Pharmacology

Intravenous immune globulin contains a broad spectrum of antibodies against bacterial, viral, and parasitic antigens that are capable of opsonization of, as well as neutralization of, microbes and toxins. Appropriate doses can restore low IgG levels to normal range.

Pharmacodynamics. Intravenous immune globulin is a modulator of the immune system and affects many different pathways to modulate the immune and inflammatory response (02). Various possible mechanisms of action are:

• Neutralization of pathogenic autoantibodies. • Suppression of cytokines. • Inhibition of complement binding. • Blockade of Fc receptors. • Modulation of T-cell function. • Selective modulation of circulating proinflammatory cytokines. • Activation of regulatory macrophages through the FcγRIIb receptor. • Modulation of adhesion molecules and cell receptors.

Pharmacokinetics. Important features are as follows:

• Bioavailability is 100% after intravenous injection. • A 5-fold rise of serum IgG following intravenous injection with a decline to 50% in 3 days and return to normal in 3 to 4 weeks. • A 2-fold rise of CSF level of IgG following intravenous injection and a return to normal within a week. • The half-life of intravenous immune globulin varies from 2 to 4 weeks.

Subcutaneous immunoglobulin (SCIG) has emerged as an alternative to intravenous immune globulin, but the dose to be prescribed needs to be determined because its pharmacokinetics differs from that of intravenous immune globulin. Dose-adjustment coefficient is used when patients are switched from intravenous immune globulin to subcutaneous immunoglobulin. A dosing method uses a higher ratio of intravenous immune globulin to subcutaneous immunoglobulin and increase of dose based on clinical status, body weight, and concurrent diseases (15). A highly concentrated (20%) immunoglobulin G preparation for subcutaneous administration provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment (05).

Clinical trials

Most of the earlier studies with intravenous immune globulin in neurologic disorders are based on anecdotal evidence or uncontrolled clinical trials. Controlled studies have been carried out in the treatment of multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, and myositis. Currently, only one double-blind placebo-controlled randomized clinical trial for Guillain-Barré syndrome is ongoing; the trial is investigating the benefit of a second intravenous immune globulin dose in patients with poor prognosis (34).

Data from a multicenter randomized clinical trial support a favorable safety and tolerability profile for administration of intravenous immune globulin maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy (10).

Indications

FDA-approved indications for the use of intravenous immune globulin are:

(1) The maintenance treatment of primary immunodeficiency states as shown below:
	Category	Disease
	T-lymphocyte disorders	DiGeorge syndrome
	B-lymphocyte disorders	X-linked agammaglobulinemia Common variable immunodeficiency
	Combined T- and B-lymphocyte disorders	Wiskott-Aldrich syndrome Ataxia telangiectasia Severe combined immunodeficiency
(2) Chronic lymphocytic leukemia
(3) Kidney transplantation involving a recipient with a high antibody titer or an ABO-incompatible donor
(4) Autologous bone marrow transplantation
(5) Pediatric HIV infection
(6) Kawasaki disease
(7) Neurologic disorders
	• chronic inflammatory demyelinating polyneuropathy • multifocal motor neuropathy

Additional approved indications with criteria, which include medical certainty of diagnosis, medical necessity owing to the failure of usual treatments, contraindications to usual treatments, rapid progression or relapse, documentation of progress, and attempts to adjust drug dosages without improvement, include the following neuromuscular disorders (19):

• Guillain-Barré syndrome • relapsing-remitting multiple sclerosis • myasthenia gravis • refractory polymyositis • polyradiculoneuropathy • Lambert-Eaton myasthenic syndrome • opsoclonus-myoclonus • birdshot retinopathy • refractory dermatomyositis

A retrospective review of prescribing practices of intravenous immune globulin in the intensive care unit revealed that it was used infrequently, and among the neurologic conditions, the most common indication was Guillain-Barré syndrome (18).

In Guillain-Barré syndrome patients with contraindications for plasma exchange, intravenous immune globulin may be beneficial. Therapeutic intravenous immune globulin is capable of neutralizing neuromuscular blocking antibodies in Guillain-Barré syndrome by a dose-dependent, antibody-mediated mechanism, which may partly explain its therapeutic efficacy. Intravenous immune globulin was used successfully to treat a patient with sarcoidosis who developed Guillain-Barré syndrome; the patient experienced full recovery of neurologic function (17).

Intravenous immune globulin is a therapeutic option for multifocal motor neuropathy. Intravenous immune globulin is considered an effective and safe treatment for autoimmune neuropathies, especially in comparison to the alternative treatments such as corticosteroids, chemotherapy, and plasmapheresis. A review of intravenous immune globulin use at the Massachusetts General Hospital showed that it was most commonly used in the treatment of chronic neuropathy, which included chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy (09). A randomized placebo-controlled trial has shown the short-term and long-term efficacy as well as safety of intravenous immune globulin for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (21). The ICE study showed intravenous immune globulin to be clinically effective for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy in both the short and long term (30). The evidence from randomized controlled trials in The Cochrane Database of Systematic Reviews shows that intravenous immunoglobulin improves disability for at least 2 to 6 weeks compared with placebo (12).

