Medical Policy

Policy Num:      05.001.008
Policy Name:    Immunoglobulin Therapy
Policy ID:          [05.001.008]  [Ac / B / M+ / P+]  [8.01.05]

Last Review:     December 05, 2024
Next Review:     November 20, 2025

Related Policies:

08.001.049 - Hematopoietic Cell Transplantation for Autoimmune Diseases
08.001.016 - Extracorporeal Photopheresis

Immunoglobulin Therapy

Summary

Description

Immunoglobulins are derived from human donor plasma and used to treat an array of disorders, including primary and secondary immune deficiency states and various autoimmune and inflammatory disorders. Human immunoglobulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G antibodies against a wide variety of bacterial and viral antigens. This evidence review addresses the use of human immunoglobulin therapy for preventing and/or treating disorders in inpatient and outpatient settings. Both intravenous immunoglobulin (IVIG) infusion and subcutaneous immunoglobulin (SCIG) infusion are addressed. However, the review only considers nonspecific pooled preparations of IVIG; it does not consider other preparations used for passive immunization to specific antigens.

Summary of Evidence

Immunodeficiency States

For individuals who have primary humoral immunodeficiency who receive intravenous immune globulin (IVIG) or subcutaneous immune globulin (SCIG) therapy, the evidence includes multiple randomized controlled trials (RCTs) and noncomparative studies. Relevant outcomes are overall survival (OS), symptoms, change in disease status, morbid events, functional outcomes, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG and SCIG therapy improved disease-related outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are undergoing hematopoietic cell transplantation who receive IVIG therapy (prophylaxis), the evidence includes a systematic review and meta-analysis. Relevant outcomes are disease-specific survival (DSS), symptoms, change in disease status, morbid events, quality of life (QOL), hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG for routine prophylaxis of infection in patients undergoing hematopoietic cell transplantation was not associated with survival benefit or reduction in infection. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are at risk of acute antibody-mediated rejection after solid organ transplants who receive IVIG therapy, the evidence consists of a systematic review, National Institutes of Health (NIH)-sponsored RCT, and nonrandomized observational studies. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. The systematic review involving variable quality studies with high to very high risk of bias concluded that there is insufficient data to support or advise against the use of IVIG prophylaxis in solid organ transplant. More adequately powered RCTs are needed. Additionally, studies have shown conflicting results that prophylaxis with IVIG in patients with high panel reactive antibody (PRA) levels prior to solid organ transplant leads to a significant reduction in PRA levels. Compared with the standard of care, IVIG for prophylaxis of infection in patients with high PRA levels was not consistently associated with a survival benefit or reduction in infection. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have acute antibody-mediated rejection after solid organ transplants who receive IVIG therapy, the evidence includes retrospective case series and a systematic review. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG treatment for antibody-mediated rejection has shown potential benefits in retrospective or small prospective studies; however, larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have chronic lymphocytic leukemia with recurrent bacterial infections associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for recurrent bacterial infections associated with hypogammaglobulinemia in chronic lymphocytic leukemia patients has shown reductions in minor and moderate infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Infections

For individuals who are HIV-infected children with recurrent bacterial infection associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes a single RCT. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for the prevention of opportunistic infections in HIV-infected children has shown reductions in minor and serious infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are preterm and low birth weight infants and at risk for sepsis who receive IVIG therapy (prophylaxis), the evidence includes a Cochrane review involving multiple RCTs. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for prophylaxis of neonatal sepsis has shown a 3% reduction in sepsis and a 4% reduction in 1 or more episodes of any serious infection (considered of marginal clinical importance) with no improvement in any of the other clinically important outcomes, including mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are preterm and low birth weight infants with sepsis who receive IVIG therapy (treatment), the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for neonatal sepsis did not differ significantly in the rates of death or major disability. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are adults with sepsis who receive IVIG therapy, the evidence includes meta-analyses. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for adult sepsis showed reductions in mortality. However, multiple factors preclude recommending the routine use of IVIG to treat sepsis. They include the preponderance of small low-quality studies, the use of heterogeneous dosing regimens, types of IVIG preparations used, and changes over time in the management of sepsis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have severe anemia associated with human parvovirus B19 who receive IVIG therapy, the evidence includes case series. Relevant outcomes are a change in disease status, treatment-related mortality, and treatment-related morbidity. Although observed improvements in outcomes have suggested potential benefits with IVIG therapy, data are retrospective. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have toxic shock syndrome who receive IVIG therapy, the evidence includes a small RCT and multiple observational studies. Relevant outcomes are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for toxic shock syndrome in patients has shown reductions in mortality in a small RCT and in multiple observational studies. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Autoimmune and Inflammatory Conditions

For individuals who have immune thrombocytopenic purpura (ITP) who receive IVIG therapy, the evidence includes multiple RCTs and noncomparative studies. Relevant outcomes are DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with corticosteroids, IVIG therapy improved platelet counts. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Guillain-Barré syndrome (GBS) who receive IVIG therapy, the evidence includes a systematic review of multiple RCTs. Relevant outcomes are OS, DSS, symptoms, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with plasma exchange or combination therapy with plasma exchange, IVIG therapy showed similar outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Kawasaki disease who receive IVIG therapy, the evidence includes a systematic review and meta-analysis of multiple RCTs. Relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. Compared with aspirin, IVIG therapy has shown significant decreases in new coronary artery abnormalities. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have granulomatosis with polyangiitis (Wegener granulomatosis) who receive IVIG therapy, the evidence includes a systematic review with a single RCT. Relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. The success of IVIG in Kawasaki disease has led to the investigation of IVIG therapy for other vasculitides such as Wegener granulomatosis. A 2013 Cochrane review identified 1 RCT on IVIG for Wegener granulomatosis. This small trial 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. The evidence is sufficient to determine that that the technology results in an improvement in the net health outcome.

For individuals who have chronic inflammatory demyelinating polyneuropathy (CIDP) who receive IVIG therapy, the evidence includes a systematic review and RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have CIDP who receive SCIG therapy, the evidence includes 1 systematic review, 3 RCTs, and 1 open-label extension study. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. A randomized, placebo-controlled study supporting the FDA approval of HYQVIA demonstrated statistical superiority in preventing relapse of CIDP. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have multifocal motor neuropathy (MMN) who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Eaton-Lambert myasthenic syndrome who receive IVIG therapy, the evidence includes a RCT and multiple observational studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful improvements in outcomes assessing muscle strength and activity. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have neuromyelitis optica who receive IVIG therapy, the evidence includes multiple observational studies. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Studies have shown that IVIG treatment may benefit patients who are refractory to first-line treatment with steroids or plasma exchange, particularly children. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have severe refractory myasthenia gravis or myasthenic exacerbation who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. Compared with plasma exchange, IVIG therapy did not show significantly improved outcomes but was better tolerated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsing-remitting multiple sclerosis (RRMS) who receive IVIG therapy, the evidence includes a technology assessment. Relevant outcomes are OS, DSS, symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. According to the technology assessment, IVIG therapy is no longer considered a treatment of choice for RRMS. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have autoimmune mucocutaneous blistering diseases who receive IVIG therapy, the evidence includes 2 RCTs and a systematic review. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. A systematic review found improvements in over 90% of patients. Randomized controlled trials have reported benefits in disease activity in the population as a whole (1 trial) or in a subgroup of patients with severe disease (1 trial). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have toxic epidural necrolysis (TEN) or Stevens-Johnson syndrome (SJS) who receive IVIG therapy, the evidence includes systematic reviews of observational studies. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. No RCTs have evaluated IVIG for TEN or SJS; most trials that have, have been uncontrolled. A 2016 pooled analysis of data from 11 studies did not find a statistically significant benefit of IVIG therapy for mortality. Compared with placebo, IVIG therapy has not shown statistically significant benefits for mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have dermatomyositis or polymyositis who receive IVIG therapy, the evidence includes systematic reviews of observational studies and RCTs. Relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. In 1 of the RCTs, compared with placebo, IVIG therapy showed significant improvements in muscle strength. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have inclusion body myositis who receive IVIG therapy, the evidence includes multiple RCTs. Relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy failed to show improvements in muscle strength. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have systemic lupus erythematosus (SLE) who receive IVIG therapy, the evidence includes systematic reviews of multiples studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Although observed improvements in outcomes have suggested potential benefit with IVIG therapy for surrogate outcomes, data are mainly retrospective. More RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have immune optic neuritis who receive IVIG therapy, the evidence includes 2 RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show improvements in vision-related outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Crohn disease who receive IVIG therapy, the evidence includes multiple case reports of single patients summarized in a systematic review. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have hemophagocytic lymphohistiocytosis who receive IVIG therapy, the evidence includes multiple case reports summarized in a systematic review and case series. Relevant outcomes are OS, DSS, change in disease status, QOL, and treatment-related mortality and morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have warm antibody autoimmune hemolytic anemia, refractory to prednisone and splenectomy, who receive IVIG therapy, the evidence includes pooled observational data and a case report. Relevant outcomes are a change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential benefits with IVIG therapy in select patients with refractory autoimmune hemolytic anemia. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have antiphospholipid syndrome who receive IVIG therapy, the evidence includes pooled data from a registry. Relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested a potential mortality benefit with IVIG therapy in catastrophic antiphospholipid syndrome. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Alloimmune Processes

For individuals who have neonatal alloimmune thrombocytopenia who receive IVIG therapy, the evidence includes multiple RCTs, a large observational study, and a systematic review. Relevant outcomes are DSS, change in disease status, and treatment-related mortality and morbidity. Compared with combination use with corticosteroids, IVIG alone did not show any additional increases in platelet counts. Multiple trials have demonstrated increased platelet counts with IVIG therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have a recurrent spontaneous abortion who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are DSS, treatment-related mortality, and treatment-related morbidity. In multiple RCTs, compared with placebo, IVIG therapy alone did not show any beneficial effects in preventing spontaneous abortions. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Miscellaneous Indications

For individuals who have pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) who receive IVIG therapy, the evidence includes 2 small RCTs. Relevant outcomes are symptoms, change in disease status, and treatment-related mortality and morbidity. The trials had mixed findings and both had small sample sizes and short intervention duration. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have autism spectrum disorder who receive IVIG therapy, the evidence includes case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Although improvements were observed in 1 case series, the other 2 reported negative findings. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have complex regional pain syndrome (CRPS) who receive IVIG therapy, the evidence includes 2 RCTs. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related mortality and morbidity. In 1 trial, compared with placebo, IVIG therapy was associated with improvements in pain scores. However, methodologic limitations restrict the conclusions drawn from data on 13 patients. In the other RCT, low-dose IVIG was ineffective in relieving pain in CRPS. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Alzheimer disease who receive IVIG therapy, the evidence includes 3 RCTs. Relevant outcomes are OS, DSS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. With the exception of a few subgroup analyses using mild cognitive impairment (MCI) status, IVIG therapy was not significantly better than a placebo for outcomes such as brain atrophy, level of plasma amyloid β 1-40, or cognition and function. Studies differed by treatment protocols, outcomes assessed, and 2 of the 3 had relatively small sample sizes. Additional RCTs could be conducted to confirm whether IVIG benefits patients with early MCI. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have paraproteinemic neuropathy who receive IVIG therapy, the evidence includes 2 small RCTs. Relevant outcomes are a change in disease status, QOL and treatment-related mortality and morbidity. Compared with placebo, IVIG showed mild and transitory improvements in 1 trial but failed to show any improvement in another. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have chronic fatigue syndrome who receive IVIG therapy, the evidence includes a RCT and anecdotal reports. Relevant outcomes are symptoms, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown no therapeutic benefits. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have acute myocarditis who receive IVIG therapy, the evidence includes a meta-analysis, RCTs, and a retrospective study. Results from a Cochrane review concluded that, after pooling the available data, there was uncertain evidence of the effect of IVIG in preventing deaths. More RCT evidence is required before IVIG can be routinely recommended in the setting of myocarditis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have refractory recurrent pericarditis who receive IVIG therapy, the evidence includes a systematic review of multiple case reports and case series. Relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Although improvements were observed in some patients, controlled trials are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have stiff-person syndrome who receive IVIG therapy, the evidence includes a small randomized crossover study. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown decreases in stiffness scores and improvements in functional outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have noninfectious uveitis who receive IVIG therapy, the evidence includes 2 small case series. Relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. The case series reported measurable improvements in visual acuity after IVIG therapy, but controlled studies are needed to draw conclusions about the efficacy of IVIG for this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have postpolio syndrome who receive IVIG therapy, the evidence includes a systematic review of multiple RCTs and nonrandomized prospective studies. Relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show reductions in the severity of pain and fatigue or improvements in muscle strength. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have necrotizing fasciitis who receive IVIG therapy, the evidence includes a RCT. Relevant outcomes are OS, symptoms, functional outcomes, and treatment-related mortality and morbidity. The RCT found that, compared with placebo, IVIG therapy did not significantly improve functional outcomes, mortality rates, or other outcomes (eg, the use of life support in the intensive care unit). Additional controlled studies are needed to draw conclusions about the efficacy of IVIG for treating necrotizing fasciitis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether intravenous and subcutaneous immunoglobulin therapies as treatments for various autoimmune and nonautoimmune conditions improve net health outcomes.

Policy

Intravenous Immunoglobulin Therapy

Intravenous immunoglobulin (IVIG) therapy may be considered medically necessary for the following indications:

Immunodeficiency States

Individuals with primary immunodeficiencies, including congenital agammaglobulinemia, hypogammaglobulinemia, common variable immunodeficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, X-linked hyperimmunoglobulinemia M syndrome, and ataxia telangiectasia.

• Individuals with primary immunodeficiency syndromes should meet all the following criteria for treatment with immunoglobulin:

  • Laboratory evidence of immunoglobulin deficiency (see Policy Guidelines section)

  • Documented inability to mount an adequate immunologic response to inciting antigens (see Policy Guidelines section)

  • Persistent and severe infections, despite treatment with prophylactic antibiotics.

• Individuals with chronic lymphocytic leukemia who have immunoglobulin G (IgG) levels less than 400 mg/dL and persistent bacterial infections.

Infections

• Individuals (children) with HIV who have IgG levels less than 400 mg/dL to prevent opportunistic infections.

• Individuals with severe anemia associated with human parvovirus B19.

• Individuals with toxic shock syndrome.

Autoimmune and Inflammatory Conditions

• Individuals with acute, severe idiopathic thrombocytopenic purpura (see Policy Guidelines section) or chronic idiopathic thrombocytopenic purpura with a disease duration of at least 6 months, presence of symptoms, and with persistent thrombocytopenia (platelet <20,000 per microliter [adult] or 30,000 per microliter [child])-despite treatment with corticosteroids and splenectomy.

• Adults with Guillain-Barré syndrome as an equivalent alternative to plasma exchange.

• Individuals with Kawasaki syndrome.

• Individuals with Wegener granulomatosis.

• Individuals with chronic inflammatory demyelinating polyneuropathy (CIDP) with progressive symptoms for at least 2 months.

• Individuals with multifocal motor neuropathy.

• Individuals with Eaton-Lambert myasthenic syndrome who have failed to respond to anticholinesterase medications and/or corticosteroids.

• Individuals with neuromyelitis optica as an alternative for those with contraindications or lack of response to first-line treatment, particularly in children.

• Individuals with severe refractory myasthenia gravis with chronic debilitating disease despite treatment with cholinesterase inhibitors, or complications from or failure of corticosteroids and/or azathioprine.

• Individuals with myasthenic exacerbation (ie, an acute episode of respiratory muscle weakness) in whom plasma exchange is contraindicated.

• Individuals with severe, progressive autoimmune mucocutaneous blistering diseases that include pemphigus, pemphigoid, pemphigus vulgaris, and pemphigus foliaceus who have failed treatment with conventional agents such as corticosteroids, azathioprine, and cyclophosphamide.

• Individuals with dermatomyositis or polymyositis that is refractory to treatment with corticosteroids; in combination with other immunosuppressive agents.

• Individuals with warm antibody hemolytic anemia who are refractory to prednisone and splenectomy.

• Individuals with catastrophic antiphospholipid syndrome.

Alloimmune Processes

• Individuals with neonatal alloimmune thrombocytopenia.

• Individuals with hemolytic disease of the fetus and newborn (erythroblastosis fetalis).

Miscellaneous

• Individuals with stiff-person syndrome not controlled by other therapies.

Intravenous immunoglobulin (IVIG) therapy is considered investigational for the following indications:

Immunodeficiency States

• Individuals who have received solid organ transplant for prophylaxis or treatment of acute antibody-mediated rejection.

• Individuals undergoing or who have undergone hematopoietic cell transplantation who have IgG levels less than 400 mg/dL.

• Prior to solid organ transplant, treatment for individuals at high risk of antibody-mediated rejection including highly sensitized individuals and those receiving an ABO-incompatible organ.

Infections

• Individuals with neonatal sepsis (prophylaxis or treatment).

• Individuals (adults) with sepsis.

Autoimmune and Inflammatory Conditions

• Individuals with toxic epidermal necrolysis and Stevens-Johnson syndrome.

• Individuals with inclusion body myositis.

• Individuals with systemic lupus erythematosus.

• Individuals with immune optic neuritis.

• Individuals with Crohn disease.

• Individuals with hemophagocytic lymphohistiocytosis.

Alloimmune Processes

• Individuals with recurrent spontaneous abortion.

Miscellaneous

• Individuals with pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections.

• Individuals with autism spectrum disorder.

• Individuals with complex regional pain syndrome.

• Individuals with Alzheimer disease.

• Individuals with paraproteinemic neuropathy.

• Individuals with chronic fatigue syndrome.

• Individuals with acute myocarditis.

• Individuals with refractory recurrent pericarditis.

• Individuals with noninfectious uveitis.

• Individuals with postpolio syndrome.

• Individuals with necrotizing fasciitis.

• Individuals with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, paraneoplastic syndromes, epilepsy, chronic sinusitis, asthma, aplastic anemia, Diamond-Blackfan anemia, red cell aplasia, acquired factor VIII inhibitors, acute lymphoblastic leukemia, multiple myeloma, immune-mediated neutropenia, nonimmune thrombocytopenia, cystic fibrosis, recurrent otitis media, diabetes mellitus, Behçet syndrome, adrenoleukodystrophy, organ transplant rejection, Fisher syndrome, IgG subclass deficiency, opsoclonus-myoclonus, birdshot retinopathy, epidermolysis bullosa acquisita, polyradiculoneuropathy (other than CIDP), refractory rheumatoid arthritis, other vasculitides besides Kawasaki disease, including polyarteritis nodosa, Goodpasture syndrome, and vasculitis associated with other connective tissue diseases.

Intravenous immunoglobulin (IVIG) is considered Investigational for:

• Individuals with relapsing-remitting multiple sclerosis.

Subcutaneous Immunoglobulin Therapy

Subcutaneous immunoglobulin therapy (SCIG) may be considered medically necessary for the following indications:

• Individuals with primary immunodeficiencies, including congenital agammaglobulinemia, hypogammaglobulinemia, common variable immunodeficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and CIDP.

Other applications of SCIG therapy are considered investigational.

Policy Guidelines

Black Box Warnings and Precautions

For intravenous immunoglobulin (IVIG):

• Thrombosis may occur with immunoglobulin products. Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

• For individuals at risk of thrombosis, administer immunoglobulin products at the minimum dose and infusion rate practicable. Ensure adequate hydration before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in individuals at risk for hyperviscosity.

• Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur with the administration of human IVIG products in predisposed individuals. Individuals predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or individuals receiving known nephrotoxic drugs.

• Renal dysfunction and acute renal failure occur more commonly in individuals receiving IVIG products that contain sucrose.

• For individuals at risk of renal dysfunction or renal failure, administer IVIG at the minimum dose and infusion rate practicable. Ensure adequate hydration before administration.

Additional warnings and precautions include:

• Immunoglobulin A (IgA)-deficient individuals with antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions.

• Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output, in individuals at risk of developing acute renal failure.

• Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in individuals receiving IVIG therapy.

• Thrombosis may occur. Monitor individuals with known risk factors for thrombosis and consider baseline assessment of blood viscosity for those at risk of hyperviscosity.

• Aseptic meningitis syndrome may occur in individuals receiving IVIG therapy, especially with high doses or rapid infusion.

• Hemolytic anemia can develop subsequent to IVIG treatment. Monitor individuals for signs and symptoms of hemolysis and hemolytic anemia.

• Monitor individuals for pulmonary adverse reactions (transfusion-related acute lung injury).

• Individuals receiving IVIG for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks may be at a higher risk for developing fever, chills, nausea, and vomiting.

• IVIG is made from human plasma and may contain infectious agents (eg, viruses and, theoretically, the Creutzfeldt-Jakob disease agent).

• Passive transfer of antibodies may confound serologic testing.

The subcutaneous immunoglobulin (SCIG) product information labels note that reactions similar to other immunoglobulin products may occur. The most common adverse events with subcutaneous injections include local reactions (ie, swelling, redness, heat, pain, and itching at the injection site).

Primary Immunodeficiency Syndromes

The diagnosis of immunodeficiency and postimmunization titers must be taken in context with the clinical presentation of the individual and may vary depending on the type of vaccine given and prior immunization history. The following parameters are examples of criteria for the diagnosis of the primary immunodeficiency syndromes.

• Laboratory evidence of immunoglobulin deficiency may include the following definitions:

  • Agammaglobulinemia (total immunoglobulin G (IgG) <200 mg/dL)

  • Persistent hypogammaglobulinemia (total IgG <400 mg/dL, or at least 2 standard deviations below normal, on at least 2 occasions)

  • Absence of B lymphocytes.

• Inability to mount an adequate antibody response to inciting antigens may include the following definitions:

  • Lack of appropriate rise in antibody titer following provocation with a polysaccharide antigen.

  • Lack of appropriate rise in antibody titer following provocation with a protein antigen

Chronic Inflammatory Demyelinating Polyneuropathy

Individuals with chronic inflammatory demyelinating polyneuropathy (CIDP) should have an established diagnosis based on criteria like those established by the American Academy of Neurology in 1991^1, or those described in guidelines from the European Federation of Neurological Societies and the Peripheral Nerve Society, published in 2006, and updated in 2010 and 2021 (as the European Academy of Neurology/Peripheral Nerve Society PNS guidelines).^2, The updated guidelines include IVIG as a recommended first-line treatment option in CIDP.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity. 

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Immunoglobulins are derived from human donor plasma and used to treat an array of disorders, including primary and secondary immunodeficiency states and various autoimmune and inflammatory disorders. Human immunoglobulin therapy provides a broad spectrum of opsonizing and neutralizing immunoglobulin G antibodies against a wide variety of bacterial and viral antigens. Two formulations of human immunoglobulin G are available: intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG). Intramuscular immunoglobulin depot injections have been largely abandoned.

Intravenous immunoglobulin is an antibody-containing solution obtained from the pooled plasma of healthy blood donors that contains antibodies to greater than 10 million antigens. This product has been used to correct immunodeficiencies in patients with inherited or acquired immunodeficiencies and has also been investigated as an immunomodulator in diseases thought to have an autoimmune basis. Several IVIG products are available for clinical use in the U.S. A variety of off-label indications have been investigated; some of the most common are inflammatory myopathies, neuropathies (eg, Guillain-Barré syndrome), myasthenia gravis, multiple sclerosis, and solid organ transplantation.

This evidence review only addresses nonspecific pooled preparations of IVIG; it does not address other immunoglobulin preparations specifically used for passive immunization to prevent or attenuate infection with specific viral diseases (eg, respiratory syncytial virus, cytomegalovirus, hepatitis B).

Regulatory Status

Several IVIG products have been approved by the U.S. Food and Drug Administration (FDA). These products include Alyglo® (GC Biopharma), Asceniv® (ADMA Biologics), Bivigam® (ADMA Biologics), Flebogamma DIF® (Instituto Grifols), Gammagard Liquid® (Takeda), Gammagard S/D® (Takeda), Gammaked® (Kedrion Biopharma), Gammaplex® (Bio Products Lab), Gamunex-C® (Grifols Therapeutics), Octagam® (Octapharma), PANZYGA® (Pfizer), Privigen® (CSL Behring) and Yimmugo® (Biotest AG).^3,4,5,

Several SCIG products have been approved by the FDA. They include Cutaquig® (Octapharma), CUVITRU® (Takeda), Gammagard Liquid (Takeda), Gammaked (Kedrion Biopharma), Gamunex-C (Grifols Therapeutics), Hizentra® (CSL Behring AG), Hyqvia® (Takeda), and Xembify® (Grifols Therapeutics).^5,

At least 1 IVIG product is FDA approved to treat the following conditions^5,:

• Primary humoral immunodeficiency

• Multifocal motor neuropathy

• B-cell chronic lymphocytic leukemia

• Immune (idiopathic) thrombocytopenic purpura

• Kawasaki syndrome

• Dermatomyositis

• Chronic inflammatory demyelinating polyneuropathy.

Rationale

This evidence review was created in December 1996 and has been updated regularly with a search of the PubMed database. The most recent literature update was performed through August 20, 2024

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Immunodeficiency States

Primary Humoral Immune Deficiencies

Clinical Context and Therapy Purpose

The purpose of intravenous immunoglobulin (IVIG) therapy and subcutaneous immunoglobulin (SCIG) therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with primary humoral immunodeficiency.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with primary humoral immunodeficiency. Primary humoral immune deficiencies refer to diseases resulting from impaired antibody production because of a molecular defect intrinsic to B cells or a failure of interactions between B and T cells. Antibody deficiency characteristically leads to recurrent, often severe upper and lower respiratory tract infections. Findings associated with severe primary humoral immunodeficiencies include failure to thrive, chronic diarrhea, recurrent fever, nodular lymphoid hyperplasia in the gut, and hepatosplenomegaly.

Interventions

The therapies being considered are IVIG and SCIG.

Comparators

The following practice is currently being used to treat primary humoral immunodeficiency: standard of care, which often consists of antibiotics, antiviral drugs, and immunoglobulin therapies.

Outcomes

The general outcomes of interest are overall survival (OS), symptoms, change in disease status, morbid events, functional outcomes, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Clinical Studies

In 2010, the National Advisory Committee on Blood and Blood Products and Canadian Blood Services published guidelines on the use of immunoglobulin therapy for patients with primary immune deficiency; recommendations were based on a systematic review of evidence by a panel of experts.^6, The search identified 3 RCTs, several cohort studies, and numerous case series.

For individuals with immunodeficiencies, both IVIG and SCIG are effective.^7,8,9, Use of SCIG for the treatment of primary immunodeficiencies was approved by the U.S. Food and Drug Administration based on an open-label, nonrandomized, prospective, multicenter study.^7, Generally, many 10% IVIG solutions can be administered subcutaneously or intravenously, but more concentrated products (eg, 20%) should not be given intravenously. The subcutaneous route is associated with fewer systemic adverse events and provides more stable serum immunoglobulin G (IgG) levels. In contrast, SCIG has not been studied as extensively in autoimmune and inflammatory disorders.

Section Summary: Primary Humoral Immune Deficiencies

The evidence for the use of IVIG and SCIG therapy in primary humoral immune deficiencies consists of multiple RCTs and noncomparative studies. The literature was summarized in an evidence-based guideline (involving 102 reports) initiated by the Canadian Blood Services and the National Advisory Committee on Blood and Blood Products. Compared with the standard of care, IVIG and SCIG therapy improved disease-related outcomes.

For individuals who have primary humoral immunodeficiency who receive intravenous immune globulin (IVIG) or subcutaneous immune globulin (SCIG) therapy, the evidence includes multiple randomized controlled trials (RCTs) and noncomparative studies. Relevant outcomes are overall survival (OS), symptoms, change in disease status, morbid events, functional outcomes, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG and SCIG therapy improved disease-related outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Hematopoietic Cell Transplantation (Prophylaxis)

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are undergoing hematopoietic cell transplantation (HCT).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who are undergoing HCT. Hematopoietic cell transplantation is the intravenous infusion of hematopoietic stem and progenitor cells designed to establish marrow and immune function in patients with various acquired and inherited malignant and nonmalignant disorders.

Interventions

The therapy being considered is IVIG therapy.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are disease-specific survival (DSS), symptoms, change in disease status, morbid events, quality of life (QOL), hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review and meta-analysis by Raanani et al (2009) included 30 trials with 4223 patients undergoing HCT.^10, There was no difference in all-cause mortality between IVIG and cytomegalovirus-IVIG compared with controls (relative risk [RR], 0.99; 95% confidence interval [CI], 0.88 to 1.12; RR, 0.86; 95% CI, 0.63 to 1.16, respectively). There was no difference in clinically documented infections with IVIG compared with control (RR, 1.00; 95% CI, 0.90 to 1.10). Reviewers concluded that routine IVIG prophylaxis in patients undergoing HCT was not associated with survival benefit or reduction in infection and therefore routine use of IVIG prophylaxis in patients undergoing HCT was not recommended.

Section Summary: Hematopoietic Cell Transplantation (Prophylaxis)

The evidence for IVIG for routine prophylaxis of infection in HCT consists of a systematic review and meta-analysis. Compared with the standard of care, IVIG for routine prophylaxis of infection in patients undergoing HCT was not associated with survival benefit or reduction in infection.

For individuals who are undergoing hematopoietic cell transplantation who receive IVIG therapy (prophylaxis), the evidence includes a systematic review and meta-analysis. Relevant outcomes are disease-specific survival (DSS), symptoms, change in disease status, morbid events, quality of life (QOL), hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG for routine prophylaxis of infection in patients undergoing hematopoietic cell transplantation was not associated with survival benefit or reduction in infection. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Acute Antibody-Mediated Rejection After Solid Organ Transplant

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are at risk of acute antibody-mediated rejection (ABMR) after a solid organ transplant or who have acute ABMR after solid organ transplant.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are individuals who are at risk of acute ABMR after a solid organ transplant or who have acute ABMR after a solid organ transplant. Acute rejection after transplant can be broadly divided into 2 categories: the more common acute cellular rejection related to activation of T cells, and the less common acute ABMR related to the presence of anti-donor antibodies. Acute ABMR is an entity now better defined and often detected earlier in the clinical course, based on the recognition of characteristic histologic findings, positive C4d staining, and the detection of donor-specific antibodies.

Interventions

The therapy being considered is IVIG therapy.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 2 years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Prophylaxis

The risk of ABMR is related to the presence of preformed alloantibodies in the recipient due to prior blood transfusions, transplants, or pregnancies. The presence of alloantibodies is assessed using a panel reactive antibody (PRA) screen. Those with a PRA screen greater than 20% are referred to as “sensitized,” and these patients often have prolonged waiting times to identify a compatible donor. Recipients of ABO mismatched donor organs are also at risk of ABMR.

Systematic Review

In 2019, Bourasssa-Blanchette and colleagues published a systematic review involving 18 trials (with 8 RCTs) investigating the impact of IVIG prophylaxis on infection, rejection, graft loss, and death following kidney transplantation.^11, Results revealed that IVIG administration did not reduce cytomegalovirus infection (odds ratio [OR], 0.68; 95% CI , 0.39 to 1.21; 6 studies, n=295), rejection (OR, 0.96; 95% CI , 0.50 to 1.82; 4 studies, n=187), or graft loss (OR, 1.03; 95% CI , 0.46 to 2.30; 6 studies, n=265) in the RCTs. Among the included nonrandomized studies, IVIG administration was associated with a reduction in rejection and graft loss but not cytomegalovirus infection or death. The authors noted that the quality of included studies was variable with a high to very high risk of bias and that additional adequately powered RCTs are needed in order to determine if IVIG is an effective intervention.

Randomized Controlled Trials

In the National Institutes of Health (NIH)-sponsored IG02 study, 101 adults with a PRA screen of 50% or higher were randomized to IVIG 2 g/kg monthly for 4 months or placebo.^12, If transplanted, additional infusions were given at 12 and 24 months. Treatment with IVIG therapy resulted in significant reductions in PRA levels compared with placebo (35% vs. 17%). Seven graft failures occurred (4 IVIG, 3 placebo) among adherent patients with similar 2-year graft survival rates (80% IVIG, 75% placebo). The investigators concluded that IVIG therapy was better than placebo in reducing anti-human leukocyte antigen antibody levels and improving transplantation rates in highly sensitized patients with end-stage renal disease. In a follow-up study, the combination of high-dose IVIG and B-cell depletion therapy reduced PRA from 77% to 44% at the time of transplantation.^13,

Nonrandomized Studies

More recent studies have failed to show a reduction in PRA levels, specifically in patients with a PRA greater than 80%.^14,15,16, Nonrandomized clinical observations have suggested that a combination of plasmapheresis plus low-dose IVIG and interleukin-2 blockade or rabbit anti-thymocyte globulin for induction was associated with improved patient survival compared with chronic dialysis for the treatment of sensitized patients.^17,18,19,

Section Summary: Prophylaxis for Acute Antibody-Mediated Rejection After Solid Organ Transplant

The evidence for the use of IVIG for prophylaxis prior to solid organ transplant consists of a systematic review, NIH-sponsored RCT, and nonrandomized observational studies. A systematic review involving variable quality studies with high to very high risk of bias concluded that there is insufficient data to support or advise against the use of IVIG prophylaxis in solid organ transplant. More adequately powered RCTs are needed. Additionally, studies have shown conflicting results that prophylaxis with IVIG in patients with high PRA levels prior to solid organ transplant leads to a significant reduction in PRA levels. Compared with the standard of care, IVIG for prophylaxis of infection in patients with high PRA levels was not associated with a consistent survival benefit or reduction in infection.

For individuals who are at risk of acute antibody-mediated rejection after solid organ transplants who receive IVIG therapy, the evidence consists of a systematic review, National Institutes of Health (NIH)-sponsored RCT, and nonrandomized observational studies. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. The systematic review involving variable quality studies with high to very high risk of bias concluded that there is insufficient data to support or advise against the use of IVIG prophylaxis in solid organ transplant. More adequately powered RCTs are needed. Additionally, studies have shown conflicting results that prophylaxis with IVIG in patients with high panel reactive antibody (PRA) levels prior to solid organ transplant leads to a significant reduction in PRA levels. Compared with the standard of care, IVIG for prophylaxis of infection in patients with high PRA levels was not consistently associated with a survival benefit or reduction in infection. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Treatment

Systematic Reviews

Most studies of IVIG treatment for ABMR are retrospective case series from single institutions. A systematic review by Roberts et al (2012) of treatments for acute ABMR in renal allografts identified 10,388 citations but only 5 small RCTs, none of which addressed the use of IVIG in the treatment of ABMR.^20, A RCT by Casadei et al (2011) demonstrated that IVIG therapy is effective for the treatment of steroid-resistant rejection^21,; however, IVIG was ineligible for inclusion in the Roberts review because 83% of the patients had Banff 1 (pure cellular) rejection on biopsy.^20, According to Roberts et al (2012), the evidence to support the use of IVIG to treat ABMR is very low (GRADE criteria).

Section Summary: Treatment of Acute Antibody-Mediated Rejection After Solid Organ Transplant

The evidence for the use of IVIG in ABMR consists of retrospective case series and a systematic review. According to a 2012 systematic review, the evidence for IVIG treatment of ABMR is very low (GRADE criteria). Compared with the standard of care, IVIG treatment for ABMR has shown potential benefits in retrospective or small prospective studies; however, larger RCTs with longer follow-up are needed to demonstrate improved health outcomes.

For individuals who have acute antibody-mediated rejection after solid organ transplants who receive IVIG therapy, the evidence includes retrospective case series and a systematic review. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Compared with the standard of care, IVIG treatment for antibody-mediated rejection has shown potential benefits in retrospective or small prospective studies; however, larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Chronic Lymphocytic Leukemia

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who have chronic lymphocytic leukemia (CLL) with recurrent bacterial infections associated with hypogammaglobulinemia.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who have CLL with recurrent bacterial infections associated with hypogammaglobulinemia. Chronic lymphocytic leukemia is a disorder characterized by progressive accumulation of functionally incompetent lymphocytes; most patients develop hypogammaglobulinemia at some point in the course of their disease. Patients experiencing recurrent bacterial infections associated with hypogammaglobulinemia are likely to benefit from monthly infusions of IVIG.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat CLL: standard of care.

Outcomes

The general outcomes of interest are OS, symptoms, morbid events, QOL, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Multiple trials and a meta-analysis comparing IVIG with placebo have shown decreased bacterial infections, but not decreased mortality.^{22,23,24,25,26,27,} Use of IVIG has not been directly compared with prophylactic antimicrobials. The randomized trials of prophylactic IVIG found that patients who receive IVIG have a decreased incidence of minor and moderate, but not major, bacterial infections. Treatment with IVIG has not been shown to increase QOL or survival. The largest study was a multicenter randomized trial in 84 patients with CLL who were at increased risk of bacterial infection due to hypogammaglobulinemia, a history of infection, or both.^22, Although minor or moderate bacterial infections were significantly less common in patients receiving IVIG, there was no impact on the incidence of major infections, mortality, or nonbacterial infections.

Section Summary: Chronic Lymphocytic Leukemia

The evidence for the use of IVIG therapy for prophylaxis of infection in CLL consists of multiple RCTs and a meta-analysis. Compared with placebo, IVIG treatment for recurrent bacterial infections associated with hypogammaglobulinemia in CLL patients has shown reductions in minor and moderate infections without a reduction in other clinically important outcomes, including mortality.

For individuals who have chronic lymphocytic leukemia with recurrent bacterial infections associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for recurrent bacterial infections associated with hypogammaglobulinemia in chronic lymphocytic leukemia patients has shown reductions in minor and moderate infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Infections

HIV-Infected Children

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in children who have human immunodeficiency virus (HIV) infection and recurrent bacterial infections associated with hypogammaglobulinemia.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is children with HIV infection and recurrent bacterial infections associated with hypogammaglobulinemia. Prevention of opportunistic infections remains a critical component of care for HIV-infected children even though the availability of combination antiretroviral therapies has substantially and dramatically decreased HIV-related opportunistic infections and deaths.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat HIV-infected children: standard of care.

Outcomes

The general outcomes of interest are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 18 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

A 1991 double-blind RCT allocated 372 HIV-infected children to IVIG or placebo every 28 days.^28, The median length of follow-up was 17 months. Results were stratified by CD4-positive counts (≥0.2×10⁹/L or <0.2×10⁹/L). After 24 months, for children with CD4-positive counts of 0.2×10⁹/L or greater, IVIG treatment compared with placebo significantly increased infection-free rates (67% vs. 48% respectively; p<.05); reduced overall the number of serious and minor bacterial infections (RR, 0.68; p<.05); and reduced the number of hospitalizations for acute care (RR, 0.65; p<.05). The effect was less marked in children with CD4-positive counts less than 0.2×10⁹/L.

Subsection Summary: HIV-Infected Children

The evidence for the use of IVIG for prophylaxis of opportunistic infections in children with HIV consists of a single RCT. Compared with placebo, IVIG therapy for the prevention of opportunistic infections in HIV-infected children has shown reductions in minor and serious infections without a reduction in other clinically important outcomes, including mortality.

For individuals who are HIV-infected children with recurrent bacterial infection associated with hypogammaglobulinemia who receive IVIG therapy, the evidence includes a single RCT. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for the prevention of opportunistic infections in HIV-infected children has shown reductions in minor and serious infections without a reduction in other clinically important outcomes, including mortality. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Neonatal Sepsis

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients who are preterm and low birth weight infants and at risk for sepsis or who have sepsis.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is infants who are preterm, low birth weight, and at risk for sepsis or who have sepsis. Preterm and low birth weight infants are prone to infection because of an immature immune system as well as increased exposure to nosocomial pathogens.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat preterm, low birth weight infants at risk for sepsis or who have sepsis: standard of care.

Outcomes

The general outcomes of interest are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Prophylaxis

A Cochrane review by Ohlsson and Lacy (2013) assessed IVIG for the prevention of infection in preterm and/or low birth weight infants.^29,Reviewers identified 19 RCTs that compared IVIG against placebo or no intervention for approximately 5000 preterm (<37 weeks of gestational age) and/or low birth weight (<2500 g) infants. Five of the 19 studies were considered to be high-quality; the other had potential biases (eg, lack of caregiver blinding in 10 studies). In a meta-analysis of 10 studies, IVIG was associated with a statistically significant reduction in sepsis (≥1 episodes; RR, 0.85; 95% CI, 0.75 to 0.98). Moreover, a meta-analysis of 16 studies showed a significant reduction in serious infection (≥1 episodes) with IVIG (RR, 0.82; 95% CI, 0.74 to 0.92). However, IVIG was not associated with a significant reduction in mortality. A meta-analysis of 15 studies that reported all-cause mortality found a RR of 0.89 (95% CI, 0.75 to 1.05), and a meta-analysis of 10 studies that reported mortality due to infection found a RR of 0.83 (95% CI, 0.56 to 1.22). Reviewers noted that a 3% reduction in sepsis and a 4% reduction in 1 or more episodes of any serious infection without a reduction in other clinically important outcomes, including mortality, were of marginal clinical importance. No major adverse events related to IVIG administration were reported.

