MP 8.01.05

Immune Globulin Replacement Therapy

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Medical Policy
Section Therapy	Original Policy Date 12/1/96	Last Review Status/Date Reviewed with literature search/1:2008
Issue 1:2008		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

Policy

Intravenous Immune globulin (IVIg) Therapy

IVIg may be considered medically necessary for the following indications:

Intravenous immunoglobulin is considered not medically necessary as a treatment of relapsing/remitting multiple sclerosis.

Other applications of intravenous immune globulin therapy are considered investigational, including, but not limited to, the following conditions:

• chronic progressive multiple sclerosis;
• refractory rheumatoid arthritis and other connective tissue diseases including systemic lupus erythematosus;
• recurrent spontaneous abortion (see below for related laboratory tests);
• inclusion-body myositis;
• polymyositis/dermatomyositis;
• myasthenia gravis in patients responsive to immunosuppressive treatment;
• other vasculitides besides Kawasaki disease, including vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA; e.g., Wegener’s granulomatosis, polyarteritis nodosa), Goodpasture’s syndrome, and vasculitis associated with other connective tissue diseases;
• thrombotic thrombocytopenic purpura;
• hemolytic uremic syndrome;
• paraneoplastic syndromes including but limited to Eaton Lambert syndrome;
• demyelinating polyneuropathy associated with IgM paraproteinemia;
• epilepsy;
• chronic sinusitis;
• asthma;
• chronic fatigue syndrome;
• aplastic anemia;
• Diamond-Blackfan anemia;
• red cell aplasia;
• acquired factor VIII inhibitors;
• hemophagocytic syndrome;
• acute lymphoblastic leukemia;
• multiple myeloma;
• immune-mediated neutropenia;
• nonimmune thrombocytopenia;
• cystic fibrosis;
• recurrent otitis media;
• diabetes mellitus;
• Behcet’s syndrome;
• adrenoleukodystrophy;
• autoimmune mucocutaneous blistering diseases: pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullous acquisita;
• post-infectious sequelae;
• stiff person syndrome;
• organ transplant rejection;
• uveitis;
• demyelinating optic neuritis;
• recent-onset dilated cardiomyopathy.

Subcutaneous Immune globulin (SCIg) Therapy

SCIg may be considered medically necessary for the treatment of primary immunodeficiencies*, including congenital agammaglobulinemia, hypogammaglobulinemia, common variable immunodeficiency (CVID), severe combined immunodeficiency, Wiskott-Aldrich syndrome, and X-linked agammaglobulinemia (XLA).

The following laboratory tests are considered investigational as techniques to investigate immunologic abnormalities affecting maternal-fetal tolerance:

• Analysis of subsets of lymphocytes, including CD-3, CD-4, CD-8, CD-19, natural killer cells, natural killer cell assay, CD3/IL-2R+, B-1 cells. (Collectively, these tests may be referred to as the reproductive immunophenotype.)
• HLA analysis of parents (DQ Alpha)
• Leukocyte antibody detection
• Embryocytotoxicity testing

* FDA-labeled indications

Policy Guidelines

Benefit Application

Rationale

IVIg Therapy

Given the heterogeneous nature and relapsing-remitting course of many of the diseases for which IVIg has been investigated as therapy, randomized controlled trials (RCTs) are important for evaluating true benefit. However, in the case of rare disease, RCTs may be neither likely nor feasible. In these cases, reports of series data from at least 10 patients and consistent trends in results may support conclusions. Aside from the labeled indications, the use of IVIg has been investigated in a variety of diseases as follows:

Guillain-Barre Syndrome

Two randomized studies comparing IVIg with plasma exchange report equivalent outcomes for the 2 treatment approaches. In addition, 1 study has reported that there is no health benefit in combining plasma exchange with IVIg. Therefore, choice of therapy may be dictated by practical concerns, i.e., access to plasma exchange and need for hospitalization. (1, 2)

Chronic Inflammatory Demyelinating Neuropathy

A double-blind placebo-controlled study comparing IVIg to placebo in patients with progressive or relapsing CIDP reports a significant effect of IVIg in 63% of patients compared to no effect in the placebo group. (3) A randomized single-blinded study comparing IVIg to plasma exchange reports equivalent beneficial outcomes for both therapies. Open-label treatment of 26 patients with type 2 diabetes and meeting electrophysiologic criteria for CIDP has shown significant improvement in 21, suggesting benefit in diabetic CIDP as well (4). A possible advantage to IVIg treatment is the ability to administer the drug in the home. (5)

