Objective.To determine the incidence of arterial thrombotic events (ATE) and venous thromboembolism (VTE) in antineutrophil cytoplasmic antibody–associated vasculitis (AAV).Methods.This is a retrospective cohort study presenting the incidence of ATE (coronary events or ischemic stroke) and VTE [pulmonary embolism (PE) or deep venous thrombosis (DVT)] in patients diagnosed with AAV between 2005 and 2014.Results.There were 204 patients with AAV who were identified. Median followup for surviving patients was 5.8 (range 1–10) years, accounting for 1088 person-years (PY). The incidence of ATE was 2.67/100 PY (1.56 for coronary events and 1.10 for ischemic stroke) and for VTE was 1.47/100 PY (0.83 for DVT only and 0.64 for PE with/without DVT). On multivariate analysis, prior ischemic heart disease (IHD) and advancing age were the only independent predictors of ATE. Among patients without prior IHD or stroke, the incidence of ATE remained elevated at 2.32/100 PY (1.26 for coronary events and 1.06 for ischemic stroke). ATE, but not VTE, was an independent predictor of all-cause mortality. Event rates for both ATE and VTE were highest in the first year after diagnosis of AAV but remained above the population incidence during the 10-year followup period. In comparison to reported rates for the UK population, the event rates in our AAV patients were 15-times higher for coronary events, 11-times higher for incident stroke, and 20-times higher for VTE.Conclusion.Patients with AAV have a high incidence of arterial and venous thrombosis, particularly in the first year after diagnosis.

We thank Dr. Rothschild for his interest 1 in our article 2 on the incidence of arterial and venous thrombosis in antineutrophil cytoplasmic antibodyassociated vasculitis (AAV). He raises the interesting issue of susceptibility to both arterial and venous thrombotic events, which is also characteristic of antiphospholipid syndrome. The question arises as to the possible role of antiphospholipid antibodies (aPL) in the thrombotic events seen in AAV. We also thought that this possibility should be examined, but unfortunately our data on aPL are limited, because we studied a retrospective cohort in which these tests were not routinely performed. In fact, we tested for anticardiolipin IgG and IgM in only 49 of the 210 patients in the study. We found positive results in 3 patients, none of whom were in the group with thrombosis 2. In the patients who had a thrombosis, we found negative results in 4 out of the 24 who had an arterial thrombosis, and 5 out of 14 who had a venous thrombosis. These findings were not reported in the original paper because of the low proportion of patients tested and because they were tested only at baseline. It is possible that some patients may have developed aPL during the course of their disease, which could have gone undetected. Even in the absence of aPL, the high incidence of arterial and venous thrombosis in patients with AAV should encourage us to consider the relative benefits and risks of antiplatelet agents or anticoagulants, as discussed by Rothschild 1 .

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ABSTRACT:Positive B cell crossmatch accompanied by high levels of pre-transplant human leukocyte antigen donor-specific antibodies are associated with adverse graft outcomes in kidney transplant recipients. Targeting plasma cells, the main antibody producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We report using a combination of bortezomib and plasmapheresis to desensitize a highly sensitized kidney transplant recipient for an ABO-incompatible living donor kidney transplant. The flow cytometric B cell crossmatch was positive on presentation. After treatment, the anti-A titres fell from 1:64 to 1:4, and a negative B flow cytometric crossmatch was achieved prior to transplantation. The combined approach of bortezomib to abrogate antibody production at the plasma cell level, followed by plasmapheresis and low-dose intravenous immunoglobulin to remove in-circulation alloantibodies, has proven to be effective in our case. Bortezomib may play a role in highly sensitized renal transplants.Kidney transplantation is the optimal mode of renal replacement therapy, offering better quality of life and survival advantage compared with chronic dialysis.1,2 There is an increasing disparity between the growing demand for kidney allografts worldwide and available donors. ABO incompatibility and HLA sensitization are the two main barriers to achieving successful transplantation, especially among the highly sensitized population, particularly patients seeking a repeat kidney transplant. 3,4 Various integrated approaches to desensitization are currently available, such as plasmapheresis (PP), intravenous immunoglobulin (IVIg; low and high dose) with or without rituximab, and immunoadsorption (IA)-based regimens [5][6][7] . The optimal desensitization protocol remains unproven, and new agents continue to be explored. The proteasome inhibitor bortezomib presents as one such promising therapy. CASE REPORTA 36 year-old man from regional New South Wales with end-stage kidney disease secondary to reflux nephropathy received a first HLA-identical kidney transplant from his brother in 2007. Despite optimal compliance, suitable matching and good early function, he developed antibodymediated rejection at 1 year post-transplant and subsequent graft failure necessitating return to peritoneal dialysis in 2011. Six months later, he was transitioned to haemodialysis and graft nephrectomy performed.Following this, the prospect of an ABO-incompatible transplant from his wife (A1 to O blood group) was explored. Repeated flow B cytometric crossmatches were found to be positive without the presence of auto-antibodies or HLA donor-specific antibodies. The search for antibodies to non-HLA polymorphic antigens was initiated, and antiangiotensin ii type-1 receptor (AT1R) antibodies and antiendothelin receptor-A antibodies were found at a titre of 23.4 U/mL (<10.0 U/mL) and 30.3 U/mL (<10.0 U/mL), respectively. Desensitization protocol and immunosuppressionThe initial desensitization protocol consisted o...

We were surprised to read the letter by Berti and colleagues 1 , commenting on our recent article on the incidence of arterial and venous thrombosis in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) 2. They make the unjustified comment that "the incidence estimates for [arterial (ATE) and venous thrombosis events (VTE)] may be inflated" when we give clear and accurate incidence rates. Our incidence of ATE was 2.67/100 patient-years (PY), whereas the 2018 article by Berti, et al 3 reports an incidence of cardiovascular disease as 5.0/100 PY. It would therefore not seem that our incidence estimates were inflated. Our comparison of the characteristics of patients who did or did not develop ATE or VTE is entirely valid. Berti, et al 1 make the point that a history of previous ATE predicts the risk of subsequent ATE. We discuss this possibility in our article, and that is why we performed the sensitivity analysis, which indeed shows a lower risk of ATE in those without a history of previous ATE. This was consistent with our regression analysis. After adjusting for other covariates, previous ischemic heart disease remains a significant risk factor for subsequent ATE. We acknowledge that the Kaplan-Meier plots are not the ideal way in which to compare survival between the 2 groups with and without thrombotic events. However, our median followup time was greater than 5 years, and the majority of thrombotic events occurred early during the disease course. The Kaplan-Meier plots provide a graphical representation of outcome (survival) limited to the followup time concerned. Regarding Berti and colleagues' point about comparing thrombotic events in AAV to crude rates in the UK population, we agree that this is not an ideal comparison, but it was not practical for us to identify appropriate matched controls. Few places have access to the population data available in Omsted County (USA). We clearly state that we are comparing our results with those of the general population and acknowledge this is not an ideal approach. We also acknowledge as a limitation the fact that we could not obtain information on all the risk factors for thrombotic events in this retrospective study. In addition, we compare our incidence rates of ATE and VTE with published literature for AAV and other inflammatory diseases. Our results seem similar to several of these previous studies and generally show a higher rate of events in the first year after diagnosis, possibly related to disease activity. Berti, et al 1 seem concerned about our statement that we were the first to report a high incidence of ischemic stroke in AAV. They reference their article published in May 2018 3. As experienced investigators, they should surely realize that our revised manuscript was submitted to The Journal of Rheumatology well before their publication was released. If their publication had been available, we would of course have quoted it, as we did others in the literature. Overall, we are disappointed by the critical tone taken by Berti, et al 1 , as w...

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