Subsection Summary: Prophylaxis of Neonatal Sepsis

The evidence for the use of IVIG therapy for prophylaxis of infection in preterm and/or low birth weight infants consists of a Cochrane review involving multiple RCTs. Compared with placebo, IVIG therapy for prophylaxis of neonatal sepsis has shown a 3% reduction in sepsis and a 4% reduction in 1 or more episodes of any serious infection (considered of marginal clinical importance) with no improvement in any of the other clinically important outcomes, including mortality.

For individuals who are preterm and low birth weight infants and at risk for sepsis who receive IVIG therapy (prophylaxis), the evidence includes a Cochrane review involving multiple RCTs. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy for prophylaxis of neonatal sepsis has shown a 3% reduction in sepsis and a 4% reduction in 1 or more episodes of any serious infection (considered of marginal clinical importance) with no improvement in any of the other clinically important outcomes, including mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Treatment

Systematic Reviews

A Cochrane review by Ohlsson and Lacy (2020) identified 9 trials that compared IVIG with placebo or standard care in neonates (<28 days old) with suspected or confirmed infection.^30, Studies included a total of 3973 infants; the largest trial had a sample size of 3493 and contributed 90% of the data. Meta-analysis of all 9 trials found no statistically significant difference in mortality rates with IVIG versus the control therapy (RR, 0.95; 95% CI, 0.80 to 1.13). Meta-analysis of 3 trials found that IVIG significantly reduced the length of the hospital stay compared with a control intervention (mean difference [MD], -4.08; 95% CI, -6.47 to -1.69). Results were not pooled for other outcomes.

Randomized Controlled Trials

The trial with a large sample size was published by the International Neonatal Immunotherapy Study group (2011); it was conducted in 9 countries.^31, Infants receiving antibiotics for suspected or confirmed serious infection were randomized to 2 infusions of IVIG at a dose of 500 mg/kg of body weight (n=1759) or a matching volume of placebo (n=1734). Infusions were given 48 hours apart. The primary study outcome was the rate of death or major disability (according to predefined criteria) at age 2 years. By age 2 years, 686 (39%) of 1759 children in the IVIG group had died or suffered major disability compared with 677 (39%) of 1734 children in the placebo group (RR, 1.00; 95% CI, 0.92 to 1.08). There were also no statistically significant differences in the primary outcome when prespecified subgroups (eg, birthweight, gestational age at birth, sex) were examined. Moreover, there were no statistically significant differences between groups in secondary outcomes, including rates of subsequent sepsis episodes. The number of reported adverse events was 12 in the IVIG group (including 2 deaths) versus 10 in the placebo group (including 4 deaths).

Section Summary: Treatment of Neonatal Sepsis

The evidence for the use of IVIG treatment for suspected or confirmed infection in neonates consists of a systematic review and multiple RCTs. Compared with placebo, IVIG treatment for neonatal sepsis did not differ significantly in the rates of death or major disability.

For individuals who are preterm and low birth weight infants with sepsis who receive IVIG therapy (treatment), the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for neonatal sepsis did not differ significantly in the rates of death or major disability. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Sepsis in Adults

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in adults with sepsis.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is adults with sepsis.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat adults with sepsis: standard of care.

Outcomes

The general outcomes of interest are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A meta-analysis by Busani et al (2016), which pooled 18 RCTs, showed that the use of IVIG reduced the mortality risk of septic patients by half (OR, 0.50; 95% CI, 0.34 to 0.71).^32, However, there was a preponderance of small, low-quality studies in the evidence base, which was further complicated by heterogeneous dosing regimens and types of IVIG preparations used across studies that were conducted over a long time horizon. Reviewers concluded that the evidence did not support the widespread use of IVIG as adjunctive therapy for sepsis in adults.

A meta-analysis by Pan et al (2023) pooled 31 RCTS (N=6,276) of IVIG use in patients (adults and neonates) with sepsis. ^33,Evidence from the pooled results found that IVIG was highly effective in lowering mortality in patients (RR 0.86, 95% CI: 0.77 to 0.95; p =.02, I² = 37%). In subgroup analyses, IVIG was shown to have an effect in reducing adult sepsis mortality specifically (RR 0.70; 95% CI, 0.57 to 0.86; p =.15, I² = 27%). Authors did note the limitation of inclusion of marginally representative data and potential confounders that may have affected the results of the meta-analysis.

Section Summary: Sepsis in Adults

The evidence for the use of IVIG treatment for sepsis in adults consists of a meta-analysis of 18 RCTs and a meta-analysis of 31 RCTs. Compared with placebo, IVIG treatment for adult sepsis showed reductions in mortality in the meta-analyses However, multiple factors preclude recommending the routine use of IVIG to treat sepsis. These factors include the preponderance of small low-quality studies, the use of heterogeneous dosing regimens, types of IVIG preparations used, and changes over time in the management of sepsis.

For individuals who are adults with sepsis who receive IVIG therapy, the evidence includes meta-analyses. Relevant outcomes are OS, symptoms, morbid events, hospitalizations, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for adult sepsis showed reductions in mortality. However, multiple factors preclude recommending the routine use of IVIG to treat sepsis. They include the preponderance of small low-quality studies, the use of heterogeneous dosing regimens, types of IVIG preparations used, and changes over time in the management of sepsis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Severe Anemia Associated With Human Parvovirus B19

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with severe anemia associated with human parvovirus B19.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with severe anemia associated with human parvovirus B19. Human parvovirus B19 is a common single-stranded DNA virus. Infections are usually mild or asymptomatic and do not require treatment. In some cases, the infection can lead to sufficiently severe complications such as transient aplastic crisis, in which case treatment is indicated and may be lifesaving.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat severe anemia associated with human parvovirus B19 virus: standard of care.

Outcomes

The general outcomes of interest are a change in disease status, and treatment-related mortality and morbidity. Follow-up at 12 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Case Series

No controlled trials have evaluated IVIG for severe anemia associated with parvovirus B19. Only small case series and case reports are available.^34,35,36, One larger case series, by Crabol et al (2013), retrospectively reported on 10 patients with documented human parvovirus B19 and pure red cell aplasia.^37, Following a mean of 2.7 courses of IVIG treatment, hemoglobin level was corrected in 9 of 10 patients. Four patients had adverse events associated with IVIG (2 cases of acute reversible renal failure, 2 cases of pulmonary edema). In the same article, the authors reported on findings of a literature search in which they identified 123 cases of pure red cell aplasia treated with IVIG (other than the 10 patients in their series). Among 86 (70%) of 123 patients available at 12-month follow-up, hemoglobin was corrected in 36 (42%) patients, and the remaining 50 (58%) patients had persistent anemia.

Section Summary: Severe Anemia Associated With Human Parvovirus B19

The evidence for the use of IVIG treatment for severe anemia associated with human parvovirus B19 consists of case series. Although observed improvements in outcomes have suggested potential benefits with IVIG therapy, data are retrospective. Randomized controlled trials are needed to demonstrate improved health outcomes.

For individuals who have severe anemia associated with human parvovirus B19 who receive IVIG therapy, the evidence includes case series. Relevant outcomes are a change in disease status, treatment-related mortality, and treatment-related morbidity. Although observed improvements in outcomes have suggested potential benefits with IVIG therapy, data are retrospective. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Toxic Shock Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with toxic shock syndrome.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with toxic shock syndrome. Toxic shock syndrome is also called Streptococcal toxic shock syndrome. Streptococcal toxins induce the release of inflammatory cytokines, which cause capillary leakage and tissue damage resulting in shock, multiorgan failure, and death.

Interventions

The therapy being considered is IVIG therapy. IVIG is used for the treatment of toxic shock syndrome to boost antibody levels via passive immunity.

Comparators

The following therapy is currently being used to treat toxic shock syndrome: corticosteroids.

Outcomes

The general outcomes of interest are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

The evidence for the use of IVIG treatment for toxic shock syndrome is limited and includes a small RCT^38, and multiple observational studies.^39,40,41,42, The RCT by Darenberg et al (2003) allocated 21 adults with toxic shock syndrome to IVIG or placebo.^38, Mortality rates were 10% and 36%, respectively, but the difference in mortality rates was not statistically significant. Additionally, the trial was originally planned to enroll 120 patients, so it was likely underpowered to detect any significant differences.

Prospective and Retrospective Studies

In a prospective observational study, Linner et al (2014) compared 23 patients receiving IVIG therapy with 44 patients receiving a placebo.^39, The odds for survival were 5.6 for IVIG versus placebo (p=.03). The proportion of patients alive at 28 days by treatment was 87% and 50%, respectively. In 2 retrospective studies, 27 patients with toxic shock syndrome treated with IVIG were compared with historical controls.^40,41, While the mortality rate was lower with IVIG than with historical controls, lack of randomization or statistical adjustment of the 2 groups poses difficulties when interpreting the results. A retrospective study by Shah et al (2009), which included 192 children with toxic shock syndrome failed to show improvement in outcomes with IVIG.^42,

Section Summary: Toxic Shock Syndrome

The evidence for the use of IVIG treatment for toxic shock syndrome consists of a small RCT and multiple observational studies. Compared with placebo, IVIG treatment for toxic shock syndrome in patients has shown reductions in mortality in a small RCT and in multiple observational studies.

For individuals who have toxic shock syndrome who receive IVIG therapy, the evidence includes a small RCT and multiple observational studies. Relevant outcomes are OS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with placebo, IVIG treatment for toxic shock syndrome in patients has shown reductions in mortality in a small RCT and in multiple observational studies. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Autoimmune and Inflammatory Conditions

Idiopathic Thrombocytopenic Purpura

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with idiopathic thrombocytopenia purpura (ITP).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with ITP. Idiopathic thrombocytopenia purpura, also known as primary immune thrombocytopenia, is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is a more common cause of thrombocytopenia in otherwise asymptomatic adults.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat ITP: corticosteroids.

Outcomes

The general outcomes of interest are DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized and Nonrandomized Trials

In 2007, the National Advisory Committee on Blood and Blood Products and the Canadian Blood Services issued guidelines on the use of IVIG for hematologic conditions, including ITP, based on 6 RCTs and 1 nonrandomized trial of IVIG for adult ITP.^43, Three of the trials compared IVIG with corticosteroids, and 4 trials evaluated different doses of IVIG. None compared IVIG with no therapy. The largest trial, by Godeau et al (2002), compared IVIG with corticosteroids in 122 patients with severe acute ITP.^44, The primary outcome, the mean number of days with a platelet count greater than 50x10⁹/L at day 21, was significantly greater in the IVIG group than in the high-dose methylprednisolone group. Two other trials, 1 nonrandomized (IVIG vs. corticosteroids)^45, and 1 randomized (IVIG alone vs. oral prednisone alone vs. IVIG plus oral prednisone)^46, found no differences in platelet counts greater than 50x10⁹/L at 48 hours or in response rates between groups, respectively.

Section Summary: Idiopathic Thrombocytopenic Purpura

For individuals who have ITP who receive IVIG therapy, the evidence includes multiple RCTs and noncomparative studies. Compared with corticosteroids, IVIG therapy improved platelet counts.

For individuals who have immune thrombocytopenic purpura (ITP) who receive IVIG therapy, the evidence includes multiple RCTs and noncomparative studies. Relevant outcomes are DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with corticosteroids, IVIG therapy improved platelet counts. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Guillain-Barré Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Guillain-Barré syndrome (GBS).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with GBS. Guillain-Barré syndrome is a heterogeneous condition with several variant forms and encapsulates many acute immune-mediated polyneuropathies. It is characterized by a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapies are currently being used to treat GBS: plasma exchange, immunoadsorption, and supportive care.

Outcomes

The general outcomes of interest are OS, DSS, symptoms, change in disease status, morbid events, and treatment-related mortality and morbidity. Follow-up at 4 weeks is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

An updated Cochrane review by Hughes et al (2014) evaluated results from randomized trials of immunotherapy for GBS.^47, Reviewers identified 12 randomized trials; none was placebo-controlled. Seven trials compared IVIG with plasma exchange, 3 trials compared IVIG with supportive treatment only, 2 trials compared plasma exchange, and 2 others compared IVIG with immunoabsorption (1 compared IVIG plus immunoabsorption with 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 change in disability level (using a 7-grade disability scale) after 4 weeks. A pooled analysis of 7 trials comparing IVIG with plasma exchange did not find significant differences between groups in change in the number of disability grades at 4 weeks (MD, -0.02; 95% CI, -0.25 to 0.20). There were also no significant differences in other outcome measures for IVIG versus plasma exchange (eg, number of patients who improved by ≥1 grade). There were insufficient data to pool results for comparisons of IVIG with other interventions or for subgroup analysis by age. However, patients assigned to IVIG were significantly less likely to discontinue treatment than patients assigned to plasma exchange (RR, 0.14; 95% CI, 0.05 to 0.36).

Most trials in this review had small sample sizes. The largest was a 1997 multicenter, randomized trial of 383 adults that compared IVIG, plasma exchange, and combination IVIG plus plasma exchange.^48, Trial objectives were to establish that IVIG is equivalent or superior to plasma exchange and to establish that plasma exchange followed by IVIG is superior to a single treatment. Noninferiority 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 and plasma exchange group was 0.09 grade (95% CI, -0.23 to 0.42); this met the predefined criterion for equivalence of these treatments. Differences were 0.29 grade (95% CI, -0.04 to 0.63) between the IVIG plus plasma exchange group and the IVIG only group, and 0.20 grade (95% CI, -0.14 to 0.54) between the IVIG plus plasma exchange group and the plasma exchange only group. Thus, neither combined treatment group proved superior to either treatment alone.

Miller Fisher syndrome is a variant of GBS characterized by impairment of eye movements (ophthalmoplegia), incoordination (ataxia), and loss of tendon reflexes (areflexia). A Cochrane review by Overell et al (2007) evaluated acute immunomodulatory therapies in Miller Fisher syndrome or its variants.^49, No RCTs were identified.

Section Summary: Guillain-Barré Syndrome

For individuals who have GBS who receive IVIG therapy, the evidence includes a systematic review of multiple RCTs. Compared with plasma exchange or combination therapy with plasma exchange, IVIG therapy showed similar outcomes.

For individuals who have Guillain-Barré syndrome (GBS) who receive IVIG therapy, the evidence includes a systematic review of multiple RCTs. Relevant outcomes are OS, DSS, symptoms, change in disease status, morbid events, and treatment-related mortality and morbidity. Compared with plasma exchange or combination therapy with plasma exchange, IVIG therapy showed similar outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Kawasaki Disease

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Kawasaki disease.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with Kawasaki disease. Kawasaki disease is a very common vasculitis of childhood; it is characterized by fever and manifestations of acute inflammation lasting for an average of 12 days without therapy. It is typically self-limiting but may cause cardiovascular complications, particularly coronary artery aneurysms, which can lead to coronary occlusion and cardiac ischemia ultimately leading to significant morbidity and even death.

Interventions

The therapy being considered is IVIG therapy. Although the mechanism of action of IVIG in Kawasaki disease is not understood, its use early in the course of the disease has reduced the prevalence of coronary artery abnormalities.

Comparators

The following practice is currently being used to treat Kawasaki disease: standard of care.

Outcomes

The general outcomes of interest are DSS, change in disease status, and treatment-related mortality and morbidity. Follow-up at 30 days is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Multiple RCTs and meta-analysis, have demonstrated the efficacy of IVIG in preventing cardiac consequences of Kawasaki disease in children. A Cochrane review of RCTs by Broderick et al (2023) identified 31 trials for meta-analysis. ^50,Comparator therapies included aspirin, prednisolone, or infliximab. Results showed a significant decrease in new coronary artery abnormalities in favor of IVIG compared with aspirin at 30 days ( OR, 0.60; 95% CI, 0.41 to 0.87). Adverse effects were similar between groups. There was low certainty evidence comparing aspirin and IVIG for acute coronary syndrome and need for additional treatment. Comparisons between IVIG and prednisolone had low certainty. Reviewers concluded that high dose IVIG probably reduces coronary artery abnormalities compared to aspirin or medium or low dose IVIG regimens.

Section Summary: Kawasaki Disease

For individuals who have Kawasaki disease who receive IVIG therapy, the evidence includes a systematic review and meta-analysis of multiple RCTs. Compared with aspirin, IVIG therapy has shown significant decreases in new coronary artery abnormalities.

For individuals who have Kawasaki disease who receive IVIG therapy, the evidence includes a systematic review and meta-analysis of multiple RCTs. Relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. Compared with aspirin, IVIG therapy has shown significant decreases in new coronary artery abnormalities. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Granulomatosis With Polyangiitis (Wegener Granulomatosis)

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with granulomatosis with polyangiitis (Wegener granulomatosis).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with granulomatosis with polyangiitis (Wegener granulomatosis).

Interventions

The therapy being considered is IVIG for maintenance therapy.

Comparators

The following practice is currently being used to treat granulomatosis with polyangiitis: standard of care.

Outcomes

The general outcomes of interest are DSS, change in disease status, and treatment-related mortality and morbidity. Follow-up at 3 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

The success of IVIG therapy for Kawasaki disease led to a study of IVIG therapy for other vasculitides such as Wegener granulomatosis. A Cochrane review by Fortin et al (2013) identified 1 RCT on IVIG for Wegener granulomatosis.^51, This trial, published by Jayne et al (2000), compared single course IVIG (n=17) with placebo (n=17) and 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.^52,

Section Summary: Granulomatosis With Polyangiitis (Wegener Granulomatosis)

For individuals who have granulomatosis with polyangiitis (Wegener granulomatosis) who receive IVIG therapy, the evidence includes a systematic review with a single relevant RCT. This small trial 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.

For individuals who have granulomatosis with polyangiitis (Wegener granulomatosis) who receive IVIG therapy, the evidence includes a systematic review with a single RCT. Relevant outcomes are disease-specific mortality, change in disease status, and treatment-related mortality and morbidity. The success of IVIG in Kawasaki disease has led to the investigation of IVIG therapy for other vasculitides such as Wegener granulomatosis. A 2013 Cochrane review identified 1 RCT on IVIG for Wegener granulomatosis. This small trial 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. The evidence is sufficient to determine that that the technology results in an improvement in the net health outcome.

Chronic Inflammatory Demyelinating Polyneuropathy

Clinical Context and Therapy Purpose

The purpose of IVIG and SCIG therapies is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with CIDP. Chronic inflammatory demyelinating polyneuropathy is an acquired neurologic disorder characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is caused by damage to the myelin sheath of the peripheral nerves. The disease is difficult to diagnose due to its heterogeneous presentation (both clinical and electrophysiological).

Interventions

The therapies being considered are IVIG and SCIG.

Comparators

The following therapies are currently being used to treat CIDP: plasma exchange, immunoadsorption, and supportive care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Follow-up as long as 48 weeks is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Intravenous Immunoglobulin Therapy

Systematic Reviews

Eftimov et al (2013) published a Cochrane review of RCTs on IVIG for treating CIDP.^53, Reviewers identified 8 RCTs that enrolled 332 patients with definite or probable CIDP and that compared IVIG with placebo, corticosteroids, or plasma exchange. Three trials compared IVIG with another active treatment,^54,55,56, and the other 5 were placebo-controlled (n=235).^{57,58,59,60,61,} The primary trial outcome was the proportion of participants with a significant improvement in disability within 6 weeks of starting treatment. Studies used a variety of disability measures. When possible, reviewers transformed the data on disability into a modified 6-point Rankin Scale for disability. Data from the 5 placebo-controlled randomized trials were pooled. The pooled RR for improvement in the IVIG group compared with the placebo group was 2.40 (95% CI, 1.72 to 3.36; p<.001). When data were pooled from 3 studies on IVIG versus placebo in which the disability measures could be converted to the Rankin Scale, the RR was similar (2.40), but not statistically significant (95% CI, 0.98 to 5.83; p=.054). Pooled analyses of data from these 3 placebo-controlled trials found a statistically higher rate of any adverse event with IVIG, but no serious adverse events. Data from studies comparing IVIG with active treatment were not pooled due to differences in comparators. Limitations of the meta-analysis included the use of different disability scales and varying definitions of clinical response.

Bus et al (2024) published an updated Cochrane review of RCTs on IVIG for treating CIDP.^62, Nine RCTs were included (N=372 patients). Only one new trial was included; however, it did not contribute any data to the meta-analysis.^63,

Randomized Controlled Trials

The ICE study reported by Hughes et al (2008), the largest included in the meta-analysis, was a double-blind, multicenter trial that randomized 117 patients to IVIG or placebo.^61, The primary outcome measure was the proportion of patients showing clinically meaningful reductions in disability at week 24. Results showed that the proportion of patients meeting the primary endpoint was significantly greater with IVIG treatment (54%) than with placebo (21%), with an absolute difference of 33.5% (95% CI, 15.4% to 51.7%). In the 24-week extension phase, 57 patients who received IVIG in the randomized phase were rerandomized to IVIG or placebo. Relapse rates were significantly lower for patients treated with IVIG (13% vs. 45%; hazard ratio [HR], 0.19; 95% CI, 0.05 to 0.70). Benefits of IVIG treatment extended to as long as 48 weeks with maintenance treatments of 1 g/kg every 3 weeks.

