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ID PMID Title PublicationDate abstract
29259050 Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the sim 2018 Apr OBJECTIVE: To evaluate the similarities between LBEC0101 (etanercept biosimilar) and the etanercept reference product (ETN-RP) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment. METHODS: This phase III, multicentre, randomised, double-blind, parallel-group, 54-week study was conducted in Japan and Korea. The primary efficacy endpoint was the change from baseline in the disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) at week 24. American College of Rheumatology 20% (ACR20) response rate, adverse events (AEs), pharmacokinetics and development of antidrug antibodies (ADAs) were also evaluated. RESULTS: In total, 374 patients were randomised to LBEC0101 (n=187) or ETN-RP (n=187). The least squares mean changes from baseline in DAS28-ESR at week 24 in the per-protocol set were -3.01 (95% CI -3.198 to -2.820) in the LBEC0101 group and -2.86 (95% CI -3.051 to -2.667) in the ETN-RP group. The estimated between-group difference was -0.15 and its 95% CI was -0.377 to 0.078, which was within the prespecified equivalence margin of -0.6 to 0.6. ACR20 response rates at week 24 were similar between the groups (LBEC0101 93.3% vs ETN-RP 86.7%). The incidence of AEs up to week 54 was comparable between the groups (LBEC0101 92.0% vs ETN-RP 92.5%), although fewer patients in the LBEC0101 group (1.6%) than the ETN-RP group (9.6%) developed ADAs. CONCLUSION: The clinical efficacy of LBEC0101 was equivalent to that of ETN-RP. LBEC0101 was well tolerated and had a comparable safety profile to ETN-RP. TRIAL REGISTRATION NUMBER: NCT02357069.
30319603 Polyphyllin I Ameliorates Collagen-Induced Arthritis by Suppressing the Inflammation Respo 2018 Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder, characterized by an increased number of M1-like macrophages in the joints. Polyphyllin I (PPI), one of the main components in the Rhizoma of Paris polyphyllin, displays a selective inhibitory effect on various tumor cells. Here we sought to investigate the anti-rheumatoid arthritis effects and mechanisms of PPI on macrophages in vivo and in vitro. Materials and Methods: In vitro, primary bone marrow-derived macrophages (BMMs) and peritoneal elucidated macrophages (PEMs) were stimulated by lipopolysaccharide (LPS) and Interferon (IFN)-γ and then treated with PPI. We determined the degree of activation of IKKα/β and p65, two key mediators of the NF-κB-mediated inflammatory pathway, by measuring their phosphorylated forms by Western blot. The p65 nuclear localization was detected by immunofluorescent staining. Further, a NF-κB-linked luciferase reporter plasmid, as well as those expressing key mediators of the Toll-like receptor 4 pathway, such as myeloid differentiation primary response 88 (MYD88), interleukin-1 receptor (IL-1R) associated kinase (IRAK)-1, TNF receptor associated factors (TRAF)-6, Transforming growth factor-b-activated kinase 1 (TAK1) and p65, were used to identify the mechanism by which PPI achieves its inhibitory effects on macrophage-mediated inflammation. Moreover, a NF-κB inhibitor, p65-targeted siRNAs, and a p65 plasmid were further used to validate the anti-inflammatory mechanism of PPI. In vivo, PPI (1 mg/kg) was administered intragastrically one time a day for 7 weeks starting on the 42nd day after the first immunization with collagen in a collagen-induced arthritis (CIA) mouse model. Micro-computed Tomography scanning, histological examination, F4/80 and iNOS double immunofluorescent staining and CD4 immunohistochemical staining were performed to determine the effect of PPI treatment on joint structure and inflammation in this model. Results: PPI reduced the inflammatory cytokines production of PEMs stimulated by LPS/IFN-γ, inhibited the phosphorylation of IKKα/β and p65, and prevented p65 nuclear localization. The NF-κB luciferase assay showed that the target of PPI was closely related to the NF-κB pathway. Moreover, NF-κB inhibition, siRNA-mediated knockdown of p65, and p65 overexpression eliminated PPI's inhibitory effect. In addition, PPI attenuated the bone erosion and synovitis, as well as M1-like macrophage and T cell infiltration, in the ankle joint of the CIA model. Conclusion: PPI demonstrated effective amelioration of synovial inflammation in the ankle joint of CIA mice while suppressing NF-κB-mediated production of pro-inflammatory effectors in activated macrophages.
29565987 PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid 2018 Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA.
29558865 GP2015 as a promising therapy for rheumatoid arthritis. 2018 Apr Rheumatoid arthritis is a common inflammatory joint disease with a myriad of systemic manifestations. Over the last 20 years its treatment has been revolutionised by the introduction of a number of different biologic drugs, including the TNF-receptor Fc fusion protein, Etanercept. However, these drugs are expensive and their widespread use puts a financial burden on healthcare systems. As many biologic treatments begin to come off patent new 'biosimilar' versions are being developed which can lead to significant cost savings. GP2015 (Erelzi®) is the second biosimilar version of Etanercept which is licensed for the treatment of rheumatoid arthritis. Areas covered: We discuss the Chemistry, pharmacokinetics and pharmacodynamics of GP2015 in relation to reference Etanercept. Preclinical trials have shown pharmacokinetic equivalence between GP2015 and the reference drug. The recently completed Phase III, randomised, double blind EQUIRA study has shown equivalent efficacy and safety between GP2015 and Etanercept in patients with rheumatoid arthritis. Expert opinion: GP2015 has shown equivalent efficacy and safety to reference Etanercept. With a growing number of biosimilar medications becoming available and another biosimilar Etanercept already being widely prescribed it is likely to be the cost of the drug that will determine if it is used widely.
30045972 Characterization of a Synovial B Cell-Derived Recombinant Monoclonal Antibody Targeting St 2018 Sep 1 Rheumatoid arthritis (RA) is characterized by formation of synovial ectopic lymphoid structures (ELS) supporting B cell autoreactivity toward locally generated citrullinated (cit) antigens, including those contained in neutrophil extracellular traps (NETs). However, only a minority of RA-rmAbs from B cells isolated from ELS(+) RA tissues react against NETs. Thus, alternative cellular sources of other potential autoantigens targeted by locally differentiated B cells remain undefined. RA fibroblast-like synoviocytes (FLS) have been implicated in the release of RA-associated autoantigens. In this study, we aimed to define stromal-derived autoantigens from RA-FLS targeted by RA-rmAbs. Seventy-one RA-rmAbs were screened toward RA-FLS by living-cell immunofluorescence (IF). Western blotting was used to identify potential autoantigens from RA-FLS protein extracts. Putative candidates were validated using colocalization immunofluorescence confocal microscopy, ELISA, immunoprecipitation assay, and surface plasmon resonance on unmodified/cit proteins. Serum immunoreactivity was tested in anti-citrullinated peptide/protein Abs (ACPA)(+) versus ACPA(-) RA patients. Ten out of 71 RA-rmAbs showed clear reactivity toward RA-FLS in immunofluorescence with no binding to NETs. One stromal-reactive RA-rmAb (RA057/11.89.1) decorated a ∼58-kDa band that mass spectrometry and Western blotting with a commercial Ab identified as calreticulin (CRT). Confocal microscopy demonstrated significant cellular colocalization between anti-CRT RA057/11.89.1 in RA-FLS. RA057/11.89.1 was able to immunoprecipitate rCRT. Deimination of CRT to cit-CRT moderately increased RA057/11.89.1 immunoreactivity. cit-CRT displayed increased blocking capacity compared with unmodified CRT in competitive binding assays. Finally, anti-cit-CRT Abs were preferentially detected in ACPA(+) versus ACPA(-) RA sera. We identified a synovial B cell-derived RA-rmAb locally differentiated within the ELS(+) RA synovium reacting toward CRT, a putative novel autoantigen recently described in RA patients, suggesting that FLS-derived CRT may contribute to fuel the local autoimmune response.
