The results from this study thus provide crucial guidelines for future investigations using complement biomarkers to define the role of complement system in disease.

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INTRODUCTION: A prospective, randomized study (NCT00713193) was undertaken to compare the efficacy and safety of cyclosporine (CSA) and prednisone (P) as adjuncts to plasma exchange therapy (PEX) in the treatment of acquired TTP. The primary objective was to determine if CSA or P given as an adjunct to PEX has a lower exacerbation rate. Secondary endpoints included the effect of CSA and P on the ADAMTS13 activity and anti-ADAMTS13 antibody concentration and their relationship to clinical outcomes. METHODS: Patients were randomized 1:1 to CSA (2-3mg/kg/d orally) or P (1mg/kg/d orally) with daily PEX until response was achieved (normal platelets , LDH). After stopping PEX CSA was continued for 6 months; P was continued at full dose for the first 4 weeks, then tapered over 4 weeks. Exacerbation was defined as recurrent thrombocytopenia requiring PEX <30 days after the last PEX, with relapse defined as recurrence >30 days after the last PEX. ADAMTS13 biomarkers were obtained pretreatment, weekly for 4 weeks after the last PEX, monthly for 5 months, and then every 3 months until 42 months of follow-up. RESULTS: Since November 2007, 26 patients were randomized to CSA (n=12) or P (n=14) and followed for a median 42 m. (range, 1 -42). The study was halted after a planned interim analysis. Response rates were comparable in both arms (CSA: 11/12(92%); P:11/14,(79%);p=0.2), with one patient dying on each arm before achieving a response, and 2 P treated patients crossing over to the CSA arm after failing to achieve a response. The exacerbation rate on the CSA arm was 3/11(27%) v. 1/11(9%) on the P arm (p=0.3). Relapses in patients that achieved remission (without exacerbation) occurred in 5/8 CSA treated patients and 4/10 P treated patients at a median of 7 m. (range, 3-39) and 16m. (range, 4-26), respectively. Serial measurements of the ADAMTS13 activity and IgG inhibitor concentrations over the first 30 days after the last PEX and over the 6 m. CSA treatment course are show in Figures 1 and 2. CONCLUSIONS: There was no significant difference in the exacerbation rate between the CSA and P arms. However, improvement in the ADAMTS13 activity and suppression of the anti-ADAMTS13 antibodies were significantly better in the P arm compared to the CSA-treated patients. These ADAMTS13 activity and inhibitor concentration data for the first time provide support for the efficacy of P as an adjunct to PEX, and the superiority of P over CSA as an adjunct to PEX therapy in the initial treatment of acquired TTP. Figure 1 Pretreatment and serial measurements of the median ADAMTS13 activity and ADAMTS13 autoantibodies over the first weeks after stopping PEX therapy Figure 1. Pretreatment and serial measurements of the median ADAMTS13 activity and ADAMTS13 autoantibodies over the first weeks after stopping PEX therapy Figure 2 Serial measurement of the median ADAMTS13 activity over the 6 months CSA dosing period of patients with a continuous remission. Patients were censored at the time of clinical events (crossover, exacerbation, relapse). Figure 2. Serial measurement of the median ADAMTS13 activity over the 6 months CSA dosing period of patients with a continuous remission. Patients were censored at the time of clinical events (crossover, exacerbation, relapse). Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Background: Thrombotic thrombocytopenic purpura (TTP) is characterized by consumptive thrombocytopenia and microangiopathic hemolytic anemia. At least a third of the patients with TTP will have one or more relapses throughout their life. There is very little data regarding the differences, if any, in clinical presentation and outcomes between the initial and subsequent TTP episodes. This information is relevant to understand if patients that present initially and those that present with a relapse can be seen as equal when being considered for clinical trials. Identifying the characteristics of patients that are prone to relapse will help guide the monitoring of patients after an acute episode of TTP to help to prevent relapse. Methods: Between March 2003 and June 2016 we collected clinical and laboratory data on all patients that presented to the Ohio State University with a diagnosis of acquired TTP (aTTP). The diagnostic criteria for aTTP included: thrombocytopenia, and a microangiopathic hemolytic anemia without an alternative explanation. The diagnosis was confirmed by the finding of severely deficient ADAMTS13 activity (<10%). Patients were consented to participate in our TTP registry and the information obtained included initial clinical presentation, platelets, LDH, kidney function, ADAMTS13 activity and inhibitor titer, number of plasma exchange (PEX) to achieve remission (defined as number of PEX needed to obtain a normal platelet count), and the outcome of the episode; clinical response (normal platelet count and LDH), exacerbation (recurrent TTP within 30 days of last PEX procedure), refractory (more than 30 PEX needed to obtain a clinical response), or death. Results: - All the patients enrolled were included in the study, except those with active cancer, leaving a total of 125 episodes from 57 patients. - 36 of the 57 patients had two or more TTP episodes (relapse rate 63.1%), with 21 of the 57 patients having 3 or more episodes. The time between episodes varied greatly, from 2 months to 8 years. - Of the 125 episodes, there were 42 initial and 83 relapses. - The initial group presented with central nervous system (CNS) symptoms more commonly than the relapse group. They also had significantly lower platelets and a higher LDH than the relapse group. - Regarding treatment, there was no significant difference in the number of PEX needed to achieve remission between the 2 groups. However, there was a significant number of patients in the initial group that needed more than 5 PEX to achieve remission, compared to the relapse group (p<0.0001) - There were no significant differences in the main clinical outcomes between the initial and relapse groups in rates of clinical response (p=0.267), exacerbation (p=0.483), refractory (p=0.075) or death (p=0.066) Conclusions: In their first episode of TTP, patients may present more ill than those patients having relapses (with more CNS symptoms, lower platelets and higher LDH), and may also require more PEX sessions to achieve remission. However, these findings do not change outcomes, and patients in their initial presentation and relapses can be seen as equal in terms of clinical response, exacerbation, refractory disease, and mortality rates. The high relapse rate seen in our registry may be due to the prolonged follow up (13 years) which is more than other series reported. Patients may have a relapse even after several years of being stable. Figure Figure. Table Table. Disclosures No relevant conflicts of interest to declare.