OVERVIEW OF MYASTHENIA GRAVIS SUBGROUPS AND ITS INFLUENCE ON PREGNANCY AND THEIR TREATMENT ADVANCES

Ankita Wal¹*, Pranay Wal¹, Ashutosh Pandey¹, Himangi Vig¹, Akash Ved², Himanshu Bhusan Samal³

ABSTRACT

Antibodies that attack the neuromuscular junction induce myasthenia gravis, an immunological illness. Such antibodies assault and degrade postsynaptic molecules in by binding to the postsynaptic muscular end-plate. As a consequence, signal transduction is disrupted, resulting in muscular weakness and fatigability. Developments in our knowledge of the immunological mechanisms that cause myasthenia gravis have paved the way for the development of new targeted immunity treatments. The majority of myasthenia gravis sufferers have a well-managed condition with just minor to moderate symptoms. The goal must be to create more targeted therapies that reduce or enhance tolerance to the well-known and particular autoimmune reactions that result in autoantibody formation and muscular weakening. Several drugs widely used in obstetrics can aggravate the condition. The impact of maternity on myasthenia varies greatly from one woman to the next, as well as from one pregnancy to the next within the same woman. Acetylcholine esterase inhibitors, corticosteroids, and other immunosuppressants, as well as proper rest, are the most common therapy. Intrauterine antibody exposure can cause in utero or neonatal effects in newborns, which are usually temporary. This review focuses on myasthenia gravis subgroups and treatment breakthroughs, as well as the influence of myasthenia gravis on pregnancy and its management.

Keywords: Myasthenia gravis, Nicotinic acetylcholine receptor, Muscle-specific tyrosine kinase, Acetylcholine esterase inhibitors, neuromuscular junction, Immunosuppressants

Introduction

Autoantibodies against neuromuscular regions proteins such as the nicotinic acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK), or low-density lipoprotein receptor-related protein 4 (LRP4) induce myasthenia gravis (MG) [1]. Most communities have an MG incidence of 100–200 per million [2]. In a bimodal manner, gender and age promote the initiation of MG. Women are more likely to be afflicted before the age of 50, whereas men are somewhat more likely to be impacted in delayed MG [3]. With better diagnosis and longer survival, the frequency is rising, particularly in the aged [4, 5], who were previously under-diagnosed. Autoimmune MG sufferers can be divided into 7 subgroups, with their own set of autoantibodies and clinical manifestations. Myasthenia gravis is an autoimmune disorder; due to the inauguration of antibodies manage to nicotinic receptors at the muscle endplate [6, 7]. Myasthenia gravis was increased due to population aging. This uncommon but treatable illness has piqued medical experts are interested in many years. Various autoimmune illnesses are more common in MG patients than in the normal community [8]. A secondary autoimmune condition affects 13–22% of MG sufferers, with females and early-onset MG having the highest rates [9]. Subgrouping is indicated in myasthenia gravis recommendations and consensus statements, [10] but specific definitions differ and novel subgroups emerge as a consequence of rising information. Myasthenia gravis autoantibodies, demography, clinical manifestations, and contraindications are all included in subgrouping [11, 12]. Categorization of related Ab has progressed as well as the knowledge of genetic predisposition. The factors of tolerance failure, as well as new medicinal breakthroughs. Type of antibody (IgG)1/IgG3 are monoclonal antibodies antigen-modulating proteins that cause significant loss of AChR and the reduction of the postsynaptic neuron [13]. Myasthenia gravis has been around for a long time regarded as a complex organism. The early-onset disease is one of three subgroups of the disease. Late-onset and thymoma-related, with different signs and symptoms clinical features, and the various routes of immune deficiency [14]. MG is more common in females in their second and third decades, which correlates with pregnancy. Medication is usually needed before, during, and after gestation to ensure the health of both the mother and the fetus. Exacerbations can happen during pregnancy, regardless of how well you controlled your symptoms before you got pregnant. Terminating a pregnancy has not been proven to be beneficial [15]. Pregnancy has no negative effects on the condition in the long run. Because myasthenic crises and mortality are more common in the first year or two following diagnosis, including in early pregnancy and after childbirth, deferring pregnancy until first year or two is common. Prior to actually conceiving, females with myasthenia gravis must consult with their neurologist to discuss the importance of thymectomy, maximize clinical benefits, and reduce the need of immunomodulatory medicines [16]. The therapy aims to reduce disease severity in the mother while reducing the potential harm to the fetus. To assist patients during pregnancy and the postpartum period, as well as prepare the best delivery methods, the medical team should comprise a neurologist, a gynecologist, and an anesthesiologist.

Epidemiology

Immune system MG has a revealed overall pervasiveness of 40–180 for every million individuals and a yearly occurrence of 4–12 for every million individuals [17]. As of late gathered figures of commonness and occurrence will, in general, be superior to more seasoned ones, particularly intended for late-onset MG, incompletely clarified by expanded case investigations and wider inescapable autoantibody analysis. Populace socioeconomics with an expanded number of old individuals and diminished MG mortality effect occurrence and commonness. AChR associated myasthenia gravis has a bimodal age example of occurrence, with a top in youthful grown-ups matured about 30 years and afterward a consistent expansion in occurrence with expanding age more seasoned than 50 years [18]. The occurrence top in youthful grown-ups is mostly a result of the great recurrence in ladies, average for some immune system messes, albeit late-beginning MG is marginally more successive in men [19]. No proof proposes that the event of this illness is expanding as a consequence of an adjustment of outer causative factors, for example, diseases or diet. In general, myasthenia gravis rate and pervasiveness show minimal topographical variety; in any case, this circulation isn't the situation for all of the group's subdivisions sicknesses [20]. Adolescent Myasthenia gravis a kind of early-stage illness, is common in East Asia, with up to half of all cases commencing before the age of 15, and many of them are accompanied by visual manifestation. Myasthenia gravis was found in 1–2 per million children in a mixed population in Canada every year, with Asian nationals being the most affected, especially in the visual category [21]. LRP4 antibodies were found in 19% of patients who did not have AChR antibodies5, while MUSK antibodies were found in 33% of patients who did not have AChR antibodies. According to epidemiological data, LRP4-related myasthenia gravis is half as serious as MUSK-related MG. The incidence of MUSK-related myasthenia gravis is estimated to be 0.3 patients per million per year [22]. Some topographical variations in this sickness and its variants are believed to be explained by hereditary predisposition as well as external variables such as contaminations or nutrition.

