Multiple Sclerosis

The previous policy statement regarding IVIg for multiple sclerosis was based on a 1998 TEC Assessment (20), 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. (21) 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

An RCT comparing IVIg plus prednisone to placebo in 15 patients with refractory dermatomyositis reported significant increases in muscle strength, as measured by mean scores on the neuromuscular symptom scale (NSS) and the modified MRC scale, in the IVIg group. At 3 months IVIg versus placebo; mean modified MRC: IVIg, 84.6 ± 4.6 versus placebo, 78.6 ± 8.2, Mean NSS: IVIg 51.4 ± 6.0 versus placebo, 45.7 ±11. (22) Repeated transfusions every 6 to 8 weeks may be required to maintain a benefit. In 2 case series of 18 and 19 patients (23, 24), a significant number of patients (67%) 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. In a double-blind, placebo-controlled crossover trial in 15 patients with refractory DM with IVIg, 5 patients had improvement in muscle strength and histopathology and additional patients had improvement in their rash. The authors noted that IVIg is not recommended as monotherapy but in combination with other immunosuppressive therapies for patients who have not adequately responded to other immunosuppressive agents. IVIg is appropriate in selected patients with resistant dermatomyositis disease but there is insufficient evidence supporting primary or long-term treatment. (25)

Polymyositis (PM) and Refractory Polymyositis

A patient series of IVIg in patients with refractory PM (26) showed significant clinical improvement in more than two thirds of patients. However, comparative trials are lacking to validate the effectiveness of IVIg in patients with polymyositis. A randomized, controlled trial of IVIg for PM has not been published, but a prospective study of IVIg in patients with refractory PM showed improvement in 25 of 35 patients and a 50% reduction of prednisone dose. With the lack of controlled trials, there is insufficient evidence to support the use of IVIg in 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). 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 (27) 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 for whom conventional therapy is otherwise contraindicated, or patients with rapidly progressive disease for 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 (27), Bachot and colleagues reported the results of an open prospective trial of 34 patients with either Stevens-Johnson syndrome or toxic epidermal necrolysis. (28) 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. (29) 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 preclude 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). (30) 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. (31, 32)

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. (33) 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. (34) Data are inadequate regarding the effectiveness of IVIg in other vasculitides including polyarteritis nodosa and rheumatoid arthritis. (35)

Recurrent Spontaneous Abortion

The policy on IVIg as a treatment of recurrent spontaneous abortion (RSA) is based on a 1998 TEC Assessment (36), which offered the following conclusions:

Two subsequent meta-analyses of 5 and 6 trials (37, 38) 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. (39) 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. (40) More recently, an RCT of 58 women with at least 4 unexplained miscarriages tested IVIg versus placebo and analyzed results by intention to treat. (41) 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. (42) 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. (43)

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. (44)

Post-Infectious Sequelae

RCTs of IVIg administered as postoperative prophylaxis in patients anergic to common recall antigens (n =40) (45) and trauma patients (n =39) (46) 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) (47).

Dilated Cardiomyopathy

Sixty-two patients with recent-onset dilated cardiomyopathy were randomized to IVIg or placebo. (48) 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 (49, 50) and 1 small RCT comparing IVIg to cyclophosphamide (51) 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. (52) 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 (53) 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 (55). Thus, data are promising but more comparative evidence is needed.

Non-Infectious Uveitis

Two small series of 18 and 10 patients (56, 57) report measurable improvement in visual acuity after IVIg therapy.

Demyelinating Optic Neuritis

Noseworthy et al. (58) 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 (59, 60). 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). (61) 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. (62, 63) 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. (63) 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. (64) 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.