Demyelinating Neuropathy Associated with Paraproteinemia or Paraneoplastic Syndromes

Results of a double-blind, placebo-controlled, crossover randomized study of IVIg versus placebo in 11 patients with paraproteinemic IgM demyelinating polyneuropathy showed only a mild and transitory effect in 3 patients. (6) A subsequent randomized study of 22 patients focused on the short-term outcomes at 2 weeks. (7) There was no significant difference between the treatment and placebo groups. Data are inadequate on the use of IVIg in paraneoplastic syndromes, such as Eaton-Lambert disease.

Multifocal Motor Neuropathy

A double-blind, placebo-controlled crossover trial of 12 patients with multifocal motor neuropathy and high titers of anti-GM1 antibody reports a significant increase in muscle strength associated with IVIg infusion. The effects were only seen in those patients with an associated conduction block. (8) Subsequent RCTs have reported similar results. (9, 10)

Myasthenia Gravis

One RCT (total n=87) (11) and 1 retrospective chart review (total n=54) (12) compare IVIg treatment to plasma exchange in acute myasthenic crisis. Myasthenic crisis was defined as an acute episode of respiratory muscle weakness, defined by a forced vital capacity (FVC) of≤1.0 liter or negative inspiratory force of≤20 cm H20, or requirement of mechanical ventilation. One crossover study (13) compares these therapies in 12 patients with moderate-to-severe disease in a stable phase. Results for all 3 trials show that IVIg and plasma exchange had similar efficacy over time, although improvement may be more rapid with plasma exchange. Series data support benefit with IVIg treatment in patients with acute exacerbations and with refractory disease or who are unable to tolerate standard treatment. One series of 10 children with refractory disease suggests short-term benefit with IVIg but limited long-term benefit. (14) Refractory myasthenia gravis has been defined as patients with persistent symptoms in spite of immunosuppressive treatment with prednisone and/or azathioprine (13) or those unable to tolerate steroid therapy. (14)

Multiple Sclerosis

The previous policy statement regarding IVIg for multiple sclerosis was based on a 1998 TEC Assessment (15), which concluded that IVIg met the TEC criteria. Therefore, it was considered medically necessary in the previous version of this policy. However, in 2002 the American Academy of Neurology published a technology assessment on therapies for multiple sclerosis. (16) This assessment provided a rating of the recommendations, including A (established as effective), B (probably effective, ineffective, or harmful), C (possibly effective, ineffective or harmful), or U (data inadequate). This assessment offered the following recommendation regarding IVIg:

 

1. The studies of intravenous immunoglobulin (IVIg) to date have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in relapsing-remitting multiple sclerosis (Type C recommendation).

2. The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression (Type C recommendation).

In contrast, the American Academy of Neurology recommended the use of interferon beta (Type B recommendation) and glatiramer acetate (Type A recommendation). This assessment suggests that IVIg is no longer considered a drug of choice for relapsing-remitting multiple sclerosis, and thus the policy statement in this policy has been revised to indicate that IVIg is not medically necessary. A literature search for the period of 2002 to December 2004 did not identify any additional randomized trials that would prompt reconsideration of the conclusions of the American Academy of Neurology assessment.

Refractory Dermatomyositis/Polymyositis

A randomized controlled trial comparing IVIg to placebo in 15 patients with refractory dermatomyositis reported significant increases in muscle strength in the IVIg group. (17) Repeated transfusions every 6 to 8 weeks may be required to maintain a benefit. In 2 case series of 18 and 19 patients (18, 19), a significant number of patients had reduction in corticosteroid use or were otherwise considered responders. In a non-randomized comparison of prednisone plus cyclosporine A, with or without IVIg, patients (12 with DM, 8 with PM) given IVIg had a higher probability of remission. Thus, the available data suggest benefit in DM, but are insufficient for firm conclusions. A recent patient series of IVIg in patients with refractory PM (20) showed significant clinical improvement in more than two thirds of patients. However, clinical trials are inadequate to validate the effectiveness of IVIg in patients with polymyositis.