Subsection Summary: Intravenous Immunoglobulin Therapy for Chronic Inflammatory Demyelinating Polyneuropathy

For individuals who have CIDP who receive IVIG therapy, the evidence includes a systematic review and RCTs. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability.

For individuals who have chronic inflammatory demyelinating polyneuropathy (CIDP) who receive IVIG therapy, the evidence includes a systematic review and RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Subcutaneous Immunoglobulin Therapy

Systematic Reviews

Ramzi et al (2024) published a systematic review and meta-analysis of SCIG therapy for CIDP. ^64, The systematic review included 50 studies whereas the meta-analysis evaluated 20 studies. The meta-analysis results showed that SCIG had fewer, milder side effects, decreased relapse rates, greatly increased muscle strength, and was highly preferred by patients compared to IVIG therapy.

Randomized Controlled Trials

In the randomized, double-blind, placebo-controlled, phase 3 PATH trial, van Schaik et al (2018) studied relapse rates in 172 patients with CIDP given SCIG and placebo.^65, Patients were randomized in a 1:1:1 ratio to a placebo group (n=57 [33%]), a low-dose group (n=57 [33%]), and a high-dose group (n=57 [33%]). The trial found that both SCIG doses were effective and well-tolerated, suggesting that SCIG can be used as maintenance treatment for CIDP. Seventy-seven patients withdrew from the trial due to relapse or other reasons: 36 (63%; 95% CI, 50% to 74%) placebo patients, 22 (39%; 95% CI, 27% to 52%) low-dose SCIG patients, and 19 (33%; 95% CI, 22% to 46%) high-dose SCIG patients (p<.001). The trial was limited by missing patient data and inadequate follow-up of those who withdrew. The PATH open-label extension trial (2019) evaluated the long-term safety and efficacy of SCIG in patients with CIDP. ^66,Eighty-two patients were enrolled in the trial and 66 patients completed the 48-week study duration. Patients treated with 0.4 g/kg had an overall relapse rate of 10%, whereas those treated with 0.2 g/kg had a rate of 48%. After dose reduction, 19 of 28 who finished the PATH study without experiencing a relapse continued to be relapse-free on the 0.2 g/kg dose. Adverse events were reported in sixty-two patients (76%), the majority of which were mild or moderate and had no associated significant adverse events.

One crossover RCT comparing IVIG and SCIG for CIDP was identified; this trial by Markvardsen et al (2017) included 20 patients.^67, Patients underwent 10 weeks of treatment with SCIG and IVIG, in random order, for a total intervention duration of 20 weeks. The primary efficacy outcome was change in isokinetic muscle strength. Fourteen (20%) of 20 patients completed the trial. Isokinetic muscle strength increased by 7.4% with SCIG and 14% with IVIG; the difference between groups was not statistically significant. Conclusions about the relative efficacy of SCIG and IVIG cannot be drawn from this trial due to the small sample size, high dropout rate, short-term follow-up, and the crossover design without a washout period.

A randomized, placebo-controlled study was evaluated for the FDA approval of HYQVIA to treat CIDP.^68, The study included participants ≥18 years of age with definite or probable CIDP (N=122). The analysis of the primary endpoint revealed a statistically significant difference in relapse rates between the HYQVIA group (n=57, 14.0%) and the placebo group (n=65, 32.3%) (p=.0314). The treatment difference of -18.3% ( -3.1%; two-sided 95% CI: -32.1%) demonstrated that HYQVIA was superior to placebo in preventing relapse of CIDP.

Section Summary: Subcutaneous Immunoglobulin Therapy for Chronic Inflammatory Demyelinating Polyneuropathy

For individuals who have CIDP who receive SCIG therapy, the evidence includes 1 systematic review, 3 RCTs, and 1 open-label extension study. A randomized, placebo-controlled study supporting the FDA approval of HYQVIA demonstrated statistical superiority in preventing relapse of CIDP.

For individuals who have CIDP who receive SCIG therapy, the evidence includes 1 systematic review, 3 RCTs, and 1 open-label extension study. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. A randomized, placebo-controlled study supporting the FDA approval of HYQVIA demonstrated statistical superiority in preventing relapse of CIDP. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Multifocal Motor Neuropathy

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with multifocal motor neuropathy (MMN).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with MMN. Multifocal motor neuropathy is a rare neuropathy characterized by progressive asymmetric weakness and atrophy without sensory abnormalities, a presentation similar to that of motor neuron disease.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat MMN: standard of care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. A follow-up at 4 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Keddie et al (2022) updated a 2005 Cochrane review identifying a total of 6 crossover RCTs (N=90 patients).^69, Studies included patients with definite or probable MMN treated with IVIG or SCIG. Outcomes included muscle strength, disability, or electrophysiological conduction block. In 3 trials (N=18) of induction treatment, IVIG improved disability in 39% of patients compared with 11% of placebo-treated patients (risk ratio, 3.00; 95% CI, 0.89 to 10.12). In the 3 trials (N=27) evaluating strength, 78% of IVIG-treated patients improved compared with 4% of placebo-treated patients (risk ratio, 11.00; 95% CI, 2.86 to 42.25). Conduction block results nonsignificantly favored IVIG to placebo in 4 trials of 28 patients (risk ratio, 7.00; 95% CI, 0.95 to 51.70). Adverse effects were increased in patients with IVIG; however, only 1 serious event (a pulmonary embolism) was documented. Most patients who responded to IVIG deteriorated with treatment withdrawal.

Section Summary: Multifocal Motor Neuropathy

For individuals who have MMN who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength.

For individuals who have multifocal motor neuropathy (MMN) who receive IVIG therapy, the evidence includes multiple RCTs and a meta-analysis. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Eaton-Lambert Myasthenic Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Eaton-Lambert myasthenic syndrome.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with Eaton-Lambert myasthenic syndrome. Eaton-Lambert myasthenic syndrome 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 most commonly with small-cell lung cancer.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat Eaton-Lambert myasthenic syndrome: standard of care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

A crossover RCT by Bain et al (1996) evaluating 9 patients treated with IVIG therapy (1 g/kg/d for 2 days) or placebo showed statistically significant improvements in serial measurements of limb, respiratory, and bulbar muscle strength associated with treatment, and a nonsignificant improvement in the resting compound muscle action potential amplitude.^70,

Observational Studies

A number of noncomparative studies have substantiated clinical benefits.^71,72,73,74,

Section Summary: Eaton-Lambert Myasthenic Syndrome

For individuals who have Eaton-Lambert myasthenic syndrome who receive IVIG therapy, the evidence includes a RCT and multiple observational studies. Compared with placebo, IVIG therapy has shown clinically meaningful improvements in outcomes assessing muscle strength and activity.

For individuals who have Eaton-Lambert myasthenic syndrome who receive IVIG therapy, the evidence includes a RCT and multiple observational studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful improvements in outcomes assessing muscle strength and activity. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Neuromyelitis Optica

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with neuromyelitis optica (NMO).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with NMO. Neuromyelitis optica is an inflammatory disorder of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting the optic nerves and spinal cord. Previously considered a variant of multiple sclerosis, it is now recognized as a distinct clinical entity.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat NMO: standard of care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 2 years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Observational Studies

A retrospective review by Elsone et al (2014) of 10 patients treated with IVIG for acute relapses after lack of response to steroids with or without plasma exchange showed improvement in about 50% of patients.^75, A case series by Magraner et al (2013) assessed 9 Spanish NMO patients and yielded positive results using bimonthly IVIG treatment (0.7 g/kg body weight per day for 3 days) for up to 2 years.^76,

Section Summary: Neuromyelitis Optica

For individuals who have NMO who receive IVIG therapy, the evidence includes multiple observational studies. Studies have shown that IVIG treatment may benefit patients who are refractory to first-line treatment with steroids or plasma exchange, particularly children.

For individuals who have neuromyelitis optica who receive IVIG therapy, the evidence includes multiple observational studies. Relevant outcomes are symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Studies have shown that IVIG treatment may benefit patients who are refractory to first-line treatment with steroids or plasma exchange, particularly children. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Severe Refractory Myasthenia Gravis or Myasthenic Exacerbation

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with severe refractory myasthenia gravis or myasthenic exacerbation.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are individuals with severe refractory myasthenia gravis or myasthenic exacerbation. Myasthenia gravis is a relatively rare autoimmune disorder in which antibodies form against acetylcholine nicotinic postsynaptic receptors at the neuromuscular junction of skeletal muscles resulting in characteristic patterns of progressively reduced muscle strength with repeated use and recovery of muscle strength after a period of rest.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat myasthenia gravis: plasma exchange.

Outcomes

The general outcomes of interest are OS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Treatment of 2 weeks is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A Cochrane review by Gadjos et al (2012) assessed IVIG therapy for acute exacerbations or for chronic long-term myasthenia gravis.^77, Reviewers identified 7 RCTs including an unpublished trial, all of which investigated short-term benefit. The trials varied in inclusion criteria, comparator interventions, and outcome measures and, thus, trial findings were not pooled. Five trials evaluated IVIG for treating myasthenia gravis worsening or exacerbation, and 2 evaluated IVIG for treatment of moderate or severe myasthenia gravis. Several trials were small, with insufficient statistical power. Reviewers concluded that there was some evidence for efficacy in exacerbations of myasthenia gravis, and that evidence for treating chronic myasthenia gravis was insufficient to form conclusions about efficacy.

Randomized Controlled Trials

Zinman et al (2007) conducted the only RCT that compared IVIG with placebo in 51 patients who had myasthenia gravis with progressive weakness.^78, The primary outcome measure was the difference between arms in the Quantitative Myasthenia Gravis Score for Disease Severity from baseline to days 14 and 28. In IVIG-treated patients, a clinically meaningful improvement in Quantitative Myasthenia Gravis Score for Disease Severity was observed at day 14 and persisted at day 28. The greatest improvement occurred in patients with more severe disease as defined by a Quantitative Myasthenia Gravis Score for Disease Severity greater than 10.5.

Other RCTs either compared IVIG with plasma exchange or compared 2 doses of IVIG. Barth et al (2011) compared IVIG with plasma exchange in 84 patients with moderate-to-severe myasthenia gravis.^79, The trial did not find a statistically significant difference in the efficacy between treatments. Gajdos et al (2005) compared 2 doses of IVIG (1 g and 2 g/kg) in 170 patients with acute exacerbation of myasthenia gravis.^80, Mean improvement in the myasthenic muscular scores did not differ significantly between doses after 2 weeks. Gajdos et al (1997) compared IVIG with plasma exchange in 87 patients with myasthenia gravis exacerbations.^81, The trial also did not find a statistically significant difference in the efficacy between the 2 treatments; however, the trial did report that IVIG was better tolerated. Nine patients experienced adverse events (8 in the plasma exchange group, 1 in the IVIG group).

Section Summary: Severe Refractory Myasthenia Gravis or Myasthenic Exacerbation

For individuals who have severe refractory myasthenia gravis or myasthenic exacerbation who receive IVIG therapy, the evidence includes multiple RCTs and systematic reviews. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. Compared with plasma exchange, IVIG therapy did not show significantly improved outcomes but was better tolerated.

For individuals who have severe refractory myasthenia gravis or myasthenic exacerbation who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown clinically meaningful reductions in disability and improvements in muscle strength. Compared with plasma exchange, IVIG therapy did not show significantly improved outcomes but was better tolerated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Relapsing-Remitting Multiple Sclerosis

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with relapsing-remitting multiple sclerosis (RRMS).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with RRMS. Relapsing-remitting multiple sclerosis is an immune-mediated inflammatory disease that attacks and destroys myelinated axons in the central nervous system, resulting in variable degrees of physical disability characterized by symptomatic episodes that occur months or years apart and affect different anatomic locations.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat RRMS: standard of care.

Outcomes

The general outcomes of interest are OS, DSS, symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Treatment of 2 weeks is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Based on a technology assessment by Goodin et al (2002), the American Academy of Neurology (AAN) recommended the use of interferon beta (type B recommendation) and glatiramer acetate (type A recommendation) for the treatment of RRMS.^82, The AAN suggested that IVIG was no longer considered a drug of choice for RRMS.

Section Summary: Relapsing-Remitting Multiple Sclerosis

For individuals who have RRMS who receive IVIG therapy, the evidence includes a technology assessment. According to the technology assessment, IVIG therapy is no longer considered a treatment of choice for RRMS.

For individuals who have relapsing-remitting multiple sclerosis (RRMS) who receive IVIG therapy, the evidence includes a technology assessment. Relevant outcomes are OS, DSS, symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. According to the technology assessment, IVIG therapy is no longer considered a treatment of choice for RRMS. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Autoimmune Mucocutaneous Blistering Diseases

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with autoimmune mucocutaneous blistering diseases.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with autoimmune mucocutaneous blistering diseases. Autoimmune mucocutaneous blistering diseases are a group of conditions that manifest with blisters on the skin or mucous membranes and include pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, and linear IgA dermatosis.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat autoimmune mucocutaneous blistering diseases: standard of care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review by Gurcan et al (2010) identified 23 studies evaluating IVIG for autoimmune mucocutaneous blistering diseases (1 RCT, 22 case series).^83, The studies included 260 patients treated with IVIG: 191 patients had pemphigus, and 69 patients had pemphigoid. Of the 260 patients, 245 (94%) improved after IVIG treatment.

Randomized Controlled Trials

Amagai et al (2017) evaluated IVIG for bullous pemphigoid in a multicenter, double-blind and placebo-controlled randomized trial that included 56 patients.^84, The IVIG group received 400 mg/kg/d for 5 days and the placebo group received saline for 5 days. The primary endpoint was the Disease Activity Score (DAS) on day 15 (lower score is a better outcome). Mean scores were 19.8 in the IVIG group and 32.3 in the placebo group, but the difference between groups was not statistically significant (p=.089). In a post hoc analysis using the DAS on day 1 as a covariate, the DAS was significantly lower in the IVIG group (19.7) than in the placebo group (32.4) at day 15 (p=.041). In patients with severe disease, there were significantly lower DAS scores in the IVIG than in the placebo group on days 8, 15, and 22; between-group scores did not differ in patients with mild or moderate disease.

Another RCT by the same research group was published by Amagai et al (2009); this study was multicenter, placebo-controlled, and double-blind in design and included adults with glucocorticoid-resistant pemphigus (defined as a failure to respond to the equivalent of prednisolone ≥20 mg/d).^85, Patients were randomized to a single cycle of IVIG 400 mg/kg/d for 5 days, IVIG 200 mg/kg/d for 5 days or a placebo infusion for 5 days. The primary endpoint was the duration of time that patients could be maintained on the treatment protocol before symptoms required additional treatment (ie, time to escape protocol). Time to escape protocol was significantly longer for patients in the IVIG 400 mg group than for patients in the placebo group, but not between the IVIG 200 mg group and the placebo group. Furthermore, a significant decrease in a pemphigus activity score was detected at all study observation points for patients in the IVIG 400 mg group and at all study observation points after day 15 in the IVIG 200 mg group. The pemphigus activity score did not decrease significantly at any time point in the placebo group.

Section Summary: Autoimmune Mucocutaneous Blistering Diseases

For individuals who have autoimmune mucocutaneous blistering diseases who receive IVIG therapy, the evidence includes 2 RCTs and a systematic review. A systematic review found improvements in over 90% of patients. Randomized controlled trials have reported benefits in disease activity in the population as a whole (1 trial) or in a subgroup of patients with severe disease (1 trial).

For individuals who have autoimmune mucocutaneous blistering diseases who receive IVIG therapy, the evidence includes 2 RCTs and a systematic review. Relevant outcomes are symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. A systematic review found improvements in over 90% of patients. Randomized controlled trials have reported benefits in disease activity in the population as a whole (1 trial) or in a subgroup of patients with severe disease (1 trial). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS).

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are individuals with TEN or SJS.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat TEN or SJS: standard of care.

Outcomes

The general outcomes of interest are DSS, symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Several systematic reviews have evaluated the literature on TEN and SJS. More recently, Huang et al (2016) identified 11 studies evaluating IVIG for TEN or SJS, none of which were RCTs.^86, Three of the studies had control groups and 2 of these included historical controls. Intravenous immunoglobulin was not found to reduce mortality in TEN or SJS. The pooled standardized mortality ratio in the 10 studies was 1.00 (95% CI, 0.76 to 1.32; p=.67). A meta-analysis by Barron et al (2015) also did not demonstrate a survival advantage of IVIG for TEN and/or SJS.^87,

Section Summary: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

For individuals who have TEN or SJS who receive IVIG therapy, the evidence includes systematic reviews of observational studies. No RCTs have evaluated IVIG for TEN or SJS; most trials that have, have been uncontrolled. A 2016 pooled analysis of data from 11 studies did not find a statistically significant benefit of IVIG therapy for mortality. Compared with placebo, IVIG therapy has not shown statistically significant benefits for mortality.

For individuals who have toxic epidural necrolysis (TEN) or Stevens-Johnson syndrome (SJS) who receive IVIG therapy, the evidence includes systematic reviews of observational studies. Relevant outcomes are DSS, symptoms, change in disease status, morbid events, QOL, and treatment-related mortality and morbidity. No RCTs have evaluated IVIG for TEN or SJS; most trials that have, have been uncontrolled. A 2016 pooled analysis of data from 11 studies did not find a statistically significant benefit of IVIG therapy for mortality. Compared with placebo, IVIG therapy has not shown statistically significant benefits for mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Idiopathic Inflammatory Myopathies

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with dermatomyositis, polymyositis, or inclusion body myositis.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are individuals with dermatomyositis, polymyositis, or inclusion body myositis. Polymyositis and dermatomyositis involve weakness of the proximal muscles such as the muscles of the hips and thighs, upper arms, and neck. Dermatomyositis is associated with various characteristic skin manifestations. In inclusion body myositis, the muscles most affected are those of the wrists and fingers and the front of the thigh.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat dermatomyositis, polymyositis, or inclusion body myositis: standard of care.

Outcomes

The general outcomes of interest are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity.

Follow-up at 39 months is of interest for dermatomyositis and polymyositis to monitor outcomes. Follow-up at 6, 12, and 24 months is of interest for inclusion body myositis to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Dermatomyositis and Polymyositis

Systematic Reviews

Xiong et al (2022) conducted a systematic review of 17 studies (3 RCTs, 14 observational) evaluating IVIG safety and efficacy in 411 patients with dermatomyositis or polymyositis.^88, Creatinine kinase, Manual Muscle Test scores, the Medical Research Council scale, and the Activities of Daily Living scale all significantly improved with IVIG treatment. Intravenous immune globulin also provided a corticosteroid-sparing effect in 72 of 88 patients evaluated. Meta-analysis of the 3 RCTs found significantly improved efficacy with IVIG compared with control/placebo (standard mean difference , 0.63; 95% CI, 0.22 to 1.03). Intravenous immune globulin was well-tolerated.

Wang et al (2012) published a systematic review on IVIG treatment for adults with refractory dermatomyositis or polymyositis.^89, Reviewers identified 14 studies including 2 RCTs, 9 prospective case series, and 3 retrospective case series. Eleven of the 14 studies included patients with refractory disease. For example, a trial by Dalakas et al (1993) compared prednisone plus IVIG with prednisone plus placebo in 15 patients with refractory dermatomyositis.^90, At 3 months, there were significant increases in muscle strength in the IVIG group, as measured by mean scores on the modified Medical Research Council scale (84.6 IVIG vs. 78.6 placebo) and the Neuromuscular Symptom Scale (51.4 IVIG vs. 45.7 placebo). Repeated transfusions every 6 to 8 weeks can be required to maintain a benefit.

Section Summary: Dermatomyositis and Polymyositis

For individuals who have dermatomyositis or polymyositis who receive IVIG therapy, the evidence includes systematic reviews of observational studies and RCTs. The evidence supports the efficacy of IVIG for improving muscle strength in these patients.

For individuals who have dermatomyositis or polymyositis who receive IVIG therapy, the evidence includes systematic reviews of observational studies and RCTs. Relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. In 1 of the RCTs, compared with placebo, IVIG therapy showed significant improvements in muscle strength. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Inclusion Body Myositis

Randomized Controlled Trials

Dalakas et al (1997) reported on a double-blind, placebo-controlled, crossover study that compared IVIG with placebo in 19 patients with inclusion body myositis.^91, There was no statistically significant improvement in overall muscle strength in the IVIG group compared with the placebo group. Two more RCTs published in 2000 and 2001 (58 IVIG patients) also found no significant functional improvement when IVIG treatment was compared with placebo.^92,93,

Section Summary: Inclusion Body Myositis

For individuals who have inclusion body myositis who receive IVIG therapy, the evidence includes multiple RCTs. Compared with placebo, IVIG therapy failed to show improvements in muscle strength.

