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INTRODUCTION Advances in the treatment of myasthenia gravis (MG) have improved quality of life and prognosis for the majority of patients. However, 10%-20% of patients present refractory MG, with frequent relapses and significant functional limitations. PATIENTS AND METHODS Patients with refractory MG were selected from a cohort of patients diagnosed with MG between January 2008 and June 2019. Refractory MG was defined as lack of response to treatment with prednisone and at least 2 immunosuppressants, inability to withdraw treatment without relapse in the last 12 months, or intolerance to treatment with severe adverse reactions. RESULTS We identified 84 patients with MG, 11 of whom (13%) met criteria for refractory MG. Mean (standard deviation) age was 47 (18) years; 64% of patients with refractory MG had early-onset generalised myasthenia (as compared to 22% in the group of patients with MG; P

Paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematologic disorder, can be treated with C5 inhibitors (C5i) such as eculizumab or ravulizumab. This retrospective study is the first to describe real-world treatment patterns and changes in hematologic PNH-monitoring laboratory tests among C5i-treated US patients. Data were extracted from TriNetX Dataworks Network and included patients with a PNH diagnosis between 1 January 2010, and 20 August 2021. Patients were stratified into three cohorts based on their C5i usage: eculizumab, ravulizumab (prior eculizumab), and ravulizumab (eculizumab naïve). Hematological markers (hemoglobin [Hb], lactate dehydrogenase [LDH], and absolute reticulocyte count [ARC]) and relevant clinical events (e.g., breakthrough hemolysis [BTH], complement-amplifying conditions [CAC], thrombosis, infection, and all-cause mortality) were captured any time within 12 months post-index treatment. Of the 143 (eculizumab), 43 (ravulizumab, prior eculizumab), and 33 (ravulizumab, eculizumab naïve) patients, mean age across cohorts was 42–51 years, 55–61% were female, 63–73% were White, and 33–40% had aplastic anemia. Among all cohorts 12 months post-C5i treatment, 50–82% remained anemic, 8–32% required ≥1 transfusion, and 13–59% had BTH, of which 33%-54% had CACs. Additionally, thrombosis was seen in 7–15% of patients, infection in 20–25%, and mortality in 1–7%. These findings suggest many C5i-treated patients experience suboptimal disease control.

Atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a dysregulation of the alternative complement pathway. Here, we report a previously healthy 38-year-old woman in whom aHUS developed after a COVID-19 vaccine booster. One day after receipt of a booster dose of mRNA-1273 vaccine, she felt ill. Because of persistent headache, nausea, and general malaise, she went to her general practitioner, who referred her to the hospital after detecting hypertension and acute kidney injury. A diagnosis of TMA was made. Her treatment consisted of blood pressure control, hemodialysis, plasma exchange, and respiratory support. Kidney biopsy confirmed the diagnosis of acute TMA. The patient was referred for treatment with eculizumab, and kidney function improved after initiation of this therapy. Genetic analysis revealed a pathogenic C3 variant. SARS-CoV-2 infection as a trigger for complement activation and development of aHUS has been described previously. In addition, there is one reported case of aHUS occurring after receipt of the adenovirus-based COVID-19 vaccine ChAdOx1 nCoV-19, but, to our knowledge, this is the first case of aHUS occurring after a booster dose of an mRNA COVID-19 vaccine in a patient with an underlying pathogenic variant in complement C3. Given the time frame, we hypothesize that the vaccine probably was the trigger for development of aHUS in this patient. ispartof: AMERICAN JOURNAL OF KIDNEY DISEASES vol:81 issue:3 pages:364-367 ispartof: location:United States status: published

Purpose To report the case of a patient presenting with newly diagnosed atypical hemolytic uremic syndrome (aHUS) and Purtscher-like retinopathy. Methods Observational case report and review of literature. Patient A 38-year-old female presented with 3 months of rashes, fevers, arthralgias, and abdominal pain. Initial workup was suggestive of hypereosinophilic syndrome or adult-onset Still's disease. The patient developed acute renal failure and progressively blurry vision bilaterally over the course of 5 days. Funduscopic exam was notable for numerous Purtscher flecken and cotton-wool spots, with rare intraretinal hemorrhages at the posterior pole. The constellation of renal failure, hemolytic anemia, and thrombocytopenia prompted a work-up for thrombotic microangiopathy that was remarkable for a mutation in the gene coding for complement protein C9. Results The patient was diagnosed with aHUS. The patient was treated with intravenous pulse dose steroids for 3 days and an extended course of eculizumab. The patient's renal failure resolved, and her visual acuity improved, though she had residual visual field constriction and developed bilateral optic atrophy. Outcomes of other cases of Purtscher-like retinopathy related to aHUS are reviewed. Conclusion Purtscher-like retinopathy is a rare, but severe ophthalmic complication of aHUS. Eculizumab is an effective treatment for the systemic illness caused by aHUS, and anatomic resolution of Purtscher-like retinopathy may follow, although visual prognosis remains guarded. Recovery of visual acuity may lag behind resolution of macular edema in these patients.

Makale, WOS:000925209300013, C3 glomerulopathy is a newly defined glomerular disease dominated by C3 complement storage and uncertain C1, C4, and immunoglobin accumulations. Hereditary mutations associated with Complement Factor H (CFH) causing hyperactivation of the alternative complement pathway were identified. Most mutations associated with C3 glomerulopathy are associated with the N-terminal end. Whether mutations are pathogenic or not will direct diagnosis and treatment. We present 2 cases, one 61-year-old and one 24-year-old attending our clinic at different times with hematuria, proteinuria, edema, and kidney failure. Both patients had C3 glomerulopathy diagnosed based on the results of kidney biopsy and were treated with eculizumab. Both cases had CFH-associated mutations.

Kidney injury caused by transplant-associated thrombotic microangiopathy (TA-TMA) in patients who underwent allogeneic hematopoietic stem cell transplantation (allo HSCT) is relatively frequent. However, it is rarely reported in patients undergoing autologous HSCT (aHSCT). There are a few studies reported that TA-TMA could occur in pediatric patients undergoing aHSCT, but the condition in adult patients is rarely described. Furthermore, almost all the patients who suffered from TA-TMA developed typical and severe manifestations which should be treated with aggressive target therapy. Nevertheless, we presented two cases of kidney injury caused by TA-TMA after aHSCT with specific clinical features. Case 1, a 33-year-old Chinese male diagnosed with Hodgkin's lymphoma developed TA-TMA -associated kidney injury 4 months after transplantation. Case 2, a 49-year-old Chinese female with central nervous lymphoma developed TA-TMA-related kidney injury 3 months after transplantation. Both patients presented "mild" and atypical features of TA-TMA and their kidney function was managed effectively with low-dose prednisone therapy. TA-TMA related kidney injury can occur in patients who underwent aHSCT. Patients with TA-TMA could develop atypically "mild" features. Low-dose prednisone may be effective in place of routine eculizumab treatment regimen. We recommend that clinicians prompt an investigation for TA-TMA in patients presenting kidney injury in the background of aHSCT to facilitate early diagnosis.

