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Intravenous immunoglobulin for immunomodulation of systemic lupus erythematosus
Autoimmunity Reviews 5 (2006) 153 – 155 www.elsevier.com/locate/autrev
Intravenous immunoglobulin for immunomodulation of systemic lupus erythematosus Yaniv Sherer, Yehuda Shoenfeld *,1 Department of Medicine ’B’ & Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer Sackler Faculty of Medicine, Tel-Aviv University, Israel Available online 19 September 2005
Abstract Intravenous immunoglobulin (IVIg) is used for replacement therapy in immunodeficiency states and for immunomodulation of various autoimmune diseases. Several case reports and series support a beneficial role of IVIg in systemic lupus erythematosus (SLE), both as salvage immunotherapy and in control of disease activity in general and amelioration of classical disease manifestations. Further, lupus nephritis can also be treated usually successfully with IVIg. A few questions remain unanswered as to the appropriate therapeutic dosage and the clinical manifestations that can be best treated with IVIg. D 2005 Elsevier B.V. All rights reserved. Keywords: Systemic lupus erythematosus; Intravenous immunoglobulin; Immunomodulation
Intravenous immunoglobulin (IVIg) is a therapy intended for the treatment of immune-deficiency states and immune-mediated diseases. In recent years, many reports of the use of IVIg in systemic lupus erythematosus (SLE), a multi-systemic autoimmune disease, have been gathered [1]. As the treatment of SLE often includes immunosuppressive drugs, IVIg offers in addition to its immunomodulatory properties, also some protection from infections to these immunodeficient patients. The experience of IVIg use in SLE began gradually with the treatment of severe manifestations of the disease not responding to other therapeutic means,
* Corresponding author. Department of Medicine ’B’ & Center for Autoimmune Diseases, Sheba Medical Center, 52621 Tel-Hashomer, Israel. Tel.: +972 3 5302652; fax: +972 3 5352855. E-mail address: [email protected] (Y. Shoenfeld). 1 Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases. 1568-9972/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2005.09.002
i.e. as a salvage immunotherapy. Representative examples from our experience include a patient with severe neuropsychiatric SLE, a patient with bilateral pleural effusions not responding to other therapies, cardiac dysfunction probably representing myocarditis, and a patient with nephritis and serositis [2–5]. These cases and many other published in the literature supported use of IVIg in selected severe cases of SLE. Case series evaluating disease activity in general are more valuable for estimation of a possible benefit of IVIg in SLE. We have conducted an open study including 20 SLE patients who were given high-dose (2 g/kg body weight) IVIg in a 5-day protocol once a month, mostly for 6 courses [6]. In this cohort, 17 of 20 patients responded to the treatment beneficially, and the SLAM disease activity index score was significantly decreased after the treatment compared with before administration of IVIg. Accordingly, daily prednisone doses used for treatment of these patients were also
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Y. Sherer, Y. Shoenfeld / Autoimmunity Reviews 5 (2006) 153–155
significantly reduced [6]. Upon analyzing the clinical manifestations response, several of them responded better to IVIg; these included: arthritis, fever, thrombocytopenia and neuropsychiatric lupus. Several other similar case series have been published detailing the use of IVIg in SLE, most of them reporting of a remission which lasts for months following IVIg therapy, reduction in circulating immune complexes, and increased complement levels, as well as a steroid sparing effect of IVIg. Some reports focused on certain manifestations of SLE such as the report by Goodfield et al. [7] of IVIg in therapy-resistant cutaneous lupus. In this study, 12 patients with histologically confirmed cutaneous LE were given IVIg, with starting doses of 1 g/kg body weight for 2 days, followed by 400 mg/kg body weight monthly until disease resolution or for 6 months. Following the treatment, 5 patients had complete or near complete clearing of their skin disease (N75%), 2 had partial improvement (N50%) and three had limited responses (b 50%) [7]. One patient developed acute cutaneous vasculitis and received no further therapy. Most interesting is the use of IVIg for lupus nephritis, as one of the dreadful adverse events of IVIg use in acute renal failure [8]. IVIg has been shown in a controlled trial to be as effective as cyclophosphamide in maintaining remission of lupus nephritis over an 18month period [9]. Thus it has been suggested that pulse IVIg can be an alternative treatment for lupus nephritis. As cytotoxic agents have many disadvantages and side effects, use of IVIg seems promising. We have reported a small series of lupus nephritis patients who had severe proteinuria, most of them also having the nephritic syndrome, who dramatically improved following IVIg infusion with decreased or almost disappearance of proteinuria in most of the patients, and normalization of other parameters of the nephrotic syndrome (albumin and cholesterol levels) [10]. In another study, 116 patients having chronic glomerulonephritis either due to idiopathic causes or lupus nephritis (all had a severe nephrotic syndrome, and 34 had renal failure) were treated with low doses of IVIg: 85 mg/kg / 24 h 3 times every other day [11]. The dosage was repeated in 84 patients after 1 month (and every 3 months for maintenance of remission) up to 7 years. It should be noted that among these patients, 98 were previously treated with corticosteroids, immunosuppression and anticoagulants without any effect [11]. As a result of IVIg therapy, proteinuria disappeared and full remission occurred in 36 patients, partial remission was present in 48 patients, and 32 patients went into end-stage renal failure and/or died.