Autoimmune Mucocutaneous Blistering Diseases

IVIg therapy has been studied in a total of 8 case series (4 from the same published report) with at least 10 patients (range, 10–21) (21). For each of 4 diseases, the total number of patients studied in these series was as follows: pemphigus vulgaris (n=48), pemphigus foliaceus (n=11), bullous pemphigoid (n=15), mucous membrane pemphigoid (n=45), and epidermolysis bullous acquisita (n=0). All series focused on patients refractory to standard treatment (i.e., corticosteroids). While initial control was achieved often within 6 or fewer months of treatment, total treatment times tended to average around 2 years to achieve a 16-week disease-free interval between cycles; in some cases, patients could not be weaned from IVIg. These trials showed consistent improvement in control of skin lesions, number of relapses, number of adverse effects from therapy, and shorter duration of steroid treatment. However, data are sparse and insufficient for firm conclusions.

The 2002 Centers for Medicare and Medicaid Services (CMS) Decision Memorandum (21) indicates intended national coverage of short-term IVIg therapy for the treatment of the diseases listed here in patients who have failed conventional therapy, patients in whom conventional therapy is otherwise contraindicated, or patients with rapidly progressive disease in whom conventional treatment did not produce a sufficiently rapid effect. In addition to all case series of any number of patients, the Medicare policy considered case reports, and expert opinion also figured largely in their recommendations. However, expert opinion suggested that IVIg was only indicated for short-term treatment (e.g., 1- to 6-month cycles), whereas series data employed much longer and sometimes indefinite treatment times. Given the small number of patients studied, the lack of agreement in treatment time, and the lack of clear patient selection criteria, as noted in the CMS Decision Memorandum, the BCBSA Medical Policy Panel concluded that more data from either larger case series or controlled clinical trials in well-characterized patient populations would be required to evaluate the effectiveness of IVIg for these indications.

Subsequent to the CMS Decision Memorandum (21), Bachot and colleagues reported the results of an open prospective trial of 34 patients with either Stevens-Johnson syndrome or toxic epidermal necrolysis. (22) Patients received a dose of 2 g/kg IVIg. Outcomes focused on the detached plus detachable proportions of the total body surface area measured before and after treatment and predicted death rate based on a validated prognostic score. There was no measurable effect of IVIg. In additional, Letko and colleagues reported on a comparative case series of 16 patients with mucous membrane pemphigoid with mucous membrane involvement. (23) Eight of the patients received IVIg and 8 received conventional immunosuppressive therapy. The median time to clinical remission was shorter in the group receiving IVIg (4 months vs. 8.5 months). However, the small size of the trial and the lack of a randomized control group precludes scientific interpretation.

Inclusion Body Myositis

Dalakas and colleagues have reported on a double-blind, placebo-controlled crossover study comparing IVIg to placebo in 19 patients with inclusion body myositis (IBM). (24) There was no statistically significant improvement in overall muscle strength in the IVIg group compared to the control placebo group. Two more recent RCTs (combined n=58) also found no significant functional improvement when IVIg treatment was compared to placebo. (25, 26)

Kawasaki Syndrome and Other Vasculitides

Randomized, multicenter studies have shown that high-dose IVIg plus aspirin, given within the first 10 days after the onset of fever, is safe and effective in reducing the prevalence of coronary artery abnormalities. (27) An RCT of single course IVIg (n=17) versus placebo (n=17) in patients with persistent active Wegener’s granulomatosis or microscopic polyangiitis associated with anti-neutrophil cytoplasmic antibody found significantly more responders in the IVIg treatment group at 3 months, but no significant differences after 3 months or in the frequency of relapse or use of other medications. (28) Data are inadequate regarding the effectiveness of IVIg in other vasculitides including polyarteritis nodosa and rheumatoid arthritis. (29)

Recurrent Spontaneous Abortion

The policy on IVIg as a treatment of recurrent spontaneous abortion (RSA) is based on a 1998 TEC Assessment (30), which offered the following conclusions:

