Social capital I: measurement and associations with economic mobility.

Social capital-the strength of an individual's social network and community-has been identified as a potential determinant of outcomes ranging from education to health1-8. However, efforts to understand what types of social capital matter for these outcomes have been hindered by a lack of social network data. Here, in the first of a pair of papers9, we use data on 21 billion friendships from Facebook to study social capital. We measure and analyse three types of social capital by ZIP (postal) code in the United States: (1) connectedness between different types of people, such as those with low versus high socioeconomic status (SES); (2) social cohesion, such as the extent of cliques in friendship networks; and (3) civic engagement, such as rates of volunteering. These measures vary substantially across areas, but are not highly correlated with each other. We demonstrate the importance of distinguishing these forms of social capital by analysing their associations with economic mobility across areas. The share of high-SES friends among individuals with low SES-which we term economic connectedness-is among the strongest predictors of upward income mobility identified to date10,11. Other social capital measures are not strongly associated with economic mobility. If children with low-SES parents were to grow up in counties with economic connectedness comparable to that of the average child with high-SES parents, their incomes in adulthood would increase by 20% on average. Differences in economic connectedness can explain well-known relationships between upward income mobility and racial segregation, poverty rates, and inequality12-14. To support further research and policy interventions, we publicly release privacy-protected statistics on social capital by ZIP code at https://www.socialcapital.org .

Social capital II: determinants of economic connectedness.

Low levels of social interaction across class lines have generated widespread concern1-4 and are associated with worse outcomes, such as lower rates of upward income mobility4-7. Here we analyse the determinants of cross-class interaction using data from Facebook, building on the analysis in our companion paper7. We show that about half of the social disconnection across socioeconomic lines-measured as the difference in the share of high-socioeconomic status (SES) friends between people with low and high SES-is explained by differences in exposure to people with high SES in groups such as schools and religious organizations. The other half is explained by friending bias-the tendency for people with low SES to befriend people with high SES at lower rates even conditional on exposure. Friending bias is shaped by the structure of the groups in which people interact. For example, friending bias is higher in larger and more diverse groups and lower in religious organizations than in schools and workplaces. Distinguishing exposure from friending bias is helpful for identifying interventions to increase cross-SES friendships (economic connectedness). Using fluctuations in the share of students with high SES across high school cohorts, we show that increases in high-SES exposure lead low-SES people to form more friendships with high-SES people in schools that exhibit low levels of friending bias. Thus, socioeconomic integration can increase economic connectedness in communities in which friending bias is low. By contrast, when friending bias is high, increasing cross-SES interactions among existing members may be necessary to increase economic connectedness. To support such efforts, we release privacy-protected statistics on economic connectedness, exposure and friending bias for each ZIP (postal) code, high school and college in the United States at https://www.socialcapital.org .

Nonclassical MHC class Ib-restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum.

The aminopeptidase ERAAP is essential for trimming peptides presented by major histocompatibility complex (MHC) class I molecules. Inhibition of ERAAP by cytomegalovirus results in evasion of the immune response by this virus, and polymorphisms in ERAAP are associated with autoimmune disorders. How normal ERAAP function is monitored is unknown. We found that inhibition of ERAAP rapidly induced presentation of the peptide FYAEATPML (FL9) by the MHC class Ib molecule Qa-1(b). Antigen-experienced T cells specific for the Qa-1(b)-FL9 complex were frequent in naive mice. Wild-type mice immunized with ERAAP-deficient cells mounted a potent CD8(+) T cell response specific for Qa-1(b)-FL9. MHC class Ib-restricted cytolytic effector cells specifically eliminated ERAAP-deficient cells in vitro and in vivo. Thus, nonclassical Qa-1(b)-peptide complexes direct cytotoxic T cells to targets with defective antigen processing in the endoplasmic reticulum.

Real-world persistence of initial targeted therapy strategy in monotherapy versus combination therapy in patients with chronic inflammatory arthritis.

OBJECTIVE: The persistence of biologic (b) and targeted synthetic (ts) disease-modifying antirheumatic drugs(DMARDs) in monotherapy versus in combination with conventional synthetic (cs) DMARDs is still a controversial topic in rheumatic diseases. To clarify this issue, the retention of the initial treatment strategy of b/tsDMARD in combination with csDMARD versus monotherapy in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients under real-life conditions was evaluated. Factors associated with maintenance of the initial strategy were analysed. METHODS: Nested cohort study within the Spanish BIOBADASER III registry. Bivariate comparisons and multivariate Cox proportional hazards models were used for the analyses. RESULTS: A total of 2521 patients were included in the study. In the multivariate model, the initial strategy of combination therapy was associated with shorter persistence in patients with RA (hazard ratio [HR] 1.58;95% confidence interval [CI] 1.00-2.50; p = .049), PsA (HR 2.48; 95% CI 1.65-3.72) and AS (HR 16.77; 95% CI 7.37-38.16; p < .001), regardless of sex, time of disease progression, baseline disease activity, glucocorticoid use or type of b/tsDMARD. Overall, the combination strategy was associated with an increased incidence of adverse events (incidence rate ratio [IRR] 1.13; 95% CI 1.05-1.21). CONCLUSIONS: In this real-life study, the strategy of combining a b/tsDMARD with a csDMARD is associated with lower persistence and worse safety profile compared to monotherapy in RA and especially in PsA and AS, suggesting that combination therapy should be rethought as first choice in RA patients, but especially in PsA and AS patients.

The complement system is linked to insulin resistance in patients with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients more commonly have insulin resistance (IR) than control subjects. Recent studies have revealed that the complement (C) system is not only a mediator of the immune system but is also related to the pathogenesis of atherosclerosis in the general population. Given that the C alteration is a characteristic of SLE, in the present work we set out to analyse if there is a relationship between the C system and IR in patients with SLE. METHODS: New generation functional assays of the three pathways of the C system were performed in 225 non-diabetic patients with SLE. In addition, the serum levels of inactive (C1q, C2, C3, C4, factor D), activated (C3a) and regulators (C1 inhibitor and factor H) molecules of the C system were evaluated. Insulin and C-peptide serum levels were measured, and insulin resistance and indices of beta cell function were calculated using the homeostatic model assessment (HOMA). Metabolic syndrome criteria fulfillments were applied. Multivariable linear regression analysis was performed to assess the relationship between C system and IR indices and the presence of metabolic syndrome. RESULTS: After adjusting for covariates that included traditional cardiovascular risk factors associated with IR and prednisone, serum C3a and factor H levels were positively related to higher levels of the HOMA2-IR index. Besides, in the multivariable analysis, after adjustment for covariates, serum levels of C1q and C3 associated with a higher odds ratio for the presence of metabolic syndrome. CONCLUSIONS: IR and metabolic syndrome are positively and independently related to higher serum levels of some serum C elements in patients with SLE with a predominant role of the alternative pathway elements.

Profibrotic Role of Inducible Heat Shock Protein 90α Isoform in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-ß, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.

Second and third TNF inhibitors in European patients with axial spondyloarthritis: Effectiveness and impact of the reason for switching.

OBJECTIVE: To investigate real-world effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA) and the association with 1) treatment line (second and third TNFi-series) and 2) reason for withdrawal from the preceding TNFi (lack of efficacy (LOE) versus adverse events (AE)). METHODS: Prospectively collected routine care data from 12 European registries were pooled. Rates for 12-month drug retention and 6-month remission (Ankylosing Spondylitis Disease Activity Score C-reactive protein inactive disease (ASDAS-ID)) were assessed in second and third TNFi-series and stratified by withdrawal reason. RESULTS: We included 8254 s and 2939 third TNFi-series; 12-month drug retention rates were similar (71%). Six-month ASDAS-ID rates were higher for the second (23%) than third TNFi (16%). Twelve-month drug retention rates for patients withdrawing from the preceding TNFi due to AE versus LOE were similar for the second (68% and 67%) and third TNFi (both 68%), while for the second TNFi, rates were lower in primary than secondary non-responders (LOE < 26 versus ≥26 weeks) (58% versus 71%, p< 0.001). Six-month ASDAS-ID rates for the second TNFi were higher if the withdrawal reason was AE (27%) versus LOE (17%), p< 0.001, while similar for the third TNFi (19% versus 13%, p= 0.20). CONCLUSION: A similar proportion of axSpA patients remained on a second and third TNFi after one year, but with low remission rates for the third TNFi. Remission rates on the second TNFi (but not the third) were higher if the withdrawal reason from the preceding TNFi was AE versus LOE.

Tocilizumab-related hypertriglyceridemia is independent of key molecules regulating lipid metabolism.

INTRODUCTION: Tocilizumab (TCZ) treatment is associated with dyslipidaemia, including a rise in triglycerides through a mechanism poorly understood. Three molecules play key roles in the regulation of triglyceride metabolism: apolipoprotein C-III (ApoC-III), angiopoietin-like protein 4(ANGPLT4) and lipoprotein lipase (LPL). The aim of this work was to analyse whether the changes in triglycerides shown by TCZ-treated RA patients could stem from the dysregulation that can occur in these regulatory molecules. METHODS: Twenty-seven RA patients included in the TOCRIVAR study who received TCZ (8 mg/kg IV/q4w) were evaluated at baseline and at Weeks 12, 24 and 52 of treatment. ANGPTL4, ApoC-III and LPL, a complete lipid profile and RA disease activity, were analysed at baseline and at each visit. Multivariable linear mixed models were performed to study changes over time in lipids and regulatory molecules. RESULTS: After 24 weeks of TCZ treatment, HDL cholesterol, apolipoprotein A1 and triglycerides increased, whereas lipoprotein (a) decreased significantly from baseline values. However, 1 year after TCZ, no significant differences in lipid pattern were observed with respect to baseline. Serum ANGPTL4 and Apo-CIII levels decreased gradually over time, both being significantly lower than baseline values at Week 52. LPL concentration did not change significantly during TCZ treatment. Remarkably, the elevation of triglycerides at Week 24 maintained its statistical significance after adjusting for the changes in ApoC-III, ANGPTL4 and LPL. CONCLUSION: In TCZ-treated RA patients basal serum levels of ANGPLT4 and ApoC-III, but not LPL, decreased significantly. However, the elevation of triglycerides after TCZ was not related to changes in these regulatory molecules.

Assessing the dynamics of CO adsorption on Cu(110) using the vdW-DF2 functional and artificial neural networks.

In this work, we revisit the dynamics of carbon monoxide molecular chemisorption on Cu(110) by using quasi-classical trajectory calculations. The molecule-surface interaction is described through an atomistic neural network approach based on Density Functional Theory calculations using a nonlocal exchange-correlation (XC) functional that includes the effect of long-range dispersion forces: vdW-DF2 [Lee et al. Phys. Rev. B, 82, 081101 (2010)]. With this approach, we significantly improve the agreement with experiments with respect to a similar previous study based on a semi-local XC functional. In particular, we obtain excellent agreement with molecular beam experimental data concerning the dependence of the initial sticking probability on surface temperature and impact energy at normal incidence. For off-normal incidence, our results also reproduce two trends observed experimentally: (i) the preferential sticking for molecules impinging parallel to the [1̄10] direction compared to [001] and (ii) the change from positive to negative scaling as the impact energy increases. Nevertheless, understanding the origin of some remaining quantitative discrepancies with experiments requires further investigations.

Prevalence of symptomatic axial osteoarthritis phenotypes in Spain and associated socio-demographic, anthropometric, and lifestyle variables.

OBJECTIVE: Axial osteoarthritis (OA) is a common cause of back and neck pain, however, few studies have examined its prevalence. The aim was to estimate the prevalence and the characteristics of symptomatic axial OA in Spain. METHODS: EPISER2016 is a cross-sectional multicenter population-based study of people aged 40 years or older. Subjects were randomly selected using multistage stratified cluster sampling. Participants were contacted by telephone to complete rheumatic disease screening questionnaires. Two phenotypes were analyzed, patients with Non-exclusive axial OA (NEA-OA) and Exclusive axial OA (EA-OA). To calculate the prevalence and its 95% confidence interval (CI), the sample design was considered and weighting was calculated according to age, sex and geographic origin. RESULTS: Prevalence of NEA-OA by clinical or clinical-radiographic criteria was 19.17% (95% CI: 17.82-20.59). The frequency of NEA-OA increased with age (being 3.6 times more likely in patients aged 80 s or more than in those between 40 and 49 years) and body mass index. It was significantly more frequent in women, as well as in the center of Spain. It was less frequent in those with a higher level of education. Lumbar OA was more frequent than cervical OA. This difference grew with increasing age and was not associated with gender. It was also greater in overweight and obese subjects. CONCLUSIONS: This is the first study on the prevalence of axial OA phenotypes in Europe describing the associated socio-demographic, anthropometric, and lifestyle variables.

L-selectin expression is regulated by CXCL8-induced reactive oxygen species produced during human neutrophil rolling.

Neutrophils destroy invading microorganisms by phagocytosis by bringing them into contact with bactericidal substances, among which ROS are the most important. However, ROS also function as important physiological regulators of cellular signaling pathways. Here, we addressed the involvement of oxygen derivatives in the regulation of human neutrophil rolling, an essential component of the inflammatory response. Flow experiments using dihydroethidium-preloaded human neutrophils showed that these cells initiate an early production of intracellular ROS during the rolling phase of the adhesion cascade, a phenomenon that required cell rolling, and the interaction of the chemokine receptor CXCR2 with their ligand CXCL8. Flow cytometry experiments demonstrated that L-selectin shedding in neutrophils is triggered by ROS through an autocrine-paracrine mechanism. Preincubation of neutrophils with the NADPH oxidase complex inhibitor diphenyleniodonium chloride significantly increased the number of rolling neutrophils on endothelial cells. Interestingly, the same effect was observed when CXCL8 signaling was interfered using either a blocking monoclonal antibody or an inhibitor of its receptor. These findings indicate that, in response to CXCL8, neutrophils initiate ROS production during the rolling phase of the inflammatory response. This very early ROS production might participate in the modulation of the inflammatory response by inducing L-selectin shedding in neutrophils.

Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum.

The parasite Toxoplasma gondii replicates in a specialized intracellular vacuole and causes disease in many species. Protection from toxoplasmosis is mediated by CD8(+) T cells, but the T. gondii antigens and host genes required for eliciting protective immunity are poorly defined. Here we identified GRA6, a polymorphic protein secreted in the parasitophorous vacuole, as the source of the immunodominant and protective decapeptide HF10 presented by the H-2L(d) major histocompatibility complex class I molecule. Presentation of the HF10-H-2L(d) ligand required proteolysis by ERAAP, the endoplasmic reticulum aminopeptidase associated with antigen processing. Consequently, expansion of protective CD8(+) T cell populations was impaired in T. gondii-infected ERAAP-deficient mice, which were more susceptible to toxoplasmosis. Thus, endoplasmic reticulum proteolysis is critical for eliciting protective immunity to a vacuolar parasite.

Impaired HDL cholesterol efflux capacity in systemic lupus erythematosus patients is related to subclinical carotid atherosclerosis.

OBJECTIVES: Lipid profiles appear to be altered in SLE patients due to disease activity and inflammation. Cholesterol efflux capacity (CEC) is the ability of high-density lipoprotein cholesterol to accept cholesterol from macrophages. CEC has been linked to cardiovascular events in the general population and is impaired in SLE patients. The aim of this study was to establish whether CEC is related to subclinical carotid atherosclerosis in SLE patients. METHODS: The present report is of a cross-sectional study that encompassed 418 individuals: 195 SLE patients and 223 controls. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed in patients and controls. Carotid intima-media thickness and carotid plaques were evaluated in SLE patients. A multivariable analysis was performed to study the relationship of CEC to SLE-related data, lipid profile and subclinical carotid atherosclerosis. RESULTS: CEC was downregulated in SLE patients [8.1 (4.2) % vs 16.9 (10.4) %, P = 0.004). This occurred independently of traditional cardiovascular risk factors, statin use or other variations in the lipid profile related to the disease. Traditional cardiovascular risk factors, both in patients and controls, and SLE-related data such as activity, severity or damage were not associated with CEC. After multivariable regression analysis including lipid profile-related molecules, CEC was inversely and independently associated with the presence of carotid plaques in SLE patients [odds ratio 0.87 (95% CI: 0.78, 0.97), P = 0.014]. CONCLUSION: CEC is impaired in SLE patients independently of other inflammation-related lipid profile modifications that occur during the disease. CEC is associated with carotid plaques in SLE patients.