A meta-analysis evaluated the role of IVIG in patients undergoing hematopoietic stem-cell transplantation and those with lymphoproliferative disorders to determine whether prophylaxis with IVIG reduces mortality or affects other outcomes in patients with hematological malignancies. All RCTs included in the evaluation compared prophylaxis of IVIG with placebo, no treatment or another immunoglobulin preparation; different administration schedules or doses for patients with hematological malignancies were included. Of the 40 trials evaluated, 30 included patients who had hematopoietic stem-cell transplantation and 10 included patients with lymphoproliferative disorders. The authors concluded that in patients undergoing hematopoietic stem-cell transplantation, routine prophylaxis with IVIG is not supported. Its use may be considered in patients with lymphoproliferative disorders who have hypogammaglobulinemia and recurrent infections to reduce clinically documented infections. (65)

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. (66) 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. (67) 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). (68) 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. (69-72) 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.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections

The National Advisory Committee on Blood and Blood Products and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for neurologic conditions. (25) Recommendations for use of IVIG were made for 14 conditions, including pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). The Panel emphasized that this syndrome is not well understood and diagnosis of PANDAS requires expert consultation. The optimum dose and duration of treatment is uncertain. The evidence review examining IVIg for PANDAS identified 1 RCT of 29 children who had new or severe exacerbations of obsessive-compulsive disorder (OCD) or tic disorder after streptococcal infections randomly assigned to IVIg plasma exchange or placebo. At 1-month follow-up, IVIg and plasma exchange had no significant differences and showed significant improvement in obsessive-compulsive symptoms. The improvement in symptoms was evident at 1-year follow-up. (73) Given that there is only 1 small study, there are insufficient data to support the use of IVIg for PANDAS.

Autism

The National Advisory Committee on Blood and Blood Products and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for neurologic conditions. IVIG was not recommended for autism. The evidence review examining IVIg for autism identified 3 case series. In 1 of the case series, 10 patients with abnormal immune parameters received IVIg monthly. After 6 months, 5 of 10 subjects showed marked improvement in several autistic characteristics. In the second case series, 1 of 10 subjects showed improvement in autistic symptoms after receiving IVIg. No improvement was observed in the third series. (25) Given there are no randomized comparative trials evaluating IVIg in autism, there are insufficient data to support the use of IVIg for autism.

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.

Subcutaneous Immune Globulin (SCIg) Therapy

SCIg replacement therapy for primary immunodeficiency (PID) has been available outside the United States for decades. (74, 75) 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. (76) 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 (77). 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). (78) 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 2 nonrandomized studies outlined here. (77, 78) Further, they were nearly identical (0.04 serious bacterial infections per patient-year) to those attained in the RCT by Chapel outlined previously. (76) 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. (74,75) 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. (75) 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. (79) 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. It has been suggested in a review article report of case series that SCIg therapy may be a viable alternative for patients having IVIg difficulties including; poor venous access, severe adverse reactions, and co-morbid conditions. Publications suggest SCIg therapy may be advantageous in selected patient populations; children, pregnant women. (80) Given that there are no RCTs for these patient types and conditions, there is insufficient evidence to support the use of SCIg.

Clinical Trials in Progress

A search on ClinicalTrials.gov for immune globulin therapy studies resulted in 4 trials in progress that were applicable to the policy. All trials included SCIg as the intervention. Two are active, not recruiting, and 2 are enrolling by invitation. (81)

References:

1. van der Meche FG, Schmitz PI. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. N Engl J Med 1992; 326(17):1123-9.
2. Plasma Exchange/Sandoglobulin Guillain-Barre Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barre syndrome. Lancet 1997; 349(9047):225-30.
3. Hughes RA, Swan AV, Raphaël JC et al. Immunotherapy for Guillain-Barré syndrome: a systematic review. Brain 2007; 130(Pt 9):2245-57.
4. Hughes RA. Treating nerves: a call to arms. J Peripher Nerv Syst 2008; 13(2):105-11.
5. Peripheral Nerve Society. The International Inflammatory Neuropathy Consortium webpage. Accessible at http://pns.ucsd.edu/INC.htm .
6. Overell JR, Hsieh ST, Odaka M et al. Treatment for Fisher syndrome, Bickerstaff's brainstem encephalitis and related disorders. Cochrane Database Syst Rev 2007; (1):CD004761.
7. Hahn AF, Bolton CF, Zochodne D et al. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study. Brain 1996; 119(pt 4):1067-77.
8. Sharma KR, Cross J, Ayyar DR et al. Diabetic demyelinating polyneuropathy responsive to intravenous immunoglobulin therapy. Arch Neurol 2002; 59(5):751-7.
9. Dyck PJ, Litchy WJ, Kratz KM et al. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 1994; 36(6):838-45.
10. Dalakas MC, Quarles RH, Farrer RX et al. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol 1996; 40(5):792-5.
11. Comi G, Roveri L, Swan A et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated with demyelinating neuropathy. J Neurol 2002; 249(10):1370-7.
12. Azulay JP, Blin O, Pouget J et al. Intravenous immunoglobulin treatment in patients with motor neuron syndromes associated with anti-GM1 antibodies: a double-blind, placebo-controlled study. Neurology 1994; 44(3 pt 1):429-32.
13. Leger JM, Chassande B, Musset L et al. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study. Brain 2001; 124(pt 1):145-53.
14. Federico P, Zochodne DW, Hahn AF et al. Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study. Neurology 2000; 55(9):1256-62.
15. Gajdos P, Chevret S, Clair B et al. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 1997; 41(6):789-96.
16. Qureshi AI, Choudhry MA, Akbar MS et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology 1999; 52(3):629-32.
17. Ronager J, Ravnborg M, Hermansen I et al. Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis. Artif Organs 2001; 25(12):967-73.
18. Selcen D, Dabrowski ER, Michon AM et al. High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol 2000; 22(1):40-3.
19. Jaretzki A 3 rd , Barohn RJ, Ernstoff RM et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Ann Thorac Surg 2000; 70(1):327-34. Accessible online at http://ats.ctsnetjournals.org/cgi/content/full/70/1/327 .
20. 1998 TEC Assessments; Tab 19.
21. Goodin DS, Frohman EM, Garmany GP et al. Disease modifying therapies in multiple sclerosis. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58(2):169-78.
22. Dalakas MC, Illa I, Dambrosia JM et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993; 329(27):1993-2000.
23. Al-Mayouf SM, Laxer RM, Schneider R et al. Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol 2000; 27(10):2498-503.
24. Gottfried I, Seeber A, Anegg B et al. High dose intravenous immunoglobulin (IVIG) in dermatomyositis: clinical responses and effect on sIL-2R levels. Eur J Dermatol 2000; 10(1):29-35.
25. Feasby T, Banwell B, Benstead T et al. Guidelines on the use of intravenous immune globulin for neurologic conditions. Transfus Med Rev 2007; 21(2 suppl 1):S57-107.
26. Cherin P, Pelletier S, Teixeira A et al. Results and long-term follow-up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum 2002; 46(2):467-74.
27. Medicare coverage policy #CAG-00109N, 2002. Available online at: http://cms.hhs.gov/coverage/8b3-kkk.asp
28. Bachot N, Revuz J Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 2003; 139(1):33-6.
29. Letko E, Miserocchi E, Daoud YJ et al. A nonrandomized comparison of the clinical outcome of ocular involvement in patients with mucous membrane (cicatricial) pemphigoid between conventional immunosuppressive and intravenous immunoglobulin therapies. Clin Immunol 2004; 111(3):303-10.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. Lockwood CM. New treatment strategies for systemic vasculitis: the role of intravenous immune globulin therapy. Clin Exp Immunol 1996; 104(suppl 1):77-82.
36. 1998 TEC Assessments; Tab 14.
37. 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.
38. Scott JR. Immunotherapy for recurrent miscarriage (Cochrane Review). In: The Cochrane Library, Issue 3, 2002. Oxford: Update Software.
39. Jablonowska B, Selbing A, Palfi M et al. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod 1999; 14(3):838-41.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. Voss LM, Wilson NJ, Neutze JM et al. Intravenous immunoglobulin in acute rheumatic fever: a randomized controlled trial. Circulation 2001; 103(3):401-6.
48. McNamara DM, Holubkov R, Starling RC et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001; 103(18):2254-9.
49. Hundt M, Manger K, Dorner T et al. Treatment of acute exacerbation of systemic lupus erythematosus with high-dose intravenous immunoglobulin. Rheumatology (Oxford) 2000; 39(11):1301-2.
