The Cause and Therapy of Myasthenia Gravis

Yucong Geng

1,*,†

, Ruocen Song

2,†

and Jiaqi Liu

3,†

University of California, Berkeley, U.S.A.

University of Southern California, Los Angeles, U.S.A.

The High School Affiliated to Renmin University of China, Beijing, China

ruocenso@usc.edu,

3038740976@qq.com

†

These authors contributed equally

Keywords: Myasthenia Gravis, Main Cause, Treatment Method, Rituximab.

Abstract: Myasthenia Gravis is essential for people to have a clearer understanding of the cause as well as the potential

treatments since this disease can happen to every person at any age and at any time. Deep research and data

collection have shown the main causes of physiological problems and gene regulation and the three most

effective types of treatments- thymectomy, blood-derived, and medications. Some clinical research data

results indicate the effectiveness of using the medication, rituximab, by using placebo studies. It turns out that

rituximab helps people lower the rate of doing blood-derived treatments. The three treatments, especially the

medication and blood-derived treatments should be used together to remain the muscle contraction of the

Myasthenia Gravis patient. With all the information collected, it is crucial for people to raise attention to

myasthenia gravis and look forward to the innovation of new treatments.

1 INTRODUCTION

The most common form of Myasthenia Gravis (MG)

is a chronic autoimmune neuromuscular disorder

characterized by fluctuating weakness of the

voluntary muscle groups. In recent days, six

categories are Ocular MG, early-onset MG, late-

onset MG, MG with thymoma, MG with anti-muscle-

specific tyrosine kinase antibodies and MG with no

defined antibodies (Gilhus 2009, Gilhus, Nacu,

Andersen, & Owe 2015).

There is no known cure for MG, but there are

many effective treatments that can make managing

life with MG easier, the symptoms can be relieved

after resting or controlled by medications. There is a

need for attention for this disease because it can

happen to anyone of any race and gender, especially

for young women, whose ages are between 20 and 30,

and men, whose ages are 50 and older. In the US, it

is estimated that 20 in 100,000 have MG;

approximately 36,000 to 60,000 cases. However, as

myasthenia gravis often remains underdiagnosed, the

prevalence is most likely higher.

The general cause of MG is the dysfunction of

nerve-muscle junction transmission. MG is

considered an autoimmune disease, which is a

neuromuscular transmission disorder related by

acetylcholine receptor (AChR), the muscle Specific

Kinase (MuSK) and the low-density lipoprotein

receptor-related protein (LRP4). The researchers

found that the HLA locus, the locus for cytotoxic T-

lymphocyte-associated protein 4 (CTLA4), PTPN22,

IL-1β, IL-10, TNF-α and IFN-γ are related to

MGound (Berrih-Aknin, & Le Panse 2013).

There are currently a lot of treatments, and most

of the medications and therapies are based on the

cause of the disease. Three main treatments are

considered more effective. Firstly, thymectomy is the

only surgical treatment that completely removes the

thymus gland, causing the MG. Secondary, blood-

derived treatments include plasmapheresis, the

replacement of good antibodies with abnormal

antibodies in the blood. Last but not least, various

medications such as anticholinesterase

immunosuppressive medicines are trying to make the

antibodies not bind to the acetylcholine receptors or

make the acetylcholine stay in the junction longer, so

they have more chance to bind to the receptors. Also,

there is an emphasis on some traditional Chinese

medications that can help relieve the symptoms and

minimize the side effects of immunosuppressive

medications (table 2) (Giraud, Vandiedonck, &

Geng, Y., Song, R. and Liu, J.

The Cause and Therapy of Myasthenia Gravis.

DOI: 10.5220/0011231600003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 92-99

ISBN: 978-989-758-596-8

Garchon 2008). This article introduces what MG is

and main causes and the recent treatment of the MG

2 BACKGROUND

INFORMATION: WHAT IS MG,

PATIENT DISTRIBUTION

Myasthenia gravis (MG) is a disease caused by an

autoimmune disorder related by antibodies of the

neuromuscular junction, resulting in Visual

problems, skeletal muscle weakness and fatigability

of body function; however, the cause of myasthenia

gravis and the cure are unknown (Meriggioli, &

Sanders 2009). In clinical diagnosis, MG may be

classified by different factors, such as the different

parts of the muscles, the age of MG onset (Guptill,

Soni, & Meriggioli 2016), and the nature of thymic

pathology.

