-
Medicina (Kaunas, Lithuania) Sep 2023Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins... (Review)
Review
Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A () gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis. This review summarizes the biology and current treatment strategies for PNH with the aim of reaching a general audience with an interest in hematologic disorders.
Topics: Humans; Hemoglobinuria, Paroxysmal; Hemolysis; Complement System Proteins; Thrombophilia; Glycosylphosphatidylinositols; Biology
PubMed: 37763731
DOI: 10.3390/medicina59091612 -
Annual Review of Pathology Jan 2024Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been... (Review)
Review
Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.
Topics: Humans; Clonal Hematopoiesis; Hematologic Neoplasms; Myelodysplastic Syndromes; Aging; Inflammation; Hematopoiesis
PubMed: 37832948
DOI: 10.1146/annurev-pathmechdis-051222-122724 -
Journal of Blood Medicine 2023Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired clonal abnormality, which renders hematopoietic cells exquisitely sensitive to complement-mediated... (Review)
Review
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, acquired clonal abnormality, which renders hematopoietic cells exquisitely sensitive to complement-mediated destruction. Classical features of PNH include intravascular hemolytic anemia, increased thrombotic risk, and manifestations related to end-organ damage (eg fatigue, chest pain, dyspnea, renal failure, and pulmonary hypertension). With supportive care alone, mortality rate of patients with PNH is approximately 35%. The anti-C5 monoclonal antibody, eculizumab, was the first targeted therapy approved for PNH, and led to improved hemoglobin, quality of life, reduced transfusion need, reduced thrombosis, and greater overall survival. More recently, therapeutics such as longer acting anti-C5 (ravulizumab) and anti-C3 (pegcetacoplan) medications have been approved, along with other novel therapeutics in late-stage clinical trials. Biosimilars of eculizumab are also now available. Proximal inhibitors (against C3, factor B, and factor D) have shown significant improvements in hemoglobin and transfusion-avoidance in patients who remain anemic despite C5 inhibition. Despite these novel therapies, some unmet challenges remain, including management of breakthrough hemolysis, clinically significant iatrogenic extravascular hemolysis, optimal management in pregnancy, and infection risk mitigation as new targets in the complement system are blocked. In addition, the use of self-administered subcutaneous and oral therapies raises concerns around treatment adherence and the risks of uncontrolled terminal complement. Given the ultra-rare nature of PNH, development is underway of a centralized international registry to capture and analyze the data as they mature for various new therapies and characterize the clinical challenges related to PNH management.
PubMed: 38084255
DOI: 10.2147/JBM.S431493 -
Lancet (London, England) Jan 2024The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated... (Review)
Review
The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated complement activity is associated with unwanted or non-resolving immune responses and inflammation, which induce or exacerbate the pathogenesis of a broad range of inflammatory and autoimmune diseases. Although the merit of targeting complement clinically has long been acknowledged, the overall complement drug approval rate has been modest. However, the success of the humanised anti-C5 antibody eculizumab in effectively treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic syndrome has revitalised efforts to target complement therapeutically. Increased understanding of complement biology has led to the identification of novel targets for drug development that, in combination with advances in drug discovery and development technologies, has resulted in a surge of interest in bringing new complement therapeutics into clinical use. The rising number of approved drugs still almost exclusively target rare diseases, but the substantial pipeline of up-and-coming treatment options will possibly provide opportunities to also expand the clinical targeting of complement to common diseases.
Topics: Humans; Complement Inactivating Agents; Complement System Proteins; Hemoglobinuria, Paroxysmal; Autoimmune Diseases; Drug Discovery
PubMed: 37979593
DOI: 10.1016/S0140-6736(23)01524-6 -
Frontiers in Neurology 2023Myasthenia gravis is a prototypic neuroimmune disorder with autoantibodies targeting the acetylcholine receptor complex at the neuromuscular junction. Patients present... (Review)
Review
Myasthenia gravis is a prototypic neuroimmune disorder with autoantibodies targeting the acetylcholine receptor complex at the neuromuscular junction. Patients present with mainly ocular muscle weakness and tend to have a generalized muscle weakness later in the clinical course. The weakness can be severe and fatal when bulbar muscles are heavily involved. Acetylcholine receptor antibodies are present in the majority of patients and are of IgG1 and IgG3 subtypes which can activate the complement system. The complement involvement plays a major role in the neuromuscular junction damage and the supporting evidence in the literature is described in this article. Complement therapies were initially studied and approved for paroxysmal nocturnal hemoglobinuria and in the past decade, those have also been studied in myasthenia gravis. The currently available randomized control trial and real-world data on the efficacy and safety of the approved and investigational complement therapies are summarized in this review.
PubMed: 37869140
DOI: 10.3389/fneur.2023.1277596 -
Blood Advances Jun 2023Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for... (Randomized Controlled Trial)
Randomized Controlled Trial
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response or intolerance to a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for ≥3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan vs control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomly assigned and stratified based on their number of transfusions (<4 or ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary end points were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n = 35) or control (n = 18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1%; 95% confidence interval [CI], 57.2-89.0; P < .0001) and change from baseline in LDH (least square mean change: pegcetacoplan, -1870.5 U/L; control, -400.1 U/L; difference, -1470.4 U/L; 95% CI, -2113.4 to -827.3; P < .0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals were observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04085601.
Topics: Adult; Humans; Hemoglobinuria, Paroxysmal; Complement Inactivating Agents; Hemolysis; Antibodies, Monoclonal, Humanized; Hemoglobins; L-Lactate Dehydrogenase
PubMed: 36848639
DOI: 10.1182/bloodadvances.2022009129