Search

Patients with rheumatoid arthritis (RA), a chronic and disabling autoimmune condition that is characterized by articular and extra-articular manifestations and a pro-inflammatory and pro-oxidant state, suffer from premature atherosclerosis and excessive cardiovascular disease burden. A key step in the pathogenesis of atherosclerosis is impaired synthesis of the endogenous messenger nitric oxide (NO) by endothelial cells which, in turn, alters local homeostatic mechanisms and favors vascular damage and plaque deposition. While the exact mechanisms of endothelial dysfunction in RA remain to be established, there is good evidence that RA patients have relatively high circulating concentrations of the methylated arginine asymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of endothelial NO synthase (eNOS). This review discusses the biological and pathophysiological role of ADMA, the interplay between ADMA, inflammation and oxidative stress, and the available evidence on the adverse impact of ADMA on endothelial function and atherosclerosis and potential ADMA-lowering therapies in RA patients.

Fibrosing interstitial lung disease (ILD) is one of the most important causes of morbidity and mortality in patients with connective tissue diseases (CTDs), which include systemic sclerosis, rheumatoid arthritis, Sjogren's syndrome, idiopathic inflammatory myositis and systemic lupus erythematosus. The treatment of CTD-ILDs is challenging due to the paucity of proven effective treatments. Recently, two antifibrotic drugs conditionally approved for use in patients with idiopathic pulmonary fibrosis, nintedanib and pirfenidone, have been trialled in CTD-ILDs based on overlapping pathological and clinical features between the two diseases. In this narrative review, we discuss the experimental evidence and clinical trials investigating the efficacy and safety of antifibrotic drugs in patients with CTD-ILDs and the potential mechanisms of action involved. Results from clinical trials suggest that nintedanib use retards lung function decline in progressive fibrotic CTD-ILDs. By contrast, the evidence for the efficacy of pirfenidone in these groups is not equally compelling. Further, well-designed randomized clinical trials are needed to evaluate the efficacy and safety of individual antifibrotic drugs in specific CTD-ILD subgroups.

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).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.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%; p0.0001). 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 (p0.001) 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.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.

Background/Objective: Chronic humoral immune response against multiple microbial antigens may play a crucial role in the etiopathogenesis of rheumatoid arthritis (RA). We aimed to assess the prevalence and magnitude of antibody response against various bacterial and viral immunogen peptides in the sera of RA patients compared with the general population. Methods: Polyclonal IgG antibodies (Abs) specific for peptides derived from Porphyromonas gingivalis (RgpA, Kpg), Aggregatibacter actinomycetemcomitans (LtxA1, LtxA2), Mycobacterium avium subsp. paratuberculosis (MAP4027), Epstein–Barr virus (EBNA1, EBVBOLF), and human endogenous retrovirus (HERV-W env-su) were detected by ELISA in serum samples from 148 consecutive RA patients and 148 sex and age-matched healthy controls (HCs). In addition, the presence of a relationship between the positivity and the titer of antibodies and RA descriptors was explored by bivariate correlation analysis. Results: RA patients exhibit a higher prevalence of humoral immune response against all tested peptides compared to HCs with a statically significant difference for MAP4027 (30.4% vs. 10.1%), BOLF (25.7% vs. 8.1%), RgpA (24.3% vs. 9.4%), HERV W-env (20.3% vs. 9.4%), and EBNA1 (18.9% vs. 9.4%) peptides. Fifty-three (35.8%) out of 148 RA serum and 93 (62.8%) out of 148 HCs were negative for all pathogen-derived peptides. There was a significant correlation between OD values obtained by ELISA test against all peptides (p &lt, 0.0001). We also found an increased titer and prevalence of Abs against LtxA1 and LtxA2 in seropositive vs. seronegative RF (p = 0.019, p = 0.018). Conclusion: This study demonstrates a significantly increased humoral response against multiple pathogens in patients with RA and implies that they could be an important factor in the pathogenesis of the disease. Therefore, the role of each individual pathogen in RA needs to be further investigated.

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.

Endothelial cell injury is an early event in systemic sclerosis (SSc) pathogenesis and several studies indicate oxidative stress as the trigger of SSc-associated vasculopathy. Here, we show that circulating factors present in sera of SSc patients increased reactive oxygen species (ROS) production and collagen synthesis in human pulmonary microvascular endothelial cells (HPMECs). In addition, the possibility that iloprost, a drug commonly used in SSc therapy, might modulate the above-mentioned biological phenomena has been also investigated. In this regard, as compared to sera of SSc patients, sera of iloprost-treated SSc patients failed to increased ROS levels and collagen synthesis in HPMEC, suggesting a potential antioxidant mechanism of this drug.

Background: The independent association between hepatic steatosis and rheumatoid arthritis is poorly defined. Methods: The presence of moderate to severe steatosis was assessed, using liver ultrasonography, in 364 consecutive non-diabetic subjects (223 patients with rheumatoid arthritis and 141 age- and sex-matched healthy controls). Adjusted multiple regression analysis was performed to explore the association between rheumatoid arthritis and moderate to severe steatosis in the overall sample and identify independent risk factors in the rheumatoid arthritis subgroup. Results: The prevalence of moderate to severe steatosis in the overall sample was 31.3%, with a significantly higher prevalence in patients with rheumatoid arthritis than healthy controls (38.7% versus 19.7%, p Conclusion: Rheumatoid arthritis is independently associated with moderate to severe steatosis, with male sex, higher body mass index and cumulative dose of methotrexate being predisposing factors. Further prospective studies are warranted to confirm our findings and to investigate the effect of steatosis on liver outcomes in the rheumatoid arthritis population.

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 Conclusion Despite increasing over time, the placebo response for ACR20 in PsA RCTs was not associated with the active treatment effect size.

Objectives: Specific anti-inflammatory and/or immunomodulating drugs (AIDs) can influence endothelial function which is often impaired in patients with rheumatoid arthritis (RA). We sought to determine whether overall patterns of AID usage are similarly associated with endothelial function.Methods: The reactive hyperaemia index (RHI), a marker of microvascular endothelial function, was measured in 868 RA patients reporting their intake of seven AIDs known to affect endothelial function. Latent class analysis (LCA) was performed to characterise patterns of AID usage. Models for 2–6 classes were compared using the AIC and BIC statistics and Lo-Mendell-Rubin likelihood ratio tests. Associations between the classes and RHI were adjusted for age, gender, body mass index, diabetes, HDL-cholesterol, LDL-cholesterol, family history of ischaemic heart disease, smoking status, RA duration, DAS28 score, steroid dose, existing hypertension, and C-reactive protein.Results: LCA identified five distinct AID usage classes: Class 1, generally low medication usage; Class 2, using either sulfasalazine or non-tumour necrosis factor (TNF) inhibitors; Class 3, methotrexate users; Class 4, TNF-inhibitor users; and Class 5, hydroxychloroquine users. The geometric mean for the RHI for subjects in classes 1 to 5 was 1.92, 1.81, 1.94, 2.10, and 2.07, respectively, with subjects in classes 4 and 5 having better endothelial function than subjects in class 2 (p = 0.003 for each). The glucocorticoid dosage did not influence the classes formed or the association between the classes and the RHI in sensitivity analyses.Conclusion: There were five broad patterns (classes) of AID usage in RA patients. The RHI was relatively lower in users of either sulfasalazine or non-TNF inhibitors. TNF inhibitors or hydroxychloroquine may counteract the negative effects of RA on endothelial function.

To explore the significance of the association between treatment with methotrexate (MTX) and liver stiffness in rheumatoid arthritis (RA) patients.We enrolled 140 consecutive RA patients under MTX treatment (MTX-treated RA; mean treatment duration: 6.2 years; mean MTX cumulative dose: 4.67 g), 33 RA patients naive to MTX (MTX-naive RA) and 100 age and sex-matched healthy blood donors (HD). Liver stiffness was assessed by real time two-dimensional shear wave elastography, with values ≥7.1 Kilopascals (kPa) defining significant liver fibrosis.kPa values in HD (4.32 ± 0.7) were lower than that in MTX-naive RA (4.92 ± 0.8) and MTX-treated RA (4.85 ± 0.9, p .0005 for trend). On the contrary, the difference in kPa between MTX-naive and MTX-treated RA was not significant (p = .89). Similarly, liver stiffness was not significantly different across strata of cumulative MTX dose (4.95 ± 0.7 kPa in MTX1 g, 4.90 ± 1.1 kPa in MTX 1-3 g and 4.80 ± 0.9 in MTX3 g, p = .610). Significant liver fibrosis was diagnosed in 4 patients in the MTX-treated RA (highest kPa value = 7.6; no liver function test abnormalities or clinical signs of hepatic failure) and in none in both the MTX-naive RA and HD groups (p = .145).Liver stiffness values, although within the normal range, are significantly higher in RA patients vs. controls, irrespective of MTX treatment. RA patients taking MTX do not have a higher prevalence of significant liver fibrosis when compared to MTX naive RA patients and the general population.

Raised circulating concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), have been reported in several rheumatic diseases (RDs). However, the strength of this relationship is unclear. Therefore, the aim of this systematic review and meta-analysis was to evaluate the magnitude and the robustness of the association between ADMA concentrations and RDs. We calculated standardized mean differences (SMD, with 95% confidence intervals, CI). Study heterogeneity was evaluated by meta-regressions and sensitivity analyses according to type of RDs, conventional cardiovascular risk factors, inflammatory markers, and type of ADMA assessment methodology. Thirty-seven studies with a total of 2,982 subjects (1,860 RDs patients and 1,122 healthy controls) were included in our meta-analysis. Pooled results showed that ADMA concentrations were significantly higher in patients with RDs than in healthy controls (SMD = 1.27 µmol/L, 95% CI 0.94–1.60 µmol/L; p

Mycophenolate mofetil (MMF) is an antimetabolite with a potent inhibitory effect on proliferation of T and B lymphocytes used since the early 1990s for the prevention of acute allograft rejection after organ transplant. MMF is also widely used for the treatment of a variety of rheumatic diseases (RDs) and their pulmonary involvement. Interstitial lung disease (ILD) is a heterogeneous group of progressive fibrotic diseases of the lung, which is often secondary to RD and represents a major cause of morbidity and mortality. MMF is considered the main alternative to cyclophosphamide as a first-line agent to treat RD-related ILD or as possible maintenance therapy after cyclophosphamide, with a lower rate of side-effects. However, as for other immunosuppressive agents, the use of MMF in RD-ILD is supported by poor scientific evidence. In this narrative review, we describe the available data and recent advances on the effectiveness and safety of MMF for the treatment of ILD related to RD, including rheumatoid arthritis, systemic sclerosis, primary Sjögren syndrome, systemic lupus erythematosus, idiopathic inflammatory myopathies, undifferentiated connective tissue disease, interstitial pneumonia with autoimmune features and antineutrophil cytoplasmic antibody-associated vasculitis.

Interstitial lung disease (ILD) represents a severe pulmonary complication of connective tissue diseases, rheumatoid arthritis (RA), and antineutrophil cytoplasmic antibody-associated vasculitis. Treatment of ILD, mainly based on immunosuppression, remains challenging. Rituximab (RTX), a monoclonal antibody binding to CD20, is considered a valuable therapeutic choice in cases of refractory ILD. Here, we review the available efficacy and safety data on the use of RTX in the treatment of rheumatic disease-related ILD. Despite controversial efficacy data, RTX seems to be able to stabilize or improve ILD related to RA and antisynthetase syndrome and in established and severe ILD complicating systemic sclerosis. Fewer data are available regarding ILD related to Sjogren syndrome, systemic lupus erythematosus, and antineutrophil cytoplasmic antibody-associated vasculitis. To date, few prospective studies are available and randomized trials are still ongoing with the purpose of exploring the role of RTX in this condition, including the supposed relationship between efficacy and ILD radiologic patterns and safety data, up to now derived mainly from RA studies. Despite an overall acceptable safety profile, concerns remain regarding an increased infectious disease risk in patients with ILD as well as possible lung toxicity and the increased rate of immune-mediated reactions in patients with connective tissue diseases. In conclusion, RTX is a relevant therapeutic option for rheumatic disease-related ILD despite the existing uncertainties; ongoing trials are expected to clarify its use.

Background: There is a paucity of head-to-head comparisons of the efficacy and harms of pharmacological treatments for systemic sclerosis-related interstitial lung disease (SSc-ILD). Methods: We conducted a network meta-analysis (NMA) in order to compare the effects of different treatments with the placebo on change in forced vital capacity (FVC), change in diffusion lung capacity for CO (DLCO), serious adverse events (SAEs), discontinuation for adverse events and mortality in SSc-ILD. Standardized mean difference (SMD) and log odds ratio were estimated using NMA with fixed effects. Results: Nine randomized clinical trials (926 participants) comparing eight interventions and the placebo for an average follow-up of one year were included. Compared to the placebo, only rituximab significantly reduced FVC decline (SMD (95% CI) = 1.00 (0.39 to 1.61)). Suitable data on FVC outcome for nintedanib were not available for the analysis. No treatments influenced DLCO. Safety and mortality were also not different across treatments and the placebo, although there were few reported events. Cyclophosphamide and pomalidomide were less tolerated than the placebo, mycophenolate, and nintedanib. Conclusion: Only rituximab significantly reduced lung function decline compared to the placebo. However, direct head-to-head comparison studies are required to confirm these findings and to better determine the safety profile of various treatments.

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 &lt, 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) = &minus, 0.003 (&minus, 0.005 to &minus, 0.0008), p = 0.008] and the presence of peripheral ED (OR (95% CI) = 1.75 (1.06&ndash, 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&ndash, 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.