Thrombotic microangiopathies (TMA) are a group of clinical syndromes associated with haemolytic anaemia, thrombocytopenia and organ dysfunction, mainly renal or neurological. They are associated with significant morbidity and mortality, so early diagnosis and treatment are essential. In this article we report two cases of TMA; a patient with thrombotic thrombocytopenic purpura (TTP) and a patient with atypical haemolytic uraemic syndrome (aHUS).

Introduction:Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis in the presence of antiphospholipid antibodies. Recently, derangement in the complement pathway has been implicated in APS pathophysiology. Refractory cases of APS with recurrent and potentially fatal thrombosis have prompted use of the monoclonal antibody eculizumab, which inhibits generation of the terminal complement complex. We present the successful use of eculizumab in controlling and preventing recurrent thrombosis in a refractory case of APS. Case Description:An 18-year-old female received a diagnosis of antiphospholipid syndrome after developing extensive unprovoked deep vein thrombosis of axillary, inferior vena caval and brachiocephalic veins. Thrombophilia evaluation revealed triple positivity for lupus anti-coagulant (LA), beta-2 glycoprotein I (GP) IgG 84.9 SGU Units, IgM 76.5 SMU Units, IgA 66.7 SAU Units and strongly positive anti-cardiolipin (aCL) antibodies (each >>40U/mL) with persistent positive titers after 12 weeks of initial evaluation. She was refractory with trials of multiple anticoagulants alone and with antiplatelet and adjunctive therapies. Anticoagulants used were enoxaparin, fondaparinux, apixaban, rivaroxaban, and warfarin; antiplatelet agents used were aspirin and clopidogrel; and adjunctive therapies included hydroxychloroquine, immunosuppression with steroids and rituximab, and plasmapheresis. Despite these interventions, she continued to develop recurrent thrombosis of subclavian, femoral, common femoral, iliac, popliteal and saphenous veins. She additionally developed a potentially life-threatening hepatic infarction and pulmonary embolism, and 6 weeks of plasma exchange failed to decrease antiphospholipid antibody titers. Following this event, eculizumab (600mg weekly x 4 weeks, followed by 900mg once on week 5, followed by 900mg every 2 weeks) was initiated in combination with fondaparinux, aspirin, clopidogrel, and hydroxychloroquine. She has remained on this regimen with additional anticoagulation and antiplatelet therapy without recurrence of thrombosis over the subsequent year. Discussion:Recent evidence has shown complement activation playing a role in pathophysiology of antiphospholipid syndrome. This is thought to occur through C3 and C5a causing platelet and endothelial activation, leading to microvascular thrombosis. Histological evidence of such processes is supported by the demonstration of anti-beta-2 GP1 IgG-C5b-9 immune complexes in microvascular organ thrombi in individuals with APS leading to thrombotic microangiopathy and multiorgan failure. Such evidence of complement induced thrombosis in antiphospholipid syndrome led us to use eculizumab following failure of available therapies including anticoagulation, antiplatelet therapy, immune modulation and plasmapheresis in a potentially life-threatening event. Absence of recurrent thrombotic events over approximately one year with eculizumab combined with anticoagulation and antiplatelet therapy highlights the potential role of complement inhibition in preventing thrombosis in APS. While the role of complement in thrombosis continues to be elucidated, we have observed no decline in antiphospholipid antibody levels in a span of one year in our patient. Importantly, there has been no recurrent thrombosis during this time. Our case suggests that eculizumab may have a role as a therapeutic option in refractory thrombosis in APS. Chronology of Events:Eculizumab initiated on 9/5/2019. No evidence of venous or arterial thrombosis since 10/2019 to present. Figure Disclosures Tarantino: Pfizer:Other;Genentech:Membership on an entity's Board of Directors or advisory committees;Octapharma:Membership on an entity's Board of Directors or advisory committees;Dova:Membership on an entity's Board of Directors or advisory committees;CDC:Membership on an entity's Board of Directors or advisory committees;Grifols:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen:Membership on an entity's Board of Directors or advisory committees;Biomarin:Membership on an entity's Board of Directors or advisory committees;NovoNordisk:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Takeda:Research Funding;HRSA:Membership on an entity's Board of Directors or advisory committees;Spark:Membership on an entity's Board of Directors or advisory committees;Sobi:Membership on an entity's Board of Directors or advisory committees.McCrae:Rigel:Consultancy;Novartis:Honoraria;Momenta Pharmaceuticals:Consultancy;Dova:Consultancy.Chaturvedi:Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees;Alexion:Honoraria, Membership on an entity's Board of Directors or advisory committees.Roberts:Octapharma:Consultancy, Speakers Bureau;uniQure:Consultancy;Sanofi:Consultancy, Speakers Bureau;Novo Nordisk:Consultancy, Speakers Bureau;Pfizer:Consultancy;Takeda:Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: eculizumab for treatment of refractory thrombosis in antiphospholipid syndrome

Objectives The aim of this study was to evaluate the cost-effectiveness of ravulizumab compared with eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) in the Netherlands. Methods A cost-effectiveness analysis was conducted based on a Markov cohort model simulating the course of patients with PNH with clinical symptom(s) indicative of high disease activity, or who are clinically stable after having been treated with eculizumab for at least the past six months. Costs, quality of life, and the incremental cost-effectiveness ratio (ICER) were estimated over a lifetime horizon from a Dutch societal perspective. Several additional analyses were performed, including a one-way sensitivity analysis, a probabilistic sensitivity analysis, and scenario analysis. Results When compared with eculizumab, ravulizumab saves €266,833 and 1.57 quality adjusted life years (QALYs) are gained, resulting in a dominant ICER. Drug costs account for the majority of the total costs in both intervention groups. Cost savings were driven by the difference in total treatment costs of ravulizumab compared with eculizumab caused by the reduced administration frequency, accounting for 98% of the total cost savings. The QALY gain with ravulizumab is largely attributable to the improved quality of life associated with less frequent infusions and BTH events. At a willingness-to-pay threshold of €20,000/QALY, there is a 76.6% probability that ravulizumab would be cost-effective. Conclusions The cost reduction and QALY gain associated with the lower rates of BTH and less frequent administration make ravulizumab a cost-saving and clinically beneficial substitute for eculizumab for adults with PNH in the Netherlands.

