Immune Globulin

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for immune globulin services. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for immune globulin services and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site.

IOM Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
• Chapter 1, Section 30 Drugs and Biologicals
• Chapter 15, Section 50 Drugs and Biologicals and Section 60 Services and Supplies
• CMS IOM Publication 100-03, Medicare National Coverage Determinations (NCD) Manual,
• Chapter 1, Part 4, Section 250.3 Intravenous Immune Globulin for the Treatment of Autoimmune Mucocutaneous Blistering Diseases
• CMS IOM Publication 100-04, Medicare Claims Processing Manual,
• Chapter 17, Section 40 Discarded Drugs and Biologicals, Section 80.6 Intravenous Immune Globulin and Section 90.2 Drugs, Biologicals, and Radiopharmaceuticals
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
• Chapter 13, Section 13.5.4 Reasonable and Necessary Provision in an LCD

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1833(e) states that no payment shall be made to any provider for any claim that lacks the necessary information to process the claim.
• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment may be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.

Compliance with the provisions in this LCD may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

Immune globulin (also referred to as gamma globulin or immunoglobulin) is a therapeutic compound prepared from pools of plasma obtained from several thousand healthy blood donors that contains antibodies to a wide spectrum of antigens. Immune globulin has been utilized for immune deficiencies identified in individuals with inherited or acquired immunodeficiencies and is used for its capacity in combating infection as a replacement therapy and for its anti-inflammatory and immunomodulating effects. The appropriate use of immune globulin can decrease morbidity and mortality and improve quality of life.^1,2

The focus of this LCD is the United States (U.S.) Food and Drug Administration (FDA) approved indications and the off-label indications for immune globulin where the evidence supports such use. Immune globulin products are not generic drugs and products are not interchangeable. A specific product needs to be matched to patient characteristics to ensure patient safety and a change of product should occur only with the active participation of the prescribing provider.³

The overall coverage of drugs is addressed in the CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Sections 50.4.1 and 50.4.2 and includes coverage for FDA-approved drugs and unlabeled use of a drug.

Covered Indications

Immune globulin products will be considered medically reasonable and necessary when administered for treatment of FDA-labeled indications (https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/immune-globulins⁴).

Off-label indications for intravenous immune globulin (IVIG) products will be considered medically reasonable and necessary in the following situations:

1. Multiple myeloma for recurrent infections with hypogammaglobulinemia and subprotective antibody levels following immunization against diphtheria, tetanus or pneumococcal infection^1,3,5-7
2. Following treatment of lymphoma utilizing B-cell depleting therapies for recurrent infections with hypogammaglobulinemia and subprotective antibody levels following immunization against diphtheria, tetanus or pneumococcal infection³
3. Recipients of hematopoietic stem cell transplants with severe combined immunodeficiency (SCID) or other primary immunodeficiencies who are functionally agammaglobulinemic because of weak B-cell engraftment³
4. Recipients of allogeneic hematopoietic stem cell transplantation with chronic graft versus host disease (GVHD), recurring bacterial infections, and subprotective antibody levels following immunization against diphtheria, tetanus or pneumococcal infection³
5. Human Leukocyte Antigen (HLA) and ABO desensitization protocols for the prevention of acute humoral rejection in renal transplantation³
6. The treatment of antibody mediated solid organ transplant rejection in combination with rituximab and plasma exchange (PE)^3,8
7. Treatment of hypogammaglobulinemia in solid organ transplants³
8. Autoimmune hemolytic anemia (AIHA) when other treatment approaches have failed^9-10
9. Systemic capillary leak syndrome (SCLS)^11-13
10. Guillain-Barré syndrome (GBS) in adults^1,3,14-15
11. Moderate to severe myasthenia gravis (MG)^2-3,10,15-18
12. Lambert-Eaton myasthenic syndrome (LEMS) in individuals who fail to respond or do not tolerate other treatments³
13. Relapsing-remitting multiple sclerosis (MS)^3,19-22
14. Neuromyelitis optica (Devic syndrome) in individuals with severe relapses not responding to corticosteroids and who are not candidates for PE³
15. Stiff-person syndrome (also referred to as stiff-man syndrome)^2-3
16. Treatment of autoimmune encephalitis, once infection is ruled out, as an alternative in patients who fail to respond or do not tolerate other treatments^23-27
17. Treatment of Susac syndrome in combination with high-dose intravenous corticosteroids²⁸
18. Severe forms of polymyositis resistant to treatment with glucocorticosteroids and immunosuppressants^29-30
19. Severe forms of inclusion body myositis with dysphagia and individuals are otherwise treatment-resistant^3,29-33
20. Immune mediated necrotizing myopathy resistant to treatment with glucocorticosteroids and immunosuppressants^29-30
21. Overlap syndrome with myositis including anti-synthetase syndrome resistant to treatment with glucocorticosteroids and immunosuppressants^29-30
22. Severe systemic lupus erythematosus (SLE) in individuals who fail to respond or do not tolerate other treatments^10,30
23. Biopsy-proven autoimmune mucocutaneous blistering diseases in individuals who fail to respond or do not tolerate other treatments and individuals with rapidly progressive disease requiring a faster response than conventional therapy (i.e., pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa acquisita)^3,30,34-39
24. Toxic epidermal necrolysis (TEN)^3,30
25. Stevens-Johnson syndrome^3,30
26. Severe scleromyxedema^3,30,40-41
27. Thyroid eye disease, also referred to as Graves’ disease in patients who have failed treatment with teprotumumab or have contraindications to the use of teprotumumab^3,42-45

Limitations

The following are considered not medically reasonable and necessary:

1. The off-label use of subcutaneous immune globulin
2. The off-label use of intravenous immune globulin not listed above in the covered indications

AND

Immune globulin for the following:

3. Routine use in the immediate peri-transplantation period for the prevention of infection or GVHD following marrow or peripheral blood allogeneic transplantation^3,46
4. Acute GVHD with hematopoietic stem cell transplantation in the immediate post-transplantation phase³
5. Hematopoietic stem cell transplantation in the immediate post-transplantation phase with a history of sinusoidal obstructive syndrome^3,46
6. Cord blood stem cell transplantation for children or adults³
7. Polyneuropathy associated with IgM monoclonal gammopathy¹⁰
8. Idiopathic neuropathies¹⁰
9. Brachial plexopathy¹⁰
10. Adrenoleukodystrophy¹⁰
11. Amyotrophic lateral sclerosis¹⁰
12. Critical illness polyneuropathy¹⁰
13. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes)¹⁰

Please refer to the CMS IOM Publication 100-03, Medicare National Coverage Determinations (NCD) Manual, Chapter 1, Part 4, Section 250.3 Intravenous Immune Globulin for the Treatment of Autoimmune Mucocutaneous Blistering Diseases for additional limitations.

Provider Qualifications

Services will be considered medically reasonable and necessary when all aspects of care are within the scope of practice of the provider’s professional licensure; and when all procedures are performed by appropriately trained providers in the appropriate setting.

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

A literature search was conducted for evidence-based guidelines and appropriate use criteria for immune globulin. The literature search was filtered to locate articles within five-ten years, full-text articles, clinical trials, and systematic reviews.

Multiple guidelines and appropriate use criteria are available for utilization of immune globulin. The goal of immune globulin therapy is to improve health outcomes of patients. In general, improved health outcomes of interest include patient mortality and morbidity, as well as patient quality of life and function.

