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.

Effectiveness of biological targeted therapies may discriminate seronegative from seropositive rheumatoid arthritis.

OBJECTIVE: To assess the real-world effectiveness of targeting biologic drugs (bDMARD) in rheumatoid arthritis (RA) patients negative for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). METHODS: We retrospectively selected 81 seronegative and 404 seropositive RA patients receiving treatment with abatacept, anti-tumor necrosis factor (TNF) alpha, or tocilizumab. Effectiveness was evaluated by analyzing drug survival using Kaplan-Meyer analysis over 10-year follow-up. Survival rates were compared by log rank test, and hazard ratios (HRs) of therapy discontinuation were estimated through multivariate Cox-regression. RESULTS: Clinical characteristics were similar between the two groups, except for a significantly higher percentage of inadequate responders to prior bDMARDs in the seronegative RA patients (p= 0.02). Among seronegative RA, tocilizumab demonstrated a survival rate of 73.9% with a mean survival time (MST) of 76.8 months (95% CI 61-92), which was significantly higher than abatacept (37.5%, MST 37.1 months (95% CI 22-51; p= 0.01). Anti-TNF alpha therapy fell in the middle (50.0%, MST 63.5 months (95% CI 47-79) but the difference was not significant. Nevertheless, seropositive RA patients did not show significantly different drug survival rates. Negative predictors of drug discontinuation were RF/ACPA positivity (HR 0.56) and sex male (HR 0.58), but treatment with abatacept (HR 1.88) or anti-TNF alpha (HR 1.79), no co-therapy with cDMARD (HR 1.74), absence of bone erosions (HR 1.41), and higher HAQ (HR 1.58) were positive predictors. CONCLUSIONS: To confirm these preliminary findings and to explore the hypothesis of a distinctive therapeutic algorithm in seronegative RA, prospective studies on larger cohorts are needed.

Immunogenicity of BNT162b2 mRNA SARS-CoV-2 vaccine in patients with psoriatic arthritis on TNF inhibitors.

BACKGROUND: Scanty data on the immunogenicity of the BNT162b2 vaccine in patients with psoriatic arthritis (PsA) on Tumor Necrosis Factor inhibitors (TNFi) have been published. OBJECTIVE: To investigate the humoral response to BNT162b2 vaccination patients with PsA on TNFi, comparing immunogenicity with healthy controls. METHODS: Forty patients with classified PsA on TNFi undergoing vaccination with the BNT162b2 mRNA SARS-CoV-2 vaccine (BioNTech/Pfizer) were enrolled. Fifteen days after the second shot, serum IgG levels against SARS-CoV-2 (Abbott ARCHITECT i2000SR, positivity cut-off 50 AU/mL) were assayed in all patients. Clinimetrics and treatment data were gathered. TNFi treatment was not discontinued throughout the whole period, whereas methotrexate (MTX) was discontinued for 1 week after each shot in those on combination therapy. Sera from healthcare professionals were considered as healthy controls for 1:1 propensity score matching; any of them was taking medication.Student's t-test and logistic regression were used for investigating differences in immunogenicity between groups and predictors of antibody response. RESULTS: Clinical Disease Activity Index did not change before and after vaccination (7.06±5.23 to 7.10±5.27, p=0.92).Patients with PsA achieved a positive anti-SARS-CoV-2 IgG level with a mean (±SD) of 13794.44±15 815.42 AU/mL. Although lower, the antibody level was not significantly different from matched controls (19227.4±11.8460.45 AU/mL, p=0.08). In the overall sample, those on MTX (12/80, 15%) had a trend toward lower immune response (p=0.07); glucocorticoid therapy (11/80, 13.8%) predicted lower antibody levels (p=0.04). CONCLUSIONS: Continuing TNFi in patients with PsA throughout the vaccination did not hamper immunogenicity.

Body mass index and adipokines/cytokines dysregulation in systemic sclerosis.

