Cees G M Kallenberg

• Head of Department at University of Groningen

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 The deregulated overproduction of interleukin (IL)−6 has been implicated in several inflammatory and antibody-mediated autoimmune diseases. Objectives To investigate serum IL-6 levels (sIL-6) during active disease, remission, and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the associ...

ANCA-associated vasculitis (AAV) is characterized by inflammation and destruction of small and medium-sized vessels. Current management strategies for AAV have been validated in large groups of patients. However, recent insights indicate that distinct patient subsets may actually exist within AAV, thereby justifying the development of more personal...

The proteinase 3 (PR3)-positive anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis (GPA) has been associated with chronic nasal S. aureus carriage, which is a risk factor for disease relapse. The present study was aimed at comparing the genetic make-up of S. aureus isolates from PR3-ANCA-pos...

Background: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed thera...

Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used t...

There is a growing need for disease related biomarkers in Takayasu arteritis (TA).The assessment of pro-inflammatory cytokines and chemokines in TA may provide a better understanding of its pathophysiology, and circulating levels of these mediators may act as biomarkers of disease activity. Serum level of interleukin 6 (IL-6) is a potential biomark...

Background: Cardiovascular diseases (CVD) are the major causes of death in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) during long-term follow-up. This study investigated risk factors for cardiovascular events (CVE) and CVD-related mortality in Chinese AAV patients. Methods: Five hundred and four AAV patients in our ce...

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in...

Background Evidence supporting the classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) based on ANCA type is accumulating.¹ Objectives To evaluate serum cytokine profiles in patients with AAV classified by ANCA specificity (proteinase 3 (PR3)-ANCA versus myeloperoxidase (MPO)-ANCA) or by clinical diagnosis (...

Background Response to rituximab (RTX) is variable in patients with ANCA-associated vasculitis (AAV), and predictors of treatment efficacy/relapse risk would be useful. Previous studies have shown that RTX pharmacokinetics (PK) is associated with treatment efficacy in patients with lymphoma. Objectives To study the determinants of RTX PK in patien...

Background Macrophages may present two distinct phenotypes indicated as M1 and M2 under different stimuli. M1 and M2 macrophages have divergent functions that range from enhancement of inflammation for M1 to tissue repair and remodeling for M2 macrophages. The objective of this study was to evaluate the distribution of M1 and M2 macrophage phenotyp...

18th International Vasculitis and ANCA Workshop, Univ Tokyo, Tokyo, JAPAN, MAR 25-28, 2017

Antineutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). Yet, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the IgM isotype often serve as markers...

Objective: We investigated the relationships between glucocorticoid use, disease activity, and changes in body mass index (BMI) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods: We analyzed AAV patients enrolled in the Rituximab in AAV trial. Glucocorticoid use, BMI, and disease activity were measured reg...

Objective: To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO)-ANCA...

Objectives: S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in AAV. This study investigated serum S100A8/A9 levels as a biomarker predicting future relapse in a large cohort of patients with severe ANCA-associated vasculitis (AAV). Methods: Serum levels of S100A8/A9 were measured at baseline, months 2, and 6 foll...

Objective: The Rituximab in ANCA- Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of ANCA-associated vasculitis. The current study determined if known single nucleotide polymorphisms (SNPs) for Fc gamma receptors (FcγRs) or cytochrome p450 (CYP450) enzymes were associated with the re...

Background The treatment of ANCA-associated vasculitis (AAV) includes high doses of glucocorticoids, the use of which has been associated with increased body-mass index (BMI)¹. A previous study suggested that this change in BMI is independent of glucocorticoid exposure². Objectives We sought to evaluate whether increases in BMI are related more di...

Background Recent studies have highlighted important phenotypic, genetic, and treatment differences between PR3- and MPO-ANCA+ ANCA-associated vasculitis (AAV) patients1,2. No study has evaluated differences in body mass index (BMI) between the PR3- and MPO-ANCA+ AAV subtypes. Objectives We sought to evaluate whether differences in BMI exist betwe...

Background Therapeutic monoclonal antibodies (mAbs) are used to treat patients with a wide range of disorders including autoimmune diseases. To perform pharmacokinetics analyses, they are commonly quantified using immunoassays (such as ELISAs) based on the specific affinity of the mAb to its target antigen. However the development of these tests is...

The vasculitides comprise a heterogeneous group of disorders characterized by inflammation of blood vessels. Definitions of these conditions have been provided by the Chapel Hill Consensus Conference (updated in 2012). A large prospective study defining and validating diagnostic and classification criteria for the vasculitides (DCVAS, ClinicalTrial...

Background Cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) positivity at remission has been associated with an increased relapse rate in patients with proteinase 3 anti-neutrophil cytoplasmic antibody-associated vasculitis (PR3-AAV) after a switch to azathioprine maintenance therapy. We therefore hypothesized that extended azathioprine ma...

Therapeutic monoclonal immunoglobulins (mAbs) are used to treat patients with a wide range of disorders including autoimmune diseases. As pharmaceutical companies bring more fully humanized therapeutic mAb drugs to the healthcare market analytical platforms that perform therapeutic drug monitoring (TDM) without relying on mAb specific reagents will...

Based on efficacy and toxicity considerations, both low-dose pulse cyclophosphamide as part of the Euro-Lupus Nephritis protocol and mycophenolate mofetil (MMF) with corticosteroids may be considered for induction of remission in patients with proliferative lupus nephritis. The long-term follow-up data available for low-dose pulse cyclophosphamide,...

Kidney involvement is a major determinant for morbidity and mortality in patients with systemic lupus erythematosus. The treatment target of lupus renal disease is to induce and maintain remission and to minimize disease or treatment-related comorbidities. Cyclophosphamide (CYC), in conjunction with glucocorticoids, has conventionally been used for...

Objectives: Relapse following remission is common in ANCA-associated vasculitis (AAV), particularly with ANCA directed at proteinase 3 (PR3-ANCA). We evaluated the association of a PR3-ANCA level rise with subsequent relapse. Methods: Data from the rituximab versus cyclophosphamide/azathioprine for AAV (RAVE) trial were utilized. Starting from t...

Objective To develop and validate ClinESSDAI (Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index), ie, ESSDAI without the biological domain. Patients and methods The 702 fictive vignettes derived from 96 real cases of primary Sjögren's syndrome of the ESSDAI development study were used. As for ESSDAI development,...

Purpose of reviewAntineutrophil cytoplasmic autoantibodies (ANCAs) are considered important diagnostic tests in the work-up of patients suspected of vasculitis. Here we discuss new developments in the methodology of testing, the pitfalls in using these tests as diagnostic tools, and the value of serial ANCA testing for the follow-up of patients wit...

Inefficient clearance of apoptotic cells and the subsequent exposure of the immune system to nuclear contents are crucially involved in the pathogenesis of systemic lupus erythematosus (SLE). Factor VII-activating protease (FSAP) is activated in serum upon contact with dead cells, and releases nucleosomes from late apoptotic cells into the extracel...

Objective To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response. Methods Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-as...

The ANCA-associated vasculitides (AAV) are characterized by pauci-immune necrotizing small to medium size vessel vasculitis frequently including necrotizing crescentric glomerulonephritis. Neutrophil activation by ANCA appears a primary pathogenic event. More recently, the complement system has been shown to be involved as well. Activation of the a...

Objectives: Granulomatosis with polyangiitis (GPA) is a relapsing small-vessel vasculitis characterized by circulating ANCA against PR3. The mechanisms that trigger PR3-ANCA production are unknown. The aim of this study was to determine whether endogenous factors [B cell activating factor (BAFF) and IL-21] and exogenous factors [oligodeoxynucleoti...

High mobility group box 1 (HMGB1) is a nuclear protein that acts as an alarmin when released into the extracellular milieu. HMGB1 is a biomarker of active disease in several systemic autoimmune diseases. Behçet's disease (BD) is a systemic inflammatory disorder with a waxing/waning course. The objective of this study is to evaluate serum HMGB1 leve...

Objective: The incidence of cardiovascular disease (CVD) is increased in RA. This study was designed to evaluate whether a reduction in disease activity influences early markers of CVD. Methods: In a prospective longitudinal study, 58 newly diagnosed RA patients and 58 age- and sex-matched healthy controls (HCs) were included. Endothelial dysfun...

