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The role of eculizumab in treating Shiga-toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) patients with neurological involvement remains unclear. We describe two distinctly different STEC-HUS patients with neurologic involvement successfully managed with eculizumab, and perform a literature review of all published cases. Both patients had complete resolution of neurological symptoms after initiation of eculizumab. Eighty patients with STEC-HUS treated with eculizumab were identified in the literature, 68.7% had complete resolution of neurological symptoms. Based on our experience and literature review, three prevailing themes were noted: 1) Early eculizumab administration optimized neurological outcomes, 2) Symptom resolution may not be immediate, neurological symptoms may initially worsen before improvement, and 3) Plasma exchange yielded no benefit. Early administration of eculizumab may reverse neurotoxicity in patients with STEC-HUS.

Introduktion: Paroxysmal nokturn hemoglobinuri (PNH) är en kronisk, förvärvad, mycket sällsynt sjukdom som kännetecknas av komplementmedierad intravaskulär hemolys och är potentiellt livshotande. Sjukdomen börjar med en störning hos en hematopoetisk stamcell vilket leder till att patienter med PNH får röda blodceller som är känsliga för aktiverat komplementsystem och membranattackkomplexet (MAC). PNH kan ge symtom som exempelvis anemi, trombos och trötthet. PNH kan behandlas med komplementhämmare som förhindrar komplementaktivering och därmed komplementmedierad intravaskulär hemolys. Den först utvecklade komplementhämmaren eculizumab är en C5-hämmare som kontrollerar intravaskulär hemolys. Många patienter visar dock tecken på extravaskulär hemolys under behandling med eculizumab. Därför utvecklades det en C3-hämmare pegcetacoplan som ska även blockera extravaskulär hemolys. Syfte: Syftet med detta arbete var att studera pegcetacoplans effektivitet i komplementhämmare-naiva patienter och effektivitet i jämförelse med eculizumab vid behandling av PNH. Syftet var även att analysera skillnader i effektivitet mellan pegcetacoplan och eculizumab vid behandling av PNH. Metod: Detta examensarbete var ett litteraturarbete där sex vetenskapliga artiklar inkluderades baserat på inklusions- och exklusionskriterier. Inklusionskriterier var klinisk studie som analyserade pegcetacoplans effektivitet hos patienter med PNH. Exklusionskriterier var bland annat post hoc-analyser och fallrapporter. Artikelsökning gjordes i databasen PubMed med sökorden ”paroxysmal nocturnal hemoglobinuria pegcetacoplan”. Resultat: Pegcetacoplan-behandling ledde till och/eller bibehöll förbättringar gällande bland annat hemoglobinnivåer och LDH-nivåer hos patienter med PNH i alla sex studier. I PHAROAH och PADDOCK/PALOMINO visades en ökning av klonal distribution av typ II och typ III röda blodceller och minskning av C3 på typ II och typ III celler, vilket tolkades som att pegcetacoplan skyddar dessa ce, Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, acquired, rare disease characterized by complement-mediated intravascular hemolysis and is potentially life-threatening. The disease begins with a disorder of a hematopoietic stem cell, which results in patients with PNH having red blood cells that are sensitive to complement activation and the membrane attack complex (MAC). PNH can cause symptoms such as anemia, thrombosis and fatigue. PNH can be treated with complement inhibitors that prevent complement activation and thereby complement-mediated intravascular hemolysis. The first complement inhibitor developed, eculizumab, is a C5 inhibitor that controls intravascular hemolysis. However, many patients show signs of extravascular hemolysis during treatment with eculizumab. Therefore, a C3 inhibitor pegcetacoplan was developed that should also block extravascular hemolysis. Aim: The aim of this study was to evaluate the efficacy of pegcetacoplan in complement inhibitor-naïve patients and efficacy in comparison with eculizumab in the treatment of PNH. The aim was also to analyze differences in effectiveness between pegcetacoplan and eculizumab in the treatment of PNH. Method: This thesis was a literature review in which six scientific articles were analyzed. Inclusion criteria were clinical trial analyzing the efficacy of pegcetacoplan in patients with PNH. Exclusion criteria included post hoc analyzes and case reports. An article search was made in the PubMed database with the keywords "paroxysmal nocturnal hemoglobinuria pegcetacoplan". Results: Pegcetacoplan treatment led to and/or maintained improvements in, among other things, hemoglobin levels and LDH levels in patients with PNH in all six studies. In the PHAROAH and PADDOCK/PALOMINO studies, an increase in the clonal distribution of type II and type III red blood cells and a decrease in C3 on type II and type III cells were shown, which was interpreted as pegcetacoplan protecting these cells

Introduktion: Paroxysmal nokturn hemoglobinuri (PNH) är en kronisk, förvärvad, mycket sällsynt sjukdom som kännetecknas av komplementmedierad intravaskulär hemolys och är potentiellt livshotande. Sjukdomen börjar med en störning hos en hematopoetisk stamcell vilket leder till att patienter med PNH får röda blodceller som är känsliga för aktiverat komplementsystem och membranattackkomplexet (MAC). PNH kan ge symtom som exempelvis anemi, trombos och trötthet. PNH kan behandlas med komplementhämmare som förhindrar komplementaktivering och därmed komplementmedierad intravaskulär hemolys. Den först utvecklade komplementhämmaren eculizumab är en C5-hämmare som kontrollerar intravaskulär hemolys. Många patienter visar dock tecken på extravaskulär hemolys under behandling med eculizumab. Därför utvecklades det en C3-hämmare pegcetacoplan som ska även blockera extravaskulär hemolys. Syfte: Syftet med detta arbete var att studera pegcetacoplans effektivitet i komplementhämmare-naiva patienter och effektivitet i jämförelse med eculizumab vid behandling av PNH. Syftet var även att analysera skillnader i effektivitet mellan pegcetacoplan och eculizumab vid behandling av PNH. Metod: Detta examensarbete var ett litteraturarbete där sex vetenskapliga artiklar inkluderades baserat på inklusions- och exklusionskriterier. Inklusionskriterier var klinisk studie som analyserade pegcetacoplans effektivitet hos patienter med PNH. Exklusionskriterier var bland annat post hoc-analyser och fallrapporter. Artikelsökning gjordes i databasen PubMed med sökorden ”paroxysmal nocturnal hemoglobinuria pegcetacoplan”. Resultat: Pegcetacoplan-behandling ledde till och/eller bibehöll förbättringar gällande bland annat hemoglobinnivåer och LDH-nivåer hos patienter med PNH i alla sex studier. I PHAROAH och PADDOCK/PALOMINO visades en ökning av klonal distribution av typ II och typ III röda blodceller och minskning av C3 på typ II och typ III celler, vilket tolkades som att pegcetacoplan skyddar dessa ce, Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, acquired, rare disease characterized by complement-mediated intravascular hemolysis and is potentially life-threatening. The disease begins with a disorder of a hematopoietic stem cell, which results in patients with PNH having red blood cells that are sensitive to complement activation and the membrane attack complex (MAC). PNH can cause symptoms such as anemia, thrombosis and fatigue. PNH can be treated with complement inhibitors that prevent complement activation and thereby complement-mediated intravascular hemolysis. The first complement inhibitor developed, eculizumab, is a C5 inhibitor that controls intravascular hemolysis. However, many patients show signs of extravascular hemolysis during treatment with eculizumab. Therefore, a C3 inhibitor pegcetacoplan was developed that should also block extravascular hemolysis. Aim: The aim of this study was to evaluate the efficacy of pegcetacoplan in complement inhibitor-naïve patients and efficacy in comparison with eculizumab in the treatment of PNH. The aim was also to analyze differences in effectiveness between pegcetacoplan and eculizumab in the treatment of PNH. Method: This thesis was a literature review in which six scientific articles were analyzed. Inclusion criteria were clinical trial analyzing the efficacy of pegcetacoplan in patients with PNH. Exclusion criteria included post hoc analyzes and case reports. An article search was made in the PubMed database with the keywords "paroxysmal nocturnal hemoglobinuria pegcetacoplan". Results: Pegcetacoplan treatment led to and/or maintained improvements in, among other things, hemoglobin levels and LDH levels in patients with PNH in all six studies. In the PHAROAH and PADDOCK/PALOMINO studies, an increase in the clonal distribution of type II and type III red blood cells and a decrease in C3 on type II and type III cells were shown, which was interpreted as pegcetacoplan protecting these cells

