Browse

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

ID PMID Title PublicationDate abstract
28546658 Endothelial Alterations in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Potentia 2017 Patients with systemic autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are prone to develop atherosclerosis and cardiovascular diseases five times more often than the general population; this increase in frequency could be partially explained by an increase in the macrovasculature endothelial damage. In these autoimmune diseases, a microvascular endothelial injury has also been reported in different organs and tissues, especially in sites where ultrafiltration processes occur. Different components that are characteristic to the immunopathology of RA and SLE could be involved in the endothelial cell activation, permeability increase, functional alteration, and vascular injury. Circulating immune complexes (IC) detected in SLE and RA have been proposed to participate in the endothelial injury. In the vascular environment, IC can generate different responses that could be mediated by monocytes, because these cells have patrolling and monitoring functions on the endothelium. However, with certain stimuli such as TLR ligands, the monocytes are retained in the lumen, releasing proinflammatory mediators that participate in the endothelial damage. This paper aims to review some aspects about the endothelial activation and dysfunction in the context of SLE and RA, as well as the potential role that monocytes apparently play in this process.
28013187 Halofuginone inhibits TNF-α-induced the migration and proliferation of fibroblast-like sy 2017 Feb Fibroblast-like synoviocytes (FLSs) display an aggressive phenotype that is a critical factor in cartilage destruction in rheumatoid arthritis (RA). Increased FLS migration and proliferation are essential to the pathology of RA. Halofuginone has been found to inhibit cell migration and proliferation in cancer cells. However, whether halofuginone has a role in the treatment of RA FLSs is unclear. In this study, we found that halofuginone reduced migration, invasion, cell proliferation and MMPs expression in RA FLSs. In addition, we demonstrated that halofuginone inhibited reorganization of the actin cytoskeleton during cell migration. To gain insight into the molecular mechanisms, we evaluated the effect of halofuginone on the MAPK and AKT pathways. Our results indicated that halofuginone inhibited the activity of MAPK and AKT. Taken together, these results suggest that halofuginone may protect against joint destruction in RA by regulating synoviocyte migration, invasion and cell proliferation by inhibiting MAPK and AKT activation.
28968699 Validation of the EULAR definition of arthralgia suspicious for progression to rheumatoid 2017 Dec 1 OBJECTIVES: Recently a EULAR-taskforce defined arthralgia suspicious for progression to RA, in order to allow inclusion of homogeneous sets of arthralgia patients in clinical studies. This longitudinal study aimed (i) to validate this definition in arthralgia patients in whom rheumatologists felt that imminent RA was more likely than other arthralgias [clinically suspect arthralgia (CSA)], that is, the target population fulfilling the entry criterion, and (ii) to explore the performance in arthralgia patients who were referred to secondary care prior to rheumatological evaluation, hence ignoring the entry criterion. METHODS: The definition was assessed in 241 Dutch patients identified with CSA by rheumatologists and 113 patients referred to the Umeå university hospital with recent-onset arthralgia in small joints. The external reference was arthritis development <2 years' follow-up. RESULTS: CSA patients with a positive definition (⩾3/7 parameters present) had an increased risk for developing arthritis compared with definition-negative CSA patients (hazard ratio = 2.1, 95% CI: 0.9, 4.7). The sensitivity was 84% and the positive predictive value 30%. In arthralgia patients in whom the definition was applied before rheumatological evaluation, a positive definition was neither sensitive (10%) nor predictive (positive predictive value 3%). CONCLUSION: The EULAR definition of arthralgia suspicious for progression to RA is sensitive when used to support the rheumatologist's opinion on imminent RA. This validation study shows that the definition, when used as designed, further homogenizes patients that rheumatologists consider at risk for RA. To arrive at a high specificity, the clinical definition needs to be combined with biomarkers.
