Cardiovascular Safety of Anti-TNF and Non-TNF Biological Therapy in Patients with Rheumatoid Arthritis

The association between cumulative inflammatory burden and increased cardiovascular (CV) risk in patients with immune-mediated inflammatory rheumatic disorders, particularly rheumatoid arthritis (RA), is widely recognized. Furthermore, the complex and dynamic interrelation between traditional cardiovascular risk factors, systemic inflammation, early accelerated atherosclerosis, and RA-related factors remains a challenge in routine practice. New European League Against Rheumatism (EULAR) 2016 recommendations have recently highlighted three key trends in cardiovascular risk assessment and management in patients with RA including optimal disease control (early diagnosis, treat-to-target strategy with the dynamic use of antirheumatic synthetic and biologic drugs) and non-pharmacological as well as pharmacological management of risk factors. The present chapter will emphasize excessive cardiovascular morbidity in RA, the optimal strategy to identify and stratify the cardiovascular risk profile, the prime selection of medication from the whole spectrum of non-biologic and biologic (TNF and non-TNF) drugs according to their cardiotoxicity

Rheumatoid Arthritis and Periodontal Disease: A Complex Interplay

Recent advances in understanding the dynamic pathways involved in the pathogenesis of rheumatoid arthritis have emphasized the pivotal role of pro-inflammatory cytokines, inflammatory cells, endothelial cell activation and matrix degradation, acting in a genetically predisposed environment. On the other hand, there are significant amounts of data highlighting the potential role of bacteria (leading periodonthopatic pathogen Porfiromonas gingivalis) in promoting different types of arthritis, as well as the influence of periodontis (an infectious-inflammatory condition) as etiological or modulating factor in different pathologies, including cardio-vascular disorders, diabetes, respiratory disease and inflammatory rheumatic disorders (such as rheumatoid arthritis, ankylosing spondylitis and lupus). The present chapter deals with the possible association between rheumatoid arthritis and periodontitis as entities with common pathological events

BAFF System in Rheumatoid Arthritis: from Pathobiology to Therapeutic Targets

Recent advances in understanding the multifaceted pathobiology of rheumatoid arthritis have highlighted the pivotal role and continuing crosstalk between activated immune cells, pro-inflammatory cytokines, and matrix-degrading mediators, promoting chronic inflammation as well as irreversible tissue damage within an autoimmune background. B cells are widely recognized as leading players in immune-mediated pathology based on their ability to produce not only different patterns of autoantibodies and driving cytokine synthesis but also as independent antigen-presenting cells and by modulating the specific activation of T cells. Overwhelming evidence emphasized the role of BAFF, a B-cell-activating factor, and BAFF receptors (TACI, BCMA, BAFF-R) in promoting B-cell homeostasis, proliferation, and survival under normal and autoimmune systemic disorders. We systematically reviewed data from literature focusing on BAFF, its homolog molecule APRIL, and BAFF-binding receptors biology, dysregulation of BAFF/BAFF receptor signaling in autoimmune settings, and current status of targeting BAFF/BAFF receptor pathway for rheumatoid arthritis

Challenges in the Delivery Room: Integrated Analysis of Biomarkers Predicting Complications in Lupus Pregnancy

Pregnancy in autoimmune rheumatic diseases remains a real challenge in clinical practice due to complex interplay between disease activity, pregnancy and drugs, and account for potential influence of pregnancy on rheumatic condition and the impact of disease on pregnancy outcomes. Indeed, innovative and successful therapies have dramatically improved the quality of life in immune-mediated rheumatic conditions and, subsequently, allowed more patients of reproductive age to plan a pregnancy/to conceive. The purpose of this chapter is to discuss emerging data about the interaction of pregnancy and systemic erythematosus lupus (SLE) focusing on modulation of the immune system by pregnancy, pregnancy outcomes in women with active lupus, biomarkers of adverse pregnancy outcomes (APO) including predictors of pre-eclampsia, predictors of obstetric complications in SLE, the influence of autoantibodies on fetal health, and, finally, evidence about rheumatologic and obstetric follow-up. There are still unmet needs in this new field of reproductive rheumatology and it becomes crucial that researchers, physicians (rheumatologists, specialists in maternofetal medicine, obstetricians) and midwifes share their knowledge and expertise in counseling women with SLE wishing to conceive, assisting pregnancy and managing different issues related to APO as well as drug optimization in preconception, during pregnancy and postpartum period

The impact of specific balneotherapy on the endocrine physio-pathological mechanism in obesity

Obesity is a complex, multifactorial metabolic pathology, within the path of modification of the endocrine system plays a significant role. Changes in growth hormone (GH) and in-sulin growth factor (IGF) have been associated with obesity in various ways, mainly through changes in GH-binding proteins, insulin and ghrelin levels. The balneal treat-ment with Techirghiol Romanian sapropelic mud has an important impact on the endo-crine system, primarily through the action on the hypothalamic-pituitary-adrenal axis. We investigated the secretory changes of the IGF-1 hormone that appeared after the balne-al treatment. It was a total number of 52 patients, divided into two groups: 1 group who performed the treatment with Techirghiol sapropelic mud at thermoneutrality tempera-tures - warm mud baths, and the second group who followed treatment with the balneal therapeutic factor in a thermal contrast regime - cold mud baths. We studied whether there are correlations between the body mass index (BMI) and the secretion of this hor-mone. We also determined the serum levels of blood glucose at admission and discharge. In the cold mud baths- thermal contrast therapy, can be observed a statistically significant increase in IGF-1 values during the balneal treatment (p = 0.044 α = 0.05). There were no statistically significant correlations between BMI and IGF-1 hormone secretion at admission and at discharge. The results showed a statistically significant decrease in blood glucose values determined at admission and discharge in the group that performed warm mud baths. The balneal treatment with sapropelic mud of Techirghiol lake, from Romania, through the impact on the endocrine system, on the hypothalamic-pituitary-adrenal axis, can be registered as a treatment with a natural therapeutic factor with an impact on obesity, ther-apy carried out within the parameters of metabolic safety, and the conduct of future re-search in this direction it will help develop new concepts and approaches to obesity

The analyse of the antioxidant effect of natural peloidotherapy in aging process

Medical research has developed remarkably in recent years, including the involvement of the glutathione peroxidase (GPx) family of enzymes in the course of human aging, with numerous clinical studies published in the literature reporting this particular fact. Thus, mud therapy and its effect on biological aging have been represented in papers that have been published to date. Papers published in the literature analyzing GPx vari-ation during sapropelic mud therapy suggest the beneficial effect of this family of en-zymes in diseases with an important inflammatory component, mainly monitored in patients with osteoarthritis. This study investigated the effects of sapropelic mud treat-ment on GPx values in patients receiving treatment with sapropelic mud at the Balneal and Rehabilitation Sanatorium of Techirghiol, Romania. We included 52 patients, split into two groups, who received treatment with cold mud baths and warm mud baths. Values close to statistical significance were found in patients who received treatment with cold mud baths in terms of mean GPx values at the four-time points studied. Fur-ther studies evaluating GPx in patients receiving sapropelic mud treatment are needed

Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions

Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman’s ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When Pv and Pm were compared for all pruned SNPs, only BMI was statistically significant (Spearman’s ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the Pv distribution (Pbinomial <0.05). SNPs from the top 1% of the Pm distribution for BMI had more significant Pv values (PMann–Whitney= 1.46×10−5), and the odds ratio of SNPs with nominally significant (<0.05) Pm and Pv was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant G×E interaction P-values (Pint<0.05) were enriched with nominally significant Pv values (Pbinomial = 8.63×10−9 and 8.52×10−7 for SNP × smoking and SNP × physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for G×E, and variance-based prioritization can be used to identify them

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease

Rare coding variants and X-linked loci associated with age at menarche.

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.UK sponsors (see article for overseas ones): This work made use of data and samples generated by the 1958 Birth Cohort (NCDS). Access to these resources was enabled via the 58READIE Project funded by Wellcome Trust and Medical Research Council (grant numbers WT095219MA and G1001799). A full list of the financial, institutional and personal contributions to the development of the 1958 Birth Cohort Biomedical resource is available at http://www2.le.ac.uk/projects/birthcohort. Genotyping was undertaken as part of the Wellcome Trust Case-Control Consortium (WTCCC) under Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk ... The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. ... SIBS - CRUK ref: C1287/A8459 SEARCH - CRUK ref: A490/A10124 EMBRACE is supported by Cancer Research UK Grants C1287/A10118, C1287/A16563 and C1287/A17523. Genotyping was supported by Cancer Research - UK grant C12292/A11174D and C8197/A16565. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. ... Generation Scotland - Scottish Executive Health Department, Chief Scientist Office, grant number CZD/16/6. Exome array genotyping for GS:SFHS was funded by the Medical Research Council UK. 23andMe - This work was supported in part by NIH Award 2R44HG006981-02 from the National Human Genome Research Institute.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/ncomms875

Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

: Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success