Introduction: The complement system serves as a crucial defense mechanism against invading pathogens; however, dysregulation of this system can result in harmful consequences. Central to the complement cascade are the classical pathway (CP) or lectin pathway (LP) and the alternative pathway (AP) convertases. Aberrant regulation of the convertases is often implicated in the development of rare complement-related diseases. However, analyzing convertase activity poses a significant challenge due to their labile nature and intricate interactions with serum proteins., Methods: In this study, we propose a novel assay for the functional evaluation of these complexes. Our approach leverages a widely available human lymphoma cell line, which when sensitized with antibodies, triggers activation of the CP with a substantial amplification by the AP. The combined action of 2, C5 blockers eculizumab and crovalimab let the cascade proceed up to the level of convertases but not further. In the next step, C5 inhibitors were washed away and guinea pig serum in ethylenediamine tetraacetic acid (EDTA) buffer supported the development of lytic sites on the platform of preexisting convertases, Results:The assay detects recombinant gain-of-function (GoF) components of both convertase types within human serum or plasma. Furthermore, we demonstrate the assay's practical utility in analyzing nephrological patients harboring C3 genetic variants and illustrate its capacity to distinguish between patients and asymptomatic relatives carrying the same pathogenic C3 variant., Conclusion: We provided a proof-of-concept of a new assay that detects convertase overactivity in individuals carrying variants of both pathogenic character or those of unknown significance in ubiquitous complement proteins such as C3.

Objective. To evaluate maternal and perinatal outcomes in pregnant women affected by Paroxysmal Nocturnal Hemoglobinuria (PNH) treated with eculizumab with a case series and literature review. Materials and Methods. This was a case series study with literature review. Clinical records of all consecutive pregnant women with PNH were included in the study. The systematic review was conducted using electronic databases from inception of each database through May 2021. No restrictions for language or geographic location were applied. All reports of women with PNH in pregnancy, treated with eculizumab, were included in the review. Reports of women not treated or treated with other drugs rather than eculizumab (e.g., low molecular weight heparin alone) were excluded from the study. Maternal and perinatal outcomes were evaluated. Results. Fifteen studies, including 24 pregnancies with PNH, were included in the review. All included women received eculizumab during the pregnancy, of them 10 received the treatment for the entire length of their gestation. Gestational age at delivery was reported in 18 cases, with preterm birth at less than 37 weeks occurring in fifteen women (83%). 57.1% of the women delivered by caesarean delivery. The cases series added three new cases in the literature. Two cases were already on eculizumab before pregnancy, while in one case eculizumab therapy was initiated in the second trimester of pregnancy. In all the three cases, there were no thrombotic complications, maternal or neonatal deaths, or foetal structural abnormalities. Conclusions. PNH in pregnant women may be associated with an increased risk of obstetric complications, such us caesarean delivery or preterm birth. Eculizumab appears to be safe and effective for managing PNH during pregnancy.

Latar Belakang: Hemolytic Uremic Syndrome (HUS) adalah bentuk trombotik mikroangiopati yang ditandai dengan trombositopenia, anemia hemolitik mikroangiopati dan gagal ginjal akut, serta dapat terjadi baik pada anak anak maupun orang dewasa. Eculizumab adalah antibodi monoklonal chimeric IgG2/4 yang berpasangan dengan protein komplemen C5 dan digunakan untuk mengobati atau mencegah kekambuhan HUS setelah transplantasi ginjal. Tujuan: Artikel ini bertujuan untuk mengetahui penggunaan eculizumab sebagai pilihan terapi pada pasien HUS yang telah menjalani transplantasi ginjal mengenai dampak dan cara pemberianya. Metode: Tinjauan literatur dari dua database yaitu Google Scholar dan PubMed yang terbit dalam rentang waktu 5 tahun yaitu dari tahun 2018-2023. Hasil: Didapatkan 11 literatur yang membuktikan eculizumab dapat dipertimbangkan sebagai pilihan terapi pada pasien HUS dengan transplantasi ginjal. Dampak eculizumab dapat menurunkan risiko kekambuhan atau timbulnya HUS pasca transplantasi ginjal. Walaupun kebanyakan efek samping pemberian eculizumab tidak serius, meningitis hingga kematian tidak dapat dikesampingkan. Maka dibutuhkan pedoman tatacara penggunaan eculizumab berdasarkan data yang lebih besar untuk mengurangi risiko infeksi dan memangkas biaya., Background: Hemolytic Uremic Syndrome (HUS) is a form of thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic hemolytic anemia and acute renal failure, occur in both children and adults. Eculizumab is a chimeric IgG2/4 monoclonal antibody that pairs with complement protein C5 and is used to treat or prevent relapse of HUS after kidney transplantation. Purpose: This article aims to determine the use of eculizumab as a therapeutic option in HUS patients with kidney transplants and explaining both the clinical effect and the method of administration. Method: Literature review from two databases, namely Google Scholar and PubMed, which were published within the last 5 years, from 2018-2023. Results: There were 11 literatures proving that eculizumab can be considered as a therapeutic option in HUS patients with kidney transplantation. Eculizumab can reduce the risk of recurrence or the emergence of HUS after kidney transplantation. Although most of the side effects of eculizumab are not serious, meningitis and death cannot be ruled out. So guidelines for the use of eculizumab are needed based on larger data to reduce the risk of infection and cost lost.

Scleroderma renal crisis is a severe complication of systemic sclerosis with a poor prognosis. Therefore, identifying precipitating factors is essential. Among known risk factors, only few are reversible. On the contrary, anti-C5 therapy appears effective, at least in some cases. We describe a 59-year-old man with diffuse cutaneous systemic sclerosis who developed life-threatening scleroderma renal crisis following ibuprofen administration. Despite aggressive management, he did not improve. Renal biopsy have displayed features of thrombotic microangiopathy but no complement deposition. We then discuss the pathomechanism of scleroderma renal crisis that could drive eculizumab treatment since some renal biopsies exhibit complement deposits and others do not., SCOPUS: ar.j, info:eu-repo/semantics/published

type:Article, Atypical hemolytic uremic syndrome (aHUS) is an extremely rare condition caused by an excessive activation of the complement pathway based on genetic or acquired dysfunctions in complement regulation, leading to thrombotic microangiopathy (TMA). A complement-amplifying condition (CAC) can trigger aHUS occurrence along with complement abnormality. We herein report a case of severe TMA after laparoscopic myomectomy in a healthy woman. This case was eventually diagnosed as complement-mediated TMA secondary to surgical invasive stress as a CAC, with no definitive diagnosis of aHUS despite a genetic test. The patient fully recovered after several eculizumab administrations.

type:Text, Ravulizumab is an anti-C5 antibody approved for treating paroxysmal nocturnal hemoglobinuria (PNH). In August 2019, a 77-year-old Japanese man with PNH, who had been on ravulizumab treatment for 2 years, was hospitalized for chest discomfort and malaise. Electrocardiography identified a right bundle block, and elevated serum troponin I and d-dimer suggested ischemic heart disease. Cardiac catheterization revealed severe stenosis in the left anterior descending coronary artery, and intracoronary stenting relieved his chest discomfort. The final diagnosis was unstable angina unrelated to ravulizumab, and the patient's ravulizumab treatment was uninterrupted with no significant complications of PNH. This case report highlights the importance of continuing complement inhibition therapy during acute coronary events.

type:Text, Ravulizumab is an anti-C5 antibody approved for treating paroxysmal nocturnal hemoglobinuria (PNH). In August 2019, a 77-year-old Japanese man with PNH, who had been on ravulizumab treatment for 2 years, was hospitalized for chest discomfort and malaise. Electrocardiography identified a right bundle block, and elevated serum troponin I and d-dimer suggested ischemic heart disease. Cardiac catheterization revealed severe stenosis in the left anterior descending coronary artery, and intracoronary stenting relieved his chest discomfort. The final diagnosis was unstable angina unrelated to ravulizumab, and the patient's ravulizumab treatment was uninterrupted with no significant complications of PNH. This case report highlights the importance of continuing complement inhibition therapy during acute coronary events.

The syndromes of thrombotic microangiopathy (TMA) are diverse and represent severe endothelial damage caused by various mechanisms. The complement system plays a major role in a subset of patients with TMA, and its recognition is of clinical importance because it guides choice and duration of treatment. We studied a well-defined cohort of patients with TMA and hypothesized that assessment of serum-induced C5b9 formation on the endothelium and screening for rare variants in complement genes can better categorize TMA. Massive C5b9 formation was found in all patients with primary atypical hemolytic uremic syndrome (/ = 11/11) and in 59% of patients with TMA and coexisting conditions (/ = 30/51). Massive C5b9 formation was associated with rare genetic variants (45% [/ = 20/44] vs. 0% [/ = 0/21] patients with normal C5b9 formation; < 0.001). Massive C5b9 formation was associated with favorable renal response to therapeutic complement inhibition in patients with TMA and coexisting conditions (86% [/ = 12/14] vs. 31% [/ = 5/16] of untreated patients; < 0.001), indicating complement-mediated TMA rather than secondary disease. Among treated patients, the odds ratio for 1-year kidney survival was 12.0 (95% confidence interval 1.2-115.4). TMA recurrence was linked to rare genetic variants in all cases. Patients with normal C5b9 formation had an acute, nonrelapsing form of TMA. C5b9 formation and genetic testing appears to categorize TMAs into different groups because it identifies complement as a driving factor of disease, with potential therapeutic and prognostic implications.

Introduction/Aims: Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti-acetylcholine receptor antibody-positive (AChR+) gMG previously treated with rituximab. Methods: This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open-label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. Results: Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous-rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no-previous-rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous-rituximab and no-previous-rituximab groups (least-squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least-squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post-intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. Discussion: Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously.

Introduction/Aims: Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti-acetylcholine receptor antibody-positive (AChR+) gMG previously treated with rituximab. Methods: This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open-label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. Results: Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous-rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no-previous-rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous-rituximab and no-previous-rituximab groups (least-squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least-squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post-intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. Discussion: Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously.

Background: Kidney transplantation (KTx) is a strong trigger for the development of either recurrent or de novo atypical haemolytic uraemic syndrome (aHUS). According to previous studies, eculizumab (ECU) is effective for prophylaxis and for treatment of recurrence., Methods: We evaluated the experiences of Spanish patients with recurrent and de novo aHUS associated with KTx, treated or not treated with ECU. In the de novo group, we classified patients as having early de novo (during the first month) or late de novo aHUS (subsequent onset)., Results: We analysed 36 cases of aHUS associated with KTx. All of the 14 patients with pre-KTx diagnosis of aHUS were considered to have high or moderate risk of recurrence. Despite receiving grafts from suboptimal donors, prophylactic ECU was effective for avoiding recurrence. The drug was stopped only in two cases with low–moderate risk of recurrence and was maintained in high-risk patients with no single relapse. There were 22 de novo aHUS cases and 16 belonged to the early de novo group. The median time of onset in the late group was 3.4 years. The early group had a better response to ECU than the late group, probably due to earlier diagnosis and use of the drug. No genetic pathogenic variant was detected in de novo aHUS cases, suggesting a secondary profile of the disease. ECU was stopped in all de novo patients with no relapses. ECU was well tolerated in all cases., Conclusions: Both groups (pre-aHUS and de novo) presented different clinical profiles, management approaches and outcomes. One should consider aHUS regardless of time after KTx. Genetic studies are crucial to stratify risks of relapse and to determine necessary lengths of treatment. We suggest short ECU treatment for de novo cases without pathogenic mutation and that ECU treatment be considered pre-emptively for patients with moderate or high risk of recurrence.

Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.

