Introduction

Intravenous immunoglobulin (IVIG) is a biological agent though developed for the therapy of immunodeficiency states, is now utilized for many types of diseases including infections, inflammatory and autoimmune diseases. While IVIG is beneficial in organ-specific diseases, especially of the skin and nervous system, it is also efficient for systemic autoimmune diseases including systemic lupus erythematosus (SLE) and vasculitis. The mechanisms of the positive of IVIG effects are manifold. The realistic goal of such therapy is to normalize the immunoregulatory system that has been compromised.

In this update, we will discuss customizing IVIG therapy for the individual patient with an off-label indication, based on updated relevant clinical and research data. We will relate to the factors to consider before initializing IVIG therapy, and thoughts about further application of a risk assessment score for each patient.

Mechanisms

The various mechanisms for IVIG in the modulation of the immune system are beyond the scope of this review and are summarized in Table 1 (1). Briefly, IVIG has multiple effects on the innate and adaptive immune systems. Mechanisms of action include Fc-receptor blocking by binding inhibitory Fc receptors (FcgR2b) and activating Fc receptor (FcgR1 and FcgR3), anti-cytokine effects, inhibition of complement activation, complement system regulation, enhanced suppressor activity, down-regulation of B and T cell function, idiotype network regulation, enhanced clearance of endogenous pathogenic autoantibodies, neutralization of autoantibodies, neutralization of superantigens, and reticuloendothelial clearance.The therapeutic effects of IVIG in antibody-mediated diseases such as SLE include direct effects on B cells. IVIG suppresses the expansion of autoreactive B lymphocytes through signaling of the FcgRIIB, idiotype-mediated inhibition of B cell receptors, and neutralization of B cell survival factors (BAFF and APRIL). (2).

Table 1

IVIg Mechanisms of action.

Recently, it was suggested that restoration of levels of sialic acid-rich IGG by therapy with IVIG can dampen inflammatory effects twofold: by inhibition of Fcgamma RIIB expression and by suppression of effector autoantibody function (3).

Much investigation has been applied to the effect of IVIG on T cell activity. IVIG modulates T regulator (Treg) cells, and cytokine activity directly. Treg regulation is altered following IVIG therapy in SLE patients (4). In addition, transforming growth factor beta (TGFβ) may contribute to the immune regulation of IVIG therapy.

If IVIG has an effect on the T arm of the immune system, then in this sense, it may be beneficial for a group of diseases characterized by a cytokine storm. These diseases include adult onset Still’s disease (AOSD) and hemophagocytic syndrome (HPS). In AOSD, IVIG was partially effective in a study of 62 patients (5)

IVIG sources and extraction

As a biological agent, scrutiny is of utmost importance to prevent contaminants entering the product which is pooled from 1,000–60,000 donors depending on the manufacturer. IVIG extraction processes are necessary, but may alter the structure of the immunoglobulin and hence its biologic activity. Different methods of extraction may generate an immunoglobulin that is suitable for intramuscular or subcutaneous administration. Fractionation leads to a product that is at least 90% pure IgG. Ion exchange chromatography may further enhance the purity of IgG to 98%. The monomeric immunoglobulin is purported to be similar to natural IgG but the form of IgG may differ among products, as it may be monomeric, dimeric, or multimeric.

Labile viruses (Hepatitis B and C) are removed by cold ethanol processes. Their transmission has been rarely reported. HIV transmission has never been reported.

IVIG does not contain preservatives because of the potential risk of causing denaturation of the proteins, as well as the large amount of preservatives that would be needed in the product that could be hazardous to the patient. Current purification methods are manifold and utilized to reduce viral and prion contamination (6).

While IVIg does not contain preservatives, many stabilizers are utilized among different IVIG products. The stabilizers include dextrose, sucrose, maltose, glucose, L-proline, D-sorbitol, glycine, albumin and polyethylene glycol (PEG). Trace amounts of detergents or solvents are identified in the final product. Sucrose containing IVIG products in the past were implicated in the development of renal failure as an adverse event to therapy. Since most manufacturers have removed sucrose from their products, renal failure has become a rare serious adverse event.

The osmolarity may vary (192–1250 mOsm/L). IVIG are available in the freeze-dried form or as ready to use standardized liquid formulations that contain 5% or 10% globulin (6).

Dose and route

Intravenous administration is the generally accepted method of therapy. However, subcutaneous treatment with IVIG is an accepted method for the treatment of immunodeficiencies. This route has not been investigated for efficacy or safety in other diseases.

Very low doses of IVIG (0/3–0.6 g/kg once monthly) are usually sufficient for treatment of immunodeficiency (7).

Low-dose IVIG protocols (400 mg/kg once monthly) are beneficial for organ-specific diseases especially neurological disorders. Some open trials have shown beneficial effects for low- moderate dose IVIG therapy for Alzheimer’s disease (8).

Low-dose IVIG (500 mg/kg once monthly) was beneficial in a study of 62 patients with SLE. There was some improvement in skin, serositis, and hematological manifestations, but not for involvement of the joints (9).

More often high doses are required for SLE and other autoimmune diseases. A currently accepted protocol is high-dose IVIG protocol (2 g/kg/course divided into 5 days or 400 mg/kg/day for 5 days).

Since no definite guidelines exist, some protocols include 1–3 g/kg/cycle. Furthermore, a cycle may be 3–5 days. In our opinion, 2 g/kg/course divided into 5 days is the protocol that should be universally employed (10, 11).

Caution should be used for overweight patients where 400 mg/kg/day for 5 days may produce protein overload. Hence, we recommend that the maximum dose should not exceed 160 grams or 30 grams per day (1).

Furthermore, the rate of infusion should be monitored. For the first timers, a slow rate should be initialized (0.5–1/0 mg/kg/minute), after 20 minutes increased to 1.5–2.5 mg/kg/min, and then increased if no adverse events are encountered.

The total time of the daily infusions on average are 5–6 hours. IVIG is to be administered in a hospital (or equivalent) day center where experienced health care providers are present throughout administration (6).

Subcutaneous administration can be done at home. The dose is 0.1g/kg/week. The infusion rate is 10–40 ml/hr, with a maximum of 20–30 ml per treatment (6).

If an adverse event occurs, the infusion rate may be decreased or discontinued according to the judgment of the experienced medical staff.

Our protocol includes premedication prior to the administration of IVIG on the first day only. Premedication includes hydrocortisone 50–200 mg intravenously (10,11).

Prophylaxis with low molecular weight heparin - enoxaprin 1 mg/kg sc as a single injection is indicated for patients with an increased risk of developing a thromboembolic event such as in patients with overlap lupus and antiphospholipid syndrome (personal communication).

Adverse events

Each patient should be screened for potential risk factors for the development of serious adverse events from IVIG therapy. We suggest using Table 2 for risk assessment, and approaching IVIG therapy cautiously if patients have more than 3 risk factors.

Table 2

Risk assessment score for IVIG therapy. More than 3 findings, we recommend that IVIG therapy should be administered cautiously.

Many IVIG preparations are available and hence may be customized to the patient that is at risk for adverse events.

Since the era of acute renal failure secondary to IVIG, sucrose (leading to 90% of cases of renal failure) has been removed from most IVIG products. Acute renal failure has become rare in the past years. Sucrose may cause damage to the tubular epithelium and cause osmotic nephrosis. Renal insufficiency develops rapidly within 1–10 days after initiation of IVIG therapy and leads to oliguric renal failure and increasing creatinine levels within 5 days. In most cases, renal failure is reversible upon discontinuation of therapy. However, 30% of patients may need hemodialysis. Mean renal function recovery time is 10 days. Hence, to date, if a sucrose containing IVIG preparation is utilized, the infusion rate should be slower than indicated for non-sucrose containing agents. Follow-up of renal function is mandatory (6, 12),

Another serious adverse effect is the increased risk of thromboembolic events (TE). The incidence of all TE events following IVIG is reported to be 0.6–3% per patient and 0.15–1.2% per treatment course (13). These are data from 8 years ago at the time when physicians were less aware of risk factors for events. Possible explanatory mechanisms include the increase in plasma viscosity, platelet and endothelial activation, and arterial spasms. A recent large scale study found the rate to be lower. Through a retrospective claims-based cohort study of individuals exposed to immunoglobulin products from 2008- 2010, using HealthCore’s Inte­grated Research Database, a longitudinal health care database, the prevalence of thromboembolic events secondary to IVIG treatment was assessed. Of 11,785 individuals exposed to IG products in the study period, 1% had TE events re­corded on the same day as immunoglobulin administration. TE rates per 1000 persons exposed ranged from 6.1 to 20.5 for different IG product groups. An increased TE risk was also found with older age (≥ 45 years), prior TE(s), and hypercoagulable state(s) (14).