50. Levy Y, Sherer Y, Ahmed A et al. A study of 20 SLE patients with intravenous immunoglobulin--clinical and serologic response. Lupus 1999; 8(9):705-12.
51. Boletis JN, Ioannidis JP, Boki KA et al. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 1999; 354(9178):569-70.
52. Dalakas MC, Fujii M, Li M et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001; 345(26):1870-6.
53. Casadei DH, del C Rial M, Opelz G et al. A randomized and prospective study comparing treatment with high-dose intravenous immunoglobulin with monoclonal antibodies for rescue of kidney grafts with steroid-resistant rejection. Transplantation 2001; 71(1):53-8.
54. Luke PP, Scantlebury VP, Jordan ML et al. Reversal of steroid- and anti-lymphocyte antibody-resistant rejection using intravenous immunoglobulin (IVIG) in renal transplant recipients. Transplantation 2001; 72(3):419-22.
55. Jordan SC, Quartel AW, Czer LS et al. Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 1998; 66(6):800-5.
56. LeHoang P, Cassoux N, George F et al. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm 2000; 8(1):49-57.
57. Rosenbaum JT, George RK, Gordon C. The treatment of refractory uveitis with intravenous immunoglobulin. Am J Ophthalmol 1999; 127(5):545-9.
58. Noseworthy JH, O'Brien PC, Petterson TM et al. A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis. Neurology 2001; 56(11):1514-22.
59. Kishiyama JL, Valacer D, Cunningham-Rundles C et al. A multicenter, randomized, double-blind, placebo-controlled trial of high-dose intravenous immunoglobulin for oral corticosteroid-dependent asthma. Clin Immunol 1999; 91(2):126-33.
60. Salmun LM, Barlan I, Wolf HM et al. Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: a double-blind, placebo-controlled, randomized trial. J Allergy Clin Immunol 1999; 103(5 pt 1):810-5.
61. Sullivan KM, Kopecky KJ, Jocom J et al. Immunoglobulin and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 1990; 323(11):705-12.
62. Bass EB, Powe NR, Goodman SN et al. Efficacy of immune globulin in preventing complications of bone marrow transplantation: a meta-analysis. Bone Marrow Transplant 1993; 12(3):273-82.
63. Guglielmo BJ, Wong-Beringer A, Linker CA. Immune globulin therapy in allogeneic bone marrow transplant: a critical review. Bone Marrow Transplant 1994; 13(5):499-510.
64. Cordonnier C, Chevret S, Legrand M et al. Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled multicenter trial. Ann Intern Med 2003; 139(1):8-18.
65. Raanani P, Gafter-Gvili A, Paul M et al. Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation. Cochrane Database Syst Rev 2008; (4):CD006501.
66. Jordan SC, Tyan D, Stablein D et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol 2004; 15(12):3256-62.
67. Jordan SC, Vo AA, Nast CC et al. Use of high-dose human intravenous immunoglobulin therapy in sensitized patients awaiting transplantation: the Cedars-Sinai experience. Clin Transpl 2003; 193-8.
68. MontgomeryRA, Zachary AA. Transplanting patients with a positive donor-specific crossmatch: a single center’s perspective. Pediatr Transplant 2004; 8(6):535-42.
69. JordanSC, Vo AA, Tyan D et al. Current approaches to treatment of antibody-mediated rejection. Pediatr Transplant 2005; 9(3):408-15.
70. Lehrich RW, Rocha PN, Reinsmoen N et al. Intravenous immunoglobulin and plasmapheresis in acute humoral rejection: Experience in renal allograft transplantation. Hum Immunol 2005; 66(4):350-8.
71. Casadei DH, del C Rial M, Opelz G et al. A randomized and prospective study comparing treatment with high-dose intravenous immunoglobulin with monoclonal antibodies for rescue of kidney grafts with steroid-resistant rejection. Transplantation 2001; 71(1):53-8.
72. Ibernon M, Gil-Vernet S, Carrera M et al. Therapy with plasmapheresis and intravenous immunoglobulin for acute humoral rejection in kidney transplantation. Transplant Proc 2005; 37(9):3743-5.
73. Perlmutter SJ, Leitman SF, Garvey MA et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 1999; 354(9185):1137-8
74. Gardulf A. Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route. BioDrugs 2007; 21(2):105-16.
75. Helbert M, Farragher A. Subcutaneous immunoglobulin for patients with antibody deficiency. Br J Hosp Med (Lond) 2007; 68(4):206-10.
76. Chapel HM, Spickett GP, Ericson D et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000; 20(2):94-100.
77. Ochs HD, Gupta S, Kiessling P et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol 2006; 26(3):265-73.
78. Gardulf A, Nicolay U, Asensio O et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies – a prospective, multi-national study. J Clin Immunol 2006; 26(2):177-85.
79. Nicolay U, Kiessling P, Berger M et al. Health-related quality of life and treatment satisfaction in North American patients with primary immune deficiency diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol 2006; 26(1):65-72.
80. Moore ML, Quinn JM. Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century. Ann Allergy Asthma Immunol 2008; 101(2):114-21
81. ClinicalTrials.gov available online at http://www.clinicaltrials.gov

