Myasthenia gravis medication strategy is here - be wary of medication crisis!

*For medical professionals only

The use of drugs has certain application contraindications and their respective characteristics, which should be selected according to the individual situation of the patient

Myasthenia gravis (MG) is primarily an organ-specific autoimmune disease
with acquired neuro-muscular junction (NMJ) delivery disorder mediated by acetylcholine receptor antibodies.

At present, there is no specific drug to cure MG at present, and the treatment of the disease is also different in different types and patient populations
.
In order to choose a safe and effective drug regimen for patients, it is necessary to have a detailed understanding
of the relevant Chinese and foreign guidelines and the progress of MG drug treatment.

1

The symptomatic therapeutic drug

pyridostigmine is a first-line agent for all types of MG and can alleviate and improve the clinical symptoms of most patients with ME
.
Pistigmine bromide should be used as the drug of choice for initial treatment in patients with MG, in combination with hormonal and other non-hormonal immunosuppression, depending on the condition
.

▎Dosage:
The first dose of general adults taking pyridostigmine bromide is 60mg (children use according to specific age), orally, 3 to 4 times / day, the maximum dose throughout the day does not exceed 480mg
.

Individualized use of the dose of pyridostigmine bromidemine should be carried out according to the sensitivity of patients with MG to pyridostigmine bromide, and the dose can be tapered or discontinued when the treatment goal is achieved
.
Adverse effects of pyridostigmine bromide include nausea, salivation, abdominal pain, diarrhea, bradycardia, and increased sweating
.
The use of pyridostigmine bromide during pregnancy is safe and effective
.

2

Non-specific immunosuppressive non-specific immunosuppressive drugs include: glucocorticoids and other oral non-hormonal immunosuppressants

, such as azathioprine, tacrolimus, mycophenolate mofetil, cyclosporine, cyclophosphamide and the like
.

1 Glucocorticoids
are still the first-line drugs for the treatment of MG and can significantly improve symptoms in 70% to 80% of patients, and 75% of patients with mild-moderate MG have a good response
to 20 mg of prednisone.

Special reminders

More than 50% of systemic patients may have transient symptoms that worsen early in the use of high-dose hormones (7-10 days), generally lasting about 1 week, and severe cases will have a crisis
.
The doctor should inform the patient to let him know; Healthcare professionals should also be closely observed and, if necessary, take countermeasures
.

▎Dosage:

Prednisone acetate is started at 20 mg/day and increases by 10 mg every 5 to 7 days to the target dose
.
The target dose is 0.
5 to 1.
0 mg/kg·d, taken in the morning, and the maximum dose does not exceed 100 mg/day
.

Generally the onset of action within 2 weeks, 6 to 8 weeks the most significant effect, after achieving the treatment goal, maintain 6 to 8 weeks after gradual reduction, every 2 to 4 weeks to reduce 5 to 10 mg, to 20 mg after every 4 to 8 weeks to reduce 5 mg
.

2 azathioprine
azathioprine in combination with glucocorticoids, helps reduce hormone doses and prevent disease recurrence, and is a first-line drug
for acetylcholine receptors (AChR) - systemic MG (GMG) and some ophthalmic myotype MG (OMG).

The onset of azathioprine is slower, more than 3 to 6 months after taking the drug, and the full effect is achieved after 1 to 2 years, which can significantly improve
the symptoms of 70% to 90% of patients.

▎Dosage:

Start with a small dose of 50 mg/day and increase the daily dose by 50 mg every 2 to 4 weeks until the effective therapeutic dose is available (children by body weight 1 to 2 mg/kg·d, adults 2 to 3 mg/kg·d, divided into 2 to 3 oral doses).

If there are no serious and/or intolerable adverse reactions, it can be taken for
a long time.
The main adverse reactions include bone marrow suppression (leukopenia, anemia, thrombocytopenia), liver function impairment, hair loss, flu-like symptoms and gastrointestinal symptoms, which occur about
6 weeks after initiation of treatment.

3

Targeted immunotherapy agentsTargeted immunotherapy agents

are therapeutic antibodies or antagonists that target immune cells, complement, neonatal Fc receptors, and cytokines
.

At present, targeted immunotherapy drugs used in clinical use for MG therapy mainly include eculizumab (Eculizumab) approved for use by the US Food and Drug Administration (FDA), rituximab (RTX) for topical use, and Aggamod for the treatment of AChR-GMG
.

1RTX RTX
is used for moderate to severe and refractory systemic MG with poor efficacy to hormones and immunosuppressants, particularly the muscle-specific receptor tyrosine kinase (MuSK), a pathogenic antibody-MG
.

The Guidelines for the Diagnosis and Treatment of Myasthenia Gravis in China (2020 Edition)[1] (hereinafter referred to as the "China Guidelines") and the latest (2020) International Guidelines[2] (prepared by 16 international experts from 10 countries including the United States, Canada, Chile, Germany, Italy, Japan, Norway, the Netherlands, Spain, and the United Kingdom, hereinafter referred to as the "International Guidelines") both indicate that RTX is suitable for MuSK-MG who do not respond well to initial immunotherapy
。 It reduces steroid drug use, reduces recurrence and myasthenic crisis, and has some safety
.

Studies have shown [3] that small doses of RTX can help patients reduce the use of immunosuppressants, or even discontinue them, reduce antibody levels, restore EMG normal, and effectively improve clinical symptoms, indicating that it is safe and beneficial
for refractory MG
For refractory MG, Chinese guidelines consider RTX to be effective against refractory GMG with poor immunosuppressants and hormones, and effective against some AChR-MG;

▎Dosage:

The induction dose is 375 mg/^m2 according to the body surface area, administered once at intervals of 1 week, administered continuously for 4 weeks, administered sequentially 1 g, and treated once every 2 weeks for a total of 2 times
.

The low-dose regimen consists of 375 mg/^m2 at body surface area at intervals of 2 weeks for a total of 2 doses
.
The maintenance dose is 375 to 750 mg/^m2 body surface area
.

2 A
2013 preliminary phase II study of ecuzumab in the treatment of refractory AChR-GMG [4] showed a clinically significant improvement
in this class of patients.

The 2017 Phase 3 randomized, double-blind, controlled, multicenter study (REGAIN)[5] further evaluated the efficacy and safety
of eclozumab in this patient population.
Overall, eclozumab has potential benefits in the treatment of AChR-GMG
.

The results of the open-label extension study of REGAIN [6] showed improvements in daily living activities, muscle strength, functional capacity, and quality of life in patients receiving eclozumab for 3 years, demonstrating the long-term benefit
of eclozumab for complement inhibition in patients with the disease.

The Chinese guidelines include economic considerations for the drug, which is expensive and recommended for moderate to severe, refractory MG for the treatment
of adult patients with AChR-GMG.

International guidelines state that before treatment with eclozumab, the recommendations of the Advisory Committee on Immunological Practice (ACIP) or other local guidelines
on meningococcal meningitis immunization should be followed.

3 The results of
a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial evaluating the effectiveness and tolerance of Agamore in the treatment of GG, showed that 67.
7% of AChR-GMG patients receiving Agamore achieved the primary study endpoint, that is, after the evaluation of the MG Activity of Living Scale (MG-ADL), the patient's score improved by at least 2 points for 4 consecutive weeks.
In the placebo group, the figure was 29.
7 percent
.

In addition, 63.
1% of patients in the Agamod-treated group showed significant remission after measuring the quantitative score for myasthenia gravis (QMGS), compared with 14.
1%
of patients in the placebo group who achieved an equivalent response.

Minimal symptomatic manifestations were achieved in 40.
0% of patients treated with aggamod, defined as Myasthenia gravis gravisibles (MG-ADL) with a score of 0 (asymptomatic) or 1, compared with 11.
1% in the placebo group [7
].
Agamore was approved by the FDA on December 17, 2021 for the treatment of AChR-GMG
.

4

Intravenous gamma globulin (IVIG) and plasmapheresis (PE)

IVIG and PE are mainly used in the acute exacerbation phase of MG and in the perioperative period, as well as before treatment with high-dose corticosteroids, to reduce or prevent hormone-induced transient exacerbations [8].


IVIG is thought to neutralize pathogenic antibodies and compete with autoantibodies for binding sites
on the postsynaptic membrane.
Therapeutic PE is isolated by blood centrifugation or plasma to remove non-cellular blood components and pathogenic antibodies, and in infected people, the therapy
is indicated only after the infection is controlled.

Both also have certain application contraindications and their respective characteristics, which should be selected
according to the individual situation of the patient.
IVIG therapy is not feasible for patients with renal impairment, and PE treatment is not feasible for patients with sepsis; IVIG
is recommended in patients with MG or refractory MG who have relative contraindications to immunosuppressants or who cannot tolerate their side effects.

In patients with moderate to severe MG in children and adolescents, IVIG has been used as a short-term replacement for corticosteroids or PE; For patients with MuSK-ME, PE therapy
is recommended.

▎IVIG Dosage:

Intravenously according to body weight 400mg/kg·d for 5 days
.
Adverse effects include headache, aseptic meningitis, flu-like symptoms, and renal impairment, so patients with renal impairment are contraindicated
.

Resources:

Chang Ting.
Chinese Guidelines for the Diagnosis and Treatment of Myasthenia Gravis (2020 Edition)[J].
Chinese Journal of Neuroimmunology and Neurology,2021,28(1):1-12.

[2] NARAYANASWAMI P，SANDERS D B，WOLFE G，et al.
In⁃ternational consensus guidance for management of myasthenia Gravis：2020 update[J].
Neurology，2021，96（3）：114-122.

Zhao Sijia, Zhang Yu, Ren Kaixi, et al.
Long-term efficacy of low-dose rituximab in the treatment of refractory myasthenia gravis[J].
Chinese Journal of Neuroimmunology and Neurology,2020,27(5):362-366.

[4] HOWARD J F Jr，BAROHN R J，CUTTER G R，et al.
A randomized，doubleblind，placebo controlled phase II study of eculizumab in patients with refractory generalized myasthenia gra⁃vis［J］.
Muscle Nerve，2013，48（1）：76-84.

[5] HOWARD J F Jr，UTSUGISAWA K，BENATAR M，et al.
Safety and efficacy of eculizumab in antiacetylcholine receptor antibodypositive refractory generalised myasthenia gravis（RE⁃GAIN）：A phase 3，randomised，double⁃blind，placebo⁃con⁃ trolled，multicentre study［J］.
Lancet Neurol，2017，16（12）：976-986.

[6] MUPPIDI S，UTSUGISAWA K，BENATAR M，et al.
Long⁃term safety and efficacy of eculizumab in generalized myasthenia gravis［J］.
Muscle Nerve，2019，60（1）：14-24.

[7] HowardJF,,BrilV,VuT,et al.
Safety,efficacy,and tolerability of efgartigimod in patients with generalised myasthenia gravis(ADAPT):a multicentre,randomised,placebo-controlled,phase 3 trial[J].
Lancet Neurol,2021,20(7):526-536.
DOI:10.
1016/s1474-4422(21)00159-9.

[8] DÍEZ⁃PORRAS L，HOMEDES C，ALBERTI M A，et al.
Intra⁃venous immunoglobulins may prevent prednisone exacerbation in myasthenia gravis［J］.
Sci Rep，2020，10（1）：13497.

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