These studies as well as others provide encouraging data and support for use of IVIg in SLE. Yet, many questions remained to be answered. First, the availability of controlled studies in this setting is very limited and thus firm conclusions regarding the efficacy of IVIg in SLE cannot be drawn. Another question relates to the appropriate therapeutic indications for IVIg. Most physicians would argue that IVIg can be used as salvage immunotherapy, i.e. in severe cases, occasionally life-threatening, not responding to conventional therapy. However, IVIg can also be suitable for dsimplerT manifestations of SLE. Finally, as IVIg is an expensive therapy, adjusting the minimal effective dose for treatment might affect treatment course prize and thus the chances that IVIg would be used more often in SLE. As recently reported by our group, the use of IVIg enriched with specific idiotypes found in SLE was much more effective in lower dosages compared with regular IVIg in an animal model of SLE [12]. These main questions deserve a thorough clinical research. Take-home messages ! Experimental animal models data support a beneficial role of IVIg in SLE. ! Several case reports support the role of IVIg as a salvage immunotherapy in SLE. ! A few open studies of SLE patients demonstrate decrease in disease activity scores and improvement of disease manifestation following IVIg administration. ! The exact indications for treatment, therapeutic dosage and duration are yet to be determined.
References [1] Toubi E, Kessel A, Shoenfeld Y. High-dose intravenous immunoglobulins: an option in the treatment of systemic lupus erythematosus. Hum Immunol 2005;66:395 – 402. [2] Sherer Y, Levy Y, Langevitz P, Lorber M, Fabrizzi F, Shoenfeld Y. Successful treatment of systemic lupus erythematosus cerebritis with intravenous immunoglobulin. Clin Rheumatol 1999;18:170 – 3. [3] Sherer Y, Levy Y, Shoenfeld Y. Marked improvement of severe cardiac dysfunction after one course of intravenous immunoglobulin in a patient with systemic lupus erythematosus. Clin Rheumatol 1999;18:238 – 40. [4] Sherer Y, Langevitz P, Levy Y, Fabrizzi F, Shoenfeld Y. Treatment of chronic bilateral pleural effusions with intravenous immunoglobulin and cyclosporin. Lupus 1999;8:324 – 7. [5] Meissner M, Sherer Y, Levy Y, Chwalinska-Sadowska H, Langevitz P, Shoenfeld Y. Intravenous immunoglobulin therapy in a patient with lupus serositis and nephritis. Rheumatol Int 2000;19:199 – 201.
Y. Sherer, Y. Shoenfeld / Autoimmunity Reviews 5 (2006) 153–155 [6] Levy Y, Sherer Y, Ahmed A, Langevitz P, George J, Fabbrizzi F, et al. A study of 20 SLE patients with intravenous immunoglobulin — clinical and serologic response. Lupus 1999;8:705 – 12. [7] Goodfield M, Davison K, Bowden K. Intravenous immunoglobulin (IVIg) for therapy-resistant cutaneous lupus erythematosus. J Dermatolog Treat 2004;14:46 – 50. [8] Sherer Y, Levy Y, Langevitz P, Rauova L, Fabrizzi F, Shoenfeld Y. Adverse effects of intravenous immunoglobulin therapy in 56 patients with autoimmune diseases. Pharmacology 2001; 62:133 – 7. [9] Boletis JN, Ioannidis JP, Boki KA, Moutsopoulos HM. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 1999;354:569 – 70.