Body fat has regulatory functions through producing cytokines and adipokines whose role in the pathogenesis of systemic sclerosis (SSc) is currently emerging. Changes in body mass, either over- or underweight, entail a dysregulation of the cytokine/adipokine network that may impact upon SSc disease activity. We evaluated serum levels of adipokines and cytokines in SSc patients and correlated them to clinical features and body mass index (BMI) categories. The study included 89 SSc patients and 26 healthy donors (HD). Serum levels of adiponectin, leptin, resistin, visfatin, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-10 and IL-17A were measured by multiplex immunoassay and correlated to BMI and disease-specific features. Student's t-test or analysis of variance (ANOVA) were used for comparisons between groups. Spearman's or Pearson's tests were used for correlation analysis. Serum levels of TNF-α, IL-2, leptin and resistin were significantly higher in SSc than in HD. Leptin levels were significantly higher in interstitial lung disease (ILD)- and pulmonary arterial hypertension (PAH)-SSc subgroups. The highest levels of IL-17A, IL-2, IL-10, leptin and visfatin were detected in SSc patients with obesity (p < 0.01). Conversely, underweight SSc patients showed the highest TNF-α levels (p < 0.05). Adipokines, IL-2, IL-10 and IL-17A were found to be increased in SSc patients with obesity, but whether or not they play a role in the pathogenesis of the disease remains to be investigated. Intriguingly, underweight patients had the highest TNF-α levels, suggesting a potential role of TNF-α in inducing the cachexia observed in long-lasting disease.

Golimumab effectiveness in biologic inadequate responding patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis in real-life from the Italian registry GISEA.

OBJECTIVE: To evaluate the clinical effectiveness of golimumab in biologic inadequate responder (IR) patients with Rheumatoid arthritis (RA), Spondyloarthritis (SpA), and Psoriatic arthritis (PsA). METHODS: We analyzed 1424 patients on golimumab from the GISEA registry. Drug survival was estimated by Kaplan-Meier analysis in biologic-naïve, 1-biologic IR, ≥2-biologics IR patients. Hazard ratios (HRs) of discontinuing golimumab at 2 years were assessed by multivariate Cox regression. Patients achieving CDAI based low disease activity (LDA) or BASDAI<4 were calculated at 6 and 12 months. RESULTS: In RA (n.370), the 2-years survival on golimumab was 61.4% in 1-biologic IR, 51.9% in≥2-biologics IR, and 73.1% in biologic-naive patients (P=0.002 vs≥2-biologics IR). In SpA (n.502), the survival was similar among 1-biologic IR (80%), ≥2-biologics IR (76.5%), and biologic-naive (74.6%) patients (P>0.05). In PsA (n.552) the survival was 72% in 1-biologic IR, 72.5% in≥2-biologics IR, and 71.8% in naïve-biologic (P>0.05). Predictors of golimumab discontinuation were monotherapy (HR 1.65) for RA, female gender for SpA (HR 2.48) and PsA (HR 1.57). In RA, patients on CDAI-LDA were lower in 1-biologic IR (40%) or≥2 biologics IR (40%) than in biologic-naïve (60%) group at 6 months (P=0.02), but no difference was observed at 12 months. In PsA and SpA, the percentage of patients on CDAI-LDA or BASDAI<4 at 6 months was almost identical across the subgroups. CONCLUSIONS: Golimumab had similar effectiveness in biologic-failure and biologic-naïve SpA and PsA, but seems to be less effective in multi-failure RA patients, especially as monotherapy. The best outcomes were seen in male patients.

Cardiovascular risk estimation with 5 different algorithms before and after 5 years of bDMARD treatment in rheumatoid arthritis.

BACKGROUND: Assessing cardiovascular (CV) risk represents a challenge for clinicians because more variables can impact CV risk. The aim of this study was to evaluate the change of CV risk after 5 years of biological treatment in rheumatoid arthritis (RA) patients and impact of prolonged low disease activity on 5 different CV risk algorithms. MATERIALS AND METHODS: We estimated the CV risk, at baseline and at 5-year follow-up (FU), with the Systematic COronary Risk Evaluation(SCORE) charts, the algorithm 'Progetto Cuore', the QRISK3-2018 score, the Reynold Risk Score(RRS) and the Expanded Risk Score in RA(ERS-RA). Clinical disease activity index(CDAI) was used to define RA activity. Wilcoxon signed-rank test was used to compare CV risk scores. RESULTS: In 110 patients with a 5-year FU on biological disease-modifying anti-rheumatic drug treatment, we observed an increase in the 10-year CV risk estimated by SCORE charts [from mean (SD) 0.9% (1.4) to 1.1% (1.5), P < .001], 'Progetto Cuore' [from mean (SD) 5.5% (7.2) to 6.2% (6.8), P < .001], QRISK3-2018 [from mean (SD) 9.3% (10.1) to 11.9% (10.8), P < .001) and RRS [from mean (SD) 5.6% (6.4) to 6.2% (7.5), P < .05], mainly due to age raise. ERS-RA highlighted a significant decrease of estimated CV risk in patients with persistent CDAI ≤ 10[from mean (SD) 9.6% (11.2) to 7.3% (6.4), P < .05], despite age increase and its impact on the CV risk score. CONCLUSIONS: Algorithms commonly used to estimate 10-year CV risk in RA perform differently. Scores that include specific inflammatory RA-related variables seem to decrease with amelioration of disease activity. Further investigations are warranted to explore the predictive value of their changing over time.

Comorbid fibromyalgia impairs the effectiveness of biologic drugs in patients with psoriatic arthritis.

OBJECTIVES: To evaluate the impact of FM on the clinical outcomes of biologics in patients with PsA in real life. METHODS: FM was diagnosed according to current criteria among PsA patients starting a first biologic drug from 2010 through 2017. At each visit, disease activity of PsA (DAPSA), minimal disease activity (MDA), HAQ, rate of patients achieving DAPSA-based low disease activity (LDA) or remission, and MDA were evaluated. Lost patients or those not achieving the target were imputed as non-responders. The drug survival was evaluated by Kaplan-Meyer analysis. Estimated hazard ratios (HRs) of discontinuing therapy or achieving MDA were assessed by multivariate regression models. RESULTS: A total of 238 patients, of whom 58 had also FM, started a first biologic drug. Compared with no-FM PsA, FM PsA patients were more frequently female (P = 0.0001) with polyarticular subset (P = 0.0001), and with higher mean BMI (P = 0.006). Drug survival was significantly lower in FM PsA (50%, mean 32 months) than in no-FM PsA (74%, mean 42 months, P = 0.0001). Rates of remission/LDA and MDA were significantly lower in FM PsA at 3, 6, 12 and 24 months (P < 0.001). Remission in FM PsA was negligible (3.4% and 0% at 3 and 6 months, respectively). Negative predictors of drug discontinuation were no FM (HR 0.51) and normal weight (HR 0.29), while no FM (HR 2.54) and male sex (HR 1.58) were positive predictors of long-standing MDA. CONCLUSIONS: Comorbid FM, along with female gender and obesity seem to be the worst combination of negative prognostic factors in PsA.

Psoriatic arthritis and obesity: the role of anti-IL-12/IL-23 treatment.

Patients with psoriatic arthritis (PsA) have an increased prevalence of obesity, but mechanisms underlying this association remain unknown and it is unclear if obesity is the cause or effect of PsA. For PsA patients, comorbid obesity may influence their clinical response to systemic treatment, and especially targeted immunomodulators such as anti-tumor necrosis factor (TNF)α. Weight gain has also been associated with anti-TNFα treatment. Consequently, modification of the therapeutic approach may be needed for patients with an inadequate response to TNFα inhibitors. In recent years, interleukin (IL)-12/IL-23 inhibitors have entered clinical practice as a new class of drug for the treatment of PsA, with some data suggesting a lower effect of body weight on their effectiveness. Recent findings demonstrate effective and sustained responses in patients with PsA to ustekinumab, an IL-12/IL-23 inhibitor. This narrative review critically discusses the link between PsA, obesity, and response to therapy. The current role of ustekinumab in this setting is also discussed.

Different drug survival of first line tumour necrosis factor inhibitors in radiographic and non-radiographic axial spondyloarthritis: a multicentre retrospective survey.

OBJECTIVES: Good drug survival of tumour necrosis factor inhibitors (TNFi) has been shown in axial spondyloarthritis (axSpA) patients treated in real-life setting. However, few studies have compared drug survival of the first TNF inhibitor between radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA) patients in real-world clinical practice. The aim of this work was to evaluate the effectiveness by assessing the retention rate of first-line TNFi in r-axSpA and nr-axSpA patients. Baseline predictive factors for TNFi discontinuation were also evaluated. METHODS: We retrospectively assessed axSpA patients, who underwent first line therapy with TNFi. Demographic and clinical data was obtained through structured interview, review of medical records and physical examination. Disease activity indices such as the Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score evaluating C Reactive Protein (ASDAS-CRP), Leeds Enthesitis Index (LEI) were assessed at baseline. Moreover Health Assessment QuestionnaireDisability Index (HAQ), erythrocyte sedimentation rate (ESR, mm/h), CRP (mg/dl) and HLA-B27 were recorded as well. Data on x-ray and magnetic resonance imaging of the sacroiliac joints were also collected. Drug retention rates were analysed using Kaplan-Meier curves; log-rank test was performed to demonstrate differences in the survival functions. Cox regression models were used to estimate the inference of several disease and clinical characteristics on drug discontinuation. RESULTS: Drug survival of first-line TNFi was significantly lower in patients who had nr-axSpA than in those with r-axSpA (p=0.005). HLA-B27 frequency was higher in patients with x-ray sacroiliitis than in those with nr-axSpA (p=0.01) as well as mean CRP serum level (p=0.0001), whereas both mean BASDAI and LEI score were higher in patients with nr-axSpA than in those with r-axSpA (p=0.018 and p=0.007, respectively). Global retention rate in our cohort was 60.34% with mean survival time (MST) of 58.68 months (95% CI 47.93-69.42). MST for patients diagnosed with r-axSpA was 66.79 months (95% CI 53.54-80.04) and 39.05 months (95% CI 24.12-53.99) for those with nr-axSpA. Moreover, nr-axSpA (HR 1.620), higher BMI (HR 1.093) and BASFI, (HR 1.192) had an impact on drug discontinuation, whereas HLA-B27 presence (HR. 0.523) had protective effect. CONCLUSIONS: Effectiveness of TNFi, seems to be lower in nr-axSpA patients than in those with r-axSpA. In addition obesity and functional disability negatively impact the persistence on first line TNFi in axSpA patients in real life setting.

Serum osteopontin negatively impacts on intima-media thickness in patients with systemic lupus erythematosus.

BACKGROUND: Ultrasound evaluation of carotid intima-media thickness (cIMT) has been extensively used for potentially improving cardiovascular (CV) risk stratification in several patients' categories. Subjects with systemic lupus erythematosus (SLE) have been investigated by both imaging and molecular biomarker approaches with contrasting results. Here, we focused on the role of osteopontin (OPN) as biomarker of subclinical atherosclerosis associated with SLE. MATERIALS AND METHODS: Eighty females (age 18-65 years) affected by SLE and eighty age-matched healthy female controls without a clinical history of CV disease underwent ultrasound evaluation of cIMT and blood sample assay of high-sensitivity C-reactive protein (hs-CRP) and OPN. RESULTS: Healthy controls and SLE patients significantly differed for CV risk factors (ie, waist circumference, hypertension and dyslipidaemia) and the inflammatory status. Noteworthy, an opposite association between cIMT and OPN was observed in the two study groups. Whereas OPN was positively associated with mean cIMT (r = 0.364; P = 0.001) in SLE patients, a negative correlation was found in healthy controls. Furthermore, in SLE patients increased circulating levels of OPN were associated with the use of hydroxychloroquine and the positivity for the anti-dsDNA autoantibodies. At linear regression analysis, only OPN remained independently associated with cIMT also after adjustment for age, smoking pack-year, Heart SCORE, disease length and steroid therapy length. CONCLUSIONS: These results indicate that serum OPN levels were strongly associated with subclinical atherosclerosis in patients with LES and it might be a useful CV biomarker that requires additional validation in larger trials.

