PubMed Health⌕ Search

Biomedical subjects

G-R Burmester

Publications and source records attributed to G-R Burmester.

At least 19 recordsLinked to original sources
PubMed2006

Anti-proteasome autoantibodies contribute to anti-nuclear antibody patterns on human larynx carcinoma cells.

BACKGROUND: Autoantibodies to the 20S proteasome represent an unspecific but common serological phenomenon in patients with systemic autoimmune diseases. Interestingly, a high prevalence of these antibodies have been observed in patients with connective tissue diseases, where anti-nuclear antibodies (ANAs) serve as an important diagnostic screening test. OBJECTIVE: To disclose interference of anti-proteasome antibodies with known ANA patterns. METHODS: Anti-proteasome antibodies were isolated for comprehensive immunofluorescence analyses. The immunofluorescence pattern of human anti-proteasome antibodies was compared with a panel of monoclonal and polyclonal reference antibodies, and colocalisation was analysed using confocal microscopy. RESULTS: Anti-proteasome antibodies clearly contributed to the ANA patterns of their respective serum samples from patients with different rheumatic disorders. In addition to the nuclear pattern, proteasomal staining was also detectable in the cytoplasm, at the endoplasmic reticulum and perinuclear regions showing features overlapping with other known autoantibodies such as those to mitochondria. The specificity of anti-proteasome antibodies was proved by competition experiments and by colocalisation with monoclonal reference antibodies in confocal microscopy. CONCLUSION: In ANA diagnostics, interference of anti-proteasome antibodies will have to be taken into account, especially in the differentiation of anti-cytoplasmatic autoantibodies.

Adult↗
PubMed2006

Membrane glucocorticoid receptors are down regulated by glucocorticoids in patients with systemic lupus erythematosus and use a caveolin-1-independent expression pathway.

BACKGROUND: Membrane-bound glucocorticoid receptors (mGCR) are up regulated on monocytes after in vitro stimulation and in patients with rheumatoid arthritis. Caveolin-1 is critical for the transport of plasma membrane oestrogen receptors to the cell surface. OBJECTIVES: To investigate the expression of mGCR in patients with systemic lupus erythematosus (SLE)-a disease with different aetiopathogenesis and treatment regimens-and to examine whether caveolin-1 is critical for the transport of mGCR to the cell surface. METHODS: Frequencies of mGCR+ peripheral blood mononuclear cells were measured using high-sensitivity immunofluorescent staining and tested for correlation with SLE disease activity and glucocorticoid treatment. Semiquantitative polymerase chain reaction, immunofluorescence, recombinant expression and confocal laser-scanning microscopy were used to search for an association of mGCR with caveolin-1. RESULTS: The frequencies of mGCR+ monocytes (CD14+) were considerably higher in patients with SLE (n = 33) than in healthy controls (n = 58), whereas B cells (CD19+) were not different in this regard. T cells (CD3+) were always mGCR-. The frequency of mGCR+ monocytes in patients with SLE did not correlate with disease activity, but did inversely correlate with glucocorticoid dosages; this inverse correlation was confirmed by corresponding in vitro experiments with stimulated monocytes. The induced up regulation of mGCR was not accompanied by an up regulation of caveolin-1, and mGCR are not colocalised with caveolin-1 in plasma membrane caveolae. CONCLUSION: mGCR are (a) up regulated in patients with SLE and by inflammatory stimuli and (b) down regulated by glucocorticoids, suggesting a negative feedback loop to control glucocorticoid action. Drugs binding selectively to mGCR may in future prove to be of therapeutic value.

Adult↗
PubMed2006

Immunoproteasome subunit LMP2 expression is deregulated in Sjogren's syndrome but not in other autoimmune disorders.

BACKGROUND: The proteasome system has a pivotal role in the control of the immune response, which suggests that it might be involved in the pathogenesis of autoimmune disorders. OBJECTIVE: To investigate the expression profile of selected proteasomal genes in human peripheral blood mononuclear cells in patients with a variety of autoimmune diseases compared with healthy subjects. METHODS: Real time quantitative RT-PCR was used to analyse the mRNA expression pattern of the proteasome activator subunits PA28alpha and PA28beta and of constitutive proteasome and interferon-gamma-inducible immunoproteasome subunits in peripheral blood mononuclear cells. Simultaneously, protein expression of selected proteasome subunits was quantified by immunoblotting. RESULTS: Under systemic inflammatory conditions the proteasome subunits LMP2 (beta1i), LMP7 (beta5i), MECL1 (beta2i), and PA28alpha were expressed abundantly at the protein level in the vast majority of systemic autoimmune disorders. However, simultaneous mRNA and protein quantification showed a characteristic proteasome expression signature in primary Sjögren's syndrome. At the transcript level, the interferon-gamma-responsive subunits LMP2 (beta1i), MECL1 (beta2i), and the proteasome activator subunit PA28alpha were markedly up regulated. In contrast, LMP2 (beta1i) deficiency was evident at the protein level, indicating deregulation of proteasome expression in Sjögren's syndrome. CONCLUSIONS: These data provide evidence for a regulatory defect in the proteasome system in human autoimmune disorders, pointing to a unique role for LMP2 (beta1i) in the pathogenesis of primary Sjögren's syndrome.

Adult↗
PubMed2006

Safety of extended treatment with anakinra in patients with rheumatoid arthritis.

OBJECTIVE: To determine the safety profile of anakinra after extended exposure in a diverse clinical trial population of patients with rheumatoid arthritis. METHODS: A six month, randomised, double blind phase comparing anakinra (100 mg/day) with placebo was followed by open label anakinra treatment for up to three years in patients with rheumatoid arthritis. Concomitant non-steroidal anti-inflammatory drugs, corticosteroids, and other disease modifying antirheumatic drugs were permitted. RESULTS: In all 1346 patients with rheumatoid arthritis received anakinra for up to three years. Patients had varying levels of disease severity, concomitant drug use, and comorbid conditions. Cumulative, exposure adjusted event (EAE) rates for all adverse events (AEs), serious AEs, and deaths were similar during each year of anakinra treatment; the overall rate (0 to 3 years) was similar to that observed for controls during the blinded phase. The most frequent AEs were injection site reactions (122.26 events/100 patient-years), rheumatoid arthritis progression (67.80 events/100 patient-years), and upper respiratory infections (26.09 events/100 patient-years). The EAE rate of serious infections was higher for patients treated with anakinra for 0 to 3 years (5.37 events/100 patient-years) than for controls during the blinded phase (1.65 events/100 patient-years). However, if the patient was not receiving corticosteroid treatment at baseline, the serious infection rate was substantially lower (2.87 event/100 patient-years). The overall incidence of malignancies was consistent with expected rates reported by SEER. Neutralising antibodies developed in 25 patients, but appeared to be transient in 12; neutralising antibody status did not appear related to occurrence of malignancies or serious infections. There were no clinically significant trends in laboratory data related to anakinra. CONCLUSION: Anakinra is safe and well tolerated for up to three years of continuous use in a diverse population of patients with rheumatoid arthritis.

Adult↗
PubMed2006

[New developments in joint ultrasonography].

Musculoskeletal ultrasonography has become an established imaging technique in rheumatology. The ability of ultrasonography to visualize soft tissue changes provides a possibility for differentiating between exudative and proliferative synovial tissue changes. Superficial cartilage and bone lesions can be detected earlier by ultrasonography than by conventional radiography. The application of Doppler and power Doppler ultrasonography is helpful for the detection of early inflammation. Current studies with ultrasound contrast media demonstrate its benefit in the differentiation of inflammatory processes. Musculoskeletal ultrasonography is helpful in the diagnosis of early arthritis, especially in patients with inconspicuous conventional radiography or suspicious clinical findings. It is a convenient method for follow-up analysis, and therefore has an impact on the monitoring of therapy. It is patient-friendly and is an important tool for the diagnostic work-up of arthritis.

Arthritis, Rheumatoid↗
PubMed2006

Synovitis score: discrimination between chronic low-grade and high-grade synovitis.

AIMS: To standardize the histopathological assessment of synovial membrane specimens in order to contribute to the diagnostics of rheumatic and non-rheumatic joint diseases. METHODS AND RESULTS: Three features of chronic synovitis (enlargement of lining cell layer, cellular density of synovial stroma, leukocytic infiltrate) were semiquantitatively evaluated (from 0, absent to 3, strong) and each feature was graded separately. The sum provided the synovitis score, which was interpreted as follows: 0-1, no synovitis; 2-4, low-grade synovitis; 5-9, high-grade synovitis. Five hundred and fifty-nine synovectomy specimens were graded by two independent observers. Clinical diagnoses were osteoarthrosis (n=212), post-traumatic arthritis (n=21), rheumatoid arthritis (n=246), psoriatic arthritis (n=22), reactive arthritis (n=9), as well as controls (n=49) from autopsies of patients without joint damage. Median synovitis scores when correlated with clinical diagnoses were: controls 1.0, osteoarthritis 2.0, post-traumatic arthritis 2.0, psoriatic arthritis 3.5, reactive arthritis 5.0 and rheumatoid arthritis 5.0. The scores differed significantly between most disease groups, especially between degenerative and rheumatic diseases. A high-grade synovitis was strongly associated with rheumatic joint diseases (P<0.001, sensitivity 61.7%, specificity 96.1%). The correlation between the two observers was high (r=0.941). CONCLUSION: The proposed synovitis score is based on well-defined, reproducible histopathological criteria and may contribute to diagnosis in rheumatic and non-rheumatic joint diseases.

Adolescent↗
PubMed2005

New onset or exacerbation of psoriatic skin lesions in patients with definite rheumatoid arthritis receiving tumour necrosis factor alpha antagonists.

BACKGROUND: Blockage of tumour necrosis factor alpha (TNFalpha) is highly effective in rheumatic diseases, especially in rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis. Furthermore, TNFalpha antagonists have also been shown to significantly reduce psoriatic skin lesions. CASE REPORTS: A series of nine patients with RA who were treated with different types of TNFalpha antagonists and who unexpectedly developed either a new onset or an exacerbation of psoriatic skin lesions are reported.

Adalimumab↗
PubMed2005

[Synovialitis score: histopathological grading system for chronic rheumatic and non-rheumatic synovialitis].

Standardization of the histopathological assessment of synovial membrane specimens might facilitate the diagnosis of chronic rheumatic and non-rheumatic joint diseases. We would like to propose a histological graduation scheme ("synovialitis score"), which is applicable to all forms of synovitis, irrespective of its etiology. This score evaluates the three compartments of chronic synovialitis [enlargement of lining cell layer, activation of synovial stroma (i. e. resident cells), leukocytic infiltrate] semiquantitatively (from 0=absent to 3=strong). Each compartment is graded separately, and the sum resembles the synovialitis score, which is interpreted as follows: 0-1: no synovialitis, 2- 3: slight synovialitis, 4-6: moderate synovialitis, 7-9: strong synovialitis (for sample photos see also www.charite.de/ch/patho/Webpage/pages/forschung/arbeitsgruppen/ag-krenn/index.htm). A total of 483 synovial specimens (resections n=462, biopsies n=21) were graded by two independent observers. Clinical diagnoses were osteoarthrosis (OA; n=153), posttraumatic arthritis (PtA; n=31), rheumatoid arthritis (RA; n=239), psoriatic arthritis (PsA; n=32), reactive arthritis (ReA; n=7), and controls (Co, n=21) from necropsies of patients without joint damage. The correlation between two observers was high (p<0.001). The correlation coefficient between the different samples from the same joint in n=112 cases was between 0.86 and 0.95. Median synovialitis scores when correlated with clinical diagnoses were: Co 0.5, OA 2, PtA 3, PsA 3, ReA 4, RA 5. The differences in scores between Co and all other groups were highly significant (p<0.001). A synovialitis score of 4 points and more was strongly associated with rheumatic joint diseases (sensitivity 73%, specificity 86%). Validation of the synovialitis score by gene expression data showed good correlations for the lining cell enlargement with MMP1 (0.685), for the leukocytic infiltrate with CD3 (0.754) and CD138 (0.744) and for the stroma activation with CD14 (0.744). The proposed synovialitis score is based on well definable histopathologic criteria and contributes to the diagnosis of rheumatic and non-rheumatic joint diseases.

Adolescent↗
PubMed2005

[Current insights into the development of new glucocorticoid receptor ligands].

Recent insights into the mechanisms of genomic and non-genomic glucocorticoid actions have stimulated the search for novel glucocorticoid receptor ligands. These efforts are driven by the need to improve the benefit-risk ratio of these important drugs. Glucocorticoids are very frequently and successfully used drugs which mediate important immunosuppressive and anti-inflammatory effects, but unfortunately they have pleiotropic effects causing a number of adverse reactions which limit their clinical use, especially at higher dosages and for longer periods. For this reason, novel glucocorticoid receptor ligands are being developed, among them selective glucocorticoid receptor agonists (SEGRAs). SEGRAs are drugs that predominantly induce transrepression effects (inhibition of protein synthesis), whereas the transactivation activity (induction of protein synthesis) is significantly reduced as compared with conventional glucocorticoid drugs. This makes sense since it became evident over the last few years that many adverse effects are predominantly caused by the transactivation mechanism, whereas anti-inflammatory effects are mostly mediated by transrepression mechanisms. Other interesting examples for exciting new developments are NO-glucocorticoids and long-circulating liposomal glucocorticoids. It is, however, true of all these developments that further in vivo and in vitro investigations and clinical trials will have to define in more detail their safety-efficacy profile in order to answer the questions whether these drugs as "improved glucocorticoids" will enter clinical medicine in the near future.

Anti-Inflammatory Agents↗