RESUMO
BACKGROUND AND OBJECTIVES: Attack prevention is crucial in managing neuromyelitis optica spectrum disorders (NMOSDs). Eculizumab (ECU), an inhibitor of the terminal complement cascade, was highly effective in preventing attacks in a phase III trial of aquaporin-4 (AQP4)-IgG seropositive(+) NMOSDs. In this article, we evaluated effectiveness and safety of ECU in routine clinical care. METHODS: We retrospectively evaluated patients with AQP4-IgG+ NMOSD treated with ECU between December 2014 and April 2022 at 20 German and 1 Austrian university center(s) of the Neuromyelitis Optica Study Group (NEMOS) by chart review. Primary outcomes were effectiveness (assessed using annualized attack rate [AAR], MRI activity, and disability changes [Expanded Disability Status Scale {EDSS}]) and safety (including adverse events, mortality, and attacks after meningococcal vaccinations), analyzed by descriptive statistics. RESULTS: Fifty-two patients (87% female, age 55.0 ± 16.3 years) received ECU for 16.2 (interquartile range [IQR] 9.6 - 21.7) months. Forty-five patients (87%) received meningococcal vaccination before starting ECU, 9 with concomitant oral prednisone and 36 without. Seven of the latter (19%) experienced attacks shortly after vaccination (median: 9 days, IQR 6-10 days). No postvaccinal attack occurred in the 9 patients vaccinated while on oral prednisone before starting ECU and in 25 (re-)vaccinated while on ECU. During ECU therapy, 88% of patients were attack-free. The median AAR decreased from 1.0 (range 0-4) in the 2 years preceding ECU to 0 (range 0-0.8; p < 0.001). The EDSS score from start to the last follow-up was stable (median 6.0), and the proportion of patients with new T2-enhancing or gadolinium-enhancing MRI lesions in the brain and spinal cord decreased. Seven patients (13%) experienced serious infections. Five patients (10%; median age 53.7 years) died on ECU treatment (1 from myocardial infarction, 1 from ileus with secondary sepsis, and 3 from systemic infection, including 1 meningococcal sepsis), 4 were older than 60 years and severely disabled at ECU treatment start (EDSS score ≥ 7). The overall discontinuation rate was 19%. DISCUSSION: Eculizumab proved to be effective in preventing NMOSD attacks. An increased risk of attacks after meningococcal vaccination before ECU start and potentially fatal systemic infections during ECU-particularly in patients with comorbidities-must be considered. Further research is necessary to explore optimal timing for meningococcal vaccinations. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that eculizumab reduces annualized attack rates and new MRI lesions in AQP4-IgG+ patients with NMOSD.
Assuntos
Anticorpos Monoclonais Humanizados , Neuromielite Óptica , Humanos , Neuromielite Óptica/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Masculino , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto , Estudos Retrospectivos , Idoso , Inativadores do Complemento/uso terapêutico , Resultado do Tratamento , Estudos de Coortes , Vacinas Meningocócicas , Aquaporina 4/imunologia , Imageamento por Ressonância MagnéticaRESUMO
Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening condition of small-vessel thrombosis with acute multiple-organ involvement and visceral damage. In this report, we present a case of a patient with CAPS who is refractory to conventional therapy. For the first time in a patient with CAPS, marked C5b-9 formation was demonstrated on microvascular endothelial cells, suggesting the usefulness of therapeutic complement inhibition in this setting. Eculizumab, a C5-blocking monoclonal antibody, is remarkably effective in the treatment of different forms of thrombotic microangiopathy by controlling complement system hyperactivation. It halted the "thrombotic storm" and promptly achieved full recovery of thrombocytopenia. However, kidney function did not recover, possibly because eculizumab was administered too late. Conceivably, the timing of treatment is crucial to achieving disease remission before irreversible structural damage occurs in target organs, thereby preventing their complete functional recovery.
