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1.  Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA) 
Annals of the Rheumatic Diseases  2010;70(5):755-759.
To confirm the effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab in patients with rheumatoid arthritis (RA) in a setting close to real-life medical care in Germany.
A multicentre open-label phase IIIb study was undertaken. Patients with active RA with a 28-joint Disease Activity Score (DAS28) >3.2 despite previous disease-modifying antirheumatic drugs (DMARDs) were treated with tocilizumab 8 mg/kg every 4 weeks. The primary end point was the proportion of patients achieving LDAS ≤3.2 at week 24; secondary end points included American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) or Clinical Disease Activity Index (CDAI) responses and decrease in acute phase. Analyses in subgroups such as rheumatoid factor (RF)-positive versus RF-negative patients and patients with an inadequate response to treatment with DMARDs (DMARD-IR) versus those with an inadequate response to tumour necrosis factor (TNF) antagonists (TNF antagonist-IR) were performed. Safety was assessed by adverse event documentation.
286 patients were treated and 83.6% completed the study. 41.6% had previously been treated with TNF antagonists. 57% of the intention-to-treat patients achieved the primary end point of LDAS, 47.6% achieved DAS remission <2.6 and a EULAR ‘good response’ was achieved by 54.9%; ACR50/70 response rates at week 24 were 50.7% and 33.9%, respectively. The mean±SD decrease in CDAI from baseline to week 24 was 71±29%. C reactive protein levels normalised rapidly within 1 week. Major improvements in fatigue, pain and morning stiffness were observed in the first 4 weeks and further improved until week 24. DAS28, EULAR and ACR responses at week 24 did not differ between RF-positive and RF-negative patients. TNF antagonist-naive patients responded better than patients who had previously failed on TNF antagonists. The safety profile of tocilizumab was comparable to that previously observed in the phase III trial programme. Serious infections were observed in 3.1% of patients.
Tocilizumab is highly effective in a setting close to real-life medical care with a rapid and sustained improvement in signs and symptoms of RA. A manageable safety profile was seen over the 24-week study period.
PMCID: PMC3070275  PMID: 21187298
2.  Anti‐proteasome autoantibodies contribute to anti‐nuclear antibody patterns on human larynx carcinoma cells 
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.
To disclose interference of anti‐proteasome antibodies with known ANA patterns.
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.
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.
In ANA diagnostics, interference of anti‐proteasome antibodies will have to be taken into account, especially in the differentiation of anti‐cytoplasmatic autoantibodies.
PMCID: PMC1798404  PMID: 16815863
3.  Immunoproteasome subunit LMP2 expression is deregulated in Sjögren's syndrome but not in other autoimmune disorders 
Annals of the Rheumatic Diseases  2006;65(8):1021-1027.
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.
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.
Real time quantitative RT‐PCR was used to analyse the mRNA expression pattern of the proteasome activator subunits PA28α and PA28β and of constitutive proteasome and interferon‐γ‐inducible immunoproteasome subunits in peripheral blood mononuclear cells. Simultaneously, protein expression of selected proteasome subunits was quantified by immunoblotting.
Under systemic inflammatory conditions the proteasome subunits LMP2 (β1i), LMP7 (β5i), MECL1 (β2i), and PA28α 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‐γ‐responsive subunits LMP2 (β1i), MECL1 (β2i), and the proteasome activator subunit PA28α were markedly up regulated. In contrast, LMP2 (β1i) deficiency was evident at the protein level, indicating deregulation of proteasome expression in Sjögren's syndrome.
These data provide evidence for a regulatory defect in the proteasome system in human autoimmune disorders, pointing to a unique role for LMP2 (β1i) in the pathogenesis of primary Sjögren's syndrome.
PMCID: PMC1798250  PMID: 16414974
proteasome; autoimmune disorders; Sjögren's syndrome; real time quantitative RT‐PCR; interferon γ
5.  Sinusoidal dilatation: a rare side effect of azathioprine 
Annals of the Rheumatic Diseases  2004;63(12):1702-1703.
PMCID: PMC1754863  PMID: 15547102

Results 1-7 (7)