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Purpose Rheumatoid arthritis (RA) can result from complex interactions between the affected person's genetic background and environment. Viral and bacterial infections may play a pathogenetic role in RA through different mechanisms of action. We aimed to evaluate the presence of antibodies (Abs) directed against two proteins of Mycobacterium avium subsp. paratuberculosis (MAP) in sera of RA subjects, which are crucial for the survival of the pathogen within macrophages. Moreover, we analyzed the correlation of immune response to both proteins with the following homologous peptides: BOLF1305-320, MAP_402718-32 and IRF5424-434 to understand how the synergic role of Epstein-Barr virus (EBV) and MAP infection in genetically predisposed subjects may lead to a possible deregulation of interferon regulatory factor 5 (IRF5). Materials and methods The presence of Abs against protein tyrosine phosphatase A (PtpA) and protein kinase G (PknG) in sera from Sardinian RA patients (n=84) and healthy volunteers (HCs, n=79) was tested by indirect ELISA. Results RA sera showed a remarkably high frequency of reactivity against PtpA in comparison to HCs (48.8% vs 7.6%; p

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.

Objective To evaluate the diagnostic accuracy of anticarbamylated protein antibodies (CarP), alone and in combination with traditional biomarkers (rheumatoid factor [RF] and anticitrullinated peptide antibodies [ACPA]), in established rheumatoid arthritis (RA). Methods A commercially available enzyme‐linked immunosorbent assay (ELISA) kit was used to assess CarP concentrations in serum samples of 200 established RA and 206 controls (115 healthy donors and 55 patients with other rheumatic diseases). Main outcome measures were sensitivity, specificity, and area under the curve (AUC; 95% confidence interval [CI]). Difference in accuracy was evaluated by comparison of the respective AUCs. Results A serum CarP cut‐off of 1.47 ng/ml or more differentiated patients with RA from controls with 30% sensitivity, 97.1% specificity, and good accuracy (AUC[95%CI] = 0.83[0.79‐0.86], P < 0.0001). However, it showed moderate diagnostic accuracy in seronegative RA patients: sensitivity 17.9%, specificity 96.9%, and AUC (95% CI) = 0.69 (0.63‐0.75). The diagnostic accuracy of CarP_ACPA and CarP_RF combinations was significantly superior to that of ACPA and RF alone (P < 0.0001 and P = 0.015, respectively), but not to that of ACPA_RF combination (P = 0.089) In addition, the CarP_ACPA_RF combination did not improve the diagnostic accuracy of the ACPA_RF combination (AUC mean difference [95% CI] = 0.006 [−0.001 to 0.015], P = 0.10). The number of positive autoantibodies (0, 1, 2, or 3) was not significantly associated with moderate‐severe disease (Disease Activity Score‐28 [DAS‐28] > 3.2) in adjusted multiple regression analysis. Conclusion CarP has good diagnostic accuracy in established RA but not in seronegative RA. The addition of CarP to ACPA and RF alone or in combination does not significantly enhance the diagnostic accuracy of ACPA_RF combination.

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

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.

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

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

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 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 Behcet's disease (BD) is a polygenic immune-mediated disorder characterized by a close association with the HLA-B*51 allele. The HLA region has a strong linkage disequilibrium (LD) and carries several genetic variants (e.g. MIC-A, TNF-α genes) identified as associated to BD because of their LD with HLA-B*51. In fact, the HLA-B*51 is inherited as part of extended HLA haplotypes which are well preserved in patients with BD. Sardinian population is highly differentiated from other Mediterranean populations because of a distinctive genetic structure with very highly preserved HLA haplotypes. Patients and methods In order to identify other genes of susceptibility to BD within the HLA region we investigated the distribution of human Allograft Inflammatory Factor-1 (AIF-1) gene variants among BD patients and healthy controls from Sardinia. Six (rs2736182; rs2259571; rs2269475; rs2857597; rs13195276; rs4711274) AIF-1 single nucleotide polymorphisms (SNPs) and related extended haplotypes have been investigated as well as their LD within the HLA region and with HLA-B*51. Overall, 64 BD patients, 43 HLA-B*51 positive healthy controls (HC) and 70 random HC were enrolled in the study. Results HLA-B*51 was the only allele with significantly higher frequency (pc = 0.0021) in BD patients (40.6%) than in HC (9.8%). The rs2259571T AIF-1 variant had a significantly reduced phenotypic, but not allelic frequency in BD patients (72.1%; pc = 0.014) compared to healthy population (91.3%). That was likely due to the LD between HLA-B*51 and rs2259571G (pc = 9E-5), even though the rs2259571G distribution did not significantly differ between BD patients and HC. Conclusion No significant difference in distribution of AIF-1 SNPs haplotypes was observed between BD patients and HC and between HLA-B*51 positive BD patients and HLA-B*51 positive HC. Taken together, these results suggest that AIF-1 gene is not associated with susceptibility to BD in Sardinia.

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

Objective To define the safety and efficacy of TNF inhibitors (TNFi) in RA patients with comorbidities. Methods A National Consensus Conference adopted a five-step process to better address the place of TNFi in the treatment of RA. Here we report the work focused on the influence of comorbidities on TNFi efficacy and the effect of TNFi on comorbidities using a Population Intervention Comparison Outcome-based strategy from 8 April 2013 to 15 January 2016. Results A total of 4453 hits were analysed, of which 10 were eligible for full review. Data show that the presence of comorbidities influences the treatment strategy and several clinical outcomes. The risk of solid cancer is similar in RA patients treated with TNFi or with conventional synthetic DMARDs, and the risk of recurrent breast cancer is not higher in RA patients treated with TNFi. The risk of developing serious infections is higher in RA patients receiving TNFi than conventional synthetic DMARDs. Patients with previous serious infections before starting TNFi are not at increased risk of subsequent serious infection. The hazard rate of hospitalization due to infections is not different among patients remaining on the same TNFi, or switching to a different TNFi or to an agent with another mechanism of action. Longer exposure to TNFi is associated with a reduction in the risk of cardiovascular events. Conclusion Comorbidities affect RA treatment strategies and the efficacy of TNFi. TNFi treatment may decrease the risk of cardiovascular diseases and their use in patients with previous infection is not associated with a higher risk of recurrences.

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.

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

To assess validity, responsiveness and interpretability of the UltraSound-CLinical ARthritis Activity (US-CLARA) index in patients with rheumatoid arthritis (RA).In this longitudinal study were involved RA patients starting treatment with abatacept. Subjects were followed along three visits in the first 6 months of therapy and underwent a comprehensive clinimetric evaluation. Validity was explored correlating the baseline scores and the cumulative inflammatory burden of the US-CLARA with the other composite indices applied. Sensitivity to change was assessed after 6 months of treatment in terms of internal and external responsiveness. Interpretability was defined in terms of determination of cutoffs against external criteria for remission (REM), low disease activity (LDA), moderate disease activity (MDA), and high disease activity (HDA) of SDAI.One-hundred and thirty patients completed the study.moderate correlations were observed between US-CLARA and both DAS28-CRP and DAS28-ESR. Higher correlations were also found between US-CLARA and both SDAI and CDAI scores. Responsiveness: internal responsiveness was wide, with SRM and ES ranging from 0.91 to 1.51. US-CLARA responsiveness was similar to that of DAS28, SDAI, or CDAI. Similarly, the area under ROC curve (AUC-ROC) of US-CLARA gives identical results. The AUC of cumulative inflammatory burden, calculated during the 6-months follow-up of all combinations were highly correlated (p0.0001). Interpretability: cutoff values for REM, US-CLARA2.0; for LDA, 2.0 ≤US-CLARA3; for MDA, 3 ≤US-CLARA ≤4.8; for HDA, US-CLARA4.8.The US-CLARA is valid and sensitive tool to assess disease activity in RA.

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.

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.

Increased iron storage represents a characteristic condition in patients with beta zero-thalassaemia intermedia. Iron overload is an important factor in cellular damage. Recent studies have shown an enhanced lysosomal fragility due to increased iron storage. 13 patients with beta-thalassaemia intermedia, aged 17-44 years, were studied. Both serum ferritin and serum N-acetyl-beta-D-glucosaminidase levels were evaluated in all subjects studied. A significant linear correlation (P less than 0.05) between serum ferritin and serum N-acetyl-beta-D-glucosaminidase levels were found.

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.

Resume Objectif Decrire les signes cliniques et radiologiques observes a la main dans la sclerodermie. Patients Nous avons realise une etude descriptive transversale chez 41 Sardes souffrant de sclerodermie (32 femmes et neuf hommes ; mediane de 58,9 ans avec des extremes de 31 et 81 ans), depuis 11,8 ans en moyenne (extremes, 1–36 ans). La maladie etait diffuse chez 26 malades et limitee chez 15 malades. Methodes Une radiographie des mains a ete realisee chez chaque malade. Les radiographies ont ete interpretees de facon independante par deux radiologues tenus dans l’ignorance du diagnostic. Les radiologues ont classe les radiographies en quatre categories : aspect normal ou subnormal, arthrose, arthrite inflammatoire et anomalies periarticulaires. Nous avons ensuite recherche des correlations entre les categories radiographiques et les signes cliniques et serologiques. Resultats Malgre l’absence de groupe temoin et le caractere transversal de l’etude, les resultats confirment la frequence des anomalies osteoarticulaires a la main dans la sclerodermie : des signes cliniques ont ete mis en evidence chez 30 (73 %) malades et des signes radiographiques chez 33 (80 %) malades. Les anomalies periarticulaires (resorption de la phalangette, calcifications des parties molles et/ou flessum) predominaient (14/41, 34,1 %). Le flessum des doigts et la resorption osseuse etaient correles a la presence d’une pneumopathie interstitielle, a une reduction de la capacite vitale forcee, a une atteinte œsophagienne et au traitement par la prostacycline. La calcinose (29,2 % des malades) etait liee a la presence d’erosions, suggerant un lien pathogenique. Un aspect radiologique inflammatoire s’est avere frequent (8/41, 19,5 %). Toutefois, les erosions, situees ailleurs qu’aux interphalangiennes distales, ont ete observees principalement chez les malades qui presentaient un tableau frontiere polyarthrite rhumatoide-sclerodermie. La calcinose etait plus frequente en cas de sclerodermie limitee, mais il n’y avait pas entre les deux groupes d’autres differences dans la prevalence des anomalies radiologiques.

Diagnosis of extrapulmonary tuberculosis (TB) is often challenging. In this work we discuss the utility of an assay for Lipoarabinomannan (LAM) antibody detection in synovial fluid. LAM is one of the three major groups of lipopolysaccharides within the Mycobacterium tuberculosis (MTB) cell wall. An ELISA based test was used to investigate the presence of antibodies against LAM in an immunocompetent patient with knee arthritis. The symptoms resolved after isoniazid treatment. LAM positivity has been used as a diagnostic tool for TB in different settings, including veterinary field. The test could be of some value to diagnose tuberculous arthritis in selected patients when gold standard test returned negative although further investigations are welcome.

The objective of this study was to determine the HLA class II associations of the anticardiolipin (aCL) and anti-beta(2)GPI (a beta(2)GPI) antibodies in a large series of European patients with systemic lupus erythematosus (SLE). A cohort of 577 European SLE patients was enrolled. aCL and a beta(2)GPI were measured by ELISA methods. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 loci was performed by the polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method. aCL of IgG, IgM and IgA isotypes were detected in 22.8%, 14% and 13.9% of patients, respectively. IgG and IgM a beta(2)GPI were detected in 20% of patients, aCL showed positive association with HLA DRB1*04, DRB1*0402, DRB1*0403, DRBI*07, DRB3*0301, DQA1*0201, DQA1*0301, DQB1*0302, and negative association with DQA1*0501, DRB3*0202. a beta(2)GPI showed positive association with DRB1*0402, DRB1*0403, DQB1*0302. DRB1*0402 carried the highest relative risk for the presence of both aCL (RR = 8.1) and a beta(2)GPI (RR = 4.6). Our results confirm the already described associations of aCL with HLA DR4 and DR7, but also demonstrate that, among the alleles at the DRB1*04 locus; the *0402 was most represented both in aCL and in a beta(2)GPI positive patients. In addition, HLA class II associations of a beta(2)GPI are for the first time extensively examined in a large cohort of European SLE patients.

Objective To compare haplotype distribution in HLA–B27–positive patients with ankylosing spondylitis (AS) and healthy control subjects possessing either AS-associated HLA–B27 alleles or the non–AS-associated HLA–B*2709 allele. Methods DNA samples from 47 HLA–B27–positive patients with AS and 76 HLA–B27–positive healthy controls (19 positive and 57 negative for B*2709) living in different areas of Sardinia were collected and typed for HLA class I and class II alleles. The third exon of the B27 gene was analyzed for the presence of Asp116 or His116, which differentiates B*2709 from the other two B27 subtypes (B*2705 and B*2702) that are mostly found in Sardinia. The parents of 6 subjects positive for B*2709 were also typed for HLA class I and class II alleles. Statistical analysis was performed by Fisher's exact test. Results In Sardinia, the B27 alleles conferring susceptibility to AS appear to be more frequently carried by a haplotype (A2;B27;Cw2;DR16) that reaches its highest frequency in patients with AS (A2 80.8%, B27 100%, Cw2 83%, and DR16 74.5%). Conversely, the non–AS-associated B*2709 allele is more frequently found together with other HLA alleles whose frequencies are inversely correlated with the disease (A32 or A30, Cw1, and DR12). Familial analysis of 6 subjects positive for HLA–B*2709 confirmed the existence of a “Sardinian” haplotype that is not associated with AS (A32;B*2709;Cw1;DR12). Conclusion In Sardinia, 2 distinct haplotypes harbor the non–AS-associated HLA–B*2709 allele or the AS-associated B27 alleles. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA–B27 may play some role in conferring susceptibility to AS.

Objective. In B27 transgenic rats, susceptibility to the development of a spondyloarthropathylike disease has been shown to correlate with the level of B27 transgene expression on lymphoid cells. The aim of this work was to study HLA-B27 molecule expression in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) and from normal controls (NC). Methods. Twenty B27 + AS patients and 16 B27 + NC were studied. HLA-B27 whole molecules and free heavy chains (HCs) and total HLA class I molecules were evaluated at the surface of PBMCs by immunofluorescence and flow cytometry. B27 subtypes were defined with the PCR-SSP (polymerase chain reaction‐sequence-specific primer) technique. Cellular activation was evaluated by the expression of CD69, CD25 molecules and interferon c (IFN-c) production. Results. B27 expression was 55 536.3 " 18 961.0 MESF (molecules of equivalent soluble fluorochromes) units in AS and 25 936.0 " 12 117.5 MESF in NC (P=0.00009), total HLA class I expression was 448 840.2 " 136 293.8 MESF in AS and 533 494.4 " 232 931.1 MESF in NC (not significant), HC expression was 10 593.4 " 6396.1 MESF in AS and 14 843.0 " 7544.2 MESF in NC (not significant). The higher B27 expression in the SA group was not due to higher cell activation as it was not correlated with CD69 and CD25 expression in PBMCs or with the level of IFN-c. HLA-B27 expression did not correlate with indexes of disease status wBath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI)x. Conclusions. We found greater expression of HLA-B27 molecules in patients with AS than in healthy subjects. This phenomenon was not accompanied by general up-regulation of HLA class I molecules or by greater expression of classical T-cell activation markers. On this basis we propose that the higher expression of the HLA-B27 molecules is a further predisposing factor for the development of AS.

We report the case of a 30-year-old caucasian woman affected by SLE who developed neurological symptoms (prosopagnosia and visual-spatial agnosia) after nine years of disease. Brain MRI showed no abnormalities while a brain SPECT scan showed diffuse uptake defects and hypoperfusion areas in the right and left frontal-parietal regions. At that time the patient was on hydroxychloroquine (400 mg/day) and oral prednisolone (0.5 mg/kg/day) as maintenance therapy. One year later the patient showed worsening of Raynaud's phenomenon with digital dystrophic lesions and was therefore treated with an intravenous infusion of Iloprost (1.5 ng/kg/min per 6h/ day for 10 days consecutively), while baseline treatment remained unchanged. One month later the patient showed a dramatic improvement in her cognitive function and subsequent SPECT scans showed the gradual disappearance of perfusion abnormalities. This first report of Iloprost treatment in CNS lupus suggests the potential therapeutic usefulness of this drug in patients with SLE and functional CNS involvement.

Psoriasis and psoriatic arthritis are linked diseases characterised by (distinct ?) immune-mediated pathogenetic mechanisms and by a genetic background interacting with environmental factors. Some candidate susceptibility genes have been studied extensively; they include HLA genes, genes within the HLA region and genes outside the HLA region; among them corneodesmosin and other genes of PSORS1 region, MICA and TNF-a polymorphisms. The main findings in the literature are discussed. Key words: Genetics, psosriasis, psoriatic arthritis

To explore the post-transcriptional regulation of the peripheral blood mononuclear cells (PBMCs) transcriptome by microRNAs in Behçet's disease (BD).Using TaqMan Low Density Array-based microRNAs expression profiling, the expression of 750 mature human microRNAs in PBMCs from 5 BD patients and 3 healthy controls (HC) was compared. The expression of deregulated microRNAs was then validated by quantitative real time-polymerase chain reaction (qRT-PCR), in 42 BD patients and 8 HC.In the initial screening, 13 microRNAs appeared deregulated in BD vs HC. Among them, the differential expression of miR-720 and miR-139-3p was confirmed by qRT-PCR, (p0.05 and FDR5%). Areas under the receiver operating characteristic curve for miR-139-3p, miR-720 and miR-139-3p+miR-720 in the validation cohort were 0.84, 0.87 and 0.92 respectively, indicating good discrimination between BD patients and HC. Post-hoc analysis showed that 9 out of 13 microRNAs from the discovery phase were significantly upregulated in active vs. quiescent BD, suggesting inflammation as a key regulator of microRNAs machinery in BD. In silico analysis revealed that several BD candidate susceptibility genes are predicted target of significantly deregulated microRNAs in active BD. A significant enrichment in microRNAs targeting elements of the Toll-like receptor (TLR) and T-cell receptor signalling pathways was also assumed.miR199-3p and miR720 deserve further confirmation as biomarkers of BD in larger studies. PBMCs from active BD displayed a unique signature of microRNAs which may be implicated in regulation of innate immunity activation and T-cell function.

Pulmonary arterial hypertension is a major complication of systemic sclerosis. Although oxidative stress, intima hyperplasia and a progressive vessel occlusion appear to be clearly involved, the fine molecular mechanisms underpinning the onset and progression of systemic sclerosis-associated pulmonary arterial hypertension remain largely unknown. Here we shows for the first time that an increase of NADPH-derived reactive oxygen species production induced by sera from systemic sclerosis patients with pulmonary arterial hypertension drives collagen type I promoter activity in primary human pulmonary artery smooth muscle cells, suggesting that antioxidant-based therapies should be considered in the treatment of systemic sclerosis-associated vascular diseases.

The aim of this study was to evaluate morphological and functional abnormalities by cerebral imaging in a series of systemic lupus erythematosus (SLE) patients with and without overt central nervous system (CNS) manifestations, and to detect possible relationships with clinical parameters and a large panel of autoantibodies, including those reactive against neurotypic and gliotypic antigens. 68 patients with SLE were investigated in a cross-sectional study which included clinical evaluation of symptoms, cerebral magnetic resonance imaging (MRI) and brain single photon emission tomography (SPECT) analysis, electroencephalography (EEG), and serological tests for antibodies directed against nuclear, cytoplasmic neuronal and glial cell-related antigens. The results of this study showed: (1) a significant positive association of (a) anti-glial fibrillary acidic protein (GFAP) serum antibodies with neuropsychiatric (NP) manifestations and (b) antiserin proteinase 3 (anti-PR3/c-ANCA) serum antibodies with pathological cerebral SPECT; (2) the presence of significantly higher values of (a) SLICC organ damage index in patients with abnormal MRI and (b) SLAM activity index in patients with abnormal SPECT; and (3) the association of (a) abnormal MRI with nonactive NP manifestations and (b) combined abnormality of brain SPECT and MRI with the occurrence of overall overt NP manifestations and with those of the organic/major type. Neuropsychiatric manifestations, namely those of the organic/major type, appeared to be significantly associated to the presence of a serum antibody against GFAP, a gliotypic antigen. There was also evidence of an association between SPECT abnormality and the presence of anti-PR3 (c-ANCA). Furthermore, brain imaging by MRI and SPECT applied to SLE patients appears to express CNS involvement significantly related to specific categories of NP manifestations. The abnormalities detected by the two tests seem to be preferentially associated with different activity phases of the NP disorder or of the lupus disease.

In Sardinia, like in other Caucasoid populations, rheumatoid arthritis (RA) is significantly associated with HLA-DR4 and DR1 antigens. To discover which DR4 and DR1 alleles were associated with the disease we selected 22 Sardinian patients affected by RA. Fifty DR4+ and 28 DR1+ healthy individuals coming from the same geographical area were used as controls. In the Sardinian patients only two DRB1*04 alleles were observed: DRB1*0405 in 11 and DRB1*0403 in three patients. The DRB1*0102 allele was observed in two patients and DRB1*0101 in six patients. Hereditary predisposition to RA in Sardinia therefore seems to be almost exclusively associated with the DRB1*0405 and DRB1*0101 alleles which share the 67LLEQRRAA74-85VG86 epitope in the peptide binding groove.

