research paper
Ciclosporin and plasma exchange in thrombotic thrombocytopenic purpura: long-term follow-up with serial analysis of ADAMTS13 activity
Spero R. Cataland,1 Ming Jin,2 Shili Lin,3 Melanie S. Kennedy,2 Eric H. Kraut,1 James N. George4 and Haifeng M. Wu2 1
Division of Hematology/Oncology, Department of
Internal Medicine, Ohio State University, 2
Department of Pathology, Ohio State University,
3
Department of Statistics, Ohio State University,
Columbus, OH, and 4Hematology-Oncology Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Received 13 July 2007; accepted for publication 30 July 2007 Correspondence: Spero R. Cataland, MD, Department of Internal Medicine, Ohio State University College of Medicine and Public
Summary We hypothesized that ciclosporin (CSA) as adjunct to plasma exchange (PE) improves the efficacy of PE in idiopathic thrombotic thrombocytopenic purpura (TTP) via suppression of the antibody inhibitor of ADAMTS13. Our preliminary findings with CSA and PE as the upfront treatment of TTP suggested that the addition of CSA to PE significantly decreased the exacerbation (disease recurrence within 30 d of the last PE) rates compared to a cohort that received corticosteroids and PE as their upfront therapy of TTP. We present an updated analysis with long-term follow-up of 18 patients with idiopathic TTP treated with concurrent CSA and PE with analysis of serial measurements of ADAMTS13 activity, antigen and inhibitor concentration in the context of clinical outcome data. Overall, 16/18 (89%) patients achieved remission, similar to historical remission rates in idiopathic TTP with PE with only one patient suffering an exacerbation. Clinical responses correlated with improvements in ADAMTS13 activity and suppression of the antibody inhibitor of ADAMTS13. These data suggest that the efficacy of CSA is at least in part related to its suppression of the antibody inhibitor of ADAMTS13 and a subsequent improvement in ADAMTS13 activity and antigen.
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Keywords: ciclosporin, idiopathic thrombotic thrombocytopenic purpura, ADAMTS13, inhibitor, exacerbation.
Idiopathic thrombotic thrombocytopenic purpura (TTP) is increasingly recognized as an autoimmune disease following the discovery and characterization of an acquired antibody inhibitor of ADAMTS13 nearly 10 years ago (Furlan et al, 1998; Tsai & Lian, 1998). This observation has stimulated interest in therapies targeting the acquired inhibitor to improve ADAMTS13 activity and clinical outcomes for patients with idiopathic TTP. We have previously investigated the use of immune-based therapy as an adjunct to plasma exchange (PE), more specifically using ciclosporin (CSA) both alone and as an adjunct to PE in the treatment of idiopathic TTP (Cataland et al, 2006, 2007). We hypothesized that CSA would inhibit the production of the inhibitor when given concurrent with PE. In this model, PE would serve as a ‘supportive therapy’, physically removing the inhibitor and inducing remission, while at the same time allowing CSA, a ‘disease-modifying therapy’, time to exert its effect. In this follow-up report of our initial
manuscript (Cataland et al, 2007), we present a larger analysis of all idiopathic TTP patients treated with CSA and PE at our institution, presenting clinical response data with long-term follow-up and serial analysis of ADAMTS13 activity, antigen and inhibitor concentrations.
Methods Clinical definitions The term ‘upfront’ refers to the initial treatment for an acute episode of TTP, and is not meant to refer to a cohort of patients being treated for the first time ever for TTP. The intent was to avoid confusion as the term ‘initial’ implies the patient’s first ever treatment for TTP. Clinical remission was defined as: (i) a normal platelet count, (ii) normalization of the lactate dehydrogenase (LDH), and (iii) stabilization or improvement in renal or neurological findings. To differentiate
ª 2007 The Authors doi:10.1111/j.1365-2141.2007.06819.x Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 139, 486–493
Concurrent Ciclosporin and Plasma Exchange in TTP CSA and PE exacerbations/refractory TTP (n = 9)
CSA and PE up front therapy analysis (n = 9)
Total enrolled CSA and PE upfront patients
Previous therapy: corticosteroids and PE (n = 8)
(n = 12)
Previous therapy: PE alone (n = 1)
Excluded- previous CSA therapy (n = 1)
Excluded-concurrent diagnosis of SLE (n = 2)
Fig 1. A schema showing patient enrolment to both studies, previous treatment, and reasons for exclusion from the analysis.
recurrent TTP related to a previous episode from a new, acute episode of TTP, patients with recurrent disease within 30 d after discontinuing PE were characterized as ‘exacerbations of TTP’. Patients with recurrent disease greater than 30 d after discontinuing PE therapy were characterized as ‘relapses of TTP’ (George et al, 2004; Willis & Bandarenko, 2005).
Ciclosporin and plasma exchange as upfront therapy of TTP Between February 2005 and March 2007, 12 consecutive eligible patients were consented and enroled on an Institu-
tional Review Board-approved study of concurrent CSA and PE therapy as upfront therapy for TTP (Fig 1). Three enroled patients were excluded from this analysis, one patient because of her enrolment on the exacerbation/refractory study described below (Patient 12), and two additional patients because of an additional diagnosis of active systemic lupus erythematosus, giving a total of nine patients with idiopathic TTP available for analysis (Table IA). Eligibility criteria included a clinical diagnosis of TTP, defined as a microangiopathic haemolytic anaemia and thrombocytopenia (
