Citations

Abstract Objectives ANCA-associated vasculitis (AAV) is currently categorized under the small vessel vasculitides. There is limited knowledge about large vessel involvement in AAV (L-AAV), mainly described in case reports and small series. L-AAV can involve temporal arteries (TA-AAV), aorta (A-AAV), and periaortic soft tissue (PA-AAV). We sought to characterize the features of patients with L-AAV. Methods Patients older than 18 years at diagnosis of TA-AAV, A-AAV and PA-AAV seen at the Mayo Clinic, Rochester between 1 January 2000 and 31 December 2021 were identified through a proprietary medical text search algorithm. Patients were included if diagnosed with L-AAV, fulfilled 2022 ACR/EULAR classification criteria for GPA, MPA or EGPA, had positive ANCA test results, and had more than one outpatient or inpatient visit. Results The study cohort consists of 36 patients with L-AAV. Of those, 23 had p-ANCA and/or MPO-ANCA, and 13 had c-ANCA and/or PR3-ANCA. Mean (s.d.) age at AAV diagnosis was 63.4 (12.79) years; 20 (56%) were male. Seventeen patients had TA-AAV, 10 had A-AAV and 9 had PA-AAV. Most patients (n = 25, 69%) were diagnosed with large vessel vasculitis and AAV within a 1-year timespan. Twenty-five (69%) patients had histopathological confirmation of AAV diagnosis in a location other than temporal artery, aorta or periaortic soft tissue. Glucocorticoids (36/36), rituximab (19/36) and methotrexate (18/36) were the most frequent treatments. Conclusion This is the largest single-centre cohort of patients with L-AAV to date. AAV can involve large arteries, albeit infrequent. AAV-targeted therapy should be considered in patients with L-AAV.

ObjectiveThis study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).MethodsAnalysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) in the Vasculitis Clinical Research Consortium (2013–2021). Disease cohorts were divided by age at diagnosis (years): children (<18), young adults (18–40), middle‐aged adults (41–65), and older adults (>65). Data included demographics, ANCA type, clinical characteristics, Vasculitis Damage Index (VDI) scores, ANCA Vasculitis Index of Damage (AVID) scores, and novel disease‐specific and non‐disease‐specific damage scores built from VDI and AVID items.ResultsAnalysis included data from 1020 patients with GPA/MPA and 357 with EGPA. Female predominance in GPA/MPA decreased with age at diagnosis. AAV in childhood was more often GPA and proteinase 3‐ANCA positive. Children with GPA/MPA experienced more subglottic stenosis and alveolar hemorrhage; children and young adults with EGPA experienced more alveolar hemorrhage, need for intubation, and gastrointestinal involvement. Older adults (GPA/MPA) had more neurologic manifestations. After adjusting for disease duration, medications, tobacco, and ANCA, all damage scores increased with age at diagnosis for GPA/MPA (P < 0.001) except the disease‐specific damage score, which did not differ (P = 0.44). For EGPA, VDI scores increased with age at diagnosis (P < 0.009), whereas all other scores were not significantly different.ConclusionAge at diagnosis is associated with clinical characteristics in AAV. Although VDI and AVID scores increase with age at diagnosis, this is driven by non‐disease‐specific damage items.image

Abstract Background and Aims A significant number of patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, eGFR&lt;15mL/min/1.73m2) despite advances in remission-induction treatment. Method A retrospective cohort study on MPO- or PR3-ANCA positive patients with AAV (MPA or GPA) and ESKD at presentation. Renal recovery, dialysis discontinuation and maintenance in ESKD after standard remission-induction, with or without the use of PLEX were compared. Results We analyzed 166 patients with biopsy proven active kidney involvement and eGFR &lt;15mL/min/1.73m2 at the time of AAV-GN diagnosis. Patients received glucocorticoids with CYC (n = 84) or with RTX (n = 72) for remission-induction, and 49 also received PLEX. The predictors for renal recovery were erythrocyte sedimentation rate, SCr at diagnosis and minimal or mild chronicity changes. We analyzed 71 patients who started dialysis with or without PLEX within 4 weeks from AAV-GN diagnosis. The predictors for dialysis discontinuation were minimal chronicity changes in kidney biopsy at the time of diagnosis (OR 6.138, [95%CI 1.389-27.118],p = 0.017) and focal glomerular involvement (OR 5.017,[95%CI 1.287-19.567],p = 0.020). Predictors for maintenance in ESKD at 12 months included higher serum creatinine (SCr) at the time of diagnosis (IRR 1.086, [95%CI 1.005-1.173],p = 0.037), moderate (IRR 3.797,[95%CI 1.090-13.225],p = 0.036), or severe chronicity changes in kidney biopsy (IRR 5.883,[95%CI 1.542–22.439],p = 0.009). Conclusion In our cohort, kidney recovery, dialysis discontinuation, and maintenance of ESKD in patients with AAV-GN and eGFR&lt;15mL/min/1.73m2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX.

Abstract Background and Aims Previous studies have shown that chronic changes on kidney biopsy are useful for stratifying the risk of kidney failure in patients with AAV-GN. We aimed to evaluate the impact of inflammatory activity for the prediction of renal outcomes. Method A retrospective cohort study of MPO- or PR3-ANCA positive patients with AAV and active renal disease. Inflammatory activity was assessed by the Activity Index (AI): a ratio between the number of crescents and/or necrosis and the total number of glomeruli (in percent). We calculated the AI score: 0-5 = 0; 6-10 = 1; 11-15 = 2; 16-20 = 3; 21-25 = 4; 26-37.5 = 5; 37.6-50 = 6; 51-65 = 7; 66-80 = 8; 80-90 = 9; 90-100 = 10. Chronicity was evaluated with the Mayo Clinic Chronicity Score (MCCS). For the combined score, we summed the MCCS and the AI. Results Results. We analyzed 326 patients with kidney biopsies available to score. The biopsies had in median (IQR), 13 glomeruli (9-20), 4 crescents (2-6) and an AI of 28.6% (15.3-47.6). The population was classified according with the risk of progression to kidney failure (KF) in 3 classes as (i) low (0-6) – 114 (35.0%), (ii) intermediate (7-11) – 152 (46.6%), and (iii) high (≥12) – 60 (18.4%). Median eGFR at baseline correlated with the overall risk categories: 42.2 vs. 22.1 vs. 13.4 mL/min/1.73 m2, p&lt;0.0001. The proportion of patients with eGFR&lt; 30 mL/min/1.73 m2 was increased in patients classified as high: 88.3% vs. 66.4% vs. 36.0%, p&lt;0.0001. Renal recovery was more frequent in patients at low risk of progression: 87.7% vs. 64.6% vs. 36.6%, p&lt;0.0001, whereas kidney failure at 12 months and dialysis were more frequent in patients at higher risk (36.7% vs. 12.4% vs. 3.8%, p&lt;0.0001; 35.6% vs. 13.0% vs. 2.9%, p&lt;0.0001, respectively). The combination of AI with MCCS independently predicted the risk of KF at 12 months (HR 1.916, 95%CI 1.210 - 3.033, p = 0.006), particularly increased in patients classified as high risk (HR 3.124, 95%CI 1.224 – 7.970, p = 0.017) and in patients with PR3-ANCA (HR 1.896, 95%CI 1.012 - 3.551, p = 0.046) independently of eGFR at AAV-GN diagnosis and adjusted for severity of renal involvement and age. Conclusion The combined assessment of acute inflammatory activity and chronic changes on kidney histology independently predicted renal outcomes in patients with AAV-GN. The impact of the inflammatory activity is cumulative to the chronic changes.

AbstractObjectiveVitamin D might participate in the pathogenesis of several immune-mediated diseases, but few related data are available for ANCA-associated vasculitis (AAV). In this study, we analysed the association between vitamin D status and disease in patients with AAV.MethodsSerum levels of 25(OH)D2/3 were measured in 125 randomly selected patients with AAV [granulomatosis with polyangiitis (n = 50), eosinophilic granulomatosis with polyangiitis (n = 50) or microscopic polyangiitis (n = 25)] enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies at the time of enrolment and a subsequent relapse visit. Sufficient, insufficient and deficient vitamin D status were defined as 25(OH)D3 levels &gt;30, 20–30 and ˂20 ng/ml, respectively.ResultsSeventy of 125 patients (56%) were female, with a mean age of 51.5 (16) years at diagnosis; 84 (67%) were ANCA positive. Mean 25(OH)D was 37.6 (16) ng/ml, with vitamin D deficiency in 13 (10.4%) and insufficiency in 26 (20.8%). In univariate analysis, lower vitamin D status was associated with male sex (P = 0.027) and disease activity (P = 0.047). In univariate and multivariate analyses, deficient vitamin D status was associated with disease activity (P = 0.015). Mean 25(OH)D status in the 21 patients with a subsequent relapse did not differ between baseline and relapse visit [37.8 (16) vs 38.0 (10) ng/ml, respectively; P = 0.92].ConclusionMost patients with AAV have sufficient 25(OH)D levels, although those with lower vitamin D status were more likely to be male and to have active disease. Whether optimization of vitamin D status alters disease manifestations or activity in AAV remains to be determined.Trial RegistrationVasculitis Clinical Research Consortium (VCRC) Longitudinal Study (LS), NCT00315380, https://clinicaltrials.gov/ct2/show/NCT00315380

Significance Statement Syphilis is a common worldwide sexually transmitted infection. Proteinuria may occur in patients with syphilis. Membranous nephropathy (MN) is the most common cause of proteinuria in syphilis. The target antigen of MN in syphilis is unknown. This study shows that MN in syphilis is associated with a novel target antigen called neuron-derived neurotrophic factor (NDNF). NDNF-associated MN has distinctive clinical and pathologic manifestations and NDNF appears to be the target antigen in syphilis-associated MN. Background Syphilis is a common sexually transmitted infection. Membranous nephropathy (MN) is a common cause of proteinuria in syphilis. The target antigen is not known in most cases of syphilis-associated MN. Methods We performed laser microdissection of glomeruli and mass spectrometry (MS/MS) in 250 cases (discovery cohort) of phospholipase A2 receptor–negative MN to identify novel target antigens. This was followed by immunohistochemistry/confocal microscopy to localize the target antigen along the glomerular basement membrane (GBM). Western blot analyses using IgG eluted from frozen biopsy tissue were performed to detect binding to target antigen. Results MS/MS studies of the discovery cohort revealed high total spectral counts of a novel protein, neuron-derived neurotrophic factor (NDNF), in three patients: one each with syphilis and hepatitis B, HIV (syphilis status not known), and lung tumor. Next, MS/MS studies of five cases of syphilis-MN (validation cohort) confirmed high total spectral counts of NDNF (average 45±20.4) in all (100%) cases. MS/MS of 14 cases of hepatitis B were negative for NDNF. All eight cases of NDNF-associated MN were negative for known MN antigens. Electron microscopy showed stage I MN in all cases, with superficial and hump-like deposits without GBM reaction. IgG1 was the dominant IgG subtype on MS/MS and immunofluorescence microscopy. Immunohistochemistry/confocal microscopy showed granular staining and colocalization of NDNF and IgG along GBM. Western blot analyses using eluate IgG of NDNF-MN showed binding to both nonreduced and reduced NDNF, while IgG eluate from phospholipase A2 receptor-MN showed no binding. Conclusion NDNF is a novel antigenic target in syphilis-associated MN.

Background The optimal strategy for remission-maintenance therapy in patients with myeloperoxidase-ANCA (MPO-ANCA)–associated vasculitis is not established. Defining parameters to guide maintenance therapy is required. Methods This was a retrospective cohort study of all patients with MPO-ANCA–associated vasculitis (microscopic with polyangiitis and granulomatosis with polyangiitis) and GN followed at the Mayo Clinic between 1996 and 2015. Relapse rate, MPO-ANCA status, and remission-maintenance therapies were reviewed. Logistic regression models, Kaplan–Meier method, and Cox proportional hazards regression models were applied. Results We analyzed 159 patients with active MPO-ANCA–associated vasculitis with GN. Sixty-six (42%) patients had at least one relapse, and 52 (33%) relapsed before 60 months. Patients with MPO-ANCA who became persistently negative did not relapse (hazard ratio [HR], 0.03; 95% confidence interval [95% CI], 0.002 to 0.431; P =0.01). The reappearance of MPO-ANCA was associated with a higher risk of relapse (HR, 1.91; 95% CI, 1.109 to 3.293; P =0.02). Immunosuppression was withdrawn in 80 (50%) patients, and this was less likely in those who received cyclophosphamide for remission induction or in patients with persistently positive MPO-ANCA (odds ratio [OR], 0.44; 95% CI, 0.228 to 0.861; P =0.02 and OR, 0.42; 95% CI, 0.213 to 0.820; P =0.01, respectively). Relapse frequency was not different between patients with persistently positive MPO-ANCA and patients with MPO-ANCA reappearance (44% versus 39%, P =0.49), irrespective of remission-maintenance treatment. Ear, nose, and throat involvement (OR, 6.10; 95% CI, 1.280 to 29.010; P =0.02) and MPO-ANCA reappearance (OR, 9.25; 95% CI, 3.126 to 27.361; P <0.001) were independently associated with relapse after treatment withdrawal. Conclusions Patients persistently MPO-ANCA negative are at low risk for relapse even without remission-maintenance therapy. Persistence or subsequent reappearance of MPO-ANCA is associated with a higher risk of relapse. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast.aspx?p=CJASN&e=2023_01_10_CJN06460622.mp3