Deficiency of functional mannose-binding lectin is not associated with infections in patients with systemic lupus erythematosus

Infection imposes a serious burden on patients with systemic lupus erythematosus (SLE). The increased infection rate in SLE patients has been attributed in part to defects of immune defence. Recently, the lectin pathway of complement activation has also been suggested to play a role in the occurrence of infections in SLE. In previous studies, SLE patients homozygous for mannose-binding lectin (MBL) variant alleles were at an increased risk of acquiring serious infections in comparison with patients who were heterozygous or homozygous for the normal allele. This association suggests a correlation between functional MBL level and occurrence of infections in SLE patients. We therefore investigated the biological activity of MBL and its relationship with the occurrence of infections in patients with SLE. Demographic and clinical data were collected in 103 patients with SLE. Functional MBL serum levels and MBL-induced C4 deposition were measured by enzyme-linked immunosorbent assay using mannan as coat and an MBL- or C4b-specific monoclonal antibody. The complete MBL-dependent pathway activity was determined by using an assay that measures the complete MBL pathway activity in serum, starting with binding of MBL to mannan, and was detected with a specific monoclonal antibody against C5b-9. Charts were systematically reviewed to obtain information on documented infections since diagnosis of SLE. Major infections were defined as infections requiring hospital admission and intravenous administration of antibiotics. In total, 115 infections since diagnosis of lupus, including 42 major infections, were documented in the 103 SLE patients (mean age 41 ± 13 years, mean disease duration 7 ± 4 years). The percentage of SLE patients with severe MBL deficiency was similar to that in 100 healthy controls: 13% versus 14%, respectively. Although deposition of C4 to mannan and MBL pathway activity were reduced in 21% and 43% of 103 SLE patients, respectively, neither functional MBL serum levels nor MBL pathway activity was associated with infections or major infections in regression analyses. In conclusion, SLE patients frequently suffer from infections, but deficiency of functional MBL does not confer additional risk

Quantification of Dynamic 11C-Phenytoin PET Studies

The overexpression of P-glycoprotein (Pgp) is thought to be an important mechanism of pharmacoresistance in epilepsy. Recently, 11C-phenytoin has been evaluated preclinically as a tracer for Pgp. The aim of the present study was to assess the optimal plasma kinetic model for quantification of 11C-phenytoin studies in humans. Methods: Dynamic 11C-phenytoin PET scans of 6 healthy volunteers with arterial sampling were acquired twice on the same day and analyzed using single- and 2-tissue-compartment models with and without a blood volume parameter. Global and regional test– retest (TRT) variability was determined for both plasma to tissue rate constant (K1) and volume of distribution (VT). Results: According to the Akaike information criterion, the reversible single-tissue-compartment model with blood volume parameter was the preferred plasma input model. Mean TRT variability ranged from 1.5% to 16.9% for K1 and from 0.5% to 5.8% for VT. Larger volumes of interest showed better repeatabilities than smaller regions. A 45-min scan provided essentially the same K1 and VT values as a 60-min scan. Conclusion: A reversible single-tissue-compartment model with blood volume seems to be a good candidate model for quantification of dynamic 11C-phenytoin studies. Scan duration may be reduced to 45 min without notable loss of accuracy and precision of both K1 and VT, although this still needs to be confirmed under pathologic conditions

Increased incidence of pregnancy complications in women who later develop scleroderma: a case control study

ABSTRACT: INTRODUCTION: Studies have shown that fetal progenitor cells persist in maternal blood or bone marrow for more than 30 years after delivery. Increased trafficking of fetal cells occurs during pregnancy complications, such as hypertension, preeclampsia, miscarriage and intra-uterine growth restriction (IUGR). Women with these pregnancy complications are significantly more often HLA-class II compatible with their spouses. Women who later develop scleroderma also give birth to an HLA-class II child more often. From these prior studies we hypothesized that preeclampsia and other pregnancy complications could be associated with increased levels of fetal cell trafficking, and later be involved in the development of scleroderma. METHODS: This study was a retrospective multi-centre matched case-control study. One-hundred-and-three women with systemic sclerosis (SSc) and 103 women with no history of SSc or other autoimmune disease were given a questionnaire regarding complications during pregnancy, such as hypertension, intra-uterine growth restriction (IUGR) and miscarriage. Conditional logistic regression analysis was used to assess associations. RESULTS: We found a statistically significantly increased incidence of having had a pregnancy history of hypertension or a fetus with IUGR in women who subsequently developed SSc compared to healthy controls. We found an odds ratio of 2.6 (95% confidence interval (CI): 1.1 to 4.6) for hypertensive complications during pregnancy and an odds ratio of 3.9 (95% CI: 1.2 to 12.3) for intra-uterine growth restriction for women with SSc compared to healthy controls. CONCLUSIONS: This is the first study to show an association between hypertensive complications during pregnancy or IUGR and the development of SSc at a later age. We speculate that the pregnancy abnormalities may have resulted in increased fetomaternal trafficking, which may have played a role in the increased incidence of SSc. Further studies are indicated to examine this putative relationship.Pathophysiology and treatment of rheumatic disease

Tracheobronchomalacia due to amyloidosis in a patient with rheumatoid arthritis

In this case report, we describe a patient with longstanding rheumatoid arthritis who developed tracheobronchomalacia with fatal outcome. Despite negative antemortem biopsies of abdominal fat and tongue, amyloid was found postmortem in the trachea and appeared to be associated with tracheobronchomalacia

A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort

<p><b>Objectives</b> The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features.</p> <p><b>Methods</b> A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers.</p> <p><b>Results</b> A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively).</p> <p><b>Conclusions</b> The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.</p&gt

Characteristics of Interstitial Fibrosis and Inflammatory Cell Infiltration in Right Ventricles of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Objective. Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a disturbed function of the right ventricle (RV) when compared to idiopathic PAH (IPAH). Systemic sclerosis may also affect the heart. We hypothesize that RV differences may occur at the level of interstitial inflammation and—fibrosis and compared inflammatory cell infiltrate and fibrosis between the RV of SScPAH, IPAH, and healthy controls. Methods. Paraffin-embedded tissue samples of RV and left ventricle (LV) from SScPAH (n = 5) and IPAH (n = 9) patients and controls (n = 4) were picrosirius red stained for detection of interstitial fibrosis, which was quantified semiautomatically. Neutrophilic granulocytes (MPO), macrophages (CD68), and lymphocytes (CD45) were immunohistochemically stained and only interstitial leukocytes were counted. Presence of epi- or endocardial inflammation, and of perivascular or intimal fibrosis of coronary arteries was assessed semiquantitatively (0–3: absent to extensive). Results. RV's of SScPAH showed significantly more inflammatory cells than of IPAH (cells/mm2, mean ± sd MPO 11 ± 3 versus 6 ± 1; CD68 11 ± 3 versus 6 ± 1; CD45 11 ± 1 versus 5 ± 1 , P < .05) and than of controls. RV interstitial fibrosis was similar in SScPAH and IPAH (4 ± 1 versus 5 ± 1%, P = .9), and did not differ from controls (5 ± 1%, P = .8). In 4 SScPAH and 5 IPAH RV's foci of replacement fibrosis were found. No differences were found on epi- or endocardial inflammation or on perivascular or intimal fibrosis of coronary arteries. Conclusion. SScPAH RVs display denser inflammatory infiltrates than IPAH, while they do not differ with respect to interstitial fibrosis. Whether increased inflammatory status is a contributor to altered RV function in SScPAH warrants further research

The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10&lt;sup&gt;−8&lt;/sup&gt;, OR = 1.22, CI 95% = 1.14–1.30; rs2004640: P = 4.60×10&lt;sup&gt;−7&lt;/sup&gt;, OR = 0.84, CI 95% = 0.78–0.90; rs10488631: P = 7.53×10&lt;sup&gt;−20&lt;/sup&gt;, OR = 1.63, CI 95% = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10&lt;sup&gt;−22&lt;/sup&gt;, OR = 1.75, CI 95% = 1.56–1.97) better explained the observed association (likelihood P-value = 1.48×10&lt;sup&gt;−4&lt;/sup&gt;), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific

Large-Vessel Vasculitis:Interobserver Agreement and Diagnostic Accuracy of (18)F-FDG-PET/CT

Introduction. F-18-FDG-PET visualises inflammation. Both atherosclerosis and giant cell arteritis cause vascular inflammation, but distinguishing the two may be difficult. The goal of this study was to assess interobserver agreement and diagnostic accuracy of F-18-FDG-PET for the detection of large artery involvement in giant cell arteritis (GCA). Methods. 31 F-18-FDG-PET/CT scans were selected from 2 databases. Four observers assessed vascularwall F-18-FDGuptake, initially without and subsequently with predefined observer criteria (i.e., vascular wall F-18-FDG uptake compared to liver or femoral artery F-18-FDG uptake). External validation was performed by two additional observers. Sensitivity and specificity of F-18-FDG-PET were determined by comparing scan results to a consensus diagnosis. Results. The highest interobserver agreement (kappa: 0.96 in initial study and 0.79 in external validation) was observed when vascular wall F-18-FDG uptake higher than liver uptake was used as a diagnostic criterion, although agreement was also good without predefined criteria (kappa: 0.68 and 0.85). Sensitivity and specificity were comparable for these methods. The criterion of vascular wall F-18-FDG uptake equal to liver F-18-FDG uptake had low specificity. Conclusion. Standardization of image assessment for vascular wall F-18-FDG uptake promotes observer agreement, enables comparative studies, and does not appear to result in loss of diagnostic accuracy compared to nonstandardized assessment

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci