Immunoglobulins play an invaluable role in the body's adaptive immunological defense system. The importance of these antibodies is evident by the severe infections suffered by people who are deficient in these proteins. The therapeutic benefit of immunoglobulin was recognized when it was first used by Bruton1 in 1952 to treat agammaglobulinemia. Since then, immunoglobulin has become the standard treatment for patients with agammaglobulinemia and hypogammaglobulinemia.
Intravenous immunoglobulin (IVIG) is a blood product derived from the plasma of thousands of healthy donors (10,000–20,000) consisting mostly of human immunoglobulin (Ig) G (>90%), small amounts of IgM and IgA, as well as Th2 cytokines and cytokine antagonists, which may also contribute to therapeutic effects.
IVIG use is evolving because of the growing number of indications for which it is approved by the US Food and Drug Administration (FDA). “Off-label” use of IVIG, however, far exceeds the FDA indications. IVIG has had a major impact in multiple areas of medicine, particularly immunology, rheumatology, hematology, neurology, infectious disease, and dermatology. This review focuses on current use of IVIG in the treatment of pediatric rheumatologic disorders. It is important to be aware that IVIG is used off-label for most of the rheumatologic diseases discussed in this article, with the exception of Kawasaki disease and autoimmune thrombocytopenia.
Mechanism of Action
The mechanism of action by which IVIG exerts its therapeutic effects is not clearly understood and likely differs in the medical diseases for which it is prescribed (Table 1). Targets for IVIG include T cells, cytokines, B cells, complement, and Fc receptors. The predominant mechanism appears to depend on both the IG dose and the pathogenesis of the disease under consideration. Low-dose IVIG (200–400 mg/kg every 3–4 weeks) has proinflammatory properties, activating complement cascade via generation of nascent C3b.2 In contrast, anti-inflammatory activities are induced by high-dose IVIG (1–2 g/kg given over 1–5 days) via (1) modulation of expression and function of Fc receptors on macrophages, causing a down-regulation of phagocytosis; (2) inhibition of complement activation and function of the membrane attack complex; (3) inhibition of cytokine production with antibodies to Th1, cytokines, interferon-gamma, interleukin (IL)-4 and IL-5, which are proinflammatory, and production of Th2 cytokines, which are anti-inflammatory; (4) reduction of pathogenic autoantibodies; and (5) down-regulation effect on dendritic cells, T cells, and B cells.3
Proposed Mechanism of Intravenous Immunoglobulin
IVIG is generally well-tolerated. Side effects during IVIG administration tend to occur early during the infusion and are usually mild and transient but may be severe. Infusion reactions include flu-like symptoms (most common), with malaise, facial flushing, chest tightness, fever, chills, myalgia, fatigue, back pain, nausea, vomiting, or diarrhea. Changes in vital signs can also occur during the infusion, including tachycardia and blood pressure changes. These immediate reactions can be managed by reduction of the flow rate, and in some cases by stopping the infusion. Pretreatment with analgesics, nonsteroidal anti-inflammatory drugs, antihistamines, or intravenous glucocorticoids may help to mollify or prevent infusion reactions. Anaphylactic reactions are rare. These are most commonly seen in patients with a severe IgA deficiency who may produce anti-IgA antibodies. An IgA-depleted IVIG preparation can be used in these patients. There is controversy as to whether screening for IgA deficiency is indicated prior to therapy with IVIG. Aseptic meningitis is another rare complication of IVIG treatment. The signs and symptoms usually begin within 48 hours after infusion (but may occur later) and last for 3 to 5 days. Thromboembolic events and pulmonary edema from fluid overload have also been reported.4 A slower infusion rate is recommended to avoid these complications. Renal toxicity is a delayed adverse effect, and preexisting renal disease is the major risk factor. This reaction usually occurs between 8 hours and 10 days after the IVIG infusion. The proposed mechanism is an osmotic injury to the proximal tubules, particularly with sucrose-containing immunoglobulin preparations.5
Intravenous Immunoglobulin use in Pediatric Rheumatologic Diseases
Juvenile dermatomyositis (JDM) is a multisystem disease of uncertain origin that results in chronic inflammation of muscle and skin, with less frequent involvement of other systems, including the gastrointestinal tract and lungs. The efficacy of IVIG was initially demonstrated in a controlled trial of adults with dermatomyositis.6 In this study, 8 of 15 patients with clinically active disease, resistant to treatment with high-dose prednisone, methotrexate, azathioprine, or cyclophosphamide given for at least 4 to 6 months prior to enrollment in the study, were randomized to receive a monthly infusion of 2 g/kg of IVIG versus placebo. Reassessment after the third infusion revealed significant improvement in muscle strength and rash in comparison to placebo.