For individuals who have inclusion body myositis who receive IVIG therapy, the evidence includes multiple RCTs. Relevant outcomes are a change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy failed to show improvements in muscle strength. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Systemic Lupus Erythematosus

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with systemic lupus erythematosus (SLE).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with SLE. Systemic lupus erythematosus is a chronic autoimmune inflammatory disease and follows a relapsing and remitting course. It is characterized by an autoantibody response to nuclear and cytoplasmic antigens and can affect any organ system, but mainly attacks the skin, joints, kidneys, blood cells, and nervous system.

Interventions

The therapy being considered is IVIG therapy. Intravenous immunoglobulin therapy is proposed for SLE because of its immunomodulatory properties and because it prevents infection in patients taking immunosuppressive drugs.

Comparators

The following practice is currently being used to treat SLE: standard of care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review by Sakthiswary et al (2014) identified 13 studies on IVIG for the treatment of SLE.^94, Three studies had control groups, and only 1 was an RCT.^95, Most studies were small; only 3 had more than 50 patients, and the single RCT included only 14 patients. In a meta-analysis of 6 studies (N=216 patients), there was a statistically significant difference in SLE disease activity in IVIG-treated groups (standardized mean difference, 0.58; 95% CI, 0.22 to 0.95). This analysis was limited because there were few data in non-IVIG-treated patients. A meta-analysis of data from 8 studies on the effect of IVIG on complement levels found a pooled response rate of 30.9% (95% CI, 22.1% to 41.3%). Findings on other outcomes were not pooled.

Cajamarca-Barón et al (2022) published a systematic review on IVIG in patients with lupus nephritis.^96, A total of 28 articles were included with case reports or series comprising the vast majority of the evidence. Only 1 RCT (N=14) was identified. In the RCT, 11 patients remained in remission after 1.5 years of follow-up. In compiled data from the case reports and case series, a complete response occurred in 30.4% of patients with 33.9% of patients having a partial response. Although IVIG appears effective for lupus nephritis based on this analysis, there is a lack of RCTs to support the use of IVIG in this setting.

There has been limited anecdotal experience and concerns about potential prothromboembolic effects and possible IVIG-associated azotemia in SLE.^97,

Section Summary: Systemic Lupus Erythematosus

For individuals who have SLE who receive IVIG therapy, the evidence includes systematic reviews, primarily of observational data. Although observed improvements in outcomes have suggested potential benefit with IVIG therapy for surrogate outcomes, data are mainly retrospective. More RCTs are needed to demonstrate improved health outcomes.

For individuals who have systemic lupus erythematosus (SLE) who receive IVIG therapy, the evidence includes systematic reviews of multiples studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Although observed improvements in outcomes have suggested potential benefit with IVIG therapy for surrogate outcomes, data are mainly retrospective. More RCTs are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Immune Optic Neuritis

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with immune optic neuritis.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with immune optic neuritis. Optic neuritis is an inflammatory demyelinating condition that causes acute, usually monocular, visual loss. It is associated with multiple sclerosis, occurring in 50% of individuals at some time during the course of their illness.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat immune optic neuritis: standard of care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at 6 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Two RCTs have evaluated the potential benefit of IVIG for immune optic neuritis. Roed et al (2005) randomized 68 patients in the acute phase of optic neuritis to IVIG (n=34) or placebo (n=34).^98, The authors found no differences in the visual outcome measure or disease activity as measured by magnetic resonance imaging (MRI) after 6 months.

Noseworthy et al (2001) planned to randomize 60 patients with persistent acuity loss after optic neuritis to IVIG or placebo.^99, The trial was terminated early after 55 patients were enrolled because investigators did not find a difference in the logarithm of the minimum angle of resolution (logMAR) visual scores at 6 months (p=.766).

Section Summary: Immune Optic Neuritis

For individuals who have immune optic neuritis who receive IVIG therapy, the evidence includes 2 RCTs. Compared with placebo, IVIG therapy has failed to show improvements in vision-related outcomes.

For individuals who have immune optic neuritis who receive IVIG therapy, the evidence includes 2 RCTs. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show improvements in vision-related outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Crohn Disease

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Crohn disease.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with Crohn disease. Crohn disease is an inflammatory condition of unknown etiology that can affect any portion of the gastrointestinal tract, from the mouth to the perianal area, with a wide spectrum of clinical presentations.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat Crohn disease: standard of care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review by Rogosnitzky et al (2012) of IVIG therapy for Crohn disease did not identify any randomized or nonrandomized controlled trials.^100, Reviewers found 5 case reports of IVIG used for single patients with Crohn disease, and the remaining literature identified included conference papers, abstracts only, or a nonsystematic review.

Section Summary: Crohn Disease

For individuals who have Crohn disease who receive IVIG therapy, the evidence includes multiple case reports of single patients summarized in a systematic review.

For individuals who have Crohn disease who receive IVIG therapy, the evidence includes multiple case reports of single patients summarized in a systematic review. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Hemophagocytic Lymphohistiocytosis

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with hemophagocytic lymphohistiocytosis.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis is an uncommon but potentially fatal syndrome of excessive immune activation resulting from overactive histiocytes and lymphocytes. It may be inherited or acquired.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapies are currently being used to treat hemophagocytic lymphohistiocytosis: supportive care alone, chemotherapy, and allogeneic cell transplantation.

Outcomes

The general outcomes of interest are OS, DSS, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review by Rajagopala et al (2012) on diagnosing and treating hemophagocytic lymphohistiocytosis in the tropics identified 156 cases; a portion of these patients were treated with IVIG.^101, Steroids were the most common treatment. Intravenous immunoglobulin was used in 30% of children and in 4% of adults. Hemophagocytic syndrome-related mortality occurred in 32% of children and in 28% of adults.

Case Series

Published literature on the use of IVIG in hemophagocytic syndrome is limited to small case series.^102,103,104,

Section Summary: Hemophagocytic Lymphohistiocytosis

For individuals who have hemophagocytic lymphohistiocytosis who receive IVIG therapy, the evidence includes multiple case reports summarized in a systematic review and case series.

For individuals who have hemophagocytic lymphohistiocytosis who receive IVIG therapy, the evidence includes multiple case reports summarized in a systematic review and case series. Relevant outcomes are OS, DSS, change in disease status, QOL, and treatment-related mortality and morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Warm Antibody Autoimmune Hemolytic Anemia

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with warm antibody hemolytic anemia, refractory to prednisone and splenectomy.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with warm antibody hemolytic anemia, refractory to prednisone and splenectomy. Also known as autoimmune hemolytic anemia, warm antibody autoimmune hemolytic anemia occurs commonly due to IgG antibodies that react with protein antigens on the red blood cell surface at body temperature.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapies are currently being used to treat warm antibody hemolytic anemia: prednisone, splenectomy, and cytotoxic medications.

Outcomes

The general outcomes of interest are a change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 3 weeks is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Nonrandomized Studies

Published literature on the use of IVIG in warm antibody autoimmune hemolytic anemia is limited to observational data for 37 patients pooled from 3 institutions^105, and a case report.^106, Overall, 29 (39.7%) of 73 patients responded to IVIG therapy. Because of limited therapeutic value, it is used in patients refractory to conventional therapy with prednisone and splenectomy or as a conjunctive therapy in patients with very severe disease. Further, the effect is usually transient, unless repeated courses are given every 3 weeks.

Section Summary: Warm Antibody Autoimmune Hemolytic Anemia

For individuals who have warm antibody autoimmune hemolytic anemia, refractory to prednisone and splenectomy, who receive IVIG therapy, the evidence includes pooled observational data and a case report. Observed improvements in outcomes have suggested potential benefits with IVIG therapy in select patients with refractory autoimmune hemolytic anemia. Randomized controlled trials are needed to demonstrate improved health outcomes.

For individuals who have warm antibody autoimmune hemolytic anemia, refractory to prednisone and splenectomy, who receive IVIG therapy, the evidence includes pooled observational data and a case report. Relevant outcomes are a change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested potential benefits with IVIG therapy in select patients with refractory autoimmune hemolytic anemia. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Antiphospholipid Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with antiphospholipid syndrome.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with antiphospholipid syndrome. Antiphospholipid syndrome is an autoimmune disease that results from the development of an antibody against phospholipid proteins, which causes venous or arterial thromboses and/or pregnancy morbidity.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapies are currently being used to treat antiphospholipid syndrome: anticoagulant and antiplatelet therapy.

Outcomes

The general outcomes of interest are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Case Reports

Published literature on the use of IVIG in antiphospholipid syndrome includes a pooled analysis of 250 single case reports from a registry.^107, Results showed that a higher proportion of patients survived after the episode of antiphospholipid syndrome if they received therapy with anticoagulants, corticosteroids, plasma exchange, and/or IVIG compared with combinations that did not use plasma exchange, IVIG, or both.

Section Summary: Antiphospholipid Syndrome

For individuals who have antiphospholipid syndrome who receive IVIG therapy, the evidence includes pooled data from a registry. Observed improvements in outcomes have suggested potential mortality benefit with IVIG therapy in catastrophic antiphospholipid syndrome. Randomized controlled trials are needed to demonstrate improved health outcomes.

For individuals who have antiphospholipid syndrome who receive IVIG therapy, the evidence includes pooled data from a registry. Relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Observed improvements in outcomes have suggested a potential mortality benefit with IVIG therapy in catastrophic antiphospholipid syndrome. Randomized controlled trials are needed to demonstrate improved health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome

Alloimmune Processes

Neonatal Alloimmune Thrombocytopenia

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with neonatal alloimmune thrombocytopenia.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is neonates with 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 (ICH) occurs in 10% to 30% of affected neonates. Currently, routine screening for this condition is not recommended and, thus, thrombocytopenia is only identified at birth. However, subsequent fetuses that are platelet-antigen positive also will be at risk for thrombocytopenia, and the severity of thrombocytopenia may be increased.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practices are currently being used to treat neonatal alloimmune thrombocytopenia: platelet transfusion and supportive care alone.

Outcomes

The general outcomes of interest are DSS, change in disease status, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Rayment et al (2011), in a Cochrane review, summarized the results of 4 RCTs on the maternal administration of corticosteroids and IVIG in pregnancies with neonatal alloimmune thrombocytopenia in 206 women.^108, Reviewers concluded that the optimal management of fetomaternal alloimmune thrombocytopenia remains unclear. Lack of complete data sets for 2 trials and differences in interventions precluded the pooling of data from these trials.

Randomized Controlled Trials

Paridaans et al (2015) evaluated the effectiveness of a lower dose of IVIG (0.5 g/kg/wk vs. 1 g/kg/wk) in an RCT of 23 women.^109, The primary outcome was fetal or neonatal ICH. The median newborn platelet count was 81×10⁹/L in the 0.5-g/kg group and 110×10⁹/L in the 1-g/kg group (p=.644).

Berkowitz et al (2007) showed good outcomes and comparable results between the IVIG group and the IVIG plus prednisone group in standard-risk pregnancies.^110, In another trial, Berkowitz et al (2006) did not demonstrate a difference in standard-risk pregnancies, but did demonstrate that IVIG and prednisone were more effective in raising the fetal platelet count in high-risk pregnancies.^111,

Bussel et al (1996) did not find any differences in the fetal platelet counts between IVIG and IVIG with steroids.^112, Although there was no placebo-controlled arm, results can be compared with the course in a prior affected sibling, because the natural history of the disease suggests that subsequent births should be similar, if not more severely, affected with thrombocytopenia. The trial reported a mean increase in platelet count of 69,000/mL. There were no instances of ICH, although hemorrhage had occurred previously in 10 untreated siblings.

There are no RCTs evaluating the efficacy of IVIG or steroids alone versus placebo in alloimmune thrombocytopenia. Trials of this nature would be unethical because of the known risk of ICH with this condition.

Observational Trial

One large, retrospective comparative study by Ernstsen et al (2022) compared neonatal outcomes in 71 untreated alloimmunized pregnancies with 403 IVIG-treated pregnancies in women who previously had a child with neonatal alloimmune thrombocytopenia.^113, In low-risk pregnancies (alloimmunized pregnancy history without ICH) IVIG did not affect neonatal outcomes; however, in high-risk pregnancies (alloimmunized pregnancy history with ICH) IVIG-treated patients had lower rates of neonates with ICH compared with untreated patients (5.6% vs. 29%).

Section Summary: Neonatal Alloimmune Thrombocytopenia

For individuals who have neonatal alloimmune thrombocytopenia who receive IVIG therapy, the evidence includes multiple RCTs, a large observational study, and a systematic review. Compared with combination use with corticosteroids, IVIG alone did not show any additional increases in platelet counts. Multiple trials have demonstrated increased platelet counts with IVIG therapy.

For individuals who have neonatal alloimmune thrombocytopenia who receive IVIG therapy, the evidence includes multiple RCTs, a large observational study, and a systematic review. Relevant outcomes are DSS, change in disease status, and treatment-related mortality and morbidity. Compared with combination use with corticosteroids, IVIG alone did not show any additional increases in platelet counts. Multiple trials have demonstrated increased platelet counts with IVIG therapy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Recurrent Spontaneous Abortion

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in women with recurrent spontaneous abortion.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is women with recurrent spontaneous abortion. Recurrent spontaneous abortion is defined as 3 or more pregnancies resulting in spontaneous abortion before 16 to 20 weeks of gestational age. Women with recurrent spontaneous abortion frequently have immunologic abnormalities, particularly antiphospholipid antibodies whose incidence may increase with each subsequent pregnancy loss.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat recurrent spontaneous abortion: supportive care.

Outcomes

The general outcomes of interest are DSS and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A Cochrane review by Porter et al (2006) assessed various immunotherapies for treating recurrent miscarriage and concluded that IVIG therapy provides no significant beneficial effect over placebo in preventing further miscarriages.^114, Meta-analyses published in 2015 and 2016 that included 11 RCTs also found no significant difference in the number of live births with IVIG versus placebo or treatment as usual.^115,116,

Randomized Controlled Trials

An RCT by Christiansen et al (2002) evaluated 58 women with at least 4 unexplained miscarriages and compared IVIG with placebo.^117, Using an intention to treat analysis, the live birth rate was similar for both groups; also, there were no differences in neonatal data (eg, birth weight, gestational age at delivery).

Likewise, a multicenter RCT by Branch et al (2000) compared heparin plus low-dose aspirin with or without IVIG in women with a lupus anticoagulant, anticardiolipin antibody, or both, and found no significant differences.^118,

A blinded RCT by Jablonowska et al (1999) assessing 41 women treated with IVIG or saline placebo also found no differences in live birth rates.^119,

Section Summary: Recurrent Spontaneous Abortion

For individuals who have a recurrent spontaneous abortion who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. In multiple RCTs, compared with placebo, IVIG therapy alone did not show any beneficial effects in preventing spontaneous abortions.

For individuals who have a recurrent spontaneous abortion who receive IVIG therapy, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are DSS, treatment-related mortality, and treatment-related morbidity. In multiple RCTs, compared with placebo, IVIG therapy alone did not show any beneficial effects in preventing spontaneous abortions. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Miscellaneous Indications

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is children with PANDAS. PANDAS is a term used to describe a subset of children whose symptoms of obsessive-compulsive disorder (or tic disorders) are exacerbated by group A streptococcal infection. This syndrome is not well-understood, and the diagnosis of PANDAS requires expert consultation.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat PANDAS: antibiotic therapy alone.

Outcomes

The general outcomes of interest are symptoms, change in disease status, and treatment-related mortality and morbidity. Follow-up at 1 month is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Williams et al (2016) randomized 35 children who met diagnostic criteria for PANDAS and had moderate-to-severe obsessive-compulsive disorder symptoms to treatment with 2 treatment sessions of IVIG or placebo.^120, After a 6-week, double-blind treatment phase, nonresponders could continue treatment on an open-label basis. The primary outcome at 6 weeks, the Children’s Yale-Brown Obsessive Compulsive Scale total score, did not differ significantly between groups. There was a mean decrease in the Children’s Yale-Brown Obsessive Compulsive Scale of 23.9% in the IVIG group and 11.7% in the placebo group (effect size, 0.28; 95% CI, -0.39 to 0.95). Improvements in other outcomes (eg, mean Clinical Global Impressions improvement scores) also did not differ significantly between groups. A total of 24 participants met the criteria for nonresponse at 6 weeks and received open-label IVIG. At week 12, scores on the Children’s Yale-Brown Obsessive Compulsive Scale improved significantly compared with 6 weeks; however, the 12-week analysis did not include a placebo comparison.

An RCT by Perlmutter et al (1999) included 30 children who had new or severe exacerbations of obsessive-compulsive disorder or tic disorder after streptococcal infections.^121, Patients were randomized to IVIG, plasma exchange, or placebo (10 per group). At the 1-month follow-up, IVIG and plasma exchange showed statistically significant improvements in obsessive-compulsive symptoms, anxiety, and overall functioning.

Section Summary: Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections

For individuals who have PANDAS who receive IVIG therapy, the evidence includes 2 small RCTs. The trials had mixed findings, and both had small sample sizes and short intervention duration.

For individuals who have pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) who receive IVIG therapy, the evidence includes 2 small RCTs. Relevant outcomes are symptoms, change in disease status, and treatment-related mortality and morbidity. The trials had mixed findings and both had small sample sizes and short intervention duration. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Autism Spectrum Disorder

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with an autism spectrum disorder.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with an autism spectrum disorder. Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in social communication and interaction and restricted repetitive patterns of behavior, interests, and activities.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat autism spectrum disorder: standard of care.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at 6 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Case Series

The evidence base supporting the use of IVIG in autism includes case series. One included 10 patients with abnormal immune parameters who received IVIG therapy monthly.^122, After 6 months, 5 of 10 patients showed marked improvement in several autistic characteristics. Another 2 case series failed to replicate these findings. In the second, 1 of 10 patients showed improvements in autistic symptoms after receiving IVIG.^123, No improvements were observed in the third series.^124,

No randomized comparative trials evaluating IVIG therapy in autism were identified.

Section Summary: Autism Spectrum Disorder

For individuals who have autism spectrum disorder who receive IVIG therapy, the evidence includes case series. Although improvements were observed in 1 case series, the other 2 reported negative findings.

For individuals who have autism spectrum disorder who receive IVIG therapy, the evidence includes case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Although improvements were observed in 1 case series, the other 2 reported negative findings. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Complex Regional Pain Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with complex regional pain syndrome (CRPS).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with CRPS. Complex regional pain syndrome is defined as a disorder of the extremities characterized by regional pain that is disproportionate in time or degree to the usual course of any known trauma or other lesions.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat CRPS: standard of care.

Outcomes

The general outcomes of interest are symptoms, morbid events, QOL, and treatment-related mortality and morbidity. Follow-up at 14 days is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Goebel et al (2017) conducted a 1:1 parallel, randomized, placebo-controlled, multicenter trial to confirm the efficacy of low-dose IVIG compared with placebo in reducing pain in adults who had CRPS of 1 to 5 years in duration.^125, Intravenous immunoglobulin 0.5 g/kg of body weight or saline placebo on days 1 and 22 were administered after 111 patients were randomized. An 11-point (0- to 10-point) rating scale was used to measure the primary outcome of 24-hour average pain intensity. Mean pain scores were 6.9 points for placebo and 7.2 points for IVIG at 6 weeks demonstrating that low-dose immunoglobulin treatment was not effective in relieving pain in moderate-to-severe CRPS.

Goebel et al (2010) reported on the use of IVIG treatment for CRPS in a crossover, double-blind RCT conducted at an academic pain management center in the U.K.^126, The trial randomized 13 patients refractory to standard treatment to IVIG or normal saline. Median daily pain intensity score for each 14-day period was 6.21 after IVIG infusion versus 7.35 after saline infusion, a difference of 1.14 points. Trialists reported that the mean pain intensity was 1.55 points lower after IVIG than after saline (95% CI, 1.29 to 1.82; p<.001).

Section Summary: Complex Regional Pain Syndrome

For individuals who have CRPS who receive IVIG therapy, the evidence includes 2 RCTs. In 1 trial, compared with placebo, IVIG therapy was associated with improvements in pain scores. However, methodologic limitations restrict the conclusions drawn from data on 13 patients. In the other RCT, low-dose IVIG was ineffective in relieving pain in CRPS.

For individuals who have complex regional pain syndrome (CRPS) who receive IVIG therapy, the evidence includes 2 RCTs. Relevant outcomes are symptoms, morbid events, QOL, and treatment-related mortality and morbidity. In 1 trial, compared with placebo, IVIG therapy was associated with improvements in pain scores. However, methodologic limitations restrict the conclusions drawn from data on 13 patients. In the other RCT, low-dose IVIG was ineffective in relieving pain in CRPS. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Alzheimer Disease

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Alzheimer disease (AD).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with AD.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat AD: standard of care.

