Showing papers by "Rille Pullerits published in 2013"

HMGB1 Levels Are Increased in Patients with Juvenile Idiopathic Arthritis, Correlate with Early Onset of Disease, and Are Independent of Disease Duration

Abstract: Objective. High mobility group box chromosomal protein 1 (HMGB1) has been implicated as a mediator of inflammation in rheumatoid arthritis (RA), while its role in juvenile idiopathic arthritis (JIA) has not been described. To evaluate the role of HMGB1 in the inflammatory process in JIA and its potential as a therapeutic target, we investigated whether extracellular HMGB1 is detectable in JIA and if so, to correlate the levels with established inflammatory markers and clinical measures. Methods. Matching samples of blood and synovial fluid (SF) were collected from 23 patients with JIA. Levels of HMGB1, soluble receptor for advanced glycation endproducts, S100A12, myeloid-related protein 8/14, and other inflammatory mediators were analyzed. Results. Significantly increased HMGB1 levels were recorded in SF compared to blood samples from patients with JIA. The amount of HMGB1 was highest in patients with early disease onset irrespective of disease duration. In contrast, the proinflammatory S100 protein and interleukin 8 were highest in patients in early phases of disease. Matrix metalloproteinase-3, a marker of cartilage destruction, was higher in patients with late disease onset, indicating similarities with RA in that patient subgroup. Conclusion. Levels of extracellular HMGB1 are increased in the inflamed joints of patients with JIA. This warrants further studies of HMGB1 as a mediator of JIA pathogenesis as well as a biomarker for inflammatory activity and as a target for therapy. The variation in levels of HMGB1 and S100 proteins in relation to disease onset indicates a difference in inflammatory phenotype during disease progression.

Anti B-cell therapy against refractory thrombocytopenia in SLE and MCTD patients: long-term follow-up and review of the literature.

Abstract: ObjectiveThe objective of this study was to retrospectively evaluate the clinical and immunological effects of anti-B cell treatment in patients with systemic lupus erythematosus (SLE) and mixed co...

Infliximab Dose Reduction Sustains the Clinical Treatment Effect in Active HLAB27 Positive Ankylosing Spondylitis: A Two-Year Pilot Study

Abstract: The rationale of the study was to evaluate the efficacy of infliximab (IFX) treatment in patients with ankylosing spondylitis (AS) and to determine whether IFX dose reduction and interval extension sustains the treatment effect. Nineteen patients were included and treated with IFX 5 mg/kg every 6 weeks for 56 weeks. All patients concomitantly received MTX with median dose 7.5 mg/weekly. During the second year, the IFX dose was reduced to 3 mg/kg every 8 weeks. Eighteen patients completed the 1-year and 15 patients the 2-year trial. The ≥50% improvement at week 16 from baseline of BASDAI was achieved in 16/19 (84%) patients. Significant reductions in BASDAI, BASFI, and BASMI scores, decrease in ESR and CRP, and improvement in SF-36 were observed at weeks 16 and 56. The MRI-defined inflammatory changes in the sacroiliac joints disappeared in 10/15 patients (67%) already at 16 weeks. IFX treatment effect was sustained throughout the second year after IFX dose reduction and interval extension. We conclude that IFX treatment is effective in well-established active AS and a dose reduction sustains the treatment effect. These observations are of clinical importance and open the opportunity to reduce the drug costs.

Intra-peritoneal sRAGE treatment induces alterations in cellular distribution of CD19+, CD3+ and Mac-1+ cells in lymphoid organs and peritoneal cavity

Abstract: Receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that binds a variety of pro-inflammatory ligands. Its soluble form, sRAGE, can compete for ligand binding and thereby have an anti-inflammatory effect. We have recently reported that sRAGE also exerts pro-inflammatory and chemotactic properties suggesting a dual role for sRAGE in immune modulation. Our present aim was to analyse the immunomodulatory properties of sRAGE in vivo with respect to acquired immunity. Naive mice were treated intra-peritoneally with sRAGE and cells from peritoneal lavage, spleens and bone marrow were examined. Mice treated with sRAGE displayed an increased leucocyte count in the peritoneal cavity, enlarged spleens and increased cellularity compared with vehicle-treated animals. Furthermore, sRAGE-treated mice had a significantly increased frequency and number of CD19+ B cells in spleen and a reduced frequency of CD19+ B cells in bone marrow compared with controls. Functionally, splenocytes from sRAGE-treated mice showed elevated IgG production and up to a four-fold increased IgM secretion compared with control animals and produced significantly higher levels of interleukin-10, interferon-γ and interleukin-6 in response to lipopolysaccharide stimulation. Our results suggest that sRAGE has immunomodulatory properties, since intra-peritoneal administration of sRAGE into healthy mice leads to rearrangements in cellular composition in the bone marrow and spleen. Moreover, the administration of sRAGE directs B cells into the spleen and towards differentiation. Our novel findings indicate that sRAGE exerts an effect on the cells of adaptive immunity.

Increased resistin in brain dead organ donors is associated with delayed graft function after kidney transplantation

Abstract: Introduction: Resistin increases during several inflammatory diseases and after intracerebral bleeding or head trauma. Resistin activates the endothelium and may initiate an inflammatory response. No data are available on resistin in brain dead donors (DBD) that regularly manifest a pronounced inflammatory state. Methods: We analyzed plasma resistin in 63 DBDs and correlated results with donor variables and the postoperative course following kidney transplantation using organs from these donors. Endocan and monocyte chemotactic protein (MCP)-1 were also studied. Twenty-six live kidney donors (LD) and the corresponding kidney transplantations were used as controls. Results: DBDs had higher resistin (median/range 30.75 ng/ml, 5.41–173.6) than LD (7.71 ng/ml, 2.41–15.74, p < 0.0001). Resistin in DBD correlated with delayed graft function (DGF) in the kidney recipients (r = 0.321, p < 0.01); receiver operating characteristic curve revealed an area under the curve of 0.765 (95% confidence interval [CI] 0.648–0.881, p < 0.01) and a cut-off value for resistin of 25 ng/ml; MCP-1 and endocan were higher in DBDs (p < 0.0001) but did not correlate with DGF or acute rejection. No relationship was found between the studied molecules and the postoperative course of LD kidney transplants. Conclusions: High resistin levels in the DBD before organ retrieval are associated with DGF after kidney transplantation. The resistin increase seems related to the inflammatory state after brain death but not to the cause of death.

AB0123 Increase in serum levels of srankl and SRANKL/OPG but stable CTX-I in patients with infliximab-treated active ankylosing spondylitis

Abstract: Background Ankylosing spondylitis is characterised by an increased pathological bone formation in the spine in association with increased prevalence of osteoporosis. The effect of treatment with TNF-inhibitors on syndesmophyte formation is disputed. Objectives To study the effect of infliximab treatment on biomarkers of bone metabolism in patients with HLA-B27 positive active ankylosing spondylitis (AS) in a prospective trial. Methods The patients (n=19) fulfilling the modified New York criteria for definitive AS were treated with infliximab 5 mg/kg for totally 52 weeks. Patients received concomitantly methotrexate (median dose 7.5 mg/week) and NSAIDs on demand. After having completed the first year, the dosage of infliximab was reduced to 3 mg/kg and median infusion interval extended to every 8 weeks and patients were followed up on a regular basis. The blood samples were obtained at baseline before treatment initiation and 2 years after infliximab dose reduction and were stored in -20° until the time of analysis. Serum levels of the biomarkers Wingless proteins (Wnt3a), Dickkopf-1 (Dkk-1), sclerostin, soluble receptor activator of nuclear factors-κB ligand (sRANKL), osteoprotegerin (OPG), interleukin 6 (IL-6), soluble IL-6 receptor (sIL-6R) and C-terminal telopeptide of type I collagen (CTX-I) were measured with sandwich enzyme-linked immunosorbent assays (ELISA). Results Fourteen men and 5 women (mean age 39±9 and mean disease duration 6.9±7.0 years; median BASDAI at inclusion 6.5 (interquartile range 5.4 – 8.0) were studied. Eighteen patients were followed up at 1 year and 15 patients completed the study at 2 years. Significant reductions in BASDAI score and inflammatory parameters were observed during the first year in comparison with baseline and the treatment effect was preserved throughout the second year after infliximab dose reduction. Two years after infliximab dose reduction 12 patients continued with this treatment regimen. We observed a significant decrease in IL-6 levels (2.55 vs. 0.91 pg/ml, p=0.003) and soluble IL-6 receptor (63097 vs. 51781 pmol/l, p=0.034) in their serum as compared to baseline. In addition, the levels of soluble RANKL increased significantly (p=0.0098) in comparison with study baseline (113.3 vs. 260.5 pmol/l) and also a significant increase in sRANKL/OPG ratio was observed (median 33.75 vs. 52.40, p=0.027). No significant changes were observed regarding Wnt3a, Dkk-1, sclerostin, CTX-I and OPG. Conclusions Our results show a decrease in the serum markers of inflammation, IL-6 and sIL-6R in association with reduced clinical disease activity. Soluble RANKL and sRANKL/OPG ratio were increased during treatment with infliximab indicating an enhanced osteoclast activity, while serum levels of CTX-I remained unchanged. These intriguing findings need to be elucidated in a larger controlled trial. Disclosure of Interest None Declared