C3:CH50 ratio as a proposed composite marker for eculizumab monitoring in atypical hemolytic uremic syndrome: Preliminary results

Abstract

Treatment of atypical hemolytic uremic syndrome (aHUS) by the complement C5 inhibitor eculizumab (Soliris®) is highly effective but unfortunately, associated with an economic pressure on the health care systems even in high incomes countries. Despite spacing infusions having been proposed as the unique solution to minimize this economic impact, no reliable laboratory assays are available to tailor such therapy optimization. We aimed to propose and evaluate a complement composite marker for eculizumab efficacy monitoring in aHUS. We have retrospectively analyzed complement profiles data of eight aHUS patients under eculizumab from the International Registry of HUS/Thrombotic Thrombocytopenia Purpura, and calculated a novel marker "C3:CH ratio" by dividing C3 value by CH one for each sample during induction and maintenance periods. The results significance was compared to the currently used biomarkers for eculizumab tailoring. In contrast to the current biomarkers used for eculizumab efficacy monitoring like CH and soluble or deposit membrane attack complexes, "C3:CH ratio" seems to be the most interesting one since its value at pre-eculizumab dosage equaled 0.92 ± 0.2 while the post-eculizumab one increased significantly to reach 24.54 ± 10.7; P < 0.001. Furthermore, this ratio correlated negatively with platelets count (r = -0.722, P = 0.018) while no correlation was found within the thrombotic microangiopathy (TMA) biomarkers and complement blockade for the other parameters that change in pre and post-eculizumab therapy. As far as we know, this is the first study that suggests a post-eculizumab parameter correlating simultaneously with drug's activity (complement inhibition) and disease activity (platelets counts). Nonetheless, the limited number of patients enrolled in this study should be considered in larger studies to guide eculizumab optimization by indicating the time when subsequent withdrawal or infusion spacing is allowed or recommended.

Monoclonal IgG4/2κ Deposition Following Eculizumab Therapy for Recurrent Atypical Hemolytic Uremic Syndrome in Kidney Transplantation

“…1,4,5 It recognizes the human complement protein C5 and blocks the cleavage of C5 to C5a and C5b, thus preventing induction of the terminal complement cascade, including the formation of the membrane attack complex (C5b-9). [4][5][6] We present a case of de novo monoclonal antibody deposition in the kidney, restricted to the IgG2 and IgG4 subclasses following eculizumab therapy, in association with de novo positive monoclonal antibody on serum immunofixation.…”

“… 1 , 4 , 5 It recognizes the human complement protein C5 and blocks the cleavage of C5 to C5a and C5b, thus preventing induction of the terminal complement cascade, including the formation of the membrane attack complex (C5b-9). 4 , 5 , 6 …”

Relapse of Atypical Hemolytic Uremic Syndrome During Pregnancy in a Patient on Eculizumab Maintenance Treatment: A Case Report

“…Unfortunately, we could not measure complement activity or Eculizumab blood levels in our patient. Nevertheless, although CH50 activity has been directly related to intravascular hemolysis and circulating free Eculizumab levels in patients with PNH [20], there is no definitive prove that its measurement can predict a relapse of aHUS [21,22], and its levels has been reported to be not reliable to tailor Eculizumab optimization [23]. Furthermore, CH50 levels gradually increase during pregnancy from 10% to 50%, complicating its correct interpretation in this context [12,24].…”

<p>Complement Inhibition for the Treatment of Myasthenia Gravis</p>

“…In fact, "C3:CH50 ratio" has been described as better marker of complement inhibition and disease activity in atypical aHUS eculizumab-treated patients than other single serological factors. 75 Despite the clear involvement of complement in MG, 3 serological complement parameters have never been investigated as possible immunological biomarkers and their role as reliable factors predictive of treatment response still needs to be evaluated. In a study by Liu and colleagues, 76 C3 levels were found to be lower in AChR + compared to AChR − gMG patients and healthy controls, according with C3 consumption due to complement activation at the NMJ.…”