The impact of coronavirus-19 vaccination on anti-nuclear cytoplasmic antibody vasculitis hospitalisations in a Sydney health network.

There have been reports of COVID-19 vaccination triggering anti-nuclear cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but no robust studies have examined the link. This retrospective cohort study assessed the impact of COVID vaccination on the rate of denovo and relapsed AAV in a Sydney Local Health District from 2018 to 2022. Despite more than 95% of the population receiving vaccination, the case rate of AAV was stable. These findings do not support a relationship between COVID vaccination and AAV.

Avacopan as an additional therapeutic intervention to promote renal recovery in severe ANCA-associated vasculitis: A case report.

Avacopan, a C5a receptor antagonist (C5aR) presents a new therapeutic option to improve outcomes in ANCA-associated vasculitis (AAV). Here we present a case report of a patient initially requiring kidney replacement therapy (KRT), where avacopan was added as an additional adjunctive therapeutic agent late in the treatment course.

Diagnostic and prognostic role of serum interleukin-6 and carotid ultrasonography to detect subclinical atherosclerosis in patients with RA and ANCA-associated vasculitis.

ANCA-associated vasculitis (AAV) can affect multiple organs with severe life-threatening manifestations. Disease monitoring is difficult due to a lack of defined biomarkers. We aimed to assess the diagnostic role of serum interleukin-6 and vascular ultrasonography in AAV and subclinical atherosclerosis. The study included 20 AAV patients and two control groups of 34 patients with rheumatoid arthritis (RA) and 35 healthy controls. The levels of Il-6, carotid intima-media thickness test (CIMT), atherosclerotic plaque, and degree of stenosis were investigated. A GRACE-risk score was calculated for AAV and RA patients. The AAV patients had elevated levels of IL-6 (115 ± 23.96) compared to the RA patients (91.25 ± 42.63) and the healthy controls (15.65 ± 3.30), p < 0.001. IL-6 showed a diagnostic accuracy of 73% in distinguishing AAV from RA patients (AUC = 0.730; 95% CI 0.591 to 0834). In the AAV group, CIMT was 1.09, above the upper reference value of 0.90, p < 0.001. The AAV patients had a higher median GRACE risk score, and 60% of them had a high risk of cardiovascular events as compared to 35% of the RA patients. Sonography of extracranial vessels and serum levels of IL-6 can be used in daily clinical practice to diagnose and monitor patients with AAV.

Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γ production.

Regulatory B (Breg) cells can dampen inflammation, autoreactivity, and transplant rejection. We investigated the frequencies, phenotypes, and function of Breg cells in granulomatosis with polyangiitis (GPA) to gain further knowledge as to whether there are numerical alterations or limitations of their ability to regulate T-cell function. Frequencies and phenotypes of CD24hiCD27+ and CD24hiCD38hi B-cells in the blood were determined with flow cytometry in 37 GPA patients (22 in remission and 15 with active disease) and 31 healthy controls (HC). A co-culture model was used to study the capacity of Breg cells to regulate T-cell activation and proliferation in cells from 10 GPA patients in remission and 12 HC. T-cell cytokine production in vitro and levels in plasma were determined with enzyme-linked immunosorbent assay. Frequencies of CD24hiCD27+ B-cells were reduced both during active disease and remission compared with HC (P = 0.005 and P = 0.010, respectively), whereas CD24hiCD38hi B-cells did not differ. Patient CD24hiCD27+ B-cells exhibited decreased expression of CD25 but increased expression of PD-L1 and PD-L2 during remission. B-cells from GPA patients regulated T-cell proliferation but failed to regulate interferon (IFN)-γ production (median T-cells alone 222 ng/ml vs. T-cells + B-cells 207 ng/ml, P = 0.426). IFN-γ was also elevated in patient plasma samples (P = 0.016). In conclusion, GPA patients exhibit altered numbers and phenotypes of CD24hiCD27+ B-cells. This is accompanied by a disability to control T-cell production of Th1-type cytokines during remission, which might be of fundamental importance for the granulomatous inflammation that characterizes the chronic phase of this disease.

Translational implications of humoral and cellular immune dysfunction in granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a rare systemic ANCA (Anti-neutrophil cytoplasmic antibodies) associated vasculitis (AAV). In the last couple of decades, GPA has emerged as a disease of concern due to rapid increase in the prevalence and incidence especially in developing countries. Unknown aetiology and rapid progression have made GPA a critical disease. Thus, establishing specific tools to facilitate early and faster disease diagnosis and efficient disease management has immense importance. GPA may develop in genetically predisposed individuals on receiving the external stimulus (i.e. microbial pathogen, pollutant etc.) that triggers the immune response. B-cell activating factor (BAFF) produced by the neutrophils, promotes the B-cell maturation and survival which leads to increased ANCA production. Abnormal B-cell and T-cell proliferation and their cytokine response plays a major role in disease pathogenesis and granuloma formation. ANCA interacts with neutrophils and induces the neutrophil extracellular traps (NETs) formation and reactive oxygen species (ROS) production which leads to the endothelial cell injury. This review article summarizes the critical pathological events and how cytokines and immune cells shape the GPA pathogenesis. Decoding this complex network would facilitate in developing tools for diagnosis, prognosis and disease management. Recently developed specific monoclonal antibodies (MAbs) targeting cytokines and immune cells are being used for safer treatment and achieving longer remission.

Skewed peripheral B- and T-cell compartments in patients with ANCA-associated vasculitis.

OBJECTIVES: To characterize lymphocytes dysregulation in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Using flow cytometry, we analysed B- and T-cell subsets in peripheral blood from 37 untreated patients with active disease (29 GPA and 8 MPA) and 22 healthy controls (HCs). RESULTS: GPA patients had increased Th2 (1.8 vs 1.0%, P = 0.02), Th9 (1.1 vs 0.2%, P = 0.0007) and Th17 (1.4 vs 0.9%, P = 0.03) cells compared with HC. Patients with MPO-ANCAs had significantly more CD21- B cells than HC or PR3-ANCA patients (6.9 vs 3.3% and 4.4%, P = 0.01). CD69 expressing B cells were significantly higher in GPA and MPA (3.0 and 5.9 vs 1.4%, P = 0.02 and P = 0.03, respectively) compared with HC, whereas B-cell activating factor-receptor expression was decreased in GPA and MPA (median fluorescence intensity ratio 11.8 and 13.7 vs 45.1 in HC, P < 0.0001 and P = 0.003, respectively). Finally, IL-6-producing B cells were increased in GPA vs HC (25.8 vs 14.9%, P < 0.0001) and decreased in MPA vs HC (4.6 vs 14.9%, P = 0.005), whereas TNF-α-producing B cells were lower in both GPA and MPA patients compared with controls (15 and 8.4 vs 30%, P = 0.01 and P = 0.006, respectively). CONCLUSION: Skewed T-cell polarization towards Th2, Th9 and Th17 responses characterizes GPA, whereas B-cell populations are dysregulated in both GPA and MPA with an activated phenotype and a decreased B-cell activating factor-receptor expression. Finally, inflammatory B cells producing IL-6 are dramatically increased in GPA, providing an additional mechanism by which rituximab could be effective.

Pulmonary manifestations and outcomes in paediatric ANCA-associated vasculitis: a single-centre experience.

