Given the heterogeneous nature and relapsing-remitting course of many of the diseases for which intravenous immunoglobulin infusion (IVIG) has been investigated as therapy, randomized controlled trials (RCTs) are important for evaluating true benefit. However, in the case of rare disease, RCTs may be less likely. In these cases, reports of series data from at least 10 patients and consistent trends in results may support conclusions. Aside from the labeled indications, the use of IVIG has been investigated in a variety of diseases as follows.
Primary Immune Deficiency
Primary immune deficiencies, a group of chronic disorders, are a U.S. Food and Drug Administration (FDA)-approved indication for immune globulin therapy. Immunoglobulin is a longstanding treatment for these disorders.
X-linked agammaglobulinemia (XLA or Bruton’s) occurs in male patients who have less than 2% or absent circulating B cells and normal T lymphocytes. (2) There are mutations in the tyrosine kinase gene (BTK gene), the defect is on the mid-portion of the X chromosome (Xp22). XLA should be suspected in infants who present with life-threatening infections in the latter part of the first year of life. This is due to passively acquired maternal antibodies waning below protective levels. Haemophilus influenza and Streptococcus pneumoniae are commonly associated infections of the sinopulmonary tract. Cellular immunity (T cell) is intact; therefore, viral and fungal infections and tuberculosis are not typically seen in XLA. It is important to recognize this condition early, using broad-spectrum antibiotics with IVIG, thereby changing the outcome and survival of these patients. (3) In order to prevent acute bacterial infections and bronchiectasis as an end organ disease in this condition, it is recommended that maintaining nadir serum IgG levels at greater than 500mg/dL is critical.
Common variable immunodeficiency (CVID) involves both B and T cell immune function. This disease presents with decreased immunoglobulin levels and abnormal antibody responses to antigens. Interestingly, CVID can affect any or all isotypes of immunoglobulin with specific antibodies affected due to inability to respond to antigen and there are diminished isohemagglutinin titers. The average age of onset is approximately 25 years. Unfortunately the mortality rate is high due to lymphoma and chronic pulmonary disease becoming more prominent with lower IgG and poorer T cell function. Similar to XLA, patients present with sinopulmonary infections and end organ bronchiectasis. In addition, the gastrointestinal tract is commonly affected, causing malabsorption or chronic diarrhea, protein-losing enteropathy, small bowel infection with Campylobacter or Giardia lamblia. There is a propensity to develop nodular lymphoid hyperplasia of the small bowel, peripheral lymph nodes, or the spleen. Incidence of malignancy is increased during the fifth and sixth decade of life. (4)
X-linked hyper-IgM is a T cell deficiency with a genetic defect in CD40 ligand molecule. Family consanguinity is frequent. These patients present with recurrent sinopulmonary and gastrointestinal tract infections in childhood. Serum IgM levels may be in excess of 1,000 mg/dL. The immunologic characteristic of this disorder is an abnormality in the process of immunoglobulin class switch recombination, therefore an inability to manufacture IgG, IgA, or IgE antibodies. Peripheral blood B cell counts (CD19) are normal. T lymphocyte counts and proliferative responses are normal. Molecular studies have shown a mutation in the AID gene (activation-induced cytidine deaminase gene).
IgG subclass deficiency has been questioned by clinical immunologists as to whether having low serum IgG subclass levels is a true immunodeficiency disease. The rationale is that low serum IgG subclass levels may be found with more sensitive assays available today, and these individuals may be otherwise healthy. Therefore, careful diagnosis and monitoring of antibody titers and immune response is a necessary component of starting and continuing IVIG therapy.
In 2010, the National Advisory Committee on Blood and Blood Products and Canadian Blood Services published a guideline on use of immune globulin therapy for patients with primary immune deficiency; recommendations were based on a systematic review of evidence that was reviewed by a panel of experts. (5) The search identified 3 RCTs, several cohort studies, and numerous case series. The panel agreed that there is sufficient evidence from 19 observational studies that immunoglobulin therapy reduces the rate of infection and hospitalization in patients with primary immune deficiency, which likely leads to a lower mortality and improved quality of life. Thus, IVIG therapy is considered medically necessary for treating primary immune deficiency diseases.
Other recommendations in the 2010 guideline in regards to IVIG treatment of primary immune deficiencies are:
- Consider the diagnosis of primary immune deficiency in patients (adults and children) with autoimmune hematological disease. To rule out primary immune deficiency in these patients, patients with autoimmune hematologic disease should have quantitative IgA, IgG, and IgM levels drawn before beginning immune globulin therapy.
- Treatment should be started at a dose of 400 to 600 mg/kg per 4 weeks for IVIG or 100 to 150 mg/kg per week for SCIG [by subcutaneous infusion] in most patients.
- If there is end-organ damage, the dose and/or frequency of immune globulin can be increased.
- Patients with primary immune deficiency may require immune globulin therapy indefinitely.
Immunologic disorders of the T cell present with clinically more severe disease that often lead to mortality in infancy or childhood. It is essential to diagnose these conditions early by screening for lymphopenia in cord blood at birth.
