R Zeuner

IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans

Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at −46 to −40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future.

Interleukin-6 and Tumour Necrosis Factor-α differentially regulate lincRNA transcripts in cells of the innate immune system in vivo in human subjects with rheumatoid arthritis

lincRNAs recently have been discovered as evolutionary conserved transcripts of non-coding DNA sequences and have been implicated in the regulation of cellular differentiation. In humans, molecular studies have suggested a functional role for lincRNAs in cancer development. The aim of the present study was to examine whether these novel molecules are specifically regulated by different cytokines in cells of the innate immune system in humans in vivo and whether lincRNAs thereby might be involved in the pathophysiology of rheumatoid arthritis (RA). Therefore, CD14(+) monocytes were isolated from RA patients before and after anti-IL-6R (tocilizumab) or anti-TNF-α (adalimumab) therapy and lincRNA transcription was analysed by a microarray based experiment. As expected, we found lincRNAs to be present in CD14(+) monocytes of RA patients. However, of the total number of 7.419 lincRNAs examined in this study only a very small number was significantly regulated by either IL-6 or TNF-α (85 lincRNAs, corresponding to 1.1%). The numbers of lincRNAs regulated was higher due to TNF-α compared to IL-6. Interestingly, none of the identified lincRNAs was influenced by both, IL-6 and TNF-α, suggesting the regulation of lincRNA transcription to be highly specific for distinct cytokines. Taken together, our results suggest (1) that lincRNAs are novel intracellular molecular effectors of specific cytokines in cells of the innate immune system in humans in vivo and (2) that lincRNAs might be involved in the molecular pathophysiology of RA.

A Randomized Trial of Plasmapheresis and Subsequent Pulse Cyclophosphamide in Severe Lupus: Design of the Lpsg Trial

A group of clinics cooperating as the Lupus Plasmapheresis Study Group (LPSG) is starting an international multicenter study of the treatment of severe systemic lupus erythematosus. The primary goal of this randomized and prospective trial is to establish whether treatment with plasmapheresis and subsequent pulse cyclophosphamide improves the outcome compared to treatment with pulse cyclophosphamide alone. The underlying rationale assumes that plasmapheresis: a) eliminates pathogenic autoantibodies and immune complexes and b) induces a compensatory activation of pathogenic lymphocyte clones through a feedback between circulating antibodies and their respective antibody-producing clones. Synchronization of plasmapheresis with subsequent pulse cyclophosphamide should enhance the deletion of pathogenic clones during the period of greatest vulnerability. This overview reviews the first results of treatment approaches based on this concept and summarizes the design of the LPSG trial

Plasma exchange in systemic lupus erythematosus

Abstract Standard treatment for severe systemic lupus erythematosus (SLE) consists of corticosteroids and immunosuppressive drugs. A number of controlled studies purport to show that parallel application of plasmapheresis is no longer tenable since it imparts no additional benefit. Three indications for plasmapheresis in SLE appear to remain: (1) emergency intervention; (2) contraindication of cytotoxic drugs in severe SLE; and (3) so-called “synchronization”, which combines plasmapheresis with subsequent high-dose pulse cyclophosphamide and has achieved repeatedly long-term, treatment-free remission in severe SLE. Immunoadsorption, especially employing an anti-immunoglobulin adsorber, appears to represent a further useful technological advance. It is questionable whether photopheresis, lymphapheresis, and cascade filtration will have a role to play in the treatment of SLE. An additional indication for apheresis may be the new procedure of autologous transplantation of purged stem cells.

Successful application of belimumab in two patients with systemic lupus erythematosus experiencing a flare during tocilizumab treatment

This case report describes two female lupus patients who both received biological treatment with tocilizumab and with belimumab. The disease course was remarkably similar in both cases. Tocilizumab resulted in a transient improvement in pleurisy and arthritis but was then followed by a clinical flare accompanied by an increase in autoantibodies and a drop in complement levels. Alike, both patients experienced a rapid and sustained improvement after institution of belimumab. The clinical benefit obtained is currently stable under ongoing belimumab therapy.

Effect of antigen-specific immunoadsorption on antibody kinetics in a rat model

The investigation of antibody kinetics following antigen-specific immunoadsorption in alkaline phosphatase immunized rats revealed significantly lower antibody levels than in untreated controls over a follow-up period of 6 weeks. A rebounding antibody synthesis as a result of specific depletion was not observed. Non-adsorption of specific antiidiotypic antibodies may explain these findings.

B Lymphocyte Stimulator (BLyS) Is Expressed in Human Adipocytes In Vivo and Is Related to Obesity but Not to Insulin Resistance

Inflammation and metabolism have been shown to be evolutionary linked and increasing evidence exists that pro-inflammatory factors are involved in the pathogenesis of obesity and type 2 diabetes. Until now, most data suggest that within adipose tissue these factors are secreted by cells of the innate immune system, e. g. macrophages. In the present study we demonstrate that B lymphocyte stimulator (BLyS) is increased in human obesity. In contrast to several pro-inflammatory factors, we found the source of BLyS in human adipose tissue to be the adipocytes rather than immune cells. In grade 3 obese human subjects, expression of BLyS in vivo in adipose tissue is significantly increased (p<0.001). Furthermore, BLyS serum levels are elevated in grade 3 human obesity (862.5+222.0 pg/ml vs. 543.7+60.7 pg/ml in lean controls, p<0.001) and are positively correlated to the BMI (r = 0.43, p<0.0002). In the present study, bariatric surgery significantly altered serum BLyS concentrations. In contrast, weight loss due to a very-low-calorie-formula-diet (800 kcal/d) had no such effect. To examine metabolic activity of BLyS, in a translational research approach, insulin sensitivity was measured in human subjects in vivo before and after treatment with the human recombinant anti-BLyS antibody belimumab. Since BLyS is known to promote B-cell proliferation and immunoglobulin secretion, the present data suggest that adipocytes of grade 3 obese human subjects are able to activate the adaptive immune system, suggesting that in metabolic inflammation in humans both, innate and adaptive immunity, are of pathophysiological relevance.

ICG-based Optical Imaging Suggests Subclinical Involvement of Asymptomatic Joints in Psoriatic Arthritis but not in Arthrosis

Material und Methodik: 20 Patienten wurden 1, 2 und 5 Jahre nach ACT im MRT (Magnetom Avanto 1,5 T, Siemens) mit dezidierter Kniespule untersucht. Das angewandte Protokoll beinhaltete Protonendichtegewichtete und Gradientenecho-Sequenzen. Die Analyse erfolgte entsprechend eines modifizierten MOCART Scores anhand folgender Kriterien: Transplantatfüllung, -integration, -oberfläche, -homogenität, Gelenkergüsse, Signalintensität in der PD und der GRE-Sequenz sowie Beurteilung der subchondralen Lamelle und Knochenstruktur. Das klinische Outcome wurde über den International Knee Documentation Score (IKDS) erfasst, 80% als gutes, ein Score unter 35% als schlechtes Outcome gewertet.