Influenza vaccine with adjuvant on disease activity in psoriatic arthritis patients under anti-TNF-α therapy.

OBJECTIVES: To evaluate the effects on disease activity of seasonal influenza vaccination with adjuvant in psoriatic arthritis (PsA) patients in stable disease activity on anti-TNF-α drugs as compared to not vaccinated PsA patients adequately matched. METHODS: An observational study was conducted on a cohort of PsA patients in stable disease activity who underwent administration of an adjuvanted vaccine for seasonal influenza. Cases (Group 1) were matched for age, sex, disease activity and therapy with not vaccinated PsA patients (Group 2). Analysis included patients data before vaccination (T0), and one month (T1) and three months (T3) after administration of the vaccination for Group 1 and at correspondent intervals for Group 2. Assessment of disease activity parameters was performed at each visit. RESULTS: Twenty-five vaccinated and 25 not vaccinated patients were included in the study. As a first approach, we analysed the data within groups. At T1, as compared to baseline, the group of vaccinated patients had a statistically significant increase in TJC (tender joint count) and ESR (erythrocyte sedimentation rate). At T3, a statistically significant difference from baseline characteristics was found only for the TJC. In Group 2, all the observed variables showed no significant differences when comparing baseline to T1 and T3. Analysis of the data between groups at T1, Group 1, as compared to Group 2, showed a significant increase of TJC, ESR, HAQ (Health Assessment Questionnaire), PtGA (patient global assessment) and PhGA (physician global assessment). These findings were also confirmed when comparing the two groups at T3 for ESR and PtGA, while they were not confirmed for TJC, HAQ and PhGA. CONCLUSIONS: Influenza vaccination is clinically efficacious in PsA patients under anti-TNF-α therapy, but it could trigger a short-lasting exacerbation of the disease.

Ex Vivo Signaling Protein Mapping in T Lymphocytes in the Psoriatic Arthritis Joints.

We assessed signaling protein mapping in total T cells, to analyze the proportions of T regulatory (Treg) and TCD4+ effector (Teff) cell phenotypes, and the respective interleukin 6Rα (IL-6Rα) expression in the inflammatory microenvironment of synovial fluid (SF) of patients with sustained psoriatic arthritis (PsA). Our approach was to measure the IL-6 level in SF using a multiplex bead immunoassay. Reverse-phase protein array was used to assess Janus kinase (JAK) 1 and JAK2, extra-cellular regulated kinase (ERK) 1 and 2, protein kinase Cδ (PKCδ), signal transducer and activator and transcription (STAT) 1, STAT3, and STAT5 phosphoproteins in total T cell lysates from SF of patients with PsA. Frequencies of CD4+IL-17A-F+IL-23+ CD4+ Th cells producing IL-17A and IL-17F (Th17) and CD4+CD25high intracellular forkhead box transcription factor+ (FOXP3+) phenotypes, and the percentage of Treg- and Teff- cells were quantified in SF and matched peripheral blood (PB) of patients with PsA and PB of healthy controls (HC) by flow cytometry. Our results were the following: In PsA SF samples, a coordinate increase of JAK1, ERK1/2, STAT1, STAT3, and STAT5 phosphoproteins was found in total T cells in SF of PsA; where IL-6 levels were higher than in PB from HC. Expanded CD4+IL-17A-F+IL-23+ Th17, CD4+ CD25- Teff- and CD4+CD25(high) FoxP3+Treg subsets, showing similar levels of enhanced IL-6Rδ expression, were confined to PsA joints. In our studies, the transcriptional network profile identified by ex vivo signaling protein mapping in T lymphocytes in PsA joints revealed the complex interplay between IL-1, IL-6, and IL-23 signaling and differentiation of Th17 cells and CD4+Tregs in sustained joint inflammation in PsA.

Remission in early, aggressive rheumatoid arthritis: a multicentre prospective observational Italian study ARPA (Artrite Reumatoide Precoce Aggressiva).

