Colocalization of ANCA-antigens and fibrinoid necrosis in ANCA-associated vasculitis

Colocalization of ANCA-antigens and fibrinoid necrosis in ANCA-associated vasculitis. A variety of antineutrophil cytoplasmic auto-antibodies (ANCAs) are known to be associated with small vessel vasculitides such as Wegener's granulomatosis and microscopic polyangiitis. To visualize colocalization patterns of the fibrinoid necrotic lesions and ANCA-antigens more accurately, we have developed a double staining technique in which an immunohistochemical staining is followed by a histological staining. Instead of using sequential biopsy slides of histologically and immunohistochemically stained sections, which may lead to an underestimation of the number and size of the lesions, our technique permits the visualization of the colocalized patterns of fibrinoid necrosis with an ANCA-antigen in a single slide. The double staining procedure is presented in this Technical Note

The effect of nasal Staphylococcus aureus colonization and antibiotic treatment on disease activity in ANCA-associated vasculitis: a retrospective cohort study in the Netherlands

The aim of this study was to identify the role of nasal Staphylococcus aureus (S. aureus) colonization and the effect of systemic or local antibiotic treatment on disease activity in patients with antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis and ear nose and throat (ENT) involvement. Clinical, laboratory and histological data from all patients with ANCA-associated vasculitis and ENT involvement, who were diagnosed in two medical centres in The Netherlands between 1981 and 2020, were retrospectively collected. Nasal S. aureus colonization was defined as at least one positive nasal swab during follow-up. Data on systemic (cotrimoxazole and azithromycin) and local (mupirocin) antibiotic use were collected. Disease activity was divided into systemic and local disease activity. Univariate analyses and regression analyses (negative binomial Poisson and binary regression) were used. Two-hundred and thirteen patients were available for analysis. Median follow-up time was 8 (IQR 3–17) years. S. aureus colonization was tested in 100 (46.9%) cases of whom 44 patients (44%) tested positive. In these 100 patients, systemic and local disease activity at baseline and at last visit were comparable between patients with and without S. aureus colonization. Twenty-eight of the 44 S. aureus positive patients received antibiotics aimed at eradication of S. aureus. No statistically significant difference was found between the treated versus non-treated group with regard to systemic and local disease activity. Nasal S. aureus colonization does not influence systemic or local disease activity. Antibiotic treatment aimed at eradication did not modify disease activity

Systemic and Local Medical or Surgical Therapies for Ear, Nose and/or Throat Manifestations in ANCA-Associated Vasculitis: A Systematic Literature Review

BACKGROUND: Ear, nose and throat (ENT) manifestations are common in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), yet how to treat these manifestations remains controversial. Therefore, we systematically reviewed the literature on the efficacy of therapies on ENT manifestations in AAV. METHODS: A systematic review was conducted in accordance with the PRISMA guidelines, searching Medline, Embase and Cochrane libraries, including clinical studies between January 2005 and January 2022, in adults with AAV and ENT involvement, reporting on the effects of local and systemic therapy. The critical appraisal was performed using tools provided by the Cochrane Library and the level of evidence (LoE) was scored according to the Oxford Centre for Evidence-based Medicine. RESULTS: After screening 5609 identified studies, 136 full-text articles were assessed. Finally, 31 articles were included for critical appraisal and data-extraction. Nearly all studies (n = 29) were retrospective and scored low on LoE. The included studies evaluated local interventions (n = 11), glucocorticoids combined with conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) (n = 8), rituximab (n = 6), or mepolizumab (n = 6). Due to heterogeneity across studies meta-analysis was not performed. Four studies on mepolizumab for sinonasal symptoms (n = 92) showed response in 33-100% and relapse in 35%. Local therapy for subglottic stenosis was effective in 80-100% of patients in 11 studies (n = 157), but relapses were common (up to 83%). In five studies, hearing improvement was observed in 56-100%, with better outcomes when glucocorticoids were combined with csDMARDs compared to glucocorticoids only. CONCLUSION: Response rates of ENT manifestations varied widely in studies and relapses were observed frequently. Heterogeneity among studies impaired comparison

ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse.

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different

ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse.

