Immunosuppressants for myasthenia gravis

Last updated Oct. 1, 2024, by Joana Carvalho, PhD
Fact-checked by Inês Martins, PhD

What are immunosuppressants?

Immunosuppressants are a class of medicines that broadly work to suppress or reduce the activity of the immune system. They are widely used in myasthenia gravis (MG) and other autoimmune conditions to prevent the immune system from attacking healthy tissues and cells, which helps to minimize further damage and ease disease symptoms. These medications are also commonly used following an organ or stem cell transplant to prevent rejection.

Several types of immunosuppressants can be used to treat MG. The choice of treatment depends on several factors, such as the severity of the disease, the presence of certain additional conditions, or comorbidities, and the desired timeframe for therapeutic action.

Importantly, the use of immunosuppressants brings with it the potential for a series of side effects, including kidney and liver toxicity, increased susceptibility to infections, fetal malformations during pregnancy, and a higher risk of cancer. For this reason, these medications may not be suitable for all patients, especially those with certain conditions, or in specific situations like pregnancy. Healthcare providers will take these factors into account when deciding if immunosuppressants are appropriate and, if so, which specific type is best suited to a patient’s individual needs.

When are immunosuppressants used in MG?

Immunosuppressants in myasthenia gravis are generally used over the long term in people who responded poorly or experienced substantial side effects from first-line medications. They’re also often considered for patients for whom first-line treatments are contraindicated, or not recommended for use.

Conventional immunosuppressants are also used as steroid-sparing agents in MG patients, helping to reduce or eliminate the need for corticosteroids. These are anti-inflammatory medications often used in MG that typically come with numerous side effects, especially when used over extended periods of time. However, unwanted side effects associated with corticosteroids can be mitigated by combining and/or replacing them with a noncorticosteroid, or nonsteroidal, immunosuppressant.

Treatment guidelines

According to the International Consensus Guidance for Management of Myasthenia Gravis, nonsteroidal immunosuppressants and/or corticosteroids should be used in all MG patients who fail to respond adequately to first-line treatment with pyridostigmine (sold as Mestinon and generics).

In patients who refuse treatment with corticosteroids, or for whom these medications are contraindicated, a nonsteroidal immunosuppressant should be used alone. A nonsteroidal immunosuppressant should also be used initially alongside corticosteroids when the risk of steroid side effects is high due to the presence of certain comorbidities.

The guidelines also state that a conventional immunosuppressive agent should be used in combination with corticosteroids in patients who:

experience significant steroid side effects
do not respond adequately to corticosteroids
cannot reduce their corticosteroid dosage due to symptom reappearance.

Regarding treatment dosage and duration, the guidelines recommend that patients who have achieved and maintained their treatment goals for six months to two years should slowly reduce their nonsteroidal immunosuppressant to the minimum effective dose. These dose adjustments should be made no more than once every 3-6 months.

Most patients will require some immunosuppressive treatment for several years, sometimes for life. Even with low-dose treatment, regular monitoring is essential to detect potential side effects and complications associated with long-term immunosuppressive therapy.

Switching to an alternative therapy should be considered for patients experiencing substantial side effects or complications that impact quality of life.

Selecting specific immunosuppressants

Because there aren’t enough studies directly comparing immunosuppressive drugs for MG, there is a lot of variation in how doctors decide which ones to prescribe in different situations. However, based on the 2020 update to the international consensus guidance, nonsteroidal immunosuppressants that can be used in MG include:

azathioprine, sold as Imuran and others and available in oral and injectable formulations
cyclosporine, sold as Neoral and others and available in oral, ophthalmic emulsion, and injectable formulations
mycophenolate mofetil, sold as Cellcept and others and available in oral and injectable formulations
tacrolimus, marketed as Prograf and others in several oral, injectable, and topical forms.

Expert consensus, as well as data from clinical trials, generally support the use of azathioprine as a first-line immunosuppressant in MG. Cyclosporine is also backed by clinical trial data in myasthenia gravis, but is typically reserved for patients who don’t respond to or can’t tolerate other immunosuppressants, as it can cause serious side effects and interact with other medications.

Clinical evidence does not support the use of mycophenolate mofetil and tacrolimus in MG. However, both drugs are widely used and recommended in several MG treatment guidelines.