OBJECTIVES: To provide a survey of disease activity in patients treated with standard care in Italian clinical practice. METHODS: This was an observational prospective cohort study in patients with early, aggressive rheumatoid arthritis (RA; duration ≤2 years but ≥6 weeks; DAS28 >3.2) naïve to anti-tumour necrosis factor (TNF) therapy who were treated with disease-modifying anti-rheumatic drugs (DMARDs) and/or biologics according to standard practice at 15 Italian ARPA (Artrite Reumatoide Precoce Aggressiva) centres. Patients were evaluated at baseline and after 6, 12 and 24 months. The primary endpoint was the proportion of patients achieving remission, as defined by disease activity score in 28 joints (DAS28) <2.6, after 1 year. RESULTS: Among the 152 patients enrolled, 92 were evaluable after 1 year and 77 after 2 years for DAS28. At baseline, patients had a mean DAS28 of 6.1±1.0. At 12 months, 62.6% of patients were treated with DMARDs (in monotherapy or in combination), and 37.4% with anti-TNFs (in monotherapy or in association with DMARDs). At 24 months, 35.1% were receiving anti-TNF therapy. The rate of DAS28 remission rates at 12 months and 24 months were 28.3% (95% confidence interval [CI] 19.1-37.5) and 41.6% (95% confidence interval [CI] 30.6-52.6), respectively. CONCLUSIONS: The remission rate was lower at 12 months compared with previous large randomised clinical trials for early, aggressive RA, but significantly improved at 24 months. These results suggest that patients in real-world clinical settings in Italy may experience a delay in receiving the best possible care.

The role of eight polymorphisms in three candidate genes in determining the susceptibility, phenotype, and response to anti-TNF therapy in patients with rheumatoid arthritis.

OBJECTIVES: Several single nucleotide polymorphisms (SNPs) have been associated with rheumatoid arthritis (RA) such as peptidylarginine deiminase-4 (PADI4), osteopontin (OPN), and perforin (PRF1) genes. Thus, we aimed at analysing the influence of eight SNPs in these candidate genes on RA susceptibility and their association with laboratory and clinical features in terms of response to anti-TNF therapy. METHODS: We performed a case-control study on 377 Caucasian RA patients and 391 healthy, ethnicity-matched, population-based controls. All subjects were genotyped for PADI4_89/94, PADI4_92, PADI4_104, PADI4_100 in PADI4; -156G/GG and +1239A/C in OPN and A91V and N252S in PRF1 genes. The patients were stratified for shared epitope (SE) HLA-DRB1. rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) were analysed. The patients started anti-TNF treatment and they were evaluated at baseline and after 12 weeks. Disease activity was evaluated with DAS28 and response to treatment with EULAR criteria. RESULTS: A statistically significant association between RA and OPN -156G/GG was found (p=0.023). SE was firmly confirmed to be associated with RA (OR=3.68; p<10-10). No other statistically significant association with clinical and laboratory features were observed. CONCLUSIONS: For the first time, in an Italian cohort, we report the association between -156G/GG in OPN gene and RA susceptibility. Short-term response to anti-TNF therapy was not influenced by the genetic variants studied.

Evaluation of finger joint synovial vascularity in patients with rheumatoid arthritis using contrast-enhanced ultrasound with water immersion and a stabilized probe.

PURPOSE.: To assess synovial microvascularity in finger joints with rheumatoid arthritis (RA) by contrast-enhanced ultrasound (CEUS), distinguishing between cases of active disease and those in remission; to standardize the technique for software analysis. METHODS.: Fifty-two finger joints of RA patients (26 with active disease and 26 in remission) were immersed in water and examined by CEUS using a fixed probe. Signal intensity curves were calculated with the software. RESULTS.: Contrast enhancement was detectable in all 26 patients with active RA (100%), but not in 25 of 26 patients in remission (96%); one of the latter patients (4%) showed minimal enhancement. The method's sensitivity and specificity in distinguishing active disease from remission were 100% and 96%. The grades of synovial enhancement correlated with clinical disease activity and software flow parameters. The peak contrast levels correlated with clinical activity, a peak of 9% representing the cutoff between remission and active disease. CONCLUSIONS.: CEUS with a fixed probe on finger joints immersed in water detected synovial vascularization in RA, producing results suitable for standardized software analysis and avoiding artifacts.

Synovial biomarkers in psoriatic arthritis.

OBJECTIVE: To find candidate biomarkers of psoriatic arthritis (PsA). A panel of synovial fluid (SF) and synovial tissue (ST) biomarkers was analyzed in patients with resistant peripheral PsA, in relation to clinical and imaging outcomes of synovitis response following serial intraarticular (IA) etanercept injections (12.5 mg). METHODS: Fourteen PsA patients with resistant knee joint synovitis were treated with 4 IA etanercept injections in a single knee joint, once every 2 weeks. Primary outcome (Thompson's knee index: THOMP) and secondary outcomes were assessed at baseline and end of study: C-reactive protein, Knee Joint Articular Index (KJAI), Health Assessment Questionnaire disability index, maximal synovial thickness (MST) by gray-scale ultrasonography, contrast-enhanced magnetic resonance imaging (C+MRI), ST-cluster differentiation (CD)45+ mononuclear cell, ST-CD31+ vessels, and ST-CD105+ angiogenic endothelial cells, along with levels of SF interleukin 1ß (IL-1ß), IL-1 receptor antagonist (Ra), and IL-6. RESULTS: At the end of the study, clinical and imaging outcomes, ST and SF biological markers were significantly reduced compared to baseline. There was a significant association between IL-6 and either THOMP or KJAI; between either ST-CD31+ or ST-CD105+ or ST-CD45+; between ST and SF biomarkers expression (CD45+ and IL-1ß) and between ST-CD45+ and both KJAI and MRI-MST. Comparing pre- versus post-IA etanercept injection changes (Δ), Δ IL-1ß was significantly correlated with both Δ IL-6 and with Δ IL-1Ra and Δ IL-6 with Δ IL-1Ra. CONCLUSION: The association to disease activity and the changes following IA treatment indicate that ST-CD45+ and ST-CD31+, along with SF-IL-6 and SF-IL-1ß, may represent candidate biomarkers of the knee synovitis response to IA tumor necrosis factor-α blockade.

Tryptophan Metabolites, Cytokines, and Fatty Acid Binding Protein 2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) differ for triggers, mode of start, associated symptoms, evolution, and biochemical traits. Therefore, serious attempts are underway to partition them into subgroups useful for a personalized medicine approach to the disease. Here, we investigated clinical and biochemical traits in 40 ME/CFS patients and 40 sex- and age-matched healthy controls. Particularly, we analyzed serum levels of some cytokines, Fatty Acid Binding Protein 2 (FAPB-2), tryptophan, and some of its metabolites via serotonin and kynurenine. ME/CFS patients were heterogeneous for genetic background, trigger, start mode, symptoms, and evolution. ME/CFS patients had higher levels of IL-17A (p = 0.018), FABP-2 (p = 0.002), and 3-hydroxykynurenine (p = 0.037) and lower levels of kynurenine (p = 0.012) and serotonin (p = 0.045) than controls. Changes in kynurenine and 3-hydroxykynurenine were associated with increased kynurenic acid/kynurenine and 3-hydroxykynurenine/kynurenine ratios, indirect measures of kynurenine aminotransferases and kynurenine 3-monooxygenase enzymatic activities, respectively. No correlation was found among cytokines, FABP-2, and tryptophan metabolites, suggesting that inflammation, anomalies of the intestinal barrier, and changes of tryptophan metabolism may be independently associated with the pathogenesis of the disease. Interestingly, patients with the start of the disease after infection showed lower levels of kynurenine (p = 0.034) than those not starting after an infection. Changes in tryptophan metabolites and increased IL-17A levels in ME/CFS could both be compatible with anomalies in the sphere of energy metabolism. Overall, clinical traits together with serum biomarkers related to inflammation, intestine function, and tryptophan metabolism deserve to be further considered for the development of personalized medicine strategies for ME/CFS.

Pathogenetic and clinical rationale for TNF-blocking therapy in psoriatic arthritis.

The classical definition of psoriatic arthritis (PsA) as an inflammatory arthritis associated with psoriasis reflects only in part the large spectrum of musculoskeletal disorders found in patients with psoriasis. In particular, enthesopathy, dactilytis, osteitis and axial involvement are frequently neglected and probably account for the unsatisfactory response of PsA to traditional drugs, such as NSAIDs, steroids and DMARDs. Furthermore, these drugs showed only a partial ability to influence radiographic progression and psoriasis. The new anti-TNF agents, in particular etanercept but also infliximab and adalimumab, have demonstrated a comprehensive effectiveness on the multiple aspects of the PsA disease, including quality of life and slowing of radiographic progression. Despite this clear efficacy, the actual mechanisms by which TNF-blocking agents are able to obtain all these effects are still incompletely understood. However, the success of this therapy suggested one of the best ways for further research in the field of PsA. In this new fashion, the most stimulating hypotheses involving TNF are those regarding genetic predisposition, angiogenesis and osteoclastogenesis.

Bayesian Quantification of Contrast-Enhanced Ultrasound Images With Adaptive Inclusion of an Irreversible Component.

Contrast Enhanced Ultrasound (CEUS) is a sensitive imaging technique to assess tissue vascularity and it can be particularly useful in early detection and grading of arthritis. In a recent study we have shown that a Gamma-variate can accurately quantify synovial perfusion and it is flexible enough to describe many heterogeneous patterns. However, in some cases the heterogeneity of the kinetics can be such that even the Gamma model does not properly describe the curve, with a high number of outliers. In this work we apply to CEUS data the single compartment recirculation model (SCR) which takes explicitly into account the trapping of the microbubbles contrast agent by adding to the single Gamma-variate model its integral. The SCR model, originally proposed for dynamic-susceptibility magnetic resonance imaging, is solved here at pixel level within a Bayesian framework using Variational Bayes (VB). We also include the automatic relevant determination (ARD) algorithm to automatically infer the model complexity (SCR vs. Gamma model) from the data. We demonstrate that the inclusion of trapping best describes the CEUS patterns in 50% of the pixels, with the other 50% best fitted by a single Gamma. Such results highlight the necessity of the use ARD, to automatically exclude the irreversible component where not supported by the data. VB with ARD returns precise estimates in the majority of the kinetics (88% of total percentage of pixels) in a limited computational time (on average, 3.6 min per subject). Moreover, the impact of the additional trapping component has been evaluated for the differentiation of rheumatoid and non-rheumatoid patients, by means of a support vector machine classifier with backward feature selection. The results show that the trapping parameter is always present in the selected feature set, and improves the classification.

Elderly psoriatic arthritis patients on TNF-α blockers: results of an Italian multicenter study on minimal disease activity and drug discontinuation rate.

Psoriatic arthritis (PsA) is an inflammatory arthropathy, associated with skin and/or nail psoriasis. Real world data on efficacy and safety of TNF-α blockers in the elderly with PsA are lacking. The aim of this study was to evaluate the effectiveness, through the achievement of minimal disease activity (MDA), drug discontinuation rate, and safety in elderly patients with PsA on TNF-α blockers. A multicenter, observational study was carried out in four Italian centers. The assessment of disease activity and safety were performed at the start of anti-TNF-α (T0), at 6 months (T6) and at 12 months (T12). A total of 145 PsA patients were included in the study. At baseline 68 (46.9%) patients were on etanercept, 60 (41.3%) on adalimumab, 11 (7.6%) on golimumab, and 6 (4.1%) on infliximab. All the variables concerning PsA activity showed a statistically significant improvement when comparing T6 and T12 with T0. After 6 and 12 months of therapy, respectively, 31 (22.6%) and 71 (51.8%) patients achieved MDA (p < 0.001). The drug discontinuation rate was 5.5% with a mean of 6.8 months (range 2-10 months), and it was due to lack of efficacy, adverse events, and lost to follow-up. Nine patients (6.2%) reported the onset of mild infections resolved with antimicrobial specific oral regimen without therapy interruption. TNF-α blockers are effective in the achievement of a low disease status and safe in elderly patients with PsA. Therefore, age should not be considered a limitation to their use.

Quantitative imaging by pixel-based contrast-enhanced ultrasound reveals a linear relationship between synovial vascular perfusion and the recruitment of pathogenic IL-17A-F+IL-23+ CD161+ CD4+ T helper cells in psoriatic arthritis joints.

To develop quantitative imaging biomarkers of synovial tissue perfusion by pixel-based contrast-enhanced ultrasound (CEUS), we studied the relationship between CEUS synovial vascular perfusion and the frequencies of pathogenic T helper (Th)-17 cells in psoriatic arthritis (PsA) joints. Eight consecutive patients with PsA were enrolled in this study. Gray scale CEUS evaluation was performed on the same joint immediately after joint aspiration, by automatic assessment perfusion data, using a new quantification approach of pixel-based analysis and the gamma-variate model. The set of perfusional parameters considered by the time intensity curve includes the maximum value (peak) of the signal intensity curve, the blood volume index or area under the curve, (BVI, AUC) and the contrast mean transit time (MTT). The direct ex vivo analysis of the frequencies of SF IL17A-F+CD161+IL23+ CD4+ T cells subsets were quantified by fluorescence-activated cell sorter (FACS). In cross-sectional analyses, when tested for multiple comparison setting, a false discovery rate at 10%, a common pattern of correlations between CEUS Peak, AUC (BVI) and MTT parameters with the IL17A-F+IL23+ - IL17A-F+CD161+ - and IL17A-F+CD161+IL23+ CD4+ T cells subsets, as well as lack of correlation between both peak and AUC values and both CD4+T and CD4+IL23+ T cells, was observed. The pixel-based CEUS assessment is a truly measure synovial inflammation, as a useful tool to develop quantitative imaging biomarker for monitoring target therapeutics in PsA.

Pixel-based approach to assess contrast-enhanced ultrasound kinetics parameters for differential diagnosis of rheumatoid arthritis.

Inflammatory rheumatic diseases are the leading causes of disability and constitute a frequent medical disorder, leading to inability to work, high comorbidity, and increased mortality. The standard for diagnosing and differentiating arthritis is based on clinical examination, laboratory exams, and imaging findings, such as synovitis, bone edema, or joint erosions. Contrast-enhanced ultrasound (CEUS) examination of the small joints is emerging as a sensitive tool for assessing vascularization and disease activity. Quantitative assessment is mostly performed at the region of interest level, where the mean intensity curve is fitted with an exponential function. We showed that using a more physiologically motivated perfusion curve, and by estimating the kinetic parameters separately pixel by pixel, the quantitative information gathered is able to more effectively characterize the different perfusion patterns. In particular, we demonstrated that a random forest classifier based on pixelwise quantification of the kinetic contrast agent perfusion features can discriminate rheumatoid arthritis from different arthritis forms (psoriatic arthritis, spondyloarthritis, and arthritis in connective tissue disease) with an average accuracy of 97%. On the contrary, clinical evaluation (DAS28), semiquantitative CEUS assessment, serological markers, or region-based parameters do not allow such a high diagnostic accuracy.

How the Mediterranean diet and some of its components modulate inflammatory pathways in arthritis.

Arthritis encompasses a heterogeneous group of diseases characterised by inflammation that leads not only to joint damage, bone erosion, severe pain and disability, but also affects other organs of the body, resulting in increased morbidity and mortality. Although the mechanisms underlying the pathogenesis of joint diseases are for the most part unknown, a number of nutrient and non-nutrient components of food have been shown to affect the inflammatory process and, in particular, to influence clinical disease progression. The Mediterranean diet model has already been linked to a number of beneficial health effects: both fat and non-fat components of the Mediterranean dietary pattern have been shown to exert important anti-inflammatory activities by affecting the arachidonic acid cascade, the expression of some proinflammatory genes, and the activity of immune cells. N-3 polyunsaturated fatty acids, in particular, have been shown to affect lymphocyte and monocyte functions, crucially involved in adaptive and innate immunity. Although some aspects concerning the mechanisms of action through which the Mediterranean diet pattern exerts its beneficial effects remain to be elucidated, arthritis patients may potentially benefit from it in view of their increased cardiovascular risk and the treatment they require which may have side effects.

Metabolic syndrome and its relationship with the achievement of minimal disease activity state in psoriatic arthritis patients: an observational study.

The aim of the study was to evaluate the influence of metabolic syndrome (MetS) on achieving minimal disease activity (MDA) in psoriatic arthritis (PsA) patients treated with anti-tumor necrosis factor (TNF)-α with a follow-up period of 24 months. A cohort of PsA patients was assessed at the University Federico II of Naples and at University of Padova. For the aim of the present study, patients' data were collected at baseline (T0), at 12 months (T1) and at 24 months (T2). Assessment of metabolic and disease activity parameters was performed at each visit. The NCEP-ACT III criteria were used to identify subjects with MetS and the MDA criteria to evaluate the disease activity. On the basis of the exclusion and inclusion criteria, 330 subjects were included in the study; 134 patients (40.7%) were classified as not having MetS and 196 (59.3%) as having MetS. An inverse association was found between presence of metabolic syndrome and the probability of achieving MDA. Univariate analysis indicated that patients with metabolic syndrome were less likely to achieve MDA than patients without metabolic syndrome (OR 0.45, p < 0.001). This inverse association remained statistically significant in the multivariate regression model (OR 0.56, p < 0.001). Metabolic syndrome is associated with a lower probability of achieving MDA in PsA patients in therapy with anti-TNF-α.

Current evidence in the field of the management with TNF-α inhibitors in psoriatic arthritis and concomitant hepatitis C virus infection.

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic inflammatory condition involving the spine, enthesis and peripheral joints, which is associated with psoriasis. PsA therapy varies from use of NSAIDs to disease-modifying anti-rheumatic agents (DMARDs). However, their use can represent a limitation in patients with concomitant hepatitis C virus (HCV) infection. In the last few decades, anti-TNF-α therapy has opened new horizons in the treatment of PsA. Hence, the purpose of this review is to explore the efficacy and safety of anti-TNF-α agents in PsA and concomitant HCV infection. AREAS COVERED: We reviewed the available medical literature to find all cases of PsA and concomitant HCV infection treated with TNF-α inhibitors. We found a total of 38 cases of patients with PsA and concomitant HCV infection in therapy with anti-TNF-α agents. EXPERT OPINION: The available literature, summarized in this review, still remains very limited. Data suggest that therapy with the anti-TNF-α agents, mainly etanercept and adalimumab, at least with short-term use, would appear efficacious and reasonably safe in the management of PsA patients with concomitant HCV infection. With regard to infliximab, efficacy and safety have been scarcely explored, whereas in the case of golimumab and certolizumab no report was found, may be due to their recent introduction on the market.

Transcriptional network profile on synovial fluid T cells in psoriatic arthritis.

The objective of the study was to quantify the transcriptional profile, as the main T cell lineage-transcription factors on synovial fluid (SF) T cells, in relation to SF cytokines and T cell frequencies (%) of psoriatic arthritis (PsA) patients. Reverse phase protein array was employed to identify interleukin (IL)-23Rp19-, FOXP3- and related orphan receptor gamma T (RORγt)- protein and Janus associated tyrosine kinases 1 (JAK1), signal transducer and activator and transcription 1 (STAT1), STAT3 and STAT5 phosphoproteins in total T cell lysates from SF of PsA patients. IL-1ß, IL-2, IL-6, IL-21 and interferon (INF)-γ were measured using a multiplex bead immunoassay in SF from PsA patients and peripheral blood (PB) from healthy controls (HC). Frequencies of CD4(+)CD25(-), CD4(+)CD25(high) FOXP3(+) and CD4(+)CD25(high) CD127(low) Treg, and either mean fluorescence intensity (MFI) of FOXP3(+) on CD4(+) Treg or MFI of classic IL-6 receptor (IL-6R) α expression on CD4(+)CD25(-) helper/effector T cells (Th/eff) and Treg cells, were quantified in SF of PsA patients and in PB from HC by flow cytometry (FC). In PsA SF samples, IL-2, IL-21 and IFN-γ were not detectable, whereas IL-6 and IL-1ß levels were higher than in SF of non-inflammatory osteoarthritis patients. Higher levels of IL-23R-, FOXP3- and RORγt proteins and JAK1, STAT1, STAT3 and STAT5 were found in total T cells from SF of PsA patients compared with PB from HC. Direct correlations between JAK1 Y1022/Y1023 and STAT5 Y694, and STAT3 Y705 and IL6, were found in SF of PsA patients. Increased proportion of CD4(+)CD25(high) FOXP3(+) and CD4(+)CD25(high) CD127(low) Treg cells and brighter MFI of IL-6Rα were observed both on CD4(+)CD25(high)- and CD4(+)CD25(-) T cells in PsA SF. The study showed a distinctive JAK1/STAT3/STAT5 transcriptional network on T cells in the joint microenvironment, outlining the interplay of IL-6, IL-23, IL-1ß and γC cytokines in the polarization and plasticity of Th17 and Treg cells, which might participate in the perpetuation of joint inflammation in PsA patients.

Vascular perfusion kinetics by contrast-enhanced ultrasound are related to synovial microvascularity in the joints of psoriatic arthritis.

The purpose of the study was to assess the relationship of the continuous mode contrast-enhanced harmonic ultrasound (CEUS) imaging with the histopathological and immunohistochemical (IHC) quantitative estimation of microvascular proliferation on synovial samples of patients affected by sustained psoriatic arthritis (PsA). A dedicated linear transducer was used in conjunction with a specific continuous mode contrast enhanced harmonic imaging technology with a second-generation sulfur hexafluoride-filled microbubbles C-agent. The examination was carried out within 1 week before arthroscopic biopsies in 32 active joints. Perfusional parameters were analyzed including regional blood flow (RBF); peak (PEAK) of the C-signal intensity, proportional to the regional blood volume (RBV); beta (ß) perfusion frequency; slope (S), representing the inclination of the tangent in the origin; and the refilling time (RT), the reverse of beta. Arthroscopic synovial biopsies were targeted in the hypervascularity areas, as in the same knee recesses assessed by CEUS; the synovial cell infiltrate and vascularity (vessel density) was evaluated by IHC staining of CD45 (mononuclear cell) and CD31, CD105 (endothelial cell) markers, measured by computer-assisted morphometric analysis. In the CEUS area examined, the corresponding time-intensity curves demonstrated a slow rise time. Synovial histology showed slight increased layer lining thickness, perivascular lymphomonocyte cell infiltration, and microvascular remodeling, with marked vessel wall thickening with reduction of the vascular lumen. A significant correlation was found between RT and CD31+ as PEAK and CD105+ vessel density; RT was inversely correlated to RBF, PEAK, S, and ß. The study demonstrated the association of the CEUS perfusion kinetics with the histopathological quantitative and morphologic estimation of synovial microvascular proliferation, suggesting that a CEUS imaging represents a reliable tool for the estimate of the synovial hypervascularity in PsA.

Impact of 24-month treatment with etanercept, adalimumab, or methotrexate on metabolic syndrome components in a cohort of 210 psoriatic arthritis patients.

Psoriatic arthritis (PsA) is a chronic inflammatory condition, characterized by an excess of metabolic disorders. Metabolic syndrome (MetS) is a cluster of classic cardiovascular risk factors, due to an imbalance between pro- and anti-inflammatory adipokines. Tumor necrosis factor (TNF)-α is a pro-inflammatory adipocytokine mainly produced by monocytes and macrophages with a central role in inflammatory responses, but it also induces adipocytes apoptosis, promotes insulin resistance, and stimulates lipolysis. The aim of this study was to evaluate the impact of therapy with etanercept (ETN), adalimumab (ADA), and methotrexate (MTX) on MetS components in a cohort of PsA patients with a follow-up period of 24 months. A retrospective study has been conducted in a cohort of PsA patients. On the basis of the inclusion criteria, we identified the first 70 consecutive patients, respectively, on ADA, ETN, and MTX, for a total of 210 patients achieving PsARC criteria during the observation period. As part of the routine clinical practice, assessment of metabolic parameters and of disease activity was recorded at baseline (T0), at 12 months (T1), and at 24 months (T2). The results show that when the specific components of the MetS were considered, taking also into account by regression analysis the effect of the confounding factors, the patients on etN and ADA show a significant improvement of the metabolic syndrome components (in detail, waist circumference, triglycerides, high-density lipoprotein cholesterol, and glucose) as compared to the MTX group. In conclusion, these data suggest that the biologic treatment in PsA can no longer be taken into consideration only for its positive effect on articular and cutaneous symptoms but also on the various aspects of this complex picture.

Long-term safety of anti-TNF-α in PsA patients with concomitant HCV infection: a retrospective observational multicenter study on 15 patients.

Psoriatic arthritis (PsA) is an inflammatory arthropathy associated with skin and/or nail psoriasis. TNF-α, in addition to its pro-inflammatory role, is an essential cytokine for the host's defense, and its depletion by treatment may facilitate the risk of viral infections or their reactivation. The aim of this study was to evaluate the efficacy and safety of TNF-α blockers in PsA patients with concurrent hepatitis C virus (HCV) infection. This is a multicenter study carried out in four Italian centers specialized in the diagnosis and treatment of PsA. At baseline and after 6 (T6) and 12 months (T12) of therapy, data concerning PsA activity and liver tests were registered. A total of 15 PsA patients with concomitant HCV infection were included in the study. At baseline, 13 patients had low viral load, and liver enzyme tests were within the normal range. During the observation period, these values remained stable. On the other hand, at baseline, a high viral load with slightly increased values of AST and ALT was detected in one patient. At T6 and T12, these values decreased. The remaining patient, at baseline, had low viral load, but with slightly increased AST and ALT values that normalized during the observation period. This is the greatest sample size available in the literature on this topic. The data suggests that anti-TNF-α agents are effective and safe in PsA patients with concomitant HCV. We suggest that the use of anti-TNF-α agents, accompanied by close monitoring, could be a therapeutic option.

JAK/STAT/PKCδ molecular pathways in synovial fluid T lymphocytes reflect the in vivo T helper-17 expansion in psoriatic arthritis.

Looking to the sustained psoriatic arthritis (PsA) joint as a model of local human inflammation, this study was designed to assess the T lymphocyte signal transduction pathways potentially involved in this chronic immune-mediated inflammatory process, as characterized by direct ex vivo analysis of T helper (Th)-17 T effector (Teff) cell phenotypes in synovial fluid (SF) and peripheral blood (PB) of clinically active PsA patients. The reverse-phase protein arrays (RPPA) technique was employed to identify STAT3, STAT1, JAK1, JAK2, PKCδ and ERK1/2 phosphoprotein levels on total T cell lysates in SF samples of PsA patients. Frequencies of T CD4(+)IL-17A-F(+) and T CD4(+)IL-23R(+) Th17 cells were quantified in SF and matched PB of PsA patients by flow cytometry and compared with PB of healthy controls (HC). Increased levels of JAK1, STAT3, STAT1 and PKCδ phosphoproteins were found in SF T cells of PsA patients, compared with PB of HC. The expansion of T CD4(+)IL-17A-F(+) cells, as well as of T CD4(+) cells expressing IL-23Rp19 (T CD4(+) IL-23R(+)), considered as the pathogenic phenotype of effector Th17 cells, was found to be confined to the joints of PsA patients, as the frequencies of both populations were significantly higher in SF than in matched PB, or in PB of HC. In conclusion, T lymphocyte signal transduction pathway mapping revealed an enhanced activation of JAK1/STAT3/STAT1 and PKCδ phosphoproteins that may drive the local inflammatory process, characterized by the in vivo expansion of T CD4(+)IL-17A-F(+) and T CD4(+)IL-23R(+) Th17 Teff cells in SF of clinically active joints of PsA patients.