Prevalence of systemic lupus erythematosus in Spain: higher than previously reported in other countries?

OBJECTIVES: Prevalence of SLE varies among studies, being influenced by study design, geographical area and ethnicity. Data about the prevalence of SLE in Spain are scarce. In the EPISER2016 study, promoted by the Spanish Society of Rheumatology, the prevalence estimate of SLE in the general adult population in Spain has been updated and its association with sociodemographic, anthropometric and lifestyle variables has been explored. METHODS: Population-based multicentre cross-sectional study, with multistage stratified and cluster random sampling. Participants were contacted by telephone to carry out a questionnaire for the screening of SLE. Investigating rheumatologists evaluated positive results (review of medical records and/or telephone interview, with medical visit if needed) to confirm the diagnosis. To calculate the prevalence and its 95% CI, the sample design was taken into account and weighing was calculated considering age, sex and geographic origin. Multivariate logistic regression models were defined to analyse which sociodemographic, anthropometric and lifestyle variables included in the telephone questionnaire were associated with the presence of SLE. RESULTS: 4916 subjects aged 20 years or over were included. 16.52% (812/4916) had a positive screening result for SLE. 12 cases of SLE were detected. The estimated prevalence was 0.21% (95% CI: 0.11, 0.40). SLE was more prevalent in the rural municipalities, with an odds ratio (OR) = 4.041 (95% CI: 1.216, 13.424). CONCLUSION: The estimated prevalence of SLE in Spain is higher than that described in most international epidemiological studies, but lower than that observed in ethnic minorities in the United States or the United Kingdom.

Proprotein convertase subtilisin/kexin type 9 in patients with systemic sclerosis.

OBJECTIVES: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor degradation, and which has been linked to cardiovascular risk. The purpose of the present study was to examine whether PCSK9 serum levels are disrupted in patients with systemic sclerosis (SS) compared to controls, and if PCSK9 is related to disease-related data and the subclinical atherosclerosis that occurs in these patients. METHODS: Cross-sectional study that encompassed 146 individuals; 73 patients with SS and 73 age- and sex-matched controls. PCSK9, lipoproteins serum concentrations, and standard lipid profiles were assessed in patients and controls. Carotid intima-media thickness (cIMT) and the presence of carotid plaques were evaluated in SS patients. A multivariable analysis, adjusted for traditional cardiovascular risk factors, was performed to evaluate the differences in PCSK9 between patients and controls, the association of SS-related manifestations with PCSK9 levels, and if PCSK9 was associated with subclinical carotid atherosclerosis in SS patients. RESULTS: After multivariable analysis, PCSK9 was downregulated in SS patients compared to controls (beta coefficient -78 (95%CI -106 - -50) ng/ml, p=0.000) and skin thickness was associated with higher serum levels of PCSK9 (beta coef. 22 (7-37) units, p=0.005). PCSK9 was significantly and positively associated with cIMT (beta coef. 0.65 (0.06-1.24) ng/ml, p=0.031) in SS patients after multivariable adjustment. CONCLUSIONS: PCSK9 serum concentration is downregulated in SS patients compared to controls and is directly associated with disease severity subrogated parameters. PCSK9 was independently related to cIMT in SS patients.

Prevalence of fibromyalgia and associated factors in Spain.

OBJECTIVES: The prevalence of fibromyalgia (FM) differs depending on the population studied. The main objective of the EPISER2016 study was to estimate the prevalence of FM in adults in Spain. The secondary objective was to evaluate the association with sociodemographic and anthropometric characteristics and smoking. METHODS: This is a population-based cross-sectional multicentre study. The random selection was based on multistage stratified cluster sampling. The final sample comprised 4916 persons aged ≥20 years. Participants were contacted by telephone for completion of a screening survey. Investigating rheumatologists evaluated positive results (review of medical records and/or telephone interview, with medical visit if needed) to confirm the diagnosis. Prevalence and 95% confidence interval were calculated, taking into account the sample design. Weighing was applied based on age, sex, and geographic origin. Predictive models were constructed to analyse which sociodemographic, anthropometric and lifestyle variables in the call centre questionnaire were associated with the presence of FM. RESULTS: 602 subjects (12.25%) had a positive screening result for FM, of which 24 were missing (3.99%). A total of 141 cases of FM were recorded. The estimated prevalence was 2.45% (95% CI, 2.06-2.90). Female sex was the variable most associated with FM, with an odds ratio (OR) of 10.156 (95% CI, 5.068-20.352). Peak prevalence was at 60-69 years (p=0.009, OR=6.962). FM was 68% more frequent in obese individuals (OR, 1.689; 95% CI, 1.036-2.755). CONCLUSIONS: The prevalence of FM in adults in Spain barely changed between 2000 and 2016 and it is similar to that observed in Europe as a whole.

Effect of IL-6 Receptor Blockade on Proprotein Convertase Subtilisin/Kexin Type-9 and Cholesterol Efflux Capacity in Rheumatoid Arthritis Patients.

The aim of the work was to examine whether abnormalities in the lipid profile that tocilizumab (TCZ), an anti-IL-6 receptor Ab, exerts in rheumatoid arthritis (RA) patients is related to changes in either proprotein convertase subtilisin/kexin-9 (PCSK9) serum concentrations or in serum cholesterol efflux capacity (CEC). TOCRIVAR is a one-year prospective clinical trial that analyzes the influence of TCZ on cardiovascular risk factors. Twenty-seven RA patients receiving TCZ (8 mg/kg IV/q4w) were assessed at baseline and weeks 12, 24, and 52. Disease activity indexes, adiposity composition, physical activity, serum CEC, PCSK9, and lipoproteins serum concentrations were assessed at every visit. Basal high-sensitivity C-reactive protein (hs-CRP) and disease activity were markedly reduced throughout one-year TCZ treatment. While initially total cholesterol and LDL cholesterol increased their plasma concentration, decreasing to basal afterwards, lipoprotein(a) was significantly lower than basal in all visits of the study. CEC increased after 24 week of treatment proportionally to hs-CRP reduction, and remained significantly higher after week 52 [median % change 32 (3-141), p=0.021]. Interestingly, variations in LDL cholesterol basal concentration along the one year of TCZ treatment correlated directly with changes of PCSK9 serum concentration (r=0.37, p=0.003). Basal abdominal adiposity, BMI, and physical activity remained stable during the study. Long-term TCZ-treated RA patients show an increment in CEC inversely proportional to hs-CRP reduction and changes in LDL cholesterol that might be explained, at least in part, by variations in PCSK9 plasma concentration. Overall, TCZ treatment produces a favorable qualitative net effect in terms of atherogenic implication in RA patients.

Antigen Processing in the Endoplasmic Reticulum Is Monitored by Semi-Invariant αß TCRs Specific for a Conserved Peptide-Qa-1b MHC Class Ib Ligand.

