This paper describes the current status of IVIg therapy for various neurologic diseases and compares the expected benefit of this therapy with that of other therapies. It discusses the recognized immunomodulatory effects of IVIg and addresses treatment issues, including the drug's safety, administration, adverse effects, and cost.

Methods

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I reviewed the data from more than 110 patients with various autoimmune neurologic diseases who have been treated with IVIg over the past 6 years at the Clinical Center of the National Institutes of Health under clinical research protocols approved by the institutional review board of the National Institute of Neurological Disorders and Stroke. I recorded common and unexpected adverse effects, new complications, and abnormal results on laboratory tests and noted the effect of IVIg on complement, cytokines, and lymphocytes in both in vivo and in vitro studies. I also reviewed original work published by other investigators over the past 6 years and screened it on the basis of its scientific merit, clinical relevance, assessment of the risks and benefits of IVIg therapy, and explication of IVIg's mechanisms of action. Direct exchange of views with these investigators was also helpful in objectively assessing the therapeutic and mechanistic role of IVIg in neurologic diseases.

Preparation and Safety

Each batch of IVIg is made by cold ethanol fractionation (the Cohn process) of human plasma derived from pools of 3000 to 10 000 donors [8, 9]. The product is purified by enzymatic treatment at a low pH, which is followed by fractionation and chromatography. The purified immunoglobulin is stabilized with glucose, maltose, glycine, sucrose, mannitol, or albumin [4, 8, 9]. The final product contains more than 95% IgG, less than 2.5% IgA, and a negligible amount of IgM. Among the IgG subclasses, IgG₁ varies from 55% to 70%, IgG₂ from 30% to 38%, IgG₃ from 0% to 6%, and IgG₄ from 0.7% to 2.6%, according to the size and composition of the donor pools used in the various proprietary IVIg preparations [10].

The IVIg preparations available in the United States are now safe with respect to the transmission of known viruses or infections. Donors are scrutinized for the human immunodeficiency virus (HIV); the human T-cell lymphotropic virus; and the hepatitis A, B, and C viruses. Furthermore, HIV and the hepatitis B virus are inactivated by the fractionation process. The effectiveness of this was confirmed experimentally by intentionally adding HIV to IVIg [8]. In addition, treatment with solvents, detergents, or enzymes and incubation at low pH, as currently applied, inactivates the hepatitis C virus and other viruses [11]. The human immunodeficiency virus has never been transmitted through the use of IVIg. In the United States, at least 137 suspected or documented cases of hepatitis C were transmitted with Gammagard (Baxter Healthcare Corp., Glendale, California) [12]. The manufacturer replaced Gammagard with Gammagard-SD, which is treated with a solvent and detergent [11]. Safety concerns prompted a pharmaceutical firm to withdraw a batch of IVIg from the market because one of the thousands of donors was found to have Creutzfeldt-Jakob disease. This action was based only on the theoretical possibility of transmission; prion proteins have not been experimentally transmitted through the use of blood products.

Despite the proven safety of IVIg and the extreme caution exercised by pharmaceutical manufacturers, clinicians need to be watchful to detect evidence of any unexpected infectious agents that may be associated with long-term use.

Clinical Pharmacology

Because IVIg preparations are derived from a large pool of human donors, they contain IgG antibodies against a wide spectrum of normal human proteins and anti-idiotypic antibodies directed against Fab, the antigen-binding region of these autoantibodies [3, 13, 14] (Figure 1). Electron microscopy of IVIg specimens has shown that 40% of the IgG molecules form dimers by double-arm or single-arm binding between their F(ab')₂ domains [15, 16] (Figure 1). The dimers, which are absent in native IgG, are readily formed in IVIg preparations and represent complexes of idiotypic-anti-idiotypic antibodies [13, 15, 16]. The larger the pool of donors, the higher the number of the F(ab')₂ dimeric pairs and the wider the expected spectrum of idiotypic-anti-idiotypic specificities [14, 17]. Preparations of IVIg also contain immunomodulating peptides, such as soluble CD4, CD8, and human leukocyte antigen molecules [18], and antibodies against exogenous antigens, viruses, and bacteria.