The HLA–B*2709 allele, originally identified among the Italian population, has not been found to be associated with ankylosing spondylitis (AS) in the populations of Sardinia or continental Italy. It has been reported to be present in a few patients with undifferentiated seronegative arthritis without axial involvement and in a patient with psoriatic arthritis with only peripheral arthritis. Structural and functional differences, which might account for differential susceptibility to AS (and sacroiliitis), have been found between the B*2705 subtype, which is associated with AS, and B*2709, which so far does not seem to be associated. The B*2709 subtype may have a neutral role in susceptibility to AS, like any other non–AS-related allele of the B locus, and some sporadic cases of B*2709 positivity among AS patients would therefore be expected to occur by chance and should be regarded as B27-negative AS. To date, however, none have been reported. Furthermore, when considering susceptibility to AS, one must take into account the fact that several genes besides B27 have been implicated. Herein we report on a patient with AS who was positive for HLA–B*2709.

Revue du rhumatisme - In Press.Proof corrected by the author Available online since dimanche 26 octobre 2014

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic eosinophilic vasculitis, belonging to the group of ANCA-associated vasculitides (AAV). EGPA pathogenesis is still elusive, but a potential role for IL-5 and Eotaxins mediated eosinophil activation has been reported. Imatinib mesylate, a tyrosine kinase (TK) inhibitor, is approved for the treatment of chronic myeloid leukaemia and FIP1L1/PDGFRA positive gene fusion hypereosinophilia. A potential role for imatinib in the treatment of idiopathic hypereosinophilic syndrome (HES) and AAV has been recently proposed.

Data about clinical-laboratory features and outcome of antiphospholipid syndrome nephropathy (APSN) in the course of lupus nephritis (LN) are scarce. To determine prevalence, clinical correlations and outcome of APSN in patients with LN, retrospective analysis of renal specimens and review of medical records from 48 LN patients were performed. APSN was found in 12/48 (25 %) of LN. Positivity for lupus anticoagulant (LAC) and double antiphospholipids positivity [LAC plus anticardiolipin (aCL)] were significantly more frequent in APSN-LN (p = 0.02 and p = 0.01, respectively) than in LN, while single aCL positivity was not. Overt antiphospholipid syndrome appeared more frequent in patients with APSN-LN (p = 0.05). There were no statistically significant differences between APSN-LN and LN in the proportion of each World Health Organization class of LN (with the exception of a trend toward fewer Class III LN in APS-LN) and in the systemic lupus erythematosus (SLE) disease duration and severity. At the time of renal biopsy, patients with APSN-LN had median serum creatinine levels significantly higher than patients with LN [1.45 (0.6–6.6) vs. 1.00 (0.7–3.0), p = 0.02]. Double antiphospholipid positivity was the only variable significantly associated with APSN-LN at multivariate regression analysis (OR 8, 95 % CI 1.7–37, p = 0,008). APSN-LN and LN did not differ significantly as regards the rate of complete (25 vs. 19.4 %, p = 0.72) and partial treatment response (25 vs. 29 %, p = 0.82) at 6 months and the progression to end-stage renal disease after a median follow-up of 8.1 ± 3.6 years (16.6 vs. 13.8 %, p = 0.82). APSN was demonstrated in a quart of LN, appeared to be independent from underlying LN class and SLE severity, and did not seem to confer a worse prognosis to LN. The findings of higher creatinine and more interstitial fibrosis in APSN should be confirmed in future prospective larger studies.

Forty randomly selected patients with systemic lupus erythematosus (SLE) were studied by clinical and serologic parameters and magnetic resonance imaging (MRI). Abnormal MRI was found in 15/40 patients (37.5%): all 15 cases showed multiple widespread small-sized areas of increased signal in T2 in the white matter; in one of these patients MRI also displayed a large area with a reduced signal in T1 and an increased signal in T2 involving both the white and the gray matter. Among the 15 patients with abnormal MRI, only 7 had neuropsychiatric symptoms. The presence of MRI changes was highest in patients with organic type symptoms and was associated to the highest disease severity scores. A long-term follow up of asymptomatic patients would be useful to establish whether the application of MRI is appropriate for the assessment of CNS involvement in SLE.