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paroxysmal nocturnal hemoglobinuria atypical hemolytic uremic syndrome

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https://www.readbyqxmd.com/read/27811836/recommendations-for-use-of-meningococcal-conjugate-vaccines-in-hiv-infected-persons-advisory-committee-on-immunization-practices-2016
#1
Jessica R MacNeil, Lorry G Rubin, Monica Patton, Ismael R Ortega-Sanchez, Stacey W Martin
At its June 2016 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of meningococcal conjugate vaccine (serogroups A, C, W, and Y; including MenACWY-D [Menactra, Sanofi Pasteur] or MenACWY-CRM [Menveo, GlaxoSmithKline]) for persons aged ≥2 months with human immunodeficiency virus (HIV) infection. ACIP has previously recommended routine vaccination of persons aged ≥2 months who have certain medical conditions that increase risk for meningococcal disease (1), including persons who have persistent (e...
November 4, 2016: MMWR. Morbidity and Mortality Weekly Report
https://www.readbyqxmd.com/read/27810992/small-molecule-factor-d-inhibitors-selectively-block-the-alternative-pathway-of-complement-in-paroxysmal-nocturnal-hemoglobinuria-and-atypical-hemolytic-uremic-syndrome
#2
Xuan Yuan, Eleni Gavriilaki, Jane A Thanassi, Guangwei Yang, Andrea C Baines, Steven D Podos, Yongqing Huang, Mingjun Huang, Robert A Brodsky
Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome...
November 3, 2016: Haematologica
https://www.readbyqxmd.com/read/27717414/overview-of-laboratory-testing-and-clinical-presentations-of-complement-deficiencies-and-dysregulation
#3
A Frazer-Abel, L Sepiashvili, M M Mbughuni, M A V Willrich
Historically, complement disorders have been attributed to immunodeficiency associated with severe or frequent infection. More recently, however, complement has been recognized for its role in inflammation, autoimmune disorders, and vision loss. This paradigm shift requires a fundamental change in how complement testing is performed and interpreted. Here, we provide an overview of the complement pathways and summarize recent literature related to hereditary and acquired angioedema, infectious diseases, autoimmunity, and age-related macular degeneration...
2016: Advances in Clinical Chemistry
https://www.readbyqxmd.com/read/27497837/eculizumab-epitope-on-complement-c5-progress-towards-a-better-understanding-of-the-mechanism-of-action
#4
Guillaume Brachet, Thomas Bourquard, Nathalie Gallay, Eric Reiter, Valérie Gouilleux-Gruart, Anne Poupon, Hervé Watier
Eculizumab is an anti-complement C5 monoclonal antibody which has greatly improved the prognosis and outcomes of nocturnal paroxysmal hemoglobinuria and atypical hemolytic and uremic syndromes. It is also known to be very species-specific for human C5, despite an important degree of conservation of the targeted macroglobulin domain, MG7, with that of other primates. However, the published eculizumab linear epitope does not explain this species specificity. Sequence analysis, in silico docking and reverse phase protein array were implemented to fully characterize the eculizumab epitope on human complement C5...
September 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27371974/modeling-complement-driven-diseases-in-transgenic-mice-values-and-limitations
#5
REVIEW
Yoshiyasu Ueda, Damodar Gullipalli, Wen-Chao Song
Remarkable advances have been made over past decades in understanding the pathogenesis of complement-mediated diseases. This has led to development of new therapies for, and in some cases re-classification of, complement-driven diseases. This success is due to not only insight from human patients but also studies using transgenic animal models. Animal models that mimic human diseases are useful tools to understand the mechanism of disease and develop new therapies but there are also limitations due to species differences in their complement systems...
October 2016: Immunobiology
https://www.readbyqxmd.com/read/27346521/therapeutic-complement-inhibition-in-complement-mediated-hemolytic-anemias-past-present-and-future
#6
REVIEW
Antonio M Risitano, Serena Marotta
The introduction in the clinic of anti-complement agents represented a major achievement which gave to physicians a novel etiologic treatment for different human diseases. Indeed, the first anti-complement agent eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria (PNH), dramatically impacting its severe clinical course. In addition, eculizumab is the first agent approved for atypical Hemolytic Uremic Syndrome (aHUS), a life-threatening inherited thrombotic microangiopathy. Nevertheless, such remarkable milestone in medicine has brought to the fore additional challenges for the scientific community...
June 2016: Seminars in Immunology
https://www.readbyqxmd.com/read/27257797/infections-associated-with-the-use-of-eculizumab-recommendations-for-prevention-and-prophylaxis
#7
Esther Benamu, José G Montoya
PURPOSE OF REVIEW: Eculizumab inhibits complement effector functions and has significantly impacted the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. However, the risks of potentially life-threatening infections, notably with Neisseria spp. in addition to its cost, are major challenges in clinical practice. In this review, we characterize and summarize the infectious complications reported with the use of eculizumab in the context of its typical and expanding indications...
August 2016: Current Opinion in Infectious Diseases
https://www.readbyqxmd.com/read/27234741/complement-inhibition-for-prevention-and-treatment-of-antibody-mediated-rejection-in-renal-allograft-recipients
#8
S C Jordan, J Choi, J Kahwaji, A Vo
Therapeutic interventions aimed at the human complement system are recognized as potentially important strategies for the treatment of inflammatory and autoimmune diseases because there is often evidence of complement-mediated injury according to pathologic assessments. In addition, there are a large number of potential targets, both soluble and cell bound, that might offer potential for new drug development, but progress in this area has met with significant challenges. Currently, 2 drugs are approved aimed at inhibition of complement activation...
April 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27194791/structural-basis-for-eculizumab-mediated-inhibition-of-the-complement-terminal-pathway
#9
Janus Asbjørn Schatz-Jakobsen, Yuchun Zhang, Krista Johnson, Alyssa Neill, Douglas Sheridan, Gregers Rom Andersen
Eculizumab is a humanized mAb approved for treatment of patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Eculizumab binds complement component C5 and prevents its cleavage by C5 convertases, inhibiting release of both the proinflammatory metabolite C5a and formation of the membrane attack complex via C5b. In this study, we present the crystal structure of the complex between C5 and a Fab fragment with the same sequence as eculizumab at a resolution of 4.2 Å. Five CDRs contact the C5 macroglobulin 7 domain, which contains the entire epitope...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27060440/terminal-complement-blockade-after-hematopoietic-stem-cell-transplantation-is-safe-without-meningococcal-vaccination
#10
Sonata Jodele, Christopher E Dandoy, Lara Danziger-Isakov, Kasiani C Myers, Javier El-Bietar, Adam Nelson, Gregory Wallace, Ashley Teusink-Cross, Stella M Davies
Eculizumab inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy (TMA) in patients with atypical hemolytic uremic syndrome and is now used as a first-line therapy in these diseases. Eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) because of an increased risk of meningococcal infections in persons without adequate functional complement...
July 2016: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/26837283/the-clinical-potential-of-affibody-based-inhibitors-of-c5-for-therapeutic-complement-disruption
#11
EDITORIAL
Magnus M Berglund, Patrik Strömberg
No abstract text is available yet for this article.
2016: Expert Review of Proteomics
https://www.readbyqxmd.com/read/26637747/complement-in-hemolytic-anemia
#12
Robert A Brodsky
Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed...
2015: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/26582375/complement-in-hemolytic-anemia
#13
REVIEW
Robert A Brodsky
Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed...
November 26, 2015: Blood
https://www.readbyqxmd.com/read/26536427/eculizumab-use-in-kidney-transplantation
#14
REVIEW
Christopher K Johnson, Nicolae Leca
PURPOSE OF REVIEW: Eculizumab suppresses the effector functions of the complement system and represents a therapeutic breakthrough for patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome (aHUS). Safety monitoring is ongoing; so far, most notable is the expected increase in infection risk with encapsulated organisms. Despite potential applicability in multiple complement-mediated disorders, the off-label use of eculizumab has been limited, mainly by its prohibitive cost...
December 2015: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/26337866/therapeutic-drug-monitoring-of-eculizumab-rationale-for-an-individualized-dosing-schedule
#15
Philippe Gatault, Guillaume Brachet, David Ternant, Danielle Degenne, Guillaume Récipon, Christelle Barbet, Emmanuel Gyan, Valérie Gouilleux-Gruart, Cécile Bordes, Alexandra Farrell, Jean Michel Halimi, Hervé Watier
The annual cost of eculizumab maintenance therapy in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS) exceeds $300,000 per patient. A better understanding of eculizumab pharmacokinetics and subsequent individual dose adjustment could reduce this cost. We measured the trough eculizumab concentration in 9 patients with maintenance therapy (aHUS, n = 7; PNH, n = 2) and determined: 1) the intra- and inter-individual variability; 2) the influence of weight on eculizumab pharmacokinetics; and 3) the rate of elimination of eculizumab following discontinuation...
2015: MAbs
https://www.readbyqxmd.com/read/26305235/the-activation-of-complement-and-its-role-in-the-pathogenesis-of-thromboembolism
#16
REVIEW
Sara Boyce, Efrem Eren, Bashir A Lwaleed, Rashid S Kazmi
It is well established that inflammation and thrombosis are intricately linked processes, and there is increasing evidence of the importance of their roles in activated complement in the pathogenesis of thromboembolism. The two systems are activated by similar stimuli simultaneously and interact, either directly or through biochemical mediators, to protect the host from microbial invasion. Diseases characterized by complement hyperactivity such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome have high rates of thrombosis...
September 2015: Seminars in Thrombosis and Hemostasis
https://www.readbyqxmd.com/read/26043392/current-and-future-pharmacologic-complement-inhibitors
#17
REVIEW
Antonio M Risitano
The availability of anticomplement therapies has been a major achievement for medicine in the last decade. Indeed, eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome and promises to do the same in several other human complement-mediated diseases. Nowadays, a 10-year experience has also taught us that there are some pitfalls that represent a challenge to improve the current anticomplement treatment. Most of these observations come from paroxysmal nocturnal hemoglobinuria, where unmet clinical needs are emerging, triggering the attention of several investigators and pharmaceutical companies...
June 2015: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/25862562/modified-ham-test-for-atypical-hemolytic-uremic-syndrome
#18
Eleni Gavriilaki, Xuan Yuan, Zhaohui Ye, Alexander J Ambinder, Satish P Shanbhag, Michael B Streiff, Thomas S Kickler, Alison R Moliterno, C John Sperati, Robert A Brodsky
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by excessive activation of the alternative pathway of complement (APC). Atypical HUS is frequently a diagnosis of exclusion. Differentiating aHUS from other TMAs, especially thrombotic thrombocytopenic purpura (TTP), is difficult due to overlapping clinical manifestations. We sought to develop a novel assay to distinguish aHUS from other TMAs based on the hypothesis that paroxysmal nocturnal hemoglobinuria cells are more sensitive to APC-activated serum due to deficiency of glycosylphosphatidylinositol- anchored complement regulatory proteins (GPI-AP)...
June 4, 2015: Blood
https://www.readbyqxmd.com/read/25824240/of-mice-and-men-the-factor-h-protein-family-and-complement-regulation
#19
REVIEW
R B Pouw, D W Vredevoogd, T W Kuijpers, D Wouters
For decades immunological research has relied, with variable success, on mouse models to investigate diseases and possible therapeutic interventions. With the approval of the first therapeutic antibody targeting complement, called eculizumab, as therapy in paroxysmal nocturnal hemoglobinuria (PNH) and more recently atypical hemolytic uremic syndrome (aHUS), the viability of targeting the complement system was demonstrated. The potent, endogenous complement regulators have become of increasing interest as templates for designing and developing new therapeutics...
September 2015: Molecular Immunology
https://www.readbyqxmd.com/read/25468724/eculizumab-treatment-during-pregnancy-does-not-affect-the-complement-system-activity-of-the-newborn
#20
Randi Fykse Hallstensen, Grethe Bergseth, Stian Foss, Steinar Jæger, Tobias Gedde-Dahl, Jan Holt, Dorte Christiansen, Corinna Lau, Ole-Lars Brekke, Elina Armstrong, Vedran Stefanovic, Jan Terje Andersen, Inger Sandlie, Tom Eirik Mollnes
Eculizumab is a humanized IgG2/4 chimeric anti-complement C5 antibody used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome. The aim of this study was to evaluate whether or not the complement activity in newborns from pregnant women who receive eculizumab is impaired. A novel eculizumab-C5 complex (E-C5) specific assay was developed and revealed that two newborns carried only 6-7% of the E-C5 detected in their eculizumab-treated PNH mothers. Serum from the pregnant women completely lacked terminal complement pathway activity, whereas the complement activity in the serum of the newborns was completely normal...
April 2015: Immunobiology
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