View larger version (80K): [in this window] [in a new window]   Figure 1. Immunoglobulin molecule and formation of dimers in intravenous immune globulin (IVIg). Left. Structure of the immunoglobulin molecule. Right. Immune globulin in a purified preparation derived from multiple donors contains 40% dimers, as the result of double-arm and single-arm binding, and 60% monomers.

After the intravenous infusion of IgG (2 g/kg of body weight, the usual dose used to treat neurologic diseases), the patient's serum IgG level increases fivefold [19, 20] and then declines by 50% in 72 hours before returning, in 21 to 28 days, to the pretreatment level. The marked initial decrease reflects extravascular redistribution. The IgG in the infusion easily enters the cerebrospinal fluid [20]. During the first 48 hours of the infusion, when the serum IgG level is high, the concentration of IgG in the cerebrospinal fluid increases as much as two-fold, but it returns to normal within a week [20].

Status of Intravenous Immune Globulin Therapy in Neurologic Diseases

In some neurologic diseases of autoimmune pathogenesis, some controlled clinical trials have established a definite or mildly beneficial effect of IVIg therapy, although the results are not consistent from trial to trial. In other neurologic diseases, evidence for the efficacy of IVIg therapy is either anecdotal or not fully substantiated. The neurologic diseases in which IVIg therapy has been studied are listed in Table 1.

Controlled Clinical Trials

The Guillain-Barre Syndrome

The Guillain-Barre syndrome is an acute demyelinating polyneuropathy that peaks within 2 weeks of onset and causes severe weakness or paralysis of the limbs and respiratory muscles [53]. Although the target antigen is still unknown, humoral and cellular immune mechanisms are implicated, as evidenced by activation of complement and deposition of membranolytic attack complex on the myelin sheath, the presence of circulating antiganglioside or glycolipid antibodies, an increase of T-cell activation products and cytokines, and invasion of the myelin sheath by sensitized macrophages [54].

During the first week of illness, the preferred therapy for patients with the Guillain-Barre syndrome who have severe disease and require assistance to walk is either plasmapheresis or IVIg. In controlled clinical trials [55], as many as 52% of patients improved after plasmapheresis compared with 38% of patients receiving sham apheresis. A controlled, randomized trial comparing IVIg therapy with plasmapheresis [21] concluded that IVIg was also effective as first-line therapy. In this study, as many as 52.7% of 74 patients receiving IVIg compared with 34% of 73 patients undergoing plasmapheresis had functional improvement of one grade or more after 4 weeks. Although IVIg therapy was clearly efficacious, the recommendation for its use as an alternative to plasmapheresis was challenged because the response to plasmapheresis in this study [21] was inferior to that in earlier studies [55]. This concern prompted a new multinational and multicenter trial that compared, in parallel, the efficacy of IVIg therapy alone, plasmapheresis alone, and plasmapheresis followed by IVIg therapy [56]. After 4 weeks of therapy and 48 weeks of follow-up, no statistically significant difference was seen between the treatments, confirming the efficacy of IVIg in the Guillain-Barre syndrome. In a pilot study of patients with the Guillain-Barre syndrome [57], the combination of IVIg and intravenous methylprednisone (500 mg) was more effective than IVIg therapy alone, prompting yet another ongoing clinical trial.

