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Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.
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Antifúngicos , Candidiasis , Animales , Ratones , Complemento C5/metabolismo , Fagocitos/metabolismoRESUMEN
Over a century after the discovery of the complement system, the first complement therapeutic was approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). It was a long-acting monoclonal antibody (aka 5G1-1, 5G1.1, h5G1.1, and now known as eculizumab) that targets C5, specifically preventing the generation of C5a, a potent anaphylatoxin, and C5b, the first step in the eventual formation of membrane attack complex. The enormous clinical and financial success of eculizumab across four diseases (PNH, atypical hemolytic uremic syndrome (aHUS), myasthenia gravis (MG), and anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD)) has fueled a surge in complement therapeutics, especially targeting diseases with an underlying complement pathophysiology for which anti-C5 therapy is ineffective. Intensive research has also uncovered challenges that arise from C5 blockade. For example, PNH patients can still face extravascular hemolysis or pharmacodynamic breakthrough of complement suppression during complement-amplifying conditions. These "side" effects of a stoichiometric inhibitor like eculizumab were unexpected and are incompatible with some of our accepted knowledge of the complement cascade. And they are not unique to C5 inhibition. Indeed, "exceptions" to the rules of complement biology abound and have led to unprecedented and surprising insights. In this review, we will describe initial, present and future aspects of protein inhibitors of the complement cascade, highlighting unexpected findings that are redefining some of the mechanistic foundations upon which the complement cascade is organized.
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Síndrome Hemolítico Urémico Atípico , Hemoglobinuria Paroxística , Humanos , Proteínas del Sistema Complemento/metabolismo , Activación de Complemento , Hemoglobinuria Paroxística/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Complemento C5/metabolismo , Complemento C5/farmacología , Complemento C5/uso terapéutico , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacologíaRESUMEN
The introduction of a therapeutic anti-C5 antibody into clinical practice in 2007 inspired a surge into the development of complement-targeted therapies. This has led to the recent approval of a C3 inhibitory peptide, an antibody directed against C1s and a full pipeline of several complement inhibitors in preclinical and clinical development. However, no inhibitor is available that efficiently inhibits all three complement initiation pathways and targets host cell surface markers as well as complement opsonins. To overcome this, we engineered a novel fusion protein combining selected domains of the three natural complement regulatory proteins decay accelerating factor, factor H and complement receptor 1. Such a triple fusion complement inhibitor (TriFu) was recombinantly expressed and purified alongside multiple variants and its building blocks. We analyzed these proteins for ligand binding affinity and decay acceleration activity by surface plasmon resonance. Additionally, we tested complement inhibition in several in vitro/ex vivo assays using standard classical and alternative pathway restricted hemolysis assays next to hemolysis assays with paroxysmal nocturnal hemoglobinuria erythrocytes. A novel in vitro model of the alternative pathway disease C3 glomerulopathy was established to evaluate the potential of the inhibitors to stop C3 deposition on endothelial cells. Next to the novel engineered triple fusion variants which inactivate complement convertases in an enzyme-like fashion, stoichiometric complement inhibitors targeting C3, C5, factor B, and factor D were tested as comparators. The triple fusion approach yielded a potent complement inhibitor that efficiently inhibits all three complement initiation pathways while targeting to surface markers.
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Factor H de Complemento , Receptores de Complemento 3b , Proteínas Recombinantes de Fusión , Humanos , Factor H de Complemento/metabolismo , Factor H de Complemento/genética , Factor H de Complemento/química , Factor H de Complemento/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/farmacología , Activación de Complemento/efectos de los fármacos , Antígenos CD55/genética , Antígenos CD55/metabolismo , Hemólisis/efectos de los fármacos , Vía Alternativa del Complemento/efectos de los fármacos , Inactivadores del Complemento/farmacología , Eritrocitos/metabolismoRESUMEN
We describe initial, current, and future aspects of complement activation and inhibition in the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare but severe hematological disorder characterized by complement-mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement-mediated pathophysiology ultimately led to regulatory approval of the first-in-class complement inhibitor, eculizumab, in 2007. This anti-complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant-resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti-C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low-level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.