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[10] Levy Y, Sherer Y, George J, Rovensky J, Lukac J, Rauova L, et al. Intravenous immunoglobulin treatment of lupus nephritis. Semin Arthritis Rheum 2000;29:321 – 7. [11] Monova D, Belovezhdov N, Altunkova I, Monov S. Intravenous immunoglobulin G in the treatment of patients with chronic glomerulonephritis: clinical experience lasting 15 years. Nephron 2002;90:262 – 6. [12] Shoenfeld Y, Rauova L, Gilburd B, Kvapil F, Goldberg I, Kopolovic J, 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.
Phosphatidylserine IgG and beta-2-glycoprotein I IgA antibodies may be a risk factor for ischemic stroke. Antiphospholipid antibodies (APLA) are established risk factors for venous thrombosis but their role in the pathogenesis of cerebral ischemia is unclear. In the present study, Kahles T. et al. (Rheumatology 2005;44:1161–5) evaluated the relevance of various APLA in patients with cryptogenic stroke (group A, n = 21) and determined causes of stroke (group B, n = 104) according to the TOAST classification in comparison with healthy volunteers without any thrombotic or ischaemic event in their history (group C, n = 84). Blood samples were tested for lupus anticoagulant (LA) and the presence of specific APLA and their antibody subclasses against cadiolipin (AclA), phosphatidylserine (ApsA), phosphatidylinositol (ApiA) and beta-2-glycoprotein I (Abeta2A). For ApsA IgG the authors found a significantly higher prevalence in stroke patients (57.7%) compared with normal subjects (4.8%; p b 0.001). Similarly, Abeta2A IgA was significantly more prevalent in stroke patients (20.8%) in comparison with normals (3.6%; p b 0.001). They did not find significant differences between stroke subtypes for any APLA. The results of this study suggest a relevant role for antiphosphatidylserine IgG and anti-beta 2- glycoprotein I IgA in stroke aetiology.
Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies. The prodromal phase of type 1 diabetes is characterized by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only beta-cell specific antibodies. This review by Franke B. et. al. (Diabetes/ Metabolism Research Reviews 2005;21:395–415) point to the general consensus that the presence of multiple Aab (z3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA.
Intravenous immunoglobulin for immunomodulation of systemic lupus erythematosus Yaniv Sherer, Yehuda Shoenfeld *,1 Department of Medicine ’B’ & Center for Autoimmune Diseases, Sheba Medical Center Tel-Hashomer Sackler Faculty of Medicine, Tel-Aviv University, Israel Available online 19 September 2005
Abstract Intravenous immunoglobulin (IVIg) is used for replacement therapy in immunodeficiency states and for immunomodulation of various autoimmune diseases. Several case reports and series support a beneficial role of IVIg in systemic lupus erythematosus (SLE), both as salvage immunotherapy and in control of disease activity in general and amelioration of classical disease manifestations. Further, lupus nephritis can also be treated usually successfully with IVIg. A few questions remain unanswered as to the appropriate therapeutic dosage and the clinical manifestations that can be best treated with IVIg. D 2005 Elsevier B.V. All rights reserved. Keywords: Systemic lupus erythematosus; Intravenous immunoglobulin; Immunomodulation
Intravenous immunoglobulin (IVIg) is a therapy intended for the treatment of immune-deficiency states and immune-mediated diseases. In recent years, many reports of the use of IVIg in systemic lupus erythematosus (SLE), a multi-systemic autoimmune disease, have been gathered [1]. As the treatment of SLE often includes immunosuppressive drugs, IVIg offers in addition to its immunomodulatory properties, also some protection from infections to these immunodeficient patients. The experience of IVIg use in SLE began gradually with the treatment of severe manifestations of the disease not responding to other therapeutic means,
* Corresponding author. Department of Medicine ’B’ & Center for Autoimmune Diseases, Sheba Medical Center, 52621 Tel-Hashomer, Israel. Tel.: +972 3 5302652; fax: +972 3 5352855. E-mail address: [email protected] (Y. Shoenfeld). 1 Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases. 1568-9972/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2005.09.002
