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ID PMID Title PublicationDate abstract
29523119 Comparison of mesenchymal stem cells obtained by suspended culture of synovium from patien 2018 Mar 9 BACKGROUND: Mobilization of mesenchymal stem cells (MSCs) from the synovium was revealed using a "suspended synovium culture model" of osteoarthritis (OA). The pathology of rheumatoid arthritis (RA) differs from that of OA. We investigated whether mobilization of MSCs from the synovium also occurred in RA, and we compared the properties of synovial MSCs collected from suspended synovium culture models of RA and OA. METHODS: Human synovium was harvested during total knee arthroplasty from the knee joints of patients with RA (n = 8) and OA (n = 6). The synovium was suspended in a bottle containing culture medium and a culture dish at the bottom. Cells were harvested from the dish and analyzed. RESULTS: No significant difference was observed between RA and OA in the harvested cell numbers per g of synovium. However, the variation in the number of cells harvested from each donor was greater for RA than for OA. The harvested cells were multipotent and no difference was observed in the cartilage pellet weight between RA and OA. The surface epitopes of the cells in RA and OA were similar to those of MSCs. CONCLUSION: Mobilization of MSCs from the synovium was demonstrated using a suspended synovium culture model for RA. The harvested cell numbers, chondrogenic potentials, and surface epitope profiles were comparable between the RA and OA models.
28555277 Association between anti-Porphyromonas gingivalis antibody, anti-citrullinated protein ant 2018 Aug OBJECTIVE: The aim of this study was to determine the relationship between anti-Porphyromonas gingivalis (anti-P. gingivalis) antibody levels and rheumatoid arthritis (RA) and its correlation with anti-citrullinated protein antibodies (ACPA). METHODS: We performed a meta-analysis of studies comparing (a) anti-P. gingivalis antibody levels in RA patients and healthy controls and (b) the correlation coefficients between the anti-P. gingivalis antibody levels and ACPA in RA patients. RESULTS: The study included 14 articles with 3829 RA patients and 1239 controls. Our meta-analysis showed that anti-P. gingivalis antibody levels were significantly higher in the RA group than in the control group (standardized mean difference [SMD] = 0.630, 95% CI = 0.272-0.989, p = 0.001). Subgroup analysis revealed that RA patients had significantly elevated anti-P. gingivalis antibody levels compared with healthy controls, but not compared with the non-RA control group and also not between different sample sizes. Anti-P. gingivalis antibody levels were significantly higher in the RA group than in the control group in the age-/sex-matched population, but not in the unmatched population. Anti-P. gingivalis antibody levels were significantly higher in the ACPA-positive group than in the ACPA-negative group (SMD = 0.322, 95% CI = 0.164-0.480, p = 6.4 × 10(-5)). Meta-analysis of the correlation coefficients showed a significant positive correlation between anti-P. gingivalis antibody levels and ACPA (correlation coefficient = 0.147, 95% CI = 0.033-0.258, p = 0.012). CONCLUSION: Our meta-analysis demonstrated that anti-P. gingivalis antibody levels were significantly higher in patients with RA and they were positively correlated with ACPA.
28324148 Comparative efficacy and tolerability of sarilumab 150 and 200 mg in patients with activ 2018 Jun OBJECTIVE: This study aimed to assess the relative efficacy and tolerability of every other week (q2w) dosing of sarilumab 150 and 200 mg in patients with active rheumatoid arthritis (RA). METHODS: In this network meta-analysis, randomized controlled trials (RCTs) examining the efficacy and tolerability of sarilumab in patients with active RA were included. A Bayesian network meta-analysis was conducted to combine the direct and indirect evidence from the RCTs. RESULTS: Four RCTs, involving 2667 patients, met the inclusion criteria. The American College of Rheumatology (ACR)50 response rate was significantly higher in the sarilumab 200 mg and sarilumab 200 mg + methotrexate (MTX) groups than in the placebo + MTX group (odds ratio, OR, of 4.05, 95% credible interval, CrI, of 2.04-8.33 and OR of 3.75, 95% CrI of 2.37-5.72, respectively). Compared to the placebo + MTX group, the sarilumab 150 mg + MTX and adalimumab 40 mg groups showed a significantly higher ACR50 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that sarilumab 200 mg was likely to achieve the best ACR50 response rate (SUCRA = 0.8518), followed by sarilumab 200 mg + MTX (SUCRA = 0.8225), sarilumab 150 mg + MTX (SUCRA = 0.5112), adalimumab 40 mg (SUCRA = 0.3072), and placebo + MTX (SUCRA = 0.0072). The ACR50 and ACR70 response rate distributions were comparable, except that sarilumab 200 mg + MTX was likely to achieve the best ACR70 response rate. The tolerability based on the number of patient withdrawals due to adverse events (AEs) did not differ significantly between the treatments, except that placebo + MTX was likely to be the best tolerated. CONCLUSION: Sarilumab 150 and 200 mg are efficacious treatments for active RA and are well tolerated.
29514803 Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira 2018 Jun OBJECTIVE: To demonstrate clinical equivalence of adalimumab biosimilar candidate BI 695501 with Humira. METHODS: Patients with active rheumatoid arthritis on stable methotrexate were randomised to BI 695501 or Humira in a double-blind, parallel-group, equivalence study. At week 24, patients were rerandomised to continue BI 695501 or Humira, or switch from Humira to BI 695501. The coprimary endpoints were the percentage of patients achieving the American College of Rheumatology 20% response criteria (ACR20) at weeks 12 and 24. Further efficacy and safety endpoints and immunogenicity were assessed up to week 58. RESULTS: 645 patients were randomised. At week 12, 67.0% and 61.1% (90% CI -0.9 to 12.7) of patients receiving BI 695501 (n=324) and Humira (n=321), respectively, achieved ACR20; at week 24 the corresponding values were 69.0% and 64.5% (95% CI -3.4 to 12.5). These differences were within prespecified margins (week 12: 90% CI (-12% to 15%); week 24: 95% CI (-15% to 15%)), demonstrating therapeutic bioequivalence. 593 patients were rerandomised at week 24. Up to week 48, mean change from baseline in Disease Activity Score 28-erythrocyte sedimentation rate and ACR20/ACR50/ACR70 response rates were similar across the switched (n=147), continuous BI 695501 (n=298) and continuous Humira (n=148) groups. Similar immunogenicity (antidrug antibodies (ADAs), ADA titres and neutralising antibodies) was seen between BI 695501 and Humira (to week 24) and across rerandomised groups (to week 48). Safety and tolerability profiles were similar between groups. CONCLUSIONS: BI 695501 demonstrated similar efficacy, safety and immunogenicity to Humira; switch from Humira to BI 695501 had no impact on efficacy, safety and immunogenicity. TRIAL REGISTRATION NUMBER: NCT02137226, Results.
29938921 Prevalence and Characteristics of Persistent Clonal T Cell Large Granular Lymphocyte Expan 2018 Dec OBJECTIVE: Up to one-third of patients with T cell large granular lymphocyte (T-LGL) leukemia display symptoms of rheumatoid arthritis (RA). In Crohn's disease and psoriasis, treatment with tumor necrosis factor (TNF) inhibitors is associated with hepatosplenic γδ T cell lymphoma and with clonal expansion of γδ T cells, respectively. This study was undertaken to determine the prevalence of clonal T-LGL cells in patients with RA and define risk factors for this rare hematologic malignancy. METHODS: A total of 529 RA patients were recruited between November 2013 and August 2015. Eight-color flow cytometry (fluorescence-activated cell sorting [FACS]) was performed to screen for aberrant T cell populations of LGLs. Molecular analysis of the T cell receptor was used to confirm the diagnosis in patients with suggestive FACS findings. Electronic patient files were used to determine risk factors. Patients with clonal populations were monitored prospectively for up to 4 years. RESULTS: The median patient age was 61 years, and 74% were female. The median duration of RA was 12 years. The median Disease Activity Score in 28 joints was 2.8, and 69.9% of patients had ever been treated with biologic disease-modifying antirheumatic drugs. We identified clonal T-LGL expansions in 19 patients, equaling a prevalence of 3.6%. The T-LGL cell clone was constant over time in most patients and was significantly associated with the duration of the exposure to TNF-blocking agents (P = 0.01). No other risk factors could be detected. CONCLUSION: RA patients with long-term exposure to TNF-blocking agents were at a greater risk of developing clonal expansions of LGLs. This finding may prompt clinicians to refrain from using these substances in RA patients with known T cell aberrations.
