Rheumatoid Arthritis: Müller GA

Schwaighofer A, Tresp V, Mayer P, Krause A, Beuthan J, Rost H, Metzger G, Müller GA, Scheel AK. · Siemens Corporate Technology, Information and Communications, CT IC4, Otto-Hahn-Ring 6, 81739 Munich, Germany. · IEEE Trans Biomed Eng. · Pubmed #12669994 No free full text.

Abstract: We describe a classification system for a novel imaging method for arthritic finger joints. The basis of this system is a laser imaging technique which is sensitive to the optical characteristics of finger joint tissue. From the laser images acquired at baseline and follow-up, finger joints can automatically be classified according to whether the inflammatory status has improved or worsened. To perform the classification task, various linear and kernel-based systems were implemented and their performances were compared. Based on the results presented in this paper, we conclude that the laser-based imaging permits a reliable classification of pathological finger joints, making it a sensitive method for detecting arthritic changes.

Scheel AK, Krause A, Rheinbaben IM, Metzger G, Rost H, Tresp V, Mayer P, Reuss-Borst M, Müller GA. · Georg-August-University Göttingen, Göttingen, Germany. · Arthritis Rheum. · Pubmed #12115221 links to  free full text

Abstract: OBJECTIVE: To evaluate a newly developed laser-based imaging technique for the study of soft tissue changes and acute inflammatory processes of the proximal interphalangeal (PIP) joints in patients with rheumatoid arthritis (RA). METHODS: A novel imaging device was developed which allows the transillumination of PIP joints using laser light in the near-infrared wavelength range. In a first clinical followup study, a total of 72 PIP joints of 22 patients with RA and 64 PIP joints of 8 healthy controls were examined both clinically and with the new laser device. At baseline and at followup after a mean of 6 weeks, clinical signs of synovitis, the joint circumference, and the degree of pain were assessed for each PIP joint in order to determine the clinical degree of inflammation. Different features were extracted from the laser images and evaluated by a neural network. RESULTS: At baseline, 72 PIP joints in the RA patients showed clinical signs of inflammation. At followup, 45 PIP joints showed clinical improvement, 13 showed steady active inflammation, and 14 showed deterioration compared with the first visit. None of the 64 PIP joints in the healthy individuals showed any signs of synovitis. The inflammatory status of 60 of the 72 RA joints examined was classified correctly by laser examination and joint circumference determination, giving a sensitivity of 80%, a specificity of 89%, and an accuracy of 83% in detecting inflammatory changes in affected joints. Laser data and joint circumference determination of healthy joints at followup resulted in an accuracy of 85% in reproducing the image. CONCLUSION: The new laser-based imaging technique allows the transillumination of PIP joints and gives information about the inflammatory status of the joint after processing through a neural network. Our data indicate that laser imaging may provide additional information in the early diagnosis of an inflammatory joint process and may prove particularly useful in assessing acute joint inflammation at followup.

Bramlage CP, Kaps C, Ungethüm U, Bramlage P, Koziolek M, Wessels J, Krenn V, Pruss A, Müller GA, Strutz F, Burmester GR, Häupl T. · Department of Medicine, Nephrology and Rheumatology, Georg-August-University Gottingen, Gottingen. · Scand J Rheumatol. · Pubmed #18830904 No free full text.

Abstract: 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.

Blaschke S, Müller GA. · Abteilung Nephrologie und Rheumatologie, Universitätsmedizin Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Deutschland. · Z Rheumatol. · Pubmed #18633630 No free full text.

Abstract: Fractalkine (CX3CL1), so far the only member of the CX3C class of chemokines, and its receptor, CX3CR1, are strongly expressed in the chronically inflamed synovial tissue of patients with rheumatoid arthritis (RA). Due to the specific binding of Fractalkine to its receptor, many proinflammatory reactions involved in the pathogenesis of RA are triggered. Functionally, fractalkine plays an important proinflammatory role in RA pathogenesis as characterized by induction of synovial angiogenesis, chemotaxis, activation of monocytes and T cells as well as the stimulation of proliferation and synthesis of matrix degrading enzymes (matrix metalloproteinases, MMP) in synovial fibroblasts. Fractalkine thus may represent a novel target molecule for therapeutic intervention in RA.

Bramlage CP, Häupl T, Kaps C, Ungethüm U, Krenn V, Pruss A, Müller GA, Strutz F, Burmester GR. · Department of Medicine, Nephrology and Rheumatology, Georg-August-University Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. · Arthritis Res Ther. · Pubmed #16542506 links to  free full text

Abstract: Bone morphogenetic proteins (BMPs) have been identified as important morphogens with pleiotropic functions in regulating the development, homeostasis and repair of various tissues. The aim of this study was to characterize the expression of BMPs in synovial tissues under normal and arthritic conditions. Synovial tissue from normal donors (ND) and from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were analyzed for BMP expression by using microarray hybridization. Differential expression of BMP-4 and BMP-5 was validated by semiquantitative RT-PCR, in situ hybridization and immunohistochemistry. Activity of arthritis was determined by routine parameters for systemic inflammation, by histological scoring of synovitis and by semiquantitative RT-PCR of IL-1beta, TNF-alpha, stromelysin and collagenase I in synovial tissue. Expression of BMP-4 and BMP-5 mRNA was found to be significantly decreased in synovial tissue of patients with RA in comparison with ND by microarray analysis (p < 0.0083 and p < 0.0091). Validation by PCR confirmed these data in RA (p < 0.002) and also revealed a significant decrease in BMP-4 and BMP-5 expression in OA compared with ND (p < 0.015). Furthermore, histomorphological distribution of both morphogens as determined by in situ hybridization and immunohistochemistry showed a dominance in the lining layer of normal tissues, whereas chronically inflamed tissue from patients with RA revealed BMP expression mainly scattered across deeper layers. In OA, these changes were less pronounced with variable distribution of BMPs in the lining and sublining layer. BMP-4 and BMP-5 are expressed in normal synovial tissue and were found decreased in OA and RA. This may suggest a role of distinct BMPs in joint homeostasis that is disturbed in inflammatory and degenerative joint diseases. In comparison with previous reports, these data underline the complex impact of these factors on homeostasis and remodeling in joint physiology and pathology.

Scheel AK, Hermann KG, Ohrndorf S, Werner C, Schirmer C, Detert J, Bollow M, Hamm B, Müller GA, Burmester GR, Backhaus M. · Department of Medicine, Nephrology and Rheumatology, Georg-August-University Göttingen, Germany. · Ann Rheum Dis. · Pubmed #16192290 links to  free full text

Abstract: OBJECTIVE: To perform a prospective long term follow up study comparing conventional radiography (CR), ultrasonography (US), and magnetic resonance imaging (MRI) in the detection of bone erosions and synovitis in rheumatoid arthritis (RA) finger joints. METHODS: The metacarpophalangeal and proximal interphalangeal joints II-V (128 joints) of the clinically dominant hand of 16 patients with RA were included. Follow up joint by joint comparisons for erosions and synovitis were made. RESULTS: At baseline, CR detected erosions in 5/128 (4%) of all joints, US in 12/128 (9%), and MRI in 34/128 (27%). Seven years later, an increase of joints with erosions was found with CR (26%), US (49%) (p<0.001 each), and MRI (32%, NS). In contrast, joint swelling and tenderness assessed by clinical examination were decreased at follow up (p = 0.2, p<0.001). A significant reduction in synovitis with US and MRI (p<0.001 each) was seen. In CR, 12 patients did not have any erosions at baseline, while in 10/12 patients erosions were detected in 25/96 (26%) joints after 7 years. US initially detected erosions in 9 joints, of which two of these joints with erosions were seen by CR at follow up. MRI initially found 34 erosions, of which 14 (41%) were then detected by CR. CONCLUSION: After 7 years, an increase of bone erosions was detected by all imaging modalities. In contrast, clinical improvement and regression of synovitis were seen only with US and MRI. More than one third of erosions previously detected by MRI were seen by CR 7 years later.

Scheel AK, Hermann KG, Kahler E, Pasewaldt D, Fritz J, Hamm B, Brunner E, Müller GA, Burmester GR, Backhaus M. · Georg-August-University Göttingen, Germany. <> · Arthritis Rheum. · Pubmed #15751062 links to  free full text

Abstract: OBJECTIVE: To develop an ultrasonographic (US) synovitis scoring system suitable for evaluation of finger joint inflammation in patients with active rheumatoid arthritis (RA) and to compare semiquantitative US scoring with quantitative US measurements. METHODS: US was performed at the palmar and dorsal sides of the second through fifth metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints in 10 healthy subjects and in the clinically more affected hand in 46 RA patients. Ten patients additionally underwent magnetic resonance imaging (MRI). Synovitis was measured, standardized, and scored according to a semiquantitative method. The 2 methods (semiquantitative US scoring, quantitative US) were compared and statistical cutoffs were identified using receiver operating characteristic (ROC) curve analysis. MRI results were compared with semiquantitative US scoring and quantitative US results. The optimal US scoring method from 6 joint combinations was identified (ROC curve analysis). RESULTS: Synovitis was most frequently detected in the palmar proximal area (86% of affected joints). We found no significant differences between individual PIP joints or between individual MCP joints, indicating that all fingers within each of these joint groups should be treated equally for statistical calculations, although each joint group as a whole should be treated separately. The optimal cutoff point to distinguish between "health" and "pathology" was 0.6 mm both for MCP joints (sensitivity 94%, specificity 89%) and for PIP joints (sensitivity 90%, specificity 88%). There was no significant difference between semiquantitative US scores and quantitative US measurements. The best results for joint combinations were achieved using the "sum of 4 fingers" (second through fifth MCP and PIP joints) and "sum of 3 fingers" (second through fourth MCP and PIP joints) methods. Comparison of MRI results with semiquantitative US scores revealed high concordance. CONCLUSION: US evaluation of finger joint synovitis can be considerably simplified by focusing on the palmar side and by applying semiquantitative grading instead of quantitative measurements. For evaluation of treatment efficacy based on synovitis in RA patients, we recommend using the "sum of 3 fingers" method in longitudinal trials.

Scheel AK, Backhaus M, Klose AD, Moa-Anderson B, Netz UJ, Hermann KG, Beuthan J, Müller GA, Burmester GR, Hielscher AH. · Department of Medicine, Nephrology and Rheumatology, Georg-August-University Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany. · Ann Rheum Dis. · Pubmed #15297282 links to  free full text

Abstract: OBJECTIVE: To identify classifiers in images obtained with sagittal laser optical tomography (SLOT) that can be used to distinguish between joints affected and not affected by synovitis. METHODS: 78 SLOT images of proximal interphalangeal joints II-IV from 13 patients with rheumatoid arthritis were compared with ultrasound (US) images and clinical examination (CE). SLOT images showing the spatial distribution of scattering and absorption coefficients within the joint cavity were generated. The means and standard errors for seven different classifiers (operator score and six quantitative measurements) were determined from SLOT images using CE and US as diagnostic references. For classifiers showing significant differences between affected and non-affected joints, sensitivities and specificities for various cut off parameters were obtained by receiver operating characteristic (ROC) analysis. RESULTS: For five classifiers used to characterise SLOT images the mean between affected and unaffected joints was statistically significant using US as diagnostic reference, but statistically significant for only one classifier with CE as reference. In general, high absorption and scattering coefficients in and around the joint cavity are indicative of synovitis. ROC analysis showed that the minimal absorption classifier yields the largest area under the curve (0.777; sensitivity and specificity 0.705 each) with US as diagnostic reference. CONCLUSION: Classifiers in SLOT images have been identified that show statistically significant differences between joints with and without synovitis. It is possible to classify a joint as inflamed with SLOT, without the need for a reference measurement. Furthermore, SLOT based diagnosis of synovitis agrees better with US diagnosis than CE.

Blaschke S, Koziolek M, Schwarz A, Benöhr P, Middel P, Schwarz G, Hummel KM, Müller GA. · Department of Nephrology and Rheumatology, Georg-August-University of Goettingen, Robert-Koch Strasse 40, 37075 Goettingen, Germany. · J Rheumatol. · Pubmed #12966591 No free full text.

Abstract: OBJECTIVE: Fractalkine (CX3CL1) represents the sole member of the so-called CX3C chemokines. In rheumatoid arthritis (RA), functional studies suggest a role for this chemokine in monocyte chemotaxis and angiogenesis in the rheumatoid synovium. We analyzed the expression of fractalkine within different T cell subsets of the peripheral blood and expression of its receptor CX3CR1 within the rheumatoid synovium to further characterize its pathogenic role in RA. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from 17 patients with RA and analyzed by flow cytometry in comparison to healthy blood donors. To identify the T helper cell cytokine profile of fractalkine-expressing cells, flow cytometric analysis of PBMC was performed after stimulation with PMA and ionomycin. Expression of fractalkine and its receptor was characterized in RA synovium by immunohistochemistry and laser capture microdissection microscopy. RESULTS: Flow cytometric analysis of fractalkine-expressing T cell subsets revealed a low proportion of fractalkine-expressing CD4+ and CD8+ T cells in both RA patients and controls. In addition, fractalkine was predominantly expressed in CD4+ T cells with a Th1-type cytokine expression profile. In RA synovium, fractalkine was detected in synovial macrophages, dendritic cells, endothelial cells, and a small proportion of T cells. The fractalkine receptor CX3CR1 was found in synovial macrophages, dendritic cells, and T cells as well as in synovial fibroblasts. Fractalkine stimulation of cultured synovial fibroblasts resulted in a marked upregulation of matrix metalloproteinase-2 (MMP-2) production. CONCLUSION: The results suggest that fractalkine may represent a Th1-type chemokine. Upregulation of MMP-2 production in synovial fibroblasts upon fractalkine stimulation in vitro supports the hypothesis of a proinflammatory role of this chemokine in RA.

Blaschke S, Middel P, Dorner BG, Blaschke V, Hummel KM, Kroczek RA, Reich K, Benoehr P, Koziolek M, Müller GA. · Department of Nephrology and Rheumatology, Georg-August-University, Robert-Koch Strasse 40, Göttingen 37075, Germany. · Arthritis Rheum. · Pubmed #12847680 links to  free full text

Abstract: OBJECTIVE: To evaluate the possible role of activation-induced, T cell-derived, and chemokine-related cytokine (ATAC)/lymphotactin (Lptn) in the pathogenesis of rheumatoid arthritis (RA). METHODS: ATAC/Lptn levels in serum and synovial fluid samples were measured by sandwich enzyme-linked immunosorbent assay. Expression of messenger RNA for ATAC/Lptn in synovial tissues was analyzed by reverse transcription-polymerase chain reaction (PCR) and by in situ hybridization, and was quantitated by real-time PCR. The phenotype of peripheral blood mononuclear cells (PBMCs) expressing ATAC/Lptn was analyzed by intracellular cytokine staining and flow cytometry. RESULTS: Levels of ATAC/Lptn were similar in sera and synovial fluids from RA patients (n = 20) and osteoarthritis controls (n = 15). In phorbol myristate acetate/ionomycin-stimulated PBMCs, ATAC/Lptn expression was detected in CD8+ T cells and in a significantly increased proportion of CD4+,CD28- T cells from RA patients as compared with healthy controls. In synovial tissues, ATAC/Lptn was predominantly localized in CD3+ T cells in the sublining layer. Lymphocytes, synovial macrophages, and, unexpectedly, fibroblast-like synoviocytes (FLS) were identified as major target cells for ATAC/Lptn in RA synovium, as determined by analysis of the ATAC/Lptn receptor XCR1. In vitro, ATAC/Lptn stimulation of FLS resulted in a marked down-regulation of matrix metalloproteinase 2 production. CONCLUSION: These data indicate that in RA synovium, ATAC/Lptn is mainly produced by T cells. Considering its function as a lymphocyte-specific chemoattractant, ATAC/Lptn might be a key modulator for T cell trafficking in the pathogenesis of RA. In addition, functional studies suggest that ATAC/Lptn may exert additional immunomodulatory effects in RA.

Blaschke S, Schulz H, Schwarz G, Blaschke V, Müller GA, Reuss-Borst M. · Department of Nephrology and Rheumatology, University of Göttingen, Germany. · J Rheumatol. · Pubmed #11196512 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology characterized by an infiltration of CD4+ T lymphocytes within the rheumatoid synovium. Cytokines have been shown to play a modulatory role in the pathogenesis of RA. We analyzed the expression of a T cell derived cytokine. interleukin 16 (IL-16), in relation to disease activity to characterize its biologic function in RA. METHODS: Secreted IL-16 was measured by enzyme immunoassay in sera and synovial fluids (SF) from 25 patients with RA in comparison to 20 control samples from patients with osteoarthritis (OA). IL-16 expression in peripheral blood mononuclear cells (PBMC) was characterized by flow cytometric analysis after intracellular cytokine staining for IL-16. In synovial tissue specimens, IL-16 mRNA expression was analyzed by real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR). In parallel, expression of IL-16 was localized in synovial tissues by in situ hybridization and immunohistochemistry. Results were analyzed in relation to disease activity. RESULTS: IL-16 was detected at significantly higher levels in sera and SF of patients with RA in comparison to OA (p < 0.001). Flow cytometry of PBMC showed that a great proportion of both CD4+ and CD8+ T cells constitutively expressed the IL-16 protein. In synovial tissues, IL-16 mRNA levels were significantly elevated in comparison to OA controls (p < 0.001). In situ hybridization for IL-16 producing cells revealed a predominant accumulation of IL- 16 positive cells within the inflammatory infiltrates. A significant correlation between IL- 16 expression and local inflammatory activity could not be established (r = 0.27, p = 0.19) by microscopic analysis of the synovial cell infiltrate. In addition, no significant association was observed between serum, SF, and synovial tissue expression of IL-16 and clinical disease activity in RA. CONCLUSION: These data suggest IL-16 might play a role in the pathogenesis of chronic inflammation in RA. The lack of significant correlation between IL-16 expression, clinical disease activity, and local inflammatory activity suggests a regulatory rather than a proinflammatory function for IL-16 in the pathogenesis of chronic synovial inflammation in RA.

Berner B, Wolf G, Hummel KM, Müller GA, Reuss-Borst MA. · Department of Nephrology and Rheumatology, University Medical Clinic, Robert-Koch-Str 40, 37075 Göttingen, Germany. · Ann Rheum Dis. · Pubmed #10700427 links to  free full text

Abstract: OBJECTIVES: The interaction between the activation induced surface glycoprotein CD40L (ligand) (CD154) on CD4+ T cells and its receptor CD40, which is expressed on various cell types, plays a crucial part in numerous cell mediated and humoral immune reactions that may be of pathogenetic importance in rheumatoid arthritis (RA). To further evaluate the pathogenetic role of CD40L in RA, expression of CD40L and various other T cell activation antigens as well as costimulatory molecules was investigated on CD4+ T cells in RA by flow cytometry. METHODS: Two colour flow cytometry was used to determine the percentage of CD4+ T cells expressing CD40L, CD69, CD25, HLA-DR, CD39, CD27 and CD28 in peripheral blood (PB) of 62 RA patients in comparison to 20 healthy controls (HC). Disease activity was assessed by clinical, laboratory and radiological examination. Status of clinical remission of RA was evaluated according to the ACR preliminary criteria for complete clinical remission of RA. RESULTS: CD40L was expressed on > 10% of CD4+ T cells in 29% of RA patients thus defining a CD40L(high+) patient group. Disease activity as estimated by C reactive protein, rheumatoid factor and status of clinical remission of disease (p = 0.049) was higher in this subgroup than in the RA CD40L(low+) group. Expression of CD69, CD25, and HLA-DR was significantly increased in both RA patient groups in comparison with HC. However, the percentage of CD39+ CD4+ T cells was increased only in the RA CD40L(high+) subgroup (versus HC p = 0.019, versus RA CD40L(low+) p = 0.044). Furthermore, expression of CD40L and CD39 on CD4+ T cells correlated positively as estimated by Spearman rank correlation (p<0.001). The percentage of CD4+ T cells lacking the costimulatory molecules CD27 (p = 0.002) and CD28 (p = 0.026) was increased in RA CD40L(low+) patients in comparison with HC. CONCLUSIONS: These data suggest that increased expression of CD40L on CD4+ T cells in RA indicates prolonged and increased activation of CD4+ T lymphocytes and is associated with active disease and possibly an unfavourable prognosis. Whether this phenotypically defined RA CD40L(high+) subgroup will preferentially respond to an anti-CD40L antibody treatment remains to be elucidated.

Reuss-Borst M, Berner B, Wulf G, Müller GA. · Medical University Clinic, Department of Nephrology and Rheumatology, Georg-August-Universitaet, Göttingen, Germany. · J Rheumatol. · Pubmed #10381062 No free full text.

Abstract: Antimalarials are well established disease modifying antirheumatic drugs. A rare and underappreciated treatment difficulty is cardiac complication, in particular conduction disturbances. We describe 2 more patients that developed complete heart block after high dose, longterm treatment. Patient 1, a 73-year-old woman with longstanding rheumatoid arthritis, had taken chloroquine (250 mg/day) for 12 years when she developed complete heart block requiring a permanent pacemaker. Patient 2, a 40-year-old woman with discoid lupus erythematosus, was taking chloroquine from 1979 until 1996. Depending on the clinical disease activity, she intermittently increased the dose from 250 to 750 mg/day. In 1994, she developed complete heart block and a permanent pacemaker had to be implanted. Intensive investigations in both cases did not reveal another underlying cause for conduction disturbances; the atrioventricular block was probably due in both cases to chloroquine related cardiac toxicity. This toxicity seems to be restricted to longterm, high dose treatment; however, it should be kept in mind in patients with preexisting conduction disturbances during longterm treatment.