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease characterized by thrombocytopenic purpura with small defective platelets, eczema, and infections with encapsulated bacteria. Clinically there is low serum IgM, elevated IgA and IgE with normal or low IgG, diminished isohemagglutinins and decreased antibody response to polysaccharide antigens. There are reduced T cells and lymphocyte response to antigens that are depressed. Identification in mutation of the WASP gene has been identified. Prenatal diagnosis of this disorder is made by chorionic villus sampling or amniocentesis if the WASP mutation occurs in the family. Mortality typically occurs in the teen years from vasculitis, infections, autoimmune cytopenias, and Epstein-Barr virus-induced lymphoreticular malignancy. (6) IVIG has been shown to increase platelet counts and prevent infections in those patients. (7)
Ataxia telangiectasia occurs because of a genetic defect in ATM (A-T mutated) that normally detects breaks in DNA. This leads to elevated serum alpha-fetoprotein. Patients present with cerebellar ataxia, oculocutaneous telangiectasias, and immunodeficiency. (8)
Severe combined immunodeficiency (SCID) represents a profound defect of immunity, often with complete absence of lymphocyte function. Clinically, patients present with failure to thrive, chronic sinopulmonary infections, chronic diarrhea, and opportunistic and disseminated sepsis that is life-threatening. A series of genetic mutations have been described in the literature recognizing the heterogeneous molecular biology underlying both X-linked and autosomal recessive inheritance patterns. Bone marrow transplantation is recommended for long-term survival in patients with SCID. (9)
Prophylaxis in the Post-Stem-Cell Transplant Setting
Prevention of infection after bone marrow transplant is a labeled indication for IVIG. The FDA approval was based on data from a randomized but not a placebo-controlled study that compared the outcomes in 369 patients undergoing bone marrow transplant for both malignant and non-malignant disease (i.e., aplastic anemia). (10) In addition, patients underwent a variety of types of stem-cell support, including allogeneic stem-cell support (both human leukocyte antigens [HLA] identical and non-identical, T cell depleted or not), autologous, or syngeneic. The majority of patients received HLA-identical allogeneic stem-cell support. In addition to type of stem-cell support, patients were stratified according to transplant type, age, serological status for cytomegalovirus, and protective isolation. The study endpoints were acute graft-versus-host disease (GVHD), infections, interstitial pneumonia, and death. In patients older than age 20 years, IVIG administration was associated with decreased incidence or risk of interstitial pneumonitis, septicemia, or acute GVHD. There was no overall improvement in survival. Since this 1990 study, there has been further discussion of the role of IVIG in the post-stem-cell transplant setting, and there appears to be no consensus about its efficacy. (11, 12) Criticisms of this study point out that the statistical significance did not take into account multiple endpoints and subgroup analyses such that some of the reported p values could be due to chance alone. In addition, the study included a heterogeneous group of patients and was not placebo controlled. Moreover, there have been improvements in supportive care, particularly prophylaxis for cytomegalovirus and fungal infection, which may attenuate any effect of IVIG. In addition, studies examining the effect of IVIG on GVHD have reported conflicting data. In 2003, Cordonnier and colleagues reported on the results of a trial that randomized 200 patients undergoing allogeneic stem-cell transplant with HLA-identical donors to receive either placebo or various doses of IVIG from 7 days prior to transplant weekly until 100 days after transplant. Doses ranged from 50 mg/kg to 500 mg/kg. The authors reported that IVIG had no benefit over placebo in terms of infection, interstitial pneumonitis, or GVHD. (13) The results of this study challenge the conclusions of the previous 1990 study, at least for the subgroup with HLA-identical donors.
A meta-analysis published in 2008 by the Cochrane Collaboration evaluated the role of IVIG in patients undergoing hematopoietic stem-cell transplantation and those with lymphoproliferative disorders to determine whether prophylaxis with IVIG reduces mortality or affects other outcomes in patients with hematological malignancies. (14) All RCTs included in the evaluation compared prophylaxis of IVIG with placebo, no treatment or another immunoglobulin preparation; different administration schedules or doses for patients with hematological malignancies were included. Of the 40 trials evaluated, 30 included patients who had hematopoietic stem-cell transplantation, and 10 included patients with lymphoproliferative disorders. The authors concluded that in patients undergoing hematopoietic stem-cell transplantation, routine prophylaxis with IVIG is not supported. Its use may be considered in patients with lymphoproliferative disorders who have hypogammaglobulinemia and recurrent infections to reduce clinically documented infections.
One of the FDA-approved indications for IVIG is its use in human immunodeficiency virus (HIV)-infected children. A study published in 1996 reported results in adults with HIV infection. (15)
Kawasaki Syndrome and Other Vasculitides
Kawasaki syndrome is an acute multisystem vasculitis that primarily affects children, manifesting itself as a constellation of clinical signs and symptoms including fever, conjunctivitis, mucosal erythema, polymorphous rash, and cervical adenopathy. Although the symptoms are self-limited, up to 25% of untreated patients may develop potentially lethal coronary artery abnormalities.
Kawasaki syndrome is an FDA-approved indication for IVIG. Although the mechanism of action of IVIG is not understood, its use early in the course of disease has been shown to reduce the prevalence of coronary artery abnormalities. The success of IVIG in Kawasaki disease has led to the investigation of IVIG in other vasculitides, such as those associated with rheumatoid arthritis, Wegener’s granulomatosis, and polyarteritis nodosa. Randomized, multicenter studies have shown that high-dose IVIG plus aspirin, given within the first 10 days after the onset of fever, is safe and effective in reducing the prevalence of coronary artery abnormalities. (16) An RCT of single course IVIG (n=17) versus placebo (n=17) in patients with persistent active Wegener’s granulomatosis or microscopic polyangiitis associated with anti-neutrophil cytoplasmic antibody found significantly more responders in the IVIG treatment group at 3 months but no significant differences after 3 months or in the frequency of relapse or use of other medications. (17) Data are inadequate regarding the effectiveness of IVIG in other vasculitides including polyarteritis nodosa and rheumatoid arthritis. (18)
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
CIDP is an FDA labeled indication for IVIG. In 2010, Goebel and colleagues published a systematic review of RCTs on IVIG for treating CIDP. (19) The authors identified 9 RCTs meeting the following inclusion criteria: enrolled patients with definite or probably CIDP; compared IVIG to placebo, corticosteroid, or plasma exchange; reported a change from baseline in both a disability score and an electrophysiological measure e.g., velocity, latency etc. Three of the trials compared IVIG with another active treatment and the other 6 were placebo-controlled. A pooled analysis of data from 4 of the 6 placebo-controlled trials found a significantly larger change in disability score with IVIG compared to placebo (standardized mean difference [SMD]: 0.65, 95% confidence interval [CI]: 0.23 to 1.08). Moreover, a pooled analysis of the proportion of patients with a response to treatment in these same studies also found a significantly greater benefit of IVIG versus placebo (relative risk [RR]: 2.74, 95% CI: 1.80 to 4.16). Data from studies comparing IVIG to an active treatment were not pooled. Limitations of the meta-analysis include that a variety of different disability scales and definitions of clinical response were used.
