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(1) Background: To date, the response of patients with rheumatoid arthritis (RA) to the various biologic DMARD available cannot be predicted due to a lack of reliable biomarkers. Based on our preliminary work on tmTNF reverse signaling, we developed a whole-blood assay measuring tmTNF crosslinking-induced IL-10 production to predict the response to TNF inhibitor (TNFi) therapy. (2) Methods: This prospective study included patients with active RA. Depending on the clinical judgment of the attending rheumatologist, either therapy with a TNF or JAK inhibitor was initiated. Clinical parameters and blood samples were obtained at baseline and after 8 weeks of therapy. The blood samples were collected using a newly developed whole-blood assay based on the principle of tmTNF reverse signalling. Subsequently, IL-10 was measured via enzyme-linked immunosorbent assay (ELISA) technique. (3) Results: 63 patients with RA were enrolled. In fifteen patients, TNFi therapy was initiated, while eight patients started a JAKi treatment. The cross-sectional analysis of all patients showed a positive correlation between tmTNF crosslinking-induced IL-10 and parameters of disease activity (CRP [r = 0.4091, p = 0.0009], DAS28 [r = 0.3303, p = 0.0082]) at baseline. In the TNFi treatment study, IL-10 was found to be significantly higher in EULAR responders than in non-responders (p = 0.0033). After initiation of JAKi treatment, in contrast, IL-10 induction was not linked to response. Longitudinal analysis of the TNFi-treated patients revealed IL-10 to decrease in responders (p = 0.04), but not in non-responders after 8 weeks of therapy. Of importance, the IL-10 production at baseline correlated inversely with TNFi response determined by ΔDAS28 in patients with TNFi treatment (r = −0.5299, p = 0.0422) while no such link was observed under JAKi therapy (p = 0.22). Receiver operation characteristics (ROC) analysis demonstrated a high performance of tmTNF/crosslinking-induced IL-10 in predicting a TNFi therapy response according to the EULAR criteria (AUC = 0.9286, 95% Confidence interval 0.7825–1.000, p = 0.0055). (4) Conclusions: In this pilot investigation, we demonstrated the feasibility of a whole-blood assay measuring tmTNF-induced IL-10 to predict clinical response to TNF inhibitor treatment. This approach might support rheumatologists in their decision for an individually tailored RA therapy.

A few days after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled the first group of recommendations for the care of patients with inflammatory rheumatic diseases in light of SARS-CoV-2/coronavirus disease 2019 (COVID-19). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registries, cross-sectional studies, case reports and case series are available, the DGRh has developed a timely update. This update is based on a literature search of publications available through 15 June 2020 and addresses preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. Driven by the commitment to let patients benefit from these new evidence-based recommendations as quickly as possible, the DGRh published the update in German on its homepage and in the Zeitschrift für Rheumatologie immediately after completion. Here we report the key recommendations to make them available to the international community, provide the scientific methodology used to develop the recommendations, give additional thoughts and advice for the management of patients with rheumatic diseases during the COVID-19 pandemic and discuss our recommendations in the context of other international recommendations.