i.e. as a salvage immunotherapy. Representative examples from our experience include a patient with severe neuropsychiatric SLE, a patient with bilateral pleural effusions not responding to other therapies, cardiac dysfunction probably representing myocarditis, and a patient with nephritis and serositis [2–5]. These cases and many other published in the literature supported use of IVIg in selected severe cases of SLE. Case series evaluating disease activity in general are more valuable for estimation of a possible benefit of IVIg in SLE. We have conducted an open study including 20 SLE patients who were given high-dose (2 g/kg body weight) IVIg in a 5-day protocol once a month, mostly for 6 courses [6]. In this cohort, 17 of 20 patients responded to the treatment beneficially, and the SLAM disease activity index score was significantly decreased after the treatment compared with before administration of IVIg. Accordingly, daily prednisone doses used for treatment of these patients were also
154
Y. Sherer, Y. Shoenfeld / Autoimmunity Reviews 5 (2006) 153–155
significantly reduced [6]. Upon analyzing the clinical manifestations response, several of them responded better to IVIg; these included: arthritis, fever, thrombocytopenia and neuropsychiatric lupus. Several other similar case series have been published detailing the use of IVIg in SLE, most of them reporting of a remission which lasts for months following IVIg therapy, reduction in circulating immune complexes, and increased complement levels, as well as a steroid sparing effect of IVIg. Some reports focused on certain manifestations of SLE such as the report by Goodfield et al. [7] of IVIg in therapy-resistant cutaneous lupus. In this study, 12 patients with histologically confirmed cutaneous LE were given IVIg, with starting doses of 1 g/kg body weight for 2 days, followed by 400 mg/kg body weight monthly until disease resolution or for 6 months. Following the treatment, 5 patients had complete or near complete clearing of their skin disease (N75%), 2 had partial improvement (N50%) and three had limited responses (b 50%) [7]. One patient developed acute cutaneous vasculitis and received no further therapy. Most interesting is the use of IVIg for lupus nephritis, as one of the dreadful adverse events of IVIg use in acute renal failure [8]. IVIg has been shown in a controlled trial to be as effective as cyclophosphamide in maintaining remission of lupus nephritis over an 18month period [9]. Thus it has been suggested that pulse IVIg can be an alternative treatment for lupus nephritis. As cytotoxic agents have many disadvantages and side effects, use of IVIg seems promising. We have reported a small series of lupus nephritis patients who had severe proteinuria, most of them also having the nephritic syndrome, who dramatically improved following IVIg infusion with decreased or almost disappearance of proteinuria in most of the patients, and normalization of other parameters of the nephrotic syndrome (albumin and cholesterol levels) [10]. In another study, 116 patients having chronic glomerulonephritis either due to idiopathic causes or lupus nephritis (all had a severe nephrotic syndrome, and 34 had renal failure) were treated with low doses of IVIg: 85 mg/kg / 24 h 3 times every other day [11]. The dosage was repeated in 84 patients after 1 month (and every 3 months for maintenance of remission) up to 7 years. It should be noted that among these patients, 98 were previously treated with corticosteroids, immunosuppression and anticoagulants without any effect [11]. As a result of IVIg therapy, proteinuria disappeared and full remission occurred in 36 patients, partial remission was present in 48 patients, and 32 patients went into end-stage renal failure and/or died.
These studies as well as others provide encouraging data and support for use of IVIg in SLE. Yet, many questions remained to be answered. First, the availability of controlled studies in this setting is very limited and thus firm conclusions regarding the efficacy of IVIg in SLE cannot be drawn. Another question relates to the appropriate therapeutic indications for IVIg. Most physicians would argue that IVIg can be used as salvage immunotherapy, i.e. in severe cases, occasionally life-threatening, not responding to conventional therapy. However, IVIg can also be suitable for dsimplerT manifestations of SLE. Finally, as IVIg is an expensive therapy, adjusting the minimal effective dose for treatment might affect treatment course prize and thus the chances that IVIg would be used more often in SLE. As recently reported by our group, the use of IVIg enriched with specific idiotypes found in SLE was much more effective in lower dosages compared with regular IVIg in an animal model of SLE [12]. These main questions deserve a thorough clinical research. Take-home messages ! Experimental animal models data support a beneficial role of IVIg in SLE. ! Several case reports support the role of IVIg as a salvage immunotherapy in SLE. ! A few open studies of SLE patients demonstrate decrease in disease activity scores and improvement of disease manifestation following IVIg administration. ! The exact indications for treatment, therapeutic dosage and duration are yet to be determined.
