Ulrich Specks

• Mayo Foundation for Medical Education and Research

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) predominantly affect individuals aged 55–75 years, with granulomatosis with polyangiitis (GPA) being diagnosed most often between 55 and 65 years and microscopic polyangiitis (MPA) between 65 and 75 years. Owing to the general increase in life expectancy, the average age at di...

This mini review explores the association of interstitial lung disease (ILD) with antineutrophil cystoplasmic antibodies (ANCA) and the clinical syndrome of microscopic polyangiitis (MPA). Reports on radiographic and histopathologic findings as well as genetic predispositions are reviewed. Based on this evidence a concept for the pathogenesis of th...

Objective The ADVOCATE trial demonstrated that treatment of active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) with avacopan was noninferior in achieving remission at week 26 and superior for sustained remission at week 52 compared with a prednisone taper. This analysis of ADVOCATE evaluated the efficacy and safety of...

Objective To assess the association of aPL and diffuse alveolar haemorrhage (DAH) in patients with SLE by performing a systematic review and meta-analysis. Methods Multiple databases were systematically searched from inception to February 2024. Studies were eligible if they included patients with SLE (population), reported aPL status (exposure), a...

Background: Traditional medical research infrastructures relying on the Centers of Excellence (CoE) model (an infrastructure or shared facility providing high standards of research excellence and resources to advance scientific knowledge) are often limited by geographic reach regarding patient accessibility, presenting challenges for study recruit...

Rationale: Fibrosing mediastinitis is an uncommon fibro-inflammatory condition without established or effective medical therapies. Infiltrating B-lymphocytes are commonly present, and progressive fibrosis compromises mediastinal structures including blood vessels and airways resulting in significant morbidity and mortality. Objective: To evaluat...

Objective Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either ritu...

Objective ANCA-negative granulomatosis with polyangiitis (GPA) remains a diagnosis of exclusion. Clinical differences between patients with ANCA-negative vs ANCA-positive GPA have not been analysed in sizable case-control studies, and the effects of ANCA-seroconversion from negative to positive are not well documented. Methods A single-centre, sex...

Myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-ANCA-associated vasculitis) is one of two major ANCA-associated vasculitis variants characterised by systemic necrotising vasculitis with few or no immune deposits. MPO-ANCA-associated vasculitis predominantly affects small blood vessels and, in con...

Introduction A significant number of patients with antineutrophil cytoplasmic antibodies (ANCA)- associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, estimated glomerular filtration rate [eGFR] <15 ml/min per 1.73 m²) despite advances in remission-induction treatment. Methods This is a retr...

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The Plasma Exchange (PLEX) and Glucocorticoids (GC) in Severe AAV (PEXIVAS;NCT00987389) trial was the largest in AAV and first to enroll participants with DAH requiring mechanical ventilation....

Reading about various disease processes is great and is what we do a majority of the time in medicine. But many of us would say we learn best through our patients. If that is true, why isn’t there a board review book with a focus on case-based learning? At our institution, the Division of Pulmonary and Critical Care Medicine has the longest success...

Objective This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods Analysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eo...

PURPOSE: Avacopan, an oral blocker of the C5a receptor, has recently been approved as an adjuvant to standard remission induction regimen for antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) [1]. Avacopan can reduce glucocorticoid exposure and improve renal outcomes [2, 3] . During the acute setting of diffuse alveolar hemorrh...

Objectives: Anti-neutrophil cytoplasmic antibody (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 so...

Introduction Although the alternative complement pathway has been implicated in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), the specific nature of its involvement is unclear. This study measured levels of urine and plasma complement fragment Ba at multiple time points in a group of patients with A...

Background Autoreactive proteinase 3 (PR3+) B cells have recently been phenotypically and functionally characterized, and the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with ANCA-associated vasculitis (AAV) has been shown. This work aimed to investigate the central tolerance-checkpoint...

Drugs are an important secondary cause of membranous nephropathy (MN) with the most common drugs associated with MN being nonsteroidal anti-inflammatory drugs (NSAIDs). Since the target antigen in NSAID-associated MN is not known, we performed laser microdissection of glomeruli followed by mass spectrometry (MS/MS) in 250 cases of PLA2R-negative MN...

Background The frequency of proteinase 3 gene (PRTN3) polymorphisms in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not fully characterised. We hypothesise that the presence of a PRTN3 gene polymorphism (single nucleotide polymorphism (SNP) rs351111) is relevant for clinical outcomes. Methods DNA variant...

Objective Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZ...

Objective Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA‐associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cel...

Objective Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3‐targeting ANCAs (PR3‐ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. Methods The recombina...

Levels of neutrophil extracellular traps (NETs) were measured in plasma of healthy controls (HC, n = 30) and patients with granulomatosis with polyangiitis (GPA, n = 123), microscopic polyangiitis (MPA, n = 61), Takayasu's arteritis (TAK, n = 58), and giant cell arteritis (GCA, n = 68), at times of remission or activity and correlated with levels o...

Objective: Vitamin 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. Methods: Serum levels of 25(OH)D2/ 3 were measured in 125 randomly selected...

Proteinase 3 (PR3) is the main target antigen of anti-neutrophil cytoplasmic antibodies (ANCA) in PR3-ANCA-associated vasculitis. A small fraction of PR3 is constitutively exposed on the surface of quiescent blood neutrophils in a proteolytically inactive form. When activated, neutrophils expose an induced form of membrane-bound PR3 (PR3mb) on thei...

Objectives Severe infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial. Methods Data on 197 patients recruited...

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 call...

Background. Optimal strategy for remission-maintenance therapy in patients with MPO-ANCA associated vasculitis is not established. Defining parameters to guide maintenance therapy is required. Methods. A retrospective cohort study of all patients with MPO-ANCA associated vasculitis (microscopic with polyangiitis and granulomatosis with polyangiitis...

Objectives ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information conce...

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of rare, primary, systemic necrotizing small-vessel vasculitides. Granulomatosis with polyangiitis and microscopic polyangiitis account for ∼80% to 90% of all AAV. Exposure to silica dust, farming, and chronic nasal Staphylococcus aureus carriage are associated wi...

The risk of progression to end-stage kidney disease (ESKD) in patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) and glomerulonephritis (AAV-GN) remains high. At 5 years of follow-up, 14% to 25% of patients will evolve to ESKD suggesting that kidney survival is not optimized in patients with AAV. The addition of...

Background Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine e...

Background Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortali...

Objectives We investigated whether soluble immune checkpoints (sICPs) predict treatment resistance, relapse and infections in patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Methods Plasma sICP concentrations from available samples obtained during conduct of the RAVE trial were measured by immunoabsorbent assays...

Idiopathic subglottic stenosis (iSGS) is a localized airway disease that almost exclusively affects females. Understanding the molecular mechanisms involved may provide insights leading to therapeutic interventions. Next-generation sequencing was performed on tissue sections from patients with iSGS (n=22), antineutrophil cytoplasmic antibody (ANCA)...

Objective To assess markers of neutrophil activation such as calprotectin and N-formyl methionine (fMET) in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and large-vessel vasculitis (LVV). Methods Levels of fMET, and calprotectin, were measured in the plasma of healthy controls (n=30) and patients with AAV (granulomatosis wi...

Background The frequency of the proteinase 3 gene (PRTN3) polymorphisms in patients with ANCA-associated vasculitis (AAV) is not well characterized. We hypothesize that PRTN3 gene polymorphisms induce allosteric changes in PR3 conformation which may alter its interaction with ligands and PR3-ANCA during inflammation with potential implications for...

Background Patient-based registries can help advance research on rare diseases such as eosinophilic granulomatosis with polyangiitis (EGPA), a complex multiorgan form of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. Objective The aim of this study is to compare patient-reported and physician-reported data on manifestations, tre...

Background: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown. Methods: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli of 250 cases of PLA2R-negative MN to detect novel antigens in M...

Humoral vaccine responses are known to be suboptimal in patients receiving B-cell targeted therapy, and little is known about vaccine induced T-cell immunity in these patients. In this study, we characterized humoral and cellular antigen-specific anti-SARS-CoV2 responses following COVID-19 vaccination in patients with ANCA-associated vasculitis (AA...

Inflammatory processes, such as an infection or drug reaction, can cause antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Although quite rare, AAV may occur with SARS-coronavirus disease 2019 (COVID-19) antigenic exposure, either from infection or immunization. We present two cases of AAV: one that developed after COVID-1...

Objective Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. Methods Twenty-two proteins were measured in 347 serum...

Background and objectives: Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on...

Objective To study the prevalence, risk and clinical associations of hypothyroidism among several forms of vasculitis. Methods Patients with giant cell arteritis (GCA), Takayasu arteritis (TAK), polyarteritis nodosa (PAN), and the three forms of ANCA-associated vasculitis (AAV, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA)...

Background: Little is known about the autoreactive B cells in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3 (PR3+) B cells. Methods: Multicolor flow cytometry in combination with bioinformatics and functional in vitro studies wer...

Background: Kidney biopsy is valuable for prognostic assessment of renal outcomes in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) but the impact of chronic changes is not determined. Methods: A retrospective cohort study of MPO- or PR3-ANCA positive patients with AAV and active renal d...

Objective To describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America. Methods Analysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from...

Constrictive bronchiolitis is one of the manifestations of small-airway involvement in primary Sjögren syndrome (SS) and is associated with fixed airflow obstruction despite treatment with bronchodilators, macrolides, corticosteroids, and corticosteroid-sparing agents. Reports have shown a beneficial effect of rituximab on interstitial lung disease...

Background Pleural and pericardial involvement are well recognized in eosinophilic granulomatosis with polyangiitis (EGPA) but considered rare manifestations of the other ANCA-associated vasculitides (AAV). Research Question What are the frequency and clinical characteristics of pleuritis and pericarditis in AAV? Study Design and Methods Using an...

BACKGROUND Patient-based registries can help advance research in rare diseases such as eosinophilic granulomatosis with polyangiitis (EGPA), a complex, multi-organ form of anti-cytoplasm neutrophil antibody (ANCA)-associated vasculitis. OBJECTIVE To compare patient-reported vs. physician-reported manifestations, treatments, and outcomes for patien...

Advances in the diagnosis and treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have led to continued improvement in survival and prognosis over the course of the last 4 decades. Nevertheless, the most acute and severe disease manifestations, including severe kidney disease and alveolar hemorrhage, continue to be associ...

Objective: A subset of ANCA-associated vasculitis (AAV) patients are known to manifest obstructive airway disease. Using low attenuation areas (LAA) in the lung on HRCT as an imaging marker for obstructive airway disease, we analyze HRCT studies in AAV patients compared to a matched non-AAV group using visual semi-quantitative and automated quanti...

Objectives: Only a few small case series, case reports, and one small clinical trial suggested some benefit of leflunomide (LEF) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and other vasculitides. We analysed the clinical efficacy and tolerability of LEF in a large cohort of patients with various vasculitides. Methods: T...

Background: The utility of ANCA testing as an indicator of disease activity in ANCA-associated vasculitis (AAV) remains controversial. This study aimed to determine the association of ANCA testing by various methods and subsequent remission and examine the utility of a widely used automated addressable laser-bead immunoassay (ALBIA) to predict dise...

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomato...

Background: Baseline expression of FCRL5, a marker of naïve and memory B cells, was shown to predict response to rituximab (RTX) in rheumatoid arthritis. This study investigated baseline expression of FCRL5 as a potential biomarker of clinical response to RTX in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Methods:...

Background: Treatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX). Methods: A retrospective cohort study of MPO- or PR3-ANCA-positive patients with AAV (MPA and GPA) and severe renal...

Lung involvement is one of the most common clinical features in ANCA-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In this review, we detail the five main presentations of pulmonary involvement in AAV: necrotizing granulomato...

This document follows up on a 2017 revised international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in granulomatosis with polyangiitis and microscopic polyangiitis and focuses on the clinical and diagnostic value of ANCA detection in patients with connective tissue diseases, idiopathic interstitial pneumonia, autoimmune liver...

An international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of EGPA patients. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinica...

Objectives Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. Methods Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospec...

Background Proteinase 3 (PR3)-reactive B cells are present in PR3-ANCA-associated vasculitis (AAV) at levels higher than healthy controls. Objectives To evaluate the dynamics of the PR3-reactive B cell repopulation in patients with PR3-AAV after treatment with rituximab, and to analyze possible associations between these immunological changes and...

Background ANCA can be detected in sera from patients with autoimmune, inflammatory, infectious or neoplastic diseases. Objectives To issue a Consensus Statement on ANCA testing and interpretation beyond systemic vasculitis. Methods This Statement was prepared by a group of experts, based on the results of a comprehensive search in PubMed. Resul...

Background Bartonellosis is an emerging anthropozoonosis caused by infection with intracellular Gram-negative Bartonella species. It leads to necrotizing granulomas and endothelial damage and causes acute and chronic human diseases, such as cat scratch disease, bacillary angiomatosis and endocarditis. Endocarditis due to Bartonella henselae and B....

The immunologic mechanisms in eosinophilic granulomatosis with polyangiitis (EGPA) are poorly understood. To characterize pulmonary EGPA’s mechanisms, we examined EGPA paraffin-embedded lung biopsies by immunostaining, RNA sequencing, and reverse transcriptase PCR, compared to normal lung. Novel type 2 findings in EGPA are basophils and increased m...

Background: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Methods: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an...

Background: The long-term clinical course of asthma in patients with Eosinophilic Granulomatosis with Polyangiitis (EGPA) remains unclear. We aimed to characterize long-term asthma in EGPA and to identify baseline predictors of long-term asthma severity. Methods: Retrospective cohort study of patients who fulfilled standardized criteria for EGPA...

Objectives Rituximab (RTX) treatment is used for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, but its benefits in eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. Our aim was to characterize asthma control and glucocorticoid (GC) sparing after RTX treatment. Methods A retrospective, computer-assisted search wa...