Immunosuppressive drugs for the treatment of myasthenia gravis (MG) include glucocorticoids and other oral non-hormonal immunosuppressive drugs such as azathioprine (AZA), tacrolimus (FK-506), morte-macrolimus (MMF), cyclosporine, methotrexate, and cyclophosphamide. The Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gravis (2020 Edition) were recently published. Regarding the application of the above drugs, the guidelines mainly cover the following
Glucocorticoids Glucocorticoids are still the first-line drugs for the treatment of MG, mainly oral prednisone acetate and methylprednisolone.
Prednisone acetate is given in the early morning at 0.5~1.0mg/(kg-d) according to body weight, with the maximum dose not exceeding 100mg/d (glucocorticoid dose conversion relationship: 5mg prednisone acetate = 4mg methylprednisolone), which usually takes effect within 2 weeks, with the most significant effect in 6~8 weeks. 75% of mild-moderate MG have good response to 200mg prednisone, starting with 20mg and increasing by 10mg every 5~7d to The dose was increased by 10mg every 5~7d to the target dose. After reaching the therapeutic target, the dose is gradually reduced after 6~8 weeks of maintenance, by 5~10mg every 2~4 weeks to 20mg and then by 5mg every 4~8 weeks, with the lowest effective dose being taken orally every other day as appropriate, and too rapid a reduction may lead to relapse. In order to avoid high oral doses of hormones, combination with other non-hormonal oral immunosuppressants at the beginning of treatment can achieve therapeutic goals more quickly.
During the use of glucocorticosteroids, it is necessary to closely observe the changes of the disease. About 40%~50% of patients have a transient aggravation of symptoms within 2~3 weeks of taking glucocorticosteroids and may induce myasthenia gravis, especially in patients with late onset, severe disease or obvious ball symptoms, and the symptoms are more likely to be aggravated in the early stage of using glucocorticosteroids, therefore, glucocorticosteroids should be used cautiously in the above patients, and IVIG or PE can be used first to stabilize the disease before using glucocorticosteroids, and be prepared to open the airway.
Long-term use of glucocorticoids may cause increased food intake, weight gain, centripetal obesity, elevated blood pressure, elevated blood sugar, cataract, glaucoma, endocrine dysfunction, mental disorders, osteoporosis, femoral necrosis, and gastrointestinal symptoms, etc., which should be given high priority. Timely supplementation of calcium and bisphosphonates can prevent or reduce osteoporosis, and the use of acid-suppressive drugs can prevent gastrointestinal complications.
Azathioprine (AZA) AZA is used in combination with glucocorticoids to facilitate hormone reduction and to prevent disease recurrence as the first-line drug for systemic MG (GMG) and some oculomotor MG (OMG). AZA has a slow onset of action, mostly starting 3-6 months after taking the drug and reaching full effect after 1~2 years, and can significantly improve symptoms in 70%~90% of MG patients.
Usage: Start with a small dose of 50mg/d and increase by 50mg every 2~4 weeks until the effective therapeutic dose [1~2mg/(kg-d) for children and 2~3mg/(kg-d) for adults according to body weight, divided into 2~3 oral doses]. If there are no serious or/and intolerable adverse reactions, it can be taken for a long time.
Major side effects include myelosuppression (leukopenia, anemia, thrombocytopenia), hepatic impairment, alopecia, flu-like symptoms and gastrointestinal symptoms, which mostly occur about 6 weeks after initiation of treatment. Thiopurine methyltransferase phenotypic or genotypic testing can predict the risk of leukopenia during AZA administration.
For long-term use of AZA, routine blood and liver and kidney function should be monitored closely, weekly for the first month, monthly for the first 6 months, and every 3 months thereafter. If the white blood cell count is lower than 4.0×109/L, AZA should be reduced; if the white blood cell count is lower than 3.0×109/L or the liver function test index is three times the upper limit of normal value, the drug should be discontinued immediately.