According to the data, table 1 shows that

geographical variations affect the different

incidences of MG (Dresser, Wlodarski, Rezania, &

Soliven 2021). Different epidemiological studies

estimate the incidence rate of MG with a range

between 1.7 and 21.3 per million people each year

(Bettini, Chaves, Cristiano, Pagotto, Perez, Giunta, &

Rugiero 2017). In Poland, the incidence rate is only

2.36 per million in 2019, which is lower than in other

countries (Sobieszczuk, Napiórkowski, Szczudlik, &

Kostera-Pruszczyk 2021). In Norway, the data shows

the average incidence rate of 1.6 per million each year

with a stable incidence rate over the last 25 years, and

the prevalence rate is 3.6–13.8 per million people

(Popperud, Boldingh, Brunborg, Faiz, Heldal,

Maniaol, Müller, Rasmussen, Oymar, & Kerty 2016).

In Sweden, the incidence of MG is 2.9 per million

people and the prevalence is 36.1 per million people

in 2016, but the incidence rate is increasing each year

(Westerberg, & Punga 2020). In addition, in North

American and Asian areas, the annual incidence rate

is not too high compared to other countries. In China,

MG's estimated annual incidence rate is between 1.55

to 3.66 per million people each year, and the

estimated prevalence of MG is 2.19–11.07 per

million people based on insurance records (Fang, Li,

Mo, Wang, Qiu, Ou, Lin, Huang, Feng, He, Wang,

Xu, Wang, Ran, & Liu 2020). In Canada, the

incidence rate is 2.1–2.6 per million, and the

prevalence rate ranges from 25.4 to 27.3 per million

in 2013 (Breiner, Widdifield, Katzberg, Barnett, Bril,

& Tu 2015). In South Africa, an annual incidence rate

is 8.5 per million (Mombaur, Lesosky, Liebenberg,

Vreede, & Heckmann 2015). However, the incidence

of MG is 38.8 cases per million in the Argentina area

(Dresser, Wlodarski, Rezania, & Soliven 2021). But

the data in table 1 may have some issues to cause the

different results in geographical regions.

Table 1: The recent increasing rate of MG in different regions.

ion Countr

Rate

er million each

ear

)

Europe

Polan

2.36

Norwa

1.6

Sweden 2.9

Asia China 1.55-3.66

North American Canada 2.1

–

2.6

South Africa Argentina 38.8

3 CAUSES OF DISEASE

3.1 Antibodies

Myasthenia gravis (MG) is an autoimmune disorder

caused by antibodies against acetylcholine receptors

(AChR) or other structural proteins of the

neuromuscular junction. This diminishes cholinergic

transmission, thus leading to exercise-induced

fatigue and sometimes manifest muscle weakness,

including the bulbar and ocular musculature

(Müllges, & Stoll 2019).

These autoantibodies bind to the nicotinic

acetylcholine receptor (AchR) itself, or muscle-

specific tyrosine kinase (MuSK), lipoprotein

receptor-related protein 4 (LRP4) and agrin involved

The Cause and Therapy of Myasthenia Gravis

in clustering of AchRs within the postsynaptic

membrane and structural maintenance of the

neuromuscular synapse. This results in the

disturbance of neuromuscular transmission and thus

the clinical manifestation of the disease (Melzer,

Ruck, Fuhr, Gold, Hohlfeld, Marx, Melms,

Tackenberg, Schalke, Schneider-Gold, Zimprich,

Meuth, & Wiendl 2016).

In the US there are about 18,000 people with MG.

Myasthenia gravis crisis (MGC) is defined as any

MG exacerbation necessitating mechanical

ventilation. Most patients presenting with MGC have

an identifiable risk factor. The diagnosis of MGC

should be suspected in all patients with respiratory

failure, particularly those with unclear etiology.

Acute management of MGC requires supportive

general and ventilatory therapy and institution of

measures to improve the neuromuscular blockade

(Bershad, Feen, & Suarez 2008).

