The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria

Hillmen, Peter; Young, Neal S.; Schubert, Jörg; Brodsky, Robert A.; Socié, Gèrard; Muus, Petra; Röth, Alexander; Szer, Jeffrey; Elebute, Modupe; Nakamura, Ryotaro; Browne, Paul; Risitano, Antonio M.; Hill, Anita; Schrezenmeier, Hubert; Fu, Chieh Lin; Maciejewski, Jaroslaw P.; Rollins, Scott A.; Mojcik, Christopher F.; Rother, Russell P.; Luzzatto, Lucio

doi:10.1056/nejmoa061648

Cited by 1,092 publications

(1,032 citation statements)

References 17 publications

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“…46 A candidate therapy in our patients would be eculizumab, a monoclonal antibody to C5 that has shown efficacy in paroxysmal nocturnal hemoglobinuria. 47 Potentially, susceptible MG patients would be screened for the polymorphism and as soon as treatment-resistant ophthalmoparesis ensues, appropriate additional anticomplement therapy may be initiated. Intravenous immunoglobulin also reduces complement factors C3a and C5a, 48 and, although expensive, would be a reasonable intervention to attempt early on in susceptible individuals in an effort to reduce the significant morbidity associated with ophthalmoplegic complications.…”

Section: Discussionmentioning

confidence: 99%

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

et al. 2009

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Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C4G SNP (odds ratio ¼ 8.6; P ¼ 0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5 0 -flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C4G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression.

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Section: Discussionmentioning

confidence: 99%

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

et al. 2009

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“…This novel drug has been shown to reduce hemolysis and stabilize hemoglobin levels, thus resulting in a decrease in transfusion requirements in PNH patients (6). Moreover, eculizumab also protects against the complications of hemolytic PNH, such as a deteriorating renal function, pulmonary hypertension, and thromHematology, Department of Medicine, Kobe University Graduate School of Medicine, Japan, Department of Hematology, Ono Municipal Hospital, Japan, Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Japan and Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Japanboembolism, and thereby contributes to an improvement of survival for such patients (7).…”

Section: Introductionmentioning

confidence: 99%

Successful Management of Obstructive Jaundice due to Gallstones with Eculizumab in a Patient with Paroxysmal Nocturnal Hemoglobinuria

et al. 2012

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Paroxysmal nocturnal hemoglobinuria (PNH) makes patients susceptible to intravascular hemolysis and thrombosis, and it can be life-threatening in stressful situations. Eculizumab, a humanized monoclonal antibody that inhibits the complement protein C5, has been evaluated as a novel therapy for PNH. We herein describe the case of a 59-year-old Japanese woman with classic PNH, who had been successfully treated with eculizumab, but who later developed acute cholecystitis/cholangitis from gallstones. Although the severe obstructive jaundice requiring endoscopic therapy following cholecystectomy was complicated, critical intravascular hemolysis and thrombosis were not observed. Therefore, utilizing eculizumab during the peri-operative management of PNH patients should be carefully taken into consideration.

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“…This drug has been shown to reduce hemolysis and greatly improve symptoms and quality of life for these patients. 8,9 Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative therapy for paroxysmal nocturnal hemoglobinuria. Eradication of the PNH clone has been achieved with both myeloablative and reduced-intensity conditioning regimens.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Santarone¹,

Bacigalupo²,

Risitano³

et al. 2009

Haematologica

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BackgroundParoxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hemopoietic stem cells for which the only curative treatment is allogeneic hematopoietic stem cell transplantation. Design and MethodsThe aim of this retrospective study was to assess the long-term clinical and hematologic results in 26 paroxysmal nocturnal hemoglobinuria patients who received hematopoietic stem cell transplantation in Italy between 1988 and 2006. The patients were aged 22 to 60 years (median 32 years). Twenty-three donors were HLA-identical (22 siblings and one unrelated) and 3 were HLA-mismatched (2 related and one unrelated). ResultsFifteen patients received a myeloablative conditioning consisting of busulfan and cyclophosphamide (in all cases from identical donor) and 11 were given a reduced intensity conditioning (8 from identical donor and 3 from mismatched donor). The cumulative incidence of graft failure was 8% (4% primary and 4% secondary graft failure). Transplant-related mortality for all patients was 42% (26% and 63% for patients transplanted following myeloablative or reduced intensity conditioning, respectively). As of October 31, 2009, 15 patients (11 in the myeloablative conditioning group and 4 in the reduced intensity conditioning group) are alive with complete hematologic recovery and no evidence of paroxysmal nocturnal hemoglobinuria following a median follow-up of 131 months (range 30-240). The 10-year Kaplan-Meier probability of disease-free survival was 57% for all patients: 65% for 23 patients transplanted from identical donor and 73% for 15 patients transplanted with myeloablative conditioning. No thromboembolic event nor recurrence of the disease were reported following transplant. ConclusionsThe findings of this study confirm that most patients with paroxysmal nocturnal hemoglobinuria may be definitively cured with hematopoietic stem cell transplantation.Key words: paroxysmal nocturnal hemoglobinuria, hematopoietic stem cell transplantation, conditioning regimen. Haematologica 2010;95:983-988. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Santarone S, Bacigalupo A, Risitano AM, Tagliaferri E, Di Bartolomeo E, Iori AP, Rambaldi A, Angelucci E, Spagnoli A, Papineschi F, Tamiazzo S, Di Nicola M, and Di Bartolomeo P. Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

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The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Hemoglobinuria

Abstract: Eculizumab is an effective therapy for PNH.

Cited by 1,092 publications

References 17 publications

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

Successful Management of Obstructive Jaundice due to Gallstones with Eculizumab in a Patient with Paroxysmal Nocturnal Hemoglobinuria

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

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