Immunoglobulin therapy

Immunoglobulin therapy is therapy with antibody (immunoglobulin) mixtures, given via intravenous, subcutaneous, or intramuscular routes of administration, used to treat or prevent a variety of diseases. Immunoglobulin as used in infusions contains the pooled polyvalent IgG antibodies extracted from the plasma of thousands of blood donors. The effects of immunoglobulin generally last between two weeks and three months, although most subcutaneous brands of immunoglobulin are designed to be administered 1–2 times a week, and for most purposes intravenous immunoglobulin is administered once every 3–4 weeks. One currently marketed preparation of subcutaneous immunoglobulin, HyQvia, uses hyaluronidase in order to allow for greater injection volumes and thus less frequent administration times than other forms of subcutaneous immunoglobulin (once every 3–4 weeks.)^[1] Additionally, some diseases, such as myasthenia gravis may only require immunoglobulin treatment once every 3–4 months.^[2]

Immunoglobulin therapy is primarily used to treat several categories of disease for which it is an approved indication. In addition, frequent off-label uses include primary immunodeficiencies such as common variable immunodeficiency (CVID), secondary immunodeficiencies such as human immunodeficiency virus (HIV), some autoimmune disorders such as immune thrombocytopenia and Kawasaki disease, some neurological diseases, some acute infections, and some complications of organ transplantation.^[3] The ability of immunoglobulin therapy to confer temporary passive immunity (which depends on the immunity of the immunoglobulin donors) is most relevant when the indication is immunodeficiency.

As biologicals, various trade names of immunoglobulin products are not necessarily interchangeable, and care must be exercised when changing between them.^[4] Trade names of intravenous immunoglobulin formulations include Flebogamma, Gamunex, Privigen and Gammagard, while trade names of subcutaneous formulations include HyQvia, Hizentra, Gamunex-C, and Gammaked.^[5] Intramuscular formulations of immunoglobulin have generally fallen out of favor, although intramuscular forms of hyperimmune globulin are still preferred for treatment of conditions such as tetanus and certain other things.^[6]

Although immunoglobulin is an important, often life-saving therapy, it can have severe side effects. The FDA requires immunoglobulin products to carry a black box warning^[7] cautioning that immunglobulin has been associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death, especially in the elderly or with simultaneous use of other nephrotoxic drugs or other pre-existing issues that affect the kidneys. Immunoglobulin is also associated with a number of other side effects detailed further in the article, and is contraindicated in any patient known to experience anaphylaxis or severe systemic reactions when exposed to immunoglobulin or any component of an individual immunglobulin product those with hereditary intolerance to fructose, anyone with IgA deficiencies coupled with antibodies against IgA (as immunoglobulin infusions contain very small amounts of IgA). Most immunoglobulin products except Hizentra and Privigen are also contraindicated in anyone with Hyperprolinemia, and intramuscular immunoglobulin injections (which are now rarely used) are contraindicated in anyone with a severe coagulation disorder.^[7]

Medical use

Immunoglobulin therapy is used in patients with a variety of conditions, many of which involve decreased or abolished antibody production capabilities, which range from a complete absence of multiple types of antibodies, to IgG subclass deficiencies (usually involving IgG2 or IgG3,) to other disorders in which antibodies are within a normal quantitative range, but lacking in quality - unable to respond to antigens as they normally should – resulting in an increased rate or increased severity of infections. In these situations, immunoglobulin infusions confer passive resistance to infection on their recipients by increasing the quantity/quality of IgG they possess. Immunoglobulin therapy is also used for a number of other conditions, including in many autoimmune disorders such as dermatomyositis in an attempt to decrease the severity of symptoms. Immunoglobulin therapy is also used in some treatment protocols for secondary immunodeficiencies such as human immunodeficiency virus (HIV,) some autoimmune disorders (such as immune thrombocytopenia and Kawasaki disease,) some neurological diseases, some acute infections, and some complications of organ transplantation.^[3]

Immunoglobulin therapy is especially useful in some acute infection cases such as pediatric HIV infection and is also considered the standard of treatment for some autoimmune disorders such as Guillain–Barré syndrome.^[8][9] The high demand which coupled with the difficulty of producing immunoglobulin in large quantities has resulted in increasing global shortages, usage limitations, and rationing of immunoglobulin.^[10] The United States is one of a handful of countries that allow plasma donors to be paid, meaning that the US supplies much of the plasma-derived medicinal products (including immunoglobulin) used across the world, including more than 50% of the European Unions supplies.^[11] The Council of Europe has officially endorsed the idea of not paying for plasma donations for both ethical reasons and reasons of safety, but studies have found that relying on entirely voluntary plasma donation leads to shortages of immunoglobulin, and forces member countries to import immunoglobulin from countries that do compensate donors.^[11]

Different national bodies and medical associations have established varying standards for the use of immunoglobulin therapy. The United Kingdom's National Health Service recommending routine use of immunoglobulin for a variety of conditions including primary immunodeficiencies and a number of other conditions, but recommending against the use of immunoglobulin in sepsis (unless a specific toxin has been identified,) multiple sclerosis, neonatal sepsis, and pediatric HIV.^[12] The American Academy of Allergy, Asthma, and Immunology most strongly supports the use of immunoglobulin for primary immunodeficiencies, while noting that such usage actually accounts for a minority of usage, and acknowledging that immunoglobulin supplementation can be appropriately used for a number of other conditions,^[13] including neonatal sepsis (citing a sixfold decrease in mortality,) considered in cases of HIV (including pediatric HIV,) considered as a second line treatment in relapsing-remitting multiple sclerosis, but recommending against its use in such conditions as chronic fatigue syndrome, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) until further evidence to support its use is found (though noting that it may be useful in PANDAS patients with an autoimmune component,) cystic fibrosis, and a number of other conditions.^[14] The National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services have also developed their own separate set of guidelines for the appropriate use of immunoglobulin therapy, which strongly support the use of immunoglobulin therapy in primary immunodeficiencies and some complications of HIV, while remaining silent on the issues of sepsis, multiple sclerosis, and chronic fatigue syndrome.^[15]

Side effects

Although immunoglobulin is frequently used for long periods of time, and is generally considered safe, immunoglobulin therapy can have severe adverse effects, both localized and systemic. Subcutaneous administration of immunoglobulin is associated with a lower risk of both systemic and localized risk when compare to intravenous administration (hyaluronidase-assisted subcutaneous administration is associated with a greater frequency of adverse effects than traditional subcutaneous administration, but still a lower frequency of adverse effects when compared to intravenous administration.) Patients who take immunoglobulin are often recommended to take acetaminophen and diphenhydramine before their infusions to reduce the rate of adverse effects, as well as sometimes (especially when first getting accustomed to a new dosage,) prednisone or another oral steroid.

Local side effects of immunoglobulin infusions most frequently include an injection site reaction (reddening of the skin around the injection site,) itching, rash, and hives.^[7] Less serious systemic side effects to immunoglobulin infusions include an increased heart rate, hyper or hypotension, an increased body temperature, diarrhea, nausea, abdominal pain, vomiting, arthralgia or myalgia, dizziness, headache, fatigue, fever, and pain.^[7] Serious side effects of immunoglobulin infusions include chest discomfort or pain, myocardial infarction, tachycardia hyponatremia, hemolysis, hemolytic anema, thrombosis, hepatitis, anaphylaxis, backache, aseptic meningitis, acute renal failure, hypokalemic nephropathy, pulmonary embolism, and transufion related lung injury.^[7] There is also a small chance that even given the precautions taken in preparing immunoglobulin preparations, an immunoglobulin infusion may pass a virus to its recipient.^[7] Some immunoglobulin solutions also contain isohemagglutinins, which in rare circumstances can cause hemolysis by the isohemagglutinins triggering phagocytosis.^[16] In the case of less serious side effects, a patient's infusion rate can be adjusted downwards until the side effects become tolerable, while in the case of more serious side effects, emergency medical attention should be sought.^[17]

Immunoglobulin therapy also interferes with the ability of the body to produce a normal immune response to an attenuated live virus vaccine for up to a year,^[7] can result in falsely elevated blood sugar levels,^[7] and can interfere with many of the IgG-based assays often used to diagnose a patient with a particular infection.^[18]

Routes of administration

After immunoglobulin therapy's discovery and description in Pediatrics in 1952, weekly intramuscular injections of immunoglobulin (IMIG) were the norm until intravenous formulations (IVIG) began to be introduced in the 1980s.^[19] Intramuscular injections were extremely poorly tolerated due to their extreme pain and poor efficacy - rarely could intramuscular injections alone raise plasma immunoglobulin levels enough to make a clinically meaningful difference.^[19] Intravenous formulations began to be approved in the 1980s, which represented a significant improvement over intramuscular objections, as they allowed for a sufficient amount of immunoglobulin to be injected to reach clinical efficacy, although they still had a fairly high rate of adverse effects (though the addition of stabilizing agents reduced this further.)^[19] The first description of a subcutaneous route of administration for immunoglobulin therapy dates back to 1980, but for many years subcutaneous administration was considered to be a secondary choice, only to be considered when peripheral venous access was no longer possible or tolerable.^[19] During the late 1980s and early 1990s, it became obvious that for at least a subset of patients the systemic adverse events associated with intravenous therapy were still not easily tolerable, and more doctors began to experiment with subcutaneous immunoglobulin administration, culminating in an ad hoc clinical trial in Sweden of 3000 subcutaneous injections administered to 25 adult patients (most of whom had previously experienced systemic adverse effects with IMIG or IVIG,) where no infusion in the ad hoc trial resulted in a severe systemic adverse reaction, and most subcutaneous injections were able to be administered in non-hospital settings, allowing for considerably more freedom for the patients involved.^[19] In the later 1990s, large-scale trials began in Europe to test the feasibility of subcutaneous immunoglobulin administration, although it was not until 2006 that the first subcutaneous-specific preparation of immunoglobulin was approved by a major regulatory agency (Vivaglobin, which was voluntarily discontinued in 2011.)^[19][20] A number of other trade names of subcutaneous immunoglobulin have since been approved, although some small-scale studies have indicated that a particular cohort of patients with CVID may suffer intolerable side effects with SCIG that they do not with IVIG.^[19]

Although intravenous was the preferred route for immunoglobulin therapy for many years, in 2006 the FDA approved the first preparation of immunoglobulin that was designed exclusively for subcutaneous use.^[19]

Mechanism of action

The precise mechanism by which immunoglobulin therapy suppresses harmful inflammation is likely multifactorial. For example, it has been reported that immunoglobulin therapy can block Fas-mediated cell death.^[21]

Perhaps a more popular theory is that the immunosuppressive effects of immunoglobulin therapy are mediated through IgG's Fc glycosylation. By binding to receptors on antigen presenting cells, IVIG can increase the expression of the inhibitory Fc receptor, FcgRIIB, and shorten the half-life of auto-reactive antibodies.^[22][23][24] The ability of immunolobulin therapy to suppress pathogenic immune responses by this mechanism is dependent on the presence of a sialylated glycan at position CH2-84.4 of IgG.^[22] Specifically, de-sialylated preparations of immunoglobulin lose their therapeutic activity and the anti-inflammatory effects of IVIG can be recapitulated by administration of recombinant sialylated IgG1 Fc.^[22]

There are several other proposed mechanisms of action and the actual primary targets of immunoglobulin therapy in autoimmune disease are still being elucidated. Some believe that immunoglobulin therapy may work via a multi-step model where the injected immunoglobulin first forms a type of immune complex in the patient.^[25] Once these immune complexes are formed, they can interact with Fc receptors on dendritic cells^[26] which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state.

Other proposed mechanisms include the possibility that donor antibodies may bind directly with the abnormal host antibodies, stimulating their removal; the possibility that IgG stimulates the host's complement system, leading to enhanced removal of all antibodies, including the harmful ones; and the ability of immunoglobulin to block the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis. Indeed, it is becoming more clear that immunglobulin can bind to a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to auto reactivity and induction of tolerance to self.^[22][27]

A recent report stated that immunoglobulin application to activated T cells leads to their decreased ability to engage microglia. As a result of immunoglobulin treatment of T cells, the findings showed reduced levels of tumor necrosis factor-alpha and interleukin-10 in T cell-microglia co-culture. The results add to the understanding of how immunoglobulin may affect inflammation of the central nervous system in autoimmune inflammatory diseases.^[28]

References

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2. Wegner, B; Ahmed, I (December 2002). "Intravenous immunoglobulin monotherapy in long-term treatment of myasthenia gravis.". Clinical neurology and neurosurgery 105 (1): 3–8. doi:10.1016/s0303-8467(02)00017-3. PMID 12445915.
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5. Berman, Keith. "SCIG: New Therapeutic Uses Beyond PI?" (PDF). IG Living (February–March 2015): 28–32. Retrieved 23 November 2015.
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9. Hughes, R.A.C.; Wijdicks, E.F.M.; Barohn, R.; Benson, E.; Cornblath, D.R.; Hahn, A. F.; Meythaler, J.M.; Miller, R.G.; Sladky, J.T.; Stevens, J.C. (22 September 2003). "Practice parameter: Immunotherapy for Guillain-Barre syndrome: Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology 61 (6): 736–740. doi:10.1212/WNL.61.6.736.
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17. "HIGHLIGHTS OF PRESCRIBING INFORMATION: HYQVIA [Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase] Solution for subcutaneous administration" (PDF). FDA.
18. Lichtiger, Lichtiger. "Laboratory Serologic Problems Associated with Administration of Intravenous IgG". Current Issues in Transfusion Medicine. he University of Texas M. D. Anderson Cancer Center. Retrieved 23 November 2015.
19. Skoda-Smith, Suzanne; Torgerson, Troy; Ochs, Hans (16 December 2009). "Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease". Therapeutics and Clinical Risk Management. 2010:6. doi:10.2147/tcrm.s4353.
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22. Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMID 25578468.
23. Gern JE (August 2002). "Antiinflammatory Activity of IVIG Mediated through the Inhibitory FC Receptor". Pediatrics 110 (2): 467–8. doi:10.1542/peds.110.2.S1.467-b.
24. Nimmerjahn F, Ravetch JV (January 2007). "The antiinflammatory activity of IgG: the intravenous IgG paradox". J. Exp. Med. 204 (1): 11–5. doi:10.1084/jem.20061788. PMC 2118416. PMID 17227911.
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28. Janke AD, Yong VW (April 2006). "Impact of IVIg on the interaction between activated T cells and microglia". Neurol. Res. 28 (3): 270–4. doi:10.1179/016164106X98143. PMID 16687052.