Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCAnegative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.

Objective The development of pathogenic anti-neutrophil cytoplasmic autoantibodies (ANCAs) can result in systemic small vessel vasculitis. However, the breakdown in immune tolerance that results in the induction and persistence of ANCAs is not well-understood. We hypothesized that abnormal T cell regulation is central to disease pathogenesis and demonstrate here two separate abnormalities in T cell regulation in ANCA-associated vasculitis patients. Methods Peripheral blood samples were obtained from patients with ANCA-associated vasculitis (n=63) and healthy controls (n=19) for flow cytometric analysis of CD4+ T cell populations. Functional T cell studies were performed with FACS sorted CD4+ T cell populations stimulated with anti-CD3/28. Results First, we show that the Treg frequency in the peripheral blood of active disease patients is increased, but Tregs from patients with ANCA-associated vasculitis have decreased suppressive function. Tregs from active disease patients disproportionately utilize a FOXP3 isoform lacking exon 2, which may alter Treg function. Second, we identify a CD4+ T cell population with increased frequency that is resistant to Treg suppression, produces pro-inflammatory cytokines, and is antigen-experienced. Conclusion ANCA-associated vasculitis is associated with disruption of the suppressive Treg network and increased frequency of a distinct pro-inflammatory effector T cell subset which comprises the majority of peripheral CD4+ T cells.

Objective How advances in the management of ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis (AAV) have impacted long-term outcomes is still unclear. We examined temporal changes over 25 years in long-term clinical outcomes, including the impact of renal function at diagnosis (a potential marker of time to disease detection) and duration of cyclophosphamide use in AAV patients with renal involvement. Methods ANCA-positive, biopsy-proven patients with AAV diagnosed in 1985–2009 followed in the Glomerular Disease Collaborative Network inception cohort were included. Outcomes included the composite outcome of end-stage renal disease (ESRD) or death as well as relapse. Cox proportional hazard or competing risk regression models were adjusted for potential baseline confounders. Results Data from 544 patients were included in the analysis. There was a decreasing 5-year risk of ESRD or death over time (log rank test for trend: p < 0.001). After adjustment for baseline characteristics, the risk of relapse was similar across the time periods (test for trend: p = 0.45). Serum creatinine at baseline was the only significant predictor of an increased risk of ESRD or death (HR 1.11 per 1 mg/dL of serum creatinine [95% CI 1.04–1.18], p = 0.002). Conclusion In patients with renal disease secondary to AAV, over 25 years the risk of ESRD or death has decreased but the risk of relapse has not changed. A higher serum creatinine at diagnosis is associated with a higher risk of ESRD or death, suggesting that earlier disease detection is potentially an important measure to improve outcomes in AAV.

SummaryBackground and objectives The optimal course of glucocorticoid therapy in anti-neutrophil cytoplasmic autoantibody (ANCA) disease is unknown. This cohort study evaluates effects of glucocorticoid therapy duration on patient outcomes and adverse events.Design, setting, participants, & measurements This study assessed 147 patients diagnosed between January 1, 2000 and January 1, 2009 who were treated with glucocorticoids and cyclophosphamide. Patients with end stage kidney disease at presentation, treatment resistance, or who had died within 6 months were excluded. Patients were divided into three groups: 0, 5, or .5 mg prednisone daily at 6 months after therapy initiation. The latter two groups were combined for assessment of adverse events. Wilcoxon rank sum, Kruskal-Wallis, or Fisher's exact tests were used for between-group comparisons. Time to relapse was evaluated by the Kaplan-Meier method with log-rank test for comparison.Results There were no differences between groups in ANCA specificity, serum creatinine, frequency of risk factors for relapse, or length of therapy with immunosuppressants. Length of glucocorticoid therapy had no impact on time to relapse (hazard ratio, 0.69 [95% confidence interval (CI), 0.2322.02]; 1.01, [95% CI, 0.5721.81] for the 5-mg and .5-mg groups, respectively), relapse-free survival, end stage kidney disease, or death. Patients receiving glucocorticoids beyond 6 months had significantly higher incidence of infections (0.64 infections per person-year versus 0.39, P,0.0001) and a marginally significant higher frequency of new-onset diabetes mellitus (odds ratio, 2.03; 95% CI, 0.9424.38).Conclusions Glucocorticoid therapy beyond 6 months is associated with a significantly greater risk of infections but not a significantly decreased risk of relapse.

More infections increase the risk of a severe infection which increases risk of all-cause mortality. Respiratory and S. aureus infections are dominant. Targeted prophylactic therapy could decrease morbidity.

Results: Twenty-one articles were included for review; all were either case reports or case series without controls. More than half of the published cases (50 of 85) came from one center where rituximab was used as primary immunosuppression for idiopathic MN. The available data suggest that rituximab, dosed either as 375 mg/m 2 once weekly for 4 wk or as 1 g on days 1 and 15, achieves a 15 to 20% rate of complete remission and a 35 to 40% rate of partial remission. The drug was well tolerated with minimal adverse events.Conclusions: Although rituximab may prove to be a better treatment option for MN than alkylating agents or calcineurin inhibitors, the current literature only supports using the drug in research protocols. Whether, when, how, and why to use rituximab in MN remains to be determined.

Background Intravenous pulse methylprednisolone (MP) is commonly included in the management of severe ANCA associated vasculitis (AAV) despite limited evidence of benefit. We aimed to evaluate outcomes in patients who had, or had not received MP, along with standard therapy for remission induction in severe AAV. Methods We retrospectively studied 114 consecutive patients from five centres in Europe and the United States with a new diagnosis of severe AAV (creatinine > 500 μmol/L or dialysis dependency) and that received standard therapy (plasma exchange, cyclophosphamide and high-dose oral corticosteroids) for remission induction with or without pulse MP between 2000 and 2013. We evaluated survival, renal recovery, relapses, and adverse events over the first 12 months. Results Fifty-two patients received pulse MP in addition to standard therapy compared to 62 patients that did not. There was no difference in survival, renal recovery or relapses. Treatment with MP associated with higher risk of infection during the first 3 months (hazard ratio (HR) 2.7, 95%CI [1.4–5.3], p = 0.004) and higher incidence of diabetes (HR 6.33 [1.94–20.63], p = 0.002), after adjustment for confounding factors. Conclusions The results of this study suggest that addition of pulse intravenous MP to standard therapy for remission induction in severe AAV may not confer clinical benefit and may be associated with more episodes of infection and higher incidence of diabetes. Electronic supplementary material The online version of this article (10.1186/s12882-019-1226-0) contains supplementary material, which is available to authorized users.

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