Introduction Takayasu arteritis (TA) and giant cell arteritis (GCA) are large vessel vasculitides (LVV) that usually present as granulomatous inflammation in arterial walls. High mobility group box 1 (HMGB1) is a nuclear protein that acts as an alarmin when released by dying or activated cells. This study aims to evaluate whether serum HMGB1 can be...

The AAV are characterized by necrotizing vasculitis of small and medium-sized blood vessels in conjunction with the presence of autantibodies directed to proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The kidneys are frequently involved with fibrinoid necrosis and paucity of immune deposits. In vitro studies show that primed neutrophils can...

To discover biomarkers involved in the pathophysiology of ANCA-associated vasculitis (AAV) and determine if low-density granulocytes (LDGs) contribute to gene expression signatures in AAV. The source of clinical data and linked biospecimens was a randomized controlled treatment trial in AAV. RNA-sequencing of whole blood from patients with AAV was...

Objective Non-severe relapses are more common than severe relapses in ANCA-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We analyzed the outcomes of non-severe relapses in the Rituximab in AAV (RAVE) trial that were treated according to a pre-specified prednisone protocol. Methods RAVE was...

Until recently, standard of care for patients with generalized or severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has consisted of an induction regimen with cyclophosphamide (CYC) and corticosteroids followed by maintenance treatment with azathioprine. This regimen is associated with significant toxicity resulting in c...

The EULAR Sjögren's syndrome (SS) disease activity index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SS. With the growing use of the ESSDAI, some domains appear to be more challenging to rate than others. The ESSDAI is now in use as a gold standard to measure disease activity...

Chronic nasal carriage of the bacterium Staphylococcus aureus in patients with the autoimmune disease granulomatosis with polyangiitis (GPA) is a risk factor for disease relapse. To date, it was neither known whether GPA patients show similar humoral immune responses to S. aureus as healthy carriers, nor whether specific S. aureus types are associa...

Supplementary Table 1-5

The article is concentrated on the topic, mental health at work. The frequently analysed increase of mental illness is critically discussed, workrelated factors of influences are explained and put into the context of workplace health management. The statutory basics and instruments concerning the risks of the assessment of mental burden are given b...

The article is concentrated on the topic, mental health at work. The frequently analysed increase of mental illness is critically discussed, workrelated factors of influences are explained and put into the context of workplace health management. The statutory basics and instruments concerning the risks of the assessment of mental burden are given b...

In this study, we sought to understand the selective pressures shaping the Ig-producing cell repertoire in the parotid glands of primary Sjögren's syndrome (pSS) patients before and after rituximab treatment (RTX). In particular, we evaluated the role of potential N-glycosylation motifs acquired by somatic hypermutation (ac-Nglycs) within Ig H chai...

Clinical immunology is in the Netherlands a separate clinical specialty within internal medicine and pediatrics. Clinical immunologists work closely together with nephrologists, rheumatologists and many other medical specialists. Apart from research and teaching, clinical immunologists are taking care of patients with immune-deficiencies, vasculiti...

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are autoimmune diseases in which the small vessels are inflamed. Clinical observations suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data and animal models, particularly for myeloperoxidase-ANCA. An in vivo pathogenic role of ANCA di...

Objective CD5+ B cells have been conceptualized as a possible surrogate for Breg cells. The aim of the present study was to determine the utility of CD5+ B cells as biomarkers in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Methods The absolute and relative numbers (percentages) of CD5+ B cells (explanatory variables) were meas...

Granulomatosis with polyangiitis and microscopic polyangiitis are anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs) that are prone to cycles of remission and relapse. The introduction of cytotoxic therapy has changed the prognosis for these diseases from typically fatal to manageable chronic illnesses with a relapsing course. Desp...

The updated nomenclature for vasculitis defines this varied group of disorders by aetiology, specific features of pathogenesis and clinical symptoms; diagnostic and classification criteria for clinical practice are in development. Here, I review some important advances in the management of vasculitis within the category of anti-neutrophil cytoplasm...

IntroductionDisease relapses are frequent in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). We evaluated the outcomes of patients re-treated with rituximab (RTX) and prednisone for severe disease relapses.Methods The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remis...

