Effects of cytotoxic T-lymphocyte-associated protein 4 compared to TNF inhibitors on lipid profile: Results from an observational multicentre rheumatoid arthritis cohort.

AIM: To evaluate the impact of selective cytotoxic T-lymphocyte-associated protein 4 (CTLA-4Ig) compared to tumor necrosis factor inhibitors (TNFi) on cardiovascular (CV) clinical and laboratory outcomes in patients with rheumatoid arthritis (RA). METHODS: We performed a prospective observational multicenter study of RA patients included in the "Cardiovascular Obesity and Rheumatic DISease (CORDIS)" Study Group database, collecting demographic, clinical, and laboratory data of those starting a CTLA-4Ig or TNFi at baseline, 6-month, and 12-month follow-up. RESULTS: Of the 206 RA patients without previous CV events enrolled in the study, 64 received a CTLA-4Ig and 142 a TNFi. The two groups did not differ in age, gender, or smoking habits, and the prevalence of hypertension, diabetes, and metabolic syndrome was similar. Over a follow-up period of 12 months, although no significant differences were found in the disease activity course, we observed that LDL cholesterol levels slightly decreased only in the CTLA-4Ig-treated patients. CONCLUSIONS: Patients treated with both CTLA-4Ig and TNFi did not differ in disease activity response and changes in traditional CV risk factors after 12 months of treatment. However, CTL-A-4Ig treatment is associated with a favorable change in lipid profile at 12-month follow-up.

Bridges or walls? A metaphorical dichotomy of Pope Francis versus Donald Trump's views of transnational migration.

Within a wider research line on policy-driven institutional discourses on migration by international/national institutions, NGO and political leaders, this contribution is aimed at illustrating the bipolarized social representations of immigrants inspiring 24 speeches by Pope Francis and US President Donald Trump. Statistical analyses using IRAMUTEQ included "specificity analysis" of discursive forms (words) and "cluster analysis." Results show that the Pope's discourse on migration (articulated into four clusters) is richer than the oversimplified Trump's discourse (originating just one cluster): the words "bridges" and "walls" emerge as representational nuclei of their bipolarized views of transnational migration, as metaphorical dichotomies of inclusive/exclusive policies. Emphasizing the need to build walls to protect the Americans, inspired by the sovereign ideology (AMERICA FIRST!), President Trump does not at all suspect that in the globalized interconnected world the AMERICA FIRST may become just AMERICA ALONE!

Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis.

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.

"Disease knowledge index" and perspectives on reproductive issues: A nationwide study on 398 women with autoimmune rheumatic diseases.

OBJECTIVE: The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age. METHODS: We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18-55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149). RESULTS: At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A "Disease Knowledge Index" (DKI) was created to investigate the degree of patients' information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning. CONCLUSION: Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication.

Clinical predictors of response and discontinuation of belimumab in patients with systemic lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study.

OBJECTIVE: To investigate efficacy, safety and survival of belimumab and to identify predictors of drug response and drug discontinuation in patients with active SLE in clinical practice. PATIENTS AND METHODS: Data of SLE patients, treated with belimumab, from 11 Italian prospective cohorts were analyzed. SLEDAI-2K, anti-dsDNA, C3, C4, prednisone daily dose, DAS-28, 24-h proteinuria, CLASIa (Cutaneous LE Disease Area and Severity Index Activity) were recorded at baseline and every 6 months. SLE Responder Index-4 (SRI-4) was calculated at 12 and 24 months. Demographic and clinical features and comorbidities were included in the univariate and multivariate analysis. Adverse events were recorded at each visit. Statistics was performed using the SPSS software. RESULTS: We studied 188 SLE patients, mean follow-up 17.5 ± 10.6 months. The most frequent manifestations, which required the use of belimumab, were polyarthritis (45.2%) and skin rashes (25.5%). SRI-4 was achieved by 77.0% and 68.7% of patients at 12 and 24-months. Independent predictors of 12-month response were SLEDAI-2K ≥ 10 (OR 40.46, p = 0.001) and polyarthritis (OR 12.64, p = 0.001) and of 24-month response were SLEDAI-2K ≥ 10 (OR 15.97, p = 0.008), polyarthritis (OR 32.36, p = 0.006), and prednisone ≥7.5 mg/day (OR 9.94, p = 0.026). We observed a low rate of severe adverse events. Fifty-eight patients (30.8%) discontinued belimumab after a mean follow-up of 10.4 ± 7.5 months. The drug survival was 86.9%, 76.9%, 69.4%, 67.1%, and 61.9% at 6, 12, 18, 24, and 30 months, respectively. No factors associated with drug discontinuation were found. CONCLUSION: Belimumab is effective and safe when used in clinical practice setting.

International consensus: What else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome)?: The unmet needs and the clinical grey zone in autoimmune disease management.

Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained. This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity.

One year in review 2017: primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a complex and heterogeneous disease. Last year, a great deal of basic and clinical research was carried out in pSS. Following the previous reviews of this publishing series, we will herewith provide a critical digest of the most recent literature on pSS pathogenesis, clinical manifestations and treatment. More specifically, we will focus on the heterogeneity of the disease, on the underlying pathogenetic pathways and on the possible new targeted treatments on the horizon.

Nano-sized polystyrene affects feeding, behavior and physiology of brine shrimp Artemia franciscana larvae.

Nano-sized polymers as polystyrene (PS) constitute one of the main challenges for marine ecosystems, since they can distribute along the whole water column affecting planktonic species and consequently disrupting the energy flow of marine ecosystems. Nowadays very little knowledge is available on the impact of nano-sized plastics on marine organisms. Therefore, the present study aims to evaluate the effects of 40nm anionic carboxylated (PS-COOH) and 50nm cationic amino (PS-NH2) polystyrene nanoparticles (PS NPs) on brine shrimp Artemia franciscana larvae. No signs of mortality were observed at 48h of exposure for both PS NPs at naplius stage but several sub-lethal effects were evident. PS-COOH (5-100µg/ml) resulted massively sequestered inside the gut lumen of larvae (48h) probably limiting food intake. Some of them were lately excreted as fecal pellets but not a full release was observed. Likewise, PS-NH2 (5-100µg/ml) accumulated in larvae (48h) but also adsorbed at the surface of sensorial antennules and appendages probably hampering larvae motility. In addition, larvae exposed to PS-NH2 undergo multiple molting events during 48h of exposure compared to controls. The activation of a defense mechanism based on a physiological process able to release toxic cationic NPs (PS-NH2) from the body can be hypothesized. The general observed accumulation of PS NPs within the gut during the 48h of exposure indicates a continuous bioavailability of nano-sized PS for planktonic species as well as a potential transfer along the trophic web. Therefore, nano-sized PS might be able to impair food uptake (feeding), behavior (motility) and physiology (multiple molting) of brine shrimp larvae with consequences not only at organism and population level but on the overall ecosystem based on the key role of zooplankton on marine food webs.

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-ß1 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-γ 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.

Biomarkers of lymphoma in Sjögren's syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: results of a multicenter study.

OBJECTIVES: To define the biomarkers associated with lymphoproliferation in primary Sjögren's syndrome (pSS) by distinguishing in separate groups the two best-recognized non-malignant prelymphomatous conditions in pSS, i.e., salivary gland swelling and cryoglobulinemic vasculitis (CV). METHODS: A multicenter study was conducted in 5 centres. Patients fulfilled the following criteria: (1) positive AECG criteria for pSS, (2) serum cryoglobulins evaluated, and (3) lack of hepatitis C virus infection. Four groups were distinguished and analysed by multinomial analyses: (1) B-cell non-Hodgkin's lymphoma (NHL), (2) CV without lymphoma, (3) salivary swelling without NHL (SW), and (4) pSS patients without NHL or prelymphomatous conditions. RESULTS: Six hundred and sixty-one patients were studied. Group 1/NHL comprised 40/661 (6.1%) patients, Group 2/CV 17/661 (2.6%), Group 3/SW 180/661 (27.2%), and Group 4/pSS controls 424/661 (64.1%). Low C4 [relative-risk ratio (RRR) 8.3], cryoglobulins (RRR 6.8), anti-La antibodies (RRR 5.2), and leukopenia (RRR 3.3) were the variables distinguishing Group 1/NHL from Group 4/Controls. As concerns the subset of patients with prelymphomatous conditions, the absence of these biomarkers provided a negative predictive value for lymphoma of 98% in patients with salivary swelling (Group 3/SW). Additional follow-up studies in patients with SW confirmed the high risk of lymphoma when at least 2/4 biomarkers were positive. CONCLUSIONS: Lymphoma-associated biomarkers were defined in a multicentre series of well-characterized patients with pSS, by dissecting the cohort in the pSS-associated prelymphomatous conditions. Notably, it was demonstrated for the first time that among the pSS patients with salivary swelling, only those with positive biomarkers present an increased risk of lymphoma evolution.

Differential ABCB and ABCC gene expression and efflux activities in gills and hemocytes of Mytilus galloprovincialis and their involvement in cadmium response.

The aim of the study was to characterize ABC transport proteins gene expression and efflux activities in gills and hemocytes of the Mediterranean mussel and to evaluate their response to Cd. At basal level a higher expression of abcb-like gene was observed in gills than in hemocytes while abcc-like gene showed similar levels. Both P-gp and MRPs inhibitors (cyclosporine and MK571) blocked efflux activities in gills; hemocytes were sensitive only to MK571. After 120 min in vitro pre-exposure to CdCl2, the efflux activity increased significantly in gills and hemocytes. In vivo exposure to CdCl2 (0.4 µM) increased abcb-like gene expression in gills without affecting efflux activity. In hemocytes abcc-like gene resulted up-regulated and Ca-AM efflux resulted enhanced. An increased uptake of Cd in gills biopsies was observed in the presence of both P-gp and MRPs inhibitors. Our results indicate that ABC transporters seem involved in the first protective response to Cd and this response is tissue-specific.

Pharmacological inhibition of microsomal prostaglandin E synthase-1 suppresses epidermal growth factor receptor-mediated tumor growth and angiogenesis.

BACKGROUND: Blockade of Prostaglandin (PG) E(2) production via deletion of microsomal Prostaglandin E synthase-1 (mPGES-1) gene reduces tumor cell proliferation in vitro and in vivo on xenograft tumors. So far the therapeutic potential of the pharmacological inhibition of mPGES-1 has not been elucidated. PGE(2) promotes epithelial tumor progression via multiple signaling pathways including the epidermal growth factor receptor (EGFR) signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: Here we evaluated the antitumor activity of AF3485, a compound of a novel family of human mPGES-1 inhibitors, in vitro and in vivo, in mice bearing human A431 xenografts overexpressing EGFR. Treatment of the human cell line A431 with interleukin-1beta (IL-1ß) increased mPGES-1 expression, PGE(2) production and induced EGFR phosphorylation, and vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression. AF3485 reduced PGE(2) production, both in quiescent and in cells stimulated by IL-1ß. AF3485 abolished IL-1ß-induced activation of the EGFR, decreasing VEGF and FGF-2 expression, and tumor-mediated endothelial tube formation. In vivo, in A431 xenograft, AF3485, administered sub-chronically, decreased tumor growth, an effect related to inhibition of EGFR signalling, and to tumor microvessel rarefaction. In fact, we observed a decrease of EGFR phosphorylation, and VEGF and FGF-2 expression in tumours explanted from treated mice. CONCLUSION: Our work demonstrates that the pharmacological inhibition of mPGES-1 reduces squamous carcinoma growth by suppressing PGE(2) mediated-EGFR signalling and by impairing tumor associated angiogenesis. These results underscore the potential of mPGES-1 inhibitors as agents capable of controlling tumor growth.

CD4(+) CD25(low) GITR(+) cells: a novel human CD4(+) T-cell population with regulatory activity.

Treg subsets play a role in sustaining peripheral tolerance, are characterized by markers such as forkhead winged-helix transcription factor (FOXP3) and CD25, and produce suppressive cytokines, such as IL-10 and TGF-ß. Glucocorticoid-induced TNF receptor family-related (GITR) protein has been suggested to regulate Treg activity in mice. The aim of our study was to investigate GITR expression in human CD4(+) T lymphocytes and its possible role in Treg function. Results indicate that a subset of CD4(+) T cells in the peripheral blood expresses GITR and low levels of CD25 (CD4(+) CD25(low) GITR(+) ). These cells show Treg features as they express FOXP3, IL-10, TGF-ß and are anergic but, as opposed to natural Tregs, express low levels of CTLA-4 and are CD127(high) . CD4(+) CD25(low) GITR(+) cells represent a low percentage of the CD4(+) T-cell population (0.32-1.74%) and are mostly memory cells. Functional experiments demonstrated that CD4(+) CD25(low) GITR(+) cells have relevant suppressive activity that depends on TGF-ß. Moreover, an anti-GITR Ab inhibited their suppressive activity, as observed in CD4(+) CD25(+) murine Tregs. Taken together, these data indicate that human CD4(+) CD25(low) GITR(+) cells represent a distinct Treg subpopulation.

Rituximab treatment for persistent scleritis associated with rheumatoid arthritis.

PURPOSE: To report a clinical case of a patient with severe scleritis associated with rheumatoid arthritis (RA) refractive to conventional treatment that was treated effectively with rituximab. METHODS AND RESULTS: A 55-year-old man with RA, on etanercept and oral methotrexate, was referred with diagnosis of acute stromal keratitis, anterior uveitis, and anterior nodular scleritis in his right eye. Cyclophosphamide induced complete regression of acute stromal keratitis and anterior uveitis, but scleritis was still active and persistent. After two 1000-mg infusions of rituximab, scleritis regressed completely and is still in remission 9 months after the second rituximab infusion, without any concomitant use of oral steroids. CONCLUSION: Rituximab may be a treatment alternative in severe scleritis that is refractive to conventional therapy. Considering its safety profile, further studies are needed to refine its mechanism of action, optimal indications, and dosing in ocular inflammation.

Functional impairment of the arterial wall in primary Sjögren's syndrome: combined action of immunologic and inflammatory factors.

OBJECTIVE: Primary Sjögren's syndrome (SS) shares clinical and serologic features with rheumatoid arthritis and systemic lupus erythematosus, 2 diseases characterized by acceleration of atherosclerosis. Signs of precocious atherosclerosis have also been shown in SS, although the pathogenic basis of early arterial damage is unclear. The arterial wall was functionally evaluated in SS subjects with analysis of the role played by disease-related factors. METHODS: Endothelium-dependent flow-mediated vasodilation (FMV) and endothelium-independent nitrate-mediated vasodilation (NMV) were evaluated in 45 women with SS and 59 age-matched female controls. In addition, serum soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1 (VCAM-1), and nitrotyrosine were detected. RESULTS: Although patient FMV values did not differ from those of control subjects (mean +/- SD 7.4 +/- 3.6 versus 7.7 +/- 1.9; not significant), NMV was lower in SS patients than in controls (mean +/- SD 8.1 +/- 3.5 versus 10.3 +/- 2.1; P

Identification of regulatory T cells in systemic lupus erythematosus.

The concept that regulatory T cells (Treg) play a key role in both development and maintenance of autoimmune response in rheumatic diseases is well accepted. In recent years, several studies analyzed Treg cell phenotype and function in systemic lupus erythematosus (SLE), the prototypical systemic autoimmune disorder in humans. Although qualitative and/or quantitative abnormalities of Treg cells have been shown, data are often conflicting. This may depend on the selection of patients with different degrees of disease activity or on immunosuppressive treatments that can alter Treg cell findings. Among several proposed surface or intracellular Treg cell markers, CD25 at high level of expression and the transcription factor Foxp3 are the two most investigated in SLE. Despite the glucocorticoid-induced TNF receptor-related protein (GITR) represents a reliable phenotypic marker of murine Treg cells, little is known about its role in humans, in particular in the course of systemic autoimmune disorders. Preliminary data seems to suggest that this marker may represent a good tool to identify cell populations included within Treg cell subsets.