Early relapse may follow the initial response of a patient with the Guillain-Barre syndrome to plasmapheresis or IVIg therapy [53, 58]. In one controlled trial [21], relapses occurred almost equally in patients receiving plasmapheresis (8.3%) and patients receiving IVIg therapy (10.8%), and the outcome was the same in both groups [58]. In two small series [59, 60] the rate of early relapse was higher in IVIg-treated patients, and some of the patients who had relapse responded only to plasmapheresis. In the second multicenter trial, however, no difference was noted in the recovery from disability up to 48 weeks later among patients receiving IVIg, plasmapheresis, or plasmapheresis followed by IVIg therapy [56]. Consequently, the question of which therapy is preferable for using first, considering their similar efficacy and cost, is a matter of convenience and practicality. Therapy with IVIg may be preferred for patients in rural areas, in hospitals in which plasmapheresis is not immediately available and not routinely used with expertise, and in small children or patients who have poor venous access, sepsis, severe autonomic dysfunction, or unstable hemodynamics. In all other situations, the use of plasmapheresis or IVIg therapy is equally appropriate. If the illness continues to worsen in the first 15 days despite a full course of plasmapheresis, a trial of IVIg therapy is warranted. Whether a second course of IVIg therapy after 3 weeks of the initial illness offers additional benefit has not yet been established. In general, when patients with the Guillain-Barre syndrome remain weak but the progression of the disease has stopped, prudence, patience, and supportive care in intensive care units with complete monitoring of autonomic and cardiac functions are the appropriate measures regardless of the therapy used. If further therapy is deemed advisable, however, repeating the original regimen rather than using an alternate therapy appears to be a prudent approach.

Chronic Inflammatory Demyelinating Polyneuropathy

Although it is often referred to as chronic Guillain-Barre syndrome because of its immunopathologic and electrodiagnostic similarities to the Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy is a distinct acquired demyelinating polyneuropathy characterized by the slow onset (over weeks to months) of weakness, areflexia, and impaired sensation [61]. Unlike the Guillain-Barre syndrome, which is a monophasic disease, chronic inflammatory demyelinating polyneuropathy requires long-term therapy to maintain improvement. Although steroids are the first choice for treating chronic inflammatory demyelinating polyneuropathy, the response to these agents is sometimes slow, and protracted therapy increases the risk for severe side effects [22]. Furthermore, many patients stop responding to steroid therapy or have unacceptable side effects, necessitating the use of other therapies. In a controlled, randomized, crossover study of IVIg or plasmapheresis in 20 patients with chronic inflammatory demyelinating polyneuropathy [22], the two therapies were equally effective in improving muscle strength and neuropathic symptoms and in increasing the amplitude of evoked muscle-action potentials. These results were confirmed by those of another randomized study [23]. However, the suggestion that a monthly infusion of 1 g (instead of 2 g) of IVIg may be satisfactory for maintenance therapy [23] needs further confirmation. The choice of therapy (prednisone, IVIg, or plasmapheresis) is judged against cost, long-term side effects, patient age, venous access, disease severity, and concurrent illnesses. If steroids are contraindicated, produce unacceptable side effects, or become ineffective, IVIg therapy is preferable because it is easier to administer than plasma-pheresis [22]. Plasmapheresis is best reserved for cases in which IVIg therapy is ineffective.

Multifocal Motor Neuropathy

Early symptoms of multifocal motor neuropathy are the very slow onset of weakness and muscular atrophy, usually of the upper extremities, with areflexia and preservation of sensation. The disease is characterized by conduction block of the motor axons and, in many patients, by the presence of antibodies to the GM1 ganglioside. Unlike chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy does not respond to steroids or plasmapheresis. However, as shown in a controlled trial [24] and several open-label studies [26, 62, 63], this neuropathy responds remarkably well to IVIg therapy. As the symptoms diminish, the electrophysiologic conduction block resolves [63] but the GM1 antibody titers may remain unchanged. In an in vitro system, IVIg inhibited the binding of GM1 antibodies to the target antigen [64]. Therapy with IVIg is currently the treatment of choice. If the efficacy of IVIg diminishes after several months, the coadministration of intravenous cyclophosphamide, as much as 1 g/m² body surface area, may be helpful. Anecdotal evidence indicates that the efficacy of IVIg in multifocal neuropathy (and in chronic inflammatory demyelinating polyneuropathy or other conditions) can be restored by a short course of plasmapheresis before the next infusion.