Two subsequent meta-analyses of 5 and 6 trials (31, 32) concluded that IVIg provides no significant beneficial effect over placebo in preventing further miscarriages. A blinded RCT of 41 women treated with IVIg or saline placebo found no differences in live birth rates. (33) A multicenter RCT comparing heparin and low-dose aspirin with versus without IVIg in women with lupus anticoagulant, anticardiolipin antibody, or both, found no significant differences. (34) More recently, an RCT of 58 women with at least 4 unexplained miscarriages tested IVIg versus placebo and analyzed results by intention to treat. (35) The live birth rate was the same for both groups; also, there was no difference in neonatal data. Other non-randomized but controlled trials also report no benefit for IVIg treatment. There is insufficient evidence in RCTs or other trials to support benefit in secondary (live birth followed by consecutive spontaneous abortions) versus primary (no prior live births) spontaneous aborters. A variety of immunologic tests may precede the initiation of IVIg therapy. These tests, including various subsets of lymphocytes, human leukocyte antigen (HLA) testing, and lymphocyte functional testing (i.e., natural killer cell assays and the embryo cytotoxicity test), are research tools that explore subtle immunologic disorders that may contribute to maternal immunologic tolerance of the fetus. However, there are no clinical data showing that the results of these tests can be used in the management of patients to reduce the incidence of recurrent spontaneous abortion, particularly since IVIg therapy has not been shown to be an effective therapy.

Fetal Alloimmune Thrombocytopenia

Case series have shown that maternal IVIg infusions are associated with an increase in the fetal platelet count. A randomized trial compared weekly IVIg with and without associated dexamethasone. (36) Although there was no placebo-controlled arm, results can be compared to the course in a prior affected sibling, since the natural history of the disease suggests that subsequent births should be similarly if not more severely affected with thrombocytopenia. The study reported a mean increase in the platelet count of 69,000/mL. There were no instances of intracranial hemorrhages, although hemorrhage had occurred previously in 10 untreated siblings.

HIV-Infected Patients

One of the FDA-approved indications for IVIg is its use in HIV-infected children. A randomized study published in 1996 reported similar results in adults with HIV infection. For example, patients in the treatment group reported a longer duration of infection-free status, a reduction in the number and duration of hospital admissions, and frequency of diarrhea. (37)

Chronic Fatigue Syndrome

Vollmer-Conna and colleagues reported no therapeutic benefit of IVIg in 99 patients with chronic fatigue syndrome randomized to receive either IVIg or placebo. (38)

Post-Infectious Sequelae

RCTs of IVIg administered as postoperative prophylaxis in patients anergic to common recall antigens (n=40) (39) and trauma patients (n=39) (40) indicated significantly fewer infections in treated patients. Each of these trials addressed a different patient population, and the evidence is insufficient for conclusions. IVIg given as prophylaxis in patients with rheumatic fever did not appear to change cardiac outcomes (n=59) (41).

Dilated Cardiomyopathy

Sixty-two patients with recent-onset dilated cardiomyopathy were randomized to IVIg or placebo. (42) There was no significant difference in left ventricular ejection fraction between IVIg and placebo treatment arms.

Systemic Lupus Erythematosus

Although systemic lupus erythematosus (SLE) is a relatively prevalent autoimmune disease, only 2 small case series (43, 44) and 1 small RCT comparing IVIg to cyclophosphamide (45) have been published since the last update of this policy. These studies and 2 earlier small case series suggest some benefit; IVIg may be a good alternative to cyclophosphamide. But results are inconsistent and short-lived in some cases, and RCTs are needed for confirmation.

Stiff Person Syndrome

Dalakas et al. (46) randomized 16 patients with disease and anti-BAD65 autoantibodies to IVIg or placebo for 3 months. After a 1-month wash-out period, patients were crossed over to 3 months of the alternate treatment. Stiffness scores decreased significantly on IVIg, but not on placebo, regardless of order. Eleven patients were able to walk more easily or without assistance; the frequency of falls decreased; and patients were able to perform work-related or household tasks. The duration of benefit lasted 6 weeks to 1 year without additional treatment. Thus, results suggest benefit, but no other comparative trials or series data with at least 10 patients are available for confirmation.

Organ Transplant Rejection

One RCT (47) of 30 patients suggests that IVIg is at least as good as anti-CD3 in combating steroid-resistant rejection of kidney transplants. One small case series (n=17) indicates benefit in patients with both steroid- and anti-lymphocyte antibody-resistant rejection of kidney transplants (48). Another small case series of 10 patients with severe allograft rejection of renal and cardiac transplants also suggests benefit (49). Thus, data are promising but more comparative evidence is needed.

Non-Infectious Uveitis

Two small series of 18 and 10 patients (50, 51) report measurable improvement in visual acuity after IVIg therapy.

Demyelinating Optic Neuritis

Noseworthy et al. (52) conducted a double-blind RCT of 55 patients randomized to IVIg or placebo. The trial was terminated due to negative results.

Asthma

Two RCTs of IVIg therapy in patients with steroid-dependent asthma found no significant decrease in steroid use compared to placebo (53, 54). A subgroup analysis in 1 trial indicated a significant effect of IVIg on steroid consumption in patients requiring corticosteroid doses greater than 2 g/yr; however, this subgroup analysis was not stated as planned in advance and involved only 17 of 38 total patients.

Prophylaxis in the Post-Stem-Cell Transplant Setting

Prevention of infection after bone marrow transplant is a labeled indication for IVIg. The FDA approval was based on data from a randomized but not placebo-controlled study that compared the outcomes in 369 patients undergoing bone marrow transplant for both malignant and non-malignant disease (i.e., aplastic anemia). (55) In addition, patients underwent a variety of types of stem-cell support, including allogeneic stem-cell support (both HLA identical and non-identical, T cell depleted or not), autologous, or syngeneic. The majority of patients received HLA-identical allogeneic stem-cell support. In addition to the type of stem-cell support, patients were stratified according to transplant type, age, serological status for cytomegalovirus, and protective isolation. The study endpoints were acute graft-versus-host disease, infections, interstitial pneumonia, and death. In patients over the age of 20, IVIg administration was associated with decreased incidence or risk of interstitial pneumonitis, septicemia, or acute graft-versus-host disease. There was no overall improvement in survival. Since this 1990 study, there has been further discussion of the role of IVIg in the post-stem-cell transplant setting, and there appears to be no consensus about its efficacy. (56, 57) Criticisms of this study point out that the statistical significance did not take into account multiple endpoints, and subgroup analyses such that some of the reported p values could be due to chance alone. In addition, the study included a heterogeneous group of patients and was not placebo controlled. Moreover, there have been improvements in supportive care, particularly prophylaxis for cytomegalovirus and fungal infection, which may attenuate any effect of IVIg. In addition, studies examining the effect of IVIg on graft-versus-host disease have reported conflicting data. (57) In 2003, Cordonnier and colleagues reported on the results of a trial that randomized 200 patients undergoing allogeneic stem-cell transplant with HLA-identical donors to receive either placebo or various doses of IVIg from 7 days prior to transplant weekly until 100 days after transplant. (58) Doses ranged from 50 mg/kg to 500 mg/kg. The authors reported that IVIg had no benefit over placebo in terms of infection, interstitial pneumonitis, or graft-versus-host disease. The results of this study challenge the conclusions of the previous 1990 study, at least for the subgroup with HLA-identical donors.

Solid Organ Transplantation

Prior to 2006, IVIg in the setting of solid organ transplant was not addressed by this policy. However, IVIg has been extensively used in this setting, both as pretransplant prophylaxis (i.e., desensitization) for highly sensitized patients at high risk of antibody-mediated rejection (AMR), and as a treatment of AMR after transplant (see Description section). The NIH IG02 was a double-blind placebo-controlled trial that randomized 101 highly sensitized renal transplant candidates to receive either 4 monthly infusions of IVIg or placebo prior to transplant. (59) If transplanted, additional infusions were given monthly for 4 months. IVIg significantly reduced PRA levels in study subjects compared to placebo, resulting in a higher transplant rate. For example, a total of 24 patients subsequently underwent transplant, 16 in the IVIg group and 8 in the placebo group. There was acceptable graft survival in both groups. Desensitization protocols vary among transplant centers; certain protocols commonly used are referred to as the Cedars-Sinai protocol and the Johns Hopkins protocol. The Cedars-Sinai protocol consists of high-dose IVIg (2 g/kg) and is offered to patients awaiting either a deceased or live donor. (60) The Johns Hopkins protocol consists of low-dose IVIg (100 mg/kg) in combination with plasmapheresis with or without treatment with anti CD-20 (i.e., Rituxan). (61) A variety of protocols also have been developed for the treatment of AMR, often in combination with other therapies, such as plasmapheresis or anti CD-20. (62-65) The majority of studies of IVIg in the transplant setting are retrospective case series from single institutions. Therefore, it is not possible to compare immunomodulatory regimens to determine their relative efficacy. Nevertheless, in part based on the large volume of literature published on this subject, it appears that IVIg is a component of the standard of care for the management of AMR.