References [1] Toubi E, Kessel A, Shoenfeld Y. High-dose intravenous immunoglobulins: an option in the treatment of systemic lupus erythematosus. Hum Immunol 2005;66:395 – 402. [2] Sherer Y, Levy Y, Langevitz P, Lorber M, Fabrizzi F, Shoenfeld Y. Successful treatment of systemic lupus erythematosus cerebritis with intravenous immunoglobulin. Clin Rheumatol 1999;18:170 – 3. [3] Sherer Y, Levy Y, Shoenfeld Y. Marked improvement of severe cardiac dysfunction after one course of intravenous immunoglobulin in a patient with systemic lupus erythematosus. Clin Rheumatol 1999;18:238 – 40. [4] Sherer Y, Langevitz P, Levy Y, Fabrizzi F, Shoenfeld Y. Treatment of chronic bilateral pleural effusions with intravenous immunoglobulin and cyclosporin. Lupus 1999;8:324 – 7. [5] Meissner M, Sherer Y, Levy Y, Chwalinska-Sadowska H, Langevitz P, Shoenfeld Y. Intravenous immunoglobulin therapy in a patient with lupus serositis and nephritis. Rheumatol Int 2000;19:199 – 201.
Y. Sherer, Y. Shoenfeld / Autoimmunity Reviews 5 (2006) 153–155 [6] Levy Y, Sherer Y, Ahmed A, Langevitz P, George J, Fabbrizzi F, et al. A study of 20 SLE patients with intravenous immunoglobulin — clinical and serologic response. Lupus 1999;8:705 – 12. [7] Goodfield M, Davison K, Bowden K. Intravenous immunoglobulin (IVIg) for therapy-resistant cutaneous lupus erythematosus. J Dermatolog Treat 2004;14:46 – 50. [8] Sherer Y, Levy Y, Langevitz P, Rauova L, Fabrizzi F, Shoenfeld Y. Adverse effects of intravenous immunoglobulin therapy in 56 patients with autoimmune diseases. Pharmacology 2001; 62:133 – 7. [9] Boletis JN, Ioannidis JP, Boki KA, Moutsopoulos HM. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 1999;354:569 – 70.
155
[10] Levy Y, Sherer Y, George J, Rovensky J, Lukac J, Rauova L, et al. Intravenous immunoglobulin treatment of lupus nephritis. Semin Arthritis Rheum 2000;29:321 – 7. [11] Monova D, Belovezhdov N, Altunkova I, Monov S. Intravenous immunoglobulin G in the treatment of patients with chronic glomerulonephritis: clinical experience lasting 15 years. Nephron 2002;90:262 – 6. [12] Shoenfeld Y, Rauova L, Gilburd B, Kvapil F, Goldberg I, Kopolovic J, 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.
Phosphatidylserine IgG and beta-2-glycoprotein I IgA antibodies may be a risk factor for ischemic stroke. Antiphospholipid antibodies (APLA) are established risk factors for venous thrombosis but their role in the pathogenesis of cerebral ischemia is unclear. In the present study, Kahles T. et al. (Rheumatology 2005;44:1161–5) evaluated the relevance of various APLA in patients with cryptogenic stroke (group A, n = 21) and determined causes of stroke (group B, n = 104) according to the TOAST classification in comparison with healthy volunteers without any thrombotic or ischaemic event in their history (group C, n = 84). Blood samples were tested for lupus anticoagulant (LA) and the presence of specific APLA and their antibody subclasses against cadiolipin (AclA), phosphatidylserine (ApsA), phosphatidylinositol (ApiA) and beta-2-glycoprotein I (Abeta2A). For ApsA IgG the authors found a significantly higher prevalence in stroke patients (57.7%) compared with normal subjects (4.8%; p b 0.001). Similarly, Abeta2A IgA was significantly more prevalent in stroke patients (20.8%) in comparison with normals (3.6%; p b 0.001). They did not find significant differences between stroke subtypes for any APLA. The results of this study suggest a relevant role for antiphosphatidylserine IgG and anti-beta 2- glycoprotein I IgA in stroke aetiology.
Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies. The prodromal phase of type 1 diabetes is characterized by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only beta-cell specific antibodies. This review by Franke B. et. al. (Diabetes/ Metabolism Research Reviews 2005;21:395–415) point to the general consensus that the presence of multiple Aab (z3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA.