Article
Medicine, General & Internal
Peter Hillmen, Jeff Szer, Ilene Weitz, Alexander Roeth, Britta Hoechsmann, Jens Panse, Kensuke Usuki, Morag Griffin, Jean-Jacques Kiladjian, Carlos de Castro, Hisakazu Nishimori, Lisa Tan, Mohamed Hamdani, Pascal Deschatelets, Cedric Francois, Federico Grossi, Temitayo Ajayi, Antonio Risitano, Regis Peffault de la Tour
Summary: The study demonstrated that Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis.
NEW ENGLAND JOURNAL OF MEDICINE
(2021)
Article
Hematology
Gloria F. Gerber, Robert A. Brodsky
Summary: This article discusses the theoretical basis and clinical studies of using C3 inhibitors in the treatment of PNH, as well as provides suggestions for treatment sequencing.
Review
Medicine, General & Internal
Bruno Fattizzo, Fabio Serpenti, Juri Alessandro Giannotta, Wilma Barcellini
Summary: Paroxysmal nocturnal hemoglobinuria (PNH) is an intriguing disease with ongoing research on its pathophysiology, diagnostics, and treatment. Advanced flow cytometry techniques have enabled detection of small PNH clones, but data interpretation remains challenging. New complement inhibitors may improve patients' quality of life and response rates, but questions regarding their use and long-term safety need further investigation.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Immunology
Melissa A. Colden, Sushant Kumar, Bolormaa Munkhbileg, Daria V. Babushok
Summary: Paroxysmal Nocturnal Hemoglobinuria (PNH) is a disease that involves mutations in a specific gene, leading to hemolysis and abnormal clonal expansion of blood cells. The mechanisms behind this expansion are still debated, but recent advancements in research and technology offer new opportunities for understanding the disease.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Medicine, Research & Experimental
Bo Xu
Summary: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening blood disease. The new targeted C3 therapy Empaveli (pegcetacoplan) has been approved by the US FDA for adult PNH patients. Pegcetacoplan targets C3 and effectively controls the complement cascade, resulting in improved hemoglobin levels and reduced need for blood transfusions.
CLINICAL AND EXPERIMENTAL MEDICINE
(2023)
Review
Hematology
Jens Panse
Summary: In the past 20 years, therapy for paroxysmal nocturnal hemoglobinuria (PNH) mainly relied on antibody-based terminal complement inhibition. PNH is a disease characterized by a mutation that causes the absence or deficiency of complement-regulatory proteins on blood cells, leading to intravascular hemolysis and related complications. Recently, there has been a development of new drugs targeting the proximal and terminal complement cascade, with the approval of the first proximal complement inhibitor targeting C3 in 2021. This article aims to provide an overview of the progress made in PNH treatment and discuss the approved therapeutic options, as well as the potential impact and consequences of current and future treatments on patients' lives.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Review
Hematology
Austin G. Kulasekararaj, Ioanna Lazana
Summary: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder characterized by deficiency of GPI-linked complement regulators. Despite the introduction of C5 inhibitors, residual hemolysis still occurs, leading to anemia and transfusion dependency in some patients. The development of longer-acting and subcutaneous formulations of C5 inhibitors, as well as proximal complement inhibitors, have shown promising results in improving hemoglobin levels and reducing hemolysis. Combination treatments have also been explored. This review discusses the current therapeutic options and emerging approaches for PNH.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Review
Hematology
Austin G. Kulasekararaj, Robert A. Brodsky, Jun-ichi Nishimura, Christopher J. Patriquin, Hubert Schrezenmeier
Summary: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder that can cause hemolysis, thrombosis, and organ damage. LDH is used as a biomarker for diagnosis. Eculizumab and ravulizumab, inhibitors of the terminal complement component 5 (C5), have shown effectiveness in treating PNH.
THERAPEUTIC ADVANCES IN HEMATOLOGY
(2022)
Review
Immunology
Nicole Galli, Loredana Pettine, Mauro Panigada, Laura Daprai, Grazia Suriano, Anna Grancini, Wilma Barcellini, Bruno Fattizzo
Summary: This case report highlights the risk of life-threatening infection by non-groupable Neisseria meningitidis in a young patient with paroxysmal nocturnal haemoglobinuria (PNH) treated with ravulizumab. Prompt diagnosis and treatment are crucial in managing such infections in PNH patients on complement inhibitors.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Hematology
Raymond S. M. Wong, Humphrey W. H. Pullon, Ismail Amine, Andrija Bogdanovic, Pascal Deschatelets, Cedric G. Francois, Kalina Ignatova, Surapol Issaragrisil, Pimjai Niparuck, Tontanai Numbenjapon, Eloy Roman, Jameela Sathar, Raymond Xu, Mohammed Al-Adhami, Lisa Tan, Eric Tse, Federico Grossi
Summary: The study evaluated the safety and efficacy of the newly approved complement inhibitor, pegcetacoplan, in patients with PNH and found that it improved clinical indicators by controlling hemolysis.
ANNALS OF HEMATOLOGY
(2022)
Review
Hematology
Robert A. Brodsky
Summary: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare complement-mediated hemolytic anemia with diverse manifestations, requiring differentiated treatment approaches; terminal complement inhibition is effective for intravascular hemolysis treatment but not bone marrow failure; novel complement inhibitors under clinical development show promising prospects for future applications.
Article
Hematology
Regis Peffault de Latour, Kohei Hosokawa, Antonio Maria Risitano
Summary: Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by intravascular hemolysis, thrombosis, and bone marrow failure. The introduction of the anti-C5 monoclonal antibody eculizumab has significantly improved treatment outcomes, but it requires lifelong infusion and some patients still experience anemia. New anti-C5 agents and proximal complement inhibitors offer potential alternatives for improving the efficacy of treatment.
SEMINARS IN HEMATOLOGY
(2022)
Review
Immunology
Antonio M. Risitano, Regis Peffault de Latour, Luana Marano, Camilla Frieri
Summary: The treatment of paroxysmal nocturnal hemoglobinuria (PNH) has been revolutionized by the introduction of the anti-C5 agent eculizumab, but extravascular hemolysis mediated by C3 remains a problem. Compstatin, a peptide that inhibits the complement cascade at the level of C3, has shown promise in improving the clinical response in PNH. Pegcetacoplan, a pegylated form of compstatin, has been evaluated in clinical studies and has shown superior results compared to eculizumab in terms of hemoglobin change and reduction in hemolysis.
SEMINARS IN IMMUNOLOGY
(2022)
Review
Medicine, Research & Experimental
Imre Bodo, Ismail Amine, Ana Boban, Horia Bumbea, Alexander Kulagin, Elena Lukina, Agnieszka Piekarska, Irena Preloznik Zupan, Juraj Sokol, Jerzy Windyga, Jaroslav Cermak
Summary: Hemolysis in PNH is complement-mediated due to the lack of complement inhibitors in the cell membranes. To manage PNH, complement inhibition is the best approach. Three complement inhibitors – eculizumab, ravulizumab, and pegcetacoplan – are approved as targeted therapy for PNH. However, current guidelines do not consider the latest clinical trial evidence. Expert recommendations were created to identify specific populations who may benefit from switching to proximal C3 inhibition.
ADVANCES IN THERAPY
(2023)
Review
Oncology
Juri Alessandro Giannotta, Bruno Fattizzo, Wilma Barcellini
Summary: Paroxysmal nocturnal hemoglobinuria (PNH) is associated with aplastic anemia and myelodysplastic syndromes, with a prevalence of PNH clones in MPN patients around 10%, commonly associated with JAK2V617F-positive myelofibrosis. Thrombotic events are a common clinical presentation in this combination, sometimes refractory to treatment, and the use of eculizumab may only provide partial effectiveness in controlling hemolytic anemia, necessitating careful evaluation of risk/benefit in this peculiar setting.
FRONTIERS IN ONCOLOGY
(2021)
Review
Immunology
Tom E. Mollnes, Benjamin S. Storm, Ole L. Brekke, Per H. Nilsson, John D. Lambris
Summary: The complement system, initially thought to protect the host from infection, has been shown to have numerous other functions and plays a major role in various diseases. Traditional reductionistic models of complement research are limited, and there is a need for holistic models that retain complement activity and allow for the study of interactions with other inflammatory systems. Two such models using anticoagulated whole blood are described here, which will be useful in further understanding complement-driven diseases.
SEMINARS IN IMMUNOLOGY
(2022)
Article
Immunology
Thyago Bispo Leonel, Joel Jose Megale Gabrili, Carla Cristina Squaiella-Baptistao, Trent M. Woodruff, John D. Lambris, Denise V. Tambourgi
Summary: This study analyzed the effects of Bothrops jararaca snake venom on the complement system and innate immunity. The venom was found to activate the complement system and induce inflammatory responses. Inhibition of the complement system may represent a potential therapeutic approach for Bothrops jararaca envenoming.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Critical Care Medicine
Relber A. Goncales, Helder Novais Bastos, Claudio Duarte-Oliveira, Daniela Antunes, Oksana Sokhatska, Maria Jacob, Rui Rolo, Claudia F. Campos, Sergio D. Sasaki, Alessia Donato, Sarah N. Mapelli, Sandra Costa, Conceicao Souto Moura, Luis Delgado, Antonio Morais, Egidio Torrado, Frank L. van de Veerdonk, Thomas Weichhart, John D. Lambris, Ricardo Silvestre, Cecilia Garlanda, Alberto Mantovani, Cristina Cunha, Agostinho Carvalho
Summary: This study reveals the role of long pentraxin PTX3 in sarcoidosis, finding that its deficiency can lead to amplified complement activation and promote granuloma formation. The results suggest that PTX3 plays a pivotal role in macrophages to restrain granulomatous inflammation and this signaling axis holds therapeutic potential for targeting granuloma formation in sarcoidosis.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2022)
Editorial Material
Immunology
Dimitrios C. Mastellos, John D. Lambris
SEMINARS IN IMMUNOLOGY
(2022)
Review
Immunology
Marco Mannes, Dimitrios C. Mastellos, Kristina N. Ekdahl, Bo Nilsson, Despina Yancopoulou, John D. Lambris, Markus Huber-Lang
Summary: Patients in the ICU often straddle the divide between life and death. The complement system plays a crucial role in diseases that may require ICU admission. Therefore, evaluating complement inhibition strategies in ICU treatment is valuable.
SEMINARS IN IMMUNOLOGY
(2022)
Review
Immunology
Tetsuhiro Kajikawa, Dimitrios C. Mastellos, Hatice Hasturk, Georgios A. Kotsakis, Despina Yancopoulou, John D. Lambris, George Hajishengallis
Summary: Periodontitis, if not properly treated, can lead to tooth loss and affect overall health. This review focuses on the potential use of a complement-targeting drug called AMY-101 in the treatment of periodontal disease and peri-implant inflammatory conditions.
SEMINARS IN IMMUNOLOGY
(2022)
Article
Engineering, Biomedical
Clement Bechtler, Sophia Koutsogiannaki, Ekaterina Umnyakova, Amal Hamid, Avneesh Gautam, Yiannis Sarigiannis, Richard B. Pouw, Christina Lamers, Said Rabbani, Christoph Q. Schmidt, John D. Lambris, Daniel Ricklin
Summary: The use of biomaterials in modern medicine has advanced drug delivery strategies and reduced morbidity and mortality. However, immune reactions remain a serious complication.
ACTA BIOMATERIALIA
(2023)
Review
Hematology
Corrado Girmenia, Wilma Barcellini, Paola Bianchi, Eros Di Bona, Anna Paola Iori, Rosario Notaro, Simona Sica, Alberto Zanella, Antonio De Vivo, Giovanni Barosi, Antonio Risitano
Summary: This article presents the results of group discussion among experts on unmet clinical needs in managing infectious risk associated with eculizumab or new terminal complement inhibitors (CIs) in paroxysmal nocturnal hemoglobinuria (PNH). The selected clinically relevant needs were optimizing infection prevention measures, developing non-pharmacological infectious risk-mitigation strategies, and improving disease management during infectious complications. Consensus opinions and proposals for advancing clinical practice were provided for each issue. The aim is to improve CI therapy and guide future studies in this field.
Letter
Hematology
Michela Sica, Federica Barone, Caterina Nannelli, Patrizia Ricci, Luana Marano, Maria De Angioletti, Eros Di Bona, Antonio M. Risitano, Rosario Notaro
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Review
Hematology
Christina Lamers, Daniel Ricklin, John D. Lambris
Summary: The number of complement inhibitors approved for therapeutic use or in late-stage clinical trials has expanded rapidly in recent years. The sudden emergence of this area in biotech start-ups and pharmaceutical companies is surprising considering the well-established involvement of the complement system in various clinical conditions. However, the complement system has unique characteristics that have delayed its recognition as a traditional drug target, such as concerns about safety and the complexity of its involvement in biological processes.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Multidisciplinary Sciences
Irene Cosi, Annalisa Moccia, Chiara Pescucci, Uday Munagala, Salvatore Di Giorgio, Irene Sineo, Silvestro G. G. Conticello, Rosario Notaro, Maria De Angioletti
Summary: ETV4, an overexpressed ETS protein in prostate cancer, promotes migration, invasion, and proliferation in prostate cells. This study identifies previously unknown ETV4 alternatively spliced transcripts in human prostate cell lines and confirms their presence in prostate tumors. The abundance of these transcripts may reflect tumor deranged splicing machinery and their potential interactions with canonical variants may contribute to the biology and clinics of prostate cancer. Further investigations are needed to understand the biological role of these ETV4 transcripts and their isoforms.
SCIENTIFIC REPORTS
(2023)
Article
Cell Biology
Amelie Kuhn, Jana Riegger, Graciosa Q. Teixeira, Markus Huber-Lang, John D. Lambris, Cornelia Neidlinger-Wilke, Rolf E. Brenner
Summary: Terminal complement complex deposition was found in human degenerated discs. The study investigated the mechanisms and effects of terminal complement activation in annulus fibrosus (AF) cells. Complement inhibitors effectively suppressed anaphylatoxin generation and TCC deposition induced by zymosan. Gene expression of ADAMTS4, MMP1, and COX2 was influenced by C3 and C5 blockade. Degenerated endplate tissue secreted soluble factors that enhanced direct C5 cleavage. These findings suggest the functional involvement of terminal complement activation in disc degeneration and the role of degenerated tissue in complement activation.
Article
Chemistry, Analytical
Marta A. Rysz, Jonny Kinzi, Anima M. Schafer, Katja In-Albon, Simone Zurcher, Seraina Schmidlin, Isabell Seibert, Oliver Schwardt, Daniel Ricklin, Henriette E. Meyer zu Schwabedissen
Summary: In this study, a bioanalytical method for simultaneous determination of atorvastatin, erlotinib, and its metabolite OSI-420 in biological samples was developed and validated. The results showed that female rats exhibited slower metabolism of erlotinib compared to male rats, and the presence of atorvastatin inhibited the metabolism of erlotinib. Non-compartmental pharmacokinetic analysis revealed a lower clearance of erlotinib when co-administered with atorvastatin.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2023)
Article
Hematology
Bojun Li, Clement Bechtler, Lorenz Jenny, Daniel Ricklin, Verena Schroeder
Summary: This study reveals that free FXIII-B has no direct role in regulating the complement system, despite its structural similarity to major complement regulators. Alpha 2MG is identified as a potential binding partner for free FXIII-B, although its direct interactions and functional effects remain to be validated.
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2022)