A 2012 multicenter double-blind RCT assigned patients with CIDP to IVIG (n=22) or IV methylprednisolone (n=24). (20) One patient dropped out of the IVIG group; the remaining patients were included in the analysis. The primary study outcome was the proportion of patients who discontinued therapy due to inefficacy or intolerance during the 6 months of therapy. A total of 3 (13%) of patients in the IVIG group and 11 (52%) of patients in the corticosteroid group discontinued treatment over 6 months. The difference between groups was statistically significant favoring the IVIG group (RR: 0.54, 95% CI: 0.34 to 0.87). Secondary outcomes, including quality-of-life, time on 10-meter walk, grip strength, etc., did not differ significantly between groups, but the study may have been underpowered to detect clinically significant differences on these outcomes.
A 2012 evidence-based guideline on IVIG for treating neuromuscular disorders, prepared by a subcommittee of the American Academy of Neurology (AAN) stated that IVIG should be offered for the long-term treatment of CIDP. (21)
Evidence from multiple RCTs and a meta-analysis of RCTs has found that IVIG is effective for treating CIDP. Thus, IVIG for treating CIDP may be considered medically necessary.
Guillain-Barre Syndrome (GBS)
IVIG has been studied in GBS, which is an acute demyelinating neuropathy. Initial treatment includes prednisone, and may be followed by plasmapheresis or IVIG in more serious cases. A Cochrane review by Hughes and colleagues, updated in 2012, reviewed the results of randomized trials of immunotherapy for GBS. (22) The review identified 12 randomized trials; none of these were placebo-controlled. Seven trials compared IVIG to plasma exchange (PE), 3 trials compared IVIG to supportive treatment only, and 2 trials compared PE and 2 compared IVIG to immunoabsorption (1 of these compared the combination of IVIG and immunoabsorption to immunoabsorption only. Four trials included adults only, 5 included children only, 1 included both and 2 included adults and possibly children. The primary outcome of the review was between-group change in disability level (using a 7-grade disability scale) after 4 weeks. A pooled analysis of 7 trials comparing IVIG to PE did not find a significant difference between groups in change in the number of disability grades at 4 weeks (mean difference [MD]: - 0.02, 95% CI: -0.25 to 0.20). There were also no significant differences in other outcome measures for IVIG versus PE, e.g., the number of patients improved by 1 or more grades. There were insufficient data to pool results for comparisons of IVIG with other types of alternative interventions or for a subgroup analysis by age. Most of the trials had small sample sizes. The largest trial was multicenter and randomized 383 adults older than 16 years of age to IVIG, PE, or the combination of IVIG and PE. (23) The objectives of the trial were to establish that IVIG is equivalent to or superior to PE and to establish that PE followed by IVIG is superior to a single treatment. Non-inferiority was defined as no more than a 0.5 grade difference in change in disability grade at 4 weeks. At 4 weeks, the difference in improvement between the IVIG group and PE group was 0.09 grade (CI: -0.23 to 0.42); this meets the pre-defined criteria for equivalence of these treatments. The difference between the IVIG plus PE group and the IVIG only group was 0.29 grade (95% CI: -0.04 to 0.63) and between the IVIG plus PE group and PE only was 0.20 grade (95% CI: -0.14 to 0.54). Thus, neither of the combined treatment groups was superior to either treatment only.
The 2012 AAN guideline, first cited earlier, concluded that IVIG should be offered to adults with GBS but that there is insufficient evidence to support or refute the use of IVIG in children. (21)
Based on the findings of the large RCT and the Cochrane review, IVIG appears to have similar efficacy to PE.
Multifocal Motor Neuropathy
Multifocal motor neuropathy is characterized by a conduction block of the motor axons. Patients frequently exhibit antibodies to GM1 ganglioside. Clinically, the disease presents as a very slow onset of weakness and muscular atrophy with preservation of sensation. Unlike other neuropathic disorders, this disease does not respond to steroids or plasmapheresis. Multifocal motor neuropathy is diagnosed based on clinical criteria, laboratory criteria including high anti-GMI antibody level, and electrodiagnostic criteria e.g., motor conduction block.
A double-blind, placebo-controlled crossover trial of 12 patients with multifocal motor neuropathy and high titers of anti-GM1 antibody reports a significant increase in muscle strength associated with IVIG infusion. The effects were only seen in those patients with an associated conduction block. (24) Subsequent RCTs have reported similar results. (25, 26)
The 2012 AAN guideline stated that IVIG should be considered for the treatment of multifocal motor neuropathy but that there are insufficient data to determine the optimal treatment interval, dosing and duration. (21)
Eaton-Lambert Myasthenic Syndrome
Eaton-Lambert is an autoimmune disease with antibodies directed against the neuromuscular junction. Patients have muscle weakness of the lower extremities, autonomic dysfunction, and extra-ocular muscle impairment. This is a paraneoplastic syndrome associated with small-cell carcinoma of the lung, most commonly. A number of studies have been cited in the literature improving disability and reducing muscle weakness, substantiating IVIG as beneficial. (27) The 2012 AAN guideline stated that IVIG is possibly effective and may be considered as a treatment for patients with Eaton-Lambert syndrome. (21)
Idiopathic Thrombocytopenic Purpura (ITP)
In 2007, the National Advisory Committee on Blood and Blood Products and Canadian Blood Services issued guidelines on the use of IVIG for hematologic conditions, including ITP, based on 6 randomized controlled trials and one nonrandomized trial of IVIG for adult ITP. (28) Three of the trials compared IVIG with corticosteroids, and 4 trials evaluated different doses of IVIG. None of the trials compared IVIG with no therapy. The largest trial that compared IVIG with corticosteroids included 122 patients with severe acute ITP. The primary outcome, mean number of days with platelet count greater than 50 x 109/L at day 21, was significantly higher in the IVIG group compared with the high-dose methylprednisolone group. Two other trials, one nonrandomized (IVIG versus corticosteroids) and one randomized (IVIG alone versus oral prednisone alone versus IVIG plus oral prednisone) found no difference in platelet counts greater than 50 x 109/L at 48 hours or response rate between groups, respectively.
The recommendations from the National Advisory Committee on Blood and Blood Products and Canadian Blood Services for adults with ITP are as follows:
- Adult acute ITP with bleeding: IVIG strongly recommended as a part of multimodality therapy for major or life-threatening bleeding complications and/or clinically important mucocutaneous bleeding.
- Adult acute ITP with severe thrombocytopenia but no bleeding: IVIG not recommended as first-line therapy alone, except for patients with contraindications to corticosteroids.
