Intravenous immunoglobulin for myasthenia gravis

Last updated Nov. 15, 2024, by Margarida Maia, PhD
Fact-checked by Joana Carvalho, PhD

What is IVIG for myasthenia gravis?

Intravenous immunoglobulin (IVIG) therapy is a type of treatment used to manage a variety of immunodeficiency and autoimmune disorders, including myasthenia gravis (MG), that broadly works to normalize the activity of the immune system.

IVIG preparations contain immunoglobulins, or antibodies, that have been pooled from the blood of thousands of healthy donors. It is thought that IVIG works in MG by temporarily modulating the immune system, for example, by tagging the disease-causing self-reactive antibodies that circulate in the bloodstream for destruction or by reducing their production.

IVIG is recommended for use as a short-term treatment for severe or rapidly worsening disease in patients who have developed life-threatening complications, such as difficulty swallowing or breathing, including in the setting of a myasthenic crisis.

International guidelines also recommend the use of IVIG before surgery to prevent complications in patients with bulbar symptoms, or those involving the face and neck, such as difficulty speaking. IVIG is also recommended when a fast treatment response is needed, as well as when other MG treatment options have failed, and before patients start treatment with corticosteroids to reduce the risk of temporary symptom worsening.

In a 2020 update to the guidelines, experts recommend early treatment with high-dose corticosteroids in combination with IVIG or plasmapheresis in patients who develop MG as a side effect of immune checkpoint inhibitors, a type of anti-cancer medication that works to boost the body’s immune response against cancer cells. The use of IVIG as a long-term maintenance treatment can also be considered in patients with refractory, or difficult-to-treat, MG, or when immunosuppressants are contraindicated.

IVIG is infused slowly into a vein over the course of a few hours, often in a hospital or clinical setting. The therapy is usually well tolerated. When side effects do occur, most are temporary and mild to moderate in severity. Some patients need repeated infusions over months or even years, which may further step up the cost of IVIG treatment for MG.

How does IVIG work?

While its exact mechanism of action is not fully understood, it is thought that IVIG works as an immunomodulator in many parallel ways.

IVIG preparations contain a concentrate of immunoglobulins, mostly IgG, the most abundant class of antibodies in circulation. Antibodies are used by the immune system to recognize and respond to specific antigens, or any substance capable of triggering an immune response that may be a potential threat. In autoimmune diseases like MG, however, the body produces self-reactive antibodies against its own proteins, causing damage.

In part, IVIG appears to work by way of anti-idiotypic antibodies, which are directed against the portion of another antibody that recognizes its specific antigen. When delivered into the bloodstream at a high dose, these naturally occurring anti-idiotypic antibodies bind to self-reactive antibodies and prevent them from attacking the body’s own tissues, reducing damage and easing symptoms.

When self-reactive antibodies bind to their targets, they can trigger the activation of the complement cascade — a group of proteins that help the immune system destroy foreign invaders, such as bacteria and viruses. Complement activation is believed to contribute to the autoimmune response that drives MG. IVIG can reduce the activation of the complement cascade by suppressing the activity of certain complement effectors.

Another way IVIG is thought to modulate the immune system is by binding to the neonatal Fc receptor (FcRn), a protein that helps antibodies stay in circulation for longer by protecting them from being destroyed. By saturating FcRn, IVIG effectively accelerates the rate at which self-reactive antibodies are eliminated from the body. In addition, IVIG prevents B-cells, the immune cells that produce antibodies, from growing in number. Together, these actions are expected to reduce the number of antibodies in the blood, including the harmful ones that cause MG.

How long does IVIG take to work in MG?

IVIG is a fast-acting rescue treatment used in patients with severe disease or during an acute exacerbation, when MG symptoms worsen suddenly, or in a myasthenic crisis. IVIG typically starts working within days, reaching a peak around seven to 10 days after an infusion. While response varies from patient to patient, most patients respond to treatment within two weeks, and the benefits can last up to about two months.

How is IVIG administered?

IVIG is given slowly using an infusion pump that delivers controlled amounts of solution directly into a vein, usually in the arm. While IVIG infusion for MG is most often done in a hospital or clinical setting, some patients receive their infusions at home by a trained nurse. An infusion can take up to several hours to be administered.

When used as a rescue treatment, patients typically receive a series of IVIG infusions over a period of three to five days, whereas for maintenance treatment, patients continue to receive their infusions as a single dose every few weeks or months.

IVIG dose for MG

The dose of IVIG for MG depends on a patient’s body weight. To treat an acute exacerbation, IVIG is usually given at a dose of 2 g/kg divided over three to five days. In countries of the European Union and the U.K., where Grifols Therapeutics’ Gamunex 10% is approved to treat severe acute exacerbations of MG, IVIG is given at a dose of 2 g/kg divided over two consecutive days.

For maintenance treatment, the usual dose is 0.4 g/kg given once every three to six weeks. The interval between doses may be adjusted depending on treatment response.

Potential risks and side effects of IVIG

In general, IVIG is well tolerated, and its side effects are usually mild to moderate in severity. Common side effects include:

• headache
• fever
• chills
• chest or back pain
• myalgia (muscle pain).

Immediate side effects tend to occur within an hour of starting the infusion. Fatigue and nausea may also occur after treatment, and usually last less than a day. Skin reactions can develop two to five days after the infusion, and may last up to a month.

In rare cases, IVIG can lead to the formation of blood clots that may cause serious side effects, such as a stroke, pulmonary embolism (blockage of a blood vessel in the lungs), or heart attack. It may also cause severe headaches due to aseptic meningitis, an inflammation of the membrane that covers the brain and spinal cord. IVIG may also cause kidney dysfunction or kidney failure, particularly in older patients with preexisting conditions affecting the kidneys.

Most side effects can be treated or even prevented with medications, such as nonsteroidal anti-inflammatory drugs. In case side effects do occur, the infusion should be slowed or stopped.

There are no absolute contraindications for treatment with IVIG. However, the treatment should be used with caution, or in some cases avoided altogether, in older patients with certain underlying conditions, particularly diabetes, kidney disease, and heart disease. As with other blood products, IVIG also carries some additional risks, including a small risk of transmission of infectious agents, such as viruses.

IVIG in clinical trials

An open-label Phase 3 clinical trial (NCT02413580) tested how safe and well tolerated Gamunex 10%, also known as Gamunex-C in the U.S., was and how well it worked to ease symptoms of MG in 49 adults who had an exacerbation despite being on long-term treatment with corticosteroids.

Patients received Gamunex 10% at a dose of 2 g/kg over two consecutive days. The study’s primary efficacy goal was to assess changes in the scores of the Quantitative MG (QMG) scale, a clinician-rated measure of MG severity, from the study’s start to day 14.

Results showed that over 14 days, or about two weeks, QMG scores decreased by a mean of 6.4 points, indicating less severe symptoms. Most patients (77%) had a decrease of three points or more in the QMG score. Significant reductions in the scores of other measures of MG severity were also seen within the same time span, with more than 80% of the patients being considered responders in each of those measures.

In an earlier controlled trial where 51 patients with worsening muscle weakness due to MG were randomly assigned to receive either IVIG at a dose of 2 g/kg or an equivalent volume of a placebo solution, IVIG outperformed the placebo at decreasing QMG scores over 14 days. The effect was sustained for up to 28 days, or about a month, and was most significant in patients with more severe symptoms.

However, results from a Phase 2 clinical trial (NCT02473965) sponsored by Grifols showed that treatment with Gamunex 10% did not allow a greater reduction in the daily dose of corticosteroids compared with a placebo. Gamunex 10% was given as a loading dose of 2 g/kg, followed by a maintenance dose of 1 g/kg every three weeks for 36 weeks, or about eight months. Tapering of corticosteroids started after three infusions of IVIG, with the proportion of patients achieving a reduction of at least 50% being similar in both groups (60% vs. 63.3%).

A number of randomized clinical trials have tested how safe IVIG is compared with plasmapheresis, a blood-cleaning procedure that reduces the number of disease-causing antibodies in circulation, and how well it works to ease symptoms of MG. Results suggest that both treatments work equally as well. For example, in a Phase 4 clinical trial (NCT01179893) where 84 patients with moderate to severe MG were randomly assigned to Gamunex 10% at a dose of 2 g/kg, divided into two days, or plasmapheresis, a similar proportion of patients saw their symptoms improve within 14 days (69% vs. 65%).

Cost of IVIG treatment for MG

IVIG can be costly. Its cost is influenced by a series of factors, including a patient’s body weight, the number of infusions needed, the length of treatment, and the specific brand used.

One U.S. study showed that patients on long-term treatment with IVIG who had more frequent episodes of exacerbation incurred median annual costs that were approximately 32 times higher compared with patients who did not receive IVIG. An earlier study estimated that the average annual costs of IVIG treatment for MG can amount to more than $90,000 in the U.S. per patient, an estimate that also accounted for the costs of hospital stays and potential complications.

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