Outcomes

The general outcomes of interest are OS, DSS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 12 or 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Three placebo-controlled, double-blind, randomized trials in patients with AD were identified. Two included patients with mild-to-moderate AD. Relkin et al (2017) reported on 390 patients treated with 1 of 2 doses of IVIG (0.2 or 0.4 g/kg every 2 weeks for 18 months) or placebo.^127, The primary outcomes were a change from baseline to 18 months on the cognitive subscale of the Alzheimer Disease Assessment scale and on the Alzheimer Disease Cooperative Study-Activities of Daily Living Inventory. Neither outcome was significantly improved in either IVIG group compared with the placebo group.

Kile et al (2017) assessed 50 patients with mild cognitive impairment (MCI) related to AD.^128, Patients were stratified into early and late MCI stages based on scores on the Clinical Dementia Rating, Sum of Boxes test (≤1 for the early MCI group and >1 for the late MCI group). Patients received a total IVIG dose of 2 g/kg over 5 sessions, or placebo. The primary outcome was brain atrophy, defined as annualized percent change in the ventricular volume measured by MRI. In unadjusted analyses, annualized percent change in the ventricular volume did not differ significantly between groups at 12 or 24 months. In a subgroup analysis, the annualized percent change in the ventricular volume was significantly lower in the IVIG compared with the placebo group in patients with early MCI but not late MCI at 12 months, and there was no significant difference at 12 months in either the early or late MCI groups. Secondary outcomes, cognition scores, and conversion to AD dementia did not differ between the IVIG and placebo groups at 12 or 24 months. As with the primary outcome, for several secondary outcomes, IVIG showed a significant benefit in the early MCI group at 12 months but not 24 months.

In a trial by Dodel et al (2013) with 56 patients, the primary outcome (area under the curve of plasma amyloid β 1-40) did not differ between the IVIG and the placebo groups.^129, Secondary outcomes, including cognitive and functional scales, also did not differ between groups.

Section Summary: Alzheimer Disease

For individuals who have AD who receive IVIG therapy, the evidence includes 3 RCTs. With the exception of a few subgroup analyses using MCI status, IVIG therapy was not significantly better than a placebo for outcomes such as brain atrophy, level of plasma amyloid β 1-40, or cognition and function. Studies differed by treatment protocols, outcomes assessed, and 2 of the 3 had relatively small sample sizes. Additional RCTs could be conducted to confirm whether IVIG benefits patients with early MCI.

For individuals who have Alzheimer disease who receive IVIG therapy, the evidence includes 3 RCTs. Relevant outcomes are OS, DSS, symptoms, change in disease status, QOL, and treatment-related mortality and morbidity. With the exception of a few subgroup analyses using mild cognitive impairment (MCI) status, IVIG therapy was not significantly better than a placebo for outcomes such as brain atrophy, level of plasma amyloid β 1-40, or cognition and function. Studies differed by treatment protocols, outcomes assessed, and 2 of the 3 had relatively small sample sizes. Additional RCTs could be conducted to confirm whether IVIG benefits patients with early MCI. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Paraproteinemic Neuropathy

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with paraproteinemic neuropathy.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with paraproteinemic neuropathy. Paraproteinemic neuropathy is a heterogeneous set of neuropathies characterized by the presence of paraproteins, which are immunoglobulins produced in excess by an abnormal clonal proliferation of B lymphocytes or plasma cells. Paraproteinemic neuropathy may be caused by the interaction of antibodies with specific antigenic targets on peripheral nerves or by deposition of immunoglobulins or amyloid.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat paraproteinemic neuropathy: standard of care.

Outcomes

The general outcomes of interest are a change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 2 weeks is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

An RCT by Comi et al (2002) focused on short-term outcomes at 2 weeks in 22 patients.^130, No significant differences were found between the treatment and placebo groups.

Results of a double-blind, placebo-controlled, randomized crossover trial by Dalakas et al (1996) comparing IVIG with placebo in 11 patients with paraproteinemic immunoglobulin M (IgM) demyelinating polyneuropathy showed only a mild and transitory effect in 3 patients.^131,

Section Summary: Paraproteinemic Neuropathy

For individuals who have paraproteinemic neuropathy who receive IVIG therapy, the evidence includes 2 small RCTs. Compared with placebo, IVIG showed mild and transitory improvements in 1 trial but failed to show any improvement in another.

For individuals who have paraproteinemic neuropathy who receive IVIG therapy, the evidence includes 2 small RCTs. Relevant outcomes are a change in disease status, QOL and treatment-related mortality and morbidity. Compared with placebo, IVIG showed mild and transitory improvements in 1 trial but failed to show any improvement in another. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Chronic Fatigue Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with chronic fatigue syndrome.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with chronic fatigue syndrome. Chronic fatigue syndrome (also called systemic exertion intolerance disease) is a complex and controversial disease with multiple definitions.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat chronic fatigue syndrome: standard of care.

Outcomes

The general outcomes of interest are symptoms, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Numerous noncomparative studies have shown subjective benefits of IVIG therapy on chronic fatigue syndrome, but a double-blind, randomized, placebo-controlled trial by Vollmer-Conna et al (1997) in 99 patients with chronic fatigue syndrome reported no therapeutic benefit of IVIG.^132,

Section Summary: Chronic Fatigue Syndrome

For individuals who have chronic fatigue syndrome who receive IVIG therapy, the evidence includes a RCT and anecdotal reports. Compared with placebo, IVIG therapy has shown no therapeutic benefits.

For individuals who have chronic fatigue syndrome who receive IVIG therapy, the evidence includes a RCT and anecdotal reports. Relevant outcomes are symptoms, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown no therapeutic benefits. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Acute Myocarditis

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with acute myocarditis.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with acute myocarditis. Acute myocarditis is a sudden inflammation of the myocardium that can occur in individuals of all ages. It is presumed to start as a viral infection, although autoimmune and idiopathic forms also occur. It remains unclear whether the primary problem is ongoing damage from a virus, a postinfectious inflammatory reaction, or a combination of the 2.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapy is currently being used to treat acute myocarditis: heart failure therapy alone.

Outcomes

The general outcomes of interest are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

The literature has been summarized in a Cochrane review by Robinson et al (2015)^133,, updated in 2020^134,, that included a 2001 placebo-controlled, randomized trial of 62 adults with recent-onset dilated cardiomyopathy^135,, a randomized, multicenter trial in Japan of 41 adults with a clinical diagnosis compatible with acute myocarditis^136,, and a randomized, placebo-controlled study from Egypt in 86 children with acute onset dilated cardiomyopathy.^137, The overall certainty of the included evidence was very low, with an unclear risk of bias in the 2 adult studies and a low risk of bias in the pediatric study. In adults, the evidence regarding the effect of IVIG on event-free survival and OS is uncertain (event-free survival: risk ratio, 1.76; 95% CI, 0.48 to 6.40 and overall survival: pooled risk ratio, 0.91; 95% CI, 0.23 to 3.62). For the pediatric study, the evidence for OS was also uncertain (risk ratio of death, 0.48; 95% CI, 0.20 to 1.15).

Huang et al (2019) published a meta-analysis assessing IVIG for patients with acute myocarditis.^138, Thirteen studies (1534 participants), published between 1994 and 2017, were included. In-hospital mortality rates (pooled results: OR, 0.44; 95% CI, 0.17 to 0.71; p<.001) were significantly reduced for the IVIG group compared with patients who did not receive IVIG, and left ventricular ejection fraction (OR, 1.73; 95% CI, 1.34 to 2.13; p<.001) was significantly increased for IVIG. The study was limited by the IVIG doses not being uniformly predefined and by the limited follow-up durations (mainly between 6 and 12 months) across the included studies.

Retrospective Studies

Heidendael et al (2017) reported on 94 children with new-onset dilated cardiomyopathy in a retrospective cohort study with a median follow-up of 33 months.^139, After viral tests were performed, 18 (19%) children met diagnostic criteria for “probably or definite viral myocarditis,” and IVIG was administered to 21 (22%) patients. Treatment was associated with a higher recovery rate within 5 years, compared with nontreated children (70% vs. 43%; p=.045) ; however, the HR for recovery with IVIG was not significant (HR, 2.1; 95% CI, 1.0 to 4.6; p=.056) after correction for possible cofounders. The authors concluded that IVIG treatment was associated with better improvement of systolic left ventricular function and better recovery but did not influence transplant-free survival.

Section Summary: Acute Myocarditis

For individuals who have acute myocarditis who receive IVIG therapy, the evidence includes a meta-analysis, RCTs, and a retrospective study. Results from a Cochrane review concluded that, after pooling the available data, there was uncertain evidence of the effect of IVIG in preventing deaths. More RCT evidence is required before IVIG can be routinely recommended in the setting of myocarditis.

For individuals who have acute myocarditis who receive IVIG therapy, the evidence includes a meta-analysis, RCTs, and a retrospective study. Results from a Cochrane review concluded that, after pooling the available data, there was uncertain evidence of the effect of IVIG in preventing deaths. More RCT evidence is required before IVIG can be routinely recommended in the setting of myocarditis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Refractory Recurrent Pericarditis

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with refractory recurrent pericarditis.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with refractory recurrent pericarditis. Refractory recurrent pericarditis is defined as recurrent pericarditis not responding to conventional anti-inflammatories such as aspirin, nonsteroidal inflammatory drugs, corticosteroids, and colchicine.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapy is currently being used to treat refractory recurrent pericarditis: heart failure therapy alone.

Outcomes

The general outcomes of interest are OS, change in disease status, QOL, and treatment-related mortality and morbidity. A follow-up to 36 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Imazio et al (2016) conducted a systematic review and summarized data of 30 patients (4 case series, 13 case reports).^140, Approximately 47% of patients had idiopathic recurrent pericarditis, 10% had an infective cause, and the remainder had a systemic inflammatory disease. Intravenous immunoglobulin was generally administered at a dose of 400 to 500 mg/kg/d for 5 consecutive days, with repeated cycles according to clinical response. Overall, recurrence occurred in 26.6% of cases after the first IVIG cycle, and 22 (73.3%) of the 30 patients were recurrence-free after a mean follow-up of approximately 33 months.

Section Summary: Refractory Recurrent Pericarditis

For individuals who have refractory recurrent pericarditis who receive IVIG therapy, the evidence includes a systematic review of multiple case reports and case series. Although improvements were observed in some patients, controlled trials are lacking.

For individuals who have refractory recurrent pericarditis who receive IVIG therapy, the evidence includes a systematic review of multiple case reports and case series. Relevant outcomes are OS, change in disease status, QOL, and treatment-related mortality and morbidity. Although improvements were observed in some patients, controlled trials are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Stiff-Person Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with stiff-person syndrome.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with stiff-person syndrome. Stiff-person syndrome is a rare, acquired neurologic disorder characterized by progressive muscle stiffness, rigidity, and spasm involving the axial muscles, resulting in severely impaired ambulation. It is caused by increased muscle activity due to decreased inhibition of the central nervous system. If left untreated, stiff-person syndrome can progress to cause difficulty walking and significantly impact a person's ability to perform routine, daily tasks.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapies are currently being used to treat stiff-person syndrome: benzodiazepines and baclofen.

Outcomes

The general outcomes of interest are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Follow-up at 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trial

The benefit of IVIG in stiff-person syndrome was confirmed in a small randomized crossover study by Dalakas et al (2001), which compared IVIG with placebo in 16 patients who had stiff-person syndrome and anti-GAD65 autoantibodies, who were maintained on current doses of benzodiazepines throughout the study.^141, After a 1-month washout period, patients were crossed over to 3 months of the alternative treatment. Stiffness scores decreased significantly on IVIG, but not on placebo, regardless of order. Eleven (69%) 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. In a cohort of patients (N=36) treated long-term, monthly IVIG maintained efficacy in 67% of patients for a median of 3.3 years.^142,

Section Summary: Stiff-Person Syndrome

For individuals who have stiff-person syndrome who receive IVIG therapy, the evidence includes a small randomized crossover study. Compared with placebo, IVIG therapy has shown decreases in stiffness scores and improvements in functional outcomes.

For individuals who have stiff-person syndrome who receive IVIG therapy, the evidence includes a small randomized crossover study. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has shown decreases in stiffness scores and improvements in functional outcomes. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Noninfectious Uveitis

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with noninfectious uveitis.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with noninfectious uveitis. Noninfectious uveitis is inflammation of the eye that results from eye trauma, anomalous immune processes, or unknown etiology.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapies are currently being used to treat noninfectious uveitis: topical glucocorticoids, difluprednate, intraocular glucocorticoids, systemic glucocorticoids, and systemic immunomodulating agents.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Follow-up at 6, 12, and 24 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Case Series

Two small case series of 18 and 10 patients, respectively, have reported measurable improvements in visual acuity after IVIG therapy.^143,144, Collectively, these 2 studies represent insufficient evidence to draw conclusions about efficacy.

Section Summary: Noninfectious Uveitis

For individuals who have noninfectious uveitis who receive IVIG therapy, the evidence includes 2 small case series. The case series reported measurable improvements in visual acuity after IVIG therapy, but controlled studies are needed to draw conclusions about the efficacy of IVIG for this population.

For individuals who have noninfectious uveitis who receive IVIG therapy, the evidence includes 2 small case series. Relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. The case series reported measurable improvements in visual acuity after IVIG therapy, but controlled studies are needed to draw conclusions about the efficacy of IVIG for this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Postpolio Syndrome

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with postpolio syndrome.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with postpolio syndrome. Although polio no longer poses a major public health threat in the U.S., many patients live with the sequelae of paralytic polio. Many polio survivors experience a modest decline in function and muscle strength over many years that may reflect the natural history of polio.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following practice is currently being used to treat postpolio syndrome: supportive care alone.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Follow-up at 3 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Huang et al (2015) published a systematic review and meta-analysis of RCTs and nonrandomized prospective studies on IVIG treatment of the postpolio syndrome.^145, Reviewers identified 3 RCTs (n=241 patients) and 5 prospective studies (n=267 patients). The primary outcomes of interest were the severity of pain, fatigue, and change in muscle strength 2 to 3 months after IVIG administration. Meta-analyses of RCT data found no statistically significant differences between IVIG- and placebo-treated groups for any of these outcomes. For example, the pooled mean difference in pain scores (0-to-10 visual analog scale) from the 3 RCTs was -1.02 (95% CI, -2.51 to 0.47). Meta-analysis of the 2 RCTs that reported a change in fatigue scores found a weighted mean difference of 0.28 (95% CI, -1.56 to 1.12). The small number of RCTs and the negative findings of this systematic review represent insufficient evidence of the efficacy of IVIG for the postpolio syndrome.

Section Summary: Postpolio Syndrome

For individuals who have postpolio syndrome who receive IVIG therapy, the evidence includes a systematic review of multiple RCTs and nonrandomized prospective studies. Compared with placebo, IVIG therapy has failed to show reductions in the severity of pain and fatigue or improvements in muscle strength.

For individuals who have postpolio syndrome who receive IVIG therapy, the evidence includes a systematic review of multiple RCTs and nonrandomized prospective studies. Relevant outcomes are symptoms, functional outcomes, QOL, and treatment-related mortality and morbidity. Compared with placebo, IVIG therapy has failed to show reductions in the severity of pain and fatigue or improvements in muscle strength. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Necrotizing Fasciitis

Clinical Context and Therapy Purpose

The purpose of IVIG therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with necrotizing fasciitis.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with necrotizing fasciitis.

Interventions

The therapy being considered is IVIG therapy.

Comparators

The following therapies and practices are currently being used to treat necrotizing fasciitis: antibiotics and surgical removal of tissue.

Outcomes

The general outcomes of interest are OS, symptoms, functional outcomes, and treatment-related mortality and morbidity. A follow-up at 3 months is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Madsen et al (2017) published a placebo-controlled, randomized trial evaluating IVIG for patients with necrotizing soft tissue infection (eg, necrotizing fasciitis).^146, The trial included 100 patients with confirmed necrotizing soft tissue infection who were admitted or had planned admission to the intensive care unit. The primary outcome was patient-reported physical function at 6 months, assessed using the Physical Component Summary score of the 36-Item Short-Form Health Survey. The mean Physical Component Summary score adjusted for the site of infection was 36 in the IVIG group and 21 in the placebo group. The difference between groups was not statistically significant (p=.81). Other outcomes (ie, mortality, use of life support in the intensive care unit, bleeding, amputation) did not differ significantly between groups.

Section Summary: Necrotizing Fasciitis

For individuals who have necrotizing fasciitis who receive IVIG therapy, the evidence includes a RCT. The RCT found that, compared with placebo, IVIG therapy did not significantly improve functional outcomes, mortality rates, or other outcomes (eg, the use of life support in the intensive care unit). Additional controlled studies are needed to draw conclusions about the efficacy of IVIG for treating necrotizing fasciitis.

For individuals who have necrotizing fasciitis who receive IVIG therapy, the evidence includes a RCT. Relevant outcomes are OS, symptoms, functional outcomes, and treatment-related mortality and morbidity. The RCT found that, compared with placebo, IVIG therapy did not significantly improve functional outcomes, mortality rates, or other outcomes (eg, the use of life support in the intensive care unit). Additional controlled studies are needed to draw conclusions about the efficacy of IVIG for treating necrotizing fasciitis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 3 physician specialty societies and 5 academic medical centers in March 2013 after this policy was under review in 2012. Input focused on intravenous immunoglobulin (IVIG) treatment for 7 rare conditions. There was consensus, or near-consensus, that IVIG is investigational for 6 of these conditions: birdshot retinopathy, epidermolysis bullosa acquisita, necrotizing fasciitis, opsoclonus-myoclonus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, and polyradiculoneuropathy (other than chronic inflammatory demyelinating polyneuropathy). Clinical input was mixed overall on the seventh condition, IVIG for treating severe anemia associated with parvovirus B19.

Additional clinical input was obtained in June 2013, focusing on severe anemia due to parvovirus B19. Input was received from 3 reviewers (all hematologists), and there was a consensus that IVIG is not investigational for this indication. There was a lack of consensus among the 3 reviewers on any specific clinical or patient characteristics that can be used to select patients with severe anemia due to parvovirus B19 for treatment with IVIG and on any treatments that should be used by these patients before IVIG.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Allergy, Asthma, and Immunology Work Group Report

In 2017, the American Academy of Allergy, Asthma, and Immunology (AAAAI) published an updated Work Group Report on the use of immunoglobulin in human disease that evaluated published data through June 2015.^147, Table 1 summarizes the conclusions of the Work Group regarding the potential benefit of immune globulin therapy for various disease states.

Table 1. American Academy of Allergy, Asthma, and Immunology Work Group Report Immune Globulin Recommendations^147,

ANCA=anti-neutrophil cytoplasmic autoantibody; BMT=bone marrow transplant; CIDP=chronic inflammatory demyelinating polyneuropathy; CMV=cytomegalovirus; GVHD=graft versus host disease; HIV=human immunodeficiency virus; Ig=immunoglobulin ; ITP=idiopathic thrombocytopenic purpura; PANDAS=pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; POEMS=polyneuropathy, organomegaly, endocrinopathy, monoclonal protein.

Disease State Guidelines

Immunodeficiency States

Primary Humoral Immune Deficiencies

National Advisory Committee on Blood and Blood Products and Canadian Blood Services

In 2010, the National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services (CBS) published guidelines on the use of immunoglobulin therapy for patients with primary immune deficiency.^6, The guidelines reported that there was sufficient evidence that immunoglobulin therapy reduces the rate of infection and hospitalization in patients with primary immune deficiency, lowers mortality, and improves quality of life. 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 subcutaneous immunoglobulin (SCIG) infusion.

American Academy of Allergy, Asthma, and Immunology

In 2015, AAAAI published practice parameters for the diagnosis and management of primary immunodeficiency.^148, The Academy advised that treatment of these conditions include antibiotic prophylaxis and immunoglobulin G (IgG) replacement.

Secondary Immunodeficiency

In 2022, AAAAI published a guideline on the diagnosis and management of secondary hypogammaglobulinemia.^149, The guideline states that using immunoglobulin replacement therapy (with either IVIG or SCIG) is a complex decision that may or may not be based on recommendations from a disease-state specific guideline. Several disease-state specific guidelines are summarized with IgG thresholds for starting therapy, if available for the disease state. The guideline also provides an algorithm that considers patient-specific factors such as history of infection and the effect of a trial of prophylactic antibiotics.

Hematopoietic Cell Transplantation (Prophylaxis)

In 2007, the NAC and CBS published guidelines on the use of IVIG for hematologic conditions.^43, The guidelines stated that evidence does not support the use of IVIG after hematopoietic cell transplantation.

