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Copyright of Zeitschrift für Rheumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Subclinical chronic inflammation could be the driving force behind the recently revealed association between abnormal nailfold capillaries as well as autoantibodies and long-term mortality in patients with incipient Raynaud's phenomenon. Whether laboratory markers that reflect a chronic inflammatory process are directly related to mortality in Raynaud's phenomenon is not known.Methods: In total, 2958 patients with incipient Raynaud's phenomenon without previously known connective tissue disease (CTD) were enrolled. At their initial presentation, laboratory tests for C-reactive protein (CRP), leucocytes, fibrinogen and the haemoglobin concentration were obtained. In addition, nailfold capillaries and antinuclear antibodies (ANA) were assessed. Patients' mortality was recorded through a median follow-up period of 9.3 years.Results: Baseline CRP, fibrinogen and haemoglobin concentration were associated with long-term mortality in an individual analysis of patients with incipient Raynaud's phenomenon. In a multivariable model including patients' age, nailfold capillaries and ANA, a low haemoglobin concentration remained independently related to future mortality. Amongst potential predictors for mortality in patients with Raynaud's phenomenon, a low haemoglobin concentration was most strongly related to patients' mortality risk.Conclusion: In Raynaud's phenomenon, laboratory markers that can be attributed to a chronic inflammatory state independently yield prognostic information in addition to the presence of abnormal nailfold capillaries and ANA. Amongst all prognostic markers, the haemoglobin concentration is most strongly related to patients' mortality in Raynaud's phenomenon. [ABSTRACT FROM AUTHOR]

Objective The binding of abatacept (CTLA-4Ig) to the B7 ligands CD80 and CD86 prevents the engagement of CD28 on T cells and thereby prevents effector T cell activation. In addition, a direct effect of CTLA-4Ig on antigen-presenting cells (APCs) could contribute to the therapeutic effect. To further elucidate the mechanism of CTLA-4Ig, we performed phenotype and functional analyses of APCs in patients with rheumatoid arthritis (RA) before and after the initiation of CTLA-4Ig therapy. Methods Peripheral blood mononuclear cells were analyzed before and at 2 and 4 weeks after the initiation of CTLA-4Ig therapy. Proportions of APCs were determined by flow cytometry. CD14+ monocytes were further analyzed for the expression of costimulatory and adhesion molecules and for their transendothelial migratory capacity in vitro. In addition, CD14+ monocytes from healthy controls were analyzed for their migratory and spreading capacity. Results Proportions and absolute numbers of monocytes were significantly increased in RA patients treated with CTLA-4Ig. The expression of several adhesion molecules was significantly diminished. In addition, monocytes displayed a significant reduction in their endothelial adhesion and transendothelial migratory capacity upon treatment with CTLA-4Ig. Likewise, isolated monocytes from healthy controls revealed a significant reduction in their migratory and spreading activity after preincubation with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Conclusion We describe direct effects of CTLA-4Ig therapy on phenotype and functional characteristics of monocytes in RA patients that might interfere with the migration of monocytes to the synovial tissue. This additional mechanism of CTLA-4Ig might contribute to the beneficial effects of CTLA-4Ig treatment in RA patients. [ABSTRACT FROM AUTHOR]

Objective To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc). Methods We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells. Results In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P = 0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P = 0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease ( P = 0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P = 0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P < 0.0001). Conclusion Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc. [ABSTRACT FROM AUTHOR]