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Kidney transplant (KT) candidates with donor-specific antibodies (DSA) exhibit exceedingly high antibody-mediated rejection (ABMR) and allograft loss rates. Currently, treatment of ABMR remains an unmet clinical need. We report the use of the anti-C5 eculizumab and the type-2 anti-CD20 obinutuzumab in two patients with early ABMR. Eculizumab (900 mg IV) led to complete inhibition of the terminal complement cascade (unremarkable AP50 and CH50 activity) and prompt stoppage of complement-dependent antibody-mediated allograft injury (clearance of intra-graft C4d and C5b-9 deposition). Despite complement inhibition, obinutuzumab (1000 mg IV) determined full and long-lasting peripheral B-cell depletion, with significant reduction in all DSA. Graft function improved, remaining stable up to three years of follow-up. No signs of active ABMR and rebound DSA were detected. Obinutuzumab B-cell depletion and inhibition of DSA production were not affected by complement blockage. Further studies are needed to confirm the potential benefit of obinutuzumab in association with complement inhibitors.
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Anticuerpos Monoclonales Humanizados , Rechazo de Injerto , Trasplante de Riñón , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Masculino , Persona de Mediana Edad , Complemento C5/antagonistas & inhibidores , Complemento C5/inmunología , Femenino , Antígenos CD20/inmunología , Adulto , Linfocitos B/inmunología , Linfocitos B/efectos de los fármacos , Inactivadores del Complemento/uso terapéutico , Isoanticuerpos/inmunologíaRESUMEN
Catastrophic antiphospholipid syndrome (CAPS) is a severe condition with high mortality. Since its description in 1992, an important effort has been made to improve and disseminate knowledge on CAPS. Most of our current knowledge comes from the studies performed using the CAPS Registry, a database created in 2000 to gather as many cases as possible in order to better define this disease. It has demonstrated that this condition has multiple faces and is often triggered by a precipitating factor that leads to a thrombotic microangiopathy and cytokine storm involving almost any organ of the body. Analysis of the CAPS Registry has also shown that patients receiving anticoagulation, glucocorticoids and plasma exchange and/or IVIG have a better prognosis. However, there are still many unresolved questions. In this review we summarize what is known and what is still a matter of research in this condition.
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Síndrome Antifosfolípido , Humanos , Inmunoglobulinas Intravenosas , Intercambio Plasmático , Plasmaféresis , Pronóstico , Enfermedad Catastrófica/terapiaRESUMEN
OBJECTIVES: neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease mainly affecting optic nerves and the spinal cord. Due to the potentially irreversible tissue damage, prevention of relapses is of utmost importance. METHODS: We describe the atypical clinical course and pathology results of a patient with anti-aquaporin-4 antibody (anti-AQP4-Ab)-associated NMOSD who developed aseptic meningitis followed by limbic-encephalitis-like presentation with extensive brain lesions upon treatment with rituximab and tocilizumab. RESULTS: The patient developed subacute cognitive decline with magnetic resonance imaging (MRI) evidence of extensive brain white matter lesions. In the hypothesis of an opportunistic brain infection, she underwent brain biopsy of the temporal pole. Pathology results revealed typical NMOSD findings with complement activation, supporting the hypothesis of an atypical presentation of anti-AQP-Ab-associated NMOSD. Accordingly, treatment with the complement-targeting drug eculizumab was started, leading to a dramatic clinical and MRI improvement. DISCUSSION: aseptic meningitis and limbic encephalitis could represent a rare phenotype of anti-AQP4-Ab-associated NMOSD.