History/Background

Immunoglobulins (also referred to as immune globulin or gamma globulin) are antibodies produced by differentiated B cells called plasma cells. The immunoglobulin molecule has a distinctive structure that has the ability to recognize specific antigenic determinants. The immune globulin formulations are generated from the pooled human plasma of thousands of healthy donors, which allows the immune globulin formulations to include a large and diverse antibody collection. The supply of immune globulin is limited as it depends on donated plasma. Therefore, it is imperative for healthcare providers to understand current levels of evidence to support immune globulin therapy as the appropriate use of immune globulin can decrease morbidity and mortality and improve quality of life. Immune globulin is a key component in the treatment for individuals with primary immunodeficiency disease affecting the humoral immune system. Intravenous formulations are significant in the treatment of other conditions as well, some for which have no available alternative treatments.^1-2

FDA-Approved Indications for IVIG

Intravenous immune globulin (IVIG) has been licensed by the FDA for the following: 1) treatment of primary immunodeficiencies (PIs); 2) prevention of bacterial infections in patients with hypogammaglobulinemia and recurrent bacterial infection due to B-cell chronic lymphocytic leukemia (CLL); 3) prevention of coronary artery aneurysms in Kawasaki disease (KD); 4) increasing platelet count in idiopathic thrombocytopenic purpura (ITP) to prevent or control bleeding; 5) treatment of chronic inflammatory demyelinating polyneuropathy (CIDP); 6) multifocal motor neuropathy (MMN); and 7) dermatomyositis (DM).⁴

Subcutaneous immune globulin (SCIG) has been licensed by the FDA for the following: 1) treatment of PIs and 2) treatment of CIDP.⁴

Perez et al³ provides evidence-based guidelines on the use of immune globulin in human disease that includes a discussion regarding categorization of evidence and basis of recommendation (see tables below):

Primary Immunodeficiency Diseases

Primary immunodeficiency diseases include a heterogenous collection of genetic disorders that affect distinct elements within the innate and adaptive immune system; these may include macrophages, natural killer cells, dendritic cells, neutrophils, complement proteins, B lymphocytes, and T lymphocytes. These diseases may occur alone or as part of a syndrome, and heterogeneity may be significant within each disorder.¹ Immune globulin replacement therapy is necessary in individuals with particular PI diseases distinguished by absent or deficient antibody production and, in general, recurrent or unusually severe infection.³

Secondary Humoral Immunodeficiencies

Secondary humoral immunodeficiencies stem from immune system compromise because of a nongenetic factor. The use of immune globulin replacement therapy has been beneficial in an assortment of conditions that lead to a secondary humoral deficiency, including hematologic malignancies, hypogammaglobulinemia associated with solid organ or bone marrow transplantation, and individuals who have received B-cell–depleting agents for therapy.¹

Multiple Myeloma

A major cause of increased morbidity and mortality in individuals with multiple myeloma (MM) is infections. An early randomized, placebo-controlled trial demonstrated that IVIG reduced the frequency of infections in individuals with MM during the plateau phase of the condition. No episodes of sepsis or pneumonia occurred in the treated group versus ten in the placebo group (P = .002), and of 57 serious infections, 38 occurred in 470 patient-months on placebo versus 19 in 449 patient-months on IVIG (P = .019). A two-year crossover study of IVIG in MM during late-phase disease also demonstrated a statistically substantial change in the prevalence of infections, with 30 infections (nine life-threatening) occurring in 250 patient-months without IVIG versus ten (0 life-threatening) occurring in 261 patient-months with IVIG (P < .02). Blimark et al,⁶ as cited by Perez,¹ conducted a population-based study for 9,253 MM patients and found that patients with MM had a seven-fold greater risk of acquiring an infection versus matched controls. Outcomes from numerous clinical trials have demonstrated a substantial reduction in the number of major infections in individuals with MM who were treated with immune globulin.³ A study by Khalafallah et al,⁷ as cited by Perez,¹ with 47 individuals with MM and a history of recurring moderate to severe bacterial infections showed that treatment with IVIG resulted in a substantial decrease in the infection rate after therapy. Results showed the rate of infection dropped from 17% to 0% in individuals with severe infection, 55% to 34% in individuals with a moderate level of infection, and 28% to 21% in individuals with a mild infection. Evidence-based literature indicates that immune globulin replacement therapy should be considered on an individualized basis for individuals with MM, hypogammaglobulinemia, and proven antibody deficit.^1,3 Evidence-based guidelines indicate that treatment should be considered in individuals with MM and individuals after lymphoma treatment with B cell–depleting therapies when the patients are hypogammaglobulinemic with recurrent bacterial infections and subprotective antibody levels following immunization against diphtheria, tetanus, or pneumococcal infection.³

Hematopoietic Cell Transplantation

A few years ago, IVIG was FDA-approved and utilized for the routine management of allogeneic transplant recipients to avert infections and provide immunomodulation in graft-versus-host disease (GVHD). The National Institutes of Health (NIH) consensus on IVIG endorsed this practice at the time, founded on data from a series of promising studies. However, this recommendation has changed since the arrival of better and less expensive infection-prophylaxis regimens, other beneficial approaches for prophylaxis against GVHD, and subsequent mixed results in larger-scale studies. In this regard, the current gold-standard treatment of acute GVHD with hematopoietic transplantation consists of corticosteroids and calcineurin inhibitors.³

In 2006, the American Academy of Allergy, Asthma & Immunology (AAAAI) expert panel indicated that IVIG may provide benefit for the prevention of infection and acute GVHD post bone marrow transplantation (evidence category Ib) (strength of recommendation A); however, the data did not support a recommendation for use of IVIG in human leukocyte antigen (HLA)–identical sibling bone marrow transplantations. The National Advisory Committee on Blood and Blood Products of Canada and Canadian Blood Services, in organizing a team of national experts to create an evidence-based practice guideline on the use of IVIG for hematologic conditions, rendered a specific recommendation for the use of IVIG in ‘‘acquired hypogammaglobulinemia (secondary to malignancy)’’ though not recommending it in hematopoietic stem cell transplantation. An additional review, in the Cochrane Database, determined that in individuals undergoing bone marrow transplantation, routine prophylaxis with IVIG is not supported.³ Presently, IVIG is not recommended for routine use in the immediate peri-transplantation period for the prevention of infection or GVHD following marrow or peripheral blood allogeneic transplantation.^3,46 Certain patients with chronic GVHD and recurring serious bacterial infections with discernable deficiency in antibody production capacity could benefit from IVIG.³ Some patients with glucocorticosteroid-refractory cytopenias might be candidates for a limited course of IVIG.³ However, IVIG should be considered as contraindicated in the immediate post-transplantation phase in individuals with a history of sinusoidal obstructive syndrome.^3,46 Furthermore, there is insufficient data to make a recommendation for use of IVIG in cord blood stem cell transplantation for children or adults.³

Post-Transplantation Immunoglobulin for Severe Combined Immunodeficiency and Other Primary Immunodeficiencies

Evidence-based guidelines indicate that recipients of hematopoietic stem cell transplants for SCID or other conditions, and who are functionally agammaglobulinemic because of weak B-cell engraftment benefit from immunoglobulin replacement. All infants with SCID should have IVIG administered before transplantation and following transplantation until humoral immunologic reconstitution occurs. Individuals with other PI disorders and nonmalignant conditions should have IVIG administered in accordance with an individualized plan of care in the peri-transplantation phase and post-transplantation phase as established by specialists in the field and in agreement with institutional transplantation center guidelines.³

Solid Organ Transplantation

The initial use of IVIG as a source of passive immunity in immunodeficient individuals has since advanced to its use as an agent with strong immunomodulatory and anti-inflammatory abilities. This advancement has extended the use of IVIG in autoimmunity and systemic inflammatory conditions. In this regard, IVIG has been utilized in solid organ transplant recipients in the last ten years. To this end, sensitization to HLAs or ABO blood group antigens has generally been an impenetrable obstacle to effective transplantation. About 30% of the individuals with end-stage renal disease pending kidney transplantation in the U.S. are considered sensitized because of exposure to blood or tissues from other humans (blood and platelet transfusions, pregnancies, and previous transplantations). Sensitized individuals stay on dialysis and encounter higher morbidity, mortality, and costs than do transplant recipients.³

