Citations

ObjectiveTo assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis (RAVE) trial and identify novel potential risk factors.MethodsVTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA‐associated vasculitis (AAV).ResultsVTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0–2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247–134.842]; P = 0.006), positive proteinase 3 (PR3)–ANCA (HR 7.731 [95% CI 1.021–58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448–10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491–69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566–185.805]; P = 0.005), PR3‐ANCA (HR 9.12 [95% CI 1.158–71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453–10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607–75.075]; P < 0.001) remained.ConclusionPatients diagnosed as having AAV with pulmonary hemorrhage, positive PR3‐ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

ObjectivePatients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population.MethodsLipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA‐Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t‐tests and multivariable linear regression were used to assess changes in lipid levels.ResultsOf the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)–ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low‐density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3‐ANCA–positive patients but not among those with relapsing disease or myeloperoxidase‐ANCA–positive patients. There was no difference in change in lipid levels between rituximab‐treated patients and cyclophosphamide‐treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure.ConclusionLipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3‐ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV.

Abstract Objectives To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease. Methods Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways. Results Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P &lt; 0.01), younger at time of diagnosis (36 vs 49 years, P &lt; 0.01), and have saddle-nose deformities (28% vs 10%, P &lt; 0.01), but were less likely to have renal involvement (39% vs 62%, P &lt; 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P &lt; 0.01), with more ENT involvement (97% vs 77%, P &lt; 0.01) and less renal involvement (42% vs 62%, P &lt; 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia. Conclusion SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA.

Significance Statement In approximately 70%–80% of cases of primary membranous nephropathy (MN), phospholipase A2 receptor (PLA2R)/Thrombospondin Type-1 Domain–Containing 7A (THSD7A) and anti-PLA2R/THSD7A antibodies form immune complexes along the glomerular basement membrane (GBM) that characterize the condition. In other cases of primary MN and all secondary MN, the target antigen is unknown. Using proteomics and immunohistochemistry, the authors detected two proteins, exostosin 1 (EXT1) and exostosin 2 (EXT2), in the GBM of PLA2R-negative MN. EXT1 and EXT2 were absent in all cases of PLA2R-associated MN and controls. Clinical and biopsy findings showed features of autoimmune disease, including membranous lupus nephritis, in 81% of the 26 EXT1/EXT2-associated MN cases the authors identified. These findings suggest that EXT1/EXT2-associated MN represents a distinct subtype of MN, most commonly associated with autoimmune diseases (secondary MN). Background In membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain–containing 7A are target antigens in approximately 70% and 1%–5% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown. Methods We studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry. Results Mass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2R-negative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 patients); only one of the 14 cases of mixed class 5 and 3/4 lupus nephritis was positive for EXT1/EXT2. Tests in seven patients with EXT1/EXT2-associated MN found no circulating anti-exostosin antibodies. Conclusions A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.