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Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and impairments in quality of life (QoL). The aim of this study was to identify the clinical drivers of improvement in patient-reported outcomes (PROs) in patients with PNH receiving the complement component 5 (C5) inhibitors eculizumab and ravulizumab.This post hoc analysis assessed clinical outcomes and PROs from 246 complement inhibitor-naive patients with PNH enrolled in a phase 3 randomized non-inferiority study that compared the C5 inhibitors ravulizumab and eculizumab (study 301; NCT02946463). The variables of interest were lactate dehydrogenase (LDH) levels, a surrogate measure of IVH, and hemoglobin (Hb) levels. PROs were collected using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess fatigue and QoL, respectively.Improvements in absolute mean LDH levels were significantly associated with improvements in mean FACIT-F score (p = 0.0024) and EORTC QLQ-C30 global health (GH) score (p < 0.0001) from baseline to day 183. Improvements in scores were achieved despite a non-significant increase in Hb levels. To understand the interaction between LDH and Hb, a regression analysis was performed: LDH response with Hb improvements was a significant predictor of improvement in fatigue. The independent effect of improved Hb did not significantly affect FACIT-F or EORTC QLQ-C30 GH scores.These findings suggest that LDH levels are an important determinant of fatigue and QoL outcomes in patients with PNH. CTR: NCT02946463, October 27, 2016.
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Hemoglobinuria Paroxística , Calidad de Vida , Humanos , Inactivadores del Complemento/uso terapéutico , Hemoglobinuria Paroxística/tratamiento farmacológico , Hemólisis , FatigaRESUMEN
INTRODUCTION/AIMS: Myasthenia gravis (MG) is a rare, life-threatening immune-related adverse effect (irAE) of immune checkpoint inhibitor (ICI) treatment. C5-complement inhibitors are effective treatments for acetylcholine receptor antibody (AChR ab) positive generalized MG. We describe the use of eculizumab/ravulizumab in two patients with MG receiving concomitant pembrolizumab. METHODS: This was a retrospective review of two medical records. RESULTS: Patient 1: An 80-year-old male with recurrent, non-muscle invasive transitional cell carcinoma of the bladder developed ICI-induced AChR ab positive MG (ICI-MG), myositis, and myocarditis 2 weeks after the first dose of pembrolizumab. Myositis responded to corticosteroids. MG responded to eculizumab, followed by ravulizumab. He died of metastatic cancer 8 months later. Patient 2: A 58-year-old male had refractory thymoma-associated AChR ab-positive MG, which responded to eculizumab. He developed metastatic Merkel cell cancer necessitating pembrolizumab. MG remained stable on eculizumab. He had no irAEs for 22 months, with positron emission tomographic resolution of cancer. He then developed mild, indolent retinal vasculitis, which responded to prednisone. Discontinuation of pembrolizumab for 5 months resulted in cancer recurrence; pembrolizumab was resumed with peri-infusion pulse prednisone. MG remained stable and he continues eculizumab. DISCUSSION: In the first patient, eculizumab, followed by ravulizumab, improved ICI-MG. In the second patient, eculizumab treatment may have had a prophylactic effect on the development of ICI-induced irAEs. The effect of complement inhibition on cancer outcomes of ICI therapy is unknown. A possible biologic basis for complement inhibitors in reducing irAEs of ICI, especially in the presence of underlying autoimmune disease, merits evaluation.
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Miastenia Gravis , Miositis , Humanos , Masculino , Anciano de 80 o más Años , Persona de Mediana Edad , Prednisona/uso terapéutico , Inactivadores del Complemento/uso terapéutico , Recurrencia Local de Neoplasia/complicaciones , Miastenia Gravis/inducido químicamente , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/complicaciones , Miositis/complicacionesRESUMEN
BACKGROUND AND HYPOTHESIS: Carfilzomib, a new proteasome inhibitor indicated for patients with relapsed/refractory myeloma, has been associated with cases of thrombotic microangiopathy (CFZ-TMA). The role of variants in the complement alternative pathway and therapeutic potential of complement blockade with eculizumab remain to be determined. METHODS: We report 37 cases of CFZ-TMA recorded in the French reference center for TMA with their clinical characteristics, genetic analysis and outcome according to treatments. RESULTS: A trigger was identified in more than half of cases, including 8 influenza and 5 SARS-CoV-2 cases. All patients presented with acute kidney injury (AKI) (KDIGO stage 3 in 31 (84%) patients) while neurological (n=13, 36%) and cardiac damage (n=7, 19%) were less frequent. ADAMTS13 and complement activity were normal (n= 28 and 18 patients tested) and no pathogenic variant in the alternative complement pathway was found in 7 patients tested.TMA resolved in most (n=34, 94%) patients but 12 (44%) still displayed stage 3 AKI at discharge. Nineteen (51%) patients were treated with therapeutic plasma exchange, 14 (38%) patients received corticosteroids and 18 (50%) were treated with eculizumab. However none of these treatments demonstrated a significant impact on outcomes. CONCLUSION: This study is the largest case series of CFZ-TMA since its approval in 2012. Patients present with severe AKI and experience frequent sequelae. Complement variants and blockade therapy do not seem to play a role in the pathophysiology and prognosis of the disease.
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BACKGROUND: Complement-mediated thrombotic microangiopathy (CM-TMA), also called atypical hemolytic uremic syndrome (aHUS), is a difficult-to-diagnose rare disease that carries severe morbidity and mortality. Anti-C5 monoclonal antibodies (aC5-mab) are standard treatments, but large studies and long-term data are scarce. Here, we report our single institution experience to augment the knowledge of CM-TMA treated with aC5-mab therapy. METHODS: We aimed to assess the short and long-term effects of aC5-mab in patients diagnosed with CM-TMA treated outside of a clinical trial. This was a retrospective study. We included all patients diagnosed with CM-TMA and treated with aC5-mab at our institution. There were no exclusion criteria. Endpoints included complete TMA response (CR) defined as normalization of hematological parameters and ≥25% improvement in serum creatinine (Cr) from baseline in patients with renal disease, relapse defined as losing the previously achieved CR, morbidity, adverse events, and survival. RESULTS: We found 28 patients with CM-TMA treated with aC5-mab. The median age was 50 years. Baseline laboratories: platelet counts 93 × 109 /L, hemoglobin 8.6 g/dL, lactate dehydrogenase 1326 U/L, serum Cr 4.7 mg/dL, and estimated glomerular filtration rate 19 mL/min. One individual was on renal replacement therapy (RRT) and 10 initiated RRT within 5 days of the first dose of aC5-mab. Genetic variants associated with CM-TMA included mutations in C3, CFB, CFH, CFHR1/3, CFI, and MCP. The mean duration of hospitalization was 24 days. The median time to initiation of aC5-mab was 10 days. Sixteen subjects received RRT. At the time of hospital discharge, 27 were alive, 14 remained on RRT, and 4 had a CR. At 6 months, 23 patients were alive, 18 continued aC5-mab, 8 remained on RRT, and 9 had a CR. At the last follow-up visit past 6 months, 20 were alive, 14 continued aC5-mab, 5 remained on RRT, 12 had a CR, and 1 was lost to follow-up. CONCLUSIONS: Our study provides real-world experience and insight into the long-term outcomes of CM-TMA treated with aC5-mab. Our findings validate that CM-TMA is an aggressive disease with significant morbidity and mortality, and confirm that aC5-mab is a relatively effective therapy for CM-TMA. Our study adds practical, real-world experience to the literature, but future research remains imperative.
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Síndrome Hemolítico Urémico Atípico , Proteínas Inactivadoras de Complemento , Microangiopatías Trombóticas , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/tratamiento farmacológico , Microangiopatías Trombóticas/etiología , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/genética , Proteínas del Sistema ComplementoRESUMEN
AIMS: Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model. METHODS: We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L). RESULTS: Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax/CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively. CONCLUSIONS: Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.
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Anticuerpos Monoclonales Humanizados , Síndrome Hemolítico Urémico Atípico , Monitoreo de Drogas , Modelos Biológicos , Dinámicas no Lineales , Humanos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Adulto , Monitoreo de Drogas/métodos , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Anciano , Relación Dosis-Respuesta a Droga , Adulto Joven , Inactivadores del Complemento/farmacocinética , Inactivadores del Complemento/administración & dosificación , Simulación por Computador , AdolescenteRESUMEN
As the number of patients living with kidney failure grows, the need also grows for kidney transplantation, the gold standard kidney replacement therapy that provides a survival advantage. This may result in an increased rate of transplantation from HLA-mismatched donors that increases the rate of antibody-mediated rejection (AMR), which already is the leading cause of allograft failure. Plasmapheresis, intravenous immunoglobulin therapy, anti-CD20 therapies (i.e., rituximab), bortezomib and splenectomy have been used over the years to treat AMR as well as to prevent AMR in high-risk sensitized kidney transplant recipients. Eculizumab and ravulizumab are monoclonal antibodies targeting the C5 protein of the complement pathway and part of the expanding field of anticomplement therapies, which is not limited to kidney transplant recipients, and also includes complement-mediated microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and ANCA-vasculitis. In this narrative review, we summarize the current knowledge concerning the pathophysiological background and use of anti-C5 strategies (eculizumab and ravulizumab) and C1-esterase inhibitor in AMR, either to prevent AMR in high-risk desensitized patients or to treat AMR as first-line or rescue therapy and also to treat de novo thrombotic microangiopathy in kidney transplant recipients.
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Proteínas Inactivadoras de Complemento , Trasplante de Riñón , Riñón , Humanos , Trasplante Homólogo , Trasplante de Riñón/efectos adversos , Aloinjertos , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & controlRESUMEN
Chronic hemolytic anemia and vascular occlusion are hallmarks of sickle cell disease (SCD). Blood transfusions are critical for supportive and preventive management of SCD complications. Patients with SCD are at risk for hyperhemolysis syndrome (HHS), a subtype of delayed hemolytic transfusion reactions. HHS management includes intravenous immunoglobulin, corticosteroids, and avoidance of further transfusions. Not all patients respond to first-line agents. Eculizumab, which blocks terminal complement activation, has been proposed as second-line management of HHS. We describe two patients who received eculizumab for refractory HHS. In our experience, eculizumab is a safe and effective option for refractory pediatric HHS.
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Anemia de Células Falciformes , Anticuerpos Monoclonales Humanizados , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Masculino , Femenino , Niño , Hemólisis/efectos de los fármacos , Adolescente , Preescolar , Reacción a la Transfusión/tratamiento farmacológicoRESUMEN
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.
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BACKGROUND: Kidney transplantation is an acceptable therapy end-stage kidney disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis with risk of disease recurrence ranging from 3% to 17%. Standard posttransplant immunosuppression is the mainstay of therapy after recurrence. Recently, new medications focused on complement regulation and avoidance of steroids have been shown to be effective in treating antineutrophil cytoplasmic antibody (ANCA) vasculitis with no studies in the pediatric population. METHODS: We report a 5-year-old patient with immediate recurrence of positive myeloperoxidase (MPO)-ANCA vasculitis after deceased donor kidney transplant and the novel use of eculizumab to salvage the graft. RESULTS: Eculizumab and transition to ravulizumab has been successful in improving graft function and maintenance of disease remission after immediate MPO-ANCA vasculitis recurrence posttransplant. CONCLUSIONS: Complement inhibitors may be used in addition to standard immunosuppression postkidney transplant in a pediatric patient with MPO-ANCA vasculitis recurrence without higher rates of infections.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Monoclonales Humanizados , Fallo Renal Crónico , Trasplante de Riñón , Humanos , Niño , Preescolar , Anticuerpos Anticitoplasma de Neutrófilos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Fallo Renal Crónico/cirugía , Fallo Renal Crónico/complicaciones , RecurrenciaRESUMEN
PURPOSE: To describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships. METHODS: The PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA). RESULTS: The two-compartment model adequately described the PK of SB12 and ECU, and the subject's weight was chosen as a clinically significant covariate affecting drugs' clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients. CONCLUSION: The population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12.
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Anticuerpos Monoclonales Humanizados , Biosimilares Farmacéuticos , Modelos Biológicos , Humanos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Adulto , Masculino , Femenino , Persona de Mediana Edad , Biosimilares Farmacéuticos/farmacocinética , Biosimilares Farmacéuticos/farmacología , Adulto Joven , Hemoglobinuria Paroxística/tratamiento farmacológico , Adolescente , AncianoRESUMEN
BACKGROUND: Infection-associated hemolytic uremic syndrome (IA-HUS), most often due to infection with Shiga toxin-producing bacteria, mainly affects young children. It can be acutely life-threatening, as well as cause long-term kidney and neurological morbidity. Specific treatment with proven efficacy is lacking. Since activation of the alternative complement pathway occurs in HUS, the monoclonal C5 antibody eculizumab is often used off-label once complications, e.g., seizures, occur. Eculizumab is prohibitively expensive and carries risk of infection. Its utility in IA-HUS has not been systematically studied. This systematic review aims to present, summarize, and evaluate all currently available data regarding the effect of eculizumab administration on medium- to long-term outcomes (i.e., outcomes after the acute phase, with a permanent character) in IA-HUS. METHODS: PubMed, Embase, and Web of Science were systematically searched for studies reporting the impact of eculizumab on medium- to long-term outcomes in IA-HUS. The final search occurred on March 2, 2022. Studies providing original data regarding medium- to long-term outcomes in at least 5 patients with IA-HUS, treated with at least one dose of eculizumab during the acute illness, were included. No other restrictions were imposed regarding patient population. Studies were excluded if data overlapped substantially with other studies, or if outcomes of IA-HUS patients were not reported separately. Study quality was assessed using the ROBINS-I tool for risk of bias in non-randomized studies of interventions. Data were analyzed descriptively. RESULTS: A total of 2944 studies were identified. Of these, 14 studies including 386 eculizumab-treated patients met inclusion criteria. All studies were observational. Shiga toxin-producing E. coli (STEC) was identified as the infectious agent in 381 of 386 patients (98.7%), effectively limiting the interpretation of the data to STEC-HUS patients. Pooling of data across studies was not possible. No study reported a statistically significant positive effect of eculizumab on any medium- to long-term outcome. Most studies were, however, subject to critical risk of bias due to confounding, as more severely ill patients received eculizumab. Three studies attempted to control for confounding through patient matching, although residual bias persisted due to matching limitations. DISCUSSION: Current observational evidence does not permit any conclusion regarding the impact of eculizumab in IA-HUS given critical risk of bias. Results of randomized clinical trials are eagerly awaited, as new therapeutic strategies are urgently needed to prevent long-term morbidity in these severely ill patients. SYSTEMATIC REVIEW REGISTRATION NUMBER: OSF Registries, MSZY4, Registration DOI https://doi.org/10.17605/OSF.IO/MSZY4 .
Asunto(s)
Anticuerpos Monoclonales Humanizados , Infecciones por Escherichia coli , Síndrome Hemolítico-Urémico , Escherichia coli Shiga-Toxigénica , Niño , Humanos , Preescolar , Síndrome Hemolítico-Urémico/microbiología , Riñón , Infecciones por Escherichia coli/complicaciones , Toxinas Shiga/uso terapéuticoRESUMEN
Historically, the complement system (classical, lectin, alternative, and terminal pathways) is known to play a crucial role in the etiopathogenesis of many kidney diseases. Direct or indirect activation in these settings is revealed by consumption of complement proteins at the serum level and kidney tissue deposition seen by immunofluorescence and electron microscopy. The advent of eculizumab has shown that complement inhibitors may improve the natural history of certain kidney diseases. Since then, the number of available therapeutic molecules and experimental studies on complement inhibition has increased exponentially. In our narrative review, we give a summary of the main complement inhibitors that have completed phase II and phase III studies or are currently used in adult and pediatric nephrology. The relevant full-text works, abstracts, and ongoing trials (clinicaltrials.gov site) are discussed. Data and key clinical features are reported for eculizumab, ravulizumab, crovalimab, avacopan, danicopan, iptacopan, pegcetacoplan, and narsoplimab. Many of these molecules have been shown to be effective in reducing proteinuria and stabilizing kidney function in different complement-mediated kidney diseases. Thanks to their efficacy and target specificity, these novel drugs may radically improve the outcome of complement-mediated kidney diseases, contributing to an improvement in our understanding of their underlying pathophysiology.
Asunto(s)
Síndrome Hemolítico Urémico Atípico , Glomerulonefritis Membranoproliferativa , Enfermedades Renales , Adulto , Niño , Humanos , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Complemento C3/metabolismo , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Activación de ComplementoRESUMEN
BACKGROUND: Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed. METHODS: In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens. RESULTS: Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients. CONCLUSIONS: Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS.