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ID PMID Title PublicationDate abstract
25607251 RANTES gene polymorphisms are not associated with rheumatoid arthritis and atopic dermatit 2015 BACKGROUND: A few recent studies have suggested that regulated on activation, normal T cell expressed and secreted (RANTES) polymorphisms (-403 G/A, -28C/G) are associated with rheumatoid arthritis (RA) and atopic dermatitis (AD). However, there still existed studies that did not confirm this correlation. OBJECTIVE: The objective of this study was to evaluate the relationships of RANTES and RA and AD using a meta-analysis. METHODS: Pubmed, Embase, and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers, and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. RESULTS: Eight studies were enrolled, including a total of 548 RA cases and 493 controls of -403G/A, 305 RA cases and 303 controls of -28C/G, and 705 AD cases and 578 controls of -403G/A in this meta-analysis. In RA, the overall OR and 95% CI of -403A were 1.41, 1.10-1.82 (p = 0.391) and 2.18, 1.30-3.66 (p = 0.335) in dominant and recessive models, respectively. The overall OR and 95% CI of -28G in RA were 1.35, 0.91-2.01 (p = 0.707) and 3.32, 1.29-8.52 (p = 0.559) in dominant and recessive models, respectively. Moreover, the overall OR and 95% CI of -403A in AD were 1.38, 1.08-1.76 (p = 0.421) and 1.06 and 0.65-1.72 (p = 0.361) in dominant and recessive models, respectively. CONCLUSIONS: This meta-analysis showed that RANTES -403G/A and -28C/G were not associated with RA and AD.
26314697 Prevalence of Renal Impairment in Patients With Rheumatoid Arthritis: Results From a Cross 2016 May OBJECTIVE: To assess the prevalence and associations of renal dysfunction in patients with rheumatoid arthritis (RA). METHODS: COMEDRA is a French nationwide cross-sectional multicenter study on comorbidities in RA. Renal function was assessed from the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation. RA characteristics and risk factors for renal impairment were collected. Two logistic regression models, 1 with and 1 without the Framingham Risk Score, were constructed from variables that were significantly associated with an eGFR of <60 ml/minute/1.73 m(2) or were clinically relevant. RESULTS: Of the 970 recruited patients, 931 were analyzed (women 79.6%, mean age 57.8 years, disease duration 11.1 years, Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] 3.1). A total of 82 patients (8.8%) had an eGFR <60 ml/minute/1.73 m(2) and 9% had proteinuria. In univariate analysis, renal impairment was associated with age (P < 0.001), history of hypertension (P < 0.001), high systolic blood pressure (P = 0.03), and the Systematic Coronary Risk Evaluation (SCORE) equation (P = 0.002), but not with sex, disease duration, disease activity (as assessed by DAS28-ESR), nonsteroidal antiinflammatory drug use, disease severity (erosions, joint replacement), or RA medications. Multivariate analysis models showed that age (odds ratio [OR] 1.05 [95% confidence interval (95% CI) 1.03-1.09]) and hypertension (OR 2.5 [95% CI 1.5-4.3]) were associated with renal impairment. A second model showed that the SCORE equation (OR 1.33 [95% CI 1.06-1.67]) was associated with renal impairment. CONCLUSION: Renal impairment is relatively common in RA and is associated with cardiovascular risk factors such as age, hypertension, and the SCORE equation but not with disease activity or severity.
25760280 Update on autoantibodies to modified proteins. 2015 May PURPOSE OF REVIEW: This article provides an update on the recent findings on autoantibodies to modified proteins in rheumatoid arthritis (RA). RECENT FINDINGS: In the past few years, the knowledge on the autoantibodies to citrullinated antigens has expanded considerably. More specifically, it is now clear that many different citrullinated protein antigens present in the synovial compartment can be recognized by anticitrullinated protein antibody (ACPA). This is most likely a consequence of the cross-reactivity the ACPA response displays to citrullinated proteins. It is now also clear that the isotype usage and the citrullinated epitope repertoire recognized by ACPA expands before the manifestation of full-blown RA and that this goes hand in hand with a rise in ACPA level. Next to ACPA, several other autoantibody systems directed against other posttranslationally modified proteins, such as proteins containing a homocitrulline residue resulting from protein carbamylation, have been identified. On the whole, the evolution of these autoantibody systems in time mimics the evolution of the ACPA response, indicating that the break of tolerance underlying different autoimmune responses present in RA occurs before disease onset, with a further maturation of these responses shortly before or concurrent with the manifestation of clinical symptoms. SUMMARY: Since the discovery of rheumatoid factor over 65 years ago, our knowledge on autoantibodies and their relevance for rheumatic disease has expanded enormously. Especially, the realization that next to rheumatoid factor, also other autoantibodies recognizing posttranslationally modified proteins are present in RA patients has contributed significantly to the understanding of disease. In the past few years, several new autoantibody systems to differentially modified proteins have been identified and their relation to clinical outcome has been scrutinized. Here, we provide an update on the recent developments in our knowledge on the presence and consequences of autoantibodies to modified proteins in RA.