- Adult ITP with no or slow response to adequate dose corticosteroids: IVIG may be considered as a possible adjunctive therapy.
- Adult chronic ITP postsplenectomy: IVIG may be considered as a possible adjunctive therapy as a corticosteroid-sparing measure.
The 2007 Canadian Committee on Blood and Blood Products guidelines recommends IVIG for select patients with chronic ITP. (28) In particular, patients with a platelet count below 20 x 109/L despite treatment with corticosteroids should be considered for IVIG therapy. Also, the use of IVIG may be considered as a corticosteroid-sparing agent in patients who require long-term corticosteroids to maintain adequate platelet counts. For chronic ITP, the minimal dose of IVIG should be used that maintains a safe platelet count. Patients should be re-evaluated every 3 to 6 months, and alternative therapies to IVIG should be considered for patients who do not achieve a durable response for a minimum of 2 to 3 weeks.
Fetal Alloimmune Thrombocytopenia
Fetal and neonatal thrombocytopenia occurs when a maternal antibody directed against a paternal platelet antigen crosses the placenta and causes thrombocytopenia in the fetus. Intracranial hemorrhage is identified in about 10–30% of affected neonates. At the present time, screening for this condition is unavailable, and thus the thrombocytopenia is only identified at the time of birth. However, subsequent fetuses that are platelet-antigen positive also will be at risk for thrombocytopenia and, similar to erythroblastosis fetalis, the severity of the thrombocytopenia may be increased. Treatment has focused on neonatal platelet transfusions, corticosteroids, and IVIG. Case series have shown that maternal IVIG infusions are associated with an increase in the fetal platelet count. A randomized trial compared weekly IVIG with and without associated dexamethasone. (29) Although there was no placebo-controlled arm, results can be compared to the course in a prior affected sibling, since the natural history of the disease suggests that subsequent births should be similarly if not more severely affected with thrombocytopenia. The study reported a mean increase in the platelet count of 69,000/mL. There were no instances of intracranial hemorrhages, although hemorrhage had occurred previously in 10 untreated siblings. Due to improvement found in the case series and RCT, IVIG may be considered medically necessary.
Myasthenia gravis is an autoimmune disease characterized by autoantibodies directed against the acetylcholine receptors of the muscle end plate that induce muscle weakness and pronounced fatigability. Initial treatment focuses on the use of cholinesterase inhibitors to overcome the post-synaptic blockade. Immunosuppressant drugs, including corticosteroids and azathioprine, are also effective. In patients with severe weakness, plasma exchange is a short-term therapy. IVIG has also been investigated in patients with myasthenia gravis as a potential alternative to plasma exchange.
One RCT (total n=87) (30) and 1 retrospective chart review (total n=54) (31) compare IVIG treatment to plasma exchange (PE) in acute myasthenic crisis. Myasthenic crisis was defined as an acute episode of respiratory muscle weakness, defined by a forced vital capacity (FVC) of </= 1.0 liter or negative inspiratory force of </= 20 cm H20, or requirement of mechanical ventilation. One crossover study compared these therapies in 12 patients with moderate-to-severe disease in a stable phase. (32) Results for all 3 trials show that IVIG and plasma exchange had similar efficacy over time, although improvement may be more rapid with PE. Case series data support benefit with IVIG treatment in patients with acute exacerbations and with refractory disease or who are unable to tolerate standard treatment. One series of 10 children with refractory disease suggests short-term benefit with IVIG but limited long-term benefit. (33) Refractory myasthenia gravis has been defined as patients with persistent symptoms in spite of immunosuppressive treatment with prednisone and/or azathioprine or those unable to tolerate corticosteroid therapy. A review article explored myasthenia gravis management and concluded that, to determine appropriate pharmacotherapy, characterization of the disease based on degree of function and muscle regions affected was critical for therapy selection. (34) The existing evidence supports the use of IVIG as a treatment option for myasthenia gravis and myasthenic crisis.
Solid Organ Transplantation
Acute rejection after transplant can be broadly divided into two categories, the more common acute cellular rejection related to activation of T cells and the less common antibody-mediated rejection reaction (AMR) related to the presence of anti-donor antibodies. While acute rejection typically responds to immunologic therapy directed at T cells, AMR does not, and, as such, has also been referred to as “steroid-resistant rejection.” The risk of AMR is related to the presence of preformed allo-antibodies in the recipient due to prior blood transfusions, transplants, or pregnancies. The presence of allo-antibodies is assessed by using a panel reactive antibody (PRA) screen, which combines the recipient’s serum with samples of antigen containing cells taken from 60 individuals who were representative of the potential donor pool. The percentage of PRA is the percentage of positive reactions. Those with a PRA greater than 20% are referred to as “sensitized,” and these patients often have prolonged waiting times to identify a compatible donor. Living donor kidney transplants have also been performed using ABO mismatched donor organs. These recipients are also at risk of AMR. As an immunomodulatory agent, IVIG has been widely used in the prevention and management of AMR, often in conjunction with PE. For example, in patients at high risk for AMR, IVIG may be given prior to transplant to reduce the numbers of allo-antibodies and the risk of AMR, thus reducing the wait time for a compatible organ. IVIG may be one component of therapy after transplant if AMR develops.
One RCT of 30 patients published in 2001 suggested that IVIG is at least as good as anti-CD3 in combating corticosteroid-resistant rejection of kidney transplants. (35) Later, in 2003-4, findings from the NIH IG02, a double-blind placebo-controlled trial, were published. (36) The trial randomized 101 highly sensitized renal transplant candidates to receive either 4 monthly infusions of IVIG or placebo prior to transplant. If transplanted, additional infusions were given monthly for 4 months. IVIG significantly reduced PRA levels in study subjects compared to placebo, resulting in a higher transplant rate. For example, a total of 24 patients subsequently underwent transplant, 16 in the IVIG group and 8 in the placebo group. There was acceptable graft survival in both groups. Desensitization protocols varied among transplant centers; certain protocols commonly used are referred to as the Cedars-Sinai protocol and the Johns Hopkins protocol. The Cedars-Sinai protocol consisted of high-dose IVIG (2 g/kg) and was offered to patients awaiting either a deceased or live donor. (37) The Johns Hopkins protocol consisted of low-dose IVIG (100 mg/kg) in combination with plasmapheresis with or without treatment with anti-CD-20 (i.e., Rituxan). (38)
A retrospective cohort study published in 2009 compared outcomes in pediatric liver transplant patients entered into a multicenter Registry who did (n=336) and did not (n=1,612) receive IVIG within 7 days of transplantation. (39) The investigators assumed that IVIG given within this timeframe was used for prophylaxis of AMR, rather than for treatment. The Kaplan-Meier probability of patient survival was not significantly different between groups (hazard ratio [HR]: 0.97, 95% CI: 0.71-1.39). However, the risk of graft rejection was significantly lower in patients treated with immunoglobulin. In the first 3 months after transplant, 31% of patients who received immunoglobulin and 40% of those not treated had an episode of graft rejection (p=0.02). Similarly, the proportion of patients with 2 or more episodes of graft rejection was significantly lower among those who received immunoglobulin (13.1%) than those who did not (19.2%), p=0.009. Patients were not randomized to treatment group, and there may have been differences in those treated or not treated with immunoglobulin that affected outcomes.
A variety of protocols also have been developed for the treatment of AMR, often in combination with other therapies, such as plasmapheresis or anti-CD-20. (35, 40-42) The majority of studies of IVIG in the transplant setting are retrospective case series from single institutions. Therefore, it is not possible to compare immunomodulatory regimens to determine their relative efficacy. Nevertheless, in part based on the large volume of literature published on this subject, it appears that IVIG is a component of the standard of care for the management of AMR.
In 2010, the National Advisory Committee on Blood and Blood Products and Canadian Blood Services produced a guideline on the use of IVIG for solid organ transplantation; a panel of experts reviewed findings from a systematic review of evidence. (43) In their literature search, they identified 3 RCTs, all on kidney transplant, and numerous observational studies or case series on several types of organ transplantation. Key recommendations of the panel are as follows:
- When kidney transplantation involves use of a living donor, IVIG is recommended to decrease donor-specific sensitization.
- There is insufficient evidence to recommend for or against the use of IVIG for ABO-incompatible kidney transplantation.
- To reduce the risk of acute antibody-mediated rejection, IVIG is recommended for kidney transplant patients who have donor-specific antibodies preoperatively. IVIG is not recommended for kidney transplant patients who do not have donor-specific antibodies.
- IVIG is recommended after plasmapheresis for patients who have received a living donor or deceased kidney donor transplant and who have acute antibody-mediated rejection. Consider IVIG when patients have corticosteroid-resistant rejection, when other therapies are deemed unacceptable or ineffective.
- There is insufficient evidence to recommend for or against the use of IVIG for desensitization for patients undergoing heart, lung, or liver transplantation.
Multiple sclerosis (MS) is a demyelinating disease accompanied by a lymphocytic infiltration in lesions. Evidence relating to pathogenesis suggests genetic, infective, and/or immune mechanisms. IVIG has been investigated in patients with relapsing/remitting MS, for whom the treatment goals are to decrease the frequency and severity of future attacks and, if possible, to improve the functional deficit to some extent in patients with chronic progressive disease.
Following an updated Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment in 1998, which concluded that IVIG for multiple sclerosis met the TEC criteria, it was considered medically necessary. (44) However, in 2002 the American Academy of Neurology (AAN) published a technology assessment on therapies for multiple sclerosis. (45) Their rating system was A (established as effective), B (probably effective, ineffective, or harmful), C (possibly effective, ineffective or harmful), or U (data inadequate). The assessment offered the following recommendations regarding IVIG:
- The studies of intravenous immunoglobulin (IVIG) to date have generally involved small numbers of patients, have lacked complete data on clinical and MRI [magnetic resonance imaging] outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIG reduces the attack rate in relapsing-remitting multiple sclerosis (Type C recommendation).
- The current evidence suggests that IVIG is of little benefit with regard to slowing disease progression (Type C recommendation).
In contrast, the American Academy of Neurology recommended the use of interferon beta (Type B recommendation) and glatiramer acetate (Type A recommendation). This assessment suggested that IVIG was no longer considered a drug of choice for relapsing-remitting multiple sclerosis. The AAN guideline on treatments for multiple sclerosis was reaffirmed in July 2008. Updated literature searches did not identify any additional randomized trials that would prompt reconsideration of the conclusions of the American Academy of Neurology assessment. Due to insufficient data, IVIG for chronic progressive multiple sclerosis is considered experimental, investigational and unproven; IVIG may be considered medically necessary for severe manifestation of relapsing/remitting type MS only when other treatment has failed, become intolerable, or is contraindicated.
Recurrent Spontaneous Abortion
Recurrent spontaneous abortion (RSA) is defined as 3 or more pregnancies resulting in a spontaneous abortion prior to 16–20 weeks of gestational age. Patients with RSA frequently have immunologic abnormalities, particularly antiphospholipid antibodies whose incidence may increase with each subsequent pregnancy loss. Since these antibodies are associated with clotting abnormalities, treatment has included aspirin and heparin. Other more subtle immune etiologies have also been investigated. For example, a variety of cytokines and other mediators may be toxic to the conceptus. These cytokines may be detected in an embryo cytotoxicity assay in which activated lymphocytes from women with RSA are shown to be toxic to placental cell lines. Elevated levels of natural killer cells, which may be associated with antiphospholipid antibodies, have also been implicated in RSA. Another theory proposes that a lack of maternal blocking antibodies to prevent immunologic rejection of the fetus may be responsible. IVIG has been explored as a treatment based on its ability to influence both T and B cell function. In fact, IVIG may be offered to those patients with antiphospholipid antibodies without a prior history of RSA who are currently pregnant or contemplating pregnancy.
A 1998 BCBSA TEC Assessment on IVIG as a treatment of recurrent spontaneous abortion (RSA) (44) concluded: 1) The scientific evidence is not sufficient to support the conclusion that IVIG reduces spontaneous abortion in women with antiphospholipid antibodies who have a history of recurrent spontaneous abortion; and 2) The scientific evidence is not sufficient to support the conclusion that IVIG therapy is superior to no treatment in women without antiphospholipid antibodies who have a history of recurrent spontaneous abortion. The assessment cited 4 randomized, blinded, controlled trials of IVIG focusing on this patient population. Only 1 of these trials showed a significant treatment effect. The treatment effect of the 4 trials was summarized by meta-analysis; the overall relative risk (RR) and odds ratio (OR) values and their confidence intervals indicate no significant treatment effect.