The FDA guidelines for the prevention of TE events following IVIG include a restricted concentration of the product (no more than 5% IG), a monitored infusion rate of 0.5 mg/kg/hour and not exceeding 4 mg/kg/hour. A risk-benefit assessment should be done on every patient.

The prevalence of aseptic meningitis is up to 11% and remains an uncommon adverse event. Special considerations are necessary for patients with a history of migraine headaches including a slow infusion (no more than 6 g/hour) and premedication with acetaminophen and antihistamines are warranted. Meningitis may be a result of the formation of macroaggregates, crossing of the blood-brain barrier by the immunoglobulin, or stimulation by antigenic determinants of the endothelial meningeal arteries.

IVIG is contraindicated in patients with IgA deficiency. However, if absolutely necessary, one may choose an IVIG product that has minimal IgA concentration.

Other high-risk patients for IVIG therapy include: patients with renal insufficiency, diabetes mellitus, following exposure to nephrotoxic drugs, hypertension, hypercholesterolemia, and polycythemia vera.

Benefit

IVIG is indicated as a first –line therapy in a few instances such as primary immunodeficiencies, Kawasaki’s disease, Guillain-Barre syndrome, and idiopathic immune thrombocytopenia (ITP). For other off-label indications, IVIG is particularly beneficial for neurological, cutaneous, and hematological organ-specific dis­eases. Hence, it is not surprising that IVIG is advantageous for these organ manifestations in other systemic diseases (1).

IVIG is not a first-line therapy. Rather, IVIG is indicated as adjunct therapy to conventional immunosuppressive treatment, or as a substitution for immunosuppression due to failure of response but more often unacceptable side effects. For example, the lupus afflicted population is predominantly young, female, and in the reproductive phase of life. These women may often refuse conservative therapy including steroids and immunosuppression due to the disfiguring side effects of steroids including obesity, hirsutism, acne, moon facies and emotional lability, or possible infertility due to side effects of potent immunosuppression. In addition, SLE patients are more prone to develop infections, either due to the inherent diseases or secondary to immunosuppression. In these cases, IVIG may have an extra advan­tage. Furthermore, IVIG has a steroid-sparing effect. This is important because often either high doses of steroids are necessary for therapy, or patients develop unacceptable side effects from prolonged steroid consumption (10).

Although no randomized controlled trials were performed for SLE, there is evidence through some open trials and many case reports in over 100 patients that IVIG is beneficial. In most cases, IVIG was given by the high dose protocol (11,15). There is some evidence that low-dose protocol may be beneficial for mild lupus (9).

IVIG is useful for many manifestations of SLE including cutaneous, joint, serositis, hematological, diffuse neuropsychiatric, and salvage for certain types of lupus nephritis. In addition, IVIG is beneficial for patients with catastrophic antiphospholipid syndrome (16).

The protocol for lupus patients at our center includes high-dose IVIG 2g/kg/course divided over 5 days, monthly, for 6 months. Some patients had a remarkable recovery and needed fewer courses (patients with myocarditis). Some patients continued therapy with IVIG every 2–3 months for up to 5 years. Long-term benefit was maintained and no serious side effects were discovered upon long-term use (11). Most of the patients had diffuse neuropsychiatric diseases with features of cognitive impairment or mood swings. Cognitive impairment was diagnosed based on the diagnosis of SLE by the ACR criteria, active SLE disease at least serologically and with inflammatory markers ( elevated ESR), neuropsychological testing, and MRI and PET scan. Because the neuropsychiatric manifestations were not life-threatening, the patients were successfully treated with IVIG (personal communication).

Controversy exists upon whether IVIG is an effective agent for Alzheimer’s disease based on the finding of naturally occurring antibodies to Aβ amyloid in the product. While there was no a significant change in antibody titers, there was an improvement in cognitive function based on the mini-mental score (8). Recently, a phase II study on Alzheimer patients enrolled to receive different doses and intervals of IVIG did not find an advantage to 6 month therapy. The treatment protocols were safe, but did not show significant benefit. Factors to consider are that a larger population is required for further studies, a longer exposure is needed, IVIG administration for early mild disease, differentiation between familial genetic, vascular, and other types of Alzheimer’s disease, and high dose IVIG protocol should be assessed (17). Lastly, perhaps, specific anti- Aβ amyloid IVIG therapy should be considered.

Many other off-label indications exist for organ-specific and systemic autoimmune diseases. This topic is reviewed extensively elsewhere (1,18).

Worldwide, guidelines are being established for the indications of IVIG therapy in autoimmune diseases.

Some of the diseases being evaluated by the European CEDIT for possible IVIG indications include neuromuscular disease including: inclusion body myositis, non multiple sclerosis demyelinating central nervous system disease, cortico-resistant polymyositis, and autoimmune encepha­litis. Other diseases include hemolytic anemia, antiphospholipid syndrome, AOSD, ANCA associated vasculitis, and pemphigus vulgaris. Similar guidelines are being established in the United Kingdom, Canada, and Australia (19).

The National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for hematologic conditions. Specific recommendations for routine use of IVIG were made for 7 conditions: 1) acquired red cell aplasia, 2) acquired hypogammaglobulinemia (secondary to malignancy), 3) fetal-neonatal alloimmune thrombocytopenia, 4) hemolytic disease of the newborn, 5) HIV-associated thrombocytopenia, 6) ITP, and 7) post-transfusion purpura. Intravenous immune globulin was not recommended for use, except under certain life-threatening circumstances, for 8 conditions including acquired hemophilia; acquired von Willebrand disease, autoimmune hemolytic anemia, autoimmune neutropenia, hemolytic transfusion reaction, hemolytic transfusion reaction associated with sickle cell disease, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, and viral-associated hemophagocytic syndrome (20).

The question remains if randomized controlled trials (RCTs) are necessary to prove efficacy and safety for these rare autoimmune diseases. Furthermore, it will be even more difficult to assess the benefit of IVIG when evaluated for specific manifestations of the systemic autoimmune disease in such rigid trials. We suggest that open trials or case series for explicit manifestations of systemic autoimmune diseases are suitable for the evaluation of the efficacy of IVIG.

The RCT and open trials for ANCA associated vasculitis emphasized the need for a standard protocol. Without standard protocols, it will be difficult to evaluate response and safety. Proper protocols should include the total dose, over which period, repeated course after which time period, total length of protocol (how many months). One such consensus exists for the autoimmune mucocutaneous blistering diseases (AMBD). Their consensus statement suggests the use of high-dose IVIG (2 g/kg/cycle over 5 days), given monthly until clinical control with a progressive increase in intervals between cycles thereafter, to 6, 8,10, 12, and 14 weeks. The last cycle is given after a 16 week interval, and is considered the end of therapy. Using this protocol, patients with AMBD responded well, and other immunosuppressive drugs including steroids were gradually discontinued. After the discontinuation of the IVIG therapy, patients had sustained clinical and serologic remission for a 2 year follow-up (19). Our protocol is similar, but we give IVIG at fixed intervals, initially monthly, thereafter every 2–3 months (11).

To date, the treatment of AOSD has been largely empirical. A study was conducted to investigate the response to therapy and prognostic factors of AOSD in 54 Korean patients. Forty-two patients were treated with non-steroidal anti-inflammatory drugs. However, they also needed corticosteroids and IVIG. Among 42% of patients resistant to corticosteroids, add-on therapy with IVIG or anti-tumor necrosis factor (TNF) agents was administered. Of the 23 patients medicated with IVIG, the prognosis was better in IVIG-responsive patients, indicating a therapeutic effect (5). In AOSD patients that developed HPS, a high dose IVIG protocol (2 gr/kg/2–5 days) was beneficial (21).

In another study on secondary HPS patients, the beneficial effects of IVIG are controversial and may depend on the cause. In those patients with severe infections/sepsis as the casue of HPS, IVIG therapy was not beneficial (23); however, the IVIG dose and protocol used were not mentioned. In another study, HPS secondary to autoimmune disease in a pediatric population treated with high dose IVIG (1 gr/kg/day for 2 days) together with steroids or other immunosuppression showed to be beneficial in some cases (24). Although not many patients have received IVIG for HPS, one should consider its utilization if the HPS is secondary to autoimmune disease or AOSD.

Evidence suggests that IVIG may be beneficial for transplantation patients with preformed anti-HLA antibodies (who are at increased risk for acute rejection) and for HLA sensitized cardiac and renal allograft recipients.

Recently, the concept of dual therapy with IVIG and rituximab has been suggested. In a study of the beneficial effects of IVIG for ANCA positive vasculitis, patients were grouped by the level of response to IVIG therapy. While many were good responders, some were partial or non-responders. Those with partial response received IVIG together with rituximab and complete response was achieved. Those that needed some further treatment following cessation of this regimen could be successfully treated with mild immunosuppression including low dose glucocorticoids.

Similar results were reported for patients with AMBD, a severe form of autoimmune skin disease. Rituximab was added to the non-responder group. Remission was achieved and the combination therapy did not result in increased adverse events (20). These studies suggest that IVIG together with a B cell depletory agent is advantageous.

Specific IVIG for different Diseases

IVIG may be beneficial for patients with sepsis. Although the studies were not performed in patients with autoimmune diseases, IVIG should be strongly considered in the patients with sepsis and possibly an add-on treatment to standard fluid resuscitation and antibiotic therapy.

Patients with sepsis are a subgroup that may benefit from specific high dose IVIG which is IgM and IgA enriched. The use of polyclonal IVIG in septic patients was beneficial and led to a major reduction in mortality (21).

Specific autoimmune diseases could possibly be treated with antibody restricted IVIG. In murine experimental models, IVIG enriched with a specific antibody that would counteract the pathological antibody responsible for disease could be effective. The rationale would be to produce an antibody enriched concentrate that would be very potent, specific, and reduce the amount of IVIG introduced, and hence possibly reduce the risk for adverse events. The specific IVIG protocol has been prepared for SLE and vasculitis murine models and found to be beneficial. The specific IVIG when compared to the regular IVIG was 200 times more potent in preventing disease (24-27).

IVIG, though a biological agent, is not more expensive than other available biological agents. The cost on average is 75$/gram but may vary among countries (28).

It is yet to be determined if specific IVIG is feasible clinically and economically for patients, but could be an excellent example for tailored therapy in patients with rare diseases.

Conclusions

IVIG is a biological agent with good efficacy and safety record over the years. While it is formally indicated for only a few diseases, it has been used for therapy for many off-label indications. Guidelines are being assessed for IVIG therapy among the different specialties. IVIG products are different and hence have the advantage that they can be customized therapy according to the patient’s comorbidities. A standard dose and duration protocol should be agreed upon so that the beneficial effect can be properly assessed. RCTs will probably not occur, and we need to depend on case series or open trials. Before considering treatment with IVIG, a risk assessment checklist should be done. No formal checklists exist, but we recommend establishing such a checklist so as to prevent serious adverse events. Some evidence is arising that IVIG can be effective and safely administered with a B cell depletion biological agent such as rituximab. This trend still needs to be evaluated.

References

1.

Katz U, Shoenfeld Y, Zandman-Goddard G. Update on intravenous immunoglobulins (IVIg) mechanisms of action and off- label use in autoimmune diseases. Curr Pharm Des. 2011;17:3166–75. [PubMed: 21864262]

2.

Zandman-Goddard G, Blank M, Shoenfeld Y. Intravenous immunoglobulin in systemic lupus erythematosus- from the bench to the bedside. Lupus. 2009;18:884–8. [PubMed: 19671787]

3.

Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. New Eng J Med. 2012;367:2015–25. [PubMed: 23171098]

4.

Costa N, Pires AE, Gabriel AM, Goulart LF, et al. Broadened T-cell repertoire diversity in ivIg-treated SLE patients is also related to the individual status of regulatory T-cells. J Clin Immunol. 2012 [PubMed: 23064977] [CrossRef]

5.

Kim HA, Sung JM, Suh CH. Therapeutic responses and prognosis in adult-onset Still’s disease. Rheumatol Int. 2012;32:1291–8. [PubMed: 21274538]

6.

Gurcan HM, Keskin DB, Ahmed AR. Information for healthcare providers on general features of IGIV with emphasis on differences between commercially available agents. Autoimmunity Reviews. 2010;9:553–59. [PubMed: 20346419]

7.

Wasserman RL. Progress in gammaglobulin therapy from immunodeficiency: from subcutaneous to intravenous infusions and back again. J Clin Immunol. 2012;32:1153–64. [PubMed: 22828788]

8.

Dodel R, Neff F, Noelker C, et al. Intravenous immunoglobulins as a treatment for Alzheimer’s disease. Drugs. 2010;70:513–28. [PubMed: 20329802]

9.

Sherer Y, Kuechler S, Jose Scali J, et al. Low dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases. Isr Med Assoc J. 2008;10:55–7. [PubMed: 18300575]

10.

Zandman-Goddard G, Krauthammer A, Shoenfeld Y. The steroid-sparing effect of intravenous immunoglobulin in patients with autoimmune diseases. Expert Rev Clin Immunol. 2007;3:773–80. [PubMed: 20477027]

11.

Zandman-Goddard G, Krauthammer A, Levy Y, Langevitz P, Shoenfeld Y. Long-term therapy with intravenous immunoglobulin is beneficial in patients with autoimmune diseases. Clin Rev Allergy Immunol. 2012;42:247–55. [PubMed: 21732045]

12.

Orbach H, Tishler, Shoenfeld Y. Intravenous gammaglobulin and the kidney- a two-edged sword. Semin Arthritis Rheum. 2004;34:593–601. [PubMed: 15609263]

13.

Paran D, Herishanu Y, Elkayam O, Shopin L, Ben-Ami R. Venous immunoglobulins. Blood Coagul Fibrinolysis. 2005;16:313–8. [PubMed: 15970713]

14.

Daniel GW, Menis M, Sridhar G, et al. Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010. Transfusion. 2012;52:2113–21. [PubMed: 22448967]

15.

Levy Y, Sherer Y, Ahmed A, et al. A study of 20 SLE patients with intravenous immunoglobulin- clinical and serologic response. Lupus. 1999;8:705–12. [PubMed: 10602441]

16.

Espinosa G, Berman H, Cervera R. Management of refractory cases of catastrophic antiphospholipid syndrome. Autoimmun Rev. 2011;10:664–8. [PubMed: 21569863]

17.

Dodel R, Rominger A, Bartenstein P, et al. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: a phase 2, randomized, double blind, placebo controlled, dose-finding trial. lancet Neurology. 2013;12:233–43. [PMC free article: PMC4986921] [PubMed: 23375965]

18.

Kivity S, Katz U, Daniel N, Nussinovitch U, Papageorgiou N, Shoenfeld Y. Evidence for the use of intravenous immunoglobulins--a review of the literature. Clin Rev Allergy Immunol. 2010;38:201–69. [PMC free article: PMC7101816] [PubMed: 19590986]

19.

Hartung HP, Mouthon L, Ahmed R, Jordon S, Laupland KB, Jolles S. Clinical applications of intravenous immunoglobulins (IVIg)- beyond immunodeficiencies and neurology. Clin Exp Immunol. 2009;158(Suppl. 1):23–33. [PMC free article: PMC2801038] [PubMed: 19883421]

20.

Anderson D, Ali K, Blanchette V, et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev. 2007;21(2 Suppl 1):S9–56. [PubMed: 17397769]

21.

Arlet JB, Le TH, Marinho A, et al. Reactive haemophagocytic syndrome in adult-onset Still’s disease: a report of six patients and a review of the literature. Ann Rheum Dis. 2006;65:1596–601. [PMC free article: PMC1798476] [PubMed: 16540551]

22.

Shabbir M, Lucas J, Lazarchick J, Shirai K. Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and a review of literature. Hematol Oncol. 2011;29:100–6. [PubMed: 20809477]

23.

Lin CI, Yu HH, Lee JH, et al. Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases. Clin Rheumatol. 2012;31:1223–1230. [PubMed: 22615046]

24.

Shoenfeld Y, Rauova L, Gilburd B, et al. Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus. Int Immunol. 2002;14:1303–11. [PubMed: 12407021]

25.

Blank M, Anafi L, Zandman-Goddard G, et al. The efficacy of specific IVIG anti-idiotypic antibodies in antiphospholipid syndrome (APS): trophoblast invasiveness and APS animal model. Int Immunol. 2007;19:857–65. [PubMed: 17576752]

26.

Svetlicky N, Blank M, Zandman-Goddard G. The beneficial effects of intravenous immunoglobulin for antineutrophil cytoplasmic antibody-positive vasculitis. Isr Med Assoc J. 2012;14:568–9. [PubMed: 23101422]

27.

Svetlicky N, Ortega-Hernandez OD, Mouthon L, et al. The advantage of specific intravenous immunoglobulin (sIVIG) on regular IVIG: Experience of the last decade. J Clin Immunol. 2013;33(Suppl 1):S27–32. [PubMed: 23229779]

28.

Mark SM. Comparison of intravenous immunoglobulin formulations: product, formulary, and cost considerations. Hosp Pharm. 2011;46:668–76.