Red Cell Distribution Width as a Predictor of Survival in Patients with Hepatocellular Carcinoma.

Background and Objectives. Hepatocellular carcinoma (HCC) and the intrahepatic biliary tract cancers are estimated to rank sixth for incidence among solid cancers worldwide, and third for mortality rates. A critical issue remains the need for accurate biomarkers for risk stratification and overall prognosis. The aim of this study was to investigate the ability of a biomarker of heterogeneity of the size of red blood cells, the red cell distribution width (RDW), to predict survival in patients with HCC. Materials and Methods. A consecutive series of patients with a histologic diagnosis of HCC were included into this study irrespective of their age, stage of the disease, and treatment administered, and followed-up for a period of three years. Demographic, anthropometric [age, sex, body mass index (BMI)], and clinical data (Charlson Comorbidity Index, Child-Pugh score, etc.), along with laboratory tests were retrieved from clinical records. Results. One-hundred and four patients were included in this study. Among them, 54 (69%) were deceased at the end of the follow-up. Higher RDW values, but not other hematological and biochemical parameters, were significantly associated with mortality in both univariate and multivariate analysis. The optimal RDW cut-off value identified with the Youden test for survival was 14.7%, with 65% sensitivity and 74% specificity (AUC = 0.718, 95% CI 0.622-0.802, p < 0.001). Kaplan-Meier survival curves showed significantly lower survival with higher RDW values (HR = 3.5204; 95% CI 1.9680-6.2975, p < 0.0001) with a mean survival of 30.9 ± 9.67 months for patients with RDW ≤ 14.7% and 22.3 ± 11.4 months for patients with RDW > 14.7%. Conclusions. The results of our study showed that RDW can perform better than other blood-based biomarkers in independently predicting prognosis in patients with HCC.

Placebo response in psoriatic arthritis clinical trials: a systematic review and meta-analysis.

OBJECTIVE: To determine the placebo response rate in PsA randomized clinical trials (RCTs), its contributing factors and impact on the effect size of active treatments. METHODS: We searched multiple databases, from inception to 20 December 2020, for placebo-controlled RCTs in PsA. We used a random-effects meta-analysis to pool the response rates for the ACR20 criteria in the placebo arm, determined the risk difference for treatment vs placebo, and used meta-regression to determine the factors associated with placebo response rates. The risk of bias was assessed in duplicate. The study protocol was registered with PROSPERO: CRD42021226000. RESULTS: We included 42 RCTs (5050 patients receiving placebo) published between 2000 and 2020. The risk of bias was low in 28 trials, high in four, and with some concerns in 10. The pooled placebo response rate was 20.3% (95% CI: 18.6%, 22.1%; predicted intervals, 11.7-29.0%), with significant between-trial heterogeneity (I2 = 56.8%, P < 0.005). The pooled risk difference for treatment vs placebo was 27% (95% CI: 24%, 31%). In the multivariable meta-regression, there was a 15% (95% CI: 2.9%, 29.8%) increase in the odds of achieving the placebo response for each 5-year increment in publication year (P = 0.016). In addition, the active treatment risk difference decreased for every 5-year increment in publication year (ß = -0.053, 95% CI: -0.099, -0.007; P = 0.024) but was not associated with the placebo response. CONCLUSION: Despite increasing over time, the placebo response for ACR20 in PsA RCTs was not associated with the active treatment effect size.

Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.

Use of Multiprognostic Index Domain Scores, Clinical Data, and Machine Learning to Improve 12-Month Mortality Risk Prediction in Older Hospitalized Patients: Prospective Cohort Study.

BACKGROUND: The Multidimensional Prognostic Index (MPI) is an aggregate, comprehensive, geriatric assessment scoring system derived from eight domains that predict adverse outcomes, including 12-month mortality. However, the prediction accuracy of using the three MPI categories (mild, moderate, and severe risk) was relatively poor in a study of older hospitalized Australian patients. Prediction modeling using the component domains of the MPI together with additional clinical features and machine learning (ML) algorithms might improve prediction accuracy. OBJECTIVE: This study aims to assess whether the accuracy of prediction for 12-month mortality using logistic regression with maximum likelihood estimation (LR-MLE) with the 3-category MPI together with age and gender (feature set 1) can be improved with the addition of 10 clinical features (sodium, hemoglobin, albumin, creatinine, urea, urea-to-creatinine ratio, estimated glomerular filtration rate, C-reactive protein, BMI, and anticholinergic risk score; feature set 2) and the replacement of the 3-category MPI in feature sets 1 and 2 with the eight separate MPI domains (feature sets 3 and 4, respectively), and to assess the prediction accuracy of the ML algorithms using the same feature sets. METHODS: MPI and clinical features were collected from patients aged 65 years and above who were admitted to either the general medical or acute care of the elderly wards of a South Australian hospital between September 2015 and February 2017. The diagnostic accuracy of LR-MLE was assessed together with nine ML algorithms: decision trees, random forests, extreme gradient boosting (XGBoost), support-vector machines, naïve Bayes, K-nearest neighbors, ridge regression, logistic regression without regularization, and neural networks. A 70:30 training set:test set split of the data and a grid search of hyper-parameters with 10-fold cross-validation-was used during model training. The area under the curve was used as the primary measure of accuracy. RESULTS: A total of 737 patients (female: 370/737, 50.2%; male: 367/737, 49.8%) with a median age of 80 (IQR 72-86) years had complete MPI data recorded on admission and had completed the 12-month follow-up. The area under the receiver operating curve for LR-MLE was 0.632, 0.688, 0.738, and 0.757 for feature sets 1 to 4, respectively. The best overall accuracy for the nine ML algorithms was obtained using the XGBoost algorithm (0.635, 0.706, 0.756, and 0.757 for feature sets 1 to 4, respectively). CONCLUSIONS: The use of MPI domains with LR-MLE considerably improved the prediction accuracy compared with that obtained using the traditional 3-category MPI. The XGBoost ML algorithm slightly improved accuracy compared with LR-MLE, and adding clinical data improved accuracy. These results build on previous work on the MPI and suggest that implementing risk scores based on MPI domains and clinical data by using ML prediction models can support clinical decision-making with respect to risk stratification for the follow-up care of older hospitalized patients.

Comprehensive arginine metabolomics and peripheral vasodilatory capacity in rheumatoid arthritis: A monocentric cross-sectional study.

BACKGROUND: The relationship between plasma arginine metabolites influencing vascular homeostasis and peripheral vasodilatory capacity in rheumatoid arthritis (RA) patients is not known. METHODS: l-arginine (Arg), monomethyl-l-arginine (MMA), l-homoarginine (hArg), asymmetric dimethyl-l-arginine (ADMA), symmetric dimethyl-l-arginine, and l-citrulline (Cit) were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 164 RA patients and 100 age- and sex-matched healthy controls without previous cardiovascular events. Log-transformed reactive hyperemia index (Ln-RHI) evaluated by flow-mediated pulse amplitude tonometry (PAT, EndoPAT2000 device) was assessed as surrogate measure of peripheral vasodilatory capacity in RA patients. Ln-RHI values <0.51 indicated peripheral endothelial dysfunction (ED). The relationship between plasma arginine metabolite concentrations, RA descriptors and peripheral vasodilatory capacity was evaluated by bivariate correlation and regression analyses. RESULTS: Plasma ADMA concentrations were significantly higher, and plasma hArg concentrations significantly lower, in RA patients than in controls (0.53 ± 0.09 vs 0.465 ± 0.07 µmol/L and 1.50 ± 0.60 vs 1.924 ± 0.78 µmol/L, respectively; p < 0.001 for both comparisons). Bivariate correlation analysis demonstrated no significant correlation between arginine metabolites and disease descriptors. In regression analysis in RA patients, higher plasma ADMA concentrations were independently associated with presence of ED [OR(95% CI) = 77.3(1.478-4050.005), p = 0.031] and lower Ln-RHI [B coefficient(95% CI) = -0.57(-1.09 to -0.05), p = 0.032]. CONCLUSIONS: ADMA was significantly, albeit weakly, associated with impaired microcirculatory vasodilatory capacity and peripheral endothelial dysfunction in RA. This suggests an important pathophysiological role of this metabolite in the vascular alterations observed in this patient group.

Oxidative Stress Biomarkers and Peripheral Endothelial Dysfunction in Rheumatoid Arthritis: A Monocentric Cross-Sectional Case-Control Study.

Previous studies have suggested that oxidative stress may heighten atherosclerotic burden in rheumatoid arthritis (RA), but direct evidence is lacking. OBJECTIVE: To evaluate the relationship between established plasma oxidative stress biomarkers and peripheral endothelial dysfunction (ED), a marker of early atherosclerosis, in RA. METHODS: Paroxonase-1 (PON-1), protein-SH (PSH), and malondialdehyde (MDA) were measured in 164 RA patient s and 100 age- and sex-matched healthy controls without previous cardiovascular events. Peripheral ED, evaluated by flow-mediated pulse amplitude tonometry, was defined by log-transformed reactive hyperemia index (Ln-RHI) values < 0.51. RESULTS: PON-1 activity and PSH concentrations were significantly reduced in RA patients compared to controls. In regression analysis, increased plasma MDA levels were significantly associated with reduced Ln-RHI [B coefficient (95% CI) = -0.003 (-0.005 to -0.0008), p = 0.008] and the presence of peripheral ED (OR (95% CI) = 1.75 (1.06-2.88), p = 0.028). Contrary to our expectations, increased PON-1 activity was significantly associated, albeit weakly, with the presence of ED (OR (95% CI) = 1.00 (1.00-1.01), p = 0.017). CONCLUSIONS: In this first evidence of a link between oxidative stress and markers of atherosclerosis, MDA and PON-1 showed opposite associations with peripheral vasodilatory capacity and the presence of ED in RA. Further studies are needed to determine whether this association predicts atherosclerotic events in the RA population.

Meta-analysis of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio in rheumatoid arthritis.

BACKGROUND: We conducted a meta-analysis to review the available evidence regarding the associations between peripheral blood neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the presence of rheumatoid arthritis (RA). METHODS: PubMed, Web of Science and Scopus, from inception to January 2018, were searched for studies reporting on NLR and PLR in RA in comparison with healthy subjects. Standardized mean difference (SMD) was calculated with a confidence interval (CI) of 95%. RESULTS: Thirteen NLR studies (1550 RA patients and 1128 healthy controls) and 8 PLR studies (380 RA patients and 305 healthy controls) were included in the meta-analysis. NLR and PLR were significantly higher in patients with RA when compared to controls (SMD = 0.79, 95% CI 0.55-1.03; P < 0.001 and SMD = 0.66, 95% CI 0.43-0.88; P < 0.001, respectively). CONCLUSIONS: The NLR and PLR are significantly associated with the presence of RA. Further studies are required to ascertain the potential clinical use of these simple and relatively inexpensive markers in RA diagnosis.

Coronary flow reserve in systemic rheumatic diseases: a systematic review and meta-analysis.

Coronary flow reserve (CFR), a measure of both obstructive coronary artery disease and microvascular dysfunction, has been evaluated in systemic rheumatic diseases (RDs), but a comprehensive critical appraisal of the available evidence is lacking. The objective of this study is to conduct a systematic review and meta-analysis of studies with small sample size investigating the associations between the presence of RDs and CFR to increase statistical power and accuracy. PubMed, Web of Science, Scopus, and Google Scholar, from inception to March 2018, were searched for studies reporting on CFR in RDs in comparison to healthy subjects. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated. Meta-regressions and sensitivity analyses assessed study heterogeneity by type of RDs, age, traditional cardiovascular risk factors, systemic inflammation, and methodology used to evaluate CFR. Twenty-one studies (709 RDs patients and 650 healthy controls) were included in the meta-analysis. Pooled results showed that CFR values were significantly lower in patients with RDs than in healthy controls (SMD = - 1.51, 95% CI - 1.91, - 1.11; p < 0.001; I2 = 90.1%, p < 0.001). The between-group differences in CFR were not associated with inflammatory burden, age, lipids, body mass index, blood pressure, or assessment methods. Patients with prevalent autoimmune features (e.g., systemic lupus erythematosus) showed a significantly lower CFR when compared to patients with mixed autoimmune and autoinflammatory features (e.g., psoriatic arthritis). This meta-analysis showed a significant impairment in CFR in patients with RDs with respect to the general population. Differences in pathogenetic mechanisms may influence the severity of CFR impairment in RDs.

Protective Effects of Hydroxychloroquine against Accelerated Atherosclerosis in Systemic Lupus Erythematosus.

Cardiovascular (CV) morbidity and mortality are a challenge in management of patients with systemic lupus erythematosus (SLE). Higher risk of CV disease in SLE patients is mostly related to accelerated atherosclerosis. Nevertheless, high prevalence of traditional cardiovascular risk factors in SLE patients does not fully explain the increased CV risk. Despite the pathological bases of accelerated atherosclerosis are not fully understood, it is thought that this process is driven by the complex interplay between SLE and atherosclerosis pathogenesis. Hydroxychloroquine (HCQ) is a cornerstone in treatment of SLE patients and has been thought to exert a broad spectrum of beneficial effects on disease activity, prevention of damage accrual, and mortality. Furthermore, HCQ is thought to protect against accelerated atherosclerosis targeting toll-like receptor signaling, cytokine production, T-cell and monocyte activation, oxidative stress, and endothelial dysfunction. HCQ was also described to have beneficial effects on traditional CV risk factors, such as dyslipidemia and diabetes. In conclusion, despite lacking randomized controlled trials unambiguously proving the protection of HCQ against accelerated atherosclerosis and incidence of CV events in SLE patients, evidence analyzed in this review is in favor of its beneficial effect.

Prevalence and Determinants of Peripheral Microvascular Endothelial Dysfunction in Rheumatoid Arthritis Patients: A Multicenter Cross-Sectional Study.

OBJECTIVES: To define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events. MATERIALS AND METHODS: Data from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis-ClinicalTrials.gov: NCT02341066) were analyzed. Log-transformed reactive hyperemia index (Ln-RHI) was evaluated by peripheral arterial tonometry (PAT) using the EndoPAT2000 device: values of Ln-RHI < 0.51 were considered indicative of peripheral ED. RESULTS: Peripheral microvascular ED was documented in one-third of RA patients (33.5%); in multiple logistic regression analysis, ACPA negativity and higher triglycerides concentrations were independently associated with the presence of peripheral ED [OR (95% CI) = 1.708 (1.218-2.396), p < 0.01 and OR (95% CI) = 1.005 (1.002-1.009), p < 0.01, respectively]. Multiple regression analysis showed a positive correlation between Ln-RHI values and systolic blood pressure and HDL cholesterol levels; furthermore, higher values of Ln-RHI were associated with ACPA positivity, while smoking habit was associated with lower Ln-RHI values. CONCLUSIONS: This study demonstrates for the first time a high prevalence of peripheral microvascular ED in patients with RA free of previous cardiovascular events that appear to be only partially driven by traditional cardiovascular risk factors. The association between ACPA negativity and ED warrants further exploration.

Association between ischemia-modified albumin (IMA) and peripheral endothelial dysfunction in rheumatoid arthritis patients.

The identification of circulating biomarkers of endothelial dysfunction (ED), a precursor to atherosclerosis, in rheumatoid arthritis (RA) would facilitate early risk stratification and prevention strategies. Ischemia-modified albumin (IMA) has emerged as a potential biomarker of oxidative stress, ischemia, and ED. However, studies examining the relationship between IMA and ED in RA patients are lacking. We measured serum IMA concentrations by using an albumin cobalt binding test and peripheral vasodilatory capacity by EndoPAT in 113 RA patients without previous cardiovascular events enrolled in the EDRA study (ClinicalTrials.gov: NCT02341066). The mean peripheral vasodilatory capacity, expressed by the log of reactive hyperemia index (logRHI), was 0.82, corresponding to 27% RA patients having ED. The mean plasma concentrations of IMA were 0.478 absorbance units. We observed a significant and inverse association between peripheral vasodilatory capacity and serum IMA concentrations (rho = - 0.22, p = 0.02). In univariate logistic regression, ED was significantly associated with serum IMA concentrations [OR 1173 (95% CI 1.3568 to 101,364), p = 0.040) and higher disease activity. In multivariate logistic regression, the independent association between ED and IMA remained significant after correction for disease activity and other RA-confounders [OR 2252 (95% CI 1.0596 to 4,787,505), p = 0.048 in Model 1; OR 7221 (95% CI 4.1539 to 12,552,859), p = 0.02 in Model 2]. Conclusions: This study suggests that IMA is a promising biomarker of ED in RA. Further research is needed to confirm our findings and determine the clinical utility of IMA in detecting and managing early atherosclerosis in RA patients.

Applying precision medicine principles to the management of multimorbidity: the utility of comorbidity networks, graph machine learning, and knowledge graphs.

The current management of patients with multimorbidity is suboptimal, with either a single-disease approach to care or treatment guideline adaptations that result in poor adherence due to their complexity. Although this has resulted in calls for more holistic and personalized approaches to prescribing, progress toward these goals has remained slow. With the rapid advancement of machine learning (ML) methods, promising approaches now also exist to accelerate the advance of precision medicine in multimorbidity. These include analyzing disease comorbidity networks, using knowledge graphs that integrate knowledge from different medical domains, and applying network analysis and graph ML. Multimorbidity disease networks have been used to improve disease diagnosis, treatment recommendations, and patient prognosis. Knowledge graphs that combine different medical entities connected by multiple relationship types integrate data from different sources, allowing for complex interactions and creating a continuous flow of information. Network analysis and graph ML can then extract the topology and structure of networks and reveal hidden properties, including disease phenotypes, network hubs, and pathways; predict drugs for repurposing; and determine safe and more holistic treatments. In this article, we describe the basic concepts of creating bipartite and unipartite disease and patient networks and review the use of knowledge graphs, graph algorithms, graph embedding methods, and graph ML within the context of multimorbidity. Specifically, we provide an overview of the application of graph theory for studying multimorbidity, the methods employed to extract knowledge from graphs, and examples of the application of disease networks for determining the structure and pathways of multimorbidity, identifying disease phenotypes, predicting health outcomes, and selecting safe and effective treatments. In today's modern data-hungry, ML-focused world, such network-based techniques are likely to be at the forefront of developing robust clinical decision support tools for safer and more holistic approaches to treating older patients with multimorbidity.

Metformin-mediated epigenetic modifications in diabetes and associated conditions: Biological and clinical relevance.

An intricate interplay between genetic and environmental factors contributes to the development of type 2 diabetes (T2D) and its complications. Therefore, it is not surprising that the epigenome also plays a crucial role in the pathogenesis of T2D. Hyperglycemia can indeed trigger epigenetic modifications, thereby regulating different gene expression patterns. Such epigenetic changes can persist after normalizing serum glucose concentrations, suggesting the presence of a 'metabolic memory' of previous hyperglycemia which may also be epigenetically regulated. Metformin, a derivative of biguanide known to reduce serum glucose concentrations in patients with T2D, appears to exert additional pleiotropic effects that are mediated by multiple epigenetic modifications. Such modifications have been reported in various organs, tissues, and cellular compartments and appear to account for the effects of metformin on glycemic control as well as local and systemic inflammation, oxidant stress, and fibrosis. This review discusses the emerging evidence regarding the reported metformin-mediated epigenetic modifications, particularly on short and long non-coding RNAs, DNA methylation, and histone proteins post-translational modifications, their biological and clinical significance, potential therapeutic applications, and future research directions.

Blood Cell Count Biomarkers, Risk, and Outcomes of Ischemia-Related Lower Limb Amputations: A Systematic Review.

Lower limb amputations due to ischemia represent an important health care and social issue. However, there are currently no specific biomarkers able to predict the risk of amputation and postamputation complications and prognosis. We conducted a systematic review of studies investigating whether blood cell count indexes of systemic inflammation are linked to the risk and the outcome of lower limb amputations due to ischemia. Overall, in 22 studies involving 8832 patients selected for review, several blood cell count indexes, particularly the neutrophil lymphocyte ratio, showed some promise in terms of predicting amputations and general outcomes of conservative and surgical treatments, as well as postamputation complications and prognosis. However, largely due to methodological limitations, further prospective studies are required to establish the clinical utility and applicability of blood cell indexes in the routine management of patients with ischemia-related lower limb amputations.

Red Blood Cell Distribution Width (RDW) Correlates to the Anatomical Location of Colorectal Cancer. Implications for Clinical Use.

PURPOSE: The pathological, clinical, and therapeutic features of colorectal cancer (CRC) depend on its anatomical localization. We investigated possible associations between the red blood cell distribution width (RDW) and CRC localization. METHODS: Two-hundred eighty-eight consecutive patients with CRC were retrospectively studied. Demographic, clinical, pathological and laboratory data were retrieved from clinical records and reports. RESULTS: Median RDW values were significantly higher in patients with right-sided CRC when compared to those with CRC in other localizations (16.2, IQR: 14.5-20.0 vs 13.8, IQR: 13.0-16.1, p < 0.0001). Anisocytosis was statistically associated to haemoglobin (Hb), mean haemoglobin concentration (MHC), and mean corpuscular volume (MCV) values in all the patient groups examined. A cut-off value of 14.3% was associated with right-sided localization with sensitivity and specificity of 76.3% and 64.2%, respectively (AUC 0.71). CONCLUSION: Median RDW values were significantly higher in right-sided CRC when compared to other tumour locations, and may represent an additional marker for differential diagnosis.

Estimated 10-year cardiovascular risk in a large Italian cohort of rheumatoid arthritis patients: Data from the Cardiovascular Obesity and Rheumatic DISease (CORDIS) Study Group.

BACKGROUND: Several cardiovascular (CV) risk algorithms are available to predict CV events in the general population. However, their performance in patients with rheumatoid arthritis (RA) might differ from the general population. This cross-sectional multicentre study aimed to estimate the 10-year CV risk using two different algorithms in a large RA cohort and in patients with osteoarthritis (OA). METHODS: In a consecutive series of RA patients and matched OA controls without prior CV events, clinical and serologic data and traditional CV risk factors were recorded. The 10-year CV risk was assessed with the Systematic COronary Risk Evaluation (SCORE) and the "Progetto Cuore" algorithms. RESULTS: 1,467 RA patients and 342 OA subjects were included. RA patients were more frequently diabetic (9.9% vs 6.4%; p=0.04) and smokers (20.4% vs 12.5%; p=0.002) but had lower prevalence of obesity (15% vs 21%; p=0.003). Dyslipidaemia was more prevalent in OA (32.5% vs 21.7%; p<0.0001). The 10-year estimated CV risk was 1.6% (95%CI 1.3-1.9) in RA and 1.4% (95%CI 1.3-1.6) in OA (p=0.002) according to SCORE and 6.5% (95%CI 6.1-6.9) in RA and 4.4% (95%CI 3.9-5.1) in OA (p<0.001) according to "Progetto Cuore". Regardless of the score used, RA patients had a 3- to-4-fold increased 10-year risk of CV events compared to OA subjects. CONCLUSION: RA patients have a significantly higher 10-year risk of CV events than OA subjects. In addition to effective disease control and joint damage prevention, specific protective measures targeting modifiable traditional CV risk factors should be implemented in RA.

C-reactive protein and 10-year cardiovascular risk in rheumatoid arthritis.

OBJECTIVES: To evaluate the association between C-reactive protein (CRP) and 10-year risk of cardiovascular (CV) events using the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), based on conventional and RA-specific risk factors but not CRP, in RA patients without previous cardiovascular events. METHODS: ERS-RA was calculated in 1,251 "Cardiovascular Obesity and Rheumatic Disease Study (CORDIS)" database patients [(age 60.4(9.3) years; 78% female; disease duration, 11.6(8) years; CDAI, 9(9); CRP, 6.8(12) mg/L]. RESULTS: The mean (SD) 10-year risk of CV events was 12.9% (10). After adjusting for the use of DMARDs and biologics, CRP concentrations were significantly associated with 10-year risk of CV events (coefficient=0.005 for each 10 mg/L CRP increment; 95%CI 0.000-0.111; p = 0.047). In mediation analysis, the association between CRP and ERS-RA was not explained by disease activity. CONCLUSION: In a large cohort of RA patients without previous cardiovascular events, a 20 mg/L increase in CRP concentrations was associated with a 1% increase in 10-year risk of CV events. This suggests that actively targeting residual inflammatory risk beyond conventional and RA-specific risk factors might further reduce CV event rates in RA patients.

Current therapeutic strategies in connective tissue disease-related interstitial lung disease: introduction to the special issue.

This Editorial introduces the Special Issue on the efficacy and safety of current treatment strategies for patients with connective tissue disease-related interstitial lung disease, including the use of immunosuppressants, such as cyclophosphamide, mycophenolate mofetil and rituximab, and antifibrotic drugs.

SARS-CoV-2 and endothelial cell interaction in COVID-19: molecular perspectives.

SARS-CoV-2 is the agent responsible for the coronavirus disease (COVID-19), which has been declared a pandemic by the World Health Organization. The clinical evolution of COVID-19 ranges from asymptomatic infection to death. Older people and patients with underlying medical conditions, particularly diabetes, cardiovascular and chronic respiratory diseases are more susceptible to develop severe forms of COVID-19. Significant endothelial damage has been reported in COVID-19 and growing evidence supports the key pathophysiological role of this alteration in the onset and the progression of the disease. In particular, the impaired vascular homeostasis secondary to the structural and functional damage of the endothelium and its main component, the endothelial cells, contributes to the systemic proinflammatory state and the multiorgan involvement observed in COVID-19 patients. This review summarizes the current evidence supporting the proposition that the endothelium is a key target of SARS-CoV-2, with a focus on the molecular mechanisms involved in the interaction between SARS-CoV-2 and endothelial cells.

Serum albumin concentrations are associated with disease severity and outcomes in coronavirus 19 disease (COVID-19): a systematic review and meta-analysis.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the most threatening pandemic in modern history. The aim of this systematic review and meta-analysis was to investigate the associations between serum albumin concentrations and COVID-19 disease severity and adverse outcomes. A systematic literature search was conducted in PubMed, from inception to October 30, 2020. Sixty-seven studies in 19,760 COVID-19 patients (6141 with severe disease or poor outcome) were selected for analysis. Pooled results showed that serum albumin concentrations were significantly lower in patients with severe disease or poor outcome (standard mean difference, SMD: - 0.99 g/L; 95% CI, - 1.11 to - 0.88, p < 0.001). In multivariate meta-regression analysis, age (t = - 2.13, p = 0.043), publication geographic area (t = 2.16, p = 0.040), white blood cell count (t = - 2.77, p = 0.008) and C-reactive protein (t = - 2.43, p = 0.019) were significant contributors of between-study variance. Therefore, lower serum albumin concentrations are significantly associated with disease severity and adverse outcomes in COVID-19 patients. The assessment of serum albumin concentrations might assist with early risk stratification and selection of appropriate care pathways in this group.