Acute Antibody-Mediated Rejection After Solid Organ Transplant

In 2010, the CBS and NAC developed guidelines addressing the use of IVIG for sensitized individuals undergoing solid organ transplantation.^150, The following conclusions were issued on non-kidney solid organ transplantation:

• For patients undergoing heart transplantation, to improve graft/overall survival or to treat rejection: insufficient evidence to recommend for or against the routine use of IVIG (however, other factors may influence decision-making)

• For desensitization for patients undergoing lung transplantation or for the treatment of rejection: insufficient evidence to make a recommendation for or against the routine use of IVIG (however, other factors may influence decision-making)

• For patients undergoing liver transplantation or for the treatment of rejection/ABO-incompatible liver transplantation: insufficient evidence to make a recommendation for or against the routine use of IVIG

• For the use of IVIG for solid organ transplantation: limited methodologically rigorous evidence

• Future studies are needed to delineate the effect of IVIG on desensitization using standardized methods for desensitization; the effect of IVIG on acute rejection rates, graft survival, and overall survival; the use of the combined modality IVIG and plasmapheresis compared either to plasmapheresis or IVIG alone; and the optimum dosage of IVIG.

Chronic Lymphocytic Leukemia

The National Comprehensive Cancer Network guidelines (v. 3.2024 ) on chronic lymphocytic leukemia (CLL) recommend IVIG as supportive care for patients with CLL for the treatment of autoimmune cytopenias and recurrent sinopulmonary infections requiring hospitalization or intravenous antibiotics (IgG levels <500 mg/dL).^151, The guidelines recommend monitoring IVIG levels and administering monthly SCIG or IVIG (0.3 to 0.5 g/kg) to maintain levels of 500 mg/dL.

Infections

Infections in HIV-Infected Children

In 2024 , updated joint guidelines on the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children were published.^152, The guidelines, endorsed by the American Academy of Pediatrics, the Infectious Diseases Society of America, and other agencies and societies, included the following statements:

• “Intravenous immune globulin is recommended to prevent serious bacterial infections in HIV-infected children who have hypogammaglobulinemia (IgG <400 mg/dL).”

• "In rare situations in which combination antiretroviral therapy and antibiotic prophylaxis are not effective in preventing frequent recurrent serious bacterial infections, IVIG prophylaxis can be considered for secondary prophylaxis."

Neonatal Sepsis

In 2018, the American Academy of Pediatrics published guidelines on the management of neonates with suspected or proven early-onset bacterial sepsis.^153, The guidelines did not address the use of IVIG to treat neonatal sepsis.

Autoimmune and Inflammatory Conditions

Idiopathic Thrombocytopenic Purpura

In 2007, the NAC and CBS issued guidelines on the use of IVIG for hematologic conditions, including idiopathic thrombocytopenic purpura (ITP).^43, Recommendations for patients 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 minimal dose of IVIG should be used that maintains a safe platelet count. Patients should be reevaluated 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.

Guillain-Barré Syndrome

The American Academy of Neurology (AAN; 2003, reaffirmed January 2022) guidelines on immunotherapy for Guillain-Barré syndrome concluded that IVIG is as efficacious as plasmapheresis and should be offered as a treatment option to adults who require aid to walk within 2 to 4 weeks of neuropathic symptom onset. ^154, The guidelines indicated that there was insufficient evidence to support or refute the use of IVIG in children but both IVIG and plasmapheresis are listed as treatment options.

Kawasaki Syndrome and Other Vasculitides

The American Heart Association (2017)^155, and the American College of Rheumatology (2021)^156, have supported the use of IVIG in the treatment of Kawasaki syndrome.

Chronic Inflammatory Demyelinating Polyneuropathy

The AAN (2012) guidelines on the treatment of neuromuscular disorders stated that IVIG is effective and should be offered as a long-term treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) (level A).^157, The guidelines indicated that data are insufficient to compare the efficacy of prednisone and IVIG in the treatment of CIDP. Of note, the AAN website states this is a "retired" guideline.

The European Academy of Neurology and the Peripheral Nerve Society published updated guidelines on the management of CIDP in 2021.^158, Recommendations regarding immunoglobulin therapy included:

• "Both IVIG and oral or intravenous corticosteroids are first-line treatments for CIDP. Based on the level of evidence, the task force did not recommend an overall preference for either treatment modality and weakly recommended either IVIG or corticosteroid treatment. "

• "Both short- and long-term effectiveness, risks, ease of implementation, and cost should be considered:

  • IVIG may be preferable when it comes to short-term treatment effectiveness, or when (relative) contraindications for corticosteroids exist.

  • There is some indication that pulsed corticosteroids may be preferable for long-term treatment effectiveness, because of a possible higher rate and longer duration of remission, or when IVIG is unaffordable or unavailable."

• "Although the evidence from studies is limited, the task force weakly recommended treatment with IVIG compared with plasma exchange, mainly based on the ease of administration of IVIG.

  • In some patients with good vascular access, plasma exchange my be an acceptable option for chronic treatment."

• "The task force strongly recommended using SCIG for maintenance treatment in CIDP."

• "The task force recommended no preference for either IVIG or SCIG for maintenance treatment in CIDP."

• "During follow-up, the dose should be tailored according to individual treatment response."

• "The task force weakly recommended against using SCIG for induction treatment in CIDP."

Multifocal Motor Neuropathy

The AAN (2012) guidelines on the treatment of neuromuscular disorders stated that IVIG is probably effective and should be considered for the treatment of multifocal motor neuropathy (level B).^157, There were insufficient data to determine the optimal treatment interval, dosing, and duration. Of note, the AAN website states this is a "retired" guideline.

Eaton-Lambert Myasthenic Syndrome

The AAN (2012) guidelines on the treatment of neuromuscular disorders stated that IVIG is possibly effective and may be considered for treating Lambert-Eaton myasthenic syndrome (level C).^157,Of note, the AAN website states this is a "retired" guideline.

Neuromyelitis Optica

According to the Neuromyelitis Optica Study Group (2024 ) updated guidelines, high-dose IVIG is potentially beneficial in the long-term treatment of neuromyelitis optica and may be used as an alternative for patients with a contraindication to other treatments or, particularly, in children; it may also be used as an add-on therapy.^159,

Severe Refractory Myasthenia Gravis or Myasthenic Exacerbation

In 2013, the Myasthenia Gravis Foundation of America appointed a task force to develop an international consensus guidance that focused on the appropriate management of myasthenia gravis.^160, The authors of this guidance recommended the use of IVIG or plasma exchange for short-term treatment in patients with myasthenia gravis with life-threatening signs such as respiratory insufficiency or dysphagia; in preparation for surgery in patients with significant bulbar dysfunction; when a rapid response to treatment is needed; when other treatments are insufficiently effective; and prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations. Additionally, the guidance notes that the choice between plasma exchange and IVIG depends on individual patient factors and availability and that each therapy is probably equally effective in the treatment of severe generalized myasthenia gravis. For milder myasthenia gravis or ocular myasthenia gravis, the efficacy of IVIG is less certain. The use of IVIG as maintenance therapy can be considered for patients with refractory myasthenia gravis or for those in whom immunosuppressive agents are relatively contraindicated.

The Myasthenia Gravis Foundation of America in conjunction with an international task force updated guidelines (2020) for myasthenia gravis.^161, The authors added a recommendation for the combination of high-dose steroids with either plasma exchange or IVIG in patients who have myasthenia gravis related to the use of immune checkpoint inhibitors.

The AAN (2012) guidelines on the treatment of neuromuscular disorders concluded that IVIG therapy is probably effective in treating patients with severe myasthenia gravis and should be considered in the treatment plan (level B).^157, There was insufficient evidence to compare IVIG and plasmapheresis in the treatment of these patients. Of note, the AAN website states this is a "retired" guideline.

Relapsing-Remitting Multiple Sclerosis

In 2002, the AAN published a technology assessment on therapies for multiple sclerosis.^82, The assessment was reviewed and reaffirmed in 2018. The assessment offered the following recommendations on IVIG:

• Studies of IVIG to date have generally involved small numbers of patients, have lacked complete data on clinical and magnetic resonance imaging (MRI) 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: possibly effective, ineffective, or harmful).

• Current evidence suggests that IVIG is of little benefit with regard to slowing disease progression (type C recommendation: possibly effective, ineffective, or harmful).

Autoimmune Mucocutaneous Blistering Diseases

In 2003, a consensus statement on the use of immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases was published.^162, The authors of this statement recommended that immune globulin products be administered in the following situations:

• failure of conventional therapy

• contraindications to, or significant adverse effects of, standard treatment

• progressive disease while receiving appropriate therapy

• uncontrolled rapidly progressive disease.

Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

The British Association of Dermatologists (2016) published guidelines on the management of toxic epidermal necrolysis and Stevens-Johnson syndrome in adults.^163, These guidelines are accredited by the NICE. The guidelines indicated that evidence for the use of IVIG in the treatment of toxic epidermal necrolysis and Stevens-Johnson syndrome was not of sufficient quality or consistency.

The British Association of Dermatologists (2019) published guidelines for the management of Stevens-Johnson syndrome and toxic epidermal necrolysis in children and young people, which said, “There is no reliable evidence on the benefits or lack of benefit of any systemic treatments including prednisolone, IVIG, anti-tumor necrosis factor (TNF) biologics or ciclosporin.”^164,

Idiopathic Inflammatory Myopathies

The AAN (2012) guidelines on IVIG for treating neuromuscular disorders have stated that IVIG is possibly effective and may be considered as a treatment for nonresponsive dermatomyositis (an idiopathic inflammatory condition) in adults (level C).^157, Of note, the AAN website states this is a "retired" guideline.

Immune Optic Neuritis

Optic neuritis presents as a manifestation of multiple sclerosis (see the Relapsing-Remitting Multiple Sclerosis section above).

Alloimmune Processes

Antiphospholipid syndrome

In 2020, the Task Force on Catastrophic Antiphospholipid Syndrome (CAPS) recommended that "For first-line treatment of patients with CAPS, the panel suggests combination therapy with glucocorticoid, heparin, and plasmapheresis or IVIG over single agents or other combinations of therapies"; however this is a conditional recommendation graded with a very low certainty of evidence.^165,

.

Neonatal Alloimmune Thrombocytopenia

The NAC and CBS (2007) published guidelines on the use of IVIG for hematologic conditions.^43,

• Treatment of fetus: Evidence is limited and weak, but given that the condition is rare and the consequences are serious, IVIG was deemed an appropriate option and should be considered the standard of care.

• Treatment of newborn: First-line therapy should be antigen-negative compatible platelets, with IVIG considered as adjunctive therapy.

Recurrent Spontaneous Abortion

The Royal College of Obstetricians and Gynecologists ( 2023) issued guidelines on the treatment of recurrent miscarriages.^166, The guideline concluded that IVIG does not prevent further miscarriage in women with recurrent miscarriages (level B).

Miscellaneous

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections

In 2007, the NAC and CBS convened a panel of national experts to develop evidence-based practice guidelines on the use of IVIG for neurologic conditions.^167, The panel recommended the use of IVIG for the treatment of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. The optimal dose and duration of treatment are uncertain.

Autism Spectrum Disorder

The NAC and CBS (2007) guidelines on neurologic conditions did not recommend IVIG for autism.^167,

The American Academy of Child and Adolescent Psychiatry (2014) published practice parameters on the assessment and treatment of autism spectrum disorder.^168, The Academy parameters did not address the use of IVIG for the treatment of autism spectrum disorder.

Chronic Fatigue Syndrome

The NICE (2007; updated 2021) issued guidance on the diagnosis and management of chronic fatigue syndrome.^169, The guidance indicated that there is no cure for chronic fatigue syndrome and that symptoms (pain, sleep disturbances, physical limitations, and debilitating fatigue) should be managed under the supervision of a specialist. The use of IVIG was not addressed.

Viral Myocarditis

The American College of Cardiology Foundation and the American Heart Association issued joint guidelines in 2013, updated in 2017 and 2022, on the management of heart failure.^170, The guidelines did not address the use of IVIG for the treatment of viral myocarditis.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

The Centers for Medicare & Medicaid Services (2002) published a national coverage determination on IVIG for the treatment of autoimmune mucocutaneous blistering diseases.^171, Intravenous immunoglobulin is covered for patients with biopsy-proven disease who have failed conventional therapy or for whom conventional therapy is contraindicated, and to supplement conventional therapy in patients with rapidly progressive disease.

No national coverage determinations on other uses of IVIG or SCIG were identified.

Ongoing and Unpublished Clinical Trials

Some ongoing or currently unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References

1. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. May 1991; 41(5): 617-8. PMID 2027473
2. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force-Second revision. J Peripher Nerv Syst. Sep 2021; 26(3): 242-268. PMID 34085743
3. Food and Drug Administration (FDA). Vaccines, Blood & Biologics: Yimmugo. 2024; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yimmugo. Accessed August 18, 2024.
4. Food and Drug Administration (FDA). Vaccines, Blood & Biologics: Alyglo. 2024; https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/alyglo. Accessed August 19, 2024.
5. Food and Drug Administration (FDA). Vaccines, Blood & Biologics: Immune Globulins. 2023; https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/immune-globulins. Accessed August 20, 2024.
6. Shehata N, Palda V, Bowen T, et al. The use of immunoglobulin therapy for patients with primary immune deficiency: an evidence-based practice guideline. Transfus Med Rev. Jan 2010; 24 Suppl 1: S28-50. PMID 19962579
7. Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. May 2006; 26(3): 265-73. PMID 16783465
8. Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies--a prospective, multi-national study. J Clin Immunol. Mar 2006; 26(2): 177-85. PMID 16758340
9. Lingman-Framme J, Fasth A. Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review. Drugs. Aug 2013; 73(12): 1307-19. PMID 23861187
10. Raanani P, Gafter-Gvili A, Paul M, et al. Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and meta-analysis. J Clin Oncol. Feb 10 2009; 27(5): 770-81. PMID 19114702
11. Bourassa-Blanchette S, Knoll GA, Hutton B, et al. Clinical outcomes of polyvalent immunoglobulin use in solid organ transplant recipients: A systematic review and meta-analysis. Clin Transplant. Jun 2019; 33(6): e13560. PMID 30938866
12. Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. Dec 2004; 15(12): 3256-62. PMID 15579530
13. Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. Jul 17 2008; 359(3): 242-51. PMID 18635429
14. Alachkar N, Lonze BE, Zachary AA, et al. Infusion of high-dose intravenous immunoglobulin fails to lower the strength of human leukocyte antigen antibodies in highly sensitized patients. Transplantation. Jul 27 2012; 94(2): 165-71. PMID 22735712
15. Kozlowski T, Andreoni K. Limitations of rituximab/IVIg desensitization protocol in kidney transplantation; is this better than a tincture of time?. Ann Transplant. 2011; 16(2): 19-25. PMID 21716181
16. Marfo K, Ling M, Bao Y, et al. Lack of effect in desensitization with intravenous immunoglobulin and rituximab in highly sensitized patients. Transplantation. Aug 27 2012; 94(4): 345-51. PMID 22820699
17. Stegall MD, Gloor J, Winters JL, et al. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant. Feb 2006; 6(2): 346-51. PMID 16426319
18. Mohan S, Palanisamy A, Tsapepas D, et al. Donor-specific antibodies adversely affect kidney allograft outcomes. J Am Soc Nephrol. Dec 2012; 23(12): 2061-71. PMID 23160511
19. Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med. Jul 28 2011; 365(4): 318-26. PMID 21793744
20. Roberts DM, Jiang SH, Chadban SJ. The treatment of acute antibody-mediated rejection in kidney transplant recipients-a systematic review. Transplantation. Oct 27 2012; 94(8): 775-83. PMID 23032865
21. Casadei DH, del C Rial M, Opelz G, et al. A randomized and prospective study comparing treatment with high-dose intravenous immunoglobulin with monoclonal antibodies for rescue of kidney grafts with steroid-resistant rejection. Transplantation. Jan 15 2001; 71(1): 53-8. PMID 11211195
22. Gale RP, Chapel HM, Bunch C, et al. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. N Engl J Med. Oct 06 1988; 319(14): 902-7. PMID 2901668
23. Boughton BJ, Jackson N, Lim S, et al. Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia. Clin Lab Haematol. Mar 1995; 17(1): 75-80. PMID 7621634
24. Molica S, Musto P, Chiurazzi F, et al. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica. 1996; 81(2): 121-6. PMID 8641639
25. Chapel H, Dicato M, Gamm H, et al. Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes. Br J Haematol. Sep 1994; 88(1): 209-12. PMID 7803248
26. Griffiths H, Brennan V, Lea J, et al. Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood. Feb 1989; 73(2): 366-8. PMID 2492832
27. Raanani P, Gafter-Gvili A, Paul M, et al. Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma. May 2009; 50(5): 764-72. PMID 19330654
28. National Institute of Child Health and Human Developments Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med. Jul 11 1991; 325(2): 73-80. PMID 1675763
29. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database Syst Rev. Jul 02 2013; (7): CD000361. PMID 23821390
30. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev. Jan 29 2020; 1(1): CD001239. PMID 31995649
31. Brocklehurst P, Farrell B, King A, et al. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med. Sep 29 2011; 365(13): 1201-11. PMID 21962214
32. Busani S, Damiani E, Cavazzuti I, et al. Intravenous immunoglobulin in septic shock: review of the mechanisms of action and meta-analysis of the clinical effectiveness. Minerva Anestesiol. May 2016; 82(5): 559-72. PMID 26474267
33. Pan B, Sun P, Pei R, et al. Efficacy of IVIG therapy for patients with sepsis: a systematic review and meta-analysis. J Transl Med. Oct 28 2023; 21(1): 765. PMID 37898763
34. Ito S, Oyake T, Uchiyama T, et al. Successful treatment with cyclosporine and high-dose gamma immunoglobulin for persistent parvovirus B19 infection in a patient with refractory autoimmune hemolytic anemia. Int J Hematol. Oct 2004; 80(3): 250-3. PMID 15540900
35. Koduri PR, Kumapley R, Khokha ND, et al. Red cell aplasia caused by parvovirus B19 in AIDS: use of i.v. immunoglobulin. Ann Hematol. 1997; 75(1-2): 67-8. PMID 9322687
36. Chuhjo T, Nakao S, Matsuda T. Successful treatment of persistent erythroid aplasia caused by parvovirus B19 infection in a patient with common variable immunodeficiency with low-dose immunoglobulin. Am J Hematol. Mar 1999; 60(3): 222-4. PMID 10072114
37. Crabol Y, Terrier B, Rozenberg F, et al. Intravenous immunoglobulin therapy for pure red cell aplasia related to human parvovirus b19 infection: a retrospective study of 10 patients and review of the literature. Clin Infect Dis. Apr 2013; 56(7): 968-77. PMID 23243178
38. Darenberg J, Ihendyane N, Sjölin J, et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis. Aug 01 2003; 37(3): 333-40. PMID 12884156
39. Linnér A, Darenberg J, Sjölin J, et al. Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study. Clin Infect Dis. Sep 15 2014; 59(6): 851-7. PMID 24928291
40. Kaul R, McGeer A, Norrby-Teglund A, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome--a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis. Apr 1999; 28(4): 800-7. PMID 10825042
41. Norrby-Teglund A, Muller MP, Mcgeer A, et al. Successful management of severe group A streptococcal soft tissue infections using an aggressive medical regimen including intravenous polyspecific immunoglobulin together with a conservative surgical approach. Scand J Infect Dis. 2005; 37(3): 166-72. PMID 15849047
42. Shah SS, Hall M, Srivastava R, et al. Intravenous immunoglobulin in children with streptococcal toxic shock syndrome. Clin Infect Dis. Nov 01 2009; 49(9): 1369-76. PMID 19788359
43. Anderson D, Ali K, Blanchette V, et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev. Apr 2007; 21(2 Suppl 1): S9-56. PMID 17397769
44. Godeau B, Chevret S, Varet B, et al. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet. Jan 05 2002; 359(9300): 23-9. PMID 11809183
45. von dem Borne AE, Vos JJ, Pegels JG, et al. High dose intravenous methylprednisolone or high dose intravenous gammaglobulin for autoimmune thrombocytopenia. Br Med J (Clin Res Ed). Jan 23 1988; 296(6617): 249-50. PMID 2449258
46. Jacobs P, Wood L. The comparison of gammaglobulin to steroids in treating adult immune thrombocytopenia. An interim analysis. Blut. Jul 1989; 59(1): 92-5. PMID 2752179
47. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. Sep 19 2014; 2014(9): CD002063. PMID 25238327
48. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Lancet. Jan 25 1997; 349(9047): 225-30. PMID 9014908
49. Overell JR, Hsieh ST, Odaka M, et al. Treatment for Fisher syndrome, Bickerstaff's brainstem encephalitis and related disorders. Cochrane Database Syst Rev. Jan 24 2007; 2007(1): CD004761. PMID 17253522
50. Broderick C, Kobayashi S, Suto M, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease. Cochrane Database Syst Rev. Jan 25 2023; 1(1): CD014884. PMID 36695415
51. Fortin PM, Tejani AM, Bassett K, et al. Intravenous immunoglobulin as adjuvant therapy for Wegener's granulomatosis. Cochrane Database Syst Rev. Jan 31 2013; 2013(1): CD007057. PMID 23440811
52. Jayne DR, Chapel H, Adu D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM. Jul 2000; 93(7): 433-9. PMID 10874052
53. Eftimov F, Winer JB, Vermeulen M, et al. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. Dec 30 2013; (12): CD001797. PMID 24379104
54. Dyck PJ, Litchy WJ, Kratz KM, et al. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. Dec 1994; 36(6): 838-45. PMID 7998769
55. Hughes R, Bensa S, Willison H, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. Aug 2001; 50(2): 195-201. PMID 11506402
56. Nobile-Orazio E, Cocito D, Jann S, et al. Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol. Jun 2012; 11(6): 493-502. PMID 22578914
57. Vermeulen M, van Doorn PA, Brand A, et al. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry. Jan 1993; 56(1): 36-9. PMID 8429321
58. Hahn AF, Bolton CF, Zochodne D, et al. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study. Brain. Aug 1996; 119 ( Pt 4): 1067-77. PMID 8813271
59. Thompson N, Choudhary P, Hughes RA, et al. A novel trial design to study the effect of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol. Mar 1996; 243(3): 280-5. PMID 8936360
60. Mendell JR, Barohn RJ, Freimer ML, et al. Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. Feb 27 2001; 56(4): 445-9. PMID 11222785
61. Hughes RA, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol. Feb 2008; 7(2): 136-44. PMID 18178525
62. Bus SR, de Haan RJ, Vermeulen M, et al. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. Feb 14 2024; 2(2): CD001797. PMID 38353301
63. Camdessanche JP, Ferraud K, Lagrange E, Viala K, Chan V, Guy Renouil N, et al. Multicentre, randomised, open-label trial to compare efficacy and tolerance of prednisone and IVIG In patients with CIDP on a one year follow up (P7.092). Neurology 2014;82(10 Suppl):P7.092. CENTRAL
64. Ramzi A, Maya S, Balousha N, et al. Subcutaneous immunoglobulins (SCIG) for chronic inflammatory demyelinating polyneuropathy (CIDP): A comprehensive systematic review of clinical studies and meta-analysis. Neurol Sci. Jun 28 2024. PMID 38937399
65. van Schaik IN, Bril V, van Geloven N, et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. Jan 2018; 17(1): 35-46. PMID 29122523
66. van Schaik IN, Mielke O, Bril V, et al. Long-term safety and efficacy of subcutaneous immunoglobulin IgPro20 in CIDP: PATH extension study. Neurol Neuroimmunol Neuroinflamm. Sep 2019; 6(5): e590. PMID 31355323
67. Markvardsen LH, Sindrup SH, Christiansen I, et al. Subcutaneous immunoglobulin as first-line therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy: randomized controlled trial study. Eur J Neurol. Feb 2017; 24(2): 412-418. PMID 28000311
68. Food and Drug Administration (FDA). HYQVIA [Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase] Solution, for subcutaneous administration Initial U.S. Approval: 2014. https://www.fda.gov/media/89844/download?attachment. Accessed September 11, 2024.
69. Keddie S, Eftimov F, van den Berg LH, et al. Immunoglobulin for multifocal motor neuropathy. Cochrane Database Syst Rev. Jan 11 2022; 1(1): CD004429. PMID 35015296
70. Bain PG, Motomura M, Newsom-Davis J, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology. Sep 1996; 47(3): 678-83. PMID 8797464
71. Muchnik S, Losavio AS, Vidal A, et al. Long-term follow-up of Lambert-Eaton syndrome treated with intravenous immunoglobulin. Muscle Nerve. Jun 1997; 20(6): 674-8. PMID 9149073
72. Rich MM, Teener JW, Bird SJ. Treatment of Lambert-Eaton syndrome with intravenous immunoglobulin. Muscle Nerve. May 1997; 20(5): 614-5. PMID 9140371
73. Takano H, Tanaka M, Koike R, et al. Effect of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome with small-cell lung cancer: correlation with the titer of anti-voltage-gated calcium channel antibody. Muscle Nerve. Sep 1994; 17(9): 1073-5. PMID 8065398
74. Bird SJ. Clinical and electrophysiologic improvement in Lambert-Eaton syndrome with intravenous immunoglobulin therapy. Neurology. Jul 1992; 42(7): 1422-3. PMID 1620360
75. Elsone L, Panicker J, Mutch K, et al. Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult Scler. Apr 2014; 20(4): 501-4. PMID 23986097
76. Magraner MJ, Coret F, Casanova B. The effect of intravenous immunoglobulin on neuromyelitis optica. Neurologia. Mar 2013; 28(2): 65-72. PMID 22841880
77. Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. Dec 12 2012; 12(12): CD002277. PMID 23235588
78. Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. Mar 13 2007; 68(11): 837-41. PMID 17353471
79. Barth D, Nabavi Nouri M, Ng E, et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. Jun 07 2011; 76(23): 2017-23. PMID 21562253
80. Gajdos P, Tranchant C, Clair B, et al. Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch Neurol. Nov 2005; 62(11): 1689-93. PMID 16286541
81. Gajdos P, Chevret S, Clair B, et al. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol. Jun 1997; 41(6): 789-96. PMID 9189040
82. Goodin DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. Jan 22 2002; 58(2): 169-78. PMID 11805241
83. Gürcan HM, Jeph S, Ahmed AR. Intravenous immunoglobulin therapy in autoimmune mucocutaneous blistering diseases: a review of the evidence for its efficacy and safety. Am J Clin Dermatol. 2010; 11(5): 315-26. PMID 20642294
84. Amagai M, Ikeda S, Hashimoto T, et al. A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid. J Dermatol Sci. Feb 2017; 85(2): 77-84. PMID 27876358
85. Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. Apr 2009; 60(4): 595-603. PMID 19293008
86. Huang YC, Chien YN, Chen YT, et al. Intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. G Ital Dermatol Venereol. Oct 2016; 151(5): 515-24. PMID 27248150
87. Barron SJ, Del Vecchio MT, Aronoff SC. Intravenous immunoglobulin in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a meta-analysis with meta-regression of observational studies. Int J Dermatol. Jan 2015; 54(1): 108-15. PMID 24697283
88. Xiong A, Qiang Y, Cao Y, et al. The therapeutic efficacy and safety of intravenous immunoglobulin in dermatomyositis and polymyositis: A systematic review and meta-analysis. Mod Rheumatol. Apr 13 2023; 33(3): 533-542. PMID 35660927
89. Wang DX, Shu XM, Tian XL, et al. Intravenous immunoglobulin therapy in adult patients with polymyositis/dermatomyositis: a systematic literature review. Clin Rheumatol. May 2012; 31(5): 801-6. PMID 22274797
90. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med. Dec 30 1993; 329(27): 1993-2000. PMID 8247075
91. Dalakas MC, Sonies B, Dambrosia J, et al. Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study. Neurology. Mar 1997; 48(3): 712-6. PMID 9065553
92. Walter MC, Lochmüller H, Toepfer M, et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol. Jan 2000; 247(1): 22-8. PMID 10701893
93. Dalakas MC, Koffman B, Fujii M, et al. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology. Feb 13 2001; 56(3): 323-7. PMID 11171896
94. Sakthiswary R, D'Cruz D. Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: a systematic review and meta-analysis. Medicine (Baltimore). Oct 2014; 93(16): e86. PMID 25310743
95. Boletis JN, Ioannidis JP, Boki KA, et al. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet. Aug 14 1999; 354(9178): 569-70. PMID 10470708
96. Cajamarca-Barón J, Buitrago-Bohórquez J, Mendoza Orozco JE, et al. Efficacy and safety of intravenous immunoglobulin in patients with lupus nephritis: A systematic review of the literature. Autoimmun Rev. Nov 2022; 21(11): 103182. PMID 36028194
97. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. Apr 2006; 117(4 Suppl): S525-53. PMID 16580469
98. Roed HG, Langkilde A, Sellebjerg F, et al. A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis. Neurology. Mar 08 2005; 64(5): 804-10. PMID 15753413
99. Noseworthy JH, O'Brien PC, Petterson TM, et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology. Jun 12 2001; 56(11): 1514-22. PMID 11402108
100. Rogosnitzky M, Danks R, Holt D. Intravenous immunoglobulin for the treatment of Crohn's disease. Autoimmun Rev. Dec 2012; 12(2): 275-80. PMID 22579561
101. Rajagopala S, Singh N. Diagnosing and treating hemophagocytic lymphohistiocytosis in the tropics: systematic review from the Indian subcontinent. Acta Med Acad. 2012; 41(2): 161-74. PMID 23331391
102. Hot A, Madoux MH, Viard JP, et al. Successful treatment of cytomegalovirus-associated hemophagocytic syndrome by intravenous immunoglobulins. Am J Hematol. Feb 2008; 83(2): 159-62. PMID 17849465
103. Ostronoff M, Ostronoff F, Coutinho M, et al. Hemophagocytic syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma; successful treatment with high-dose intravenous immunoglobulin. Bone Marrow Transplant. Apr 2006; 37(8): 797-8. PMID 16518425
104. Arlet JB, Le TH, Marinho A, et al. Reactive haemophagocytic syndrome in adult-onset Still's disease: a report of six patients and a review of the literature. Ann Rheum Dis. Dec 2006; 65(12): 1596-601. PMID 16540551
105. Flores G, Cunningham-Rundles C, Newland AC, et al. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. Dec 1993; 44(4): 237-42. PMID 8237993
106. Macintyre EA, Linch DC, Macey MG, et al. Successful response to intravenous immunoglobulin in autoimmune haemolytic anaemia. Br J Haematol. Jun 1985; 60(2): 387-8. PMID 4005186
107. Bucciarelli S, Espinosa G, Cervera R, et al. Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum. Aug 2006; 54(8): 2568-76. PMID 16868979
108. Rayment R, Brunskill SJ, Soothill PW, et al. Antenatal interventions for fetomaternal alloimmune thrombocytopenia. Cochrane Database Syst Rev. May 11 2011; (5): CD004226. PMID 21563140
109. Paridaans NP, Kamphuis MM, Taune Wikman A, et al. Low-Dose versus Standard-Dose Intravenous Immunoglobulin to Prevent Fetal Intracranial Hemorrhage in Fetal and Neonatal Alloimmune Thrombocytopenia: A Randomized Trial. Fetal Diagn Ther. 2015; 38(2): 147-53. PMID 25896635
110. Berkowitz RL, Lesser ML, McFarland JG, et al. Antepartum treatment without early cordocentesis for standard-risk alloimmune thrombocytopenia: a randomized controlled trial. Obstet Gynecol. Aug 2007; 110(2 Pt 1): 249-55. PMID 17666597
111. Berkowitz RL, Kolb EA, McFarland JG, et al. Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopenia. Obstet Gynecol. Jan 2006; 107(1): 91-6. PMID 16394045
112. Bussel JB, Berkowitz RL, Lynch L, et al. Antenatal management of alloimmune thrombocytopenia with intravenous gamma-globulin: a randomized trial of the addition of low-dose steroid to intravenous gamma-globulin. Am J Obstet Gynecol. May 1996; 174(5): 1414-23. PMID 9065105
113. Ernstsen SL, Ahlen MT, Johansen T, et al. Antenatal intravenous immunoglobulins in pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia: comparison of neonatal outcome in treated and nontreated pregnancies. Am J Obstet Gynecol. Sep 2022; 227(3): 506.e1-506.e12. PMID 35500612
114. Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev. Apr 19 2006; (2): CD000112. PMID 16625529
115. Egerup P, Lindschou J, Gluud C, et al. The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data. PLoS One. 2015; 10(10): e0141588. PMID 26517123
116. Wang SW, Zhong SY, Lou LJ, et al. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis. Reprod Biomed Online. Dec 2016; 33(6): 720-736. PMID 27720163
117. Christiansen OB, Pedersen B, Rosgaard A, et al. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod. Mar 2002; 17(3): 809-16. PMID 11870141
118. Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol. Jan 2000; 182(1 Pt 1): 122-7. PMID 10649166
119. Jablonowska B, Selbing A, Palfi M, et al. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod. Mar 1999; 14(3): 838-41. PMID 10221723
120. Williams KA, Swedo SE, Farmer CA, et al. Randomized, Controlled Trial of Intravenous Immunoglobulin for Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections. J Am Acad Child Adolesc Psychiatry. Oct 2016; 55(10): 860-867.e2. PMID 27663941
121. Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet. Oct 02 1999; 354(9185): 1153-8. PMID 10513708
122. Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. Aug 1996; 26(4): 439-52. PMID 8863094
123. Plioplys AV. Intravenous immunoglobulin treatment of children with autism. J Child Neurol. Feb 1998; 13(2): 79-82. PMID 9512308
124. DelGiudice-Asch G, Simon L, Schmeidler J, et al. Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord. Apr 1999; 29(2): 157-60. PMID 10382136
125. Goebel A, Bisla J, Carganillo R, et al. Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome: A Randomized Trial. Ann Intern Med. Oct 03 2017; 167(7): 476-483. PMID 28973211
126. Goebel A, Baranowski A, Maurer K, et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med. Feb 02 2010; 152(3): 152-8. PMID 20124231
127. Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology. May 02 2017; 88(18): 1768-1775. PMID 28381506
128. Kile S, Au W, Parise C, et al. IVIG treatment of mild cognitive impairment due to Alzheimer's disease: a randomised double-blinded exploratory study of the effect on brain atrophy, cognition and conversion to dementia. J Neurol Neurosurg Psychiatry. Feb 2017; 88(2): 106-112. PMID 26420886
129. Dodel R, Rominger A, Bartenstein P, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. Mar 2013; 12(3): 233-43. PMID 23375965
130. Comi G, Roveri L, Swan A, et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol. Oct 2002; 249(10): 1370-7. PMID 12382151
131. Dalakas MC, Quarles RH, Farrer RG, et al. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol. Nov 1996; 40(5): 792-5. PMID 8957021
132. Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, et al. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med. Jul 1997; 103(1): 38-43. PMID 9236484
133. Robinson J, Hartling L, Vandermeer B, et al. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. May 20 2015; (5): CD004370. PMID 25992494
134. Robinson J, Hartling L, Vandermeer B, et al. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. Aug 19 2020; 8(8): CD004370. PMID 32835416
135. McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation. May 08 2001; 103(18): 2254-9. PMID 11342473
136. Kishimoto C, Shioji K, Hashimoto T, et al. Therapy with immunoglobulin in patients with acute myocarditis and cardiomyopathy: analysis of leukocyte balance. Heart Vessels. May 2014; 29(3): 336-42. PMID 23702697
137. El-Saiedi SA. Randomized controlled trial on the use of intravenous immune globulin in acute pediatric myocarditis. J Clin Res Bioethics. 2013;5(1):1-5. https://www.longdom.org/open-access/randomized-controlled-trial-on-the-use-of-intravenous-immune-globulin-2155-9627-5-170.pdf.
138. Huang X, Sun Y, Su G, et al. Intravenous Immunoglobulin Therapy for Acute Myocarditis in Children and Adults. Int Heart J. Mar 20 2019; 60(2): 359-365. PMID 30745539
139. Heidendael JF, Den Boer SL, Wildenbeest JG, et al. Intravenous immunoglobulins in children with new onset dilated cardiomyopathy. Cardiol Young. Jan 2018; 28(1): 46-54. PMID 28797313
140. Imazio M, Lazaros G, Picardi E, et al. Intravenous human immunoglobulins for refractory recurrent pericarditis: a systematic review of all published cases. J Cardiovasc Med (Hagerstown). Apr 2016; 17(4): 263-9. PMID 26090917
141. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. Dec 27 2001; 345(26): 1870-6. PMID 11756577
142. Yi J, Dalakas MC. Long-term Effectiveness of IVIg Maintenance Therapy in 36 Patients With GAD Antibody-Positive Stiff-Person Syndrome. Neurol Neuroimmunol Neuroinflamm. Sep 2022; 9(5). PMID 35798561
143. LeHoang P, Cassoux N, George F, et al. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm. Mar 2000; 8(1): 49-57. PMID 10806434
144. Rosenbaum JT, George RK, Gordon C. The treatment of refractory uveitis with intravenous immunoglobulin. Am J Ophthalmol. May 1999; 127(5): 545-9. PMID 10334347
145. Huang YH, Chen HC, Huang KW, et al. Intravenous immunoglobulin for postpolio syndrome: a systematic review and meta-analysis. BMC Neurol. Mar 22 2015; 15: 39. PMID 25886512
146. Madsen MB, Hjortrup PB, Hansen MB, et al. Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised, blinded, placebo-controlled trial. Intensive Care Med. Nov 2017; 43(11): 1585-1593. PMID 28421246
147. Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. Mar 2017; 139(3S): S1-S46. PMID 28041678
148. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. Nov 2015; 136(5): 1186-205.e1-78. PMID 26371839
149. Otani IM, Lehman HK, Jongco AM, et al. Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees. J Allergy Clin Immunol. May 2022; 149(5): 1525-1560. PMID 35176351
150. Shehata N, Palda VA, Meyer RM, et al. The use of immunoglobulin therapy for patients undergoing solid organ transplantation: an evidence-based practice guideline. Transfus Med Rev. Jan 2010; 24 Suppl 1: S7-S27. PMID 19962580
151. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed August 20, 2024.
152. Centers for Disease Control (CDC). Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: bacterial infections. 2024; https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-pediatric-opportunistic-infections/updates-guidelines-prevention. Accessed August 20, 2024.
153. Puopolo KM, Benitz WE, Zaoutis TE, Committee on Fetus Newborn, Committee on Infectious Diseases. Management of neonates born at > or =35 0/7 weeks' gestation with suspected or proven early-onset bacterial sepsis. Pediatrics. 2018; 142(6):e20182894. https://pediatrics.aappublications.org/content/pediatrics/142/6/e20182894.full.pdf.
154. Hughes RA, Wijdicks EF, Barohn R, et al. Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Sep 23 2003; 61(6): 736-40. PMID 14504313
155. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. Apr 25 2017; 135(17): e927-e999. PMID 28356445
156. Gorelik M, Chung SA, Ardalan K, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Kawasaki Disease. Arthritis Rheumatol. Apr 2022; 74(4): 586-596. PMID 35257501
157. Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. Mar 27 2012; 78(13): 1009-15. PMID 22454268
158. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force - second revision. J Peripher Nerv Syst. 2021;1-27. https://onlinelibrary.wiley.com/doi/10.1111/jns.12455.
159. Kümpfel T, Giglhuber K, Aktas O, et al. Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management. J Neurol. Jan 2024; 271(1): 141-176. PMID 37676297
160. Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. Jul 26 2016; 87(4): 419-25. PMID 27358333
161. Narayanaswami P, Sanders DB, Wolfe G, et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. Jan 19 2021; 96(3): 114-122. PMID 33144515
162. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol. Aug 2003; 139(8): 1051-9. PMID 12925395
163. Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. Jun 2016; 174(6): 1194-227. PMID 27317286
164. McPherson T, Exton LS, Biswas S, et al. British Association of Dermatologists' guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in children and young people, 2018. Br J Dermatol. 2019;181:37-54. doi: 10.1111/bjd.17841. https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.17841.
165. Cervera R, Rodríguez-Pintó I, Legault K, et al. 16th International Congress on Antiphospholipid Antibodies Task Force Report on Catastrophic Antiphospholipid Syndrome. Lupus. Oct 2020; 29(12): 1594-1600. PMID 32819183
166. Royal College of Obstetricians and Gynecologists. Recurrent Miscarriage. Royal College of Obstetricians and Gynecologists Green-Top Guidelines No. 17. 2023; https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_17.pdf. Accessed September 6, 2023.
167. Feasby T, Banwell B, Benstead T, et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev. Apr 2007; 21(2 Suppl 1): S57-107. PMID 17397768
168. Volkmar F, Siegel M, Woodbury-Smith M, et al. Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. Feb 2014; 53(2): 237-57. PMID 24472258
169. National Institute for Health and Care Excellence (NICE). Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management [NG206]. 2021; https://www.nice.org.uk/guidance/ng206. Accessed August 18, 2024.
170. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. May 03 2022; 145(18): e895-e1032. PMID 35363499
171. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination for intravenous immune globulin for the treatment of autoimmune mucocutaneous blistering diseases (250.3). 2002; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=158. Accessed August 19, 2024.

Codes