Die Behandlung von rheumatischen Erkrankungen mit Biologika hat die Prognose der Patienten deutlich verbessert. Heute stehen in Deutschland 13 Praparate fur die Behandlung von Patienten mit entzundlich rheumatischen Erkrankungen zur Verfugung. Diese Originalpraparate geniesen meist 15 Jahre Patentschutz, Unterschiede der einzelnen Lander ausen vor gelassen. Sobald dieser abgelaufen ist, konnen behordlich zugelassene Nachahmerprodukte, sog. Biosimilars, in den Verkehr gebracht werden. Fur die Zulassung eines Biosimilars verlangen Behorden wie die European Medical Agency oder die amerikanische Food and Drug Administration den Nachweis der grostmoglichen Vergleichbarkeit zum Original- oder Referenzprodukt hinsichtlich Wirksamkeit und Sicherheit. In der Europaischen Union, den USA, Japan und in anderen Landern wurden seit 2015 Biosimilars von Infliximab, Adalimumab, Etanercept und Rituximab zugelassen. Fur diese Referenzprodukte sind weitere Biosimilars fur die Behandlung rheumatologischer Erkrankungen in Entwicklung. Aus gesellschaftlicher und arztlicher Sicht eroffnet dies Moglichkeiten, die Verfugbarkeit biopharmazeutischer Produkte fur Patienten aufgrund niedrigerer Preise zu erhohen. In Deutschland wird diese Moglichkeit bereits genutzt: Kassenarztliche Vereinigungen haben Quoten fur Biosimilars eingefuhrt, um ihre und die Ausgaben im Gesundheitswesen zu senken. Das kann zu Preissenkungen der Originalprodukte fuhren, was in Deutschland bereits geschehen ist. Biosimilars konnen bei Neueinstellungen auf die Substanz eingesetzt werden oder als Wechsel vom Original zum Nachahmerpraparat. Beim Wechsel wird zwischen dem individuellen Wechsel („interchangeability“), der in individueller Absprache zwischen Arzt und Patient getroffen wird, und dem „nonmedical switching“ („substitution“) unterschieden. Letzteres geschieht anhand systematischer Entscheidungen auf gesellschaftlicher oder staatlicher Ebene, die im Rahmen der Kostendammung im Gesundheitswesen getroffen und dann z. B. auf Apothekerebene umgesetzt werden. Zur Substitution liegen inzwischen erste Daten aus Norwegen und Danemark auf Basis von Ergebnissen groser Studien bzw. von Registern vor, in denen systematisch gewechselt wurde. Das bisherige Fazit ist, dass sich hieraus fur die Patienten keine neuen Probleme ergeben. Die Deutsche Gesellschaft fur Rheumatologie erkennt die Vorteile der Einfuhrung von Biosimilars in Deutschland, empfiehlt deren Einsatz aber vor allem basierend auf einer gemeinsamen Entscheidung von behandelndem Arzt und Patienten.

Objective Leukocyte immunoglobulin-like receptor 1 (LIR-1) is up-regulated by cytomegalovirus (CMV), which in turn, has been associated with premature aging and more severe joint disease in patients with rheumatoid arthritis (RA). The aim of this study was to investigate the expression and functional significance of LIR-1 in CMV-positive RA patients. Methods We determined the phenotype, cytolytic potential, CMV-specific proliferation, and HLA–G–triggered, LIR-1–mediated inhibition of interferon-γ secretion of LIR-1+ T cells in RA patients and healthy controls. Results We found increased frequencies of CD8+ T cells with CMV pp65–specific T cell receptors in CMV-positive RA patients as compared to CMV-positive healthy controls. CMV-specific CD8+ T cells in these patients were preferentially LIR-1+ and exhibited a terminally differentiated polyfunctional phenotype. The numbers of LIR-1+CD8+ T cells increased with age and disease activity, and showed high levels of reactivity to CMV antigens. Ligation of LIR-1 with soluble HLA–G molecules in vitro confirmed an inhibitory role of the molecule when expressed on CD8+ T cells in RA patients. Conclusion We propose that latent CMV infection in the context of a chronic autoimmune response induces the recently described “chronic infection phenotype” in CD8+ T cells, which retains anti-infectious effector features while exhibiting autoreactive cytolytic potential. This response is likely dampened by LIR-1 to avoid overwhelming immunopathologic changes in the setting of the autoimmune disease RA. The known deficiency of soluble HLA–G in RA and the observed association of LIR-1 expression with disease activity suggest, however, that LIR-1+ T cells are insufficiently controlled in RA and are still likely to be involved in the pathogenesis of the disease.

Objective Dysregulated apoptosis of monocytes is a pathogenic feature of rheumatoid arthritis (RA). The aim of this study was to investigate the role of TRAIL and TRAIL-induced apoptosis in patients with RA. Methods Cell surface expression and serum concentrations of TRAIL were determined in 63 patients with RA, and TRAIL-induced monocyte apoptosis was quantified. Surface expression of TRAILR-1, TRAILR-2, TRAILR-3, TRAILR-4, CXCR1, and CXCR2 was determined, and intracellular signal transduction was investigated. In 8 patients with RA, clinical and laboratory parameters of disease activity were investigated longitudinally, before and after initiation of treatment with tumor necrosis factor (TNF) inhibitors. Results Serum concentrations of both TRAIL and interleukin-8 (IL-8) were increased in patients with RA, while cell surface expression of the TRAIL receptors TRAILR-1, TRAILR-2, TRAILR-3, and TRAILR-4 was diminished. TRAIL-induced monocyte apoptosis was significantly decreased in RA due to increased TRAIL-induced IL-8 secretion by RA monocytes. The combined effect of TRAIL and IL-8 on monocytes resulted in activation of antiapoptotic pathways, including p42/44 MAPK and p38. Susceptibility to TRAIL-induced apoptosis was restored in RA monocytes after 3 months of TNF inhibition. Conclusion In RA, circulating monocytes with the potential to produce proinflammatory cytokines appear to have defects in several pathways of apoptosis induction, among which is a deficiency in TRAIL-induced apoptosis. Although this resistance to apoptosis might contribute to perpetuation of the disease, it remains to be determined whether specific induction of apoptosis could be therapeutically beneficial.