Beginning stage AChR antibodies in myasthenia gravis: Early-onset myasthenia gravis have its early symptoms before the age of 50, according to the criteria. Antibodies to AChR in the plasma are identified by standard indicative testing [23]. This myasthenia gravis subgroup excludes patients who have a thymoma discovered on imaging or after medical treatment. Thymic follicular hyperplasia is common, although it isn't necessary, and this group reacts to thymectomy [24]. By a factor of three, female cases outnumber male ones. Beginning stage myasthenia gravis has a relationship with HLA-DR3, HLA-B8, and other immune system hazard qualities, and all immune system issues are more generally announced in family members of individuals in this myasthenia gravis subgroup. Such investigations recommend subgroup variations in the aetiology of myasthenia gravis [25]. The illness is somewhat more oftentimes detailed in guys than females, and feeble HLA affiliations happen with HLADR2, HLA-B7, and HLA-DRB1* [26].

Myasthenia Gravis Subgroups

Myasthenia Gravis Produced by Sporadic Cases

Thymoma-related Muscular dystrophy is a kind of cancer that affects the muscles. By far the most well-known immune system disease associated with evidence of infection is myasthenia gravis. Thymoma is also linked to red aplasia and neuromyotonia; however, this relationship does not exist in other immune system disorders. A thymoma is observed in 10–15 basis points of all muscular dystrophy patients. Everybody has detectable AChR antibodies and psychiatric conditions. About 30two - thirds of patients with pheochromocytoma develop myasthenia gravis, while an even greater percentage of AChR antibodies are without muscular dystrophy [27] Figure 2.

Myasthenia Gravis Linked to MuSK

MUSK is a protein that is conveyed in the postsynaptic myometrium and is necessary to sustain AChR function. On average, 1–4two - thirds of individuals with myasthenia gravis have blood MUSK antibodies, although, with more sensitive test measures, additional instances will most certainly be found [28]. Adults with MUSK-associated myasthenia gravis seem to be more likely to identify than children or the elderly [29]. There have been no thymus obsessive modifications to adjust for, and most patients get little response following thymectomy. MuSK IgG antibodies are predominantly from the IgG4 subtype. MuSK antibodies are immediately toxic and operationally monovalent, particularly if they do not link to complement [30]. MuSK antibodies lower the postsynaptic concentration of AChRs and impede their orientation between the motor nerve terminal and the postsynaptic membrane, rather than modifying AChR activity. MuSK antibodies attach to the AChR's extracellular N-terminal Ig-like regions.

Myasthenia Gravis Linked to AChR

Antibodies to AChR can be found in 70 percent of MG cases using standard techniques [31]. Antibodies against the AChR attach to the receptor's outer regions, preventing signal transduction, according to studies. Antibodies to AChR are predominantly from the IgG1 and IgG3 subcategories, which initiate the complement cascade, causing postsynaptic membrane injury. Furthermore, because the antibodies are bivalent, they can modulate antigenicity. Certain AChR antibodies address the receptor's acetylcholine interaction region, potentially disrupting the signaling cascade; nonetheless, such antibodies are uncommon and likely only affect a small number of patients. Because antibodies against the AChR subunit are highly harmful than antibodies towards the subunit, the AChR epitope sequence determines symptom severness [32]. A rise in antibody quantity is considered to signify MG aggravation, while a constant or falling level could suggest illness stability. Conversely, it is the depletion of functioning AChRs, not the level of AChR antibodies, that causes MG symptoms: Decreased receptor counts correspond with illness severity, and receptor loss is influenced by autoantibody sequence and non-antibody variables in addition to overall AChR-antibody proportion [33, 34].

Myasthenia Gravis Linked to LRP4

LRP4 is a receptor for nerve-derived agrin and a MUSK activator that is required for AChR activity. It is generated in the postsynaptic muscular membrane. LRP4 antibodies have been found in myasthenia gravis individuals who do not have AChR or MUSK antibodies [35]. The majority of these individuals have ophthalmic or generalized moderate MG, and roughly 20% of them have only had ocular fatigue. Although in a subset with extra MUSK antibodies, pulmonary weakness is extremely infrequent. The thymus is abnormal and typical for age in two-thirds of individuals with LRP4-linked MG, however, hyperplasia has been recorded [36].    

Myasthenia Gravis and Pregnancy

The impact of gestation on myasthenia differs significantly from one woman to the next, as well as from one pregnancy to the next within the same woman [37]. Pregnancy physiological responses, such as early pregnancy nausea and vomiting, higher blood volume, variations in renal excretion, and digestive absorption modifications, may modify the short-term course of myasthenia gravis by changing pharmaceutical dosage demands [38]. Any infection connected with pregnancy, such as cystitis or chorioamnionitis, increases the risk of illness aggravation. Pregnancy, on the other hand, has little effect on the disease's long-term fate [39]. Symptom exacerbations are much more common in the first trimester, although symptom relief is more common in the second and third trimester, possibly due to hormone-mediated immunosuppression that occurs in typically developing pregnancies [40]. Though illness exacerbations typically resolve following spontaneous abortion, pregnancy termination does not affect the relative likelihood or severity of myasthenic aggravation. Miscarriages are not increased in women with myasthenia gravis. The diaphragm gets further raised during pregnancy, and intercostal muscles participate more actively to satisfy higher breathing demands. In pregnancy, it's crucial to keep a close eye on your breathing [41].