IVIG efficacy was also demonstrated in a case series of nine children with JDM that was resistant to therapy with prednisone, azathioprine, and cyclosporine, either in combination or alone.7 Improvement in strength was noted in all patients 2 weeks after the first infusion, and the prednisone dose could also be reduced in 6 of 8 patients.
IVIG was noted to be effective for JDM in a retrospective study with an inception cohort that compared the courses of 30 patients who were either steroid resistant or steroid dependent and treated monthly with 2 g/kg of IVIG versus 48 controls who had responded to first-line therapy (prednisone with/without methotrexate).8 The IVIG group included two subgroups of patients: steroid-resistant patients (who failed to respond to 6 weeks of initial therapy with corticosteroids, often with methotrexate or who had severe disease with dysphagia or weakness) and steroid-dependent patients (who improved with the initial 6 weeks of treatment but flared after subsequent dose reduction of corticosteroids). The IVIG group started with greater disease activity, which is a confounder, but bias-reduction methods were used for analysis. One month to 4 years after treatment, similar or lower disease activity was found in the patients treated with IVIG, particularly in patients with steroid-refractory disease, in comparison with controls.8
IVIG was initially reserved for second-line treatment for children with JDM resistant to first-line therapy (ie, corticosteroids and methotrexate). However, given the risks of poorer outcomes for patients with undertreated or longstanding disease and the adverse effects of high-dose, long-term corticosteroid use, the Childhood Arthritis and Rheumatology Research Alliance developed a consensus treatment protocol with recommendations for the initial therapy of patients with moderate to severe JDM.9 This population includes patients with severe weakness, dysphagia, gastrointestinal ulceration, or calcinosis. One of the three proposed treatment arms includes monthly IVIG in addition to standard therapy with corticosteroids and methotrexate. Data from this study may help define more accurately the benefit of IVIG in the management of JDM.
In summary, IVIG has been documented in the literature to be effective in children with JDM, including refractory cases. The evidence suggests it may also be beneficial as initial therapy in patients with moderate to severe JDM. JDM is the second most-common pediatric rheumatologic disorder (after Kawasaki disease) in which IVIG is considered and used.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies and multiorgan system involvement. Most data regarding the use of IVIG in patients with SLE comes from case reports and small uncontrolled series. The effects of IVIG in SLE were initially reported in 1989 in adult patients with mild SLE treated with monthly IVIG infusions of 300 to 500 mg/kg.10 Improvement of symptoms, including fatigue and vasculitic rash, was noted in all patients, and maintenance prednisone doses could be reduced in two-thirds of the patients. A retrospective study in pediatric SLE patients also suggested that IVIG may be effective in SLE.11 Six children (three with severe thrombocytopenia, one with Evan's syndrome, one with antiphospholipid syndrome, one with chorea) had clinical and laboratory improvement with IVIG treatment.9
The widely reported success of IVIG in the treatment of idiopathic thrombocytopenic purpura led to its increased use in patients with SLE-associated thrombocytopenia. Although there are no controlled trials of IVIG for thrombocytopenia in SLE, successful treatment has been demonstrated anecdotally. In a case series, seven patients with thrombocytopenia and SLE were treated with 400 mg/kg per day of IVIG for 5 days.12 Five of the seven patients had a >50% increase in their platelet counts by day 28 after the IVIG course. Four of these patients had a sustained benefit of at least 6 months in duration. In another cohort study, involving 59 SLE patients with severe thrombocytopenia associated with lupus, IVIG at a dose of 2 g/kg was given to 31 of the patients and resulted in positive responses in 65%; however, the response often was not sustained.13 Currently, IVIG in SLE-related thrombocytopenia is generally reserved for severe thrombocytopenia or thrombocytopenia refractory to treatment with corticosteroids.
Catastrophic antiphospholipid syndrome (CAPS) is a rare but recognized complication occurring in patients with SLE, and is associated with the presence of antiphospholipid antibodies (APLAs), which may increase the risk of thrombosis. Approximately one-third of SLE patients have APLAs.14 CAPS is a severe disorder characterized by diffuse vascular thrombosis leading to multiorgan failure. It occurs in at least 1% of patients APLAs.15 Given the rarity of the condition and that there are no prospective studies, treatment of CAPS is not currently standardized. Data from an international CAPS registry suggests that IVIG in combination with anticoagulation, corticosteroids, and plasma exchange may improve outcome and decrease mortality.16 Further study is needed to more clearly delineate the role of IVIG in the management of CAPS.
There are limited case reports and no controlled studies in children assessing the efficacy of IVIG treatment for other SLE-related complications. The only report found in the literature of IVIG use in children with lupus nephritis (LN) is a case series of nine children with biopsy-proven class IV (five patients), class V (two patients), or class IV/V (two patients) LN who had not responded to intravenous cyclophosphamide and methylprednisolone pulses.17 Three of the 5 patients with class IV LN had improvement of renal function and decreases in IgG deposits on repeat biopsy. Partial response was seen in the other children, with the least effectiveness in patients with class V LN. There are case reports of other SLE manifestations successfully treated with IVIG, including psychosis,18 and serositis.19 In sum, the lack of case reports and clinical trials in the literature provides inadequate evidence to support IVIG efficacy in SLE. It is rarely used in SLE, with the exception of patients with severe thrombocytopenia.
The incidence of congenital heart block (CHB) in the offspring of mothers with SSA and/or SSB autoantibodies ranges between 1% and 2%.20 The recurrence rate in subsequent pregnancies after the birth of a child with CHB is 20%. A prospective study assessed whether IVIG (400 mg/kg) every 3 weeks during the second trimester would decrease CHB recurrence in subsequent births to SSA- and/or SSB-positive mothers.21 The results suggested that IVIG was ineffective at reducing the recurrence rate of CHB in neonatal lupus (NL). However, a study by Trucco et al.22 suggested a benefit of high-dose IVIG combined with corticosteroids to treat NL-related cardiomyopathy when administered either prenatally or postnatally. The fetuses of 6 of 9 mothers given 1 g/kg of IVIG had improved fetal ventricular systolic function within 1 to 3 weeks of treatment. After being born, 17 infants received IVIG; at a median follow-up of 2.9 years, 80% of the offspring had normal systolic ventricular function, suggesting that IVIG treatment of NL-associated fetal cardiomyopathy potentially improves outcome.22 Further study is necessary to better determine the efficacy of IVIG to prevent the development of CHB and cardiomyopathy secondary to NL.
