Massimo Cugno1, Valentina Capone2, Samantha Griffini3, Elena Grovetti3, Giulia Pintarelli4, Luigi Porcaro4, Emilio Clementi5, Gianluigi Ardissino2. 1. Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università Degli Studi di Milano, Via Pace, 9, 20122, Milano, Italy. massimo.cugno@unimi.it. 2. Center for HUS Prevention, Control and Management at Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy. 3. Medicina Interna, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università Degli Studi di Milano, Via Pace, 9, 20122, Milano, Italy. 4. Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy. 5. Department of Biomedical and Clinical Sciences "L. Sacco", Unit of Clinical Pharmacology, Luigi Sacco University Hospital, ASST Fatebenefratelli-Sacco, Università Degli Studi di Milano, Milano, Italy.
Abstract
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is characterized by platelet consumption, hemolysis, and renal injury. Eculizumab, a humanized antibody that blocks complement activity, has been successfully used in aHUS, but the best treatment schedule has not yet been clearly defined. METHODS: Herein we report our experience with eculizumab maintenance treatment, in which the interval between subsequent doses was adjusted based on classical complement pathway (CCP) activity, targeted to < 30% for the prevention of relapses. Trough circulating levels of free eculizumab were determined by an immunoenzymatic method. Genetic and serologic characteristics of the patients were also assessed. RESULTS: We report on 38 patients with aHUS with a median age of 25.0 years (range 0.5-60.0 years) treated with eculizumab. Once stable disease remission was obtained, the interval between eculizumab doses was extended based on target CCP activity. With this approach, presently, 22 patients regularly receive eculizumab infusion every 28 days and 16 receive it every 21. During a median observation period of 32.3 months (range 4.0-92.4 months) and a cumulative period of 1295 months, no patient relapsed. An inverse correlation between CCP activity and eculizumab circulating levels was present (r = - 0.690, p = 0.0001), with CCP activity being inhibited as long as free eculizumab was measurable in serum. CONCLUSIONS: In patients with aHUS on eculizumab maintenance treatment, complement activity measurement can be used as a proxy for circulating levels of the drug. Monitoring complement activity allows for safe tailoring of the frequency of eculizumab administration, thus avoiding excessive drug exposure while keeping the disease in remission.
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is characterized by platelet consumption, hemolysis, and renal injury. Eculizumab, a humanized antibody that blocks complement activity, has been successfully used in aHUS, but the best treatment schedule has not yet been clearly defined. METHODS: Herein we report our experience with eculizumab maintenance treatment, in which the interval between subsequent doses was adjusted based on classical complement pathway (CCP) activity, targeted to < 30% for the prevention of relapses. Trough circulating levels of free eculizumab were determined by an immunoenzymatic method. Genetic and serologic characteristics of the patients were also assessed. RESULTS: We report on 38 patients with aHUS with a median age of 25.0 years (range 0.5-60.0 years) treated with eculizumab. Once stable disease remission was obtained, the interval between eculizumab doses was extended based on target CCP activity. With this approach, presently, 22 patients regularly receive eculizumab infusion every 28 days and 16 receive it every 21. During a median observation period of 32.3 months (range 4.0-92.4 months) and a cumulative period of 1295 months, no patient relapsed. An inverse correlation between CCP activity and eculizumab circulating levels was present (r = - 0.690, p = 0.0001), with CCP activity being inhibited as long as free eculizumab was measurable in serum. CONCLUSIONS: In patients with aHUS on eculizumab maintenance treatment, complement activity measurement can be used as a proxy for circulating levels of the drug. Monitoring complement activity allows for safe tailoring of the frequency of eculizumab administration, thus avoiding excessive drug exposure while keeping the disease in remission.
Authors: M Cugno; R Gualtierotti; I Possenti; S Testa; F Tel; S Griffini; E Grovetti; S Tedeschi; S Salardi; D Cresseri; P Messa; G Ardissino Journal: J Thromb Haemost Date: 2014-07-16 Impact factor: 5.824
Authors: C M Legendre; C Licht; P Muus; L A Greenbaum; S Babu; C Bedrosian; C Bingham; D J Cohen; Y Delmas; K Douglas; F Eitner; T Feldkamp; D Fouque; R R Furman; O Gaber; M Herthelius; M Hourmant; D Karpman; Y Lebranchu; C Mariat; J Menne; B Moulin; J Nürnberger; M Ogawa; G Remuzzi; T Richard; R Sberro-Soussan; B Severino; N S Sheerin; A Trivelli; L B Zimmerhackl; T Goodship; C Loirat Journal: N Engl J Med Date: 2013-06-06 Impact factor: 91.245
Authors: Larry A Greenbaum; Marc Fila; Gianluigi Ardissino; Samhar I Al-Akash; Jonathan Evans; Paul Henning; Kenneth V Lieberman; Silvio Maringhini; Lars Pape; Lesley Rees; Nicole C A J van de Kar; Johan Vande Walle; Masayo Ogawa; Camille L Bedrosian; Christoph Licht Journal: Kidney Int Date: 2016-01-28 Impact factor: 10.612
Authors: Timothy H J Goodship; H Terence Cook; Fadi Fakhouri; Fernando C Fervenza; Véronique Frémeaux-Bacchi; David Kavanagh; Carla M Nester; Marina Noris; Matthew C Pickering; Santiago Rodríguez de Córdoba; Lubka T Roumenina; Sanjeev Sethi; Richard J H Smith Journal: Kidney Int Date: 2016-12-16 Impact factor: 10.612