3.2 The Thymus Gland

The thymus gland is a small gland located in the

upper chest beneath the sternum. It helps control the

immune system, and when it malfunctions, it may

cause MG. Many people with MG have a large or

overactive thymus gland. Some even develop tumors

on their thymus gland. These tumors are called

thymomas. These tumors can be harmless, but also

can turn into cancer or cause lasting health issues.

Research has shown that in most cases, MG

patients have increased numbers of cells in the

thymus, and about 10-15 percent of affected

individuals have thymomas (tumors) in the thymus.

Researchers suggest that the thymus of an MG patient

may trigger or maintain the production of the

antibodies that block the transmission of nerve

signals. Thus, the malfunction of the thymus gland

may cause MG, and the treatment was directed at the

thymus gland.

3.3 Human Leukocyte Antigen (HLA)

The HLA gene contains several genetic loci (HLA-A,

B, C and D) (COMPSTON, VINCENT, NEWSOM-

DAVIS, & BATCHELOR 1980). It has a relationship

with a large number of diseases, such as

hemochromatosis. According to the bulk clinical

experiments, the major histocompatibility complex

has been identified to be associated with autoimmune

MG with thymus hyperplasia, and the major

histocompatibility complex plays an important role in

MG as the first and the most important factor (Giraud,

Vandiedonck, & Garchon 2008). In addition, MG and

thymus hyperplasia are associated with HLA, and

HLA-DR3 and HLA-DR7 show opposite influences

on MG patients (Giraud, Beaurain, Yamamoto,

Eymard, Tranchant, Gajdos, & Garchon 2001).

In previous studies, the relationship between the

disease and different ethnic groups was identified

(Giraud, Vandiedonck, & Garchon 2008).

Myasthenia gravis (MG) in European Caucasoids has

found that they are associated with HLA-B8 and

HLA-DR3. The significant increase in HLA-A1,

HLA-B8 and HLA-DR5 in American blacks with

generalised adult-onset myasthenia gravis or ocular

myasthenia gravis (OMG) (Christiansen, Pollack,

Garlepp, & Dawkins 1984). MG in China shows

differences with the patients in Caucasians. Patients,

who are in the first 20 years of life, restricted ocular

myasthenia in them has a relationship with absence

or low titres of acetylcholine receptor antibody and

HLA-DR9; however, restricted ocular myasthenia in

the patients, whose age is older than 20 years old, has

high titres of acetylcholine receptor antibody

(Hawkins, Yu, Wong, Woo, Ip, & Dawkins 1989). In

another study, OMG in Chinese is associated with

HLA-BW46 (Hawkins, Ip, Lam, Ma, Wy, Yeung, &

Dawkins 1986). In conclusion, compared to

European Caucasoids, MG in Chinese is at an earlier

age at onset, more ocular forms, and less clinically

severe illness. HLA-DR9 and HLA-Bw46 (Chen,

Chiu, & Hseih 1993) have strongly impacted them.

In other Asian countries, Japanese in the childhood

with MG are associated with HLA-DR9 and HLA-

DRw13 (or DQw1 and DQw3), which act

synergistically in the disease; however, no significant

association was shown in Japanese with adult-onset

MG, and the risk of MG decreases with the age of

onset. Moreover, no patients had HLA-B8 and HLA-

DR3 which are related to European Caucasoids. So

MG in Japanese individuals differs from European

Caucasoids with MG (Matsuki, Juji, Tokunaga,

Takamizawa, Maeda, Soda, Nomura, & Segawa

1990). Thus, according to the previous studies,

patients in China are similar to those in Japan because

both of them are associated with HLA-DR9.