Juvenile Idiopathic Arthritis
Juvenile idiopathc arthritis (JIA) is the most common rheumatologic condition in childhood. The use of IVIG in JIA is controversial, and its role in the management of JIA has decreased during the past 15 years with the availability of effective biologics to treat this disease. In a small uncontrolled trial with 8 patients with active systemic JIA, IVIG was given monthly at a dose of 1 g/kg for 2 consecutive days for 6 to 13 months.23 Arthritis improved in 5 of 8 patients. Extra-articular features, steroid requirements, and laboratory parameters improved in 7 of 8 patients. However, a larger double-blind, randomized controlled trial of 31 children with active refractory systemic JIA showed limited clinical efficacy of IVIG.24 Patients were randomized to receive 1.5 g/kg of IVIG or placebo (0.1% albumin) every 2 weeks for 2 months, and then monthly for 4 more months. IVIG was not more effective than placebo in improving systemic manifestations, joint activity, or laboratory studies. A randomized controlled study of children with polyarticular JIA treated with IVIG (dose of 1.5 to 2 g/kg monthly for 2 months) demonstrated more clinical improvement in the treatment group, but the beneficial effect was short.25
High-dose IVIG therapy is the first-line treatment for Kawasaki disease (KD). The usefulness of IVIG in KD has been demonstrated in both uncontrolled and controlled trials26–28 and has now become the standard therapy for this condition. The first controlled trial of IVIG treatment in patients with KD was in 1986.26 This study compared the use of IVIG plus aspirin versus aspirin alone. A significant reduction in the frequency of coronary artery dilation (CAD) in patients treated with IVIG plus aspirin was observed compared with those receiving aspirin alone. A study of 160 children evaluated the effect of timing of IVIG treatment on KD outcomes.27 Patients receiving IVIG on days 11 to 20 post-symptom onset were compared to patients who received IVIG on days 4 to 8 of illness. Laboratory parameters improved in both groups; however, the occurrence of CAD during the convalescent phase was significantly higher in the late compared to the early IVIG-treatment group. Subsequently, the recommendation was made to treat children with KD within 10 days of symptom onset whenever feasible. A study in 1999 evaluated the efficacy and outcomes of treatment of patients with KD with 400 mg/kg per day of IVIG for 5 days versus 2 g/kg given in a single dose.28 There was a significant reduction of CAD and duration of fever in those children treated with the 2-g/kg dose. It was also found more cost-effective. Therefore, a single IVIG dose of 2 g/kg infused over 10 to 12 hours is the current standard of therapy.
The use of IVIG has been described in the treatment of other vasculitides, but data are limited. An open-label multicenter, prospective study evaluated the efficacy of IVIG to treat relapse in 22 adults with antineutrophil cytoplasmic autoantibody-associated vasculitis.29 IVIG, given monthly for 6 months, was added to patients' current treatment with corticosteroids and other immunosuppressant therapies. A proportion of patients entered and remained in remission at 24 months. The authors concluded that IVIG therapy, added to conventional treatments, may promote remission and facilitate a reduction in the corticosteroid doses.28 A few case reports describe the use of IVIG in the treatment of cutaneous polyarteritis nodosa (PAN).30 Rapid remission was achieved with IVIG infusions in an 8-year-old boy with severe cutaneous PAN resistant to conventional treatment.30 A few isolated case reports suggest beneficial effects of IVIG in infants with Takayasu arteritis.31
In conclusion, the effectiveness of IVIG in KD is well-established. However, its use in other vasculitides cannot be recommended given the limited available data that is complicated by inability to accurately assess the efficacy of IVIG in patients administered multiple immunosuppressive and other treatments.
Autoimmune encephalitis is a diverse group of neuropsychiatric disorders thought to be associated with the presence of antibodies directed against various central nervous system proteins. Clinical manifestations may include alteration of consciousness, cognitive decline, seizures, and abnormal movements. IVIG has been suggested to be efficacious in this antibody-mediated inflammatory brain disease. Although there are no randomized clinical trials, protocols have been developed that include IVIG in combination with corticosteroids and rituximab, with or without plasma exchange.32
There are excellent data to support the treatment of KD with IVIG, and it is now standard therapy for it. IVIG has also been demonstrated to be efficacious in JDM. Further study will help delineate if it should be used only in patients who are resistant to standard therapy or earlier in the disease course, especially in those children with more severe disease expression. IVIG for treatment of lupus-associated thrombocytopenia is supported by the literature, but its use may be limited by the transient response in platelet count. Treatment of other categories of pediatric rheumatologic diseases, such as JIA and non-KD vasculitis, is not well established by the literature.
- Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722–728.
