[Relevance of big data for molecular diagnostics]. / Bedeutung von Big Data für die molekulare Diagnostik.

Big data analysis raises the expectation that computerized algorithms may extract new knowledge from otherwise unmanageable vast data sets. What are the algorithms behind the big data discussion? In principle, high throughput technologies in molecular research already introduced big data and the development and application of analysis tools into the field of rheumatology some 15 years ago. This includes especially omics technologies, such as genomics, transcriptomics and cytomics. Some basic methods of data analysis are provided along with the technology, however, functional analysis and interpretation requires adaptation of existing or development of new software tools. For these steps, structuring and evaluating according to the biological context is extremely important and not only a mathematical problem. This aspect has to be considered much more for molecular big data than for those analyzed in health economy or epidemiology. Molecular data are structured in a first order determined by the applied technology and present quantitative characteristics that follow the principles of their biological nature. These biological dependencies have to be integrated into software solutions, which may require networks of molecular big data of the same or even different technologies in order to achieve cross-technology confirmation. More and more extensive recording of molecular processes also in individual patients are generating personal big data and require new strategies for management in order to develop data-driven individualized interpretation concepts. With this perspective in mind, translation of information derived from molecular big data will also require new specifications for education and professional competence.

[Biomarkers and imaging for diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the BMBF consortium ArthroMark]. / Biomarker und Bildgebung zur Diagnose und Stratifizierung der rheumatoiden Arthritis und Spondylarthritis im BMBF-Verbund ArthroMark.

Rheumatic diseases are among the most common chronic inflammatory disorders. Besides severe pain and progressive destruction of the joints, rheumatoid arthritis (RA), spondyloarthritides (SpA) and psoriatic arthritis (PsA) impair working ability, reduce quality of life and if treated insufficiently may enhance mortality. With the introduction of biologics to treat these diseases, the demand for biomarkers of early diagnosis and therapeutic stratification has been growing continuously. The main goal of the consortium ArthroMark is to identify new biomarkers and to apply modern imaging technologies for diagnosis, follow-up assessment and stratification of patients with RA, SpA and PsA. With the development of new biomarkers for these diseases, the ArthroMark project contributes to research in chronic diseases of the musculoskeletal system. The cooperation between different national centers will utilize site-specific resources, such as biobanks and clinical studies for sharing and gainful networking of individual core areas in biomarker analysis. Joint data management and harmonization of data assessment as well as best practice characterization of patients with new imaging technologies will optimize quality of marker validation.

[Fifteen years of the histopathological synovitis score : Review and further developments of a diagnostic score]. / 15 Jahre histopathologischer Synovialitis-Score : Rückblick und Weiterentwicklung eines diagnostischen Scores.

The histopathological synovitis score evaluates in a graded approach, as is largely usual for diagnostic histopathological scores, the immunological and inflammatory changes caused by synovitis. A synovitis score of between 1 and ≤ 4 is classified as low-grade (osteoarthritis-related synovitis, post-traumatic synovitis, meniscopathy-related synovitis and synovitis in hemochromatosis). Synovitis scores of between ≥ 5 and 9 are classified as high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme's arthritis, post-infection/reactive arthritis and peripheral arthritis in Bechterew disease); sensitivity is 61.7% and sensitivity 96.1%. According to receiver operating characteristic (ROC) analysis (AUC: 0.8-0.9), diagnostic value is good. National and international acceptance of the synovitis score has grown since the first publication in 2002 and a related follow-up publication in 2006. PubMed data analysis (as of 11.01.2017) yielded the following citation values according to "cited by PubMed Central articles" for two publications relating to the synovitis score: there were 29 cited-by-PubMed articles for DOI: 10.1078/0344-0338-5710261 , and 44 cited-in-PubMed articles for the second publication, DOI: 10.1111/j.1365-2559.2006.02508 . This makes a total of 73 PubMed citations over a period of 15 years, thereby evidencing the score's international acceptance. Immunohistochemical determination of a number of CD antigens relevant to inflammation has been proposed to further specify the synovitis score for the purposes of risk stratification of high-grade synovitis (e.g., risk of progression and sensitivity to biological agents).

Intermediates caught in the act: tracing insulin amyloid fibril formation in time by combined optical spectroscopy, light scattering, mass spectrometry and microscopy.

Interest in the topic of amyloid formation by peptides and proteins has increased dramatically in recent years, transforming it from a puzzling phenomenon associated with a small number of diseases into a major subject of study in disciplines ranging from material science to biology and medicine. The tendency of numerous (also non-pathogenic) proteins such as insulin to self-assemble into amyloid-like fibrils is well known. While fibrils are usually easily detected, the observation of transient intermediates is a big challenge in general. They are the key and the 'holy grail' for a molecular understanding of mechanisms in this context. Here we show that intermediates, i.e. oligomers, can be detected and their hydrodynamic radius RH as well as their overall conformation and structure can be monitored and the aggregation dynamics as well as structure formation can be detected in time with a suitable combination of experimental techniques. We have observed transient intermediates that resemble large oligomers held together in solution by non-covalent forces. The oligomers appear to convert into building blocks for mature fibrils with largely beta-sheet conformation resembling key players in a mechanism, which is termed 'nucleated conformation conversion' in the literature. Structural transformations of oligomers in time towards dominant beta-sheet conformations have been observed for the first time. The structures can even be observed in liquid phase AFM experiments. With this approach we have successfully shed new light into the aggregation and fibrilization process of insulin being possibly a model system for other amyloid systems.

[Biomarkers and personalized medicine]. / Biomarker und personalisierte Medizin.

Biomarkers form the basis for patient stratification and the development of individualized treatment strategies. As the understanding of the pathophysiological processes underlying rheumatic diseases increases, novel biomarkers will become available and established markers can be used more efficiently. Autoantibodies in rheumatoid arthritis (RA), for example, define a subgroup of patients with a specific risk profile and response to therapy. For this reason they have been added to the classification criteria for RA and are part of current treatment guidelines. In addition, novel markers are being evaluated and validated. For the concept of personalized medicine this indicates that the use of future therapeutic substances will be more frequently coupled to the detection of specific biomarkers. While this will decrease the number of patients who become eligible for certain treatments, it will increase efficacy and safety for patients and potentially the cost-effectiveness.

[New aspects on the pathogenesis of myositis]. / Neues zur Pathogenese der Myositiden.

Idiopathic inflammatory myopathies (IIM) are chronic inflammatory diseases of muscle characterized by proximal muscle weakness. There are three main groups of diseases, dermatomyositis, polymyositis and inclusion body myositis. The muscle tissue is invaded by the humoral autoantibody producing immune system (B-cells) and by the cellular immune system with autoaggressive and inflammation modulating cells (e.g. dendritic cells, monocytes/macrophages, CD4 + and CD8 + T-cells and natural killer cells). The presence of specific or associated autoantibodies and inflammatory cellular infiltrates with cytotoxic and immune autoreactive properties are characteristic for IIM diseases. The pathogenesis is still unknown; nevertheless, there are several hints that exogenic factors might be involved in initiation and disease progression and bacterial, fungal and viral infections are thought to be possible initiators. Up to now information on prognostic markers to help with decision-making for individual treatment are limited. In addition, there has been only limited therapeutic success including conventional or novel drugs and biologicals and comparative validation studies are needed using similar outcome measurements. Moreover, to facilitate the use and development of novel therapies, elaboration of intracellular and cell-specific regulation could be useful to understand the etiopathogenesis and allow a better diagnosis, prognosis and possibly also a prediction for individualized subgroup treatment.

[Biomarkers in rheumatology. Biomarkers and imaging for the diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the ArthroMark network funded by the Federal Ministry of Education and Research]. / Biomarker in der Rheumatologie. Biomarker und Bildgebung zur Diagnose und Stratifizierung der rheumatoiden Arthritis und Spondylarthritis im BMBF-Verbund ArthroMark.

The introduction of biologics has continuously increased the demand for biomarkers for early diagnosis and therapeutic stratification. ArthroMark, a research network funded by the Federal Ministry of Education and Research, aims to establish such biomarkers for rheumatoid arthritis and spondyloarthritides. Biobanks and previous work on genotyping, gene expression and autoreactivity profiling build the basis. Bioinformatic networks will help to harmonize the investigations and a clinical study with modern imaging techniques to characterize the functional relevance of the new biomarkers as effectively as possible. To validate the markers for diagnostic application the network aims to expand gradually.

Monitoring of patients with rheumatoid arthritis by indocyanine green (ICG)-enhanced fluorescence optical imaging treated with anti-TNFα therapy.

BACKGROUND: Fluorescence optical imaging (FOI) enables visualisation of inflammation in both hands in rheumatoid arthritis (RA). OBJECTIVE: To investigate the usefulness of FOI in treatment monitoring under anti-TNFα therapy with certolizumab pegol (CZP) in patients with RA in comparison to clinical and laboratory outcome parameters. METHODS: CZP-naïve patients with RA were eligible for this open-label study with an observational period of 52 weeks. Disease activity was monitored by the clinical score DAS28, tender/swollen joint count (TJC-28/SJC-28) and laboratory outcomes for systemic inflammation (CRP and ESR). FOI results were analysed in three different phases (P1-3) and PrimaVistaMode (PVM) by the FOI activity score (FOIAS). RESULTS: Twenty-eight RA patients (median age 52.5 years, 26 females, thirteen with a history of other biologic therapy) were included. DAS28 (CRP) decreased from moderate disease activity at baseline (median 4.6, IQR 1.8) to low disease activity at week (w)52 (median 2.7, IQR 2.1; p < 0.001). Statistically significant decreases could also be demonstrated for SJC-28 and TJC-28. CRP/ESR were reduced numerically from baseline to w52. FOIAS in P1 (early phase) showed a continuous decrease of enhancement during the course of treatment period: from baseline (median 1.5, IQR 9.3) over w6 (median 1.0, IQR 3.0; p = 0.069), w12 (median 0.5, IQR 3.0; p = 0.171), w24 (n = 27, median 0.0, IQR 3.0; p = 0.004), until w52 (n = 18, median 0.0, IQR 2.8; p = 0.091), which could not be presented for FOIAS in P2, P3 and PVM. CONCLUSION: FOI in P1 appears to be a valuable tool for fast and easy monitoring of treatment response to certolizumab in a clinical setting.

[DNA microarrays]. / DNA-Microarrays.

Since their development in the 1990s DNA microarrays have advanced to one of the most important technologies for biomedical research. Miniaturization enables up to 1 million different sequence-specific DNA hybridization tests to be performed on an area of less than 2 cm². Depending on the selection of oligonucleotide sequences, which are assembled on a microarray and on the treatment of samples prior to hybridization, up to genome-wide analyses for genotypes, gene expression, epigenetic changes or promoter activation can be performed. Increasing knowledge about the human genome advances commercial pre-assembly of DNA microarrays with selected oligonucleotide sequences for specialized applications. In clinical rheumatology gene expression analyses in treatment studies are of increasing importance. Similarly, this technique also identified new biomarkers that allow even better assessment of the current disease activity. The varieties of application enable the possibility of systematic research on the immunological response to specific patterns after stimulation. This opens up opportunities to detect and differentiate immunological reaction patterns better.

Does gene expression analysis inform us in rheumatoid arthritis?

Transcription profiling has become a standard technology in research. It is mainly applied in the search for biomarkers to improve diagnostic and prognostic classification, to quantify disease activity and to predict or indicate response to therapy. This review will focus on rheumatoid arthritis and discuss considerations for sample selection, prerequisites for functional interpretation of data and the current status of information deduced in the field of biomarkers for the various clinical questions. In the next few years, prediction of response to treatment is the most important aim of biomarker research. With the growing number of new biological agents, there is increasing pressure to identify molecular parameters that will not only guide the therapeutic decision but also help to define the most important targets for which new biological agents should be tested in clinical studies.

Chemokine profile of synovial fluid from normal, osteoarthritis and rheumatoid arthritis patients: CCL25, CXCL10 and XCL1 recruit human subchondral mesenchymal progenitor cells.

OBJECTIVE: The microfracture technique activates mesenchymal progenitors that enter the cartilage defect and form cartilage repair tissue. Synovial fluid (SF) has been shown to stimulate the migration of subchondral progenitors. The aim of our study was to determine the chemokine profile of SF from normal, rheumatoid arthritis (RA) and osteoarthritis (OA) donors and evaluate the chemotactic effect of selected chemokines on human subchondral progenitor cells. METHOD: Chemokine levels of SF were analyzed using human chemokine antibody membrane arrays. The chemotactic potential of selected chemokines on human mesenchymal progenitors derived from subchondral cortico-spongious bone was tested using 96-well chemotaxis assays. Chemokine receptor expression of subchondral progenitors was assessed by real-time gene expression analysis and immuno-histochemistry. RESULTS: Chemokine antibody array analysis showed that SF contains a broad range of chemokines. Ten chemokines that showed significantly reduced levels in RA or OA compared to normal SF or robustly high levels in all SF tested were used for further chemotactic analysis. Chemotaxis assays showed that the chemokines MDC/CCL22, CTACK/CCL27, ENA78/CXCL5 and SDF1α/CXCL12 significantly inhibited migration of progenitors, while TECK/CCL25, IP10/CXCL10 and Lymphotactin/XCL1 effectively stimulated cell migration. MCP1/CCL2, Eotaxin2/CCL24 and NAP2/CXCL7 showed no chemotactic effect on subchondral progenitors. Gene expression and immuno-histochemical analysis of corresponding chemokine receptors document presence of low levels of chemokine receptors in subchondral progenitors, with the CXCL10 receptor CXCR3 showing the highest expression level. CONCLUSION: These results suggest that SF contains chemokines that may contribute to the recruitment of human mesenchymal progenitors from the subchondral bone in microfracture.

Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis.

BACKGROUND: Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anti-cyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting the course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, both of which have been implicated in anti-CCP generation, are assumed to be associated with RA. OBJECTIVES: To elucidate whether PADI4 affects the clinical characteristics of RA, and whether it would modulate the effect of anti-CCPs on clinical course. The combined effect of SE and PADI4 on autoantibody profile was also analysed. METHODS: 373 patients with RA were studied. SE, padi4_94C>T, rheumatoid factor, anti-CCPs and antinuclear antibodies (ANAs) were determined. Disease severity was characterised by cumulative therapy intensity classified into ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score. RESULTS: CTI was significantly associated with disease duration, erosive disease, disease activity score (DAS) 28 and anti-CCPs. The association of anti-CCPs with CTI was considerably influenced by padi4_94C>T genotype (C/C: OR(adj) = 0.93, p(adj) = 0.92; C/T: OR(adj) = 2.92, p(adj) = 0.093; T/T: OR(adj) = 15.3, p(adj) = 0.002). Carriage of padi4_94T exhibited a significant trend towards higher Steinbrocker scores in univariate and multivariate analyses. An association of padi4_94C>T with ANAs was observed, with noteworthy differences depending on SE status (SE-: OR(adj) = 6.20, p(adj)<0.04; SE+: OR(adj) = 0.36, p(adj) = 0.02) and significant heterogeneity between the two SE strata (p = 0.006). CONCLUSIONS: PADI4 genotype in combination with anti-CCPs and SE modulates clinical and serological characteristics of RA.

[MMP- and FAP-mediated non-inflammation-related destruction of cartilage and bone in rheumatoid arthritis]. / MMP- und FAP-vermittelte inflammationsunabhängige Destruktion von Knochen und Knorpel in der rheumatoiden Arthritis.

INTRODUCTION: Due to morphological similarities of high-grade synovitis in rheumatoid Arthritis (RA) and mesenchymal, semimalignant tumors and the hypothesis that RA progression is not only inflammation-related, but also determined by tumor-like mechanisms, a comparison was made between expression profiles of RA, giant cell tumor of bone (GCT) and normal synovium (ND). METHODS: Array data of selected genes were validated through immunohistochemical staining of paraffin-embedded and deep frozen tissue samples of GCT, RA and normal synovium. RESULTS: With microarray analysis, CCR1, CCR5, MMP-1, MMP-2, MMP-3, MMP-9, MMP-14 and FAP were found to be significantly upregulated in RA and GCT compared to ND. A significant upregulation in RA and GCT compared to ND could be validated by immunohistochemistry for MMP-1, MMP-9, MMP-14 and FAP. DISCUSSION: For MMPs, and MMP-9 in particular, an important role in early cartilage destruction of RA was suggested. The presence of FAP in RA and in stroma of a semimalignant tumor indicates tumor-like tissue destruction in chronic synovitis associated with RA.

Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis.

OBJECTIVE: Bone marrow (BM) mesenchymal stem cells (MSCs) are being considered as potential therapeutic agents in various inflammatory autoimmune diseases for their tissue-repair and anti-inflammatory tissue-protective properties. This study investigates the reserves and function, the molecular and proteomic profile and the differentiation potential of BM MSCs in patients with active rheumatoid arthritis (RA). METHODS: We evaluated the frequency of MSCs in the BM mononuclear cell fraction using a limiting dilution assay, the proliferative/clonogenic potential and the capacity of cells to differentiate towards the osteogenic/chondrogenic/adipogenic lineages using appropriate culture conditions. We also assessed the molecular and proteomic characteristics in terms of inflammatory cytokine gene and protein expression, the relative telomere length and the survival characteristics of BM MSCs. RESULTS: MSCs from patients with RA (n = 26) and age- and sex-matched healthy individuals (n = 21) were similar in frequency, differentiation potential, survival, immunophenotypic characteristics, and protein profile. Patient MSCs, however, had impaired clonogenic and proliferative potential in association with premature telomere length loss. Transcriptome analysis revealed differential expression of genes related to cell adhesion processes and cell cycle progression beyond the G1 phase. Previous treatment with methotrexate, corticosteroids, anti-cytokine and biological agents or other disease-modifying anti-inflammatory drugs did not correlate with the clonogenic and proliferative impairment of BM MSCs. CONCLUSION: In spite of some restrictions related to the impaired clonogenic and proliferative potential, our findings support the use of autologous BM MSCs in RA and may have important implications for the ongoing efforts to repair tissue injury commonly seen in the course of the disease.

Interaction between rheumatoid arthritis and pregnancy: correlation of molecular data with clinical disease activity measures.

OBJECTIVE: The factors that induce remission of RA during pregnancy and the relapse occurring after delivery remain an enigma. In a previous study, we investigated gene-expression profiles of peripheral blood mononuclear cells (PBMC) in patients with RA and healthy women in late pregnancy and postpartum. Profiles of samples from both groups were similar in late pregnancy with elevated monocyte and decreased lymphocyte signatures. Postpartum, in RA PBMC the high level of monocyte transcripts persisted. Further increase was observed in adhesion, migration and signalling processes related to monocytes but also in lymphocytes despite similar clinical activity due to intensified drug treatment. This prompted us to investigate correlations between clinical parameters of disease activity and gene profiles. METHODS: Transcriptome data were correlated with RADAI, CRP, monocyte and lymphocyte counts. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations, monocytes and lymphocytes signatures were used as reference information. RESULTS: Comparative analysis of PBMC expression profiles from RA patients during and after pregnancy with RADAI and CRP revealed a correlation of these disease activity parameters predominantly with monocyte transcripts. Genes related to cellular programs of adhesion, migration and response to infections were upregulated. Comparing clinically active and not-active RA patients postpartum revealed a cluster of 19 genes that could also identify active disease during pregnancy. CONCLUSION: The data suggest that an increase of the RADAI and an elevation of CRP is a consequence of molecular activation of monocytes. Furthermore, they indicate that molecular activation of T lymphocytes may remain clinically unrecognized postpartum. It is conceivable that a set of 19 genes may qualify as molecular disease activity marker.

Modulatory effects of inflammation and therapy on GDF-5 expression in rheumatoid arthritis synovium.

OBJECTIVE: Growth differentiation factor-5 (GDF-5), a member of the transforming growth factor (TGF)-beta family, is involved in joint development during embryogenesis and has the potential to regenerate cartilage in adult animals. As progression of chronic joint diseases is influenced by cytokines of the synovial tissue, we examined the expression and effects of GDF-5 in this tissue. METHODS: Microarray experiments were investigated for differential expression of GDF-5 in synovial tissues, synovial fibroblasts, and peripheral blood cells. GDF-5 expression was validated by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry, double immunofluorescence, and in situ hybridization in synovial tissue of normal donors (ND) and patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Effects of inflammation and therapy were investigated in RA and OA fibroblasts after stimulation with interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha, methotrexate (MTX), and prednisolone. The influence of GDF-5 on macrophages was studied by chemotaxis assay. RESULTS: Microarray analysis and immunostaining revealed expression predominantly in synovial fibroblasts. Compared to patients without immunomodulating drugs, expression of GDF-5 was decreased significantly in patients receiving glucocorticoids and/or disease-modifying antirheumatic drugs (DMARDs) (p = 0.007), but did not differ between the total group of ND, OA, and RA. Stimulation with prednisolone and TNFalpha reduced GDF-5 expression in OA and RA fibroblasts, whereas MTX and IL-1beta revealed minor or no relevant change. GDF-5 also reduced cell migration of macrophages (p<0.001). CONCLUSION: GDF-5 is expressed in synovial fibroblasts and may counteract macrophage infiltration. Its modulation by inflammation and therapy suggests that glucocorticoids play a conflicting role by suppressing not only inflammation but also putative mechanisms of repair.

A novel epitope on the C-terminus of SmD1 is recognized by the majority of sera from patients with systemic lupus erythematosus.

The SmD1 protein is a specific target for the autoantibody response in SLE. To further analyze this reactivity epitope, mapping was performed with cellulose-bound 13-mer peptides overlapping 10 amino acids (aa). In this initial approach, 4 out of 15 SLE sera recognized more than five overlapping peptides of the SmD1 C-terminus. Therefore, longer oligopeptides of up to 37 aa of this region were generated and probed for as antigens by ELISA. For the SmD1 aa 83-119 polypeptide, there was a striking increase of reactivity with 70.0% positive reactions out of 167 SLE sera. In contrast, 105 healthy control sera were negative, and only 8.3% of sera from patients with other inflammatory diseases (n = 267) exhibited a response, which was of low level only. The anti-SmD183-119 reactivity was significantly higher in anti-dsDNA antibody positive vs. negative sera (P < 0.001) and correlated with disease activity. Four of five human monoclonal anti-dsDNA antibodies also reacted with SmD183-119. The specificity for SmD1 was demonstrated by inhibition experiments and immunization of rabbits with SmD183-119 inducing SmD1-specific antibodies. In conclusion, the SmD183-119 peptide was demonstrated to be an important and highly specific target of the autoimmune response in SLE. The high sensitivity of this ELISA probably depends on a conformational epitope, which appears not to be accessible in the full-size SmD1 protein.

15 years of the histopathological synovitis score, further development and review: A diagnostic score for rheumatology and orthopaedics.

The histopathological synovitis score evaluates the immunological and inflammatory changes of synovitis in a graduated manner generally customary for diagnostic histopathological scores. The score results from semiquantitative evaluation of the width of the synovial surface cell layer, the cell density of the stroma and the density of the inflammatory infiltration into 4 semiquantitative levels (normal 0, mild 1, moderate 2, severe 3). The addition of these values results in a final score of 0-9 out of 9. On the basis of this summation the condition is divided into low-grade synovitis and high-grade synovitis: A synovitis score of 1 to≤4 is called low-grade synovitis (arthrosis-associated/OA synovitis, posttraumatic synovitis, meniscopathy-associated synovitis and synovitis with haemochromatosis). A synovitis score of≥5 to 9 is called high-grade synovitis (rheumatoid arthritis, psoriatic arthritis, Lyme arthritis, postinfection/reactive arthritis and peripheral arthritis with Bechterew's disease). By means of the synovitis score it is therefore possible to distinguish between degenerative/posttraumatic diseases (low-grade synovitis) and inflammatory rheumatic diseases (high-grade synovitis) with a sensitivity of 61.7% and a specificity of 96.1%. The diagnostic accuracy according to ROC analysis (AUC: 0.8-0.9) is good. Since the first publication (2002) and an associated subsequent publication (2006), the synovitis score has nationally and internationally been accepted for histopathological assessment of the synovitis. In a PubMed data analysis (status: 14.02.2017), the following citation rates according to Cited by PubMed Central articles resulted for the two synovitis score publications: For DOI: 10.1078/0344-0338-5710261 there were 29 Cited by PubMed Central articles and for the second extended publication DOI:10.1111/j.1365-2559.2006.02508 there were 44 Cited by PubMed Central articles. Therefore a total of 73 PubMed citations are observed over a period of 15 years, which demonstrates an international acceptance of the score. This synovitis score provides for the first time a diagnostic, standardised and reproducible histopathological evaluation method enabling a contribution to the differential diagnosis of chronic inflammatory general joint diseases. This is particularly the case by incorporation into the joint pathology algorithm. To specify the synovitis score an immunohistochemical determination of various inflammation-relevant CD antigens is proposed to enable a risk stratification of high-grade synovitis (e.g.: progression risk and sensitivity for biologicals).