Dermatomyositis

Dermatomyositis is an acquired myopathy; the first symptoms are weakness of the proximal muscles and a violaceous rash on the face and extremities [65]. In many cases, the creatine kinase level is elevated. Immunopathologically, the early deposition of membranolytic attack complex on the endomysial capillaries leads to capillary destruction, muscle ischemia, and inflammation. The disease responds to steroids but often becomes steroid-resistant, and some patients find the side effects of steroids unacceptable. Azathioprine, methotrexate, or cyclosporine may offer modest benefit in some cases [65].

In a double-blind study of IVIg therapy for refractory dermatomyositis [25], patient strength improved and, as documented by blindly read repeated muscle biopsy specimens, histologic and immunopathologic abnormalities resolved. Clinical improvement was clearly evident by the second monthly infusion. The benefits of IVIg therapy were short-lived, however, and repeated infusions were required every 6 to 8 weeks to maintain improvement. Repeated biopsies showed that IVIg inhibited the deposition of membranolytic attack complex on the endomysial capillaries by intercepting the incorporation of C3 into the C5 convertase assembly [25, 66] and downregulated the expression of the intercellular adhesion molecule-1 (ICAM-1) and the major histocompatibility complex class I (MHC-I) [25] antigen on the endomysial capillaries and muscle fibers. Because dermatomyositis responds to steroids, IVIg therapy is reserved for steroid-resistant patients or patients in whom steroids are contraindicated.

Preliminary Results and Open-Label Trials

Preliminary results of controlled trials, the results of open-label trials involving small numbers of patients, and case reports provide some information about the efficacy of IVIg therapy for various other neurologic conditions (Table 1). However, the appropriateness of this costly therapy for the management of these disorders has not been established.

Inclusion-body myositis, the most common acquired inflammatory myopathy in persons 50 years of age and older, is unresponsive to immunotherapies [67]. In a controlled, double-blind study of 19 patients [27], IVIg therapy produced an increase in muscle strength compared with placebo, but these gains were minor and not statistically significant. However, a modest, transitory, but functionally important improvement was noted in 6 of 19 patients (31.5%). Some benefit of IVIg therapy for this myopathy was also reported from a small, open-label trial [28]. Results from another, larger trial are being analyzed.

Several open-label studies [29, 30] and results from a controlled trial in nine patients with the Lambert-Eaton myasthenic syndrome [31] showed that IVIg therapy produced clinical and electrophysiologic improvement, with a decrease in the number of circulating antibodies against voltagegated calcium channels.

In patients with myasthenia gravis, the prototype of all autoimmune diseases characterized by pathogenic cross-linking or complement-fixing antibodies against the acetylcholine receptors, several reports suggest that IVIg therapy may have a moderate-to-dramatic benefit in as many as 60% of patients and an efficacy similar to that of plasmapheresis [32, 33]. Because many variables are involved in the therapeutic responses of patients with myasthenia gravis, well-designed controlled studies are needed to establish the efficacy of IVIg therapy in specific stages of the illness.

Results of a double-blind, placebo-controlled, cross-over trial in 11 patients who had paraproteinemic IgM demyelinating polyneuropathy with antiglycolipid antibodies against peripheral nerve [34] showed a modest and transitory beneficial effect of IVIg therapy in 3 of the patients. The antibodies against myelin-associated glycoprotein or gangliosides did not change appreciably in the treated patients. Open-label trials [35, 36] have also claimed that IVIg had modest therapeutic efficacy in some patients with this neuropathy.

Therapy with IVIg reduced the frequency of convulsive seizures in eight of nine patients with the Rasmussen syndrome [37]; such patients often have antibodies to glutamate receptors. Among a few patients with intractable childhood epilepsy, the West syndrome, or the Lennox-Gastaut syndrome [38] who were treated with IVIg on the assumption that the seizures were caused by postviral encephalitis, anecdotal reports indicated better seizure control after IVIg therapy.

Therapy with IVIg produced variable, mild-to-moderate improvement in as many as 70% of patients with polymyositis [39] and in some patients with relapsing remitting multiple sclerosis [40] or optic neuritis [42], prompting an ongoing controlled clinical trial. In a recently completed double-blind, placebo-controlled study of 148 patients with relapsing-remitting multiple sclerosis, monthly infusions of IVIg for 2 years significantly improved the course of clinical disability and significantly reduced the frequency of relapses [41]. However, changes in demyelinating lesions shown by magnetic resonance imaging were not studied. Therapy with IVIg produced variable improvement in a few patients with the stiff-man syndrome [43], paraneoplastic cerebellar degeneration with anti-Yo antibodies [44], paraneoplastic encephalomyelitis and sensory neuropathy with anti-Hu antibodies [45], myelopathy caused by human T-cell lymphotropic virus-1 infection [46], systemic vasculitis [47], autoimmune diabetic neuropathy [48], acute idiopathic dysautonomic neuropathy [49], or Vogt-Koyanagi-Harada syndrome (uveomeningitis associated with depigmentation of the skin and central nervous system involvement) [50]. However, in patients with amyotrophic lateral sclerosis [26], polyneuropathy of critical illness [51], or adrenoleukodystrophy [52], IVIg therapy appears to have had no benefit.

Immunomodulatory Actions

The mechanisms by which IVIg exerts a therapeutic effect on some neurologic diseases with diverse causes have not been explored, but they are probably various immunomodulatory actions (Table 2) operating alone or in combination.

Intravenous immune globulin supplies anti-idiotypic antibodies that bind to and neutralize pathogenic autoantibodies, preventing their interaction with the autoantigen [3, 13, 14]. Binding of the anti-idiotypic antibodies to antigenic determinants and surface IgM or IgG on B cells could also cause negative signals on B cells and could result in down-regulation of antibody production [9, 68, 81]. Furthermore, the antibodies against CD5 molecules in IVIg [69] may inactivate the autoantibody-producing CD20⁺ (B1) subset of B cells [82].

Intravenous immune globulin contains high-affinity neutralizing antibodies against interleukin-1a, interleukin-6, and tumor necrosis factor- [70, 71] in quantities sufficient to suppress circulating pathogenic cytokines or downregulate the synthesis of cytokines by the T cells [70]. It also contains neutralizing antibodies against epitopes of superantigens [72] and antibodies against the V ß 3, V ß 8, and V ß 17 gene families of the T-cell receptor peptides [73]. Because superantigens (for example, bacterial toxins, enterotoxins, and viruses) stimulate a large fraction of V ß chain-expressing unsensitized T cells and cytokine secretion, their inhibition prevents the activation and clonal expansion of superantigen-triggered cytotoxic T cells [72].

The binding of infused IgG molecules to Fc receptors on the surface of phagocytic cells that invade the target tissues of patients with various autoimmune neurologic diseases can prevent Fc receptor-mediated phagocytosis of antigen-bearing target cells or inhibit antibody-dependent cell-mediated cytotoxicity by saturating or altering the affinity of the Fc receptors [74, 75].

The formation of covalent and noncovalent complexes between IVIg and the products of complement activation, notably C3b and C4b [76], prevents the incorporation of C3 molecules into the C5 convertase assembly [66] and interferes with the formation and deposition of membranolytic attack complex on target cells, as shown in Figure 2. The deposition of membranolytic attack complex mediates the destruction of myelin and axons in the Guillain-Barre syndrome, the postsynaptic region of the neuromuscular junction in myasthenia gravis, and the endomysial capillaries in dermatomyositis.

View larger version (71K): [in this window] [in a new window]   Figure 2. Effect of immune globulin on complement deposition. Activation of the complement pathway on the cell surface begins by the binding of the C1q on the antigen-antibody complex, triggering the cascade of C3 activation. This leads to the activation of C3b fragments and the formation of membranolytic attack complex (MAC), which causes cell lysis. Immune globulin inhibits complement deposition (wavy arrows) by acting on the C3b fragments and preventing the incorporation of C3 molecules into the C5 convertase assembly [25, 65, 75]. The effect is the inhibition of membranolytic attack complex formation and prevention of cell lysis. In addition, intravenous immune globulin (IVIg) may saturate the CR1 and CR3 receptors (red ovals) on activated macrophages (Ø) and inhibit opsonization of immune complexes by preventing the binding of C3b and C3bi complement fragments.