Outcome data are inadequate to validate the use of IVIg in other conditions including, but not limited to, those listed in the Policy section as investigational.

2007 - 2008 Update

Intravenous Immune Globulin (IVIg) Therapy

No randomized trials were identified that would change the current policy statements. 

Subcutaneous Immune Globulin (SCIg) Therapy

SCIg replacement therapy for primary immunodeficiency (PID) has been available outside the United States for decades. (66, 67) A randomized, 2-year duration, crossover study performed in Europe in the mid-1990s compared SCIg and IVIg replacement therapies in 40 adults (mean age 44 years, range 18–67 years) with PAD that included CVID, IgG subclass deficiencies, or specific antibody deficiency. (68) The primary endpoint, the number of infections and their severity during the two treatment periods, did not differ significantly as a function of the IgG delivery method. The mean infections scores with the two regimens were 4.12 for IVIg and 3.82 for SCIg, with the vast majority (>85%) being infections in the respiratory tract. There were 3 major infections, 2 in the IVIg group (1 chest, 1 sinusitis) and 1 in the SCIg group (urinary tract). No statistically significant differences were shown for the numbers of days off from work or school between regimens. Treatment-related adverse events were reported in 5% of IVIg recipients compared to 10.4% of SCIg patients, but none was serious enough to stop infusions, comprising primarily symptoms such as headache, minor rigors (shivering), and fatigue. Pain and erythema at the infusion sites accounted for about two-thirds of all adverse events in the SCIg patients. Pharmacokinetic analyses showed median serum IgG trough concentrations of 7.8–8.4 g/L during the IVIg regimen versus 8.0–9.1 g/L during SCIg treatment, following doses that ranged from 414–629 mg/kg per month and 494–632 mg/kg per month, respectively. 

Clinical data are available for the first SCIg product (Vivaglobin) available in the United States. An open-label, nonrandomized, prospective, multicenter study reported outcomes of SCIg replacement therapy in adults and children (older than 2 years with bodyweight 10 kg or more) with common variable immune deficiency (CVID) or X-linked agammaglobulinemia that had been treated with IVIg for at least 4 months (69). A total of 65 patients (mean age: 34 +/- 15 years, range: 2 to older than 65 years, 57% male) were enrolled. Most (78%) had CVID, 22% had XLA. The study included 3 phases: baseline (3-4 weeks), wash-in/wash-out (12 weeks), and efficacy (52 weeks). During the baseline period, each patient received usual IVIg treatment, during and after which vital signs were collected, baseline biochemical and viral tests were performed, and serum IgG trough levels were measured. One week following the last IVIg dose, once-weekly SCIg therapy was administered for at least 3 months (wash-in/out phase), using a dose equivalent to 137% of the IVIg dose. The 12-month efficacy phase began after the wash-in/out phase, using a mean weekly dose of 158 mg/kg (range, 155–165 mg/kg). The mean pre-infusion IgG level increased from 7.9 g/L at baseline to 10.4 g/L during SCIg treatment, representing a 39% increase. Trough levels remained relatively stable throughout the study. During the efficacy phase, 2 serious bacterial infections (pneumonias) were reported in 2 patients, resulting in an annual rate of 0.04 episodes per patient-year (upper 99% confidence limit: 0.14). Thirty-two patients (63%) missed a total of 192 days of school or work due to infections during the efficacy phase, resulting in an overall rate of 3.7 days per patient-year. Four patients were hospitalized due to infection (including the 2 with pneumonia), for a total of 12 days or 0.23 hospital days per patient-year. Of a total of 3,656 infusions, 2,584 treatment-emergent adverse events were reported (0.71 per infusion), with 1,901 considered to be treatment related (0.52 per infusion). The most frequent type of adverse event, infusion-site reaction, was observed at least once in 60 cases (91%); the vast majority (96%) were of mild or moderate intensity and short duration (1 or 2 days). Importantly, the incidence of infusion-related adverse events declined by 50% over time, from 85% after the first infusion session to 41% after the 33rd session, after which the rate remained relatively stable. Three subjects withdrew from treatment due to infusion-site reactions. No deaths or notable changes in hematologic or other laboratory parameters were noted, nor were any virus-related safety issues reported.

A parallel study by Gardulf and colleagues of the same product (Vivaglobin) in Europe and Brazil among 60 patients (16 children, 44 adults, age range, 2–75 years) with a diagnosis of PID produced almost identical annualized rates of mild-to-moderate overall infections and serious bacterial infections (0.04 episodes per patient). (70) However, Gardulf used a SCIg dose equivalent to 100% of the previous IVIg dose, compared to 137% in the North American study. The rates, intensity, and types of adverse events in the Gardulf report were similar to the North American study and also showed a similar decline in incidence with subsequent infusions. Among children in the Gardulf study, serum IgG trough levels increased from a mean 7.8 g/L to a mean 9.2 g/L during the efficacy phase; adult levels rose from a mean 8.6 g/L to 8.9 g/L. Six of the children and 10 adults missed days from school (range, 1–9 days) or work (range, 1–36 days). No deaths or notable changes in hematologic or other laboratory parameters were noted, nor were any virus-related safety issues reported. 

The results for the Vivaglobin SCIg replacement therapy are consistent in terms of efficacy over a period of 12 months in the two nonrandomized studies outlined here. (69, 70) Further, they were nearly identical (0.04 serious bacterial infections per patient-year) to those attained in the RCT by Chapel outlined previously. (68) However, the pharmacokinetics of IVIg and SCIg are quite different. Thus, IVIg infusion results in very high peak serum concentrations that fall quickly as the Ig is distributed into the extravascular space. (66, 67) In contrast, weekly SCIg administration results in smoother, more consistent serum IgG concentrations with greater stability in levels between infusions, due to a reservoir effect of SCIg in the subcutaneous tissues. 

The clinical implications of the pharmacokinetic differences between IVIg and SCIg are not clear. However, it is plausible that they could be beneficial in terms of fewer systemic adverse effects and reduction in break-through infections secondary to rapid falls in serum Ig levels. (67) Furthermore, evidence is available to show that PID patients who switch from IVIg replacement therapy delivered in the hospital or other outpatient site to home-based SCIg self-infusions perceive their health-related quality of life as significantly improved. (71) Thus, taken together, the similar clinical efficacy of SCIg replacement therapy versus IVIg, in the context of more favorable pharmacokinetic parameters and a simpler delivery method for chronic therapy, suggests SCIg treatment may be considered medically necessary in lieu of IVIg to prevent recurrent infections in patients with PID who require lifelong immunoglobulin replacement therapy.  

 

References:

