Single Dose Of Eculizumab Research Articles

Paroxysmal Cold Hemoglobinuria Successfully Treated with Complement Inhibition

Introduction: Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) that causes intravascular hemolysis and profound, sometimes life-threatening anemia. It most commonly occurs in children following viral infection, and presents with acute onset anemia, pallor, jaundice, and hemoglobinuria. PCH is caused by a biphasic immunoglobulin G (IgG) autoantibody that targets the P-antigen on red blood cells (RBCs) with complement fixation at low temperatures. Subsequent warming in the central circulation leads to complement activation and intravascular hemolysis. Management of PCH has been primarily supportive, with environmental warming to prevent autoantibody binding and transfusion with warmed packed red blood cells (PRBCs) as clinically indicated. Efficacy of corticosteroids has not been demonstrated. We report on successful treatment of PCH by complement blockade using a single dose of eculizumab. Case Description: We treated a previously healthy 4-year-old boy who presented with 5-day history of transient maculopapular rash, 3-day history of fatigue, thigh and abdominal pain, 2-day history of cough, chills, vomiting, diarrhea and high-grade fevers, and on the day of presentation, developed jaundice and dark urine. Hemoglobin (Hgb) level was 6.4 g/dL at a primary care visit. On admission, he was febrile, tachycardic, with scleral icterus and pallor, worsening anemia (Hgb 5.6 g/dL) which 1 hour later dropped to 4.5 g/dL, with reticulocytopenia, spherocytosis, and positive direct antiglobulin test (DAT). Initially he received methylprednisolone as empiric treatment for AIHA. Monospecific DAT was positive for C3d and negative for IgG, leading to suspicion of cold-antibody mediated AIHA (cAIHA). Due to hemoglobinuria consistent with intravascular hemolysis, PCH was suspected and a Donath-Landsteiner (DL) test was ordered. Despite environmental warming and azithromycin for potential Mycoplasma pneumoniae induced cold agglutinin syndrome, he developed worsening anemia (nadir Hgb 3.0 g/dL) with signs of shock including altered mental status, tachycardia, lactic acidosis, and high oxygen extraction, and continued transfusion requirement. On hospital day 4, we decided to treat him with eculizumab 600 mg intravenously. That afternoon, definitive testing for PCH with the DL test returned positive, confirming PCH diagnosis. Markers of hemolysis, including lactate dehydrogenase and bilirubin, decreased immediately following eculizumab administration. No further transfusion was required. Hgb levels stabilized, and reticulocyte counts increased daily. Steroids were discontinued on hospital day 6. Complete complement blockade following a single dose of eculizumab was confirmed on hospital day 7, with total complement level (CH50) reported as <13.8 U/mL. The patient continued to improve and was discharged home on hospital day 15 with Hgb 6.6 g/dL, improving to 9.1 g/dL 6 days later. Diagnostic tests for infectious and toxin-mediated causes of PCH remained negative. He was given prophylaxis for encapsulated bacterial infections with penicillin VK, given increased risk of infection from ongoing complement blockade and his unvaccinated status. This was discontinued when CH50 levels normalized, 42 days after eculizumab administration. Discussion: To our knowledge, this is the first published observation of successful complement blockade for the treatment of PCH. Complement is a key effector of intravascular hemolysis in PCH. Eculizumab, an anti-C5 monoclonal antibody that blocks the terminal complement pathway, resulted in an efficient, complete, and sustained clinical improvement following a single dose. We observed no adverse effects. This case suggests a need for further investigation of complement-blockade, either at the terminal pathway or classical pathway level, in the treatment of this disease. Figure Disclosures Berentsen: Apellis: Consultancy, Honoraria; Alexion: Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Mundipharma: Research Funding; True North Therapeutics: Consultancy, Honoraria. OffLabel Disclosure: Eculizumab for paroxysmal cold hemoglobinuria

Eculizumab deposits in vessel walls in thrombotic microangiopathy

Terminal complement inhibition therapy with eculizumab (a humanized monoclonal antibody to C5) has revolutionized the treatment of patients with thrombotic microangiopathy (TMA). Successful responders are often placed on long-standing therapy to prevent disease recurrence in the native kidney or allograft. The tissue deposition of eculizumab in patients with C3 glomerulopathy has been described but no studies have yet investigated tissue deposition of eculizumab in cases where it was indicated for thrombotic microangiopathy which, unlike C3 glomerulopathy, does not usually show immune-type electron dense deposits. To evaluate this, we reviewed biopsies from 13 patients who received eculizumab for TMA treatment or prevention of recurrence. We found IgG2, IgG4, and kappa positivity within arterioles corresponding to eculizumab deposits, with similar distribution to C5b-9, in all but one patient. In that patient eculizumab therapy had been discontinued 24 months prior to biopsy. Deposits in arterioles could be seen as early as one day after infusion and after a single dose of eculizumab, and were detected up to 162 days after therapy discontinuation. This may play a role in controlling local complement activation-associated vascular changes in these patients. Thus, IgG subclass staining by immunofluorescence is important to avoid misdiagnoses of immune-complex or monoclonal immunoglobulin deposition disease in patients with TMA who received eculizumab.

