Eculizumab in a child with atypical haemolytic uraemic syndrome and haemophagocytic lymphohistiocytosis triggered by cytomegalovirus infection.
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SUBMITTER: Fraga-Rodriguez GM
PROVIDER: S-EPMC5534672 | biostudies-other | 2017 Apr
REPOSITORIES: biostudies-other
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Project description:BackgroundComplement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab.MethodsWe identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 10 9 /L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration.ResultsTwenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses.ConclusionShort treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition.
| S-EPMC5410989 | biostudies-literature
Project description:BackgroundThe introduction of eculizumab has significantly improved the outcome of patients with atypical haemolytic uraemic syndrome (aHUS). Because of the risk of relapse after discontinuation, eculizumab was proposed as life-long therapy. However, data on the outcome of relapse are limited. In the Netherlands, patients with aHUS are treated with a restrictive eculizumab regime and are included in a national observational study (CUREiHUS, Dutch Trial Register NTR5988/NL5833).MethodsFor this interim safety analysis, we evaluated the outcome of all adult patients with a suspected relapse, defined as the need to intensify eculizumab after tapering or withdrawal of therapy.ResultsWe describe 11 patients who received renewed eculizumab therapy because of suspected relapse. In three patients with aHUS in native kidneys, estimated glomerular filtration rate (eGFR) returned to baseline value and remained stable without overt proteinuria after follow-up. Six out of eight transplanted patients responded to eculizumab therapy with improvement in eGFR. After a median follow-up of 24.6 months, a reduction of eGFR ≥25% was observed in three of these transplanted patients, which was attributed to the aHUS relapse in only one patient.ConclusionsThis interim analysis suggests that re-treatment with eculizumab after relapse is safe and feasible. We will continue to use our restrictive treatment strategy.
| S-EPMC8496203 | biostudies-literature
Project description:ObjectiveTo determine the efficacy and safety of eculizumab for patients with atypical haemolytic uraemic syndrome (aHUS), compared with current treatment options.DesignA systematic review was performed according to the general principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All study designs were included, except case histories.ParticipantsAll patients diagnosed with aHUS were included; no age restrictions were used.InterventionsEculizumab compared with current treatment options.Identification of studies12 databases were searched. Additional searches were performed through the Food and Drug Administration (FDA) and the Electronic Medicines Compendium websites, Google internet searches and contacting clinical experts. Reference lists of relevant articles were checked for additional studies.Results2 small, uncontrolled prospective multinational, multicentre studies and one small uncontrolled multinational, multicentre retrospective study were included. No meta-analyses were performed. Compared with baseline measures, thrombotic microangiopathy event-free status was achieved in 84% of patients in the prospective studies. Adverse events, as documented by enrolling investigators were frequent, with upper-respiratory tract infection affecting a third of patients. No deaths or episodes of meningitis or meningococcal septicaemia occurred in the prospective studies. Results of the study extension phases up to 114 weeks indicate that the benefits of the treatment are sustained.ConclusionsEculizumab is clinically effective for the treatment of aHUS. Further research is needed to evaluate eculizumab, ideally using patient-related clinical outcomes. If randomised studies are not feasible, study investigators should ensure that the threat of bias is minimised in future studies of eculizumab with respect to the reporting of patient recruitment and selection.
| S-EPMC3822313 | biostudies-literature
Project description:Disorders in complement regulation are a major cause of atypical haemolytic-uraemic syndrome (aHUS). Eculizumab, a monoclonal antibody targeting complement C5 and blocking the terminal complement cascade, should theoretically be useful in this disease, particularly when associated with specific complement pathway anomalies such as Factor H deficiency. Eculizumab is emerging as an effective treatment for post-transplant aHUS recurrence and may have a role in treating de novo aHUS, halting the haemolytic process. In this case report, we describe the fourth case of aHUS treated with eculizumab. In our patient, with a known complement Factor H mutation, not only has the disease process become quiescent but also this therapy has led to significantly improved renal function so that dialysis is no longer necessary.
| S-EPMC4400463 | biostudies-literature
Project description:Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based on long-term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient-years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy-six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit-risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.
| S-EPMC6594003 | biostudies-literature
Project description:BackgroundAtypical haemolytic uraemic syndrome (aHUS) is a rare, potentially life-threatening condition caused by dysregulation of the complement pathway. Eculizumab is currently the only approved treatment for this disorder.ObjectiveOur objective was to investigate the impact of early administration of eculizumab on inpatient resource use and hospitalisation costs in 222 patients with aHUS.MethodsWe conducted a retrospective analysis of the Premier Perspective® Hospital Database, including patients with a diagnosis of aHUS and evidence of eculizumab use for aHUS. Early initiation was defined as having received eculizumab within 7 days of admission, with late initiation defined as starting eculizumab on day 8 or later. This date represents the average time required to obtain a specific diagnostic test to discriminate aHUS from a similar haemolytic syndrome that requires a different treatment. Outcome measures were time from first eculizumab initiation to discharge, discharge status or death, days spent in the intensive care unit (ICU), readmission indicators, dialysis indicators, and total hospital costs. Time from first eculizumab initiation to discharge was analysed using a generalised linear model with a log link and an assumed underlying negative binomial distribution. Logistic regression models were used to test the statistical significance of early versus late initiation as a predictor of the occurrence of readmissions, dialysis, and death. Total hospital costs were analysed using a generalised linear model with a log link and an assumed underlying gamma distribution.ResultsBefore modelling, total length of stay and ICU duration were significantly longer for late initiators than for early initiators, and significantly more late initiators were readmitted within 90 days. Late initiation was associated with significantly higher hospital costs than early initiation. After multivariable analysis, late initiators were 3.2 times more likely to require dialysis. However, there was no significant association between early initiation and time to discharge, readmission, or death for any definition or early initiation after multivariable analysis. Estimated total hospital costs (year 2017 values) were $US103,557 in late initiators and $US85,776 in early initiators (p = 0.0024).ConclusionInitiation of eculizumab within 7 days of hospitalisation is associated with lower dialysis rates, less time in ICU, less plasmapheresis, and lower hospitalisation costs compared with late initiation.
| S-EPMC7045788 | biostudies-literature
Project description:BackgroundEculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient.MethodsWe evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies.ResultsA PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target.ConclusionsA patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.
| S-EPMC9923710 | biostudies-literature
Project description:Haemolytic uraemic syndrome (HUS) remains a leading cause of paediatric acute kidney injury (AKI). Haemolytic uraemic syndrome is characterised by the triad of microangiopathic haemolytic anaemia, thrombocytopenia and AKI. In ~ 90% of cases, HUS is a consequence of infection with Shiga toxin-producing E. coli (STEC), most commonly serotype O157:H7. Acute mortality from STEC-HUS is now less than 5%; however, there is significant long-term renal morbidity in one third of survivors. Currently, no specific treatment exists for STEC-HUS. There is growing interest in the role of complement in the pathogenesis of STEC-HUS due to the discovery of inherited and acquired dysregulation of the alternative complement system in the closely related disorder, atypical HUS (aHUS). The treatment of aHUS has been revolutionised by the introduction of the anti-C5 monoclonal antibody, eculizumab. However, the role of complement and anti-complement therapy in STEC-HUS remains unclear. Herein, we review the current evidence of the role of complement in STEC-HUS focusing on the use of eculizumab in this disease.
| S-EPMC6660499 | biostudies-literature
Project description:Background:Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Methods:In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. Results:Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P?=?0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P?=?0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. Conclusions:As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.
| S-EPMC6452204 | biostudies-literature
Project description:Ravulizumab (Ultomiris®), a humanized monoclonal antibody that inhibits complement protein C5, is indicated for the treatment of atypical haemolytic uraemic syndrome (aHUS) in several countries, including the USA and those of the EU. Ravulizumab has been re-engineered from eculizumab to extend its terminal elimination half-life, resulting in a more convenient maintenance dosage regimen of once every 4-8 weeks compared with once every 2-3 weeks for eculizumab. In single-arm phase 3 trials, ravulizumab resolved thrombotic microangiopathy in 54% and 78% of treatment-naïve adult and paediatric patients with aHUS, respectively, within 26 weeks. Ravulizumab was also effective in patients with postpartum aHUS and paediatric patients who responded to eculizumab and later switched to ravulizumab. Ravulizumab was generally well tolerated, with no unexpected safety events. The most common treatment-related adverse events with ravulizumab in treatment-naïve patients include headache, diarrhoea and vomiting. With its convenient once every 4-8 weeks maintenance regimen, ravulizumab is an important treatment option for aHUS in adult and paediatric patients.
| S-EPMC8052220 | biostudies-literature