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different

Immunosuppressive Therapies in Ear, Nose, and Throat Involvement in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results From a Multicenter Retrospective Cohort Study

OBJECTIVE: The aim of this study was to evaluate the response of ear, nose, and throat (ENT) symptoms to different immunosuppressive therapies in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: In this cohort study, patients with AAV treated between January 2010 and April 2020 at 2 Dutch hospitals were included. Clinical, histological, and laboratory data were collected retrospectively. ENT involvement was defined as follows: (1) ≥ 1 ENT symptom according to the Birmingham Vasculitis Activity Score (version 3; BVAS3), and/or (2) presence of saddle nose deformity. Associations between therapy and ENT activity were assessed using logistic regression analysis. RESULTS: A total of 320 patients with AAV were included, of whom 209 (65.3%) had ENT involvement at some point throughout the disease course. In these 209 patients, median age at disease onset was 52.0 years (IQR 40.0-62.0) and 45.5% were male. Median BVAS3 was 12.0 (IQR 6.0-18.0) at diagnosis. Despite immunosuppressive therapy, 50% (n = 77) of the patients had ENT symptoms at relapse and 29.1% (n = 59) had ENT activity at their last visit. No statistically significant difference in ENT activity at last visit was observed between patients treated with oral or intravenous cyclophosphamide (CYC, n = 137) compared to rituximab (RTX, n = 55; adjusted odds ratio 0.59, 95% CI 0.33-1.06; P = 0.08). Lower age at disease onset and female sex were independently associated with ENT activity at last follow-up. CONCLUSION: In this cohort, CYC and RTX therapy had similar therapeutic effects on ENT symptoms in AAV. Persistent ENT activity is a common feature despite immunosuppressive therapy

Renal relapse in antineutrophil cytoplasmic autoantibody-associated vasculitis : unpredictable, but predictive of renal outcome

Objectives: To determine predictors of renal relapse and end-stage renal failure (ESRF) in patients with ANCA-associated vasculitis. Methods: Data from four European Vasculitis Society randomized controlled trials, conducted roughly simultaneously between 15 March 1995 and 30 September 2002, was pooled to determine predictors of long-term renal outcome. The respective trial inclusion criteria covered the entire spectrum of disease severity. Baseline predictors of time to first renal relapse and time to ESRF were assessed by competing events analysis and Cox proportional hazards regression. The effect of renal relapse on time to ESRF was assessed by adding renal relapses to the competing events analysis as a time-varying covariate. Results: The number of patients participating was 535; mean serum creatinine (±s.d.) at entry was 341 ± 321 µmol/l and 19.7% developed ESRF. One or more renal relapse(s) was experienced by 101 patients. Multivariable regression analysis demonstrated that, in addition to impaired baseline renal function, developing ⩾1 renal relapse was an independent risk factor for ESRF (subhazard ratio 9; 95% CI 4, 19; P < 0.001). No predictive factors for renal relapse were found. Conclusion: In addition to baseline renal function, the occurrence of renal relapses is an important determinant of ESRF in patients with ANCA-associated vasculitis. We did not find any clinical predictors for renal relapse itself, including disease activity elsewhere. In light of the silent nature of renal relapse in ANCA-associated vasculitis, we stress the need for long-term vigilant monitoring for early signs of renal relapse and propose performing 3-monthly urinalysis. This will enable timely treatment and help further improve renal outcome

Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis

Background Granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA) are subgroups of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) defined historically by clinical and histological features. GPA and MPA are heterogeneous entities with overlapping phenotypes. To identify novel subgroupings, cluster analysis was used to explore the phenotypic spectrum of AAV. Methods This study used a dataset of patients newly diagnosed as having GPA and MPA enrolled in five clinical trials. One cluster model included nine clinical baseline variables as input variables, and a second cluster model additionally included ANCA specificities. The clustering process involved multiple correspondence analyses followed by hierarchical ascendant cluster analysis. The clinical relevance of the generated clusters was analysed by their summary characteristics and outcomes. Results The analyses involved data for 673 subjects: 396 (59%) with GPA and 277 (41%) with MPA. Both cluster models resulted in five partially redundant clusters of subjects, and the model including ANCA resulted in more pertinent separations. These clusters were named 'renal AAV with proteinase 3 (PR3)-ANCA' (40% of subjects), 'renal AAV without PR3-ANCA' (32%) and 'non-renal AAV' (12%), 'cardiovascular AAV' (9%) and 'gastrointestinal AAV' (7%). The five clusters had distinct death and relapse rates. On the basis of 4 variables, 651 subjects (97%) could be accurately allocated to 1 of the 5 classes. Conclusions This analysis suggests that AAV encompasses five classes associated with different outcomes. As compared with the traditional GPA-MPA separation, this classification system may better reflect the phenotypic spectrum of AAV