3.4 Other Genes

Cytotoxic T-lymphocyte-associated protein

4(CTLA4), Protein tyrosine phosphatase, non-

receptor type 22(PTPN22), meanwhile, Fc fragment

of IgG, low-affinity IIIb(FCGR3B) are not specific to

MG, which also encode proteins related to lymphoid

cell activation and other autoimmune diseases

(Giraud, Vandiedonck, & Garchon 2008). CTLA4

plays an important role in downregulating to control

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

the cellular and the humoral responses by controlling

responses of activated T cells (Huang, Liu, Norén,

Xia, Trifunovic, Pirskanen, & Lefvert 1998). It is

estimated to protect patients from MG in thymoma

patients against several autoimmune diseases;

however, it also increases the risk to lead to

paraneoplastic MG in thymoma patients (Chuang,

Ströbel, Gold, Nix, Schalke, Kiefer, Opitz, Klinker,

Müller-Hermelink, & Marx 2005). PTPN22 reduces

T-cell activation and generation of interleukin-2, and

it has been associated with various autoimmune

diseases. Hungarian and German MG patients are

highly overrepresented of the common autoimmune

polymorphism PTPN22 1858C/T (Greve, Hoffmann,

Illes, Rozsa, Berger, Weissert, & Melms 2009).

Moreover, PTPN22 is associated with early-onset

MG and thymoma-associated MG (Chuang, Ströbel,

Belharazem, Rieckmann, Toyka, Nix, Schalke, Gold,

Kiefer, Klinker, Opitz, Inoue, Kuo, Müller-

Hermelink, & Marx 2009). The Fcgamma receptors

include FcgammaRIIa, FcgammaRIIIa, and

FcgammaRIIIb, and they have different abilities for

IgG binding and phagocytosis. Thymoma MG

patients have a high expression on the

FcgammaRIIA-H/H genotype, so FcgammaRIIa-

R/R131 genotype is a biomarker for susceptibility to

MG (Raknes, Skeie, Gilhus, Aadland, & Vedeler

1998). In summary, different associations with MG

are highly diverse and in order to better define their

relationship, future studies need to focus on different

controls, such as the region, age and gender of

patients, thymus pathology, subtypes of MG.

4 TREATMENT

4.1 Thymectomy

Thymectomy is considered the first treatment that

people have found, as well as the only surgical

treatment that is found to be effective. However,

there are still a lot of controversies and risks about it.

Thymus anomalies can occur in the majority of MG

patients with MG and AChr antibodies. It is observed

that 60% -70% have abnormalities of the gland,

including hyperplasia and 10%–15% tend to develop

thymoma. These findings lead to the development of

thymectomy, but this procedure heavily depends on

the age of the patient, the severity of the disease, the

presence of AChr antibodies or MuSK antibodies,

and so on (Romi 2011). Until today, those researchers

have settled down the age limit of thymectomy

surgery for patients under 65 years old. It is because

the elderly cannot respond well due to “high thymic

involution incidence,” and the side effects may

overturn the benefits. Other than the age limit,

thymectomy is best processed with mild and

moderate MG. The remission of the mild MG patient

is much higher through studies from 1985 to 2014

and especially effective when it is performed 6 to 12

months after the first symptoms occurred (Mao, Hu,

Lu, & Hackett, 2015). In addition, MG patients with

the absence of AChR are recommended if they do not

respond well to IS therapy that thymectomy can

minimize the effects of IS therapy (Mao, Hu, Lu, &

Hackett 2015). After the surgical procedure, it was

found that patients in the surgical group had

approximately twice the rate of remission and

improvement as those in the control group. Within a

few months after surgery, about 60% to 80% of

patients were in remission (U.S. Department of

Health and Human Services.). However, there are

also risks for patients who have thymic tumors.

Patients with thymoma should have surgery to

remove the tumor, but it will not guarantee an

improvement in MG, and further treatments need to

be based on patients. If thymectomy is performed

aggressively, these patients did not respond well to

the thymectomy and were generally more seriously

ill (Mao, Hu, Lu, & Hackett 2015).

There is always a desire for the best procedure of

thymectomy. Some common procedures are

transsternal thymectomy, transcervical thymectomy,

and it turns out that minimally invasive techniques,

which use some tiny incision in the chest, have

become increasingly popular due to their low

procedural morbidity and mortality, short hospital

stay, optimal cosmesis, minor surgical access trauma,

better preservation of pulmonary function (Marulli,

& Rea 2015). Especially for young patients,

clinicians want to ensure that the young patients can

have a regular and comfortable life after the surgery,

especially for children with generalized AChR

antibody-positive MG, “possibility of a congenital

myasthenic syndrome or other neuromuscular

condition should be entertained” and these should be

exclaimed before the thymectomy (Sanders 2016).