29540200 Hypogalactosylation of immunoglobulin G in rheumatoid arthritis: relationship to HLA-DRB1 2018 Mar 14 BACKGROUND: Galactosylation of immunoglobulin G (IgG) is reduced in rheumatoid arthritis (RA) and assumed to correlate with inflammation and altered humoral immunity. IgG hypogalactosylation also increases with age. To investigate dependencies in more detail, we compared IgG hypogalactosylation between patients with RA, patients with axial spondyloarthritis (axSpA), and healthy control subjects (HC), and we studied it in RA on the background of HLA-DRB1 shared epitope (SE), anticitrullinated protein antibodies (ACPA), and/or rheumatoid factor (RF) status. METHODS: Patients with RA (n = 178), patients with axSpA (n = 126), and HC (n = 119) were characterized clinically, and serum IgG galactosylation was determined by capillary electrophoresis. Markers of disease activity, genetic susceptibility, and serologic response included C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), DAS28, SE, HLA-B27, ACPA, and RF. Expression of glycosylation enzymes, including beta 1-4 galactosyltransferase (B4GALT3) activity, were estimated from transcriptome data for B-cell development (GSE19599) and differentiation to plasma cells (GSE12366). RESULTS: IgG hypogalactosylation was restricted to RA and associated with increasing CRP levels (p < 0.0001). In axSpA, IgG hypogalactosylation was comparable to HC and only marginally increased upon elevated CRP. Restriction to RA was maintained after correction for CRP and age. Treatment with sulfasalazine resulted in significantly reduced IgG hypogalactosylation (p = 0.003) even after adjusting for age, sex, and CRP (p = 0.009). SE-negative/ACPA-negative RA exhibited significantly less IgG hypogalactosylation than all other strata (vs SE-negative/ACPA-positive, p = 0.009; vs SE-positive/ACPA-negative, p = 0.04; vs SE-positive/ACPA-positive, p < 0.02); however, this indicated a trend only after Bonferroni correction for multiple testing. In SE-positive/ACPA-negative RA IgG hypogalactosylation was comparable to ACPA-positive subsets. The relationship between IgG hypogalactosylation and disease activity was significantly different between strata defined by SE (CRP, p = 0.0003, p(Bonferroni) = 0.0036) and RF (CRP, p < 0.0001, p(Bonferroni) < 0.0012), whereas ACPA strata revealed only a nonsignificant trend (p = 0.15). Gene expression data indicated that the key enzyme for galactosylation of immunoglobulins, B4GALT3, is expressed at lower levels in B cells than in plasma cells. CONCLUSIONS: Increased IgG hypogalactosylation in RA but not in axSpA points to humoral immune response as a precondition. Reduced B4GALT3 expression in B cells compared with plasma cells supports relatedness to early B-cell triggering. The differential influence of RA treatment on IgG hypogalactosylation renders it a potential diagnostic target for further studies.