- Anthony RM, Nimmerjahn F, Ashline DJ, et al. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science. 2008;320(5874):373–376. doi:10.1126/science.1154315 [CrossRef]
- Basta M, Dalakas MC. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest. 1994;94(5):1729–1735. doi:10.1172/JCI117520 [CrossRef]
- Benadiba J, Robitaille N, Lambert G, Itaj NK, Pastore Y. Intravenous immunoglobulin-associated thrombosis: is it such a rare event? Report of a pediatric case and of the Quebec Hemovigilance System. Transfusion. 2015;55(3):571–575. doi:10.1111/trf.12897 [CrossRef]
- Kwan TH, Tong MK, Siu YP, et al. Acute renal failure related to intravenous immunoglobulin infusion in an elderly woman. Hong Kong Med J. 2005;11(1):45–49.
- Dalakas MC, Illa I, Dambrosia J, 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. doi:10.1056/NEJM199312303292704 [CrossRef]
- Sansome A, Dubowitz V. Intravenous immunoglobulin in juvenile dermatomyositis - four year review of nine cases. Arch Dis Child. 1995;72:25–28. doi:10.1136/adc.72.1.25 [CrossRef]
- Lam CG, Manlhiot C, Pullenayegum EM, Feldman BM. Efficacy of intravenous Ig therapy in juvenile dermatomyositis. Ann Rheum Dis. 2011;70(12):2089–2094. doi:10.1136/ard.2011.153718 [CrossRef]
- Huber A, Robinson A, Reed A, et al. Consensus treatments for moderate juvenile dermatomyositis: Beyond the first two months. Arthritis Care Res. 2012;64(4):546–553. doi:10.1002/acr.20695 [CrossRef]
- Ballow M, Parke A. The uses of intravenous immune globulin in collagen vascular disorders. J Allergy Clin Immunol. 1989;84(4):608–612. doi:10.1016/0091-6749(89)90198-X [CrossRef]
- Zuber Z, Gornica-Banach M, Szymanowska Z, et al. The use of intravenous immunoglobulin in pediatric rheumatology. Reumatologia. 2014;52(3):160–165. doi:10.5114/reum.2014.44085 [CrossRef]
- Maier WP, Gordon DS, Howard RF, et al. Intravenous immunoglobulin therapy in systemic lupus erythematosus-associated thrombocytopenia. Arthritis Rheum. 1990;33:1233–1239. doi:10.1002/art.1780330825 [CrossRef]
- Arnal C, Piette JC, Léone J, et al. Treatment of severe immune thrombocytopenia associated with systemic lupus erythematosus: 59 cases. J Rheumatol. 2002;29:75–83.
- McClain MT, Arbuckle MR, Heinlen LD, et al. The prevalence, onset and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematous. Arthritis Rheum. 2004;50(4):1226–1232. doi:10.1002/art.20120 [CrossRef]
- Bayraktar UD, Erkan D, Bucciarelli S, Espinosa G, Asherson RCatastrophic Antiphospholipid Syndrome Project Group. The clinical spectrum of catastrophic antiphospholipid syndrome in the absence and presence of lupus. J Rheumatol. 2007;34:346–352.
- Cervera R, Rodríguez-Pintó I, Colafrancesco S, et al. 14th International Congress on antiphospholipid antibodies task force report on catastrophic antiphospholipid syndrome. Autoimmun Rev. 2014:13(7)699–707. doi:10.1016/j.autrev.2014.03.002 [CrossRef]
- Lin CY, Hsu HC, Chiang H, et al. Improvement of histological and immunological change in steroid and immunosuppressive drug-resistant lupus nephritis by high-dose intravenous gamma globulin. Nephron. 1989;53(4)303–310. doi:10.1159/000185772 [CrossRef]
- Milstone A, Meyers K, Elia J, et al. Treatment of acute neuropsychiatric lupus with intravenous immunoglobulin (IVIG): a case report and review of the literature. Clin Rheum. 2005;24(4)394–397. doi:10.1007/s10067-004-1046-9 [CrossRef]
- Meissner M, Sherer Y, Levy Y, et al. Intravenous immunoglobulin therapy in a patient with lupus serositis and nephritis. Rheumatol Int. 2000;19(5):199–201. doi:10.1007/s002960000053 [CrossRef]
- Brucato A. Prevention of congenital heart block in children of SSA-positive mothers. Rheumatology (Oxford). 2008;47:iii35–iii37. doi:10.1093/rheumatology/ken153 [CrossRef]
- Friedman DM, Llanos C, Izmirly PM, et al. Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: results of a multicenter, prospective, open-label clinical trial. Arthritis Rheum. 2010;62:1138–1146. doi:10.1002/art.27308 [CrossRef]
- Trucco SM, Jaeggi E, Cuneo B, et al. Use of intravenous gamma globulin and corticosteroids in the treatment of maternal autoantibody-mediated cardiomyopathy. J Am Coll Cardiol. 2011;57:715–723. doi:10.1016/j.jacc.2010.09.044 [CrossRef]
- Silverman E, Laxer R, Greenwald M, et al. Intravenous gamma globulin therapy in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1990;33(7):1015–1022. doi:10.1002/art.1780330714 [CrossRef]
- Silverman ED, Cawkwell GD, Lovell DJ, et al. Intravenous immunoglobulin in the treatment of systemic juvenile rheumatoid arthritis: a randomized placebo controlled trial. J Rheumatol. 1996;23(5):910–918.