OBJECTIVES: ANCA-associated vasculitis (AAV) usually involves the renal and respiratory systems, but the paediatric literature on pulmonary manifestations and outcomes is limited. We aimed to describe pulmonary manifestations and outcomes after therapy in a cohort of paediatric AAV (pAAV) patients. METHODS: A retrospective chart review of all patients <19 years presenting to our institution with AAV between 1/2008 and 2/2018 was conducted. Patient demographics, clinical presentation, diagnostic testing, therapy and pulmonary outcomes over the first 3 years after presentation were evaluated. RESULTS: A total of 38 patients were included; all had ANCA positivity by immunofluorescence. A total of 23 had microscopic polyangiitis (MPA), 13 had granulomatosis with polyangiitis and 2 had eosinophilic granulomatosis with polyangiitis. A total of 30 (79%) had pulmonary manifestations, with cough (73%) and pulmonary haemorrhage (67%) being the most common. Abnormalities were noted in 82% of chest CT scans reviewed, with nodules and ground-glass opacities being the most common. At 6, 12 and 36 months follow-up, respectively, 61.8%, 39.4% and 29% of patients continued to show pulmonary manifestations. Five MPA patients with re-haemorrhage are described in detail. CONCLUSION: MPA was more common than granulomatosis with polyangiitis, with pulmonary involvement being common in both. MPA patients had more severe pulmonary manifestations. Chest CT revealed abnormal findings in a majority of cases. A subgroup of young MPA patients experienced repeat pulmonary haemorrhage. Treatment modality and response were comparable in different subtypes of AAV, except for this young MPA group. Additional prospective studies are needed to better understand the different phenotypes of pAAV.

ANCA-Associated Vasculitis: Core Curriculum 2020.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA. Clinical disease phenotypes include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis. Serologic classification of AAV into proteinase 3-ANCA disease and myeloperoxidase-ANCA disease correlates with a number of disease characteristics. AAV has a predilection for the kidney, with >75% of patients having renal involvement characterized by rapidly progressive glomerulonephritis. The cause and pathogenesis of AAV are multifactorial and influenced by genetics, environmental factors, and responses of the innate and adaptive immune system. Randomized controlled trials in the past 2 decades have refined the therapy of AAV and transformed AAV from a fatal disease to a chronic illness with relapsing course and associated morbidity. This article in AJKD's Core Curriculum in Nephrology series provides a detailed review of the epidemiology, pathogenesis, diagnosis, and advances in the management of AAV.

[Anca-associated vasculitides in elderly people].

Antineutrophil cytoplasmic antibodies (ANCA) play a key role in the pathogenesis of ANCA-associated vasculitides (AAV). These diseases are rare, occur in every age, but most commonly in adults and elder patients. Among them there are: granulomathosis with poyangiitis (GPA), microscopic poyangiitis (MPA) and eosinophilic granulomathosis with polyangiitis (EGPA). In the article we try to analyse the course of AAV in eldery patients, according to accessible literature. Among AAV patients, those with MPA diagnosis are elder than GPA and EGPA patients. Elder AAV patients present more frequently severe kidney and lung involvement. Elder patients are more at risk to develop complications in the course of disease, but also treatment-related, including severe infections. In elder patients immunosupresive agents dosage, therethore, should be tapered and adjusted to the renal function.

Th17 and Treg lymphocytes as cellular biomarkers of disease activity in Granulomatosis with Polyangiitis.

Granulomatosis with Polyangiitis (GPA) (formerly known as Wegener's granulomatosis) is a vasculitis of unknown etiology affecting predominantly small- to medium-sized vessels, usually involving the upper and lower respiratory tract and kidneys. Anti-neutrophil cytoplasmic autoantibodies are probably the initial cause of the inflammatory process that leads to the typical necrotizing lesions. In this issue of the European Journal of Immunology, Szczeklik et al. [Eur. J. Immunol. 2017. 47: 724-733] report some interesting findings on the possible involvement of T-cell subsets in the pathogenesis of the disease. This prospective study, performed on a large cohort of patients, identifies Th17 lymphocytes as the possible pathogenic subset of GPA, and Treg cells as the possible suppressors of the inflammatory process. These two subsets in peripheral blood could be used as cellular biomarkers of disease activity, and this would result particularly useful in the follow-up of patients once the immunosuppressive treatment has been initiated.

Skewing toward Treg and Th2 responses is a characteristic feature of sustained remission in ANCA-positive granulomatosis with polyangiitis.

The objective of our study was to evaluate the T-helper (Th) and regulatory T (Treg) cell profile in ANCA-positive granulomatosis with polyangiitis (GPA) and its relation to disease activity. In a prospective study, we studied two groups of GPA patients: (i) disease flare (active-GPA, BVAS>6, n = 19), (ii) sustained remission (≥ 1-year prior enrollment, inactive-GPA, BVAS = 0, n = 18). 24 age-sex matched healthy subjects served as controls. Active-GPA patients were followed for 6 months and reevaluated during remission (early remission; n = 13). We analyzed subsets of Th-cells (flow cytometry), production of signature cytokines by in vitro stimulated lymphocytes, and broad spectrum of serum cytokines (Luminex). In all GPA patients we observed expansion of effector Th17 cells, and increased production of IL-17A by in vitro stimulated T cells, as compared to controls. Disease flare was characterized by marked reduction in Treg cells, whereas in sustained remission we showed expansion of both Treg and Th2 subset. Finally, analyzing the cytokine profile, we identified CCL23 and LIGHT, as potential biomarkers of active disease. We conclude that in GPA, expansion of Treg and Th2 lymphocytes in parallel to increased Th17 response is a characteristic feature of sustained remission. In contrast, Treg cells are markedly decreased in disease flare.

Rituximab in ANCA-Associated Vasculitis.

PURPOSE OF REVIEW: The purpose of this review is to describe the efficacy and safety of rituximab (RTX) as a remission induction and maintenance therapy in ANCA-associated vasculitis (AAV). RECENT FINDINGS: A PubMed search was carried out to track down articles published between February 2006 and February 2016. Randomized controlled trials (RCTs) that encompassed patients with AAV were included. The American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) 2014-2015 online abstracts were also reviewed whether they were RTCs or not. Ten PubMed RCTs were analyzed along with eight ACR and four EULAR abstracts. RTX was not inferior to cyclophosphamide (CYC) for remission induction in AAV; it was superior to CYC in patients with relapsing disease and superior for remission maintenance in comparison with azathioprine (AZA). Rituximab is a therapeutic option to induce and maintain remission in patients with AAV.

Characteristics and Outcomes of Granulomatosis With Polyangiitis (Wegener) and Microscopic Polyangiitis Requiring Renal Replacement Therapy: Results From the European Renal Association-European Dialysis and Transplant Association Registry.

BACKGROUND: This study describes the incidence and outcomes of European patients requiring renal replacement therapy (RRT) for kidney failure due to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 12 renal registries providing individual RRT patient data to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry in 1993-2012 participated. PREDICTOR: Cause of primary kidney disease: AAV (ie, granulomatosis with polyangiitis [Wegener] and microscopic polyangiitis) versus 3 separate matched control groups without AAV: (1) primary glomerulonephritis, (2) diabetes mellitus, and (3) disease other than diabetes mellitus as the cause of primary kidney disease, including glomerulonephritis (termed "nondiabetes"). OUTCOMES: Incidence, causes of death, and survival. MEASUREMENTS: ERA-EDTA primary renal disease codes. RESULTS: 2,511 patients with AAV (1,755, granulomatosis with polyangiitis; 756, microscopic polyangiitis) were identified, representing an incidence of 1.05 per million population (pmp) for granulomatosis with polyangiitis (predominating in Northern Europe) and 0.45 pmp for microscopic polyangiitis (prevailing in Southern Europe). Kidney transplantation was performed in 558 (22.2%) patients with vasculitis. The 10-year probability for survival on RRT after day 91 was 32.5% (95% CI, 29.9%-35.1%) in patients with vasculitis. Survival on RRT after day 91 did not differ between AAV and matched nondiabetes patients. Patient and transplant survival after kidney transplantation, adjusted for time period and country, was better in AAV than in matched nondiabetes patients (HRs of 0.81 [95% CI, 0.67-0.99] and 0.82 [95% CI, 0.69-0.96], respectively). LIMITATIONS: No data for extrarenal manifestations, treatment, and relapses. CONCLUSIONS: Geographical differences in the incidence of RRT for kidney failure due to granulomatosis with polyangiitis and microscopic polyangiitis copied their distribution in the general population. Overall survival on RRT after day 91 for patients with AAV was similar to that for patients with nondiabetes diagnoses. Our results suggest that patients with AAV are suitable candidates for kidney transplantation with favorable survival outcomes.

Gastric presentation (vasculitis) mimics a gastric cancer as initial symptom in granulomatosis with polyangiitis: a case report and review of the literature.

Granulomatosis with polyangiitis (GPA), formerly called Wegener's Granulomatosis, is characterized by necrotizing granulomatous inflammation and belongs to the family of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. The main clinical symptoms of GPA are vasculitis primarily involving upper and lower respiratory tracts, as well as kidneys. Gastrointestinal manifestations of GPA are less common (0-20 %), with gastric presentation mimicking a gastric cancer as an initial symptom. This is a descriptive case report of one patient, together with systematic review of the literature. We described a 31-year-old Chinese woman who presented with complaints of abdominal distention, anorexia for 2 months. Gastroscopy was carried out for three times, and stomach cancer was suspected. However, histopathology of gastric biopsy revealed a chronic inflammation with mucosal ulceration, frequent neutrophils and lymphocytes infiltration, and local granulomatous formation, whereas no sign of stomach carcinoma was observed. In view of the positive cANCA test, a diagnosis of GPA was considered. From the onset of the GPA in the patients, no other organs have been involved in the disease. The patient was successfully treated with corticosteroids and cyclophosphamide. As shown in the report, patients who present only with gastrointestinal manifestations represent challenges to diagnosis. ANCA testing can serve as a decisive diagnostic tool. Although uncommon, GI involvement may be a major feature in GPA, sometimes presenting as gastric tumor-like lesions. Diagnosis should be considered in patients presenting with GI symptoms accompanied by evidence of systemic vasculitis, and ANCA test should be used as a diagnostic measurement to clarify differential diagnosis.

Circulating T follicular helper cell and regulatory T cell frequencies are influenced by B cell depletion in patients with granulomatosis with polyangiitis.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is a rare and sometimes fatal systemic autoimmune disease. ANCAs specific for PR3 are associated with GPA. Remission in GPA can be achieved through B cell depletion (BCD) therapy. Our aim was to understand whether the frequencies of T cell subsets are influenced by BCD. METHODS: The frequencies of circulating T follicular helper cells (cTFHs) and regulatory T cells (Tregs) from 36 GPA patients including 11 rituximab-treated patients and 10 healthy controls were studied by flow cytometry. The functional capacity of Tregs was assessed by in vitro co-culture assays. RESULTS: We observed an increased frequency of cTFHs and a reduced frequency of antigen-experienced Tregs in peripheral blood from GPA patients on conventional therapies but not in those treated with rituximab compared with healthy controls. Furthermore, the ratio of cTFHs to Tregs was significantly higher in GPA patients on conventional therapies than in GPA patients treated with rituximab who were clinically improved or controls. Whereas Tregs were numerically reduced in GPA patients on conventional therapy, the suppressive capacity of Tregs on a per cell basis was not significantly altered in these individuals. CONCLUSION: Our study illustrated increased cTFHs with decreased antigen-experienced Tregs in GPA patients on conventional therapies, but in B cell-depleted patients the levels of cTFHs and Tregs were similar to healthy controls. The negative correlation between cTFHs and Tregs implies the balance between T cell subsets and its B cell dependence impact on disease activity in GPA.

Atypical presentation of granulomatosis with polyangiitis: a case report and review of the literature.

Background: Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by necrotizing granulomatous vasculitis of the small- and medium-sized vessels. Classical GPA affects the upper and lower airways and kidneys. It commonly affects the nose and paranasal sinuses, middle and inner ear, and subglottic region of the larynx. Therefore, otolaryngological involvement is common in GPA and can sometimes be the initial presentation. In rare cases, otologic signs and symptoms can be the initial manifestations of this disease, including recurrent otitis media, otitis media with effusion, and sensorineural hearing loss. Case Description: In the present study, we describe an atypical case of GPA of a 22-year-old female. The patient presented with severe and complicated otitis media with hearing loss and polyneuropathy (facial nerve paralysis and trigeminal nerve impairment), in addition to nasopharyngeal and parotid infiltration, in the absence of other otolaryngologic and systemic manifestations of GPA. Conclusions: The diagnosis of GPA can be challenging due to its wide range of clinical manifestations. Otologic signs and symptoms are rare in this disease and can sometimes be the initial manifestations. Early diagnosis and treatment are important to prevent serious and permanent complications of the disease. Otolaryngologists should have high index of suspicion to systemic diseases such as GPA.

Severe Granulomatosis With Polyangiitis Treated With Low-Dose Cyclophosphamide, Rituximab, Glucocorticoids, and Plasma Exchange: A Case Report.

Granulomatosis with polyangiitis (GPA) is a systemic vasculitis that affects blood vessels and presents with vague constitutional symptoms, but more serious manifestations can develop, including pulmonary complications and glomerulonephritis. Currently, there are no definitive treatment guidelines. We present a case of a 66-year-old male with no previous medical history who was admitted for generalized constitutional symptoms for the past month. Imaging of the patient's brain revealed dural enhancement. Bronchoalveolar lavage was done and revealed diffuse alveolar hemorrhage (DAH). A kidney biopsy revealed granulomatosis with polyangiitis. The patient's hospital course was complicated by acute renal failure and required hemodialysis. Due to the patient's multi-organ involvement, the patient was treated aggressively with cyclophosphamide, rituximab, plasma exchange (PE), and steroids. GPA is a systemic vasculitis that can present with multi-organ involvement. A prompt diagnosis is necessary to initiate treatment and preserve organ function. More research is needed to determine which combination therapies are the best treatment modalities in cases of severe multi-organ system involvement.

Granulomatosis With Polyangiitis: A Rare Cause of Recurrent Breast Abscesses.

This case report highlights the importance of recognizing granulomatosis with polyangiitis (GPA) as a rare but potential cause of recurrent granulomatous mastitis and breast abscesses. The case report describes a patient who presented with recurrent breast abscesses over many years, initially misdiagnosed as infectious mastitis, until a breast tissue biopsy revealed granulomatous inflammation. Further evaluation confirmed the diagnosis of GPA based on elevated anti-neutrophil cytoplasmic antibodies (ANCA). The authors emphasize that, while breast involvement is exceedingly rare in GPA, it should be considered in cases of refractory granulomatous mastitis, even in the absence of typical systemic GPA manifestations. Early recognition can prevent misdiagnosis, allow timely initiation of immunosuppressive treatment, and avoid unnecessary procedures. The report calls for improved awareness and further research into the clinical characteristics and optimal management strategies for GPA presenting with breast lesions.

A Rare Presentation of Wegener's Granulomatosis With Perinuclear Antineutrophil Cytoplasmic Antibody Positivity.

Wegener's granulomatosis (WG), also termed granulomatosis with polyangiitis, is a vasculitic condition with numerous systemic manifestations. It is mainly a pauci-immune vasculitis which involves small and medium-sized vessels. Herein, we report a case of a 72-year-old female with a background history of type 2 diabetes mellitus and hypertension. She presented to the hospital with recurrent nasal congestion, headache, and intermittent facial pain for two months' duration. At the initial presentation, she was diagnosed with pansinusitis, for which she was treated with antibiotics and was discharged. Two weeks later, she presented with progressively worsening bilateral lower limb numbness and weakness for one week's duration. With serial investigations, she was diagnosed with WG and was treated with intravenous methylprednisolone along with cyclophosphamide, after which she made a significant improvement in her clinical status.

Granulomatosis With Polyangiitis Presenting As Orbital Apex Syndrome.

Granulomatosis with polyangiitis (GPA) is a rare small-vessel vasculitis that typically presents with a triad of sinonasal, pulmonary, and renal symptoms. Here, we present the case of a 43-year-old female with a history of substance use disorder who presented with vision changes and worsening left eye pain over five days. Previous evaluations raised concerns about GPA versus cocaine-induced vasculitis, but diagnostic confirmation was hindered by a lack of medical follow-up. Prompt multidisciplinary intervention led to significant improvement following steroid therapy and IV antibiotics, and the patient was ultimately diagnosed with a high GPA. This case highlights the complexities involved in diagnosing and managing GPA presenting as orbital apex syndrome, particularly in patients with comorbidities and non-adherence to medical follow-up.