The pathophysiology of numerous human disorders, such as atherosclerosis, diabetes, obesity and Alzheimer's disease, is accompanied by increased production of reactive oxygen species (ROS). ROS can oxidatively damage nearly all biomolecules, including lipids, proteins and nucleic acids. In particular, (poly)unsaturated fatty acids within the phospholipid (PL) structure are easily oxidized by ROS to lipid peroxidation products (LPP) carrying reactive carbonyl groups. Carbonylated LPP are characterized by high in vivo toxicity due to their reactivity with nucleophilic substrates (Lys-, Cys-and His-residues in proteins or amino groups of phosphatidylethanolamines [PE]). Adducts of unsaturated LPP with PE amino groups have been reported before, whereas less is known about the reactivity of saturated alkanals – which are significantly increased in vivo under oxidative stress conditions – towards nucleophilic groups of PLs. Here, we present a study of new alkanal-dipalmitoyl-phosphatidylethanolamine (DPPE) adducts by MS-based approaches, using consecutive fragmentation (MSn) and multiple reaction monitoring techniques. At least eight different DPPE–hexanal adducts were identified, including Schiff base and amide adducts, six of which have not been reported before. The structures of these new compounds were determined by their fragmentation patterns using MSn experiments. The new PE-hexanal adducts contained dimeric and trimeric hexanal conjugates, including cyclic adducts. A new pyridine ring containing adduct of DPPE and hexanal was purified by HPLC, and its biological effects were investigated. Incubation of peripheral blood mononuclear cells and monocytes with modified DPPE did not result in increased production of TNF-α as one selected inflammation marker. However, incorporation of modified DPPE into 1,2-dipalmitoleoyl-sn-phosphatidylethanolamine multilamellar vesicles resulted in a negative shift of the transition temperature, indicating a possible role of alkanal-derived modifications in changes of membrane structure. © 2014 The Authors. Journal of Mass Spectrometry published by John Wiley & Sons, Ltd.

Inhibition of return (IOR) is an important psychological construct describing inhibited responses to previously attended locations. In humans, it is investigated using Posner’s cueing paradigm. This paradigm requires central visual fixation and detection of cued stimuli to the left or right of the fixation point. Stimuli can be validly or invalidly cued, appearing in the same or opposite location to the cue. Although a rat version of the spatial cueing paradigm (the covert orienting of attention task) does exist, IOR has so far not been demonstrated. We therefore investigated whether IOR could be robustly demonstrated in adult male rats using the covert orienting of attention task. This task is conducted in holed wall operant chambers with the central three holes mimicking the set-up for Posner cueing. Across four samples of rats (overall n = 84), we manipulated the following task parameters: stimulus onset asynchronies (Experiments 1–3), cue brightness (Experiment 1b) and the presence of a central reorienting event (Experiment 4). In Experiment 1, we also investigated strain differences by comparing Lister Hooded rats to Sprague–Dawley rats. Although Lister Hooded rats briefly showed evidence of IOR (Experiment 1a, and see Online Resource 1 data), we were unable to replicate this finding in our other experiments using different samples of this strain. Taken together, our findings suggest that IOR cannot be robustly demonstrated in the rat using the covert orienting of attention task conducted in holed wall operant chambers.

