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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

The opioid crisis is a public health emergency in the United States of America. It is important to understand factors associated with outpatient opioid use. Our primary aim was to assess post-cesarean outpatient opioid use. The secondary aim was to identify characteristics associated with use.We conducted a prospective cohort analysis of women who underwent cesarean delivery at an urban academic center. Phone surveys were done on post-discharge days three, seven, and 14. The primary outcome was post-discharge opioid use.Of 205 eligible patients contacted, 190 (91%) agreed to participate and 173 (84%) participated in all three surveys. Median amount of opioid prescribed was 75 mg morphine equivalents (MME) (interquartile range 60-113) and participants used a median of 15 MME (0-53) by discharge day 14. Most patients (139/190) filled their opioid prescription but 42% (80/190) did not consume the opioids prescribed. Outpatient opioid use was associated with increased in-hospital opioid consumption (P=0.0003), gravidity (P=0.003), parity (P=0.004) and number of previous cesarean deliveries (P=0.02). Higher amounts of in-hospital opioid use (P=0.0004), higher gravidity (P=0.02), higher outpatient pain scores (3/10, P=0.01), and poor pain control (P=0.04) were associated with consuming all prescribed opioids. Patients used opioids for a median of two days post-discharge. Use of non-opioid pain medication was not associated with opioid use.Opioids were prescribed in excess of consumption and many patients did not use any opioids. Next steps include developing a prescribing algorithm to incorporate factors we found predictive of opioid use.

BACKGROUND & AIMS: Altered interactions between the mucosal immune system and intestinal microbiota contribute to pathogenesis of inflammatory bowel diseases (IBD). It is not clear how inhibitors of cytokines, such as antagonists of tumor necrosis factor (anti-TNF), affect the intestinal microbiome. We investigated the effects of anti-TNF agents on gut microbe community structure and function in a longitudinal 2-step study of patients with IBD. We correlated our findings with outcomes of treatment and investigated patterns of metabolites in fecal samples before and after anti-TNF therapy. METHODS: We performed a prospective study of 2 cohorts of patients in Germany; the discovery cohort comprised 12 patients with IBD, 17 patients with rheumatic disease, and 19 healthy individuals (controls); fecal samples were collected at baseline and 2, 6, and 30 weeks after induction of anti-TNF therapy. The validation cohort comprised 23 patients with IBD treated with anti-TNF or vedolizumab (anti-α4β7 integrin) and 99 healthy controls; fecal samples were collected at baseline and at weeks 2, 6, and 14. Fecal microbiota were analyzed by V3-V4 16S ribosomal RNA gene amplicon sequencing. Clinical response and remission were determined by clinical disease activity scores. Metabolic network reconstruction and associated fecal metabolite level inference was performed in silico using the AGORA (Assembly of Gut Organisms through Reconstruction and Analysis) resource. Metabolomic analyses of fecal samples from a subset of patients were performed to validate metabolites associated with treatment outcomes. RESULTS: Anti-TNF therapy shifted the diversity of fecal microbiota in patients with IBD, but not with rheumatic disease, toward that of controls. Across timepoints, diversity indices did not vary significantly between patients with IBD who did or did not achieve clinical remission after therapy. In contrast, in silico modeling of metabolic interactions between gut microbes found metabolite exchange to be significantly reduced at baseline in fecal samples from patients with IBD and to be associated with later clinical remission. Predicted levels of butyrate and substrates involved in butyrate synthesis (ethanol or acetaldehyde) were significantly associated with clinical remission following anti-TNF therapy, verified by fecal metabolomic analyses. CONCLUSIONS: Metabolic network reconstruction and assessment of metabolic profiles of fecal samples might be used to identify patients with IBD likely to achieve clinical remission following anti-TNF therapy and increase our understanding of the heterogeneity of IBD. ispartof: GASTROENTEROLOGY vol:157 issue:5 pages:1279-+ ispartof: location:United States status: published

Chronic inflammatory diseases (CID) are associated with a profound increase in cardiovascular (CV) risk resulting in reduced life expectancy. However, LDL-cholesterol is reported to be low in CID patients which is referred to as the "LDL paradoxon". The aim of the present study was to investigate whether LDL-particles in CID exhibit an increased content of the highly atherogenic small-dense LDL subfraction (sdLDL).In this prospective, single center, observational study we enrolled 141 patients with CID (RA n = 59, inflammatory bowel disease (IBD) n = 35, ankylosing spondylitis (SpA) n = 25, Psoriasis n = 22) in 2011 through 2013 to evaluate sdLDL levels before as well as 6 and 26 weeks after initiation of different anti-cytokine therapies (anti-TNFα, anti-IL-6R antibodies). sdLDL levels were compared to 141 healthy individuals in a case control design. Compared to healthy controls, all CID patients displayed a significantly higher sdLDL content within the LDL cholesterol fraction: RA 35.0 ± 9.2% (p 0.001), SpA 42.5 ± 10.5% (p 0.001), IBD 37.5 ± 7.1% (p 0.001), Psoriasis 33.6 ± 4.6% (p 0.01). Furthermore, the sdLDL/LDL ratio was significantly higher in male compared to female RA subjects (p 0.05). Neither anti-TNFα nor anti-IL6R medication altered sdLDL levels despite a significant improvement of disease activity.In several different chronic inflammatory disease entities, LDL-cholesterol is shifted toward a pro-atherogenic phenotype due to an increased sdLDL content which might in part explain the LDL paradoxon. Since premature CV disease is a major burden of affected patients, specifically targeting lipid metabolism should be considered routinely in clinical patient care.Registration at German Clinical Trial Register (DRKS): DRKS00005285.

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.

Objectives Low copy numbers and deletion of complement C4 genes are potent risk factors for systemic lupus erythematosus (SLE). However, it is not known whether this genetic association affects the clinical outcome. We investigated C4 copy number variation and its relationship to clinical and serological features in a Northern European lupus cohort. Methods We genotyped the C4 gene locus using polymerase chain reaction (PCR)-based TaqMan assays in 169 patients with SLE classified according to the 1997 revised American College of Rheumatology (ACR) criteria and in 520 matched controls. In the patient group the mean C4 serum protein concentrations nephelometrically measured during a 12-month period prior to genetic analysis were compared to C4 gene copy numbers. Severity of disease was classified according to the intensity of the immunosuppressive regimens applied and compared to C4 gene copy numbers, too. In addition, we performed a TaqMan based analysis of three lupus-associated single-nucleotide polymorphisms (SNPs) located inside the major histocompatibility complex (MHC) to investigate the independence of complement C4 in association with SLE. Results Homozygous deficiency of the C4A isotype was identified as the strongest risk factor for SLE (odds ratio (OR) = 5.329; p = 7.7 × 10−3) in the case-control comparison. Moreover, two copies of total C4 were associated with SLE (OR = 3.699; p = 6.8 × 10−3). C4 serum levels were strongly related to C4 gene copy numbers in patients, the mean concentration ranging from 0.110 g/l (two copies) to 0.256 g/l (five to six copies; p = 4.9 × 10−6). Two copies of total C4 and homozygous deletion of C4A were associated with a disease course requiring cyclophosphamide therapy (OR = 4.044; p = 0.040 and OR = 5.798; p = 0.034, respectively). Homozygous deletion of C4A was associated with earlier onset of SLE (median 24 vs. 34 years; p = 0.019) but not significant after correction for multiple testing. SNP analysis revealed a significant association of HLA-DRB1*0301 with SLE (OR = 2.231; p = 1.33 × 10−5). Conclusions Our findings confirm the important role of complement C4 genes in the development of SLE. Beyond the impact on the susceptibility for lupus, C4 copy numbers may be related to earlier onset and a more severe course of the disease. The association of homozygous deletion of C4A and SLE is accompanied by the presence of HLA-DRB1*0301 without a proven pathophysiological mechanism.

