Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
25587178 Does reduction of disease activity improve early markers of cardiovascular disease in newl 2015 Jul OBJECTIVE: The incidence of cardiovascular disease (CVD) is increased in RA. This study was designed to evaluate whether a reduction in disease activity influences early markers of CVD. METHODS: In a prospective longitudinal study, 58 newly diagnosed RA patients and 58 age- and sex-matched healthy controls (HCs) were included. Endothelial dysfunction was measured by small artery elasticity (SAE) and endothelial cell activation was assessed by measuring soluble vascular cellular activation molecule 1(sVCAM-1) and von Willebrand factor (vWF). Advanced glycation end products (AGEs) were quantified by skin autofluorescence. After 1 year, measurements were repeated in all RA patients. RESULTS: At entry, SAE was decreased in RA vs HCs [median 3.4 ml/mmHg100 (range 1.2-9.0) vs 6.1 (range 5.0-15.3), P < 0.0001] and sVCAM-1 and vWF were increased: 391 ng/ml (range 256-680) vs 341 (range 223-691) (P = 0.0015) and 120 ng/ml (range 26.5-342) vs 99 (range 22-298) (P = 0.02), respectively. SAE was inversely correlated with the 28-joint DAS (DAS28; r = -0.31, P = 0.016). AGEs were increased by 2.55 arbitrary units (range 1.29-4.65) vs 2.12 (range 1.32-3.82) in HCs (P = 0.003). In multivariate analysis, the presence of RA, age and systolic blood pressure were independently and inversely related to SAE. After 1 year, SAE had significantly improved in RA, from 3.4 (range 1.2-9.0) to 3.8 (range 1.5-10.3) (P = 0.03). CONCLUSION: Endothelial dysfunction is present in newly diagnosed RA patients, independently of traditional risk factors and is inversely correlated with disease activity. By reducing disease activity, endothelial dysfunction improves, although not to normal values. Also, a reduction in disease activity targeting traditional risk factors remains important in preventing CVD in RA.
25880932 An external validation study reporting poor correlation between the claims-based index for 2015 Apr 13 INTRODUCTION: We conducted an external validation study to examine the correlation of a previously published claims-based index for rheumatoid arthritis severity (CIRAS) with disease activity score in 28 joints calculated by using C-reactive protein (DAS28-CRP) and the multi-dimensional health assessment questionnaire (MD-HAQ) physical function score. METHODS: Patients enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and Medicare were identified and their data from these two sources were linked. For each patient, DAS28-CRP measurement and MD-HAQ physical function scores were extracted from BRASS, and CIRAS was calculated from Medicare claims for the period of 365 days prior to the DAS28-CRP measurement. Pearson correlation coefficient between CIRAS and DAS28-CRP as well as MD-HAQ physical function scores were calculated. Furthermore, we considered several additional pharmacy and medical claims-derived variables as predictors for DAS28-CRP in a multivariable linear regression model in order to assess improvement in the performance of the original CIRAS algorithm. RESULTS: In total, 315 patients with enrollment in both BRASS and Medicare were included in this study. The majority (81%) of the cohort was female, and the mean age was 70 years. The correlation between CIRAS and DAS28-CRP was low (Pearson correlation coefficient = 0.07, P = 0.24). The correlation between the calculated CIRAS and MD-HAQ physical function scores was also found to be low (Pearson correlation coefficient = 0.08, P = 0.17). The linear regression model containing additional claims-derived variables yielded model R(2) of 0.23, suggesting limited ability of this model to explain variation in DAS28-CRP. CONCLUSIONS: In a cohort of Medicare-enrolled patients with established RA, CIRAS showed low correlation with DAS28-CRP as well as MD-HAQ physical function scores. Claims-based algorithms for disease activity should be rigorously tested in distinct populations in order to establish their generalizability before widespread adoption.