The generation of T cell receptor excision circle (TREC)–positive recent thymic emigrants (RTEs) in humans declines progressively with increasing age. Homeostatic proliferation is possibly an extrathymic mechanism for the generation of new T cells, and lymphopenia and common γ-chain cytokines appear to be the main driving force (1). However, thymic generation of TREC-positive RTEs can be restimulated throughout adult life if an increased supply of T cells is required under conditions of lymphopenia. Rheumatoid arthritis (RA) is associated with phenotypic alterations of T helper lymphocytes reminiscent of premature immunosenescence (2). In addition, RA is characterized by an age-inappropriate decrease in the number of CD4+ naive T cells and TREC-positive T cells (3), indicating decreased thymic output, diluting effects due to increased homeostatic maintenance proliferation, or both. Accelerated homeostatic proliferation of CD4+ T cells has also been observed in individuals who were thymectomized in early childhood, resulting in premature aging of T cells (4). In theory, thymic output in RA could be insufficient due to a shortage of thymus-seeding precursor cells. In the human system, those precursors were initially characterized in bone marrow as lineage-negative (Lin−) CD34+CD10+ common lymphoid progenitors (CLPs) (5), and their phenotype was subsequently refined to Lin−CD34highCD45RA+CD10+ (6). Six et al showed that CD34+CD10+CD24− progenitor cells are capable of migrating from the bone marrow and seeding the thymus (7). CLPs have recently been shown to have robust T cell potential regardless of CD7 expression, which appears to be a less important marker (8). Therefore, we decided to use CD10 expression as a marker defining the lymphoid commitment of human cells, in order to analyze the frequency of the best-characterized lymphoid-restricted progeny of hematopoietic stem cells (HSCs) (i.e., Lin−CD34+CD10+ CD24− CLPs) in the peripheral blood of patients with RA and healthy control subjects. In order to simultaneously determine thymic output, we measured the frequency of CD4+CD31+CD45RA+ T cells, which represents a well-established surrogate marker for TREC-positive RTEs (9). The results of the current study show a strong correlation between the frequencies of CLPs and RTEs in healthy control subjects. Compared with control subjects, patients with RA had a deficiency of RTEs despite a significantly increased number of thymic progenitors. Therapy with the tumor necrosis factor (TNF) inhibitor etanercept increased the frequency of thymic progenitors even further and almost normalized the deficient thymic output.

Objective The cytokine tumor necrosis factor (TNF) plays a central role in the pathogenesis of rheumatoid arthritis (RA), but its disease-specific effector mechanisms have not been fully elucidated. This study was undertaken to investigate the role of TNF in T cell accumulation and migration in the synovitic joints of RA patients. Methods Vital tissue sections from rheumatoid synovium were generated using a horizontally oscillating microtome and were coincubated with fluorescence-labeled CD4+ T cells. Migration was detected by fluorescence and confocal microscopy. Migrating T cells were recovered from the tissue and analyzed for phenotype. Chemotaxis of CD4+ T cells from RA patients in response to increasing concentrations of TNF was analyzed in Transwell experiments. Results CD4+ T cells from RA patients migrated into the tissue sections in significantly higher numbers than T cells from healthy controls. Migrating CD4+ T cells differed from nonmigrating ones in their increased expression of TNF receptor type I (TNFRI), which was expressed on a fraction of circulating CD4+ T cells from RA patients, but not from controls. CD4+ T cells from the peripheral blood of RA patients were also found to migrate along TNF concentration gradients ex vivo. Accordingly, blockade of either TNF or TNFRI nearly abrogated in vitro T cell migration in synovial tissue. Conclusion Our findings indicate that the interaction of TNF with TNFRI is pivotal for T cell migration in synovial tissue in vitro, and thereby suggest a relevant role of the cytokine for in vivo T cell trafficking to synovitic joints.

Activated CD4+ T-cells are found in joints of patients with rheumatoid arthritis and are involved in the joint destroying autoimmune response. Besides proinflammatory cytokine production T-cells are indispensable for the activation of B-cells, the so-called T-cell help for B-cells. However, the recognition of autoantigens by T-cells seems of utmost importance for the pathogenesis of rheumatoid arthritis. Selective inhibition of this process is therefore one of the most interesting therapeutic targets for the future.

Rheumatoid arthritis (RA) is a chronic rheumatic disease of unknown aetiology and variable severity. It is now well known that several risk factors are involved in its pathogenesis, including genetic factors and sex hormones as well as environmental factors, i.e. infections and stress. In particular stress is now recognised as an important risk factor for the onset and even more for the modulation of disease activity in RA. Many studies have clearly shown that chronic mild stress (family or professional stress) may lead to proinflammatory effects, increasing disease activity. Furthermore, a positive correlation between the stress level at the onset of RA and radiological progression could be demonstrated. The onset of RA was associated with moderate stress at work, underlining the possible interactions between the various stress systems and the immune system. In this respect it could be demonstrated that coping strategies reduce stress episodes and change stress management with a positive impact on disease activity in RA. However, more studies are warranted to further explore the pathophysiological implications of stress on onset and activity of chronic autoimmune diseases.

Genome-wide association studies have dramatically increased our knowledge about the genetic contribution to autoimmune diseases. The identified genes are indicators for signal transduction pathways involved in disease pathogenesis and could contribute to potential new therapeutic approaches.

Die rheumatoide Arthritis (RA) ist mit einer gesteigerten kardiovaskularen Morbiditat und Mortalitat verbunden. Erhohte Konzentrationen von Akute-Phase-Proteinen und Zytokinen sowie die endotheliale Dysfunktion, welche auch bei Fehlen der traditionellen Risikofaktoren nachweisbar ist, werden hierfur verantwortlich gemacht. Modifiziert wird das Auftreten von kardiovaskularen Ereignissen durch die antirheumatische Therapie.

T cells, in particular CD4(+) T cells, have been implicated in mediating many aspects of rheumatoid inflammation. In rheumatoid arthritis (RA), CD4(+) T cells display various functional abnormalities in the synovium as well as in the peripheral circulation. Current evidence suggests, however, that the role of CD4(+) T cells in the development of rheumatoid inflammation exceeds that of activated pro-inflammatory effector T cells that drive the chronic autoimmune response. Subsets of CD4(+) T cells with regulatory capacity, such as CD25(+) Tregs, have been identified in mice and man, and recent observations suggest that in RA, the function of these regulatory T cells is severely impaired. Thus, in RA, defective regulatory immune mechanisms might allow the breakdown of peripheral tolerance, following which the detrimental CD4(+) T-cell-driven immune response evolves and proceeds to chronic inflammation. Here, we review the functional abnormalities and the contribution of different T-cell subsets to rheumatoid inflammation.

Die Rheumatoide Arthritis ist gekennzeichnet durch eine massive Produktion der Monokine TNFα, IL-6 und IL-1β in der Synovialmembran, wobei Monozyten und Makrophagen die Hauptproduzenten dieser Zytokine sind. Bisher ist noch unklar, wie es zu einer Aktivierung dieser Zellen kommt. Ein moglicher Mechanismus ist die zellkontaktabhangige Aktivierung der Monozyten/Makrophagen durch aktivierte T-Zellen. Der direkte Zellkontakt von Monozyten/Makrophagen und T-Zellen fuhrt zu einer starken Produktion von proinflammatorischen Zytokinen, wie z. B. TNFα und IL-1β. Unter nicht-pathologischen Bedingungen muss dieser Mechanismus einer strengen Kontrolle unterliegen, um systemische inflammatorische Reaktionen zu vermeiden. Das Vorhandensein von inhibitorischen Faktoren im Serum konnte einen solchen Mechanismus reprasentieren. Im Serum von gesunden Spendern wurde Apolipoprotein A-I als ein solcher Faktor identifiziert. Apolipoprotein A-I ist als negatives Akut- Phase-Protein bei Patienten mit Rheumatoider Arthritis in deutlich verminderten Konzentrationen im Serum zu finden. Die Rolle dieses und ahnlicher inhibitorischer Serummolekule bei Autoimmunerkrankung, Sepsis und Arteriosklerose wird diskutiert.

Das klinische Syndrom der rheumatoiden Vaskulitis (RV) hat sich in den letzten 40 Jahren als Begriff in der Rheumatologie etabliert, ohne das es bisher eine feststehende Begriffsdefiniton gibt. Bei der rheumatoiden Arthritis (RA), einer chronisch entzundlichen Erkrankung des Bindegewebes mit bevorzugtem Befall der Gelenkinnenhaut und daraus resultierender Knorpel- und Knochendestruktion werden haufig extraartikulare Erscheinungen beobachtet, deren bekannteste das Auftreten von Rheumaknoten darstellt (Rheumatismus nodosus). Auch bei der Riesenzellarteriitis (RZA) ergeben die Laborbefunde oft ausgepragte Entzundungskonstellationen, obwohl das morphologische Substrat dieser Entzundung noch nicht restlos geklart zu sein scheint. Das klinische Syndrom der Polymyalgia rheumatica (PMR) ist mit der RZA sehr haufig assoziiert, aber auch die RA im hoheren Lebensalter bereitet differentialdiagnostisch wegen ihrer zu Beginn haufig polymyalgiformen Symptomatik grose Probleme, zumal auch fluchtige Synovitiden vor allem an Knie- und Handgelenken bei der PMR beobachtet werden. Aus der Entzundung und Schadigung von Blutgefasen resultieren Lumeneinengung und damit Ischamie im vom betroffenen Gefas versorgten Gewebe, die bei der Arteriitis cranialis zur Erblindung fuhren kann. Aus Permeabilitatsstorungen der Endstrecken im Gefasbett entstehen Schadigungen der molekularen Austauschflachen in Organen wie Niere oder Lunge bis hin zum Organversagen.

The pathophysiology of numerous human disorders, such as atherosclerosis, diabetes, obesity and Alzheimer's disease, is accompanied by increased production of reactive oxygen species (ROS). ROS can oxidatively damage nearly all biomolecules, including lipids, proteins and nucleic acids. In particular, (poly)unsaturated fatty acids within the phospholipid (PL) structure are easily oxidized by ROS to lipid peroxidation products (LPP) carrying reactive carbonyl groups. Carbonylated LPP are characterized by high in vivo toxicity due to their reactivity with nucleophilic substrates (Lys-, Cys-and His-residues in proteins or amino groups of phosphatidylethanolamines [PE]). Adducts of unsaturated LPP with PE amino groups have been reported before, whereas less is known about the reactivity of saturated alkanals – which are significantly increased in vivo under oxidative stress conditions – towards nucleophilic groups of PLs. Here, we present a study of new alkanal-dipalmitoyl-phosphatidylethanolamine (DPPE) adducts by MS-based approaches, using consecutive fragmentation (MSn) and multiple reaction monitoring techniques. At least eight different DPPE–hexanal adducts were identified, including Schiff base and amide adducts, six of which have not been reported before. The structures of these new compounds were determined by their fragmentation patterns using MSn experiments. The new PE-hexanal adducts contained dimeric and trimeric hexanal conjugates, including cyclic adducts. A new pyridine ring containing adduct of DPPE and hexanal was purified by HPLC, and its biological effects were investigated. Incubation of peripheral blood mononuclear cells and monocytes with modified DPPE did not result in increased production of TNF-α as one selected inflammation marker. However, incorporation of modified DPPE into 1,2-dipalmitoleoyl-sn-phosphatidylethanolamine multilamellar vesicles resulted in a negative shift of the transition temperature, indicating a possible role of alkanal-derived modifications in changes of membrane structure. © 2014 The Authors. Journal of Mass Spectrometry published by John Wiley & Sons, Ltd.

Introduction Peripheral blood monocytes are no longer regarded as a homogeneous cell population, but can be differentiated both phenotypically and functionally into various subpopulations. In rheumatoid arthritis, the subpopulation of CD14bright/CD16+ monocyte is expanded and prone towards generation of Th17 cells. CD56+ monocytes represent a different subpopulation, which is also expanded in conditions associated with autoimmunity like inflammatory bowel diseases. The aim of the study was the quantification and functional characterization of the CD56+ monocyte subset in rheumatoid arthritis (RA). Methods Frequencies of peripheral blood monocyte subpopulations were analyzed by flow cytometry in 86 healthy controls and 75 RA patients. In 16 patients, anti-tumor necrosis factor (TNF) therapy was initiated, and the CD56+ monocyte frequency was monitored longitudinally. Lipopolysaccharide (LPS)-induced cytokine production of CD56+ and CD56– monocytes was determined by intracellular staining or cytokine secretion assays. Results In healthy individuals, 8.6% ± 0.6 of the monocytes co-expressed CD56, with the majority of CD56+ monocytes being CD14bright (7.9% ± 0.5), while only a minor population was CD14dim (0.7% ± 0.1). We found a strong positive correlation between an individual’s age and the frequency of CD56+ monocytes. Upon stimulation with LPS, CD56+ monocytes became more frequently positive for TNF, IL-10 and IL-23 than CD56– monocytes. In addition, CD56+ monocytes spontaneously produced more reactive oxygen intermediates than CD56- monocytes. In RA patients, the frequency of CD56+ monocytes was significantly higher than in healthy controls (12.2% ± 0.9 vs. 7.9% ± 0.5, p = 0.0002), and this difference most pronounced in RA patients below 40 years of age (11.1% ± 1.6 vs. 4.1% ± 0.4, P < 0.0001). Treatment of the patients with an anti-TNF blocking agent significantly reduced CD56+ monocyte frequencies (baseline 12.4% vs. 24 weeks treatment 8.0%, P = 0.0429), and the magnitude of this decrease was found to correlate with the change in disease activity under the therapy. Conclusion The CD14bright/CD56+ monocyte subset is expanded in aging individuals as well as in patients with RA. The pro-inflammatory production of cytokines and reactive oxygen species as well as the elimination of those cells in patients with a good response towards TNF inhibiting agents indicates a possible contribution of those monocytes in the inflammatory response in RA.

Introduction Suitable biomarkers are essential for therapeutic strategies in personalized medicine in terms of diagnosis as well as of prognosis. With highly specific biomarkers, it is possible, for example, to identify patients with poor prognosis, which enables early intervention and intensive treatment. The aim of this study was to identify and validate biomarkers and possible combinations for a prospective use in immunoscintigraphy, which may improve diagnosis of rheumatoid arthritis (RA) patients with consideration of inflammatory activity in the affected joints. Therefore, we tested several monoclonal antibodies (mAbs) directed against cellular-surface molecules on cells likely to be involved in the pathogenesis of RA. Methods Synovial tissue from patients with long-standing RA (accompanied by synovitis with varying states of current activity) and patients with acute non-RA arthritis were stained for surface molecules on different cell types by using fluorochrome-labeled antibodies. Tissue analysis was done by laser scanning cytometry (LSC), and statistical evaluation, by discriminant analysis and ROC analysis. Results CD11b, HLA-DR, CD90, and CD64 revealed significant differences between tissues from patients with RA and acute non-RA arthritis. Especially with the expression of CD64, both patient cohorts could be discriminated with high sensitivity and specificity. RA classification was improved by simultaneously investigating the expression of two or three different surface proteins, such as HLA-DR, CD90, and CD29 in the tissue. The simultaneous analysis of CD64 together with CD304 or the combination of CD11b and CD38 was suitable for the identification of RA patients with high current activity in synovitis. Conclusions In this study, we showed that LSC is a novel reliable method in biomarker prevalidation in RA. Hence, identified mAbs in situ may allow their potential use in in vivo approaches. Moreover, we proved that biomarker-combination analysis resulted in better discrimination than did single-marker analysis. Combinations of these markers make a novel and reliable panel for the discrimination between RA and acute non-RA arthritis. In addition, further expedient combinations may be novel promising biomarker panels to identify current activity in synovitis in RA.

Currently there is a great need for process and organizational innovation for the project execution in customer-specific machinery and plant engineering. Drawbacks result from inefficient project execution processes, insufficient information flow or inappropriate computer systems. As a result, the productivity of enterprises is diminished. The main reason for the unused potential in this domain is the lack of standards for the project execution. In this paper we present some solutions to overcome this lack of standards.

Background Treatment with TNF inhibitors is very efficient in the majority of the patients with rheumatoid arthritis (RA), but it does not achieve a sufficient treatment response in 40–50% of the cases. Goal of the study was to assess functional ex vivo-tests of RA monocytes as prognostic parameters of the subsequent treatment response. Methods 20 anti-TNF naïve RA patients were enrolled in a prospective, open-label trial, and Etanercept therapy was initiated. Prior to treatment, reverse signaling was induced in peripheral blood monocytes by tmTNF crosslinking via TNFR2:Ig construct Etanercept in a standardized ex vivo-assay. Released cytokine and cytokine receptor concentrations were determined as parameters of the monocyte response. Results Crosslinking of tmTNF and consecutive reverse signaling led to production of pro- and anti-inflammatory cytokines and of soluble cytokine decoy receptors such as sTNFR1 and sIL-1R2. Several of the measured concentrations were found to correlate with the treatment response according to the EULAR criteria. The correlation was most pronounced in sTNFR1 concentrations (r = −0.657, p = 0.0031), which also predicted a good clinical response with the highest sensitivity and specificity according to EULAR criteria. Conclusions Herein we propose that the tmTNF crosslinking-triggered shedding of soluble decoy receptors and production of anti-inflammatory cytokines could contribute to the clinical efficacy of TNF inhibitors, and that in vitro quantification of this secretion by RA monocytes prior to treatment can be used to predict the clinical response. Further development of such standardized tests could be a step towards personalized medicine by providing rheumatologists with a rational choice for first line biological therapy in patients with RA.