Principles of Therapy
Treatment goals should focus on complete remission, or minimal manifestations, while causing the least possible side effects.
Pharmacological therapy
In addition to symptomatic therapy, disease-modifying immunotherapy
should also be provided.
Anticholinesterase Agents (AChE-I)
These are the first-line symptomatic therapy for
all forms of MG. Patients usually experience partial improvement. However,
complete improvement may occur in few patients. It must be noted that there is
no difference in the efficacy between the different anticholinesterase agents,
and that they do not stop the natural progression of the disease state. The
dose and frequency should be tailored to the patient's individual needs. The
muscarinic effects (eg diarrhea, abdominal cramps, etc) associated with these
agents may limit the tolerated dose. The drug Propantheline may be used to
block unwanted autonomic side effects. While, Loperamide may be used to treat
diarrhea.
Distigmine
This agent is longer-acting compared to
other pharmacotherapy, but is rarely used for MG because of the increased risk
of cholinergic crisis.
Neostigmine
Neostigmine is an analog of Pyridostigmine
with therapeutic effect at approximately 4 hours. It has a shorter duration of
action, less effective and with more muscarinic side effects.
Pyridostigmine
Pyridostigmine
is the primary AChE-I used for the symptomatic therapy of all forms of MG. It may be used as a
long-term treatment in patients with milder disease. The effect begins within
30 minutes, peaks at about 2 hours, and lasts for 3-4 hours. It may be
preferable to Neostigmine because of its longer duration of action with less
muscarinic side effects.
Corticosteroids
Prednisolone (Prednisone)
Prednisolone generally results in
improvement of weakness in MG patients, this is based on observational studies
which showed remission or marked improvement that occurs in 70-80% of patients within 2-4 weeks. It is used with or
without Azathioprine as first-line agents for immunosuppression. Prednisolone may be initiated in patients with extraocular muscle
weakness despite maximally tolerated treatment of Pyridostigmine for 4-6 weeks. Prednisolone
should be started at a low dose to avoid temporary worsening of MG, then
increase the dose slowly until there is marked clinical improvement is seen. In moderate to severe generalized MG, early
high-dose Prednisone may be considered. After which, maintain the dose for 1-3 months. When remission occurs, reduce the dose to a minimum
effective dose that is given on alternate days. Note that patients need to be
observed closely for adverse effects.
Immunosuppressants
Immunosuppressants should be
considered in patients with progressive MG symptoms.
They should also be considered in patients requiring ≥7 mg/day of Prednisolone to maintain remission. It
must be noted that abrupt discontinuation of immunosuppressants in
insufficiently stabilized disease may lead to recurrence of symptoms and
progression to a myasthenic crisis.
Azathioprine
Azathioprine is used
extensively as a steroid-sparing immunosuppressant. Azathioprine is the most
widely used immunosuppressant agent. It is a widely used immunosuppressant therapy for MuSK-MG. It may be combined
with corticosteroids to add therapeutic effect and/or allow the steroid dose to
be reduced. It may take 4-12 months to see beneficial effects, with the
maximum effect seen at 6-24 months. Long term treatment (≥10 years) is not recommended due to the
risk of malignancy.
Ciclosporin
Ciclosporin may be as effective as
Azathioprine. It may be used alone but is usually combined with steroids to
allow for a reduction of steroid dose. This drug is considered as a third-line
therapy and should only be used in patients intolerant or unresponsive to corticosteroids or other immunosuppressants (eg
Azathioprine). Beneficial effects of Ciclosporin are seen in 1-3 months.
Cyclophosphamide
It has been demonstrated to be
effective in treatment-resistant MG cases. However, the risk of adverse effects
limits its use.
Mychophenolate
Mycophenolate may be considered for
long-term therapy if refractory to the first-line treatment. This drug has been
shown in small studies to improve functional status or as a steroid-sparing
agent. It may be better tolerated than other immunomodulators due to its
relative lack of side effects. However, Mycophenolate is costly and its
beneficial effects may take months before being seen.
Complement
Inhibitors
Example
drugs: Eculizumab, Ravulizumab, Zilucoplan
Complement
inhibitors bind to C5 and inhibits the formation of C5b-induced membrane attack
complex. They are approved by the United States Food and Drug Administration
(US-FDA) and European Medicines Agency (EMA) for refractory generalized MG that
is AChR antibody-positive. They are used in addition to immunosuppressant therapy.
In a double-blind clinical trial, Eculizumab showed significant benefit in
daily living, quality of life starting in the first 4 weeks of treatment. An
extension study also showed a reduced exacerbation rate of 75% compared to the
baseline rate before study entry. Discontinuation should be considered if no
clinical improvement is observed after 3-month treatment trial. Ravalizumab and
Zilucoplan are approved by the US FDA for generalized AChR-positive MG.
Neonatal
Fc Receptor (FcRn) Antagonists
Example
drugs: Efgartimod, Nipocalimab, Rozanolixizumab
Neonatal
Fc receptor antagonists are antibody fragments that bind to the FcRn, thereby
preventing FcRn from recycling IgG back into the blood. Their use results in
overall reduction of IgG, including the abnormal AChR antibodies. They were
recently approved by the US FDA for the treatment of generalized MG that is
AChR antibody-positive. A multi-center, randomized, double-blind study showed
improvement of 67.7% in activities of daily living compared to placebo (29.7%).
Nipocalimab is approved by the US FDA for both AChR-positive or MuSK-positive
MG. Rozanolixizumab is approved by the Medicines and Healthcare Products Agency
(MHRA), US FDA, and EMA as add-on to standard therapy in adults for generalized
disease in both AChR-positive and MuSK-positive MG.
Intravenous Immunoglobulin (IVIg)
IVIg may be used to treat
MG crisis or to improve a patient’s condition prior to thymectomy or as an
adjuvant to minimize side effects with long-term immunosuppressant therapy. It
may be used as an alternative to plasmapheresis or immunosuppressive therapy in
patients with refractory MG or as a preoperative treatment prior to thymectomy.
Its use should be considered as continuous
therapy in patients with comorbidities, recurrent infections, or intolerance
reactions to other immunosuppressants. With IVIg, rapid
improvement occurs in 70% of patients within 4-5 days of treatment. IVIg can be
used in the presence of systemic infection, and its beneficial effects may last
for months. However, this drug is notably expensive.
Other Therapies
Methotrexate
According to randomized clinical
trials, oral Methotrexate may be beneficial in generalized MG who cannot
tolerate or do not respond to steroid-sparing agents.
Rituximab
In studies, Rituximab appears to be
particularly effective in patients with MuSK-positive MG that often
respond relatively poorly to first-line immunosuppressive therapies. A
retrospective cohort study showed benefit in terms of clinical remission for
new-onset generalized MG and refractory disease. Rituximab
can be considered for use in early moderate to severe AChR-positive generalized
MG. Pneumocystis pneumonia prophylaxis should be considered for
longer-term (>6 months) combination therapies with other agents.
Tacrolimus
It is widely used in Japan for the
management of MG in patients who underwent thymectomy and with poor response to
steroid therapy.
Myasthenia Gravis_ManagementNonpharmacological
Lifestyle
Modification
Sleep
hygiene, a balanced diet, avoidance of excess alcohol consumption, and aerobic
exercise are also recommended in patients with myasthenia gravis. Multiple
studies show that aerobic exercise is safe, well-tolerated, and may enhance
strength and functional capacity. For stable myasthenia gravis patients, 150
minutes per week of moderate intensity exercise is recommended.
Psychological
Intervention
It is
important to note that support groups along with optimal treatment increases
the patient's level of function. Psychological support and referral to a
psychologist should be offered to patients.
Plasmapheresis
Plasmapheresis may be used to treat MG
crisis or to improve a patient’s condition prior to thymectomy. It is considered equivalent to IV IgG in the treatment of
myasthenic crisis. With this, pathogenic antibodies are separated from the
blood cells mechanically. It is useful in decreasing symptoms when starting
immunosuppressive therapy. Around 5 exchanges are performed, with 3-4 liters
per exchange, over a 2-week period. It showed rapid short-term clinical
improvement in most patients due to reduction in anti-AChR antibodies. However,
plasmapheresis is not recommended in patients with cardiac failure, sepsis,
hypotension, and pregnancy. It is also not recommended as a treatment to obtain
a continuous and lasting immunosuppression in MG. Lastly, it is also not
considered to be a suitable procedure in pediatric patients.
Immunoadsorption
Immunoadsorption
is considered equally effective as plasmapheresis in the treatment of MG. IgG
is semi-selectively removed by protein binding as the plasma passes through
protein A-columns or a tryptophan-polyvinyl gel matrix. This may be considered
in pregnancy or hemodynamically unstable patients.
Surgery
Thymectomy
There is currently no
consensus in place on which surgical method is the first line. However, based
on a study, more severe cases of MG may benefit from thymectomy compared to
patients with mild MG. It is advisable that the patient be stabilized with immunotherapy before undergoing
thymectomy to reduce perioperative morbidity and mortality. Thymectomy should also be considered for all AChR antibody-positive
patients below 50 years old. Patients with AChR antibody-positive, early
onset generalized MG with insufficient response to Pyridostigmine are suitable
candidates for thymectomy. In a prospective randomized study, there was
significant benefit for thymectomized patients with AChR antibody-positive MG
in terms of symptoms, with a steroid- and immunosuppressant-sparing effect
occurring 1-5 years after thymectomy. In seronegative MG, thymectomy may be
justified after exhaustion of all non-surgical approaches.
Video-assisted
thoracoscopic surgery (VATS) may be considered in preference to the
transsternal approach, with many papers demonstrating superior results of VATS
in terms of hospital stay, operative blood loss, and patient satisfaction
compared to the transsternal approach. This reduces the required dose of immunosuppressants, which helps extend
the duration of treatment for immunotherapy.
Patients
with thymomas must undergo thymectomy at any age regardless of disease
severity. During the surgery, the tumor and adherent structures should be completely
removed, and the chest cavity be inspected for tumor implants. If the patient with a suspected thymoma is not suitable for
surgery, biopsy and conservative therapy (radiotherapy) must be performed. Around 66% of
patients with MG and nonmalignant thymoma were found to be symptom-free at 6
months to 7 years after thymectomy and treatment with Prednisolone and/or
Azathioprine.
In the absence of a tumor, thymectomy
offers a possibility of long-term benefit for those with generalized MG and anti-AChR
antibodies. Thymectomy in these cases may increase the probability of
improvement or drug-free remission. Though studies showing improvement have
conflicting differences in baseline characteristics of prognostic factors and
confounding variables (eg age, severity of MG), most of these have found
improvement or remission in patients undergoing thymectomy. However, the
improvement is slow and may take months or years.
Lastly, ophthalmic surgery may be done
to correct ptosis and/or diplopia.