Increasing Transplantation Rates in Highly Sensitized Patients with IVIG

Some transplantation facilities have modified HLA- and ABO-desensitization protocols to increase transplantation rates in this immunologically disadvantaged group. This modification was founded on studies from the 1990s demonstrating that high-dose IVIG could decrease anti-HLA antibody levels in sensitized individuals and eventually increase transplantation rates. Present protocols involve the use of low-dose IVIG with plasma exchange (PE), or high-dose IVIG with or without B-cell depletion utilizing rituximab. Regardless of this substantial experience, there continues to be no FDA-approved drug for use in desensitization, though IVIG has the most supporting clinical data. In general, the application of IVIG for desensitization has been well accepted, although recent, smaller-scale studies have questioned its effectiveness. Desensitization protocols using IVIG have included patients awaiting heart and lung transplants. However, data to back its use is not as strong as in kidney transplant recipients. One study recently reported on the utilization of high-dose IVIG and high-dose IVIG with rituximab in lung allograft recipients in whom donor-specific HLA antibodies (DSAs) developed following transplantation; these antibodies seem to be a significant risk factor for bronchiolitis obliterans syndrome. Out of 65 individuals who became DSA positive, the subgroup in whom DSAs failed to clear had greater mortality and bronchiolitis obliterans syndrome scores at 3 years. Among the individuals in whom DSAs cleared, the combination of IVIG with rituximab was more effective than with only high-dose IVIG.³

IVIG with Rituximab for Immunomodulation in Sensitized Patients

The application of IVIG with rituximab as a desensitization protocol has been broadly studied. The effectiveness, clinical outcomes, and cost-effectiveness of this protocol contrasted with sustaining individuals on long-term dialysis were recently investigated. Transplantation rates in highly sensitized individuals treated with IVIG and rituximab surpassed the transplantation rates in individuals desensitized with only IVIG, and the utilization of rituximab seemed to have prohibited B-cell memory responses and anti-HLA antibody rebound. Another trial recently demonstrated that the application of IVIG with rituximab and PE was more effective contrasted with IVIG alone in the prevention of long-term antibody-mediated injury to allografts. Ongoing studies of IVIG with rituximab will ultimately define which protocol is most favorable. Evidence-based guidelines indicate that IVIG may provide benefit in the prevention of acute humoral rejection in renal transplantation (evidence category Ib) (strength of recommendation A). Also, evidence shows that IVIG may provide benefit in the treatment of acute humoral rejection in renal transplantation (evidence category III) (strength of recommendation C).³

IVIG in the Treatment of Antibody-Mediated Rejection

Solid organ transplantation is utilized to treat irreversible failure of the kidneys, heart, liver, and lungs. A primary obstacle to organ transplantation is immunologic rejection of the allograft; destruction of the organ by the recipient’s immune system. Antibody mediated transplant rejection (AMR) is a major cause of long-term allograft failure.⁴⁷ While no controlled studies are currently available concerning the most suitable treatments of AMR, the advantages of high-dose IVIG and PE with low-dose IVIG have been well portrayed. In a recent report of a small-scale, retrospective analysis of high-dose IVIG versus PE followed by high-dose IVIG with rituximab for the treatment of AMR, researchers discovered that the combined therapies were more effective contrasted with IVIG alone, with 36-month graft survival being 91.7% versus 50% with long-term suppression of DSA levels. Results from another retrospective study were comparable. Consequently, the current methodology for the treatment of AMR requires a combination of IVIG with rituximab and PE.^3,47

Secondary Hypogammaglobulinemia in Transplant Recipients

The utilization of potent immunosuppressive drugs in transplant recipients can cause a secondary immunodeficiency with hypogammaglobulinemia. This tendency appears to be increasing, particularly in individuals who are given both T cell– and B cell–depleting drugs. Individuals frequently have recurring or multiple infections comparable to those observed in individuals with PI. Following transplantation, individuals should be monitored for hypogammaglobulinemia. Monthly replacement with IVIG is recommended.³

Complications of IVIG Therapy in Transplant Recipients

Preliminary results from a placebo-controlled trial indicate that IVIG was well tolerated and not correlated with escalated adverse events or severe adverse events in highly sensitized patients pending transplantation. Lyophilized products that are hyperosmolar should not be administered following transplantation, as they are apt to trigger osmotic nephropathy and renal failure. Newer, chromatographically derived IVIG drugs are iso-osmolar but might have greater concentrations of anti–blood group antibodies (anti-A, anti-B). These products seem to present an increased risk for hemolysis after high-dose IVIG infusions when individuals are on dialysis. Individuals with blood type A, B, or AB should be monitored carefully for hemolysis following high-dose IVIG therapy.³

Autoimmune Diseases

Immune globulin has been utilized for therapy in many autoimmune disorders. Because this category involves several different autoimmune disorders (e.g., hematologic, neurologic, organ-specific), effectiveness of immune globulin differs. The treatment methodology for these disorders has noticeably changed and advanced with the use of biologic and immunomodulating drugs for therapy.¹

Autoimmune Hemolytic Anemia

An evidence-based treatment for autoimmune hemolytic anemia (AIHA) has not been established. Literature indicates that first-line therapy for warm AIHA is corticosteroids, which are effective in 70-85% of patients and should be slowly decreased over a period of 6-12 months.⁴⁸

For refractory/relapsed cases, the current sequence of second-line therapy is splenectomy (effective in about two out of three cases, but with a presumed cure rate of up to 20%), rituximab, a monoclonal antibody directed at the CD20 antigen express on B cells (effective in about 80-90% of cases), and subsequently any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are IVIG (frequently used alone in AIHA or with prednisone mostly in children possibly due to the proven effectiveness in primary immune thrombocytopenia, and the low rate of adverse effects compared to other therapy options-based on small case series), danazol (a synthetic anabolic steroid with mild androgenic properties), PE, and alemtuzumab with high-dose cyclophosphamide as last resort options. As the study of rituximab progresses, it is likely that this drug will be recommended early in the therapy regimen of warm AIHA, before more toxic immunosuppressants, and in place of splenectomy in some cases. In cold hemagglutinin disease, rituximab is currently recommended as first-line treatment.⁴⁸

Utilization of IVIG provided a good response in five patients with recurrent warm AIHA linked with CLL, the recovery of the hemoglobin levels being quicker when prednisone and high-dose IVIG were used together. In a retrospective study of 73 patients, a response was noted in 40% of cases, only 15% attaining hemoglobin levels of 10 g/dL or greater; children were more apt to respond (54%). Perez et al¹⁰ reported that numerous anecdotal reports establish value for the utilization of IVIG in AIHA. These reports indicate that IVIG should only be used when other treatment approaches have failed.

Systemic Capillary Leak Syndrome

Eo et al¹¹ performed a systematic review to assess the clinical and laboratory data, treatment regimens, and mortality rates of individuals with systemic capillary leak syndrome (SCLS) and to discover influencing aspects leading to mortality. A total of 133 case reports (161 patients) and five case series (102 patients) of idiopathic SCLS were included in the review. The 133 case reports included 161 patients with idiopathic SCLS, the average age was 42.6 + 18.3 years of age and 11.8% were pediatric cases. The ratio of males to females was about 5:4 (89:72). The principal symptoms were hypotension (81.4%), edema (64.6%), previous flu-like illness (34.2%), abdominal pain (24.8%), oliguria (24.8%), fever (24.8%), vomiting (23%), pleural effusion (18%), weight gain (17.4%), and malaise (17.4%). Laboratory findings demonstrated that leukocytosis was noted in 87.1% of patients, polycythemia in 90.6%, hemoconcentration in 93.1%, and hypoalbuminemia in 84.3%. Monoclonal gammopathy was observed in 75.4% of patients. No children (age < 20 years) had monoclonal gammopathy (zero of ten) and the percentage of adults (age > 20 years) with monoclonal gammopathy was 81.9% (95 of 116). A total of 64.2% of patients with monoclonal gammopathy of undetermined significance had immunoglobulin gamma (IgG) kappa paraprotein.¹¹

During the acute phase, patients with SCLS were treated with volume replacement (87%), inotropes (43.5%), steroids (41.3%), IVIG (18.8%), methylxanthines (8.7%), and beta2-agonists (3.6%). Each of the other measures or procedures were used in less than 5% of patients, except continuous renal replacement therapy (5.1%). Of these patients, 23.9% received only one treatment strategy, which was volume replacement in most cases (19.6%); 36.2% received two types of therapy, with about half of them (18.8%) receiving volume replacement plus inotropes; 22.5% received three kinds of therapy; and 17.3% received more than four kinds of therapy with different combinations of treatment.¹¹

To inhibit the recurrence or decrease the frequency of attacks, patients were treated with methylxanthines (72.5%), beta2-agonists (65.9%), IVIG (28.6%), and steroids (14.3%). Each treatment was utilized in less than 5% of patients, except antihistamines (5.5%); 24.2% received one treatment method; 45.1% received two types of treatment, chiefly beta2-agonists plus methylxanthines (35.2%); 23.1% received three types of therapy; and 7.7% received more than four types of treatment.¹¹

Acute renal impairment developed in 62.7% of patients. Rhabdomyolysis developed in 41.3% and 31% were diagnosed with compartment syndrome; additionally, fasciotomies had to be performed in 64% of those patients and 7.9% of patients with SCLS suffered from neuropathy. Pulmonary edema developed in 26.2% of patients and 10.3% of patients went into cardiac arrest. Ischemic stroke and multiorgan failure developed in 4% and disseminated intravascular coagulation (DIC) in 3.2%.¹¹

There were five case series (102 patients) included in the systematic review that reported age, sex, treatments, and outcome of patients. The median age at onset for the idiopathic SCLS ranged from 44 to 52 years and average age at diagnosis ranged from 43.2 to 52.9 years and average time to diagnosis from symptom onset ranged from seven to 13 months. Fifty-nine cases were males and 43 were females. Seventy-one of the 102 patients (70%) received beta2-agonists and/or methylxanthines and 45 (44%) received IVIG. Median follow-up duration ranged from 37 to 84 months and 19 patients (19%) died.¹¹

Findings of this systemic review demonstrate that SCLS is characterized by recurrent shock, hemoconcentration, and hypoalbuminemia. Patients had hypotension (81.4%), edema (64.6%), and previous flu-like illness (34.2%). This disorder was misdiagnosed as hypovolemic shock, septic shock, polycythemia vera, or angioedema. Thirty-seven patients died (23%) primarily because of SCLS itself (78.4%). There were substantial differences in the survival rates between patients treated with prophylactic beta2-agonists, methylxanthines, and IVIG, and those who were not. The estimated one, five, and ten-year survival rate of patients treated with IVIG was 100%, 94%, and 94%, respectively. The use of IVIG and theophylline may be treatment options during the acute phase. The results of this review propose that prophylactic use of IVIG is the most effective treatment in decreasing the mortality rate among agents used empirically; therefore, IVIG is recommended as first-line therapy for patients with SCLS irrespective of age or the presence of monoclonal gammopathy.¹¹

Xie et al¹³ assessed IVIG prophylactic therapy in a longitudinal follow up study that included a cohort of 29 adult patients with SCLS from 2008 to 2014. Of the 29 patients, 22 patients completed and returned a questionnaire that recorded symptoms starting with their first documented episode of SCLS. Of these 22 patients, 18 patients received monthly prophylaxis with IVIG for an average of 32 months during the study period with minimal side effects (e.g., transient headache, rash, and fatigue). The average annual SCLS occurrence was 2.6 per patient before IVIG therapy and zero per patient after beginning IVIG prophylaxis (P = 0.001). Of the 18 patients, 15 patients with a history of one or more acute SCLS episodes had no further symptoms while on IVIG therapy. The ideal dose, schedule, and duration of IVIG therapy have not been established. While most patients (78%) received 2 g/kg/month, three patients remained episode-free for greater than two years on 1-1.25 g/kg/month.

The average age of SCLS onset was 46 years of age (range 32-66 years) and an official diagnosis was not made for > two years following the initial episode in 41% of patients. Complications of SCLS were common; compartment syndrome/fasciotomies/limb amputation (50%), sensorimotor neuropathy/foot drop (33%), renal failure (14%), thrombosis/pulmonary embolism (14%), and pericardial effusion/tamponade (9%). The conclusion for this study indicates IVIG prophylaxis is correlated with a significant decrease in SCLS episodes in most patients with minimal side effects. This study was limited due to its small sample size, its retrospective method, and dependence on historical data. The rareness of this disorder, its unpredictable course, and the devastating complications of SCLS episodes render the possibility of a randomized, placebo-controlled study doubtful.¹³

Immunoglobulin in Autoimmune Neurologic Conditions

Some efficacy has been shown for IVIG therapy in several disorders of the peripheral and central nervous systems.

Demyelinating Peripheral Neuropathies

Two neurologic indications have recently been FDA-approved for treatment with immune globulin; chronic inflammatory demyelinating polyneuropathy (to improve neuromuscular disability and impairment, and for maintenance therapy to prevent relapse) and multifocal motor neuropathy (as maintenance therapy to improve muscle strength and disability in adult patients).^3-4

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is usually treated with a blend of IVIG, corticosteroids, and PE. Results of randomized clinical trials (RCTs) have implied that IVIG begun within 14 days of the onset of GBS symptoms hastens recovery similar to PE (PE is deemed superior to supportive care alone). However, studies have found that patients are more likely to complete the IVIG therapy as opposed to PE due to its convenience and availability, as well as less adverse effects. Evidence-based guidelines indicate that IVIG is definitely beneficial for the treatment of GBS (evidence category Ib) (strength of recommendation B).¹ Intravenous immunoglobulin is equal in effectiveness as plasmapheresis and is recommended for treatment of GBS in adults (strength of recommendation A).¹⁵

Data from the first large-scale, randomized, open-label, controlled trial of IVIG (0.4 g/kg/day for five days) versus PE suggested that the clinical outcomes were comparable. A multicenter, randomized, blinded, controlled trial including 383 patients from Europe, Australia, and North America showed no substantial variances in mean disability grade between individuals treated with PE, IVIG, or PE followed by IVIG. In a multicenter, randomized, double-blind, placebo-controlled trial that included 233 patients, adding methylprednisolone (0.5 g/day for five days) following a course of IVIG did not show a substantial benefit. Many other studies that have contrasted IVIG to supportive measures or PE in children and adults demonstrated comparable results; however, patients were not always randomized, and investigators were not blinded to the therapies. A systematic review of data from randomized studies showed no substantial variances in any of the outcome measures between IVIG and PE. None of the therapies substantially decreased mortality. Several Cochrane reviews have offered moderate quality evidence that, in severe disease, IVIG started within two weeks from onset accelerates recovery similar to PE. Adverse events did not occur substantially more with either treatment, but IVIG was significantly more likely to have been completed than was PE. Giving IVIG after PE did not demonstrate substantial additional benefit. The use of IVIG may accelerate recovery in children compared with supportive care alone. Evidence is insufficient to support or refute the use of IVIG in children with GBS.^3,14

Further research is needed in mild disease and in individuals whose treatment is started > two weeks after onset. Dose-ranging trials are also necessary. The risk for thromboembolic complications with IVIG is not negligible in individuals with neuropathy, particularly with daily doses > 35 g. The age of the individual, the presence of preceding diarrhea, and the seriousness of disability in the initial course of disease were correlated with poor response to IVIG in one study. New therapy approaches are under investigation with adapted IVIG dosages founded on prognostic factors.³

Autoimmune Neuromuscular Junction Syndromes

Utilization of IVIG has been assessed in the treatment of myasthenia gravis and Lambert-Eaton myasthenic syndrome.³

Myasthenia Gravis

Sanders et al¹⁷ provides international consensus guidance for management of myasthenia gravis (MG). This evidence-based guideline recommends pyridostigmine, a synthetic acetylcholinesterase inhibitor, be used as part of the initial treatment in most individuals with MG. In addition, corticosteroids or immunosuppressive therapy is recommended in all individuals with MG who have not met treatment goals after an adequate trial of pyridostigmine. Nonsteroidal immunosuppressive drugs, such as azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, and tacrolimus may be used if corticosteroids are contraindicated or may be used in conjunction with corticosteroids if the risk of steroid side effects is high based on comorbidities. The use of IVIG or PE is recommended for the following: 1) refractory MG, 2) short-term therapy during life-threatening situations such as respiratory insufficiency or dysphagia, 3) preparation for surgery in individuals with substantial bulbar dysfunction, 4) a rapid response to therapy if needed, 5) when other treatments have failed, and 6) before starting corticosteroids if needed to prevent or minimize exacerbations. Intravenous immunoglobulin and PE may be equivalent for the treatment of severe generalized MG.¹⁷

The benefit in MG using IVIG was similar to the benefit of PE in two randomized, comparative trials, with a reduction in the acetylcholine receptor antibody concentration in one trial and a reduction in the quantified MG clinical score in the other trial. In the older study, patient tolerance of IVIG was typically better than for PE. Class I evidence that IVIG and PE have similar effectiveness and are comparably tolerated in adult patients with moderate to severe MG within two weeks of therapy was recently reported, and the only element predicting response to therapy was baseline disease severity. Nonetheless, a randomized, placebo-controlled trial was unable to show a substantial effect after six weeks of IVIG therapy. Older studies showed IVIG was of possible benefit in myasthenic crises, juvenile myasthenia, and in preparing myasthenic patients for surgery.³

In exacerbation of MG, one RCT of IVIG versus placebo demonstrated some evidence of the effectiveness of IVIG, and two did not illustrate a substantial difference between IVIG and PE. Another indicated no considerable variance in effectiveness between 1 and 2 g/kg of IVIG. An additional underpowered study revealed no substantial difference between IVIG and oral methylprednisolone. A retrospective chart review of data for 53 patients with muscle-specific kinase antibody–positive MG at nine university-based centers in the U.S. demonstrated the best clinical response was to corticosteroids and PE, and the worst response was to IVIG. In chronic MG, there is inadequate evidence from RCTs to establish whether IVIG is effective.³ Literature indicates that IVIG is recommended as a rescue therapy in patients with worsening myasthenia gravis.² Evidence-based guidelines indicate that IVIG is probably beneficial for the treatment of moderate to severe MG (evidence category Ib) (strength of recommendation B).^3,15

A meta-analysis review¹⁶ was performed to evaluate the effectiveness of IVIG in the treatment of acute exacerbations of MG or for chronic long term, persistent MG. Seven RCTs were found, all of which evaluated short-term effectiveness. These trials vary in inclusion criteria, comparison with alternative treatment, and outcomes. In one trial contrasting IVIG with placebo, 51 study participants had worsening MG, the mean difference (MD) in the quantitative MG score (QMGS) (MD 95% CI) after 14 days was 1.60 (95% CI - 3.23 to 0.03); this result was borderline statistically substantial in support of IVIG. In an unblinded trial of 87 study participants with exacerbation contrasting IVIG and PE there was no difference in myasthenic muscle score (MMS) after 15 days of treatment (MD -1.00; 95% CI -7.72 to 5.72). In a trial of 84 study participants with worsening MG there was no difference in change in QMGS 14 days after IVIG or PE (MD -1.50; 95% CI -3.43 to 0.43). In a trial of 12 study participants with moderate or severe MG, which was at high risk of bias from skewed allocation, the mean fall in QMGS for both IVIG and PE after four weeks was significant (P < 0.05). A trial with 15 study participants with mild or moderate MG discovered no difference in QMGS 42 days after IVIG or placebo treatment (MD 1.60; 95% CI -1.92 to 5.12). A trial comprised of 33 study participants with moderate exacerbations of MG demonstrated no difference in QMGS 14 days after IVIG or methylprednisolone treatment (MD -0.42; 95% CI -1.20 to 0.36). All three of these smaller studies were underpowered. The last trial that included 168 study participants with exacerbations, demonstrated no evidence of superiority with IVIG 2 g/kg over IVIG 1 g/kg on the modification of MMS after 15 days (MD 3.84; 95% CI -0.98 to 8.66). Adverse events associated with IVIG, which were noted in all trials were moderate (fever, nausea, headache), self-limiting and subjectively less severe than with PE (although, given the available data, no statistical comparison was possible). In general, the studies were at low risk of bias; however, the methodological quality of these studies was questionable at times.

For severe worsening MG or for exacerbation, one RCT comparing IVIG versus placebo demonstrated some evidence of the effectiveness of IVIG and two RCTs did not demonstrate a substantial difference between IVIG and PE. Another RCT demonstrated no substantial difference in effectiveness between 1 g/kg and 2 g/kg of IVIG. A further, but underpowered study demonstrated no substantial difference between IVIG and oral methylprednisolone. There is inadequate evidence from RCTs to determine whether IVIG is effective for chronic (moderate or severe but stable) MG.¹⁶

Lambert-Eaton Myasthenic Syndrome

Limited but moderate- to high-quality evidence from RCTs has indicated that 3,4-diaminopyridine over three to eight days or IVIG for up to eight weeks was correlated with better muscle strength scores and compound muscle action potential amplitudes in study participants with Lambert-Eaton myasthenic syndrome (LEMS). In one trial, eight of nine patients showed clinical improvement within two to four weeks of IVIG infusion, although it worsened after eight weeks, associated with a rebound of serum calcium channel antibody concentrations. A comparable response and absence of serious adverse events have been conveyed in other case reports and uncontrolled trials. The use of IVIG appears to have a positive short-term effect in LEMS (recommendation level based on good practice point). Evidence-based guidelines indicate that IVIG is probably beneficial for the treatment of LEMS (evidence category Ib) (strength of recommendation B). Utilization of IVIG is recommended as an alternative treatment in patients who fail to respond or do not tolerate other treatments of LEMS.³

Immune-Mediated Diseases of the Central Nervous System

Utilization of IVIG has been assessed in the treatment of multiple sclerosis, neuromyelitis optica, stiff-person syndrome, autoimmune encephalitis, and Susac syndrome.

Multiple Sclerosis

Three randomized, double-blind, placebo-controlled trials have shown some benefit of IVIG therapy in decreasing exacerbations of multiple sclerosis (MS). Combining the data from these trials, 34% of IVIG recipients had decreased exacerbations versus 15% of placebo recipients. The largest trial (148 participants) showed that IVIG (0.15-0.2 g/kg monthly for two years) was linked with decreased clinical disability. When higher doses were undertaken (1 g/kg/day for two days at four-week intervals), 65% (of 25 patients) had no exacerbations in six months versus 35% of the control group. Nonetheless, its effectiveness noticeably trails behind that of b-interferon due to smaller study samples, partial deficits in study design, and undetermined optimal dosage. One RCT determined that providing IVIG therapy in the first year from onset of the first neurologic event implied demyelinating disease considerably reduced the occurrence of a second attack and decreased disease activity. A meta-analysis of data from 265 individuals showed substantial decreases in the disability score (Expanded Disability Status Scale), annual relapse rate, proportion of patients who deteriorated, and new lesions per magnetic resonance imaging (MRI). Treatment with IVIG was reported to be effective in five patients with CIDP associated with definite relapsing MS.

A multicenter, randomized, placebo-controlled study determined that monthly IVIG infusion could postpone the progression of disease in individuals with primary progressive MS. However, IVIG does not appear to be effective in improving chronic visual symptoms or established weakness and has not exhibited a substantial effect on the course of illness in secondary progressive MS. A multicenter, randomized, double-blind, placebo-controlled study that involved 127 patients with relapsing-remitting MS did not demonstrate a beneficial effect of IVIG at doses ranging from 0.2 to 0.4 g/kg. More recently, an IVIG dose of 0.4 g/kg/day for five days did not demonstrate inferiority contrasted with IV methylprednisolone in the treatment of an acute MS relapse utilizing both clinical and MRI assessment.

Evidence demonstrates that IVIG should be considered a potentially effective second-line treatment in relapsing-remitting MS. However, the optimum dosage remains undetermined. Evidence-based guidelines indicate that IVIG may provide benefit in the treatment of relapsing-remitting MS (evidence category Ia) (strength of recommendation A).³

Neuromyelitis Optica

Use of IVIG therapy may be beneficial in treating neuromyelitis optica (Devic syndrome), an idiopathic CNS inflammatory demyelinating disease (causing optic neuritis, transverse myelitis, and other central nervous system syndromes) which is linked with autoantibodies against the astrocyte water channel called aquaporin-4. There are no RCTs of first-line therapies using IVIG for neuromyelitis optica. Relapse is generally inhibited using azathioprine, mycophenolate mofetil, or rituximab, founded on retrospective and prospective open-label trials only. Prevention of relapse was investigated in a prospective, open-label, uncontrolled observational trial assessing the tolerability and clinical effects of IVIG in neuromyelitis optica spectrum disorders and showed statistically noteworthy reductions in relapse rate, from 1.8 in the previous year to 0.006 during follow-up, and in Expanded Disability Status Scale score, which dropped from 3.3 to 2.6. In relapse treatment, this and other anecdotal reports propose that IVIG might be considered in individuals with severe relapses not responding to corticosteroids, who are not candidates for PE.³

Stiff-Person Syndrome

Stiff-person syndrome (SPS) is a rare and disabling autoimmune disorder of the CNS distinguished by muscle rigidity, episodic muscle spasms, and antibodies to glutamic acid decarboxylase 65.² In a double-blind, placebo-controlled study in individuals with SPS and increased anti–glutamate decarboxylase antibodies, IVIG was linked with improvement in stiffness and improved sensitivity scores and progress in patients’ ability to perform daily activities. The IVIG therapy was also correlated with suppressed anti–glutamate decarboxylase antibody concentrations, probably via an anti-idiotypic effect.³ In a placebo-controlled, crossover study, IVIG substantially reduced stiffness scores, and significantly increased walking and functions of daily activities, concluding that IVIG is an effective therapy in SPS. Literature indicates that IVIG is beneficial as a second-line therapy for SPS.² Evidence-based guidelines indicate that IVIG is probably beneficial for the treatment of SPS (evidence category Ib) (strength of recommendation B).³

Autoimmune Encephalitis

While there are no established guidelines available for treatment of autoimmune encephalitis (AE), peer-reviewed literature regarding clinical experience, retrospective series and expert opinion indicates that once infection is ruled out based on basic cerebrospinal fluid (CSF) results (e.g., number of cells) and if biopsy for primary CNS lymphoma or neurosarcoidosis is not a consideration, acute immunotherapy with high dose corticosteroids is recommended (or IVIG or plasma exchange if steroids are not preferred or are contraindicated). If there is no clinical response, rituximab and cyclophosphamide are used. A recent randomized blinded study showed IVIG efficacy over placebo in controlling seizures in a small number of patients with LGI1-antibody and CASPR2-antibody AE.^23-27

Susac Syndrome

Susac syndrome is a rare disorder characterized by hearing loss, encephalopathy, and branch retinal artery occlusions. Currently, there are no established guidelines for treatment of Susac syndrome. The majority of recommendations for therapy are attained from anecdotal reports and clinical experience which shows that aggressive and timely first-line treatment with high-dose intravenous corticosteroids (followed by oral steroids) and simultaneous use of IVIG has shown significant effectiveness.²⁸

Rheumatic Diseases

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous category of autoimmune diseases, chiefly described by inflammation of the skeletal muscles, but also commonly involve internal organs such as the lungs, heart, and esophagus.²⁹

Autoimmune Inflammatory Myopathies

Inflammatory disorders of the skeletal muscle involve polymyositis (PM), dermatomyositis (DM), (immune mediated) necrotizing myopathy (NM), overlap syndrome with myositis (overlap myositis [OM]) including anti-synthetase syndrome [ASS], and inclusion body myositis [IBM]). These inflammatory myopathies are referred to briefly as myositis.

Individuals with myositis usually respond to immunosuppressive therapy, whereas IBM is largely refractory to treatment. Glucocorticosteroids are the foundation of the treatment for PM, DM, NM, and OM. Also, long-term immunosuppression should be started with the steroid, unless only a very moderate disease course is present. Immunosuppressants include methotrexate, azathioprine or mycophenolate mofetil. A Cochrane analysis compared all available clinical studies with these and other agents in myositis and could not identify any significant effectiveness. However, in view of a variety of case series and expert experience and given the known pathogenesis of the disorders, it is an international consensus to use glucocorticosteroids as well as immunosuppressants for treatment of myositis in an off-label fashion. If treatment with glucocorticosteroids and immunosuppressants is unsuccessful, oral ciclosporin or IVIG is recommended. Ciclosporin (cyclosporine A, CsA) (or its modified drug tacrolimus) is an effective immunosuppressant that can be used either as a replacement or in combination with other immunosuppressive drugs. Several clinical studies and case series utilizing IVIG as an alternative or add-on therapy in the treatment of myositis have demonstrated effectiveness, especially for DM and NM. Individualized dosing should be determined during the treatment cycles, depending on the effectiveness of the IVIG and how it is tolerated. Possible side effects include allergic reactions, headache, fever, thrombosis, and hemolysis, which may be linked to the dose and infusion rate. If standard immunosuppression and IVIG are not adequate, rituximab or cyclophosphamide should be considered. In a recent study, 200 juvenile and adult patients with myositis were treated with rituximab. While the primary endpoint was not reached, likely due to the study design, the overall reaction to rituximab is largely interpreted as successful given that most of the patients clearly improved.²⁹

Several clinical studies utilizing the standard immunosuppressive regimen with glucocorticosteroids and immunosuppressants have failed to demonstrate improved muscle strength in IBM and are therefore not recommended.²⁹ Evidence-based guidelines³ indicate that IVIG is unlikely to be beneficial for treatment of this disorder (evidence category Ib) (strength of recommendation B). However, three placebo-controlled clinical trials evaluated IVIG in IBM over three to six months; two of the studies noted a small increase in swallowing function. Utilization of IVIG was also assessed in several uncontrolled case-series, which demonstrated an improvement of dysphagia and muscular weakness. However, all clinical IVIG studies did not achieve their primary outcome, possibly because of the short duration of the studies (three months in two studies and six months in one study), which prevents a reliable conclusion for the use of IVIG in IBM to be reached. Nonetheless, because of the positive case series in this devastating disorder, treatment with IVIG seems to be justifiable in such patients. Naddaf et al³² recommends consideration of IVIG treatment for individuals with IBM with significant dysphagia. Also, Barsotti et al³³ indicates that patients with IBM who suffer with dysphagia and are otherwise treatment-resistant should be considered for treatment with IVIG.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease which is prone to relapses and remissions. This disease can be fatal and substantially increases the risk of cardiovascular disease. A retrospective study for individuals with SLE demonstrated a transient clinical improvement in 65% of individuals treated with IVIG. Case reports demonstrate that patients who were given high-dose IVIG treatments achieved disease resolution for SLE affecting specific organs, including lupus nephritis, lupus myocarditis, polyradiculopathy, lupus-induced bone marrow suppression, and lupus-induced multiorgan disease. Vigilant utilization of high-dose IVIG is always recommended in individuals with SLE, as well as other disorders (especially neurologic disorders), due to possible prothromboembolic effects. While there is the potential for adverse effects with high-dose IVIG, since high-dose infusions of IVIG seem to be useful in patients with severe, life-threatening SLE and/or its complicating morbidities, guarded use with careful monitoring to diminish the risks for some of these concerns is recommended. Evidence-based guidelines indicate that IVIG may provide benefit in the treatment of SLE (evidence category III) (strength of recommendation D).¹⁰ Enk et al³⁰ provided European guidelines on the use of high-dose IVIG in dermatology and recommends the use of IVIG for all severe cases of SLE provided no other treatment options exist. Additionally, the use of IVIG for the treatment of SLE with lupus nephritis is considered effective. Utilization of IVIG is usually not a first-line treatment option. Previous combination treatment with steroids and another immunosuppressive agent correlated with a poor response or severe complications is considered an indication for the use of IVIG, which should be given with adequate immunosuppressive therapy.

