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Xu W, Ding W, Zhang Y, Wang S, Yan X, Xu Y, Zhi X, Liu R. The Role of T Cells in the Pathogenesis of Narcolepsy Type 1: A Narrative Review. Int J Mol Sci 2024; 25:11914. [PMID: 39595997 PMCID: PMC11593411 DOI: 10.3390/ijms252211914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Narcolepsy type 1 (NT1) is an uncommon, persistent sleep disorder distinguished by significant daytime sleepiness, episodes of cataplexy, and irregularities in rapid eye movement sleep. The etiology of NT1 is linked to the destruction of hypothalamic neurons responsible for the synthesis of the wake-promoting neuropeptide known as hypothalamic orexin. The pathophysiological mechanisms underlying NT1 remain inadequately elucidated; however, a model that incorporates the interplay of genetic predisposition, environmental influences, immune system factors, and a deficiency in hypocretin (HCRT) provides a framework for elucidating the pathogenesis of NT1. The prevalence of NT1 has been observed to rise following influenza A (H1N1) pdm09 and the administration of the Pandemrix influenza vaccine. The strong association between narcolepsy and the HLA-DQB1*06:02 allele strongly indicates an autoimmune etiology for this condition. Increasing evidence suggests that T cells play a critical role in this autoimmune-mediated HCRT neuronal loss. Studies have identified specific T cell subsets, including CD4+ and CD8+ T cells, that target HCRT neurons, contributing to their destruction. Clarifying the pathogenesis of NT1 driven by autoimmune T cells is crucial for the development of effective therapeutic interventions for this disorder. This review examines the risk factors associated with the pathogenesis of NT1, explores the role of T cells within the immune system in the progression of NT1, and evaluates immune-mediated animal models alongside prospective immunotherapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | | | - Rongzeng Liu
- Department of Immunology, College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang 471003, China
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Koczanowski S, Morrisroe K, Fairley J, Nikpour M, Oon S, Brown Z. Role of intravenous immunoglobulins in systemic sclerosis (SSc): A systematic literature review. Semin Arthritis Rheum 2024; 68:152471. [PMID: 38954999 DOI: 10.1016/j.semarthrit.2024.152471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/30/2024] [Accepted: 05/20/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Systemic sclerosis (SSc) is a heterogenous, multi-system autoimmune disease that causes progressive fibrosis of the skin and internal organs, resulting in high morbidity and mortality. Intravenous Immunoglobulin (IVIG) is a therapeutic option for SSc; however, reports of its efficacy have been variable, and its use across multiple organ manifestations of SSc has not been comprehensively reviewed. AIM The aim of this study was to systematically assess the existing literature on the role of IVIG use across a range of SSc manifestations. METHODS Medline, Embase, Cochrane, Web of Science and Scopus were searched from 01/01/2003-15/04/2024 using terms related to SSc and IVIG. Included studies were English-language full texts, where ≥5 adults with SSc received IVIG, and where a reportable outcome was documented. RESULTS Of 418 potentially relevant records, 12 were included in this review, comprising 266 patients across one randomised control trial, two pilot studies, one open label study, seven retrospective studies and one case control study. Eighteen outcomes were documented across five different organ systems: cutaneous, respiratory, musculoskeletal, gastrointestinal, and other (clinical improvement and corticosteroid sparing benefit). Results showed a favourable effect of IVIG in reducing the extent of skin thickening, muscle and joint pain, gastrointestinal symptoms, steroid dosing and improving patient/physician reported quality of life. Whilst IVIG may appear to be less beneficial for respiratory disease, the stabilisation in pulmonary function tests and radiological features may be considered a positive outcome in itself. Limitations included a lack of high-quality studies, and the use of concomitant therapies in many studies, rendering the efficacy of IVIG alone difficult to ascertain. CONCLUSION IVIG showed benefit in treating some manifestations of SSc, however there was a lack of convincing evidence for the efficacy in others. The lack of high-quality data highlights the need for further well-designed clinical trials to confirm these findings and inform guidelines for IVIG use.
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Affiliation(s)
| | - Kathleen Morrisroe
- Department of Medicine, The University of Melbourne, Australia; Department of Rheumatology, St. Vincent's Hospital, Melbourne, Australia
| | - Jessica Fairley
- Department of Medicine, The University of Melbourne, Australia; Department of Rheumatology, St. Vincent's Hospital, Melbourne, Australia
| | - Mandana Nikpour
- Department of Medicine, The University of Melbourne, Australia; Department of Rheumatology, St. Vincent's Hospital, Melbourne, Australia
| | - Shereen Oon
- Department of Medicine, The University of Melbourne, Australia; Department of Rheumatology, St. Vincent's Hospital, Melbourne, Australia
| | - Zoe Brown
- Department of Medicine, The University of Melbourne, Australia; Department of Rheumatology, St. Vincent's Hospital, Melbourne, Australia
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Bauhofer A, Balaban Ü, Schimo S, Mayer M, Schüttrumpf J, Borte S. Adequate IVIG dosing is associated with an improved long-term outcome in secondary immunodeficiency: A prospective, non-interventional study. Int J Clin Pharmacol Ther 2024; 62:448-459. [PMID: 39078054 PMCID: PMC11425087 DOI: 10.5414/cp204595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 09/18/2024] [Indexed: 07/31/2024] Open
Abstract
OBJECTIVE To assess the safety, tolerability, and effectiveness of the intravenous immunoglobulin (IVIG) Intratect 50 g/L in immunoglobulin replacement therapy (IgRT) in a prospective, large-scale non-interventional study (NIS). The analysis focused upon patients with secondary immunodeficiency (SID), the most frequent indication for IgRT in this NIS. MATERIALS AND METHODS Patients were enrolled at 123 centers in Germany. Each patient received IVIG as prescribed by the physician, guided by the Summary of Product Characteristics. Data were acquired from medical records and patients' questionnaires. RESULTS In the NIS, 3,563 patients were documented. The main indication for IgRT was SID (73.2%), followed by primary immunodeficiency (14.7%), immune thrombocytopenia (5.8%), and other indications (6.2%). Among the SID patients, 52.9% were male, mean age was 66.5 years, and most (63.8%) were IVIG-naïve. Their annual infection rate improved from 3.7 before documentation in the NIS to 1.1 during the first year of the study. IgG trough plasma levels increased during treatment (> 6 g/L: 44.5% of SID patients at study entry and 64.8% in long-term treatment) and were associated with a trend toward reduced infection rate (p = 0.08). A 1-year infection analysis showed a significantly lower infection risk in the medium- and high-dose groups than in the low-dose group (p = 0.028 and p = 0.017, respectively). Patients' treatment satisfaction and quality of life improved from baseline. Adverse drug reactions (ADRs) in SID occurred at a low frequency with 0.8% at infusion level. On the patient level, ADRs occurred in 251 (15.3%) SID patients, with chills (7.4%) and pyrexia (0.9%) reported most frequently. CONCLUSION Effectiveness, safety, and quality of life confirmed the positive benefit-risk profile of IgRT. Higher IVIG dosages per body weight led to higher IgG plasma trough levels, in turn leading to reduced infection rates. Obese patients may need body-weight-adjusted treatment to reduce the risk of infection.
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Affiliation(s)
| | | | | | | | | | - Stephan Borte
- Immune Defect Center, Clinic St. Georg, Leipzig, Germany
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Adreana Kleinveld VE, Wanschitz J, Löscher WN, Hotter A, Cornelia Horlings CG. Deterioration in multifocal motor neuropathy upon treatment of immune-related adverse events of checkpoint inhibition. Immunotherapy 2024; 16:597-601. [PMID: 39052281 PMCID: PMC11287915 DOI: 10.1080/1750743x.2024.2342238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/09/2024] [Indexed: 07/27/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have significantly improved the clinical outcome in multiple types of advanced or metastatic malignancies and are prescribed increasingly. However, immune-related adverse events (irAEs) occur frequently. Here, we present a patient with multifocal motor neuropathy and melanoma, with worsening of muscle weakness upon ICI therapy and concomitant use of steroids for the treatment of hepatitis, which was considered an irAE. Upon treatment with highly dosed immunoglobulins and steroid tapering, the patients' muscular symptoms improved while hepatitis resolved. This case highlights the importance of careful evaluation of patients with multifocal motor neuropathy treated with ICIs, highlights the risks of treatment with steroids in multifocal motor neuropathy patients and suggests an alternative treatment of irAEs with intravenous immunoglobulins.
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Affiliation(s)
| | - Julia Wanschitz
- University Hospital of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Wolfgang N Löscher
- University Hospital of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Anna Hotter
- University Hospital of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
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Bolcato M, Jommi C. Shortage of plasma-derived medicinal products: what is next? narrative literature review on its causes and counteracting policies in Italy. Front Pharmacol 2024; 15:1375891. [PMID: 38769998 PMCID: PMC11102971 DOI: 10.3389/fphar.2024.1375891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 04/05/2024] [Indexed: 05/22/2024] Open
Abstract
Introduction: This paper describes the peculiarities of the plasma-derived medicinal product (PDMP) market and illustrates the results of a review of the literature on policies aimed at counteracting the shortage of PDMPs. Characteristics of PDMPs: Plasma is primarily used for the industrial production of blood products (80%). The demand for PDMPs, particularly immunoglobulins (IGs), is increasing. However, the production of PDMPs is complex, long (7-12 months), and expensive, accounting, according to US estimates, for 57% of the total costs of PDMPs compared to 14% for small molecules. PDMP market: Unexpected increases in clinical need cannot be addressed in the short term. Once the demand for some diseases is satisfied, the collection and fractionation of plasma will only be used to supply some specific patients. Hence, the full weight of the marginal costs, which remain constant, are borne by a few products. According to last liter economics, the industry stops producing when the marginal revenue equals the marginal cost, thereby reducing the convenience of producing the most commonly used PDMPs (albumin and IG). The imbalance between the demand and supply of PDMPs was exacerbated by the COVID-19 pandemic, which further increased the cost of plasma collection. Shortage issue and possible solutions: Policies to counteract this imbalance have also been discussed. If the demand is inappropriate, it should be reduced. If the demand is appropriate and supply cannot be increased, the demand should be prioritized for patients for whom PDMPs are the only available treatment. If the shortage depends on insufficient supply and technical and allocative efficiency, both production and supply should be improved, together with incentives for all stakeholders involved in the PDMP market to increase the sustainability of production/supply. The paper is focused on this second issue, that is supply-driven unbalance.
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Affiliation(s)
- Matteo Bolcato
- Department of Neuroscience, University of Padova, Padova, Italy
| | - Claudio Jommi
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy
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Arimura Y, Sobue G, Hattori N, Takashima H, Harigai M, Nagata K, Makino H. Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial. Mod Rheumatol 2023; 33:1125-1136. [PMID: 36346309 DOI: 10.1093/mr/roac137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 11/03/2022] [Indexed: 11/08/2023]
Abstract
OBJECTIVES We conducted a Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) in patients with glucocorticoid-refractory neuropathy associated with microscopic polyangiitis. METHODS Patients received immunoglobulin or placebo intravenously for 5 consecutive days at baseline and after 4 weeks. The IVIg and placebo groups received IVIg and placebo, respectively, after 8 weeks. The primary and major secondary end-points were the least squares mean of the change in the manual muscle test (MMT) sum score after 8 and 4 weeks, respectively. RESULTS A total of 37 patients were randomised into two groups (IVIg [19] and placebo [18]). The least squares mean for the change in the MMT sum score was 9.02 for IVIg and 6.71 for placebo (difference 2.32, 95% confidence interval -2.60 to 7.23, p = .345) after 8 weeks and 6.81 and 2.83 (difference 3.99, 95% confidence interval -1.22 to 9.19, p = .129), respectively, after 4 weeks. There were no new safety concerns for IVIg. CONCLUSIONS MMT sum scores improved with IVIg compared with placebo after 8 weeks of dosing and two courses of treatment, but the differences were not statistically significant, and the results showed no clear efficacy of IVIg in this patient population. No new safety concerns were raised.