The consensus also cites two other immunosuppressants that can be used in specific cases:

Methotrexate (sold as Jylamvo and others) can sometimes be used as a steroid-sparing agent in people with generalized MG who haven’t tolerated or responded well to other steroid-sparing medications. However, due to lack of clinical evidence, it should be considered for use only when there are no available medications better supported by clinical data.
Cyclophosphamide (sold as Cytoxan) is generally reserved for use in people with treatment-resistant, or refractory, MG, because it can cause potentially serious side effects.

Factors to consider

When choosing the best immunosuppressant for a patient, a physician will consider a number of factors, including how quickly the medication is expected to take effect. Typically, immunosuppressants take a fairly long time to exert the desired effect, but some therapies act faster than others. For instance, azathioprine and mycophenolate mofetil may take 6-12 months to work,while cyclosporine and tacrolimus may start to show effects within the first three months.

MG severity is another key aspect to consider when deciding which immunosuppressant to use. In patients with milder forms of MG who are content with a slow rate of improvement, nonsteroidal immunosuppressants may be used as a first treatment option. In those with severe or refractory MG, more potent and faster-acting immunosuppressants may be preferred.

How do immunosuppressants work?

Immunosuppressant drugs for myasthenia gravis generally belong to three classes: antimetabolites, alkylating agents, and calcineurin inhibitors.

Antimetabolite immunosuppressants — such as azathioprine, mycophenolate mofetil, and methotrexate — and alkylating agents like cyclophosphamide all work by interfering with the cell cycle, preventing the growth of immune B- and T-cells that are involved in MG.

The cell cycle is the process by which cells divide to create two identical copies. It consists of several stages, including one phase where DNA is duplicated, and another in which the duplicated material is evenly distributed between two daughter cells. While antimetabolites primarily target the DNA duplication phase of the cell cycle, alkylating agents can disrupt the process at any stage.

Calcineurin inhibitors such as cyclosporine and tacrolimus, meanwhile, work to reduce T-cell activation and function by interfering with an enzyme called calcineurin.

Benefits of immunosuppressants

One of the key benefits of immunosuppressants for myasthenia gravis is their steroid-sparing effects. Using such treatments may enable those with MG to reduce their corticosteroid dose or stop using those medications altogether. This is particularly important for patients, as lowering corticosteroid use can help avoid steroid side effects such as weight gain, bone loss, diabetes, and high blood pressure.

Beyond their steroid-sparing effects, nonsteroidal immunosuppressants are generally considered highly effective therapies, providing significant and lasting symptom relief for most MG patients, including those who have not responded to other treatments.

Risks and side effects

A notable drawback of conventional immunosuppressants is a delayed onset of action, meaning patients may experience only gradual improvements over time. Additionally, these medications are associated with a range of side effects. Potential immunosuppressant side effects may include:

flu-like symptoms
headache
digestive problems, such as nausea, vomiting, and diarrhea
tremors
hair loss and excessive hair growth in other parts of the body
mouth sores.

Other notable risks associated with the use of immunosuppressants are:

infections
liver, kidney, and lung toxicity
decreased bone marrow activity
low white blood cell counts (leukopenia)
infertility
fetal malformations
cancer.

The specific side effects and risks of immunosuppressants can vary based on the medication being used and the patient’s underlying health issues. A physician will carefully assess these factors before determining whether immunosuppressants are appropriate for a particular patient, and if so, which one(s).

Pregnancy and breastfeeding

Some immunosuppressants are teratogenic, meaning they can interfere with normal fetal development and cause malformations. For this reason, these medications are contraindicated for use during pregnancy.

According to the U.S. Food and Drug Administration (FDA) classification of teratogenic drugs, mycophenolate mofetil, methotrexate, and cyclophosphamide are all contraindicated during pregnancy due to known teratogenic effects in humans.

The FDA classifies azathioprine, cyclosporine, and tacrolimus as category C, indicating that human fetal risk cannot be completely ruled out, even though available data does not suggest these medications are teratogenic. While all three can be used during pregnancy, azathioprine is generally safer and is typically used to replace cyclophosphamide, mycophenolate mofetil, and methotrexate in pregnant patients.

Immunosuppressants can pass into breast milk, so they should be used with caution by nursing women. In such cases, breastfed infants should be closely monitored for any signs of immunosuppression or toxicity. Patients should consult their doctor if they wish to breastfeed while using these medications.

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