27465842 CCN1 Promotes VEGF Production in Osteoblasts and Induces Endothelial Progenitor Cell Angio 2017 Jan Angiogenesis is the formation of new capillaries from preexisting vasculature. The perpetuation of angiogenesis plays a critical role in the pathogenesis of various disease states including rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61 or CCN1) is an important proinflammatory cytokine in RA. Here, we investigated the role of CCN1 in angiogenesis associated with vascular endothelial growth factor (VEGF) production and osteoblasts. We found higher expression of CCN1 and VEGF in synovial fluid from RA patients compared with healthy controls. CCN1 induced VEGF expression in osteoblasts and increased endothelial progenitor cells (EPCs) angiogenesis by inhibiting miR-126 via the protein kinase C-alpha (PKC-α) signaling pathway. CCN1 knockdown inhibited angiogenesis in both in vitro and in vivo models. Inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA (shRNA) ameliorated articular swelling, cartilage erosion, and angiogenesis in the ankle joint of mice with collagen-induced arthritis (CIA). Our study is the first to describe how CCN1 promotes VEGF expression in osteoblasts and increased EPCs angiogenesis in RA disease. CCN1 may serve as a potential target for RA treatment. © 2016 American Society for Bone and Mineral Research.
26555655 Impact of Treatment With Biologic Agents on the Use of Mechanical Devices Among Rheumatoid 2016 Jul OBJECTIVE: To assess trends and predictors of mechanical devices/aids use by rheumatoid arthritis (RA) patients since the introduction of biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: Sociodemographic characteristics, disease characteristics, and mechanical aid use (assessed using the Health Assessment Questionnaire) were compared among RA patients ages >17 years at diagnosis, enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) registry during January 2001 to December 2003 and January 2010 to December 2012. Univariate and multivariate logistic regression analyses were used to identify predictors of mechanical aid use among patients in both cohorts. RESULTS: Sociodemographic characteristics were similar between 1,096 patients in the 2001-2003 cohort and 11,140 patients in the 2010-2012 cohort. Disease activity was significantly lower among patients in the 2010-2012 cohort (mean ± SD Clinical Disease Activity Index score 10.1 ± 11.1 versus 17.0 ± 13.8; P < 0.001). A greater proportion of patients in the 2010-2012 cohort received biologic DMARDs (50.7% versus 32.5%; P < 0.001) and fewer were biologic-naive (39.1% versus 61.6%; P < 0.001). Fewer patients in the 2010-2012 cohort used any mechanical devices/aids (31.1% versus 40.8%; P < 0.001). In multivariate analysis, patients in the 2010-2012 cohort and those with a history of biologic agent use were less likely to use devices/aids (odds ratio [OR] 0.77 [95% confidence interval (95% CI) 0.66-0.90] and OR 0.68 [95% CI 0.62-0.75], respectively). Predictors of greater devices/aids usage included older age, female sex, higher disease activity, and less employment. Effect sizes were greatest for disease activity and employment. CONCLUSION: Mechanical devices/aids use among patients with RA was significantly lower during 2010-2012 versus 2001-2003 and among biologic-experienced patients, suggesting reduced disability.
26980135 Generation mechanism of RANKL(+) effector memory B cells: relevance to the pathogenesis of 2016 Mar 16 BACKGROUND: The efficacy of B cell-depleting therapies for rheumatoid arthritis underscores antibody-independent functions of effector B cells such as cognate T-B interactions and production of pro-inflammatory cytokines. Receptor activator of nuclear factor κB ligand (RANKL) is a key cytokine involved in bone destruction and is highly expressed in synovial fluid B cells in patients with rheumatoid arthritis. In this study we sought to clarify the generation mechanism of RANKL(+) effector B cells and their impacts on osteoclast differentiation. METHODS: Peripheral blood and synovial fluid B cells from healthy controls and patients with rheumatoid arthritis were isolated using cell sorter. mRNA expression of RANKL, osteoprotegerin, tumor necrosis factor (TNF)-α, and Blimp-1 was analyzed by quantitative real-time polymerase chain reaction. Levels of RANKL, CD80, CD86, and CXCR3 were analyzed using flow cytometry. Functional analysis of osteoclastogenesis was carried out in the co-culture system using macrophage RAW264 reporter cells. RESULTS: RANKL expression was accentuated in CD80(+)CD86(+) B cells, a highly activated B-cell subset more abundantly observed in patients with rheumatoid arthritis. Upon activation via B-cell receptor and CD40, switched-memory B cells predominantly expressed RANKL, which was further augmented by interferon-γ (IFN-γ) but suppressed by interleukin-21. Strikingly, IFN-γ also enhanced TNF-α expression, while it strongly suppressed osteoprotegerin expression in B cells. IFN-γ increased the generation of CXCR3(+)RANKL(+) effector B cells, mimicking the synovial B cell phenotype in patients with rheumatoid arthritis. Finally, RANKL(+) effector B cells in concert with TNF-α facilitated osteoclast differentiation in vitro. CONCLUSIONS: Our current findings have shed light on the generation mechanism of pathogenic RANKL(+) effector B cells that would be an ideal therapeutic target for rheumatoid arthritis in the future.
26503956 A Truncated Variant of ASCC1, a Novel Inhibitor of NF-κB, Is Associated with Disease Seve 2015 Dec 1 Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-κB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-κB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-κB target genes (TRAIL, TNF-α, cIAP-1, IL8) and blocks activation of a NF-κB-luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-κB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-κB and the secretion of TNF-α in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-κB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA.
25573503 Separate and overlapping specificities in rheumatoid arthritis antibodies binding to citru 2015 Jan 9 INTRODUCTION: Our objective was to find out if there are antibodies binding to homocitrulline-containing type I and II collagen carboxyterminal telopeptides in sera of patients with rheumatoid arthritis (RA), and if these antibodies cross-react with citrulline and homocitrulline in the same peptide sequence. METHODS: A total of 72 RA and 72 control sera were analyzed for binding using enzyme-linked immunosorbent assay to citrulline- or homocitrulline-containing type I and II collagen carboxyterminal telopeptides, as well as to cyclic citrullinated peptide (CCP) and to mutated citrullinated vimentin (MCV). Specificities of the antibodies were tested using inhibition-ELISA. RESULTS: Of the RA sera, 39 (54%) and 41 (57%) were positive for binding to CCP and MCV, respectively. Further, 34 (47%) and 30 (42%) of the patients had specific antibodies binding to and being inhibited by citrulline-containing type I collagen telopeptides and by citrulline-containing type II collagen carboxyterminal telopeptides, respectively. The corresponding figures regarding homocitrulline-containing type I and homocitrulline-containing type II collagen telopeptides were 16 (22%) and 14 (19%). Most of the patients, who were seropositive for citrullinated peptides, showed binding in multiple assays. A total of 10 (14%) RA patients were positive for all the tested peptide pairs, while 28 (39%) of them had antibodies that contained overlapping specifities between citrulline and homocitrulline in the same peptide sequence. CONCLUSIONS: Antibodies to both citrulline and homocitrulline containing type I and II collagen telopeptides can be found in sera of RA patients. These antibodies are not constant from one RA patient to another, but contain separate or overlapping specificities within the same peptide sequence varying between individuals. Our results suggest some relationship between citrulline and homocitrulline-recognizing antibodies, since homocitrulline antibodies exist mainly in individuals seropositive to anti-CCP and anti-MCV.
27178205 Arthritis, Depression, and Falls Among Community-Dwelling Older Adults: Evidence From the 2018 Sep The aims of this study were to examine the association between different types of arthritis and falls and to investigate whether clinically significant depression symptoms (CSDS) moderate these relationships. The study used nationally representative data from the 2008 Health and Retirement Study ( n = 7,715, M age = 75, 62% female, and 90% White). Among the respondents, 42% experienced at least one fall during the previous 2 years. About one third had some form of arthritis: 22% osteoarthritis (OA), 4.8% rheumatoid arthritis (RA), 2.3% both OA and RA, and 7.9% with other arthritis types. About one fifth of respondents had CSDS. OA and CSDS are associated with the odds of falling (17% and 29%, respectively), adjusting for socio-demographic characteristics, lifestyle, health conditions, and psychiatric medications. There was no statistically significant interaction between types of arthritis and CSDS. Health care providers should pay attention to managing arthritis, especially OA, and CSDS to prevent falls among older adults.
27255212 A systematic review of randomised controlled trials in rheumatoid arthritis: the reporting 2016 Jun 2 BACKGROUND: Most reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome. The aims of this review were to assess the range of missing data rates in primary composite outcomes and to document the current practice for handling and reporting missing data in published RA trials compared to the Consolidated Standards of Reporting Trials (CONSORT) recommendations. METHODS: A systematic search for randomised controlled trials was conducted for RA trials published between 2008 and 2013 in four rheumatology and four high impact general medical journals. RESULTS: A total of 51 trials with a composite primary outcome were identified, of which 38 (75 %) used the binary American College of Rheumatology responder index and 13 (25 %) used the Disease Activity Score for 28 joints (DAS28). Forty-four trials (86 %) reported on an intention-to-treat analysis population, while 7 trials (14 %) analysed according to a modified intention-to-treat population. Missing data rates for the primary composite outcome ranged from 2-53 % and were above 30 % in 9 trials, 20-30 % in 11 trials, 10-20 % in 18 trials and below 10 % in 13 trials. Thirty-eight trials (75 %) used non-responder imputation and 10 (20 %) used last observation carried forward to impute missing composite outcome data at the primary time point. The rate of dropout was on average 61 % times higher in the placebo group compared to the treatment group in the 34 placebo controlled trials (relative rate 1.61, 95 % CI: 1.29, 2.02). Thirty-seven trials (73 %) did not report the use of sensitivity analyses to assess the handling of missing data in the primary analysis as recommended by CONSORT guidelines. CONCLUSIONS: This review highlights an improvement in rheumatology trial practice since the revision of CONSORT guidelines, in terms of power calculation and participant's flow diagram. However, there is a need to improve the handling and reporting of missing composite outcome data and their components in RA trials. In particular, sensitivity analyses need to be more widely used in RA trials because imputation is widespread and generally uses single imputation methods, and in this area the missing data rates are commonly differentially higher in the placebo group.
27929683 Frequency of Arthritis-Like MRI Findings in the Forefeet of Healthy Volunteers Versus Pati 2017 Feb OBJECTIVE: The objective of the present study is to evaluate arthritis-like findings on MRI studies of the forefeet of healthy volunteers versus patients with symptomatic rheumatoid arthritis (RA) or psoriatic arthritis (PsA). MATERIALS AND METHODS: Two observers analyzed MR images of the forefeet of 31 healthy volunteers, 30 patients with symptomatic RA, and 30 patients with symptomatic PsA, to identify MRI patterns of RA or PsA (e.g., bone marrow edema [BME], erosions, tenosynovitis, joint effusion, periarticular soft-tissue edema, or bony proliferations) on the basis of the Outcome Measures in Rheumatoid Arthritis Clinical Trial RA MRI scoring system and the PsA MRI scoring system. The Mann-Whitney test with Bonferroni correction was used for statistical analysis. RESULTS: Reader 1 found BME in 14 healthy volunteers (45%), whereas reader 2 found BME in 10 volunteers (32%). Tenosynovitis was observed by reader 1 in three healthy volunteers (10%). Joint effusion was found by reader 1 in seven healthy volunteers (23%) and by reader 2 in three volunteers (10%); the mean intensity grades for these findings were low (range, 1-1.33). Erosions, soft-tissue edema, and bony proliferations were not found in the forefeet of healthy volunteers. Reader 1 and reader 2 observed all arthritis-like features on the MR images of patients with RA. The percentages of patients with RA who had such MRI features, as identified by reader 1 and reader 2, respectively, were as follows: BME, 83% and 80%; erosions, 40% and 40%; tenosynovitis, 33% and 17%; effusion, 87% and 53%; soft-tissue edema, 20% and 27%; and bony proliferations, 3% and 3%. The percentages of patients with PsA who were found to have arthritis-like findings on MR images, as determined by reader 1 and reader 2, respectively, were as follows: BME, 70% and 67%; erosions, 20% and 20%; tenosynovitis, 57% and 50%; effusion, 70% and 37%; and soft-tissue edema, 60% and 53%. Bony proliferations were observed by reader 2 only in 7% of patients with PsA. The mean minimum intensity grade was 1 (for tenosynovitis in patients with RA, as observed by reader 2), whereas the maximum intensity grade was 2.53 (for erosions in patients with RA, as observed by reader 1). Tenosynovitis and soft-tissue edema were observed more frequently in patients with PsA than in patients with RA (p = 0.001-0.059). CONCLUSION: On the forefoot of healthy volunteers, mild BME is a common finding, and tenosynovitis and joint effusion are occasional findings. The frequency and intensity of arthritis-like findings on MRI are similar in patients with RA and PsA, with the exception of tenosynovitis and soft-tissue edema, which are more frequently observed in patients with PsA than in patients with RA.
27029339 Abatacept monotherapy compared with abatacept plus disease-modifying anti-rheumatic drugs 2016 Mar 30 BACKGROUND: Retention rate, efficacy, and safety of abatacept (ABA) was compared between patients with rheumatoid arthritis receiving ABA as monotherapy to those in combination ABA + conventional synthetic DMARD (csDMARD). METHODS: The patients were obtained from the ORA registry. The retention rate was analysed in two ways: (1) therapeutic strategy retention, in which the addition of a csDMARD was considered to indicate failure of the monotherapy strategy; and (2) ABA retention, which was assessed by the discontinuation of ABA regardless of other treatment modifications. Efficacy and safety were compared between ABA initiated alone and ABA used in combination with a csDMARD. RESULTS: The retention rate at month 6 (M6) was evaluated in 569 patients. A significant difference was identified in the retention rate between the ABA monotherapy strategy and the ABA + csDMARD strategy (58.5 % [110/188] vs. 68 % [258/381], respectively, p = 0.031). No significant difference was identified in the ABA retention rate initiated either as a monotherapy or in combination with csDMARDs (75 % [142/188] vs. 76 % [291/381], respectively, p = 0.824). Data regarding ABA efficacy were available for 444 patients. There was no significant difference in the responder proportion after 6 months of treatment between ABA monotherapy and ABA + csDMARD treatment (60.2 % [88/146] vs. 60 % [179/298], respectively, p = 0.967). CONCLUSIONS: This "real-life" analysis, which is relevant for bedside practice, emphasised the satisfactory efficacy and safety of ABA used in monotherapy, which provides an acceptable alternative when csDMARDs are undesirable.
26847319 Effects of serial casting in the treatment of flexion contractures of proximal interphalan 2016 Jan AIM: To analyze the effects of serial casting (SC) in the treatment of proximal interphalangeal (PIP) joint flexion contractures in patients with rheumatoid arthritis and juvenile idiopathic arthritis. STUDY DESIGN: Retrospective case-series. METHODS: The data of 18 patients treated with SC were obtained from their patient records. The angular changes in the finger joints were analyzed and compared statistically using t-tests. RESULTS: A total of 49 fingers were serially casted with plaster of Paris over a 14-year period. The SC resulted in significant (26.8°; p < 0.001) reduction in the PIP joint extension loss. Small, but statistically significant, losses in flexion were associated with these gains. (p < 0.001). Angular changes were also observed in the other finger joints. The magnitude of the initial extension loss was the only factor to explain the amount of motion gained (p < 0.001; R2 = 0.38). CONCLUSION: SC is an effective method to correct flexion contractures in PIP joints in selected patients with arthritis. The gain is partially related to the magnitude of initial extension loss.
25065011 Relationship between types of radiographic damage and disability in patients with rheumato 2015 Jan OBJECTIVE: The aim of this study was to assess if any of the different types of radiographic damage [true joint space narrowing (JSN), (sub)luxation and erosions] are preferentially related to disability in patients with RA. METHODS: Longitudinal data from 167 RA patients from the European Research on Incapacitating Diseases and Social Support study over 10 years were analysed to investigate the relationship between the three types of radiographic damage and disability [grip strength, HAQ and the dexterity scale in the Arthritis Impact Measurement Scales (AIMS)]. A longitudinal analysis including separate models per type of damage and joint group and combined models including all information was conducted. RESULTS: All types of damage were inversely related to grip strength in the analysis of separate models, but only true JSN independently remained statistically significant in the combined analysis [β = -0.087 (95% CI -0.151, -0.022)]. Neither JSN, (sub)luxation nor erosions were associated with HAQ score, while erosions were associated with AIMS dexterity only in the analysis of separate models. After stratifying for hand joint group, erosions at MCP joints [β = -0.288 (95% CI -0.556, -0.019)] and true JSN at the wrist [β = -0.132 (95% CI -0.234, -0.030)] were significantly related to grip strength. Erosions at the PIP [β = 0.017 (95% CI 0.005, 0.028)] and MCP joints [β = 0.114 (95% CI 0.010, 0.217)] was the only type of damage associated with HAQ and AIMS dexterity, respectively. CONCLUSION: All types of radiographically visible joint damage interfere with important aspects of physical functions. True JSN is most closely related to hand function.
26667261 Investigating CD11c expression as a potential genomic biomarker of response to TNF inhibit 2015 Dec 14 INTRODUCTION: Gene expression profiling is rapidly becoming a useful and informative tool in a much needed area of research. Identifying patients as to whether they will respond or not to a given treatment before prescription is not only essential to optimise treatment outcome but also to lessen the economic burden that such drugs can have on healthcare resources. In rheumatoid arthritis (RA), there is of yet no genetic/genomic biomarker which can accurately predict response to TNF inhibitor biologics prior to treatment, despite much interest in this area. Multiple studies have reported findings on potential candidate genes; however, due to relatively small sample sizes or lack of sufficient validation, results have been disappointingly inconsistent. The aim of this research was to further explore the predictive value of a previously reported association between CD11c expression and response to the TNF inhibitor biologics, adalimumab and etanercept. METHODS: Real-time qPCR was performed using whole blood RNA samples obtained from seventy-five rheumatoid arthritis patients about to commence treatment with a TNF inhibitor biologic drug, whose response status was determined at 3-month follow-up using the EULAR classification criteria. Relative quantification of CD11c using the comparative CT method outputted differential expression between good-responders and non-responders as a fold-change. RESULTS: Relative expression of CD11c in patients receiving TNF inhibitor biologics yielded a decrease of 1.025 fold in good-responders as compared to non-responders (p-value = 0.36). Upon stratification of patients dependent upon the specific drug administered, adalimumab or etanercept, similar findings to the full cohort were observed, decreases of 1.015 (p-value = 0.33) and 1.032 fold (p-value = 0.13) in good-responders compared to non-responders, respectively. CONCLUSION: The results from this study reveal that CD11c expression does not correlate with response to TNF inhibitor biologics when tested for within pre-treatment whole blood samples of rheumatoid arthritis patients.
27762190 Automated joint space width quantification of hand and wrist joints: a proof of concept st 2016 Sep OBJECTIVES: To compare as proof of concept the sensitivity to change of automated quantification of radiographic wrist and hand joint space width (JSW) with scoring JSW according to the Sharp/van der Heijde scoring method (SHS) in two strategy groups of a treat-to-target and tight-control early rheumatoid arthritis (RA) study. METHODS: Digital radiographs were assessed for JSW changes of 134 patients of the 236 patients participating in the second Computer Assisted Management in Early Rheumatoid Arthritis trial, of whom both baseline and year 2 radiographs were available (year 1 radiographs n=125). Of those 134 patients, 70 started with methotrexate and prednisone (MTX+Pred) and 64 with MTX and placebo (MTX+Plac). JSW change over 1 and 2 years of the hands and wrists was assessed, applying both the joint space narrowing (JSN) subscore of the SHS by 2 readers and the automated assessment with the JSW quantification software 'JSQ'. For both methods, progression of JSW change of the hand and wrist was analysed using linear mixed modelling (dependent variable 'JSW', factor 'strategy group', covariate 'follow-up time in years', interaction term 'strategy group*follow-up time'; radiographs of baseline, year 1 and year 2 were used). For each method the standardised mean difference (SMD) for the change in JSW from baseline to year 2 between the treatment strategies was obtained using a non-parametric method. RESULTS: Patient characteristics of the current subpopulation were similar to those of the whole study population. JSN of the hand and wrist according to SHS at 2 years was present in 16 vs. 23% in the MTX+Pred group vs. the MTX+Plac group. The mean yearly progression rates of JSW change of the hands and wrists using JSQ were -0.00mm (95% confidence interval (CI) -0.01; 0.01) for MTX+Pred vs. -0.02mm (95%CI -0.03; -0.01) for MTX+Plac, p=0.045, and using SHS JSN they were 0.19 units (95%CI 0.09; 0.30) vs. 0.30 units (95%CI 0.14; 0.45) for MTX+Pred vs. MTX+Plac, p=0.271. The SMD for the change from baseline to year 2 between the treatment strategies was 0.37 for JSQ and 0.13 for SHS JSN. CONCLUSIONS: In this proof of concept study the yearly progression rate of JSW change of hand and wrist joints, according to the automated JSW quantification software package 'JSQ', was higher in the group initiating MTX+Plac than in the group initiating MTX+Pred. A similar trend was seen with the JSN assessment according to the SHS method of the hand and wrist. However, JSN of the hand and wrist according to SHS, the current gold standard to assess radiographic progression, was seen in only about 20%. Therefore, further studies are needed to conclude firmly that JSQ should be incorporated into quantitative scoring of radiographs in RA.
26571131 Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Su 2015 OBJECTIVES: To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US). RESULTS: RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed. CONCLUSIONS: In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA.
27881147 p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibrob 2016 Nov 24 BACKGROUND: Dominant-negative somatic mutations of p53 has been identified in the synovium of patients with rheumatoid arthritis (RA), in which interleukin (IL)-6 has been established as a pivotal inflammatory cytokine. The aim of this study was to clarify the significance of p53 in the longstanding inflammation in RA by modulating IL-6. METHODS: We established adjuvant-induced arthritis (AIA) in Lewis rats and treated them with p53 activator, and then analyzed the histopathology of the synovium and IL-6 expression. Human fibroblast-like synoviocytes (FLS) were cultured and transfected with p53-siRNA or transduced with adenovirus (Ad)-p53, and then assessed with MTT, TUNEL staining, and luciferase assay. IL-1β, tumor necrosis factor (TNF)-α and IL-17 were used to stimulate FLS, and subsequent IL-6 expression as well as relevant signal pathways were explored. RESULTS: p53 significantly reduced synovitis as well as the IL-6 level in the AIA rats. It controlled cell cycle arrest and proliferation, but not apoptosis. Proinflammatory cytokines inhibited p53 expression in FLS, while p53 significantly suppressed the production of IL-6. Furthermore, IL-6 expression in p53-deficient FLS was profoundly reduced by NF-kappaB, p38, JNK, and ERK inhibitors. CONCLUSION: Our findings reveal a novel function of p53 in controlling inflammatory responses and suggest that p53 abnormalities in RA could sustain and accelerate synovial inflammation mainly through IL-6. p53 may be a key modulator of IL-6 in the synovium and plays a pivotal role in suppressing inflammation by interaction with the signal pathways in RA-FLS. Interfering with the p53 pathway could therefore be an effective strategy to treat RA.
25457216 [Pleuro-pericarditis developed under a leflunomide therapy]. 2015 Feb Leflunomide is an immunosuppressant drug used in rheumatoid arthritis and psoriatic arthritis. This product may cause rare but serious interstitial lung disease that appear at the beginning of treatment. This is why leflunomide should be prescribed and monitored in hospital. We present the case of a 71 years old woman who presented a pleuro-pericarditis with an increase of CA 125 during a treatment with leflunomide. This is the second case reported in the literature. The outcome was favorable after discontinuation of leflunomide.
26062018 Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Art 2015 Jun 4 T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORγt) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B-cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL-23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease.