Norbert Blank

evaplan at the University Hospital Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (92)340.06 Total impact

  • N. Blank · U. Hegenbart · S. Schönland
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    ABSTRACT: Background Systemic amyloidoses are rare protein deposition disorders, which are often diagnosed in an advanced stage of the disease due to non-specific symptoms. Any chronic inflammatory disease can lead to an AA-type amyloidosis. Aim This paper summarizes the current state of the art of diagnosis and treatment of AA amyloidosis and presents data from the past 10 years of our amyloidosis center. Material and Methods Our data represents an analysis of our cohort of patients with amyloidosis and a selective research in the PubMed database for AA amyloidosis. Results The underlying diseases comprise autoinflammatory syndromes, polyarthritis, and chronic inflammatory bowel and lung diseases. Renal organ involvement is the most prevalent in AA amyloidosis. It can be detected early through the evaluation of proteinuria. The treatment depends on the individual underlying disease. Patients without an associated inflammatory disease are considered to have idiopathic AA amyloidosis and empiric treatment is mandatory. Discussion Survival of this fatal disease has recently improved due to the new diagnostic tools and treatment options; however, early diagnosis plays a crucial role in the prevention of end-stage renal failure. New therapeutic strategies aim to remove existing amyloid deposits.
    No preview · Article · Jan 2016 · Zeitschrift für Rheumatologie
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    ABSTRACT: Objective: Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive IL-1β release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1β and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of canakinumab in CAPS. Methods: A multi-centre study of consecutive children and adults with CAPS treated with canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted. Results: A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%). Conclusion: Real-life effectiveness of canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS.
    No preview · Article · Dec 2015 · Rheumatology
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    ABSTRACT: Introduction: The role of CD3-CD56+ natural killer (NK) cells in granulomatosis with polyangiitis (GPA) is poorly understood. Recently, it has been shown that peripheral blood NK cells can kill renal microvascular endothelial cells, suggesting a pathogenic role of NK cells in this disease. So far, subset distribution, phenotype, and function of peripheral blood NK cells in relation to GPA disease activity have not been elucidated. Moreover, it is not known whether NK cells infiltrate GPA tissue lesions. Methods: Paraffin sections of GPA granulomas and controls were stained with anti-CD56 and anti-CD3 antibodies. Peripheral blood lymphocyte subsets were analyzed by flow cytometry. NK cell degranulation was analyzed using cocultures of patient PBMCs with target cells and surface expression of CD107a. Clinical data were extracted from medical records. Statistical analysis was performed in an exploratory way. Results: CD56+ cells were not detectable in active granulomatous GPA lesions but were found frequently in granulomas from tuberculosis and sarcoidosis patients. In GPA, the proportion of NK cells among peripheral blood lymphocytes correlated negatively with the Birmingham Vasculitis Activity Score (BVAS) (n = 28). Accordingly, NK cell percentages correlated positively with the duration of remission (n = 28) and were significantly higher in inactive GPA (BVAS = 0, n = 17) than in active GPA, healthy controls (n = 29), and inactive control diseases (n = 12). The highest NK cell percentages were found in patients with long-term remission and tapered immunosuppressive therapy. NK cell percentages >18.5 % of peripheral blood lymphocytes (n = 12/28) determined GPA inactivity with a specificity of 100 %. The differentiation into CD56(dim) and CD56(bright) NK cell subsets was unchanged in GPA (n = 28), irrespective of disease activity. Similar surface expression of the activating NK cell-receptors (NKp30, NKp46, and NKG2D) was determined. Like in healthy controls, GPA NK cells degranulated in the presence of NK cell receptor ligand bearing epithelial and lymphatic target cells. Conclusions: NK cells were not detectable in GPA granulomas. Peripheral blood NK cell percentages positively correlate with the suppression of GPA activity and could serve as a biomarker for GPA activity. Peripheral blood NK cells in GPA patients are mature NK cells with preserved immune recognition.