Intravenous immune globulin induces transient lymphopenia, reduces the number of natural killer cells [77, 78], and appears to downregulate the expression of lymphocyte function-associated antigen-1 on activated T cells [79]. In addition, the presence of soluble CD4, CD8, and MHC-II molecules in IVIg [18] theoretically could interfere with antigen recognition by the T cells. The function of CD8⁺ T cells may also be inhibited by antibodies in IVIg directed against a conserved region of MHC-I molecules [80].

Treatment Considerations

Selection and Administration

All proprietary preparations of IVIg are more or less similar in efficacy, safety, and cost. Although the different pools of human donors used by the various manufacturers contain a wide range of anti-idiotypic antibody specificities, no difference in the efficacy of a certain product or a particular lot for a given patient or a specific disease has been documented.

The therapeutic dose of IVIg is empirically set at 2 g/kg. Although some practitioners divide the total dose for infusion into five daily doses of 400 mg/kg each, it may be preferable to divide the total dose into two daily doses of 1 g/kg each, provided that the patient does not have such underlying conditions as congestive heart failure, renal insufficiency, or high serum viscosity. In our experience, the 2-day infusion in medically healthy persons is not associated with more adverse reactions than the 5-day infusion, provided that the rate of infusion does not exceed 200 mL per hour or 0.08 mL/kg per minute. Considering the drug's rapid diffusion to the extravascular space, achieving a high concentration of IVIg within 2 days may enhance efficacy. Experimental studies, both in vitro and in vivo, have suggested a superior effect on cytokine neutralization [71], Fc receptor manipulation [74], and inhibition of C3 fragments [76] when IVIg concentrations equivalent to 2 g/kg were given in a bolus infusion rather than in divided doses. In children with the Kawasaki syndrome, one 2-g/kg dose of IVIg given in a 10-hour infusion was more effective than four daily infusions of 400 mg/kg each [6]. In long-term therapy, the IVIg infusion is repeated every 4 to 8 weeks according to patient response and objective signs of disease recurrence. The efficacy of lower doses of IVIg in maintaining improvement, as suggested for patients with chronic inflammatory demyelinating polyneuropathy [23], remains to be determined.

Adverse Reactions and Risk Factors

In general, adverse reactions to IVIg therapy are usually minor and occur in no more than 10% of patients. Mild-to-moderate headache, which responds to nonsteroidal anti-inflammatory drugs, is common. Chills, myalgia, or chest discomfort may develop in the first hour of the infusion and usually respond to cessation of the infusion for 30 minutes and resumption of it at a slower rate. Fatigue, fever, or nausea may occur after infusion and may last as long as 24 hours. The cause of these reactions is unclear, but activation of complement by aggregated immunoglobulin molecules or various stabilizing agents in the IVIg preparation has been implicated [4, 5]. A slow rate of infusion is advisable in patients with a compromised cardiovascular system or congestive heart failure to avoid rapid fluid overload.

Serum Viscosity and Thromboembolic Events

Therapy with IVIg increases serum viscosity. In patients with high normal serum viscosity in conditions such as cryoglobulinemia, hypercholesterolemia, or hypergammaglobulinemia, viscosity increases even further [19]. Serum viscosity greater than 2.5 centipoise (normal, 1.2 to 1.8 centipoise) increases the risk for thromboembolic events, which probably accounts for the rare cases of stroke or pulmonary embolism after IVIg therapy [19, 83-85]. Therapy with IVIg can also induce a hyperviscosity syndrome in children with HIV infection who have high pretreatment levels of serum immunoglobulins [86]. Reversible cerebral vasospasm has occurred in a patient treated with IVIg [87].

