Norbert Blank

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (80)315.77 Total impact

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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.
    Arthritis research & therapy 06/2015; 17(1):165. DOI:10.1186/s13075-015-0673-7 · 3.75 Impact Factor
  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):819.2-819. DOI:10.1136/annrheumdis-2015-eular.4669 · 10.38 Impact Factor
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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.
    Journal of Cell Science 06/2015; 128(14). DOI:10.1242/jcs.162735 · 5.33 Impact Factor
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    ABSTRACT: 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. Here, primary B cells from healthy donors were polyclonally activated and cocultured with SF of non-synovitic origin from patients with osteoarthritis. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases 05/2015; DOI:10.1136/annrheumdis-2014-206965 · 10.38 Impact Factor
  • Norbert Blank · Hanns-Martin Lorenz
    DMW - Deutsche Medizinische Wochenschrift 02/2015; 140(3):191-193. DOI:10.1055/s-0041-100067 · 0.55 Impact Factor
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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.
    Amyloid 11/2014; 22(1):1-7. DOI:10.3109/13506129.2014.980942 · 2.51 Impact Factor
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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.
    Arthritis and Rheumatology 10/2014; 66(10). DOI:10.1002/art.38742
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    ABSTRACT: Background Vasculopathy is a major pathophysiological problem in patients with systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcerations (DU), pulmonary arterial hypertension (PAH). It is not known, how SSc patients are treated with vasoactive agents in daily practice. Objectives To determine, to which extent SSc patients are treated with vasoactive drugs. Methods Data of 3248 patients of the registry of German Network for Systemic Scleroderma were analyzed. Results Patients were treated with vasoactive drugs in 54.9% (1784) cases. Of these, 53% received calcium channel inhibitors (CCI), followed by 23.5% treated with intravenous Prostanoids (Iloprost, Prostavasin), 11.8% with beta-blockers, 11.3% with Pentoxifylline, 9.7% with Endothelin 1 receptor antagonists (ETRA), 4.6% with PDE5 inhibitors, 2.7% with topical vasodilative agents and 3.2% with others. Patients with RP received vasoactive therapy in 47,4%, with DU in 66,8% and with PAH in 71,6% of cases. Logistic regression analysis revealed, that patients who suffered from PAH were significantly more often treated with PDE5 inhibitors (odds ratio (OR) 7.2; p<0.0001) and ETRA (OR 6.9; p<0.0001) and those with digital ulcers with ETRA (OR 2.8; p<0.0001) and intravenous prostanoids (OR 1.7; p<0.0001). Patients were more frequently treated with β-blockers, when they had arterial hypertension (OR 4.2; p<0.0001) and were male (OR 1.9; p<0.0001). In addition 25,6% (830) patients were treated with ACE-inhibitors or AT1-receptor antagonists. They were often male and suffered from the diffuse form of SSc (p<0.001). Logistic regression analysis within this group clearly indicated that patients with hypertension (OR 4.9; p<0.0001) and renal insufficiency (OR 3.0; p<0.0001) were significantly more often treated with ACE inhibitors. When patients, registered after 2009, were compared to patients registered prior to 2004, it was found that after 2009 significantly more patients received ETRA (12% vs 5.5%; p<0.0001), beta-blockers (14.1% vs 7.6%; p<0.001), AT1R antagonists (12.5% vs 4.6%; p<0.0001), intravenous prostanoids (26.6% vs 18.2%; p<0.001) and ACE inhibitors (28.6% vs 23.1%; p<0.008). Conclusions These data clearly indicate that many SSc patients with RP, DU, and PAH do not yet receive sufficient vasoactive therapy. Furthermore, in recent years a marked change of treatment regimens can be observed. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4946
    Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):564-564. DOI:10.1136/annrheumdis-2014-eular.4946 · 10.38 Impact Factor
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    ABSTRACT: Whereas the association between sarcoidosis and malignant diseases has been well described, it remains controversial whether this association is merely a coincidence or the consequence of a common pathophysiologic mechanism. We investigated the incidence of malignancies in a large cohort of patients with sarcoidosis from a German University Hospital. Patients with a malignant disease were identified in a retrospective analysis of a cohort of 425 patients with sarcoidosis at the Medical Center of the University of Heidelberg. The type of malignancies and the onset before, concomitant or after sarcoidosis were analyzed. Sixty-one patients with a malignant disease were identified in our cohort of 425 patients with sarcoidosis. Among them, there were 18 patients with malignant lymphoma, 13 with breast cancer and 5 with cervical cancer. Malignant lymphoma was diagnosed up to 30 years after sarcoidosis with a median of 6.9 years. Breast or cervical cancers were diagnosed up to 20 years before or after sarcoidosis, and the median was 0.0 years. A high prevalence of B-cell lymphoma, breast and cervical cancers was found in our sarcoidosis cohort. In most patients, B-cell lymphoma was diagnosed many years after chronic sarcoidosis. In contrast, the diagnosis of breast or cervical cancer was evenly distributed before, around and after the diagnosis of sarcoidosis. Our hypothesis is that the immune dysregulation which persists during or after chronic sarcoidosis might represent a contributing factor for the development of B-cell lymphoma.
    Rheumatology International 03/2014; 34(10). DOI:10.1007/s00296-014-2983-5 · 1.63 Impact Factor
  • 41st Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung; 03/2014
  • Pneumologie 02/2014; 68(S 01). DOI:10.1055/s-0034-1367757
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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 and initiated a registry gathering information on diagnosis, clinical symptoms and therapy of SSc patients. Methods 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. Disease progress between initial patient registration (year 0) and fourth follow-up (year 4) was measured using organ involvement and present symptoms as indicators. Results Recent analyses revealed that 49% of patients suffer from limited SSc (lSSc), 31% from diffuse SSc (dSSc) and 10% of patients were diagnosed with an overlap-syndrome. 8% had an undifferentiated form while Scleroderma sine scleroderma was present in 0.7% of patients. Follow-up data are available from 1595 patients after one year, from 901 patients followed for two years, 573 patients followed for three years and 386 followed for at least four years. After four years a significant increase was detected in the frequency of pulmonary hypertension (PAH) (14.4% to 24.2%, p=0.001), lung fibrosis (38.8% to 47.6%, p=0.006), oesophagus involvement (58.5% to 74.8%, p=0.0001), bowel involvement (13.6% to 19.9%, p=0.03), Kidney (10.7% to 15.8%, p=0.03) and Heart (13.4% to 24.0%, p<0.0001) involvement. Disease subsets were associated with different organs being more frequently involved, i.e. lcSSc with PAH (13.5% to 25.0%, p=0.007), oesophagus (60.7% to 77.0%, p=0.0001) and colon involvement (7.3% to 11.6%, p=0.002); dcSSc with PAH (19.0% vs. 25.9%, p=0.035), lung fibrosis (63.5% vs. 71.4%, p=0.02) and heart involvement (19.1% vs. 27.7%, p=0.007). Interestingly, patients with overlap syndrome showed no significant change in organ involvement over time. Conclusions After four years of follow-up in a large well defined SSc cohort, a significant increase in frequency of organ involvement was observed, particularly with respect to the lung, GI-tract and heart. Patients with SSc should be followed at least annually for organ involvement, the frequency of follow-ups being increased depending on the disease activity. Disclosure of Interest None Declared
    Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):396-397. DOI:10.1136/annrheumdis-2012-eular.2701 · 10.38 Impact Factor
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    ABSTRACT: Background Overlap syndromes are a very heterogeneous and remarkable group of patients, who present at least two connective tissue diseases (CTDs) at the same time, usually with a specific autoantibody status. Currently it is still debated, whether SSc patients showing signs of overlaps to other connective tissue diseases should be regarded as a specific disease subset. Objectives To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited (lcSSc) and diffuse cutaneous SSc (dcSSc). Methods We here present the data of a prospective study, involving well-defined 3323 patients, registered (with yearly follow-up informations) in a database of the German network for systemic sclerosis (DNSS). The following statistical methods were used: Kaplan-Meier analysis, cox regression, logistic regression, McNemar test as well as א2test/Fisher’s exact test. Results Among 3323 registered patients, 10% (325/3240) were diagnosed as SSc-overlap syndrome. Of these, 82.5% (268/325) were female with a mean age of 49, 2 ± 1.2 years. Significantly more of them developed musculoskeletal involvement, compared to lcSSc and dcSSc patients (37.8 %, 47.8%; p<0.0001) and carried significantly more often other antibodies (71.1%; p<0.0001), which were separated into U1RNP- (22.7%), Ro- (16.8%), PmScl- (11.5%) antibodies, followed by 10.8% with rheumatoid factors, 7.5% with La-, 5.8% with dsDNA- and 2.8% with Jo-1- and 2.6% with Ku-antibodies. The Kaplan-Meier analysis of the onset of organ involvement revealed a clear inclined position of overlap patients between patients suffering from lcSSc and dcSSc, especially regarding lung fibrosis and heart involvement. Patients suffering from PAH, oesophagus involvement and kidney involvement, overlap and lcSSc patients showed nearly similar curve progression (log rank<0.0001). Furthermore musculoskeletal involvement was significantly more frequent and more progressive in patients with overlap disease, followed by patients with dcSSc and lcSSc (log rank<0.0001). Conclusions These data support the current concept, that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different course of the disease, different proportional distribution of specific autoantibodies and skin/organ involvement. Disclosure of Interest None Declared
    Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A645-A646. DOI:10.1136/annrheumdis-2013-eular.1917 · 10.38 Impact Factor
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    ABSTRACT: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies.These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.
    Annals of the rheumatic diseases 01/2014; 74(4). DOI:10.1136/annrheumdis-2013-204487 · 10.38 Impact Factor
  • Pediatric Rheumatology 12/2013; 11(Suppl 2):P214. DOI:10.1186/1546-0096-11-S2-P214 · 1.62 Impact Factor
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    Pediatric Rheumatology 12/2013; 11(Suppl 2):P321. DOI:10.1186/1546-0096-11-S2-P321 · 1.62 Impact Factor
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    ABSTRACT: Objective. Patients with RA suffer from a higher risk of periodontal attachment loss and increased oral inflammation. We hypothesize that there are pathogenetic and immunological interactions between these diseases that go beyond impaired manual dexterity accompanying advanced RA. The primary objective of the present study was to determine whether a loss of alveolar bone can be detected in RA patients during the early course of the disease.Methods. In this cross-sectional, epidemiological case-control study, 22 patients with early RA (ERA) were compared with 22 matched healthy controls. Oral and periodontal status, clinical activity, and socio-demographic parameters were determined. Oral microbiota were analysed using real-time quantitative PCR specific for leading oral pathogens.Results. More advanced forms of periodontitis were found in ERA patients compared with controls. ERA patients had a greater number of missing teeth [ERA 5.7 (s.d. 5.0), controls 1.9 (s.d. 1.0), P = 0.002], deeper periodontal pockets [clinical attachment level: ERA 3.4 (s.d. 0.5 mm), controls 2.7 (s.d. 0.3 mm), P < 0.000], and greater bleeding on probing [ERA 18.6% (s.d. 9.0%), controls 10.5% (s.d. 5.1%), P = 0.001] despite comparable oral hygiene. Tannerella forsythia (6.77-fold, P = 0.033) subgingivally and Streptococcus anginosus (3.56-fold, P = 0.028) supragingivally were the characteristic pathogens in ERA.Conclusion. Increased loss of periodontal attachment and alveolar bone can be detected in patients with ERA, therefore we propose that the consulting rheumatologists inform the patients that they have a higher risk of periodontal disease. It would be beneficial if these patients were referred directly for intensive dental care.
    Rheumatology (Oxford, England) 11/2013; 53(3). DOI:10.1093/rheumatology/ket362 · 4.44 Impact Factor
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    Pediatric Rheumatology 11/2013; 11(Suppl 1):A255. DOI:10.1186/1546-0096-11-S1-A255 · 1.62 Impact Factor
  • Pediatric Rheumatology 11/2013; 11(Suppl 1):A182. DOI:10.1186/1546-0096-11-S1-A182 · 1.62 Impact Factor
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    Pediatric Rheumatology 11/2013; 11(Suppl 1):A181. DOI:10.1186/1546-0096-11-S1-A181 · 1.62 Impact Factor

Publication Stats

1k Citations
315.77 Total Impact Points

Institutions

  • 2005–2015
    • Universität Heidelberg
      • • Department of Rheumatology
      • • V. Medicine Clinic
      Heidelburg, Baden-Württemberg, Germany
  • 2008
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2000–2002
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Department of Clinical and Molecular Virology
      Erlangen, Bavaria, Germany