Treatment of myasthenia gravis (MG) is individualized according to clinical presentation and subtype in order to restore function as soon as possible and minimize adverse effects. The treatment of MG includes cholinesterase inhibitors to improve symptoms, glucocorticoids (“hormones”), azathioprine, cyclosporine, tacrolimus (FK506) and other immunosuppressants, cyclophosphamide (CTX) for refractory MG, and rituximab. The drugs such as plasma exchange (PE) and intravenous immunogIobulin (IVlg) are also used for myasthenia gravis and thymectomy.
1.Cholinesterase inhibitors
Cholinesterase inhibitors are the first-line treatment for MG. Oral administration of these drugs can increase the amount of acetylcholine (ACh) in the synaptic gap of the neuromuscular junction (NMJ). Cholinesterase inhibitors do not affect the disease process. Only in rare cases can sustained, complete remission of MG symptoms be achieved. The drug alone is sufficient to relieve symptoms in patients with non-progressive mild and simple oculomotor forms.
The most commonly used drug is bromipyridamole. The starting dose for adults is usually 15-30 mg/(4-6) h. The dose is gradually increased to the optimal effective dose. Patients with medullary palsy can take the drug 30-60 min before meals. A total daily dose of more than 450 mg of bromipyridamole may lead to increased muscle weakness due to depolarization block of neuromuscular transmission. Patients with renal failure may experience increased muscle weakness at doses below this level. Overdose of these drugs often results in symptoms such as excessive salivation, bradycardia, excessive sweating, lacrimation, pupil narrowing and other toxoplasma-like symptoms.
2.Immunotherapy
(1) Short-term immunotherapy: plasma exchange therapy (PE) and high-dose immunoglobulin (IVIg) are commonly used in the short-term treatment of MG exacerbation and rapid improvement of symptoms.
PE reduces the level of anti-acetylcholine receptor (AChR) antibodies in the peripheral circulation and promotes the dissociation of antibodies bound to NMJ. It can improve the symptoms of most MG patients (including those with severe MG) within a few days, but the effect lasts only a few weeks. A single dose of PE replacement fluid is usually performed at l to 2 times the plasma volume, once every other day, for a total of 4 to 6 times. common adverse effects of PE include hypotension, hypocalcemia due to citrate, venipuncture-related infections and thrombosis, and other complications. Repeated PE treatment can also reduce coagulation factors in peripheral blood leading to bleeding tendencies.
Immunosorbent columns with immobilized AChR as adsorbent can also remove anti-AChR antibodies, and this technique has the potential to be a safe and effective alternative to PE.
IVlg is widely used in patients with exacerbated or worsening MG symptoms, and the dose of gammaglobulin is 1 to 2 g/(kg・d) by body mass. Randomized controlled trials have shown that IVIg has similar efficacy to PE, and both doses of 1 g/kg and 2 g/kg are equally effective. The mechanism of action of IVIg therapy is still unclear and may be related to the competition of autoantibodies for the binding site of Fc receptors. The disadvantage of this treatment is that it requires a large amount of highly viscous fluid infusion and is more expensive.
(2) Hormones: Hormones were the first immunosuppressive drugs used in the treatment of MG. It is still the most commonly used therapy. They are usually used in patients whose symptoms do not improve adequately with cholinesterase inhibitors alone. Previous studies have shown that. Most patients with significant improvement or remission of symptoms after treatment with various doses of hormones. About 1/3 of patients experience a transient exacerbation of symptoms within the first 7 to lO d of prednisone treatment that lasts for several days. Once symptoms improve, hormone-induced exacerbations rarely occur again.
Furthermore, hormones may delay or reduce the progression of oculomotor MG to systemic MG. Patients with mild MG are usually treated with cholinesterase inhibitors. Those with pharyngeal or respiratory muscle involvement may receive PE or IVIg prior to prednisone therapy to block or slow the progression of exacerbations and to allow for rapid drug onset. Generally, high-dose shock therapy is given at the beginning: 0.75-1.0 mg/(kg・d) of prednisone by body mass. The dose is then gradually reduced or maintained at a low dose for several years.
Hormone therapy can also be used in small dose increments, i.e., the starting dose of prednisone is 10-25 mg every other day, gradually increasing to 60-100 mg every other day, and then gradually reducing the dose after achieving maximum efficacy. For patients with oculomotor MG, prednisone can be given at 20 mg/d and increased by 5-10 mg every 3 days until symptoms improve, with an average dosage of 20-40 mg/d. Because hormone therapy requires long-term use, it is important to be alert to its adverse effects. Common adverse effects and complications of hormone therapy include: sodium and water retention, obesity, potassium loss, hypertension, abnormal glucose tolerance, osteoporosis, psychosis, anxiety, and other complications. Osteoporosis, psychiatric disorders, anxiety, cataracts, glaucoma.
Steroid myopathy and growth inhibition, etc.
(3) Non-hormonal immunosuppressants.
(1) Azathioprine: This drug can interfere with T and B cell proliferation, and can be used alone or as an alternative to hormone reduction, generally with a starting dose of 50 mg/d, increasing by 50 mg per week to 2-3 mg/(kg・d) by body mass. When combined with prednisone, its efficacy and tolerability can be improved. Retrospective studies have shown that azathioprine is effective in 70% to 90% of patients with MG. However, the onset of action may be slow. It takes effect at 12 months of use.
About 15% to 20% of patients with MG develop an influenza-like idiosyncratic reaction within 10 to 14 d of treatment with azathioprine, at which point the drug should be discontinued. Common adverse reactions to azathioprine are hepatotoxicity and leukopenia, which can be avoided by early detection and prompt discontinuation or dose reduction. Thiopurine methyltransferase levels should be measured before and early in the course of azathioprine therapy in patients with significant azathioprine-associated leukopenia. Long-term use of azathioprine may increase the risk of certain solid cancers, skin cancers and blood-related cancers, and this risk may be dose- and regimen-related, so care should be taken to use the minimum effective maintenance dose.
(2) Cyclosporine: The recommended starting dose is 4-6 mg/(kg・d) according to body weight. It should be divided into 2 doses. The maintenance dose is 3~4 mg/(kg・d). Cyclosporine is mainly indicated for patients who cannot tolerate azathioprine. Common adverse effects include hirsutism, tremor, gingival hyperplasia, anemia, hypertension, and nephrotoxicity. Hypertension and nephrotoxicity limit its use.
(3) FK506: Its mechanism of action is similar to cyclosporine at a dose of 3-5 mg/d. It is indicated for hormone reduction in patients with MG who are intolerant or unresponsive to azathioprine and cyclosporine.
(4) Others: For a small number of patients with refractory MG or those who cannot tolerate the adverse effects of combined treatment with hormones and one or more of the above immunosuppressive agents, the application of cyclophosphamide (CTX) and rituximab treatment can be considered.
CTX works mainly by weakening the immune system of the body. A single high dose of CTX (50 mg/kg by body mass) given intravenously for 4 d in patients with refractory MG, supplemented with granulocyte colony-stimulating factor to stimulate hematopoiesis to avoid severe myelosuppression, has been reported to have a significant therapeutic response and to last for several years without recurrence. Common adverse effects include myelosuppression, hemorrhagic cystitis, infection, and increased risk of malignancy.
The dose of rituximab for MG treatment is 2000 mg administered intravenously in 2 doses 14 days apart.
3.Thymectomy
Thymectomy was initially used to treat MG based only on experimental observations of symptomatic improvement in patients after thymectomy. Currently, its only absolute indication is thymoma. The results of a large meta-analysis showed that thymectomy is effective in treating MG, so currently medical experts tend to prefer thymectomy for patients with generalized MG who are anti-AChR antibody positive and less than 50 years of age at onset. Some people also recommend thymectomy for patients negative for anti-AChR antibodies, and there have been reports of non-thymomatous MG patients around 70 years of age receiving thymectomy.
4.Treatment of two special cases
(1) Treatment of myasthenia gravis: Myasthenia gravis is the most common clinical crisis in MG patients and requires tracheal intubation with ventilator-assisted ventilation or airway protection therapy. The indications for intubation include respiratory muscle fatigue, shortness of breath and decreased tidal volume, hypoxemia, hypercapnia and difficulty in handling secretions, etc. PE is the best treatment for myasthenia gravis because of its rapid onset of action. The effect of PE is short-lived. Long-acting immune-directed therapy should be administered to maintain long-term efficacy. IVlg is also effective in myasthenia gravis.
(2) Relapse of myasthenia gravis: The remission status of MG after intervention has three conditions: complete stable remission, drug-maintained remission, and the least clinical symptoms. If MG-related symptoms reappear or the mildest clinical symptoms worsen. MG relapse is indicated. Treatment should be restarted at the minimum effective dose. Or a large or moderate dose of prednisone, or increase or change the immunosuppressive therapy. In severe cases, PE or IVlg therapy may be used.