30068353 Prospective assessment of cardiovascular risk parameters in patients with rheumatoid arthr 2018 Aug 1 BACKGROUND: The study presents a prospective follow-up assessment of cardiovascular (CV) risk parameters in patients with rheumatoid arthritis (RA) in comparison with control subjects. METHODS: The study group consisted of 41 RA patients. The following parameters were assessed at subsequent visits [initial (T0), follow-up after 6 years (T6)]: traditional CV risk factors, carotid intima media thickness (cIMT), QTc duration, serum concentration of amino-terminal pro-brain natriuretic peptide (NT-proBNP). A comparative cIMT assessment was performed on 23 healthy controls of comparable age. RESULTS: The mean (SD) cIMT value in RA patients was significantly higher at T6 than at T0 [0.87 (0.21) vs 0.76 (0.15) mm, p < 0.001], the increase in patients with atherosclerotic plaques was noted. Patients with plaques were significantly older, had higher inflammatory parameters. The mean cIMT was significantly higher in RA patients than in controls at both T6, T0 visits. Certain traditional CV risk factors exacerbated during follow up. Unfavorable metabolic parameters and significantly higher cIMT were found in male patients than in female patients at T6. During follow-up, no significant differences in NT-proBNP, QTc were found. There were no significant relationships between cIMT, NT-proBNP, QTc and parameters of disease activity at T6. CONCLUSIONS: During the 6-year course of established RA, significant exacerbation of atherosclerosis was found, revealed by higher cIMT. A careful monitoring should be applied to patients with atherosclerotic plaques and of male gender due to higher burden of CV risk. In long-standing disease, traditional CV risk factors seem to play a key role, beyond the inflammatory activity.
28644744 Add-on iguratimod as a therapeutic strategy to achieve remission in patients with rheumato 2018 Mar OBJECTIVES: In this study, iguratimod (IGU) was added to rheumatoid arthritis (RA) patients inadequately responding to 24-week or longer treatment with biological disease-modifying antirheumatic drug (bDMARDs), its effectiveness was assessed, and factors contributing to remission were evaluated. METHODS: RA patients who fulfilled the following criteria were included: (i) ≥ 24-week of bDMARDs; (ii) 2.6 < disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) < 5.1 or the presence of synovitis with a power Doppler (PD) score ≥2 in at least 1 of the 28 joints on joint ultrasonography. Disease activity and joint ultrasound findings were evaluated at baseline and at 12 and 24 weeks. RESULTS: DAS assessing 28 joints with ESR (DAS28-ESR) decreased significantly from 3.45 ± 0.92 at baseline to 2.85 ± 1.13 at 24 weeks (p < .001). Overall, 38.3% achieved clinical remission (c-remission). The total PD score decreased significantly from 8.7 ± 6.1 at baseline to 5.5 ± 5.0 at 24 weeks (p < .001). A lower baseline DAS28-ESR was related to c-remission after 24 weeks (p =.002). Shorter duration of disease (p =.020) was related to ultrasound remission, in addition to a lower baseline DAS28-ESR (p < .001). CONCLUSIONS: IGU add-on therapy can be a therapeutic strategy to achieve remission in RA patients inadequately responding to ≥24-week treatment with bDMARDs.
29168332 Associative role of HLA-DRB1 SNP genotypes as risk factors for susceptibility and severity 2018 Feb Rheumatoid arthritis (RA) is a complex, multifactorial, systemic autoimmune disease. Reports are suggestive of the role of HLA especially HLA-DRB1 alterations in RA pathogenesis. Existing data involving different geographical populations on the role of alterations in specific locus of HLA-DRB1 in RA susceptibility and severity are equivocal, with no data available from ethnically distinct North-east Indian population, where RA cases are alarmingly increasing. This study aimed to evaluate the association of HLA-DRB1 gene SNPs (rs13192471, rs660895 and rs6457617) with susceptibility and severity of RA in an ethnically distinct North-east Indian population. Whole blood was collected from clinically characterized RA cases (satisfying the American College of Rheumatology 1987 criteria) (n = 123) and community-based age and sex-matched healthy controls (n = 156) with informed consent. The HLA-DRB1 SNP analysis was performed for all the RA and control cases using ARMS-PCR using case and control genomic DNA as template. Statistical analysis was performed by SPSSv13.0 software. The HLA-DRB1 rs660895 showed both wild (AA) and heterozygote (AG) genotype but the heterozygote allele was found to be associated with reduced risk of RA compared to controls [OR = 0.531, p = .024]. The difference in distribution of rs6457617 polymorphism between RA and control cases was comparable [OR = 0.525, p = .079]. Significantly higher distribution of variant rs13192471 genotype was observed in RA cases (69.92%) compared to controls (46.75%) (p < .001) and was associated with increased risk of susceptibility to RA [OR = 2.576, p < .001] compared to controls, as well as progression to severity in RA cases [OR = 2.404, p = .048]. Combinatorially also, the presence of rs13192471 variant genotype was associated with increased risk of RA susceptibility [OR = 8.267, p = .026] and RA severity [OR = 3.647, p = .280]. Alterations in HLA-DRB1 are associated with RA susceptibility. HLA-DRB1 rs13192471 SNP plays a critical role in RA susceptibility and severity in North-east Indian cases and has prognostic significance in RA.
29521424 Carnosic acid inhibits inflammation response and joint destruction on osteoclasts, fibrobl 2018 Aug The discovery of new therapeutic drugs with the ability of preventing inflammation and joint destruction with less adverse effects is urgently needed for rheumatoid arthritis (RA). Carnosic acid (CA), a major phenolic compound isolated from the leaves of Rosemary (Rosmarinus officinalis L.), has been reported to have antioxidative and antimicrobial properties. However, its effects on RA have not been elucidated. Here, we investigated the effects of CA on osteoclasts and fibroblast-like synoviocytes in vitro and on collagen-induced arthritis (CIA) in Wistar rats in vivo. Our in vitro and in vivo studies showed that CA suppressed the expression of pro-inflammatory cytokines including TNFɑ, IL-1β, IL-6, IL-8, IL-17 and MMP-3, and downregulated the production of RANKL. More importantly, we observed that CA inhibited osteoclastogenesis and bone resorption in vitro and exerted therapeutic protection against joint destruction in vivo. Further biochemical analysis demonstrated that CA suppressed RANKL-induced activations of NF-κB and MAPKs (JNK and p38) leading to the downregulation of NFATc1. Taken together, our findings provide the convincing evidence that rosemary derived CA is a promising natural compound for the treatment of RA.
29526961 Choledochoduodenal Fistula during Chemotherapy with Brentuximab Vedotin for Methotrexate-a 2018 Aug 1 We herein report a patient with a history of rheumatoid arthritis treated with methotrexate, which caused methotrexate-associated lymphoproliferative disorder and obstructive jaundice due to an enlarged lymph node. The obstructive jaundice was treated with endoscopic biliary stenting. A histopathological examination revealed features of Hodgkin's lymphoma, and chemotherapy with brentuximab vedotin was administered. Cholangiography and duodenoscopy after four rounds of chemotherapy revealed a choledochoduodenal fistula that developed in response to chemotherapy. It should be noted that, in cases of lymphoma infiltrating the gastrointestinal wall, fistulae can occur because of rapid regression due to regimens comprising monoclonal antibodies, such as rituximab and brentuximab vedotin.
