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ABSTRACT: Interleukin (IL)-18 is involved in host defense mechanisms and inflammatory diseases, among them rheumatoid arthritis (RA). High levels of IL-18 expression in RA joints are contrasted by reduced IL-18 expression in RA peripheral blood mononuclear cells (PBMC). Here, we investigated a putative IL-18 regulating role of corticosteroids.
IL-18 transcript and protein levels in PBMC from untreated and prednisolone treated RA patients, and from healthy donors were assessed by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting. IL-18 regulation was determined in PBMC and U937 cells upon exposure to prednisolone in vitro by RT-PCR and Northern Blot analysis, by ELISA in cell culture supernatants, and in transiently transfected THP-1 cells by IL-18 promoter activity luciferase assays.
In RA PBMC, IL-18 transcript levels were dose dependently restored, in parallel with administered prednisolone treatment, to subnormal levels. The corresponding intracellular IL-18 deposits in contrast were depleted. In cultured PBMC and promonocytic cell lines, prednisolone up-regulated IL-18 transcription in parallel with increasing the IL- 18 protein release into cell culture supernatants.
Prednisolone increases IL-18 expression and release in PBMC and monocytic cell lines.
Inflammation Research 10/2002; 51(9):457-63. · 2.11 Impact Factor
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ABSTRACT: Synovial fluid (SF) analysis was a mandatory investigation in rheumatological practice. In recent time, synovial fluid analysis lost importance predominantly due to unclear defined guidelines for the practical use.
To evaluate the clinical value of the determination of the complement components C'3c and C'4 and immunoglobulines IgG, IgA and IgM synovial fluid concentrations with regard to pathophysiology and currently used RA and SpA classification criteria.
Synovial fluid samples were obtained from 22 patients fulfilling ACR criteria for rheumatoid arthritis (RA), and 18 patients suffering from seronegative spondyloarthropathy (SpA) according to the ESSG criteria. Sixteen osteoarthritis (OA) SF samples were used as controls. IgG, IgA, IgM, C'3c and C'4 in SF and sera were determined by nephelometry. Comparison of the diseases, and linear as well as stepwise logistic regression analyses were performed in order to determine the interrelation of the determined parameters and a ranking of their diagnostic value for the identification of RA or SpA synovial fluids.
SF-IgA, SF-IgG and SF-IgM concentrations were closely correlated with their corresponding serum levels (p < 0.01), while SF-C'3c and SF-C'4 depended on articular factors (p < 0.01). Determination of SF-C'3c (accuracy = 80.4%, improved chi 2 = 22.02, p < 0.001) and SF-C'4 (accuracy = 75.0%, improved chi 2 = 21.81, p < 0.001) both provided a good predictive value for the diagnosis of SpA when exceeding the cut off level of about 40 mg/dl (C'3c) or 15 mg/dl (C'4), respectively. Calculation of the C'-SF/S ratios did not provide an additional diagnostic benefit. SF-IgG, IgA and IgM as well as the calculated SF/S ratios were within the same range in RA and SpA fluids.
SF concentration of complement components primarily depends on local articular factors. Significant differences of SF complement concentrations in established RA and SpA give reason for prospective analysis of these parameters in early undifferentiated oligoarthritis and evaluation in large studies, e.g. when re-evaluating the preliminary criteria for spondyloarthropathy.
Zeitschrift für Rheumatologie 02/2002; 61(1):48-57. · 0.46 Impact Factor
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ABSTRACT: Die Untersuchung der Synovialflüssigkeit hat in den letzten Jahren in der rheumatologischen Praxis an Akzeptanz verloren.
Fragestellung Welche diagnostische Wertigkeit besitzen quantitative Komplement- (C′3c und C′4) und Immunglobulin-Isotyp-Bestimmungen (IgG,
IgA und IgM) in der Synovialflüssigkeit für die Arthritis-Differentialdiagnostik unter Berücksichtigung pathophysiologischer
Zusammenhänge und der derzeit gültigen Klassifikationskriterien der rheumatoiden Arthritis und Spondylarthropathie? Methodik Untersuchung von 22 nach den ACR-Kriterien klassifizierten Patienten mit rheumatoider Arthritis (RA), 18 Patienten mit seronegativer
Spondylarthropathie (SpA) entsprechend den Klassifikationskriterien der ESSG und 16 Gelenkpunktaten von Patienten mit Gonarthrose/Osteoarthritis
(OA). Nephelometrische Bestimmung von IgG, IgA, IgM, C′3c und C′4 in Serum und Synovialflüssigkeit. Vergleich der Krankheitsgruppen
und lineare Regressionsanalysen zur Ermittlung statistischer Zusammenhänge zwischen einzelnen Parametern. Schrittweise logistische
Regressionsanalyse zur Bestimmung der diagnostischen Wertigkeit einzelner und miteinander verknüpfter Parameter. Ergebnisse SF-IgA, SF-IgG und SF-IgM Konzentrationen hängen in erster Linie von den korrespondierenden Serumwerten ab (p<0,01), während
die Konzentrationen von C′3c und C′4 bei RA und SpA primär von artikulären Faktoren und nicht von den korrespondierenden Serumwerten
abhängen (p<0,01). Die Bestimmung von C′3c- und C′4-Synoviaspiegeln wie auch die Berechnung der Synovia/Serum-Ratio (SF/S-Ratio)
bietet eine differentialdiagnostische Hilfe für die Zuordnung eines Punktates zur Spondylarthropathiegruppe: SpA-Punktate
konnten anhand der C′3c-Bestimmung (Grenzwert 40mg/dl) zu 80,4% (χ2=22,02, p<0,001) und mittels C′4 zu 75,0% (χ2=21,81, p<0,001) korrekt zugeordnet werden. Die zusätzliche Berechnung der C′3c- und C′4-SF/Serum-Ratio verbesserte die Validität
der Komplementdiagnostik nicht. Die IgG-, IgA- und IgM-Synoviakonzentrationen und deren SF/S-Ratio waren bei RA und SpA gleich
verteilt. Schlussfolgerungen Die Konzentration von Komplementfaktoren in der Synovialflüssigkeit unterliegt sowohl bei der RA als auch der SpA primär
artikulären Einflüssen. Die beobachtbaren Unterschiede zwischen diesen beiden Krankheitsgruppen sind zumindest bei etablierter
Krankheit so groß, dass eine prospektive Analyse bei undifferenzierten Mon- und Oligoarthritiden und eine Evaluation dieser
Parameter in großen Kollektiven mit niedrigerer Krankheitsprävalenz, z.B. im Rahmen eventueller Neuklassifikationen von Spondylarthropathien,
gerechtfertigt erscheint.
Synovial fluid (SF) analysis was a mandatory investigation in rheumatological practice. In recent time, synovial fluid analysis
lost importance predominantly due to unclear defined guidelines for the practical use. Objective To evaluate the clinical value of the determination of the complement components C′3c and C′4 and immunoglobulines IgG, IgA
and IgM synovial fluid concentrations with regard to pathophysiology and currently used RA and SpA classification criteria.
Methods Synovial fluid samples were obtained from 22 patients fulfilling ACR criteria for rheumatoid arthritis (RA), and 18 patients
suffering from seronegative spondyloarthropathy (SpA) according to the ESSG criteria. Sixteen osteoarthritis (OA) SF samples
were used as controls. IgG, IgA, IgM, C′3c and C′4 in SF and sera were determined by nephelometry. Comparison of the diseases,
and linear as well as stepwise logistic regression analyses were performed in order to determine the interrelation of the
determined parameters and a ranking of their diagnostic value for the identification of RA or SpA synovial fluids. Results SF-IgA, SF-IgG and SF-IgM concentrations were closely correlated with their corresponding serum levels (p<0.01), while SF-C′3c
and SF-C′4 depended on articular factors (p<0.01). Determination of SF-C′3c (accuracy=80.4%, improved χ2=22.02, p<0.001) and SF-C′4 (accuracy=75.0%, improved χ2=21.81, p<0.001) both provided a good predictive value for the diagnosis of SpA when exceeding the cut off level of about
40 mg/dl (C′3c) or 15 mg/dl (C′4), respectively. Calculation of the C′-SF/S ratios did not provide an additional diagnostic
benefit. SF-IgG, IgA and IgM as well as the calculated SF/S ratios were within the same range in RA and SpA fluids. Conclusions SF concentration of complement components primarily depends on local articular factors. Significant differences of SF complement
concentrations in established RA and SpA give reason for prospective analysis of these parameters in early undifferentiated
oligoarthritis and evaluation in large studies, e.g. when re-evaluating the preliminary criteria for spondyloarthropathy.
Zeitschrift für Rheumatologie 01/2002; 61(1):48-57. · 0.46 Impact Factor
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ABSTRACT: To investigate whether treatment of anemia of chronic disease (ACD) in patients with rheumatoid arthritis (RA) with recombinant human erythropoietin (rHu-Epo) in combination with intravenous (i.v.) iron influences health related quality of life (HRQoL) and clinical outcome including disease activity.
Thirty patients with ACD and RA were treated with 150 IU/kg rHu-Epo twice weekly for 12 weeks. As well, in case of functional iron deficiency 200 mg of iron-sucrose per week was given intravenously. Vitality and fatigue as dimensions of HRQoL were evaluated by the vitality subscale of the Short Form-36 (SF-36-VT) and the Multidimensional Assessment of Fatigue (MAF). Muscle strength was measured by the Muscle Strength Index.
All 28 patients completing the study responded to treatment; 23/28 patients developed functional iron deficiency and received i.v. iron (mean absolute dose 710 +/- 560 mg). Average hemoglobin concentration increased from 10.7 +/- 1.1 to 13.2 +/- 1.0 g/dl after a mean treatment period of 8.7 +/- 2.3 weeks. Muscle strength increased from 43.5 +/- 11.2 to 49.1 +/- 12.9 and SF-36-VT from 28.2% +/- 14.3% to 47.1% +/- 20.8%. while fatigue decreased (MAF from 34.7 +/- 9.3 to 25.0 +/- 11.3). Among the disease activity variables the number of swollen/tender joints, erythrocyte sedimentation rate, Disease Activity Score, and RA Disease Activity Index improved significantly during treatment.
Treatment of ACD in RA patients with rHu-Epo and i.v. iron is safe and effective in correction of anemia, increases muscle strength. improves vitality, and lowers fatigue. In addition we observed a reduction of disease activity.
The Journal of Rheumatology 12/2001; 28(11):2430-6. · 3.69 Impact Factor
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ABSTRACT: To investigate the expression of and monokine induction by interleukin 18 (IL-18; also called interferon-gamma inducing factor, IGIF), in peripheral blood mononuclear cells (PBMC) and cultured synoviocytes from rheumatoid arthritis (RA) patients.
We carried out IL-18 Western blotting and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) of cytokines in PBMC [IL-18, IL-1beta and tumour necrosis factor alpha (TNF-alpha)] and long-term cultured fibroblast-like synoviocytes (FLS) [IL-18, IL-1beta, TNF-alpha, IL-6, interferon gamma (INF-gamma) and [granulocyte-macrophage colony stimulating factor (GM-CSF)] from RA patients and controls. FLS were isolated from RA synovial membranes (FLS(SM)) and RA synovial fluids (FLS(SF)), osteoarthritis (OA) FLS(SM) and FLS(SF) from spondyloarthropathy patients. FLS were characterized by fluorescence-activated cell sorting of the FLS. PBMC and FLS from RA patients and control subjects were stimulated with recombinant human IL-18 and IL-1beta (rHuIL-18/rHuIL-1beta), and TNF-alpha, IL-1beta and MMP-1 were measured by ELISA in supernatants.
Constitutive expression of IL-18 mRNA was significantly reduced whereas that of TNF-alpha was enhanced in RA PBMC. Persistent low expression of IL-18, TNF-alpha, GM-CSF and IL-1beta was observed in RA and OA FLS(SM) as well as spondyloarthropathy FLS(SF). In contrast, high constitutive expression of IL-18 in FLS (CD90/Thy-1- and CD54-positive, CD14- and CD86-negative), accompanied by persistent high levels of TNF-alpha, GM-CSF and IL-1beta expression, was restricted to synovial fluid-derived FLS obtained from RA patients. IFN-gamma was not detectable in any culture, but IL-6 mRNA was equally expressed in all FLS cultures. rHuIL-18 was effective in stimulating TNF-alpha and IL-1beta secretion in PBMC from healthy controls, but failed to stimulate TNF-alpha and IL-1beta secretion from PBMC in 11 of 12 RA patients, and all FLS cultures. rHu-IL-1beta, but not rHu-IL-18, induced interstitial collagenase (MMP-1) in FLS.
Persistent high production of proinflammatory cytokines in RA-FLS(SF) may be relevant for chronic progression in RA synovitis. Levels of TNF-alpha and IL-1beta expression are increased in RA-FLS(SF), but are independent of IL-18. The pathological function of enhanced IL-18 expression in RA-FLS(SF) remains to be further elucidated.
Rheumatology 04/2001; 40(3):302-9. · 4.06 Impact Factor
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ABSTRACT: To search for RA specific processes among T cell accumulation, T cell activation, or cytokine expression in CD4+ and CD8+ synovial fluid (SF) T cells.
Flow cytometry of CD4+, CD8+, CD45RA+, CD45RO+, CD69 double or triple stained peripheral blood (PB) and SF T cells. IL-2, IL-10, and IFN-gamma expression was determined in PMA + ionomycin stimulated T cells on the single cell level. Concentrations of secreted IL-2, IL-4, IL-10, and IFN-gamma were quantified in the sera and synovial fluids by enzyme linked immunosorbent assay (ELISA).
A preferential recruitment of CD45RO+ memory T cells was found for CD4+ helper T cells, and in similar also for CD8+ suppressor T cells. An elevated CD69 expression was detected in memory, but also in CD45RA+ naive CD4+ and CD8+ SF T cells, whilst IL-2 expression was only demonstrable in a minor proportion of T cells populations. Preferential recruitment of memory T cells, but incomplete activation of naive and memory, CD4+ and CD8+ T cells were in similar found in RA and control patients. In RA but not in the control patients, a relevant proportion of CD4+ and CD8+ PB and SF T cells expressed IL-10 and IFN-gamma. High concentrations of IL-10, that were correlated with the amounts of secreted TNF-alpha, were only detected in RA joints.
Memory and naive T cell state of CD4+ and CD8+ T cell accumulates in the joints, and early T cell activation occur in similar patterns in RA and control patients. High IL-10 SF concentrations in contrast, and elevated percentages of IFN-gamma and IL-10 expressing CD4+ and CD8+ T cells in the PB and SF were characteristic for RA. Here, CD8+ T cells may contribute to high IL-10 concentrations in RA joints.
Clinical and experimental rheumatology 20(6):813-22. · 2.15 Impact Factor
