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ID PMID Title PublicationDate abstract
28732135 Synovial Immunophenotype and Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis 2017 Nov OBJECTIVE: Serum anti-citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status. METHODS: Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment. Radiologic assessment was performed at the time of clinical follow-up. Synovial tissue was immunostained for specific markers of B cells (CD19), T cells (CD3, CD4, and CD8), macrophages (CD68), and blood vessels (factor VIII). Serum CXCL13 levels were quantified by enzyme-linked immunosorbent assay. Synovial tissue sections were analyzed for immunophenotype according to ACPA status, using a validated semiquantitative scoring method, and also analyzed for the presence of lymphoid aggregates. Response to treatment with nonbiologic or biologic disease-modifying antirheumatic drugs was assessed using the European League Against Rheumatism (EULAR) response criteria. RESULTS: In total, 123 subjects (78 ACPA+) were included. Compared to ACPA- RA patients, synovium from ACPA+ RA patients was characterized by significantly higher levels of CD19+ B cells and CD3+ and CD8+ T cells (each P < 0.05), and CD19+ B cell levels were significantly higher in patients who were naive to treatment. The CD19+ B cell infiltrate level was higher in patients with erosions at follow-up (P = 0.0128). Levels of lymphoid aggregates of CD19+ B cells were significantly higher in ACPA+ patients (P < 0.05), and this was associated with increased serum CXCL13 levels. The EULAR response was significantly associated with the level of CD3+ T cell infiltrates (P < 0.05), while CD68+ macrophage and CD8+ T cell levels were predictive of the response to tumor necrosis factor inhibitors (P < 0.05). CONCLUSION: The results of this prospective study demonstrate that the levels of synovial B cell infiltrates and lymphoid aggregates were significantly higher in ACPA+ RA patients, especially those who were naive to treatment. In addition, ACPA+ subjects developed more erosions during progression of the disease and had higher serum levels of CXCL13. The EULAR response to therapy in ACPA+ RA patients was associated with increased levels of T cell and macrophage markers.
27585710 Cyr61 participates in the pathogenesis of rheumatoid arthritis via promoting MMP-3 express 2017 May OBJECTIVES: The aim of this study was to investigate the effect and potential mechanism of Cysteine-rich 61 (Cyr61) on stimulating MMP-3 expression by fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. METHODS: Primarily cultured RA FLS were treated with exogenous Cyr61 protein or Cyr61-siRNA, then, MMP-3 expression was analyzed by real-time PCR, western blotting and ELISA. Signal transduction pathways in Cyr61-induced MMP-3 production were examined by real-time PCR, western blotting, confocal microscopy, luciferase reporter assay. Mice with collagen-induced arthritis (CIA) were treated with anti-Cyr61 monoclonal antibodies (mAb), or IgG1 as control and MMP-3 in the joint was detected by IHC, real-time PCR and western blotting. RESULTS: High expressed MMP-3 and Cyr61 were positively correlated in RA ST; Cyr61 stimulated MMP-3 production in FLS of RA patients in an IL-1β and TNF-α independent manner. Cyr61 induced MMP-3 could further enhance the invasive ability of RA FLS. Mechanistically, we found that Cyr61 promoted MMP-3 production via the P38, JNK-dependent AP-1 signaling pathway. Blockage of Cyr61 function with monoclonal antibody could decrease MMP-3 expression in the joints of CIA mice. CONCLUSION: This study provides new evidence that Cyr61 participates in RA pathogenesis not only as a pro-inflammatory factor but also plays a key role in bone erosion via promoting MMP-3 expression. We suggest that targeting of Cyr61 may represent a potential strategy in RA treatment.