Possible role of adipocytokines in systemic sclerosis-associated small pericardial effusion.

Introduction: Pericardial effusion is a common manifestation of systemic sclerosis, but its pathogenesis has been poorly investigated. Adipokines and interleukins may play a role in the pathophysiology of pericardial effusion. This study aimed at evaluating serum levels of adipokines and interleukins in systemic sclerosis patients with and without pericardial effusion. Methods: A total of 87 systemic sclerosis patients (age 52.6 ± 14 years; disease duration 8.2 ± 6.7 years) were recruited in this study. Demographics, body mass index, and clinical characteristics were recorded in each patient. Pericardial effusion was considered pathologic when ≥50 mL was detected by echocardiography. Serum levels of adiponectin, leptin, resistin, visfatin, tumor necrosis factor-α, interferon-γ, interlueukin-2, interlueukin-10, and interlueukin-17 were measured using Multiplex Immunoassay (Bioplex 200 System). Results: In all, 11 (13%) systemic sclerosis patients had pericardial effusion. Systemic sclerosis patients with and without pericardial effusion did not differ in age, sex, and body mass index. Systemic sclerosis patients with pericardial effusion had significantly higher levels of visfatin (median/interquartile range: 1546 pg/mL (interquartile range: 8590) vs 388 pg/mL (interquartile range: 103), p = 0.03) and interlueukin-17 (1.33 pg/mL (interquartile range: 3.5) vs 0.05 pg/mL (interquartile range: 0.56), p = 0.04), but lower levels of adiponectin (2,845,000 pg/mL (interquartile range: 4,132,900) vs 5,272,100 pg/mL (interquartile range 8,243,600), p = 0.02) than patients without pericardial effusion. Interstitial lung disease, pulmonary arterial hypertension, and "limited" or "diffuse" cutaneous subset did not correlate to adipokines or interleukin levels. Conclusion: Visfatin and adiponectin may play an important role in the pathogenesis of systemic sclerosis-related pericardial effusion. Further longitudinal studies are needed to unravel a possible role of these molecules as biomarkers of pericardial effusion in systemic sclerosis patients.

Golimumab in real-life settings: 2 Years drug survival and predictors of clinical outcomes in rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis.

OBJECTIVES: To assess the drug survival of golimumab, and predictors thereof, in patients affected with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA) in a prospective observational cohort. METHODS: This is a non-interventional, longitudinal study on RA, SpA, and PsA patients starting treatment with golimumab. Endpoints were the 2 years persistence rate of golimumab and predictors of therapy discontinuation. Drug retention was analyzed using Kaplan-Meier and Cox models. Hazard ratios (HR) of golimumab discontinuation were estimated by Cox-regression hazard models. RESULTS: Of 416 patients starting golimumab, 171 biologic-naïve and 245 inadequate responders to prior biologic drugs, 88 had RA, 147 SpA, and 181 PsA. Global 2 years drug retention was 70.2%, with no different hazard of discontinuation among diseases or line of biologic treatment. The strongest predictor of golimumab discontinuation was female gender (HR = 1.95). Golimumab monotherapy was associated with higher risk drug interruption (HR = 1.67). Within SpA, predictors of golimumab discontinuation were female sex (HR = 4.19), and absence of extra-articular manifestations (HR = 4.60). In PsA, duration of disease was negatively associated to drug interruption (HR = 0.93), whereas golimumab monotherapy was positively (HR = 2.21) associated. Interestingly, failing to achieve a good EULAR response at 3 months was the only predictor of golimumab discontinuation for RA patients (HR = 3.03). CONCLUSIONS: This study provided evidence that golimumab has high retention rate in real-life settings. SpA male patients with extra-articular manifestations, PsA patients on co-therapy with DMARDs, and RA patients attaining an early clinical response had the highest probability to continue golimumab over 2 years.

Anti-TNF treatment response in rheumatoid arthritis patients with moderate disease activity: a prospective observational multicentre study (MODERATE).

OBJECTIVES: Rheumatoid arthritis (RA) patients with moderate disease activity show progression of joint damage and have impaired quality of life, physical function, work and daily activities. Little is known about management of patients with moderate RA. The aim of the study was to assess the 1-year response to anti-TNF in biologic-naïve RA patients with moderate (3.2 3.2 and ≤5.1), and were naïve to anti-TNF treatment. RESULTS: Among 157 RA patients, 93 (59%) underwent etanercept, 43 (22%) adalimumab, 26 (17%) certolizumab, 10 golimumab and 2 infliximab; 80% of patients were still in treatment after 12-month observation. One-year clinical remission was achieved by 27 RA patients (21%), reduction of DAS28 score greater than 1.2 was observed in 75 (58%) patients. Moderate and good response according to EULAR criteria was observed in 59 (46%) and 45 (35%) patients, respectively. CONCLUSIONS: Results confirm the efficacy of anti-TNF alpha also in moderate RA patients, who may achieve a substantial decrease of disease activity, and improve their quality of life. The low rate of patients achieving remission may suggest that therapeutic strategies should be more timely and aggressive.

Effective tumour necrosis factor-blocking therapy reduces reactive oxygen metabolite level in rheumatoid arthritis.

OBJECTIVE: To assess circulating levels of derived reactive oxygen metabolites (ROMs) in patients with active rheumatoid arthritis (RA), before and during antitumour necrosis factor (TNF)-α therapy. METHODS: Patients with active RA and failed previous treatment with disease-modifying antirheumatic drugs received subcutaneous anti-TNF-α for 52 weeks. Circulating hydrogen peroxide was quantified as a marker of oxidative stress at baseline and at 24 and 52 weeks. RESULTS: The study included 40 patients. Circulating dROM levels were significantly reduced compared with baseline after 24 and 52 weeks' of anti-TNF-α treatment (33.2 ± 10.0 mgH2O2/dl, 29.5 ± 7.0 mgH2O2/dl and 29.3 ± 9.0 mgH2O2/dl, respectively). There was a significant direct correlation between disease activity score and ROM levels. CONCLUSION: TNF-α inhibition can control disease activity and reduce circulating levels of reactive oxygen species in patients with RA.

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell.

Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV-siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of c-Fos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement.

The use of an interferon-gamma release assay as a biomarker of response to anti-TNF-alpha treatment.

Tumor necrosis factor alpha (TNF-α) is a pleiotropic cytokine that plays a central role in the immune system functioning and in the pathogenesis of rheumatoid arthritis (RA). TNF-α inhibition has been demonstrated effective to treat RA; however, response to anti-TNF-α therapies is heterogeneous, with roughly one-third of patients not achieving disease control. Identification of a biological marker to assess the effectiveness of TNF-α inhibition may help to discriminate patients with a reduced response to anti-TNF-α agents. The aim of this study was to assess whether anti-TNF-α treatment was able to modify the cytokine network interfering with interferon gamma (INFγ) release after phytohemagglutinin (PHA) stimulation of peripheral blood mononuclear cells (PBMCs) from RA patients, according to disease activity. We found that RA patients with active disease had low release of INFγ after PHA stimulation, but anti-TNF-α agents were able to modify INFγ production. In anti-TNF-α responders, we observed a higher release of INFγ, achieving levels comparable with those seen in healthy subjects. The ability of PBMCs from RA patients to release INFγ may serve as a biomarker of disease activity and response to anti-TNF-α. Larger studies are needed to validate these data.

Lipid profile of rheumatoid arthritis patients treated with anti-tumor necrosis factor-alpha drugs changes according to disease activity and predicts clinical response.

