Eculizumab and drug-induced haemolytic-uraemic syndrome.

The monoclonal anti-C5 antibody eculizumab has been successfully tested in atypical haemolytic-uraemic syndrome (aHUS), with or without mutations in the regulatory proteins of the alternative pathway of the complement, and less convincingly in enterohaemorrhagic Escherichia coli-associated HUS. Here, we report a patient with mitomycin-C-induced HUS unresponsive to plasma exchanges. Eculizumab infusion was followed by a dramatic improvement of haematological parameters and renal function, suggesting a role of complement blockade in the management of refractory, drug-related HUS.

Introduction

The monoclonal anti-C5 antibody eculizumab is an inhibitor of the terminal complement complex formation, successfully tested in atypical haemolytic-uraemic syndrome (aHUS), with or without mutations in the regulatory proteins of the alternative pathway of the complement, and less convincingly in enterohaemorrhagic Escherichia coli-associated HUS [1-3]. Several drugs, including mitomycin-C and interferon-β, may also trigger HUS, but the therapeutic impact of eculizumab in this setting remains elusive. Here, we show that eculizumab may prove efficient in drug-induced HUS unresponsive to plasma exchanges.

Case report

A female patient developed severe HUS during mitomycin-C treatment for relapsing metastatic breast cancer. Enterohaemorrhagic HUS was ruled out, serum levels of complement components C3 and C4 were normal and screening for mutations in the genes encoding complement regulatory proteins CFH, CFI, MCP, and anti-ADAMTS13 or anti-CFH autoantibodies were negative. Before genetic testing and report, all patients gave a written informed consent as recommended by French law.

Despite termination of drug exposure and daily plasma exchanges, the lack of improvement of haematological parameters and the requirement for dialysis (see Figure 1) prompted us to consider eculizumab therapy. Eculizumab was administered 30 days after diagnosis of HUS. Following the first infusion (900 mg), we observed an early and dramatic improvement of haematological parameters with normalization of platelet counts and lactate dehydrogenase levels within 7 days. Seven additional infusions of eculizumab were performed, allowing partial renal recovery at 3 months. Renal function remained stable (eGFR: 20 mL/min/1.73 m2) and no relapse of HUS occurred during 18 months of follow-up.

Fig. 1.

Response to eculizumab therapy in a patient with drug-induced haemolytic–uraemic syndrome. Shown are the data indicating a rapid biological and clinical improvement of thrombotic microangiopathy after administration of the monoclonal anti-C5 antibody eculizumab. Lactate dehydrogenase level (left y-axis), platelet count and plasma creatinine level (right y-axis) are represented by white triangle, cross and black triangles, respectively.

Discussion

The striking coincidence of eculizumab infusion and improvement of HUS parameters suggest a beneficial role of transient complement blockade in this patient. The pathophysiology of drug exposure-related HUS remains poorly elucidated. In mitomycin-C-related HUS, circulating immune complexes that cause platelet aggregation, complement activation and subsequent endothelial damage have been reported [4], supplying a molecular explanation for the striking effect of eculizumab. Since no change in plasma levels of C3 and C4 was detected, the rapid normalization of haemolysis parameters and platelet counts in both of the patients despite suspension of plasma exchanges might be related to local blockade of complement activation.

Thus, our data plead for a role of complement blockade in the management of refractory, drug-related HUS.

Conflict of interest statement

None declared.