Acquired thrombotic thrombocytopenic purpura with isolated CFHR3/1 deletion\u2014rapid remission following complement blockade

BackgroundThrombotic thrombocytopenic purpura (TTP) is caused by the abundance of uncleaved ultralarge von Willebrand factor multimers (ULvWF) due to acquired (autoantibody-mediated) or congenital vWF protease ADAMTS13 deficiency. Current treatment recommendations include plasma exchange therapy and immunosuppression for the acquired form and (fresh) frozen plasma for congenital TTP.Case-diagnosis/treatmentA previously healthy, 3-year-old boy presented with acute microangiopathic hemolytic anemia, thrombocytopenia, erythrocyturia and mild proteinuria, but normal renal function, and elevated circulating sC5b-9 levels indicating complement activation. He was diagnosed with atypical hemolytic uremic syndrome and treated with a single dose of eculizumab, followed by prompt resolution of all hematological parameters. However, undetectably low plasma ADAMTS13 activity in the pre-treatment sample, associated with inhibitory ADAMTS13 antibodies, subsequently changed the diagnosis to acquired TTP. vWF protease activity normalized within 15 months without further treatment, and the patient remained in long-term clinical and laboratory remission. Extensive laboratory workup revealed a homozygous deletion of CFHR3/1 negative for anti-CFH antibodies, but no mutations of ADAMTS13, (other) alternative pathway of complement regulators or coagulation factors.ConclusionsThis case, together with a previous report of a boy with congenital TTP (Pecoraro et al. Am J Kidney Dis 66:1067, 2015), strengthens evolving in-vitro and ex-vivo evidence that ULvWF interferes with complement regulation and contributes to the TTP phenotype. Comprehensive, prospective complement studies in patients with TTP may lead to a better pathophysiological understanding and novel treatment approaches for acquired or congenital forms.

G.P.299: Novel use of eculizumab in a patient with Guillain–Barré syndrome

Guillain–Barre syndrome (GBS) is a rare but life-threatening polyneuropathy. We describe the novel use of eculizumab in a patient with this disorder. Case A previously well 13 year old boy presented with an acute onset of ascending paralysis and was diagnosed with GBS. Despite receiving intravenous immunoglobulins on Day 3 of presentation, he continued to deteriorate and required ventilatory support and a subsequent tracheostomy. He remained non-responsive to a further course of 2 g/kg intravenous immunoglobulin. His GBS was complicated by severe life-threatening autonomic instability so plasmapheresis was not felt to be a suitable option. A single dose of eculizumab was given, after which the patient showed signs of improvement. He continued to convalesce over the next 8 weeks, at which stage he was mobilising independently. Discussion GBS poses a mortality rate of 10% despite medical advances. Intravenous immunoglobulins and plasmapheresis have been shown to improve outcome but beyond these, management is mainly supportive at present. Eculizumab, a monoclonal antibody, is currently used in patients with other immunological disorders but not GBS. Recent animal studies suggest that complement activation may play a role in the development of paralysis in GBS. Complement inhibitors such as eculizumab have been shown to have promising benefits in murine models. Further research is necessary but we believe eculizumab may have a role in improving outcome, especially in those with severe GBS. As far as we are aware, this is the first case report in literature of eculizumab being used in a patient with GBS. Our case suggests potentially favourable outcomes and clinical trials are needed to assess this further.

Eculizumab Treatment of Acute Antibody-Mediated Rejection in Renal Transplantation: Case Reports

The occurrence of acute antibody-mediated rejection (AMR), especially in more severe cases, continues to be associated with a poor prognosis for implant survival. Here, we have reported the results of treatment of two patients who developed AMR associated with thrombotic microangiopathy immediately after transplantation. We used a single dose of eculizumab at an early stage jointly with conventional modalities of steroid boluses, plasmapheresis, intravenous immunoglobulin, and rituximab. In both cases, the clinical course was favorable. Eculizumab, a monoclonal antibody with a high affinity for complement protein C5, prevents generation of the final membrane attack complex, blocking this cascade. To date, there are a few reports of the usefulness of eculizumab in AMR. Eculizumab can help to stop endothelial damage, especially in severe cases that show a risk of progression to cortical necrosis, by providing a therapeutic window until the other modalities begin to control the immune response. In our experience, the use of eculizumab can be beneficial in the treatment of AMR.

Successful Treatment of De Novo Posttransplant Thrombotic Microangiopathy With Eculizumab

Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by complement hyperactivation secondary to defects in complement genes and acquired autoantibodies against complement regulatory proteins (1). The clinical features include thrombotic microangiopathy (TMA), hemolytic anemia, thromb