MicroRNAs in Axial Spondylarthritis: an Overview of the Recent Progresses in the Field with a Focus on Ankylosing Spondylitis and Psoriatic Arthritis.

PURPOSE OF REVIEW: To highlight the recent discoveries and lines of evidence on the role of microRNAs in ankylosing spondylitis (AS) and psoriatic arthritis (PsA), focusing on their expression profiling and mechanisms of action. RECENT FINDINGS: AS and PsA are chronic inflammatory musculoskeletal diseases with axial manifestations and represent an excellent model for studying microRNAs contribution to the disease pathogenesis, particularly through immunomodulation, inflammation, and bone remodelling, or their value as candidate diagnostic and prognostic biomarkers. MicroRNAs are single-stranded nucleotides able to regulate gene expression. They are a key component of the epigenetic machinery, involved in physiological and pathological processes. The contribution of microRNAs in AS and PsA (such as miR-29a in regulating bone metabolism) is highlighted by several works in the field but their utility as possible markers must be still confirmed, particularly in larger patients' cohorts.

Reciprocal effects of systemic inflammation and brain natriuretic peptide on adiponectin biosynthesis in adipose tissue of patients with ischemic heart disease.

OBJECTIVE: To explore the role of systemic inflammation in the regulation of adiponectin levels in patients with ischemic heart disease. APPROACH AND RESULTS: In a cross-sectional study of 575 subjects, serum adiponectin was compared between healthy subjects, patients with coronary artery disease with no/mild/severe heart failure (HF), and patients with nonischemic HF. Adiponectin expression and release from femoral, subcutaneous and thoracic adipose tissue was determined in 258 additional patients with coronary artery bypass grafting. Responsiveness of the various human adipose tissue depots to interleukin-6, tumor necrosis factor-α, and brain natriuretic peptide (BNP) was examined by using ex vivo models of human fat. The effects of inducible low-grade inflammation were tested by using the model of Salmonella typhi vaccine-induced inflammation in healthy individuals. In the cross-sectional study, HF strikingly increased adiponectin levels. Plasma BNP was the strongest predictor of circulating adiponectin and its release from all adipose tissue depots in patients with coronary artery bypass grafting, even in the absence of HF. Femoral AT was the depot with the least macrophages infiltration and the largest adipocyte cell size and the only responsive to systemic and ex vivo proinflammatory stimulation (effect reversible by BNP). Low-grade inflammation reduced circulating adiponectin levels, while circulating BNP remained unchanged. CONCLUSIONS: This study demonstrates the regional variability in the responsiveness of human adipose tissue to systemic inflammation and suggests that BNP (not systemic inflammation) is the main driver of circulating adiponectin in patients with advanced atherosclerosis even in the absence of HF. Any interpretation of circulating adiponectin as a biomarker should take into account the underlying disease state, background inflammation, and BNP levels.

Subclinical myocardial inflammation and diffuse fibrosis are common in systemic sclerosis--a clinical study using myocardial T1-mapping and extracellular volume quantification.

BACKGROUND: Systemic sclerosis (SSc) is characterised by multi-organ tissue fibrosis including the myocardium. Diffuse myocardial fibrosis can be detected non-invasively by T1 and extracellular volume (ECV) quantification, while focal myocardial inflammation and fibrosis may be detected by T2-weighted and late gadolinium enhancement (LGE), respectively, using cardiovascular magnetic resonance (CMR). We hypothesised that multiparametric CMR can detect subclinical myocardial involvement in patients with SSc. METHODS: 19 SSc patients (18 female, mean age 55 ± 10 years) and 20 controls (19 female, mean age 56 ± 8 years) without overt cardiovascular disease underwent CMR at 1.5T, including cine, tagging, T1-mapping, T2-weighted, LGE imaging and ECV quantification. RESULTS: Focal fibrosis on LGE was found in 10 SSc patients (53%) but none of controls. SSc patients also had areas of myocardial oedema on T2-weighted imaging (median 13 vs. 0% in controls). SSc patients had significantly higher native myocardial T1 values (1007 ± 29 vs. 958 ± 20 ms, p < 0.001), larger areas of myocardial involvement by native T1 >990 ms (median 52 vs. 3% in controls) and expansion of ECV (35.4 ± 4.8 vs. 27.6 ± 2.5%, p < 0.001), likely representing a combination of low-grade inflammation and diffuse myocardial fibrosis. Regardless of any regional fibrosis, native T1 and ECV were significantly elevated in SSc and correlated with disease activity and severity. Although biventricular size and global function were preserved, there was impairment in the peak systolic circumferential strain (-16.8 ± 1.6 vs. -18.6 ± 1.0, p < 0.001) and peak diastolic strain rate (83 ± 26 vs. 114 ± 16 s-1, p < 0.001) in SSc, which inversely correlated with diffuse myocardial fibrosis indices. CONCLUSIONS: Cardiac involvement is common in SSc even in the absence of cardiac symptoms, and includes chronic myocardial inflammation as well as focal and diffuse myocardial fibrosis. Myocardial abnormalities detected on CMR were associated with impaired strain parameters, as well as disease activity and severity in SSc patients. CMR may be useful in future in the study of treatments aimed at preventing or reducing adverse myocardial processes in SSc.

Cardiovascular magnetic resonance characterization of myocardial and vascular function in rheumatoid arthritis patients.

BACKGROUND: Rheumatoid arthritis (RA) is a multisystem, autoimmune disorder and confers one of the strongest risks for cardiovascular disease (CVD) morbidity and mortality. OBJECTIVE: To assess myocardial function and vascular stiffness in RA patients with and without cardiovascular risk factors (CVRFs) using cardiovascular magnetic resonance (CMR). METHODS: Twenty-three RA patients with no CVRFs (17 female, mean age 52 ± 13 years), 46 RA patients with CVRFs (32 female, mean age 53 ± 12), 50 normal controls (32 female, mean age 50 ± 11 years), and 13 controls with CVRFs (7 female, mean age 55 ± 7 years), underwent CMR at 1.5 Tesla, including evaluation of left ventricular (LV) ejection fraction, strain, and vascular elasticity (aortic distensibility [AD] and pulse wave velocity [PWV]). Disease activity and duration were recorded for each patient. Subjects with known symptomatic CVD were excluded. RESULTS: LV volumes, mass, and ejection fraction were similar in the four groups. RA patients with CVRFs showed the greatest abnormality in mid short-axis circumferential systolic strain, peak diastolic strain rate, and vascular indices. RA patients without CVRFs showed a similar degree of vascular dysfunction and deformational abnormality as controls with CVRFs. AD and total PWV correlated with myocardial strain and RA disease activity. On multivariate regression analysis, strain was related to age, RA disease activity, AD, and PWV. CONCLUSION: CMR demonstrates impaired myocardial deformation and vascular function in asymptomatic RA patients, worse in those with CVRFs. Subclinical cardiovascular abnormalities are frequent and appear to be incremental to those due to traditional CVRFs and likely contribute to the excess CVD in RA.

RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis-Novel Targets for Therapy?

Susceptibility to ankylosing spondylitis (AS) is polygenic with more than 100 genes identified to date. These include HLA-B27 and the aminopeptidases (ERAP1, ERAP2, and LNPEPS), which are involved in antigen processing and presentation to T-cells, and several genes (IL23R, IL6R, STAT3, JAK2, IL1R1/2, IL12B, and IL7R) involved in IL23 driven pathways of inflammation. AS is also strongly associated with polymorphisms in two transcription factors, RUNX3 and T-bet (encoded by TBX21), which are important in T-cell development and function. The influence of these genes on the pathogenesis of AS and their potential for identifying drug targets is discussed here.

Anti-TNF modulation reduces myocardial inflammation and improves cardiovascular function in systemic rheumatic diseases.

BACKGROUND: Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are common disorders associated with increased rates of cardiovascular disease (CVD), but the contribution of cytokine-induced inflammation to impaired cardiovascular function in these conditions remains poorly understood. OBJECTIVES: We assessed the effect of anti-TNF therapy on myocardial and vascular function, myocardial tissue characteristics and perfusion in inflammatory arthropathy and systemic rheumatic disease (IASRD) patients, using cardiovascular magnetic resonance (CMR). METHODS: 20 RA patients, 7 AS patients, 5 PsA patients without previously known CVD scheduled to commence anti-TNF therapy and 8 RA patients on standard disease modifying antirheumatic drugs underwent CMR at 1.5 T, including cine, tagging, pulse wave velocity (PWV), T2-weighted, native and postcontrast T1 mapping, ECV quantification, rest and stress perfusion and late gadolinium enhancement (LGE) imaging. RESULTS: Following anti-TNF therapy, there was significant reversal of baseline subclinical cardiovascular dysfunction, as evidenced by improvement in peak systolic circumferential strain (p < 0.001), peak diastolic circumferential strain rate (p < 0.001), and total aortic PWV, (p < 0.001). This was accompanied by a reduction in myocardial inflammation, as assessed by T2-weighted imaging (p = 0.005), native T1 mapping (p = 0.009) and ECV quantification (p = 0.001), as well as in serum inflammatory markers like CRP (p < 0.001) and ESR (p < 0.001), and clinical measures of disease activity (DAS28-CRP, p = 0.001; BASDAI, p < 0.001). A trend towards improvement in myocardial perfusion was observed (p = 0.07). Focal myocardial fibrosis, as detected by LGE CMR was not altered by anti-TNF therapy (p = 0.92). CONCLUSIONS: Anti-TNF therapy reduces subclinical myocardial inflammation and improves cardiovascular function in RA, AS and PsA. CMR may be used to track disease progression and response to therapy. Future CMR-based studies to demonstrate effect of anti-TNF therapy modulation of vascular structure and function on hard clinical events and outcomes would be useful.

Osteoclast differentiation and bone resorption in multicentric reticulohistiocytosis.

Multicentric reticulohistiocytosis (MR) is a systemic disease of unknown cause characterized by the presence of a heavy macrophage infiltrate in skin and synovial tissues and the development of an erosive polyarthritis. The synovial fluid in MR is known to contain numerous mononuclear cells. In this study, we have determined whether these cells contribute to joint destruction in MR by differentiating them into osteoclasts. Synovial fluid mononuclear cells were isolated from the knee joint of a 44-year-old male with MR. These cells were cultured with various combinations of macrophage-colony stimulating factor, receptor activator for nuclear factor kappaB ligand (RANKL), tumor necrosis factor alpha, interleukin-1alpha, osteoprotegerin, and zoledronate. Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase, vitronectin receptor, and the extent of lacunar resorption. Most MR synovial fluid mononuclear cells expressed a macrophage phenotype (CD14(+), CD68(+), HLA-DR(+), CD11b(+)). Extensive osteoclast formation and lacunar resorption were noted in macrophage-colony stimulating factor/RANKL-treated cell cultures. MR synovial fluid contained increased tumor necrosis factor alpha and decreased osteoprotegerin compared with osteoarthritis synovial fluid. Lacunar resorption was inhibited in cultures containing zoledronate. Pamidronate treatment of the patient also reduced the number of synovial fluid macrophages and resulted in less osteoclast formation and lacunar resorption. MR synovial fluid contains numerous macrophages that are capable of differentiating into osteoclasts by the RANKL signaling pathway. Inhibitors of osteoclast formation and resorption activity may be of use in preventing the severe joint destruction that commonly occurs in MR.

Exome-wide study of ankylosing spondylitis demonstrates additional shared genetic background with inflammatory bowel disease.

Ankylosing spondylitis (AS) is a common chronic immune-mediated arthropathy affecting primarily the spine and pelvis. The condition is strongly associated with HLA-B*27 as well as other human leukocyte antigen variants and at least 47 individual non-MHC-associated variants. However, substantial additional heritability remains as yet unexplained. To identify further genetic variants associated with the disease, we undertook an association study of AS in 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. A novel association achieving genome-wide significance was noted at CDKAL1. Suggestive associations were demonstrated with common variants in FAM118A, C7orf72 and FAM114A1 and with a low-frequency variant in PNPLA1. Two of the variants have been previously associated with inflammatory bowel disease (IBD; CDKAL1 and C7orf72). These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having similar aetiopathogenesis.

Diffuse Myocardial Fibrosis and Inflammation in Rheumatoid Arthritis: Insights From CMR T1 Mapping.

OBJECTIVES: The goal of this study was to assess the diffuse myocardial fibrosis and edema in rheumatoid arthritis (RA) using multiparametric cardiac magnetic resonance (CMR) and the association of myocardial T1 and extracellular volume (ECV) with disease activity, duration, and cardiac function. BACKGROUND: RA is a connective tissue disorder, with frequent cardiovascular disease. Myocardial inflammation and diffuse fibrosis can be detected noninvasively by using native T1 mapping and ECV quantification on CMR. METHODS: Thirty-nine RA patients (28 women; mean age 50 ± 12 years) and 39 matched control subjects (28 women; mean age 49 ± 12 years) underwent CMR at 1.5-T, including cine, tagging, T2-weighted, native T1 mapping (shortened modified Look-Locker inversion recovery), late gadolinium enhancement (LGE), and ECV imaging. RESULTS: Focal fibrosis on LGE was found in 46% of RA patients compared with none of the control subjects. Patients with RA had larger areas of focal myocardial edema (10% vs. 0%), higher native T1 values (973 ± 27 ms vs. 961 ± 18 ms; p = 0.03), larger areas of involvement as detected by native T1 >990 ms (35% vs. 2%; p < 0.001), and expansion of ECV (30.3 ± 3.4% vs. 27.9 ± 2.0%; p < 0.001) compared with control subjects. Left ventricular volumes, mass, and ejection fraction were similar between RA patients and control subjects. Peak systolic circumferential strain (-16.9 ± 1.3 vs. -18.7 ± 1.2; p < 0.001) and peak diastolic circumferential strain rate (83 ± 21 s(-1) vs. 112 ± 20 s(-1); p < 0.001) were impaired in RA patients. Myocardial T1 and ECV were correlated with myocardial strain and RA disease activity. CONCLUSIONS: Subclinical cardiovascular disease is frequent in RA, including focal and diffuse myocardial fibrosis and inflammation, which are associated with impaired strain and RA disease activity. CMR T1 mapping provides potential added value as a biomarker for disease monitoring and study of therapies aimed at reducing diffuse myocardial fibrosis in RA.