Did you mean: ecuilizumab
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Cureus Jun 2022Eculizumab, first-line therapy for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), has infectious side effects in addition to... (Review)
Review
Eculizumab, first-line therapy for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), has infectious side effects in addition to its therapeutic benefits. This study aims to discuss the mechanism of development of infections, prevention, and timely treatment to prevent complications such as septic shock and mortality. The study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist and reporting guidelines for systematic review. Inclusion and exclusion criteria were determined. A total of 10 research papers were extracted after exploring Pubmed and Google Scholar from 2001 to 2021. The New Castle Ottawa Questionnaire for non-randomized clinical trials and the National Institutes of Health (NIH) quality assessment tool for case reports and case series were used to assess the risk of bias. The studies included in this systematic review describe infections with , , unusual species, , and . The main goal of this review is to impress upon the seriousness of the infectious complications associated with eculizumab. Health care providers should maintain a high index of suspicion for early identification and treatment.
PubMed: 35784997
DOI: 10.7759/cureus.25640 -
Frontiers in Neurology 2023Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory CNS demyelinating disease. Two groups of monoclonal antibodies (mAbs) are used to prevent...
INTRODUCTION
Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory CNS demyelinating disease. Two groups of monoclonal antibodies (mAbs) are used to prevent disease relapse, i.e., Food and Drug Administration (FDA)-approved mAbs (e.g., eculizumab satralizumab, inebilizumab), and off-label mAb drugs (e.g., rituximab and tocilizumab). The FDA-approved mAbs have high efficacy but more expensive compared to the off-labels, and thus are less accessible. This systematic review and network meta-analysis (NMA) was to assess the efficacy and safety of both classes of mAbs compared to the current standard treatments.
METHODS
Systematically searches were conducted in MEDLINE and SCOPUS from inception until July 2021. Randomized-controlled trials (RCTs) were eligible if they compared any pair of treatments (mAbs, immunosuppressive drugs, or placebo) in adult patients with NMOSD. Studies with AQP4-IgG positive or negative were used in the analysis. Probability of relapse and time to event were extracted from the Kaplan-Meier curves using Digitizer. These data were then converted into individual patient time-to-event data. A one-stage mixed-effect survival model was applied to estimate the median time to relapse and relative treatment effects using hazard ratios (HR). Two-stage NMA was used to determine post-treatment annualized relapse rate (ARR), expanded disability status score (EDSS) change, and serious adverse events (SAE). Risk of bias was assessed using the revised cochrane risk of bias tool.
RESULTS
A total of 7 RCTs with 776 patients were eligible in the NMA. Five of the seven studies were rated low risk of bias. Both FDA-approved and off-label mAbs showed significantly lower risk of relapse than standard treatments, with HR (95% CI) of 0.13 (0.07, 0.24) and 0.16 (0.07, 0.37) respectively. In addition, the FDA-approved mAbs had 20% lower risk of relapse than the off-label mAbs, but this did not reach statistical significance. The ARRs were also lower in FDA-approved and off-label mAbs than the standard treatments with the mean-difference of-0.27 (-0.37,-0.16) and-0.31(-0.46,-0.16), respectively.
CONCLUSION
The off-label mAbs may be used as the first-line treatment for improving clinical outcomes including disease relapse, ARR, and SAEs for NMOSD in countries where resources and accessibility of the FDA-approved mAbs are limited.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=283424, identifier: CRD42021283424.
PubMed: 37082442
DOI: 10.3389/fneur.2023.1166490 -
Frontiers in Neurology 2021Approximately 10-20% of patients WITH myasthenia gravis (MG) are refractory to conventional immunotherapies. The purpose of this study was to conduct a systematic...
Approximately 10-20% of patients WITH myasthenia gravis (MG) are refractory to conventional immunotherapies. The purpose of this study was to conduct a systematic review and meta-analysis to explore the optimal therapies for refractory MG. Correlative studies were performed through a search in PubMed, Cochrane Library, and Embase databases. The primary outcome was defined by changes in the quantitative myasthenia gravis score (QMG). Secondary outcomes were defined by the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL), Myasthenia Gravis Foundation of America (MGFA) post intervention status, adverse events, and disease exacerbation after treatment. A total of 16 studies were included with 403 patients with refractory MG on therapies with rituximab, eculizumab, tacrolimus, and cladribine. Therapeutic efficacy of rituximab and eculizumab was identified with an estimated reduction in QMG score (4.158 vs. 6.928) and MG-ADL (4.400 vs. 4.344), respectively. No significant changes were revealed in efficacy or exacerbation density between the two independent therapeutic cohorts. The estimated adverse event density of eculizumab was more significant than that in the rituximab group (1.195 vs. 0.134 per patient-year), while the estimated serious event density was similar. The efficacy and safety of rituximab and eculizumab have been approved in patients with refractory MG. Rituximab had a superior safety profile than eculizumab with a lower incidence of adverse events. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021236818, identifier CRD42021236818.
PubMed: 34925206
DOI: 10.3389/fneur.2021.725700 -
Advances in Therapy Jun 2023Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making...
INTRODUCTION
Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making complement inhibition the best approach to manage PNH. Three complement inhibitors are approved by the European Medicines Agency as targeted therapy for PNH: eculizumab and ravulizumab, two humanized monoclonal antibodies targeting the same complement 5 (C5) epitope, approved in 2007 and 2019, respectively, and the more recently approved cyclic peptide, the complement 3 (C3) inhibitor pegcetacoplan. Although national and international PNH treatment guidelines exist, they do not take into consideration the latest clinical trial evidence. Given the lack of evidence-based data for some clinical situations encountered in real life, we identified specific populations of patients who may benefit from switching to proximal C3 from terminal C5 inhibition.
METHODS
The expert recommendations presented here were created using a Delphi-like process by a group of expert PNH specialists across Central Europe. Based on an initial advisory board meeting discussion, recommendations were prepared and reviewed as part of a Delphi survey to test agreement.
RESULTS
Using a systematic approach, literature databases were searched for relevant studies, and 50 articles were reviewed by the experts and included as supporting evidence.
CONCLUSION
Implementation of these recommendations uniformly across healthcare institutions will promote the best use of complement inhibition in managing PNH, and has the potential to positively impact patient outcomes in Central Europe and worldwide.
Topics: Humans; Hemoglobinuria, Paroxysmal; Expert Testimony; Complement Inactivating Agents; Complement C3; Complement C5; Europe
PubMed: 37072660
DOI: 10.1007/s12325-023-02510-4 -
Frontiers in Immunology 2021Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system involvement. Since the AChR on the postsynaptic membrane is destroyed by an immune attack, sufficient endplate potential cannot be generated, resulting in the development of a synaptic transmission disorder at the neuromuscular junction and in muscle weakness. The role of the complement system in MG has been demonstrated in animal models and clinical tests, and it has been determined that complement inhibition in patients with MG can prevent disease induction and reverse its progression. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and prevents autoimmune damage; additionally, it has received subsequent approval by the Federal Drug Administration of the United States for MG treatment. However, various concerns regarding the use of eculizumab persist. In this review, we have discussed the treatment time, cost effectiveness, long-term efficacy, and tolerability of eculizumab for MG treatment. We have also summarized historical information and have presented perspectives on this new therapeutic modality.
Topics: Animals; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Combined Modality Therapy; Complement Inactivating Agents; Complement System Proteins; Disease Management; Disease Susceptibility; Drug Development; Humans; Myasthenia Gravis; Treatment Outcome
PubMed: 34456922
DOI: 10.3389/fimmu.2021.715036 -
SAGE Open Medicine 2023C5 inhibitors such as eculizumab and ravulizumab are the first-line treatment in the management of paroxysmal nocturnal hemoglobinuria (PNH). However, some patients... (Review)
Review
OBJECTIVES
C5 inhibitors such as eculizumab and ravulizumab are the first-line treatment in the management of paroxysmal nocturnal hemoglobinuria (PNH). However, some patients develop novel symptoms as part of their treatment with eculizumab, and the disease is termed as eculizumab refractory PNH. The aim of this study was to conduct a systematic review on the available treatment modalities for the management of eculizumab refractory PNH.
METHODS
Two authors independently searched two databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 70 studies were obtained: 4 out 70 studies were found to meet the inclusion criteria.
RESULTS
Four studies were found to meet the inclusion criteria of our study. Two studies were published in 2021 and two studies were published in 2020. All four studies were multicenter clinical trials. Two studies were phase III clinical trials, one study was a phase II clinical trial, and one study was a phase I clinical trial. Two studies were about pegcetacoplan, one was about danicopan, and one was about iptacopan.
CONCLUSION
Based upon the findings of our systematic review, we recommend an individualized treatment plan based on the mechanism of eculizumab refractoriness and the mechanism of PNH breakthrough. This recommendation is subject to the available resources and clinical expertise available at different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs should be performed to accurately assess the different medications and aid in designing guidelines of the management of eculizumab refractory PNH.
LEVEL OF EVIDENCE
Level I.
PubMed: 37388903
DOI: 10.1177/20503121231181267 -
Frontiers in Immunology 2020Transplant-associated thrombotic microangiopathy (TA-TMA) is a dangerous and life-threatening complication in patients undergoing hematopoietic stem cell transplantation... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Transplant-associated thrombotic microangiopathy (TA-TMA) is a dangerous and life-threatening complication in patients undergoing hematopoietic stem cell transplantation (HSCT). Eculizumab has been used in the treatment of TA-TMA, and several studies have confirmed the benefit of Eculizumab in patients with TA-TMA. However, the results remain controversial. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Eculizumab for TA-TMA.
MATERIALS AND METHODS
We searched PubMed and Embase for studies on the efficacy and safety of Eculizumab in TA-TMA patients. Efficacy outcomes consisted of overall response rate (ORR), complete response rate (CRR), and survival rate at the last follow-up (SR). Safety outcomes were adverse events (AEs), including infection, sepsis, impaired liver function, infusion reactions, and death.
RESULTS
A total of 116 patients from six studies were subjected to meta-analysis. The pooled estimates of ORR, CRR, and SR for TA-TMA patients were 71% (95% CI: 58-82%), 32% (95% CI: 11-56%), and 52% (95% CI: 40-65%), respectively. Only one patient presented with a severe rash, and infection was the most common AEs. The main causes of death were infection and GvHD.
CONCLUSION
Current evidence suggests that Eculizumab improves SR and ORR in patients with TA-TMA and that Eculizumab is well tolerated. However, the number of studies is limited, and the findings are based mainly on data from observational studies. Higher quality randomized controlled trials and more extensive prospective cohort studies are needed.
Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Complement Inactivating Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Middle Aged; Observational Studies as Topic; Survival Rate; Thrombotic Microangiopathies; Treatment Outcome; Young Adult
PubMed: 33552043
DOI: 10.3389/fimmu.2020.564647 -
Cureus Sep 2023Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy and is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute... (Review)
Review
Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy and is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. The complement cascade plays an integral role in aHUS. Mutations in the complement cascade, especially in the alternative pathway (AP) lead to an unregulated and continuous activation of the cascade. Eculizumab and ravulizumab are humanized monoclonal antibodies that inhibit the complement cascade. This systematic analysis reviews the evidence for both antibodies to compare them in terms of safety and efficacy. This review will also assess the evidence for biomarker associations with interventions, the role of genetic mutations in the prognosis of disease, and the financial burden of both treatment options. An in-depth search was conducted across PubMed, Science Direct, and Cochrane Library following the PRISMA 2020 guidelines. Both eculizumab and ravulizumab were comparable in safety and efficacy but ravulizumab was preferred by patients and their caregivers as it posed a lower financial burden and had less frequent dosing. Soluble complement 5b-9 (sC5b), especially in urine, has the potential to be used as a biomarker to assess response to treatment. Genetic mutations, especially mutations in complement factor I (CFI), membrane cofactor protein (MCP), and complement factor H (CFH), were associated with a higher risk of recurrence, and therefore care should be taken when attempting to discontinue treatment in this subset of patients. Treatment with a monoclonal antibody should be initiated as soon as a genetic mutation is identified. Blinded, double-arm, clinical trials preferably with larger sample sizes are needed to effectively compare both the monoclonal antibodies.
PubMed: 37905269
DOI: 10.7759/cureus.46185 -
The Cochrane Database of Systematic... Mar 2021Atypical haemolytic uraemic syndrome (aHUS) is a rare disorder characterised by thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. The... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atypical haemolytic uraemic syndrome (aHUS) is a rare disorder characterised by thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. The condition is primarily caused by inherited or acquired dysregulation of complement regulatory proteins with ~40% of those affected aged < 18 years. Historically, kidney failure and death were common outcomes, however, improved understanding of the condition has led to discovery of novel therapies.
OBJECTIVES
To evaluate the benefits and harms of interventions for aHUS.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies for randomised controlled studies (RCTs) up to 3 September 2020 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. MEDLINE(OVID) 1946 to 27 July 2020 and EMBASE (OVID) 1974 to 27 July 2020 were searched for non-RCTs.
SELECTION CRITERIA
All randomised and non-randomised clinical trials comparing an intervention with placebo, an intervention with supportive therapy, or two or more interventions for aHUS were included. Given the rare nature of the condition in question, prospective single-arm studies of any intervention for aHUS were also included.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted pre-specified data from eligible studies and evaluated risk of bias using a newly developed tool based on existing Cochrane criteria. As statistical meta-analysis was not appropriate, qualitative analysis of data was then performed.
MAIN RESULTS
We included five single-arm studies, all of which evaluated terminal complement inhibition for the treatment of aHUS. Four studies evaluated the short-acting C5 inhibitor eculizumab and one study evaluated the longer-acting C5 inhibitor ravulizumab. All included studies within the review were of non-randomised, single-arm design. Thus, risk of bias is high, and it is challenging to draw firm conclusions from this low-quality evidence. One hundred patients were included within three primary studies evaluating eculizumab, with further data reported from 37 patients in a secondary study. Fifty-eight patients were included in the ravulizumab study. After 26 weeks of eculizumab therapy there were no deaths and a 70% reduction in the number of patients requiring dialysis. Complete thrombotic microangiopathic (TMA) response was observed in 60% of patients at 26 weeks and 65% at two years. After 26 weeks of ravulizumab therapy four patients had died (7%) and complete TMA response was observed in 54% of patients. Substantial improvements were seen in estimated glomerular filtration rate and health-related quality of life in both eculizumab and ravulizumab studies. Serious adverse events occurred in 42% of patients, and meningococcal infection occurred in two patients, both treated with eculizumab.
AUTHORS' CONCLUSIONS
When compared with historical data, terminal complement inhibition appears to offer favourable outcomes in patients with aHUS, based upon very low-quality evidence drawn from five single-arm studies. It is unlikely that an RCT will be conducted in aHUS and therefore careful consideration of future single-arm data as well as longer term follow-up data will be required to better understand treatment duration, adverse outcomes and risk of disease recurrence associated with terminal complement inhibition.
Topics: Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Bias; Complement Inactivating Agents; Glomerular Filtration Rate; Humans; Non-Randomized Controlled Trials as Topic; Quality of Life; Thrombotic Microangiopathies
PubMed: 33783815
DOI: 10.1002/14651858.CD012862.pub2 -
Renal Failure Dec 2023The long-term mortality of kidney transplantation patients with atypical hemolytic uremic syndrome remains high, and the efficacy of the main treatment eculizumab is... (Meta-Analysis)
Meta-Analysis Review
New findings in preventing recurrence and improving renal function in AHUS patients after renal transplantation treated with eculizumab: a systemic review and meta-analyses.
BACKGROUND
The long-term mortality of kidney transplantation patients with atypical hemolytic uremic syndrome remains high, and the efficacy of the main treatment eculizumab is still controversial.
OBJECTIVE
A comprehensive systematic review and meta-analysis of clinical trials using eculizumab in renal transplant patients with atypical hemolytic uremic syndrome was conducted to evaluate the efficacy of this therapy and its impact on renal function.
METHODS
A comprehensive systematic search was conducted across multiple reputable databases, including Ovid (MEDLINE, EMBASE), PubMed, and the Cochrane Library (since database inception), to identify relevant studies exploring the use of eculizumab in patients with atypical hemolytic uremic kidney transplantation. Various renal function parameters, such as dialysis, rejection, glomerular filtration rate, serum creatinine, lactate dehydrogenase, and platelet count, along with patient relapse rates, were extracted and summarized using a combination of robust statistical methods, including fixed effects, random effects, and general inverse variance methods.
RESULT
Eighteen trials with 618 subjects were analyzed. Our analysis suggests that the use of eculizumab is associated with a reduced likelihood of AHUS recurrence (odds ratio (OR) = 0.05, 95% CI: 0.00-0.13), as well as a significant reduction in the need for dialysis (odds ratio (OR) = 0.13, 95% CI: 0.01-0.32). Additionally, eculizumab treatment led to lower serum creatinine levels (mean differences (MD) = 126.931μmoI/L, 95% CI: 115.572μmoI/L-138.290μmoI/L) and an improved glomerular filtration rate (mean differences (MD) = 59.571 ml/min, 95% CI: 57.876 ml/min-61.266 mL/min). Our results also indicate that the use of eculizumab reduces the likelihood of rejection (odds ratio (OR) = 0.09, 95% CI: 0.01-0.22). Furthermore, the drug was effective in improving platelet counts (×10∧9/L) (mean differences (MD) = 163.421, 95% CI: 46.998-279.844) and lactate dehydrogenase levels (mean differences (MD) = 336.608 U/L, 95% CI: 164.816 U/L-508.399 U/L).
CONCLUSIONS
Based on the meta-analysis, treatment with eculizumab can reduce dialysis rates and improve patients' quality of life by enhancing renal function.
Topics: Humans; Atypical Hemolytic Uremic Syndrome; Creatinine; Kidney; Kidney Transplantation; Lactate Dehydrogenases; Quality of Life; Recurrence
PubMed: 37563792
DOI: 10.1080/0886022X.2023.2231264