Identifying predictors of inadequate response to methotrexate (MTX) in rheumatoid arthritis (RA) is key to move from a “trial and error” to a “personalized medicine” treatment approach where patients less likely to adequately respond to MTX monotherapy could start combination therapy at an earlier stage. This study aimed to identify potential predictors of inadequate response to MTX in RA patients naïve to disease modifying anti-rheumatic drugs. Data from a real-life cohort of newly diagnosed RA patients starting MTX (baseline, T0) as first-line therapy were analyzed. Outcomes, assessed after 6 months (T1), were defined as failure to achieve a disease activity score 28 (DAS28) low disease activity (LDA) or a good/moderate response to MTX, according to the European League Against Rheumatism (EULAR) response criteria. Logistic regression was used to assess the associations between baseline variables and the study outcomes. Overall, 294 patients (60.5% females, median age 54.5 years) with a median disease duration of 7.9 months were recruited. At T1, 47.3% of subjects failed to achieve LDA, and 29.3% did not have any EULAR-response. In multivariate analysis, significant associations were observed between no LDA and current smoking (adjusted odds ratio [adjOR] 1.79, P = .037), female gender (adjOR 1.68, P = .048), and higher DAS28 (adjOR 1.31, P = .013); and between no EULAR-response and current smoking (adjOR: 2.04, P = .019), age (adjOR: 0.72 per 10-years increases, P = .001), and higher erythrocyte sedimentation rate (adjOR: 0.49; P = .020). By contrast, there were no associations between past smoker status and study outcomes. In summary, in our real-life cohort of disease modifying anti-rheumatic drug naïve RA patients, current smoking habit independently predicts inadequate response to MTX. This, together with other independent predictors of response to treatment identified in our study, might assist with personalized monitoring in RA patients. Further studies are required to investigate whether smoking quitting strategies enhance the therapeutic response to MTX.

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 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 peripheral arterial tonometry (PAT, EndoPAT2000 device) was assessed as surrogate measure of peripheral vasodilatory capacity in RA patients. Ln-RHI values

Background: Treatment of rheumatoid arthritis (RA)-related interstitial lung disease (ILD) is challenging, and many conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) have been associated with ILD development or progression. The aim of this multicentric retrospective study was to analyze the evolution of ILD in Italian RA-ILD patients treated with abatacept (ABA). Methods: All RA-ILD patients treated with ABA for at least six months were retrospectively evaluated. Serology, previous and concurrent therapies, chest high-resolution computer tomography (HRCT), forced vital capacity (FVC), and lung diffusion of carbon monoxide (CO, DLCO) were collected. Results: Forty-four patients were included, HRCT, FVC, and DLCO were analyzed at baseline, at one year, and at the end of follow-up. A remission or a low disease activity of RA was reached in 41/44 patients. Overall, FVC and DLCO remained stable or increased in 86.1% and 91.7% of patients, respectively, while HRCT was stable or improved in 81.4% of them. Previous and concurrent treatments, in particular, methotrexate, serology, age, sex, joint and lung disease duration were not associated with the outcome at univariate analysis. Conclusion: The management of RA-ILD patients remains a critical unmet medical need. Waiting for prospective controlled studies, ABA has shown a good safety profile in our cohort of Italian RA-ILD patients.

INTRODUCTION Thyroid hormones have multiple effects on lipid metabolism as well as on the cardiovascular system function. These negative cardiovascular effects have long been recognized in overt hypothyroidism but can be reversed by treatment with levothyroxine. EVIDENCES ACQUISITION We performed on PubMed a literature search for the articles published until March 2019 by using the search terms "subclinical hypothyroidism," "cardiovascular disease," "cholesterol," "LDL," "HDL," "triglycerides," "coronary heart disease," "heart failure," "atherosclerosis," "all-cause mortality," "levothyroxine." EVIDENCES SYNTHESIS Subclinical hypothyroidism, defined as an elevated thyrotropin (TSH) with a normal free thyroxine (FT4), is frequent in the general population and increase with age. Subclinical hypothyroidism has been linked to cardiovascular risk factors, dyslipidemia and increased atherosclerosis. Although some studies have demonstrated that lipids are elevated in subclinical hypothyroidism, other studies did not confirm these data. Clinical trials have also demonstrated there is no clear evidence that levothyroxine therapy in subjects with milder form (TSH

Introduction Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV). Objectives The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset. Materials and methods A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed. Results One-hundred and six patients were included (median age at onset of 55 years [IQR 42–67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13–77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4–9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51–13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality. Conclusions Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.

About 20% of patients with a history of atherosclerotic cardiovascular disease will experience further cardiovascular events despite maximal pharmacological treatment with cardioprotective drugs. This highlights the presence of residual cardiovascular risk in a significant proportion of patients and the need for novel, more effective therapies. These therapies should ideally target different pathophysiological pathways involved in the onset and the progression of atherosclerosis, particularly the inflammatory and immune pathways. Methotrexate is a first-line disease-modifying antirheumatic drug that is widely used for the management of autoimmune and chronic inflammatory disorders. There is some in vitro and in vivo evidence that methotrexate might exert a unique combination of anti-inflammatory, blood pressure lowering, and vasculoprotective effects. Pending the results of large prospective studies investigating surrogate end-points as well as morbidity and mortality, repurposing methotrexate for cardiovascular risk management might represent a cost-effective strategy with immediate public health benefits. This review discusses the current challenges in the management of cardiovascular disease; the available evidence on the effects of methotrexate on inflammation, blood pressure, and surrogate markers of arterial function; suggestions for future research directions; and practical considerations with the use of methotrexate in this context.

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

Environmental factors such as bacterial infections may play an important role in the development of autoimmune diseases. Mycobacterium avium subsp. paratuberculosis (MAP) is an obligate pathogen of ruminants able to use the host&rsquo, s cholesterol for survival into macrophages and has been associated with multiple sclerosis (MS), type 1 diabetes (T1DM) and rheumatoid arthritis (RA) through a molecular mimicry mechanism. Here, we aimed at investigating the correlation between humoral reactivity against MAP and serum lipoprotein levels in subjects at T1DM risk (rT1DM) grouped by geographical background and in patients affected by MS or RA. Our results showed significant differences in HDL, LDL/VLDL and Total Cholesterol (TC) levels between patients and healthy controls (p &lt, 0.0001). Patients positive to anti-MAP Abs (MAP+) had lower HDL levels in comparison with Abs negative (MAP-) subjects, while opposite trends were found for LDL/VLDL concentrations (p &lt, 0.05). TC levels varied between MAP+ and MAP- patients in all three assessed diseases. These findings suggest the implication of anti-MAP Abs in fluctuations of lipoprotein levels highlighting a possible link with cardiovascular disease. Further studies will be needed to confirm these results in larger groups.

