Ein Leibniz Institute

Berlin, Germany

Ein Leibniz Institute

Berlin, Germany
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Hutloff A.,ein Leibniz Institute
Zeitschrift fur Rheumatologie | Year: 2016

The T and B lymphocytes in secondary lymphoid organs, such as the spleen and lymph nodes, normally reliably protect our body from infectious diseases; however, in rheumatoid arthritis they infiltrate tissues and substantially contribute to tissue destruction in rheumatic joints by production of inflammatory chemokines and autoreactive antibodies. It was previously unclear whether these lymphocytes infiltrate tissues as fully differentiated effector cells from neighboring lymph nodes or whether they are locally generated. A recent study has now shown that T and B cells actively cooperate together even outside lymphoid tissue. A follicular T‑helper cell-like population promotes the local generation of germinal center-like B cells and high-affinity plasma cells. © 2016 Springer-Verlag Berlin Heidelberg


Cossarizza A.,University of Modena and Reggio Emilia | Nolan J.,La Jolla Bioengineering Institute | Radbruch A.,Ein Leibniz Institute | Radbruch A.,Charité - Medical University of Berlin | Tarnok A.,University of Leipzig
European Journal of Immunology | Year: 2012

Cytometry is a key technology for immunology. It allows researchers to scrutinize the cells of the immune system in molecular detail, and to assess phenotype and function at the level of individual cells, no matter how rare these cells may be. The International Society for the Advancement of Cytometry, ISAC, by way of its meetings, online resources and publications (e.g. Cytometry Part A and Current Protocols in Cytometry, which are all published by Wiley) track the ever advancing developments regarding cytometry instrumentation and reagents, and the analysis of complex data sets. In June this year in Leipzig, Germany, ISAC held its annual conference "CYTO 2012", a marketplace of innovation in cytometry. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Smiljanovic B.,Ein Leibniz Institute | Grun J.R.,Ein Leibniz Institute | Biesen R.,Charité - Medical University of Berlin | Schulte-Wrede U.,Ein Leibniz Institute | And 8 more authors.
Journal of Molecular Medicine | Year: 2012

Many cytokines are involved in the pathogenesis of autoimmune diseases and are recognized as relevant therapeutic targets to attenuate inflammation, such as tumor necrosis factor (TNF)-α in rheumatoid arthritis (RA) and interferon (IFN)-α/γ in systemic lupus erythematosus (SLE). To relate the transcriptional imprinting of cytokines in a cell type- and disease-specific manner, we generated gene expression profiles from peripheral monocytes of SLE and RA patients and compared them to in vitro-generated signatures induced by TNF-α, IFN-α2a, and IFN-γ. Monocytes from SLE and RA patients revealed disease-specific gene expression profiles. In vitro-generated signatures induced by IFN-α2a and IFN-γ showed similar profiles that only partially overlapped with those induced by TNF-α. Comparisons between disease-specific and in vitro-generated signatures identified cytokine-regulated genes in SLE and RA with qualitative and quantitative differences. The IFN responses in SLE and RA were found to be regulated in a STAT1-dependent and STAT1-independent manner, respectively. Similarly, genes recognized as TNF-α regulated were clearly distinguishable between RA and SLE patients. While the activity of SLE monocytes was mainly driven by IFN, the activity from RA monocytes showed a dominance of TNF-α that was characterized by STAT1 down-regulation. The responses to specific cytokines were revealed to be disease-dependent and reflected the interplay of cytokines within various inflammatory milieus. This study has demonstrated that monocytes from RA and SLE patients exhibit disease-specific gene expression profiles, which can be molecularly dissected when compared with in vitro-generated cytokine signatures. The results suggest that an assessment of cytokine-response status in monocytes may be helpful for improvement of diagnosis and selection of the best cytokine target for therapeutic intervention. © 2012 Springer-Verlag.


Listing J.,Ein Leibniz Institute | Kekow J.,Otto Von Guericke University of Magdeburg | Manger B.,Friedrich - Alexander - University, Erlangen - Nuremberg | Burmester G.-R.,Charité - Medical University of Berlin | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2015

Objectives: To investigate the impact of disease activity, the course of the disease, its treatment over time, comorbidities and traditional risk factors on survival. Methods: Data of the German biologics register RABBIT were used. Cox regression was applied to investigate the impact of time-varying covariates (disease activity as measured by the DAS28, functional capacity, treatment with glucocorticoids, biologic or synthetic disease modifying antirheumatic drugs (DMARDs)) on mortality after adjustment for age, sex, comorbid conditions and smoking. Results: During 31 378 patient-years of follow-up, 463 of 8908 patients died (standardised mortality ratio: 1.49 (95% CI 1.36 to 1.63)). Patients with persistent, highly active disease (mean DAS28 > 5.1) had a significantly higher mortality risk (adjusted HR (HRadj)=2.43; (95% CI 1.64 to 3.61)) than patients with persistently low disease activity (mean DAS28 < 3.2). Poor function and treatment with glucocorticoids > 5 mg/d was significantly associated with an increased mortality, independent of disease activity. Significantly lower mortality was observed in patients treated with tumour necrosis factor α (TNFα) inhibitors (HRadj=0.64 (95% CI 0.50 to 0.81), rituximab (HRadj=0.57 (95% CI 0.39 to 0.84), or other biologics (HRadj =0.64 (95% CI 0.42 to 0.99), compared to those receiving methotrexate. To account for treatment termination in patients at risk, an HRadj for patients ever exposed to TNFα inhibitors or rituximab was calculated. This resulted in an HRadj of 0.77 (95% CI 0.60 to 0.97). Conclusions Patients with long-standing high disease activity are at substantially increased risk of mortality. Effective control of disease activity decreases mortality. TNFα inhibitors and rituximab seem to be superior to conventional DMARDs in reducing this risk. © 2015, BMJ Publishing Group.


PubMed | Otto Von Guericke University of Magdeburg, Friedrich - Alexander - University, Erlangen - Nuremberg, Ein Leibniz Institute and Charité - Medical University of Berlin
Type: Journal Article | Journal: Annals of the rheumatic diseases | Year: 2015

To investigate the impact of disease activity, the course of the disease, its treatment over time, comorbidities and traditional risk factors on survival.Data of the German biologics register RABBIT were used. Cox regression was applied to investigate the impact of time-varying covariates (disease activity as measured by the DAS28, functional capacity, treatment with glucocorticoids, biologic or synthetic disease modifying antirheumatic drugs (DMARDs)) on mortality after adjustment for age, sex, comorbid conditions and smoking.During 31378 patient-years of follow-up, 463 of 8908 patients died (standardised mortality ratio: 1.49 (95% CI 1.36 to 1.63)). Patients with persistent, highly active disease (mean DAS28>5.1) had a significantly higher mortality risk (adjusted HR (HRadj)=2.43; (95% CI 1.64 to 3.61)) than patients with persistently low disease activity (mean DAS28<3.2). Poor function and treatment with glucocorticoids >5mg/d was significantly associated with an increased mortality, independent of disease activity. Significantly lower mortality was observed in patients treated with tumour necrosis factor (TNF) inhibitors (HRadj=0.64 (95% CI 0.50 to 0.81), rituximab (HRadj=0.57 (95% CI 0.39 to 0.84), or other biologics (HRadj=0.64 (95% CI 0.42 to 0.99), compared to those receiving methotrexate. To account for treatment termination in patients at risk, an HRadj for patients ever exposed to TNF inhibitors or rituximab was calculated. This resulted in an HRadj of 0.77 (95% CI 0.60 to 0.97).Patients with long-standing high disease activity are at substantially increased risk of mortality. Effective control of disease activity decreases mortality. TNF inhibitors and rituximab seem to be superior to conventional DMARDs in reducing this risk.


PubMed | ein Leibniz Institute
Type: Journal Article | Journal: Zeitschrift fur Rheumatologie | Year: 2016

The T and B lymphocytes in secondary lymphoid organs, such as the spleen and lymph nodes, normally reliably protect our body from infectious diseases; however, in rheumatoid arthritis they infiltrate tissues and substantially contribute to tissue destruction in rheumatic joints by production of inflammatory chemokines and autoreactive antibodies. It was previously unclear whether these lymphocytes infiltrate tissues as fully differentiated effector cells from neighboring lymph nodes or whether they are locally generated. Arecent study has now shown that Tand Bcells actively cooperate together even outside lymphoid tissue. A follicular Thelper cell-like population promotes the local generation of germinal center-like Bcells and high-affinity plasma cells.


Zink A.,Ein Leibniz Institute | Zink A.,Charité - Medical University of Berlin | Manger B.,Friedrich - Alexander - University, Erlangen - Nuremberg | Krause A.,Immanuel Diakonie Group | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objective: To evaluate the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score for serious infections in patients with rheumatoid arthritis (RA). Methods: The RABBIT Risk Score for serious infections was developed in 2011 on a cohort of RA patients enrolled in the German biologics register RABBIT between 2001 and 2007. To evaluate this score, we used data from patients enrolled in RABBIT after 1 January 2009. Expected numbers of serious infections and expected numbers of patients with at least one serious infection per year were calculated by means of the RABBIT Risk Score and compared with observed numbers in the evaluation sample. Results: The evaluation of the score in an independent cohort of 1522 RA patients treated with tumour necrosis factor α (TNFα) inhibitors and 1468 patients treated with non-biological disease-modifying antirheumatic drugs (DMARDs) showed excellent agreement between observed and expected rates of serious infections. For patients exposed to TNF inhibitors, expected as well as observed numbers of serious infections were 3.0 per 100 patient-years (PY). For patients on non-biological DMARDs the expected and observed numbers were 1.5/100 PY and 1.8/100 PY, respectively. The score was highly predictive in groups of patients with low as well as with high infection risk. Conclusions: The RABBIT Risk Score is a reliable instrument which determines the risk of serious infection in individual patients based on clinical and treatment information. It helps the rheumatologist to balance benefits and risks of treatment, to avoid high-risk treatment combinations and thus to make informed clinical decisions.


Strangfeld A.,Ein Leibniz Institute | Eveslage M.,Ein Leibniz Institute | Schneider M.,Heinrich Heine University Düsseldorf | Bergerhausen H.J.,Klinik fuer Rheumatologie | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective: To examine the risk of serious infection conveyed by tumour necrosis factor α (TNFα) inhibitors in the treatment of rheumatoid arthritis (RA). Methods: Data from patients with RA enrolled in the German biologics register RABBIT were used for analysis. Baseline patient characteristics, time-varying risk factors (treatment changes, functional capacity) and selection processes caused by dropout, death or switching to non-anti-TNF treatment were taken into account to estimate the adjusted incidence rate ratios (IRR adj ) of serious infection during treatment with TNF inhibitors compared with non-biological disease-modifying antirheumatic drug treatment. Results: Data were available on 5044 patients, in whom 392 serious infections occurred. The crude rates of serious infections in patients treated with TNF inhibitors declined over the first 3 years of observation (from 4.8 to 2.2/100 patient-years). This decline was driven by (1) treatment termination or loss to follow-up in patients at increased risk and (2) a risk reduction through decreasing glucocorticoid doses and improvement in function. Adjusted for selection processes and time-varying risk factors, the following parameters assessed at baseline (age, chronic diseases) or at follow-up prior to the infection were significantly associated with an increased risk: age >60 years, chronic lung or renal disease, low functional capacity, history of serious infections, treatment with glucocorticoids (7.5-14 mg/day, IRR adj 2.1 (95% CI 1.4 to 3.2); ≥15 mg/day, IRR adj 4.7 (95% CI 2.4 to 9.4)) and treatment with TNFα inhibitors (IRR adj 1.8 (95% CI 1.2 to 2.7)). Conclusion: Reasons for the decline in infection rates observed at the group level were identified. The results enable expected infection rates to be calculated in individual patients based on their risk profiles.


PubMed | Friedrich - Alexander - University, Erlangen - Nuremberg, Charité - Medical University of Berlin, Immanuel Diakonie Group and Ein Leibniz Institute
Type: Evaluation Studies | Journal: Annals of the rheumatic diseases | Year: 2014

To evaluate the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score for serious infections in patients with rheumatoid arthritis (RA).The RABBIT Risk Score for serious infections was developed in 2011 on a cohort of RA patients enrolled in the German biologics register RABBIT between 2001 and 2007. To evaluate this score, we used data from patients enrolled in RABBIT after 1 January 2009. Expected numbers of serious infections and expected numbers of patients with at least one serious infection per year were calculated by means of the RABBIT Risk Score and compared with observed numbers in the evaluation sample.The evaluation of the score in an independent cohort of 1522 RA patients treated with tumour necrosis factor (TNF) inhibitors and 1468 patients treated with non-biological disease-modifying antirheumatic drugs (DMARDs) showed excellent agreement between observed and expected rates of serious infections. For patients exposed to TNF inhibitors, expected as well as observed numbers of serious infections were 3.0 per 100 patient-years (PY). For patients on non-biological DMARDs the expected and observed numbers were 1.5/100PY and 1.8/100PY, respectively. The score was highly predictive in groups of patients with low as well as with high infection risk.The RABBIT Risk Score is a reliable instrument which determines the risk of serious infection in individual patients based on clinical and treatment information. It helps the rheumatologist to balance benefits and risks of treatment, to avoid high-risk treatment combinations and thus to make informed clinical decisions.


PubMed | Ein Leibniz Institute, Charité - Medical University of Berlin, Heinrich Heine University Düsseldorf and Wedau Klinikum
Type: Comparative Study | Journal: Rheumatology (Oxford, England) | Year: 2015

To compare the 24-month course of health-related quality of life (HRQoL) in patients with long-standing RA treated with a conventional synthetic (cs) or a first, second or third biologic (b) DMARD in daily rheumatological care.Patients enrolled in the German biologics register RABBIT who were observed over at least 12 months were stratified according to the nth bDMARD started at enrolment. HRQoL was captured by the SF36 health survey. Within strata of sequential bDMARD therapy, we examined patients HRQoL at baseline and at follow-ups in comparison with the general population, the 24-month course of HRQoL of different bDMARDs and the proportion of patients exceeding the minimal detectable improvement of physical and mental health sum scores.All patients reported remarkably lower scores of physical and mental health than the general population at baseline and month 12. In each stratum of sequential bDMARD therapy, patients improved significantly by month 12 and remained stable until month 24. The improvement of HRQoL was not attributable to a particular bDMARD. The following proportions of patients exceeded the minimal detectable improvement of at least 17.85 Physical Component Scale scores or 22.18 Mental Component Scale score points: csDMARD (n = 1113) 31.1%/22.3%, first bDMARD (n = 1352) 39.9%/29.7%, second bDMARD (n = 730) 37.3%/26.2% and third bDMARD (n = 680) 34.2%/30.9%.Lasting improvement of both physical and mental health is achievable even for severely affected RA patients with a history of more than one bDMARD failure. Nevertheless, impairment of HRQoL in RA patients is enormous compared with the general population.

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