THU0400 Response to Eculizumab in the Antiphospholipid Antibody Syndrome

Abstract

BackgroundAntiphospholipid syndrome (APS) is defined as the occurrence of venous or arterial thrombosis or pregnancy morbidity, in the presence of serological evidence of antiphospholipid antibodies (including IgM and IgG anticardiolipin antibodies, IgM and IgG anti-beta-2 glycoprotein I antibodies, or lupus anticoagulant). Whereas most patients with focal thrombotic events respond to anticoagulation, patients with multifocal occlusive disease are occasionally refractory to standard therapeutic interventions. Eculizumab, a monoclonal antibody that binds to complement protein C5 and prevents the conversion of C5 to C5a and C5b, may be an effective treatment for patients with APS. This is based on the data in pre-clinical APS models as well as anecdotal experience in humans. We administered eculizumab to four patients with severe refractory APS (two with primary APS and two with lupus and APS).MethodsFour patients with APS, unresponsive to conventional anticoagulant therapy, were treated with a loading dose of eculizumab followed by dosing every other week. Patients received appropriate vaccinations prior to treatment. The platelet count served as a surrogate marker of APS activity. During therapy, the patients were monitored for platelet counts, thrombotic events, and infections. Follow-up ranged from four months to one and one-half years, and remains ongoing.ResultsAt their lowest values, the patients had platelet counts of 35, 22, 18, and 85 (K/mL). One of the patients was steroid-dependent to maintain her platelet count at an adequate level. After initiation of eculizumab, the patient was able to taper steroids as the platelet count rose from a low of 35 to average counts of 100. The second patient's platelet count rose to over 200 from 22 within 10 days of receiving eculizumab. After one dose of eculizumab, the third patient's platelet count rose from 18 to 50 within four days, and has now stabilized at around 100. The fourth patient's platelet count rose to over 200. The increases in platelet counts were sustained other than during brief periods when therapy was delayed. During the treatment period, there were no new thrombotic events or infections in all four patients. One patient with long-standing renal disease expired after refusing dialysis.ConclusionsEculizumab has shown favorable results in our patients with refractory APS. Longer follow-up of these patients is needed in order to discern the effect on thrombosis. The role of complement inhibitors as a therapeutic intervention in this syndrome needs to be further elucidated.ReferencesShapira I et al. Induction of sustained remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum 2012; 64(8):2719-2723.Comarmond C and Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 2013; 12(7):752-757.Barilla-LaBarca M, Toder K, Furie R. Targeting the complement system in systemic lupus erythematosus and other diseases. Clin Immunol 2013; 14...

Characteristics of Patients With Antiphospholipid Antibody Positivity in the APS ACTION International Clinical Database and Repository

“…While anticoagulation is the mainstay in treatment of aPL-related clinical events in thrombotic APS (33), alternative treatments are needed in patients with refractory disease or microvascular APS (24,(34)(35)(36)(37)(38)(39). Although the majority of APS patients overall received anticoagulation therapy, less than half received aspirin or immunosuppression treatment, and few received other treatments, such as intravenous immunoglobulin, plasma exchange, or rituximab.…”

“…Other Immunosuppression 10 297 (37) 57 ( 35) 240 ( 37) 18 ( 24) 174 ( 39) 48 (39) No medications 11 (1) 9 (6) 2 2 0 0…”

Atypical hemolytic uremic syndrome: a syndrome in need of clarity

“…These observations have been known for decades. In addition, recent basic research and clinical reports of patients with APS and catastrophic APS (CAPS) lend further support to the role of complement activation and direct endothelial damage (as opposed to cell membrane injury caused by the MAC) in the pathogenesis of TMA when present in these disorders [90][91][92][93][94][95][96][97]. These case reports illustrate the potential efficacy of eculizimab when plasmapheresis and other immunosuppressive therapies are not effective.…”

Neutrophil Extracellular Traps, Antiphospholipid Antibodies and Treatment

“…The possibility to modulate NETosis demands more research on new therapeutic opportunities. Among molecules that have potential effect on neutrophil and NETs formation are: DNase 1 (enzymatic degradation of NETs) [52,53], eculizumab (anti-C5a monoclonal antibody, reduce neutrophil activation) [94], rituximab and belimumab (B cell depletion, downregulation of NETs formation through control of antibodies production) and Resatrovid (TAK-242, a small-molecule-specific inhibitor of Toll-like receptor 4 signaling, inhibitor of NETs release by human neutrophils) [19,95].…”