27903979 Elevated plasma midkine and pleiotrophin levels in patients with systemic lupus erythemato 2017 Jun 20 Emerging evidence suggests that two heparin-binding growth factor, midkine and pleiotrophin are implicated in the pathogenesis of autoimmune diseases including SLE. To investigate the plasma midkine and pleiotrophin levels in SLE patients, as well as their correlation with major clinical parameters and interleukin-17 (IL-17) level in SLE, 83 SLE patients and 123 controls including 20 rheumatoid arthritis (RA) patients, 21 Sjögren's syndrome (SS) patients and 82 healthy controls (HCs) were recruited. Plasma midkine, pleiotrophin and IL-17 levels were detected by ELISA. Midkine and pleiotrophin levels were significantly higher in SLE, RA and SS patients compared with HCs (all P < 0.05). There were significantly lower midkine and pleiotrophin levels in SLE compared to SS (P < 0.05 and P < 0.01, respectively). No significant differences in midkine and pleiotrophin levels were found between SLE and RA (P = 0.240 and P = 0.074, respectively). Both plasma midkine and pleiotrophin levels were associated with rash and anti-SSA in SLE. In addition, both midkine and pleiotrophin levels were positively associated with IL-17 level in SLE (both P < 0.001). Area under curve (AUC) of the receiver operating characteristic (ROC) curve for midkine and pleiotrophin were 0.606 (0.527-0.681) and 0.605 (0.526-0.680) respectively. In conclusion, elevated plasma midkine and pleiotrophin levels and their associations with rash, anti-SSA and IL-17 in SLE patients suggest their involvement in this disease.
28598786 Prevalence and risk factors for liver fibrosis detected by transient elastography or shear 2017 Nov OBJECTIVES: Emerging technologies for monitoring subclinical liver fibrosis include transient elastography (TE) and shear wave elastography (SWE). A systematic review was conducted to assess the prevalence and report on predictors of liver fibrosis as detected by these technologies in inflammatory arthritis (IA) patients, including rheumatoid arthritis, spondyloarthritis and juvenile idiopathic arthritis. METHODS: MEDLINE, EMBASE and Web of Science were searched from inception to 06/27/2016 using search terms for IA or DMARDs and TE/SWE. Studies reporting on prevalence and/or risk factors for liver fibrosis as detected by TE/SWE were included. A meta-analysis was not conducted due to study heterogeneity. RESULTS: Seven cross-sectional and three case-control studies were included. The cut-off values to define liver fibrosis ranged from 5.3-8.6 kPa. The prevalence of liver fibrosis in RA detected by TE/SWE ranged from 3-23%, with higher prevalence found in studies using a 5.3kPa cut-off. In two studies fibrosis was reported in 16-17% of PsA patients with no JIA studies identified. Obesity was the most consistently reported independent predictor of fibrosis in three studies. Liver function tests (LFTs) were found to independently predict increased liver stiffness in one study, while cumulative dose of either methotrexate or leflunomide were predictors in two studies. CONCLUSIONS: Methotrexate or leflunomide cumulative dose was not consistently reported as an independent predictor of liver fibrosis; whereas, obesity was more consistently identified. Of note, LFTs did not consistently predict elevated TE/SWE measures. Further studies are needed to evaluate the prevalence and predictors of liver fibrosis and to explore the utility of using TE/SWE in IA patients.
28448562 The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumat 2017 OBJECTIVE: To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. METHODS: This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. RESULTS: Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. CONCLUSION: ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. TRIAL REGISTRATION: This study was registered on www.ClinicalTrials.gov (NCT01981473).
28187781 Priming in response to pro-inflammatory cytokines is a feature of adult synovial but not d 2017 Feb 10 BACKGROUND: It has been hypothesized that chronic inflammatory diseases such as rheumatoid arthritis (RA) may be caused by a failure of negative feedback mechanisms. This study sought to examine negative feedback mechanisms in fibroblast-like synoviocytes (FLS), one of the most abundant cell types in the joint. We hypothesized that prior exposure of healthy FLS to an inflammatory stimulus would attenuate their responses to a second inflammatory stimulus, in the same way that negative feedback mechanisms desensitize macrophages to repeated stimulation by lipopolysaccharide. We further hypothesized that such negative feedback mechanisms would be defective in FLS derived from the joints in RA. METHODS: Synovial fibroblasts and dermal fibroblasts from non-inflamed joints and joints affected by RA and a fibroblast cell line from neonatal foreskin were stimulated twice with tumour necrosis factor (TNF) α or interleukin (IL)-1α, with a 24-h rest period between the two 24-h stimulations. Differences between response to the first and second dose of cytokine were examined by assessing secretion of inflammatory factors and intracellular signalling activity. RESULTS: FLS from both non-inflamed joints and joints affected by RA mounted an augmented response to re-stimulation. This response was site-specific, as primary dermal fibroblasts did not alter their response between doses. The fibroblast priming was also gene-specific and transient. Assessment of signalling events and nuclear localization showed prolonged activation of nuclear factor (NF)-κB during the second stimulation. CONCLUSION: This study aimed to examine mechanisms of negative regulation of inflammatory responses in FLS. Instead, we found a pro-inflammatory stromal memory in FLS obtained from both non-inflamed joints and joints affected by RA. This suggests the joint is an area at high risk of chronic inflammation, and may provide a piece in the puzzle of how chronic inflammation is established in RA.
29247153 The Use of the OMERACT Ultrasound Tenosynovitis Scoring System in Multicenter Clinical Tri 2018 Feb OBJECTIVE: To test the sensitivity to change of the Outcome Measures in Rheumatology Clinical Trials (OMERACT) ultrasound (US) scoring system for tenosynovitis when applied in a multicenter design. METHODS: RA patients with US-verified tenosynovitis were recruited when scheduled for treatment intensification. Tenosynovitis was assessed at baseline, and 3 and 6 months followup, using the semiquantitative OMERACT scoring system. RESULTS: Expressed in median (25th; 75th percentiles), the overall greyscale and Doppler score decreased significantly from baseline at 4 (2; 7) and 3 (2; 6), to 6 months at 2 (0; 3) and 0 (0; 1, p < 0.01), respectively, and showed high responsiveness (standardized response mean ≥ 0.8). CONCLUSION: The OMERACT US scoring system for tenosynovitis showed high responsiveness, supporting its use for diagnosing and monitoring tenosynovitis in multicenter trials.
28916915 Inflammatory diseases and bone fragility. 2017 Dec Systemic osteoporosis and increased fracture rates have been described in chronic inflammatory diseases such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, inflammatory bowel diseases, and chronic obstructive pulmonary disease. Most of these patients receive glucocorticoids, which have their own deleterious effects on bone. However, the other main determinant of bone fragility is the inflammation itself, as shown by the interactions between the inflammatory mediators, the actors of the immune system, and the bone remodelling. The inflammatory disease activity is thus on top of the other well-known osteoporotic risk factors in these patients. Optimal control of inflammation is part of the prevention of osteoporosis, and potent anti-inflammatory drugs have positive effects on surrogate markers of bone fragility. More data are needed to assess the anti-fracture efficacy of a tight control of inflammation in patients with a chronic inflammatory disorder. This review aimed at presenting different clinical aspects of inflammatory diseases which illustrate the relationships between inflammation and bone fragility.
28980085 Real-world experience of tocilizumab in rheumatoid arthritis: sub-analysis of data from th 2018 Feb To assess the long-term effectiveness and safety of tocilizumab, abatacept, and tumor necrosis factor-α inhibitors (TNFi), in the Italian real-world setting of rheumatoid arthritis (RA). The records of adult RA patients from the Italian biologics' registry Gruppo Italiano Studio Early Arthritis (GISEA) were analyzed. Demographic and clinical data were obtained at entry. The disease remission rate (28-joint disease activity score calculated using the erythrocyte sedimentation rate [DAS28-ESR] ≤ 2.6) and frequency of adverse events (AEs) were evaluated at 2 years. From 1999 to 2014, 7539 patients were treated with biologics (61.3% in first- and 22.6% in second-line), 68% of cases received TNFi, 9.1% tocilizumab, and 8.6% abatacept. Treatment groups showed a similar DAS28 at entry. As first-line, tocilizumab induced a significantly higher remission rate than abatacept or TNFi at 6 (51 vs 23.3 and 26.2%, respectively; p < 0.0001) and 24 months (52.3 vs 33.3 and 34.4%, respectively; p < 0.01). A similar pattern was observed in later lines. The most common AEs reported were infections, reactions to biologics (more frequent among TNFi-treated patients), increased transaminase (more frequent among TCZ-treated patients), and cardiovascular events. In clinical practice, TCZ induced a rapid and long-lasting remission and in a higher percentage of patients compared to abatacept and TNFi, with a good safety profile.
28341765 Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthri 2017 Sep BACKGROUND: Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care. METHODS: Patients with RA in the Clinical Practice Research Datalink starting MTX between 1987 and 2016 were included. Hepatotoxicity was defined as transaminitis: alanine transaminase or aspartate aminotransferase more than three times the upper limit of normal. Crude rates of transaminitis were calculated per 1000 person-years, categorised by weekly alcohol consumption in units. Cox proportional hazard models tested the association between alcohol consumption and transaminitis univariately, then age and gender adjusted. RESULTS: 11 839 patients were included, with 530 episodes of transaminitis occurring in 47 090 person-years follow-up. Increased weekly alcohol consumption as a continuous variable was associated with increased risk of transaminitis, adjusted HR (95% CI) per unit consumed 1.01 (1.00 to 1.02); consuming between 15 and 21 units was associated with a possible increased risk of hepatotoxicity, while drinking >21 units per week significantly increased rates of transaminitis, adjusted HR (95% CI) 1.85 (1.17 to 2.93). CONCLUSIONS: Weekly alcohol consumption of <14 units per week does not appear to be associated with an increased risk of transaminitis.
28535740 Etodolac transdermal cubosomes for the treatment of rheumatoid arthritis: ex vivo permeati 2017 Nov In this study, transdermal etodolac-loaded cubosomes were developed in order to relieve patient pain and joints stiffness by providing stable etodolac concentration at the targeting sites through controlled drug delivery via the noninvasive skin route with more sustaining and less frequent dosing. Different ratios and percentages of poloxamer 407 and monoolein were used to formulate the cubosomes using emulsification and homogenization processes. The etodolac-loaded cubosomes showed particle size values ranging from 135.95 to 288.35 nm and zeta potential values ranging from -18.40 to -36.10 mV. All the cubosomes offered an encapsulation efficiency value of about 100% and showed drug loading capacity ranging from 1.28 to 6.09%. The in vitro drug release studies revealed a controlled drug release profile with a drug release rate up to 15.08%/h. Increasing poloxamer concentration in etodolac-loaded cubosomes resulted in nanoparticles with less particle size and faster drug release. The particles exhibited cubic and hexagonal shapes. The DSC and X-ray analysis demonstrated that the drug was encapsulated in the cubosomes bicontinuous structures in amorphous form. In addition, investigated cubosomes exhibited fast drug penetration through excited mice skin followed by slower drug penetration for up to 24 h. The pharmacokinetic study in human volunteers showed that the selected etodolac-loaded cubosomes enhanced the bioavailability of etodolac as compared to the oral capsules (266.11%) with evidence of longer half-life and higher MRT that reached 18.86 and 29.55 h, respectively. The etodolac-loaded cubosomes propose a promising system for treatment of arthritis simply through skin application.
27283333 Is ankylosing spondylitis a risk factor for cardiovascular disease, and how do these risks 2017 Feb AIMS: To assess and compare the incidence of cardiovascular (CV) events, by CV phenotype, between patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA) and the general population. METHODS: Using linkages of national and population-based registers, we identified one cohort of prevalent patients with AS (n=5358), one with RA (n=37 245) and one with matched general population subjects (n=25 006). These cohorts were identified in 2006 through 2011 and were followed in 31 December 2012, for first ever occurrence of acute coronary syndromes (ACS), deep venous thromboembolism, pulmonary embolism and stroke, respectively. For each outcome, we calculated incidence rates standardised to the age and sex distribution of the AS cohort, as well as relative risks using Cox proportional hazards models. RESULTS: Based on 69 ACS events during 20 251 person-years of follow-up of the patients with AS, and 966 events during 127 014 person-years in the RA cohort, the age/sex-adjusted relative risks for ACS compared with the general population was 1.3 (95% CI 1.0 to 1.7) for AS and 1.7 (1.4 to 2.0) for RA. For thromboembolic events, the corresponding risks were 1.4 (1.1 to 1.9) in AS and 1.8 (1.5 to 2.1) in RA. Finally, for stroke, the relative risks were 1.5 (1.1 to 2.0) in AS and 1.5 (1.2 to 1.8) in RA, compared with the general population. CONCLUSIONS: Prevalent patients with AS are at a 30%-50% increased risk of incident CV events. When compared with patients with RA, this level of increase was similar for stroke, but only half as high for ACS and thrombotic events.
28031442 Decreased platelet size is associated with platelet activation and anti-phospholipid syndr 2017 Mar 1 OBJECTIVES: . SLE is an autoimmune disease with increased cardiovascular morbidity and platelet activation. In the general population, increased platelet size predicts platelet reactivity and cardiovascular disease. The aim of this study was to investigate whether platelet size related to platelet activation and cardiovascular disease in SLE. METHODS: . Fresh blood samples from SLE patients ( n = 148), healthy volunteers ( n = 79) and disease controls ( n = 40) were analysed for platelet size and activation by flow cytometry, ELISA and cell count. Associations to manifest cardiovascular disease, venous thrombosis and APS were adjusted for traditional cardiovascular risk factors using logistic regression analysis. RESULTS: . SLE patients had decreased platelet size as compared with healthy controls ( P = 0.003). In SLE, decreased platelet size was related to increased platelet activation, in particular microparticle formation ( P < 0.0001, r = -0.46) and release of serotonin from dense granules ( P < 0.001, r = 0.57). SLE patients with aCL had decreased platelet size ( P = 0.02) and aCL decreased platelet size in vitro ( P = 0.007). In contrast to the general population, increased platelet size was not associated with cardiovascular disease. Instead, decreased platelet size was associated with secondary APS, even after adjusting for traditional cardiovascular risk factors ( P = 0.01, odds ratio 3.58). CONCLUSION: . Platelet size is decreased in SLE patients and associated with microparticle formation and APS. Future studies are needed to determine the underlying mechanism(s) as well as the potential predictive value of small platelets for disease complications in SLE.
28737053 Efficacy of baricitinib in the treatment of rheumatoid arthritis. 2017 Sep although the outcome for patients with rheumatoid arthritis (ra) has improved in the past decades, adequate disease control cannot be achieved in a substantial proportion of patients. new drugs with a novel mechanism of action, may represent a valuable addition to the current armamentarium. Areas covered: This review focuses on the pharmacodynamics and pharmacokinetics of baricitinib. Furthermore, the article summarizes and comments the drug's efficacy and safety profile in RA patients. Expert opinion: Baricitinib is an oral targeted synthetic (ts) disease-modifying antirheumatic drug (DMARD) that mainly inhibits JAK1 and JAK2. Baricitinib monotherapy, or in combination with conventional synthetic (cs) DMARDs, has demonstrated its efficacy while having an acceptable safety profile in early active RA naive to DMARDs, and active RA with an inadequate response to csDMARDs and/or biologic (b)DMARDs. The future place of baricitinib in the management of RA patients will depend on several factors. However, baricitinib offer few advantages: oral administration, rapidity of action, efficacy in monotherapy and over adalimumab in one study and non-immunization. However, pending further safety data, current practice would be to start a bDMARD when the treatment target is not achieved with csDMARDs. Availability of additional long-term safety data may influence prescribing decisions.
28835429 A rare case of pulmonary toxoplasmosis in a patient with undifferentiated inflammatory art 2017 Aug 23 Pulmonary toxoplasmosis is a serious pulmonary condition caused by the protozoan Toxoplasma gondii It typically affects immunocompromised patients presenting acutely with cough, fever, myalgias, arthralgias and lymphadenopathy, and chronically with persistent cough and dyspnoea. Because of its protean features, it can mimic many more common lung conditions in the immunocompromised patient, including atypical pneumonia, Pneumocystis pneumonia and interstitial lung disease. In this article, we present the case of a 55-year-old woman who presented to our hospital with persistent dyspnoea and cough, initially suspected to have an arthritis-related interstitial lung disease. She received a final diagnosis of pulmonary toxoplasmosis after lung biopsy demonstrated Toxoplasma cysts, later confirmed by serology. Treatment with trimethoprim-sulfamethoxazole resulted in significant improvement of her respiratory symptoms after 3 months.
28648867 An initial investigation into endothelial CC chemokine expression in the human rheumatoid 2017 Sep Rheumatoid arthritis (RA) is a destructive and chronic autoimmune inflammatory disease. Synovial inflammation is a major feature of RA and is associated with leukocyte recruitment. Leukocytes cross the endothelial cells (ECs) into the synovial tissue and fluid and this migration is mediated via a range of chemokines and adhesion molecules on the ECs. As important mediators of leukocyte extravasation, a number of chemokines from each of the chemokine families have been established as expressed in the RA joint. However, as little information is available on which chemokines are expressed/presented by the ECs themselves, the purpose of the study was to ascertain which of the CC chemokines were localised in RA ECs. Immunofluoresence was used to assess the presence of the CC-family chemokines in RA synovial ECs using von-Willebrand factor (VWF) as a pan-endothelial marker and a range of human chemokine antibodies. The percentage of VWF positive vessels which were positive for the chemokines was determined. The presence of the four most highly expressed novel chemokines were further investigated in non-RA synovial ECs and the sera and synovial fluid (SF) from patients with RA and osteoarthritis (OA). Statistical analysis of immunofluorescence data was carried out by Student's t-test. For analysis of ELISA data, Kruskal-Wallis ANOVA followed by Dunn's multiple comparison test was utilised to analyse differences in sera and SF levels for each chemokine between RA and OA. Spearman rank correlations of sera and SF chemokine levels with a range of clinical variables were also performed. Chemokine detection varied, the least abundant being CCL27 which was present in 8.3% of RA blood vessels and the most abundant being CCL19 which was present in 80%. Of the 26 chemokines studied, 19 have not been previously observed in RA ECs. Four of these novel chemokines, namely CCL7, CCL14, CCL16 and CCL22 were present on ≥60% of vessels. CCL14 and CCL22 were shown to be increased in RA ECs compared to non-RA ECs, p=0.0041 and p=0.014 respectively. EC chemokines CCL7, CCL14, CCL16 and CCL22 also occurred in RA synovial fluid and sera as established by ELISA. CCL7 was shown to be significantly increased in sera and SF from RA patients compared to that from osteoarthritis (OA) patients (p<0.01), and to have a highly significant correlation with the level of anti-CCP (R=0.93, p=0.001). Less abundant chemokines shown to be present in RA ECs were CCL1-3, CCL5, CCL10-13, CCL15, CCL17, CCL18, CCL20, CCL21 and CCL23-28. In conclusion, this initial study is the first to show the presence of a number of CC chemokines in RA ECs. It provides evidence that further validation and investigation into the presence and functionality of these novel chemokines expressed at RA synovial ECs may be warranted.
28367100 PADI4 Epigenetically Suppresses p21 Transcription and Inhibits Cell Apoptosis in Fibroblas 2017 Rheumatoid arthritis (RA) is characterized by synovial lining hyperplasia, which involves abnormal growth of fibroblast-like synoviocytes (FLSs). This study aimed to investigate the function and molecular mechanism of peptidylarginine deiminase type 4 (PADI4) in FLSs isolated from RA patients (RA-FLSs). FLSs were isolated from RA patients and transfected with small interfering RNAs (siRNAs) or PADI4 overexpression plasmid. FLSs were treated by Adriamycin (ADR) to induce apoptosis, and apoptotic cells were detected by flow cytometry. The expression of PADI4, p53 and p21 was detected by qRT-PCR and Western blot analysis. The recruitment of PADI4 and histone H3 arginine modifications to p21 promoter was measured by chromatin immunoprecipitation. The results showed that knockdown of PADI4 promoted the apoptosis of RA-FLSs and the expression of p53 and p21. Ectopic expression of PADI4 inhibited ADR-induced apoptosis of RA-FLSs, and down-regulated the expression of p53 and p21. In RA-FLSs, global H3 citrullination (CitH3) and H3 arginine 17 methylation levels were dynamically changed by PADI4 and ADR treatment. PADI4 and H3 could bind p21 promoter region to regulate p21 expression. In conclusion, PADI4 contributes to the pathogenesis of RA by protecting FLSs from apoptosis. PADI4 suppresses p21 transcription through altering histone H3 arginine modifications on p21 promoter region. Our study provides new insight into the anti-apoptotic role of PADI4 in RA development.
28012569 Efficacy of Methylprednisolone Acetate Versus Triamcinolone Acetonide Intra-articular Knee 2017 Jan PURPOSE: Triamcinolone hexacetonide (TH), triamcinolone acetonide (TA), and methylprednisolone acetate (MPA) are commonly used intra-articular steroid preparations. Studies suggest that intra-articular TH is more efficacious than MPA and TA in chronic inflammatory arthritis. However, it is unclear which of the latter two preparations has better efficacy. Thus, we compared intra-articular knee injections of MPA and TA in patients with chronic inflammatory arthritis. METHODS: This double-blind, randomized controlled trial included patients with rheumatoid arthritis or spondyloarthritis with an acutely swollen knee joint (≥1 week, <24 weeks). They were randomly assigned (1:1) to intra-articular knee injection with MPA or TA (80 mg, 2 mL of each). Evaluations were performed at 4, 12, and 24 weeks. Primary outcome was time to relapse (Kaplan-Meier) over 24 weeks, with relapse defined as return to baseline pain or swelling ≥1 week. Secondary outcomes were change in pain and swelling (using a numerical rating scale), range of movement, and occurrence of adverse effects. Primary analysis was intention to treat, with last observation carried forward. FINDINGS: One hundred patients (89 with rheumatoid arthritis) were randomly assigned in equal numbers to the MPA and TA groups. Nine patients relapsed in each group over 24 weeks. The mean time to relapse was not significantly different between the MPA and TA groups (20.8 [95% CI, 18.8-22.7] weeks and 20.9 [95% CI, 19.0-22.8] weeks, respectively; P = 0.9; hazard ratio = 1.0 [95% CI, 0.4-2.5]). In both groups, there was a significant decline in pain and swelling scores at all visits (P < 0.001); however, there were no significant intergroup differences. At 24 weeks, mean change in pain in the MPA (-4.4 [3.1]) and TA groups (-3.9 [2.8]) was not significantly different (P = 0.46). No infection, hematoma or hypopigmentation occurred in any patient. In addition, no significant intergroup differences were found in joint swelling, range of movement, modified (28 joint) Disease Activity Score using 3 variables, or Health Assessment Questionnaire over 24 weeks. IMPLICATIONS: No significant differences were found in efficacy between intra-articular knee injections with MPA and TA in these patients with chronic inflammatory arthritis. However, results need to be extrapolated cautiously because of the small sample size. Three-quarters of the patients remained relapse free at 24 weeks. Clinical Trials Registry of India (www.ctri.nic.in) identifier: CTRI/2015/09/006187.
28516886 Patterns of tocilizumab use, effectiveness and safety in patients with rheumatoid arthriti 2017 Nov OBJECTIVES: To observe patients with rheumatoid arthritis (RA) treated with the interleukin-6 receptor-alpha inhibitor tocilizumab (TCZ) in routine clinical practice. METHODS: Data on concomitant medications, effectiveness and safety were pooled from independent, multinational studies in patients with RA initiating intravenous TCZ according to local label recommendations observed in routine practice for 6 months. Patients were grouped by TCZ monotherapy or combination therapy with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). The primary endpoint was the proportion of patients receiving TCZ after 6 months. RESULTS: Of 1336 patients enrolled, 506 (37.9%) received TCZ monotherapy and 830 (62.1%) received combination therapy. Kaplan-Meier analysis estimated that 80% (95% CI, 76%-83%) of monotherapy and 87% (95% CI, 84%-89%) of combination therapy patients continued to receive TCZ at 6 months (log-rank p<0.001). During the observation period, TCZ was discontinued by 113 (22.3%) monotherapy patients and 116 (14.0%) patients on combination therapy. The mean prednisone-equivalent oral corticosteroid dose was 8.4 mg/day for monotherapy and combination therapy patients at baseline and 7.7 and 7.6 mg/day, respectively, at month 6. Adverse events or laboratory abnormalities requiring TCZ dose modification were reported for 66 (13.0%) monotherapy and 130 (15.7%) combination therapy patients. Effectiveness at 6 months was similar between groups; mean (SD) change from baseline in Clinical Disease Activity Index (CDAI) was -20.3 (14.18) for monotherapy and -22.3 (16.09) for combination therapy (p=0.7347). CONCLUSIONS: In routine clinical practice, 38% of patients received TCZ as monotherapy. Persistence on monotherapy or in combination therapy with csDMARDs was high, with a slight trend towards a higher rate with combination therapy, and effectiveness was similar between groups.
28093419 The risk of fracture among patients with psoriatic arthritis and psoriasis: a population-b 2017 May OBJECTIVE: To determine the risk of fracture and osteoporosis among patients with psoriatic arthritis (PsA) and psoriasis, compared with the general population and patients with rheumatoid arthritis (RA). METHODS: A population-based cohort study was performed in The Health Improvement Network in the UK using data from 1994 to 2014. Patients aged 18-89 years with PsA or psoriasis and up to five unexposed controls matched by practice and start date within that practice were included. Patients with RA and matched controls were included for comparison. Severe psoriasis was defined by a code for psoriasis and either phototherapy or a systemic medication for psoriasis. Incidence and adjusted HRs (aHR) for fracture (all, hip, vertebral) were calculated. RESULTS: Patients with PsA (n=9788), psoriasis (n=158 323) and controls (n=821 834) were identified. Patients with PsA had an elevated risk of all fracture aHR 1.26 (1.06 to 1.27). Patients with mild psoriasis had elevated risk of all fractures, vertebral and hip fracture: aHR 1.07 (1.05 to 1.10), 1.17 (1.03 to 1.33) and 1.13 (1.04 to 1.22). Patients with severe psoriasis had significantly elevated risk of all fracture and vertebral fracture: aHR 1.26 (1.15 to 1.39) and 2.23 (1.54 to 3.22). CONCLUSIONS: PsA and psoriasis are associated with an elevated risk for fracture.