- Giannini EH, Lovell DJ, Silverman ED, et al. Intravenous immunoglobulin in the treatment of polyarticular juvenile rheumatoid arthritis: a phase I/II study. Lancet. 1984;324(8411):1055–1058.
- Newburger J, Takahashi M, Burns J, et al. The treatment of Kawasaki syndrome with intravenous gammaglobulin. N Engl J Med. 1986;315:341–347. doi:10.1056/NEJM198608073150601 [CrossRef]
- Muta H, Ishii M, Yashiro M, et al. Late intravenous immunoglobulin treatment in patients with Kawasaki disease. Pediatrics. 2012;129(2):e291–e297. doi:10.1542/peds.2011-1704 [CrossRef]
- Sato N, Sugimura T, Akagi T, et al. Selective high dose gamma-globulin treatment in Kawasaki disease: assessment of clinical aspects and cost effectiveness. Pediatr Int. 1999;41(1):1–7. doi:10.1046/j.1442-200X.1999.t01-1-01014.x [CrossRef]
- Martinez V, Cohen P, Pagnoux C, et al. Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients. Arthritis Rheum. 2008;58:308–317 doi:10.1002/art.23147 [CrossRef]
- Breda L, Franchini S, Marzetti V, et al. Intravenous immunoglobulins for cutaneous polyarteritis nodosa resistant to conventional treatment. Scand J Rheum. 2016;45(2):169–170. doi:10.3109/03009742.2015.1092582 [CrossRef]
- Kierzkowska B, Lipińska J, Barańska D, et al. Takayasu's arteritis mimicking Kawasaki disease in 7-month-old infant, successfully treated with glucocorticosteroids and intravenous immunoglobulins. Rheumatol Int. 2012;32(11):3655–3659. doi:10.1007/s00296-010-1518-y [CrossRef]
- BrainWorks. The International Inflammatory Brain Disease Outcome Study. 2014. Protocol for antibody-mediated inflammatory brain disease: Severe disease. http://www.sickkids.ca/pdfs/Research/BrainWorks/62062-Antibody%20IBrainD.pdf. Accessed December 14, 2016.
Proposed Mechanism of Intravenous Immunoglobulin
||Mechanism of Action
||Reduction in cytokines
Blockade of Fc receptor on macrophages
Provision of the anti-idiotypic antibodies
Blocking the interaction between endothelial cells and natural killer cells
Augmenting T-cell suppressor activity, suppression of antibody synthesis, neutralization of bacterial superantigens
||Inhibition of complement-mediated damage by binding C3b and C4b
Decrease expression of adhesion molecules and cytokine production
|Systemic lupus erythematosus10–13
||Blockade of Fc receptor on macrophages, which inhibits autoantibody-coated targets (important in thrombocytopenia)
Inhibition of complement-mediated damage by binding C3b and C4b
||Anti-idiotype effect (IVIG contains natural antibodies that can bind to the variable regions of ANCA and inhibit their binding to the autoantigen)