The objective of this study is to evaluate urinary HMGB1 levels as markers for active nephritis in patients with ANCA-associated vasculitis (AAV) in comparison with urinary CD4+ effector memory T-cells and urinary monocyte chemoattractant protein-1 (MCP-1). Twenty-four AAV patients with active nephritis and 12 healthy controls (HC) were evaluated....

Objective Differential gene expression in CD177+ and CD177− neutrophils was investigated, in order to detect possible differences in neutrophil function which could be related to the pathogenesis of ANCA-associated Vasculitides (AAV). Methods Neutrophils were isolated from healthy controls (HC) with high, negative or bimodal CD177 expression, and...

We read with great interest the article by Brkic and colleagues in a recent issue of Arthritis Research & Therapy[1]. In that study, the authors investigated the distribution of T helper (Th) subsets which produce IL-17A, IL-17 F, IL-21, and IL-22 in patients with systemic lupus erythematosus (SLE) in relation to their genetic IFN type I signature....

Infections have been suggested to contribute to disease induction and reactivation in many of the idiopathic vasculitides. This review describes and evaluates the evidence that microbes are involved in the etiopathogenesis of these diseases. Large-vessel vasculitis has recently been associated with two specific bacteria. Mycobacterium tuberculosis...

The objective of this study was to evaluate whether levels of high mobility group box 1 (HMGB1) in granulomatosis with polyangiitis (GPA) patients are associated with carotid atherosclerosis, related to levels of soluble receptor for advanced glycation end-products (sRAGE) and influenced by immunosuppressive or lipid-lowering therapy. Twenty-three...

Objective: Regulatory B cells (Bregs) constitute a subset of B cells with immunomodulatory properties. Numerical and functional alterations in the Breg compartment have been associated with autoimmunity. The aim of this study was to assess the frequency and function of Bregs in patients with ANCA-associated vasculitis (AAV). Methods: B cell subs...

Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immu...

To discuss in detail the efficacy and safety of rituximab (RTX) for induction and maintenance of remission in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) who are either treatment naive, relapsing or refractory to standard of care. In treatment naive AAV patients, RTX without maintenance treatment is as e...

Background In ankylosing spondylitis (AS), objective measurements evaluating the effect of tumor necrosis factor-alpha (TNF-α) blocking therapy are lacking. Objectives To investigate the predictive value of bone turnover markers (BTM) in relation to discontinuation of TNF-α blocking therapy in patients with AS. Methods 111 consecutive AS outpatient...

Background Physical activity questionnaires are considered to be the most applicable method to assess daily physical activity in population studies because of participant convenience, minimal cost, and scoring flexibility. The International Physical Activity Questionnaire (IPAQ) and the Short QUestionnaire to Asses Health-enhancing physical activit...

Background High mobility group box 1 (HMGB1) is a nuclear non-histone protein that acts as an alarmin when released in the extra-cellular medium by necrotic or activated cells. High serum HMGB1 levels have been found in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and active nephritis as well as in patients w...

Background Bone formation and bone loss are both present in ankylosing spondylitis (AS). New bone formation can lead to the formation of syndesmophytes, ankylosis of the spine and sacroiliac joints, and bone formations on enthesal sites. Objectives To investigate the relation between the presence of syndesmophytes and bone turnover markers (BTM) in...

Microscopic Polyangiitis (MPA) is a small vessel vasculitis. The disease is defined by the 2012 revised Chapel Hill Consensus Conference Nomenclature of Vasculitides [1] as necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (i.e. capillaries, venules, or arterioles). Necrotizing arteritis involving small a...

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is strongly associated with autoantibodies against myeloperoxidase (MPO) and proteinase 3 (PR3). No clear consensus has been reached on the pathogenicity of these autoantibodies. Animal models for MPO-ANCA, in vitro data suggesting pathogenicity of ANCA, and one case of a n...

Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivi...

Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed to proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) are sensitive and specific markers for their associated diseases, granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) and microscopic polyangiitis (MPA), respectively. Clinical observations suggest but do not pr...

Background: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. Methods: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then...

Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivi...

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic inflammatory disorders that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), Churg-Strauss syndrome and renal limited vasculitis (RLV). Extra-cellular high mobility group box 1 (HMGB1) acts as an alarmin and has been shown to be a bi...