4.2 Blood-derived Treatments

As time goes, blood-derived treatments,

plasmapheresis, becomes accessible as people get

more knowledge that the antibodies in the blood are

blocking the receptors in the neuro junction.

Plasmapheresis (PLEX) is simply replacing the

plasma in MG patients with healthy plasma. And

later, intravenous immunoglobulin (IVIg), the

injection of healthy antibodies to temporarily change

The Cause and Therapy of Myasthenia Gravis

the immune system's working (U.S. Department of

Health and Human Services.). Unlike thymectomy

that has a chance to remission the disease, PLEX and

IVIg can only keep the symptoms away within six

days to six weeks depending on the half-life of AChr

Ab, as a result, patients have to do the procedure

repeatedly. It is recommended to serve MG patients

with life-threatening problems. Other than that,

people often use them as an add-on to medication to

enhance the best effect of restoring muscle

contraction. However, there are also some

unavoidable side effects. As the clinical studies show,

10%~15% of patients produce toxic symptoms due to

plasma exchange therapy to enter more citron acid,

which causes low blood calcium. Some symptoms

include numbness around the mouth and lip, nausea,

vomiting, cardiac arrhythmia, which can be

alleviated by using supplemental calcium. The other

side effects are Hypovolemic or hypotension that can

occur during plasma separation because more blood

volume is required for cardiopulmonary bypass. In

mild cases, tachycardia, sweating, nausea, tinnitus,

and other symptoms may occur. In severe cases,

seizures of syncope or heart or cerebral infarction

may occur. It is required that the blood sampling

speed should not be too fast, and the colloidal

substances should be properly supplemented to

correct the adverse reactions (Sedef Iskit 2018). In

short, both PLEX and IVIg also do need a lot of

caution with the consultation of patients’ conditions.

4.3 Medications, the Rising of

Rituximab

With more interest as well as a deeper understanding

of the cause and process of MG, clinicians start to

figure out drugs that can make the acetylcholine stay

long during the junction so it has a better chance to

bind to the receptor or try to remove the bad

antibodies. Anticholinesterase medications, which

slow down the breakdown of acetylcholine, and

immunosuppressive drugs that suppress the

production of antibodies are some conventional

medications that can treat MG. For children MG

patients. It is shown that steroid medications can have

some severe side effects, such as the probability of

infection, growth failure. Considering all the factors,

it illustrates that immunosuppressive drugs,

corticosteroids, should be used as a long-term

treatment to minimize side effects. The more novel

medications have shown for better effectiveness,

including monoclonal antibodies, attack the process

when the bad antibodies bind to the acetylcholine

receptors (U.S. Department of Health and Human

Services.) and B cell depletion, such as, rituximab

(RTX), which was developed in the 2000s for cancer

and other autoimmune disorders and is a murine-

human chimeric anti-CD20 glycoprotein monoclonal

antibody (Menon, Barnett, & Bril 2020). The

clinicians gave a placebo test to the MG patients, it

turned out that the MMT score has been stable for

patients who took rituximab and the frequency of

doing the blood-derived treatments had been lowered

(Anderson, Phan, Johnston, & Siddiqi 2016) as

shown in Figure 1. Traditional Chinese medicine

treatment of myasthenia gravis is getting more and

more attention. MG is considered in the category of

"impotence". According to the theory of traditional

Chinese medicine, the addition of traditional Chinese

medicine in the treatment can reduce the side effects

caused by immunosuppressants, play an escort role in

the treatment of myasthenia gravis, and rebuild the

effect of the autoimmune function. Other than that,

Chinese therapy, acupuncture, also can be add-on

treatments to delay and reduce the symptoms of MG.

Table 2: Summary of Three Treatments.

Thera

Pur

ose Outcome

Thymectomy Removal of thymoma or hyperplastic 60 to 80% are in remission.

Intravenous immunoglobulin (IVIg) Inject the healthy antibodies to alter the

operations of the immune system.