Background: Hemolytic uremic syndrome (HUS) is rare in neonates. It is probably an under-recognized condition in the early postnatal period as it presents similarly to the most common perinatal asphyxia and to differentiate the two conditions is challenging. We describe the clinical presentation of a potential new subtype of neonatal HUS triggered by hypoxic-ischemic event. Our patient was successfully treated by a single dose of Eculizumab as early as at 9 days of life. Case Report: A 35-weeks infant was born with low hemoglobin and subsequently developed respiratory distress, hypotension, and acidosis. Blood transfusion was administered, acidosis corrected, neurological examination remained reassuring. Few hours later he developed renal failure, macroscopic hematuria, hemobilia, thrombocytopenia and coagulopathy refractory to platelet and fresh frozen plasma transfusions. No infection was found. Haptoglobin was non-measurable, and schistocytes present, complement factors C3, C4 and B were low, FBb increased. HUS was suspected. A single dose of Eculizumab™ was administered on day 9 of life. No genetic mutation of atypical HUS was found. He was discharged with improving renal function and developing cholestasis. Conclusion: In neonates with hemolytic anemia, thrombocytopenia, hematuria and renal failure, HUS should be suspected. In neonatal HUS Eculizumab should be considered as first-line therapy and discontinuation can be considered if no genetic mutation is found and clinical condition improves. In very young patients, cholestasis could appear as potential side effect of Eculizumab™., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Eculizumab is approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Its use off-label is frequently reported. The aim of this study was to describe the broader use and outcomes of a cohort of pediatric patients exposed to eculizumab. METHODS: A retrospective, cohort analysis was performed on the clinical and biomarker characteristics of eculizumab-exposed patients < 25 years of age seen across 21 centers of the Pediatric Nephrology Research Consortium. Patients were included if they received at least one dose of eculizumab between 2008 and 2015. Traditional summary statistics were applied to demographic and clinical data. RESULTS: A total of 152 patients were identified, mean age 9.1 (+/-6.8) years. Eculizumab was used off-label in 44% of cases. The most common diagnoses were aHUS (47.4%), Shiga toxin-producing Escherichia coli HUS (12%), unspecified thrombotic microangiopathies (9%), and glomerulonephritis (9%). Genetic testing was available for 60% of patients; 20% had gene variants. Dosing regimens were variable. Kidney outcomes tended to vary according to diagnosis. Infectious adverse events were the most common adverse event (33.5%). No cases of meningitis were reported. Nine patients died of noninfectious causes while on therapy. CONCLUSIONS: This multi-center retrospective cohort analysis indicates that a significant number of children and young adults are being exposed to C5 blockade for off-label indications. Dosing schedules were highly variable, limiting outcome conclusions. Attributable adverse events appeared to be low. Cohort mortality (6.6%) was not insignificant. Prospective studies in homogenous disease cohorts are needed to support the role of C5 blockade in kidney outcomes.

Background: The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension. Methods: Attainment of ‘minimal symptom expression’ was evaluated using patient-reported outcome measures of gMG symptoms [MG activities of daily living scale (MG-ADL), 15-item MG quality of life questionnaire (MG-QOL15)] at the completion of REGAIN and during the open-label extension. ‘Minimal symptom expression’ was defined as MG-ADL total score of 0–1 or MG-QOL15 total score of 0–3. Results: At REGAIN week 26, more eculizumab-treated patients achieved ‘minimal symptom expression’ versus placebo [MG-ADL: 21.4% vs 1.7%; difference 19.8%; 95% confidence interval (CI) 8.5, 31.0; p = 0.0007; MG-QOL15: 16.1% vs 1.7%; difference 14.4%; 95% CI 4.3, 24.6; p = 0.0069]. During the open-label extension, the proportion of patients in the placebo/eculizumab group who achieved ‘minimal symptom expression’ increased after initiating eculizumab treatment and was sustained through 130 weeks of open-label eculizumab (MG-ADL: 1.7 to 27.8%; MG-QOL15: 1.7 to 19.4%). At extension study week 130, similar proportions of patients in the eculizumab/eculizumab and placebo/eculizumab groups achieved ‘minimal symptom expression’ (MG-ADL: 22.9% and 27.8%, respectively, p = 0.7861; MG-QOL15: 14.3% and 19.4%, respectively, p = 0.7531). The long-term tolerability of eculizumab was consistent with previous reports. Conclusions: Patients with AChR+ refractory gMG who receive eculizumab can achieve sustained ‘minimal symptom expression’ based on patient-reported outcomes. ‘Minimal symptom expression’ may be a useful tool in measuring therapy effectiveness in gMG. Trial registration: ClinicalTrials.gov NCT01997229, NCT02301624.

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome.

BACKGROUND: Untreated microangiopathic hemolytic anemia in pregnancy is associated with adverse maternal and perinatal outcomes. Accurate diagnosis is challenging owing to nonspecific clinical features and pathologic findings. Timely initiation of appropriate management is essential to optimize maternal and perinatal outcomes. CASE: A 26-year-old primiparous woman presented at 20 weeks of gestation with new-onset microangiopathic hemolytic anemia on a background of poorly controlled type 1 diabetes. She received eculizumab for presumed atypical hemolytic uremic syndrome. At 24 weeks of gestation, she developed superimposed early-onset preeclampsia; she delivered at 27 weeks of gestation after continuing eculizumab. CONCLUSION(S): Eculizumab may prolong pregnancy in early-onset preeclampsia. Additional research is needed to assess short-term and long-term maternal and newborn outcomes.

BACKGROUND: Untreated microangiopathic hemolytic anemia in pregnancy is associated with adverse maternal and perinatal outcomes. Accurate diagnosis is challenging owing to nonspecific clinical features and pathologic findings. Timely initiation of appropriate management is essential to optimize maternal and perinatal outcomes. CASE: A 26-year-old primiparous woman presented at 20 weeks of gestation with new-onset microangiopathic hemolytic anemia on a background of poorly controlled type 1 diabetes. She received eculizumab for presumed atypical hemolytic uremic syndrome. At 24 weeks of gestation, she developed superimposed early-onset preeclampsia; she delivered at 27 weeks of gestation after continuing eculizumab. CONCLUSION(S): Eculizumab may prolong pregnancy in early-onset preeclampsia. Additional research is needed to assess short-term and long-term maternal and newborn outcomes.

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome.

Hemolytic Uremic Syndrome is an endemic disease in Latin America. Argentina is one of the countries where most cases are reported, with a rate of ten cases per 100,000 children under five years old. It is the first cause of acute renal failure (ARF), and responsible for 9% of kidney transplants. This pathology is characterized by a classic triad: microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. The main etiological agent of HUS is the bacterium Shiga toxin-producing Escherichia coli. HUS has an acute mortality lower than 5%.(1-2)There is evidence of the active role of the Shiga toxin in the activation of the complement by binding to factor H. Eculizumab is a monoclonal antibody which inhibits the formation of the membrane attack complex (C5b-9), given its great affinity for C5 of the complement cascade. Its infusion is approved to treat atypical HUS, posing its usefulness to treat severe typical HUS with acute neurological involvement as an alternative to inhibit the complement cascade and stop toxin damage.We present two pediatric patients with SUH diagnosis with shiga toxin rescue; these patients, who showed severe neurological involvement, were treated with Eculizumab and had a favorable response., El síndrome urémico hemolítico típico es una enfermedad endémica en América Latina. Argentina es uno de los países con más casos reportados, con una tasa de diez casos cada 100.000 menores de cinco años. Es la primera causa de insuficiencia renal aguda, y responsable del 9% de los trasplantes renales. Esta patología se caracteriza por una tríada clásica: anemia microangiopática, trombocitopenia e insuficiencia renal aguda. El principal agente etiológico del Síndrome Urémico Hemolítico es la bacteria Escherichia coli, productora de la toxina Shiga. El Síndrome Urémico Hemolítico tiene una mortalidad aguda inferior al 5%.(1-2)Existe evidencia acerca del rol activo de la shiga toxina en la activación del complemento a través de su unión al factor H. El eculizumab es un anticuerpo monoclonal que inhibe la formación del complejo de ataque de membrana (C5b-9), por su alta afinidad a C5 de la cascada del complemento. Su infusión está aprobada para el tratamiento del Síndrome Urémico Hemolítico atípico, planteándose su utilidad en casos de Síndrome Urémico Hemolítico típico grave con compromiso neurológico severo como alternativa para inhibir la cascada de complemento, y así detener el daño producido por la toxina.Se presentan dos casos de pacientes pediátricos con diagnóstico Síndrome Urémico Hemolítico con rescate de Shiga toxina, con compromiso neurológico grave y que recibieron tratamiento con eculizumab con respuesta favorable.