Two subsequent meta-analyses of 5 trials and 6 trials, respectively, concluded that IVIG provides no significant beneficial effect over placebo in preventing further miscarriages. (46, 47) A blinded RCT of 41 women treated with IVIG or saline placebo found no differences in live birth rates. (48) A multicenter RCT comparing heparin and low-dose aspirin with versus without IVIG in women with lupus anticoagulant, anticardiolipin antibody, or both, found no significant differences. (49) In addition, an RCT of 58 women with at least 4 unexplained miscarriages tested IVIG versus placebo and analyzed results by intention to treat. (50) The live birth rate was the same for both groups; also, there was no difference in neonatal data. Other non-randomized but controlled trials also report no benefit for IVIG treatment. There is insufficient evidence in RCTs or other trials to support benefit in secondary (live birth followed by consecutive spontaneous abortions) versus primary (no prior live births) spontaneous abortions. A variety of immunologic tests may precede the initiation of IVIG therapy. These tests, including various subsets of lymphocytes, human leukocyte antigen (HLA) testing, and lymphocyte functional testing (i.e., natural killer cell assays and the embryo cytotoxicity test), are research tools that explore subtle immunologic disorders that may contribute to maternal immunologic tolerance of the fetus. However no clinical data show that the results of these tests can be used in the management of patients to reduce the incidence of recurrent spontaneous abortion, particularly since IVIG therapy has not been shown to be an effective therapy.
Two RCTs of IVIG therapy in patients with corticosteroid-dependent asthma found no significant decrease in corticosteroid use compared to placebo. (51, 52) A subgroup analysis in one trial indicated a significant effect of IVIG on corticosteroid consumption in patients requiring corticosteroid doses greater than 2 g per year; however, this subgroup analysis was not stated as planned in advance and involved only 17 of 38 total patients. Thus, IVIG for asthma is considered experimental, investigational and unproven.
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections
The National Advisory Committee on Blood and Blood Products and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for neurologic conditions; findings were published in 2007. (53) Recommendations for use of IVIG were made for 14 conditions, including pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). The Panel emphasized that this syndrome is not well-understood and diagnosis of PANDAS requires expert consultation. The optimum dose and duration of treatment is uncertain. The evidence review examining IVIG for PANDAS identified 1 RCT of 29 children who had new or severe exacerbations of obsessive-compulsive disorder (OCD) or tic disorder after streptococcal infections randomly assigned to IVIG plasma exchange or placebo. At 1-month follow-up, IVIG and plasma exchange had no significant differences and showed significant improvement in obsessive-compulsive symptoms. The improvement in symptoms was evident at 1-year follow-up. (54) Given that there is only 1 small study, there are insufficient data to support the use of IVIG for PANDAS.
The Canadian guideline on neurologic conditions, cited above, did not recommend IVIG for autism. (53) The evidence review examining IVIG for autism identified 3 case series. In 1 of the case series, 10 patients with abnormal immune parameters received IVIG monthly. After 6 months, 5 of 10 subjects showed marked improvement in several autistic characteristics. In the second case series, 1 of 10 subjects showed improvement in autistic symptoms after receiving IVIG. No improvement was observed in the third series. Given there are no randomized comparative trials evaluating IVIG in autism, a relatively common condition, data are insufficient to support the use of IVIG for autism.
Autoimmune Mucocutaneous Blistering Diseases (AMBDs)
Nonrandomized studies and a systematic review on IVIG for AMBDs (55-57) showed that IVIG therapy for specific patients prevented the progression of disease and showed significant clinical benefit. The 2010 systematic review by Gurcan et al. identified 23 studies evaluating IVIG for AMBDs; 22 case series and 1 RCT. (56) The studies included a total of 260 patients treated with IVIG; 191 patients with pemphigus and 69 patients with pemphigoid. Of the 260 patients, 245 improved after IVIG treatment. IVIG can be used as an adjunctive agent to taper or discontinue use of corticosteroids and/or immunosuppressive treatments. In effect, IVIG served as a corticosteroid-sparing agent.
The article suggests that IVIG be considered with the following criteria:
- Patients who are non-responsive to either high-dose systemic corticosteroids and/or multiple immunosuppressive agents;
- Patients unable to tolerate conventional therapy due to effects of the drugs or the disease severity, culminating in poor quality of life.
A 2012 systematic review by Huang and colleagues focused on IVIG for treating toxic epidermal necrosis (TEN). (58) The authors identified 17 studies with a total of 221 with TEN treated with IVIG; 5 studies were retrospective, non-randomized controlled studies, and the remaining 11 studies were case series. Twelve out of the 17 studies supported use of IVIG. Overall, the mean time from initiation of IVIG to response was 2.4 days, and the mean time from initiation of IVIG to remission was 10.9 days. The mean length of hospital stay was 17.4 days, and the mortality rate was 19.9%.
In summary, the literature available to date has shown that IVIG can be efficacious in the treatment of AMBDs and can be a corticosteroid-sparing agent.
In 2007, a Cochrane Collaboration systematic review was published on acute immunomodulatory therapies in Fisher syndrome or its variants. (59) Fisher syndrome is one of the regional variants of Guillain-Barré syndrome, characterized by impairment of eye movements (ophthalmoplegia), incoordination (ataxia), and loss of tendon reflexes (areflexia). IVIG and plasma exchange are often used as treatments in this patient group. No RCTs were identified; the authors concluded that, due to the lack of controlled studies, there is insufficient evidence on which to base practice.
Inflammatory myopathies are broadly subdivided into polymyositis (PM), dermatomyositis (DM), and inclusion-body myositis (IBM). PM and DM are characterized clinically by proximal muscle weakness, and pathologically by an inflammatory microangiopathy leading to subsequent muscle ischemia. In DM, these symptoms are accompanied by a characteristic erythematous rash. The inflammatory infiltrate in DM contains a high percentage of B cells and components of the complement cascade. In contrast, in PM the inflammatory infiltrates are not perivascular in location, and contain activated T cells, natural killer cells, and macrophages. PM has no unique clinical features, and is typically a diagnosis of exclusion in patients with slowly progressive muscle weakness. Both PM and DM respond to corticosteroids or immunosuppressive drugs but can become refractory to such treatment. IBM is characterized clinically by slowly progressive muscle weakness and atrophy affecting proximal and distal muscle groups, particularly the quadriceps and the long finger flexors. Pathologically, IBM is characterized by granular inclusions within the muscle cells. Unlike DM or PM, IBM rarely responds to immunosuppressive therapy. For all of these conditions, IVIG has been investigated as a treatment, particularly for cases refractory to corticosteroids or immunosuppressive drugs.
Dermatomyositis is an autoantibody end-complement attack against vascular endothelium. Clinically, patients develop weakness of the muscles and a skin rash. In 2012, Wang and colleagues published a systematic review of the literature on IVIG for treating adults with dermatomyositis/polymyositis. (60) The authors identified 14 studies including 2 RCTs, 9 prospective case series and 3 retrospective case series. Eleven out of 14 studies included patients with refractory disease. Both RCTs found a benefit of IVIG treatment. For example, a trial by Dalakas and colleagues compared prednisone plus IVIG to prednisone plus placebo in 15 patients with refractory dermatomyositis. (61) There were significant increases in muscle strength in the IVIG group, as measured by mean scores on the neuromuscular symptom scale (NSS) and the modified Medical Research Council (MRC) scale. Results at 3 months for IVIG versus placebo were mean modified MRC: IVIG 84.6+4.6 versus placebo 78.6+8.2, Mean NSS: IVIG 51.4+6.0 versus placebo 45.7+11. Repeated transfusions every 6 to 8 weeks may be required to maintain a benefit.
An additional RCT was published in 2012 by Miyasaka and colleagues in Japan. (62) The study included 26 patients with corticosteroid-resistant polymyositis/dermatomyositis who had received high-dose corticosteroid therapy for at least 1 month. Patients were randomly assigned to treatment with IVIG (n=12) or placebo (n=14) once daily for 6 consecutive days. The primary endpoint was the difference in mean manual muscle test (MMT) scores between baseline and 8 weeks. Change in mean MMT was 11.8 points in the IVIG group and 9.9 points in the placebo group. There was not a statistically significant between-group difference: 1.9 points, 95% CI: -4.8 to 8.5. Other outcomes were also not significantly different between groups.
The 2012 American Academy of Neurology guideline on IVIG for treating neuromuscular disorders stated that IVIG may be considered as a treatment of non-responsive dermatomyositis in adults. (21)
Most but not all of the published studies on refractory dermatomyositis found a benefit of IVIG, and national guidelines support use of this therapy. Treatment with IVIG has the advantage of being corticosteroid- and/or chemotherapy-sparing.
Polymyositis (PM) and Refractory Polymyositis
A case series of IVIG in patients with refractory PM showed significant clinical improvement in more than two thirds of patients. (67) However, comparative trials are lacking to validate the effectiveness of IVIG in patients with polymyositis. An RCT of IVIG for polymyositis has not been published, but a prospective study of IVIG in patients with refractory PM showed improvement in 25 of 35 patients and a 50% reduction of prednisone dose. With the lack of controlled trials, there is insufficient evidence to support the use of IVIG in polymyositis.
Inclusion Body Myositis
Dalakas and colleagues have reported on a double-blind, placebo-controlled crossover study comparing IVIG to placebo in 19 patients with inclusion body myositis. (68) There was no statistically significant improvement in overall muscle strength in the IVIG group compared to the control placebo group. Two more recent RCTs (combined n=58) also found no significant functional improvement when IVIG treatment was compared to placebo. (69, 70) Due to the lack of benefit found in RCTs, there is insufficient evidence to support the use of IVIG for inclusion body myositis.
Complex Regional Pain Syndrome
A double-blind RCT was published in 2010; the study was conducted at an academic pain management center in the U.K. (19) To be eligible, patients needed to be diagnosed with stable complex regional pain syndrome (CRPS) of 6 to 30 months’ duration; patients were also eligible if their disease had a longer duration and had spread to a previously uninvolved limb within the past 30 months. Patients needed to have tried standard medical treatment and, despite other treatments, to report a pain intensity of 5 or higher on an 11-point scale (0-10 with 10=worst pain imaginable) for each of 7 days they completed a diary. Patients received an infusion of IVIG and saline (2 doses each) in random order, with a 28-day washout period between treatments. The primary outcome was 24-hour pain using the scale described above on days 6 to 19 after each treatment. A total of 13 patients were randomized; data on pain after IVIG were missing for 1 patient. According to the article’s Appendix Table 3, the median daily pain intensity score for each 14-day period was 6.21 after IVIG infusion and 7.35 after saline infusion, a mean difference of 1.14 points. In the text of the article, the authors report that the mean pain intensity was 1.55 points lower after IVIG than after saline (95% CI: 1.29 to 1.82, p<0.001). This is a short-term RCT with a small number of patients, and findings need to be confirmed in larger trials with longer follow-up. Moreover, the optimum dose and treatment regimen are unknown.
Several small studies have been published, most recently an open-label randomized study with 8 patients by Relkin and colleagues. (63) The goal of the trial was to evaluate the safety of repeated injections of IVIG in Alzheimer’s disease patients and examine change in the level of antibodies against beta-amyloid; it was not powered to detect changes in cognition. Eligibility criteria included a diagnosis of probably Alzheimer’s disease, ability to give informed consent and comply with the study protocol, assistance from a suitable caregiver and on a stable dose of an approved AD medication for at least 3 months. After an initial test dose of 0.4 g/kg of IVG, patients were randomly assigned to 6 months of treatment with 1 of 4 doses (0.4 g/kg per 2 weeks, 0.4 g/kg per week, 1 g/kg per 2 weeks, and 2 g/kg per 4 weeks). This was followed by a 3-month washout period and an additional treatment period in which all patients received 1 g/kg every 2 weeks for months 10-12 and 0.4 g/kg every 2 weeks for months 13-18. All patients completed the study; only 7 patients underwent sampling at the 9-month follow-up. Cerebrospinal fluid antibodies against beta-amyloid decreased significantly after 6 months of treatment, returned to baseline levels at the end of the 3-month wash-out and remained stable during the second treatment period. No serious adverse events occurred, and all mild symptoms resolved spontaneously and without sequelae. Although not a primary outcome, the authors reported patients’ scores on the Mini-Mental State Examination (MMSE). At baseline, the mean score was 23.5 (maximum possible score is 30). The mean score increased to 26.0 after 6 months of treatment, decreased to 23.9 at the end of the washout period, and was 24.0 after an additional 9 months of treatment. The authors conclude that further studies with larger samples are needed to determine efficacy, safety, and the optimal dosing regimen in Alzheimer’s disease patients.
An additional study conducted by the Relkin research team is underway. A Phase III study was initiated in 2009 and, as of July 2012, is active but not recruiting participants. (64) In this study, 390 patients are being randomly assigned to receive IVIG or placebo for 70 weeks. The primary outcome is change in cognition and global function after 9 months; a secondary outcome is cognitive change after 18 months. There is lack of published randomized trials with sufficiently large sample sizes to evaluate safety and efficacy of IVIG for treatment of Alzheimer’s disease.
Demyelinating Neuropathy Associated with Paraproteinemia or Paraneoplastic Syndromes
Results of a double-blind, placebo-controlled, crossover randomized study of IVIG versus placebo in 11 patients with paraproteinemic IgM demyelinating polyneuropathy showed only a mild and transitory effect in 3 patients. (65) A subsequent randomized study of 22 patients focused on the short-term outcomes at 2 weeks. (66) No significant difference was found between the treatment and placebo groups. Data are inadequate on the use of IVIG in paraneoplastic syndromes.
Chronic Fatigue Syndrome
Vollmer-Conna and colleagues reported no therapeutic benefit of IVIG in 99 patients with chronic fatigue syndrome randomized to receive either IVIG or placebo. (71)
RCTs of IVIG administered as postoperative prophylaxis in patients anergic to common recall antigens (n=40) (72) and trauma patients (n=39) (73) indicated significantly fewer infections in treated patients. Each of these trials addressed a different patient population, and the evidence is insufficient for conclusions. IVIG given as prophylaxis in patients with rheumatic fever did not appear to change cardiac outcomes (n=59). (74)
Sixty-two patients with recent-onset dilated cardiomyopathy were randomized to IVIG or placebo. (75) There was no significant difference in left ventricular ejection fraction between IVIG and placebo treatment arms.
Systemic Lupus Erythematosus
IVIG is proposed for the treatment of systemic lupus erythematosus because of its immunomodulatory properties and also to prevent infection in patients who are taking immunosuppressive drugs. Although this is a relatively prevalent autoimmune disease, only several small case series (76, 77) and 1 small RCT comparing IVIG to cyclophosphamide (78) have been published. These studies suggest some benefit; IVIG may be a good alternative to cyclophosphamide. However, results are inconsistent and short-lived in some cases.
Stiff Person Syndrome
Stiff person syndrome is a rare central nervous system disorder characterized by fluctuating muscle rigidity of truncal and proximal limb muscles with periodic spasms, resulting in a significant disability. The condition is thought to be immunologic in origin; elevated levels of anti-GAD antibodies are detected in most patients. Initial therapy is typically diazepam, but frequently the high doses required are poorly tolerated. IVIG has been investigated as an alternative therapy.
Dalakas et al. randomized 16 patients with disease and anti-GAD65 autoantibodies to IVIG or placebo for 3 months. (79) After a 1-month washout period, patients were crossed over to 3 months of the alternate treatment. Stiffness scores decreased significantly on IVIG, but not on placebo, regardless of order. Eleven patients were able to walk more easily or without assistance; the frequency of falls decreased, and patients were able to perform work-related or household tasks. The duration of benefit lasted 6 weeks to 1 year without additional treatment. Thus, results suggest some benefit for patients with GAD antibodies when other therapies have failed.
Two small series of 18 and 10 patients, respectively, report measurable improvement in visual acuity after IVIG therapy.(80, 81) These 2 studies represent insufficient data to draw conclusions about efficacy of IVIG for non-infectious uveitis.
Demyelinating Optic Neuritis
Noseworthy et al. (82) conducted a double-blind RCT of 55 patients randomized to IVIG or placebo. The trial was terminated due to negative results. Due to the findings of this study, and lack of other comparative trials, IVIG for demyelinating optic neuritis is considered experimental, investigational and unproven.
A 2012 systematic review of IVIG for treating Crohn’s disease did not identify any randomized or non-randomized controlled trials. (83) There were 5 published case reports of IVIG used for single patients with Crohn’s disease, and the remaining articles identified by the authors were conference papers, abstracts-only, or a non-systematic review. Thus, there is insufficient evidence of effectiveness of IVIG for treating Crohn’s disease.
Autoimmune Hemolytic Anemia
Flores et al. conducted a study to determine whether warm-antibody autoimmune hemolytic anemia (AIHA) responds to treatment with intravenous gammaglobulin. Of 72 patients with warm-antibody autoimmune hemolytic anemia, approximately 40% responded to IVIG treatment. Those with hepatomegaly and a low pretreatment hemoglobin had the best response to IVIG. The investigators suggest IVIG as adjunctive treatment only in select cases. (84)
A randomized, placebo-controlled study with IVIG demonstrated beneficial effects when given to outpatients with stable-phase multiple myeloma. This phase is associated with a high incidence of bacterial infections since humoral immune suppression persists (85) The 2013 National Comprehensive Cancer Network Guideline on Multiple Myeloma states that IVIG should be considered in the setting of recurrent life-threatening infection. (86)
Autoimmune Limbic Encephalitis in Children
Autoimmune limbic encephalitis (LE) is rare in children under 18 years of age. Symptoms may include subacute onset of memory impairment, disorientation and agitation, and can also include seizures, hallucinations and sleep disturbance. Diagnostic studies may include cerebrospinal fluid (CSF) analysis, electroencephalography (EEG), magnetic resonance imaging (MRI) and other imaging, and neuronal antibodies in the serum and CSF. Differential diagnosis must exclude several other conditions, including herpes simplex encephalitis Autoimmune LE may respond to corticosteroids, IVIG or plasma exchange, but evidence of efficacy in published reports is scarce. (87)
Outcome data are inadequate to validate the use of IVIG in other conditions including, but not limited to conditions listed in the Coverage section as experimental, investigational and unproven, and not otherwise discussed in the Rationale.
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