Introduction: Since 2016, kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) in the Netherlands is performed without eculizumab prophylaxis. Eculizumab is given in case of posttransplant aHUS recurrence. Eculizumab therapy is monitored in the CUREiHUS study. Methods: All participating kidney transplant patients who received eculizumab therapy for a suspected posttransplant aHUS recurrence were evaluated. Overall recurrence rate was monitored prospectively at Radboud University Medical Center. Results: In the period from January 2016 until October 2020, we included 15 (12 females, 3 males; median age 42 years, range 24−66 years) patients with suspected aHUS recurrence after kidney transplantation in this study. The time interval to recurrence showed a bimodal distribution. Seven patients presented early after transplantation (median 3 months, range 0.3−8.8 months), with typical aHUS features: rapid loss of estimated glomerular filtration rate (eGFR) and laboratory signs of thrombotic microangiopathy (TMA). Eight patients presented late (median 46 months, range 18−69 months) after transplantation. Of these, only 3 patients had systemic TMA, whereas 5 patients presented with slowly deteriorating eGFR without systemic TMA. Treatment with eculizumab resulted in improvement or stabilization of eGFR in 14 patients. Eculizumab discontinuation was tried in 7 patients; however, it was successful only in 3. At the end of the follow-up (median 29 months, range 3–54 months after start of eculizumab), 6 patients had eGFR 2. Graft loss had occurred in 3 of them. Overall, aHUS recurrence rate without eculizumab prophylaxis was 23%. Conclusions: Rescue treatment of posttransplant aHUS recurrence is effective; however, some patients suffer from irreversible loss of kidney function, likely caused by delayed diagnosis and treatment and/or too aggressive discontinuation of eculizumab. Physicians should be aware that recurrence of aHUS can present without evidence of systemic TMA.

SARS-CoV-2 causes thrombotic microangiopathy (TMA) through the activation of an alternative and lectin complement pathway. TMA is one of the main reasons for acute kidney injury development in patients with COVID-19. In this study, we present 3 TMA cases with severe kidney injury triggered by SARS-CoV-2. In the absence of other TMA causes, we diagnosed the atypical hemolytic uremic syndrome, triggered by SARS-CoV-2 due to abnormal complement activation. Because of both coagulation factors activation, and the high level of D-dimer in patients with COVID-19, it is crucial to differentiate disseminated intravascular coagulation from TMA. The use of anticomplement therapies such as eculizumab should be considered in refractory cases of progressive COVID-19. Controlled clinical trials are required before a definitive statement can be made.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease defined by attacks on the central nervous system that cause irreversible damage. Recent approval of NMOSD therapies warrants investigations of comparative efficacy to inform treatment decisions. A network meta-analysis (NMA) of all U.S. Food and Drug Administration-approved therapies (eculizumab, inebilizumab, and satralizumab) for adults with aquaporin-4 immunoglobulin G-positive (AQP4+) NMOSD was conducted via a systematic literature review (SLR) using data from randomized controlled trials (RCTs). Database searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were executed for the SLR. A fixed-effects proportional hazards Bayesian NMA was used to estimate relative treatment effects based on data extracted from RCTs identified during the SLR (search end date: 11 September 2020). Four unique RCTs (N-MOmentum, PREVENT, SAkuraSky, and SAkuraStar) were identified, and data from 29 publications were extracted for analysis. Network scenarios describing the most comparable patient population groups (such as by treatment settings) were evaluated in our analyses. Relative treatment effects were evaluated based on time-to-first relapse and were expressed as hazard ratios (HRs) with 95% credible intervals (CrIs). In patients treated with a monoclonal antibody only, eculizumab was associated with a lower risk of relapse compared with satralizumab (HR 0.10, 95% CrI 0.01, 0.65) and inebilizumab (HR 0.11, 95% CrI 0.02, 0.68). In patients treated with monoclonal antibody with or without background immunosuppressive therapy (IST), patients treated with eculizumab ± IST were also less likely to relapse than patients treated with satralizumab ± IST (HR 0.24, 95% CrI 0.06, 0.98). The NMA results suggest that complement component 5 (C5) inhibition prevents NMOSD relapses more effectively than broader mechanisms of action. Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by inflammation that damages the brain and spinal cord. Many patients with NMOSD produce antibodies against a protein called aquaporin-4 (AQP4+). In the past two years, three drugs (eculizumab, inebilizumab, and satralizumab) have been approved by the U.S. Food and Drug Administration for the treatment of adults with AQP4+ NMOSD. Comparing the efficacy of these three drugs would help physicians make treatment decisions for their patients. In the absence of clinical trials directly comparing these three drugs, we conducted a Bayesian network meta-analysis in order to allow for simultaneous comparisons of these three drugs and estimate relative treatment effects between any pair of interventions in a connected network. With a Bayesian methodology, it is also possible to estimate the probability of being the best treatment out of all other interventions in a connected network. While all three drugs are safe and shown to prevent relapses in placebo-controlled trials, the results of our analysis suggests that eculizumab was the most efficacious in preventing relapses when compared with inebilizumab or satralizumab. These findings may help to inform physicians and their patients when determining the best treatment option for preventing the occurrence of relapses in adults with AQP4+ NMOSD.

Hemolytic Uremic Syndrome (HUS) is a constellation of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Shiga toxin-producing Escherichia coli- (STEC-) mediated HUS is a common cause of acute renal failure in children and can rarely result in severe neurological complications such as encephalopathy, seizures, cerebrovascular accidents, and coma. Current literature supports use of eculizumab, a monoclonal antibody that blocks complement activation, in atypical HUS (aHUS). However, those with neurologic complications from STEC-HUS have complement activation and deposition of aggregates in microvasculature and may be treated with eculizumab. In this case report, we describe a 3-year-old boy with diarrhea-positive STEC-HUS who developed severe neurologic involvement in addition to acute renal failure requiring renal replacement therapy. He was initiated on eculizumab therapy, with clinical improvement and organ recovery. This case highlights systemic complications of STEC-HUS in a pediatric patient. The current literature is limited but has suggested a role for complement mediation in cases with severe complications. We review the importance of early recognition of complications, use of eculizumab, and current data available.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) affecting the kidneys. Compared with typical HUS due to an infection from shiga toxin-producing Escherichia coli, atypical HUS involves a genetic or acquired dysregulation of the complement alternative pathway. In the presence of a mutation in a complement gene, a second trigger is often necessary for the development of the disease. We report a case of a 54-year-old female, with a past medical history of pulmonary tuberculosis, who was admitted to the emergency service with general malaise and reduction in urine output, 5 days after vaccination with ChAdOx1 nCoV-19. Laboratory results revealed microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Given the clinical picture of TMA, plasma exchange (PEX) was immediately started, along with hemodialysis. Complementary laboratory workup for TMA excluded thrombotic thrombocytopenic purpura and secondary causes. Complement study revealed normal levels of factors H, B, and I, normal activity of the alternate pathway, and absence of anti-factor H antibodies. Genetic study of complement did not show pathogenic variants in the 12 genes analyzed, but revealed a deletion in gene CFHR3/CFHR1 in homozygosity. Our patient completed 10 sessions of PEX, followed by eculizumab, with both clinical and laboratorial improvement. Actually, given the short time lapse between vaccination with ChAdOx1 nCoV-19 and the clinical manifestations, we believe that vaccine was the trigger for the presentation of aHUS in this particular case.