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Affiliation(s)
- Yoshihiro Arimura
- Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Tokyo, Japan
- Department of Internal Medicine, Kichijoji Asahi Hospital, Tokyo, Japan
| | - Gen Sobue
- Aichi Medical University, Aichi, Japan
| | - Naoki Hattori
- Department of Neurology, Toyota Kosei Hospital, Aichi, Japan
| | - Hiroshi Takashima
- Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Masayoshi Harigai
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Koichi Nagata
- Clinical Development Department, Teijin Pharma Limited, Tokyo, Japan
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Anwendung von humanen Immunglobulinpräparaten bei Lieferengpässen. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2023; 66:1184-1189. [PMID: 37768373 DOI: 10.1007/s00103-023-03759-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/29/2023]
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Magri SJ, Ugarte-Gil MF, Brance ML, Flores-Suárez LF, Fernández-Ávila DG, Scolnik M, Sato EI, de Souza AWS, Saldarriaga-Rivera LM, Babini AM, Zamora NV, Felquer MLA, Vergara F, Carlevaris L, Scarafia S, Guppy ERS, Unizony S. Pan American League of Associations for Rheumatology Guidelines for the treatment of ANCA-associated vasculitis. THE LANCET. RHEUMATOLOGY 2023; 5:e483-e494. [PMID: 38251580 DOI: 10.1016/s2665-9913(23)00128-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 01/23/2024]
Abstract
Considerable variability exists in the way health-care providers treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in Latin America. The most frequently used treatments for ANCA-associated vasculitis are cyclophosphamide and prolonged glucocorticoid tapers; however, randomised controlled trials conducted over the past 30 years have led to the development of several evidence-based treatment alternatives for these patients. Latin America faces socioeconomic challenges that affect access to care, and the use of certain costly medications with proven efficacy ANCA-associated vasculitis is often restricted. For these reasons, the Pan American League of Associations for Rheumatology developed the first ANCA-associated vasculitis treatment guidelines tailored for Latin America. A panel of local vasculitis experts generated clinically meaningful questions related to the treatment of ANCA-associated vasculitis using the Population, Intervention, Comparator, and Outcome (PICO) format. Following the Grading of Recommendations Assessment, Development, and Evaluation methodology, a team of methodologists conducted a systematic literature review. The panel of vasculitis experts voted on each PICO question and made recommendations, which required at least 70% agreement among the voting members. 21 recommendations and two expert opinion statements for the treatment of ANCA-associated vasculitis were developed, considering the current evidence and the socioeconomic characteristics of the region. These recommendations include guidance for the use of glucocorticoids, non-glucocorticoid immunosuppressants, and plasma exchange.
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Affiliation(s)
- Sebastián Juan Magri
- Rheumatology Unit, Hospital Italiano de La Plata, La Plata, Buenos Aires, Argentina
| | | | | | - Luis Felipe Flores-Suárez
- Primary Systemic Vasculitides Clinic, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | | | - Marina Scolnik
- Rheumatology Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Emilia Inoue Sato
- Medicine Department, Universidad Federal de São Paulo, São Paulo, Brazil
| | | | | | | | | | | | | | | | - Santiago Scarafia
- Rheumatology Unit, Hospital Municipal San Cayetano, Virreyes, Argentina
| | | | - Sebastian Unizony
- Vasculitis and Glomerulonephritis Center, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Bekele B, Masresha Z, Alemayehu M, Seyoum B, Wassie L, Abebe M. Intravenous Immunoglobulin G (IVIG) Need Assessment Survey Toward Local Manufacturing of IVIG Using a Mini-Pool Plasma Fractionation Technique. Health Serv Insights 2023; 16:11786329231157467. [PMID: 36860668 PMCID: PMC9969427 DOI: 10.1177/11786329231157467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 01/27/2023] [Indexed: 02/27/2023] Open
Abstract
Immunoglobulin therapy has a crucial role in the treatment of primary and secondary immunodeficiencies as well as in a multitude of neurologic, hematologic, infectious, and autoimmune conditions. In the current study, a preliminary pilot scale needs assessment survey was conducted to examine the need for IVIG among patients in Addis Ababa, Ethiopia, and in so doing justify local manufacturing of IVIG products. The survey was performed by administering a structured questionnaire to private and government hospitals, a national blood bank, a regulatory body, and healthcare researchers working in academia and pharmaceutical companies. The questionnaire encompassed demographics and specific IVIG-related questions designed for each institution. Responses supplied in the study provide qualitative data. Our findings indicated that IVIG has been registered by the regulatory body for use in Ethiopia and there is a demand for the product in the country. The study also highlights that patients go as far as to clandestine markets to procure IVIG products at a cheaper price. To impede such illegal routes and make the product readily accessible, a small-scale and low-cost approach such as a mini-pool plasma fractionation technique could be implemented to locally purify and prepare IVIG using plasma collected through the national blood donation program.
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Affiliation(s)
- Bisrat Bekele
- Bisrat Bekele, Armauer Hansen Research
Institute, Biotechnology and Bioinformatics Directorate, Jimma Road, ALERT
Campus, P.O. Box 1005, Addis Ababa 1005, Ethiopia.
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10
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Tocut M, Kolitz T, Shovman O, Haviv Y, Boaz M, Laviel S, Debi S, Nama M, Akria A, Shoenfeld Y, Soroksky A, Zandman-Goddard G. Outcomes of ICU patients treated with intravenous immunoglobulin for sepsis or autoimmune diseases. Clin Exp Rheumatol 2022; 21:103205. [PMID: 36195246 DOI: 10.1016/j.autrev.2022.103205] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 09/28/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVES To evaluate the outcomes of hospitalized patients in two intensive care units (ICU) treated with intravenous immunoglobulin (IVIg) added to standard-of-care therapy. The indications for IVIg therapy were sepsis or autoimmune disease. METHODS We conducted a retrospective study involving adult patients with sepsis and autoimmune diseases, who received IVIg in the ICU at Wolfson and Sheba Medical Centers. A predefined chart was compiled on Excel to include a complete demographic collection, patient comorbidities, chronic medication use, disease severity scores (Charlson Comorbidity Index; SOFA and APACHE II index scores), indication and dosage of IVIg administration, duration of hospitalization and mortality rates. RESULTS Patients (n - 111) were divided into 2 groups: patients with sepsis only (n-67) and patients with autoimmune disease only (n-44). Septic patients had a shorter ICU stay, received IVIg early, and had reduced mortality if treated with high dose IVIg. Patients with autoimmune diseases did not have a favorable outcome despite IVIg treatment. In this group, IVIg was administered later than in the sepsis group. CONCLUSIONS IVIg therapy improved the outcomes for ICU patients with sepsis.
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Affiliation(s)
- Milena Tocut
- Department of Medicine C, Wolfson Medical Center, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Israel; The Center for Autoimmune Diseases
| | - Tamara Kolitz
- Sackler Faculty of Medicine, Tel-Aviv University, Israel; Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center
| | - Ora Shovman
- Sackler Faculty of Medicine, Tel-Aviv University, Israel; The Center for Autoimmune Diseases; Department of Medicine B
| | - Yael Haviv
- Sackler Faculty of Medicine, Tel-Aviv University, Israel; Intensive Care Unit, Sheba Medical Center, Israel
| | - Mona Boaz
- Nutrition Sciences Department, Ariel University, Israel
| | - Shira Laviel
- Department of Medicine C, Wolfson Medical Center, Israel
| | - Stav Debi
- Department of Medicine C, Wolfson Medical Center, Israel
| | - Mona Nama
- Department of Medicine C, Wolfson Medical Center, Israel
| | - Amir Akria
- Department of Medicine C, Wolfson Medical Center, Israel
| | - Yehuda Shoenfeld
- Sackler Faculty of Medicine, Tel-Aviv University, Israel; The Center for Autoimmune Diseases; Ariel University, Ariel, Israel; I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | - Arie Soroksky
- Sackler Faculty of Medicine, Tel-Aviv University, Israel; Intensive Care Unit, Wolfson Medical Center, Israel
| | - Gisele Zandman-Goddard
- Department of Medicine C, Wolfson Medical Center, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Israel.
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Ojueromi OO, Oboh G, Ademosun AO. Effect of black seeds (Nigella sativa) on inflammatory and immunomodulatory markers in Plasmodium berghei-infected mice. J Food Biochem 2022; 46:e14300. [PMID: 35833536 DOI: 10.1111/jfbc.14300] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 05/14/2022] [Accepted: 05/25/2022] [Indexed: 12/29/2022]
Abstract
Nigella sativa, a core dietary supplement and food additive in folklore is one of the most broadly studied seed plants in the global nutraceutical sector. Malaria infection impairs the ability of principal cells of the immune system to trigger an efficient inflammatory and immune response. Ninety-six mice, weighing 20-25 g, were grouped into 12 consisting of 8 animals each. The mice were infected with standard inoculum of the strain NK65 Plasmodium berghei (chloroquine sensitive) and the percentage parasitemia suppression were evaluated. The individual effect of black seed supplemented diet and its combinatory effect with chloroquine (CQ) were investigated on reactive oxygen species (ROS), glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione-S-transferase (GST), serum immunoglobulins (IgG and IgM), and the hematological parameters (hemoglobin, packed cell volume, and red blood cell count) in P. berghei infected mice. The inflammatory cytokines, tumor necrosis factor (TNF-α), interleukin (IL-6 and IL-10), as well as IgG and IgM were assayed in the serum. The mice temperature and behavioral changes were observed. Infected mice treated with the dietary supplementation of black seed with a percentage inclusion (2.5%, 5%, 10%) showed significantly decreased parasitemia and ROS levels (p < 0.05) compared with the untreated mice. The result demonstrated a significant suppression in the pro-inflammatory cytokines (TNF-α, IL-6) levels and a notable elevation in the anti-inflammatory cytokine (IL-10), antioxidant markers as well as the immunoglobulin levels of the P. berghei-infected mice treated with black seed. The study revealed that black seed enhanced host antioxidant status, modulated inflammatory and immune response by regulating some inflammatory cytokines and immunomodulatory mediators. PRACTICAL APPLICATIONS: Black seed (Nigella sativa) has been a dietary supplement and natural remedy for many centuries. Inflammatory and immune diseases are the most notable cause of mortality in the world and more than 50% of deaths have been attributed to it. However, there is paucity of information on the effect of N. sativa on anti-inflammatory and immunomodulatory ability during malaria infection. The result suggests that N. sativa produced antioxidant, anti-inflammatory, and immunomodulatory effect in Plasmodium berghei-infected mice via the participation of glutathione antioxidant system, serum antibodies, and some inflammatory cytokines.
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Affiliation(s)
- Opeyemi Oluwafemi Ojueromi
- Functional Foods and Nutraceuticals Unit, Department of Biochemistry, Federal University of Technology, Akure, Ondo State, Nigeria
| | - Ganiyu Oboh
- Functional Foods and Nutraceuticals Unit, Department of Biochemistry, Federal University of Technology, Akure, Ondo State, Nigeria
| | - Ayokunle Olubode Ademosun
- Functional Foods and Nutraceuticals Unit, Department of Biochemistry, Federal University of Technology, Akure, Ondo State, Nigeria
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CIDP: Current Treatments and Identification of Targets for Future Specific Therapeutic Intervention. IMMUNO 2022. [DOI: 10.3390/immuno2010009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder of the peripheral nervous system. This clinically heterogeneous neurological disorder is closely related to Guillain–Barré syndrome and is considered the chronic counterpart of that acute disease. Currently available treatments are mostly empirical; they include corticosteroids, intravenous immunoglobulins, plasma exchange and chronic immunosuppressive agents, either alone or in combination. Recent advances in the understanding of the underlying pathogenic mechanisms in CIDP have brought a number of novel ways of possible intervention for use in CIDP. This review summarizes selected pre-clinical and clinical findings, highlights the importance of using adapted animal models to evaluate the efficacy of novel treatments, and proposes the outlines of future directions to ameliorate the conditions of patients with CIDP.
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Lu CH, Li KJ, Wu CH, Shen CY, Kuo YM, Hsieh SC, Yu CL. The FcγRIII Engagement Augments PMA-Stimulated Neutrophil Extracellular Traps (NETs) Formation by Granulocytes Partially via Cross-Talk between Syk-ERK-NF-κB and PKC-ROS Signaling Pathways. Biomedicines 2021; 9:biomedicines9091127. [PMID: 34572313 PMCID: PMC8472361 DOI: 10.3390/biomedicines9091127] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/14/2021] [Accepted: 08/30/2021] [Indexed: 12/16/2022] Open
Abstract
Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cell in the circulation capable of neutrophil extracellular traps (NETs) formation after stimulation. Both NADPH oxidase-dependent and -independent pathways are involved in NET formation. The IgG is the most abundant immunoglobulin in human serum. However, the impact of the circulating IgG on NET formation is totally unexplored. In this study, the all-trans retinoic acid (ATRA)-induced mature granulocytes (dHL-60) were pre-treated with monomeric human IgG, papain-digested Fab fragment, crystallizable IgG Fc portion, rituximab (a human IgG1), or IgG2. The NET formation of the dHL-60 in the presence/absence of phorbol 12-myristate 13-acetate (PMA) stimulation was then measured by the fluorescent area after SYTOX green nucleic acid stain. The intracellular reactive oxygen species (ROS) generation was measured by flow cytometry. Total and phosphorylated Syk, SHP-1, and ERK were detected by immunoblot. We found that human monomeric IgG and its subclasses IgG1 and IgG2 per se induced negligible NET formation of dHL-60, but the FcγRIII engagement by these IgG subclasses and Fc portion augment PMA-stimulated dHL-60 NET formation in a dose-dependent manner. Furthermore, we found that increased Syk and ERK phosphorylation, intracellular ROS generation, and pro-inflammatory cytokines, IL-8 and TNF-α, production could be induced after FcγRIII engagement. Blocking FcγRIII engagement by a specific antibody diminished the augmented NET formation. In conclusion, we discovered that cross-talk between FcγRIII engagement-induced Syk-ERK and PMA-induced PKC signaling pathways augment NET formation of dHL-60 via increased ROS generation and pro-inflammatory cytokines, IL-8 and TNF-α, production.
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Affiliation(s)
- Cheng-Hsun Lu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Ko-Jen Li
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
| | - Cheng-Han Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Chieh-Yu Shen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Yu-Min Kuo
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan
| | - Song-Chou Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
| | - Chia-Li Yu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan; (C.-H.L.); (K.-J.L.); (C.-H.W.); (C.-Y.S.); (Y.-M.K.); (S.-C.H.)
- Correspondence:
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14
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Bongomin F, Asio LG, Ssebambulidde K, Baluku JB. Adjunctive intravenous immunoglobulins (IVIg) for moderate-severe COVID-19: emerging therapeutic roles. Curr Med Res Opin 2021; 37:903-905. [PMID: 33722106 PMCID: PMC8022334 DOI: 10.1080/03007995.2021.1903849] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Felix Bongomin
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Gulu University, P.O. BOX, 166, Gulu, Uganda
| | - Lucy Grace Asio
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Gulu University, P.O. BOX, 166, Gulu, Uganda
| | - Kenneth Ssebambulidde
- College of Health Sciences, Infectious Diseases Institute, Makerere University, Kampala, Uganda
| | - Joseph Baruch Baluku
- Division of Pulmonology, Kiruddu National Referral Hospital, Kampala, Uganda
- Directorate of Programs, Mildmay Uganda, Wakiso, Uganda
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15
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Adigbli D, Rozen V, Darbar A, Janin P. Early intravenous immunoglobulin therapy for group A β-haemolytic streptococcal meningitis with toxic shock syndrome. BMJ Case Rep 2021; 14:e238472. [PMID: 33664027 PMCID: PMC7934773 DOI: 10.1136/bcr-2020-238472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2021] [Indexed: 11/03/2022] Open
Abstract
A woman in her forties was transferred to a Sydney (Australia)-based tertiary hospital, following presentation to a regional hospital with group A Streptococcus (GAS) otomastoiditis; complicated by meningitis, venous sinus thrombosis, haemorrhagic cerebral infarction and subdural empyema. She rapidly deteriorated with profound cardiovascular collapse. Despite initiation of high dose vasoactive therapy, she remained shocked and developed multiorgan dysfunction syndrome. Early intravenous immunoglobulin therapy (140 g in two doses) was initiated as an adjunct to antimicrobial, surgical and supportive care for refractory streptococcal toxic shock syndrome. Over the course of a twelve-day intensive care unit stay she made good progress with de-escalation of her vasoactive supportive care and reversal of her organ injuries. She was subsequently discharged to ward-based care. At her three-month follow-up appointment she had significantly reduced neurological deficit. Five months following her presentation to hospital she had returned to full-time work.
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Affiliation(s)
- Derick Adigbli
- Intensive Care Unit, Northern Sydney Local Health District, St Leonards, New South Wales, Australia
| | - Valerie Rozen
- Haematology, Northern Sydney Local Health District, St Leonards, New South Wales, Australia
| | - Archie Darbar
- Microbiology, Northern Sydney Local Health District, St Leonards, New South Wales, Australia
| | - Pierre Janin
- Intensive Care Unit, Northern Sydney Local Health District, St Leonards, New South Wales, Australia
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16
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Cao W, Liu X, Hong K, Ma Z, Zhang Y, Lin L, Han Y, Xiong Y, Liu Z, Ruan L, Li T. High-Dose Intravenous Immunoglobulin in Severe Coronavirus Disease 2019: A Multicenter Retrospective Study in China. Front Immunol 2021; 12:627844. [PMID: 33679771 PMCID: PMC7933558 DOI: 10.3389/fimmu.2021.627844] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/11/2021] [Indexed: 12/15/2022] Open
Abstract
Background The effective treatment of coronavirus disease 2019 (COVID-19) remains unclear. We reported successful use of high-dose intravenous immunoglobulin (IVIg) in cases of severe COVID-19, but evidence from larger case series is still lacking. Methods A multi-center retrospective study was conducted to evaluate the effectiveness of IVIg administered within two weeks of disease onset at a total dose of 2 g/kg body weight, in addition to standard care. The primary endpoint was 28-day mortality. Efficacy of high-dose IVIg was assessed by using the Cox proportional hazards regression model and the Kaplan-Meier curve adjusted by inverse probability of treatment weighting (IPTW) analysis, and IPTW after multiple imputation (MI) analysis. Results Overall, 26 patients who received high-dose IVIg with standard therapy and 89 patients who received standard therapy only were enrolled in this study. The IVIg group was associated with a lower 28-day mortality rate and less time to normalization of inflammatory markers including IL-6, IL-10, and ferritin compared with the control. The adjusted HR of 28-day mortality in high-dose IVIg group was 0.24 (95% CI 0.06–0.99, p<0.001) in IPTW model, and 0.27 (95% CI 0.10–0.57, p=0.031) in IPTW-MI model. In subgroup analysis, patients with no comorbidities or treated in the first week of disease were associated with more benefit from high-dose IVIg. Conclusions High-dose IVIg administered in severe COVID-19 patients within 14 days of onset was linked to reduced 28-day mortality, more prominent with those having no comorbidities or treated at earlier stage.
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Affiliation(s)
- Wei Cao
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaosheng Liu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Ke Hong
- Department of Infectious Diseases, Jin Yin-tan Hospital, Wuhan, China
| | - Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yuelun Zhang
- Medial Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Ling Lin
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yang Han
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhengyin Liu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Lianguo Ruan
- Department of Infectious Diseases, Jin Yin-tan Hospital, Wuhan, China
| | - Taisheng Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.,Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
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17
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McAtee CL, Lubega J, Underbrink K, Curry K, Msaouel P, Barrow M, Muscal E, Lotze T, Srivaths P, Forbes LR, Allen C, Bernhardt MB. Association of Rituximab Use With Adverse Events in Children, Adolescents, and Young Adults. JAMA Netw Open 2021; 4:e2036321. [PMID: 33533931 PMCID: PMC7859842 DOI: 10.1001/jamanetworkopen.2020.36321] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
IMPORTANCE Rituximab is among the most frequently used immunotherapies in pediatrics. Few studies have reported long-term adverse events associated with its use for children. OBJECTIVE To describe the use of rituximab and to assess whether its use is associated with short- or long-term adverse events, infections, or time to immune reconstitution in a diverse group of young people. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included 468 patients aged younger than 21 years who received rituximab for diverse indications between October 1, 2010, and December 31, 2017, at Texas Children's Hospital, a large pediatric referral hospital. Patterns of adverse events, infections, and immune recovery are described. Data analyses were conducted from December 2019 to June 2020. EXPOSURE One or more doses of rituximab. MAIN OUTCOMES AND MEASURES Adverse drug events (eg, anaphylaxis), incidence of mild and severe infections, and time to recovery of B lymphocyte subset counts and immunoglobulin levels. Survival models and logistic regression analyses and were used to identify associated risk factors of infectious and noninfectious adverse drug events. RESULTS We identified 468 patients receiving at least 1 dose of rituximab. The total follow-up time was 11 713 person-months. Of the 468 patients, 293 (62.6%) were female, the median (interquartile range) age at receipt of dose was 14.3 (9.9-16.8) years, and 209 (44.7%) were self-reported White Hispanic. Adverse events associated with rituximab infusion occurred in 72 patients (15.4%), and anaphylaxis occurred in 17 patients (3.6%). Long-term adverse events, such as prolonged neutropenia and leukoencephalopathy, were absent. Infections occurred in 224 patients (47.9%); 84 patients (17.9%) had severe infections, and 3 patients (0.6%) had lethal infections. Concurrent use of intravenous chemotherapy, treatment of systemic lupus erythematosus, neutropenia, and use of intravenous immunoglobulin were associated with increased risk of infection. Among 135 patients (28.8%) followed up to B cell count recovery, CD19+ or CD20+ cell numbers normalized in a median of 9.0 months (interquartile range, 5.9-14.4 months) following rituximab use; 48 of 95 patients (51%) evaluated beyond a year had low-for-age B cell counts. Recovery of CD27+ memory B cell number occurred in a median of 15.7 months (interquartile range, 6.0-22.7 months). Among patients with normal baseline values, low immunoglobulin G (IgG) levels developed in 67 of 289 patients (23.2%) and low IgM levels in 118 of 255 patients (40.8%); of these patients evaluated beyond 12 months from rituximab, 16 of 117 (13.7%) had persistently low IgG and 37 (33.9%) of 109 had persistently low IgM. CONCLUSIONS AND RELEVANCE Rituximab is well tolerated among young people and is associated with few serious adverse events, but infections are common, corresponding to a prolonged period of B cell count recovery often lasting for longer than a year. Further examination of strategies to prevent infections following rituximab should be pursued.
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Affiliation(s)
- Casey Lee McAtee
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Joseph Lubega
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Kristen Underbrink
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Kristen Curry
- Department of Pharmacy, Texas Children’s Hospital, Houston
| | - Pavlos Msaouel
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston
| | - Martha Barrow
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Eyal Muscal
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Timothy Lotze
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Poyyapakkam Srivaths
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Lisa R. Forbes
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Carl Allen
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - M. Brooke Bernhardt
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
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18
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Perricone C, Triggianese P, Bursi R, Cafaro G, Bartoloni E, Chimenti MS, Gerli R, Perricone R. Intravenous Immunoglobulins at the Crossroad of Autoimmunity and Viral Infections. Microorganisms 2021; 9:121. [PMID: 33430200 PMCID: PMC7825648 DOI: 10.3390/microorganisms9010121] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/24/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023] Open
Abstract
Intravenous immunoglobulins (IVIG) are blood preparations pooled from the plasma of donors that have been first employed as replacement therapy in immunodeficiency. IVIG interact at multiple levels with the different components of the immune system and exert their activity against infections. Passive immunotherapy includes convalescent plasma from subjects who have recovered from infection, hyperimmune globulin formulations with a high titer of neutralizing antibodies, and monoclonal antibodies (mAbs). IVIG are used for the prevention and treatment of several infections, especially in immunocompromised patients, or in case of a poorly responsive immune system. The evolution of IVIG from a source of passive immunity to a powerful immunomodulatory/anti-inflammatory agent results in extensive applications in autoimmune diseases. IVIG composition depends on the antibodies of the donor population and the alterations of protein structure due to the processing of plasma. The anti-viral and anti-inflammatory activity of IVIG has led us to think that they may represent a useful therapeutic tool even in COVID-19. The human origin of IVIG carries specific criticalities including risks of blood products, supply, and elevated costs. IVIG can be useful in critically ill patients, as well as early empirical treatment. To date, the need for further well-designed studies stating protocols and the efficacy/tolerability profile of IVIG and convalescent plasma in selected situations are awaited.
