Analysis of foot structural damage in rheumatoid arthritis: clinical evaluation by validated measures and serological correlations

Objective: To examine foot involvement in rheumatoid arthritis (RA) and to characterize structural alterations in patients with anti-cyclic citrullinated peptide (CCP) antibody-positive and -negative disease. Methods: Seventy-eight patients with RA with foot pain were consecutively enrolled. The Manchester Hallux Valgus (MHV) rating scale was used to evaluate the hallux valgus deformity degree. The Foot Posture Index (FPI6), a novel, foot-specific outcome measure, was adopted in order to quantify variation in the position of the foot. The findings were correlated with disease duration and presence or absence of anti-CCP antibodies. Results: About 84.6% patients had different degrees of hallux valgus and 65.4% subjects had a pronated foot. These two foot alterations were prevalently found in patients with long-standing disease and circulating anti-CCP antibodies. On the contrary, RA patients without anti-CCP and early disease essentially displayed a supinated foot without relevant hallux valgus deformity. Conclusion: Our findings allowed to identify different anatomic foot alterations in RA patients according to disease duration and negative prognostic factors such as anti-CCP antibodies. Our findings support the role of an accurate analysis of foot structural damage and may suggest the usefulness of a correct plantar orthosis prescription also in early phases of the disease

[Glucocorticoid induced TNFR-related protein (GITR) as marker of human regulatory T cells: expansion of the GITR(+)CD25⁻ cell subset in patients with systemic lupus erythematosus].

Objectives: Regulatory T cells (TREG) represent a T cell subset able to modulate immune response by suppressing autoreactive T-lymphocytes. The evidence of a reduced number and an impaired function of this cell population in autoimmune/ inflammatory chronic diseases led to the hypothesis of its involvement in the pathogenesis of these disorders. Glucocorticoid-induced TNFR-related protein (GITR) is a well known marker of murine TREG cells, but little is known in humans. The aim of this study was to investigate the characteristics of TREG cells in systemic lupus erythematosus (SLE) and the potential role of GITR as marker of human TREG. Methods: Nineteen SLE patients and 15 sex- and age-matched normal controls (NC) were enrolled. CD4+ T cells were magnetic sorted from peripheral blood by negative selection. Cell phenotype was analyzed through flow-cytometry using primary and secondary antibodies and real time polymerase-chain reaction (PCR) using TaqMan probes. Results: The CD25highGITRhigh subset was significantly decreased in SLE patients with respect to NC (0.37±0.21% vs 0.72±0.19%; p<0.05). On the opposite, the CD25-GITRhigh cell population was expanded in the peripheral blood of SLE patients (3.5±2.25 vs 0.70±0.32%, p<0.01). Interestingly, FoxP3 at mRNA level was expressed in both CD25- GITRhigh and CD25highGITRhigh cells, suggesting that both cell subsets have regulatory activity. Conclusions: CD4+CD25-GITRhigh cells are increased in SLE as compared to NC. The expression of high level of GITR, but not CD25, on FoxP3+ cells appears to point to a regulatory phenotype of this peculiar T cell subset

FRI0565 PREVALENCE AND SIGNIFICANCE OF ANTIBODIES AGAINST CITRULLINATED ALPHA-ENOLASE (ANTI-CEP1) IN CONNECTIVE TISSUE DISEASES.