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

The following criteria are adapted from the Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst. 2005;10:220-228. The EFNS/PNS diagnostic criteria were designed to balance specificity and sensitivity.

I. Inclusion Criteria

1. Typical CIDP - Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least 2 months; cranial nerves may be affected; and absent or reduced tendon reflexes in all extremities
2. Atypical CIDP
   One of the following, but otherwise as in typical CIDP (tendon reflexes may be normal in unaffected limbs):

Predominantly distal weakness (distal acquired demyelinating symmetric, DADS)

Pure motor or sensory presentations, including chronic sensory immune polyradiculoneuropathy affecting the central process of the primary sensory neuron

Asymmetric presentations (multifocal acquired demyelinating sensory and motor, MADSAM, Lewis-Sumner syndrome

Focal presentations (e.g., involvement of the brachial plexus or of one or more peripheral nerves in one upper limb

Central nervous system involvement (may occur with otherwise typical or other forms of atypical CIDP)

II. Exclusion Criteria

Diphtheria, drug or toxin exposure likely to have caused the neuropathy

Hereditary demyelinating neuropathy, known or likely because of family history, foot deformity, mutilation of hands or feet, retinitis pigmentosa, ichthyosis, liability to pressure palsy

Presence of sphincter disturbance

Multifocal motor neuropathy

Antibodies to myelin-associated glycoprotein

III. Electrodiagnostic Criteria

1. Definite

At least one of the following:

At least 50% prolongation of motor distal latency above the upper limit of normal values in two nerves, or

At least 30% reduction of motor conduction velocity below the lower limit of normal values in two nerves, or

At least 20% prolongation of F-wave latency above the upper limit of normal values in two nerves (> 50% if amplitude of distal negative peak CMAP, 80% of lower limit of normal values), or

Absence of F-waves in two nerves if these nerves have amplitudes of distal negative peak CMAPs at least 20% of lower limit of normal values + at least one other demyelinating parameter* in at least one other nerve, or

Partial motor conduction block: at least 50% amplitude reduction of the proximal negative peak CMAP relative to distal, if distal negative peak CMAP at least 20% of lower limit of normal values, in two nerves, or in one nerve + at least one other demyelinating parameter* in at least one other nerve, or

Abnormal temporal dispersion (> 30% duration increase between the proximal and distal negative peak CMAP) in at least two nerves, or

Distal CMAP duration (interval between onset of the first negative peak and return to baseline of the last negative peak) of at least 9 ms in at least one nerve + at least one other demyelinating parameter* in at least one other nerve

2. Probable

At least 30% amplitude reduction of the proximal negative peak CMAP relative to distal, excluding posterior tibial nerve, if distal negative peak CMAP at least 20% of lower limit of normal values, in two nerves, or in one nerve + at least one other demyelinating parameter* in at least one other nerve

3. Possible

As in (1) but in only one nerve

CMAP, compound muscle action potential. To apply these criteria, the median, ulnar (stimulated below the elbow), peroneal (stimulated below the fibular head), and tibial nerves on one side are tested. Temperatures should be maintained at least 33° C at the palm and 30° C at the external malleolus (good practice points).

* Any nerve meeting any of the criteria

IV. Supportive Criteria

Elevated cerebrospinal fluid protein with leukocyte < 10/mm3 (level A recommendation)

Magnetic resonance imaging showing gadonlinium enhancement and /or hypertrophy of the cauda equine, lumbosacral or cervical nerve roots, or the brachial or lumbosacral plexus (level C recommendation)

Nerve biopsy showing unequivocal evidence of demyelination and/or remyelination in > 5 fibers by electron microscopy or in > 6 of 50 teased fibers

Clinical improvement following immunomodulatory treatment (level A recommendation)