Summary Of Evidence

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. 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, quality of life, 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 a meaningful improvement in the net health outcome.

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.

Pure red cell aplasia 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. 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. 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.

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.

Secondary hypogammaglobulinemia - the literature reviewed shows the following evidence:

There is an association between the administration of certain pharmaceuticals and the development of hypogammaglobulinemia. Not all forms of secondary hypogammaglobulinemia confer an increased risk of infection. There is insufficient evidence to conclude that IVIG reduces the incidence or severity of infection in patients with drug induced secondary hypogammaglobulinemia.

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 <400 mg/dl. We note the quality of evidence on their scale (graded CIII) does not meet the reasonable and necessary criteria of 1862(a)(1)(A) which supports the decision not to add this indication as covered. The same applies to routine prophylaxis in the absence of confirmed hypogammaglobulinemia in patients >100 days post transplant. There is however, support for the use of IVIG in patients with chronic GVHD with confirmed hypogammaglobulinemia (IgG < 400 mg/dl) and who have experienced at least one serious infection.

Systemic lupus erythematosus (SLE) 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. SLE can affect any organ system, but it mainly attacks the skin, joints, kidneys, blood cells, and nervous system. For individuals who have SLE who receive IVIG therapy, the evidence includes a systematic review of multiple studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, health status measures, quality of life, 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 the effects of the technology on health outcomes.

Scleromyxedema 

Data on the efficacy and safety of IVIG are primarily limited to case reports and case series; no randomized trials have been performed. Examples of published reports that have offered support for the efficacy of IVIG for this disease include:

In a retrospective study, 13 of 31 patients (42 percent) with scleromyxedema (without features of dermato-neuro syndrome or mucinous cardiac involvement) treated with IVIG (2 g/kg monthly for the first six months) as a first- or second-line therapy achieved a complete clinical response. Patients were treated with IVIG for a median of 16 months.

In a review of eight adults with scleromyxedema who were treated with monthly cycles of IVIG (2 g/kg per cycle divided over two to five days), two achieved a complete response and six achieved a partial response after up to six cycles of IVIG. Treatment was followed by maintenance therapy every 6 to 12 weeks as needed.

?In a multicenter, retrospective study of 30 patients with scleromyxedema, three of the six patients treated with IVIG (2 g/kg per monthly cycle) achieved complete clinical remissions. The three remaining patients achieved partial responses.

In the first study, a complete clinical response was defined as complete clinical improvement from baseline. In the latter two studies, complete responses were defined as an absence of systemic symptoms or skin findings of scleromyxedema, and partial responses consisted of a decrease in skin changes and improvement in systemic symptoms. In these and other reports, responders to IVIG have included both patients who received IVIG as initial treatment and patients who had previously failed other therapies.

Systemic Capillary Leak Syndrome (SCLS) or Clarkson’s Disease 

In the last decade, multiple case reports have described apparently successful use of monthly infusions of IVIG to reduce the frequency of attacks in some patients.

In a series of 28 patients followed for a median of 55 months (range 1 to 161 months), all five of the patients who did not receive prophylactic IVIG therapy died, compared with only 3 out of the 23 patients who received prophylactic IVIG therapy. Eight of the patients receiving IVIG had no new attacks over multiple years of follow-up. Doses ranged from 0.4 grams to 2 grams per kg per month.

In a case-series of 69 patients with monoclonal gammopathy-associated systemic capillary leak syndrome (Clarkson disease) in whom several preventative agents were used, prophylactic treatment with IVIG (48 patients) was an independent predictor of survival (hazard ratio 0.27, 95% CI 0.1 to 0.7 and 0.35 95% CI 0.13 to 0.96, respectively). Five- and 10-year survival rates in patients treated with IVIG were 91 and 77 percent, respectively, compared with 47 and 37 in patients not treated with IVIG. In addition, compared with no IVIG treatment, IVIG reduced the rate of recurrence and severity of attacks and severity of attacks.

However, a few case reports have described treatment failures.

Immune-mediated Necrotizing Myositis (IMNM)

Kocoloski A et al⁵⁴ concluded, based on a case series of 20 adult IMNM patients from 2014 to 2019 at the University of Pittsburgh that IVIG was associated with marked improvement in IMNM patients, with 85% of patient meeting clinically significant response, with significant reduction in the mean (SD) dose of prednisone. Based on objective, meaningful improvement in manual muscle strength testing and CK as well as marked reduction in prednisone doses with acceptable tolerability, early implementation of IVIG should be considered in adult IMNM.

Weeding et al⁵⁵ concluded that “Treatment guidelines suggested by an ENMC [European Neuromuscular Centre] working group (Neuromuscul Disord. 2018;28(1):87–99) propose a combination of corticosteroids and methotrexate as appropriate first-line therapy for IMNM in general. For patients with anti-HMGCR IMNM, the addition of intravenous immunoglobulin (IVIG) instead of or in addition to methotrexate is recommended.”

Lundberg IE et al⁵⁶ stated that “In patients with IMNM, high doses of glucocorticoids have traditionally been used as induction therapy together with methotrexate or azathioprine. However, several case series have suggested a more aggressive approach with the use of rituximab and/or IVIG in these patients, especially owing to the often refractory nature of disease as well as the risk of early muscle atrophy in patients who are anti-SRP positive.”