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Affiliation(s)
- Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Paola Triggianese
- Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome, 00133 Rome, Italy; (M.S.C.); (R.P.)
| | - Roberto Bursi
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Giacomo Cafaro
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Elena Bartoloni
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Maria Sole Chimenti
- Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome, 00133 Rome, Italy; (M.S.C.); (R.P.)
| | - Roberto Gerli
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Roberto Perricone
- Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome, 00133 Rome, Italy; (M.S.C.); (R.P.)
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19
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Fallet B, Walker UA. Current immunosuppressive and antifibrotic therapies of systemic sclerosis and emerging therapeutic strategies. Expert Rev Clin Pharmacol 2020; 13:1203-1218. [PMID: 33008265 DOI: 10.1080/17512433.2020.1832466] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Systemic sclerosis (SSc) is a rare, difficult to treat disease with profound effects on quality of life and high mortality. Complex and incompletely understood pathophysiologic processes and greatly heterogeneous clinical presentations and outcomes have hampered drug development. AREAS COVERED This review summarizes the currently available immunosuppressive and antifibrotic therapies and discusses novel approaches for the treatment of SSc. We reviewed the literature using the MEDLINE and ClinicalTrial.gov databases between May and September 2020. EXPERT OPINION Available immunosuppressive and antifibrotic drugs only modestly impact the course of the disease. Most drugs are currently only investigated in the subset of patients with early diffuse cutaneous SSc. In this patient population, hematopoietic stem-cell transplantation is currently the only treatment that has demonstrated reversal of lung involvement, enhanced quality of life and reduced long-term mortality, but carries the risk of short-term treatment-related mortality. A great need to provide better therapeutic options to patients exists also for those patients who have limited cutaneous skin involvement. A better understanding of SSc pathophysiology has enabled the identification of numerous new therapeutic targets. The progress made in the design of clinical trials and outcome parameters will likely result in the improvement of effective management options.
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Affiliation(s)
- Bénédict Fallet
- Department of Rheumatology, University Hospital Basel , Basel, Switzerland
| | - Ulrich A Walker
- Department of Rheumatology, University Hospital Basel , Basel, Switzerland
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20
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Liu X, Cao W, Li T. High-Dose Intravenous Immunoglobulins in the Treatment of Severe Acute Viral Pneumonia: The Known Mechanisms and Clinical Effects. Front Immunol 2020; 11:1660. [PMID: 32760407 PMCID: PMC7372093 DOI: 10.3389/fimmu.2020.01660] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 06/22/2020] [Indexed: 12/30/2022] Open
Abstract
The current outbreak of viral pneumonia, caused by novel coronavirus SARS-CoV-2, is the focus of worldwide attention. The WHO declared the COVID-19 outbreak a pandemic event on Mar 12, 2020, and the number of confirmed cases is still on the rise worldwide. While most infected individuals only experience mild symptoms or may even be asymptomatic, some patients rapidly progress to severe acute respiratory failure with substantial mortality, making it imperative to develop an efficient treatment for severe SARS-CoV-2 pneumonia alongside supportive care. So far, the optimal treatment strategy for severe COVID-19 remains unknown. Intravenous immunoglobulin (IVIg) is a blood product pooled from healthy donors with high concentrations of immunoglobulin G (IgG) and has been used in patients with autoimmune and inflammatory diseases for more than 30 years. In this review, we aim to highlight the known mechanisms of immunomodulatory effects of high-dose IVIg therapy, the immunopathological hypothesis of viral pneumonia, and the clinical evidence of IVIg therapy in viral pneumonia. We then make cautious therapeutic inferences about high-dose IVIg therapy in treating severe COVID-19. These inferences may provide relevant and useful insights in order to aid treatment for COVID-19.
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Affiliation(s)
- Xiaosheng Liu
- Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Wei Cao
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Taisheng Li
- Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
- Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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21
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Patel V, Cowan J. Discontinuation of immunoglobulin replacement therapy in patients with secondary antibody deficiency. Expert Rev Clin Immunol 2020; 16:711-716. [PMID: 32588670 DOI: 10.1080/1744666x.2020.1788939] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Secondary immunodeficiency is becoming a greater medical concern as the usage of immunosuppressive and biological treatments has increased. Individuals with certain medical conditions, such as hematological malignancies, can also have secondary immunodeficiency. Immunoglobulin replacement therapy (IGRT), which has been used for decades in inherited or primary immunodeficiency, provides some protection to patients with acquired and predominant antibody deficiency, i.e. secondary antibody deficiency (SAD). However, IGRT is costly, and supplies are limited. Although there are clinical guidelines on when to initiate IGRT, there is no guideline on when to discontinue it. AREAS COVERED The authors reviewed existing literature and provided an overview of the current state of knowledge regarding IGRT discontinuation in SAD patients. EXPERT OPINION Long-term supplementary immunoglobulin may not be necessary. Although it is possible to successfully transition away from IGRT in individuals with SAD, evidence-based practices are limited. Without clear guidelines and reliable prognostic markers, IGRT discontinuation practices are restricted to clinical judgment. For this reason, additional research should be conducted to identify markers that indicate the recovery of humoral immunity. Furthermore, the derivation and validation of a set of combined clinical and laboratory criteria to allow safe and timely IGRT discontinuation is warranted.
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Affiliation(s)
- Vishesh Patel
- Faculty of Medicine, University of Ottawa , Ottawa, Canada
| | - Juthaporn Cowan
- Division of Infectious Diseases, Department of Medicine, University of Ottawa , Ottawa, Canada.,Clinical Epidemiology Program, Ottawa Hospital Research Institute , Ottawa, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa , Ottawa, Canada.,Centre for Infection, Immunity and Inflammation (CI3), University of Ottawa , Ottawa, Canada
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22
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Gomes JP, Santos L, Shoenfeld Y. Intravenous immunoglobulin (IVIG) in the vanguard therapy of Systemic Sclerosis. Clin Immunol 2018; 199:25-28. [PMID: 30543921 DOI: 10.1016/j.clim.2018.12.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Systemic Sclerosis (SSc) is a rare autoimmune disease that is characterized by a progressive skin fibrosis, an obliteration of the microvasculature and an exaggerated extracellular matrix deposition, which lead to a multisystemic dysfunction. Various pathogenetic mechanisms were described. The lack of a successful therapy make SSc a disease with a poor prognosis. The intravenous immunoglobulin (IVIG) has been used for a long time in different autoimmune diseases, and firstly used in SSc patients in 2000. IVIG has multiple non-specific mechanisms of action and, beyond an impressive improvement in muscle symptoms, a French nationwide cohort demonstrated that IVIG ameliorates the skin disease and systemic inflammation, and helps the daily dose corticosteroid's tapering at the end of the treatment. The benefits on gastrointestinal symptoms of IVIG was reported by a recent English article, in which the patients consistently reported a decrease in the gastro-esophageal reflux disease symptoms and their frequencies. The impact on the lung involvement still remains unclear. One of the advantages of IVIG is its safe profile. Few adverse effects were reported and most of them are mild, and can be managed and usually they do not relapse. Harmful effects were described, but they can be avoid with cautious and judicious use of this therapy.
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Affiliation(s)
- João Pedro Gomes
- Zabludowicz Center for Autoimmune Disease, Sheba Medical Center, Tel Hashomer, Israel; Department A of Internal Medicine, Hospital and University Centre of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
| | - Lèlita Santos
- Department A of Internal Medicine, Hospital and University Centre of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
| | - Yehuda Shoenfeld
- Sackler Faculty of Medicine, Tel Aviv University, Israel; Zabludowicz Center for Autoimmune Disease, Sheba Medical Center, Tel Hashomer, Israel.
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Intravenous immunoglobulin replacement treatment reduces in vivo elastase secretion in patients with common variable immune disorders. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2018; 17:103-111. [PMID: 30036181 DOI: 10.2450/2018.0043-18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 05/28/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Intravenous immunoglobulin (IVIg) treatment partially replaces antibody defects and modulates innate and adaptive immune cells in patients with primary antibody deficiencies. MATERIALS AND METHODS This study was focused on the evaluation of the effects of in vivo IVIg administration on neutrophils from patients with common variable immune disorders (CVID). We examined polymorphonuclear neutrophil (PMN) phagocytosis, PMN oxidative burst, release of neutrophil elastase, serum level of interleukin-8 and PMN expression of CXCR1, CD11c and CD66b. RESULTS CVID patients on chronic IVIg treatment had reduced elastase release, but normal expression of CXCR1, CD66b and CD11c receptors on PMN, normal phagocytic ability and normal secretion of interleukin-8. We found that IVIg infusions rapidly reduced the serum level of interleukin-8, the expression of its receptor, CXCR1, and the release of neutrophil elastase, suggesting that IVIg exert a dampening effect on neutrophil activity. In contrast, IVIg infusions did not alter neutrophil phagocytosis or the expression of the other receptors analysed. DISCUSSION These findings add further information regarding the anti-inflammatory role of immunoglobulins and suggest additional benefits in keeping with recent attempts to use new therapies targeting neutrophil inflammation.
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Ramalho CC, Neves CMSS, Quental MV, Coutinho JAP, Freire MG. Separation of immunoglobulin G using aqueous biphasic systems composed of cholinium-based ionic liquids and poly(propylene glycol). JOURNAL OF CHEMICAL TECHNOLOGY AND BIOTECHNOLOGY (OXFORD, OXFORDSHIRE : 1986) 2018; 93:1931-1939. [PMID: 30270961 PMCID: PMC6161813 DOI: 10.1002/jctb.5594] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND The use of antibodies, such as immunoglobulin G (IgG), has faced a significant growth in the past decades for biomedical and research purposes. However, antibodies are high cost biopharmaceuticals, for which the development of alternative and cost-effective purification strategies is still in high demand. RESULTS Aqueous biphasic systems (ABS) composed of poly(propylene glycol) (PPG) and cholinium-based ionic liquids (ILs) were investigated for the separation of IgG. The ABS phase diagrams were determined and characterized whenever required. Initial optimization studies with commercial IgG were carried out, followed by the extraction of IgG from rabbit serum. In all ABS, IgG preferentially partitions to the IL-rich phase, unveiling preferential interactions between IgG and ILs. Good results were obtained with commercial IgG, with extraction efficiencies ranging between 93% and 100%, and recovery yields ranging between 20% and 100%. Two of the best and two of the worst identified ABS were then evaluated in what concerns their performance to separate and recover IgG from rabbit serum. With these ABS, extraction efficiencies of 100% and recovery yields > 80% were obtained, indicating an increase in the recovery yield and extraction efficiencies when using real matrices. Under the best conditions studied, IgG with a purity level of 49% was obtained in a single-step. This purity level of IgG is higher than those previously reported using other IL-polymer ABS. CONCLUSION IgG preferentially migrates to the IL-rich phase in ABS formed by ILs and polymers, allowing the design of effective separation systems for its recovery from serum samples.
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Tenti S, Fabbroni M, Mancini V, Russo F, Galeazzi M, Fioravanti A. Intravenous Immunoglobulins as a new opportunity to treat discoid lupus erythematosus: A case report and review of the literature. Autoimmun Rev 2018; 17:791-795. [PMID: 29885539 DOI: 10.1016/j.autrev.2018.02.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 02/09/2018] [Indexed: 10/14/2022]
Abstract
Discoid lupus erythematosus (DLE) is a chronic dermatological disease that can lead to scarring, alopecia and dyspigmentation, if not properly treated. Actually, no drugs are specifically approved for the treatment of CLE, although the first-line therapy usually consists of photoprotection associated to topical or oral steroids, topical calcineurin inhibitors and hydroxychloroquine (HCQ). In cases of DLE refractory to these medications, many other agents have been employed, such as dapsone, methotrexate, azathioprine, cyclophosphamide, biologic drugs and Intravenous Immunoglobulin (IVIG). We described the case of a DLE patient resistant to combination therapy with steroid and HCQ who was successfully treated with cyclical IVIG therapy. The treatment with IVIG resulted rapidly effective with persistent efficacy and low rates of relapses, although more cycles of IVIG are needed to achieve a stable clinical remission. We also discussed the beneficial and promising effects of IVIG in patients with Cutaneous Lupus reporting the previously published data.
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Affiliation(s)
- Sara Tenti
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
| | - Marta Fabbroni
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
| | - Virginia Mancini
- Pathology Section, Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Filomena Russo
- Dermatology Section, Department of Clinical Medicine and Immunological Science, University of Siena, Siena, Italy
| | - Mauro Galeazzi
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy
| | - Antonella Fioravanti
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
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Ahn H, Tay J, Shea B, Hutton B, Shorr R, Knoll GA, Cameron DW, Cowan J. Effectiveness of immunoglobulin prophylaxis in reducing clinical complications of hematopoietic stem cell transplantation: a systematic review and meta-analysis. Transfusion 2018; 58:2437-2452. [PMID: 29770447 DOI: 10.1111/trf.14656] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 03/16/2018] [Accepted: 03/27/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Prophylactic immunoglobulin has been used with varying efficacy to reduce complications in hematopoietic stem cell transplant recipients. STUDY DESIGN AND METHODS A systematic review and meta-analysis was conducted of randomized controlled trials that assessed clinical outcomes (overall survival, transplant-related mortality, graft-versus-host disease [GVHD], veno-occlusive disease [VOD], interstitial pneumonitis, disease relapse, cytomegalovirus [CMV] infection and disease, non-CMV infection) of immunoglobulin prophylaxis versus placebo in hematopoietic stem cell transplant recipients. MEDLINE, EMBASE, EBM Reviews, and the Cochrane Central Register of Controlled Trials were searched up to June 2017. Quality of included studies and outcomes were evaluated via Risk of Bias assessment and Grading of Recommendations, Assessment, Development and Evaluation criteria, respectively. RESULTS Of 899 citations screened, 27 studies (n = 3934) were included. Immunoglobulin prophylaxis had no impact on survival (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.88-1.01; 11 studies, n = 1962) but decreased risk of acute GVHD (RR, 0.78; 95% CI, 0.65-0.94; eight studies, n = 1097) and CMV disease (RR, 0.52; 95% CI, 0.28-0.97; two studies, n = 167). Meta-analysis revealed increased risk of VOD (RR, 3.04; 95% CI, 1.10-8.41; three studies, n = 384) and disease relapse (RR, 1.26; 95% CI, 1.07-1.49; seven studies, n = 1647). Other outcomes were small in sample size or nonsignificant. Results should be interpreted cautiously given the low quality of studies and evidence of outcomes. CONCLUSION Immunoglobulin prophylaxis did not have a significant effect on survival. Positive clinical effects were shown for acute GVHD and CMV disease and negative effects against VOD and disease relapse. No studies examined the effect of immunoglobulin treatment in hypogammaglobulinemic patients despite current guidelines, warranting further studies in this population.
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Affiliation(s)
- Hilalion Ahn
- Department of Medicine, University of Ottawa, Ottawa, Canada
| | - Jason Tay
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.,Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, Canada.,Department of Medicine, University of Calgary, Calgary, Canada
| | - Beverley Shea
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.,School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Brian Hutton
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.,School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
| | - Risa Shorr
- Learning Services, The Ottawa Hospital, Ottawa, Canada
| | - Greg A Knoll
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.,Renal Transplantation, Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Canada
| | - Donald William Cameron
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.,School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.,Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Canada
| | - Juthaporn Cowan
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada.,Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Canada
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Shemer A, Kivity S, Shoenfeld Y. Clinical indications for intravenous immunoglobulin utilization in a tertiary medical center: a 9-year retrospective study. Transfusion 2017; 58:430-438. [PMID: 29193136 DOI: 10.1111/trf.14427] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 10/08/2017] [Accepted: 10/08/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Intravenous immunoglobulins (IVIG) are a biologic product originally developed to treat immunocompromised patients. In the past decades, there has been increased utilization of IVIG in autoimmune conditions. The objectives were to evaluate the clinical use of IVIG in the largest tertiary medical center in Israel and to determine top uses, estimate off-label usage, and assess consumption of this blood product. STUDY DESIGN AND METHODS We conducted an observational, retrospective study involving all patients who received IVIG from 2007 through 2015. Subjects were classified into five groups according to the indication for treatment. RESULTS A total of 1117 patients were identified. The mean (±SD) ages of adults and children were 55 ± 17 and 8 ± 7 years, respectively. Most common indication for treatment were immune-mediated conditions (54%), followed by secondary immunodeficiency (28%), primary immunodeficiency (10%), infections (4%), and miscellaneous (4%). The main immune-mediated conditions treated were hematologic disorders (305 patients, 27%), neurologic disorders (219 patients, 20%), and rheumatologic conditions (79 patients, 7%). Overall, a significant change in study period was observed in the number of patients (p < 0.001), consumption of IVIG (p < 0.01), and amount of IVIG administered per patient (p < 0.01). Fifty-six percent of the IVIG infusions were given for off-label Food and Drug Administration (FDA) indications. CONCLUSION In this study, we demonstrated that immune-mediated conditions represent the majority of indications for treatment with IVIG. We observed a 417% increase in IVIG administration (g) over time, attributed mainly to autoimmune diseases. Many indications are still off-label according to FDA recommendations.
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Affiliation(s)
- Asaf Shemer
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Zabludowicz Center for Autoimmune Diseases
| | - Shaye Kivity
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Zabludowicz Center for Autoimmune Diseases.,Department of Medicine A, Sheba Medical Center, Tel-Hashomer, Israel
| | - Yehuda Shoenfeld
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Zabludowicz Center for Autoimmune Diseases
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Sordé L, Spindeldreher S, Palmer E, Karle A. Massive immune response against IVIg interferes with response against other antigens in mice: A new mode of action? PLoS One 2017; 12:e0186046. [PMID: 29023507 PMCID: PMC5638328 DOI: 10.1371/journal.pone.0186046] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 09/25/2017] [Indexed: 11/19/2022] Open
Abstract
Administration of high dose intravenous immunoglobulin (IVIg) is widely used in the clinic to treat autoimmune and severe inflammatory diseases. However, its mechanisms of action remain poorly understood. We assessed the impact of IVIg on immune cell populations using an in vivo ovalbumin (Ova)-immunization mouse model. High dose IVIg significantly reduced the Ova-specific antibody response. Intriguingly, the results obtained indicate an immediate and massive immune reaction against IVIg, as shown by the activation and expansion of B cells and CD4+ T cells in the spleen and draining lymph nodes and the production of IVIg-specific antibodies. We propose that IVIg competes at the T-cell level with the response against Ova to explain the immunomodulatory properties of IVIg. Two monoclonal antibodies did not succeeded in reproducing the effects of IVIg. This suggests that in addition to the mouse response against human constant domains, the enormous sequence diversity of IVIg may significantly contribute to this massive immune response against IVIg. While correlation of these findings to IVIg-treated patients remains to be explored, our data demonstrate for the first time that IVIg re-directs the immune response towards IVIg and away from a specific antigen response.
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Affiliation(s)
- Laetitia Sordé
- Novartis Pharma AG, Integrated Biologics Profiling Unit, Immunogenicity Risk Assessment, Basel, Switzerland
| | - Sebastian Spindeldreher
- Novartis Institute for Biomedical Research, Drug Metabolism and Pharmacokinetics, Biologics, Basel, Switzerland
| | - Ed Palmer
- University Hospital Basel, Department of Biomedicine, Transplantation Immunology and Nephrology, Basel, Switzerland
| | - Anette Karle
- Novartis Pharma AG, Integrated Biologics Profiling Unit, Immunogenicity Risk Assessment, Basel, Switzerland
- * E-mail:
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29
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Ravindranath MH. HLA Class Ia and Ib Polyreactive Anti-HLA-E IgG2a Monoclonal Antibodies (TFL-006 and TFL-007) Suppress Anti-HLA IgG Production by CD19+ B Cells and Proliferation of CD4+ T Cells While Upregulating Tregs. J Immunol Res 2017; 2017:3475926. [PMID: 28634589 PMCID: PMC5467321 DOI: 10.1155/2017/3475926] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 03/18/2017] [Accepted: 03/23/2017] [Indexed: 12/20/2022] Open
Abstract
The anti-HLA-E IgG2a mAbs, TFL-006 and TFL-007, reacted with all HLA-I antigens, similar to the therapeutic preparations of IVIg. Indeed, IVIg lost its HLA reactivity, when its HLA-E reactivity was adsorbed out. US-FDA approved IVIg to reduce antibodies in autoimmune diseases. But the mechanism underlying IVIg-mediated antibody reduction could not be ascertained due to the presence of other polyclonal antibodies. In spite of it, the cost prohibitive high or low IVIg is administered to patients waiting for donor organ and for allograft recipients for lowering antiallograft antibodies. A mAb that could mimic IVIg in lowering Abs, with defined mechanism of action, would be highly beneficial for patients. Demonstrably, the anti-HLA-E mAbs mimicked several functions of IVIg relevant to suppressing the antiallograft Abs. The mAbs suppressed activated T cells and anti-HLA antibody production by activated B cells, which were dose-wise superior to IVIg. The anti-HLA-E mAb expanded CD4+, CD25+, and Foxp3+ Tregs, which are known to suppress T and B cells involved in antibody production. These defined functions of the anti-HLA-E IgG2a mAbs at a level superior to IVIg encourage developing their humanized version to lower antibodies in allograft recipients, to promote graft survival, and to control autoimmune diseases.
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30
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Sanges S, Rivière S, Mekinian A, Martin T, Le Quellec A, Chatelus E, Lescoat A, Jego P, Cazalets C, Quéméneur T, Le Gouellec N, Senet P, Francès C, Deroux A, Imbert B, Fain O, Boukari L, Sené T, Deligny C, Mathian A, Agard C, Pugnet G, Speca S, Dubucquoi S, Hatron PY, Hachulla É, Launay D. Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature. Autoimmun Rev 2017; 16:377-384. [PMID: 28232167 DOI: 10.1016/j.autrev.2017.02.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 12/26/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND As intravenous immunoglobulins (IVIG) exhibit immunomodulatory and antifibrotic properties, they may be a relevant treatment for systemic sclerosis (SSc). The objectives of this work were thus to report on the efficacy and safety of IVIG in a population of SSc patients and to review the available literature. METHODS 46 patients from 19 French centers were retrospectively recruited. They were included if they had a diagnosis of SSc and received at least 1 IVIG infusion at a dosage >1g/kg/cycle. Relevant data collected at IVIG discontinuation were compared to those collected at IVIG initiation. A comprehensive literature review was performed. RESULTS We observed a significant improvement of muscle pain (74% vs. 20%, p<0.0001), muscle weakness (45% vs. 21%, p=0.01), joint pain (44% vs. 19%, p=0.02), CK levels (1069±1552UI vs. 288±449UI, p<0.0001) and CRP levels (13.1±17.6mg/L vs. 9.2±16.6mg/L, p=0.001). We also noted a trend for an improvement of gastro-esophageal reflux disease (68% vs. 53%, p=0.06) and bowel symptoms (42% vs. 27%, p=0.06). Skin and cardiorespiratory involvements remained stable. Finally, corticosteroid daily dose was significantly lower by the end of treatment (13.0±11.6mg/day vs. 8.9±10.4mg/day, p=0.01). Only two severe adverse events were reported (one case of deep vein thrombosis and one case of diffuse edematous syndrome). CONCLUSION Our work suggests that IVIG are a safe therapeutic option that may be effective in improving musculoskeletal involvement, systemic inflammation, digestive tract symptoms and could be corticosteroid sparing.
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Affiliation(s)
- Sébastien Sanges
- Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France; INSERM, U995, F-59000 Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), F-59000 Lille, France; Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET)
| | - Sébastien Rivière
- AP-HP, Hôpital Saint Antoine, Service de Médecine Interne, Paris, France; UPMC Université Paris 06, Faculté de Médecine Pierre et Marie Curie, Paris, France
| | - Arsène Mekinian
- AP-HP, Hôpital Saint Antoine, Service de Médecine Interne, Paris, France; UPMC Université Paris 06, Faculté de Médecine Pierre et Marie Curie, Paris, France
| | - Thierry Martin
- Service d'Immunologie Clinique, Hôpitaux universitaires de Strasbourg, UPR CNRS 3572, Strasbourg, France
| | - Alain Le Quellec
- Service de Médecine Interne et Maladies Multi-Organiques de l'Adulte, Hôpital Saint-Éloi, Centre Hospitalier Régional Universitaire de Montpellier, Montpellier, France
| | - Emmanuel Chatelus
- Hôpitaux Universitaires de Strasbourg, CHU Hautepierre, Service de Rhumatologie, Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, INSERM UMR 1109, Strasbourg, France
| | - Alain Lescoat
- Service de Médecine Interne, Centre Hospitalo-Universitaire de Rennes, Université de Rennes 1, Rennes, France
| | - Patrick Jego
- Service de Médecine Interne, Centre Hospitalo-Universitaire de Rennes, Université de Rennes 1, Rennes, France
| | - Claire Cazalets
- Service de Médecine Interne, Centre Hospitalo-Universitaire de Rennes, Université de Rennes 1, Rennes, France
| | - Thomas Quéméneur
- Service de Médecine Interne, Néphrologie et Médecine Vasculaire, Centre Hospitalier de Valenciennes, Valenciennes, France
| | - Noémie Le Gouellec
- Service de Médecine Interne, Néphrologie et Médecine Vasculaire, Centre Hospitalier de Valenciennes, Valenciennes, France
| | - Patricia Senet
- Service de Dermatologie, Hôpital Tenon, AP-HP, UPMC, Paris, France
| | - Camille Francès
- Service de Dermatologie, Hôpital Tenon, AP-HP, UPMC, Paris, France
| | - Alban Deroux
- Service de Médecine Interne, Université Grenoble Alpes, Centre Hospitalier Universitaire (CHU) de Grenoble, Grenoble, France
| | - Bernard Imbert
- Service de Médecine Interne, Université Grenoble Alpes, Centre Hospitalier Universitaire (CHU) de Grenoble, Grenoble, France
| | - Olivier Fain
- AP-HP, Hôpital Saint Antoine, Service de Médecine Interne, Paris, France; UPMC Université Paris 06, Faculté de Médecine Pierre et Marie Curie, Paris, France
| | - Latifatou Boukari
- Service de Médecine Interne, Hôpital Jean-Verdier, AP-HP, Université Paris-13, Bondy, France
| | - Thomas Sené
- Service de Médecine Interne et Rhumatologie, GH Diaconesses Croix Saint Simon, Paris, France
| | - Christophe Deligny
- Service de Médecine Interne et Rhumatologie 3C/5D, Centre Hospitalier Universitaire Pierre Zobda-Quitman, Fort-de-France, Martinique
| | - Alexis Mathian
- Service de Médecine Interne 2, Centre de Référence National pour le Lupus et le Syndrome des Antiphospholipides, institut E3M, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France; Sorbonne universités, UPMC université Paris 06, 75013 Paris, France
| | - Christian Agard
- Service de Médecine interne, Hôtel-Dieu, CHU de Nantes, Université de Nantes, Nantes, France
| | - Grégory Pugnet
- CHU, Université de Toulouse, Faculté de Médecine, Service de Médecine Interne, Toulouse, France; INSERM, UMR 1027, Toulouse, France
| | - Silvia Speca
- Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France; INSERM, U995, F-59000 Lille, France
| | - Sylvain Dubucquoi
- Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France; INSERM, U995, F-59000 Lille, France
| | - Pierre-Yves Hatron
- Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), F-59000 Lille, France; Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET)
| | - Éric Hachulla
- Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France; INSERM, U995, F-59000 Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), F-59000 Lille, France; Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET)
| | - David Launay
- Univ. Lille, INSERM U995 - LIRIC - Lille Inflammation Research International Center, F-59000 Lille, France; INSERM, U995, F-59000 Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France; Centre National de Référence Maladies Systémiques et Auto-immunes Rares (Sclérodermie Systémique), F-59000 Lille, France; Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET).
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Ammann EM, Haskins CB, Fillman KM, Ritter RL, Gu X, Winiecki SK, Carnahan RM, Torner JC, Fireman BH, Jones MP, Chrischilles EA. Intravenous immune globulin and thromboembolic adverse events: A systematic review and meta-analysis of RCTs. Am J Hematol 2016; 91:594-605. [PMID: 26973084 DOI: 10.1002/ajh.24358] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 03/07/2016] [Indexed: 01/25/2023]
Abstract
Prior case reports and observational studies indicate that intravenous immune globulin (IVIg) products may cause thromboembolic events (TEEs), leading the FDA to require a boxed warning in 2013. The effect of IVIg treatment on the risk of serious TEEs (acute myocardial infarction, ischemic stroke, or venous thromboembolism) was assessed using adverse event data reported in randomized controlled trials (RCTs) of IVIg. RCTs of IVIg in adult patients from 1995 to 2015 were identified from Pubmed, Embase, ClinicalTrials.Gov, and two large prior reviews of IVIg's therapeutic applications. Trials at high risk of detection or reporting bias for serious adverse events were excluded. 31 RCTs with a total of 4,129 participants (2,318 IVIg-treated, 1,811 control) were eligible for quantitative synthesis. No evidence was found of increased TEE risk among IVIg-treated patients compared with control patients (odds ratio = 1.10, 95% CI: 0.44, 2.88; risk difference = 0.0%, 95% CI: -0.7%, 0.7%, I(2) = 0%). No significant increase in risk was found when arterial and venous TEEs were analyzed as separate endpoints. Trial publications provided little specific information concerning the methods used to ascertain potential adverse events. Care should be taken in extrapolating the results to patients with higher baseline risks of TEE. Am. J. Hematol. 91:594-605, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Eric M Ammann
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Cole B Haskins
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Kelsey M Fillman
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Rebecca L Ritter
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Xiaomei Gu
- Hardin Library for the Health Sciences, University of Iowa, Iowa City, Iowa
| | - Scott K Winiecki
- Office of Biostatistics and Epidemiology, Center for Biologics Evaluation & Research, U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Ryan M Carnahan
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - James C Torner
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa
| | - Bruce H Fireman
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Michael P Jones
- Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa
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32
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Prezzo A, Cavaliere FM, Bilotta C, Iacobini M, Quinti I. Intravenous immunoglobulin replacement treatment does not alter polymorphonuclear leukocytes function and surface receptors expression in patients with common variable immunodeficiency. Cell Immunol 2016; 306-307:25-34. [PMID: 27264689 DOI: 10.1016/j.cellimm.2016.05.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 05/11/2016] [Accepted: 05/26/2016] [Indexed: 01/15/2023]
Abstract
The study of the expression of CD16, CD11b and Siglec 9 receptors and the oxidative burst provides insights on polymorphonuclear leukocytes (PMN) functionality in common variable immunodeficiency (CVID) and on the possible effects of intravenous immunoglobulin (IVIg) infusion. We evaluated in vivo before and soon after IVIg administration the CD16, CD11b and Siglec 9 expression on unstimulated and Escherichia coli-stimulated PMN and the oxidative burst induced by Escherichia coli and PMA. The E. coli stimulation up-regulated CD16 and Siglec 9 expression and it induced a strong CD11b up-regulation at baseline and soon after IVIg. The oxidative burst overlapped that observed in healthy donors when induced by Escherichia coli while it increased when induced by PMA. Soon after IVIg infusion, the oxidative burst decreased only when induced by PMA. Our results showed that the IVIg infusion in vivo had a minimal effect on CVID's PMN.
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Affiliation(s)
- Alessandro Prezzo
- Department of Molecular Medicine, Sapienza University of Rome, Italy
| | | | - Caterina Bilotta
- Department of Molecular Medicine, Sapienza University of Rome, Italy
| | | | - Isabella Quinti
- Department of Molecular Medicine, Sapienza University of Rome, Italy.