Primary focal segmental glomerulosclerosis (FSGS) is a podocytopathy with an irregular response to immunosuppressive therapies. FSGS relapse occurs in 30% to 80% of kidney grafts, and poor survival outcomes include large proteinuria and the nephrotic syndrome's cardinal clinical features. Thrombotic microangiopathy (TMA) is caused by endothelial injury due to complement dysregulation including acute kidney injury, proteinuria, and severe hypertension common renal presentations. Both pathologies have well-described genetic forms, but their relationship remains uncertain. FSGS lesions can be found in kidney biopsy specimens in patients with TMA, and TMA has been reported in patients with collapsing glomerulopathy. However, this combination has not been clearly described in renal transplant recipients. We present the case of a 22-year-old man who received his second kidney allograft and developed an early graft disfunction with nephrotic syndrome and clinical TMA. His background was remarkable for primary, biopsy-confirmed FSGS in childhood, and he started hemodialysis in 2006 and received a living donor kidney graft the same year. He presented with a FSGS relapse with malignant hypertension and seizures in the first posttransplant month and had an irregular response to plasma exchange and rituximab, and dialysis was reinitiated 10 years later. A total of 3 biopsies were performed after his second kidney transplant showing the evolution of a FSGS relapse with histologic and clinical TMA in the absence of identified genetic mutations. Partial responses to treatments with plasma exchange, eculizumab, and rituximab were obtained, but the allograft was lost after 26 months. This case is the first report of concomitant FSGS and TMA in a renal transplant recipient.

Clinical Practice Points • Carfilzomib (CFZ) has rarely been associated with atypical hemolytic uremic syndrome (aHUS). • Patients with heterozygous complement factor H related protein 3 (CFHR)/CFHR1 deletions may be predisposed to CFZ-induced aHUS. • The benefit of eculizumab in the treatment of CFZ-induced aHUS that fails to improve with drug withdrawal and supportive care remains uncertain.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory CNS disease that primarily manifests as relapsing episodes of severe optic neuritis and myelitis. Diagnosis of NMOSD is supported by the detection of IgG autoantibodies that target the aquaporin 4 (AQP4) water channel, which, in the CNS, is an astrocyte-specific protein. AQP4 antibody binding leads to AQP4 internalization, complement-dependent and antibody-dependent cellular cytotoxicity, and water channel dysfunction. Cumulative attack-related injury causes disability in NMOSD, so the prevention of attacks is expected to prevent disability accrual. Until recently, no regulator-approved therapies were available for NMOSD. Traditional immunosuppressant therapies, including mycophenolate mofetil, azathioprine and rituximab, were widely used but their benefits have not been assessed in controlled studies. In 2019 and 2020, five phase II and III randomized placebo-controlled trials of four mechanism-based therapies for NMOSD were published and demonstrated that all four effectively prolonged the time to first relapse. All four drugs were monoclonal antibodies: the complement C5 antibody eculizumab, the IL-6 receptor antibody satralizumab, the B cell-depleting antibody inebilizumab, which targets CD19, and rituximab, which targets CD20. We review the pathophysiology of NMOSD, the rationale for the development of these mechanism-based drugs, the methodology and outcomes of the five trials, and the implications of these findings for the treatment of NMOSD.

Transplant-associated thrombotic microangiopathies (TA-TMAs) are inflammatory and thrombotic disorders of the microvasculature characterized by hemolytic anemia, thrombocytopenia, and organ dysfunc...

Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare and genetically mediated systemic disease most often caused by uncontrolled and chronic complement activation that leads to systemic thrombotic microangiopathy, renal and extra-renal damage. Materials and methods This is descriptive, retrospective and multicenter study, which reports demographic, clinical, laboratory, and genetic characteristics, as well as their treatment response and outcome of 20 aHUS patients diagnosed between 2014 and 2018. Results Most patients were female adults (75%) and 30% were associated to pregnancy/postpartum, 15% to autoimmune disease, and 65% to infections. Gastrointestinal involvement (75%) was the most frequent extra-renal organ damage. Antenatal mortality and mortality rate were 5% and 10%, respectively. 25% of the patients progressed to end-stage renal disease. In 4/8 of patients treated within 1 week of presentation, eculizumab treatment restored multi-organ function after 4 weeks of treatment. CFH (37%) and CFI (25%) mutations were the most frequent. Conclusion This is the first series of aHUS cases of Colombian Caribbean region which reports the clinical and epidemiological characteristics of this condition in this region.

Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury that may be primary or secondary to infections, autoimmune diseases and haematological disorders. Primary C3G and IC-MPGN are rare and the prognosis is unfavourable. Based on immunofluorescence findings, MPGN has been classified into complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, this classification leaves a number of issues unresolved. The finding of genetic and acquired complement abnormalities in both C3G and IC-MPGN indicates that they represent a heterogeneous spectrum rather than distinct diseases. An unsupervised hierarchical clustering in a cohort of patients with primary C3G and IC-MPGN identified four distinct pathogenetic patterns, characterized by specific histologic and clinical features, and genetic and acquired complement abnormalities. These results provide the groundwork for a more accurate diagnosis and the development of targeted therapies. The drugs that are currently used, such as corticosteroids and immunosuppressants, are frequently ineffective in primary C3G and IC-MPGN. Eculizumab, an anti-C5 monoclonal antibody, has been used occasionally in single cases or small series. However, only a few patients have achieved remission. This heterogeneous response could be related to the extent of terminal complement activation, which may vary substantially from patient to patient. Several drugs that target the complement system at different levels are under investigation for C3G and IC-MPGN. However, clinical trials to test new therapeutics will be challenging and heavily influenced by the heterogeneity of these diseases. This creates the need to characterize each patient to match the specific complement abnormality with the type of intervention.

Objectives Antibody-mediated rejection in patients with positive crossmatches can be severe and result in sudden onset of oliguria, leading to graft loss. In an attempt to prevent posttransplant oliguria, we adopted a preoperative desensitization protocol involving the use of high-dose intravenous immunoglobulin/plasmapheresis and the anti-CD20 antibody, rituximab, in 41 transplant recipients with positive crossmatch test results. Materials and methods We retrospectively examined the clinical courses of the 41 kidney transplant recipients, paying special attention to renal graft function, urine volume, and changes in the titers of donor-specific antibodies. Results Four grafts were lost during an average of 4.5-year follow-up. Average graft function was excellent, with a serum creatinine level of 1.3 ± 0.4 mg/dL. Sufficient urine output, with no oliguria or anuria, was achieved postoperatively in 40 of the 41 patients. However, among the 34 patients who underwent graft biopsies, the biopsies revealed acute antibody-mediated rejection in 21 patients (62%), and chronic antibodymediated rejection in 10 patients (30%). Conclusions The high-dose intravenous immunoglobulin treatment included in our desensitization protocol was shown to be safe and effective for achieving successful transplant outcomes and allowed the avoidance of more aggressive B-cell-targeted treatments, such as C5 inhibitors and/or proteosome inhibitors, for preventing posttransplant oliguria and anuria.

Anti−glomerular basement membrane (anti-GBM) disease is characterized by pathogenic autoantibodies targeting the α-3 chain of type IV collagen located in the glomerular and alveolar basement membranes. Clinically, it causes rapidly progressive glomerulonephritis and pulmonary hemorrhage. Observational data and mechanistic rationale have largely informed current treatment strategies, including plasmapheresis, glucocorticoids, cyclophosphamide, and rituximab. However, overall and renal prognosis remain guarded, and advancements in therapy are needed. Emerging data have implicated the complement system in the pathogenesis of anti-GBM disease.1, 2, 3, 4, 5 Eculizumab is an anti-C5 monoclonal antibody that blocks the cleavage of C5, which prevents the formation of C5a, the potent leukocyte chemoattractant, and C5b, the initial reagent in the formation of the membrane attack complex (MAC; also known as C5b-9). This provides an immediate inhibition of the downstream proinflammatory and cytotoxic sequelae of the complement system. Here, we report the use of eculizumab as rescue therapy in 2 patients with progressive anti-GBM disease on standard therapies, which, to our knowledge, has not been reported to date. We also present kidney biopsy results with extensive complement staining that add to a limited but growing body of literature on the possible role of complement in the renal damage from anti-GBM disease.

Purpose of review Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication that can occur in both allogeneic and autologous haematopoietic cellular therapy (HCT) recipients and is associated with significant morbidity and mortality. Although TA-TMA is a complex disease, there is emerging evidence that complement activation and endothelial dysfunction play a key role in the pathophysiology of the disease. The use of eculizumab has improved survival in patients with high risk and severe disease, but mortality rates in treated patients still exceed 30%, highlighting the need for novel approaches. Recent findings There are multiple ongoing and planned clinical trials investigating novel complement agents in TA-TMA and other TMAs. Drugs vary by targets of the complement system, mechanism, and form of administration. Clinical trial designs include single arm studies that span across multiple age groups including children, and double-blind, randomized, placebo-controlled studies. These studies will provide robust data to inform the care of patients with TA-TMA in the future. In addition to multiple promising therapeutic agents, preventing TA-TMA is an emerging strategy. Agents known to protect the endothelium from damage and augment endothelial function by promoting anti-inflammatory and antithrombotic effects may have a role in preventing TA-TMA or ameliorating the severity, though additional studies are needed. Summary Novel therapeutic agents for TA-TMA inhibition of the complement system are under investigation and prophylactic strategies of endothelial protection are emerging. Further understanding of the pathophysiology of the disease may identify additional therapeutic targets. Multiinstitutional, collaborative clinical trials are needed to determine the safety and efficacy of these agents going forward.

Previous studies have demonstrated residual complement-mediated deposits in repeat kidney biopsies of C3 glomerulopathies (C3G) (dense deposit disease (DDD) and C3 glomerulonephritis) following eculizumab treatment, despite some clinical improvement. With residual complement deposition, it is difficult to determine whether there is a reduced complement-mediated endothelial cell injury. We validated that myeloperoxidase (MPO) immunohistochemical staining identified glomerular endothelial cell injury in crescentic glomerulonephritis and C3G. We report that MPO staining in the glomerular endothelium of the post-treatment kidney biopsy was significantly reduced after 3 years of eculizumab treatment and clinical improvement in a 5-year-old boy with initial DDD and secondary crescent formation. We find that immunostaining for MPO is a useful method to compare glomerular endothelial injury in C3G following eculizumab treatment. This finding also supports the notion that eculizumab, a C5 blocker, may not mainly block C3 deposits in the glomeruli but significantly blocks final activation of the complement cascade, thus reducing glomerular endothelial cell injury.

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.

Background: Pregnancy outcomes in patients with atypical hemolytic uremic syndrome (aHUS) are not well-documented. Here, we present characteristics of and outcomes for patients with aHUS who became pregnant while enrolled in the Global aHUS Registry. Methods: The observational Global aHUS Registry (NCT01522183), initiated in April 2012, collects demographics, disease history, treatment, and outcomes data for patients with aHUS, regardless of treatment approach. This descriptive analysis includes patients from the Registry with evaluable pregnancy data supplemented with pharmacovigilance information; the number of pregnancies, outcomes, and exposure to eculizumab were evaluated. Results: As of April 1, 2019, 44 pregnancies were recorded in 41 patients, with 24 pregnancies exposed to eculizumab. Pathogenic variants were identified in 48.8% of patients. Three patients were on dialysis and 6 patients had a kidney graft at the time of pregnancy. Excluding elective terminations, 85.3% of pregnancies resulted in live births. Elective terminations were recorded in 22.7% of pregnancies, miscarriages occurred in 9.1% of pregnancies, and late fetal death in 2.3% of pregnancies. No malformations or anomalies were reported. Conclusions: Our results show that in women with aHUS, even on dialysis or with a kidney graft, pregnancy is possible with careful monitoring for aHUS flares and prematurity. Prophylactic or therapeutic eculizumab offers disease control with low-risk of fetal abnormalities.

Obstetric atypical hemolytic-uremic syndrome (aHUS) is an emergency with an unfavorable prognosis. The implementation of the complement-blocking drug Eculizumab into clinical practice significantly improved prognosis of patients with obstetric aHUS. In 2019, the first biosimilar of Eculizumab was developed in Russia by GENERIUM.

We present two cases of infants admitted with febrile COVID19 infection and developing atypical hemolytic uremic syndrome (aHUS) during the first week of hospitalization. aHUS is a rare disease due to uncontrolled activation of the complement system and characterized by systemic thrombotic microangiopathy (TMA), mainly in the kidneys, leading to acute renal failure. There is increasing evidence that COVID-19 is associated with microvascular injury. Furthermore complement activation plays a role in the pathogenesis of severe COVID-19-disease. First case: A 4-month-old boy, ex-premature of 26 weeks, was admitted with a febrile COVID-19 infection. On day 5 typical signs of HUS developed (anemia, thrombocytopenia, high LDH and progressive kidney failure) and the boy was admitted to the PICU on day 8 for Tenckhoff-catheter implantation, peritoneal dialysis and management of Hypertension. Due to high suspicion of aHUS, eculizumab was given on day 8. With this treatment he improved constantly and peritoneal dialysis could be stopped after 4 weeks. Thrombotic thrombocytopenic Purpura (TTP) was excluded by normal ADAMTS-13 values. The boy was discharged after 6 weeks with remaining serious arterial hypertension. Second Case: A 4,5-month-old boy was admitted with fever, diarrhea and reduced drinking for 3 days. SARS-CoV-2 PCR testing was positive, initial blood cell count, infection signs, lumbar punction and chest X-ray were unremarkable, blood gas showed mild dehydration. Kidney ultrasound was normal on admission. Initially he received fluid resuscitation and antipyretic treatment. On day 4, he developed anemia, thrombocytopenia, rising LDH, schistocytes and echogenic kidneys. Given the clinical suspicion of atypical HUS we immediately treated with Eculizumab. Despite this treatment the child developed acute kidney failure with anuria, severe arterial hypertension, requiring PICU admission and peritoneal dialysis on day 8. Initially arterial hypertension was refractory to triple IV-continuous treatment. However, during dialysis de-escalation was slowly possible. As for case 1, TTP was ruled out by normal ADAMTS-13 values. Stool screening was unremarkable. Further complement functional studies and genetic screening are ongoing. Discussion: It is well known that aHUS can be triggered by infectious disease, so in our two cases the Covid-19-infection might just have served as trigger, but in general aHUS is a rare disease, so two similar cases within a month is very unexpected. There is growing evidence that severe Covid-19 disease is linked to disproportionate complement activation leading to thrombotic complications and poor outcome. So, the development of a complement-mediated thrombotic microangiopathy in our two cases might be the result of a severe Covid-19 infection with overactivated complement system directly due to the Covid virus and not due to an underlying genetic complement disorder.

