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Intravenous Immunoglobulin and Autoimmunity Gisele Zandman-Goddard MD

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Intravenous Immunoglobulin and Autoimmunity Gisele Zandman-Goddard MD IMAJ • VOL 12 • JANUARY 2010 EDITORIALS Intravenous Immunoglobulin and Autoimmunity Gisele Zandman-Goddard MD Department of Medicine C, Wolfson Medical Center, Holon, and Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel lupus erythematosus. The manifestations receptor blocking by binding inhibitory KEY WORDS: intravenous immunoglobulin, IVIG, include autoimmune hemolytic anemia, Fc receptors (FcgR2b) and activating vasculitis, mixed cryoglobulinemia, acquired von Willebrand disease, pure Fc receptor (FcgR1 and FcgR3), anti- systemic lupus erythematosus red cell aplasia, thrombocytopenia, pan- cytokine effects, inhibition of comple- IMAJ 2010; 12: 45–46 cytopenia, pleural effusion, pericarditis, ment activation, complement system myocarditis, nephritis, psychosis, vascu- regulation, enhanced suppressor activ- litis and others [6-8]. IVIG was adminis- ity, down-regulation of B and T cell tered for renal disease in more than 100 function, idiotype network regulation, ixed cryoglobulinemia is associated cases [8]. enhanced clearance of endogenous M with vasculitis and hepatitis C virus In Europe, therapy with IVIG in pathogenic autoantibodies, neutraliza- infection, which reflects the impact of neurological diseases, such as Guillain- tion of autoantibodies, neutralization environmental triggers in autoimmune Barré syndrome, acute exacerbations of of superantigens, and augmentation diseases [1]. In this issue of IMAJ, Almog myasthenia gravis, and chronic inflam- of the reticuloendothelial clearance and co-researchers [2] provide further matory demyelinating polyradiculoneu- by increasing the size of inflammatory evidence for the beneficial effects of intra- ropathy, is well established [9]. circulating immune complexes due venous immunoglobulin in yet another Evidence for the therapeutic effect of to the addition of exogenous antibod- autoimmune disorder – mixed cryoglobu- IVIG in vasculitic disorders also exists. ies. The therapeutic effects of IVIG in linemia. The patient described in this case High dose IVIG was beneficial for vas- antibody-mediated diseases such as SLE report had mixed cryoglobulinemia with culitic neuropathies, as reported in a include direct effects on B cells. IVIG evidence of cytomegalovirus infection case series on patients with vasculitic suppresses the expansion of autoreactive (IgM positive) but without HCV exposure. peripheral neuropathy [10]. The French B lymphocytes through signaling of the The initial clinical manifestations were Vasculitis Study Group examined the FcgRIIB, idiotype-mediated inhibition purpura and arthralgia. Renal involve- role of short-term high dose IVIG in 22 of B cell receptors and neutralization of ment and peripheral neuropathy devel- patients with anti-neutrophil cytoplasmic cytokines such as the B cell survival fac- oped later. The patient's disease worse- antibody-positive relapsing disease. After tors (BAFF and APRIL). IVIG can induce ned and she suffered a relapse despite 6 months of monthly therapy, 14 patients the secretion of IgG, which reacts against conventional immunosuppressive ther- reached remission and no serious adverse various self and non-self antigens from apy. Rapid improvement and remission events were encountered [11]. a unique set of human B lymphocytes occurred with adjuvant high dose IVIG While therapy with high dose IVIG [15]. therapy [2]. is significantly beneficial, there is some Recently, a novel regulatory pathway IVIG is a potent biological drug that evidence that non-specific low dose IVIG with anti-inflammatory effects towards is used routinely for idiopathic throm- therapy may be warranted not only in members of the Siglec family inhibitory bocytopenic purpura, Kawasaki’s disease, neurologic diseases but also in systemic lectin receptors and their influence on and dermato/polymyositis. In addition, it autoimmune disease [12]. The benefi- death signals was discovered [16]. is administered experimentally for neu- cial effect of targeted specific IVIG in roimmunological, infectious, skin, blood, lupus and antiphospholipid syndrome cardiac, inflammatory and malignant in experimental models is mounting SAFETY PROFILES disorders [3-5]. Over the past two decades, [13,14]. Among the advantages of IVIG com- IVIG has been used extensively for var- pared to other biologic agents is its ious manifestations of the prototypic good safety profile. In a patient who systemic autoimmune disease – systemic MECHANISMS OF ACTION OF IVIG is not IgA deficient and who does not IVIG has multiple effects on the in- have thrombophilia, renal failure, or IgM = immunoglobulin M HCV = hepatitis C virus nate and adaptive immune systems. IVIG = intravenous immunoglobulin G Mechanisms of action comprise Fc- SLE = systemic lupus erythematosus 45 EDITORIALS IMAJ • VOL 12 • JANUARY 2010 substantial cardiovascular disease, ients with concomitant acute infec- Intravenous immunoglobulin therapy and systemic lupus erythematosus. Clin Rev Allergy and the use of IVIG agents that do not tions, its role has yet to be established Immunol 2005; 29: 219-28. include sucrose, IVIG has an excellent for chronic infectious diseases that may 8. Orbach H, Tishler M, Shoenfeld Y. Intravenous safety profile with only minor adverse reactivate, such as hepatitis virus or immunoglobulin and the kidney – a two-edged sword. Semin Arthritis Rheum 2004; 34: 593- events in most cases [17]. IVIG therapy cytomegalovirus. HCV, while shown to 601. is associated predominantly with mild be involved in polyarteritis nodosa and 9. Griffin JW, Hughes RAC. Intravenous immu- and transient adverse effects and has an mixed cryoglobulinemia, may also be noglobulin for neuromuscular disease: costs, benefits and reimbursement. Nature Clin Pract overall estimated rate of 36% adverse a factor in other autoimmune diseases, Neurol 2009; 5: 119. effects in high dose IVIG-treated pa- such as pemphigus vulgaris, vasculitis, 10. Levy Y, Uziel Y, Zandman-Goddard G, et al. tients [18]. The immediate adverse secondary antiphospholipid syndrome, Response of vasculitic peripheral neuropathy to effects usually comprise headache, Hashimoto's thyroiditis, and inflamma- intravenous immunoglobulin. Ann NY Acad Sci 2005; 1051: 779-86. flushing, malaise, chest tightness, fever, tory bowel disease [20]. 11. Martinez V, Cohen P, Pagnoux C. Intravenous chills, myalgia, fatigue, dyspnea, back With this reported case of mixed cryo- immunoglobulin for relapses of systemic vascul- pain, nausea, vomiting, diarrhea, blood globulinemia, as part of the vasculitic itides associated with antineutrophilic cyto- plasmic autoantibodies: results of a multicenter, pressure changes, tachycardia, and ana- spectrum and with overt multi-organ prospective, open-label study of twenty-two phylactic reactions especially in IgA- involvement, IVIG may be considered as patients. Arthritis Rheum 2008; 58: 308-17. deficient patients. Immediate adverse yet another beneficial and safe therapy 12. Sherer Y, Kuechler S, Scali JJ, et al. Low dose intravenous immunoglobulin in systemic lupus effects appear early, and in many cases for this condition. erythematosus: analysis of 62 Cases. IMAJ Isr during the first 30 minutes of the infu- Med Assoc J 2008; 10: 55-7. sion. Late adverse effects are rare and Correspondence: 13. Shoenfeld Y, Rauova L, Gilburd B, et al. Efficacy Dr. G. Zandman-Goddard of IVIG affinity-purified anti-double-stranded include acute renal failure, thromboem- Head, Dept. of Medicine C, Wolfson Medical DNA anti-idiotypic antibodies in the treatment bolic events, aseptic meningitis, neutro- Center, Holon 58100, Israel of an experimental murine model of systemic penia, autoimmune hemolytic anemia, Phone: (972-3) 502-8674 lupus erythematosus. Int Immunol 2002; 14: Fax: (972-3) 502-8810 1303-11. pseudo-hyponatremia, skin reactions, email: [email protected] 14. Blank M, Anafi L, Zandman-Goddard G, et and rare events of arthritis [17]. al. The efficacy of specific IVIG anti-idiotypic IVIG may have a steroid-sparing References antibodies in antiphospholipid syndrome (APS): trophoblast invasiveness and APS animal model. effect, although this needs further inves- 1. Shoenfeld Y, Zandman-Goddard G, Stojanovich Int Immunol 2007; 19: 857-65. L, et al. The mosaic of autoimmunity: hormonal tigation. Our group evaluated the clinical and environmental factors involved in auto- 15. Zandman-Goddard G, Blank M, Shoenfeld Y. outcome and the steroid-sparing effect immune diseases – 2008. IMAJ Isr Med Assoc J Intravenous immunoglobulins in systemic lupus 2008; 10: 8-12. erythematosus: from the bench to the bedside. in 17 patients with autoimmune dis- Lupus 2009; 18: 884-8. 2. Almog O, Berlin T, Rotman-Pikielny P, Levy Y. eases. All patients were treated with high A dramatic response to intravenous immuno- 16. von Gunten S, Simon HU. Natural anti-Siglec dose IVIG (2 g/kg over a 5 day period globulin in a patient with mixed cryoglobulinemia. autoantibodies mediate potential immu- IMAJ Isr Med Assoc J 2010; 12: 53-54. noregulatory mechanisms: implications for the once a month for 6 months, followed by clinical use of intravenous immunoglobulins therapy every 2–3 months) and steroids. 3. Seite JF, Shoenfeld Y, Youinou P, Hillion S. (IVIg). Autoimmun Rev 2008; 7: 453-6. What is the contents of the magic draft IVIg? IVIG harbored a steroid-sparing effect. Autoimmun Rev 2008; 7: 435-9. 17. Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin – adverse effects The average prednisone consumption 4. Sapir T, Blank M, Shoenfeld Y. Immunomodu-
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