Clinical and biochemical landmarks in systemic autoinflammatory diseases.

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immune system characterized by seemingly unprovoked inflammation recurring at variable intervals and involving skin, serosal membranes, joints, and gastrointestinal apparatus, with reactive amyloidosis as a possible severe long-term complication. Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, and hereditary pyogenic and granulomatous disorders: the vast majority of these conditions are related to the activation of the interleukin-1 pathway, which results in (or from?) a common unifying pathogenetic mechanism. Their diagnostic identification derives from the combination of clinical data, evaluation of acute phase reactants, clinical efficacy in response to specific drugs, and recognition of specific mutations in the relevant genes, although genetic tests may be unconstructive in some cases. This review will discuss clinical and laboratory clues useful for a diagnostic approach to systemic autoinflammatory diseases

Elevated antiphospholipid antibody titers and adverse pregnancy outcomes: analysis of a population-based hospital dataset

<p>Abstract</p> <p>Background</p> <p>The primary objective of this study was to determine if elevated antiphospholipid antibody titers were correlated with the presence of preeclampsia/eclampsia, systemic lupus erythematosus (SLE), placental insufficiency, and a prolonged length of stay (PLOS), in women who delivered throughout Florida, USA.</p> <p>Methods</p> <p>Cross-sectional analyses were conducted using a statewide hospital database. Prevalence odds ratios (OR) were calculated to quantify the association between elevated antiphospholipid antibody titers and four outcomes in 141,286 women who delivered in Florida in 2001. The possibility that the relationship between elevated antiphospholipid antibody titers and the outcomes of preeclampsia/eclampsia, placental insufficiency, and PLOS, may have been modified by the presence of SLE was evaluated in a multiple logistic regression model by creating a composite interaction term.</p> <p>Results</p> <p>Women with elevated antiphospholipid antibody titers (n = 88) were older, more likely to be of white race and not on Medicaid than women who did not have elevated antiphospholipid antibody titers. Women who had elevated antiphospholipid antibody titers had an increased adjusted odds ratio for preeclampsia and eclampsia, (OR = 2.93 p = 0.0015), SLE (OR = 61.24 p < 0.0001), placental insufficiency (OR = 4.58 p = 0.0003), and PLOS (OR = 3.93 p < 0.0001). Patients who had both an elevated antiphospholipid antibody titer and SLE were significantly more likely than the comparison group (women without an elevated titer who did not have SLE) to have the outcomes of preeclampsia, placental insufficiency and PLOS.</p> <p>Conclusion</p> <p>This exploratory epidemiologic investigation found moderate to very strong associations between elevated antiphospholipid antibody titers and four important outcomes in a large sample of women.</p

HLA class II DNA typing in a large series of European patients with systemic lupus erythematosus: correlations with clinical and autoantibody subsets

We conducted this study to determine the HLA class II allele associations in a large cohort of patients of homogeneous ethnic derivation with systemic lupus erythematosus (SLE). The large sample size allowed us to stratify patients according to their clinical and serologic characteristics. We studied 577 European Caucasian patients with SLE. Antinuclear antibodies (Hep-2 cells), anti-dsDNA antibodies (Crithidia luciliae), and antibodies to extractable nuclear antigens Ro (SS-A), La (SS-B), U1-RNP, Sm, Jo1, SCL70, and PCNA, were detected in all patients. Molecular typing of HLA-DRB1, DRB3, DQA1, and DQB1 loci was performed by the polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method. We found a significantly increased frequency of DRB1*03, DRB1*15, DRB1*16, DQA1*0102, DQB1*0502, DQB1*0602, DQB1*0201, DQB1*0303, and DQB1*0304 in lupus patients as compared with healthy controls. In addition, DRB1*03 was associated with anti-Ro, anti-La, pleuritis, and involvement of lung, kidney, and central nervous system. DRB1*15 and DQB1*0602 were associated with anti-dsDNA antibodies; DQB1*0201 with anti-Ro and anti-La, leukopenia, digital skin vasculitis, and pleuritis; and DQB1*0502 was associated with anti-Ro, renal involvement, discoid lupus, and livedo reticularis. In conclusion, our study shows some new HLA clinical and serologic associations in SLE and further confirms that the role of MHC genes is mainly to predispose to particular serologic and clinical manifestations of this disease

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Influence of antisynthetase antibodies specificities on antisynthetase syndrome clinical spectrum time course

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies

Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern

Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits

Diagnostic tools in Rhinology EAACI position paper

This EAACI Task Force document aims at providing the readers with a comprehensive and complete overview of the currently available tools for diagnosis of nasal and sino-nasal disease. We have tried to logically order the different important issues related to history taking, clinical examination and additional investigative tools for evaluation of the severity of sinonasal disease into a consensus document. A panel of European experts in the field of Rhinology has contributed to this consensus document on Diagnostic Tools in Rhinology

Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis

Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with HLA region polymorphisms. To determine if associations can be explained by classical HLA determinants we studied Italian 676 cases and 1440 controls with genotyped with dense single nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (p = 1.59 × 10(−11)) was the strongest predisposing allele where as DRB1*11 (p = 1.42 × 10(−10)) was protective. Additionally DRB1*14 and the DPB1 association (DPB1*03:01) (p = 9.18 × 10(−7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC

Search for High-Mass Resonances Decaying to τν in pp Collisions at √s=13 TeV with the ATLAS Detector

A search for high-mass resonances decaying to τν using proton-proton collisions at √s=13 TeV produced by the Large Hadron Collider is presented. Only τ-lepton decays with hadrons in the final state are considered. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1 fb−1. No statistically significant excess above the standard model expectation is observed; model-independent upper limits are set on the visible τν production cross section. Heavy W′ bosons with masses less than 3.7 TeV in the sequential standard model and masses less than 2.2–3.8 TeV depending on the coupling in the nonuniversal G(221) model are excluded at the 95% credibility level