High-Dose Intravenous Immunoglobulins: An Option in the Treatment of Systemic Lupus Erythematosus

doi:10.1016/j.humimm.2005.01.022

Human Immunology

Volume 66, Issue 4, April 2005, Pages 395-402

https://doi.org/10.1016/j.humimm.2005.01.022 Get rights and content

Abstract

Despite encouraging reports on the efficacy of intravenous immunoglobulin (IVIG) therapy in systemic lupus erythematosus (SLE), the clinical value of this treatment is not well established, and most of the data are based on case reports and small series of patients. IVIG has been used successfully to treat SLE patients with a broad spectrum of clinical manifestations, such as refractory thrombocytopenia, pancytopenia, central nervous system (CNS) involvement, secondary antiphospholipid syndrome, and lupus nephritis. The beneficial effects of IVIG on overall disease activity are usually prompt, with marked improvement within a few days, but they are often of limited duration. Improvement lasts for several weeks after the last infusion, although clinical response could be maintained by continuous monthly IVIG infusions. IVIG therapy immunomodulates autoimmune diseases by interacting with various Fcγ receptors in such a way that it downregulates activating FcRIIA and FcRIIC and/or upregulates inhibitory FcRIIB. However, in SLE, additional mechanisms include inhibition of complement-mediated damage, modulation of production of cytokines and cytokine antagonists, modulation of T- and B-lymphocyte function, induction of apoptosis in lymphocytes and monocytes, downregulation of autoantibody production, manipulation of the idiotypic network, and neutralization of pathogenic autoantibodies. At present, IVIG in SLE is indicated either in severe cases that are nonresponsive to other therapeutic modalities, or when SLE can be controlled only with high-dose steroids; in such patients, IVIG thus becomes a useful steroid-sparing agent. However, this needs to be confirmed in double-blind, placebo-controlled studies.

Introduction

Mild systemic lupus erythematosus (SLE) is treated with nonsteroidal antiinflammatory drugs, low-dose corticosteroids, and antimalarial compounds. In moderate SLE, patients are treated with cytotoxic agents, cyclophosphamide, methotrexate, and azathioprine, whereas severe cases are managed with high-dose steroids and intravenous pulse cyclophosphamide. This therapy provides broad-spectrum immunosuppression with a risk of developing secondary infections and myelosuppressive side effects. The aim of modern therapy for SLE is to regulate rather than suppress the immune response. This is achieved by manipulation of idiotypes with intravenous immunoglobulins (IVIGs), manipulation of second signal pathways in T- and B-cell interaction with anti-CD40L or anti-BLyS monoclonal antibodies (Abs), or manipulation of cytokines [1].

Despite encouraging reports on the use of IVIG in autoimmune disorders, the clinical efficacy and indication in SLE patients remain undetermined. It was successfully used for severe complications of SLE such as refractory thrombocytopenia, lupus nephritis, and central nervous system (CNS) involvement. Efficacy of IVIG was also demonstrated in the treatment of an experimental murine model of SLE [2, 3].

Section snippets

Mechanisms of action of IVIG in SLE

Autoimmune diseases, including SLE, are the result of a dysregulation of the FcγR system where the balance between activating and inhibitory FcγR signaling is disrupted [4]. Intravenous immunoglobulin may induce a reversible blockade of the Fc receptors on phagocytic cells by saturating, altering, or downregulating the affinity of Fc receptors, a process that may render sensitized phagocytic cells unable to function, e.g., in idiopathic thrombocytopenic purpura [5]. Intravenous immunoglobulin

IVIG in murine and other in vitro models of SLE

Two decades ago, monoclonal anti-Id Abs against anti-dsDNA auto-Abs were demonstrated to be beneficial in murine SLE. Early studies by Hahn and Ebling [21] demonstrated the suppression of pathogenic Abs to DNA in NZB/WF1 female mice when monoclonal anti-Id Abs were repeatedly inoculated to these mice. One hundred micrograms of the anti-Id were inoculated intraperitoneally every 2 weeks, beginning at 6 weeks of age (nondiseased mice, no circulating anti-DNA or proteinuria) or 20 weeks of age

Therapeutic doses of IVIG in SLE

Most of the data regarding IVIG in SLE are based on small series and are limited by the heterogeneity of both the therapeutic protocols applied and the manifestations treated. The therapeutic dose of IVIG in SLE was empirically set at a high dose of total 2 g/kg and was divided into five daily doses of 400 mg/kg each in order to prevent the risk of adverse reactions. Dividing the total dose into two daily doses of 1 g/kg each, or giving one 2 g/kg dose of IVIG during a 10-hour infusion may

IVIG in human SLE

Many clinical studies (i.e., small series and case reports) have documented the significant improvement and apparent lack of toxicity in SLE patients treated with IVIG. The advantage of using IVIG early in patients with active SLE over conventional therapies (i.e., high-dose steroids and immunosuppressants), or in combination, is that IVIG has not been found to increase the risk of opportunistic infections; and it obviates ovarian toxicity, hemorrhagic cystitis, and carcinogenicity caused by

