LCD L39314: Off-Label Use of Intravenous Immune Globulin (IVIG)

NGS Abstract:

Intravenous Immune Globulin (IVIG) is a blood product containing human immunoglobulins specifically prepared for intravenous infusion. IVIG is used in the treatment of primary immunodeficiency diseases featuring low or dysfunctional antibody levels to prevent infection and for certain inflammatory, autoimmune and other diseases featuring to interfere with harmful antibodies and/or for blocking damage from immune cells.

This LCD addresses off-label uses for IVIG. We define off-label as not in Medicare approved compendia or in the FDA label.

NGS has approved IVIG for the following off label uses:

• Autoimmune retinopathy (AIR) that is sight threatening and refractory to corticosteroid and immunosuppressant therapy

• Induction Dose - 1.5g/kg in divided dose over 3 days.

• Maintenance Dose - 0.4 to 1.5 g/kg in single or divided doses monthly.

• The aim should be to use the lowest dose possible that achieves the appropriate clinical outcome for each patient.

• Chronic Graft versus Host Disease (GVHD) IVIG is indicated in patient with chronic GVHD who meet all of the following criteria:

• Laboratory proven hypogammaglobulinemia with IgG levels

• Hematopoetic Stem Cell Transplantation (HSCT) - IVIG is indicated to prevent the risk of acute graft-versus-host disease, associated interstitial pneumonia (infectious or idiopathic) and infections (e.g., cytomegalovirus infections [CMV], varicella-zoster virus infection, and recurrent bacterial infection) after HSCT in patients 20 years of age or older during the first 100 days after transplantation. It is not indicated in HSCT patients younger than 20 years of age, nor is it recommended for autologous transplants. The evidence is sufficient to conclude that the complications of stem cell transplantation are independent of the source of stem cells.

• Hypogammaglobulinemia for Graft vs. Host Disease (GVHD) -

• There is sufficient evidence to conclude that patients who require ongoing immunosuppression for the treatment of chronic GVHD are at increased risk when compared to their peers who do not require such treatment.

• There is sufficient evidence that such patients who are hypogammaglobulinemic (IgG

• Immune-mediated Necrotizing Myositis (IMNM)

• IVIG plays a critical role in the medication management of this disease. IVIG is also a critical therapeutic option for the management of other myositis syndromes, and was FDA-approved 7/15/2021 for the management of dermatomyositis

• Pure red cell aplasia related to human parvovirus B19 infection - IVIG therapy is considered medically necessary for severe, refractory anemia associated with bone marrow suppression, with parvovirus B19 viremia.

• Scleromyxedema -Systemic therapy is the treatment method of choice for patients with scleromyxedema. Intravenous immunoglobulin (IVIG) is a first choice for therapy based upon multiple case reports and case series that support its efficacy and the generally well-tolerated nature of this nonimmunosuppressive treatment .

The mechanism through which IVIG improves scleromyxedema is unclear. Suggested mechanisms focus on the immunomodulatory effects of IVIG, including neutralization of circulating autoantibodies by anti-idiotype antibodies, functional blockade of fragment crystallizable receptors on macrophages, and inhibition of fibrosis via modulation of the production of cytokines and cytokine antagonists .

IVIG is usually administered at the dose of 2 g/kg per month divided over two to four consecutive days per month according to the preparation and concentration of IVIG. Improvement in skin and extracutaneous symptoms, especially rheumatologic symptoms, often is evident after the first one or two cycles of IVIG. Almost all patients exhibit at least partial improvement within four to six cycles. Patients with an unsatisfactory response to IVIG after six cycles are typically transitioned to other therapies.

Lower doses of IVIG may also be effective. A patient with skin-limited disease who had failed to respond to systemic glucocorticoids, extracorporeal photophoresis, and interferon had a reduction in clinical findings within two cycles of IVIG given at a dose of 0.5 g/kg given over five days at four-week intervals.

Although remissions persisting for a few months to three years after cessation of IVIG infusions have been reported, the response to IVIG is usually transient. Maintenance IVIG cycles every six to eight weeks are generally required to maintain remission. IVIG is typically administered over two to four days at a dose of 2 g/kg of IVIG every six weeks or 1.5 g/kg of IVIG every four weeks.

• Secondary hypogammaglobulinemia - there is an association between the administration of certain pharmaceuticals and the development of hypogammaglobulinemia.

• Stiff-person syndrome may be treated with IVIG when/if standard treatment with Diazepam is no longer effective. IVIG therapy is considered medically necessary for stiff-person syndrome when the following criteria are met:

• Diagnosis has been confirmed by anti-glutamic acid decarboxylase (GAD) antibody testing; and

• Member had an inadequate response to first-line treatment (benzodiazepines and/or baclofen).

• Dosage guideline is 500 mg/kg body weight given on days –7 and –2 pre-transplantation, then weekly through day 90 post-transplantation.

• Susac Syndrome - There is sufficient evidence to conclude that IVIG may be used for refractory or relapsing disease.

• Systemic Capillary Leak Syndrome (SCLS) or Clarkson’s Disease - Systemic Capillary Leak Syndrome is a rare illness of unknown origin which has been reported through registries, case studies and case series. Due to the rarity of the illness, large studies are not expected to be generated. Diagnosis in the most recent review and registry review is associated with monoclonal gammopathy. Prophylaxis with IVIG given on a routine monthly basis has been associated with increased survival. This monthly prophylaxis should be tapered to the lowest effective dose. Medicare is expanding coverage for this illness on a trial basis when associated with monoclonal gammopathy and used for prophylaxis but can be withdrawn or altered based on subsequent literature. All other claims will have the appeals process for potential coverage where medical documentation and submitted literature can be reviewed for individual consideration.

The dose used in most case reports has been 2 grams per kg intravenously per month, although 1 gram per kg per month was noted to be effective in another report.

• Systemic Lupus Erythematosus - The routine use of IVIG is not usually recommended. IVIG may be used in patients with severe active systemic lupus erythematosus for whom other interventions have been unsuccessful, have become intolerable or are contraindicated.

Autoimmune retinopathy - while there is little high level evidence conclusively demonstrating benefit of Ig therapy, autoimmune retinopathy (AIR) is a very rare condition and open label studies and case series do demonstrate some benefit including recent publications. It is important to acknowledge that AIR is sight threatening and when refractory to corticosteroid and immunosuppressant therapy, observational studies conclude that Ig therapy is well-tolerated and effective in arresting disease in some patients.

Chronic Graft versus Host Disease (GVHD)

The ISDA guidelines provides a summary of evidence which supports that risk of infection is, among other things, related to the presence or absence of GVHD. Patients with chronic GVHD, who require ongoing immunosuppressive therapy to prevent complications of GVHD, may have ongoing impaired immunity as demonstrated by any number of objective tests. This being said, the ISDA does not recommend routine administration of IVIG during the first 100 days post transplant and indicates that IVIG treatment as prophylaxis “may be considered” in patients with IgG levels 100 days post transplant. There is however, support for the use of IVIG in patients with chronic GVHD with confirmed hypogammaglobulinemia (IgG Hematopoetic Stem Cell Transplantation (HSCT)

The Infectious Disease Society of America (IDSA) in their guideline for preventing infectious complications among HSCT recipients, defines HSCT to include any stem cell transplant, regardless of type or source. While there are differences in the risks and complications of HSCT between different sources, the effects on immune function are similar.