29136759 Novel function of hydroxychloroquine: Down regulation of T follicular helper cells in coll 2018 Jan Hydroxychloroquine (HCQ) is an immunosuppressive agent widely used in rheumatoid arthritis (RA). T follicular helper (Tfh) cells play a vital role in the pathogenesis of RA. However, whether HCQ suppresses arthritis development through interfering with Tfh cells have never been reported. To address this issue, we investigated the percent of Tfh cells in newly diagnosed RA patients and found that they were up-regulated in peripheral blood. Importantly, in ex vivo experiments of peripheral blood mononuclear cells (PBMCs) from healthy volunteers, we proved that the percentage of Tfh cells in PBMCs and purified CD4(+) T cells were decreased after HCQ treatment. In in vivo experiments of collagen-induced arthritis (CIA) model, we discovered that HCQ suppressed the incidence and score of arthritis, reduced the secretion of proinflammatory cytokines in serum. Similar to ex vivo study, the ratio of Tfh cells in HCQ treated CIA mice declined to the level of vehicle-treated group. Further research demonstrated that HCQ inhibited the generation of Tfh cells stimulated by IL-12 and IL-21. In conclusion, our study indicates a previously unrecognized mechanism of HCQ in RA, that HCQ directly suppresses the generation of Tfh cells by blocking IL-12 and IL-21 signaling pathways probably.
29481307 Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and 2018 Jul Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.
29766257 The impact of exercise on sleep (time, quality, and disturbance) in patients with rheumato 2018 Jul Poor sleep is an issue for people with rheumatoid arthritis (RA), which may curtail their ability to function appropriately and reduce their activity levels. This paper describes a protocol for a pilot randomised controlled trial of an aerobic exercise intervention compared with exercise advice designed to improve sleep in people with RA. Objectives are to obtain reliable estimates regarding recruitment rates, participant retention and protocol adherence and to generate potential effect size estimates for a main trial. Participants will be identified from an existing database held at a University Hospital and in person at weekly rheumatology clinics. Participants meeting the inclusion criteria will be randomised into an intervention or control group. Those in the intervention group will participate in an 8-week walking-based exercise intervention consisting of 28 walking sessions, with 1 session per week being supervised by a trained physiotherapist, spread over a maximum of 8 weeks (2-5 times/week), while those in the control group will receive advice on the benefits of exercise for people with RA. Results will provide data for efficient recruitment and data collection, to determine if a larger, statistically powered main trial could be generalised to a multi-centre rheumatoid arthritis population. Given recent information that sleep is commonly reduced in people with RA and that physical activity and exercise profiles are lower, this study will contribute data to the field of exercise and sleep that is currently lacking and importantly will include people with RA in the study process prior to any fully powered trial.Trial registration number: ClinicalTrials.gov Identifier: NCT03140995 (April 25th, 2017).
30339889 Targeted delivery of p-coumaric acid encapsulated mannosylated liposomes to the synovial m 2018 Dec The current study aimed to target the delivery of p-coumaric acid (CA), a dietary polyphenol to the synovial macrophages of AIA rats via mannose incorporated liposomal delivery system (ML) with reference to osteoclastogenesis and bone resorption. In vivo imaging and in vitro drug release study indicated the efficiency of mannosylated liposomes to localize at the site of inflammation and increased sustain drug release respectively. Morphological assessment of isolated synovial macrophages with respect to CD86 (synovial macrophages) and CD51 (pre-/osteoclast) indicated that p-coumaric acid encapsulated mannosylated liposomes (ML-CA) inhibited the osteoclasts differentiation. ML-CA treatment inhibited the TRAP staining, downregulated the expression of MMP-9 and NFATc1 and inflammatory cytokines. The ex-vivo study specified the ability of CA to induce the OPG production in bone marrow stromal cell triggered macrophage-osteoclasts differentiation and to preserve the calcium content. Taken together, our results demonstrated that ML-CA could intervene in the osteoclast formation.
29563318 Response to comment on "Aggregatibacter actinomycetemcomitans-induced hypercitrullination 2018 Mar 21 Antibodies to leukotoxin A are markers that link Aggregatibacter actinomycetemcomitans-associated periodontitis and rheumatoid arthritis.
29693176 PU.1 attenuates TNF‑α‑induced proliferation and cytokine release of rheumatoid arthri 2018 Jun The present study aimed to determine the role of transcription factor PU.1 (PU.1) in tumor necrosis factor‑α (TNF‑α)‑induced proliferation and cytokine release of rheumatoid arthritis fibroblast‑like synoviocytes (RA‑FLS). It was determined that TNF‑α induced proliferation of RA‑FLS, whereas transfection with PU.1 3'untranslated region (UTR) inhibited this proliferation. Additionally, PU.1 3'UTR attenuated TNF‑α‑induced production of interleukin (IL)‑6 and IL‑1β, and downregulated the expression level of micro RNA (miR)‑155 in a dose‑dependent manner. Furthermore, transfection with PU.1 3'UTR significantly attenuated TNF‑α‑induced decrease in forkhead box protein O3 (FOXO3) expression level in RA‑FLS and these effects were consistent with the effects of miR‑155 inhibition. PU.1 and FOXO3 formed a competing endogenous RNA (ceRNA) network that regulated miR‑155 activity. In this competing endogenous RNA network, PU.1 3'UTR modulated FOXO3 expression in a miRNA‑ and 3'UTR‑dependent manner. Downregulation of FOXO3 expression reversed the PU.1 3'UTR‑mediated protective effects. Therefore, the results of the present study indicate that PU.1 3'UTR attenuates TNF‑α‑induced proliferation and cytokine release of RA‑FLS by acting as a ceRNA for FOXO3 to regulate miR‑155 activity.
29521247 Evaluating the Effect of Oral N-acetylcysteine as an Adjuvant Treatment on Clinical Outcom 2018 OBJECTIVE: Oxidative stress and Overproduction of pro-inflammatory cytokines are contributed in Rheumatoid Arthritis (RA) pathogenesis. N-acetylcysteine (NAC) is an antioxidant and antiinflammatory agent which demonstrated analgesic effects in some studies. This study is designed to assess the effects of oral NAC as an adjuvant therapy on the clinical outcomes of patients with active RA. METHODS: In this randomized clinical trial, 51 RA patients with active RA were studied in 2 groups: NAC group (27 patients) received standard treatment of RA and 600 mg NAC twice a day for 12 weeks, and placebo group (24 patients) received the standard treatment of RA and placebo. Disease activity score (DAS28) was used to assess the activity of RA, Visual Analog Scale (VAS) for the severity of pain, Health Assessment Questionnaire (HAQ) for the patients' physical performance, and Global Health (GH) parameter for the patients' assessment of their disease activity. The number of tender and swollen joints and Erythrocyte Sedimentation Rate (ESR) were also determined for each patient. Data were analyzed using SPSS version 16.0 (Chicago, IL, USA). RESULTS: After 12 weeks of intervention, there were no significant differences between two groups in DAS28 score and ESR (P values were 0.4 and 0.6, respectively). However, GH, VAS, and HAQ scores were improved significantly in the NAC group compared to the placebo group. CONCLUSION: Our findings indicate that oral administration of NAC may be associated with improving health status in RA patients and considered as an adjuvant therapy in these patients. Further studies with larger sample size, longer study duration and higher doses of NAC are needed to confirm the effects of oral NAC in RA patients.
27894239 Do Biologic Agents Increase the Risk of Infection in Patients Undergoing Lower Limb Arthro 2018 Apr 20 BACKGROUND: Biologic agents have contributed significantly to the management of patients with in rheumatoid arthritis (RA). A significant proportion of patients with RA still require arthroplasty procedures however. It is unclear whether these agents increase the risk of post operative infection after lower limb arthroplasty. METHOD: A literature search was performed for articles published over the last 10 years in the English language examining the association between anti-tumour necrosis factor inhibitors and the incidence of post operative infection in patients with RA undergoing hip and knee arthroplasty procedures. RESULTS: One large meta-analysis has been published suggesting a 2-fold increase in infection rates following orthopaedic surgery in patients receiving biological agents. When subgroup analysis of arthroplasty cases alone was performed the finding failed to reach significance. However, several further studies have demonstrated both an increased risk for surgical site infection with the use of biological agents and several conflicting articles argue the opposite. CONCLUSION: There is no current consensus on this topic. The safety of continuation of perioperative anti-TNF-α therapy in patients undergoing lower limb arthroplasty procedures is unclear. There is also little robust guidance from specialist rheumatologic societies. There is need for large scale multicentre randomised controlled trials to address this issue.
29618584 Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentiall 2018 Jun Methotrexate (MTX) is the gold standard drug for the treatment of rheumatoid arthritis (RA), and it is frequently combined with leflunomide (LEF) to enhance its clinical efficacy. However, this combination can exacerbate liver toxicity, and the underlying mechanism has not yet been clarified. We investigated whether LEF affects the pharmacokinetics of MTX and its primary toxic metabolite, 7-hydroxyl methotrexate (7OH MTX), in mice. LEF significantly increased the plasma concentration (area under the plasma concentration-time curve) of MTX and 7OH MTX (2.4 and 4.5 times, respectively), decreased their bile excretion, and increased their accumulation in the liver and kidneys. When we investigated the effect of LEF on the MTX absorption, distribution, metabolism, and excretion process, we found that LEF had little effect on liver aldehyde oxidase and 7OH MTX formation. However, LEF significantly decreased the expression of the apical efflux transporter multidrug resistance-associated protein 2 (Mrp2) and increased that of the basolateral efflux transporters Mrp3/4, except there was no significant change in Mrp4 protein expression. Mrp2/3/4 alteration changed the distribution of MTX and 7OH MTX in plasma and tissues. Further studies suggested that LEF indirectly activated peroxisome proliferator-activated receptor α (PPARα), which was likely responsible for the Mrp2/3/4 alteration in the liver. The MTX plasma concentration change induced by LEF was reversed by the PPARα-specific antagonist GW6471. These results may partially explain the exacerbated liver toxicity caused by combination treatment with MTX and LEF and may raise concerns regarding the risk of potential drug-drug interactions between PPARα agonists and Mrp substrates in the clinic.
29803505 Selective killing of proinflammatory synovial fibroblasts via activation of transient rece 2018 Aug BACKGROUND: Studies in rheumatoid arthritis synovial fibroblasts (RASF) demonstrated the expression of several transient receptor potential channels (TRP) such as TRPV1, TRPV2, TRPV4, TRPA1 and TRPM8. Upon ligation, these receptors increase intracellular calcium but they have also been linked to modulation of inflammation in several cell types. TNF was shown to increase the expression of TRPA1, the receptor for mustard oil and environmental poisons in SF, but the functional consequences have not been investigated yet. METHODS: TRPA1 was detected by immunocytochemistry, western blot and cell-based ELISA. Calcium measurements were conducted in a multimode reader. Cell viability was assessed by quantification of lactate dehydrogenase (LDH) in culture supernatants and "RealTime-Glo" luminescent assays. IL-6 and IL-8 production by SF was quantified by ELISA. Proliferation was determined by cell titer blue incorporation. RESULTS: After 72 h, mimicking proinflammatory conditions by the innate cytokine TNF up-regulated TRPA1 protein levels in RASF which was accompanied by increased sensitivity to TRPA1 agonists AITC and polygodial. Under unstimulated conditions, polygodial elicited calcium flux only in the highest concentrations used (50 µM and 25 µM). TNF preincubation substantially lowered the activation threshold for polygodial (from 25 µM to 1 µM). In the absence of TNF pre-stimulation, only polygodial in high concentrations was able to reduce viability of synovial fibroblasts as determined by a real-time viability assay. However, following TNF preincubation, stimulation of TRPA1 led to a fast (<30 min) viability loss by necrosis of synovial fibroblasts. TRPA1 activation was also associated with decreased proliferation of RASFs, an effect that was also substantially enhanced by TNF preincubation. On the functional level, IL-6 and IL-8 production was attenuated by the TRPA1 antagonist A967079 but also polygodial, although the latter mediated this effect by reducing cell viability. CONCLUSION: Simulating inflamed conditions by preincubation of synovial fibroblasts with TNF up-regulates and sensitizes TRPA1. Subsequent activation of TRPA1 increases calcium flux and substantially reduces cell viability by inducing necrosis. Since TRPA1 agonists in the lower concentration range only show effects in TNF-stimulated RASF, this cation channel might be an attractive therapeutic target in chronic inflammation to selectively reduce the activity of proinflammatory SF in the joint.
29379122 Rheumatoid arthritis patient antibodies highly recognize IL-2 in the immune response pathw 2018 Jan 29 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive joint damage due to largely unknown environmental factors acting in concert with risk alleles conferring genetic susceptibility. A major role has been attributed to viral infections that include past contacts with Epstein-Barr virus (EBV) and, more recently, to non-protein coding sequences of human endogenous retrovirus K (HERV-K) integrated in the human genome. Molecular mimicry between viral and self proteins is supposed to cause the loss of immune tolerance in predisposed hosts. There are evidences that anti-IL-2 antibodies (Abs) are present in subjects affected by autoimmune diseases and may be responsible for alterations in regulatory T cell responses. In this study, we evaluated the levels of Abs against IL-2, viral epitopes and interferon regulatory factor 5 (IRF5) in 140 RA patients and 137 healthy controls (HCs). Ab reactivity reached the highest levels for IRF5, EBV and IL-2 (56%, 44% and 39%, respectively) in RA with significantly lower values among HCs (7-9%, p < 0.0001), which suggests a possible cross-reaction between IRF5/EBV homologous antigens and shifts in T cell balance disrupted by anti-IL-2 Abs.
29409414 Postoperative Infection Related with the Total Elbow Arthroplasty (Kudo's Prosthesis) in R 2018 Mar BACKGROUND: Total Elbow Arthroplasty (TEA) for the rheumatoid arthritis (RA) has been popularized since 1980s. The outcomes of TEA using any type of implant design for RA has been satisfactory. On the other hand, many orthopedicians experience several postoperative complications. Among them, postoperative infection has still being the most troublesome and difficult to treat. This study is to clarify the causes of postoperative infection of TEA using Kudo's prosthesis for RA and discuss how to manage and prevent infection. METHODS: 421 TEAs were performed for 405 cases with RA at the authors' institute during the period between 1982 and 2007. They were followed up for 1~25 years (Av. 12.3 years). The authors examined pain, the range of motion, roentgenograms and complications postoperatively. We were able to start treatment within 4 weeks after occurrence of infection. For surgical management of infected TEAs, debridement of the synovium and removal of the prosthesis with loosening were performed for all cases. In addition, all cases have been regularly and strictly followed-up with the elbow protector to prevent recurrence of infection since 2008. RESULTS: There were 98 TEAs with the postoperative complications (23.3%). Eight out of 98 TEAs were infected (1.9%). Five of eight infected TEAs were primarily at the surgical scar site infection (SSSI) (60%), unknown causes in two, hematogenous course in 1. It's obvious that surgical scar site infection (SSSI) was the leading cause of postoperative infection in this study. Thus, the authors made the elbow proctor to avoid injuries of the skin around surgical scar site (SSS). Since 2008, all of the TEAs and revised TEAs have been applied with this protector. CONCLUSIONS: The authors reported 8 infected TEAs: 5 cases were revised, 2 with the brace, 1 had above the elbow amputated. The regular and meticulous follow up and application of the elbow protector were useful to prevent infection of post-TEAs using Kudo's prosthesis in RA. Since 2008, there have been no infection of post TEAs and revised TEAs.
30160189 Improvements in productivity and increased participation in daily activities over 52 week 2019 Oct Objectives: To report changes in productivity and social participation - alongside clinical and patient-reported outcomes (PROs) - in patients with rheumatoid arthritis (RA) receiving certolizumab pegol (CZP) during routine clinical practice in Belgium. Methods: This was a prospective, non-interventional study, in which patients were prescribed CZP at their physicians' discretion and followed during routine clinical visits. The primary outcomes were household productivity and social participation at the last visit (~52 weeks), measured through responses to the Work Productivity Survey. Secondary outcomes included workplace productivity and achievement of DAS28(ESR) clinical response, low disease activity and remission at the last visit. Baseline demographics and adverse events (AEs) were recorded for all patients who received ≥1 dose CZP. Results: A total of 141 patients were enrolled in the study, of whom 119 (84.4%) formed the full analysis set (received ≥1 dose CZP and had ≥1 post-baseline measurement for ≥1 primary outcome). At Visit 1 (baseline), patients reported an average of 11.0 paid work days, 16.8 household work days and 5.5 days of social participation affected by their disease over the previous month. Rapid improvements in household productivity and social participation were evident from Visit 2 (2-8 weeks). By the final visit, mean improvements were observed for all aspects of productivity, participation and clinical/PROs. A total of 24 AEs were reported. Conclusion: CZP has a positive impact on productivity and social participation in patients with RA in the Belgian daily practice setting, with safety and efficacy profiles that mirror those observed in the trial setting.
29524864 Subclinical impairment of myocardial and endothelial functionality in very early psoriatic 2018 Apr BACKGROUND AND AIMS: Cardiovascular (CV) morbidity is increased in inflammatory joint diseases (IJD), as rheumatoid (RA) and psoriatic arthritis (PsA). Whereas increased prevalence of subclinical atherosclerosis has been reported in these conditions, whether an early myocardial functionality is also impaired remains unknown. The aim of this study was to evaluate the myocardial functionality by speckle-tracking echocardiography (STE) in recent onset RA and PsA patients and its potential associations with the levels of circulating CD34 (+) cells, vitamin D, and with disease activity. METHODS: STE was used to assess the myocardial functionality in patients with very early RA (n = 41) and PsA (n = 35) without traditional CV risk factors, and 58 matched healthy controls (HC). Global longitudinal and circumferential strain (GLS and GCS) was estimated. Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) were measured as surrogate markers of atherosclerosis. Circulating CD34 (+) counts were evaluated by flow cytometry and vitamin D levels were quantified by HPLC. Disease activity was assessed by Disease Activity Score-28 (DAS28). RESULTS: RA patients exhibited impaired GLS and GCS (both p < 0.001) as compared to HC, GLS being also altered in PsA (p = 0.020 vs. HC). DAS28 was correlated to GLS (r = 0.908, p < 0.001) and GCS (r = 0.868, p < 0.001) in RA, these findings being confirmed by multivariate regression analyses adjusted for confounders and Principal Component Analyses. GLS and GCS were impaired in PsA patients with high disease activity as compared to HC, and GLS was found to be a predictor of cIMT in this condition. On the other hand, vitamin D was negatively associated with cIMT in HC (r = -0.308, p = 0.026) but not in PsA or RA, although decreased levels were observed (both p < 0.001). Vitamin D was an independent predictor of decreased CD34 (+) levels in PsA and RA. CD34 (+) counts negatively correlated DAS28, GLS and GCS in RA. CONCLUSIONS: Subclinical myocardial dysfunction is observed in IJD patients with preserved left-ventricular function and without traditional CV risk factors. Subclinical myocardial dysfunction was found to be a very early event in IJD. Disease activity was the main predictor of myocardial strain impairment. Interestingly, myocardial function was altered and associated with cIMT also in PsA patients with high disease activity.