Early use of eculizumab for catastrophic antiphospholipid syndrome

Abstract

The role of complement activation in catastrophic antiphospholipid syndrome (CAPS) has recently emerged owing to the detection of genetic variations in the proteins of the alternative complement pathway in a subset of patients,1 the protective effect of C5 deficiency in mouse models of CAPS,2 and the anecdotal reports of thrombotic microangiopathy reversal in patients with refractory CAPS and receiving the C5 inhibitor eculizumab as salvage therapy.3 Because CAPS is a very rare condition, optimal therapeutic management remains elusive and the role of eculizumab beyond the conventional triple regimen including unfractionated heparin, glucocorticoids (GCs) and plasma exchanges (PEx) is still debated.4 Yelnik et al.5 reported a series of 11 patients with severe CAPS who received eculizumab as salvage therapy after a median (range) delay of 25 (3–100) days. Five patients responded to treatment (45%), but six had no response. As outlined by the authors, haematological failure was especially responsive to eculizumab, but the delayed introduction may have hampered clinical response. Thus, there is a need to better describe the outcomes of patients with CAPS receiving eculizumab and define the subset of patients who may benefit from this expensive treatment and the optimal timing of administration. The aim of the present study was to better characterise the survival and organ response when eculizumab is administered early during CAPS. In the present retrospective study, all consecutive patients with CAPS followed in the Referral Centre of Rare Kidney Diseases of the University Hospital of Toulouse (France) and who received eculizumab (inclusion period 2017–2021) were included. Diagnosis of APS and CAPS fulfilled the international classification criteria.6 Clinical and biological characteristics were retrieved from the institutional computerised database. Due to the retrospective nature of the study, the Institutional Review Board of the University Hospital of Toulouse waived the need for written informed consent. A total of five patients [median (range) age of 47 (19–56) years; one male] were included in the study. One patient developed two episodes of CAPS; six episodes of CAPS were thus analysed. APS was known before the development of CAPS in four patients and was newly diagnosed in one. Three patients had a triple positive status (lupus anticoagulant, anticardiolipin antibody, and anti-β2-glycoprotein-1 antibody). A triggering factor was identified in all patients. Characteristics at presentation are summarised in Table I. All patients were admitted to the intensive care unit. All patients developed acute kidney injury, including four with a presentation suggestive of kidney thrombotic microangiopathy. Two received mechanical ventilation, one received high-flow oxygenation, two required a kidney replacement and two received vasoactive support. All patients presented severe CAPS with more than three organs or systems involved simultaneously. Triple positivity ANA+, no anti-ENA C3, C4, CH50 normal No relapse (FU 3 years) eGFR 80 ml/min/1·73m2 No proteinuria CEI, VKA No relapse (FU 2 years) eGFR 70 ml/min/1·73m2 No proteinuria LVEF 45% CEI, VKA, Hydroxychloroquine No relapse (FU 3 years) eGFR 90 ml/min/1·73m2 No proteinuria, SLEDAI 0 CEI, VKA, Hydroxychloroquine Triple positivity ANA+ C3, C4, CH50 normal Triple positivity ANA+ C3, C4, CH50 normal No relapse (FU 1 year) ESKD at 1 year SRL, Prednisone, Hydroxychloroquine, VKA, CEI Double positivity (aCL/lupus anticoagulant) C3, C4, CH50 normal Tamponade, Haemophagocytic lymphohistiocytosis Death at day 35 A triple therapy including GCs, PEx, and heparin was first introduced during all episodes except one relapse of CAPS, which was treated with GfcCs, heparin, and eculizumab as front-line therapy. Rituximab was added in five of the six episodes (375 mg/m2 once a week for 4 weeks). Eculizumab was given intravenously at 900 mg once a week for 4 weeks followed by 1200 mg bi-monthly (median eight injections, range two to 30). Eculizumab was given for CAPS flare-ups despite triple therapy regimen (n = 2) or as salvage therapy given the severity of the presentation (n = 4). The median (range) delay between the diagnosis of CAPS and the first dose of eculizumab was 7 (2–15) days. After eculizumab administration, PEx were withdrawn. Prophylaxis included ceftriaxone (1 g/day) and the recommended vaccination against Streptococcus Pneumoniae and Neisseria Meningitidis. Four patients (five episodes) responded to treatment with rapid correction of haematological disorders [median (range) 9 (2–14) days], as well as cardiac and kidney improvements (Table I). One heart transplant recipient developed refractory CAPS with multiorgan failure and secondary haemophagocytic lympho-histiocytosis and ultimately died on day 35. At the end of follow-up [median (range) 3 (0–5) years], four were alive (80%). Three patients had normal estimated glomerular filtration rates and haematological blood tests and did not relapse. One patient had a CAPS relapse at month 22 and eculizumab was resumed for 3 months, leading to remission but with severe chronic kidney disease resulting in end-stage kidney disease 1 year later. Catastrophic antiphospholipid syndrome is a life-threatening disease with a mortality rate of ˜30%.7 Due to the rarity of the disease, randomised controlled studies are not available and treatment options mainly relies on knowledge of CAPS pathophysiology and observational descriptive studies. In this context, it is of upmost importance to better describe the patients’ response to eculizumab and to report treatment failures. In the present study, we showed that an aggressive therapeutic strategy including early use of eculizumab was associated with good overall and organ survival. Only one out of the five patients died from refractory CAPS and superimposed haemophagocytic lymphohistiocytosis, whereas all the others responded well to eculizumab, including one who received eculizumab without PEx during a CAPS relapse. Consistent with the data from Yelnik et al.,5 we observed a rapid improvement of the haematological failures after eculizumab administration, suggesting that its early use may prevent end-stage organ failure, reduce the risk of severe bleeding and subsequently improve the survival rate. Optimal duration of treatment should also be determined. In most of our present patients, we pursued eculizumab for ˜3 months to reduce the risk of early relapse in the setting of systemic inflammation, but shorter duration may also be appropriate in patients with complete response and optimal anticoagulation. To date, no predictive factors of eculizumab failure have been identified; this will require further analyses in larger cohorts. Interestingly, only one patient (a heart transplant recipient with multiorgan failure and profound immunosuppression) developed sepsis during follow-up. The retrospective nature of the present study, the lack of complement functional assays, and the small size of the cohort did not allow firm conclusions to be drawn but new important data can be underlined. The early use of eculizumab in the most severe forms of CAPS is feasible and not associated with an overtly increased risk of infection. The haematological response is frequent and expected in the days after the first injection. Early organ improvement translated into good functional outcomes (heart and kidney functions). No patient relapsed while receiving eculizumab. In summary, aggressive treatment of CAPS with a multitarget regimen including early administration of eculizumab is feasible, safe, and may improve the overall outcome and organ outcomes. Prospective studies with a standardised protocol of early eculizumab use are mandatory to fully address its benefits in patients with CAPS. David Ribes received fees from Alexion® for scientific board. Stanislas Faguer and David Ribes designed the study, collected and analysed the data, and wrote the manuscript. Due to the retrospective nature of the study, the Institutional Review Board of the University Hospital of Toulouse (Direction de la Recherche Clinique) waived the need for written informed consent. This study fulfilled the principles of Declaration of Helsinki, as revised in 2004. The datasets used during the present study are available from the corresponding author on reasonable request.

Topics & Concepts