A Comparison of Disease Burden in Rheumatoid Arthritis,Psoriatic Arthritis and Axial Spondyloarthritis

Objective

The main objective of this study was to compare disease burden in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (ax-SpA).

Methods

In this cross-sectional study, all the RA (1093), PsA (365) and ax-SpA (333) patients who visited the out-patient clinic of the Hospital of Southern Norway Trust during the year 2013 were included; the RA patients all had a RA diagnosis verified by the treating rheumatologist, the PsA patients all fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria and the ax-SpA patients all fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for ax-SpA. Patient-reported health status, demographic variables, medications, and composite scores of disease activity were assessed. The main analyses were performed using General Linear Models adjusted for age, sex and multiple comparisons. Correlation analyses were performed using Spearman’s rho.

Results

The reported pain, joint pain, patient’s global assessment and fatigue were similar in PsA and ax-SpA, but significantly lower in RA. The 28-joint Disease Activity Score (DAS28) (0.3±0.1, p = 0.003), Clinical Disease Activity Index (CDAI) (1.0±0.4, p = 0.028) and Routine Assessment of Patient Index Data 3 (RAPID3) (0.4±0.1, p = 0.004) were all significantly higher in PsA vs. RA. RAPID3 showed moderate to high correlation with DAS28 (rho = 0.521, p<0.001) and CDAI (rho = 0.768, p<0.001) in RA and PsA, and with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (rho = 0.902, p<0.001) and Bath Ankylosing Spondylitis Functional Index (BASFI) (0.865, p<0.001) in ax-SpA and PsA.

Conclusion

In conclusion, patient- reported outcome measures were similar in our population of PsA and ax-SpA patients, but significantly lower for the RA patients. Composite disease activity measures were lower in RA than in PsA and ax-SpA, but the magnitude of these differences was small and probably not of clinical significance. Our study indicates that disease burden in RA, PsA and ax-SpA may be more similar than previously demonstrated.     

Serum lipidomics meets cardiac magnetic resonance imaging: profiling of subjects at risk of dilated cardiomyopathy

Dilated cardiomyopathy (DCM), characterized by left ventricular dilatation and systolic dysfunction, constitutes a significant cause for heart failure, sudden cardiac death or need for heart transplantation. Lamin A/C gene (LMNA) on chromosome 1p12 is the most significant disease gene causing DCM and has been reported to cause 7-9% of DCM leading to cardiac transplantation. We have previously performed cardiac magnetic resonance imaging (MRI) to LMNA carriers to describe the early phenotype. Clinically, early recognition of subjects at risk of developing DCM would be important but is often difficult. Thus we have earlier used the MRI findings of these LMNA carriers for creating a model by which LMNA carriers could be identified from the controls at an asymptomatic stage. Some LMNA mutations may cause lipodystrophy. To characterize possible effects of LMNA mutations on lipid profile, we set out to apply global serum lipidomics using Ultra Performance Liquid Chromatography coupled to mass spectrometry in the same LMNA carriers, DCM patients without LMNA mutation and controls. All DCM patients, with or without LMNA mutation, differed from controls in regard to distinct serum lipidomic profile dominated by diminished odd-chain triglycerides and lipid ratios related to desaturation. Furthermore, we introduce a novel approach to identify associations between the molecular lipids from serum and the MR images from the LMNA carriers. The association analysis using dependency network and regression approaches also helped us to obtain novel insights into how the affected lipids might relate to cardiac shape and volume changes. Our study provides a framework for linking serum derived molecular markers not only with clinical endpoints, but also with the more subtle intermediate phenotypes, as derived from medical imaging, of potential pathophysiological relevance.     

Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects--a monozygotic twin study

Both genetic and environmental factors are involved in the etiology of obesity and the associated lipid disturbances. We determined whether acquired obesity is associated with changes in global serum lipid profiles independent of genetic factors in young adult monozygotic (MZ) twins. 14 healthy MZ pairs discordant for obesity (10 to 25 kg weight difference) and ten weight concordant control pairs aged 24-27 years were identified from a large population-based study. Insulin sensitivity was assessed by the euglycemic clamp technique, and body composition by DEXA (% body fat) and by MRI (subcutaneous and intra-abdominal fat). Global characterization of lipid molecular species in serum was performed by a lipidomics strategy using liquid chromatography coupled to mass spectrometry. Obesity, independent of genetic influences, was primarily related to increases in lysophosphatidylcholines, lipids found in proinflammatory and proatherogenic conditions and to decreases in ether phospholipids, which are known to have antioxidant properties. These lipid changes were associated with insulin resistance, a pathogonomic characteristic of acquired obesity in these young adult twins. Our results show that obesity, already in its early stages and independent of genetic influences, is associated with deleterious alterations in the lipid metabolism known to facilitate atherogenesis, inflammation and insulin resistance.     

Inter-twin relationships and mental health.

We evaluated dominance-submissiveness between co-twins and its relationship to mental health in a cohort study of 419 twins followed from pregnancy to 22-30 years of age. Dominance-submissiveness between co-twins was assessed from three separate perspectives: physical dominance, psychological dominance, and verbal dominance. Depressive, nervous, and psychosomatic symptoms were analyzed in different twin groups. In the physical domain, males were more commonly dominant than females at school age and in adulthood. Before and at school age, girls were more dominant than boys in the psychological and verbal domains, as well as in total dominance. These differences disappeared in adulthood, and 81% of adult twins felt themselves equal to their co-twin in total dominance. Submissiveness in the psychological domain seemed to be associated with increased depressiveness, nervous complaints and psychosomatic symptoms in males of male-female twin pairs. Verbally submissive males in same-sex twin pairs had more depression and psychosomatic symptoms. Among females of same-sex twin pairs, submissiveness in the psychological domain was most clearly associated with depressive symptoms, whereas psychological or verbal dominance-submissiveness among females from male-female twin pairs was not associated with symptoms. Psychologically dominant males and females of same-sex twin pairs expressed greater nervousness than did their co-twins. We conclude that being submissive, especially in the psychological domain, to a female twin partner seems to be stressful, whereas it is easier, especially for females, to be submissive to a male twin partner.     

Smoking-gender interaction and risk for rheumatoid arthritis

The present case-control study was conducted to investigate the relationship between smoking and rheumatoid arthritis, and to investigate formally the interaction between sex, smoking, and risk for developing rheumatoid arthritis. The study was performed in the Central District of Finland. Cases were patients with rheumatoid arthritis and the control group was a random sample of the general population. Logistic regression models were used to evaluate the effect of smoking on risk for rheumatoid arthritis, after adjusting for the effects of age, education, body mass index, and indices of general health and pain. Overall, 1095 patients with rheumatoid arthritis and 1530 control individuals were included. Patients were older, less well educated, more disabled, and had poorer levels of general health as compared with control individuals (all P < 0.01). Preliminary analyses revealed the presence of substantial statistical interaction between smoking and sex (P < 0.001). In separate multivariable analyses, past history of smoking was associated with increased risk for rheumatoid arthritis overall in men (odds ratio 2.0, 95% confidence interval 1.2-3.2) but not in women. Among men, this effect was seen only for rheumatoid factor-positive rheumatoid arthritis. There were significant interactions between smoking and age among women but not among men. We conclude that sex is a biologic effect modifier in the association between smoking and rheumatoid arthritis. The role of menopause in the etiology of rheumatoid arthritis merits further research.     

Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis

The prevalence of ischemic heart disease and atherosclerosis is increased in patients with rheumatoid arthritis (RA). In the general population, but not in patients with systemic lupus erythematosus, the Framingham risk score identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. We examined the hypothesis that the Framingham score is increased and associated with coronary-artery atherosclerosis in patients with RA. The Framingham score and the 10-year cardiovascular risk were compared among 155 patients with RA (89 with early disease, 66 with long-standing disease) and 85 control subjects. The presence of coronary-artery calcification was determined by electron-beam computed tomography. The Framingham score was compared in patients with RA and control subjects, and the association between the risk score and coronary-artery calcification was examined in patients. Patients with long-standing RA had a higher Framingham score (14 [11 to 18]) (median [interquartile range]) compared to patients with early RA (11 [8 to 14]) or control subjects (12 [7 to 14], P < 0.001). This remained significant after adjustment for age and gender (P = 0.015). Seventy-six patients with RA had coronary calcification; their Framingham risk score was higher (14 [12 to 17]) than that of 79 patients without calcification (10 [5 to 14]) (P < 0.001). Furthermore, a higher Framingham score was associated with a higher calcium score (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.12 to 1.29, P < 0.001), and the association remained significant after adjustment for age and gender (OR = 1.15, 95% CI 1.02 to 1.29, P = 0.03). In conclusion, a higher Framingham risk score is independently associated with the presence of coronary calcification in patients with RA.     

Triacylglycerol fatty acid composition in diet-induced weight loss in subjects with abnormal glucose metabolism--the GENOBIN study

Background

The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects with features of metabolic syndrome in a 33-week intervention.

Methodology/Principal Findings

Plasma samples of 9 subjects in the weight reduction group and 10 subjects in the control group were analyzed using mass spectrometry based lipidomic and fatty acid analyses. Body weight decreased in the weight reduction group by 7.8±2.9% (p<0.01). Most of the serum triacylglycerols and phosphatidylcholines were reduced. The decrease in triacylglycerols affected predominantly the saturated short chain fatty acids. This decrease of saturated short chain fatty acid containing triacylglycerols correlated with the increase of insulin sensitivity. However, levels of several longer chain fatty acids, including arachidonic and docosahexanoic acid, were not affected by weight loss. Levels of other lipids known to be associated with obesity such as sphingolipids and lysophosphatidylcholines were not altered by weight reduction.

Conclusions/Significance

Diet-induced weight loss caused significant changes in global lipid profiles in subjects with abnormal glucose metabolism. The observed changes may affect insulin sensitivity and glucose metabolism in these subjects.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00621205","term_id":"NCT00621205"}}NCT00621205     

Dexamethasone regulates expression of BRUCE/Apollon and the proliferation of neural progenitor cells

Glucocorticoid hormones (GHs) regulate cell proliferation of neural progenitor cells (NPCs) contributing to reduction of neurogenesis after stress. We show here that dexamethasone (Dex) decreases BRUCE/Apollon (BRUCE) in cultured NPCs in a GH-receptor-dependent manner. Downregulation of BRUCE by Dex or using silencing RNA reduced the number of proliferating NPCs, whilst overexpression of BRUCE counteracted the effect of Dex. Dex also elevated the deubiquitinating enzyme, Usp8/Ubpy, which via Nrdp1 decreases BRUCE. The results show that BRUCE is a target for GHs in the NPCs, and that BRUCE controls cell division of NPCs and possibly of other stem cells.

Structured summary

MINT-7148564: Nrdp1 (uniprotkb:Q8BH75) physically interacts (MI:0914) with BRUCE (uniprotkb:O88738) by anti bait co-immunoprecipitation (MI:0006)MINT-7148555: Nrdp1 (uniprotkb:Q8BH75) physically interacts (MI:0914) with Usp8 (uniprotkb:Q80U87) by anti bait co-immunoprecipitation (MI:0006)     

Regulation of angiotensin-converting enzyme production by nicotine in human endothelial cells

Nicotine, a component of cigarette smoke, has been implicated in the pathogenesis of cardiovascular disease. We examined whether nicotine regulates angiotensin-converting enzyme (ACE), an enzyme that plays an important role in the pathophysiology of atherosclerosis and hypertension. Human umbilical cord vein endothelial cells were treated with nicotine (0.1-1 microM) alone or in combination with vascular endothelial growth factor (VEGF; 0.5 nM) or GF-109203X (GFX; 2.5 microM). The amount of ACE in intact endothelial cells was measured by an inhibitor-binding assay method, and ACE mRNA levels were quantified using LightCycler technology. Phosphorylated PKC levels were measured by Western immunoblotting. Nicotine did not modulate basal ACE production but significantly potentiated VEGF-induced ACE upregulation. Treatment of endothelial cells with the PKC inhibitor GFX totally blocked VEGF- and nicotine-induced ACE upregulation. VEGF induced PKC phosphorylation, which was potentiated by cotreatment with nicotine. We conclude that nicotine significantly potentiated VEGF-induced ACE upregulation. This effect was probably mediated by PKC phosphorylation. The interaction of nicotine with VEGF in ACE induction may contribute to the pathogenesis of smoking-related cardiovascular disease.     

Elaidic and trans-vaccenic acids in plasma phospholipids as indicators of dietary intake of 18:1 trans-fatty acids

Octadecenoic (18:1) trans-fatty acid fractions from margarine, butter and plasma phospholipids (PL) were isolated by silver ion TLC, and nine positional isomers (n-11-n-3) were identified by GC-MS based on their ozonolysis products. The GC analysis of the isolated fractions gave similar peak profiles and separated seven trans-isomers (n-11-n-6 and n-3). Without a preceding isolation step, the reproducibility of the Gc method for plasma PL elaidic (18:1 n-9 trans) and trans-vaccenic acids (n-7) was 3.4 and 2.7% (R.S.D.), respectively. These trans-isomers were rapidly incorporated and cleared in plasma PL and they closely reflected both increased and decreased intake of 18:1 trans-fatty acids during moderate fat substitutions. Significant associations between high-density lipoprotein cholesterol (HDL-C) and PL elaidic and trans-vaccenic acids appeared in habitual margarine users only.