Background: The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension. Methods: Attainment of ‘minimal symptom expression’ was evaluated using patient-reported outcome measures of gMG symptoms [MG activities of daily living scale (MG-ADL), 15-item MG quality of life questionnaire (MG-QOL15)] at the completion of REGAIN and during the open-label extension. ‘Minimal symptom expression’ was defined as MG-ADL total score of 0–1 or MG-QOL15 total score of 0–3. Results: At REGAIN week 26, more eculizumab-treated patients achieved ‘minimal symptom expression’ versus placebo [MG-ADL: 21.4% vs 1.7%; difference 19.8%; 95% confidence interval (CI) 8.5, 31.0; p = 0.0007; MG-QOL15: 16.1% vs 1.7%; difference 14.4%; 95% CI 4.3, 24.6; p = 0.0069]. During the open-label extension, the proportion of patients in the placebo/eculizumab group who achieved ‘minimal symptom expression’ increased after initiating eculizumab treatment and was sustained through 130 weeks of open-label eculizumab (MG-ADL: 1.7 to 27.8%; MG-QOL15: 1.7 to 19.4%). At extension study week 130, similar proportions of patients in the eculizumab/eculizumab and placebo/eculizumab groups achieved ‘minimal symptom expression’ (MG-ADL: 22.9% and 27.8%, respectively, p = 0.7861; MG-QOL15: 14.3% and 19.4%, respectively, p = 0.7531). The long-term tolerability of eculizumab was consistent with previous reports. Conclusions: Patients with AChR+ refractory gMG who receive eculizumab can achieve sustained ‘minimal symptom expression’ based on patient-reported outcomes. ‘Minimal symptom expression’ may be a useful tool in measuring therapy effectiveness in gMG. Trial registration: ClinicalTrials.gov NCT01997229, NCT02301624.

Background: The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension. Methods: Attainment of ‘minimal symptom expression’ was evaluated using patient-reported outcome measures of gMG symptoms [MG activities of daily living scale (MG-ADL), 15-item MG quality of life questionnaire (MG-QOL15)] at the completion of REGAIN and during the open-label extension. ‘Minimal symptom expression’ was defined as MG-ADL total score of 0–1 or MG-QOL15 total score of 0–3. Results: At REGAIN week 26, more eculizumab-treated patients achieved ‘minimal symptom expression’ versus placebo [MG-ADL: 21.4% vs 1.7%; difference 19.8%; 95% confidence interval (CI) 8.5, 31.0; p = 0.0007; MG-QOL15: 16.1% vs 1.7%; difference 14.4%; 95% CI 4.3, 24.6; p = 0.0069]. During the open-label extension, the proportion of patients in the placebo/eculizumab group who achieved ‘minimal symptom expression’ increased after initiating eculizumab treatment and was sustained through 130 weeks of open-label eculizumab (MG-ADL: 1.7 to 27.8%; MG-QOL15: 1.7 to 19.4%). At extension study week 130, similar proportions of patients in the eculizumab/eculizumab and placebo/eculizumab groups achieved ‘minimal symptom expression’ (MG-ADL: 22.9% and 27.8%, respectively, p = 0.7861; MG-QOL15: 14.3% and 19.4%, respectively, p = 0.7531). The long-term tolerability of eculizumab was consistent with previous reports. Conclusions: Patients with AChR+ refractory gMG who receive eculizumab can achieve sustained ‘minimal symptom expression’ based on patient-reported outcomes. ‘Minimal symptom expression’ may be a useful tool in measuring therapy effectiveness in gMG. Trial registration: ClinicalTrials.gov NCT01997229, NCT02301624.

C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

Background : t- PA can increase BBB permeability and trigger the infiltration of immune cells into the central nervous system. Few plasmin- dependent and - independent pathways participate in this phenomenon, for example, activation of Rho- Kinase 2 and platelet derived growth factor C, respectively. Since plasmin also possesses pro- inflammatory properties, including C3 and C5 convertase activity, we hypothesized that complement activation plays an additional role in this process. Aims : We aimed to evaluate the effect of complement inhibition on t- PA- and plasminogen (plg)- mediated opening of the BBB using an established in vitro model with C5 and C5a- receptor 1 (C5aR1) inhibitors. Methods : An in vitro model of the BBB was assembled on porous membranes of Transwell inserts as a co- culture system of human brain endothelial cells on the luminal surface and human immortalized astrocytes on the abluminal surface. The luminal compartment was stimulated with t- PA and plasminogen in the presence of PMX205 (non- competitive inhibitor of C5aR1), Avacopan (C5aR1 antagonist) or eculizumab (humanised monoclonal inhibitor of human C5). BBB permeability was assessed at both 4hr and 24hr post- stimulation by evaluation of fluorescent albumin passage from the luminal to the abluminal chambers over 1hr. Permeability changes were calculated relative to non- treated controls. Results : PMX205 and Avacopan decreased t- PA mediated increase in BBB permeability by almost 50%, at both the 4 and 24hr time points. Interestingly, our preliminary results indicate that eculizumab was without any significant effect. Conclusions : t- PA- and plasmin- mediated increase in BBB permeability is partly driven by C5a receptor activation. Inhibition of C5 or C5aR1 may have therapeutic implications in traumatic brain injury and stroke thrombolysis, where either endogenous or administered t- PA can compromise the BBB, leading to secondary insults.

Background : t- PA can increase BBB permeability and trigger the infiltration of immune cells into the central nervous system. Few plasmin- dependent and - independent pathways participate in this phenomenon, for example, activation of Rho- Kinase 2 and platelet derived growth factor C, respectively. Since plasmin also possesses pro- inflammatory properties, including C3 and C5 convertase activity, we hypothesized that complement activation plays an additional role in this process. Aims : We aimed to evaluate the effect of complement inhibition on t- PA- and plasminogen (plg)- mediated opening of the BBB using an established in vitro model with C5 and C5a- receptor 1 (C5aR1) inhibitors. Methods : An in vitro model of the BBB was assembled on porous membranes of Transwell inserts as a co- culture system of human brain endothelial cells on the luminal surface and human immortalized astrocytes on the abluminal surface. The luminal compartment was stimulated with t- PA and plasminogen in the presence of PMX205 (non- competitive inhibitor of C5aR1), Avacopan (C5aR1 antagonist) or eculizumab (humanised monoclonal inhibitor of human C5). BBB permeability was assessed at both 4hr and 24hr post- stimulation by evaluation of fluorescent albumin passage from the luminal to the abluminal chambers over 1hr. Permeability changes were calculated relative to non- treated controls. Results : PMX205 and Avacopan decreased t- PA mediated increase in BBB permeability by almost 50%, at both the 4 and 24hr time points. Interestingly, our preliminary results indicate that eculizumab was without any significant effect. Conclusions : t- PA- and plasmin- mediated increase in BBB permeability is partly driven by C5a receptor activation. Inhibition of C5 or C5aR1 may have therapeutic implications in traumatic brain injury and stroke thrombolysis, where either endogenous or administered t- PA can compromise the BBB, leading to secondary insults.

C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

C3 glomerulopathy (C3G) is a severe kidney disease, which is caused by defective regulation of the alternative complement pathway. Disease pathogenesis is heterogeneous and is caused by both autoimmune and genetic factors. Here we characterized IgG autoantibodies derived from 33 patients with autoimmune C3 glomerulopathy. Serum antibodies from all 33 patients as well as purified IgGs bound to the in vitro assembled C3-convertase. Noteworthy, two groups of antibodies were identified: group 1 with strong (12 patients) and group 2 with weak binding C3-convertase autoantibodies (22 patients). C3Nef, as evaluated in a standard C3Nef assay, was identified in serum from 19 patients, which included patients from group 1 as well as group 2. The C3-convertase binding profile was independent of C3Nef. Group 1 antibodies, but not the group 2 antibodies stabilized the C3-convertase, and protected the enzyme from dissociation by Factor H. Also, only group 1 antibodies induced C3a release. However, both group 1 and group 2 autoantibodies bound to the C5-convertase and induced C5a generation, which was inhibited by monoclonal anti-C5 antibody Eculizumab in vitro. In summary, group 1 antibodies are composed of C3Nef and C5Nef antibodies and likely over-activate the complement system, as seen in hemolytic assays. Group 2 antibodies show predominantly C5Nef like activities and stabilize the C5 but not the C3-convertase. Altogether, these different profiles not only reveal a heterogeneity of the autoimmune forms of C3G (MPGN), they also show that in diagnosis of C3G not all autoimmune forms are identified and thus more vigorous autoantibody testing should be performed.

Purpose: To evaluate the effect of eculizumab on perceived fatigue in patients with anti-acetylcholine receptor antibody-positive, refractory, generalized myasthenia gravis (MG) using the Quality of Life in Neurological Disorders (Neuro-QOL) Fatigue subscale, and to evaluate correlations between improvements in Neuro-QOL Fatigue and other clinical endpoints. Methods: Neuro-QOL Fatigue, MG Activities of Daily Living (MG-ADL), Quantitative MG (QMG), and the 15-item MG Quality of Life (MG-QOL15) scales were administered during the phase 3, randomized, placebo-controlled REGAIN study (eculizumab, n = 62; placebo, n = 63) and subsequent open-label extension (OLE). Data were analyzed using repeated-measures models. Correlations between changes in Neuro-QOL Fatigue and in MG-ADL, QMG, and MG-QOL15 scores were determined at REGAIN week 26. Results: At REGAIN week 26, eculizumab-treated patients showed significantly greater improvements in Neuro-QOL Fatigue scores than placebo-treated patients (consistent with improvements in MG-ADL, QMG, and MG-QOL15 scores previously reported in REGAIN). Improvements with eculizumab were sustained through OLE week 52. Correlations between Neuro-QOL Fatigue and MG-QOL15, MG-ADL, and QMG scores were strong for eculizumab-treated patients at REGAIN week 26, and strong, moderate, and weak, respectively, for placebo-treated patients. Conclusions: Compared with placebo, eculizumab was associated with improvements in perceived fatigue that strongly correlated with improvements in MG-specific outcome measures. Trial ID Registration: NCT01997229, NCT02301624.

Malignant hypertension is listed among the causes of secondary thrombotic microangiopathy (TMA), but pathogenic mutations in complement genes have been reported in patients with hypertension-induced TMA. Here we investigated the frequency and severity of hypertension in 55 patients with primary atypical hemolytic uremic syndrome (aHUS). A genetic analysis was performed in all patients, and funduscopic examination was performed in all the patients with Grades 2 and 3 hypertension. A cohort of 110 patients with malignant hypertension caused by diseases other than aHUS served as control. Thirty-six patients with aHUS presented Grade 2 or Grade 3 hypertension and funduscopic examination showed malignant hypertension in 19. Genetic abnormalities in complement were found in 19 patients (37% among patients with malignant hypertension). Plasmapheresis was performed in 46 patients and 26 received eculizumab. Renal and hematological responses were significantly lower after plasmapheresis (24%) than after eculizumab (81%). Renal survival was significantly higher in patients treated with eculizumab (85% at one, three and five years) compared to patients who did not receive this treatment (54%, 46% and 41%), respectively. Response to eculizumab was independent of hypertension severity and the presence of complement genetic abnormalities. Among patients with malignant hypertension caused by other diseases the prevalence of TMA was very low (5%). Thus, severe and malignant hypertension are common among patients with aHUS and eculizumab treatment leads to a higher renal survival when compared to plasmapheresis. However, TMA is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS.

Paroxysmal nocturnal hemoglobinuria (PNH), term established by Enneking in 1925, is a rare, clonal, and acquired disease of the hematopoietic stem cells. Generally, it starts with a mutation in the PIG -A gene, causing a deficiency of membrane proteins, such as CD55 and CD59. However, recent studies treveal that the clonal architecture of the disease is far more complex. Due to the deficiency of these proteins, there is an uncontrolled activation of the complement, which is associated with hemolysis and other clinical manifestations very variable among patients. PNH is also associated with aplastic anemia, in fact, it has been observed that both diseases are closely related, being able to derive one from the other over time. Because of the great variability of symptoms, the diagnosis of the disease has always been an arduous task. But this paper study a recent technique that has facilitated this work: flow cytometry. Until recently, there were only two main therapies for patients with PNH; allogeneic bone marrow transplantation and supportive treatment against symptoms. But at the beginning of the millennium, Eculizumab, marketed as Soliris®, a huma nized anti -C5 monoclonal antibody, protein of the complement system, was introduced, which has been a major advance in the treatment of the disease. As a result of its discovery, new strategies of complement inhibition have been investigated. Due to the hi gh morbimortality and the great impact on patients with PNH, the latest advances in research during the last decade could not be more encouraging, La Hemoglobinuria Paroxística N octurna (HPN), término establecido en 1925 por Enneking, es una enfermedad rara, clonal y adquirida de las células madr e hematopoyéticas. Generalmente se inicia con una mutación en el gen PIG -A, causando una deficiencia de proteínas membranales, como CD55 y CD59. Sin embargo, estudios más recientes ponen de manifiesto que la arquitectura clonal de la enfermedad es bastante más compleja. Debido a la deficiencia de dichas proteínas, se produce una activación descontrolada del complement o, que se asocia a hemó lisis y a otras manifestaciones clínicas muy variables entre pacientes. La HPN también se asocia a la anemia aplásica, de hecho, se ha observado que ambas enfermedades están estrechamente relacionadas, pudiendo derivar una en la otra con el tiempo. A causa de la gran variabilidad de síntomas, el diagnóstico de la enfermedad ha sido siempre una ardua tarea. En este ensayo se estudia una técnica recien te que ha facilitado esta labor, la citometría de flujo. Hasta hace poco, solo existí an dos terapias principales para los pacientes con HPN; el trasplante alogénico de médula ósea y el tratamiento de apoyo contra los síntomas. Pero a principios del milenio, se introdujo en el esquema terapéutico el Eculizumab, comercializado como Soliris®, un anticuerpo monoclonal humanizado anti -C5, proteína del sistema del complemento. Ha constituido un avance primordial para el tratamiento de la enfermedad, a raíz de su descubrimiento, se ha comenzado a investigar nuevas estrategias de inhibición del complemento. Debido a la alta morbimortalidad y el gran impacto que supone la HPN en quien la padece, que se esté avanzando tanto en la última década resulta alentador

Introduction: Myasthenia gravis (MG) is an autoimmune neuromuscular disorder with no cure and conventional treatments limited by significant adverse effects and variable benefit. In the last decade, therapeutic development has expanded based on improved understanding of autoimmunity and financial incentives for drug development in rare disease. Clinical subtypes exist based on age, gender, thymic pathology, autoantibody profile, and other poorly defined factors, such as genetics, complicate development of specific therapies. Areas covered: Clinical presentation and pathology vary considerably among patients with some having weakness limited to the ocular muscles and others having profound generalized weakness leading to respiratory insufficiency. MG is an antibody-mediated disorder dependent on autoreactive B cells which require T-cell support. Treatments focus on elimination of circulating autoantibodies or inhibition of effector mechanisms by a broad spectrum of approaches from plasmapheresis to B-cell elimination to complement inhibition. Expert commentary: Standard therapies and those under development are disease modifying and not curative. As a rare disease, clinical trials are challenged in patient recruitment. The great interest in development of treatments specific for MG is welcome, but decisions will need to be made to focus on those that offer significant benefits to patients.

Introduction: Thrombotic microangiopathies (TMAs) are a spectrum of disorders involving microangiopathic haemolytic anaemia (MAHA), thrombocytopenia and organ injury. In pregnancy, differentiating between TMAs can be clinically challenging but is important due to the impact on fetal and maternal outcomes. Case Summary: We present the case of a 26-year-old primipara referred to our tertiary centre at 20 weeks gestation with a TMA of unclear cause in the setting of poorly-controlled type 1 diabetes mellitus. She reported fatigue and mild pedal oedema, and was normotensive. Investigations demonstrated a new-onset MAHA (haemoglobin [Hb] 70 g/L, moderate schistocytes, haptoglobin <0.06 g/L, LDH 747 U/L) and thrombocytopenia (platelets 98 x 10/L). Her renal function was preserved (serum creatinine [sCr] 50 ivmol/L, urea 6.6 mmol/L) but there was microscopic haematuria (370 x 10 cells/L) with glomerular morphology and heavy proteinuria (urine protein: creatinine ratio 0.5 g/mmol) on a background of baseline macroalbuminuria (pre-pregnancy urine albumin:creatinine ratio 132 mg/mmol). Fetal morphology and Doppler studies were normal. Thrombotic thrombocytopenic purpura was excluded. Regular blood transfusions were required to maintain Hb >80 g/L. Renal function worsened slightly over the following two weeks, and kidney biopsy demonstrated moderately advanced diabetic nephropathy and TMA without glomerular endotheliosis. Genetic testing for common atypical haemolytic uraemic syndrome (aHUS) genes returned a heterozygous mutation of unknown significance in exon 2 of the CFI gene (c.292A>G, p.Thr98Ala). Eculizumab was commenced for presumed aHUS, with minimal improvement in platelet count, renal function and blood transfusion frequency. Over the subsequent 5 weeks she developed hypertension, hyperreflexia, headache with visual disturbance, worsening oedema and increased proteinuria. Caesarean section was performed at 27 + 4 weeks gestation for pre-eclampsia, with a live infant

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.Copyright © 2018 Asian Pacific Society of Nephrology

A 26-year-old primiparous female was referred at 20 weeks gestation with a thrombotic microangiopathy (TMA) of unclear cause in the setting of poorly controlled type 1 diabetes mellitus. She reported fatigue and mild pedal oedema, but was otherwise asymptomatic and normotensive. Routine investigations demonstrated a microangiopathic haemolytic anemia (haemoglobin [Hb] 70 g/L, moderate schistocytes, haptoglobin <0.06 g/L, LDH 747 U/L) and new thrombocytopenia (platelets 98 x 109/L from 273 x 109/L in early pregnancy). Her renal function was preserved (serum creatinine [sCr] 50 micromol/L, urea 6.6 mmol/L), but there was microscopic hematuria (370 x106 cells/L) with glomerular morphology, and heavy proteinuria (urine protein:creatinine ratio 0.5 g/mmol) in the setting of baseline macroalbuminuria (pre-pregnancy urine albumin:creatinine ratio 132 mg/mmol). Foetal morphology and Doppler studies were normal. Thrombotic thrombocytopenic purpura was excluded (ADAMTS13 activity 95%). Regular blood transfusions were required to maintain a Hb > 80 g/L. Renal function worsened slightly (sCr 85umol/L, urea 14 mmol/L) over a period of two weeks, and kidney biopsy demonstrated moderately advanced diabetic nephropathy and TMA without glomerular endotheliosis. Genetic testing for a panel of atypical haemolytic uraemic syndrome (aHUS) genes returned a heterozygous mutation of unknown significance in exon 2 of the CFI gene (c.292A > G, p.Thr98Ala). Eculizumab was commenced for presumed aHUS, however there was minimal improvement in platelet count, renal function and blood transfusion frequency. Over the subsequent 5 weeks she developed hypertension, hyperreflexia, and increased proteinuria. Caesarean section was successfully performed at 27 + 4 weeks for pre-eclampsia. Within 48 h her platelet count normalised, haemolysis substantially improved and renal function stabilized (sCr 96 micromol/L, eGFR 71 mL/min), however hypertension persisted. We discuss our approach to distinguishing

При різних захворюваннях нирок успішно застосовується імунобіологічна терапія на основі моноклональних антитіл із різним механізмом дії. До таких лікарських засобів належать: ритуксимаб (взаємодія з рецептором CD20 і елімінування В-клітин), екулізумаб (інгібування розщеплення С5 комплементу), буросумаб (блокування фактора росту фібробластів FGF23), адалімумаб (анти-TNF-α агент), абатацепт (блокує костимуляцію Т-клітин шляхом зв’язування з CD80), фрезолімумаб (нейтралізація TGF-β). Ці лікарські засоби застосовуються при системних захворюваннях нирок, фокально-сегментарному гломерулосклерозі, вовчаковому нефриті, мембранозній нефропатії, при трансплатації нирки., With various diseases of the kidneys, immunobiological monoclonal antibody-based therapy with a different mechanism of action is successfully used. These drugs include: rituximab (interaction with the CD20 receptor and elimination of B cells), eсulizumab (inhibition of C5 complement clea­vage), burosumab (blocking fibroblast growth factor 23), adalimumab (anti-tumor necrosis factor α agent), abatacept (blocks co-stimulation of T cells by binding to CD80), fresolimumab (neutralization of transforming growth factor β). These drugs are used for systemic kidney diseases, focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, kidney transplantation., При различных заболеваниях почек успешно применяется иммунобиологическая терапия на основе моноклональных антител с различным механизмом действия. К таким лекарственным препаратам относятся: ритуксимаб (взаимодействие с рецептором CD20 и элиминирование В-клеток), экулизумаб (ингибирование расщепления С5 комплемента), буросумаб (блокирование фактора роста фибробластов FGF23), адалимумаб (анти-TNF-α агент), абатацепт (блокирует костимуляцию Т-клеток путем связывания с CD80), фрезолимумаб (нейтрализация TGF-β). Эти лекарственные препараты применяются при системных заболеваниях почек, фокально-сегментарном гломерулосклерозе, волчаночном нефрите, мембранозной нефропатии, трансплантации почки.

Despite its considerable morbidity and mortality, paroxysmal nocturnal haemoglobinuria (PNH) is still underdiagnosed. Patients with PNH can suffer from cardiovascular, gastro-intestinal, neurological or haematological symptoms and refer to several specialists. The aim of this paper is to review the diagnosis and the management of PNH patients, with the primary focus on identifying high-risk groups. Additionally, the implementation and prognostic value of the defined high-risk groups will be commented on and the management of PNH patients is discussed from a Belgian perspective. Finally, based on the available data, recommendations are provided. Eculizumab is a potent C5 complement inhibitor and reduces intravascular haemolysis and thrombosis in PNH patients and improves their quality of life. As thrombosis is the main cause of death in PNH patients, identifying high-risk PNH patients in need of therapy is essential. Currently, novel complement inhibitors are in development and the first data seem promising. Another challenge in PNH is to identify new markers to assess the thrombotic risk to achieve a better risk-based prophylactic anti-thrombotic management. Finally, because of the low prevalence of the disease, PNH patients should be included in the prospective PNH registry, which will offer new insights on the natural course of the disease and the impact of treatment of PNH. This article is protected by copyright. All rights reserved.

Paroxysmal nocturnal hemoglobinuria (PNH), term established by Enneking in 1925, is a rare, clonal, and acquired disease of the hematopoietic stem cells. Generally, it starts with a mutation in the PIG -A gene, causing a deficiency of membrane proteins, such as CD55 and CD59. However, recent studies treveal that the clonal architecture of the disease is far more complex. Due to the deficiency of these proteins, there is an uncontrolled activation of the complement, which is associated with hemolysis and other clinical manifestations very variable among patients. PNH is also associated with aplastic anemia, in fact, it has been observed that both diseases are closely related, being able to derive one from the other over time. Because of the great variability of symptoms, the diagnosis of the disease has always been an arduous task. But this paper study a recent technique that has facilitated this work: flow cytometry. Until recently, there were only two main therapies for patients with PNH; allogeneic bone marrow transplantation and supportive treatment against symptoms. But at the beginning of the millennium, Eculizumab, marketed as Soliris®, a huma nized anti -C5 monoclonal antibody, protein of the complement system, was introduced, which has been a major advance in the treatment of the disease. As a result of its discovery, new strategies of complement inhibition have been investigated. Due to the hi gh morbimortality and the great impact on patients with PNH, the latest advances in research during the last decade could not be more encouraging, La Hemoglobinuria Paroxística N octurna (HPN), término establecido en 1925 por Enneking, es una enfermedad rara, clonal y adquirida de las células madr e hematopoyéticas. Generalmente se inicia con una mutación en el gen PIG -A, causando una deficiencia de proteínas membranales, como CD55 y CD59. Sin embargo, estudios más recientes ponen de manifiesto que la arquitectura clonal de la enfermedad es bastante más compleja. Debido a la deficiencia de dichas proteínas, se produce una activación descontrolada del complement o, que se asocia a hemó lisis y a otras manifestaciones clínicas muy variables entre pacientes. La HPN también se asocia a la anemia aplásica, de hecho, se ha observado que ambas enfermedades están estrechamente relacionadas, pudiendo derivar una en la otra con el tiempo. A causa de la gran variabilidad de síntomas, el diagnóstico de la enfermedad ha sido siempre una ardua tarea. En este ensayo se estudia una técnica recien te que ha facilitado esta labor, la citometría de flujo. Hasta hace poco, solo existí an dos terapias principales para los pacientes con HPN; el trasplante alogénico de médula ósea y el tratamiento de apoyo contra los síntomas. Pero a principios del milenio, se introdujo en el esquema terapéutico el Eculizumab, comercializado como Soliris®, un anticuerpo monoclonal humanizado anti -C5, proteína del sistema del complemento. Ha constituido un avance primordial para el tratamiento de la enfermedad, a raíz de su descubrimiento, se ha comenzado a investigar nuevas estrategias de inhibición del complemento. Debido a la alta morbimortalidad y el gran impacto que supone la HPN en quien la padece, que se esté avanzando tanto en la última década resulta alentador

Background Severe hypertension can induce thrombotic microangiopathy (TMA) in the renal vasculature, the occurrence of which has been linked to mechanical stress to the endothelium. Complement defects may be the culprit of disease in patients who present with severe renal disease and often progress to ESRD, despite BP control.Methods We studied a well defined cohort of 17 patients with hypertension-associated TMA to define the prevalence of complement defects by a specific ex vivo serum-based microvascular endothelial cell assay.Results Compared with normal human serum and samples from patients with hypertensive arterionephrosclerosis, 14 of 16 (87.5%) serum samples collected at presentation from 16 patients with hypertension-associated TMA induced abnormal C5b9 formation on microvascular endothelial cells. We detected rare variants in complement genes in eight of 17 (47%) patients. ESRD occurred in 14 of 17 (82%) patients, and recurrent TMA after transplant occurred in seven of 11 (64%) donor kidneys. Eculizumab improved the renal function in three patients and prevented TMA recurrence in an allograft recipient.Conclusions These observations point to complement defects as the key causative factor of ESRD and recurrent TMA after transplant in patients presenting with severe hypertension. Complement defects can be identified by measurements of complement activation on microvascular endothelial cells, which should substantially influence treatment and prognosis.