Assuntos
Anticorpos Monoclonais Humanizados , Síndrome Antifosfolipídica , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Síndrome Antifosfolipídica/tratamento farmacológico , Feminino , Resultado do Tratamento , Inativadores do Complemento/uso terapêutico , Doença Catastrófica , Masculino , Adulto , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/diagnóstico , Complexo de Ataque à Membrana do Sistema Complemento/metabolismoRESUMO
The role of complement in the pathogenesis of IgA nephropathy has been heavily explored over the past 50 years. This has led to the general acceptance that complement plays an important role in the clinical presentation and risk for progression of disease in patients with IgA nephropathy. Herein, we review the evidence for complement activation in IgA nephropathy, focusing on evidence that the lectin and alternate pathways are the main actors. We are entering an era of intense investigation of various inhibitors of complement, which should ultimately be the best indicator of contributions of the lectin, alternate and common complement pathways to disease burden. More importantly, we will see if these efforts result in the discovery of clinically relevant options in managing this important disease.
Assuntos
Ativação do Complemento , Inativadores do Complemento , Glomerulonefrite por IGA , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/tratamento farmacológico , Humanos , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/farmacologia , Ativação do Complemento/efeitos dos fármacos , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Animais , Via Alternativa do Complemento/efeitos dos fármacos , Via Alternativa do Complemento/imunologiaRESUMO
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, including the complement regulatory proteins CD55 and CD59. With decreased or a lack of CD55 and CD59 expression on their membranes, PNH red blood cells become susceptible to complement-mediated hemolysis (symptoms of which include anemia, dysphagia, abdominal pain, and fatigue), leading to thrombosis. State-of-the-art PNH treatments act by inhibiting the dysregulated complement at distinct points in the activation pathway: late at the C5 level (C5 inhibitors, eculizumab, ravulizumab, and crovalimab), centrally at the C3 level (C3/C3b inhibitors and pegcetacoplan), and early at the initiation and amplification of the alternative pathway (factor B inhibitor, iptacopan; factor D inhibitor, danicopan). Through their differing mechanisms of action, these treatments elicit varying profiles of disease control and offer valuable insights into the molecular underpinnings of PNH. This narrative review provides an overview of the mechanisms of action of the six complement inhibitors currently approved for PNH, with a focus on the C3/C3b-targeted therapy, pegcetacoplan.
Assuntos
Inativadores do Complemento , Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/metabolismo , Inativadores do Complemento/uso terapêutico , Antígenos CD59/metabolismo , Antígenos CD59/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Ativação do Complemento/efeitos dos fármacos , Antígenos CD55/metabolismo , Antígenos CD55/genéticaRESUMO
A woman in her 40s with no medical history presented on hospital day #0 with 3 days of epigastric pain, nausea, vomiting and bloody diarrhoea. Initial blood work demonstrated acute kidney injury with metabolic acidosis with an elevated anion gap, thrombocytopenia, an elevated lactate dehydrogenase, and an undetectable haptoglobin. She was quickly diagnosed with haemolytic uraemic syndrome from Shiga toxin-producing O157:H7 Escherichia coli Her microangiopathic haemolytic anaemia and renal failure progressively worsened and only improved after the initiation of eculizumab, a monoclonal antibody directed against complement component C5. We report a case of Shiga toxin-producing E. coli-haemolytic uraemia syndrome with a complement-mediated component.
Assuntos
Anticorpos Monoclonais Humanizados , Síndrome Hemolítico-Urêmica , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Adulto , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/complicações , Escherichia coli O157 , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Inativadores do Complemento/uso terapêuticoRESUMO
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients' quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.
