Obstetric antiphospholipid syndrome is not associated with an increased risk of subclinical atherosclerosis.

OBJECTIVES: The persistent positivity of aPLs, either isolated or associated with thrombotic and/or obstetric events (APS), has been associated with the increase of intima-media thickness (IMT) and carotid plaques. Despite the fact that aPLs can promote both thrombotic and obstetric complications, some pathogenic differences have been documented between the two entities. This study aimed to evaluate whether the atherosclerotic risk differs between subjects with obstetric and thrombotic APS. METHODS: A total of 167 APS women (36 obstetric and 131 thrombotic) were compared with 250 aPLs negative controls. IMT of the common carotid artery (CCA) and of the bulb and the prevalence of carotid plaques were assessed. RESULTS: CCA- and bulb-IMT were significantly higher in women with thrombotic APS, while being similar between the obstetric APS and the controls [CCA-IMT: mean (s.d.) 0.97 (0.49), 0.78 (0.22) and 0.81 (0.12) mm for the thrombotic, obstetric and control groups, respectively, P < 0.001 between thrombotic and controls, P = 0.002 between thrombotic and obstetric; bulb-IMT: mean (s.d.) 1.38 (0.79), 0.96 (0.27) and 0.96 (0.51) mm for the thrombotic, obstetric and control groups, P < 0.001]. Women with thrombotic APS had significantly increased risk of presenting carotid plaques. This risk was significantly lower in obstetric APS. CONCLUSION: Unlike thrombotic APS, obstetric APS is not associated with an increase of markers of subclinical atherosclerosis. If confirmed on wider populations, these results could suggest different pathogenetic role of aPLs in promoting atherosclerosis in vascular and obstetric APS, and raise questions on the risk-benefit profile of thromboprophylaxis in obstetric APS outside pregnancy periods.

Subclinical atherosclerosis in asymptomatic carriers of persistent antiphospholipid antibodies positivity: A cross-sectional study.

BACKGROUND: Whereas the relationship between subclinical atherosclerosis and antiphospholipid syndrome (APS) has been widely investigated, little is known about subclinical atherosclerosis in asymptomatic carriers with isolated antiphospholipid antibodies positivity (APP). METHODS: Consecutive APP carriers, APS subjects and matched controls were enrolled. Intima-media thickness of the common carotid artery (CCA-IMT) and of the Bulb (Bulb-IMT) and the prevalence of carotid plaques were assessed in all enrolled subjects. RESULTS: A total of 104 APP carriers, 221 APS subjects, and 325 matched controls were recruited. As compared with controls, APP carriers and APS subjects showed a higher CCA-IMT (0.90 ±â€¯0.24 vs 0.82 ±â€¯0.12, p = 0.014 and 0.93 ±â€¯0.42 vs 0.82 ±â€¯0.12, p < 0.001, respectively), Bulb-IMT (1.10 ±â€¯0.44 vs 0.95 ±â€¯0.18, p = 0.006 and 1.22 ±â€¯0.68 vs 0.95 ±â€¯0.18, p < 0.001, respectively) and an increased prevalence of carotid plaques (33.7% vs 10.2%, p < 0.001 and 38.5% vs 10.2%, p < 0.001, respectively). These results were confirmed stratifying for antibody isotype, after excluding subjects with systemic lupus erythematosus or other autoimmune diseases and after adjusting for major clinical and demographic variables. CCA-IMT, Bulb-IMT and the prevalence of carotid plaques were higher in subjects with high-titer antibodies and progressively increased for an increasing number of positive antibodies. CONCLUSIONS: Similar to APS subjects, APP carriers have enhanced subclinical atherosclerosis, a more severe disease being observed in the presence of high-titer antibodies and multiple antibodies positivity. These data argue for a strict monitoring of subclinical signs of atherosclerosis and of cardiovascular risk factors in asymptomatic APP carriers.

Impact of cardiovascular and immunologic variables on subclinical carotid atherosclerosis in subjects with anti-phospholipid antibodies.

Whereas some previous data on carriers with isolated antiphospholipid antibodies positivity (APP) suggested an increased risk of arterial events in this clinical setting, no data are available on subclinical atherosclerosis in this clinical setting. This article reports data on intima-media thickness of the common carotid artery (CCA-IMT) and of the Bulb (Bulb-IMT) and on the prevalence of carotid plaques in APP carriers and in subjects with antiphospholipid syndrome (APS) specifically stratifying for the presence of thrombotic manifestations, cardiovascular risk factors, antibody isotype and concomitant Systemic Lupus Erythematosus (SLE) or other autoimmune diseases.

The association of adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) with cardiovascular disease in subjects with antiphospholipid antibodies.

BACKGROUND AND AIMS: Cardiovascular disease (CVD), including coronary artery disease and stroke/peripheral artery disease, is less commonly reported than venous thromboembolism in subjects with antiphospholipid antibodies (aPLs) and little is known about the association of CVD with adjusted Global AntiphosPholipid Syndrome Score (aGAPSS). METHODS: Consecutive aPLs subjects were enrolled to assess the association of CVD with aGAPSS. Moreover, additional risk factors of CVD were identified by means of multivariate analysis to design an aGAPSS specific for CVD (aGAPSSCVD). RESULTS: A total of 192 aPLs subjects (34 males, 158 females, mean age 49.84 ±â€¯12.0 years) were enrolled. CVD was reported in 52 subjects (27.1%), 26 episodes of coronary artery disease and 26 stroke/peripheral artery disease. The prevalence of CVD increased for increasing aGAPSS ranging from 20.5% in the lowest aGAPSS category, up to 37.9% in the highest category (p = 0.027). ROC analysis showed that aGAPSS detected 63.0% of CVD and was associated with OR for CVD of 2.52 (95%CI: 1.24-5.10, p = 0.010). When including obesity, diabetes and smoking habit in the score, we found that aGAPSSCVD detected 71.4% of CVD (72.4% for early-CVD and 69.0% for CVD after 50 years) with an OR for CVD of 4.68 (95%CI: 2.31-9.51, p < 0.001). CONCLUSIONS: The aGAPSSCVD, obtained after adding obesity, smoking habit and diabetes to the standard aGAPSS, showed a higher detection rate of CVD in aPLs subjects, particularly of early-CVD. These results need to be validated in ad hoc designed prospective studies.

Impact of body weight on the achievement of minimal disease activity in patients with rheumatic diseases: a systematic review and meta-analysis.

BACKGROUND: In this study, we evaluated the impact of obesity and/or overweight on the achievement of minimal disease activity (MDA) in patients with psoriatic arthritis (PsA) and patients with rheumatoid arthritis (RA) receiving an anti-rheumatic treatment. Obesity can be considered a low-grade, chronic systemic inflammatory disease and some studies suggested that obese patients with rheumatic diseases exhibit a lower rate of low disease activity achievement during treatment with anti-rheumatic drugs. METHODS: A systematic search was performed in major electronic databases (PubMed, Web of Science, Scopus, Embase) to identify studies reporting MDA achievement in obese and/or overweight patients with RA or PsA and in normal-weight RA or PsA control subjects. Results were expressed as Odds Ratios (ORs) with pertinent 95% Confidence Intervals (95%CIs). RESULTS: We included 17 studies (10 on RA and 7 on PsA) comprising a total of 6693 patients (1562 with PsA and 5131 with RA) in the analysis. The MDA achievement rate was significantly lower in obese patients than in normal-weight subjects (OR 0.447, 95% CI 0.346-0.577, p < 0.001, I 2 = 62.6%, p < 0.001). Similarly, overweight patients showed a significantly lower prevalence of MDA achievement than normal-weight subjects (OR 0.867, 95% CI 0.757-0.994, p = 0.041, I 2 = 64%, p = 0.007). Interestingly, the effect of obesity on MDA was confirmed when we separately analyzed data on patients with RA and patients with PsA. In contrast, when we evaluated the effect of overweight, our results were confirmed for PsA but not for RA. A meta-regression analysis showed that follow-up duration, age, male sex, and treatment duration are covariates significantly affecting the effect of obesity/overweight on MDA achievement. CONCLUSIONS: The results of our meta-analysis suggest that obesity and overweight reduce the chances to achieve MDA in patients with rheumatic diseases receiving treatment with traditional or biologic disease-modifying antirheumatic drugs.

Thrombosis in Autoimmune Diseases: A Role for Immunosuppressive Treatments?

Autoimmune diseases are not infrequently associated with arterial or venous thrombotic events. Chronic inflammation and immune system impairment are considered the main pathogenetic mechanisms. Some of the drugs used in the treatment of such diseases have been associated with an increased risk of thrombosis. On the contrary, their anti-inflammatory and immune modulator activity could correct some mechanisms leading to thrombosis. In this review, recent evidence available on this topic is examined. There is a lack of adequate studies, but available evidence suggests that glucocorticoids and high-dose immunoglobulins are associated with an increased incidence of venous thromboembolism. Although available data do not allow drawing definite conclusions and more data are needed from future studies and registries, physicians should be aware of these associations.

Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research.

Gastrointestinal bleeding (GIB) is a potentially fatal and avoidable medical condition that poses a burden on global health care costs. Current understanding of the roles of platelet activation and thrombin generation/activity in vascular medicine has led to the development of effective antithrombotic treatments. However, in parallel with a sustained coronary and cerebral flow patency, the increasingly intensive treatment with warfarin; direct oral anticoagulant drugs [DOACs], and/or with aspirin ± clopidogrel (or ± prasugrel or ± ticagrelor), has increased the burden of GIBs related to the use of antithrombotic agents. Compelling evidence concerning this issue is accumulating to indicate that: 1) the risk of GIB related to the use of antithrombotic drugs dramatically differs in different clinical settings; and 2) the characteristics of patients (e.g., severity of illness, comorbidities) in whom it is used exert a greater impact on the risk of GIB than the type of antithrombotic agent employed. The latter concept argues for the occurrence of GIB as reflecting the presence of patients at the highest risk for adverse outcomes. The HAS-BLED score identifies subjects at risk of bleeding among those untreated and those treated with warfarin, DOACs and/or low-dose aspirin. Its use within the frame of a severity score (e.g., the CHA2DS2-VASc score in patients with atrial fibrillation) helps balance the benefits and the risks of an antithrombotic treatment and identify those patients in whom the absolute gain (vascular events prevented) outweighs the risk of GIB. Potential implications of the latter information in settings other than atrial fibrillation is thoroughly discussed.

Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the effect of body weight (BW) on safety and efficacy of direct oral anticoagulants (DOACs). METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) comparing DOACs with vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE). Efficacy (prevention of recurrent VTE or VTE-related death) and safety (occurrence of major or clinically relevant non-major bleeding) outcomes were stratified according to patients' BW (low, normal, and high). RESULTS: Six RCTs with a total of 27,023 patients were included. DOACs showed a similar efficacy to VKA in patients with high BW, normal BW, and low BW (RR 0.98, 95% CI 0.72, 1.35; RR 0.91, 95% CI 0.75, 1.09; and RR 0.84, 95% CI 0.57, 1.24, respectively). Safety was comparable among DOACs and VKA in patients with high BW and low BW (RR 0.93, 95% CI 0.65, 1.32; and RR 0.80, 95% CI 0.54, 1.20), whereas DOACs were marginally safer than VKA in normal-BW subjects (RR 0.82, 95% CI 0.67, 1.00). However, the difference among DOACs and VKA in the rate of bleeding episodes appeared similar in the three BW groups. CONCLUSIONS: Results of our meta-analysis suggested that DOACs might be a safe and effective therapeutic option for the treatment of acute VTE even in the patients with extreme body weights. However, other studies with larger study populations are warranted to confirm our findings.

Could metabolic syndrome lead to hepatocarcinoma via non-alcoholic fatty liver disease?

It was estimated that from 2002 to 2008 the risk of developing cancer increased a quarter-fold in men and two-fold in women due to excessive BMI. Obesity, metabolic syndrome and type 2 diabetes mellitus are strictly related and are key pathogenetic factors of non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease worldwide. The most important consequence of the "metabolic epidemics" is the probable rise in the incidence of hepatocarcinoma (HCC), and NAFLD is the major causative factor. Adipose tissue is not merely a storage organ where lipids are preserved as an energy source. It is an active organ with important endocrine, paracrine, and autocrine actions in addition to immune functions. Adipocytes produce a wide range of hormones, cytokines, and growth factors that can act locally in the adipose tissue microenvironment and systemically. In this article, the main roles of insulin growth factor (IGF)-1 and IGF-2 are discussed. The role of IGF-2 is not only confined to HCC, but it may also act in early hepato-carcinogenesis, as pre-neoplastic lesions express IGF-2 mRNA. IGF-1 and IGF-2 interact with specific receptors (IGF-1R and IGF-2R). IGF-1R is over-expressed in in vitro and in animal models of HCC and it was demonstrated that IGF ligands exerted their effects on HCC cells through IGF-1R and that it was involved in the degeneration of pre-neoplastic lesions via an increase in their mitotic activity. Both IGF-2R and TGF ß, a growth inhibitor, levels are reduced in human HCC compared with adjacent normal liver tissues. Another key mechanism involves peroxisome proliferator-activated receptor (PPAR)γ. In in vitro studies, PPARγ inhibited various carcinomas including HCC, most probably by regulating apoptosis via the p21, p53 and p27 pathways. Finally, as a clinical consequence, to improve survival, efforts to achieve a "healthier diet" should be promoted by physicians and politicians.

What does irritable bowel syndrome share with non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS) are two very common diseases in the general population. To date, there are no studies that highlight a direct link between NAFLD and IBS, but some recent reports have found an interesting correlation between obesity and IBS. A systematic PubMed database search was conducted highlighting that common mechanisms are involved in many of the local and systemic manifestations of NAFLD, leading to an increased cardiovascular risk, and IBS, leading to microbial dysbiosis, impaired intestinal barrier and altered intestinal motility. It is not known when considering local and systemic inflammation/immune system activation, which one has greater importance in NAFLD and IBS pathogenesis. Also, the nervous system is implicated. In fact, inflammation participates in the development of mood disorders, such as anxiety and depression, characteristics of obesity and consequently of NAFLD and, on the other hand, in intestinal hypersensitivity and dysmotility.

Liver-spleen axis: intersection between immunity, infections and metabolism.

Spleen has been considered a neglected organ so far, even though is strictly linked to liver. The spleen plays an important role in the modulation of the immune system and in the maintenance of peripheral tolerance via the clearance of circulating apoptotic cells, the differentiation and activation of T and B cells and production of antibodies in the white pulp. Moreover, splenic macrophages are able to remove bacteria from the blood and protect from sepsis during systemic infections. We review the spleen function and its assessment in humans starting from the description of spleen diseases, ranging from the congenital asplenia to secondary hyposplenism. From the literature data it is clear that obesity in humans affects different compartments of immune system, even thought there are still few data available on the implicated mechamisms. The intent is to enable clinicians to evaluate the newly recognized role of metabolic and endocrine functions of the spleen with special emphasis to obesity and nonalcoholic fatty liver disease in the context of the available literature. Moreover, understanding the spleen function could be important to develop appropriate prevention strategies in order to counteract the pandemia of obesity. In this direction, we suggest spleen longitudinal diameter at ultrasonography, as simple, cheap and largely available tool, be used as new marker for assessing splenic function, in the context of the so-called liver-spleen axis.

Enteropathic spondyloarthritis: from diagnosis to treatment.

Enteropathic arthritis (EA) is a spondyloarthritis (SpA) which occurs in patients with inflammatory bowel diseases (IBDs) and other gastrointestinal diseases. Diagnosis is generally established on the medical history and physical examination. It was, generally, made according to the European Spondyloarthropathy Study Group (ESSG) criteria. Rheumatic manifestations are the most frequent extraintestinal findings of IBD with a prevalence between 17% and 39%, and IBD is associated, less frequently, with other rheumatic disease such as rheumatoid arthritis, Sjogren syndrome, Takayasu arteritis, and fibromyalgia. Although the pathogenesis of EA has not been plainly clarified, the most popular theory supposes that joint inflammation occurs in genetically predisposed subjects with bacterial gut infections, provided an important evidence for a possible relationship between inflammation of the gut mucosa and arthritis. The management of patients with EA requires an active cooperation between the gastroenterologist and rheumatologist.

Herbal products: benefits, limits, and applications in chronic liver disease.

Complementary and alternative medicine soughts and encompasses a wide range of approaches; its use begun in ancient China at the time of Xia dynasty and in India during the Vedic period, but thanks to its long-lasting curative effect, easy availability, natural way of healing, and poor side-effects it is gaining importance throughout the world in clinical practice. We conducted a review describing the effects and the limits of using herbal products in chronic liver disease, focusing our attention on those most known, such as quercetin or curcumin. We tried to describe their pharmacokinetics, biological properties, and their beneficial effects (as antioxidant role) in metabolic, alcoholic, and viral hepatitis (considering that oxidative stress is the common pathway of chronic liver diseases of different etiology). The main limit of applicability of CAM comes from the lacking of randomized, placebo-controlled clinical trials giving a real proof of efficacy of those products, so that anecdotal success and personal experience are frequently the driving force for acceptance of CAM in the population.