Use of IVIG in Rare Conditions with Few or No Therapeutic Alternatives

The effectiveness of IVIG has been assessed in several conditions that have been suggested to result from an aberrant immunologic response. Many of these conditions have few or no therapeutic alternatives and deserve consideration of IVIG therapy based on the available evidence.³

Nonatopic Dermatologic Disorders

Autoimmune Blistering Skin Diseases

The blistering skin diseases category of autoimmune disorders comprises pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid (also referred to as cicatricial pemphigoid), epidermolysis bullosa acquisita, and variations that can cause severe complications and even death. A single, randomized, placebo-controlled trial (2009) that included 61 study participants showed a benefit of IVIG in individuals with poor response to corticosteroids. A review of data from > 200 additional individuals included in anecdotal reports and case series indicated a benefit of IVIG in 94% of treated individuals. Case reports and series extend to pregnant, adolescent, and infant patients.^3,30 A consensus statement from the American Academy of Dermatology regarding the utilization of IVIG in blistering skin diseases is conservative due to the absence of high-quality studies (this statement predates the single, randomized trial and the literature review noted above). The consensus document provides a guideline on the indications of IVIG, including failure of conventional treatment with prednisone for six weeks, failure of treatment with immunosuppressive agents, a history of adverse reaction to corticosteroids or immunosuppressive agents, progressive disease, and uncontrolled rapid progression of disease, and recommends monthly IVIG treatment, with a gradual increase in the intervals between the cycles after control has been attained. Per a recent review,³⁴ IVIG effectively reduces the levels of pathogenic autoantibodies and is best utilized as adjuvant therapy concurrently with an immunosuppressive agent. In patients who are refractory to IVIG and immunosuppressants, rituximab has been included, but its function in immunobullous disease necessitates additional research. Evidence-based guidelines³ indicate that IVIG may provide benefit for the treatment of autoimmune blistering skin diseases (evidence category III) (strength of recommendation C).

The goal of most therapies for these conditions is to improve symptoms by decreasing serum autoantibodies, either directly or through generalized immune suppression. Published guidelines for therapy generally rely on expert consensus, given the paucity of randomized clinical studies with large sample sizes and rigorous randomization techniques. Corticosteroids are recommended as first-line therapy and steroid-sparing immunosuppressive agents and IVIG are recommended for patients with severe or refractory conditions requiring adjunctive treatments.^35-38

Enk et al³⁰ provided European guidelines on the use of high-dose IVIG in dermatology and recommends utilization of IVIG for all severe forms of autoimmune blistering diseases that are refractory to therapy or relapsing after therapy. However, contraindications to standard immunosuppressive therapy may warrant utilization of IVIG as first-line therapy in unique cases. Therefore, immunoglobulins should mainly be used as a second-line therapy following appropriate combination therapy with steroids and another immunosuppressive agent. IVIG should be given while continuing the conventional immunosuppressive therapy. The use of IVIG may also be considered in patients treated with rituximab who fail to attain satisfactory disease control. Monotherapy with IVIG is usually not recommended.

Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

Some case reports, as well as prospective and retrospective, multicenter studies have demonstrated that prompt administration of high-dose IVIG for patients with toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) aided to stop the advancement of disease and decrease fatality. Most patients were treated with IVIG in combination with other drugs, such as corticosteroids. A more recent and relatively large-scale (65 individuals), retrospective study of IVIG (with corticosteroids) for these disorders also demonstrated a tendency for quicker resolution and decreased mortality, though outcomes were not statistically noteworthy. A recent systematic review and meta-analysis of 17 trials indicated an insignificant inclination for decreased mortality with IVIG therapy for TEN and determined that the current evidence does not support a clinical benefit of IVIG and that randomized clinical studies are required. However, evidence-based guidelines indicate that IVIG is probably beneficial for the treatment of TEN and SJS (evidence category IIa) (strength of recommendation B).³

Scleromyxedema

The body of evidence on effective treatment of scleromyxedema with IVIG has significantly expanded since the first report of efficacy in 2000. In this regard, use of IVIG is recommended for treatment of all severe cases of scleromyxedema. Utilization of IVIG is considered the therapy of choice for refractory cases of scleromyxedema with either fast deterioration of skin symptoms, the dermato-neuro syndrome or life-threatening involvement of internal organs. Enk et al³⁰ provided European guidelines on the use of high-dose IVIG in dermatology and indicates that scleromyxedema is refractory to most standard immunosuppressive therapies, but responds quickly to treatment with IVIG, as reported in many case reports and in small case series. For milder cases, initial treatment with immunosuppressive regimens should be undertaken with failure to respond or contraindications to such treatments warranting initiation of treatment with IVIG. In scleromyxedema no additional treatments are needed besides IVIG. If severe, life threatening relapses should occur, long-term therapy may be needed in unique cases.^30,40-41

Thyroid Eye Disease

Thyroid eye disease (TED) is also referred to as Graves’ ophthalmopathy, Graves’ orbitopathy or thyroid-associated ophthalmopathy. In more severe disease, corticosteroids have been the primary treatment; however, IVIG has been correlated with fewer adverse effects and might be a better option in some individuals. Also, B-cell depletion with rituximab is emerging as an alternative, particularly in severe disease, as it effectively reduces autoantibodies. Multispecialty management, involving endocrinology and ophthalmology, is recommended because of other therapy approaches available, depending on severity, including radiation and surgical decompression.

Recently, a RCT contrasting rituximab with methylprednisone showed a better clinical response with rituximab, supporting the results from other preliminary trials in the use of rituximab for Graves’ ophthalmopathy. A previous randomized trial for individuals with active Graves’ ophthalmopathy compared systemic corticosteroids to six courses of IVIG at 1 g/kg for two consecutive days every three weeks. Both treatment methods were equally effective, but the adverse effects were more frequent and serious in the corticosteroid-treated group. In a separate case report, IVIG demonstrated more effectiveness contrasted with systemic corticosteroids in controlling Graves’ ophthalmopathy. In milder disease, treatment involves addressing the underlying hyperthyroidism, and symptomatic care. Evidence-based guidelines indicate that IVIG is definitely beneficial in the treatment for Graves’ ophthalmopathy (evidence category Ib) (strength of recommendation A).³

The Treatment of Graves’ Orbitopathy to Reduce Proptosis with Teprotumumab Infusions in an Open-Label Clinical Extension Study (OPTIC-X) is a teprotumumab treatment and re-treatment trial following the placebo-controlled teprotumumab Phase 3 Treatment of Graves’ Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study (OPTIC) trial. The OPTIC-X trial assessed the safety and effectiveness of teprotumumab therapy and re-treatment in patients from the double-masked OPTIC trial which provided additional information regarding patients with longer disease duration, re-treatment effectiveness in initial non-responders or those who undergo disease flare, and additional safety assessments. The OPTIC-X trial included patients who previously received a placebo (n = 37) or teprotumumab (n =14) in the OPTIC trial. The primary outcome measure was the proptosis responder rate at week 24 from entry into the trial. The secondary outcome measure was the percentage of patients with a clinical activity score (CAS) of 0 or 1 (disease inactivation) at week 24, mean change to week 24 in proptosis (in millimeters), diplopia responder rate, and average change to week 24 in Graves’ ophthalmopathy-specific quality-of life (GO-QOL) questionnaire aggregate score.^43-44

When treated with teprotumumab in OPTIC-X, 33 of the 37 placebo-treated OPTIC patients (89.2%) became proptosis responders (mean + standard deviation, -3.5 + 1.7 mm). Patient responses were comparable to the OPTIC trial. In these patients, proptosis, CAS of 0 or 1, and diplopia responses were sustained in 29 of 32 patients (90.6%), 20 of 21 patients (95.2%), and 12 of 14 patients (85.7%), respectively, at week 48 for follow-up. The average TED duration was 12.9 months versus 6.3 months in patients treated with teprotumumab in the OPTIC trial. Of the five OPTIC teprotumumab non-responders re-treated in OPTIC-X, two patients responded, one demonstrated a proptosis decrease of 1.5 mm from OPTIC baseline, and two patients withdrew from the trial. Of the OPTIC teprotumumab patients who experienced flare, five of eight (62.5%) responded when re-treated (mean proptosis reduction, 1.9 + 1.2 mm from OPTIC-X baseline and 3.3 + 0.7 mm from OPTIC baseline). Adverse events included mild hearing impairment; four events occurred during the first course of treatment, and two events reoccurred after retreatment.

The study demonstrated that patients who had a longer duration of disease (previous placebo patients in the OPTIC study) responded comparably to patients treated with teprotumumab in the phase 2 and phase 3 (OPTIC) studies and no additional safety issues were noted. The authors of the study concluded that the results of this trial add to the previous trials which have indicated that teprotumumab has disease-modifying activity and durability in patients with TED.⁴⁴

Teprotumumab, a recombinant, human immunoglobulin G1k monoclonal antibody received FDA-approval on January 21, 2020, for the treatment of TED. Teprotumumab (Tepezza^®) is currently the only FDA-approved therapy for this condition.^42,45

Subcutaneous Immunoglobulin

As in IVIG therapy, subcutaneous immune globulin (SCIG) administration should be individualized for each patient. Currently, SCIG therapy is FDA-approved for use in the treatment of PI diseases and CIDP only. Many studies have shown that SCIG and IVIG therapy are equivalent for managing PI diseases, and noninferiority has been a standard prerequisite of FDA approval. Outcome measures in patients receiving reduced doses of SCIG contrasted with IVIG are not available, with the exception of hospitalization, which was 30% higher in those receiving the reduced dose.³

Consultation Summary

N/A

For more than 20 years, IVIG has been used in the treatment of a wide range of primary and secondary immunodeficiencies. Utilization of IVIG now represents a standard therapeutic option for many antibody deficiencies. Immune globulin is progressively identified as a therapy for an assortment of disorders for its capacity in combating infection as a replacement therapy and for its anti-inflammatory and immunomodulating effects. The proper utilization of immunoglobulin can be lifesaving.

The prudent and efficient utilization of IVIG involves consideration of several concerns associated to both the IVIG product and the patient. The administration of IVIG, the diagnosis, and management of adverse events are complex and require expert practice. It is vital for the prescribing provider to carefully evaluate and monitor patients receiving IVIG for therapy to be optimized.

Most IVIG adverse reactions are rate-related, are mild, and occur in only 5-15% of infusions. They are normally described as back or abdominal pain, nausea, breathing difficulties, chills, flushing, rash, anxiety, low-grade fever, arthralgia, myalgias, and/or headache. More serious adverse events include acute renal failure, neurodegeneration, and thromboembolic events, such as myocardial infarction (MI), stroke, deep vein thrombosis, and pulmonary embolism. These adverse reactions are very rare and are more likely to occur in individuals receiving larger doses of IVIG but have been reported in patients with PIs. Rare but potentially serious or life-threatening adverse events are reported during or within days following IVIG infusions, particularly thromboembolic events (including transient ischemic attack [TIA], stroke and MI), acute renal dysfunction and/or failure, and acute hemolysis. While certain causes and risk factors have been identified in specific products at specific times, FDA requires a “Black Box Warning” about potential thromboembolic and renal adverse effects on all pooled, plasma-derived IgG products.⁴⁷ Risk factors for these reactions include preexisting cardiovascular disease, diabetes mellitus, dehydration, age > 65 years, sepsis, paraproteinemia, increased blood viscosity, hypercholesterolemia, and hypertension.

To date, immune globulin has been licensed by the FDA for the following indications: 1) treatment of primary immunodeficiencies (PIs); 2) prevention of bacterial infections in patients with hypogammaglobulinemia and recurrent bacterial infection due to B-cell chronic lymphocytic leukemia (CLL); 3) prevention of coronary artery aneurysms in Kawasaki disease; 4) increasing platelet count in idiopathic thrombocytopenic purpura (ITP) to prevent or control bleeding; 5) treatment of chronic inflammatory demyelinating polyneuropathy (CIDP); 6) multifocal motor neuropathy (MMN); and 7) dermatomyositis (DM). For specific details relating to a given indication, providers should refer to the prescriber information for the specific immune globulin product⁴: https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/immune-globulins.

Evidence-based guidelines show that IVIG replacement therapy has been beneficial and is recommended in the following conditions/situations that lead to a secondary humoral deficiency: 1) Multiple myeloma and after lymphoma treatment with B cell–depleting therapies for recurrent infections with hypogammaglobulinemia and subprotective antibody levels following immunization against diphtheria, tetanus or pneumococcal infections, 2) Recipients of hematopoietic stem cell transplants for SCID or other primary immunodeficiency conditions who are functionally agammaglobulinemic because of weak B-cell engraftment, 3) Recipients of allogeneic hematopoietic stem cell transplants with chronic graft versus host disease, recurring bacterial infections, and subprotective antibody levels following immunization against diphtheria, tetanus or pneumococcal infections, 4) HLA and ABO desensitization protocols for the prevention of acute humoral rejection in renal transplantation, 5) The treatment of antibody mediated solid organ transplant rejection in combination with rituximab and plasma exchange, and 6) The treatment of hypogammaglobulinemia in solid organ transplants.

Evidence-based guidelines demonstrate support for immune globulin replacement therapy and recommend IVIG in the following autoimmune disorders: 1) Guillain-Barré syndrome (GBS) in adults, 2) Autoimmune hemolytic anemia (AIHA) when other treatment approaches have failed, 3) Systemic capillary leak syndrome (SCLS), 4) Moderate to severe myasthenia gravis (MG), 5) Lambert-Eaton myasthenic syndrome (LEMS) in individuals who fail to respond or do not tolerate other treatments, 6) Relapsing-remitting multiple sclerosis (MS), 7) Neuromyelitis optica in individuals with severe relapses not responding to corticosteroids and are not candidates for PE, 8) Stiff-person syndrome, 9) Severe forms of polymyositis resistant to treatment with glucocorticosteroids and immunosuppressants, 10) Severe forms of inclusion body myositis with dysphagia and individuals are otherwise treatment-resistant, 11) Immune mediated necrotizing myopathy resistant to treatment with glucocorticosteroids and immunosuppressants, 12) Overlap syndrome with myositis including anti-synthetase syndrome resistant to treatment with glucocorticosteroids and immunosuppressants, 13) Severe systemic lupus erythematosus (SLE) in individuals who fail to respond or do not tolerate other treatments, and 14) Biopsy-proven autoimmune mucocutaneous blistering diseases in individuals who fail to respond or do not tolerate other treatments and individuals with rapidly progressive disease requiring a quicker response than conventional therapy (i.e., pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid (also referred to as cicatricial pemphigoid), and epidermolysis bullosa acquisita).

Evidence-based guidelines also recommend IVIG replacement therapy for the following rare conditions: 1) Toxic epidermal necrolysis, 2) Stevens-Johnson syndrome, 3) Severe scleromyxedema, and 4) Thyroid eye disease in patients who have failed treatment with teprotumumab or have contraindications to the use of teprotumumab.

Peer-reviewed medical literature lends support for IVIG replacement therapy for the following rare conditions: 1) Treatment of autoimmune encephalitis, once infection is ruled out, as an alternative in patients who fail to respond or do not tolerate other treatments and 2) Treatment of Susac syndrome in combination with high-dose intravenous corticosteroids.

Coverage has been extended for the above conditions consistent with FDA approvals, current evidence-based guidelines, and peer-reviewed medical literature.

The quality of evidence in the literature is insufficient to support IVIG for the following conditions: 1) Routine use in the immediate peri-transplantation period for the prevention of infection or GVHD following marrow or peripheral blood allogeneic transplantation,^3,46 2) Acute GVHD with hematopoietic stem cell transplantation in the immediate post-transplant phase,³ 3) Hematopoietic stem cell transplantation in the immediate post-transplantation phase with a history of sinusoidal obstructive syndrome,^3,46 4) Cord blood stem cell transplantation for children or adults,³ 5) Polyneuropathy associated with IgM monoclonal gammopathy,¹⁰ 6) Idiopathic neuropathies,¹⁰ 7) Brachial plexopathy,¹⁰ 8) Adrenoleukodystrophy,¹⁰ 9) Amyotrophic lateral sclerosis,¹⁰ 10) Critical illness polyneuropathy,¹⁰ and 11) POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes).¹⁰

As in IVIG therapy, subcutaneous immunoglobulin (SCIG) administration should be individualized for each patient. Currently, SCIG therapy is FDA-approved for use in the treatment of PI diseases only; with the exception of one SCIG product that is also approved for maintenance therapy in CIDP. Currently, data is lacking in the literature for more widespread use of SCIG. Thus, the use of SCIG for off-label conditions cannot be recommended at this time.

Please refer to the related Local Coverage Article: Billing and Coding Article: Immune Globulin, A56786 for documentation requirements, utilization parameters and all coding information as applicable.

N/A

This bibliography presents those sources that were obtained during the development of this policy. The Contractor is not responsible for the continuing viability of Website addresses listed below.

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