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Immunoglobulin Use in Immune Deficiency and Autoimmune Disease States
Elena E. Perez, MD, PhD
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Leslie J. Vaughan, BS, RPh
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Immunoglobulin Use in Immune Deficiency and Autoimmune Disease States

Elena E. Perez, MD, PhD
Although immunoglobulin (Ig) has been available since the 1950s for replacement therapy in primary immune deficiency, many other effective uses of this class of biologics have been investigated and evolved over recent decades. Ig administration has become common practice in the treatment of the immunocompromised patient and has recently expanded into the treatment of those patients with an inflammatory disease and autoimmune neuropathies per established clinical guidelines. As research into the genetic basis of disease advances, clinicians should better assess complex data surrounding safe and effective uses of Ig to treat patients who present with B-cell and T-cell deficiencies, along with those harboring gene deletions or genetic anomalies who may potentially benefit from Ig therapy. Evidence-based clinical indications for the use of Ig include idiopathic thrombocytopenic purpura, B-cell chronic lymphocytic leukemia, Kawasaki disease, chronic idiopathic demyelinating polyneuropathy, multifocal motor neuropathy, bone marrow transplantation, and pediatric HIV infection, among others, and have evolved over time. Ig is also often tried in refractory cases that might benefit from its anti-inflammatory effects or empirically in off-label situations. Due to its anti-inflammatory effects, high-dose Ig has been used for numerous off-label indications with varying levels of effectiveness and evidence to support its use. A review of all autoimmune conditions for which Ig has been used is beyond the scope of this article and newer treatments are available for many of these disorders. Here the focus will be on selected conditions in which Ig has clear benefit. Because there is a limited supply of Ig and a need for further research into optimal use, it is important for healthcare professionals to better understand current and developing indications and data/levels of evidence to support Ig therapy as its role continues to evolve. 

Am J Manag Care. 2019;25:-S0
Overview of the History of the Use of Immunoglobulin

The history of treating disease with antibodies began in the 1800s after tetanus and diphtheria toxins were discovered, leading to the realization that immunity to the infections caused by these organisms could be transferred through immune serum. Results of research determined that antibody proteins could be isolated and used as a defense against infectious disease. The arrival of scientific methods to separate antibodies from plasma for safe human injection was the starting point for development of human gamma globulin for individuals with inherited antibody deficiencies.1

However, these early immunoglobulin (Ig) treatments were limited by an intramuscular or subcutaneous (SC) route of administration due to low product purity. Ig was shown to be effective for prophylaxis for those exposed to measles or hepatitis A infections. The standard dose at the time was approximately 100 to 150 mg/kg; however, intravenous (IV) administration of these doses to children with measles resulted in severe adverse effects (AEs), including convulsions, fever, restlessness, chills, and even vasomotor collapse. These reactions limited Ig use to administration via intramuscular or SC routes at that time.1,2 The desire to deliver larger Ig doses led to changes in manufacturing to produce safe IV injectable formulations. This administration route allowed for Ig to be used for a wider variety of clinical conditions. Treatment with Ig was expanded to allow for larger doses for disease suppression in inflammatory and autoimmune disorders. Further research led to more concentrated Ig formulations that can be injected SC for therapy. In addition, home-based SC infusion methods entered the treatment landscape, allowing for improved and more convenient access for patients who needed Ig therapy.1

Immunoglobulins are antibodies produced by differentiated B cells called plasma cells. The Ig molecule has a distinctive structure that has the ability to recognize specific antigenic determinants. Ig formulations are produced from the pooled human plasma of thousands of healthy donors, which allows the Ig formulations to contain a large and diverse antibody repertoire.3 It is important to understand that the supply of Ig is finite because it depends on donated plasma. Appropriate administration of Ig can be lifesaving, and clinicians must be familiar with how to manage any associated AEs. Clinicians prescribing Ig need to better recognize current clinical indications for Ig therapy and the levels of evidence to support its use in immune disorders.4

Disease State Overviews, Place of Immunoglobulin in Therapy, and Evidence for Use

Primary Immunodeficiency Diseases

Primary immunodeficiency diseases comprise a heterogenous collection of genetic disorders that impact distinct elements within the innate and adaptive immune system; these may include macrophages, natural killer cells, dendritic cells, neutrophils, complement proteins, B lymphocytes, and T lymphocytes.3 Primary immunodeficiencies are relatively uncommon. They are inherited genetic disorders that may occur alone or as part of a syndrome, and heterogeneity may be substantial within each disorder. Primary immunodeficiencies tend to become apparent during infancy or childhood, but many primary immunodeficiencies present in adulthood. The estimated overall incidence of primary immunodeficiencies is 1 per 1200 individuals.5,6 Originally, a male-to-female ratio ranging from 2:1 to 1.4:1 was reported; however, this ratio was found to be closer to 1:1 in more recent data from a US cohort.7,8 Recent advances in molecular and cellular characterizations of these disorders have delineated their genetic complexity with an estimated 354 inborn errors of immunity defined as of February 2017.9


Agammaglobulinemia comprises a class of primary immunodeficiency diseases characterized by absent or very low serum antibodies caused by the absence of B lymphocytes in both blood and bone marrow.4,10 Although the exact incidence of agammaglobulinemia has yet to be elucidated, it has been estimated overall to affect approximately 1 in 300,000 individuals, with X-linked agammaglobulinemia (XLA), having an estimated prevalence ranging between 1 in 350,000 to 1 in 700,000.11,12 This disorder is further classified into 3 subclasses: XLA, XLA with growth hormone deficiency, and autosomal recessive agammaglobulinemia.10 The XLA form of the disorder is caused by a defect in the Bruton tyrosine kinase gene, which is vital to B-cell maturation and development. Because this gene is located on the X chromosome, only males are affected, whereas females are carriers. This form of the disorder comprises approximately 85% of agammaglobulinemia cases.11

The major symptoms associated with agammaglobulinemia are frequent and severe bacterial infections due to failures in immune response related to the B-cell defects.10 They usually manifest as recurrent upper and lower respiratory tract infections and begin within the first few years of life in patients with XLA.13 The respiratory infections related to agammaglobulinemia are most often caused by bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type B, Streptococcus pyogenes, and Pseudomonas. Antibody binding is critical for the clearance of these microorganisms. The recurrence of respiratory infections in young patients creates substantial morbidity during the active illness and may also increase the patient’s risk for developing chronic lung disease. Repeated episodes of pneumonia can result in chronic airway inflammation, such as bronchiectasis and scarring.11,13,14

Agammaglobulinemia caused by a lack of B cells is the clearest indication for the replacement of Ig.4 Historical retrospective data of children with agammaglobulinemia have demonstrated that both the number and severity of complications related to infection are inversely correlated with intravenous immunoglobulin (IVIG) dose administrations.4,15,16 In fact, serious bacterial illness was prevented when immunoglobulin G (IgG) trough levels were maintained above 500 mg/dL.4,16

More recently, a study by Orange et al centered on the question of the effect of trough level on the incidence of pneumonia. The investigators performed a meta-analysis of clinical trial studies evaluating trough IgG and pneumonia incidence in patients with hypogammaglobulinemia primary immunodeficiencies. This encompassed 17 studies with 676 total patients and 2127 patient-years of follow-up. Results demonstrated that the incidence of pneumonia declined by 27% with each 100 mg/dL increment in trough IgG level. The pneumonia risk for patients at trough levels of 1000 mg/dL was one-fifth of those whose trough levels were 500 mg/dL. Overall, the findings suggest that pneumonia risk can be progressively reduced by higher trough IgG levels.4,17,18


Hypogammaglobulinemia occurs when Ig levels in the serum decrease or there is a significant lack of IgG antibody response to an antigen vaccine challenge. In these patients, deficient antibody production leads to decreased Ig concentrations and a considerable inability of a patient to have an IgG antibody response to challenge with an antigen. Notable diagnostic factors associated with hypogammaglobulinemia include recurrent infections (S pneumoniae or H influenzae), infections caused by atypical pathogens, and repeated use of antibiotics for treatment. Primary hypogammaglobulinemia affects young children and adults. Examples of primary immunodeficiencies that fall into this category include combined immunodeficiency disorders, combined immunodeficiency with syndromic features, such as Wiskott-Aldrich syndrome (WAS), hyper-immunoglobulin M (IgM) syndromes, and diseases of immune dysregulation with autoimmunity.4

Ig replacement is indicated for patients with recurrent bacterial infections and reduced serum Ig levels who also fail to respond to a protein or polysaccharide vaccine challenge. For example, a patient may be unable to make IgG antibodies against the tetanus toxoid and/or pneumococcal polysaccharide vaccines. A patient with common variable immunodeficiency (CVID) is a typical example, as CVID is the most frequently diagnosed heterogenous disorder related to antibody deficiency.4 An international consensus definition of CVID was recently published and includes the following criteria for diagnosis: a low IgG level measured on at least 2 occasions 3 weeks apart (repeated measurement may be eliminated if the IgG level is 100-300 mg/dL), low IgM and/or IgA, impaired antibody response (vaccine responses) to at least 1 type of T dependent or independent antigen, and exclusion of other types of hypogammaglobulinemia.19 CVIDs are the most common culprit identified in symptomatic primary antibody failure in both children and adults.20

Data from a cohort of patients with confirmed CVIDs in a medical center over a 22-year period assessed Ig doses for IVIG therapy, finding that the doses had been adjusted in accordance to infection severity versus treated to any trough IgG level. Trough IgG levels ranging from 5 g/L to 17 g/L were found to prevent breakthrough infection. Doses of replacement Ig used for preventive purposes ranged from 0.2 g/kg/month to 1.2 g/kg/month. There was a strong correlation between baseline serum IgG levels and the increases to IgG levels, at which point patients were free of infection. Complications also played a significant role. Patients with bronchiectasis received higher Ig doses than those without bronchiectasis. In addition, the clinical phenotype of each CVID was an important factor. Patients who had enteropathy, cytopenias, and polyclonal lymphoproliferation needed substantially higher Ig doses to prevent infection than patients with lymphoid malignancies. Results overall hallmarked the importance of Ig therapy in these patients; replacement doses required to keep a patient bacterial infection-free have to be individualized for each patient. This highlights the heterogeneity of the patient population, CVID phenotypes, and the need for individualized management of each patient with CVID and hypogammaglobulinemia who requires Ig replacement.4,18,20

Specific Antibody Deficiency

Specific antibody deficiency (SAD), also termed selective antibody deficiency, is a primary immunodeficiency characterized by normal levels of Igs but that is impaired by specific antibody production.4,6 Patients with SAD have normal IgA, IgM, total IgG, and IgG subclass levels; however, they also have recurrent infections and poor antibody responses to polysaccharide antigens after vaccination. SAD presents complex diagnostic and therapeutic challenges because there is a lack of consensus over both areas. The overall clinical significance of SAD disorders is not well understood.21 Four phenotypes of SAD have been defined: memory, mild, moderate, and severe. Any of the phenotypes may require antibiotic prophylaxis, Ig replacement, or both depending on the individual patient and actual clinical illness. Patients who can initially mount adequate antibody concentrations against polysaccharide antigens but have a waning response to an antigen challenge over a 6-month period have the memory phenotype.4,22

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