BackgroundCumulative damage from multiple relapses in neuromyelitis optica spectrum disorder (NMOSD) is associated with poor health-related quality of life (HRQoL) and long-term disability in patients positive for anti-aquaporin 4 antibodies (AQP4+). This study assessed the effect of an individual relapse on HRQoL and disability outcomes in AQP4+ NMOSD.MethodsPost hoc analyses of data pooled from the PREVENT study and its open-label extension, which evaluated the efficacy and safety of eculizumab in AQP4+ NMOSD, examined the effect of a single relapse on 3 disability and 4 HRQoL outcome measures. Assuming the effect of 1 relapse extends to multiple relapses, an extrapolation was done to assess the effect of 2 relapses on these outcomes.ResultsIn 27 patients (placebo: n = 20; eculizumab: n = 7) experiencing an independently adjudicated relapse, 1 relapse led to significantly worse disability (modified Rankin Scale and Expanded Disability Status Scale [EDSS]) and HRQoL (36-item Short-Form Health Survey mental and physical component summaries; European Quality of Life 5-Dimension questionnaire 3-Level visual analogue scale and utility index) scores. In 4 of 7 outcomes, clinically meaningful worsening was more likely for relapsing versus non-relapsing patients (n = 116). Extrapolating the effect of 2 relapses predicted that clinically meaningful worsening was more likely in 6 out of 7 outcomes, including EDSS, for patients experiencing multiple relapses versus patients experiencing no relapses.ConclusionFindings from these clinical trial data demonstrate that a single NMOSD relapse can worsen disability and HRQoL, underscoring the role of relapse prevention in improving long-term outcomes in patients with AQP4+ NMOSD.

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.

What is known and objective Hyperhaemolytic transfusion reactions are rare life-threatening events predominantly affecting patients with haemoglobinopathies. We report two cases in β-thalassaemia major patients on chronic transfusion therapy and highlight the role of eculizumab in its management. Case summary Patient 1 presented with intravascular haemolysis on day 7 (D7) post-transfusion and responded to treatment with corticosteroids and intravenous immunoglobulin. However, patient 2 presented with severe symptomatic anaemia (D4 post-transfusion) unresponsive to the aforementioned measures. Eculizumab administration led to resolution of the hyperhaemolysis. What is new and conclusion We report the successful management of hyperhaemolysis with eculizumab in a β-thalassemia major patient.

Currently, eculizumab is the main effective treatment for paroxysmal nocturnal hemoglobinuria (PNH). The aim of this randomized multicenter noninferiority study was to evaluate the efficacy and safety of the Biosimilar (Elizaria) in comparison with the Originator (Soliris) in patients with PNH. Biosimilar and Originator were administered at a dose of 600 mg weekly for 4 weeks at the initial stage in naive patients, as well as for maintenance therapy at a dose of 900 mg every 2 weeks in all patients. The primary endpoint was a comparative assessment of hemolytic activity based on the area under the lactate dehydrogenase (LDH) concentration–time curve during the maintenance therapy. Thirty-two (32) patients were randomized for therapy with Biosimilar (n = 16) or Originator (n = 16). The mean values of LDH concentration–time curve were similar in both treatment groups without statistically significant differences (p > 0.05). Evaluation of secondary endpoints has shown no statistically significant differences between the groups. Safety values were comparable in both treatment groups. The data obtained confirm that the Biosimilar is not inferior to the Originator in terms of the main efficacy parameter, and is also comparable with it in terms of safety and additional efficacy parameters. Clinicaltrials.gov identifier: NCT04463056

IgA nephropathy pathogenesis is incompletely understood, and this limits the development of disease-specific biomarkers and effective therapies. Evidence of complement activity in IgA nephropathy is well established. However, a growing body of research indicates complement activity is an important contributor to IgA nephropathy pathology. In particular, multiple associations have been identified between complement alternative, lectin and terminal pathway proteins and IgA nephropathy severity. Recently, we have also gained insight into possible mechanisms that could link glomerular IgA deposition, complement activity, glomerular inflammation and disease severity. Ongoing clinical trials of therapeutic complement inhibitors will provide insight into the importance of complement activity to IgA nephropathy pathogenesis. Further research into mechanisms of complement activity is essential to improving our understanding and management of patients with IgA nephropathy.

Our objective was to establish the rate of neurological involvement in Shiga toxin-producing Escherichia coli–hemolytic uremic syndrome (STEC-HUS) and describe the clinical presentation, management and outcome. A retrospective chart review of children aged ≤ 16 years with STEC-HUS in Children’s Health Ireland from 2005 to 2018 was conducted. Laboratory confirmation of STEC infection was required for inclusion. Neurological involvement was defined as encephalopathy, focal neurological deficit, and/or seizure activity. Data on clinical presentation, management, and outcome were collected. We identified 240 children with HUS; 202 had confirmed STEC infection. Neurological involvement occurred in 22 (11%). The most common presentation was seizures (73%). In the neurological group, 19 (86%) were treated with plasma exchange and/or eculizumab. Of the 21 surviving children with neurological involvement, 19 (91%) achieved a complete neurological recovery. A higher proportion of children in the neurological group had renal sequelae (27% vs. 12%, P = .031). One patient died from multi-organ failure.Conclusion: We have identified the rate of neurological involvement in a large cohort of children with STEC-HUS as 11%. Neurological involvement in STEC-HUS is associated with good long-term outcome (complete neurological recovery in 91%) and a low case-fatality rate (4.5%) in our cohort. What is Known:• HUS is associated with neurological involvement in up to 30% of cases.• Neurological involvement has been reported as predictor of poor outcome, with associated increased morbidity and mortality. What is New:• The incidence of neurological involvement in STEC-HUS is 11%.• Neurological involvement is associated with predominantly good long-term outcome (90%) and a reduced case-fatality rate (4.5%) compared to older reports.

Pegcetacoplan (Empaveli™) is a PEGylated pentadecapeptide developed by Apellis Pharmaceuticals for the treatment of complement-mediated diseases. It binds to complement component 3 (C3) and its activation fragment C3b, controlling the cleavage of C3 and the generation of the downstream effectors of complement activation and thus both C3b-mediated extravascular haemolysis and terminal complement-mediated intravascular haemolysis. Pegcetacoplan is the first C3-targeted paroxysmal nocturnal haemoglobinuria (PNH) therapy to be approved (in May 2021) in the USA, where it is indicated for the treatment of adults with PNH, including those switching from C5 inhibitor therapy with eculizumab and ravulizumab. A regulatory assessment of pegcetacoplan for the treatment of PNH is currently underway in the EU and Australia. Pegcetacoplan is also being investigated as a therapeutic option in other complement-mediated diseases, including age-related macular degeneration, C3 glomerulopathy and autoimmune haemolytic anaemia. The recommended dosage regimen of pegcetacoplan is 1080 mg twice weekly, administered as a subcutaneous infusion via an infusion pump with a ≥ 20 mL reservoir. This article summarizes the milestones in the development of pegcetacoplan leading to this first approval for the treatment of adults with PNH.

Background In atypical hemolytic-uremic syndrome (aHUS), various defects of the complement system have been reported to explain pathophysiology. Therapeutic options for complement inhibition are well-recognized; however, the links between various immune-derived diseases and aHUS are unclear, and their interference with treatment efficacy during long-term complement-blocking therapy is scarcely known. Case-diagnosis/treatment We present a pediatric patient who developed aHUS with acute kidney injury in parallel with the onset of Crohn’s disease (CD), and who required long-term complement-blocking therapy with eculizumab (ECU). Unexpectedly, during the 6-year ECU treatment, an important intra-patient variation of the degree of complement inhibition was observed. In spite of continuous and stable doses of complement-blocking therapy, periods of incomplete blockade were observed in strong association with relapses of CD. When conventional and later biological therapy with adalimumab was introduced, with CD going into remission, complement blockade became complete again. Despite periodically low ECU levels and insufficient complement inhibition, no clinical or hematological signs of aHUS recurrence were detected during CD relapses. Conclusion In aHUS cases secondary to CD, close monitoring of both complement inhibition and serum ECU levels is needed as intestinal disease can interfere with complement-blocking treatment. Increased doses of ECU may be necessary to maintain therapeutic blood levels of ECU and full complement blockade, especially if the intestinal disease is not under control.

Background ABP 959 is one of the first proposed biosimilars to eculizumab reference product (RP), a recombinant IgG2/4Ƙ monoclonal antibody (mAb) that binds human C5 complement protein and inhibits C5 cleavage to C5a and C5b, preventing the generation of the terminal complement complex C5b-9. Eculizumab RP is approved for the treatment of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis in patients who are anti-acetylcholine receptor antibody positive, and neuromyelitis optica spectrum disorder in patients who are anti-aquaporin-4 antibody positive. Objectives The objective of this work was to comparatively assess analytical (structural and functional) similarity between ABP 959 and eculizumab RP using sensitive, state-of-the art analytical methods capable of detecting minor differences in product quality attributes. Methods Comprehensive analytical (structural and functional) characterization utilizing orthogonal techniques was performed using multiple lots of ABP 959 and eculizumab RP over several years applying > 40 state-of-the-art assays. Comparisons were performed to investigate the primary structure and post-translational modifications including glycans, higher-order structure, particles and aggregates, product-related structures and impurities, thermal stability and forced degradation, general properties, and biological properties mediated by target binding. Results Results confirmed that ABP 959 had the same amino acid sequence, similar primary structure, higher-order structure, post-translational profiles, and the same protein content and concentration (e.g., ABP 959: 9.4–10.0; eculizumab EU: 9.4–10.0; eculizumab US: 9.3–10.3 mg/mL) as well as biological activity as eculizumab RP. Conclusions Based on these results, it can be concluded that ABP 959 is analytically similar to eculizumab RP.

Background A 3-year-old girl with clinical features of atypical HUS (complement Factor I mutation inherited from an asymptomatic mother and Factor H autoantibodies) was treated with plasma exchange, progressed to kidney failure (KF) aged 4 years, and received an en bloc kidney DCD transplant aged 8 years with primary graft non-function necessitating transplant nephrectomy at the time of transplantation. She subsequently underwent re-transplantation from her father. This is a retrospective study of electronic patient records and medical notes. Case-diagnosis/treatment A 9-year-old girl received an ABO-incompatible (ABOi) living-related kidney transplant from her father with recipient and donor blood groups of O and A, respectively, with baseline recipient anti-A titers 1:128 reducing to 1:4 at the time of transplant with B lymphocyte depletion with rituximab and four sessions of immunoadsorption. Six hours post-transplant, she had recurrence of aHUS and received the first dose of eculizumab. She continues on monthly home eculizumab infusions with stable kidney allograft function and negative anti-A titers 7 years post-kidney transplantation. Conclusions This is the first report of a pediatric high-risk ABOi living-related kidney transplantation in whom early relapse of aHUS was successfully treated with eculizumab with good long-term patient and allograft outcome.

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre-formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%-97%) and 6250 (5000-10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14-0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.

Background Atypical hemolytic uremic syndrome is a rare disease caused by complement dysregulation that can lead to progressive kidney damage or death if untreated. Owing to its rarity, the impact of atypical hemolytic uremic syndrome and available therapies (eculizumab and ravulizumab) on patients’ health-related quality of life is difficult to describe, but such data are required for an economic evaluation. Objective The objective of this study was to estimate utility values for atypical hemolytic uremic syndrome-related attributes in five countries for an economic evaluation. Methods Using discrete choice experiment surveys, key atypical hemolytic uremic syndrome-related attributes (life expectancy, administration frequency, risk of meningitis, need for hospitalization, and risk of kidney impairment) were evaluated in adult general population samples from Australia, Canada, the Netherlands, Sweden, and the UK. Survey choice sets were constructed using a published orthogonal array. A mixed-effects logit model estimated preference strength for each attribute. Utilities were estimated using marginal substitution rates between overall survival and other attributes, weighted against average life expectancy. Results Across all countries (N = 2382), utility weights revealed a consistent pattern: participants were averse to the risk of kidney impairment (disutility/utility weight range: −0.185 to −0.158), risk of meningitis (−0.041 to −0.032), and the need for hospitalization (−0.063 to −0.048), but preferred 8-weekly vs 2-weekly infusions over 1 h (0.013–0.039). Conclusions Although all attributes played a role in determining treatment preferences, the largest drivers were life expectancy and risk of kidney impairment. Participants favored 8-weekly dosing (corresponding to ravulizumab administration frequency) vs 2-weekly dosing. The discrete choice experiment was designed such that estimated (dis)utility weights can be used in future cost-effectiveness models in atypical hemolytic uremic syndrome. Supplementary Information The online version contains supplementary material available at 10.1007/s40273-021-01059-w.

Background Bevacizumab is a recombinant monoclonal antibody against the vascular endothelial growth factor A (VEGF-A) ligand that is used in the management of various solid malignancies. The adverse effect profiles of angiogenesis inhibitors, such as bevacizumab, have become increasingly well characterized and include renal manifestations such as hypertension, proteinuria, and thrombotic microangiopathy. Eculizumab inhibits terminal-complement activation and is used to treat atypical hemolytic uremic syndrome. There has been growing usage of eculizumab to treat bevacizumab-associated thrombotic microangiopathy. Materials and methods We performed a systematic review of the literature to identify full-text articles that describe the use of eculizumab for bevacizumab-associated thrombotic microangiopathy. Results Our systematic review identified 522 unique articles of which 5 were included in the final review. 9 cases, including 2 new cases presented in this review, were identified in which eculizumab was used in the management of bevacizumab-associated thrombotic microangiopathy. Hematologic parameters and kidney function stabilized or improved in all cases, and the 2 patients who required renal replacement therapy were able to discontinue dialysis. Conclusions Given the findings of this systematic review, the use of eculizumab in the treatment of bevacizumab-associated thrombotic microangiopathy warrants further study, particularly in severe cases.