SUMMARY Defects of T cell (Tc) proliferation have been demonstrated in several autoimmune diseases. Detailed mechanisms governing activation and proliferation of Tc are still not completely known. Here we show that under certain conditions human peripheral blood lymphocytes, once activated by anti-CD3, fail to respond to a subsequent restimulation via the Tc-receptor. Peripheral blood mononuclear cells (PBMC) were preactivated by anti-CD3 for 96 h following restimulation by anti-CD3, interleukin (IL)-2 and other mitogens. In control experiments unstimulated PBMC were incubated in medium alone. Immunophenotypes were analysed by flow cytometry. Cytokine production was determined by reverse transcription-polymerase chain reaction and intracellular signalling protein contents of Tc were compared by Western blotting. Furthermore, apoptosis was detected by terminal deoxyribose transferase-mediated deoxyuridine triphosphate nick end labelling assay. Unstimulated PBMC proliferate well after subsequent stimulation with anti-CD3, whereas IL-2 induces only limited proliferation. In contrast, preactivated cells respond only minimally to restimulation with anti-CD3, but IL-2 induces a marked proliferation. Both preactivated and unstimulated Tc respond well to restimulation by phytohaemagglutinin (PHA). In contrast, preactivated Tc show only a weak response to concanavalin A. Interestingly, when cells have been allowed to rest for 168 h, the responsiveness of preactivated Tc is restored. Immunoblots reveal that preactivated cells have a higher intracellular content of ζ -chain and p56lck. No differences are found concerning apoptosis after restimulation with anti-CD3 or the expression of ERK 1/2. The unresponsiveness to restimulation is due to an impairment of the transcription of the IL-2 gene and this defect is temporary. Despite the lack of proliferation, preactivated Tc phenotypically maintain an intermediate stage of activation. These data show how the same cell population can change its functional phenotype into a non-responder state. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical and immunogenetic aspects of antibody formation against Ro/SSA and La/SSB as well as their linear B cell epitopes in patients with primary Sjögren's syndrome (pSS) from different European countries.Patients and Methods: Ninety patients with pSS from six European centres were studied. Serum samples from all patients were tested in a control laboratory for anti-Ro/SSA and anti-La/SSB autoantibodies by RNA precipitation assay and autoantibodies to the previously reported B cell linear epitopes of Ro 60 kDa (p169-190aa and p211-232aa) and La/SSB (p147-154aa, p291-302aa, p301-318aa, and p349-364aa). DNA from 88 patients was used for the determination of HLA-DRB1, -DQA1, and -DQB1 genotypes. Analysis of the results was performed in the 88 patients who were genotyped and tested also for antipeptide antibodies.Results: Antibodies to B cell epitopes of Ro 60 kDa were detected at a low frequency (range 10-37%). In contrast, B cell epitopes of La/SSB were detected frequently (range 58-86%) among the anti-La/SSB positive sera. Autoantibodies to the La/SSB epitope, p349-364aa, were significantly positively associated with longer disease duration (p<0.05), recurrent or permanent parotid gland enlargement (p<0.005), and a higher proportion of non-exocrine manifestations (p<0.005), compared with patients without autoantibodies. The presence of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly associated with the presence of HLA-DRB1*03 and DQB1*02 (p=0.038 and p=0.034, respectively). This association was even more prominent and extended to HLA-DQA1*0501 when patients were stratified according the presence of autoantibodies to discrete La/SSB B cell epitopes in comparison with autoantibody negative patients (p<0.01). They were found also to be highly associated with the alleles HLA-DQB1*02 and HLA-DQA1*0501 as well as the presence of a shared amino acid motif in the region 59-69aa of DQB1 first domain (p<0.01, respectively).Conclusions: Autoantibodies against La/SSB, binding to four synthetic peptides, derived from the sequence of the La protein were identified with increased frequency in sera of patients with pSS. The formation of autoantibodies against B cell epitope analogues of La/SSB in European patients with pSS may be dependent on the presence of a permissive HLA-DQ heterodimer, most prominently represented by the HLA-DQA1*0501/DQB1*0201 heterodimer, suggesting that a model of HLA restricted presentation of La/SSB peptide determinants is crucial for the autoimmune response against La/SSB. [ABSTRACT FROM AUTHOR]

Objective: To determine the presence of adhesion molecules on monocytes/macrophages (Mphi) from peripheral blood (PB) and synovial fluid (SF) in patients with osteoarthritis (OA) and inflammatory joint diseases (rheumatoid (RA) and reactive arthritis (ReA)) in order to improve our understanding of the possible mechanisms underlying the inflammatory process.Methods: Whole blood and SF cells were stained with monoclonal antibodies against CD11a (LFA-1), CD15 s (sialyl-Lewis X), CD44, CD54, VLA-4, and HLA-DR counterstained with anti-CD14 antibodies as a Mphi marker for dual fluorescence analysis by flowcytometry.Results: On PB-Mphi, CD15s was markedly increased in both RA as well as ReA compared with OA. Furthermore, in the PB LFA-1, CD44, and HLA-DR showed a higher surface density on Mphi in ReA than in OA. Comparison between SF and PB showed significantly higher CD44 and CD54 expression on SF-Mphi. These molecules play an important part in lymphocyte-Mphi interaction.Conclusion: In PB from patients with inflammatory joint diseases, Mphi are activated, allowing recruitment into the synovial compartment. These disorders, in contrast with OA seem to be "systemic" in nature. Within the SF, different adhesion molecules are expressed on CD14(+) Mphi as compared with PB. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy represents a major complication in patients with insulin-dependent diabetes mellitus (IDDM). Intervention trials using angiotensin-converting enzyme (ACE) inhibitors have pointed towards the important pathogenetic role of the renin-angiotensin system. Recently an insertion/deletion (I/D) polymorphism for the gene encoding the ACE has been described, the deletion type being associated with higher plasma ACE levels. As the intrarenal renin-angiotensin system might also be activated in this setting, we determined the ACE genotype together with other risk factors for the development of diabetic nephropathy in 122 patients with IDDM from a single centre with ( n = 63) and without ( n = 59) nephropathy. Long-term glycaemic control was evaluated using mean HbA1c values from the last 10 years. The two patient group were comparable with regard to duration of diabetes and glycaemic control as assessed by current HbA1c values. However, mean long-term HbA1c values were significantly higher in patients with diabetic nephropathy as was systemic blood pressure. The DD genotype was more prevalent in patients with renal disease. In the subgroup of patients who had had diabetes for more than 20 years ( n = 90), the DD genotype was even more frequent in patients with nephropathy, and blood pressure and long-term HbA1c values were also higher in patients with renal disease. Logistic regression analysis revealed long-term glycaemic control, blood pressure and the ACE genotype to be independent risk factors for the prevalence of diabetic nephropathy. [Diabetologia (1997) 40: 327–331] [ABSTRACT FROM AUTHOR]

We investigated the effects of photopheresis in systemic sclerosis by analysing its influence on lymphocytes with regard to apoptosis and expression of bcl-2 and fas. Peripheral blood lymphocytes isolated immediately before and 24 h after photopheresis were investigated for apoptosis, bcl-2 and fas expression by fluorocytometry, and compared to controls. In addition, leucocytes from systemic sclerosis patients taken directly from the photopheresis system were tested for apoptosis after 24 h in culture. fas expression was similar in controls and patients with systemic sclerosis just before photopheresis, but increased 24 h after photopheresis, mainly due to an increase of CD4+CD95+ cells. bcl-2 was overexpressed in scleroderma peripheral lymphocytes, but not influenced by photopheresis. As compared to healthy controls, the percentage of apoptotic cells 24 h after photopheresis was high in cultured lymphocytes, but not ex vivo. The significant increase in fas on peripheral lymphocytes observed in this study may be a major operative mechanism of photopheresis in addition to (and possibly related to) the induction of apoptosis. [ABSTRACT FROM PUBLISHER]

Copyright of Der Radiologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Recurrent arthritis, fever and lymphadenopathy are symptoms of adult onset of Still's disease (AOSD). Differential diagnosis requires the exclusion of infections or malignant lymphomas. We report on a case of AOSD showing destructive lymphadenopathy, immunophenotyping of peripheral blood leucocytes revealed strong activation of T-lymphocytes. Bone marrow biopsy also showed an increase of lymphopoietic cells to 23%. Analysis of peripheral blood lymphocytes (PBL) after remission showed no remaining signs of activation. Analysis of lymphocyte activation by flow cytometry correlated with disease activity. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate bone mineral density and biochemical parameters of bone metabolism in ambulatory premenopausal female patients with systemic lupus erythematosus (SLE).Methods: 30 women who fulfilled the ARA criteria for the classification of SLE were studied. Lumbar and femoral bone mineral density was determined by dual energy x ray absorptiometry. Various laboratory parameters including serum calcium, serum phosphorus, alkaline phosphatase, bone specific isoform of alkaline phophatase, propeptide of type 1 procollagen, deoxypyridinoline excretion, telopeptide of type 1 collagen, serum creatinine, osteocalcin, parathyroid hormone, 25-OH vitamin D, testosterone, progesterone, estradiol, follicle stimulating hormone and luteinotropic hormone were measured.Results: According to the WHO criteria 39% of all patients with SLE studied had normal bone mineral density, 46% had osteopenia and 15% had osteoporosis at the lumbar spine; at the femoral neck 38.5% had normal bone mineral density, 38.5% had osteopenia and 23% suffered from osteoporosis. Significantly lower osteocalcin levels were found in SLE patients. All other bone resorption and formation markers measured were not statistically different, but higher serum albumin corrected calcium and lower phosphorus values were found in the SLE group. Of all sex hormones tested lower testosterone and higher follicle stimulating hormone concentrations were seen in patients with SLE.Conclusion: A high incidence was found of osteopenia and osteoporosis in premenopausal patients with SLE. Bone diminution in SLE seems to be attributable, at least in part, to decreased bone formation in SLE patients. [ABSTRACT FROM AUTHOR]

The article presents an abstract of a research paper that investigates the role of the Pre B-cell colony-enhancing factor (PBEF)-1001T>G and PBEF -1543C>T polymorphisms in the genetic predisposition to systemic sclerosis (SSc) susceptibilit, submitted at the 5th European Workshop on Immune-Mediated Inflammatory Diseases in Sitges-Barcelona, Spain from December 1-3, 2010.

Aim Pre-B cell colony-enhancing factor (PBEF) is intricately involved in inflammation and fibrosis, functional polymorphisms of PBEF have been previously shown to influence PBEF expression and pulmonary damage. Systemic sclerosis (SSc) is a disease in which inflammation, fibrosis and pulmonary deterioration are prominent hallmarks. Therefore the authors here investigate the role of the and polymorphisms in the genetic predisposition to SSc susceptibility and pulmonary involvement. Patients and methods The authors genotyped DNA from 2737 SSc patients and 1913 matched healthy controls, both from eight different ethnic populations. Genotyping was performed using custom Taqman 5' allelic discrimination assays. In addition, PBEF serum expression levels were measured by ELISA and correlated with genotypes. Results In two separate populations and in a meta-analysis, the combined , hence carrying no minor alleles, was found associated with SSc susceptibility (p=0.009 OR 1.20 (95% CI 1.05 to 1.37)). In addition, these subjects showed an increased decline in forced vital capacity over 15 years follow-up (p=0.02) (HR 1.64, 95% CI 1.02 to 2.64) and a higher PBEF serum concentration (p<0.01), compared to carriers of minor alleles. On the other hand, patients with genotype were at lower risk for PAH development within 15 years of disease onset compared to the carriers with genotypes and (p<0.001) (HR 3.29, 95% CI 1.52 to 7.12). Conclusions This data identify PBEF as a novel candidate gene that influences SSc susceptibility, pulmonary function and the development of PAH. [ABSTRACT FROM PUBLISHER]

Aim Polymorphisms in the interleukin 4 (IL-4), IL-13 and their corresponding receptors have previously been found associated with systemic sclerosis (SSc). In this study the authors aim to validate these previous observations and scrutinise their effects on gene expression. Patients and methods The authors genotyped a cohort consisting of 2488 SSc patients and 2246 healthy controls, derived from The Netherlands, Spain, UK, Italy, Germany and France. Taqman assays were used for genotyping two single-nucleotide polymorphisms (SNPs) within (/rs1801275) and the (/rs2243250). In the gene two SNPs were genotyped (rs20541) and (rs1800925.) In the gene, the (rs6646259) variant was genotyped. In addition, the authors investigated the effect of these polymorphisms on corresponding gene expression with RT-PCR in B cells, T cells, plasmacytoid dendritic cells, monocytes and myeloid dendritic cells. Results None of these polymorphisms was found to be enriched in the SSc population or in any SSc clinical subtype and there was no influence of these polymorphisms on development of either pulmonary arterial hypertension and declineer of forced vital capacity in 15 years of follow-up. In addition, the authors did not observe an effect on expression levels in the cell subtypes. Conclusions This data show that these polymorphisms do not play a role in SSc and do not influence gene expression levels. [ABSTRACT FROM PUBLISHER]

The article presents an abstract of a research paper that analyzes polymorphisms in the interleukin 4 (IL4), interleukin 13 (IL13) and their corresponding receptors, submitted at the 5th European Workshop on Immune-Mediated Inflammatory Diseases in Sitges-Barcelona, Spain from December 1-3, 2010.