IVIG and thrombocytopenia

Intravenous immunoglobulin rapidly raises the platelet count in SLE-associated thrombocytopenia. However, most studies recommend limiting IVIG to patients with life-threatening thrombocytopenia who are refractory to oral prednisone. In one study [31] where seven SLE patients were treated with IVIG, five had a more than 50% increase in their platelet counts, and four of them had a sustained benefit for at least 6 months. In another study, Arnal et al. [32] evaluated the treatment response of

IVIG and nephritis

Several studies analyzed the benefit of IVIG in lupus nephritis. Most of these studies included only small numbers of patients. The largest, conducted by Monova et al. [34], included 58 patients with lupus nephritis who were recruited during 15 years. Intravenous immunoglobulin had been applied once a day in a dose of 85 mg/kg three times every other day. Depending on the clinical improvement, the course was repeated after 1 to 3 months. A full remission (improved renal function, disappearance

IVIG in CNS lupus

There are few reports on the use of IVIG in CNS lupus. Intravenous immunoglobulin was successful in a patient with SLE and acute severe CNS disease [38], and in a 23-year-old patient with lupus with severe psychosis manifested by depression, delusions, and the inability to perform minimal daily activities [39]. Another patient with psychosis and mood changes also responded to IVIG treatment [29]. Winder et al. [40] reported on the successful outcome in a patient with lupus pneumonitis and

IVIG in cutaneous lupus

Extensive SLE skin lesions can be refractory to treatment, even to systemic steroids and immunosuppressive drugs. We and others reported on the beneficial and steroid-sparing effects of combined antimalarial drugs (i.e., hydroxychloroquine and quinacrine) [43]. In this regard IVIG was also reported to improve therapy-resistant cutaneous lupus [44]. Eleven patients with refractory cutaneous lupus were treated with IVIG at a starting dose of 1 g/kg for 2 days, followed by 400 mg/kg monthly. Five

Miscellaneous

Several case reports describe the benefit of IVIG treatment in cardiac manifestations [45, 46], pleural effusion [47, 48], secondary antiphospholipid syndrome [49], pure red-cell aplasia [50], and myelofibrosis [51].

Conclusions

Our impression is that high-dose IVIG should be used as an adjunctive therapy in SLE when standard therapies are not sufficient or when immunosuppressives are contraindicated. Future studies should focus on determining the best treatment protocol of IVIG (dose, duration of treatment) for various clinical involvements in SLE. In our experience, the administration of high-dose IVIG, 2 g/kg during 5 consecutive days, is both beneficial and safe. Further double-blind multicenter trials are

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High-Dose Intravenous Immunoglobulins: An Option in the Treatment of Systemic Lupus Erythematosus

Abstract

Introduction

Section snippets

Mechanisms of action of IVIG in SLE

IVIG in murine and other in vitro models of SLE

Therapeutic doses of IVIG in SLE

IVIG in human SLE

IVIG and thrombocytopenia

IVIG and nephritis

IVIG in CNS lupus

IVIG in cutaneous lupus

Miscellaneous

Conclusions

Eur J Intern Med

Transfus Clin Biol

Curr Opin Immunol

Allergy Clin Immunol

Blood

Semin Arthritis Rheum

Intravenous immunoglobulin therapy in SLE associated with thrombocytopenia

Arthritis Rheum

Abrogation of experimental systemic lupus erythematosus and primary anti-phospholipids syndrome with intravenous gamma globulin

J Rheumatol

Roles of Fc receptors in autoimmunity

Nat Rev Immunol

Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor

Science

IgG Fc receptors

Annu Rev Immunol

Immunoglobulin for rheumatic diseases in the twenty-first centurytake it or leave it

Curr Opin Rheumatol

Intravenous immunoglobulin treatment in women with recurrent abortionsincreased cytokine levels and reduced Th1/Th2 lymphocyte ratio in peripheral blood

Am J Reprod Immunol

The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease

J Clin Invest

Immunomodulation of auto-immune and inflammatory diseases with IVIG

N Engl J Med

Immunomodulation of various autoimmune diseases by intravenous immunoglobulin

Drugs Today

Detection and purification of antiidiotypic antibody against anti-DNA in IVIG

J Clin Immunopathol

Pooled human immunoglobulins contain anti-idiotypes with reactivity against the SLE-associated 4B4 cross-reactive idiotype

Clin Exp Rheumatol

Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis

Science

Antibodies to a conserved region of HLA class I molecules, capable of modulating CD8 T cell-mediated function, are present in pooled normal immunoglobulin for therapeutic use

J Clin Invest

Modulation of complement-mediated immune damage by IVIG

Clin Exp Immunol

Induction of protective therapy for autoimmune diseases by targeted DNA vaccines encoding pro-inflammatory cytokines and chemokine

Curr Opin Mol Ther

Suppression of murine lupus nephritis by administration of an anti-idiotypic antibody to anti-DNA

J Immunol

Suppression of anti-DNA antibody production in MLR mice by treatment with anti-idiotypic antibodies

Clin Exp Immunol

Efficacy of IVIG affinity-purified anti-dsDNA anti-idiotypic antibodies in the treatment of an experimental murine model of SLE

Int Immunol