Intravenous immunoglobulin treatment for acute exacerbations of myasthenia gravis has been shown in several open-label studies. Intravenous immunoglobulin maintenance therapy is also a valid method of treatment for patients with myasthenia gravis who are resistant to conventional therapy (29).

Conditions for which use of intravenous immune globulin is not recommended. According to the guidelines on the use of intravenous immune globulin for neurologic conditions, intravenous immune globulin was not recommended for 8 conditions, including adrenoleukodystrophy, amyotrophic lateral sclerosis, autism, critical illness polyneuropathy, inclusion body myositis, intractable childhood epilepsy, paraproteinemic neuropathy, and POEMS syndrome (16).

Off-label and investigational uses. An extensive review of the unlabeled uses of intravenous immune globulin showed that the most common off-label indications include graft-versus-host disease in transplant patients, prevention of antiphospholipid syndrome in miscarriage, and progression of human immunodeficiency virus after delivery (23). Intravenous immune globulin is prescribed for 90 different indications in Canada, 6 of which are licensed. The use of intravenous immune globulin in neurologic disorders is considered in antibody-mediated autoimmune disorders. It has been used in the following conditions:

	• Severe acute disseminated encephalomyelitis
	• Pontine myelinolysis
	• Stiff-man syndrome
	• Dysphagia of inclusion body myositis
	• Hereditary recurrent brachial plexus neuropathy
	• Intravenous immune globulin is effective in preventing attacks and enhancing neurologic recovery in relapses of neuromyelitis optica (13).
	• Diabetic amyotrophy
	• Hereditary inclusion body myopathy
	• Alzheimer disease
	• Low-dose intravenous immunoglobulin may substantially reduce pain in some patients with refractory complex regional pain syndrome (20).
	• Treatment with intravenous immune globulin has been reported to benefit 80% of children with unexplained pain syndromes and evidence of small-fiber polyneuropathy (27).
	• A systematic review and metaanalysis of literature concluded that the use of intravenous immune globulin is associated with significant reduction in disease activity of systemic lupus erythematosus (28).
	• Statin-triggered autoimmune myopathy (25)
	• Idiopathic inflammatory myopathies that are refractory to other treatments or in patients with severe dysphagia or concomitant infections (26)
	• Intravenous immune globulin therapy has been reported to result in the complete reversal of the movement and sleep disorders in postencephalitic parkinsonism (07).
	• Intravenous immunoglobulin followed by dexamethasone treatment has been reported to result in recovery from coma in a patient with Hashimoto encephalitis, a complication of Hashimoto thyroiditis with antineuronal antibodies to glutamate receptor alfa-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR), which is important for synaptic transmission (36).
	• A patient with Gastaut-Geschwind syndrome had symptomatic relief following treatment with steroids and intravenous immune globulin (03).
	• Steroids plus intravenous immune globulin has been used for treatment of immune-mediated necrotizing myopathy (24).
	• Effectiveness of intravenous immune globulin in COVID-19 is controversial. In an uncontrolled study, intravenous immune globulin was claimed to reduce the use of artificial ventilation, shorten the length of hospital stay, and reduce mortality in COVID-19 patients with severe pneumonia (35). Findings of a randomized placebo-controlled trial did not support the use of intravenous immunoglobulin in combination with hydroxychloroquine and lopinavir/ritonavir in treatment of severe COVID-19 cases (31).
	• A patient with COVID-19-associated meningoencephalitis improved after treatment with intravenous immunoglobulin (14).

Contraindications

Contraindications for intravenous immune globulin include patients with selective IgA deficiency who possess antibodies to IgA and patients who have had severe systemic reactions to previous injections of human immune globulin.

Goals and duration of treatment

Intravenous immune globulin is a safe and effective therapy for Guillain-Barré syndrome, but some cases may not respond to it or may get worse. Treatment is usually long-term.

Intravenous immune globulin is the preferred first-line treatment for chronic inflammatory demyelinating polyradiculoneuropathy and is effective in two thirds of patients. Rebound relapses may occur and require supplementary treatments with prednisone and cyclophosphamide.

Intravenous immune globulin is an adjunctive therapy for myasthenia gravis where no other therapy is effective. It may be used as an interim therapy until other treatments start to take effect and can be used on a monthly or bimonthly basis.

In myositis, improvement of muscle strength is seen in some patients, but it is short-lived (1 to 2 months), and treatments need to be repeated. In some patients it has been used for several years. Some patients may not require any intravenous immune globulin and maintain the improvement.

Currently, no evidence supports the efficacy of intravenous immune globulin in multiple sclerosis.

Dosing

The usual dose is 200 mg/kg of body weight administered once a month by intravenous injection. In immunodeficiency states, immunoglobulins should be administered in sufficient doses to maintain plasma trough levels of greater than 500 mg/dL; this usually requires a monthly dose of between 400 and 500 mg/kg. The administered dose can be calculated based on plasma immunoglobulin level, which increases approximately 250 mg/dL for every 100 mg/kg infused. Because of the drug half-life differences among individuals, the dose must be individualized, with immunoglobulin trough levels monitored every 3 months for the first 4 to 8 months.

Special considerations

Administration of intravenous immune globulin can cause serologic challenges for transfusion service, including ABO discrepancies, positive direct antiglobulin tests, positive antibody detection tests, and incompatible crossmatches (06).

Anesthesia. No special precautions need to be taken.

Pregnancy. Animal reproduction studies have not been carried out with intravenous immune globulin. It should be used in pregnancy only if indicated. Intravenous immune globulin can cross the placental barrier into fetal circulation.

Pediatric. No specific hazards.

Geriatric. No specific hazards.

Interactions

Antibodies in intravenous immune globulin may interfere with response to vaccines containing live viruses.

Adverse effects

Although intravenous immunoglobulins are plasma-derived and may, therefore, carry the risk of transmitting viral infections, they have been used safely for years. This is due to the well-established fractionation and viral inactivation procedures used in their production. Adverse reactions are rare and occur in less than 1% of patients. The following are worth noting:

	• A retrospective study of the use of intravenous immune globulin for patients with neuromuscular disorders has shown that it is generally safe, but women, myasthenia gravis patients, and those receiving their first course or a higher total dose of the drug are at an increased risk of experiencing an adverse event (33).
	• Patients who receive intravenous immune globulin treatment for the first time may have an acute inflammatory reaction manifested by fever, nausea, and vomiting, which may lead to shock. The patient's vital signs should be monitored, and epinephrine should be available for treatment of an acute anaphylactic reaction.
	• Thromboembolic events due to increased serum viscosity are liable to occur in patients with hypercholesterolemia and cryoglobulinemia. Because of this effect, a warning has been issued by the manufacturer and the FDA since 2002. Hemodilution therapy may be required. Although the exact cause of the clot-related problems is unknown, rapid infusion of intravenous immunoglobulin is considered a possible risk factor. Statements advising caution in administering intravenous immunoglobulin to patients with cardiovascular disease or previous clot-related problems have been added to the labeling of the product, and healthcare workers have been advised to carefully evaluate patients with risk factors such as coronary artery disease, hypertension, cerebrovascular disease, and diabetes. In a retrospective study on patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia or multiple myeloma on intravenous immune globulin therapy, a statistically insignificant increase in risk of 0.3% compared with a baseline risk of 1.1% was observed for the venous thromboembolic endpoint (01).

A patient with Miller Fisher syndrome made an unremarkable recovery with intravenous immunoglobulin therapy but later developed a cerebral infarct with hemorrhagic transformation, which was attributed to a combination of circulating intravenous immunoglobulins and low blood pressure (08). As a preventive measure, a lower rate of infusion and smaller dosages of intravenous immune globulin should be used with close monitoring of patients for potential stroke.

	• Intravenous immune globulin-induced nephropathy. Acute renal tubular necrosis may occur rarely with intravenous immune globulin therapy in patients with preexisting renal disease, and it is likely due to intravenous solutions containing hypertonic sucrose. Dilution of intravenous immune globulin preparation and a slowing of the rate of infusion lower the risk.
	• Cases of aseptic meningitis have been reported. Aseptic meningitis has observed in both low-dose and high-dose regimens of intravenous immune globulin, and females are affected nearly 4 times more frequently than males, but subcutaneous administration may be associated with a lower rate of this adverse reaction compared with intravenous administration (04).
	• Headache is a common adverse effect associated with the administration of IVIG. Migraine headaches could be triggered in patients with a previous history of migraine. This can be prevented by pretreatment with propranolol. The headache can be managed by sumatriptan. A personalized approach should take into consideration the patient's condition, specific IVIG product used, history of migraine, and previously failed and successful therapies (32).
	• Cerebrovascular events have been reported: hemiplegia, cerebral infarction, and encephalopathy believed to be due to reversible cerebral vasospasm. Acute hypertension, leukoencephalopathy, ischemic as well as hemorrhagic strokes, and reversible cerebral arterial vasoconstriction developed shortly after initiating intravenous immune globulin therapy in a patient with Guillain-Barré syndrome (11). In most of the cases, patients recovered after discontinuation of intravenous immune globulin, and no special treatment was required.
	• Transmission of viral infections is extremely rare; although hepatitis C has been reported. There is a theoretical concern about Creutzfeldt-Jakob disease, but no case has been reported so far.