Background:Rheumatoid arthritis (RA) is associated with an increased risk of atherosclerotic cardiovascular disease (CVD). The Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA) estimates the 10-year risk of myocardial infarction, stroke or CVD-related death based on conventional and RA-specific (clinical disease activity index, CDAI, disease duration, glucocorticoid use) risk factors (1).Objectives:We evaluated the associations between ERS-RA 10-year risk of CVD, high-sensitivity C-reactive protein (hs-CRP) concentrations, and pharmacological treatment in 1,251 RA patients collected by the “Cardiovascular Obesity and Rheumatic Disease Study (CORDIS)” group of the Italian Society of Rheumatology (SIR).Methods:We assessed independent associations between ERS-RA risk score and each relevant variable using multivariate regression (ENTER approach; listwise deletion analysis). Given the relatively high number of missing hs-CRP data (n=385), regression analysis was also performed using multiple imputation (10 sets, Stata 16.1). Regression models were not adjusted for independent variables included in the ERS-RA score.Results:Among 1,251 RA patients [mean (SD) age 60.4(9.3), range (40-80) years; 78% female; mean (SD) disease duration, 11.6(8) years; mean (SD) CDAI, 9(9); mean (SD) HAQ, 0.77(0.7); mean (SD) hs-CRP, 6.8(12) mg/L] the estimated 10-year CVD risk was 11.6(0.9) % [mean (SD)]. Regarding treatment, 539(43%) received glucocorticoids, 676(54%) a biological or targeted synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) (n missing=1), and 885(81%) at least one conventional synthetic DMARD (csDMARD). Ninety-three (7.4%) patients did not receive any treatment. After adjusting for the use of b/tsDMARD and csDMARD, hs-CRP concentrations were significantly associated with 10-year risk of CVD both in standard multiple regression (n=865; coefficient=0.005 for each 10 mg/L hs-CRP increment, 95% confidence interval (0.000-0.100), p=0.043) and after multiple imputation (n=1,251; coefficient=0.005 for each 10 mg/L hs-CRP increment, 95% confidence interval (0.000-0.114), p=0.035) (Table 1). This corresponds to an increase of 10-year CV risk of 1% for every 20 mg/L increase in hs-CRP concentrations.Conclusion:In a large cohort of RA patients, we observed a significant, positive, and independent association between hs-CRP concentrations and 10-year CV risk estimated by ERS-RA. The cross-sectional design of the study did not allow to establish a cause-effect relationship between hs-CRP and CV risk. Given that conventional CV risk factors and inflammation-related variables are accounted for in the ERS-RA risk score, other, unexplored, mechanisms may underlie the observed association between hs-CRP and CV risk.References:[1]Solomon, D. H., et al. “Derivation and internal validation of an expanded cardiovascular risk prediction score for rheumatoid arthritis: a Consortium of Rheumatology Researchers of North America Registry Study.” Arthritis & rheumatology 67.8 (2015): 1995-2003.Table 1.Multiple regression modelsModel 1n= 865Model 2n= 1, 251ERS-RA scoreCoefficient95% CI, pCoefficient95% CI, phs-CRP, every 10 mg/L increment0.0050.000 to 0.100, 0.0430.0050.000 to 0.011, 0.035b/tsDMARD use-0.002-0.005 to 0.001, 0.199-0.000-0.002 to 0.002, 0.963csDMARD use0.002-0.003 to 0.007, 0.3940.002-0.002 to 0.006, 0.371Prob >F, model with only CRP0.030.03Prob >F, full model0.070.08A multiple linear regression (ENTER method) was performed for the dependent variable ERS-RA score using a listwise deletion analysis (Model 1) and a multiple imputation analysis (Model 2).Disclosure of Interests:None declared

Objective To investigate whether levels of asymmetric dimethylarginine (ADMA), as a measure of endothelial dysfunction, are higher in patients with rheumatoid arthritis compared with healthy control subjects. The relationships between ADMA and surrogate measures of arterial stiffness were evaluated. Methods Patients with rheumatoid arthritis and healthy control subjects were recruited. ADMA was quantified via enzyme-linked immunosorbent assay. Arterial stiffness was evaluated using pulse wave analysis. Results There was no significant difference in plasma ADMA concentration between patients with rheumatoid arthritis ( n = 30) and healthy controls ( n = 30). Aortic augmentation pressure was significantly higher in patients than in controls. C-reactive protein and Health Assessment Questionnaire score were independent predictors of arterial stiffness in patients. There was no relationship between ADMA concentration and aortic augmentation pressure in the study population as a whole. Conclusions Arterial stiffness appears to be increased in rheumatoid arthritis and independently associated with systemic inflammation and physical disability. ADMA concentration was not increased in this small group of patients with rheumatoid arthritis compared with healthy controls; nor was it associated with arterial stiffness.

To evaluate the performance of different blood cells-derived indexes in the diagnosis of rheumatoid arthritis (RA). Neutrophil-to-lymphocyte ratio (NLR), lymphocyte to monocyte ratio, platelet to lymphocyte ratio (PLR), systemic inflammation response index (SIRI), and aggregate inflammation systemic index were calculated in 199 consecutive RA patients and 283 sex and age-matched controls (147 healthy donors and 136 patients with other rheumatic diseases). Area under the curve (AUCs), sensitivity and specificity were calculated to evaluate the accuracy of indexes in discriminating between RA and controls. Association between indexes and RA variables was explored by multiple linear regression analyses. Blood cells-derived indexes did not demonstrate good accuracy in differentiating RA from controls with lymphocyte to monocyte ratio, the index with the best diagnostic performance, having 63.6% of sensitivity and 65.3% specificity [AUC (95%CI) = 0.67 (0.62–0.72]. The accuracy of the indexes in differentiating RA from healthy donors was significantly higher than that (AUCs

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by chronic erosive polyarthritis. A complex interaction between a favorable genetic background, and the presence of a specific immune response against a broad-spectrum of environmental factors seems to play a role in determining susceptibility to RA. Among different pathogens, mycobacteria (including Mycobacterium avium subspecies paratuberculosis, MAP), and Epstein–Barr virus (EBV), have extensively been proposed to promote specific cellular and humoral response in susceptible individuals, by activating pathways linked to RA development. In this review, we discuss the available experimental and clinical evidence on the interplay between mycobacterial and EBV infections, and the development of the immune dysregulation in RA.

We read with interest the paper published by Gianfrancesco et al 1 describing the epidemiological findings associated with hospitalisation for COVID-19 in 600 patients with rheumatic diseases. Multivariate adjusted models proved a significant increased risk of hospitalisation for older age (>65 years), prednisone doses of ≥10 mg/day and presence of comorbidities, such as cardiovascular (CV) and lung diseases or diabetes. The use of biological or targeted synthetic disease-modifying antirheumatic drug (DMARD) appeared to decrease hospitalisation risk. Underlying CV comorbidities seem to increase the susceptibility to SARS-CoV-2 infection and to contribute to myocardial injury, arrhythmia, acute coronary syndrome and venous thromboembolism also in non-rheumatic patients.2 3 Pathophysiological mechanisms underlying cardiac injury in patients with SARS-CoV-2 infection are poorly understood. However, biological features of SARS-CoV-2 and its interaction with the immune system seem to have a pivotal role in organ damage and, in particular, in CV manifestations.3 Clinical and demographic characteristics of patients with rheumatic disease suffering from COVID-19 have been explored by several Italian groups, with the highest number of COVID-19 cases observed in the North, particularly in Lombardy. In this setting, Fredi et al , on behalf of the Brescia Rheumatology COVID-19 Study Group,4 confirmed that patients with COVID-19 were older and more likely to have arterial hypertension and obesity, while no association with CV …

Background:Systemic lupus erythematosus (SLE) patients are at high risk for CV events, and EULAR recommends assessing the 10-year CV-risk using the Systematic Coronary Risk Evaluation (SCORE) [1]. The QRISK3, another score to assess CV-risk in UK population, considers different factors among which also SLE. The Progetto Cuore score (PCS) is validated to estimate CV risk in Italian people and largely replicates the SCORE project [2].Objectives:This cross-sectional study aimed to estimate CV-risk using SCORE, QRISK3 and, for the first time, PCS in a multicentric cohort of Italian SLE patients.Methods:During 2019 we evaluated 173 SLE patients (87.7% female; age 40±16 years; disease duration 138±105 months), fulfilling the 1997 ACR classification criteria. Clinical and laboratory data were registered, and individual CV-risk was calculated using suitable algorithms for the SCORE, QRISK3 and PCS. Statistical analysis was performed using Graphpad Instat 8.0 (San Diego, CA-USA).Results:In 13 (7%) SLE patients a previous CV event was recorded. Hypertension was present in 60 (37.5%) and diabetes in 27 (16.9%) patients. Mean total cholesterol was 184±39 mg/dL, HDLc 58±18 mg/dL, LDLc 124±37 mg/dL, triglycerides 105±63 mg/dL; dyslipidaemia was reported in 58 (36.2%) patients and 29 (18.1%) were on statin. Mean BMI was 24.9±5.3 Kg/sm, 60 (37.5%) and 23 (14.3%) patients were overweight and obese, while 25 (15.6%) patients were smokers. 87 (54.3%) SLE patients had a SLEDAI7.5 mg/day. The CV-risk of SLE patients according to SCORE, QRISK3 and PCS was 1.1±2.1%, 10.5±12.3% and 3.7±5.4%, respectively. Stratifying patients at low, moderate or high CV risk according to the PCS and SCORE a double proportion of patients was at moderate (8% vs 3.9%) or high (1.9% vs 0.9%) CV risk (p=0.03). Finally, CV-risk according to QRISK3 was higher than 20% (high risk) in 32/160 (20%) patients.Conclusion:This multicentre study demonstrated that the mean estimated CV-risk in SLE patients is globally low using the SCORE, QRISK3 and PCS. The PCS seems to better intercept those patients at moderate/high risk, at least in Italian SLE patients, while QRISK3 predicts the highest CV risk. The lack of disease-specific CV-risk factors (such as autoantibodies profile or organ involvement) probably account for the underestimation of CV risk using the SCORE and PCS.References:[1]ARD 2019;78(6):736-745.[2]ARD 2019;0:1–2.doi:10.1136/annrheumdis-2019-215715Disclosure of Interests:Fabio Cacciapaglia Speakers bureau: BMS; Roche; Pfizer; Abbvie, Andreina Manfredi: None declared, Gianluca Erre: None declared, Elena Bartoloni Bocci: None declared, Garifallia Sakellariou Speakers bureau: Abbvie, Novartis, MSD, Ombretta Viapiana: None declared, Sergio Colella: None declared, Anna Abbruzzese: None declared, Marco Fornaro: None declared, Giacomo Cafaro: None declared, Maria Antonietta Fenu: None declared, Bianca Lucia Palermo: None declared, Martina Dessì: None declared, Adalgisa Palermo: None declared, Alessandro Giollo: None declared, Elisa Gremese Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Francesca Romana Spinelli Grant/research support from: Pfizer, Speakers bureau: Lilly, BMS, Celgene, Fabiola Atzeni: None declared, Matteo Piga: None declared

Background:Rheumatoid arthritis (RA) patients present high cardiovascular (CV) morbidity and mortality and EULAR recommends estimating their CV-risk [1]. The Systematic Coronary Risk Evaluation (SCORE) algorithm is suggested if National Guidelines are lack, but few data are available about different strategies.Objectives:To estimate the 10-years CV-risk using different algorithms in RA compared to osteoarthritis (OA) patients, as control group.Methods:A total of 1467 RA patients (78.3% female; mean age 59.8±11.5 years; mean disease duration 131±109 months), fulfilling the 2010 EULAR/ACR classification criteria, and 342 age and sex matched patients with OA (79.8% female; mean age 58.7±11.5 years) were enrolled in this multicentre cross-sectional study during 2019. Clinical and laboratory data were registered, and individual CV-risk was calculated using: SCORE chart, “Progetto Cuore” model (PCM), QRisk3, Reynolds Risk Scores (RRS) and Expanded Risk Score in RA (ERS-RA), as stated by suitable algorithms. Statistical analysis was performed using the Statistical System Graphpad Instat 8.0 (San Diego, CA-USA).Results:In 46 (3%) RA patients a previous CV event was observed. Among traditional CV-risk factors, RA patients presented higher frequency of diabetes (9.9% vs 6.4%; p=0.04) and lower prevalence of dyslipidaemia (21.7% vs 32.5%; pConclusion:Our study demonstrates a higher estimated CV-risk in RA compared to OA patients. The commonly used algorithms to estimate CV-risk in clinical practice perform differently, evaluating different traditional CV-risk factors and disease specific characteristic, as for QRisk3 or ERS-RA. Rheumatologist should impact on both traditional and RA related modifiable CV-risk factors.References:[1]Agca R, et al. Ann Rheum Dis 2017;76:17–28.Disclosure of Interests:Fabio Cacciapaglia Speakers bureau: BMS; Roche; Pfizer; Abbvie, Matteo Piga: None declared, Gianluca Erre: None declared, Andreina Manfredi: None declared, Elena Bartoloni Bocci: None declared, Garifallia Sakellariou Speakers bureau: Abbvie, Novartis, MSD, Ombretta Viapiana: None declared, Sergio Colella: None declared, Anna Abbruzzese: None declared, Martina Dessì: None declared, Caterina Vacchi: None declared, Floriana Castagna: None declared, Giacomo Cafaro: None declared, Bianca Lucia Palermo: None declared, Alessandro GIollo: None declared, Marco Fornaro: None declared, Elisa Gremese Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Francesca Romana Spinelli Grant/research support from: Pfizer, Speakers bureau: Lilly, BMS, Celgene, Fabiola Atzeni: None declared

