The long-acting C5 inhibitor, ravulizumab, is effective and safe in pediatric patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment

Ariceta, Gema; Dixon, Bradley P.; Kim, Seong Heon; Kapur, Gaurav; Mauch, Teri Jo; Ortiz, Stephan; Vallée, Marc; Denker, Andrew E.; Kang, Hee Gyung; Greenbaum, Larry A.; Lovell, Heather; Muff-Luett, Melissa; Malone, Kristin; Adeagbo, Oluwasegun; Wilkerson, Alexandria; Fraga, Gloria; Sarri, Scherezade; Cheong, Hae Il; Ahn, Yo Han; Han, Kyoung Hee

doi:10.1016/j.kint.2020.10.046

Cited by 64 publications

(54 citation statements)

References 25 publications

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“…Although the authors concluded that stopping eculizumab in controlled patients is safe, the risk of relapse needs to be discussed with patients and caregivers and eculizumab should be promptly available if necessary. In addition to eculizumab, a newer formulation of long-acting C5 inhibitor ravulizumab is now available for treatment of aHUS; data from phase 3 trials have demonstrated good efficacy and safety results in adult and pediatric patients [ 59 , 60 ].…”

Section: Complement-mediated Atypical Hemolytic Uremic Syndromementioning

confidence: 99%

Thrombotic microangiopathy in children

et al. 2022

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The syndrome of thrombotic microangiopathy (TMA) is a clinical-pathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ involvement. It comprises a spectrum of underlying etiologies that may differ in children and adults. In children, apart from ruling out shigatoxin-associated hemolytic uremic syndrome (HUS) and other infection-associated TMA like Streptococcus pneumoniae -HUS, rare inherited causes including complement-associated HUS, cobalamin defects, and mutations in diacylglycerol kinase epsilon gene must be investigated. TMA should also be considered in the setting of solid organ or hematopoietic stem cell transplantation. In this review, acquired and inherited causes of TMA are described with a focus on particularities of the main causes of TMA in children. A pragmatic approach that may help the clinician tailor evaluation and management is provided. The described approach will allow for early initiation of treatment while waiting for the definitive diagnosis of the underlying TMA.

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Section: Complement-mediated Atypical Hemolytic Uremic Syndromementioning

confidence: 99%

Thrombotic microangiopathy in children

et al. 2022

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“…The terminal blockade of the complement pathway by eculizumab or ravulizumab has considerably improved the prognosis of patients with primary HUS. It also decreased the proportion of patients who die or suffer from end-stage renal disease within 1 year of diagnosis from 56% to less than 15% [4,71,72]. As a consequence, the quick recognition of patients with potential complement dysregulation has become of crucial importance among patients with TMA.…”

Section: What Is the Impact Of Complement Dysregulation In Hus Patients Care?mentioning

confidence: 99%

Complement Blockade Is a Promising Therapeutic Approach in a Subset of Critically Ill Adult Patients with Complement-Mediated Hemolytic Uremic Syndromes

Prével

Delmas

Guillotin

et al. 2022

JCM

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Thrombotic microangiopathy (TMA) gathers consumptive thrombocytopenia, mechanical haemolytic anemia, and organ damage. Hemolytic uremic syndromes (HUS) are historically classified as primary or secondary to another disease once thrombotic thrombocytopenic purpura (TTP), Shiga-toxin HUS, and cobalamin C-related HUS have been ruled out. Complement genetics studies reinforced the link between complement dysregulation and primary HUS, contributing to reclassifying some pregnancy- and/or post-partum-associated HUS and to revealing complement involvement in severe and/or refractory hypertensive emergencies. By contrast, no firm evidence allows a plausible association to be drawn between complement dysregulation and Shiga-toxin HUS or other secondary HUS. Nevertheless, rare complement gene variants are prevalent in healthy individuals, thus providing an indication that an investigation into complement dysregulation should be carefully balanced and that the results should be cautiously interpreted with the help of a trained geneticist. Several authors have suggested reclassifying HUS in two entities, regardless of they are complement-mediated or not, since the use of eculizumab, an anti-C5 antibody, dramatically lowers the proportion of patients who die or suffer from end-stage renal disease within the year following diagnosis. Safety and the ideal timing of eculizumab discontinuation is currently under investigation, and the long-term consequences of HUS should be closely monitored over time once patients exit emergency departments.

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“…Ariceta et al contrarily observed 90.9% and 59% of children on eculizumab experience adverse side effects (cough, fever, abdominal pain, respiratory tract infections, and diarrhea) and serious complications (elevated severity of the aforementioned), respectively [ 60 ]. Eculizumab is ineffective in patients with polymorphic forms of C5, as it is unable to bind to C5 variants; hence, it is unable to block the cleavage of C5 in patients.…”

Section: Current Therapeuticsmentioning

confidence: 99%

“…Ravulizumab has also been analyzed in pediatric aHUS patients who have not been treated with complement inhibition therapy. Ariceta et al described the first prospective phase III trial which demonstrated that Ravulizumab is safe and successful in treating complement inhibitor-naïve pediatric patients [ 60 ]. Patients less than 20 kg were given infusions every 4 weeks and patients more than 20 kg were given infusions every 8 weeks.…”

Section: Current Therapeuticsmentioning

confidence: 99%

“…Tanaka et al observed recurring oropharyngeal pain (30%) and upper respiratory tract infections (40%) in pediatric participants in their study [ 63 ]. Ariceta et al reported that 47.6% of participants in their study had drug induced complications, including pyrexia, nasopharyngitis, vomiting, diarrhea, and headaches [ 60 ]. However, both studies concluded that the benefits outweighed these risks.…”

Section: Current Therapeuticsmentioning

confidence: 99%

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Pediatric Atypical Hemolytic Uremic Syndrome Advances

Raina

Vijayvargiya

Khooblall

et al. 2021

Cells

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Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework. Additional markers that are less understood, but continue to be acknowledged, include the unique autoantibodies to complement factor H and complement factor I which are pathogenic drivers in aHUS. Interventional therapeutics have undergone the most advancements, as pharmacokinetic and pharmacodynamic properties are modified as needed in addition to their as biosimilar counterparts. As data continues to be gathered in this field, future advancements will optimally decrease the mortality and morbidity of this disease in children.

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The long-acting C5 inhibitor, ravulizumab, is effective and safe in pediatric patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment

Cited by 64 publications

References 25 publications

Thrombotic microangiopathy in children

Thrombotic microangiopathy in children

Complement Blockade Is a Promising Therapeutic Approach in a Subset of Critically Ill Adult Patients with Complement-Mediated Hemolytic Uremic Syndromes

Pediatric Atypical Hemolytic Uremic Syndrome Advances

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