Introduction Activation of the complement pathway by immune complexes is a key feature of systemic lupus erythematosus (SLE) and SLE glomerulonephritis, which translates into low levels of C3 and C4 during active disease. C3 glomerulonephritis (C3GN) is part of a broader group of rare renal diseases, the C3 glomerulopathies, characterized by prominent C3 accumulation in the glomeruli with minimal to no immunoglobulin (Ig) deposition secondary to dysregulation of the alternative pathway of the complement system. Distinguishing lupus nephritis from other complement-mediated kidney disorders, including C3GN, represents a diagnostic challenge with potential therapeutic implications. Methods We report an unusual case of a 55-year-old woman with SLE and previous biopsy-proven class IV lupus nephritis, subsequently diagnosed with C3GN. Furthermore, we review the available literature published from January 2010—March 2021 on the clinical features and management of C3GN in the setting of SLE. Results In addition to our case, very few reports exist in the literature regarding C3GN in association with SLE. The underlying pathogenic mechanism of C3GN consists of dysregulation of the alternative pathway of the complement system, either due to genetic variation in complement-related genes or to acquired autoantibodies targeting C3 or C5 convertases; the latter mechanism could explain the occurrence of C3GN in the setting of autoimmune diseases, although it was not definitively identified in our patient or others with SLE. Similar to some of the previous reports, after suboptimal renal response on mycophenolate mofetil and rituximab, our patient has been successfully treated with eculizumab, thus far with >50% improvement in proteinuria. Conclusions C3GN represents an additional mechanism of renal injury in SLE mediated by alternative complement pathway dysregulation. Although rare, patients with SLE and persistent proteinuria with very low C3 would benefit from expedited renal biopsy to evaluate for C3GN as well as genetic testing, since this entity could require a different therapeutic approach.

Contains fulltext : 244005.pdf (Publisher’s version ) (Open Access) The complement system is an important defense mechanism against pathogens; however, in certain pathologies, the system also attacks human cells, such as red blood cells (RBCs). In paroxysmal nocturnal hemoglobinuria (PNH), RBCs lack certain complement regulators which sensitize them to complement-mediated lysis, while in autoimmune hemolytic anemia (AIHA), antibodies against RBCs may initiate complement-mediated hemolysis. In recent years, complement inhibition has improved treatment prospects for these patients, with eculizumab now the standard of care for PNH patients. Current complement inhibitors are however not sufficient for all patients, and they come with high costs, patient burden, and increased infection risk. This review gives an overview of the underlying pathophysiology of complement-mediated hemolysis in PNH and AIHA, the role of therapeutic complement inhibition nowadays, and the high number of complement inhibitors currently under investigation, as for almost every complement protein, an inhibitor is being developed. The focus lies with novel therapeutics that inhibit complement activity specifically in the pathway that causes pathology or those that reduce costs or patient burden through novel administration routes.

Introduction Eculizumab has been shown to be efficacious in acetylcholine receptor antibody positive (AChR+), Myasthenia Gravis Foundation of America (MGFA) Class II-IV generalized myasthenia gravis (gMG) patients. However, it has not been studied in MGFA Class V gMG patients. Methods We report three AChR+, refractory, MGFA Class V, gMG patients, treated with eculizumab. MGFA class, MG-Composite score (MGC) and MG-Activity of Daily Living (MG-ADL) scores were assessed before and after eculizumab. Results Two of 3 gMG patients, refractory to IVIG, plasmapheresis, prednisone and (in one) rituximab, showed a robust response to eculizumab with marked improvement in MGFA, MG-ADL and MGC. The third patient showed a partial response to eculizumab but remained on noninvasive ventilation (NIV) and gastrostomy-tube. Patients 1 and 2 achieved minimal manifestation (MM) status at week 4 and week 6 respectively and showed continued improvement in MG-ADL and MGC through week 55 and 43, respectively, with eculizumab. The third patient showed a partial response at week 10, followed by a slight decline in his MG-ADL score but noted a slow but an incomplete improvement afterwards in MG-ADL and MGC, possibly due to delay in his eculizumab infusion. Discussion Eculizumab may play a role in the treatment of patients with MGFA class-V, refractory gMG. Larger studies are required to provide further evidence. This article is protected by copyright. All rights reserved.

This study aims to review all empirical evidence regarding the effect of eculizumab on long-term outcomes in infection-associated hemolytic uremic syndrome.

Background Autoimmune hemolytic anemia (AIHA) results in red blood cell destruction by auto-antibodies directed against surface antigens and is rarely fatal. Here we describe a case of AIHA, refractory to both standard and experimental therapies, complicated by multiorgan failure, and rapidly leading to death. Case report and results A 65 year-old man who presented with progressive dyspnea and jaundice was found to have hemolytic anemia. Diagnostic work-up revealed a positive direct antiglobulin test and a strong pan-reactive antibody in the plasma reacting to a titer of 1:1024 with strongest reactivity at 37 °C Coombs' phase with reagent anti-IgG. The red cell eluate contained a pan-agglutinin. The patient received multiple lines of treatment including glucocorticoids, intravenous immunoglobulin, rituximab, eculizumab, splenectomy and etoposide. Despite these interventions, he continued to experience brisk hemolysis and remained transfusion dependent. Repeat testing on day 16 demonstrated persistent high titer IgG auto-antibodies, suggesting minimal suppressive effect of therapy. His course was complicated by acute renal and liver failure, venous thrombosis, and worsening coagulopathy, and he ultimately died from multiorgan failure on day 18. Conclusion Severe cases of AIHA can result in multiorgan failure and a fatal outcome. The rapid development of liver failure in this setting has been described in only few case reports to date, and represents an important complication for clinicians to be aware of when treating patients with AIHA.

Thrombosis is a leading cause of morbidity and mortality in paroxysmal nocturnal hemoglobinuria (PNH). Multiple factors are responsible for the thrombotic tendency in these patients. Endothelial progenitorcells (EPCs) originate from primitive hematopoietic stem cells. The EPC count is considered indicative of potential damage and restoration capacity in vascular disease; lower EPC counts are deemed as a risk factor in cardiovascular diseases. We aimed to investigate the count of circulating EPCs in PNH and aplastic anemia (AA) patients receiving eculizumab treatment or not receiving treatment and their relationship with thrombosis. Seventeen PNH patients, 18 AA patients, and 10 healthy volunteers were included in the study. The CD309, CD133, and CD34 antibodies were used to determine counts of circulating EPCs using flowcytometry. EPC levels were compared between the PNH, AA, and healthy control groups. Kolmogorov–Smirnov test. ANOVA, Kruskal–Wallis, and Mann–Whitney U testswereperformedto analyze the quantitative data, while χ2 testing was performed to analyze the qualitative data. Therewasnosignificantdifference in EPC levelsbetweenpatientswithandwithout a history of thrombosis (P > 0.05). Further, therewasnosignificantdifference in thelevels of EPCsbetweenthe AA and PNH groups (P > 0.05). However, there was a significant positive correlation between levels of EPCs and lactate dehydrogenase (LDH) in multivariate analysis (P