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21. Medicare coverage policy #CAG-00109N, 2002. Available online at: http://cms.hhs.gov/coverage/8b3-kkk.asp
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24. Dalakas MC, Sonies B, Dambrosia J et al. Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study. Neurology 1997; 48(3):712-6.
25. Walter MC, Lochmuller H, Toepfer M et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol 2000; 247(1):22-8.
26. Dalakas MC, Koffman B, Fujii M et al. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 2001; 56(3):323-7.
27. Newburger JW, Takahashi M, Beiser AS et al. A single intravenous infusion of gamma globulin compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991; 324(23):1633-9.
28. Jayne DR, Chapel H, Adu D et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000; 93(7):433-9.
29. Lockwood CM. New treatment strategies for systemic vasculitis: the role of intravenous immune globulin therapy. Clin Exp Immunol 1996; 104(suppl 1):77-82.
30. 1998 TEC Assessments; Tab 14.
31. American Society of Reproductive Medicine. Intravenous Immunoglobulin (IVIG) and Recurrent Spontaneous Pregnancy Loss: A Practice Committee Report; A Committee Opinion. 1998. Available at http://www.asrm.org/Media/Practice/ivig.html  Accessed October 2002.
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34. Branch DW, Peaceman AM, Druzin M et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol 2000; 182(1 pt 1):122-7.
35. Christiansen OB, Pedersen B, Rosgaard A et al. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod 2002; 17(3):809-16.
36. Bussel JB, Berkowitz RL, Lynch L et al. Antenatal management of alloimmune thrombocytopenia with intravenous immunoglobulin: a randomized trial of the addition of low-dose steroid to intravenous gamma-globulin. Am J Obstet Gynecol 1996; 174(5):1414-23.
37. Kiehl MG, Stoll R, Broder M et al. A controlled trial of intravenous immune globulin for the prevention of serious infections in adults with advanced human immunodeficiency virus infection. Arch Intern Med 1996; 156(22):2545-50.
38. Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D et al. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med 1997; 103(1):38-43.
39. Kress HG, Scheidewig C, Schmidt H et al. Reduced incidence of postoperative infection after intravenous administration of an immunoglobulin A- and immunoglobulin M-enriched preparation in anergic patients undergoing cardiac surgery. Crit Care Med 1999; 27(7):1281-7.
40. Douzinas EE, Pitaridis MT, Louris G et al. Prevention of infection in multiple trauma patients by high-dose intravenous immunoglobulins. Crit Care Med 2000; 28(1):8-15.
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Index

Policy History

Appendix

 

Diagnostic Criteria for Diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

 

The following criteria are adapted from the Task Force Report of the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. (Neurology 1991; 41(5):617-8) The report included mandatory, supportive, and exclusionary diagnostic criteria. Only the mandatory criteria are excerpted here. The criteria are based on a combination of clinical observations, physiologic studies, pathologic features (i.e., nerve biopsy), and studies of the cerebrospinal fluid (CSF).

 

I. Clinical

 

Mandatory

 

1. Progressive or relapsing motor and sensory, rarely only motor or sensory, dysfunction of more than 1 limb or a peripheral nerve nature, developing over at least 2 months.

2. Hypo- or areflexia. This will usually involve all 4 limbs.

 

II. Physiologic Studies

 

Mandatory

 

Nerve conduction studies including studies of proximal nerve segments in which the predominant process is demyelination.

 

Must have 3 of 4:

 

1. Reduction in conduction velocity (CV) in 2 or more motor nerves:

 

2. Partial conduction block or abnormal temporal dispersion in 1 or more motor nerves: either peroneal nerve between ankle and below fibular head, median nerve between wrist and elbow, or ulnar nerve between wrist and below elbow.

Criteria suggestive of partial conduction block less than 15% change in duration between proximal and distal sites and greater than 20% drop in negative peak (p) area or peak to peak (p-p) amplitude between proximal and distal sites.

Criteria for abnormal temporal dispersion and possible conduction block: greater than 15% change in duration between proximal and distal sites and greater than 20% drop in p area or p-p amplitude between proximal and distal sites and greater than 20% drop in p or p-p amplitude between proximal and distal sites. These criteria are only suggestive of partial conduction block as they are derived from studies of normal individuals. Additional studies, such as stimulation across short segments or recording of individual motor unit potentials, are required for confirmation.

 

3. Prolonged distal latencies in 2 or more nerves:

• greater than 125% of upper limit of normal (LEN) is amplitude greater than 80% of LLN
• greater than 150% of LEN if amplitude <80% of="of" LLN.

 

4. Absent F waves or prolonged minimum

• greater than 120% of ULN if amplitude greater than 80% of LLN
• greater than 150% of ULN if amplitude <80% of="of" LLN.less than 80% of LLN

 

III. Pathologic Features

 

Mandatory

 

Nerve biopsy showing unequivocal evidence of demyelination and remyelination.

Demyelination by either electron microscopy(greater than 5 fibers) or teased fiber studies greater than12% of 50 fibers, minimum of 4 internodes each, demonstrating demyelination/remyelination.

 

IV. CSF Studies

 

Mandatory

 

1. Cell count less than 10 per cubic mm if HIV-seronegative or less than 50 per cubic mm is HIV seropositive

 

2. Negative VDRL

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