Eculizumab in secondary atypical haemolytic uraemic syndrome

Abstract

Background. Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods. We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Results. Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition.

Safety and effectiveness of eculizumab for adult patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

“…This interim analysis included 27 patients with TMA complicated by underlying diseases, which is classified as secondary TMA in Japanese clinical guides 2015 [2] and as secondary aHUS in other reports [8,14]. Median age (range) at first eculizumab administration was 50 (18-89) years, and median (range) total duration of eculizumab treatment was 2 (0-52) weeks.…”

When to Stop Eculizumab in Complement-Mediated Thrombotic Microangiopathies

“…No comment on recurrent TMA was made. This study did, however, report a significantly reduced median cost of inpatient care and DOI: 10.1159/000492033 TA-TMA following solid-organ transplant has been reported in a wide spectrum of donor organ types including renal, small bowel, lung, liver, heart, and pancreas [12,14,40]. In existing case series, better outcomes have been observed in TA-TMA associated with solid organs.…”

“…In this series, a median of 5 doses of eculizumab were given, and at a median follow-up of 21 weeks, all survivors were without recurrent TMA. In a more recent series including 15 cases of TA-TMA (13 of which were solid-organ transplants), responses to eculizumab were seen in 12/15 (80%) cases, with treatment duration lasting anywhere from 2 to 30 weeks [12]. The follow-up duration varied for each patient, though no recurrences of TMA were reported after a maximum of 17.5 months follow-up [12].…”

“…In a more recent series including 15 cases of TA-TMA (13 of which were solid-organ transplants), responses to eculizumab were seen in 12/15 (80%) cases, with treatment duration lasting anywhere from 2 to 30 weeks [12]. The follow-up duration varied for each patient, though no recurrences of TMA were reported after a maximum of 17.5 months follow-up [12]. Similarly, in a recent smaller case series, responses were observed in 100% of those with solid-organ transplants [40].…”

“…While dysregulated complement activity is not the primary driver of typical HUS, infectious pathogens do activate complement to varying degrees [3,5,9], and several case series have shown favorable outcomes with early use of eculizumab, particularly in patients with severe neurologic symptoms [10,11]. Eculizumab has also been increasingly explored for the treatment of sHUS, including in cases associated with drugs, solid organ, and stem cell transplant [12][13][14][15]. An important question that has been raised in all cases of complement-mediated TMAs is if and when eculizumab can safely be stopped.…”