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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.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/ard.2010.139725
PMCID: PMC3070275  PMID: 21187298
2.  “Bubbles in the brain”: an unusual complication of dermatomyositis 
Annals of the Rheumatic Diseases  2006;65(4):550-551.
doi:10.1136/ard.2005.043752
PMCID: PMC1798104  PMID: 16531553
dermatomyositis; pneumomediastinum; pneumoencephalon; oesophagus perforation
3.  Transdifferentiation of polymorphonuclear neutrophils to dendritic-like cells at the site of inflammation in rheumatoid arthritis: evidence for activation by T cells 
Annals of the Rheumatic Diseases  2005;64(10):1436-1442.
Objectives: To investigate infiltrated cells in the synovial fluid (SF) of inflamed joints of patients with rheumatoid arthritis (RA), with special reference to polymorphonuclear neutrophils (PMN) and their interaction with T cells.
Methods: Expression on PMN of activation associated receptors CD14, CD64, CD83, and major histocompatibility complex (MHC) class II was examined in the SF of 15 patients with RA, as were the infiltrated T cells. SF cytokines were determined by enzyme linked immunosorbent assay (ELISA). To mimic the in vivo situation, co-culture experiments were carried out using PMN and T cells of healthy donors.
Results: The SF contained activated T lymphocytes and abundant PMN. SF PMN expression of CD14 and CD64 was enhanced compared with peripheral blood. Of special interest was the observation that only the SF PMN expressed MHC class II antigens and CD83. Exposure to SF, which contained considerable amounts of cytokines (for example, interferon γ (IFNγ), tumour necrosis factor α, and interleukin 2), induced a similar receptor pattern on blood derived PMN of healthy donors. Furthermore, PMN acquired MHC class II and CD83 within 24 to 48 hours, when co-cultured with autologous T cells or T cell lines. This effect was also achieved by T cell supernatants, was dependent on protein synthesis, and could be inhibited by antibodies against IFNγ.
Conclusions: SF PMN from patients with RA undergo major alterations, including transdifferentiation to cells with dendritic-like characteristics, probably induced by T cell derived cytokines. Because MHC class II positive PMN are known to activate T cells, the mutual activation of PMN and T cells might contribute to the perpetuation of the local inflammatory process, and eventually to the destructive process in RA.
doi:10.1136/ard.2004.034132
PMCID: PMC1755243  PMID: 15778239
4.  Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis 
Annals of the Rheumatic Diseases  2004;64(4):630-633.
Objective: To determine the safety/tolerability and efficacy of anakinra in patients with SLE with leading joint involvement.
Methods: In patients with SLE with active polyarthritis and no other uncontrolled systemic/organ manifestations, 100 mg/day anakinra was self administered subcutaneously for 3 months. Disease activity was assessed by VAS, number of swollen/tender joints, ECLAM score, and serological and immunological measures.
Results: Four patients with SLE were studied; anakinra was safe in all four patients and no drug related serious adverse events occurred. A subjective benefit was seen in all patients and a trend towards better activity measures after 4 weeks. After an initial response, one patient left the study because of an arthritic flare after 6 weeks.
Conclusion: In this study anakinra was apparently safe and well tolerated and led to clinical and serological improvement. Anakinra might be an interesting alternative in individual patients with lupus arthritis not responding to conventional treatments.
doi:10.1136/ard.2004.025858
PMCID: PMC1755442  PMID: 15345502
6.  First clinical trials of a new heteropolymer technology agent in normal healthy volunteers and patients with systemic lupus erythematosus: safety and proof of principle of the antigen-heteropolymer ETI-104 
Annals of the Rheumatic Diseases  2004;63(9):1104-1112.
Background: The heteropolymer technology was developed to remove pathogens from the circulation.
Objectives: To evaluate the safety and tolerability of a single administration and to establish proof of principle for ETI-104 in normal healthy volunteers (NHV) and patients with systemic lupus erythematosus (SLE)
Methods: The drug was given intravenously to 11 NHV and six patients with SLE. Over 28 days, vital signs were noted, a haematological and chemical analysis of blood and urine was carried out, and adverse events were recorded. CR1 receptor numbers, the ability of antigen based heteropolymers to bind to red blood cells (RBCs), and the clearance of high avidity and total anti-dsDNA antibodies were measured by Farr assays and FACS analysis.
Results: No safety measure differed significantly from normal in both groups; no drug related serious adverse events occurred. ETI-104 rapidly bound to RBCs in NHV and patients with SLE. Binding of the drug to RBCs of patients with SLE also caused a rapid reduction of circulating anti-dsDNA antibodies in the plasma 15 minutes after administration, with a maximum reduction of 55% (range 43–62). At 28 days statistically significant decreases were maintained in three patients, while in the other three the values had returned to baseline levels.
Conclusion: These clinical trials established the safety and the proof of principle of the new immunoconjugate ETI-104. This provides the basis for further development of this technology for numerous indications—for example, therapeutic options for autoimmune diseases or viral and bacterial infections.
doi:10.1136/ard.2003.016691
PMCID: PMC1755118  PMID: 15308520

Results 1-6 (6)