Background Patient reported outcome measures are comprised of either sets of questionnaires or patient global assessment based on visual analogue scale (VAS). These patient-reported outcome measures lack accuracy and/or clinical feasibility when comparing heterogeneous patient groups with different diseases, or when characterizing patients with systemic disease involving different organ systems. Objectives Developing a clinical feasible patient-reported outcome measure based VAS assessment of different organ systems. Methods Patients were asked to rate their health status in a 10cm VAS (0–100%) concerning their global health as well as of different organ systems, namely heart, lung, muscle and joints, gastro-intestinal, metabolic, uro-genital, skin, neuro-psychiatric, eyes and ears. All VA-scales were “anchored”. Patients were advised to rate their health status below 75% if they felt “medical action is needed”, they should rate the health status 336 patients from different outpatient clinics (cardiologic, pneumologic, gastro-intestinal, nephrologic, neurologic, dermatologic, rheumatologic, ophthalmologic and obesity outpatient clinic) as well as patients from internal emergency clinics and a general practitioner clinic were evaluated. Both, patients and the attending physicians completed the Popgen-OSSA. In addition the attending physician was asked to document ranking of the 5 most important diagnoses of the patient. Statistical analysis was carried out using non-parametric testing. Furthermore, to predict main diagnoses based on patients9s as well as physician9s OSSA state-of-the-art machine learning tools, namely support vector machines (SVMs), were applied. To assess model performance multi-class AUC (area under the ROC curve) according to Hand and Till (2001) was estimated based on repeated cross validation (10 folds, 5 repeats), optimizing the SVM9s hyperparamters using grid search. Results The test showed a good reproducibility. With a mean percentage of 74±0.98 SE and 66±1.17 SE, respectively, the physicians OSSA rating was significantly higher than the rating of the patients (pwilcoxon Conclusions In this preliminary trial with low sample size the Popgen-OSSA showed a good reproducibility and allowed a correct allocation of the patient9s clinical problem to involved organ system by SVM analysis with multi-class AUC of up to 73.4%. These data merit further investigation and development of the Popgen-OSSA on larger patient cohorts. References David J. Hand and Robert J. Till (2001). A Simple Generalisation of the Area Under the ROC Curve for Multiple Class Classification Problems. Machine Learning 45(2), p. 171–186. DOI: 10.1023/A:1010920819831. Disclosure of Interest R. Zeuner Grant/research support from: Pfizer, Novartis, UCB, U. Gsell: None declared, M. Hubenthal: None declared, S. Schreiber: None declared, A. Franke: None declared, M. Laudes Grant/research support from: Roche, Lilly, MSD, J. Schroder: None declared

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, CD 14(+) monocytes were isolated from RA patients before and after anti-IL-6R (tocilizumab) or anti-TNF-alpha (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-alpha (85 lincRNAs, corresponding to 1.1%). The numbers of lincRNAs regulated was higher due to TNF-alpha compared to IL-6. Interestingly, none of the identified lincRNAs was influenced by both, IL-6 and TNF-alpha, 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. (C) 2014 Elsevier Ltd. All rights reserved.

Die Eosinophilie ist wegen der Vielzahl moglicher Ursachen eine differentialdiagnostische Herausforderung. Eine erste Schwierigkeit besteht haufig schon darin, zwischen bedrohlichen Krankheitsbildern und eher harmlosen Begleitreaktionen zu unterscheiden. Ein hochdynamischer klinischer Verlauf mit schwerer Einschrankung lebensnotwendiger Funktionen, wie beispielsweise der Atmung, kann ein rasches Handeln notwendig machen. Exemplarisch sei hierfur die akute eosinophile Pneumonie genannt, die haufig nur durch den schnellen Einsatz hochdosierter Steroide beherrscht werden kann. Allerdings darf eine periphere Bluteosinophilie nicht reflexartig noch vor den wichtigsten Kernuntersuchungen zum Einsatz von Steroiden fuhren, da hierdurch weitere diagnostische Masnahmen beeintrachtigt werden konnen. Auch weniger dramatische Verlaufe erfordern ein sorgfaltiges Aufarbeiten einer Eosinophilie. Verschiedene pneumologische, infektiologische, rheumatologische oder hamatologische / onkologische Krankheitsbilder mit prolongiertem Verlauf konnen eine ernste Entwicklung nehmen, wenn sie nicht rechtzeitig erkannt und gezielt therapiert werden. Eine Leitlinie fur eosinophile Krankheitsbilder insgesamt existiert nicht. Schon Empfehlungen fur eine strukturierte Diagnostik sind sparlich und haufig auf einen internistischen Schwerpunkt konzentriert.

Background: Subjects with Chronic inflammatory diseases (CID) exhibit a profound increase of cardiovascular risk (CVR) resulting in reduced life expectancy. At the same time LDL-cholesterol serum levels seem to be low in these patients suggesting a special type of “rheumatic dyslipidemia”.[for full text, please go to the a.m. URL], 44. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 30. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 26. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by specific organ manifestations and the production of autoantibodies to nuclear antigens. SLE can induce severe organ damage and carries the risk of fatal outcome. During recent years, no major progress has been made regarding new treatment options except for the introduction of mycophenolate mofetil. Therefore, the results of several large clinical trials using biological agents for treatment of SLE were hopefully awaited. Yet, the application of abatacept, belimumab and rituximab, respectively, to non-renal or renal lupus patients surprisingly has not been successful. Other studies using different agents have not been completed yet. Nevertheless, the results available so far will have a significant impact on the design of future clinical trials and will stimulate the debate on new targets for treatment of SLE.

HISTORY AND CLINICAL FINDINGS For nine years a 54-year-old woman had been suffering from worsening treatment-resistant cold-dependent purpura of the limbs as well as cutaneous ulcerations and arthralgia, which recently had occurred even at a even slight decrease in room temperature. INVESTIGATIONS A special form of cryofibrinogenemia was identified by affinity-chromatographic separation of a plasma cryoprecipitate. From this cryoprecipitate a monoclonal antifibrinogen antibody (IgG-kappa) was isolated which, in the cold, formed a precipitating complex with fibrinogen. Paraproteinaemia was not demonstrated by conventional serum and plasma electrophoresis. There was no evidence of neoplasma. TREATMENT AND COURSE Attempted treatment with steroids, fibrinolytic agents and intravenous cyclophosphamide was unsuccessful. But long-term repeated plasmaphereses and anti-immunoglobulin adsorption improved the symptoms. After 5 years of this treatment-14 years after onset of symptoms-the patient died of the consequences of fulminant pulmonary embolism. CONCLUSION To establish the diagnosis of monoclonal cryofibrinogenemia it is necessary, first, to identify the cryoprecipitate in plasma; secondly, to undertake affinity-chromatographic separation of the cryoprecipitate with subsequent analysis of its components.

Objective: To quantify 18-fluorodeoxyglucose (FDG) accumulation in large vessels in patients with polymyalgia rheumatica by positron emission tomography (PET), and to compare these data with serological markers of inflammation. Methods: 13 untreated patients with active polymyalgia rheumatica underwent FDG positron emission tomography; eight were analysed in a second PET when in clinical remission. Six patients with other highly inflammatory conditions served as controls. For quantitative analysis, FDG uptake over nine defined vascular regions, divided by an individual background value, was expressed as a region of interest (ROI) index. These data were compared with the clinical status of the patient and with erythrocyte sedimentation rate (ESR), C reactive protein, haemoglobin, and platelet and leucocyte counts. Results: By visual evaluation, 12 of the 13 patients showed an increased tracer uptake of the aorta or its major branches. By quantitative analysis, FDG uptake was significantly increased in polymyalgia rheumatica. In patients with active disease, the mean ROI index for all vascular regions exceeded that of controls by 70% (mean (SD): 1.58 (0.37) v 0.93 (0.12); p

Eosinophilia presents a challenge to differential diagnostics due to the multitude of possible causes. An initial difficulty is often to distinguish between threatening disease symptoms and relatively harmless secondary reactions. A highly dynamic clinical progression with severe impairment of the vital functions, like breathing, for example, can make swift action necessary. An example of this is known as acute eosinophile pneumonia, which can often only be controlled with the rapid use of high steroid doses. However, a peripheral blood eosinophilia must not lead to an automatic use of steroids before the most important core tests, as this can compromise further diagnostic measures. Furthermore, less dramatic courses require careful handling of an eosinophilia. Various pneumological, infectological, rheumatological or haematological / oncological disease patterns with a prolonged course can develop seriously if they are not recognised in time and treated in a targeted manner. There is no guideline for eosinophile clinical pictures in general. Already the recommendations for a structured diagnosis are scarce and are often concentrated on internist emphases.

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.

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

Since the effectiveness of high dose intravenous immunoglobulin (IVIg) was first demonstrated in autoimmune thrombocytopenia, IVIg has been investigated in the treatment of various autoimmune rheumatic disorders. Controlled randomised studies have established the efficacy of IVIg in Kawasaki's syndrome, for which combined IVIg and aspirin (acetylsalicylic acid) now constitutes the standard treatment. Another controlled study has demonstrated the benefit of IVIg in dermatomyositis. IVIg treatment in juvenile rheumatoid arthritis has produced contradictory results. Uncontrolled studies and case reports on the application of IVIg in systemic lupus erythematosus, ANCA-associated vasculitides and adult rheumatoid arthritis generally describe short term positive effects. Various mechanisms are thought to underlie the effect of IVIg on autoimmune rheumatic diseases, such as: blockade of Fc receptors;immunomodulation via anti-idiotypic interactions;inhibition of complement-mediated tissue damage;modulation of cytokine expression by leucocytes and endothelial cells; andinhibition of superantigen-mediated T cell activation. IVIg is considered to be a low-risk form of treatment. Reported adverse effects include headache, aseptic meningitis and transient impairment of renal function. Haemolysis and anaphylactic reactions are rare. The effect profile of IVIg makes it a relevant, although still experimental, form of treatment in autoimmune rheumatic disorders, but its high cost renders it unsuitable as a first-line treatment. Because IVIg does not weaken patients' resistance to infection, it might serve as a therapeutic option in bridging clinical situations where immunosuppressive or cytotoxic approaches are contraindicated in patients with autoimmune disorders, such as intercurrent infection or in the period immediately before and after surgery.

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.

Fabry disease, an X-linked lipid storage disorder, is associated early morbidity and mortality. Since enzyme replacement therapy is available, accurate detection of unrecognized cases is important. Characteristic early symptoms are recurrent episodes of burning and lancinating pain in the distal extremities associated with small fiber neuropathy. The aim was to develop and validate an easy diagnostic questionnaire in combination with three simple bedside tests, the “FabryScan”, for the detection of Fabry disease in patients with chronic extremity pain. Questions related to relevant clinical characteristics of Fabry disease (mainly related to pain) were compiled by Fabry specialists and pain experts. Furthermore, three bedside tests assessing sensory small and large fiber function were established. The provisional version was tested in a prospective multicenter trial of 138 patients with chronic extremity pain due to Fabry disease (n = 55), painful polyneuropathy (n = 40), and rheumatoid arthritis (n = 43). Identification of the most discriminant combinations of items for Fabry disease and their calculation of sensitivity and specificity were based on multivariate analyses. We retained only 10 questions and three bedside tests for the final version of the FabryScan. A cut-off score of 12/33 (corresponding to the number of positive points) resulted in a high proportion of correctly identified patients (76 %) with a sensitivity of 88 % and a specificity of 87 %. The FabryScan is a combination of a brief and simple questionnaire with three simple bedside tests with good discriminative value for the identification of Fabry patients in patients with chronic extremity pain.

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

Aim of the study was to compare the expression of monocytes C1qRp (CD93) in patients with systemic lupus erythematosus (SLE) with that of healthy controls and to determine the influence of glucocorticoids and LPS on C1qRp expression. Thirty-six SLE patients and 20 healthy controls were analyzed by flow cytometry. Additionally, monocytes from five patients and five controls were cultured and stimulated with dexamethasone, interferon-gamma and LPS, respectively, before the measurement of C1qRp expression. There was no difference in C1qRp expression between SLE and HC. SLE patients with no or only low dose steroids had a significantly higher C1qRp expression than those with higher doses. However, in vitro dexamethasone did not stimulate or down-regulate C1qRp expression. Upon LPS stimulation, C1qRp was significantly up regulated on monocytes both from patients and from controls. In conclusion, C1qRp expression and regulation was not altered in SLE patients. Possible relations with disease activity and medication need further investigations.

We report on a 54-year-old female patient with arthritis and a severe cold-induced leukocytoclastic vasculitis of the skin caused by a rare form of cryofibrinogenemia ("type II" cryofibrinogen). Affinity chromatography of cryoprecipitates from the patient's plasma revealed reversible cryoprecipitability of complexes composed of fibrinogen and a monoclonal antifibrinogen antibody (IgG3 kappa). Conventional serum and plasma electrophoresis did not detect the paraprotein. Control of symptoms was achieved by long-term plasmapheresis.

There is evidence from animal and human studies that IL-1 might play an important role in the development and maintainence of inflammation in systemic lupus erythemathosus (SLE). We hypothesized that, in SLE, there might be a relative deficiency in the physiologic antagonist of IL-1, IL-1 receptor antagonist (IL-1RA). We therefore treated three patients with active SLE in whom conventional therapy has failed with the human IL-1RA, Anakinra. In two of the three patients there was a transient effect on muscle pain and/or polyarthritis. In one patient with lupus myositis there was no effect at all. The therapy was well tolerated and the only significant side effect was a transient drop in complement levels (C3 and C4) without clinical or laboratory signs of increased SLE activity in all three patients.

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.

Composite steel-concrete slabs that have integral steel shuttering at the soffit of a reinforced concrete slab are commonplace in building infrastructure. Inevitable shrinkage of the concrete represents an indirect (or non-mechanical) strain that results in deformations of the composite slab, resulting in long-term effects in which creep of the concrete also plays a role. Because the impervious steel sheeting prevents moisture egress at the slab soffit whereas at the top of the slab such moisture egress can occur, there is a variation of the shrinkage strain through the depth of the slab, resulting in warping-type deformations. In addition, the composite action between the steel and concrete results in partial shear interaction between these elements, and this interacts with the shrinkage response. Surprisingly little appears in the published literature on rational modelling of the behaviour of composite slabs incorporating partial interaction that are subjected to shrinkage straining, despite its practical importance and significance. Based on fundamental principles of mechanics, a theoretical model of this shrinkage behaviour that includes partial interaction is developed, and prescriptive equations are derived. These may be used to assess the deflections and stresses in the concrete due to restrained shrinkage which may lead to cracking of the slab. It is also shown that the two effects of partial interaction and shrinkage straining counteract each other when slab deflections are considered.

The hydrolysis of Zr(IV) compounds was investigated using the horizontal zone electromigration method and zirconium 95 as radioactive indicator. For this reason the ion mobility of Zr(IV) was measured detecting the γ-rays of zirconium 95 at 298 Kin dependence on pH and for the both concentrations of czr ≲ 10−8 M and czr = 4 · 10−3 M. At the lower concentration of Zr ions the hydrolysis constants of Zr ions were determined for the mononuclear hydroxides (i = 1 … 4). At the higher concentration (czr = 4 · 10−3 M) polynuclear cationic species are formed.