Tacrolimus Tacrolimus is indicated for MG patients who cannot tolerate the side effects of hormones and other immunosuppressive drugs or are poorly treated with them, especially those who are positive for RyR antibodies. Tacrolimus has a rapid onset of action, usually in about 2 weeks, with a dose-dependent effect.
Usage: 3.0mg/d orally in 2 divided doses on an empty stomach or 0.05~0.10mg/(kg-d) according to body weight. Recommendations: Blood levels can be screened 3-4 d after dosing or dose adjustment. ideal trough concentrations are 2-9 ng/mL. studies have shown that tacrolimus trough concentrations ≥4.8 ng/mL are achieved in 92% of patients with minimal status (MMS) or better.
Major side effects include elevated blood glucose, decreased blood magnesium, tremor, hepatic and renal impairment, and, rarely, bone marrow suppression.
Mortylmacrolate (MMF)MMF use: starting dose 0.5~1.0g/d, divided into 2 oral doses; maintenance dose 1.0~1.5g/d, reduce the dose no more than 500mg/d per year after the symptoms are stabilized. sudden discontinuation or rapid dose reduction can lead to relapse and worsening of the disease. MMF should not be used simultaneously with AZA.
Common adverse reactions are nausea, vomiting, diarrhea, abdominal pain and other gastrointestinal reactions, white blood cell depression, urinary tract infection and viral infection.
MMF is teratogenic and is contraindicated in women who are pregnant or preparing for pregnancy.
Cyclosporine Cyclosporine takes 3-6 months to work and is used for patients who have poor response to hormones and AZA or who cannot tolerate their side effects. Early use of cyclosporine in combination with hormones can significantly improve the symptoms of muscle weakness and reduce the titer of AChR antibody in blood, but it is more nephrotoxic.
Usage: 2~4mg/(kg-d) orally according to body weight. Plasma cyclosporine drug concentration should be monitored during use, the recommended blood concentration is 100~150ng/mL, and the cyclosporine dose should be adjusted according to the concentration.
The main side effects include renal impairment, increased blood pressure, tremor, gingival hyperplasia, myalgia and flu-like symptoms. Monitor the blood routine and liver and kidney function at least once a month and monitor blood pressure closely during the drug administration. Cyclosporine is not recommended as a first choice due to its high nephrotoxicity and interactions with other drugs.
Cyclophosphamide Cyclophosphamide is used for refractory MG and MG with thymoma that has failed to respond to other immunosuppressive therapy. combination with hormones significantly improves symptoms of muscle weakness and results in a reduction in hormone dosage at 6-12 months.
Usage: Adults take 400~800mg/week intravenously or 100mg/d orally in 2 divided doses until total 10~20g, individual patients need to take up to 30g; children take 3~5mg/(kg-d) orally in 2 divided doses (not more than 100mg) according to body weight, and reduce the dose after improvement, 2mg/(kg-d). It should be used with caution in children.
Side effects include leukopenia, alopecia, nausea, vomiting, diarrhea, hemorrhagic cystitis, bone marrow suppression, teratogenicity, and risk of distant tumors. Blood tests and liver and kidney function need to be reviewed before each use.
MethotrexateMethotrexate is used as a third-line agent for refractory MG or MG with thymoma that has failed to respond to other immunosuppressive therapy.
Usage: Oral, starting at 10 mg per week and gradually increasing to 20 mg/week. If the oral formulation is not tolerated for gastrointestinal adverse effects, an intramuscular formulation is also available, which generally allows patients to tolerate higher doses.
Side effects include gastrointestinal reactions and abnormal liver function, which may be accompanied by stomatitis, rash, pulmonary fibrosis, and leukopenia. Treatment should be accompanied by folic acid 1mg/d to prevent stomatitis, and side effects such as bone marrow suppression and hepatic impairment should be closely monitored. Methotrexate has reproductive teratogenicity and is contraindicated in pregnancy or in pregnancy preparation.
