Rheumatoid Arthritis: Märker-Hermann E

Märker-Hermann E. · Klinik Innere Medizin IV, Dr. Horst Schmidt Kliniken (HSK) GmbH, HSK Wilhelm Fresenius Klinik, Aukammallee 39, 65191, Wiesbaden, Deutschland. · Z Rheumatol. · Pubmed #17006701 No free full text.

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Märker-Hermann E, Bauer H, Gromnica-Ihle E. · Klinik Innere Medizin IV (Rheumatologie, klinische Immunologie und Nephrologie), HSK Dr. Horst Schmidt Klinik GmbH, Wiesbaden. · Dtsch Med Wochenschr. · Pubmed #18988134 No free full text.

Abstract: Rheumatic diseases can influence the reproduction, the course of pregnancy and the development of the fetus. The inflammatory rheumatic disease itself can be modulated in its activity in terms of amelioration or exacerbation of the rheumatic symptoms. The associations between rheumatic diseases and pregnancy will be illustrated with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and systemic lupus erythematosus as examples. Antirheumatic drug therapy during pregnancy and the breast feeding period has to be adapted critically.

Schwarting A, Märker-Hermann E. · I. Medizinische Klinik und Poliklinik der Johannes-Gutenberg-Universität, 55101 Mainz, Germany. · Z Rheumatol. · Pubmed #15756496 No free full text.

Abstract: Inflammatory rheumatic diseases are frequently complicated by subclinical or overt renal manifestations. This is well known for the connective tissue diseases and vasculitides in which renal disease can be of significant prognostic value and therapeutic implication. However, rheumatoid arthritis and the spondyloarthritides can also be associated with direct renal manifestation or with secondary renal AA-amyloidosis. The clinician should be aware of the different glomerular (i. e. nephritic or nephritic syndrome, rapidly progressive renal disease) and tubulo-interstitial syndromes. In any case of renal dysfunction in a rheumatic patient, the differential diagnosis should include renal disease independent from the rheumatic condition, infection, and drug-induced renal toxicity.

Märker-Hermann E, Behrens F. · Klinik Innere Medizin IV (Rheumatologie, klinische Immunologie und Nephrologie), HSK Dr. Horst Schmidt Kliniken GmbH, -, 65199, Wiesbaden. · Z Rheumatol. · Pubmed #19148655 No free full text.

Abstract: Psoriatic arthritis (PsA) has increasingly attracted the attention of clinical research in recent years with regard to long-term clinical registries, studies on epidemiology, genetics, and therapy. However, the methodology for assessing disease activity, damage and progression, as well as the resulting definition of treatment outcome parameters have progressed far less in PsA as compared to other rheumatic diseases such as rheumatoid arthritis (RA). Most of the assessment methodologies have been adapted from clinical trials on RA, ankylosing spondylitis, or psoriasis, but have not yet been validated for use in PsA. This article gives an overview of general rheumatological and PsA-specific assessment methods and outcome parameters of PsA therapy.

May E, Dulphy N, Frauendorf E, Duchmann R, Bowness P, Lopez de Castro JA, Toubert A, Märker-Hermann E. · Department of Biology II, Ludwig Maximillans-Universität München, Munich, Germany. · Tissue Antigens. · Pubmed #12472659 No free full text.

Abstract: Previous work suggested that expanded CD8+ T-cell clones in the synovial fluid (SF) of HLA-B27+ patients with reactive arthritis (ReA) preferentially use the T-cell receptor variable region (TCRBV) 1, similar CDR3 sequences, and joining region (BJ) 2S3. To determine the range of conservation and disease-specificity of CDR3-sequences, we analyzed the TCRBV1-J2S3 repertoire from 33 healthy HLA-B27+ individuals, patients with various types of spondyloarthropathies (SpA), and with rheumatoid arthritis (RA) by CDR3-spectratyping. After collection and database submission of all available TCRB-CDR3 from HLA-B27-restricted or SpA-derived T cells, we systematically screened the entire human sequence database for sequences similar to the B27/SpA-related CDR3. Spectratyping revealed expanded T cell clones using conserved TCRBV1J2S3 in the SF from 5/6 of the patients with acute ReA but not among the controls. In database searches, 50 HLA-B27 or SpA-related CDR3-sequences generated similar clusters of matched sequences, and matched reciprocally. Identical or closely related sequences were identified in 15 different individuals and a canonical ReA-associated TCRB was defined [BV1-CASSVG(V/I/L)(Y/F)STDTQYF-J2S3]. All but one patient-derived conserved sequences originated from acute stage ReA-patients, and were not present among approximately 3800 other human TCRB sequences in the database. Five of the conserved sequences originated from T cell clones that recognized uninfected cells in an HLA-B27-restricted fashion, implying a role of HLA-B27-restricted CD8+ T cells specific for a ubiquitous self- or cross-reactive microbial determinant in the early phase of ReA. Related sequences were independently identified in four different laboratories. The consensus TCRB motif could be a helpful diagnostic marker in HLA-B27-associated 'undifferentiated arthritis'.

Gu J, Rihl M, Märker-Hermann E, Baeten D, Kuipers JG, Song YW, Maksymowych WP, Burgos-Vargas R, Veys EM, De Keyser F, Deister H, Xiong M, Huang F, Tsai WC, Yu DT. · University of California Los Angeles, 90095, USA. · J Rheumatol. · Pubmed #12375327 No free full text.

Abstract: OBJECTIVE: To use gene expression profiles of spondyloarthropathy (SpA) synovial fluid mononuclear cells (SFMC) to determine if there are transcripts that support the unfolded protein response (UPR) hypothesis, and to identify which cytokines/chemokines are being expressed and which cell fractions are involved. METHODS: Gene expression profiles were generated by microarray screening of SFMC of 5 patients with SpA, 5 patients with rheumatoid arthritis (RA), and peripheral blood mononuclear cells (PBMC) of 6 controls. Results were validated by reverse transcription polymerase chain reaction using samples from a larger panel of subjects. RESULTS: The repertoires of proinflammatory cytokines/chemokines expressed by SpA and RA SFMC were very similar: monocyte chemotractant protein 1 (MCP-1), interleukin 8 (IL-8), IL-1beta, endothelial-monocyte activating polypeptide II, interferon-gamma, and tumor necrosis factor-alpha. MCP-1 was highly expressed in SpA SFMC. There was enhanced expression of immunoglobulin heavy chain binding protein (BiP) in SpA, which is compatible with the UPR hypothesis. BiP was most highly expressed in the adherent fraction of SpA SFMC. CONCLUSION: Previous data postulating UPR in SpA are based on in vitro experiments with transfected cell lines. Our patient derived data suggest that it also occurs in vivo in the macrophages of SpA joints.

Gu J, Märker-Hermann E, Baeten D, Tsai WC, Gladman D, Xiong M, Deister H, Kuipers JG, Huang F, Song YW, Maksymowych W, Kalsi J, Bannai M, Seta N, Rihl M, Crofford LJ, Veys E, De Keyser F, Yu DT. · University of California at Los Angeles, CA 90095, USA. · Rheumatology (Oxford). · Pubmed #12096225 links to  free full text

Abstract: OBJECTIVES: To identify genes which are more highly expressed in the peripheral blood mononuclear cells (PBMC) of patients with spondyloarthropathy (SpA), rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in comparison to normal subjects. METHODS: A 588-gene microarray was used as a screening tool to select a panel of such genes from PBMC of these subjects and of normal subjects. Results were then validated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The following genes were more highly expressed in arthritis patients than in normal subjects: macrophage differentiation marker MNDA (myeloid nuclear differentiation antigen), MRP8 and MRP14 (migratory inhibitory factor-related proteins); signalling molecules JAK3 (janus kinase 3) and MAP kinase p38 (mitogen-activated protein kinase); receptors TNFR2/p75, C-C-chemokine receptor type 1 (CCR1), C-X-C-chemokine receptor type 4 (CXCR4) and integrin beta1; and the cytokines/chemokines interleukin (IL) 1beta and IL-8. Expression of CXCR4 was unexpectedly high among all arthritis subjects. Using RT-PCR, ELISA and immunohistology, expression of stromal cell-derived factor 1 (SDF-1) was demonstrated in arthritis joints. CONCLUSIONS: The CXCR4/SDF-1 is a potential pro-inflammatory axis for RA, PsA and SpA.

Böcher W, Galle PR, Märker-Hermann E. · I. Medizinische Klinik und Poliklinik der Johannes Gutenberg-Universität Mainz, Germany. · Dtsch Med Wochenschr. · Pubmed #11935470 No free full text.

Abstract: CASE HISTORY: While being treated with corticosteroids and methotrexate for rheumatoid arthritis, a 63-year-old man developed livid nodules on his lower arms, hands and feet, as well as fever, necrotizing skin ulcers and rupture of a finger extensor tendon. INVESTIGATIONS: No vasculitis was found in a biopsy of one of the nodules on the lower arm. Fast growing mycobacteria, classified as M. marinum by PCR, were cultured from wound swabs. Treatment and course: The lesions healed on administration of ciprofloxacin, ethambutol and clarithromycin as well as local treatment. CONCLUSION: Cutaneous lesions of an atypical mycobacterial infection are often misdiagnosed. This is especially so in immunocompromised patients and in the differential diagnosis of vasculitis.

Seta N, Granfors K, Sahly H, Kuipers JG, Song YW, Baeten D, Veys EM, Maksymowych W, Märker-Hermann E, Gu J, Huang F, Kirveskari J, Yu DT. · University of California Los Angeles, USA. · Arthritis Rheum. · Pubmed #11315932 links to  free full text

Abstract: OBJECTIVE: Reactive arthritis (ReA) is postulated to be caused by a defective host defense against gram-negative bacteria. HLA-B27 could play a role in this process, but does not account for the many HLA-B27 negative patients. The objective of this study was to test the expression of 3 macrophage scavenger receptors (SRs) that are responsible for innate immunity against gram-negative bacteria: SR class A type I (SR-AI), SR-AII, and the macrophage receptor with collagenous structure (MARCO). We postulate that defects in such receptors might also contribute to the host risk factors that increase the predisposition to ReA and perhaps other subtypes of spondylarthropathy (SpA). METHODS: Peripheral blood, synovial fluid, and synovial tissue samples were obtained from patients with recent Salmonella infection, ReA, other SpA, and rheumatoid arthritis (RA). The expression of SRs receptors was assessed by semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: Evaluation of the peripheral blood mononuclear cells (PBMC) from 4 patients who were recently infected with Salmonella, showed that PBMC from 2 patients who developed ReA expressed positive levels of MARCO, while PBMC from 2 patients who recovered from infection without sequelae did not. The synovial fluid mononuclear cells (SFMC) from some ReA patients expressed MARCO, but the levels were only moderate. The level of MARCO in the SFMC from the SpA patient group was low. In marked contrast, MARCO expression was high in almost all samples of RA SFMC. These findings also extended to synovial tissues. CONCLUSION: Expression of the host defense gene MARCO was susceptible to modulation, not only during infections, but also in the inflammatory arthritis conditions RA and SpA. MARCO is a variable to be considered as a candidate factor that might contribute to ReA.

Duchmann R, Lambert C, May E, Höhler T, Märker-Hermann E. · Internal Medicine II, University of the Saarland, Hamberg. inrduc2med-rz.uni-sb.de · Clin Exp Immunol. · Pubmed #11207664 links to  free full text

Abstract: Ankylosing spondylitis (AS) is a complex genetic disease in which both MHC and non-MHC genes determine disease susceptibility. To determine whether the T cell repertoires of individuals with AS show signs of increased stimulation by exogenous antigens, CD4+ and CD8+ T cell subsets of five monozygotic HLA-B27+ twins (two concordant and three discordant for AS) and CD8+ T cell repertoires of three healthy HLA-B27+ individuals were characterized by TCR beta-chain (TCRB) CDR3 size spectratyping. Selected TCRB-CDR3 spectra were further analysed by BJ-segment analysis and TCRB-CDR3 from expanded T cell clones were sequenced. In an analysis of all data (519/598 possible TCRB-CDR3 spectra), AS was associated with increased T cell oligoclonality in both CD8+ (P = 0.0001) and CD4+ (P = 0.033) T cell subsets. This was also evident when data were compared between individual twins. Nucleotide sequence analysis of expanded CD8+ or CD4+ T cell clones did not show selection for particular TCRB-CDR3 amino acid sequence motifs but displayed sequence homologies with published sequences from intra-epithelial lymphocytes or synovial T cells from rheumatoid arthritis patients. Together, these results provide support for the hypothesis that responses to T cell-stimulating exogenous or endogenous antigens are involved in the induction and/or maintenance of AS.

Thomssen H, Hoffmann B, Schank M, Elewaut D, Meyer zum Büschenfelde KH, Märker-Hermann E. · 1st Medical Department, University Hospital, Mainz, Germany. · Med Microbiol Immunol. · Pubmed #10917158 No free full text.

Abstract: The initiation or exacerbation of psoriasis vulgaris is associated with infections by group A streptococci. T lymphocytes specific for streptococcal antigens or expressing a restricted, for streptococcal superantigens typical T cell receptor Vbeta chain repertoire have been described in psoriatic skin lesions. The aim of our study was, therefore, to clarify whether streptococci-reactive T lymphocytes played a role in the pathogenesis of psoriatic arthritis (PsA), and by which antigens they might be stimulated. Synovial membrane mononuclear cells from patients with PsA and other arthropathies, separated by collagenase digestion, were expanded in interleukin-2-supplemented medium and subsequently cloned in a representative cloning procedure. The T cell lines and about 30% of the T cell clones proliferated in response to preparations of group A streptococci but not to other bacteria as tested by [3H]thymidine incorporation assays. Interestingly, they did not proliferate in response to exotoxin-negative streptococci, but did so in response to the streptococcal pyrogenic exotoxins A and C, which are known to be superantigens. Accordingly, no HLA-DR restriction was seen for the proliferative response. The remaining 70% of the established T cell clones did not react to an antigen of group A streptococci. Our results show that in patients with PsA, osteoarthritis or rheumatoid arthritis a significant number of synovial T lymphocytes were responsive to streptococcal superantigens, but not to conventional streptococcal antigens. A disease-specific role of streptococci-reactive T lymphocytes in the pathogenesis of PsA is, therefore, unlikely.

Kaluza W, Meyer zum Büschenfelde KH, Galle PR, Märker-Hermann E. · First Department of Medicine, Johannes Gutenberg University of Mainz, Germany. · Clin Exp Rheumatol. · Pubmed #10728442 No free full text.

Abstract: OBJECTIVE: To determine the role of lymphocyte proliferation assay of synovial fluid mononuclear cells (SFMC) with whole fraction bacteria in the diagnosis of reactive arthritis (ReA) or arthritis of unknown origin. METHODS: We stimulated SFMC of 52 unselected patients who consecutively presented in our rheumatology outpatient clinic with the following diagnoses: ReA (n = 8), rheumatoid arthritis (RA) (n = 16), ankylosing spondylitis (AS) (n = 6), osteoarthritis (OA) (n = 5), psoriatic arthritis (PsA) (n = 5) and arthritis of varying origin (AVO) (n = 12) and peripheral blood MC (PBMC) of 10 healthy controls with arthritogenic (Y. entero-colitica, S. enteritidis, C. trachomatis) and non-arthritogenic (E. coli, K. pneumoniae, S. pyogenes, C. albicans) bacteria/mitogens and Tetanus toxoid. T cell proliferation was measured in a standard [3H] Thymidine uptake assay. RESULTS: In all groups of patients tested, SFMC could be stimulated both by arthritogenic and non-arthritogenic bacteria. So-called specific responses were observed in patients with ReA, but also in RA and AS. CONCLUSION: Our findings show that a lymphocyte proliferation assay with SFMC with whole fraction bacteria is not an adequate diagnostic tool to confirm bacterial involvement in inflammatory arthritis.

Trinder PK, Märker-Hermann E, Loos M, Maeurer MJ. · Institute of Medical Microbiology & Hygiene, Hochhaus am Augustusplatz, Mainz, Germany. · Scand J Immunol. · Pubmed #10607312 No free full text.

Abstract: A synthetic peptide representing the C1q epitope KGEQGEPGA has been shown to suppress or delay the onset of CII-induced arthritis when applied intravenously (i.v.) prior to an intradermal (i.d.) challenge, in a mouse model; the phenomenon being associated with the development of immunoglobulin (Ig)M antibodies specific for the KGEQGEPGA epitope. Here we show that this amino acid sequence provides an immunodominant B cell epitope that is recognised by autoantibodies present in the sera of patients with chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, two diseases associated with an immune response to C1q. The peptide's ability to produce peptide specific IgM when applied i.v. in both normal and athymic mice but not in mice exhibiting the x-linked B-cell associated Bruton's tyrosine kinase defect permits classification of the KGEQGEPGA peptide as a T-cell independent antigen type-2 (TI-2). IgM monoclonal antibodies raised against the peptide are able to functionally block activation of the complement cascade by C1q, via a mechanism that inhibits the C4 consumption. Antibodies to this immunodominant epitope may therefore modulate inflammatory processes by interfering with the activation of the classical pathway of the complement.

Hildner K, Finotto S, Becker C, Schlaak J, Schirmacher P, Galle PR, Märker-Hermann E, Neurath MF. · Laboratory of Immunology, I. Medical Clinic, University of Mainz, Mainz, Germany. · Clin Exp Immunol. · Pubmed #10540171 links to  free full text

Abstract: Methotrexate (MTX) is an effective immunosuppressive agent in various chronic inflammatory diseases such as rheumatoid arthritis (RA). However, its mechanisms of action are only partially understood. In this study, we assessed the effects of MTX on the differentiation of peripheral blood (PB) CD4+CD45RA 'naive' and CD4+CD45RO 'memory' T cells from healthy controls and patients with RA. Accordingly, purified T cells were primed and restimulated in vitro via the T cell receptor (TCR) in the presence of IL-2 to generate effector T cells secreting large amounts of Th1 and Th2 cytokines. We observed that low doses of MTX strongly suppress TNF and to a lesser extent interferon-gamma (IFN-gamma) production by T cells from both healthy donors and RA patients when present during T cell priming via the TCR. Similar data were obtained for TCR-primed synovial fluid mononuclear cells in RA. In contrast, production of IL-4 by TCR-primed CD45RA T cells was significantly increased upon MTX treatment. Interestingly, MTX did not enhance IL-4 production when present during restimulation of effector CD45RO T cells, although it still suppressed TNF production. The results indicate that MTX effects depend on the stage of T cell activation and identify TNF production by TCR-primed T lymphocytes as a target for low-dose MTX treatment in RA. These findings could explain the delayed clinical effects of MTX and may contribute to its potent anti-inflammatory and immunoregulatory properties.

Neurath MF, Hildner K, Becker C, Schlaak JF, Barbulescu K, Germann T, Schmitt E, Schirmacher P, Haralambous S, Pasparakis M, Meyer Zum Büschenfelde KH, Kollias G, Märker-Hermann E. · Laboratory of Immunology, I Medical Clinic, University of Mainz, Germany. · Clin Exp Immunol. · Pubmed #9933419 links to  free full text

Abstract: Immunosuppressive therapy with methotrexate (MTX) has been established as effective treatment for patients with rheumatoid arthritis. To analyse the therapeutic potential and mechanisms of action of MTX, we determined serum cytokine levels and cytokine production by splenic T cells and macrophages in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX in a murine model of experimental arthritis induced by collagen type II (CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor (TNF) production by splenic T cells but not by macrophages from healthy mice in vitro in a dose-dependent manner. In contrast, interferon-gamma (IFN-gamma) production was less strikingly reduced and IL-4 production was virtually unaffected. In addition, treatment of healthy mice with MTX in vivo led to reduced TNF serum levels and diminished TNF production by splenic T cells and macrophages. Intraperitoneal administration of MTX prior to the onset of arthritis completely prevented clinical and pathological signs of CIA. This was associated with a striking reduction of TNF production by spleen cells from MTX-treated mice. The role of TNF in MTX-mediated effects on cytokine production was further underlined by the finding that MTX effects on IFN-gamma production were augmented in TNF-transgenic mice but abrogated in mice in which the TNF-alpha gene had been inactivated by homologous recombination. Thus, MTX specifically modulates spontaneous and IL-15-induced TNF-alpha production in mice and prevents experimental murine CIA. These data suggest that TNF production by T cells is an important target of MTX and may serve as a basis to understand and further analyse MTX-mediated mechanisms of immunosuppression in patients with RA.