Assuntos
Anticorpos Monoclonais Humanizados , Complemento C3 , Aprovação de Drogas , Hemoglobinúria Paroxística , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C3/metabolismo , Hemólise/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Complemento C3b/metabolismo , United States Food and Drug AdministrationRESUMO
BACKGROUND: Thrombotic microangiopathy (TMA) is a rare complication after lung transplantation (LT) that has seldom been characterized in detail. Recent evidence has linked TMA other than primary atypical hemolytic uremic syndrome (aHUS) with hyperactivation of the complement alternative pathway. The focus of this investigation was to analyze the treatment response with eculizumab in TMA after LT. METHODS: Case series where we have studied 11 patients with TMA after LT from 2 Spanish tertiary healthcare centers. Clinical data and response rates to eculizumab are provided. RESULTS: The main indication for lung transplant was chronic obstructive pulmonary disease (COPD) (36%) and most cases (82%) received bilateral LT. The median time to TMA diagnosis was 11.6 months (4.7-28.9) and the TMA trigger in the majority of cases (73%) was immunosuppressive drugs. Platelet and hemoglobin nadir were 58 × 103/µL (24-108) and 7.7 g/dL (7.1-7.9), respectively. All cases presented acute kidney injury (AKI) with a median creatinine of 4 mg/dL (3.2-4.8) and 54.5% required acute dialysis. Eculizumab was started after a median time of 8 days (6-14) with a median duration of 3 weeks (2-8). Complete TMA response was observed in 7 (63.6%) cases and hematologic response in 10 (90.9%). The time to hematologic and renal response was 23 days (13-29) and 28 days (14-46), respectively. CONCLUSIONS: TMA after LT is infrequent but potentially devastating. Our findings suggest that short cycles of eculizumab may be effective for severe TMA after LT.
Assuntos
Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Transplante de Pulmão , Terapia de Salvação , Microangiopatias Trombóticas , Humanos , Feminino , Masculino , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/tratamento farmacológico , Transplante de Pulmão/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Pessoa de Meia-Idade , Seguimentos , Prognóstico , Adulto , Inativadores do Complemento/uso terapêutico , Idoso , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/tratamento farmacológico , Testes de Função Renal , Sobrevivência de Enxerto/efeitos dos fármacosRESUMO
Fucoidans, a group of high molecular weight polysaccharides derived mainly from brown algae, are characterized by their high fucose content, degree of sulfation (DS), and intra- and interspecific structural variation. Fucoidans are increasingly recognized due to various reported bioactivities, potentially beneficial for human health. To unlock their potential use within biomedical applications, a better understanding of their structure-functional relationship is needed. To achieve this, systematic bioactivity studies based on well-defined, pure fucoidans, and the establishment of standardized, satisfactory purification protocols are required. We performed a comprehensive compositional and structural characterization of crude and ultra-purified fucoidans from three kelps: Saccharina latissima (SL), Alaria esculenta (AE) and Laminaria hyperborea (LH). Further, the complement-inhibiting activity of the purified fucoidans was assessed in a human whole blood model. The purification process led to fucoidans with higher DS and fucose and lower concentrations of other monosaccharides. Fucoidans from SL and LH resembles homofucans, while AE is a heterofucan rich in galactose with comparably lower DS. Fucoidans from SL and LH showed complement-inhibiting activity in blood and blood plasma, while no inhibition was observed for AE under the same conditions. The results emphasize the importance of high DS and possibly fucose content for fucoidans' bioactive properties.
Assuntos
Algas Comestíveis , Kelp , Laminaria , Phaeophyceae , Polissacarídeos , Humanos , Inativadores do Complemento/química , Inativadores do Complemento/isolamento & purificação , Inativadores do Complemento/farmacologia , Algas Comestíveis/química , Fucose/química , Fatores Imunológicos/farmacologia , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Kelp/química , Laminaria/química , Phaeophyceae/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/isolamento & purificação , Água/químicaRESUMO
Myasthenia gravis (MG) is a chronic autoimmune disease mediated by autoreactive T- and B-cells and manifested by progressive pathological muscle weakness and fatigue. Traditional immunomodulatory treatment does not always lead to the clinical picture significant improvement, despite adequate dosage and duration of use. Refractory myasthenia gravis requires new therapeutic approaches development and implementation. The range of target innovative agents in refractory MG includes monoclonal antibodies, which act directly on individual components of the complement system. Based on the results of randomized controlled trials, data on the effectiveness and safety of eculizumab, which inhibits the C5 component of the complement system, is presented. We present our own clinical experience of using eculizumab in a young woman with refractory generalized AChR-positive MG with a rapid decrease in the severity of symptoms to a minimum level and restoration of ability to work, and the absence of adverse events during therapy.
Assuntos
Anticorpos Monoclonais Humanizados , Miastenia Gravis , Humanos , Miastenia Gravis/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Adulto , Resultado do Tratamento , Inativadores do Complemento/uso terapêuticoRESUMO
Primary membranous nephropathy (PMN) is a predominant cause of adult nephrotic syndrome, with its incidence witnessing a progressive surge over time. Approximately 35% to 47% of patients progress to renal failure within 10 years, causing a huge social burden. Within China, the proportion of PMN in primary glomerular disease exhibits a gradual ascension. Recent studies have shown that the 3 activation pathways of complement: the classical pathway, mannose-binding lectin pathway, and alternative pathway, are all involved in the pathogenesis of PMN. Despite historical limitations in detecting C1q deposits on the glomeruli of PMN in the past, recent studies have confirmed the classical pathway is implicated in patients with PMN. Considering the dysregulation of the complement system has been observed in PMN, complement inhibitors become increasingly promising. Several clinical trials are presently underway to evaluate the efficacy of complement inhibitors, such as MASP2 antagonists (OMS721), C3 and C3b antagonists (APL2), FD inhibitors (BCX9930), C3aR antagonists (SB290157 and JR14a), FB inhibitors (LNP023). This article reviews the recent research progress on the role of the complement pathway in the pathogenesis of PMN, and underscores the importance of continued research into the complement pathway and its inhibitors, which may pave the way for groundbreaking advancements in the management of PMN.
Assuntos
Glomerulonefrite Membranosa , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/tratamento farmacológico , Humanos , Proteínas do Sistema Complemento , Inativadores do Complemento/uso terapêutico , Ativação do Complemento , Via Alternativa do Complemento/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: Guillain-Barré syndrome (GBS) is an acute, self-limited, immune-mediated peripheral neuropathy. Current treatments for GBS include intravenous immunoglobulin (IVIg) and plasma exchange, which may not sufficiently benefit severely affected patients. This study evaluated the efficacy and safety of eculizumab add-on therapy to IVIg (standard-of-care treatment) in patients with severe GBS. METHODS: This phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial (NCT04752566), enrolled Japanese adults (age ≥ 18 years) with severe GBS (Hughes functional grade [FG] score FG3 or FG4/FG5 within 2 weeks of onset of GBS). Participants were randomized 2:1 to receive intravenous infusion of eculizumab or placebo (once weekly for 4 weeks) with IVIg treatment with 20 weeks of follow-up. Primary efficacy endpoint was the time to first reach FG score ≤1 (able to run). Key secondary endpoints were proportion of participants achieving FG ≤1 at weeks 8 and 24 and FG improvement ≥3 at week 24. Pharmacodynamic analysis of serum free C5 concentration over time was performed. Safety was evaluated. RESULTS: The analysis included 57 participants (eculizumab, n = 37; placebo, n = 20). Primary endpoint was not achieved (hazard ratio, 0.9; 95% CI, 0.45-1.97; p = .89). Key secondary endpoints did not reach statistical significance. Serum C5 concentration was reduced by 99.99% at 1 h postdose and sustained to week 5 but returned to baseline at the end of follow-up period. No new safety signals for eculizumab were identified. INTERPRETATION: Although well tolerated, eculizumab treatment did not show significant effects on motor function recovery compared to placebo in patients with GBS.
Assuntos
Anticorpos Monoclonais Humanizados , Síndrome de Guillain-Barré , Humanos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Masculino , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/fisiopatologia , Método Duplo-Cego , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/farmacologia , Inativadores do Complemento/efeitos adversos , Resultado do TratamentoRESUMO
Geographic atrophy (GA) remains a leading cause of central vision loss with no known cure. Until recently, there were no approved treatments for GA, often resulting in poor quality of life for affected patients. GA is characterized by atrophic lesions on the retina that may eventually threaten the fovea. Emerging treatments have demonstrated the ability to reduce the rate of lesion growth, potentially preserving visual function. Avacincaptad pegol (ACP; Astellas Pharma Inc), a complement component 5 inhibitor, is an FDA-approved treatment for GA that has been evaluated in numerous clinical trials. Here we review the current clinical trial landscape of ACP, including critical post hoc analyses that suggest ACP may reduce the risk of severe loss among patients with GA.