Only last within six days to sie

weeks

Plasmapheresis (PLEX) Plasma exchange to get the health antibodies. Only last within six days to sie

weeks

Immunosuppressive Reduce the production of abnormal

antibodies

Corticosteroid,

cyclophosphamide

Monoclonal antibody Targets the process by which acetylcholine

antibodies injure the neuromuscular junction

Rituximab

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

The left, intermediate and right graphs represent prednisone dose, IVIG frequency, PLEX frequency, respectively.

Figure 1: Rituximab Effectiveness (compare premedication with post medication) (Anderson, Phan, Johnston, & Siddiqi

2016).

5 CONCLUSIONS

To sum up, Antibodies to the acetylcholine receptor,

the muscle-specific tyrosine kinase, and the

lipoprotein receptor protein 4, characterize disease

subtypes with distinct clinical traits and immune-

pathogenic mechanisms. Also, experiments found

that MG and thymus hyperplasia are associated with

HLA, and HLA-DR3 and HLA-DR7 show the

opposite influence on MG patients. Besides, CTLA4,

PTPN22, and FCGR3B are not specific to MG, which

also encode proteins related to lymphoid cell

activation and other autoimmune diseases. In order to

solve this disease, there are many kinds of treatment,

like Thymectomy, Intravenous, immunoglobulin,

plasmapheresis, immunosuppressive and

Monoclonal antibodies, which both are effective

treatments that can make managing life with MG

easier. However, some issues need to be addressed to

find better treatment in future research. For example,

it is unclear how HLA or other genes control MG. In

the future, a huge amount of clinical research is

needed to find out the other causes or treatments of

MG. In this article, understanding the disease

mechanism, the cause and the treatment method of

MG will provide a brief summary to future

researchers and conduct further research.

REFERENCES

Anderson, D., Phan, C., Johnston, W. S., & Siddiqi, Z. A.

(2016). Rituximab in refractory myasthenia gravis: a

prospective, open‐label study with long‐term follow‐

up. Annals of Clinical and Translational Neurology,

3(7), 552–555.

Berrih-Aknin, S., & Le Panse, R. (2013). Myasthenia

gravis: A comprehensive review of immune

dysregulation and etiological mechanisms. Journal of

Autoimmunity, 52, 90–100.

Bershad, E. M., Feen, E. S., & Suarez, J. I. (2008).

Myasthenia gravis crisis. Southern medical journal,

101(1), 63–69.

Bettini, M., Chaves, M., Cristiano, E., Pagotto, V., Perez,

L., Giunta, D., & Rugiero, M. (2017). Incidence of

Autoimmune Myasthenia Gravis in a Health

Maintenance Organization in Buenos Aires, Argentina.

Neuroepidemiology, 48(3-4), 119–123.

Breiner, A., Widdifield, J., Katzberg, H. D., Barnett, C.,

Bril, V., & Tu, K. (2015). Epidemiology of myasthenia

gravis in Ontario, Canada. Neuromuscular Disorders:

NMD, 26(1), 41–46.

Chen, W. H., Chiu, H. C., & Hseih, R. P. (1993).

Association of HLA-Bw46DR9 combination with

juvenile myasthenia gravis in Chinese. Journal of

neurology, neurosurgery, and psychiatry, 56(4), 382–

385.

Christiansen, F. T., Pollack, M. S., Garlepp, M. J., &

Dawkins, R. L. (1984). Myasthenia gravis and HLA

antigens in American blacks and other races. Journal of

Neuroimmunology, 7(C), 121–129.

Chuang, W. Y., Ströbel, P., Belharazem, D., Rieckmann,

P., Toyka, K. V., Nix, W., Schalke, B., Gold, R.,

Kiefer, R., Klinker, E., Opitz, A., Inoue, M., Kuo, T.

T., Müller-Hermelink, H. K., & Marx, A. (2009). The

PTPN22 gain-of-function+1858T (+) genotypes

correlate with low IL-2 expression in thymomas and

predispose to myasthenia gravis. Genes and immunity,

10(8), 667–672.

Chuang, W. Y., Ströbel, P., Gold, R., Nix, W., Schalke, B.,

Kiefer, R., Opitz, A., Klinker, E., Müller-Hermelink,

H. K., & Marx, A. (2005). A CTLA4 high genotype is

associated with myasthenia gravis in thymoma

patients. Annals of neurology, 58(4), 644–648.

COMPSTON, D. A. S., VINCENT, A., NEWSOM-

DAVIS, J., & BATCHELOR, J. R. (1980).

CLINICAL, PATHOLOGICAL, HLA ANTIGEN

AND IMMUNOLOGICAL EVIDENCE FOR

DISEASE HETEROGENEITY IN MYASTHENIA

GRAVIS. Brain (London, England: 1878), 103(3),

The Cause and Therapy of Myasthenia Gravis

579–601.

Dresser, L., Wlodarski, R., Rezania, K., & Soliven, B.

(2021). Myasthenia Gravis: Epidemiology,

Pathophysiology and Clinical Manifestations. Journal

of clinical medicine, 10(11), 2235.

Fang, W., Li, Y., Mo, R., Wang, J., Qiu, L., Ou, C., Lin, Z.,

Huang, Z., Feng, H., He, X., Wang, W., Xu, P., Wang,

L., Ran, H., & Liu, W. (2020). Hospital and healthcare

insurance system record–based epidemiological study

of myasthenia gravis in southern and northern China.

Neurological Sciences, 41(5), 1211–1223.

Gilhus, N. E. (2009). Autoimmune myasthenia gravis.

Expert Review of Neurotherapeutics, 9(3), 351–358.

Gilhus, N. E., Nacu, A., Andersen, J. B., & Owe, J. F.

(2015). Myasthenia gravis and risks for comorbidity.

European Journal of Neurology, 22(1), 17–23.

Giraud, M., Beaurain, G., Yamamoto, A. M., Eymard, B.,

Tranchant, C., Gajdos, P., & Garchon, H. J. (2001).

Linkage of HLA to myasthenia gravis and genetic

heterogeneity depending on anti-titin antibodies.

Neurology, 57(9), 1555–1560.

Giraud, M., Vandiedonck, C., & Garchon, H.-J. (2008).

Genetic Factors in Autoimmune Myasthenia Gravis.

Annals of the New York Academy of Sciences,

1132(1), 180–192.

Giraud, M., Vandiedonck, C., & Garchon, H.-J. (2008).

Genetic Factors in Autoimmune Myasthenia Gravis.

Annals of the New York Academy of Sciences,

1132(1), 180–192.

Greve, B., Hoffmann, P., Illes, Z., Rozsa, C., Berger, K.,

Weissert, R., & Melms, A. (2009). The autoimmunity-

related polymorphism PTPN22 1858C/T is associated

with anti-titin antibody-positive myasthenia gravis.

Human immunology, 70(7), 540–542.

Guptill, J. T., Soni, M., & Meriggioli, M. N. (2016).

Current Treatment, Emerging Translational Therapies,

and New Therapeutic Targets for Autoimmune

Myasthenia Gravis. Neurotherapeutics, 13(1), 118–

131.

Hawkins, B. R., Ip, M. S., Lam, K. S., Ma, J. T., Wy, C. L.,

Yeung, R. T., & Dawkins, R. L. (1986). HLA antigens

and acetylcholine receptor antibody in the

subclassification of myasthenia gravis in Hong Kong

Chinese. Journal of neurology, neurosurgery, and

psychiatry, 49(3), 316–319.

Hawkins, B. R., Yu, Y. L., Wong, V., Woo, E., Ip, M. S.,

& Dawkins, R. L. (1989). Possible evidence for a

variant of myasthenia gravis based on HLA and

acetylcholine receptor antibody in Chinese patients.

The Quarterly journal of medicine, 70(263), 235–241.

Huang, D., Liu, L., Norén, K., Xia, S. Q., Trifunovic, J.,

Pirskanen, R., & Lefvert, A. K. (1998). Genetic

association of Ctla-4 to myasthenia gravis with

thymoma. Journal of neuroimmunology, 88(1-2), 192–

198.

Mao, Z., Hu, X., Lu, Z., & Hackett, M. L. (2015).