27632997 Magnetic resonance imaging-detected inflammation is associated with functional disability 2016 Dec OBJECTIVES: MRI sensitively detects inflammation, but the clinical relevance of MRI-detected inflammation is undetermined in early arthritis. Therefore, the aim of this cross-sectional study was to investigate the association between MRI-detected inflammation of hands and feet and functional disability in early arthritis. METHODS: Five hundred and fourteen early arthritis patients, consecutively included in the Leiden Early Arthritis Clinic, were studied. At baseline a unilateral 1.5 T MRI of the wrist, MCP and MTP joints was performed and functional disability was measured using the HAQ. MRIs were scored for tenosynovitis, synovitis and bone marrow oedema (BME) by two readers. The sum of these types of MRI-detected inflammation yielded the total MRI-inflammation score. Linear and nonlinear regression analyses were performed with HAQ as outcome. RESULTS: The total MRI-inflammation score was associated with the HAQ score (β = 0.014, P < 0.001), as were tenosynovitis (β = 0.046, P < 0.001), synovitis (β = 0.039, P < 0.001) and bone marrow oedema scores (β = 0.015, P < 0.001) separately. Analysing these three types of MRI-detected inflammation in one multivariable model revealed that only tenosynovitis was independently associated with the HAQ score (β = 0.039, P < 0.001). Also after correction for age, gender, joint counts, CRP and auto-antibodies, this association remained significant (β = 0.034, P < 0.001). MRI-detected inflammation at wrists or MCP joints associated significantly with impairments in hand functioning (e.g. difficulties with opening milk cartons or jars). Exploring the relation between MRI-detected inflammation and HAQ scores showed no evidence of a floor effect, suggesting that even low scores of MRI-detected inflammation are functionally relevant. CONCLUSION: MRI-detected inflammation, and tenosynovitis in particular, is associated with functional disability. This demonstrates the functional relevance of MRI-detected inflammation in early arthritis.
27107149 Patient education as a status passage in life - An ethnographic study exploring participat 2016 Jun In this paper, we apply the theory of status passage to the empirical field of group-based patient education. On the basis of ethnographic fieldwork carried out in the context of a local Danish patient education programme aimed at people diagnosed with rheumatoid arthritis, we illustrate how participation in the programme for the recently diagnosed is a regularised status passage symbolising a transition in life from a novice to a more experienced person with chronic illness. We demonstrate how central properties of status passage are at play and how they are shaped by interactions among the different agents: participants, lay experts and health professionals. We highlight how the unique biographical situation of the individual and the individual timing of participation is an important factor affecting whether the patient education programme succeeds in regularising the status passage. We highlight the ambiguity of the role of the health professionals in directing the status passage of the recently diagnosed. On one hand, health professionals empowered the participants by giving them access to professional knowledge and guidance and thereby supporting the status passage. On the other hand, the effort to direct responsibility back to the participants did not consider individual biographical situations, and thereby risked leaving the participants frustrated and unable to pass. Further, we point to the special significance of the socialising process between the participants, with the recently diagnosed being the novices asking questions and seeking guidance and the lay experts and the experienced participants taking the role of coaches, guiding the recently diagnosed managing the status passage into chronic illness.
26932340 Effects of Rituximab and Infliximab Treatment on Carboxypeptidase B and Its Substrates in 2016 May OBJECTIVE: We evaluated the synovial effects of 2 potent biologic rheumatoid arthritis (RA) therapies, focusing on their effect on the expression level of carboxypeptidase B (CPB) and its substrates. METHODS: Patients with RA receiving infliximab (IFX; n = 9) or rituximab (RTX; n = 5) had an arthroscopic synovial biopsy at baseline and 16 weeks posttherapy. Expression of CPB, C5a, osteopontin (OPN), CD3, CD20, CD55, and CD68 was assessed by immunohistochemistry and image analysis, and compared with OA synovium. RA disease activity score was assessed at multiple timepoints. Serial serum samples were analyzed for soluble CPB and C5a levels. RESULTS: The baseline clinical characteristics of patients receiving IFX and RTX were similar. At the time of the second biopsy, 50% of patients had achieved a European League Against Rheumatism good or moderate response. At baseline, expression of CPB, C5a, and OPN was markedly higher in RA compared with OA synovium and correlated with mononuclear cell infiltration. There was an overall reduction in synovial expression of CPB, C5a, and OPN paralleling a reduction in mononuclear cell infiltration, but these changes were not associated with clinical response. After an early reduction in serum C5a levels, these returned to baseline levels at later timepoints. CONCLUSION: In response to IFX and RTX treatment, RA synovial expression of CPB, C5a, and OPN decrease independently of the clinical response, reflecting the complex proinflammatory and antiinflammatory effects of this pathway.
25832994 An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein a 2015 May OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA-DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA-DRB1 and ACPA levels in patients with RA. METHODS: We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA-DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA. RESULTS: HLA-DRB1*09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. HLA-DRB1*08:03 and DRB1*14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P = 1.9 × 10(-51) ). The association was mainly conferred by alanine residue (P = 4.5 × 10(-51) ). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA-DRB1 alleles (HLA-DRB1*08:03, DRB1*09:01, DRB1*14:06, DRB1*15:01, and DRB1*15:02). CONCLUSION: Amino acid position 74 in HLA-DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap.
27183869 Genome-wide identification and functional annotation of miRNAs in anti-inflammatory plant 2017 May MicroRNAs (miRNAs) are newly discovered non-coding small (~17-24 nucleotide) RNAs that regulate gene expression of its target mRNA at the post-transcriptional levels. In this study, total 12,593 ESTs of Curcuma longa were taken from database of expressed sequence tags (dbEST) and clustered into 2821 contigs using EGassembler web server. Precursor miRNAs (pre-miRNAs) were predicted from these contigs that folded into stem-loop structure using MFold server. Thirty-four mature C. longa miRNAs (clo-miRNAs) were identified from pre-miRNAs having targets involved in various important functions of plant such as self-defence, growth and development, alkaloid metabolic pathway and ethylene signalling process. Sequence analysis of identified clo-miRNAs indicated that 56% miRNAs belong to ORF and 44% belong to non-ORF region. clo-mir-5 and clo-mir-6 were established as the conserved miRNAs, whereas clo-mir-20 was predicted to be the most stable miRNA. Phylogenetic analysis carried out by molecular evolutionary genetics analysis (MEGA) software indicated close evolutionary relationship of clo-mir-5075 with osa-MIR5075. Further, identified clo-miRNAs were checked for their cross-kingdom regulatory potential. clo-mir-14 was found to regulate various gene transcripts in humans that has been further investigated for its biostability in foetal bovine serum (FBS). The results indicated higher degree of stability of clo-mir-14 (48 h) in FBS. Thus, contribution of this miRNA to the cellular immune response during the inflamed condition of rheumatoid arthritis and adequate stability may make it a good choice for the therapeutic agent in near future.
25305139 Inflammatory burden interacts with conventional cardiovascular risk factors for carotid pl 2015 May OBJECTIVE: Patients with RA have an increased risk of atherosclerosis and cardiovascular (CV) diseases compared with the general population. The aim of this study was to evaluate the role of inflammatory burden in the formation of carotid plaques in patients with RA. METHODS: We performed carotid artery US to measure the carotid intima-media thickness (IMT) and plaques in 406 patients with RA and 209 age- and sex-matched healthy controls. To assess the inflammatory burden, the area under the curve (AUC) of ESR over time was calculated. RESULTS: The carotid plaque frequency and mean IMT were significantly increased in patients with RA relative to controls. After adjustment for age and gender, the presence of carotid plaques in patients with RA was associated with HAQ score, tender joint count (TJC), swollen joint count (SJC), 28-joint DAS, ESR, CRP, LEF use, current corticosteroid dose and the number of conventional CV risk factors. After multivariate regression analysis, the factors significantly associated with plaque formation were TJC (P = 0.002), ESR (P = 0.002) and the number of conventional CV risk factors (P = 0.041). Among 194 RA patients with ESR AUC data, the presence of carotid plaque was independently associated with both the ESR AUC and number of conventional CV risk factors, which showed a synergistic interaction. CONCLUSION: Cumulative inflammatory burden contributes to the development of carotid atherosclerosis through a synergistic interaction with conventional CV risk factors in patients with RA.
24924607 25-Hydroxy vitamin D and its relationship with clinical and laboratory parameters in patie 2015 Feb The objective of this study is to evaluate the prevalence of vitamin D insufficiency in patients with rheumatoid arthritis (RA) and its association with disease activity, severity and physical disability. We included patients with rheumatoid arthritis followed in Rheumatology Department of Hassan II University Hospital, Fez, Morocco. Patients suffering from liver and kidney insufficiency and those who had received vitamin D in the previous 12 months have been excluded. Statistical analysis was done using SPSS v 18. A bivariate analysis and logistic regression were used to identify factors associated with vitamin D deficiency. One hundred seventy patients were included with a mean age of 50 ± 12.1 [17-83] years, and a female predominance (88.1%). All of our patients had hypovitaminosis D. The prevalence of 25(OH)-D insufficiency and deficiency was 64.5 and 35.5% successively. In unadjusted analysis, vitamin D concentration was inversely associated with pain visual analog scale VAS score (p < 0.001), asthenia VAS (p < 0.001), morning stiffness (p = 0.03), number of tender joints (p = 0.004), number of swollen joints (p < 0.001), inflammatory markers (p = 0,012), Disease Activity Score (p = 0.009), physical disability using Health Assessment Questionnaire (HAQ) (p = 0.001), and severity of the disease (p < 0.001). After logistic regression persisted association with female sex (OR = 4.3, CI = [0.94 to 20.976], p = 0.05), asthenia VAS (OR = 1.029, CI = [1.011 to 1.046], p = 0.001), and with the severity of the disease (OR = 2.910, CI = [1.314-6.441], p = 0.008). The vitamin D deficiency is common in our patients with RA. This deficiency is associated with female sex, severe asthenia, and the severity of the disease.
25880754 CD4 T-cell transcriptome analysis reveals aberrant regulation of STAT3 and Wnt signaling p 2015 Mar 22 INTRODUCTION: Rheumatoid arthritis (RA) is a systemic autoimmune disease in which T cells play a pivotal role in the pathogenesis. Knowledge in terms of the CD4 T-cell transcriptome in RA is limited. The aim of this study was to examine the whole-genome transcription profile of CD4 T cells in RA by comparing patients with RA to healthy controls. METHODS: Peripheral blood CD4 T cells were isolated from 53 RA patients with active disease and 45 healthy individuals; 13 cases and 10 controls were enrolled in microarray analysis. The remaining 40 cases and 35 controls were recruited as an independent cohort for the validation study. Bioinformatics was performed on Gene Ontology (GO), gene-gene interaction networks, and pathway analysis. The gene modules, by combining the results from GO, gene networks, and pathway analysis, were selected for further validation. RESULTS: The CD4 T cells showed 1,496 differentially expressed (DE) genes in RA patients relative to healthy individuals. GO analysis revealed that the DE genes were enriched in immune response, T-cell response, apoptosis process, and Wnt receptor signaling. Pathway analysis also identified that 'Wnt signaling pathway' was differentially regulated between two groups (P=2.78×10(-10)). By gene-gene network analysis, we found that the DE genes were enriched in T-cell receptor (TCR), JAK-STAT signaling, and Wnt signaling pathway. By gene module analysis, we found that a number of DE genes overlapped in the three different analyses. In total, 23 genes were selected for further validation, and nine genes were confirmed. Of these, four genes (SOCS3, CBL, IFNAR1, and PIK3CA) were involved in STAT3 (signal transducer and activator of transcription 3) signaling, and three genes (CBL, KLF9, and CSNK2A1) were involved in the Wnt signaling pathway. Additionally, several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) were confirmed. CONCLUSIONS: We report here the first case-control study of the CD4 T-cell transcriptome profile in RA. Our data provide evidence that CD4 T cells from patients with RA have abnormal functional networks in STAT3 signaling and Wnt signaling. Our results also suggest that the aberrant expression of several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) may be potential pathogenic factors for RA.
26233506 Comparison of Photo Optical Imaging with Musculoskeletal Ultrasound and Clinical Examinati 2015 Sep OBJECTIVE: Lightscan is a novel, rapid, low-cost, easily operated and noninvasive imaging technology used to assess inflammatory activity in proximal interphalangeal (PIP) joints. The results are calculated automatically. To our knowledge, this is the first comparative study of photo optical imaging (POI), with clinical examination (CE), disease activity score at 28 joints (DAS28)-erythrocyte sedimentation rate (ESR), and musculoskeletal ultrasonography (US) in healthy subjects and patients with rheumatoid arthritis (RA) or osteoarthritis (OA). METHODS: There were 688 PIP joints of both hands examined in 87 subjects (38 RA, 21 OA, 28 healthy) by Lightscan and compared with CE for clinically swollen and tender joints, DAS28-ESR (only RA), and US. RESULTS: With US as reference, POI had a sensitivity of 74% and a specificity of 93%. In the receiver-operating curve (ROC) analysis, the Lightscan showed a higher sensitivity and specificity [area under the curve (AUC) 0.879] for the distinction of healthy subjects versus patients (OA, RA) than US in greyscale (GSUS; AUC 0.797) and power Doppler (PDUS; AUC 0.67). POI correlated significantly with GSUS (r 0.473, p < 0.01) and PDUS (r 0.486, p < 0.01). The agreement rates between POI and GSUS were up to 79%, between POI and PDUS up to 92%, and between POI and CE up to 66%. POI did not correlate with DAS28-ESR. CONCLUSION: The Lightscan is a new technology offering sensitive imaging detection of inflammatory changes in subjects with RA and OA with PIP arthritis. POI was more sensitive than CE and correlated significantly to GSUS and PDUS, while presenting a higher sensitivity and specificity for the detection of healthy subjects versus patients (RA, OA) based on the ROC analysis.
27458626 [Anemic syndrome in rheumatoid arthritis: Diagnostic approaches and treatment opportunitie 2016 Anemia of chronic disease (ACD) is a leading cause of anemic syndrome in patients with rheumatoid arthritis (RA). Enhanced hepcidin production mainly stimulated by excess interleukin-6 levels is a key pathodgentic component of ACD (frequently known as anemia of inflammation) by causing the degradation of the transmembrane protein ferroportin, hepcidin impairs iron metabolism. On the basis of the material of recent publications the review gives present-day views on the pathodgenesis of ACD in RA, approaches to the diagnosis and differential diagnosis of ACD, especially in its concomitance with iron-deficiency anemia, as well as approaches to therapy for the type of anemic syndrome with the complex mechanism for its development.
26232893 IL-17A and IL-17F polymorphisms in rheumatoid arthritis and Sjögren's syndrome. 2016 Apr OBJECTIVE: The aim of this study was to evaluate the influence of Th17 polymorphisms on the susceptibility or severity of rheumatoid arthritis (RA) and Sjögren's syndrome (SS). MATERIALS AND METHODS: The study sample comprised 206 individuals of both genders divided into three groups: exclusive rheumatoid arthritis (RA-100 patients), rheumatoid arthritis and Sjögren's syndrome (RA/SS-31 patients), and healthy controls (C-75 individuals). All the individuals were submitted to clinical evaluation, unstimulated sialometry, and Schirmer test; some patients with RA were also submitted to minor salivary gland biopsy for definition of SS diagnosis. Saliva samples were collected for isolation of DNA and genotyping of Th17 genes; IL-17A (-197G/A) and IL-17F (7488T/C). RESULTS: IL-17A (-197G/A) and IL-17F (7488T/C) SNPs were not associated with susceptibility to RA or secondary SS (sSS, p > 0.05 for both SNPs). In addition, they did not influence RA activity or clinical markers of SS. CONCLUSION: IL-17A (-197G/A) and IL-17F (7488T/C) polymorphisms are not associated with the susceptibility nor to the severity of RA and sSS in the studied population. CLINICAL RELEVANCE: A better understanding of the pathogenesis of SS is demanded to an adequate treatment as well as to the development of new management strategies.
26762210 Foot and ankle characteristics associated with falls in adults with established rheumatoid 2016 Jan 13 BACKGROUND: People with rheumatoid arthritis (RA) have an increased risk of falls. The foot is a common site of pathology in RA and foot problems are reported in up to 90% of patients with established disease. The aim of this study was to determine whether foot and ankle characteristics are associated with falls in people with RA. METHODS: Adults with RA were recruited from rheumatology outpatient clinics in Auckland, New Zealand. Participants reported whether they had fallen in the preceding year, and the number of falls. Clinical characteristics, common fall risk factors, and foot and ankle variables were measured. Univariate parametric and non-parametric analysis compared fallers and non-fallers on all variables to determine significant differences. Logistic regression analysis identified variables independently associated with falls. RESULTS: Two hundred and one participants were prospectively recruited. At least one fall in the preceding 12-months was reported by 119 (59%) participants. Univariate analysis showed that fallers had significantly longer mean disease duration, more co-morbid conditions, an increase in lower limb tender joints, higher midfoot peak plantar pressures and were more likely to have a history of vascular disease than non-fallers. Fallers also reported greater difficulty with activities of daily living, increased fear of falling and greater self-reported foot impairment. Logistic regression analysis revealed that increased midfoot peak plantar pressures (odds ratio (OR) 1.12 [for each 20 kPa increase], 95% confidence interval (CI) 1.00-1.25), self-reported foot impairment (OR 1.17 [for each three point increase], 95% CI 1.05-1.31) and history of vascular disease (OR 3.22, 95% CI 1.17-8.88) were independently associated with a fall in the preceding 12 months. CONCLUSIONS: Elevated midfoot peak plantar pressures, self-reported foot impairment and vascular disease are associated with falls in people with RA. Assessment of foot deformity, foot function and self-reported foot impairment may be of benefit when considering falls prevention strategies in people with RA. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry (trial ACTRN12612000597897).
27770823 Body mass index and extent of MRI-detected inflammation: opposite effects in rheumatoid ar 2016 Oct 22 BACKGROUND: In the population a high body mass index (BMI) has been associated with slightly increased inflammatory markers. Within rheumatoid arthritis (RA), however, a high BMI has been associated with less radiographic progression; this phenomenon is unexplained. We hypothesized that the phenomenon is caused by an inverse relationship between BMI and inflammation in hand and foot joints with RA. To explore this hypothesis, local inflammation was measured using magnetic resonance imaging (MRI) in early arthritis patients presenting with RA or other arthritides and in asymptomatic volunteers. METHODS: A total of 195 RA patients, 159 patients with other inflammatory arthritides included in the Leiden Early Arthritis Clinic, and 193 asymptomatic volunteers underwent a unilateral contrast-enhanced 1.5 T MRI scan of metacarpophalangeal, wrist, and metatarsophalangeal joints. Each MRI scan was scored by two readers on synovitis, bone marrow edema (BME), and tenosynovitis; the sum yielded the total MRI inflammation score. Linear regression on log-transformed MRI data was used. RESULTS: A higher BMI was associated with higher MRI inflammation scores in arthritides other than RA (β = 1.082, p < 0.001) and in asymptomatic volunteers (β = 1.029, p = 0.040), whereas it was associated with lower MRI inflammation scores in RA (β = 0.97, p = 0.005). Evaluating the different types of inflammation, a higher BMI was associated with higher synovitis, BME, and tenosynovitis scores in arthritides other than RA (respectively β = 1.084, p < 0.001, β = 1.021, p = 0.24, and β = 1.054, p = 0.003), but with lower synovitis and BME scores in RA (respectively β = 0.98, p = 0.047 and β = 0.95, p = 0.002). CONCLUSIONS: Increased BMI is correlated with less severe MRI-detected synovitis and BME in RA. This might explain the paradox in RA where obesity correlates with less severe radiographic progression.
24665115 The autoimmune-associated genetic variant PTPN22 R620W enhances neutrophil activation and 2015 Aug OBJECTIVES: A genetic variant of the leukocyte phosphatase PTPN22 (R620W) is strongly associated with autoimmune diseases including rheumatoid arthritis (RA). Functional studies on the variant have focussed on lymphocytes, but it is most highly expressed in neutrophils. We have investigated the effects of the variant on neutrophil function in health and in patients with RA. METHODS: Healthy individuals and patients with RA were genotyped for PTPN22 (R620W) and neutrophils isolated from peripheral blood. Neutrophil adhesion and migration across inflamed endothelium were measured. Calcium (Ca(2+)) release and reactive oxygen species (ROS) production in response to fMLP stimulation were also assessed. RESULTS: Expression of R620W enhanced neutrophil migration through cytokine activated endothelium (non-R620W=24%, R620W=45% migrating cells, p<0.001). Following fMLP stimulation, neutrophils that were heterozygous and homozygous for R620W released significantly more Ca(2+) when compared to non-R620W neutrophils, in healthy individuals and patients with RA. fMLP stimulation, after TNF-α priming, provoked more ROS from neutrophils heterozygous for R620W in patients with RA (non-R620W vs R620W=∼1.75-fold increase) and healthy individuals (non-R620W vs R620W=fourfold increase) and this increase was statistically significant in healthy individuals (p<0.001) but not in patients with RA (p<0.25). CONCLUSIONS: Expression of PTPN22 (R620W) enhanced neutrophil effector functions in health and RA, with migration, Ca(2+) release and production of ROS increased. Neutrophils are found in large numbers in the RA joint, and this hyperactivity of R620W cells may directly contribute to the joint damage, as well as to the initiation and perpetuation of the chronic immune-mediated inflammatory processes driving the disease.
26356639 Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Mul 2015 Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra/rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept [corrected]. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.
25779331 CCR2 Expression in Neutrophils Plays a Critical Role in Their Migration Into the Joints in 2015 Jul OBJECTIVE: Infiltration of neutrophils into the joints plays an important role in bone erosion and articular destruction in rheumatoid arthritis (RA). Neutrophil trafficking during inflammation is a process that involves activation of chemotactic receptors. Recent findings suggest that changes in chemotactic receptor patterns could occur in neutrophils under certain inflammatory conditions. The aim of this study was to evaluate the gain of responsiveness of neutrophils to CCL2 in RA patients and to assess the role of CCL2 in driving neutrophil infiltration into the joints. METHODS: Neutrophils were purified from the peripheral blood of patients with RA or from mice with antigen-induced arthritis (AIA). Expression of CCR2 was evaluated using polymerase chain reaction, flow cytometry, and immunofluorescence analyses. In vitro chemotaxis to CCL2 was assayed to evaluate the functional significance of de novo CCR2 expression. The murine AIA model was used to evaluate the in vivo role of CCR2 in neutrophil infiltration into the joints. RESULTS: High CCR2 expression and responsiveness to CCL2 were observed in neutrophils from the blood of patients with early RA and in neutrophils from the blood and bone marrow of mice with AIA. Genetic deficiency or pharmacologic inhibition of CCR2 protected against the infiltration of neutrophils into the joints. This protection was not associated with an impairment of the neutrophil chemotactic ability or CXC chemokine production in the joints. Moreover, adoptive transfer of wild-type mouse neutrophils to CCR2-deficient mice restored neutrophil infiltration and the articular mechanical hyperalgesia associated with joint inflammation. CONCLUSION: These findings suggest that CCR2 is directly involved in the detrimental infiltration of neutrophils into the joints in patients with RA, showing a new inflammatory role of CCR2 during RA flares or active disease.
25201241 Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease 2015 May OBJECTIVE: To evaluate whether the risks of herpes zoster (HZ) differed by biologic agents with different mechanisms of action (MOAs) in older rheumatoid arthritis (RA) patients. METHODS: Using Medicare data from 2006-2011, among RA patients with prior biologic agent use and no history of cancer or other autoimmune diseases, this retrospective cohort study identified new treatment episodes of abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Followup started on initiation of the new biologic agent and ended at any of the following: first incidence of HZ, a 30-day gap in current exposure, death, a diagnosis of other autoimmune disease or cancer, loss of insurance coverage, or December 31, 2011. We calculated the proportion of RA patients vaccinated for HZ in each calendar year prior to biologic agent initiation and HZ incidence rate for each biologic agent. We compared HZ risks among therapies using Cox regression adjusted for potential confounders. RESULTS: Of 29,129 new biologic treatment episodes, 28.7% used abatacept, 15.9% adalimumab, 14.8% rituximab, 12.4% infliximab, 12.2% etanercept, 6.1% tocilizumab, 5.8% certolizumab, and 4.4% golimumab. The proportion of RA patients vaccinated for HZ prior to biologic agent initiation ranged from 0.4% in 2007 to 4.1% in 2011. We identified 423 HZ diagnoses with the highest HZ incidence rate for certolizumab (2.45 per 100 person-years) and the lowest for golimumab (1.61 per 100 person-years). Neither the crude incidence rate nor the adjusted hazard ratio differed significantly among biologic agents. Glucocorticoid use had a significant association with HZ. CONCLUSION: Among older patients with RA, the HZ risk was similar across biologic agents, including those with different MOAs.
27622457 The Proportion of Regulatory T Cells in Patients with Rheumatoid Arthritis: A Meta-Analysi 2016 BACKGROUND: Regulatory T cells (Tregs) have important functions in peripheral immune tolerance. Dysfunction of Tregs is considered to be a pivotal cause of autoimmune diseases, including rheumatoid arthritis (RA). However, previous reports describing the proportion of Tregs among CD4+ T cells in RA patients were controversial because a range of markers are used to identify Tregs with little consensus. To clarify the status of Tregs in RA, we investigated the proportion of Tregs with focusing on the definitions of them. METHODS: We identified the studies reporting the proportion of Tregs in RA patients using PubMed and Google Scholar. We performed a systematic review of them and a meta-analysis to evaluate the proportion of Tregs (FOXP3-positive and/or CD25-positive) among CD4+ T cells in peripheral blood (PB) and synovial fluid (SF) of RA patients and control subjects. RESULTS: A total 31 studies were selected. The proportion of Tregs defined by all definitions among CD4+ T cells in PB was not significantly different between RA patients and control subjects (-0.65, [-1.30, 0.01]). Then we performed sub-analyses based on individual definitions. The proportion of Tregs defined by either CD25 or FOXP3 alone did not differ between RA patients and control subjects. The proportion of Tregs defined by both FOXP3 and CD25 was lower in RA patients than that in control subjects (-2.42 [-3.49, -1.34]). The proportion of Tregs defined by both FOXP3 and CD25 was higher in SF than that in PB among RA patients (3.27 [0.40, 6.14]). CONCLUSION: The status of Tregs varied according to the definition system. The proportion of Tregs defined by stricter and functionally validated methods decreased in PB and increased in SF among RA patients. If the proportion of Tregs differs in RA, accurate and functionally relevant definitions of Tregs are necessary to elucidate their status in RA.