Migraine Headache

In patients with a history of migraine, IVIg therapy may trigger a migraine attack, which can sometimes be prevented by propranolol prophylaxis [88]. The incidence of aseptic meningitis, discussed below, is also high in these patients [20]. Therapy with IVIg was associated with stroke in a young woman with a history of migraine [85].

Aseptic Meningitis

Aseptic meningitis develops in as many as 10% of patients treated with IVIg and is unrelated to the commercial source of the IVIg product, the infusion rate, or the underlying disease [20, 89]. Prophylaxis with intravenous steroids is often ineffective. The symptoms respond to strong analgesia and subside in 24 to 48 hours. Additional diagnostic testing is rarely necessary [89].

Skin Reactions

Skin reactions to IVIg therapy, although rare, can develop 2 to 5 days after infusion and may last as long as 30 days. They include urticaria, pruritus of the palms, and petechiae of the extremities (Figure 3). Skin reactions associated with various lots of IVIg occurred in seven of the patients we have treated. Alopecia [90] and leukocytoclastic vasculitis occurring in a patient with cryoglobulinemia [91] are other, extremely rare, reactions to IVIg.

View larger version (83K): [in this window] [in a new window]   Figure 3. Petechiae on the dorsum of a patient's foot 3 to 5 days after an intravenous infusion of immune globulin.

Severe Anaphylactic Reactions

A severe anaphylactic reaction may occur in patients who have a serious deficiency of IgA associated with anti-IgE or anti-IgG antibodies against IgA, which react with the IgA in the IVIg preparation. The reaction is rare (the incidence of IgA deficiency in the general population is 1:1000, with as much as a 30% chance that anti-IgA antibodies are present) and occurs primarily in patients with common variable immunodeficiency [92, 93]. Nevertheless, we routinely determine the serum IgA level before starting therapy. The use of Gammagard-SD (Baxter Healthcare), which contains only small amounts of IgA, is recommended for treating patients with low serum IgA levels.

Renal Tubular Necrosis

Acute renal tubular necrosis, usually reversible, occurs rarely with IVIg therapy in patients who have preexisting kidney disease and volume depletion, especially elderly, diabetic, or poorly hydrated patients [94]. This complication has been associated with the high concentration of sucrose in one proprietary IVIg product [95]. Osmotic tubular nephrosis, caused by intravenous solutions containing a concentration of hypertonic sucrose similar to that in IVIg preparations, is also a rare reaction; diluting the IVIg preparation and slowing the rate of infusion minimizes the risk for this event [95].

Spurious Results on Serologic Tests

After IVIg therapy, the erythrocyte sedimentation rate increases sixfold or more [96], probably as a result of enhanced rouleaux formation and reduced surface area caused by the infused gammaglobulin. The increase can persist for 2 to 3 weeks and should not be considered a sign of developing vasculitis.

Hyponatremia, with sodium concentrations as low as 130 mg/L (normal, 135 to 145 mg/L), has occurred after IVIg therapy but not after placebo in our controlled studies [96]. The occurrence of hyponatremia seems to be related to the assay method, in which additional dilution of the sample is required because of the high serum protein concentration [97].

Passive infusion with IVIg of antiviral or antibacterial antibodies may increase viral titers and may affect serologic test results for as long as 30 days after IVIg therapy.

Cost of Treatment

Hospital or retail pharmacies pay the wholesale price of approximately $18 to $25 per gram of IVIg. However, health insurers are charged $46 to $80 per gram by hospitals, home infusion companies, and physicians who administer the drug. This amounts to a retail cost of $6440 to $11 200 per month for the drug alone to treat a patient weighing 70 kg. The cost of treatment also depends on whether the drug is administered in a hospital, an outpatient clinic, or a home-infusion program and on whether it is given in 2 days or 5 days. When these costs are added to the price of the drug, the total monthly charges can range from $8500 to $20 000.

Comparisons of the cost of IVIg and alternate therapies, such as plasmapheresis or long-term immunosuppressive drugs, are not available. However, plasmapheresis is almost as expensive as IVIg therapy, is more cumbersome to administer, is not readily available, and usually has more adverse effects. Corticosteroids or immunosuppressants, although much less expensive than IVIg, can be costly in terms of iatrogenic complications with long-term use and the potential loss of wages associated with inadequate disease control. Although actual cost in dollars will strongly influence the choice of therapy, other factors, such as the adverse effects of long-term treatment (as with steroids); the medical costs of treatment complications; and, not least, the patient's safety, comfort, quality of life, and potential for a faster and better therapeutic response should also be considered.

Future Directions

Therapy with IVIg has a substantial beneficial effect on patients with certain disabling neurologic diseases that are often unresponsive to other immunotherapies. This therapy is, however, extremely expensive. Although a monophasic disease such as the Guillain-Barre syndrome can be treated successfully with only one set of infusions, other diseases require repeated infusions, which escalates the cost of therapy. Establishing the efficacy of IVIg therapy in rigorously controlled clinical trials is therefore essential. Questions about optimal dosage, frequency of administration, synergistic effects, penetrance, donor selection for specific idiotypes, potential toxicity with long-term use, and the precise mechanisms by which this natural human product exerts its effects remain unanswered and will continue to tantalize and challenge clinical researchers.

Glossary

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Antibody-dependent cell-mediated cytotoxicity: The killing of an antibody-coated target cell by cells (for example, macrophages) whose Fc receptors recognize the Fc region of the bound antibody.

Complement: A group of plasma proteins that, when activated, bind to a target antigen or pathogen.

Complement receptors: Cell-surface proteins (for example, on macrophages) that allow cells to recognize and bind to proteins or pathogens coated with complement, facilitating the uptake and phagocytosis of the pathogen.

Convertase: An enzyme that converts a complement protein into its reactive form.

Cytokines: A group of proteins that are made by cells and that affect the function of other cells; when made by lymphocytes, they are known as lymphokines or interleukins.

CD5 cells: A subset of B cells that produces antibodies against carbohydrate antigens.

Epitope: The site of an antigen recognized by an antibody.

Fc receptor: A cell-membrane protein that binds to the Fc region of an antibody.

Fc and Fab: Fragments generated when the IgG molecule (antibody) is cleaved by papain digestion. Three fragments are generated: two identical Fab (antibody-binding) fragments and one Fc (crystallizable) fragment. Fab has one antigenic binding site; F(ab')₂ has two binding sites and can cross-link an antigen.

Idiotope: An antigenic determinant on the variable region of an antibody that can be recognized by the variable (combining) site of other antibodies.

Idiotype: All antigenic determinants present on and characteristic of an antibody, located in the variable (combining) region.

Intercellular adhesion molecule: A cell-surface molecule that serves as a ligand for certain cell-surface proteins on lymphocytes called integrins; the integrin that interacts with the intercellular adhesion molecule for binding to certain cells is the lymphocyte function-associated antigen-1.

Major histocompatibility complex (MHC): A gene on chromosome 6 that encodes MHC molecules; MHC-I presents endogenous peptides to cytotoxic CD8⁺ T cells, and MHC-II presents exogenous and degraded peptides to CD4⁺ T cells. Human MHC is also called human leukocyte antigen.

Membranolytic attack complex: A lytic component of the complement pathway, initiated by the deposition of C5b on a cell membrane and the assembly of C6, C7, C8, and C9 to form the C5b-9 membranolytic attack complex.

Opsonization: The coating or alteration of a pathogen's surface by complement, immune complexes, or microorganisms for phagocytosis by macrophages or neutrophils.

Superantigen: A toxin, bacterium, or virus that stimulates T cells by binding directly, without antigen presentation, to the V ß chain of the T-cell receptor.

T-cell receptor: A heterodimer of two variable chains. The and ß chains are expressed on the T-cell membrane, and the and delta chains are expressed on a subset of T cells.