Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis

Wehling, Cyrill; Kirschfink, Michael

doi:10.1111/jth.12639

Cited by 13 publications

(10 citation statements)

References 18 publications

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“…It appears that especially patients with an altered therapy regimen and children have a tendency to accumulate eculizumab towards trough levels partially exceeding 1000 lg/ml [30,45]. Levels above 500 mg/ml were confirmed recently in a case of long-term application of eculizumab in aHUS [46], and pharmacokinetic modelling correlated drug accumulation to low body weight [47].…”

Section: Complement and Eculizumab Monitoringmentioning

confidence: 86%

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

Wehling

Amon

Bommer

et al. 2016

Clinical and Experimental Immunology

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SummaryVarious complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n 5 12), C3 glomerulopathies (C3G, n 5 9) and acute antibody-mediated renal graft rejection (AMR, n 5 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b-9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme-linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082 lg/ml point to drug accumulation, especially in paediatric patients. Loss of the therapeutic antibody via urine with concentrations up to 56 lg/ml correlated with proteinuria. In aHUS patients, effective complement inhibition was demonstrated by significant reductions of CH50, APH50, C3d and sC5b-9 levels, whereas C5a levels were only reduced significantly after 6 months' treatment. C3G patients presented increased C3d and consistently low C3 levels, reflecting ongoing complement activation and consumption at the C3 level, despite eculizumab treatment. A comprehensive complement analysis together with drug monitoring is required to distinguish mode of complement activation and efficacy of eculizumab treatment in distinct renal disorders. Accumulation of the anti-C5 antibody points to the need for a patient-orientated tailored therapy.

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Section: Complement and Eculizumab Monitoringmentioning

confidence: 86%

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

Wehling

Amon

Bommer

et al. 2016

Clinical and Experimental Immunology

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“…Because the formation of the MAC is essential for host defence against Neisseria species, vaccination of patients against Neisseria meningitides is required prior to beginning treatment. Contemporary treatment of aHUS has been reviewed in detail [18,61,[64][65][66][67][68][69].…”

Section: Therapeutic Agentsmentioning

confidence: 99%

Complement regulators in human disease: lessons from modern genetics

Liszewski

Atkinson

2015

J Intern Med

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“…1 Both the title and the text of the commentary seem to recommend comprehensive complement analysis for monitoring eculizumab treatment [2]. In our opinion, the strength of our approach measuring global complement activity is derived from its simplicity combined with its high sensitivity: the test is inexpensive, fast, feasible in any laboratory, and reliable for clearly identifying patients not covered by the biological activity of anti-C5 antibody [1].…”

mentioning

confidence: 99%

“…Thus, in aHUS patients, sensitive markers of complement activation might need a long period of remission to normalize and do not seem to be of help in monitoring short-term effects of the therapy. 2 We do not recommend a period of eculizumab interval extension before trying to discontinue the treatment in all aHUS patients as suggested in the commentary [2]. In patients with abnormalities involving complement factor H, a kidney transplant, or a previous relapse, interval extension can be used based on the high risk of relapse [5,6].…”

mentioning

confidence: 99%

“…We are very thankful to Dr Wehling and Dr Kirschfink for their commentary regarding our article on monitoring the eculizumab regimen in patients with atypical hemolytic uremic syndrome (aHUS) [1], in which they provide an expert overview of our management strategy [2]. However, from a practical point of view, we have two additional points to raise and to share with the scientific community:…”

mentioning

confidence: 99%

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Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis: comment

Cugno

Tedeschi

Ardissino

2015

Journal of Thrombosis and Haemostasis

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To cite this article: Cugno M, Tedeschi S, Ardissino G. Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis: comment. J Thromb Haemost 2015; 13: 485-6.See also Wehling C, Kirschfink M. Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis. J Thromb Haemost 2014; 12: 1437-9.We are very thankful to Dr Wehling and Dr Kirschfink for their commentary regarding our article on monitoring the eculizumab regimen in patients with atypical hemolytic uremic syndrome (aHUS) [1], in which they provide an expert overview of our management strategy [2]. However, from a practical point of view, we have two additional points to raise and to share with the scientific community:1 Both the title and the text of the commentary seem to recommend comprehensive complement analysis for monitoring eculizumab treatment [2]. In our opinion, the strength of our approach measuring global complement activity is derived from its simplicity combined with its high sensitivity: the test is inexpensive, fast, feasible in any laboratory, and reliable for clearly identifying patients not covered by the biological activity of anti-C5 antibody [1]. Comprehensive complement analysis is of great importance in the setting of an initial patient's workup as well as in a research setting to provide a better understanding of the mechanisms underlying complement-mediated diseases. Our experience with a cumulative observation period of now > 400 months in 18 patients without a single relapse strongly supports our simplified approach. In our caselist, studying 11 aHUS patients during active disease and 90 samples collected during a remission period lasting from 1 to 10 weeks, we found elevated plasma levels of terminal C5b-9 complement complex (TCC) both during the active phase (mean [95% CI] 1128 ng mL À1 [588- Active HUS Remission HUS (n = 11) (n = 90) Fig. 1. Plasma levels of the terminal C5b-9 complement complex (TCC) in 11 patients with atypical hemolytic uremic syndrome (aHUS) during active disease, in 90 samples collected during remission periods, and in 20 healthy controls. TCC levels were measured in ethylenediaminetetraacetic acid (EDTA) plasma using an enzymelinked immunosorbent assay (Microvue Complement SC5b-9 Plus EIA kit, Quidel, San Diego, CA, USA). TCC values are expressed as ng mL À1 . Horizontal lines represent means. TCC plasma levels were significantly increased both during the acute phase (mean AE SD, 1128 AE 913 ng mL À1 ; P = 0.005) and remission (912 AE 712 ng mL À1 ; P = 0.0001) compared with healthy subjects (135 AE 32 ng mL À1). Student's t-test for unpaired values was used to assess statistical significance of differences.

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Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis

Cited by 13 publications

References 18 publications

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

Monitoring of complement activation biomarkers and eculizumab in complement-mediated renal disorders

Complement regulators in human disease: lessons from modern genetics

Tailored eculizumab regimen for patients with atypical hemolytic uremic syndrome: requirement for comprehensive complement analysis: comment

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