Ag processing in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with Ag processing (ERAAP) is central to presentation of a normal peptide-MHC class I (MHC I) repertoire. Alternations in ERAAP function cause dramatic changes in the MHC I-presented peptides, which elicit potent immune responses. An unusual subset of CD8+ T cells monitor normal Ag processing by responding to a highly conserved FL9 peptide that is presented by Qa-1b, a nonclassical MHC Ib molecule (QFL) in ERAAP-deficient cells. To understand the structural basis for recognition of the conserved ligand, we analyzed the αß TCRs of QFL-specific T cells. Individual cells in normal wild-type and TCRß-transgenic mice were assessed for QFL-specific TCR α- and ß-chains. The QFL-specific cells expressed a predominant semi-invariant TCR generated by DNA rearrangement of TRAV9d-3-TRAJ21 α-chain and TRBV5-TRBD1-TRBJ2-7 ß-chain gene segments. Furthermore, the CDR3 regions of the α- as well as ß-chains were required for QFL ligand recognition. Thus, the αß TCRs used to recognize the peptide-Qa-1 ligand presented by ERAAP-deficient cells are semi-invariant and likely reflect a conserved mechanism for monitoring the fidelity of Ag processing in the ER.

Efficacy and safety of biological therapy compared to synthetic immunomodulatory drugs or placebo in the treatment of Behçet's disease associated uveitis: a systematic review.

The aim of this study is to compare the efficacy and safety of biological therapy with cyclosporin A (CsA), azathioprine (AZA), or placebo in uveitis flares and other ocular outcomes in patients with Behçet disease. A comprehensive and sensitive search in MEDLINE, EMBASE, and the Cochrane Library was performed. We selected articles including: (1) adult patients with Behçet's and uveitis; (2) on biological therapies; (3) placebo or active control with CsA or AZA; (4) analyzing efficacy (number of uveitis flares, macular edema, etc.) and/or safety outcomes. Meta-analyses, systematic reviews, clinical trials, and observational studies with > 10 patients were included. The selection, data collection and quality assessment (Oxford scale) was carried out by 2 reviewers independently. Nine articles of moderate quality were included (6 randomized clinical trials and 3 retrospective studies) involving 378 patients. Most of them, apart from the study drugs received systemic corticosteroids and other immunosuppressant drugs. Infliximab was more effective than CsA in reducing short-term uveitis flares and severe complications of retinal vasculitis in the long term. Rituximab was similar to a combination of cytotoxic drugs in improving inflammatory activity. In patients with active uveitis adalimumab was associated with a lower risk of uveitic flare or visual impairment, and in patients with inactive uveitis to a significantly lowered the risk of flare upon corticosteroid withdrawal. Secukinumab and daclizumab were not superior to placebo in reducing uveitis flares, like interferonα compared to other drugs. Our results highlight the need for better designed comparative studies on Behçet's uveitis.

Factors associated with long-term retention of treatment with golimumab in a real-world setting: an analysis of the Spanish BIOBADASER registry.

The retention rate of a biological drug (percentage of patients remaining on treatment over time) provides an index of a drug's overall effectiveness. The golimumab retention rate as first-line biological therapy was high in clinical trial extensions lasting 5 years. Real-world studies also indicate good retention rates but have been of shorter duration. The probability of retention with golimumab treatment was assessed, as any line of anti-tumor necrosis factor-alpha therapy, for up to 5 years in patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA) or psoriatic arthritis (PsA), associated factors were analyzed. A retrospective database analysis of the Spanish registry of patients with rheumatic disorders receiving biological drugs (BIOBADASER) was performed. Among 353 patients, 29.8% had RA, 41.6% SpA and 28.6% PsA. Golimumab was the first biological drug in 40.1% of patients, second in 30.1% and third/later in 29.8%. The overall probability of retention of golimumab at years 1, 2, 3, 4 and 5 was 85.9% (95% confidence interval 81.4-89.5%), 73.7% (67.1-79.1%), 68.5% (60.5-75.1%), 60.6% (50.2-69.5%) and 57.1% (44.9-67.5%), respectively. Retention was similar across indications (p = 0.070) but was greater when golimumab was used as the first biological agent compared with later therapy lines (p < 0.001). Factors associated with higher retention of golimumab treatment (Cox regression) were use as a first-line biological and concomitant methotrexate treatment; corticosteroid need was associated with lower retention. The long-term probability of golimumab retention was high in this real-world study of patients with rheumatic diseases, especially when used as the first biological drug.