Background A subgroup of patients with chronic spontaneous urticaria (CU) exhibits IgE antibodies directed against autoantigens, such as thyroperoxidase (TPO). We conducted this study to investigate ...whether such patients with CU with IgE against TPO benefit from treatment with omalizumab, a humanized anti-IgE mAb licensed for the treatment of severe persistent allergic (IgE-mediated) asthma. Objectives We sought to assess the efficacy of omalizumab treatment in patients with CU with IgE autoantibodies against TPO. Methods In this multicenter, randomized, double-blind, placebo-controlled study patients with CU (male/female, 18-70 years of age) with IgE autoantibodies against TPO who had persistent symptoms (wheals and pruritus) despite standard antihistamine therapy were randomized to receive either omalizumab (75-375 mg, dose determined by using the approved asthma dosing table) or placebo subcutaneously once every 2 or 4 weeks for 24 weeks. The primary end point was the change from baseline in mean weekly urticaria activity score after 24 weeks of treatment, as calculated from patients’ diaries. The safety and tolerability of omalizumab were also assessed. Results Of the 49 randomized patients (omalizumab, n = 27; placebo, n = 22), 42 completed the study. At week 24, patients demonstrated a mean reduction in the weekly urticaria activity score from baseline of 17.8 with omalizumab and 7.9 with placebo ( P = .0089). Complete protection from wheal development was observed in 19 (70.4%) patients in the omalizumab group compared with only 1 (4.5%) patient in the placebo group. The rate of adverse events was similar in both groups. Conclusions The results of this study indicate that omalizumab is an effective treatment option for patients with CU with IgE autoantibodies against TPO who are refractory to conventional treatment.
Abstract Background Vein graft disease is a major and yet unsolved problem in cardiac revascularization surgery. Although accumulation of extracellular matrix is characteristic for vein graft ...disease, detailed analysis of the fibrotic material is lacking. Because alterations of collagen cross-links are typical for organ fibrosis, we performed a comprehensive analysis of collagen and elastin in vein graft disease. Methods Collagen, elastin, and their respective cross-links were analyzed using histology and amino acid analysis. The expression of collagen-modifying enzymes was analyzed using SYBR Green quantitative real-time polymerase chain reaction. Fibrillin expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction. Results Diseased vein grafts showed a marked increase of collagen and of intermediate collagen cross-links, which are markers for newly synthesized collagen. Furthermore, we identified in vein graft disease increased levels of mature hydroxylysine aldehyde-derived cross-links typical for skeletal tissues. This was accompanied by upregulation of lysyl hydroxylase 2 and lysyl oxidase expression. Furthermore, vein graft disease showed a reduction of the elastin/collagen ratio, using elastin cross-links as a marker of elastin content, which was accompanied by an increase of fibrillin-1. Conclusions Vein graft disease was accompanied by marked alterations in the composition of the extracellular matrix. The altered collagen cross-link pattern and the reduced elastin/collagen ratio might synergistically increase the stiffness in diseased vein grafts. Furthermore, hydroxylysine aldehyde-derived cross-links can cause a decreased degradability of collagens by matrix-metalloproteinases. Our data suggest collagen cross-links as a therapeutic target in vein graft disease.
ObjectiveLumbar spinal stenosis is one of the most commonly diagnosed spinal disorders in older adults. Although the pathophysiology of the clinical syndrome is not well understood, a narrow central ...canal or intervertebral foramen is an essential or defining feature. The aim of the present study was to estimate the magnitude of genetic versus environmental influences on central lumbar spinal stenosis and to investigate disc degeneration and stature or bone development as possible genetic pathways. MethodsA classic twin study with multivariate analyses considering lumbar level and other covariates was conducted. The study sample comprised 598 male twins (147 monozygotic and 152 dizygotic pairs), 35-70 years of age, from the population-based Finnish Twin Cohort. The primary phenotypes were central lumbar stenosis as assessed qualitatively on magnetic resonance imaging (MRI) and quantitatively measured dural sac cross-sectional area. Additional phenotypes (to examine possible genetic pathways) included disc bulging and standing height, as an indicator of overall skeletal size or development. ResultsThe heritability estimate (h(2)) for qualitatively assessed central lumbar spinal stenosis on MRI was 66.9% (95% confidence interval 95% CI 56.8, 74.5). The broad-sense heritability estimate for dural sac cross-sectional area was 81.2% (95% CI 74.5, 86.1), with a similar magnitude of genetic influences across lumbar levels (h(2) = 72.4-75.6). The additive genetic correlation of quantitatively assessed stenosis and disc bulging was extremely high. There was no indication of shared genetic influences between stenosis and stature. ConclusionCentral lumbar spinal stenosis and associated dural sac dimensions are highly genetic, and disc degeneration (bulging) appears to be one pathway through which genes influence spinal stenosis.
Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain ...insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.
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