Prognostic factors of remission in myasthenia gravis

after thymectomy. European Journal of Cardio-

Thoracic Surgery, 48(1), 18–24.

Marulli, G., & Rea, F. (2015). Myasthenia gravis and

thymectomy: many doubts and few certainties.

European Journal of Cardio-Thoracic Surgery, 48(1),

46–47.

Matsuki, K., Juji, T., Tokunaga, K., Takamizawa, M.,

Maeda, H., Soda, M., Nomura, Y., & Segawa, M.

(1990). HLA antigens in Japanese patients with

myasthenia gravis. The Journal of clinical

investigation, 86(2), 392–399.

Melzer, N., Ruck, T., Fuhr, P., Gold, R., Hohlfeld, R.,

Marx, A., Melms, A., Tackenberg, B., Schalke, B.,

Schneider-Gold, C., Zimprich, F., Meuth, S. G., &

Wiendl, H. (2016). Clinical features, pathogenesis, and

treatment of myasthenia gravis: a supplement to the

Guidelines of the German Neurological Society.

Journal of neurology, 263(8), 1473–1494.

Menon, D., Barnett, C., & Bril, V. (2020). Novel

Treatments in Myasthenia Gravis. Frontiers in

Neurology, 11, 538–538.

Meriggioli, M. N., & Sanders, D. B. (2009). Autoimmune

myasthenia gravis: emerging clinical and biological

heterogeneity. Lancet Neurology, 8(5), 475–490.

Mombaur, B., Lesosky, M. R., Liebenberg, L., Vreede, H.,

& Heckmann, J. M. (2015). Incidence of acetylcholine

receptor-antibody-positive myasthenia gravis in South

Africa. Muscle & Nerve, 51(4), 533–537.

Müllges, W., & Stoll, G. (2019). Myasthenia gravis

[Myasthenia gravis]. Der Nervenarzt, 90(10), 1055–

1066.

Popperud, T., Boldingh, M., Brunborg, C., Faiz, K., Heldal,

A., Maniaol, A., Müller, K., Rasmussen, M., Oymar,

K., & Kerty, E. (2016). Juvenile myasthenia gravis in

Norway: A nationwide epidemiological study.

European Journal of Paediatric Neurology, 21(2), 312–

317.

Raknes, G., Skeie, G. O., Gilhus, N. E., Aadland, S., &

Vedeler, C. (1998). FcgammaRIIA and FcgammaRIIIB

polymorphisms in myasthenia gravis. Journal of

neuroimmunology, 81(1-2), 173–176.

Romi, F. (2011). Thymoma in Myasthenia Gravis: From

Diagnosis to Treatment. Autoimmune Diseases,

2011(1), 474512–474515.

Sanders, D. B., Wolfe, G. I., Benatar, M., Evoli, A., Gilhus,

N. E., Illa, I., Kuntz, N., Massey, J. M., Melms, A.,

Murai, H., Nicolle, M., Palace, J., Richman, D. P.,

Verschuuren, J., & Narayanaswami, P. (2016).

International consensus guidance for management of

myasthenia gravis: Executive summary. Neurology,

87(4), 419–425.

Sedef Iskit, P. D. (2018, April 18). Plasmapheresis.

Myasthenia Gravis News.

https://myastheniagravisnews.com/role-

plasmapheresis-myasthenia-gravis/.

Sobieszczuk, E., Napiórkowski, L., Szczudlik, P., &

Kostera-Pruszczyk, A. (2021). Myasthenia Gravis in

Poland: National Healthcare Database Epidemiological

Study. Neuroepidemiology, 55(1), 62–69.

U.S. Department of Health and Human Services. (n.d.).

Myasthenia gravis fact sheet. National Institute of

Neurological Disorders and Stroke.

https://www.ninds.nih.gov/Disorders/Patient-

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

Caregiver-Education/Fact-Sheets/Myasthenia-Gavis-

Fact-Sheet#4.

Westerberg, E., & Punga, A. R. (2020). Epidemiology of

Myasthenia Gravis in Sweden 2006–2016. Brain and

Behavior, 10(11), e01819–n/a.

The Cause and Therapy of Myasthenia Gravis