Patients with active rheumatoid arthritis (RA) frequently show an atherogenic lipid profile, which has been linked with the inflammatory reaction. Inflammatory cytokines, and particularly tumor necrosis factor-alpha (TNF-α), are implicated in the pathogenesis of both atherosclerosis and RA, and also involved in the development of the impaired lipid profile detected in active RA. Although anti-TNF-α agents have been proven effective in controlling joint damage and systemic inflammation, controversy remains about the effect of these drugs on the lipid profile; therefore, the aim of our study was to investigate the effect of anti-TNF-α treatment, in combination with disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroid therapy, on the lipid profile of patients with active RA. Our data suggest that the combination anti-TNF-α/DMARDs/steroids do not significantly interfere with the lipid profile of RA patients. However, analysis of clinical response data showed that patients achieving low disease activity or remission seem to have a protective lipid profile, suggesting that better control of inflammation and disease activity can affect lipid metabolism. The available evidence indicates that high inflammation interferes with lipid metabolism, whereas good control of the chronic inflammatory state may positively influence the lipid profile and cardiovascular risk. Low cholesterol levels at baseline could predict a favorable outcome with anti-TNF-α treatment, but these data need to be confirmed by large prospective studies with long-term follow-up.

Low level tumor necrosis factor-alpha protects cardiomyocytes against high level tumor necrosis factor-alpha: brief insight into a beneficial paradox.

Whether tumor necrosis factor-alpha (TNFα) caused beneficial or detrimental cardiovascular effects remains poorly defined. Anti-TNFα agents improved cardiac end points in chronic rheumatic diseases characterized by progressive deterioration of cardiac function. In contrast, anti-TNFα agents did not always improve but actually worsened cardiac function in non-rheumatic patients with heart failure (HF), in spite of that HF usually accompanies with high circulating levels of TNFα. To shed light on these mixed findings, we characterized the effects of TNFα in H9c2 cardiomyocytes. Cells were incubated for 24 h with increasing concentrations of TNFα, hydrogen peroxide, aminotriazole, or etoposide. Posttreatment cell viability was assessed by antimycin A-inhibitable reduction of 3-(4,dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the IC50 value of each test compound was defined. H9c2 cells were also preconditioned with a low non-toxic concentration of TNFα and then re-challenged with increasing concentrations of TNFα and other stressor agents. In re-challenge experiments, all of the IC50 values increased significantly, with the IC50 value of TNFα increasing approximately 16-fold. TNFα preconditioning increased cardiomyocytes shedding of the external portion of transmembrane type 1 and type 2 TNFα receptors [(soluble TNFα receptors (sTNFR)]. Levels of survival-oriented soluble TNFR2 (sTNFR2) always exceeded those of death-oriented sTNFR1. When exposed to TNFα at its IC50 value, preconditioned cardiomyocytes showed an increased release of sTNFR2 but not sTNFR1. These results denoted that preconditioning by "low TNFα" helped cardiomyocyte to withstand toxicity from "high TNFα" or other agents. These results also suggested that beneficial or detrimental effects of anti-TNFα agents might well depend on whether these agents spared or intercepted discrete amounts of TNFα that preconditioned cardiomyocytes and made them more resistant to high concentrations of TNFα.

Cardiovascular safety of anti-TNF-alpha therapies: facts and unsettled issues.

Tumor necrosis factor alpha (TNFa) plays a central role in the pathogenesis of both rheumatoid arthritis (RA) and heart failure (HF). Over the last years RA could benefit from TNFa inhibitors that mitigated disease activity, decreased structural damage, and prevented cardiovascular events. Contraindications to clinical use of TNFa inhibitors may include infections, autoimmune disorders, demyelinating disease, cancer, and heart failure. Overall, these pathological conditions do not appear to increase significantly during treatment with TNFa antagonists compared to placebo. Clinical trials probed these drugs in non RA HF patients produced disappointing results and formed the basis to contraindicate TNFa inhibitors in patients with moderate-severe HF. Although National Registries provide apparently encouraging data about HF safety of anti-TNFa therapies, they cannot adequately assess the actual risk, as these drugs are administered to patients with no cardiac dysfunction. These findings introduced a "rheumatological dilemma" in the clinical management of RA with anti-TNFa. Probably, in RA patients anti-TNFa agents would intercept TNFa and prevent its toxic effects on heart function, while in patients with advanced heart damage (NYHA class III-IV HF), anti-TNFa agents would interfere with the beneficial preconditioning effects of TNFa.