27792870 Phenome-Wide Association Study of Autoantibodies to Citrullinated and Noncitrullinated Epi 2017 Apr OBJECTIVE: Patients with rheumatoid arthritis (RA) develop autoantibodies against a spectrum of antigens, but the clinical significance of these autoantibodies is unclear. Using a phenome-wide association study (PheWAS) approach, we examined the association between autoantibodies and clinical subphenotypes of RA. METHODS: This study was conducted in a cohort of RA patients identified from the electronic medical records (EMRs) of 2 tertiary care centers. Using a published multiplex bead assay, we measured 36 autoantibodies targeting epitopes implicated in RA. We extracted all International Classification of Diseases, Ninth Revision (ICD-9) codes for each subject and grouped them into disease categories (PheWAS codes), using a published method. We tested for the association of each autoantibody (grouped by the targeted protein) with PheWAS codes. To determine significant associations (at a false discovery rate [FDR] of ≤0.1), we reviewed the medical records of 50 patients with each PheWAS code to determine positive predictive values (PPVs). RESULTS: We studied 1,006 RA patients; the mean ± SD age of the patients was 61.0 ± 12.9 years, and 79.0% were female. A total of 3,568 unique ICD-9 codes were grouped into 625 PheWAS codes; the 206 PheWAS codes with a prevalence of ≥3% were studied. Using the PheWAS method, we identified 24 significant associations of autoantibodies to epitopes at an FDR of ≤0.1. The associations that were strongest and had the highest PPV for the PheWAS code were autoantibodies against fibronectin and obesity (P = 6.1 × 10(-4) , PPV 100%), and that between fibrinogen and pneumonopathy (P = 2.7 × 10(-4) , PPV 96%). Pneumonopathy codes included diagnoses for cryptogenic organizing pneumonia and obliterative bronchiolitis. CONCLUSION: We demonstrated application of a bioinformatics method, the PheWAS, to screen for the clinical significance of RA-related autoantibodies. Using the PheWAS approach, we identified potentially significant links between variations in the levels of autoantibodies and comorbidities of interest in RA.
28254559 Aberrant expression of interleukin-10 in rheumatoid arthritis: Relationship with IL10 hapl 2017 Jul Interleukin 10 (IL-10) is an immunomodulatory cytokinethat plays a central rolein the pathogenesis of autoimmune diseases. Different studies consistently show increased IL-10 serum levels in rheumatoid arthritis (RA) and it appears to be caused by genetic variants. Three polymorphisms situated at positions -1082, -819 and -592 of IL10 gene and its major haplotypes have been associated with regulating IL10 promoter activity. In this study, we evaluated whether IL10 haplotypes are associated with mRNA expression and IL-10 serum levels as well as susceptibility to RA in a Western Mexican population. A total of 240 RA patients and 240 control subjects (CS) were included. Genotyping of IL10 polymorphisms was performed by PCR and PCR-RFLP, respectively. IL10 mRNA expression was determined by real-time PCR and IL-10 serum levels were measured using an ELISA kit. IL10 mRNA expression was 50-fold higher in RA patients than CS (p<0.001), while IL-10 serum levels did not show differences between groups. However, high IL-10 serum levels were positively related to a higherseropositivityfor rheumatoid factor (FR) and anti-CCP antibodies (p<0.05). No significant differences between the distribution of haplotype frequencies were observed between both study groups, but GCC haplotype was associated with higher IL-10 serum levels compared with the ACC and ATA haplotypes in RA patients (p<0.05). In addition, patients carrying ATA and GCC haplotypes showed higher mRNA expression than ACC (5.4-fold and 8.8-fold, respectively) and surprisingly, this trend was reversed in the controls, although it was not significant. In conclusion, our findings suggest that IL10 (GCC, ACC, and ATA) haplotypes may not be a susceptibility marker for RA in a population from Western Mexico. Nevertheless, independently of the presence of these variants, there is an aberrant overexpression of IL10 gene in RA, and it may play an important role in the pathogenesis of RA.
