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    • Treatment of acquired TTP involves plasma exchange PEX to pr

    2018-11-13

    Treatment of acquired TTP involves plasma exchange (PEX) to provide a new source of ADAMTS13. Steroids are used to target the autoimmune component of the disease. Therapy with rituximab reduces rates of recurrence (Scully et al., 2011; Westwood et al., 2013). Recombinant ADAMTS13 is currently undergoing trials for the treatment of inherited TTP. However, its effectiveness in the more prevalent acquired form of the disease (~95% cases), with inhibitory anti-ADAMTS 13 IgG antibodies, is unknown.
    Methods
    Results
    Discussion To date, this is the largest cohort in which the domain specificity of anti-ADAMTS13 IgG at presentation has been analysed (Zheng et al., 2010; Pos et al., 2011), and the first to report longitudinally through therapy, remission and relapse. The accompanying clinical and outcome data enabled the clinical significance of different antibody patterns to be explored. Unlike previous studies, our competition ELISA enables estimation of the proportion of anti-ADAMTS13 purchase A-1210477 recognising the N-terminal domains (Fig. 2B), rather than merely assessing whether a domain fragment-specific antibody is present/absent. Our results at presentation broadly support findings from other studies, with 97% of patient samples having antibodies against the MDTCS domains (Klaus et al., 2004; Zheng et al., 2010; Pos et al., 2011). 41% of presentation samples had antibodies that only recognise these N-terminal domains. The remaining 59% of patient samples had antibodies against C-terminal domains (28% TSP2–8 and 31% CUB1/2). In contrast to previous studies, we found no evidence of antibodies recognising either MD or MDTC (Klaus et al., 2004; Zheng et al., 2010). Domain specificity of anti-ADAMTS13 antibodies at presentation had no prognostic implication for disease severity in terms of mortality, likelihood of a neurological/cardiac presentation, or number of PEX to remission, suggesting that domain specificity of anti-ADAMTS13 IgG is unlikely a major determinant of their pathogenicity. A previous study found the presence of IgG antibodies against TSP2–8 and/or CUB was inversely correlated with patient platelet counts on admission (Zheng et al., 2010). However in our cohort, there was no difference in median platelet count between patients with antibodies directed against the C-terminal domains and those with solely anti-N-terminal antibodies, once the potential confounding factor of first versus relapsed presentation was removed. In keeping with two previous studies, we found no association between autoantibody/inhibitor titre and domain specificity (Klaus et al., 2004; Zheng et al., 2010). Analysis of longitudinal samples revealed that patients that relapsed may have an altered domain specificity profile from those at first presentation (Fig. 6B–C). Whilst this may, in part, be explained by the failure of rituximab to eradicate all the clones of autoimmune B cells responsible for the anti-ADAMTS13 immune response, the epitope spreading seen in one patient (Fig. 6C) suggests a further development of the autoimmune response in some patients, rather than simple re-emergence of the clones responsible for the initial anti-ADAMTS13 immune response. It may be that the autoimmune response to ADAMTS13 can be reconstituted from escaped CD20 positive B cells or long lived memory cells (CD20 positive or negative) hiding in secondary lymphoid organs: indeed the spleen has been shown to harbour ADAMTS-13 specific memory B cells following acute acquired TTP (Schaller et al., 2014). Our results are the first to formally demonstrate the critical role of anti-spacer antibodies in mediating ADAMTS13 inhibition (Figs. 3, 4A–B). We detected no antibodies other than those directed against the spacer domain that were capable of inhibiting MDTCS function. This suggests that, even if antibodies that recognise MDTC are present, their inhibitory contribution relative to those targeting the spacer domain is not significant. The spacer domain has long been suspected as the primary antigenic target for inhibitory antibodies, corroborated by mutagenesis studies (Jian et al., 2012), and also a recent analysis of monoclonal antibodies derived from two acquired TTP patients (Schaller et al., 2014). However, no other study has demonstrated in this many patients that inhibitory antibodies are limited to those that recognise the spacer domain. Despite their high frequency, anti-spacer domain antibodies are not a prerequisite for the development of TTP, as 3/92 patients at presentation had no evidence of anti-MDTCS antibodies and yet presented with severe ADAMTS13 deficiency.