Allenbach I et al⁵⁷ review showed that “ENMC [European Neuromuscular Centre] guidelines also recommended the use of intravenous immunoglobulins (IVIGs) in addition to the above-mentioned [methotrexate] treatment for patients with anti-HMGCR-positive IMNM if no adequate response was observed within 6 months of treatment (Neuromuscul. Disord (2018) 28, 87–99). Indeed, IVIGs were reported to be efficacious in treating IMNM.

De Souza JM et al⁵⁹ concluded that a Retrospective study of 13 patients with defined IMNM (nine patients positive for the anti-signal recognition particle and four patients positive for hydroxyl-methyl-glutaryl coenzyme A reductase) who were followed from 2012 to 2018. International Myositis Assessment and Clinical Studies Group (IMACS) scoring assessed the response to a standardized treat-to-target protocol with disease activity core-set measures and late magnetic resonance imaging (MRI). All IMACS core-set measurements improved significantly after initial treatment. Nine patients achieved complete clinical response and among them 2 had complete remission. Eleven patients had discontinued glucocorticoid use by the end of the study. Only 2 patients had moderate muscle atrophy or fat replacement observed by MRI, with the remainder presenting normal or mild findings. Patients with IMNM treated with an aggressive immunosuppressant therapy had a marked improvement in all IMACS core-set domains

Oldroyd AGS et al⁶⁰ described in this review a global guideline set of recommendations for the broad set of inflammatory muscle diseases, in the section regarding recommendations for treatment of adults with myositis, it is stated "intravenous immunoglobulin should be considered as a treatment of severe and/or refractory muscle inflammation (grade 1 strong recommendation, moderate degree of evidence)". This recommendation has direct applicability to immune mediated necrotizing myositis (IMNM) as it is an inflammatory muscle disorder that is quite often severe and refractory to conventional immunosuppressive therapy.

Scleroderma/ systemic Sclerosis

Denton⁶¹ concluded that there is an urgent need to improve our repertoire of antifibrotic agents and develop novel therapeutic approaches to systemic sclerosis (SSc). A growing understanding of the cellular and molecular events that lead to fibrosis and improvements in technology provide a favorable basis for the development of effective agents. Potentially promising approaches for the treatment of SSc include the following:

Intravenous immunoglobulin (Investigational approach) — There are case series and small trials suggesting potential benefit from intravenous immunoglobulin for skin fibrosis as well as other symptoms, including gastrointestinal tract manifestations, of SSc. Clinical trials are being planned, but the mechanism of action for antifibrotic activity remains unclear. Several small, uncontrolled studies have evaluated the effect of intravenous administration of immune globulin on dermal fibrosis, each with reported improvement^62,63. The largest series to evaluate the effect of IVIG on active cutaneous disease included 30 patients with refractory dcSSc, the majority of whom were on concomitant immunosuppressive therapy⁶³. A significant improvement in skin thickening was detected at 12 months compared with historical controls from negative clinical trials. In addition, a group of patients treated with IVIG demonstrated an improvement in the mRSS that was similar to a group of patients treated with mycophenolate mofetil (MMF).

Analysis of Evidence

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.

Use of IVIG for the treatment of secondary hypogammaglobulinemia induced by various medications.

While evidence from the peer reviewed medical literature documents an association between various agents which suppress the immune system and low immunoglobulin levels, the literature does not address whether this finding equates to a higher incidence of serious and/or life threatening infections or that the administration of immune globulin offers a beneficial effect by reducing either the frequency of said infections, or the morbidity/mortality associated with them.

Use of IVIG for hypogammaglobulinemia associated with hematopoetic stem cell transplant (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. In light of this, NGS will no longer cover indications for bone marrow transplant (BMT) recipients only, but will extend the same coverage currently in place of BMT recipients, to all HSCT recipients.

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 <400 mg/dl. We note the quality of evidence on their scale (graded CIII) does not meet the reasonable and necessary criteria of 1862(a)(1)(A) which supports the decision not to add this indication as covered. The same applies to routine prophylaxis in the absence of confirmed hypogammaglobulinemia in patients >100 days post transplant. There is however, support for the use of IVIG in patients with chronic GVHD with confirmed hypogammaglobulinemia (IgG < 400 mg/dl) and who have experienced at least one serious infection.

Immune-mediated Necrotizing Myositis (MNM)

It is clear from the recent literature that 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.

Scleroderma/ systemic Sclerosis

The paucity of literature does not support blanket coverage at this time.

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:

• 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:
  1. Diagnosis has been confirmed by anti-glutamic acid decarboxylase (GAD) antibody testing; and
  2. Member had an inadequate response to first-line treatment (benzodiazepines and/or baclofen).
• 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.
• 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.
• 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.

• • Dosage guideline is 500 mg/kg body weight given on days –7 and –2 pre-transplantation, then weekly through day 90 post-transplantation.
• Secondary hypogammaglobulinemia - there is an association between the administration of certain pharmaceuticals and the development of hypogammaglobulinemia.
• 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 <400 mg/dl.
  • At least one acute infection requiring hospitalization and/or parenteral antibiotics
  • Confirmed diagnosis of chronic GVHD
  • At least 100 days post transplant.
• 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 < 400 mg/d) and have experienced one serious infection may benefit from treatment of IVIG
  • There is insufficient evidence that prophylactic treatment of HSCT patients with IVIG provides a benefit in the absence of hypogammaglobulinemia

• 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.
• 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.

• 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.

• 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.