Uncover gMG | A chronic autoimmune disease causing muscle weakness

The biology
behind the disease

Patient portrayal

gMG is a chronic, debilitating, IgG-mediated autoimmune disease^1,2

Patients can experience fluctuating weakness across critical muscle groups³

Bulbar

Impaired speech, chewing, or swallowing⁴

Respiratory

Dyspnea, risk of myasthenic crisis⁴

Gross motor

Impaired mobility, muscle fatigability⁵

Ocular

Diplopia, ptosis¹

of patients with gMG initially present with ocular symptoms.⁶

gMG=generalized myasthenia gravis; IgG=immunoglobulin G.

IgG autoantibodies are a key driver of gMG^1,7,8*

Pathogenic IgG autoantibodies target multiple components of the NMJ, including AChR, MuSK, and LRP4^1,7,8:

KEY

IgG autoantibody

AChR protein receptor

MuSK protein receptor

LRP4 protein receptor

Acetylcholine

1. Functional blockade

IgG autoantibodies bind to AChR, MuSK, and LRP4 receptors, creating a functional blockade. Acetylcholine is unable to bind to AChR, disrupting the interaction between MuSK and LRP4, which decreases the clustering of AChR^5-10

2. Cross-linking

IgG autoantibodies cross-link AChR and LRP4 receptors, leading to internalization and degradation^5-9

3. Complement activation

IgG autoantibodies activate the autoantibody dependent complement system (C1 complex)^5-9

1. Functional blockade
2. Cross-linking
3. Complement activation

~85%

of patients have autoantibodies against AChR⁸

~5%

of patients have autoantibodies against MuSK^1,8

~1%-3%

of patients have autoantibodies against LRP4¹

~10%

of patients are triple seronegative with no detectable autoantibodies, but may still have IgG-mediated disease^1,9

~85%

of patients have autoantibodies against AChR⁸

~5%

of patients have autoantibodies against MuSK^1,8

~1%-3%

of patients have autoantibodies against LRP4¹

~10%

of patients are triple seronegative with no detectable autoantibodies, but may still have IgG-mediated disease^1,9

Symptom onset and disease course vary

Anti-MuSK positive gMG is commonly associated with rapid onset of bulbar symptoms. For all patients, even symptoms considered mild can be life-altering.^1,10,11

AChR=acetylcholine receptor; gMG=generalized myasthenia gravis; IgG=immunoglobulin G; LRP4=low-density lipoprotein receptor-related protein 4; MuSK=muscle-specific tyrosine kinase; NMJ=neuromuscular junction.

FcRn plays a critical role in IgG regulation^8,12,13

FcRn plays a critical role in enabling damage at the NMJ by: 

1. Binding IgG antibodies, including autoantibodies
2. Rescuing them from lysosomal degradation
3. Recycling them back into circulation

In doing so, FcRn helps maintain high levels of circulating IgG antibodies, including IgG autoantibodies.

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This recycling process prolongs the half-life of IgG antibodies and maintains high concentrations of pathogenic IgG autoantibodies that attack vital components of the NMJ.^13-16

FcRn=neonatal Fc receptor; IgG=immunoglobulin G; NMJ=neuromuscular junction.

See how these mechanisms affect life with gMG

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gMG=generalized myasthenia gravis.

References: 1. Gilhus NE. N Engl J Med. 2016;375(26):2570-2581. doi:10.1056/NEJMra1602678 2. Jackson K et al. Neurol Ther. 2023;12(1):107-128. doi:10.1007/s40120-022-00408-x 3. Gilhus NE et al. Nat Rev Neurol. 2016;12(5):259-268. doi:10.1038/nrneurol.2016.44 4. Dewilde S et al. BMJ Open. 2023;13(1):e066445. doi:10.1136/bmjopen-2022-066445 5. Twork S et al. Health Qual Life Outcomes. 2010;8:129. doi:10.1186/1477-7525-8-129 6. Grob D et al. Muscle Nerve. 2008;37(2):141-149. doi:10.1002/mus.20950 7. Rødgaard A et al. Clin Exp Immunol. 1987;67(1):82-88. 8. Behin A, Le Panse R. J Neuromuscul Dis. 2018;5(3):265-277. doi:10.3233/JND-170294 9. Wolfe GI et al. J Neurol Sci. 2021;430:118074. doi:10.1016/j.jns.2021.118074 10. Pasnoor M et al. Presented at: American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023. Boston, MA. 11. Dewilde S et al. Adv Ther. 2024;41(1):271-291. doi:10.1007/s12325-023-02704-w 12. Zhu LN et al. Neural Regen Res. 2023;18(8):1637-1644. doi:10.4103/1673-5374.363824 13. Roopenian DC, Akilesh S. Nat Rev Immunol. 2007;7(9):715-725. doi:10.1038/nri2155 14. Ward ES, Ober RJ. Trends Pharmacol Sci. 2018;39(10):892-904. doi:10.1016/j.tips.2018.07.007 15. Ulrichts P et al. J Clin Invest. 2018;128(10):4372-4386. doi:10.1172/JCI97911 16. Mantegazza R, Antozzi C. Front Neurol. 2020;11. doi:10.3389/fneur.2020.00981

The biology behind the disease

gMG is a chronic, debilitating, IgG-mediated autoimmune disease1,2

Patients can experience fluctuating weakness across critical muscle groups3

Bulbar

Respiratory

Gross motor

Ocular

IgG autoantibodies are a key driver of gMG1,7,8*

Pathogenic IgG autoantibodies target multiple components of the NMJ, including AChR, MuSK, and LRP41,7,8:

~85%

~5%

~1%-3%

~10%

~85%

~5%

~1%-3%

~10%

FcRn plays a critical role in IgG regulation8,12,13

See how these mechanisms affect life with gMG

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The biology
behind the disease

gMG is a chronic, debilitating, IgG-mediated autoimmune disease^1,2

Patients can experience fluctuating weakness across critical muscle groups³

IgG autoantibodies are a key driver of gMG^1,7,8*

Pathogenic IgG autoantibodies target multiple components of the NMJ, including AChR, MuSK, and LRP4^1,7,8:

FcRn plays a critical role in IgG regulation^8,12,13