Background:Anti-cyclic citrullinated peptide (anti-CCP) auto-antibodies represent the current gold standard for the diagnosis of rheumatoid arthritis (RA). However, growing evidence suggests that a variety of other citrullinated self-proteins may act as autoantigens and lead to the production of autoantibodies (1). Furthermore, autoantibodies believed to be RA-specific have been detected also in patients with connective tissue diseases (CTDs). We recently demonstrated that antibodies against citrullinated alpha-enolase (anti-CEP1) are a biomarker of erosive disease and RA-associated interstitial lung disease (2).Objectives:The purpose of this study was to investigate the prevalence and possible prognostic value of anti-CEP-1 in patients with CTDs.Methods:Two hundred and twelve consecutive patients with CTDs (51 systemic lupus erythematosus (SLE), 85 primary Sjogren's syndrome (pSS) and 76 systemic sclerosis (SSc)) were studied and compared to 97 sex and age matched normal controls (NC) and 267 patients with RA. Anti-CEP1 IgG were detected in serum samples with a commercial ELISA kit (Euroimmun).Results:The overall prevalence of anti-CEP1 in CTDs was 7% (15/212 patients). In detail, these antibodies were detectable in 4 out of 85 pSS (5%), 5 out of 51 SLE (10%) and 6/76 SSc (8%). The prevalence and the titer of anti-CEP1 in CTDs was significantly higher compared to NC and significantly lower compared to RA. Anti-CEP1 positive patients did not display a specific clinical and serological picture. Unlike in RA, anti-CEP1 did not correlate with CTD-associated ILD.Conclusion:This is the first study assessing anti-CEP1 in a large cohort of patients with CTDs. We demonstrated that the association of these autoantibodies with ILD is specific for RA since it is not observed in SLE, pSS and SSc. Furthermore, although being significantly more prevalent and at higher titer compared to NC, anti-CEP1 do not allow to discriminate different patient subsets displaying peculiar clinical or serological phenotypes. Based on our results, the application of anti-CEP1 in CTDs is not advisable, however larger studies may possibly identify correlations not evident in our cohort.References:[1] Bonifacio AF, Alunno A, La Paglia GMC, Valentini E, Leone MC, Bartoloni E, Gerli R. Novel autoantibodies in rheumatoid arthritis. Reumatismo 2019;71(1):1-12[2] Alunno A, Bistoni O, Pratesi F, La Paglia GMC, Puxeddu I, Migliorini P, Gerli R. Anti-citrullinated alpha enolase antibodies, interstitial lung disease and bone erosion in rheumatoid arthritis. Rheumatology (Oxford). 2018;57(5):850-855Disclosure of Interests:Alessia Alunno: None declared, Francesco Carubbi Speakers bureau: Francesco Carubbi received speaker honoraria from Abbvie and Celgene outside this work., Onelia Bistoni: None declared, Matteo Antonucci: None declared, Elena Bartoloni Bocci: None declared, Roberto Giacomelli Grant/research support from: Actelion, Pfizer, Speakers bureau: Abbvie, Roche, Actelion, BMS, MSD, Ely Lilly, SOBI, Pfizer, Roberto Gerli: None declare

IL-17-producing double-negative T cells are expanded in the peripheral blood, infiltrate the salivary gland and are partially resistant to corticosteroid therapy in patients with Sjögren's syndrome

A small CD3+ T-cell population, that lacks both CD4 and CD8 molecules, defined as double negative (DN), is expanded in the peripheral blood of patients with systemic lupus erythematosus, produces IL-17 and accumulates in the kidney during lupus nephritis. Since IL-17 production is enhanced in salivary gland infiltrates of patients with primary Sjögren's syndrome (pSS), we aimed to investigate whether DN T cells may be involved in the pathogenesis of salivary gland damage. Fifteen patients with SS and 15 normal controls (NC) were enrolled. Peripheral blood mononuclear cells were stimulated with anti-CD3 antibody and cultured in presence or absence of dexamethasone (Dex). Phenotypic characterization was performed by flow cytometry in freshly isolated cells and after culture. Minor salivary glands (MSG) from pSS were processed for immunofluorescence staining. Total circulating DN T cells were increased in pSS compared to NC (4.7±0.4% vs 2.6±0.4%). NC and pSS freshly isolated DN T cells produce consistent amounts of IL-17 (67.7±5.6 in NC vs 69.2±3.3 in pSS). Notably, DN T cells were found in the pSS-MSG infiltrate. Dex was able to down-regulate IL-17 in vitro production in NC (29±2.6% vs 15.2±1.9% vs 13±1.6%) and pSS (49±4.8% vs 16±3.8% vs 10.2±0.8%) conventional Th17 cells and in DN T cells of NC (80±2.8% vs 3.8±2.1% vs 4.2±1.8%), but not of pSS (81±1.5% vs 85.4±0.8% vs 86.2±1.7%). DN T cells are expanded in pSS PB, produce IL-17 and infiltrate pSS MSG. In pSS, conventional Th17 cells are inhibited by Dex, but DN T cells appear to be resistant to this effect. Taken together, these data suggest a key role of this T-cell subset in the perpetuation of chronic sialoadenitis and eventually in pSS prognosis

subclinical atherosclerosis in young patients with rheumatoid arthritis and low disease activity

Background: There is an increasing body of evidence suggesting that subjects with rheumatoid arthritis (RA) are characterized by acceleration of atherosclerotic process of arterial wall. However, all investigations performed so far to evaluate subclinical atherosclerosis in RA included subjects without selection for age and degree of disease activity that may represent confounding factors in such an evaluation. Objectives: To verify signs of accelerated subclinical atherosclerosis in young subject suffering from RA but with low disease activity. Methods: Thirty-two patients with RA and 28 age- and sex-matched control subjects with non-inflammatory rheumatic diseases were enrolled. Inclusion criteria were age less than 60 and low disease activity with score £3.2 according to DAS28, while subjects with traditional risk factors for and/or overt cardiovascular disease were ruled out from the study. Both patients and controls underwent evaluation of carotid and femoral artery intima-media thickness by ultrasounds. Results: Patients had higher intima-media thickness than controls of all the sites evaluated at carodit artery level, whereas there were no differences at the comparison of the superficial and common femoral artery wall. At the univariate analysis, a positive correlation between LDL cholesterol levels and intima-media thickness at the carotid bifurcation was found. Conclusions: Young patients with RA and low disease activity have acceleration of atherosclerosis development as shown by increased intima-media thickness of carotid artery with respect to subjects without inflammatory rheumatic disease. It is conceivable that the organic damage of arterial wall could be the result of persistent endothelial dysfunction induced by chronic inflammation and immune dysregulation which characterize RA

H2FPEF score predicts atherosclerosis presence in patients with systemic connective tissue disease

Background: Cardiovascular diseases are common cause of morbidity and mortality in patients with systemic connective tissue diseases (SCTD) due to accelerated atherosclerosis which couldn't be explained by traditional risk factors (CVDRF). Hypothesis: We hypothesized that recently developed score predicting probability of heart failure with preserved ejection fraction (H2FPEF), as well as a measure of right ventricular-pulmonary vasculature coupling [tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio], are predictive of atherosclerosis in SCTD. Methods: 203 patients (178 females) diagnosed with SCTD underwent standard and stress-echocardiography (SE) with TAPSE/PASP and left ventricular (LV) diastolic filling pressure (E/e') measurements, carotid ultrasound and computed tomographic coronary angiography. Patients who were SE positive for ischemia underwent coronary angiography (34/203). The H2FPEF score was calculated according to age, body mass index, presence of atrial fibrillation, ≥2 antihypertensives, E/e' and PASP. Results: Mean LV ejection fraction was 66.3 ± 7.1%. Atherosclerosis was present in 150/203 patients according to: 1) intima-media thickness>0.9 mm; and 2) Agatstone score > 300 or Syntax score ≥ 1. On binary logistic regression analysis, including CVDRF prevalence, echocardiographic parameters and H2FPEF score, only H2FPEF score remained significant for the prediction of atherosclerosis presence (χ2 = 19.3, HR 2.6, CI 1.5-4.3, p < 0.001), and resting TAPSE/PASP for the prediction of a SE positive for ischemia (χ2 = 10.4, HR 0.01, CI = 0.01-0.22, p = 0.004). On ROC analysis, the optimal threshold value for identifying patients with atherosclerosis was a H2FPEF score ≥2 (Sn 60.4%, Sp 69.4%, area 0.67, SE = 0.05, p < 0.001). Conclusions: H2FPEF score and resting TAPSE/PASP demonstrated clinical value for an atherosclerosis diagnosis in patients diagnosed with SCTD

Functional Improvement of Regulatory T Cells From Rheumatoid Arthritis Subjects Induced by Capsular Polysaccharide Glucuronoxylomannogalactan

Objective: Regulatory T cells (Treg) play a critical role in the prevention of autoimmunity, and the suppressive activity of these cells is impaired in rheumatoid arthritis (RA). The aim of the present study was to investigate function and properties of Treg of RA patients in response to purified polysaccharide glucuronoxylomannogalactan (GXMGal). Methods: Flow cytometry and western blot analysis were used to investigate the frequency, function and properties of Treg cells. Results: GXMGal was able to: i) induce strong increase of FOXP3 on CD4+ T cells without affecting the number of CD4+CD25+FOXP3+ Treg cells with parallel increase in the percentage of non-conventional CD4+CD25-FOXP3+ Treg cells; ii) increase intracellular levels of TGF-beta1 in CD4+CD25-FOXP3+ Treg cells and of IL-10 in both CD4+CD25+FOXP3+ and CD4+CD25-FOXP3+ Treg cells; iii) enhance the suppressive activity of CD4+CD25+FOXP3+ and CD4+CD25-FOXP3+ Treg cells in terms of inhibition of effector T cell activity and increased secretion of IL-10; iv) decrease Th1 response as demonstrated by inhibition of T-bet activation and down-regulation of IFN-gamma and IL-12p70 production; v) decrease Th17 differentiation by down-regulating pSTAT3 activation and IL-17A, IL-23, IL-21, IL-22 and IL-6 production. Conclusion: These data show that GXMGal improves Treg functions and increases the number and function of CD4+CD25-FOXP3+ Treg cells of RA patients. It is suggested that GXMGal may be potentially useful for restoring impaired Treg functions in autoimmune disorders and for developing Treg cell-based strategies for the treatment of these diseases

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

ps4 79 long term follow up of 320 chilren born to mothers with systemic autoimmune diseases a multicentre survey from 24 rheumatology centres in italy

Background Rheumatic Diseases (RD) frequently affect women during reproductive age, therefore counselling on family planning is crucial for their quality of life. Children's outcome is a major topic, but no large studies are available. This study aimed at assessing the long-term health conditions of children born to women with RD. Methods 24 Italian Rheumatology Centres distributed the questionnaire (65 multiple-choice and 12 open-answer questions) to consecutive patients (aged 18–55) during September 2015. Data were analysed dividing children upon maternal diagnosis: Chronic Arthritides (CA) and Connective Tissue Diseases (CTD). Results Data were collected for 320 children born to 184 mothers (63 CA and 121 CTD). At the time of interview, children had a mean age of 17.1±9.6 years. Pre-term delivery ( The occurrence of an autoimmune/inflammatory disease (AIID) and/or neurodevelopmental disorders (ND)/learning disabilities (LD) is reported in table 1. Twelve children (3.7%) were diagnosed with an AIID, mostly coeliac disease (8/12, 67%). Eleven children (3.4%) were diagnosed as having a ND and/or LD by a Paediatric Neuropsychiatrist. Data of in utero exposure to maternal autoantibodies and/or anti-rheumatic drugs were retrieved for 280 children (87.5%) and a comparison was performed between affected (n=11) and not-affected children (n=258). No association was found with ND/LD and in utero exposure to autoantibodies (ANA, anti-Ro, anti-dsDNA, aPL) or drugs (HCQ,AZA or steroids), neither with sex, preterm birth, birth weight or maternal diagnosis. Conclusions The long-term follow-up of children born to mothers with RD did not raise particular concerns in terms of relevant health problems. In particular, each AIID did not display a significantly increased frequency as compared to the literature. Children with ND/LD had a tendency to cluster in the group of mothers with CTD, especially after maternal diagnosis, with a higher frequency as compared to GPP (7.9% vs 3%). Our data suggest that the development of ND/LD in children of patients with RD cannot be linked exclusively to maternal disease. The results of this study can be reassuring for patients with RD about problems in the offspring possibly related to their disease