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Hollis C, Pennant M, Cuenca J, Glazebrook C, Kendall T, Whittington C, Stockton S, Larsson L, Bunton P, Dobson S, Groom M, Hedderly T, Heyman I, Jackson GM, Jackson S, Murphy T, Rickards H, Robertson M, Stern J. Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis. Health Technol Assess 2016; 20:1-viii. [PMID: 26786936 PMCID: PMC4781241 DOI: 10.3310/hta20040] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Tourette syndrome (TS) is a neurodevelopmental condition characterised by chronic motor and vocal tics affecting up to 1% of school-age children and young people and is associated with significant distress and psychosocial impairment. OBJECTIVE To conduct a systematic review of the benefits and risks of pharmacological, behavioural and physical interventions for tics in children and young people with TS (part 1) and to explore the experience of treatment and services from the perspective of young people with TS and their parents (part 2). DATA SOURCES For the systematic reviews (parts 1 and 2), mainstream bibliographic databases, The Cochrane Library, education, social care and grey literature databases were searched using subject headings and text words for tic* and Tourette* from database inception to January 2013. REVIEW/RESEARCH METHODS For part 1, randomised controlled trials and controlled before-and-after studies of pharmacological, behavioural or physical interventions in children or young people (aged < 18 years) with TS or chronic tic disorder were included. Mixed studies and studies in adults were considered as supporting evidence. Risk of bias associated with each study was evaluated using the Cochrane tool. When there was sufficient data, random-effects meta-analysis was used to synthesize the evidence and the quality of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. For part 2, qualitative studies and survey literature conducted in populations of children/young people with TS or their carers or in health professionals with experience of treating TS were included in the qualitative review. Results were synthesized narratively. In addition, a national parent/carer survey was conducted via the Tourettes Action website. Participants included parents of children and young people with TS aged under 18 years. Participants (young people with TS aged 10-17 years) for the in-depth interviews were recruited via a national survey and specialist Tourettes clinics in the UK. RESULTS For part 1, 70 studies were included in the quantitative systematic review. The evidence suggested that for treating tics in children and young people with TS, antipsychotic drugs [standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -1.08 to -0.41; n = 75] and noradrenergic agents [clonidine (Dixarit(®), Boehringer Ingelheim) and guanfacine: SMD -0.72, 95% CI -1.03 to -0.40; n = 164] are effective in the short term. There was little difference among antipsychotics in terms of benefits, but adverse effect profiles do differ. Habit reversal training (HRT)/comprehensive behavioural intervention for tics (CBIT) was also shown to be effective (SMD -0.64, 95% CI -0.99 to -0.29; n = 133). For part 2, 295 parents/carers of children and young people with TS contributed useable survey data. Forty young people with TS participated in in-depth interviews. Four studies were in the qualitative review. Key themes were difficulties in accessing specialist care and behavioural interventions, delay in diagnosis, importance of anxiety and emotional symptoms, lack of provision of information to schools and inadequate information regarding medication and adverse effects. LIMITATIONS The number and quality of clinical trials is low and this downgrades the strength of the evidence and conclusions. CONCLUSIONS Antipsychotics, noradrenergic agents and HRT/CBIT are effective in reducing tics in children and young people with TS. The balance of benefits and harms favours the most commonly used medications: risperidone (Risperdal(®), Janssen), clonidine and aripiprazole (Abilify(®), Otsuka). Larger and better-conducted trials addressing important clinical uncertainties are required. Further research is needed into widening access to behavioural interventions through use of technology including mobile applications ('apps') and video consultation. STUDY REGISTRATION This study is registered as PROSPERO CRD42012002059. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Chris Hollis
- Division of Psychiatry and Applied Psychology, Institute of Mental Health, University of Nottingham Innovation Park, University of Nottingham, Nottingham, UK
| | - Mary Pennant
- National Collaborating Centre for Mental Health, Royal College of Psychiatrists, London, UK
| | - José Cuenca
- Division of Psychiatry and Applied Psychology, Institute of Mental Health, University of Nottingham Innovation Park, University of Nottingham, Nottingham, UK
| | - Cris Glazebrook
- Division of Psychiatry and Applied Psychology, Institute of Mental Health, University of Nottingham Innovation Park, University of Nottingham, Nottingham, UK
| | - Tim Kendall
- National Collaborating Centre for Mental Health, Royal College of Psychiatrists, London, UK
| | - Craig Whittington
- National Collaborating Centre for Mental Health, Royal College of Psychiatrists, London, UK
| | - Sarah Stockton
- National Collaborating Centre for Mental Health, Royal College of Psychiatrists, London, UK
| | - Linnéa Larsson
- National Collaborating Centre for Mental Health, Royal College of Psychiatrists, London, UK
| | - Penny Bunton
- School of Psychological Sciences, University of Manchester, Manchester, UK
| | - Suzanne Dobson
- Tourettes Action, The Meads Business Centre, Farnborough, Hampshire, UK
| | - Madeleine Groom
- Division of Psychiatry and Applied Psychology, Institute of Mental Health, University of Nottingham Innovation Park, University of Nottingham, Nottingham, UK
| | - Tammy Hedderly
- Paediatric Neurology Department, Kings College Hospital NHS Foundation Trust, London, UK
| | - Isobel Heyman
- Department of Child and Adolescent Mental Health, Great Ormond Street Hospital for Children, London, UK
| | - Georgina M Jackson
- Division of Psychiatry and Applied Psychology, Institute of Mental Health, University of Nottingham Innovation Park, University of Nottingham, Nottingham, UK
| | - Stephen Jackson
- School of Psychology, University of Nottingham, Nottingham, UK
| | - Tara Murphy
- Institute of Neurology, University College London, London, UK
| | | | - Mary Robertson
- Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Jeremy Stern
- Tourettes Action, The Meads Business Centre, Farnborough, Hampshire, UK
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Svetlicky N, Kivity S, Odeh Q, Shovman O, Gertel S, Amital H, Gendelman O, Volkov A, Barshack I, Bar-Meir E, Blank M, Shoenfeld Y. Anti-citrullinated-protein-antibody-specific intravenous immunoglobulin attenuates collagen-induced arthritis in mice. Clin Exp Immunol 2015; 182:241-50. [PMID: 26132809 DOI: 10.1111/cei.12673] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2015] [Indexed: 02/02/2023] Open
Abstract
Administration of intravenous immunoglobulin (IVIg) is a recognized safe and efficient immunomodulation therapy for many autoimmune diseases. Anti-idiotypic antibody binding to pathogenic autoantibodies was proposed as one of the mechanisms attributed to the protective activity of IVIg in autoimmunity. The aim of this study was to fractionate the anti-anti-citrullinated protein anti-idiotypic-antibodies (anti-ACPA) from an IVIg preparation and to test it as a treatment for collagen-induced arthritis in mice. IVIg was loaded onto an ACPA column. The eluted fraction was defined as ACPA-specific-IVIg (ACPA-sIVIg). Collagen-induced-arthritis (CIA) was induced in mice. Mice were treated weekly with ACPA-sIVIg, low-dose-IVIg, high-dose-IVIg and phosphate-buffered saline (PBS). Sera-ACPA titres, anti-collagen anitbodies and cytokine levels were analysed by enzyme-linked immunosorbent assay (ELISA); antibody-forming-cell activity by enzyme-linked imunospot (ELISPOT) assay; and expansion of regulatory T cell (Treg ) population by fluorescence activated cell sorter (FACS). ACPA-sIVIg inhibited ACPA binding to citrullinated-peptides (CCP) in vitro 100 times more efficiently than the IVIg compound. ACPA-sIVIg was significantly more effective than the IVIg-preparation in attenuating the development of collagen-induced arthritis. Splenocytes from CIA mice treated with ACPA-sIVIg reduced the ACPA and anti-collagen-antibody titres, including the number of anti-collagen and ACPA antibody-forming cells. In parallel, splenocytes from ACPA-sIVIg treated mice secreted higher levels of anti-inflammatory cytokines and lower proinflammatory cytokines. The ACPA-sIVIg inhibitory potential was accompanied with expansion of the Treg population. Low-dose IVIg did not affect the humoral and cellular response in the CIA mice in comparison to the PBS-treated mice. Based on our results, IVIg may be considered as a safe compound for treating patients with rheumatoid arthritis by neutralizing pathogenic autoantibodies, reducing proinflammatory cytokines and expanding the Treg population.
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Affiliation(s)
- N Svetlicky
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv
| | - S Kivity
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv.,Internal Medicine B, Sheba Medical Center, Tel-Hashomer
| | - Q Odeh
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv
| | - O Shovman
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv
| | - S Gertel
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv
| | - H Amital
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv.,Internal Medicine B, Sheba Medical Center, Tel-Hashomer
| | - O Gendelman
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv.,Internal Medicine B, Sheba Medical Center, Tel-Hashomer
| | - A Volkov
- Institute of Pathology, Sheba Medical Center, affiliated with the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv
| | - I Barshack
- Institute of Pathology, Sheba Medical Center, affiliated with the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv
| | - E Bar-Meir
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv.,Poria Medical Center affiliated to Faculty of Medicine in the Galilee Bar-ilan University, Poria Israel
| | - M Blank
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv
| | - Y Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, affiliated to the Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv
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Cowan J, Cameron DW, Knoll G, Tay J. Protocol for updating a systematic review of randomised controlled trials on the prophylactic use of intravenous immunoglobulin for patients undergoing haematopoietic stem cell transplantation. BMJ Open 2015; 5:e008316. [PMID: 26297369 PMCID: PMC4550736 DOI: 10.1136/bmjopen-2015-008316] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Haematopoietic stem cell transplantation (HSCT) is commonly employed in the management of haematological malignancies. This intervention results in an increased risk of infectious and immune-related complications. Prophylactic immunoglobulin therapy has been used to prevent post-HSCT complications, including infections, with varying efficacy. We sought to update the current evidence supporting the use of immunoglobulins in the modern HSCT era. METHODS/ANALYSIS Using a structured search strategy, we will perform a systematic review of the literature from MEDLINE, EMBASE and all EBM Reviews databases. We will include randomised clinical trials investigating clinical outcomes of prophylactic polyvalent immunoglobulin or cytomegalovirus (CMV)-specific immunoglobulin or plasma in patients undergoing HSCT. Clinical outcomes will include overall survival, transplant-related mortality, CMV infection, CMV disease, graft-versus-host disease, interstitial pneumonitis/fibrosis and hepatic veno-occlusive disease. Studies that only reported the results of biochemical tests will be excluded. Data will be extracted by two investigators independently. Study quality assessment will be evaluated using a validated five-point system as proposed by Jadad. Trial quality will be further assessed by identifying whether there was adequate allocation concealment. Where appropriate, a meta-analysis will be performed where relative risk will be used as the primary summary measure with 95% CIs. Pooled measures will be calculated for randomised clinical trials using a random-effects model. The Cochrane Q/χ(2) test and I(2) statistic will also be calculated to evaluate heterogeneity. We will also use a visual inspection of a funnel plot to assess potential publication bias. DISCUSSION This systematic review aims to provide current evidence to justify the use of immunoglobulin prophylaxis in HSCT recipients. We will discuss whether current HSCT guidelines are supported by the current evidence, and whether further trials are needed, given the changing landscape of patients undergoing HSCT and the immunoglobulin manufacturing process. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42015016684.
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Affiliation(s)
- Juthaporn Cowan
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - D W Cameron
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Greg Knoll
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Renal Transplantation, Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Jason Tay
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, Ontario, Canada
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The role of intravenous immunoglobulins in the treatment of rheumatoid arthritis. Autoimmun Rev 2015; 14:651-8. [PMID: 25870941 DOI: 10.1016/j.autrev.2015.04.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Accepted: 04/02/2015] [Indexed: 12/11/2022]
Abstract
Intravenous immunoglobulins (IVIGs) are beneficial and safe for various diseases other than primary immunodeficiencies. Over the years, IVIG has been given for autoimmune diseases as an off-label adjunct therapy. While other biologic agents are indicated for rheumatoid arthritis (RA), IVIG may have a role for specific subgroups of RA patients where anti-cytokine blockers or rituximab may be unwarranted. Such subgroups may include patients with vasculitis, overlap rhupus syndrome, severe infections with active disease, and pregnancy. In addition, IVIG may be considered for juvenile chronic arthritis (JCA) and adult Still's disease. We review the literature for IVIG treatment in RA patients and for these subgroups.
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Caforio AL, Angelini A, Blank M, Shani A, Kivity S, Goddard G, Doria A, Schiavo A, Testolina M, Bottaro S, Marcolongo R, Thiene G, Iliceto S, Shoenfeld Y. Passive transfer of affinity-purified anti-heart autoantibodies (AHA) from sera of patients with myocarditis induces experimental myocarditis in mice. Int J Cardiol 2015; 179:166-77. [DOI: 10.1016/j.ijcard.2014.10.165] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 10/21/2014] [Accepted: 10/27/2014] [Indexed: 12/23/2022]
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Tjon ASW, van Gent R, Jaadar H, Martin van Hagen P, Mancham S, van der Laan LJW, te Boekhorst PAW, Metselaar HJ, Kwekkeboom J. Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2014; 192:5625-34. [PMID: 24808368 DOI: 10.4049/jimmunol.1301260] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
High-dose i.v. Ig (IVIg) is a prominent immunomodulatory therapy for various autoimmune and inflammatory diseases. Recent mice studies suggest that IVIg inhibits myeloid cell function by inducing a cascade of IL-33-Th2 cytokine production causing upregulation of the inhibitory FcγRIIb, as well as by modulating IFN-γ signaling. The purpose of our study was to explore whether and how these mechanisms are operational in IVIg-treated patients. We show that IVIg in patients results in increases in plasma levels of IL-33, IL-4, and IL-13 and that increments in IL-33 levels correlate with rises in plasma IL-4 and IL-13 levels. Strikingly, no upregulation of FcγRIIb expression was found, but instead a decreased expression of the activating FcγRIIa on circulating myeloid dendritic cells (mDCs) after high-dose, but not after low-dose, IVIg treatment. In addition, expression of the signaling IFN-γR2 subunit of the IFN-γR on mDCs was downregulated upon high-dose IVIg therapy. In vitro experiments suggest that the modulation of FcγRs and IFN-γR2 on mDCs is mediated by IL-4 and IL-13, which functionally suppress the responsiveness of mDCs to immune complexes or IFN-γ. Human lymph nodes and macrophages were identified as potential sources of IL-33 during IVIg treatment. Interestingly, stimulation of IL-33 production in human macrophages by IVIg was not mediated by dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). In conclusion, high-dose IVIg treatment inhibits inflammatory responsiveness of mDCs in humans by Th2 cytokine-mediated downregulation of FcγRIIa and IFN-γR2 and not by upregulation of FcγRIIb. Our results suggest that this cascade is initiated by stimulation of IL-33 production that seems DC-SIGN independent.
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Affiliation(s)
- Angela S W Tjon
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands
| | - Rogier van Gent
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands
| | - Haziz Jaadar
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands
| | - P Martin van Hagen
- Department of Internal Medicine and Immunology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands
| | - Shanta Mancham
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands; and
| | - Peter A W te Boekhorst
- Department of Hematology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands
| | - Herold J Metselaar
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands
| | - Jaap Kwekkeboom
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands;
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Trépanier P, Chabot D, Bazin R. Intravenous immunoglobulin modulates the expansion and cytotoxicity of CD8+ T cells. Immunology 2014; 141:233-41. [PMID: 24128001 DOI: 10.1111/imm.12189] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 09/26/2013] [Accepted: 10/10/2013] [Indexed: 12/12/2022] Open
Abstract
Intravenous immunoglobulin (IVIg) is successfully used in the treatment of autoimmune diseases involving self-reactive CD8(+) T cells. However, its direct influence on the cytotoxic response remains unknown. Using an antigen cross-presentation assay and a mouse model of ovalbumin (OVA) immunization, we showed that IVIg decreases the in vitro activation, proliferation and cytokine secretion of OVA-specific CD8(+) T cells (OT-I), as well as the in vivo generation of OVA-specific CD8(+) T cells. In addition, IVIg significantly decreases the proportion of perforin- and CD107a-expressing CD8(+) T cells, and inhibits the cytotoxic activity of OVA-activated OT-I cells. The interference of IVIg with the CD8(+) T-cell response is associated with T-cell receptor blockade, therefore reducing the interaction between effector and target cells. A similar blockade is observed on human CD8(+) T cells, suggesting that the observations reported here could apply to the IVIg-mediated improvement of CD8(+) T-cell-mediated autoimmune conditions in human patients.
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Affiliation(s)
- Patrick Trépanier
- Department of Research and Development, Héma-Québec, Québec, QC, Canada; Department of Biochemistry, Microbiology and Bioinformatics, Laval University, Québec, QC, Canada
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Sun A, Teschner W, Yel L. Improving patient tolerability in immunoglobulin treatment: focus on stabilizer effects. Expert Rev Clin Immunol 2014; 9:577-87. [DOI: 10.1586/eci.13.39] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Open-label study on treatment with 20 % subcutaneous IgG administration in polymyositis and dermatomyositis. Clin Rheumatol 2014; 33:531-6. [DOI: 10.1007/s10067-013-2478-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Revised: 12/20/2013] [Accepted: 12/23/2013] [Indexed: 10/25/2022]
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Wu YW, Champagne J, Toueille M, Gantier R, Burnouf T. Dedicated removal of immunoglobulin (Ig)A, IgM, and Factor (F)XI/activated FXI from human plasma IgG. Transfusion 2013; 54:169-78. [DOI: 10.1111/trf.12243] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 03/30/2013] [Accepted: 03/30/2013] [Indexed: 11/28/2022]
Affiliation(s)
- Yu-Wen Wu
- Institute of Medical Biomaterials and Tissue Engineering, College of Oral Medicine; Taipei Medical University; Taipei Taiwan
- Research and Development, Chromatography Applications; Pall Life Sciences; Cergy France
- Pall Life Sciences; Northborough Massachusetts
- Human Protein Process Sciences (HPPS); Lille France
| | - Jérôme Champagne
- Institute of Medical Biomaterials and Tissue Engineering, College of Oral Medicine; Taipei Medical University; Taipei Taiwan
- Research and Development, Chromatography Applications; Pall Life Sciences; Cergy France
- Pall Life Sciences; Northborough Massachusetts
- Human Protein Process Sciences (HPPS); Lille France
| | - Magali Toueille
- Institute of Medical Biomaterials and Tissue Engineering, College of Oral Medicine; Taipei Medical University; Taipei Taiwan
- Research and Development, Chromatography Applications; Pall Life Sciences; Cergy France
- Pall Life Sciences; Northborough Massachusetts
- Human Protein Process Sciences (HPPS); Lille France
| | - René Gantier
- Institute of Medical Biomaterials and Tissue Engineering, College of Oral Medicine; Taipei Medical University; Taipei Taiwan
- Research and Development, Chromatography Applications; Pall Life Sciences; Cergy France
- Pall Life Sciences; Northborough Massachusetts
- Human Protein Process Sciences (HPPS); Lille France
| | - Thierry Burnouf
- Institute of Medical Biomaterials and Tissue Engineering, College of Oral Medicine; Taipei Medical University; Taipei Taiwan
- Research and Development, Chromatography Applications; Pall Life Sciences; Cergy France
- Pall Life Sciences; Northborough Massachusetts
- Human Protein Process Sciences (HPPS); Lille France
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Cationized IVIg as a potential substitute to IVIg for the treatment of experimental immune thrombocytopenia. Int Immunopharmacol 2013; 16:409-13. [PMID: 23665226 DOI: 10.1016/j.intimp.2013.04.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 04/16/2013] [Accepted: 04/23/2013] [Indexed: 12/21/2022]
Abstract
In this study, we evaluated the possibility of using cationized IVIg (cIVIg) instead of IVIg as a more effective therapy for the treatment of experimental immune thrombocytopenia in mice. The pharmacokinetics (PK) and biodistribution of cIVIg and IVIg in mice were compared. cIVIg displayed a shorter plasma half-life and an increased organ uptake in both the spleen and liver compared to IVIg, suggesting that cIVIg could be more potent than IVIg to prevent platelet clearance in a mouse model of thrombocytopenia. However, although the biodistribution of cIVIg in the spleen and liver was improved, its ability to prevent platelet clearance in mice remained similar to that of IVIg. Altogether, our data demonstrate the possibility of using chemical cationization of IVIg preparations to increase organ uptake, and also highlight the challenges of developing effective substitutes to IVIg.
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Rosman Z, Shoenfeld Y, Zandman-Goddard G. Biologic therapy for autoimmune diseases: an update. BMC Med 2013; 11:88. [PMID: 23557513 PMCID: PMC3616818 DOI: 10.1186/1741-7015-11-88] [Citation(s) in RCA: 150] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2012] [Accepted: 01/11/2013] [Indexed: 12/15/2022] Open
Abstract
Biologic therapies for rheumatologic diseases, which are targeted at molecules involved in the mechanisms of the immune system, provide an alternative to the existing treatment methods of disease-modifying anti-rheumatic drugs and other immunosuppressive medications. However, the current drawbacks of biologic therapies, including the inconvenience of intravenous administration, the high costs of these drugs, and the adverse events associated with them, prevent their wide use as first-line medications. This review provides an update of the recent literature on the new biologic therapies available. The review concentrates on nine drugs: tocilizumab, rituximab, ofatumumab, belimumab, epratuzumab, abatacept, golimumab, certolizumab, and sifalimumab, which are used as therapies for rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, or vasculitis.
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Affiliation(s)
- Ziv Rosman
- Department of Medicine C, Wolfson Medical Center, 61 Halochamim Street, POB 63, Holon, 58100 Israel
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Immunoglobulin-Mediated Neuro-Cognitive Impairment: New Data and a Comprehensive Review. Clin Rev Allergy Immunol 2013; 45:248-55. [DOI: 10.1007/s12016-013-8357-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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46
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Immunoglobulin therapy. Clin Immunol 2013. [DOI: 10.1016/b978-0-7234-3691-1.00098-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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47
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Nursing guidelines for administration of immunoglobulin replacement therapy. JOURNAL OF INFUSION NURSING 2012; 36:58-68. [PMID: 23271153 DOI: 10.1097/nan.0b013e3182798af8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Immunoglobulin (Ig) replacement therapy, given as regular infusions of pooled human Ig, is the recognized treatment of humoral immunodeficiencies characterized by hypogammaglobulinemia and impaired antibody responses. It is a safe, effective therapy when delivered by nurses who have been educated to oversee and/or provide these infusions. Guidelines for administration have been developed by the Immune Deficiency Foundation Nurse Advisory Committee to provide a framework and guidance to those nurses administering this therapy.
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The advantage of specific intravenous immunoglobulin (sIVIG) on regular IVIG: experience of the last decade. J Clin Immunol 2012; 33 Suppl 1:S27-32. [PMID: 23229779 DOI: 10.1007/s10875-012-9842-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2012] [Accepted: 11/21/2012] [Indexed: 12/22/2022]
Abstract
During the last decade it has been shown that some components of intravenous immunoglobulin (IVIG) are responsible for their broadly therapeutic application. Currently, such specific subfractions are defined as specific IVIG (sIVIG) and are affinity-purified from commercial IVIGs that target specific antigens/antibodies related to a specific autoimmune disease. A remarkable example of the therapeutic potential of sIVIG is the proven enhanced anti-inflammatory potency of sialylated and recombinant sialylated IVIG obtained from total IVIG. In other experimental models, it has also been demonstrated that sIVIG work in many other contrivances, such as revealing anti-idiotypic networks blocking pathogenic antibodies ameliorating disease activity. sIVIG has also been shown to exert its action by modulating specific receptors expressed on immune cells in both inflammatory and autoimmune diseases. Indeed, sIVIG has emerged as a novel approach to treat different immune-mediated conditions in a more accurate antigen-specific manner. Herein we review experimental evidence supporting sIVIG-efficacy in treating autoimmune diseases and inflammation.
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Nussinovitch U, Shoenfeld Y. The diagnostic and clinical significance of anti-muscarinic receptor autoantibodies. Clin Rev Allergy Immunol 2012; 42:298-308. [PMID: 21207192 DOI: 10.1007/s12016-010-8235-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The role of autoimmunity in cardiovascular diseases has become one of the focal points of research studies. Autoimmune response and autoreactive autoantibodies have been found in dilated cardiomyopathy, heart failure, rheumatic fever, myocarditis, atherosclerosis, and other diseases. Autoantibodies may appear due to tissue injury and exposure of autoantigens, in addition to molecular mimicry and cross-reactivity with antigens found in infectious agents in predisposed individuals. In the early 1990s, autoantibodies reacting with the M2 muscarinic receptor were found in patients with dilated cardiomyopathy and subsequently, in patients with Chagas heart disease and arrhythmic disorders. Immunization of animals with the corresponding antigen triggered cardiac abnormalities also appearing in dilated cardiomyopathy of humans. It has been suggested that antibodies against M2 muscarinic receptors play a role in the pathogenesis of cardiac diseases and may also alter the electrophysiological properties of cardiac tissue. Herein, we review the current knowledge of antibodies against M2 muscarinic receptors and the possible use of a targeted therapy against these autoantibodies.
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Affiliation(s)
- Udi Nussinovitch
- Department of Internal Medicine B and Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Ramat-Gan, 52621, Israel
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Raithatha AH, Bryden DC. Use of intravenous immunoglobulin therapy in the treatment of septic shock, in particular severe invasive group A streptococcal disease. Indian J Crit Care Med 2012; 16:37-40. [PMID: 22557832 PMCID: PMC3338238 DOI: 10.4103/0972-5229.94433] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Group A streptococcus (GAS) is a β-hemolytic bacterium often found in the throat and skin. The two most severe clinical manifestations of GAS are streptococcal toxic shock syndrome and necrotizing fasciitis. Intravenous immunoglobulin (IVIg) is a gamma globulin made from purified pooled plasma of thousands of donors, consisting mainly of IgG. We report the case of a 40-year-old man admitted after 2 days of vomiting and severe right-sided chest pain. He was hypotensive with a sinus tachycardia, pyrexial, and vasodilated. The only other positive finding was a swollen and erythematous chest wall. Muscle layer biopsies and blood cultures soon grew extensive GAS, and an initial diagnosis of necrotizing fasciitis was made. The clinical syndrome was of severe septic shock secondary to invasive GAS. The patient quickly deteriorated with a worsening metabolic acidosis. Despite maximal intensive care therapy including fluids, vasoactive agents, and also activated protein C, the patient continued to remain profoundly hypotensive. A decision was made to commence IVIg, with the aim of immunomodulation of the inflammatory cascade seen in sepsis. Over the next 24 hours the patient improved, was extubated 3 days later, and subsequently discharged from hospital after 2 weeks. Although the evidence for the use of IVIg in severe invasive GAS disease is limited, we feel that on reviewing the available literature its use in this case was justified. The limited worldwide supply and high costs, together with a limited evidence base, warrant restricting its use to cases in which conventional therapy has failed. The literature for use of intravenous immunoglobulin in invasive GAS infection will be reviewed in this article.
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Affiliation(s)
- Ajay H Raithatha
- Department of Critical Care, Northern General Hospital, Sheffield Teaching Hospitals NHS Trust, Herries Road, Sheffield, UK
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