The danger of maternal death is greatest within the first year after a diagnosis of MG, and it is lowest seven years afterward [42]. As a result, women with MG should postpone childbearing for at least two years from the commencement of the disease [43]. Despite these concerns, pregnancy has not been found to have a long-term negative impact on MG [44].

Myasthenia Gravis's Impact on Pregnancy and Fetus

Generally, MG has no significant negative consequences on pregnancy [45]. There is no evidence that women with MG have a higher chance of spontaneous abortions or early births [46]. Infants, on the other hand, may experience transitory neonatal MG. Because of placental transmission of immunoglobulin G antibodies in the second and third trimesters, this occurs in 10% to 20% of instances [47]. Breathing issues, muscle cramps, wimpy cries, poor latching, and ptosis are common symptoms in newborns 2 to 4 days after delivery, demanding thorough monitoring. Due to the breakdown of antibodies acquired from the mother, this syndrome normally resolves without complications after 3 weeks [48]. Another more significant and fatal type of congenital myasthenia can develop in some newborns. It affects the children of mothers who produce antibodies targeting fetal AChR instead of the more prevalent adult AChR. Early in the pregnancy, it causes problems with how the fetus moves, which can lead to polyhydramnios and joint damage from arthrogryposis multiplex. Premature membrane disruption can cause spontaneous preterm labour [49].

Treatment Advances

Several medicines have been linked to the progression of MG. In MG, such medicines should be taken cautiously and only when necessary. The link between drug usage and MG aggravation can be causative or coincidental. Patients with MG who are starting a new medication should always be advised about the risk of side effects, particularly MG aggravation. Patients with persistent disease and evident symptoms of bulbar or breathing impairment are more at risk. Most patients with limited disease activity or complete remission, on the other hand, will handle most of these medicines pretty well, especially when used for a short period. Various therapy advancements are discussed in further detail. 

Immunosuppressive Drugs

Immunosuppressive medicines should be initiated in individuals with MG in all divisions who do not achieve a completely desired outcome with symptomatic medication solely. To decrease autoantibody synthesis and autoantibody-induced harmful impacts at the neuromuscular junction, almost all individuals with delayed MG, thymoma MG, and MuSK-MG need immunosuppressive medication. Early-stage MG can often be treated with symptomatic treatment solely, however, the group of cases with early-onset MG need pharmaceutical immunosuppression; although, this is often only a temporary requirement. Because LRP4-MG is usually moderate, immunosuppression is rarely required. There are two therapeutic goals for ocular MG: improving manifestations (ptosis and diplopia) and preventing generalized weakness. Immunosuppression can do both [50]. Both the therapy and the detrimental consequences are dose-dependent. It's just as vital to finding the best dose of medication for each patient as it is to find the best drug. For most patients, a combination of immunosuppressive medications is desirable to maximize benefits while minimizing side effects [51]. Table 1 provides more information about immunosuppressive medications. 

Table 1. Enlist the categorization and characteristics of immunosuppressive medicines

Thymectomy

Thymectomy has been shown to have a major impact on myasthenia gravis in multiple studies. We advocate a thymectomy for initial myasthenia gravis patients shortly after symptoms start. All of the thymus tissue must be excised. Patients often prefer video-supported thoracoscopic and robotic-assisted techniques [60]. Thymectomy can be performed safely on children with myasthenia gravis up to the age of five [61]. Because both thymus follicular hyperplasia and thymoma play a significant role in pathophysiology, AChR-MG is frequently linked to thymus alterations. The significance of thymus follicular hyperplasia in sensitizing against AChR and as a reservoir of particular antibodies underpins the justification for thymectomy in individuals without thymoma [62]. Healing concerning thymectomy happens gradually over several months and can last up to two years, as per follow-up investigations [63]. After thymectomy, no additional autoimmune illnesses have been found to improve. When a thymoma is identified or highly suspected, a thymectomy must be performed as an oncological treatment to refrain from localized compression and progression to the pleural cavity. For the thymoma grouping, any beneficial impact on myasthenia gravis is much more unexpected than for the early-onset category [64]. 

Individuals with MUSK, LRP4, or ocular types of MG should avoid thymectomy because no treatment benefit has been demonstrated. Thymus hyperplasia is difficult to detect on visualizing in MG individuals with generalized MG and lesser-affinity AChR antibodies. Individuals with MG who are antibody negative are required to respond to thymectomy, but they are not discriminated against by those other individuals with MG who are not. Thymectomy must be completed as quickly as possible, but it should never be performed in a crisis; individuals should be in good health. Immediate intravenous immunoglobulin or plasma interchange before surgery will help to alleviate myasthenia gravis complaints, lower the threat of comorbidities, and speed up recovery [65].

Recent Therapies

Compliment Inhibitors

Eculizumab

Eculizumab is the earliest complement inhibitor to be approved by the FDA and put on the market. It's a humanized recombinant monoclonal antibody that attaches to the C5 complement and shields it from cleaving into C5a and C5b [66]. The phase III REGAIN trial was done in individuals with refractory, AChR antibody-positive, non-thymomatous, generalized MG after a phase II trial indicated a three-point gain in quantitative MG (QMG) ratings compared to placebo in patients with widespread myasthenia [67]. The heightened rate of contamination with Neisseria meningitides while using complement inhibitors is a big issue. Participants in the REGAIN trial were obliged to be immunized, and one non-fatal instance of meningococcal meningitis was discovered in phase III and open-label extension studies. In individuals initiating complement inhibitor medication, vaccination is suggested at least two weeks before onset and therefore should be given after 2 years [68]. 

Zilucoplan

Zilucoplan attaches to the C5 region that correlates to C5b and inhibits the formation of the terminating complementary complex by inhibiting C5 fragmentation into C5a and C5b and preventing C5b attachment to C6 [69]. It also varies from eculizumab in that it is a synthesized macrocyclic peptide that is administered subcutaneously. Zilucoplan as well as other second-generation complement inhibitors fix issues with eculizumab, such as the requirement for intravenous treatment and hereditary resistance seen in paroxysmal nocturnal hemoglobinuria (PNH), the illness for which it was first licensed [70].

Ravulizumab

Owing to an amino acid alteration in the Fc portion of eculizumab, ravulizumab is a new complement inhibitor with a greater affinity for C5 and a fast and persistent decrease in C5 [71]. Because of this structural reform, eculizumab is recycled by the newborn Fc receptor pathway and has a four-fold higher half-life over eculizumab. As a consequence, sufferers can get ravulizumab intravenously every eight weeks, as opposed to biweekly with eculizumab [72]. In generalized MG, a phase III randomized placebo-controlled multicentre research is being conducted to assess the effectiveness and safety of ravulizumab given once every 15 days.

FcRn Receptor Inhibitor

Nipocalimab

Nipocalimab (M281) is a deglycosylated monoclonal IgG1 anti-FcRn antibody that adheres to FcRn with extraordinary selectivity across both endosomal and external pH, thereby preventing IgG adherence to FcRn. It binds the FcRn receptor with great specificity all through cell growth [73]. Solo (0.3, 3, 10, 30, and 60 mg/kg) as well as repeated rising intravenous infusions (15 mg/kg or 30 mg/kg weekly) were employed in phase I investigations. With 30 or 60 mg/kg doses, Nipocalimab quickly established FcRn receptor activation and up to an 80% drop in IgG levels with no major side effects [74]. However, the data have still not been reported, Momenta has disclosed good results from a phase II trial in AChRab or MuSK- positive generalized MG to investigate the safety and quality of nipocalimumab. Its likely safety profile in expecting women is an extra advantage, and a research investigation is ongoing in expectant mothers at a greater danger of hemolytic illness of the fetus and new-born [75].

Efgartigimod

Efgartigimod is an Fc segment produced from human anti-IgG1 that has been engineered to improve Fc/FcRn interaction at physiologic and acidic pH levels, while normal IgG-FcRn adhering occurs exclusively at acidic pH. It binds to the FcRn receptor with a strong affinity, causing IgG to accumulate in lysosomes and be degraded. An individual dose of 50 mg/kg was demonstrated to minimize total IgG levels by around 50% in phase I tests, and successive treatments subsequently decreased IgG levels by an overall of 75%, with IgG levels returning to around basal values after about 8 weeks [76]. This IgG drop is equivalent to plasma swap, which results in a reduction of 73.4 percent after treatment and 38.5 percent after three weeks [77].

Rozanolixizumab

Rozanolixizumab is a humanized anti-FcRn monoclonal IgG4 antibody with a greater affinity. Animal trials indicated a significant reduction in IgG amounts when given 50 and 150 mg/kg every three days for four weeks, with the best impact on day ten. In a phase I randomized placebo-controlled trial, eligible participants were randomly assigned to receive a single intravenous or subcutaneous dose of razonolixizumab of 1, 4, or 7 mg/kg. Nausea, headache, and chills have been the most common side effects, all of which occurred significantly with intravenous therapy than with subcutaneous injection [78].

CAR- T Cell Therapy

Adoptive T cell treatment, wherein the participant's original T-cells are taken and altered ex-vivo to focus cancer cells, amplified, and afterward re-infused within the sufferer to cure specific solid organ malignancies, inspired the notion of chimeric antigen receptor T cell therapy (CART). 50 Subsequent advancements allowed T cells to be genetically engineered to generate chimeric antigen receptors (CAR), that can recognizing specific tumor cell antigens, adhere to them, and eliminate them [79]. CAR-T cell therapy is presently being used to cure B cell leukemias and lymphomas, with anti-CD 19 CAR-T cell therapy having a remarkable rate of response [80]. CAR-T cell therapy's value associated with the healing of autoimmune illnesses is both appealing and achievable. CAR-T cells, which have been engineered to contain chimeric autoantibody receptors and are used to address autoreactive B cells, hold a lot of promise [81]. Cytokine releasing syndrome (CRS), which can vary from moderate constitutional symptoms to severe CRS (cytokine storm) contributing to multi-organ failure, is a contraindication of this medication [82].

CAAR T Cell Therapy  

Chimeric autoantibody receptor T cells, or CAAR-T cells, are T cells that have been engineered to address receptors on autoreactive B cells [83]. Animal models research of autoimmune illnesses has also shown efficacy. CAAR-T cells, which are engineered to have autoantibody receptors, attach to B cells and eliminate them using the particular autoantibodies they express. This type of intervention was proven to be both harmless and successful in initial in vitro testing in an animal model employing MUSK CAAR T cells. MuSK chimeric autoantibody receptor T cells for antigen-specific cellular immunization exclusively hit B cells that produce the anti-Musk antibody on its exterior, making it extremely particular for only pathogenic B cells while leaving normal B cells alone [84].

Myasthenia Gravis Management and Treatment During Pregnancy

Gynecologists and neurosurgeons should collaborate to provide the best care for pregnant women with MG. When contrasted to anyone who has had a thymectomy, ladies who have not had a thymectomy have a greater percentage of comorbidities during gestation [85]. Moreover, babies born to thymectomy patients had a lower probability of acquiring neonatal MG. Women with MG who are contemplating a pregnancy must be encouraged to have their thymectomy beforehand [86]. The goal of medical therapy for MG is to raise ACh levels while lowering the formation of autoantibodies. Pharmacologic therapy must not be interrupted during gestation; nevertheless, based on the intensity of the condition or exacerbations, it may need to be adjusted [87, 88]. The following are some of the treatment options for myasthenia gravis during pregnancy.

Acetylcholine Esterase Inhibitors

 Pyridostigmine and neostigmine are two drugs commonly prescribed to cure MG. Since there is insufficient information on the use of acetylcholine esterase inhibitors throughout pregnancy, the research suggests that there is no elevated incidence of deformity or other negative pregnancy outcomes [89]. For individuals with minor disease signs or localized ocular symptoms, symptomatic therapy with pyridostigmine may be adequate. The fetus is unaffected by doses of less than 600 mg per day. Due to the obvious potential of uterine contractions, systemic cholinesterase inhibitors must be avoided as far as possible [90].

Corticosteroids

Prednisone and its physiologically active component, prednisolone, are extensively used in the treatment of MG [91, 92]. Women having MG who are taking corticosteroids should be notified of the enhanced danger of mouth clefts before conceiving [93]. As a result, starting corticosteroid medication after week 12 is one alternative. Immunosuppressive medication is required for patients who are not in remission or who have inadequate symptom management on pyridostigmine [94]. When administered in the first trimester, corticosteroids (prednisone) are the therapy of choice due to their minimal teratogenic risk to the fetus and just a tiny higher likelihood of cleft palate [95]. Early breaking of the membranes and gestational diabetes have been linked to higher corticosteroid dosages.

Immunoglobulins

IVIG is used to address myasthenic distress in pregnancy and to manage complaints of MG which do not resolve with corticosteroids or pyridostigmine. The efficacy of IVIG in gestation has not been studied in MG, but it has been extensively studied in other illnesses. Hyperviscosity and volume overloading, for example, maybe more prevalent during pregnancy [96].

Plasmapheresis

Plasmapheresis could potentially trigger premature labor due to substantial hormonal fluctuations. Differences in oncotic pressure can produce blood pressure oscillations, which can obstruct the passage of placental blood. When coagulation factors and IgG are removed, the probability of bleeding and contamination increases. Despite these theoretical issues, plasmapheresis has been effectively utilized in pregnant MG women and for other purposes [97].

There are, however, some medications used to treat myasthenia gravis that is prohibited during pregnancy due to potential negative effects. Table 2 lists some such medications.

Table 2. list of myasthenia gravis medicines contraindicated in pregnancy.

Conclusions and Future Perspectives

MG is caused by various distinct autoantibodies, all of which are focused on targeting proteins in the neuromuscular junction's postsynaptic membrane, causing muscle paralysis. The clinical features, reactions to symptomatic and immunoreactive medication, and MG etiology differ among MG subgroups based on the autoantibody trend. The main well-known antigen candidates for symptom-generating antibodies found till now are AChR, MuSK, and LRP4. Absolute antibody quantity is less relevant than epitope precision and antibody properties in determining illness severity. Every individual MG therapy should be tailored to their specific needs. When it comes to pharmacotherapy, proper MG subgrouping is a must. Such subgrouping is based on autoantibody type, onset age, thymus pathology, and the level of muscle weakness. Symptomatic and immunosuppressive medicines, as well as supportive treatments and, in certain cases, thymectomy, are used to treat the condition. To tailor medication to the exact symptoms and minimize further exacerbations, specialized follow-up is required. Target-specific immunomodulation is becoming more common in the management of MG. Several medicines from diverse pharmacological families, such as complement inhibitors, FcRn receptor blockers, direct and indirect B cell inhibitors, and CAR-T cell therapy, have been demonstrated to be effective and safe in clinical testing or are in several stages of research. In reality, mab, a complement inhibitor, has already received universal regulatory clearance for administration in AChR-Ab positive, refractory MG. Numerous medicines show great potential in the mass of MG sufferers, but present trial models and inclusion/exclusion criteria leave gaps in their use in diverse MG subsets such as ocular and seronegative MG. Additionally, there is a scarcity of information on how to start, stop, or switch therapy, as well as potential drug-drug interactions. There is no confirmation that MG harms pregnancy complications, and most symptom-controlling drugs tend to be quite safe during pregnancy. Even though MG does not influence fertility in and of itself, immunosuppressive drugs often used in MG do. Interactions concerning fertility and pregnancy planning between a woman with MG and her neurologist must start early, such as when considering an immunosuppressive drug. Methotrexate and mycophenolate mofetil are prohibited in women who are trying to conceive and therefore should be stopped three months and six weeks before conception, respectively. Azathioprine and corticosteroids are still being used because they don't appear to have any effect on fertility. If a patient wants to get pregnant but hasn't undergone a thymectomy yet, it's a good idea to consider it to improve illness control. Rising knowledge of MG as potential harm for pregnancy really shouldn't hinder MG patients from becoming parents, but rather encourage doctors and specialists to work more closely with gynecologists and pediatricians to optimize MG therapy and reduce risks.

Acknowledgments: I would like to express my sincere gratitude to the pharmacy department at Pranveer Singh institute of technology for giving me the chance to write this review article.

Conflict of interest: None

Financial support: None

Ethics statement: All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content.

1.        Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012;69(4):445-51.

2.        Nacu A, Andersen JB, Lisnic V, Owe JF, Gilhus NE. Complicating autoimmune diseases in myasthenia gravis: a review. Autoimmunity. 2015;48(6):362-8.

3.        Kubiszewska J, Szyluk B, Szczudlik P, Bartoszewicz Z, Dutkiewicz M, Bielecki M, et al. Prevalence and impact of autoimmune thyroid disease on myasthenia gravis course. Brain Behav. 2016;6(10):e00537.

4.        Andersen JB, Heldal AT, Engeland A, Gilhus NE. Myasthenia gravis epidemiology in a national cohort; combining multiple disease registries. Acta Neurol Scand. 2014;129:26-31.

5.        Alkhawajah NM, Oger J. Late‐onset myasthenia gravis: a review when incidence in older adults keeps increasing. Muscle Nerve. 2013;48(5):705-10.

6.        Håkansson I, Sandstedt A, Lundin F, Askmark H, Pirskanen R, Carlson K, et al. Successful autologous hematopoietic stem cell transplantation for refractory myasthenia gravis–a case report. Neuromuscul Disord. 2017;27(1):90-3.

7.        Mao ZF, Yang LX, Mo XA, Qin C, Lai YR, He NY, et al. Frequency of autoimmune diseases in myasthenia gravis: a systematic review.  Int J Neurosci. 2011;121(3):121-9.

8.        Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8(5):475-99.

9.        Querol L, Illa I. Myasthenia and the neuromuscular junction. Curr Opin Neurol. 2013:26(5):459-65.

10.     Zisimopoulou P, Brenner T, Trakas N, Tzartos SJ. Serological diagnostics in myasthenia gravis based on novel assays and are recently identified as antigens. Autoimmun Rev. 2013;12(9):924-30.

11.     Changeux JP. The nicotinic acetylcholine receptor: the founding father of the pentameric ligand-gated ion channel superfamily. J Biol Chem. 2012;287(48):40207-15.

12.     Sheikh S, Alvi U, Soliven B, Rezania K. Drugs that induce or cause deterioration of myasthenia gravis: an update. J Clin Med. 2021;10(7):1537.

13.     Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res. 2016;5.

14.     Wong SH, Huda S, Vincent A, Plant GT. Ocular myasthenia gravis: controversies and updates. Curr Neurol Neurosci Rep. 2014;14(1):1-0.

15.     Heldal AT, Eide GE, Romi F, Owe JF, Gilhus NE. Repeated acetylcholine receptor antibody-concentrations and association to clinical myasthenia gravis development. PLoS One. 2014;9(12):e114060.

16.     Mohan N, Nelson-Piercy C. Neurological disease in pregnancy. Obstet Gynaecol Reprod Med. 2022;32(1):14-9.

17.     Anil R, Kumar A, Alaparthi S, Sharma A, Nye JL, Roy B, et al. Exploring outcomes and characteristics of myasthenia gravis: rationale, aims and design of registry–the EXPLORE-MG registry. J Neurol Sci. 2020;414:116830.

18.     Hendricks TM, Bhatti MT, Hodge DO, Chen JJ. Incidence, epidemiology, and transformation of ocular myasthenia gravis: a population-based study. Am J Ophthalmol. 2019;205:99-105.

19.     Chimedregzen O, Jambal S, Rentsenbat M, Dagvajantsan B. Incidence and clinical feature of Myasthenia gravis: A five-year data analysis in Ulaanbaatar, Mongolia. Neurosci. Res. 2021;4(3Suppl):47-54.

20.     Pedersen EG, Hallas J, Hansen K, Jensen PE, Gaist D. Late‐onset myasthenia not on the increase: a nationwide register study in D enmark, 1996–2009. Eur J Neurol. 2013;20(2):309-14.

21.     VanderPluym J, Vajsar J, Jacob FD, Mah JK, Grenier D, Kolski H. Clinical characteristics of pediatric myasthenia: a surveillance study. Pediatrics. 2013;132(4):e939-44.

22.     Khan AA, Khan MW, Kundi TA, Khan AW, Ali-Qazalbash ZM. A Diagnostic Dilemma of Dysphonia: A Case Report on Laryngeal Myasthenia Gravis. Cureus. 2021;13(8).

23.     Nakamura Y, Sato H, Miyano Y, Murakami R, Motoki M, Shigekiyo T, et al. Whole-exome sequencing and human leukocyte antigen analysis in familial myasthenia gravis with thymoma: Case report and literature review. Clin Neurol Neurosurg. 2021;208:106864.

24.     Renton AE, Pliner HA, Provenzano C, Evoli A, Ricciardi R, Nalls MA, et al. A genome-wide association study of myasthenia gravis. JAMA Neurol. 2015;72(4):396-404.

25.     Klein R, Marx A, Ströbel P, Schalke B, Nix W, Willcox N. Autoimmune associations and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis. Hum Immunol. 2013;74(9):1184-93.

26.     Mihailescu N, Haskoylu ME, Ristoscu C, Bostan MS, Sopronyi M, Eroğlu MS, et al. Gradient multifunctional biopolymer thin-film assemblies synthesized by combinatorial MAPLE. Appl Surf Sci. 2019;466:628-36.

27.     Nikolic AV, Andric ZP, Simonovic RB, Rakocevic Stojanovic VM, Basta IZ, Bojic SD, et al. High frequency of DQB 1 05 and absolute absence of DRB 1 13 in muscle‐specific tyrosine kinase positive myasthenia gravis. Eur J Neurol. 2015;22(1):59-63.

28.     Lazaridis K, Tzartos SJ. Autoantibody specificities in myasthenia gravis; implications for improved diagnostics and therapeutics. Front Immunol. 2020;11:212.

29.     Verschuuren JJ, Huijbers MG, Plomp JJ, Niks EH, Molenaar PC, Martinez-Martinez P, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmune Rev. 2013;12(9):918-23.

30.     Gilhus NE. Myasthenia and the neuromuscular junction. Curr Opin Neurol. 2012;25(5):523-9.

31.     Kordas G, Lagoumintzis G, Sideris S, Poulas K, Tzartos SJ. Direct proof of the in vivo pathogenic role of the AChR autoantibodies from myasthenia gravis patients. PLoS One. 2014;9(9):e108327.

32.     Shao K, Yue YX, Zhao LM, Hao HJ, Ding XJ, Jiang P, et al. Optimization of the cut-offs in acetylcholine receptor antibodies and diagnostic performance in myasthenia gravis patients. Clin Chim Acta. 20221;533:122-30.

33.     Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population-based epidemiological studies in Myasthenia Gravis. BMC Neurol. 2010;10(1):1-9.

34.     Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol. 2011;69(2):418-22.

35.     Salari N, Fatahi B, Bartina Y, Kazeminia M, Fatahian R, Mohammadi P, et al. Global prevalence of myasthenia gravis and the effectiveness of common drugs in its treatment: a systematic review and meta-analysis. J Transl Med. 2021;19(1):1-23.

36.     Hantaï D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Cur Opin Neurol. 2004;17(5):539-51.

37.     Waters J. Management of myasthenia gravis in pregnancy. Neurol Clin. 2019;37(1):113-20.

38.     Grover KM, Sripathi N. Myasthenia gravis and pregnancy. Muscle Nerve. 2020;62(6):664-72.

39.     Coté JJ, Granger P, Mishra A, Sorini G. COVID-19 in a pregnant cystic fibrosis carrier with myasthenia gravis: A case report. Case Rep Womens Health. 2022;34:e00406.

40.     Iijima S. Clinical and pathophysiologic relevance of autoantibodies in neonatal myasthenia gravis. Pediatr Neonatol. 2021;62(6):581-90.

41.     Varner M. Myasthenia gravis and pregnancy. Clin Obstet Gynecol. 2013;56(2):37281.

42.     Drachman D. Myasthenia gravis. N Engl J Med. 1994;330:1797-810.

43.     Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2:44.

44.     Srivastava S, Tandon M, Kataria S, Daimee M, Sultan S. New onset of ocular myasthenia gravis in a patient with COVID-19: a novel case report and literature review. J Neurol. 2021;268(8):2690-6.

45.     Pasnoor M, Dimachkie MM, Farmakidis C, Barohn RJ. Diagnosis of myasthenia gravis. Neurol Clin. 2018;36(2):261-74.

46.     Newsom-Davis J. The emerging diversity of neuromuscular junction disorders. Acta Myologica. 2007;26(1):5-10.

47.     Bacchi S, Kramer P, Chalk C. Autoantibodies to low-density lipoprotein receptor-related protein 4 in double seronegative myasthenia gravis: a systematic review. Can J Neurosci Nurs. 2018;45(1):62-7.

48.     Frykman H, Kumar P, Oger J. Immunopathology of autoimmune myasthenia gravis: implications for improved testing algorithms and treatment strategies. Front Neurol. 2020;11:596621.

49.     Gilhus NE. Myasthenia gravis can have consequences for pregnancy and the developing child. Front Neurol. 2020;11:554.

50.     Kerty EF, Elsais A, Argov Z, Evoli A, Gilhus NE. EFNS/ENS Guidelines for the treatment of ocular myasthenia. Eur J Neurol. 2014;21(5):687-93.

51.     Giglio D, Berntsson H, Fred Å, Ny L. Immune Checkpoint Inhibitor-Induced Polymyositis and Myasthenia Gravis with Fatal Outcome. Case Rep Oncol. 2020;13(3):1252-7.

52.     Fortin E, Cestari DM, Weinberg DH. Ocular myasthenia gravis: an update on diagnosis and treatment. Curr Opin Ophthalmol. 2018;29(6):477-84.

53.     Benatar M, Sanders DB, Wolfe GI, McDermott MP, Tawil R. Design of the efficacy of prednisone in the treatment of ocular myasthenia (EPITOME) trial. Ann N Y Acad Sci. 2012;1275(1):17-22.

54.     The Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology. 2008;71(6):394-9.

55.     Hehir MK, Burns TM, Alpers J, Conaway MR, Sawa M, Sanders DB. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis; outcomes in 102 patients. Muscle Nerve. 2010;41(5):593-8.

56.     Iorio R, Damato V, Alboini PE, Evoli A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol. 2015;262(5):1115-9.

57.     Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis—autoantibody characteristics and their implications for therapy. Nat Rev Neurol. 2016;12(5):259-68.

58.     Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med. 2013;86(2):255-60.

59.     Jacob S, Viega S, Leite MI. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol. 2012;69(8):994-1001.

60.     Gronseth GH, Barohn RJ. Thymectomy for autoimmune myasthenia gravis (an evidence-based review). Neurology. 2000;55(1):7-15.

61.     Cea G, Benatar M, Verdugo RJ, Salinas RA. Thymectomy for nonthymomatous myasthenia gravis. Cochrane Database Syst Rev. 2013;cd008111.

62.     Ye B, Tantai JC, Li W, Ge XX, Feng J, Cheng M. Video-assisted thoracoscopic surgery versus robotic-assisted thoracoscopic surgery in the surgical treatment of Masaoka stage I thymoma. World J Surg Oncol. 2013;11(1):157-62.

63.     Liew WKM, Kang PB. Update on juvenile myasthenia gravis. Curr Opin Pediatr. 2013;25(6):694-700.

64.     Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14(10):1023-36.

65.     Ng WC, Hartley L. Effectiveness of thymectomy in juvenile myasthenia gravis and clinical characteristics associated with better outcomes. Neuromuscul Disord. 2021;31(11):1113-23.

66.     Wisma KL, Ter Heine R, Moes DJ, Langemeijer S, Schols SE, Volokhina E, et al. Pharmacology, pharmacokinetics and pharmacodynamics of eculizumab, and possibilities for an individualized approach to eculizumab. Clin Pharmacokinet. 2019;58(7):859-74.

67.     Howard Jr JF, Barohn RJ, Cutter GR, Freimer M, Juel VC, Mozaffar T et al. A randomized, double‐blind, placebo‐controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve.   2013;48(1):76-84.

68.     Howard Jr JF, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (REGAIN): a phase 3, randomized, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976-86.

69.     Howard Jr JF, Vissing J, Gilhus NE, Leite MI, Utsugisawa K, Duda PW, et al. Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody–Positive Generalized Myasthenia Gravis. Expert Opin Investig Drugs. 2021;30(5):483-93.

70.     Fattizzo B, Kulasekararaj AG. Second-generation C5 inhibitors for paroxysmal nocturnal hemoglobinuria. BioDrugs. 2020;34(2):149-58.

71.     Sheridan D, Yu ZX, Zhang Y, Patel R, Sun F, Lasaro MA, et al. Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action. PloS one. 2018;13(4):e0195909.

72.     Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor–experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540-9.

73.     Benamu E. Infectious risks associated with biologics targeting janus kinase-signal transducer and activator of transcription signaling and complement pathway for inflammatory diseases. Infect Dis Clin North Am. 2020;34(2):271-310.

74.     Gamble KL, Guptill JT. Antagonism of the neonatal Fc receptor as an emerging treatment for myasthenia gravis. Front Immunol. 2020;10:3052.

75.     Ling LE, Hillson JL, Tiessen RG, Bosje T, van Iersel MP, Nix DJ, et al. M281, an anti‐FcRn antibody: pharmacodynamics, pharmacokinetics, and safety across the full range of IgG reduction in a first‐in‐human study. Clin Pharmacol Ther. 2019;105(4):1031-9.

76.     Ulrichts P, Guglietta A, Dreier T, van Bragt T, Hanssens V, Hofman E, et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. 2018;128(10):4372-86.

77.     Guptill JT, Juel VC, Massey JM, Anderson AC, Chopra M, Yi JS, et al. Effect of therapeutic plasma exchange on immunoglobulins in myasthenia gravis. Autoimmunity. 2016;49(7):472-9.

78.     Kiessling P, Lledo-Garcia R, Watanabe S, Langdon G, Tran D, Bari M, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017;9(414):eaan1208.

79.     Miliotou AN, Papadopoulou LC. CAR T-cell therapy: a new era in cancer immunotherapy. Curr Pharm Biotechnol. 2018;19(1):5-18. 

80.     Chen Y, Sun J, Liu H, Yin G, Xie Q. Immunotherapy deriving from CAR-T cell treatment in autoimmune diseases. J Immunol Res. 2019;2019.

81.     Zhang C, Liu J, Zhong JF, Zhang X. Engineering CAR-T cells. Biomark Res. 2017;5(1):22. 

82.     Maldini CR, Ellis GI, Riley JL. CAR T cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol.  2018;18(10):605-16.

83.     Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther-Oncolytics. 2016;3:16011.

84.     Haddadi MH, Hajizadeh-Saffar E, Khosravi-Maharlooei M, Basiri M, Negahdari B, Baharvand H. Autoimmunity as a target for chimeric immune receptor therapy: a new vision to therapeutic potential. Blood Rev. 2020;41:100645.

85.     Albrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353(6295):179-84.

86.     Vincent SC, Arulappan J, Prabhakaran H, Al Hasani WS. Nursing Care of a Women with Myasthenia Gravis During Pregnancy− A Case Report. Int J Nutr Pharmacol Neurol Dis. 2020;10(4):235.

87.     Alharbi M, Menon D, Barnett C, Katzberg H, Sermer M, Bril V. Myasthenia gravis and pregnancy: Toronto specialty center experience. Can J Neurol Sci. 2021;48(6):767-71.

88.     Menon D, Barnett C, Bril V. Novel treatments in myasthenia gravis. Front Neurol. 2020;11:538.

89.     Hoff JM, Daltveit AK, Gilhus NE. Myasthenia gravis in pregnancy and birth: identifying risk factors, optimizing care. Eur J Neurol. 2007;14(1):38-43.

90.     Gilhus NE, Owe JF, Hoff JM, Romi F, Skeie GO, Aarli JA. Myasthenia gravis: a review of available treatment approaches. Autoimmune Dis. 2011;2011:847393.

91.     Ferrero S, Esposito F, Biamonti M, Bentivoglio G, Ragni N. Myasthenia gravis during pregnancy. Expert Rev Neurother. 2008;8(6):979-88.

92.     Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87(4):419-25.

93.     Briggs G, Freeman R, Yaffe S. Drugs in pregnancy and lactation. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

94.     Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 2000;62(6):385-92.

95.     Ciafaloni E, Massey JM. Myasthenia gravis and pregnancy. Neurol Clin. 2004;22(4):771-82.

96.     Feasby T, Banwell B, Benstead T, Bril V, Brouwers M, Freedman M, et al. Guidelines on the use of intravenous immuneglobulin for neurologic conditions. Transfus Med Rev. 2007;21(2 Suppl 1):S57-107.

97.     Marson P, Gervasi MT, Tison T, Colpo A, De Silvestro G. Therapeutic apheresis in pregnancy: general considerations and current practice. Transfus Apher Sci. 2015;53(3):256-61.

98.     Hamel J, Ciafaloni E. An update: myasthenia gravis and pregnancy. Neurol Clin. 2018;36(2):355-65.

99.     Skorpen CG, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75(5):795-810.

100.  Bansal R, Goyal MK, Modi M. Management of myasthenia gravis during pregnancy. Indian J Pharmacol. 2018;50(6):302.