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      Intravenous Immunoglobulin in the Therapeutic Armamentarium of Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis

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      , MRCP, , FRCP
      Medicine
      Wolters Kluwer Health

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          Abstract

          Prepared from the plasma of thousands of blood donors, therapeutic intravenous immunoglobulin (IVIg) mostly consists of human polyspecific immunoglobulin G (IgG). The use of IVIg in systemic lupus erythematosus (SLE) is still considered experimental without any clear indications.

          The purpose of this systematic review is, therefore, to evaluate the available evidence to determine the therapeutic role of IVIg in SLE.

          A comprehensive, computerised search was performed in the MEDLINE (Pubmed), Scopus, EMBASE, and Cochrane controlled trials.

          The study eligibility criteria were randomized controlled trials, and prospective and retrospective observational studies that examined the efficacy of IVIg in adult patients with SLE who were considered the participants.

          IVIg therapy was the mode of intervention in these patients.

          Data abstracted included the study design, study population, changes in the disease activity scores (Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure, and Lupus Activity Index-Pregnancy), steroid dose, complement levels, autoantibodies, and renal function. Thereafter, data analysis established statistical procedures for meta-analysis.

          Thirteen studies (including 3 controlled and 10 observational) were eligible for inclusion. There was significant reduction in the SLE disease activity scores with IVIg therapy with a standard mean difference of 0.584 ( P = 0.002, 95% confidence interval [CI] 0.221–0.947). In terms of rise in complement levels, the response rate was 30.9% ( P = 0.001, 95 CI 22.1–41.3). The effects of IVIg on other clinical outcome measures including anti-double-stranded DNA, antinuclear antibody, average steroid dose, and renal function could not be determined because of the limited numbers of trials.

          The limitations of this review were lack of well-designed controlled trials with adequate sample size on the use of IVIg in SLE.

          In conclusion, the use of IVIg is associated with significant reduction in SLE disease activity and improvement in complement levels.

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          Most cited references34

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          The use and interpretation of quasi-experimental studies in infectious diseases.

          Quasi-experimental study designs, sometimes called nonrandomized, pre-post-intervention study designs, are ubiquitous in the infectious diseases literature, particularly in the area of interventions aimed at decreasing the spread of antibiotic-resistant bacteria. Little has been written about the benefits and limitations of the quasi-experimental approach. This article outlines a hierarchy of quasi-experimental study design that is applicable to infectious diseases studies and that, if applied, may lead to sounder research and more-convincing causal links between infectious diseases interventions and outcomes.
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            A decrease in complement is associated with increased renal and hematologic activity in patients with systemic lupus erythematosus.

            To determine the degree to which changes in C3 and C4 precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 global activity indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M-SLEDAI), modified Lupus Activity Index (M-LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M-BILAG), and to evaluate the association between changes in C3 and C4 levels and SLE activity in individual organ systems. Fifty-three lupus patients were observed monthly for 1 year in a longitudinal study. Lupus disease activity and complement levels were measured at each visit. Lupus flare was defined as a 1.0 (or greater) increase in the PGA, a 3-point increase in the M-SLEDAI, a 0.1 increase in the M-LAI, a 3-point increase in the SLAM, or a 4-point increase in the M-BILAG within a 1-month period. Flare rates were calculated for subgroups defined by previous (1 month before) or concurrent changes in complement levels. Logistic regression models were used to determine the significance of the association between recent changes in complement levels and flare, controlling for prednisone dosage. Similar models were used to assess the association between changes in C3 or C4 levels and increased SLE activity in specific organ systems. Lupus flares occurred at 12% of visits based on the PGA, 19% based on the M-SLEDAI, 25% based on the M-LAI, 13% based on the SLAM, and 12% based on the M-BILAG. Recent changes in C3 and C4 levels were not associated with flares based on 3 of the 5 activity indices. Flares defined by the M-LAI were more frequent when there was a concurrent decrease in C3 (odds ratio [OR] 1.9, 95% confidence interval [95% CI] 1.1-3.1) or C4 (OR 2.1, 95% CI 1.3-3.6). Higher flare rates, as defined by the SLAM, were associated with previous increases in C3 (OR 1.6, 95% CI 1.0-2.6) and C4 (OR 2.2, 95% CI 1.2-3.9). When individual organ systems were analyzed, decreases in C3 and C4 were associated with a concurrent increase in renal disease activity (OR 2.2, 95% CI 1.4-3.5 and OR 1.9, 95% CI 1.1-3.4, respectively). Decreases in C3 were also associated with concurrent decreases in the hematocrit (OR 4.6, 95% CI 1.7-12.3), platelet (OR 2.5, 95% CI 1.5-4.1), and white blood cell (OR 2.2, 95% CI 1.3-3.6) counts. Previous increases in C3 levels were associated with a decrease in platelets (OR 1.7, 95% CI 1.1-2.7). A decrease in C4 was associated with a concurrent decrease in the hematocrit level (OR 3.2, 95% CI 1.3-7.5) and platelet count (OR 1.6, 95% CI 1.0-2.5). Decreases in complement levels were not consistently associated with SLE flares, as defined by global measures of disease activity. However, decreasing complement was associated with a concurrent increase in renal and hematologic SLE activity.
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              Tregitope update: mechanism of action parallels IVIg.

              In the course of screening immunoglobulin G (IgG) sequences for T cell epitopes, we identified novel Treg epitope peptides, now called Tregitopes, contained in the highly conserved framework regions of Fab and Fc. Tregitopes may provide one explanation for the expansion and stimulation of Treg cells following intravenous immunoglobulin (IVIg) therapy. Their distinguishing characteristics include in silico signatures that suggest high-affinity binding to multiple human HLA class II DR and conservation across IgG isotypes and mammalian species with only minor amino acid modifications. Tregitopes induce expansion of CD4(+)/CD25(hi)/FoxP3(+) T cells and suppress immune responses to co-incubated antigens in vitro. By comparing the human IgG Tregitopes (hTregitopes 167 and 289, located in the IgG CH1 and CH2 domains) and Fab to murine sequences, we identified class II-restricted murine Tregitope homologs (mTregitopes). In vivo, mTregitopes suppress inflammation and reproducibly induce Tregs to expand. In vitro studies suggest that the Tregitope mechanism of action is to induce Tregs to respond, leading to production of regulatory signals, followed by modulation of dendritic cell phenotype. The identification of Treg epitopes in IgG suggests that additional Tregitopes may also be present in other autologous proteins; methods for identifying and validating such peptides are described here. The discovery of Tregitopes in IgG and other autologous proteins may lead to the development of new insights as to the role of Tregs in autoimmune diseases. Copyright © 2012 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                October 2014
                03 October 2014
                : 93
                : 16
                : e86
                Affiliations
                Department of Medicine (RS), Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Cheras, Malaysia; and Louise Coote Lupus Unit (DD), Gassiot House, St Thomas’ Hospital, London, United Kingdom
                Author notes
                Correspondence: Rajalingham Sakthiswary, Universiti Kebangsaan Malaysia, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur (e-mail: sakthis5@ 123456hotmail.com ).
                Article
                00086
                10.1097/MD.0000000000000086
                4616295
                25310743
                e16e00d1-a288-4680-8a0d-e8c0dae6f83f
                © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

                This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                : 7 June 2014
                : 4 July 2014
                : 1 August 2014
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