Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy.

AIMS: Inflammation is an important driver of hypertension. Periodontitis is a chronic inflammatory disease, which could provide a mechanism for pro-hypertensive immune activation, but evidence of a causal relationship in humans is scarce. We aimed to investigate the nature of the association between periodontitis and hypertension. METHODS AND RESULTS: We performed a two-sample Mendelian randomization analysis in the ∼750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies participants using single nucleotide polymorphisms (SNPs) in SIGLEC5, DEFA1A3, MTND1P5, and LOC107984137 loci GWAS-linked to periodontitis, to ascertain their effect on blood pressure (BP) estimates. This demonstrated a significant relationship between periodontitis-linked SNPs and BP phenotypes. We then performed a randomized intervention trial on the effects of treatment of periodontitis on BP. One hundred and one hypertensive patients with moderate/severe periodontitis were randomized to intensive periodontal treatment (IPT; sub- and supragingival scaling/chlorhexidine; n = 50) or control periodontal treatment (CPT; supragingival scaling; n = 51) with mean ambulatory 24-h (ABPM) systolic BP (SBP) as primary outcome. Intensive periodontal treatment improved periodontal status at 2 months, compared to CPT. This was accompanied by a substantial reduction in mean SBP in IPT compared to the CPT (mean difference of -11.1 mmHg; 95% CI 6.5-15.8; P < 0.001). Systolic BP reduction was correlated to periodontal status improvement. Diastolic BP and endothelial function (flow-mediated dilatation) were also improved by IPT. These cardiovascular changes were accompanied by reductions in circulating IFN-γ and IL-6 as well as activated (CD38+) and immunosenescent (CD57+CD28null) CD8+T cells, previously implicated in hypertension. CONCLUSION: A causal relationship between periodontitis and BP was observed providing proof of concept for development of clinical trial in a large cohort of hypertensive patients. ClinicalTrials.gov: NCT02131922.

TNF-α Inhibitors Decrease Classical CD14hiCD16- Monocyte Subsets in Highly Active, Conventional Treatment Refractory Rheumatoid Arthritis and Ankylosing Spondylitis.

Monocytes are pivotal cells in inflammatory joint diseases. We aimed to determine the effect of TNF-α inhibitors (TNFi) on peripheral blood monocyte subpopulations and their activation in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) patients with high disease activity. To address this, we studied 50 (32 AS, 18 RA) patients with highly active disease with no prior history of TNFi use who were recruited and assigned to TNFi or placebo treatment for 12 weeks. Cytometric and clinical assessment was determined at baseline, four, and 12 weeks after initiation of TNFi treatment. We observed that treatment with TNFi led to a significant decrease in CD14hiCD16- monocytes in comparison to placebo, while circulating CD14dimCD16+ monocytes significantly increased. The TNFi-induced monocyte subset shifts were similar in RA and AS patients. While the percentage of CD14dimCD16+ monocytes increased, expression of CD11b and CD11c integrins on their surface was significantly reduced by TNFi. Additionally, CD45RA+ cells were more frequent. The shift towards nonclassical CD14dimCD16+ monocytes in peripheral blood due to TNFi treatment was seen in both AS and RA. This may reflect reduced recruitment of these cells to sites of inflammation due to lower inflammatory burden, which is associated with decreased disease activity.

Adipokines in Rheumatoid Arthritis: Emerging Biomarkers and Therapeutic Targets.

Rheumatoid arthritis (RA) is a chronic inflammatory disease manifested by joint involvement, extra-articular manifestations, and general symptoms. Adipose tissue, previously perceived as an inert energy storage organ, has been recognised as a significant contributor to RA pathophysiology. Adipokines modulate immune responses, inflammation, and metabolic pathways in RA. Although most adipokines have a pro-inflammatory and aggravating effect on RA, some could counteract this pathological process. The coexistence of RA and sarcopenic obesity (SO) has gained attention due to its impact on disease severity and outcomes. Sarcopenic obesity further contributes to the inflammatory milieu and metabolic disturbances. Recent research has highlighted the intricate crosstalk between adipose tissue and skeletal muscle, suggesting potential interactions between these tissues in RA. This review summarizes the roles of adipokines in RA, particularly in inflammation, immune modulation, and joint destruction. In addition, it explores the emerging role of adipomyokines, specifically irisin and myostatin, in the pathogenesis of RA and their potential as therapeutic targets. We discuss the therapeutic implications of targeting adipokines and adipomyokines in RA management and highlight the challenges and future directions for research in this field.

1,2,3,4,6-Penta-O-galloyl-ß-d-glucose modulates perivascular inflammation and prevents vascular dysfunction in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Hypertension is a multifactorial disease, manifested by vascular dysfunction, increased superoxide production, and perivascular inflammation. In this study, we have hypothesized that 1,2,3,4,6-penta-O-galloyl-ß-d-glucose (PGG) would inhibit vascular inflammation and protect from vascular dysfunction in an experimental model of hypertension. EXPERIMENTAL APPROACH: PGG was administered to mice every 2 days at a dose of 10 mg·kg-1 i.p during 14 days of Ang II infusion. It was used at a final concentration of 20 µM for in vitro studies in cultured cells. KEY RESULTS: Ang II administration increased leukocyte and T-cell content in perivascular adipose tissue (pVAT), and administration of PGG significantly decreased total leukocyte and T-cell infiltration in pVAT. This effect was observed in relation to all T-cell subsets. PGG also decreased the content of T-cells bearing CD25, CCR5, and CD44 receptors and the expression of both monocyte chemoattractant protein 1 (CCL2) in aorta and RANTES (CCL5) in pVAT. PGG administration decreased the content of TNF+ and IFN-γ+ CD8 T-cells and IL-17A+ CD4+ and CD3+ CD4- CD8- cells. Importantly, these effects of PGG were associated with improved vascular function and decreased ROS production in the aortas of Ang II-infused animals independently of the BP increase. Mechanistically, PGG (20 µM) directly inhibited CD25 and CCR5 expression in cultured T-cells. It also decreased the content of IFN-γ+ CD8+ and CD3+ CD4- CD8- cells and IL-17A+ CD3+ CD4- CD8- cells. CONCLUSION AND IMPLICATION: PGG may constitute an interesting immunomodulating strategy in the regulation of vascular dysfunction and hypertension. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

Age determines response to anti-TNFα treatment in patients with ankylosing spondylitis and is related to TNFα-producing CD8 cells.

Younger age is a predictor of good clinical response to treatment with tumour necrosis factor (TNF) α inhibitors in ankylosing spondylitis (AS) patients; therefore, the aim of the study was to determine age-related differences in cellular functions, which can predict the response. High disease activity AS patients were treated with TNFα inhibitors for 12 weeks. Based on the percentage of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) improvement, patients were divided into responding or non-responding groups. Cytometric and clinical assessment were determined at baseline, 4, and 12 weeks after initiation of anti-TNFα treatment. Expression of activation markers on T cells and intracellular cytokine staining was performed. Baseline percentage of TNFα-producing CD8 cells was lower in responders than in non-responders (20.8 ± 2.9 vs 40.7 ± 8.2; P = 0.04 in T test) and increased in the responding group during the first month of treatment (20.8 ± 2.9 vs 30.3 ± 2.5; P = 0.02). Moreover, its baseline level correlated with age (r = 0.7; P = 0.0009) but not with BASDAI improvement adjusted for age. There were no differences in the baseline percentage of IL-4, IL-17A, and IFNγ within CD4 and CD8 cells nor in the expression of CD25, CD28, and CD69 on these cells between responders and non-responders. However, baseline level of CD4+CD28null cells correlated with the percentage of BASDAI improvement while analysed as a continuous variable adjusted for age (r = - 0.4; P = 0.048). Clinical predictors of response were also determined. Influence of age on the response to anti-TNFα treatment in AS patients could be mediated by TNFα-producing CD8 cells.

Microvascular dysfunction in ankylosing spondylitis is associated with disease activity and is improved by anti-TNF treatment.

Ankylosing spondylitis (AS) is associated with high cardiovascular morbidity and mortality. Recent studies indicate that microvascular dysfunction may underlie cardiovascular risk in AS. We hypothesized, that microvascular morphology and dysfunction is linked to AS activity and is modifiable by TNF-α inhibitor (TNFi) treatment. Functional Laser Doppler Flowmetry with post-occlusive reactive hyperemia, and structural nailfold capillaroscopy were performed in 54 patients with AS and 28 matched controls. Active AS was diagnosed based on BASDAI ≥ 4 (n = 37). Effects of 3-month TNFi on microcirculation in active AS were studied. AS was associated with prolonged time to peak hyperemia compared to healthy controls. High disease activity was associated with increased time to peak hyperemia and decreased peak hyperemia when compared to patients with inactive AS. In capillaroscopy, AS was associated with morphological abnormalities indicating increased neoangiogenesis and pericapillary edema compared to controls. Microvascular function improved following 3 months of TNFi in reference to basal flow as well as post-occlusive parameters. TNFi reduced pericapillary edema, while other parameters of capillary morphology remained unchanged. Microvascular dysfunction and capillary neovascular formation are associated with disease activity of AS. Anti-TNF-α treatment may restore microcirculation function and capillary edema but does not modify microvascular structural parameters.