27814279 Alterations in skin microvascular function in patients with rheumatoid arthritis and ankyl 2017 OBJECTIVE: To evaluate the relationship between systemic inflammation and skin microcirculation in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS: We assessed skin microcirculation flux (laser Doppler flowmetry), classical cardiovascular risk factors, inflammatory markers and disease activity (Disease Activity Score 28, Bath Ankylosing Spondylitis Disease Activity Index) in 75 patients with arthritis with a median disease duration of 4 years, and in 26 healthy subjects. RESULTS: In patients with arthritis inflammatory markers (C-reactive protein, interleukin 6, fibrinogen) were increased, peak flux velocity after the occlusion at the temperature of 36.6°C and maximal heat flux velocity after the heating were significantly lower. These findings were accompanied by the slower increase in the flux rate during local heating. There were positive correlations between inflammatory markers and microcirculation parameters in patients with RA and AS, but only for RA patients between peak flux velocity and disease activity. There were no significant intergroup differences when the classical cardiovascular risk factors were compared except for the lower HDL cholesterol in arthritis patients. CONCLUSIONS: Patients with chronic systemic inflammatory arthritis presented altered microvascular function and reduced vasodilator capacity of the forearm skin microcirculation.
29257239 Elevated expression of PD‑1 on T cells correlates with disease activity in rheumatoid ar 2018 Feb It is well known that lymphocytes are important in rheumatoid arthritis (RA). Programmed cell death-1 (PD‑1) is one of the immunosuppressive costimulatory molecules, which mediates an inhibitory effect. However, its role in RA remains to be fully elucidated. In the present study, the expression levels of PD‑1 on T cells in the peripheral blood (PB) and synovial fluid (SF) were determined using flow cytometry. In addition, the expression levels of PD‑1 on T cells in the PB and SF of patients with RA were further analyzed to determine correlation with markers of the autoimmune response, inflammation and disease activity in RA. Compared with healthy controls, the expression of PD‑1 on T cells in the PB was significantly elevated in patients with RA (P<0.0001). The expression of PD‑1 on T cells in the SF of patients with RA was significantly increased, compared with that in the autologous PB (P<0.0001). It was also found that the expression of PD‑1 on T cells in the PB of patients with RA was increased significantly in subjects with a high rheumatoid factor titer, high levels of inflammatory markers and a high disease activity score 28 (DAS28). The expression of PD‑1 on T cells in the SF of patients with RA was increased significantly in subjects with a high DAS28. These data showed that the expression of PD‑1 on T cells was elevated in patients with RA and was correlated with the disease activity.
28151971 EQ-5D utility, response and drug survival in rheumatoid arthritis patients on biologic mon 2017 OBJECTIVES: Biologic agents have dramatically changed treatment of rheumatoid arthritis (RA). To date only scarce head-to-head data exist especially when the biological therapies are given as monotherapy without concomitant disease modifying drugs (DMARDs). Thus the objective of the current study is to evaluate treatment response of all available biological therapies with special focus on utility (EQ-5D-3L) and drug survival of biologic DMARDs (bDMARDs) prescribed as monotherapy in RA patients in southern Sweden. MATERIALS AND METHODS: All RA patients registered in a regional database as initiating bDMARD as monotherapy, i.e. without concomitant conventional synthetic DMARDs (csDMARDs), from 1st of January 2006 through 31st of December 2012, were included. Patients were followed from initiation of the first dose of bDMARD monotherapy treatment until withdrawal from treatment, loss of follow-up or 31st of December 2012. Descriptive statistics for utility (EQ-5D-3L), effectiveness, and drug survival of bDMARD monotherapy were calculated. RESULTS: During the study period, a total of 554 patients were registered in SSATG as initiating bDMARD monotherapy. Most of the patients were women (81%), with a mean age of 57 years. The average disease duration was more than 12 years, and on average the patients had previously been treated with approximately four different csDMARDs. Fifty-five percent of the patients were initiating their first bDMARD, 26% their second, and 19% their third or more. At baseline the average EQ-5D-3L was 0.34. Most patients had moderate to high disease activity, with a mean DAS28 of 5.0, and were substantially disabled, with an average HAQ score of 1.4. At 6 months´ follow-up, the EQ-5D-3L in patients still on the biologic drug had increased by mean 0.23 (SD 0.4) with no differences between type of bDMARD (p = 0.49). The mean change in EQ-5D-3L ranged from 0.11 (rituximab and infliximab) to 0.42 (tocilizumab). Although the changes were numerically different, no distinct pattern favored any particular bDMARD for EQ-5D-3L (p = 0.49) or other clinical outcomes. Overall, DAS28 defined remission and low disease activity were achieved in 20% and 43% of patients, respectively. Drug survival rates were statistically significantly different between bDMARDs (p = 0.01), with the highest rates observed for rituximab, followed by etanercept. After failing first course of anti-TNF, patients switching to another mode of action had significantly higher drug survival than those switching to a second course of anti-TNF therapy (p = 0.02). CONCLUSIONS: Utility (EQ-5D-3L) increased after 6 months of all bDMARD treatments in monotherapy, indicating improvement of patients' quality of life. After failure of anti-TNF treatment in monotherapy, switching to another mode of action may be associated with better drug survival than starting a second TNF-inhibitor.
28478964 The risk factor of preoperative deep vein thrombosis in patients undergoing total knee art 2017 Jul OBJECTIVES: The objective of this retrospective study was to investigate the prevalence of asymptomatic deep vein thrombosis (DVT) and the risk of DVT in patients admitted to hospital for total knee arthroplasty (TKA). METHODS: From September of 2003 to December of 2013, 322 patients admitted for TKA were eligible for this retrospective study. A diagnosis of DVT was confirmed by Doppler ultrasonography. The prevalence of silent DVT in the lower limbs in patients before TKA was assessed. The risk factors for preoperative DVT were investigated, as well as the correlation of DVT in the patient's background and medical history. RESULTS: Preoperative DVT was diagnosed in 56 patients (17.4%) including 3 patients with proximal DVT. Significantly elevated risks of DVT were found in patients undergoing revision TKA (p < 0.01), patients with rheumatoid arthritis (RA) (p < 0.005), patients with connective tissue diseases (CTDs) (p < 0.05), and female patients (p < 0.05) on univariate analyses. Multiple linear regression analysis showed that RA, CTDs and admission for revision TKA were independent risk factors for preoperative DVT. CONCLUSIONS: A high prevalence of preoperative DVT was found in patients admitted to hospital for TKA. Admission to the hospital for RA, CTDs and revision TKA were risk factors for preoperative DVT.
27627584 Proteome Analysis of Rheumatoid Arthritis Gut Mucosa. 2017 Jan 6 Rheumatoid arthritis (RA) is an inflammatory joint disease leading to cartilage damage and ultimately impaired joint function. To gain new insight into the systemic immune manifestations of RA, we characterized the colon mucosa proteome from 11 RA-patients and 10 healthy controls. The biopsies were extracted by colonoscopy and analyzed by label-free quantitative proteomics, enabling the quantitation of 5366 proteins. The abundance of dihydrofolate reductase (DHFR) was statistically significantly increased in RA-patient biopsies compared with controls and correlated with the administered dosage of methotrexate (MTX), the most frequently prescribed immunosuppressive drug for RA. Additionally, our data suggest that treatment with Leflunomide, a common alternative to MTX, increases DHFR. The findings were supported by immunohistochemistry with confocal microscopy, which furthermore demonstrated that DHFR was located in the cytosol of the intestinal epithelial and interstitial cells. Finally, we identified 223 citrullinated peptides from 121 proteins. Three of the peptides were unique to RA. The list of citrullinated proteins was enriched in extracellular and membrane proteins and included known targets of anticitrullinated protein antibodies (ACPAs). Our findings support that the colon mucosa could trigger the production of ACPAs, which could contribute to the onset of RA. The MS data have been deposited to ProteomeXchange with identifiers PXD001608 and PXD003082.
28187783 Development of three-dimensional prints of arthritic joints for supporting patients' aware 2017 Feb 10 BACKGROUND: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) result in severe joint destruction and functional disability if left untreated. We aim to develop tools that help patients with RA and PsA to understand and experience the impact of inflammatory joint disease on the integrity of their (juxta-articular) bone and increase adherence to medical treatment. In this study, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to develop 3D prototypes of patients' finger joints. METHODS: HR-pQCT (XtremeCT, Scanco) measurements were performed in healthy individuals and patients with inflammatory joint disease, followed by a 3D print using the objet30 printer. Healthy participants (n = 10), and patients (n = 15 with RA and 15 with PsA) underwent a detailed, standardized interview with demonstration of printed joints. RESULTS: Utilizing HR-pQCT images of metacarpophalangeal (MCP) heads, high quality and exact 3D prints as prototypes were created. Erosions in different sizes and the trabecular network printed in detail were visualized, demonstrating structural reduction in arthritic vs. healthy bone. After demonstration of 3D prints (healthy vs. erosive joint, visual and haptic) 26/39 (66%) participants (including healthy volunteers) were deeply affected, often quoting "shock". Of the patients with RA and PsA, 13/15 (86%) and 11/15 (73%), respectively, stated that they would rethink their attitude to medication adherence. More importantly, 21/24 patients with RA or PsA (87.5%) expressed that they would have wished to see such 3D prints during their first disease-specific conversations. CONCLUSION: Using arthro-haptic 3D printed prototypes of joints may help to better understand the impact of inflammatory arthritides on bone integrity and long-term damage.
28121216 Left ventricular function at two-year follow-up in treatment-naive rheumatoid arthritis pa 2017 Nov OBJECTIVES: In rheumatoid arthritis (RA), the role of autoimmunity, especially anti-cyclic citrullinated peptide antibody (anti-CCP) level, and the time-course of left ventricular (LV) function is unknown. The objective was to assess LV function and the amount of coronary calcium in relation to anti-CCP levels in a cohort of treatment-naive RA patients, and to assess changes in these parameters during a 2 year follow-up period. METHOD: Sixty-six steroid- and disease-modifying anti-rheumatic drug-naive RA patients were treated with methotrexate according to the Danish national guidelines. We assessed LV function by conventional echocardiography and speckle-tracking echocardiography. We estimated the amount and progression of coronary calcium by coronary computed tomography. Patients were examined at the time of diagnosis and after 2 years. RESULTS: Patients with elevated anti-CCP at baseline and after 2 years, compared to those with non-persistently elevated anti-CCP, had significantly less improvement in S´ (1 ± 1.4 cm/s vs 0.2 ± 0.9 cm/s; p = 0.04) and a worsening in global longitudinal systolic strain (GLS) (0.6 ± 1.8% vs -1 ± 2.8%; p = 0.04). There was a significant correlation between ΔGLS over 2 years and anti-CCP at 2 year follow-up (r = 0.36; p = 0.006). We observed a small progression of coronary calcium score during the 2 year follow-up period. No differences in progression were found between patients with high anti-CCP titres at baseline and 2 year follow-up (n = 12) and patients with normal/low anti-CCP titres (n = 32) (23.8 ± 40.3 vs 22.6 ± 68.9; p = 0.96). CONCLUSIONS: Deformation analysis by speckle-tracking echocardiography is a valuable tool to detect early development of myocardial dysfunction despite normal ejection fraction in RA.
28710095 Acute coronary syndrome in new-onset rheumatoid arthritis: a population-based nationwide c 2017 Oct BACKGROUND: Acute coronary syndrome (ACS) and other cardiovascular diseases are the main drivers of the increased morbidity and preterm mortality in rheumatoid arthritis (RA). ACS in RA has been linked to inflammation and RA severity. During recent years and with new therapeutic options and treat-to-target strategies, increasing efforts have been made to reach RA remission as soon as possible after diagnosis, and the average level of RA disease activity has declined. Whether this has resulted in declining excess risks for RA comorbidities remains unclear. METHODS: We performed a nationwide population-based cohort study of patients with new-onset RA from 1997 to 2014, and matched general population comparators. In the Swedish healthcare system, all residents have equal access to healthcare services. Healthcare is monitored using high-quality population-based registers that can be linked together. 15 744 patients with new-onset RA, identified from the Swedish Rheumatology Quality Register, and 70 899 general population comparator subjects were included. RESULTS: Seven hundred and seventy two patients with RA developed an ACS during 103 835 person-years of follow-up (crude incidence, 7.4 per 1000), corresponding to an overall HR versus the general population of 1.41 (95% CI 1.29 to 1.54). Whereas the ACS incidence declined over calendar time in both the RA and the general population cohort, the excess and the relative risks of ACS remained the same. CONCLUSIONS: Despite improved disease control in new-onset RA, the elevated risk of ACS in RA remains a concern.
28681716 Psychosomatic syndromes in fibromyalgia. 2017 May OBJECTIVES: The aim of this study was to compare the prevalence of psychosomatic symptoms in patients with fibromyalgia (FM) or rheumatoid arthritis (RA). METHODS: Seventy-six consecutive women with FM and 80 with RA without concomitant FM were assessed using the Diagnostic Criteria for Psychosomatic Research (DCPR) interview to evaluate the presence of psychosomatic syndromes. Beck Depression Inventory - II (BDI-II) and Form Y of the State-Trait Anxiety Inventory (STAI-Y) were administered in order to assess the symptoms of anxiety and depression. RESULTS: Significantly higher levels of anxiety and depression were found in the FM patients (p<0.001), and each FM patient (as against 79% of the RA patients) presented at least one DCPR syndrome. Comparisons of psychological distress between the FM patients with and without each of the psychosomatic syndromes revealed high levels of anxiety and depression in the patients with the psychosomatic condition. CONCLUSIONS: The findings of this study highlight the greater presence of psychological distress and psychosomatic syndromes in patients with FM than in RA patients. The FM patients with psychosomatic symptoms also showed high levels of psychological distress. A better understanding of the psychosomatic manifestations of FM syndrome could allow clinicians to structure tailored interventions that take more account of the emotional distress associated with the physical complaints.
28514293 The role of circulating miR-146a in patients with rheumatoid arthritis treated by Triptery 2017 May Rheumatoid arthritis (RA) is polygenic autoimmune disease with unclear etiology. MicroRNAs (miRNAs) play a critical role in the pathogenesis of RA. The objective of this study was to evaluate the role of miR-146a in patients with RA receiving Tripterygium wilfordii Hook F (TwHF) treatment.In total, 69 patients with RA and 69 healthy controls (HC) were included in the study, and patients with RA received TwHF treatment for 24 weeks. Blood samples were collected from RA patients and HC, and peripheral blood mononuclear cells (PBMCs) were isolated. Expression of miR-146a was analyzed in RA patients (baseline, 12 weeks and 24 weeks) and HC.Circulating miR-146a expression was markedly increased in patients with RA compared with healthy controls (P < .001), ROC analysis of miR-146a for diagnosis for RA showed that the AUC was 0.908 (95% CI: 0.862-0.955) with a sensitivity of 87.0% and a specificity of 82.6% at best cutoff. And miR-146a expression was positively associated with the DAS28 score and CRP level (P = .002 and P = .019). Moreover, miR-146a expression was markedly reduced after TwHF therapy (P < .001), and baseline miR-146a level was observed to present an increased tendency in responders compared with non-responders at 24 weeks (P = .066).Our study presented that circulating miR-146a level was correlated with risk and disease activity of RA patients by TwHF treatment, which could strikingly decrease expression of miR-146a in RA patients, and miR-146a may have a value in predicting clinical response of TwHF treatment. It indicates that circulating miR-146a plays a prominent role in RA patients treated by TwHF.
27493089 Anti-apoptotic effect of interleukin-22 on fibroblast-like synoviocytes in patients with r 2017 Feb AIM: Inadequate apoptosis of fibroblast-like synoviocytes (FLS) plays a crucial role in the immunopathogenesis of rheumatoid arthritis (RA). Interleukin-22 (IL-22) is a novel member of the cytokine network that has been found to be involved in the immunological process underlying RA. In this study, we investigated the effect of IL-22 on the survival of RA-FLS from RA patients and examined the possible mechanism to determine new therapeutic strategies for RA. METHODS: FLS obtained from patients with RA were cultured in vitro and treated with sodium nitroprussiate (SNP) to induce apoptosis in the presence or absence of IL-22. RA-FLS viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RA-FLS apoptosis was analyzed by annexin V/propidium iodide staining (AV/PI). The levels of IL-22R1, pSTAT3-Y705, pSTAT3-S727, total STAT3, Bcl-xL and Bcl-2 were detected by Western blot analysis. RESULTS: IL-22R1 was expressed on RA-FLS. IL-22 pretreatment at concentrations ranging from 10 to 100 ng/mL increased RA-FLS viability and prevented SNP-induced apoptosis. Treatment with the STAT3 inhibitors, HO3867 or STA21, reversed the protective effect of IL-22 on SNP-induced apoptosis of RA-FLS. IL-22-induced phosphorylation of STAT3 (pSTAT3-Y705 and pSTAT3-S727) was increased in RA-FLS. Also IL-22 increased Bcl-2 expression in SNP-treated RA-FLS, and the effect was reversed by treatment with HO3867 or STA21. CONCLUSION: IL-22 protects against SNP-induced apoptosis in RA-FLS by activating the STAT3 pathway and the downstream target gene, Bcl-2. Therefore, therapeutic strategies that target the IL-22/STAT3 pathway are implicated as candidates for RA treatment.
28523420 Cost-utility analysis of certolizumab pegol in combination with methotrexate in patients w 2017 Sep We aimed to evaluate the cost-effectiveness of certolizumab pegol (CZP), a pegylated fc-free anti-TNF, as add-on therapy to methotrexate (MTX) versus etanercept, adalimumab, or golimumab in patients with moderate-to-severe active rheumatoid arthritis (RA) not responding to the conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). A Markov model (6-month cycle length) assessed health and cost outcomes of CZP versus other anti-TNFs recommended for RA in Greece over a patient's lifetime. Following discontinuation of first-line anti-TNF, patients switched to second anti-TNF and then to a biologic with another mode of action. Sequential use of csDMARDs followed third biologic. Clinical data and utilities were extracted from published literature. Analysis was conducted from third-party payer perspective in Greece. Costs (drug acquisition, administration, monitoring, and patient management) were considered for 2014. Results presented are incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year (QALY). Probabilistic sensitivity analysis (PSA) ascertained robustness of base-case findings. Base-case analysis indicated that CZP+MTX was more costly and more effective compared with Etanercept+MTX (base-case ICER: €3,177 per QALY), whilst versus adalimumab/golimumab, CZP was dominant (less costly, more effective). For all comparisons, CZP treatment resulted in greater improvements in life expectancy and QALYs. PSA indicated that at the willingness-to-pay threshold of €34,000/QALY, CZP+MTX was associated with a 71.6, 97.9, or 99.2% probability of being cost-effective versus etanercept, golimumab, or adalimumab, respectively, in combination with MTX. This analysis demonstrates CZP+MTX to be a cost-effective alternative over Etanercept+MTX and a dominant option over Adalimumab+MTX and Golimumab+MTX for management of RA in Greece.
27998029 Incidence and Prevalence of Cardiovascular Risk Factors Among Patients With Rheumatoid Art 2017 Oct OBJECTIVE: To estimate prevalence and incidence of cardiovascular (CV) risk factors of hypertension, diabetes mellitus, hyperlipidemia, and obesity in patients with rheumatoid arthritis (RA), psoriasis, or psoriatic arthritis (PsA). METHODS: Patients with RA, psoriasis, or PsA were identified based on medical and pharmacy claims from the MarketScan claims databases from January 1, 2002 through December 31, 2014. Primary outcomes included age- and sex-standardized prevalence of CV risk factors during the 12 months preceding diagnosis date and incidence rates per 1,000 patient-years, with 95% confidence intervals (95% CIs) during followup. RESULTS: Prevalence for RA, psoriasis, and PsA cohorts for hypertension was 18.6% (95% CI 18.3-18.8), 16.6% (95% CI 16.3-17.0), and 19.9% (95% CI 19.4-20.4), respectively; for diabetes mellitus 6.2% (95% CI 6.1-6.4), 6.3% (95% CI 6.0-6.5), and 7.8% (95% CI 7.4-8.2); for hyperlipidemia 9.9% (95% CI 9.7-10.1), 10.4% (95% CI 10.2-10.7), and 11.6% (95% CI 11.2-12.0); and for obesity 4.4% (95% CI 4.2-4.6), 3.8% (95% CI 3.5-4.0), and 6.0% (95% CI 5.6-6.5). Incidence rates per 1,000 patient-years during followup for RA, psoriasis, and PsA cohorts, respectively, for hypertension were 74.0 (95% CI 72.5-75.5), 68.2 (95% CI 65.9-70.4), and 79.8 (95% CI 76.3-83.3); for diabetes mellitus 10.6 (95% CI 10.1-11.1), 13.0 (95% CI 12.1-13.8), and 14.7 (95% CI 13.5-16.0); for hyperlipidemia 40.3 (95% CI 39.4-41.3), 47.1 (95% CI 45.4-48.7), and 52.0 (95% CI 49.6-54.3); and for obesity 24.4 (95% CI 23.4-25.4), 26.4 (95% CI 25.0-27.8), and 32.9 (95% CI 30.6-35.2). CONCLUSION: Patients with RA, psoriasis, and PsA have high prevalence and incidence of CV risk factors, suggesting the need for risk factor monitoring of these patients.
28696805 Relevance of P-glycoprotein on CXCR4(+) B cells to organ manifestation in highly active rh 2018 Mar INTRODUCTION: In rheumatoid arthritis (RA), P-glycoprotein (P-gp) expression on activated B cells is associated with active efflux of intracellular drugs, resulting in drug resistance. CXCR4 is associated with migration of B cells. This study was designed to elucidate the relevance of P-gp expression on CXCR4(+) B cells to clinical manifestations in refractory RA. METHODS: CD19(+) B cells were analyzed using flow cytometry and immunohistochemistry. RESULTS: P-gp was highly expressed especially on CXCR4(+)CD19(+) B cells in RA. The proportion of P-gp-expressing CXCR4(+) B cells correlated with disease activity, estimated by Simplified Disease Activity Index (SDAI), and showed marked expansion in RA patients with high SDAI and extra-articular involvement. In highly active RA, massive infiltration of P-gp(+)CXCR4(+)CD19(+) B cells was noted in CXCL12-expressing inflammatory lesions of RA synovitis and RA-associated interstitial pneumonitis. In RA patient with active extra-articular involvement, intracellular dexamethasone level (IDL) in lymphocytes diminished with expansion of P-gp(+)CXCR4(+) CD19(+) B cells. Adalimumab reduced P-gp(+)CXCR4(+) CD19(+) B cells, increased IDL in lymphocytes, and improved the clinical manifestation and allowed tapering of concomitant medications. CONCLUSIONS: Expansion of P-gp(+)CXCR4(+) B cells seems to be associated with drug resistance, disease activity and progressive destructive arthritis with extra-articular involvement in RA.
28475762 Epigenome-wide association study of rheumatoid arthritis identifies differentially methyla 2017 Jul 15 Epigenetic regulation of immune cell types could be critical for the development and maintenance of autoimmune diseases like rheumatoid arthritis (RA). B cells are highly relevant in RA, since patients express autoantibodies and depleting this cell type is a successful therapeutic approach. Epigenetic variation, such as DNA methylation, may mediate the pathogenic activity of B cells. In this study, we performed an epigenome-wide association study (EWAS) for RA with three different replication cohorts, to identify disease-specific alterations in DNA methylation in B cells. CpG methylation in isolated B lymphocytes was assayed on the Illumina HumanMethylation450 BeadChip in a discovery cohort of RA patients (N = 50) and controls (N = 75). Differential methylation was observed in 64 CpG sites (q < 0.05). Six biological pathways were also differentially methylated in RA B cells. Analysis in an independent cohort of patients (N = 15) and controls (N = 15) validated the association of 10 CpG sites located on 8 genes CD1C, TNFSF10, PARVG, NID1, DHRS12, ITPK1, ACSF3 and TNFRSF13C, and 2 intergenic regions. Differential methylation at the CBL signaling pathway was replicated. Using an additional case-control cohort (N = 24), the association between RA risk and CpGs cg18972751 at CD1C (P = 2.26 × 10-9) and cg03055671 at TNFSF10 (P = 1.67 × 10-8) genes was further validated. Differential methylation at genes CD1C, TNFSF10, PARVG, NID1, DHRS12, ITPK1, ACSF3, TNFRSF13C and intergenic region chr10p12.31 was replicated in a cohort of systemic lupus erythematosus (SLE) patients (N = 47) and controls (N = 56). Our results highlight genes that may drive the pathogenic activity of B cells in RA and suggest shared methylation patterns with SLE.