NCN 2021 ｜Interview with Professor Lu Jiahong and Yang Huan: Diagnosis points, treatment dilemmas and new hopes of myasthenia gravis

Myasthenia gravis (Myasthenia Gravis, MG) is an autoimmune disease caused by the transmission dysfunction of the nerve-muscle junction, and it is also a rare disease
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The main points of diagnosis, differential diagnosis, therapeutic drugs and drug research progress of MG are all issues that clinicians pay attention to
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At the 24th National Conference on Neurology (NCN 2021) held from September 23 to 26, the special report hosted by Professor Lu Jiahong of Huashan Hospital Affiliated to Fudan University and Professor Yang Huan from Xiangya Hospital of Central South University The progress of MG treatment was presented wonderfully.
Yimaitong was also fortunate to interview the two professors after the meeting to answer the questions that the doctors were concerned about
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Expert profile Professor Lu Jiahong, chief physician, doctoral supervisor, and deputy director of the Department of Neurology, Huashan Hospital Affiliated to Fudan University Member, Member of the Academic Expert Committee of the National Training Center for Neuromuscular Diseases, Director of the National Training Center for Neuromuscular Diseases Professor of Neurology, Chief Physician, Doctor of Medicine, Doctoral Supervisor, and Director of Neuroimmunology and Neuromyopathy Subspecialty, Department of Neurology, Xiangya Hospital, Central South University
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He is currently a member of the Neuromyopathy Group of the Neurology Branch of the Chinese Medical Association, a member of the Peripheral Neuropathy Collaboration Group, the executive director of the Hunan Immunological Society, the chairman of the Neuroimmune Branch, the executive director of the Hunan Rehabilitation Medicine Association, the Hunan Rehabilitation Medicine Association Myopathy and Peripheral Chairman of the Professional Committee of Neurology, Member of the Professional Committee of Neurology of Hunan Province, Leader of the Neuroimmunology Group, Member of the Standing Committee of the Hunan Society of Rare Diseases, Member of the Standing Committee of the New Technology Professional Committee of the Hunan Medical Education Science and Technology Society, and the professional technical review of the Neurology Department of Hunan Province Group expert; editorial board member of "Chinese Journal of Neurology", "Chinese Journal of General Practitioners", "Journal of Modern Medicine", and associate editor of SCI journal "Journal of Neuroimmunology"
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Obtained projects including 6 National Natural Science Funds, 1 "New Century Excellent Talent Fund of the Ministry of Education", and 2 Natural Science Funds of Hunan Province
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Participated in the formulation of the US NIH "Guidelines for Preclinical Testing Standards for Myasthenia Gravis"
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There are more than 60 papers by the first or corresponding author, including more than 30 by SCI journals such as JCI and JI
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Participated in the compilation of 5 monographs and teaching materials
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Diagnosis and Differential Diagnosis of MG As a rare and treatable neurological disease, MG has a more complicated clinical manifestation and may be similar to a variety of neuromuscular diseases, making the differential diagnosis challenging
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The accurate diagnosis of MG has a guiding role for subsequent individualized treatment and prognostic evaluation, so mastering the differential diagnosis of MG plays an important role
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Professor Lu Jiahong said that although the clinical manifestations of MG are extremely heterogeneous and can affect the whole body of skeletal muscles, its most important feature is fluctuating muscle weakness, and the symptoms are "light in the morning and heavy in the evening"
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For example, the most common ocular muscle type MG, its symptoms can be manifested as fluctuations during the day, that is, the cleft eye is relatively large in the morning, and worsens in the afternoon and evening; it can also be manifested as a drooping right eyelid for a period of time, and a drooping left eyelid after a period of time.
We call it "alternative ptosis"
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In the whole course of the disease, it can also be fluctuating.
For example, the symptoms are severe for a period of time, medication or self-improvement, and after a period of time, the symptoms become worse due to hormone reduction, or colds, fatigue and other inducements
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In terms of differential diagnosis, the ocular muscle type in MG is more common and needs to be distinguished from chronic progressive extraocular muscle palsy (CPEO), blepharospasm, and senile blepharoptosis.
External muscle paralysis
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The biggest difference between it and ocular muscle myasthenia gravis is that CPEO has a chronic progressive course without obvious volatility, electrophysiological examination shows myogenic damage, and low-frequency repetitive electrical stimulation is negative
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CPEO belongs to mitochondrial encephalomyopathy, so muscle biopsy and genetic examination can help confirm the diagnosis
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➤Blephalic spasm: There are two types of eye cracks, one is caused by contraction of the orbicularis oculi muscle, and the other is caused by ptosis
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Blephar spasm is the spontaneous excessive contraction of the orbicularis oculi muscle, which is often mistaken for ptosis
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It can be distinguished by observing the eyebrows.
When the eyelids are drooping, the eyebrows want to be lifted, and when the eyelid spasm, the eyebrows are often frowned
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➤Ptosis of the senile: caused by weakness of the levator muscles, ptosis may occur
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➤ bulbar muscle involvement-based MG and motor neuron disease differentiated: bulbar paralysis of motor neuron disease to bulbar onset muscle weakness, manifested as dysphagia, dysarthria and so on
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The difference between the two is that MG is fluctuating, and bulbar palsy of motor neuron disease progresses slowly
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Electromyography helps to distinguish between the two
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In addition, the positive rate of MG antibody for systemic myasthenia gravis is relatively high (80%-90%)
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➤Other limb weakness needs to be distinguished from inflammatory myopathy: MG needs to be distinguished from acute inflammatory demyelinating polyneuropathy when the onset of the disease is rapid
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Challenges and difficulties in the field of MG treatment At present, MG patients have a variety of treatment options, including cholinesterase inhibitors, glucocorticoids, immunosuppressants, intravenous immunoglobulin (IVIG), plasma exchange (PE), etc.
However, these treatment options still have certain limitations
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And compared with the United States, the proportion of Chinese patients using immunosuppressive therapy is lower, and the overall quality of life is worse
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All this shows that China's MG treatment still faces many challenges and difficulties
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Regarding the many challenges and difficulties faced by domestic MG treatment, Professor Lu Jiahong believes that there are many drugs that can be used to treat MG.
Among them, the cholinesterase inhibitor brombistigmine is a classic symptomatic treatment drug, but it is Treating the symptoms does not cure the root cause, and it cannot meet the treatment needs of systemic patients
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Glucocorticoids have many side effects, including weight gain, increased blood sugar, high blood pressure, osteoporosis, and neuropsychiatric disorders
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In addition, glucocorticoids can also increase the risk of worsening the condition
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The therapeutic effects of tacrolimus, rituximab, gamma globulin, and PE are relatively good, but they are expensive, have low patient accessibility, and each drug may have specific side effects or drug intolerance.
Moreover, treatment methods such as PE that require blood products cannot be implemented in many hospitals due to limited sources
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Therefore, we hope that there will be more safer, more effective and more economical drugs to treat MG
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Later, Professor Yang Huan also said that there are indeed many difficulties in the selection of MG treatment, among which effectiveness, safety and accessibility are the main problems at present
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It believes that four aspects need to be considered when choosing drugs, namely safety, effectiveness, accessibility, and economy
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But at present, there are very few drugs that can meet these needs at the same time, so I still hope that there will be more drug choices based on the existing drugs.
Of course, if there is a treatment method that can meet the above four needs at the same time, it is the best.
Okay
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Potentially effective treatment options for patients with refractory MG-unmet treatment needs.
For most MG patients, under the condition of standardized treatment, the use of existing treatment drugs can meet their treatment needs to a certain extent
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However, there are still some patients with poor response to traditional immunosuppressive drugs, or hormone resistance, or drug intolerance.
Such refractory patients have a poor prognosis and there is currently no ideal treatment strategy
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Professor Lu Jiahong said that although immunosuppressants are often used to treat MG patients, 15%-20% of patients still have poor treatment results, which are refractory MG
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For some patients with sudden worsening of myasthenia crisis and respiratory failure, they need to use treatments that can quickly improve their symptoms in a short period of time, such as PE, gamma bulb, and rituximab
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However, as mentioned above, these treatments have problems such as low accessibility, high price and patient intolerance, so it is still hoped that more drugs will appear to solve these problems
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In this regard, Professor Yang Huan added that there is currently no uniform standard for refractory MG.
Based on existing research evidence, China’s guidelines define it as: traditional glucocorticoids or at least two immunosuppressive agents (in sufficient amounts, Foot treatment) The treatment is ineffective, and the state is unchanged or worse after intervention; cannot tolerate the side effects of immunosuppressive agents or has contraindications to the use of immunosuppressants, and needs to be given IVIG or PE repeatedly to relieve the condition; or myasthenia is recurring during the course of the disease elephant
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The point that needs to be emphasized here is that only when the standardized treatment is ineffective or the effect is not good, it can be regarded as a refractory patient
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So for these patients, hormones and immunosuppressive agents may not be the best treatment methods, and IVIG or PE treatment should be selected when conditions permit
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Dawn-FcRn antagonist efgartigimod will be used to treat adult systemic MG.
In recent years, new therapeutic targets based on MG immunopathogenesis have continued to emerge.
Among them, targeting neonatal Fc receptors (FcRn) is a popular research direction.
Therapeutic drugs targeting this are constantly being developed
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Among them, efgartigimod took the lead in completing the global multi-center phase III clinical trial (ADAPT study), and published the research results in the "Lancet Neurology" in June this year, bringing hope to patients with systemic MG and severe MG
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Its experimental design is also instructive for the subsequent development of MG treatment drugs
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Professor Yang Huan said that the results of the ADAPT study showed that compared with the placebo group, efgartigimod treatment of adult systemic MG patients can effectively improve their clinical symptoms and quality of life, and is well tolerated
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This makes many doctors who pay attention to MG feel very excited and feel that they are very bright
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This brings hope to some refractory MG patients who need to clear antibodies quickly
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At the same time, the research also gave us a lot of inspiration for how to conduct clinical research on MG, how to conduct research design, and how to evaluate a new drug: ➤First, the drug has a unique mechanism of action
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MG is an autoimmune disease mediated by antibodies, dependent on cellular immunity and complement participation
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The main mechanism may be that under the effects of genetic susceptibility and molecular simulation, T cells specifically recognize the antigen-presenting cell (APC)-MHC class II molecule-polypeptide complex, leading to the up-regulation of IL-6 and other cytokines, which in turn activates B cells Produce acetylcholine receptor antibody (AChR-Ab)
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After the combination of AChR-Ab and AChR, with the participation of complement, the signal transmission obstacle of nerve and muscle is caused
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In recent years, new therapeutic targets based on the immune pathogenesis of MG have continued to emerge
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Targeted B cell drugs can deplete B cells and reduce or eliminate MG patient-specific autoantibodies
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Complement inhibitors can inhibit the activation of C3 and C5
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Drugs targeting cytokines can inhibit the upregulation of cytokines
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Targeting T cells can inhibit the production of specific autoantibodies or prevent T cells from reactivating
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What is worth paying attention to is the new target FcRn, which can transport and recycle immunoglobulin G (IgG), avoid IgG degradation and extend its half-life
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FcRn antagonists bind to FcRn to block the IgG circulation, and can specifically and efficiently target and eliminate IgG antibodies
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In the clinical practice of MG, some patients with myasthenia crisis need to take emergency measures to quickly eliminate antibodies.
As an FcRn antagonist, efgartigimod can replace plasma exchange and other methods to quickly eliminate antibodies
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Although the ADAPT study included patients with systemic MG, not patients with myasthenia crisis (this part of the clinical study is difficult to obtain ethical approval), it can be used to treat patients with refractory MG from the perspective of its mechanism of action
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➤Secondly, the experimental design is rigorous and the evaluation indicators are more comprehensive
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The ADAPT study comprehensively observed various indicators for evaluating the efficacy of MG treatment, including myasthenia gravis activity of daily living scale (MG-ADL) score, myasthenia gravis quantitative score (QMG), QoL score and so on
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Among them, the primary endpoint of the study is to assess the proportion of patients with MG-ADL response in AChR-Ab-positive patients after the first treatment cycle (8 weeks).
The secondary endpoints include the assessment of AChR-Ab after the first treatment cycle.
The proportion of patients who achieved QMG response among positive patients and the proportion of patients who achieved MG-ADL response among all patients
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MG-ADL is a self-rating scale for the quality of life of patients with myasthenia gravis, and QMG is a doctor's assessment scale.
The combination of the two can make up for the shortcomings
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In addition, the study also involves biological indicators, such as the observation of total IgG and IgG subtypes, we can judge whether a drug has rebound phenomenon from the change level of IgG
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Judging from the results of this study, there is no rebound phenomenon for this drug
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➤Finally, the design of statistical methods is also very comprehensive, from the effectiveness of the drug, the intensity of the effect, the onset time, the maintenance time, and the percentage of the score improvement stratification
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These are what clinicians want to know about a new drug, and they are also important indicators for evaluating whether a new drug can effectively treat MG
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In short, MG is a rare disease with complex clinical manifestations and needs to be differentiated from a variety of neuromuscular diseases
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At the time of diagnosis, pay attention to observe whether the patient has the characteristics of fluctuating myasthenia, and make judgments in conjunction with auxiliary examinations such as electrophysiology and antibodies
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In terms of treatment, there are currently more drugs to choose from, but they all have certain limitations.
There is an urgent need for more safe, effective, and economically feasible drugs to solve the unmet treatment needs of patients
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Finally, the release of the world's first phase III clinical study of the FcRn antagonist efgartigimod brings hope to patients, and its research design also brings enlightenment to the research and development of MG drugs.
At the same time, it is hoped that this drug will be approved for marketing in China as soon as possible
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