Geographic atrophy (GA) is an advanced form of eye disease age-related macular degeneration. In people with GA, light-sensitive cells at the back of the eye (the retina) start to die, forming lesions. GA lesions usually get bigger over time and can lead to blindness. New medicines are being studied that work by slowing the growth of GA lesions. Avacincaptad pegol (ACP) is one medicine that acts on the immune system and is designed to block the C5 protein, helping stop the immune system from attacking cells in the retina. Based on clinical studies, ACP was shown to slow the growth of GA over time and has been approved by the FDA. This review article summarizes research on ACP.
Assuntos
Atrofia Geográfica , Humanos , Atrofia Geográfica/tratamento farmacológico , Complemento C5/antagonistas & inibidores , Ensaios Clínicos como Assunto , Inativadores do Complemento/uso terapêutico , Animais , Qualidade de VidaRESUMO
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder characterized by a loss of glycosyl-phosphatidyl-inositol-linked (GPI) proteins on various hematopoietic cells. Some GPI proteins are involved in the regulation of the complement system, and their absence renders erythrocytes susceptible to complement-mediated lysis. Current standard of care in PNH is to block the complement system at the level of C5 using ravulizumab or eculizumab; however, some patients with PNH may develop extravascular hemolysis (EVH) during treatment with C5 inhibitors. The proximal complement inhibitor iptacopan has recently been shown to be efficacious in patients with PNH. This article reports on a 43-year-old female patient with PNH who was successfully treated with iptacopan. The patient had received ravulizumab for several years and developed a clinically relevant EVH. After obtaining informed consent, the patient received oral iptacopan 200â¯mg twice daily and ravulizumab was discontinued. Over the next few weeks hemoglobin levels and reticulocyte counts normalized. The patient reported mild flushes with erythema, chills, and mild muscle pain, all of which resolved during follow-up. No breakthrough hemolysis occurred, and no severe adverse events were recorded.
Assuntos
Anticorpos Monoclonais Humanizados , Hemoglobinúria Paroxística , Hemólise , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Feminino , Adulto , Administração Oral , Resultado do Tratamento , Hemólise/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/efeitos adversosRESUMO
Systemic COVID-19 disease is associated with a variety of organ involvement in infected patients. A rarely reported complication is the induction of complement-mediated thrombotic microangiopathy (TMA). TMA is an extremely rare pathological condition that results in thrombosis in capillaries and small arterioles, due to an endothelial injury. It is often combined with thrombocytopenia, Coombs-negative hemolytic anemia, and end-organ damage. This case involves a patient who was admitted to our hospital for the purpose of diagnosis and treatment of acute kidney injury (AKIN 3) with severe proteinuria after a preceding SARS-CoV-2 infection. A 77-year-old male patient had COVID-19 pneumonia in January 2021 with the need of high-flow oxygen therapy in the intensive care unit. In March 2021, he was hospitalized again due to elevated serum creatinine levels and proteinuria. The patient exhibited normal vital parameters. A renal biopsy showed severe TMA. A diagnosis of COVID-19-associated TMA was made, and treatment with high-dose glucocorticoid therapy and plasma exchange was initiated. Additionally, therapy with eculizumab was established. Unfortunately, the kidney failure was initially progressive, so that hemodialysis (HD) was temporarily necessary. In May 2021, kidney function recovered to an estimated glomerular filtration rate of ~ 30 mL/min/1.73m2 corresponding to chronic kidney disease stage 3bA3 - 4A3. COVID-19-associated TMA is an extremely rare disease. TMA may be a possible long-term complication with the risk of end-stage renal disease if not properly diagnosed and treated.
Assuntos
COVID-19 , Microangiopatias Trombóticas , Humanos , COVID-19/complicações , COVID-19/terapia , Masculino , Idoso , Microangiopatias Trombóticas/terapia , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/diagnóstico , SARS-CoV-2 , Glucocorticoides/uso terapêutico , Troca Plasmática , Anticorpos Monoclonais Humanizados/uso terapêutico , Injúria Renal Aguda/terapia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/diagnóstico , Inativadores do Complemento/uso terapêutico , Diálise RenalRESUMO
BACKGROUND/OBJECTIVES: The phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States. METHODS: A retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis-Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use. RESULTS: In total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p < 0.001). At 24 months after eculizumab initiation, MSE was achieved by 19% of patients. MMS or better was achieved by 30% of patients at 24 months. Additionally, 64% of patients receiving prednisone at eculizumab initiation had their prednisone dosage reduced during eculizumab treatment and 13% discontinued prednisone; 32% were able to discontinue nonsteroidal immunosuppressant therapy. DISCUSSION: Eculizumab treatment was associated with sustained improvements in MG-ADL total scores through 24 months in adults with MG. Prednisone dosage was reduced in approximately two-thirds of patients, suggesting a steroid-sparing effect for eculizumab.
Assuntos
Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Imunossupressores , Miastenia Gravis , Humanos , Miastenia Gravis/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , Idoso , Estados Unidos , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/uso terapêutico , Atividades CotidianasRESUMO
INTRODUCTION: Eculizumab, a complement active antibody, and efgartigimod, an Fc fragment that blocks neonatal Fc receptor, are both approved to treat generalized myasthenia gravis (gMG) patients. The objective of this study is to describe the clinical response to both treatments in a real-life setting. METHODS: We collected baseline and follow-up clinical data using the Myasthenia Gravis-Activities of Daily Living (MG-ADL), and Quantitative Myasthenia Gravis (QMG). We included 63 patients, 32 treated with eculizumab and 31 with efgartigimod. Of the efgartigimod-treated patients, 22 were anti-acetylcholine receptor antibody-positive (AChR-Ab +) and 9 were AChR-Ab- (3 MuSK-Ab + and 6 seronegative). RESULTS: Both treatments showed similar efficacy relative to the MG-ADL scale reduction (p = 0.237). Efgartigimod had a similar effect on both AChR-Ab + and AChR-Ab- (p = 0.280). Eculizumab was superior to efgartigimod relative to the QMG score reduction for the entire dataset (p = 0.003) and was more likely to achieve a clinical response at the QMG compared to efgartigimod (OR 1.373; p = 0.016). Steroid-sparing effect was higher for eculizumab than efgartigimod ( - 16.7 vs - 5.2 mg of the baseline daily dose at follow-up; p = 0.001). Mean speed of prednisone reduction was - 13.1 mg of the daily dose for each month of follow-up for eculizumab-treated patients and - 3.2 for efgartigimod (p = 0.001). We found three serious events, all not related to treatment in the investigator's opinion. One eculizumab-treated patient experienced a severe pneumonia and died despite treatment. CONCLUSIONS: Our study provides evidence that eculizumab and efgartigimod can be used in clinical practice to reduce disability in gMG patients. Eculizumab-treated patients had a higher QMG response and steroid sparing effect. Efgartigimod may offer a more flexible schedule due to its cyclical use, no need for vaccination, and efficacy in AChR-Ab- patients.
Assuntos
Anticorpos Monoclonais Humanizados , Miastenia Gravis , Humanos , Miastenia Gravis/tratamento farmacológico , Feminino , Masculino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Pessoa de Meia-Idade , Adulto , Idoso , Resultado do Tratamento , Receptores Colinérgicos/imunologia , Inativadores do Complemento/farmacologia , Inativadores do Complemento/administração & dosagem , Atividades Cotidianas , SeguimentosRESUMO
Introduction: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematologic disease characterised by intravascular haemolysis, thrombophilia and bone marrow failure. There is a lack of established clinical guidance on the screening, diagnosis and manage-ment of PNH in Singapore. A relatively low level of awareness among healthcare professionals regarding PNH manifestations further contributes to diagnostic delays. Additionally, limited access to complement inhibitors, like eculizumab, may delay treatment and impact patient outcomes. Method: Nine haematologists from different institu-tions in Singapore convened to formulate evidence-based consensus recommendations for optimising the diagnosis and management of patients with PNH and improving access to novel treatments. The experts reviewed the existing literature and international guidelines published from January 2010 to July 2023, focusing on 7 clinical questions spanning PNH screening, diagnostic criteria, investigations, treatment and monitoring of subclinical and classic disease, PNH with underlying bone marrow disorders, and PNH in pregnancy. A total of 181 papers were reviewed to formulate the statements. All experts voted on the statements via 2 rounds of Delphi and convened for an expert panel discussion to finetune the recommendations. Results: Sixteen statements have been formulated for optimising the screening, diagnosis and management of PNH. Upon confirmation of PNH diagnosis, individuals with active haemolysis and/or thrombosis should be considered for anti-complement therapy, with eculizumab being the only approved drug in Singapore. Conclusion: The current recommendations aim to guide the clinicians in optimising the screening, diagnosis and management of PNH in Singapore.
Assuntos
Anticorpos Monoclonais Humanizados , Hemoglobinúria Paroxística , Feminino , Humanos , Masculino , Gravidez , Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Consenso , Técnica Delphi , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/terapia , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/terapia , Complicações Hematológicas na Gravidez/tratamento farmacológico , SingapuraRESUMO
BACKGROUND: Although complement component 5 inhibitors (C5is) eculizumab and ravulizumab improve paroxysmal nocturnal hemoglobinuria (PNH) outcomes, patients may experience persistent anemia. This post hoc analysis investigated whether the complement component 3-targeted therapy pegcetacoplan also improved hematologic outcomes and reduced fatigue in patients with PNH and mild/moderate anemia. METHODS: Patients with PNH and hemoglobin ≥10.0 g/dL at baseline of PADDOCK (N = 6), PRINCE (N = 8), and PEGASUS (N = 11) were included. Before receiving pegcetacoplan, PADDOCK and PRINCE patients were C5i-naive; PEGASUS patients had hemoglobin <10.5 g/dL despite stably dosed eculizumab. Hemoglobin concentrations, percentages of patients with concentrations ≥12 g/dL, and sex-specific normalization were assessed at baseline and after 16 weeks of pegcetacoplan, as were absolute reticulocyte counts (ARCs) and normalization and fatigue scores and normalization. RESULTS: From baseline to week 16, mean (SD) hemoglobin concentrations increased in C5i-naive patients (PADDOCK: 10.5 [0.4] to 12.7 [1.1] g/dL; PRINCE: 11.3 [1.0] to 14.0 [1.3] g/dL) and those with suboptimal eculizumab responses (PEGASUS: 10.2 [0.2] to 12.8 [2.6] g/dL). Percentage of patients with hemoglobin ≥12 g/dL increased (PADDOCK: 0 to 60.0% [3 of 5 patients]; PRINCE: 25.0% [2 of 8] to 87.5% [7 of 8]; PEGASUS: 0 to 72.7% [8 of 11]). Sex-specific hemoglobin normalization at week 16 occurred in 40.0% (2 of 5) (PADDOCK), 62.5% (5 of 8) (PRINCE), and 63.6% (7 of 11) (PEGASUS). In all studies, mean ARCs decreased from above normal to normal and ARC normalization increased. Mean Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from below to above or near normal. Two patients had serious adverse events (PEGASUS: post-surgery sepsis, breakthrough hemolysis); breakthrough hemolysis resolved without study discontinuation. CONCLUSION: Patients with PNH and mild/moderate anemia who were C5i-naive or who had suboptimal hemoglobin concentrations despite eculizumab treatment had improved hematologic outcomes and reduced fatigue after initiating or switching to pegcetacoplan. TRIAL REGISTRATION: Trial registration numbers: PADDOCK (NCT02588833), PRINCE (NCT04085601; EudraCT, 2018-004220-11), PEGASUS (NCT03500549).