Background:Interstitial lung disease (ILD) is one of the more frequent and potentially severe extra-articular manifestation of rheumatoid arthritis (RA). ILD significantly decreases the survival and quality of life of patients and influences the treatment approach to the patient.Despite its clinical relevance, the prevalence, incidence and survival of RA-ILD is unknown and supposed on the base of retrospective data or registry-based studies.Objectives:For the first time, the Lung Involvement in Rheumatoid Arthritis (LIRA) study aims to investigate epidemiology, features and prognosis of RA-ILD patients in a prospective international multicentre study.Methods:All RA patients referring to the involved centres will be evaluated every six months with a digital stethoscope and a software able to identify velcro crackles with a diagnostic accuracy of 83.9% (VECTOR). In fact, velcro crackles are virtually identified in all stages of fibrosing alveolitis like RA-ILD, and their search is as a simple and reliable method to screening patients to be undergone to high resolution computed tomography (HRCT).For each patient, clinical and serological data are recorded at baseline and every six months; when velcro crackles or other conditions suspicious for ILD, such as cough or dyspnoea, are detected, a HRCT is requested to confirm ILD. Patients with ILD periodically perform pulmonary function tests to monitor lung function evolution.Results:At now, 205 RA patients have been enrolled (female/male 161/44, mean age 64.8±12.9 years, mean disease duration 14.2±8.9 years), anti-citrullinated peptides antibodies (ACPA) and rheumatoid factor (RF) were positive in 77.1% and 78.1%, respectively. The prevalence of ILD was 21% (43 patients). In other 13 patients the HRCT is ongoing; therefore, we could suppose up to a prevalence of 27.3%. Patients with ILD were symptomatic in 53.5% of cases (23 patients), they are more frequently males and were older than patients without ILD (mean age 73.2±7.4 and 62.7±13.2; pConclusion:The prevalence and the incidence of RA-ILD is still not well defined. Preliminary data of our study confirm a prevalence of ILD higher than 20%, patients are asymptomatic in almost the half of cases and more frequently males and elderly. Our study can help to define the clinical history of these patients, the possible association with clinical and serological features and the supposed role of some drugs.References:[1]Manfredi A, et al. Diagnostic accuracy of a velcro sound detector (VECTOR) for interstitial lung disease in rheumatoid arthritis patients: the InSPIRAtE validation study (INterStitial pneumonia in rheumatoid ArThritis with an electronic device). BMC Pulm Med. 2019;19:111.[2]Bendstrup E, et al. Interstitial Lung Disease in Rheumatoid Arthritis Remains a Challenge for Clinicians. J Clin Med. 2019:8Disclosure of Interests:Marco Sebastiani: None declared, Caterina Vacchi: None declared, Giulia Cassone: None declared, Fabiola Atzeni: None declared, Martina Biggioggero: None declared, Antonio Carriero: None declared, Gian Luca Erre: None declared, Anna Laura Fedele: None declared, Federica Furini: None declared, Paola Tomietto: None declared, Vincenzo Venerito: None declared, Belén Atienza-Mateo: None declared, Giovanni Della Casa: None declared, Stefania Cerri: None declared, Gilda Sandri: None declared, Adalgisa Palermo: None declared, Elena Galli: None declared, Fabrizio Pancaldi: None declared, Miguel A González-Gay Grant/research support from: Pfizer, Abbvie, MSD, Speakers bureau: Pfizer, Abbvie, MSD, Carlo Salvarani: None declared, Andreina Manfredi: None declared

We read with great interest the paper by Graef and colleagues, ‘Festina lente: hydroxychloroquine, covid-19 and the role of the rheumatologist’.1 As the authors correctly point out, despite firm evidence that their efficacy and safety are lacking,2 antimalarials are being widely prescribed for the treatment of patients with COVID-19. This, as also underlined with some concern by the European League Against Rheumatism President Iain McInness,3 has rapidly led to antimalarial supply shortages worldwide, primarily affecting patients with rheumatic disease, such as those with systemic lupus erythematosus and rheumatoid arthritis (RA). In these groups, low-dose antimalarials (hydroxychloroquine up to 6 mg/kg/day and chloroquine up to 4 mg/kg/day) are the mainstay to control immunological response and to prevent flare in view of their favourable efficacy and safety profile. However, electrophysiological experiments in isolated cardiac preparations and animal models, and some case reports in rheumatic patients, have reported a proarrhythmic effect of antimalarials. Arrhythmias, potentially triggered by hypoxia, metabolic/electrolyte derangement and viral myocarditis, have been reported in 16.7% of hospitalised patients with COVID-19.4 While this suggests that antimalarial use may further …

Background Diffuse alveolar haemorrhage (DAH) is a rare and severe manifestation of ANCA-associated vasculitides (AAV). Objectives To identify predictors of survival in patients with AAV-DAH. Methods A retrospective study of 102 consecutive patients (50% females; mean age 59±17 years) from 27 Italian Centres diagnosed with AAV-DAH was planned. Cox regression unadjusted analyses were performed. Results Among AAV patients, 47% had Granulomatosis with Polyangiitis (GPA), 47% Microscopic Polyangiitis (MPA) and 6% Eosinophilic Granulomatosis with Polyangiitis (EGPA). At DAH onset, mean BVAS was 20±8 and most patients had renal involvement (RI). Admission to Intensive Care Unit was needed in 27% of patients, while ventilatory support (VS) was required in 46%. At least one cardiovascular risk factor (CVRF) was recorded in 48%. Over a median follow-up of 39 months (25%–75% IQR 66 months), 19/102 patients (18.6%) died (figure 1). All patients received high-dose glucocorticoids in association with Cyclophosphamide (CYC 78%, mean cumulative dose 8±7 g) or Rituximab (37%). Plasma exchange was performed in 46%. Infections occurred in 38%. Age>65 years (HR 3.05 [95% CI 1.18–7.9], p=0.04), CVRF ≥2 (HR 8.85 [95% CI [AG7] 2.34–33.50], p=0.01), BVAS (v.3) (HR 1.07 [95% CI 1.01–1.13], p=0.01) were associated with mortality, whereas FFS was not. The need for VS (HR 4.54 [95% CI 1.48–13.85], p=0.008) and infections (HR 3.98 [95% CI 1.48–10.69] were also associated with mortality. Conclusions Older age, VS, CVRF and infections affect the survival in AAV. There is a need for specific outcome measeures. Disclosure of Interest None declared

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive joint damage due to largely unknown environmental factors acting in concert with risk alleles conferring genetic susceptibility. A major role has been attributed to viral infections that include past contacts with Epstein-Barr virus (EBV) and, more recently, to non-protein coding sequences of human endogenous retrovirus K (HERV-K) integrated in the human genome. Molecular mimicry between viral and self proteins is supposed to cause the loss of immune tolerance in predisposed hosts. There are evidences that anti-IL-2 antibodies (Abs) are present in subjects affected by autoimmune diseases and may be responsible for alterations in regulatory T cell responses. In this study, we evaluated the levels of Abs against IL-2, viral epitopes and interferon regulatory factor 5 (IRF5) in 140 RA patients and 137 healthy controls (HCs). Ab reactivity reached the highest levels for IRF5, EBV and IL-2 (56%, 44% and 39%, respectively) in RA with significantly lower values among HCs (7–9%, p

A role for Epstein-Barr Virus (EBV) infection in the etiology of autoimmune diseases, including rheumatoid arthritis (RA), has long been suggested. However, data about EBV burden in RA patients from Sardinian population, a genetic isolate with high prevalence of autoimmune diseases, have not yet been reported. One hundred thirty-five, Sardinian subjects (77 RA patients and 58 demographically matched healthy donors, HDs) were enrolled in a cross-sectional case-control study. EBV-DNA was quantified by quantitative real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMCs). Prevalence and titers of anti-Early Antigen IgG (anti-EA-IgG) and anti-Epstein-Barr Nuclear Antigen 1 IgG (anti-EBNA-1 IgG) were determined by immunoenzimatic assay. EBV-DNA positivity was more frequent in RA PBMCs than in HD PBMCs (79.2% vs. 56.9% respectively, p=0.008). Similarly EBV relative load was increased in RA than in HD PBMCs [2.83 (6.5) vs. 0.53 (1) 2(-ΔCt) EBV-DNA, respectively, p=0.02]. Moreover, Sardinian RA patients were found to have increased prevalence of anti-EBNA-1 IgG (90% vs. only 69% of HD, p=0.006) and anti-EA IgG (37% compared with only 10.3% of HD, p=0.002). Subgroup analysis revealed that PBMCs from RA receiving Tocilizumab, an anti-interleukin-6 (IL-6) receptor monoclonal inhibitor, have significantly lower EBV viral loads in comparison to PBMCs from RA under other immunosuppressors (p=0.03). These data suggest an association between EBV infection and RA in the Sardinian population. The potential influence of IL-6 inhibition on EBV viral load in RA patients should be further explored in prospective trials.

Important advances from both therapeutic and clinical assessment have recently been reported in psoriatic arthritis (PsA). Moreover, the constant challenge to provide a more comprehensive assessment of this heterogeneous disease results in a variety of clinical instruments that help the clinician for a global evaluation of both disease activity and responsiveness. The current European League Against Rheumatism (EULAR) recommendations on the use of imaging suggest the use of ultrasound (US) in chronic arthritis to increase the diagnostic accuracy and improvement of its management as compared to clinical examination alone. Although US findings are not firmly established in daily clinical practice, it demonstrated several positive aspects such as good sensitivity and specificity, acceptable reliability, and adequate sensitivity to change, especially in the peripheral PsA. Additionally, recent works introduced the role of US in the assessment of skin and nails opening interesting area of research. The aim of this paper is to describe the potential role of US in the assessment of PsA and to discuss the current evidence supporting its application in daily clinical practice.

Patients with autoimmune rheumatic conditions, particularly rheumatoid arthritis, have an increased cardiovascular risk when compared with the general population. Methotrexate is a relatively old, yet effective, immunomodulatory drug for the management of autoimmune and chronic inflammatory disorders, such as rheumatoid arthritis, particularly in terms of symptom control, quality of life, and disease progression. Recent meta-analyses have also shown that methotrexate treatment is associated with a lower risk of cardiovascular events when compared with other disease-modifying antirheumatic drugs. This suggests that methotrexate might exert specific protective effects against atherosclerosis and thrombosis. This mini-review discusses the mechanisms associated with the increased cardiovascular risk in rheumatoid arthritis, the pharmacokinetics and pharmacodynamics of methotrexate, the available evidence on the in vitro and in vivo effects of methotrexate on modifiable cardiovascular risk factors, and suggestions for future research directions.

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.

There is good epidemiological evidence that patients with autoimmune rheumatic disease states, particularly rheumatoid arthritis, have an increased risk of cardiovascular morbidity and mortality when compared to the general population. The presence of a chronic systemic proinflammatory state in this patient group disrupts the structural and functional integrity of the endothelium and the arterial wall, favouring the onset and progression of atherosclerosis. A significant role in the detrimental effects of inflammation on endothelial function and vascular homeostasis is played by specific proatherosclerotic cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). Recent systematic reviews and meta-analyses have shown that treatment with methotrexate, a first-line disease-modifying antirheumatic drug (DMARD), is associated with a significant reduction in atherosclerosis-mediated cardiovascular events, such as myocardial infarction and stroke, and mortality, when compared to other DMARDs. This suggests that methotrexate might exert specific protective effects against vascular inflammation and atherosclerosis in the context of autoimmune rheumatic disease. This review discusses the available evidence regarding the potential antiatherosclerotic effects of methotrexate through the inhibition of TNF-α, IL-1, and IL-6 and provides suggestions for future experimental and human studies addressing this issue.

Background Endogenous Retroviruses (HERV) are believed to be pathogenic in several autoimmune diseases. Among them, HERV-K viruses have been recently reported to be involved in the pathogenesis of rheumatoid arthritis (RA). Objectives In this study we have explored the role of humoral immune response against HERV-K as a potential pathogenetic mechanism in RA. Methods Four different peptides from the extracellular portion of the env protein of HERV-K (env-su 19–37, env-su 109–26, env-su 164–205, env-su 209–226) were selected by bioinformatic analysis on the basis of their putative immunogenicity. Indirect ELISA was then carried out to quantify antibodies against those peptides on blood samples from RA patients and healthy controls (HC). Differences between the two groups were analysed using the Mann-Whitney rank-sum and chi-square tests. Potential correlations between RA laboratory, clinical descriptors and IgGs levels were explored by bivariate regression analysis. Results Seventy consecutive RA patients and seventy-one HC crossed by age and sex were enrolled in the study. Serum autoantibodies against three out of the four tested peptides, anti HERV-Ksu19–37, HERV-K env-su109–126 and HERV-K env-su205–226, were significantly more prevalent in RA than in HC (19% vs 3%,p=0.0001;9% vs 3%, p=0.0001; and 6% vs 3%, p=0.0001 respectively) (See Fig. 1) Subgroup analysis showed no association between anti-HERV-K peptide humoral response and clinical, serological and clinimetric RA disease descriptors. Conclusions Serum from RA patients in our series significantly reacted against different HERV-K peptides in comparison to the general population suggesting a role for the HERV-K related, secondary antigenic driven immune response in the pathogenesis of RA. Further studies are needed to confirm these results and to explore the role of HERV-K surface peptides as potential therapeutic targets. Disclosure of Interest None declared

Background RA patients suffer of a life expectancy significantly reduced with respect to the general population mainly due to cardiovascular (CV) disease. Endothelial dysfunction (ED), the early step in atherosclerotic process, is more evident in RA than in the general population. Peripheral arterial tonometry (PAT), a simple, rapid, and objective tool for evaluation of ED, measures small digital artery reactive hyperaemia after an ischemic stimulus in forearm. PAT shows high grade of correlation with coronary ED and predicts future CV events in the general population. Objectives To define prevalence and determinants of peripheral ED in RA. Methods Data from 633 RA patients free of previous CV events prospectivelly enrolled in the EDRA study* (ClinicalTrials.gov: NCT02341066) were analysed. Reactive hyperemia index (LnRHI) was evaluated by PAT using the EndoPAT2000 device: ED was defined by LnRHI Results Peripheral ED was documented in 212 out of 633 RA patients (33.3%). A linear regression for multiple variables (stepwise method) performed including into the models variables showing significant association with LnRHI at the univariate regression analysis (systolic blood pressure, HDL cholesterol levels, triglycerides levels, smoking habit and ACPA positivity; Age and gender were forced) showed that only higher levels of triglycerides [B coefficient (95%IC) = -0,001 (-0,001–0,00); p Conclusions This study demonstrates for the first time a very high prevalence of peripheral ED in patient with RA free of previous CV events. Triglycerides levels and smoking habit, among traditional cardiovascular risk factor, showed a significant correlation with lower peripheral ED. Surprisingly ACPA negativity confers an increased risk for ED in RA population. Moreover, other than expected, systemic inflammation does not appear to influence peripheral ED in RA population. In conclusion our data further support the notion that atherogenesis in RA is only partially driven by traditional CV factors. The negative association between ACPA and ED warrants further investigation. Acknowledgements *The EDRA study is a project funded by Italian Ministry of Health and by Regione Sardegna (RAS) (GR-2011–02352816; Ricerca Finalizzata 2011). Disclosure of Interest None declared

Summary Endogenous retroviruses (HERV) are believed to be pathogenic in several autoimmune diseases. Among them, HERV-K viruses have been reported recently to be involved in the pathogenesis of rheumatoid arthritis (RA). In this study we have explored the role of humoral immune response against HERV-K as a potential pathogenetic mechanism in RA. Four different peptides from the extracellular portion of the env protein of HERV-K (env-su19–37, env-su109–126, env-su164–186, env-su209–226) were selected by bioinformatic analysis on the basis of their putative immunogenicity. Indirect enzyme-linked immunosorbent assay (ELISA) was then carried out to quantify antibodies against those peptides on blood samples of 70 consecutive RA patients and 71 healthy controls (HC). Differences between the two groups were analysed using the Mann–Whitney test. Potential correlations between RA laboratory, clinical descriptors and immunoglobulin (Ig)G levels were explored by bivariate regression analysis. Serum autoantibodies against one of four tested peptides of HERV-K (env-su19–37) were significantly higher in RA than in HC (19 versus 3%, P = 0·0025). Subgroup analysis showed no association between anti-HERV-K peptide humoral response and clinical, serological and clinimetric RA disease descriptors. Serum from RA patients in our series reacted significantly against HERV-K env-su19–37 peptide in comparison to the general population suggesting a role for the HERV-K- related, secondary antigenic-driven immune response in the pathogenesis of RA. Further studies are needed to confirm these results and to explore the role of this HERV-K surface peptide as a potential therapeutic target.

Ultrasound (US) is a cost-effective, noninvasive, accessible imaging modality that clinicians use at the point of care to assess disease activity and therapeutic efficacy in different rheumatic conditions. However, its utility has been prevalently demonstrated in the field of chronic arthritides. Only in the last few years there was an interest to explore the potential of US beyond the musculoskeletal area. In this way, preliminary US data about the assessment of the different targets involved in systemic sclerosis such as joints, tendons, skin, vessels, and lung have been provided. The main purpose of this US review is to provide an overview of the potential role of US in the multi-target assessment of SSc and to discuss the current evidence supporting its relevance and applications in daily clinical practice.

Diagnosis of postenteritic reactive arthritis (ReA) is a challenge and might have a broad range of differential diagnoses. A 50-year-old man was referred to our attention because of persistent inflammatory low back pain and asymmetric oligoarthritis. The clinical history was positive for diarrhoea in the previous 3 months. Inflammatory bowel disease, Whipple and celiac diseases were carefully excluded. In addition, serology, stool cultures, biopsies from the upper gastrointestinal tract yielded negative results for infections. A presumptive diagnosis of ReA was done and a non-steroidal anti-inflammatory drug trial prescribed. Persistence of symptoms prompted us for a second look of the colon. Biopsy collected from the terminal ileum were cultured and surprisingly colonies of Hafnia alvei, a rod-shaped Enterobacteriaceae, were detected. Treatment with ciprofloxacin leads to fast symptoms resolution. Although enterocolitis from H. alvei has been rarely reported, the culture of intestinal specimens might be recommended in the work-up of patients with suspected postenteritic ReA.

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

Conclusive data about the prevalence of endothelial dysfunction and atherosclerotic process in ankylosing spondylitis (AS) patients with respect to the general population are lacking. Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been reported in clinical conditions associated with endothelial dysfunction and atherosclerotic disease. We performed a cross-sectional study to evaluate plasma ADMA levels and atherosclerotic disease in AS patients. Seventeen consecutive AS patients free of any cardiovascular disease and 17 healthy controls [strictly matched for sex, age (±5 years) and atherosclerotic risk factors] were recruited. Plasma ADMA levels were assessed by capillary electrophoresis. Common carotid artery intima-media thickness (CCA-IMT), flow-mediated dilatation (FMD) and arterial stiffness (aS) were registered as surrogate markers of atherosclerotic disease. Plasma ADMA levels appeared significantly (p = 0.001) higher in AS patients (0.65 ± 0.10 μmoli/L) than in the control subjects (0.54 ± 0.07 μmoli/L) while no statistically significant differences between AS and controls were demonstrated in CCA-IMT, FMD, and aS. AS patients showed increased plasma ADMA levels with respect to control subjects. On the contrary, we were not able to document a significant difference in atherosclerotic process between patients and controls.

Objective To assess the clinical and radiographic features of hand involvement in patients with systemic sclerosis (SSc). Methods Forty-one unselected Sardinian SSc patients (32 women, 9 men; mean age 58.9, range 31–81 years; mean disease duration 11.8 years, range 1–36 years) were evaluated in this observational cross-sectional study. Twenty-six patients had diffuse scleroderma (dSSc) and 15 limited scleroderma (lSSc). Radiological examination of the hands was performed and the films were read by two independent rheumatologists blinded to the diagnosis using a classification system of four predefined radiological patterns (normal/minimal changes, articular degenerative, articular inflammatory and periarticular pattern). Correlations between radiological pattern, clinical and serological features were assessed. Results The skeletal and articular involvement of the hand was frequent in SSc, being clinically evident in 30/41 (73%) and radiologically in 33/41 (80%) of patients. The periarticular pattern (defined as the occurrence of bone resorption of ungueal tufts, soft tissue calcifications and/or flexion deformities) was the most frequent pattern detected (14/41, 34.1%) and finger flexion contractures and bone resorptions were significantly associated with interstitial lung disease, reduced FVC, oesophagus involvement and prostacycline therapy. Calcinosis (29.2%) was found to be associated with erosions, suggesting a pathogenic link. An inflammatory pattern was also radiologically frequent (8/41, 19.5%), but erosions, with the exception of those localized at distal interphalangeal joints, were demonstrated mainly in patients with clinical picture of rheumatoid arthritis overlapped with SSc. We found no significant differences in terms of radiographic findings between lSSc and dSSc with the exception of calcinosis, which was more frequent in patients with lSSc. Conclusion This cross-sectional study confirms that the skeletal and articular involvement of the hand is frequent in SSc.