    Preview · Article · Dec 2015 · Arthritis Research & Therapy
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    ABSTRACT: Adult-onset Still’s disease (AOSD), a rare autoinflammatory disorder, resembles systemic juvenile idiopathic arthritis (SJIA). The superimposable systemic clinical features of AOSD and SJIA suggest both clinical phenotypes represent the same disease continuum with different ages of onset. To further characterize the similarity between AOSD and SJIA at the molecular level, 2 previously identified response gene sets in SJIA were used to investigate how genes that respond to interleukin (IL)-1β inhibition with canakinumab in SJIA patients behave in AOSD patients with active disease prior to IL-1β targeting therapy, relative to healthy subjects. All genes downregulated in SJIA patients following canakinumab treatment were upregulated in most patients with active AOSD prior to canakinumab treatment, relative to healthy subjects. A few patients with milder AOSD had expectedly gene-expression patterns that resembled those in healthy subjects. Comparison of the gene-expression patterns with neutrophil counts showed a correlation between elevated neutrophil numbers and upregulation of canakinumab-responsive genes. Correspondingly, most genes upregulated following canakinumab treatment in patients with SJIA patients were downregulated in the majority of AOSD patients. These results further support the concept of a Still’s disease continuum that includes both a pediatric/juvenile onset (SJIA) and adult onset (AOSD) form.
    Preview · Article · Dec 2015 · Pediatric Rheumatology
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    ABSTRACT: Objective: Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. Methods: The data of 3248 patients with SSc were analyzed. Results: Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. Conclusion: These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.
    Full-text · Article · Nov 2015 · The Journal of Rheumatology
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    ABSTRACT: For patients with severe and refractory autoimmune diseases, high-dose chemotherapy and autologous hematopoietic stem cell transplantation has been established as a considerable therapeutic option in recent years.In this retrospective single center analysis we assessed the feasibility and efficacy of peripheral blood stem cells (PBSC) mobilization and collection in 35 patients with refractory autoimmune disease (AID). The mobilization data of 15 patients with systemic sclerosis (SSc), 11 patients with multiple sclerosis (MS) and 9 patients with other AID were analyzed.Stem cell mobilization with cyclophosphamide chemotherapy 2x2 g/m2 (n=16) or 1x2 g/m2 (n=17) and G-CSF followed by PBSC collection was performed between 1999 and 2015. Leukapheresis was performed in 16 inpatients and 19 outpatients. All patients reached their collection goal and no collection failures were observed. The median PBSC collection result was 12.2 (SSc), 8.0 (MS) and 8.2 (other AID) x106 CD34+ cells/kg, respectively. Twenty-five of 35 (71%) patients achieved a sufficient collection with one leukapheresis session, while 6 patients (17%) required two and 4 patients (11%) required three or more leukapheresis sessions. No correlation of the collected PBSC number was observed regarding age, body weight, diagnosis, disease duration, skin sclerosis or previous cyclophosphamide. Mobilization chemotherapy with cyclophosphamide 2x2 g/m2 and 1x2 g/m2 delivered comparable mobilization results with leukapheresis on day 13 or 14.In summary, we demonstrate that PBSC collection is safe and feasible in patients with AID. Mobilization chemotherapy with cyclophosphamide 1x2 g/m2 and 2x2 g/m2 is equally effective in those patients.This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2015 · European Journal Of Haematology

  • No preview · Article · Sep 2015 · Pediatric Rheumatology

  • No preview · Article · Sep 2015 · Pediatric Rheumatology

  • No preview · Article · Sep 2015 · Pediatric Rheumatology
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    B Buhl · H-M Lorenz · N Blank

    Preview · Article · Sep 2015 · Pediatric Rheumatology
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    ABSTRACT: Background: Systemic amyloidosis is a rare protein deposition disorder in which diagnosis is often delayed due to the non-specific symptoms at disease onset; however, renal involvement can be detected early during the evaluation of proteinuria. This article gives an overview of current data regarding diagnosis, prognosis and treatment of systemic amyloidosis. Conclusion: The prognosis of this fatal disease has recently improved due to the new diagnostic tools and treatment options; however, early diagnosis plays a crucial role in order to circumvent, e.g. dialysis.
    No preview · Article · Jul 2015
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    ABSTRACT: In patients with systemic sclerosis (SSc) associated pulmonary arterial hypertension (SSc-APAH) is the leading cause for death. The objective of this prospective screening study was to analyse sensitivity and specificity of stress-Doppler echocardiography (SDE) in detecting pulmonary hypertension (PH). Pulmonary artery pressures and further parameters of PH were assessed by echocardiography and right heart catheterization (RHC) at rest and during exercise in SSc-patients. Investigators of RHC were blinded to the results of non-invasive measurements. Of 76 SSc patients (64 female, mean age 58 ± 14 years), 22 (29 %) had manifest PH confirmed by RHC, with 4 due to concomitant left heart diseases, 3 with lung diseases and 15 patients with SSc-APAH. Echocardiography at rest missed PH-diagnosis in 5 of 22 PH patients using a cut-off value for systolic pulmonary arterial pressures (PASP) > 40 mmHg at rest. The sensitivity of echocardiography at rest was 72.7 % (95 % Confidence Interval (CI) 0.52-0.88), specificity 88.2 % (95 % CI 0.78-0.95). Stress-Doppler-echocardiography missed PH-diagnosis in 1 of the 22 PH-patients using a cut-off value for PASP > 45 mmHg during low-dose exercise and improved sensitivity to 95.2 % (95 % CI 0.81-1.0) but reduced specificity to 84.9 % (95 % CI 0.74-0.93). Reduction of specificity was partly due to concomitant left heart disease. The results of this prospective, cross-sectional study using RHC as gold standard in all patients showed that SDE markedly improved sensitivity in detecting manifest PH to 95.2 % compared to 72.7 % using echocardiography at rest only. Thus, for PH-screening in SSc-patients echocardiography should be performed at rest and during exercise. Clinicaltrials.gov NCT01387035 . Registered 29 June 2011.
    Full-text · Article · Jun 2015 · Arthritis research & therapy
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    ABSTRACT: Background To improve detection and follow-up of patients with systemic sclerosis, the German Network for Systemic Scleroderma (DNSS) was founded 2003 and comprise rheumatologists, dermatologists, pulmonologists and nephrologists from more than 40 medical centers. Renal crisis is rare but still a medical emergency in patients with SSc. Objectives Up to date, more than 3000 patients have been grouped into four descriptive disease subsets, i.e. limited cutaneous disease (lcSSc), diffuse cutaneous disease (dcSSc), overlap-syndrome and undifferentiated connective tissue disease (UCTD) with scleroderma features. Methods In this analysis, we have focused on renal crisis within the three main subsets, e.g. lcSSc, dcSSc and overlap-syndromes to identify baseline aspects, which are predictive for future SSc associated renal crisis. Results Recent analyses of up to now 3180 patients revealed that 56% of patients suffer from limited SSc (lcSSc), 34% from diffuse SSc (dcSSc) and 11% of patients were diagnosed with an overlap-syndrome. Eighteen patients developed a renal crisis (1.4%, 18/3180), while 10% (315/3180) were classified with kidney involvement and 8% (257/3180) with proteinuria. Of these, 66.7% (12/18) were diagnosed with the diffuse form of SSc, while just 27.8% (5/18) were diagnosed with lcSSc and 5.6% (1/18) with SSc-overlap syndromes. Predictive factors for renal crisis in our patient cohort included the diffuse form of SSc (odds ratio (OR) 4.6, p=0.005, 95%>confidence interval (CI) 1.6-13.5), a modified Rodnan skin score (mRSS) of more than 15 (OR 4.7; p=0.002, 95%>CI 1.7-13), positive anti-RNA polymerase (RNAP) autoantibodies (OR 24.6, p<0.0001, 95%>CI 6.1-99.5), tendon friction rubs (OR 5.4, p=0.004, 95%>CI 1.7-16.9), hypertension (OR 6.1, p<0.0001, 95%>CI 2.3-16.5), proteinuria (OR 11.8, p<0.0001, 95%>CI 4.3-32.1) and elevated CK-levels (OR 5.1, p=0.01, 95%>CI 1.4-18.9). Interestingly, positive anti-topoisomerase autoantibodies did not predict a higher risk for renal crisis. Patients diagnosed with renal crisis were significantly more frequent on ACE-inhibitors (61.1%, 11/18, p=0.001). Of these, 5 patients also suffered from proteinuria and 7 patients from hypertension. Patients on systemic glucocorticoids had also an increased risk to develop a renal crisis (OR 5.1, p=0.002, 95%>CI 1.8-14.3), independent of the dosage (> or <7.5mg/day). Conclusions Renal crisis has become a rare complication in SSc. The highest risk was associated with the detection of RNAP antibodies, followed by proteinuria, hypertension, tendon friction rubs, elevated CK-levels and a modified Rodnan skin Score above 15. Close monitoring of patients at high risk for SSc associated renal crisis is mandatory. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Adult-onset Still's disease (AOSD) is a rare auto-inflammatory disorder resembling a similar pediatric syndrome known as systemic juvenile idiopathic arthritis (SJIA).1 The superimposable systemic and clinical features in SJIA and AOSD suggest that both clinical phenotypes represent a disease continuum with a pediatric (SJIA) and more adult-onset (AOSD). The authors believe that the analyses of gene expression profiles can be useful not only for disease classification, diagnosis, and prognosis, but also to identify disease specific treatment effects that counteract the underlying pathological mechanisms. In the analysis described here, we address the question: How do genes that respond to canakinumab treatment in SJIA patients2 behave in AOSD patients with active disease relative to healthy controls and prior to IL-1 targeting therapy? Objectives To determine how genes that respond to IL-1β blockade with canakinumab in SJIA patients behave in AOSD patients relative to healthy controls. Methods SJIA gene expression profiles pre- and post canakinumab treatment were compared with AOSD patients relative to healthy subjects using Affymetrix U133Plus 2 DNA microarrays. Expression values of genes are shown for healthy subjects and AOSD patients prior to canakinumab treatment (genes are shown in rows and patient samples in columns). Results Consistently, all genes down-regulated in SJIA following canakinumab treatment were upregulated in a majority of AOSD patients with active disease relative to healthy subjects and prior to canakinumab treatment. A few of the AOSD patients resembled healthy subjects (Figure). Comparison of the gene expression patterns to neutrophil counts suggested that elevated neutrophil numbers were closely correlated to the up-regulation of IL-1 associated gene expression. Conclusions Results are consistent with and further support the concept of a Still's disease continuum that presents as pediatric/juvenile SJIA or adult-onset Still's disease. Moreover, they suggest that AOSD is an IL-1 driven condition that is also mechanistically similar to SJIA and that the observed canakinumab response signature is likely to show a comparable treatment response to IL-1β blockade in AOSD. References Disclosure of Interest A. Brachat Employee of: Novartis, E. Feist Grant/research support from: Novartis, Consultant for: Novartis, Speakers bureau: Novartis, F. Behrens Grant/research support from: Pfizer, Roche, Abbvie, Chugai, Consultant for: Abbvie, Pfizer, Celgene, Novartis, Chugai, Astra Zeneca, Lilly, Janssen, Merck, Morphosys, Speakers bureau: Abbvie, Pfizer, Celgene, Novartis, Chugai, UCB, Astra-Zeneca, Janssen, Roche, Lilly, N. Blank Grant/research support from: Novartis, SOBI, Amgen, BMS, Pfizer, Roche, Abbvie and others, Speakers bureau: Novartis, SOBI, Amgen, BMS, Pfizer, Roche, Abbvie and others, N. Nanguneri Employee of: Novartis, C. Specker: None declared, M. Witt: None declared, J. Zernicke: None declared, A. Martini Grant/research support from: Abbott, Bristol Myers and Squibb, Francesco Angelini S.P.A., Glaxo Smith & Kline, Janssen Biotech Inc Novartis,Pfizer Inc,Roche,Sanofi Aventis,Schwarz Biosciences GmbH: I declare that the GASLINI Hospital which is the public Hospital where I work as full time employee has received contributions to support the research activities of the network of PRINTO (www.printo.it), Consultant for: Bristol Myers and Squibb, Centocor Research & Development,Glaxo Smith & Kline, Novartis, Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, I declare that the Gaslini Hospital which is the public Hospital where I work as full time employee has received contributions to support the PRINTO research activities from the industries above mentioned., Speakers bureau: Abbott, Abbvie, Amgen, Biogenidecm Bristol MyersSquibb, Astellas, Behringer, Italfarmaco, Janssen, MedImmune, Novartis, NovoNordisk, Pfizer, Sanofi, Roche, Servier., G. Junge Employee of: Novartis
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: The dysregulation in clearance of apoptotic material is considered a major pathogenetic factor for the emergence of autoimmune diseases. Apoptotic cell-derived membrane microparticles (AdMPs), released from the cell surface during apoptosis, have been implicated in the pathogenesis of autoimmunity. Also of importance are cytokines such as interferon-alpha (IFN-α), known as a major player in patients with systemic lupus erythematosus (SLE). This study investigates the combined effect of AdMPs and IFN-α on professional phagocytes.In the presence of IFN-α, phagocytosis of AdMPs by human monocytes was significantly increased in a dose-dependent manner. The combination of AdMPs and raised IFN-α concentrations resulted in an increase in the secretion of pro-inflammatory cytokines and an upregulation of surface molecule expression involved in antigen uptake. Also, macrophage polarisation was shifted towards a more inflammatory type of cell. The synergism between IFN-α and AdMPs seems to be mediated by an upregulation of phosphorylated STAT1.Our results indicate that IFN-α together with AdMPs amplify the initiation and maintenance of inflammation. Especially in disorders with a defective clearance of apoptotic material, this mechanism might play a crucial role. © 2015. Published by The Company of Biologists Ltd.
    No preview · Article · Jun 2015 · Journal of Cell Science
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    ABSTRACT: Background Women with auto-inflammatory disease on long-term IL-1 blockade increasingly ask about the safety and outcomes of pregnancy but little data is available. Objectives To analyse the outcomes of pregnancy in women on long-term anti-IL-1 therapy. Methods We obtained the clinical details and pregnancy outcomes of women exposed to anti-IL-1 agents in 7 countries. Results We identified 13 women aged 16 – 38 years, with a total of 15 pregnancies exposed to IL-1 blockade. 9 women had CAPS, 2 Adult Onset Stills Disease, 1 TRAPS, 1 FMF and 1 Idiopathic Pericarditis. 4 received canakinumab, 2 stopped treatment after conception, 2 switched to anakinra. 13 foetuses were exposed to anakinra. 3 women started anakinra during pregnancy, 3 stopped treatment following conception. All pregnancies were completed. The shortest term was 35 weeks. APGAR score was 9-10 at 10 mins in all cases. Birth weight range 2.02-3.94 kilos. 5 were breast fed for 3 – 40 weeks. Age at last contact was from 1 week – 8 years. Only 1 child had developmental abnormalities; growth hormone deficiency due to ectopic neurohypophysis and unilateral renal agenesis. We also identified 11 children with paternal exposure to anti-IL-1 therapies, all developmentally normal to date. Conclusions These successful pregnancies significantly extend our knowledge of pregnancy outcomes in parents receiving anti-IL-1 therapies. A co-author has previously reported the intrauterine death of a foetus (of a twin pregnancy) with bilateral renal agenesis exposed to anakinra. The surviving twin is developmentally normal. Although numbers are small the data provide reassurance to physicians caring for these patients. The relationship between IL-1 inhibition and renal agenesis requires further study. Each pregnancy should be assessed and risks and benefits of maintaining therapy individually discussed with potential parents. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background: Cross-talk between synovial fibroblasts (SF) and immune cells is suggested to play a crucial role in inflammation and chronification of rheumatoid arthritis (RA). The contribution of B cells in this process is poorly defined. Methods: Here, primary B cells from healthy donors were polyclonally activated and cocultured with SF of non-synovitic origin from patients with osteoarthritis. Results: In B-SF cocultures the concentrations of interleukin 6 (IL-6) and IL-8 increased manifold compared with single cultures even under physical separation and remained stable for several days after B-cell removal. Intracellular staining confirmed SF as key producers of IL-6 and IL-8, and B cells as main producers of tumour necrosis factor alpha (TNFα) and IL-1ß. Blocking experiments with a combination of anti-TNFα-antibodies and rIL-1RA significantly reduced SF cytokine production by up to 90%, suggesting that B-cell-derived TNFα and IL-1ß were crucial mediators of SF activation. Interestingly, B-cell cytokine production, CD25 expression and proliferation decreased in cocultures by at least 50%, demonstrating a negative regulatory loop towards the activated B cells. Inhibition of activin receptor-like kinase 5, a crucial component of the tumour growth factor ß (TGFß) signalling pathway, partly restored B-cell proliferation, suggesting a contribution of SF-derived TGFß in B-cell suppression. Besides cytokines, B-cell-activated SF also upregulated secretion of matrix metalloproteases such as MMP-3, thereby acquiring potential tissue destructive properties. This was confirmed by their invasion into human cartilage in the severe combined immunodeficiency mouse fibroblast invasion model in vivo. Conclusions: Interaction with activated B cells leads to conversion of non-arthritic SF into SF with a proinflammatory and aggressive RA-like phenotype, thereby suggesting a new, so far unrecognised role for B cells in RA pathogenesis.
    No preview · Article · May 2015 · Annals of the rheumatic diseases
  • Norbert Blank · Hanns-Martin Lorenz

    No preview · Article · Feb 2015 · DMW - Deutsche Medizinische Wochenschrift
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    ABSTRACT: Abstract Objective: To identify risk factors for serum amyloid-A (AA) amyloidosis in patients living in Germany. Methods: Clinical and genetic data were obtained from 71 patients with AA amyloidosis. SAA1 genotypes were analyzed in 231 individuals. Control groups comprised 45 patients with long-standing inflammatory diseases without AA amyloidosis and 56 age-matched patients without any inflammatory disease. Results: The most frequent underlying diseases of AA amyloidosis were familial Mediterranean fever (FMF) (n = 24, 34%) and inflammatory rheumatic diseases (n = 30, 42%). Patients without any known underlying disease (n = 11, 16%) were considered as having idiopathic AA amyloidosis. Patients with FMF were significantly younger at disease onset and younger at diagnosis of AA amyloidosis compared with patients with rheumatic diseases. Patients with idiopathic AA amyloidosis were older than patients with definite rheumatic diseases. Patients with FMF and high penetrance MEFV gene mutations had a relative risk of 1.73 for AA amyloidosis. Patients with FMF or a rheumatic disease and the SAA1 α/α genotype had a relative risk of 4.86 and 2.53, respectively, for developing an AA amyloidosis. The prevalence of this risk genotype was 36% in German patients without an inflammatory disease, 92% in German patients with AA amyloidosis and 100% in German patients with idiopathic AA amyloidosis. Conclusions: Risk factors for AA amyloidosis are the presence of a hereditary autoinflammatory or chronic rheumatic disease, elevated C-reactive protein and SAA serum levels, a long delay of a sufficient therapy, an advanced age and the SAA1α/α genotype.
    No preview · Article · Nov 2014 · Amyloid
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    ABSTRACT: ObjectiveB cells with immunoregulatory properties (Breg cells) have been described in mice, but their role in the control of human immune responses is not well defined. We recently identified a human population of activated FSChigh B cells that exhibited regulatory activity toward T helper cells. The aim of the present study was to test such induced Breg (iBreg) cells in patients with autoimmune disease. Methods Purified CD19+FSChigh B cells derived from patients with systemic lupus erythematosus (SLE) or from healthy donors, which were activated via their B cell receptor, were cocultured with CD3-stimulated CD4+ T helper cells from SLE patients or healthy donors. H-3-thymidine incorporation, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) were used to analyze proliferation, cytokine secretion, and surface marker expression. ResultsAlthough under costimulatory conditions, FSChigh SLE B cells supported the proliferation of healthy donor T cells to a similar extent as donor B cells, their regulatory function was significantly diminished in B cell suppressor assays. Similar effects were seen when SLE T cells were used, confirming that SLE T cells were equally susceptible to iBreg cell signals as healthy donor T cells and that SLE iBreg cell defects were independent of T cell origin. B cell viability and expression of surface markers (CD25, CD80, and B7-H1) or cytokines (interleukin-6 [IL-6], tumor necrosis factor , and IL-10) were comparable in the two B cell populations. There was no correlation between the extent of iBreg cell-induced inhibition and disease activity. CD19+FSChigh B cells from patients with another systemic autoimmune disease, granulomatosis with polyangiitis (Wegener's) (GPA), exhibited no regulatory defects, which suggests that the iBreg cell defects were SLE-specific and not a general consequence of autoimmunity or inflammation. Conclusion Induced Breg cells from SLE patients, but not GPA patients, are less effective in the control of T helper cell proliferation, which supports the reported skewed B cell repertoire in SLE. The malfunctioning SLE iBreg cells might allow the overstimulation of immune responses and contribute to the initiation and/or perpetuation of disease.
    No preview · Article · Oct 2014 · Arthritis and Rheumatology

Publication Stats

1k Citations
340.06 Total Impact Points

Institutions

  • 2015
    • evaplan at the University Hospital Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 2005-2015
    • Universität Heidelberg
      • • Department of Rheumatology
      • • V. Medicine Clinic
      Heidelburg, Baden-Württemberg, Germany
  • 2002
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
  • 2000-2002
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Department of Clinical and Molecular Virology
      Erlangen, Bavaria, Germany