Susanne Schinke

Prospective long-term follow-up of patients with localised Wegener's granulomatosis: does it occur as persistent disease stage?

Objective To identify patients with localised Wegeners granulomatosis (locWG) to assess whether it occurs as a long-term disease stage or phenotype and to characterise its outcome. Methods Patients in a ‘localised stage’ with histological criteria compatible with WG and a follow-up period of ≥1 year were included. They were prospectively followed at the Vasculitis Center Schleswig-Holstein from 1989 to 2009 and the clinical manifestations, antineutrophil cytoplasmic autoantibodies (ANCA) status and damage were evaluated. Immunosuppression was adapted to disease activity and severity in a step-up regimen. Results Of 1024 patients with suspected WG, 99 were clinically diagnosed with locWG and 50 fulfilled the inclusion criteria (72% women, median age 43 years, 46% ANCA-positive). The median follow-up was 48 months. All achieved a response to treatment, 34% achieved complete remission, 1–4 relapses occurred in 46%, 5 (10%) had generalised disease (median 6 years after onset). ANCA status was not associated with relapse (p=0.98), transition to generalised disease (p=0.51) or refractory manifestations (p=0.60). 47% required cyclophosphamide for localised manifestations, 36% of them for pulmonary masses and 24% for orbital masses. 66% developed organ damage, mostly due to bony destruction or space obturation (28% saddle nose, 24% septal perforation, 10% orbital wall destruction). There were two deaths that were not related to WG. Conclusion There is evidence that locWG is a long-term disease stage or phenotype (5% of all patients with WG), 46% of whom are ANCA-positive. LocWG is characterised by destructive and/or space-consuming lesions associated with high relapse rates (46%) and local damage.

Autoantibodies against the bactericidal/permeability-increasing protein from inflammatory bowel disease patients can impair the antibiotic activity of bactericidal/permeability-increasing protein

Bactericidal/permeability-increasing protein (BPI) is an antineutrophil cytoplasmic autoantibody (ANCA) target antigen in inflammatory bowel disease (IBD). The aim of this study was to characterize binding regions of BPI-autoantibodies and to analyze their ability to block the antibiotic effect of BPI. Sera of 24 ulcerative colitis and Crohn’s disease patients were examined in indirect immuno-fluorescence, ANCA enzyme-linked immunosorbent assay (ELISA), and by epitope mapping with 13mer peptides and Western blot for presence of BPI-autoantibodies. IgG preparations were used to determine inhibition of BPI’s antimicrobial function by BPI-autoantibodies in a bacterial growth inhibition assay. BPI-autoantibodies were detected by ELISA in 18/24 patients. Epitope mapping and western blotting revealed an additional 3 patients with BPI-autoantibodies. IgG preparations of all patients with Crohn’s disease and 9 of 12 ulcerative colitis patients could inhibit the antibiotic function of BPI in vitro as compared with healthy control subjects. Inhibiting BPI-autoantibodies correlated with extraintestinal manifestations, peripheral blood leukocyte counts, and anemia. BPI-autoantibodies recognizing the N-terminal portion were associated with greater mucosal damage and intestinal extent of disease. BPI is a frequent target antigen of autoantibodies in ulcerative colitis and Crohn’s disease. Inhibition of the antibiotic function mediated by the N-terminal region of BPI by these autoantibodies may contribute to a proinflammatory environment in IBD patients.

Clinical presentation and long-term outcome of 144 patients with microscopic polyangiitis in a monocentric German cohort

OBJECTIVE To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. METHODS We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. RESULTS Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. CONCLUSION MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort.

Risk of infection by biologics

Tumor necrosis factor (TNF-alpha) plays an essential role in the orchestration of inflammatory processes including autoimmune disorders, host defence and granuloma formation. TNF antagonists are highly effective in the therapy of rheumatoid arthritis, but they compromise host defence mechanisms, especially concerning bacterial infections inducing granuloma formation, such as tuberculosis. Other biologics have been developed and approved for the therapy of rheumatoid arthritis, e.g. an interleukin (IL-1) blocking agent (anakinra), an antibody that depletes CD20 positive B-cells (rituximab) and an inhibitor of T-cell co-stimulation (abatacept). In spite of initial skepticism regarding side effects, such as an increased risk of infections, biologics now play an essential role in the therapy of autoimmune diseases due to the implementation of efficient screening measures concerning side effects (such as reactivation of tuberculosis). This review summarizes the current available data regarding risk of infection and gives and overview on recommended screening, contraindications and events that require withdrawal of therapy.

Infektionsrisiko durch Biologika

Tumor necrosis factor (TNF-alpha) plays an essential role in the orchestration of inflammatory processes including autoimmune disorders, host defence and granuloma formation. TNF antagonists are highly effective in the therapy of rheumatoid arthritis, but they compromise host defence mechanisms, especially concerning bacterial infections inducing granuloma formation, such as tuberculosis. Other biologics have been developed and approved for the therapy of rheumatoid arthritis, e.g. an interleukin (IL-1) blocking agent (anakinra), an antibody that depletes CD20 positive B-cells (rituximab) and an inhibitor of T-cell co-stimulation (abatacept). In spite of initial skepticism regarding side effects, such as an increased risk of infections, biologics now play an essential role in the therapy of autoimmune diseases due to the implementation of efficient screening measures concerning side effects (such as reactivation of tuberculosis). This review summarizes the current available data regarding risk of infection and gives and overview on recommended screening, contraindications and events that require withdrawal of therapy.

SAT0019 Disease-associated micro-RNA profiles in granulomatosis with polyangiitis nasal tissue indicate a regulatory network targeting pathophysiological processes

Background Micro-RNA (miRNA) are small noncoding RNAs that regulate gene expression at a posttranslational level. Alteration of miRNA expression with a diagnostic and prognostic character has been described not only in oncogenesis but also in chronic inflammatory diseases such as RA, SLE, Sjögren’s syndrome or chronic inflammatory bowel disease. In this context, no investigations in vasculitides have been described (1). Objectives To characterize for the first time miRNA profiles associated with GPA and to identify new miRNA targets of potential pathophysiological relevance. Methods Nasal tissue samples of 20 GPA-patients, 10 disease controls (CRS: chronic rhinosinusitis with polyps) and of 10 healthy controls (HC) were selected for genome-wide miRNA screening using an Affymetrix miRNA-microarray displaying 847 human miRNAs. Significantly differentially expressed miRNAs were identified by Mann-Whitney U-test; fold changes were based on the ratios of the medians of each experimental group. Visualization of the results was generated using TIBCO Spotfire. Putative miRNA targets were predicted by combining three different computational methods: (i) PubMed search, (ii) Tarbase 5.0 (Diana labs), an algorithm for experimentally validated targets and (iii) microRNA Data Integration Portal (mirDIP), a tool combining up to 12 different algorithms for target prediction. Results 1. GPA specific miRNA expression pattern: From 847 human miRNA screened, 99 were found to be differentially expressed when comparing GPA to HC (p≤0.05). At a cut-off level of a twofold up- or downregulation, 25 miRNAs remained. Of those 25 miRNAs, 24 displayed a GPA-specific expression pattern. Furthermore, 3 miRNAs (unregulated: miR-1228 and -532-5p: downregulated: miR-708 in GPA) were inversely regulated in GPA compared to CRS. 2. Target prediction revealed previously experimentally validated targets involved in T- and B-cell, in fibroblast and osteoblast proliferation and differentiation, apoptosis, hypoxia, angiogenesis and cellular adhesion. These are known pathways in the pathogenesis of GPA. Potential targets also include proteinase-3, the specific GPA autoantigen, and lysosomal membrane protein-2, only recently described as an alternative autoantigen in GPA. Conclusions This explorative survey for the first time documents disease associated miRNA profiles in nasal tissue samples of GPA patients when compared to healthy individuals and disease controls. Target prediction of these 24 GPA specific miRNAs suggests involvement in known pathological pathways of GPA. Considering the promising diagnostic, prognostic and therapeutical applications of miRNAs in other diseases (2), validating the clinical relevance of the presented data will help to understand the GPA on a molecular level, which represents a key element in developing new therapies. References O’Connell R, et.al. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10(2):111-22 Sandhu, S. Potential applications of microRNAs in cancer diagnosis, prognosis, and treatment. Seminars in Oncology 2011; 38(6), 781-7 Disclosure of Interest None Declared

Pathogenetic and Clinical Aspects of Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitides

Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidase expressed by innate immune cells (neutrophils and monocytes) are salient diagnostic and pathogenic features of small vessel vasculitis, comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA. Genetic studies suggest that ANCA-associated vasculitides (AAV) constitute separate diseases, which share common immunological and pathological features, but are otherwise heterogeneous. The successful therapeutic use of anti-CD20 antibodies emphasizes the prominent role of ANCA and possibly other autoantibodies in the pathogenesis of AAV. However, to elucidate causal effects in AAV, a better understanding of the complex interplay leading to the emergence of B lymphocytes that produce pathogenic ANCA remains a challenge. Different scenarios seem possible; e.g., the break of tolerance induced by a shift from non-pathogenic toward pathogenic autoantigen epitopes in inflamed tissue. This review gives a brief overview on current knowledge about genetic and epigenetic factors, barrier dysfunction and chronic non-resolving inflammation, necro-inflammatory auto-amplification of cellular death and inflammation, altered autoantigen presentation, alternative complement pathway activation, alterations within peripheral and inflamed tissue-residing T- and B-cell populations, ectopic lymphoid tissue neoformation, the characterization of PR3-specific T-cells, properties of ANCA, links between autoimmune disease and infection-triggered pathology, and animal models in AAV.

Infektionsrisiko durch Biologika@@@Risk of infection by biologics

Tumor necrosis factor (TNF-alpha) plays an essential role in the orchestration of inflammatory processes including autoimmune disorders, host defence and granuloma formation. TNF antagonists are highly effective in the therapy of rheumatoid arthritis, but they compromise host defence mechanisms, especially concerning bacterial infections inducing granuloma formation, such as tuberculosis. Other biologics have been developed and approved for the therapy of rheumatoid arthritis, e.g. an interleukin (IL-1) blocking agent (anakinra), an antibody that depletes CD20 positive B-cells (rituximab) and an inhibitor of T-cell co-stimulation (abatacept). In spite of initial skepticism regarding side effects, such as an increased risk of infections, biologics now play an essential role in the therapy of autoimmune diseases due to the implementation of efficient screening measures concerning side effects (such as reactivation of tuberculosis). This review summarizes the current available data regarding risk of infection and gives and overview on recommended screening, contraindications and events that require withdrawal of therapy.