Predictive score for oral corticosteroid-induced initial worsening of seropositive generalized myasthenia gravis". Journal of the Neurological Sciences. 396: 8–11. doi:10.1016/j.jns.2018.10.018.
  33. ↑ Gilhus NE (2023). "Myasthenia gravis, respiratory function, and respiratory tract disease". Journal of Neurology. 270 (7): 3329–3340. doi:10.1007/s00415-023-11733-y.
  34. ↑ Cea G, Salinas RA (2021). "Antibiotics in myasthenia gravis: Thinking outside the black box". Muscle & Nerve. 64 (2): 123–124. doi:10.1002/mus.27346.
  35. ↑ Miegel L, Hickstein J, Reibelt A, Heesen C, Schubert C (2026). "Myasthenia gravis and pregnancy: A systematic review and meta-analysis". Journal of Neurology. 273 (3): 184. doi:10.1007/s00415-026-13724-1.
  36. ↑ O'Connor L, Gabrysch K, Wikström AK, Rostedt Punga A (2026). "Risk of myasthenia gravis exacerbation during pregnancy and postpartum: A nationwide cohort study". Neurology. 106 (12): e218082. doi:10.1212/WNL.0000000000218082.
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