28939234 Persistence of biologic disease-modifying antirheumatic drugs in patients with rheumatoid 2018 Feb OBJECTIVES: This study examined and compared the persistence of adalimumab, etanercept, infliximab, or abatacept as first- and subsequent-line treatment for rheumatoid arthritis in the South Korean clinical practice. METHODS: We conducted a retrospective cohort study with patients receiving adalimumab, etanercept, infliximab, or abatacept between July 1, 2009 and December 31, 2012, using the nationwide Korean National Health Insurance database. Patients who were receiving a newly initiated biologic treatment and those who switched from other biologic treatment were identified and classified into first- and subsequent-use cohorts, respectively. Treatment patterns during the 1-year after treatment initiation were measured as persistence, and discontinuation including restarting, switching, and stopping. The Cox proportional hazard model was used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for discontinuation of biologic treatments. RESULTS: We identified 4114 patients for the first-use cohort and 992 patients for the subsequent-use cohort. Treatment persistence with adalimumab, etanercept, and infliximab was observed in 52.5%, 56.1%, and 52.6% of the patients, respectively, in the first-use cohort, without significant differences in duration of persistence among the treatments according to the Cox proportional hazard model. In the subsequent-use cohort, treatment persistence with adalimumab, etanercept, infliximab, and abatacept was observed in 45.7%, 58.5%, 43.0%, and 60.4% of the patients, respectively. The Cox proportional hazard model found that the patients who were receiving etanercept (HR = 0.68, 95% CI: 0.52-0.88) and abatacept (HR = 0.53; 95% CI: 0.37-0.74) were significantly less likely to discontinue the treatment than those who were receiving infliximab. CONCLUSIONS: Adalimumab, etanercept, and infliximab had similar levels of persistence during the 1-year after treatment initiation, when used as first-line treatment. However, when used as a subsequent-line treatment, etanercept and abatacept had higher persistence than infliximab or adalimumab. Persistence could be a consideration when selecting the subsequent-line biologic treatment for patients with rheumatoid arthritis in South Korea.
29957269 Increased mortality among patients with rheumatoid arthritis and COPD: A population-based 2018 Jul OBJECTIVES: Only few studies have addressed the prognostic impact of chronic obstructive pulmonary disease (COPD) among patients with rheumatoid arthritis (RA), although both diseases are frequent and smoking is a shared risk factor. The objectives of the present study were to investigate the burden of COPD among RA patients and the subsequent mortality. METHODS: We included patients who had a first-time diagnosis of RA in the Danish National Patient Registry between 2004 and 2016. RA patients with COPD were identified and matched with RA patients without COPD for year of birth, gender, and age at RA diagnosis. Mortality risks were assessed using Kaplan-Meier mortality curves. Adjusted hazard rate ratios (aHRRs) for death were estimated using Cox regression models. RESULTS: The study population included 31,333 individuals with RA. 3254 of those (10.4%) had a diagnosis of COPD and were matched to 9706 RA patients without COPD. The mortality risks in RA patients with COPD and RA patients without COPD were 4.5% and 1.5% within 2-6 months (aHRR = 3.0, CI 2.3-3.9), and 59.3% and 39.8% within 0.5-10 years (aHRR = 2.1, CI 1.9-2.1). CONCLUSION: Mortality was significantly increased among RA patients with COPD. The relative mortality risk remained significantly increased throughout the course of follow up.
29961696 Do Poor Prognostic Factors in Rheumatoid Arthritis Affect Treatment Choices and Outcomes? 2018 Oct OBJECTIVE: To characterize patients with rheumatoid arthritis (RA) by number of poor prognostic factors (PPF: functional limitation, extraarticular disease, seropositivity, erosions) and evaluate treatment acceleration, clinical outcomes, and work status over 12 months by number of PPF. METHODS: Using the Corrona RA registry (January 2005-December 2015), biologic-naive patients with diagnosed RA having 12-month (± 3 mos) followup were identified and categorized by PPF (0-1, 2, ≥ 3). Changes in medication, Clinical Disease Activity Index (CDAI), and work status (baseline-12 mos) were evaluated using linear and logistic regression models. RESULTS: There were 3458 patients who met the selection criteria: 1489 (43.1%), 1214 (35.1%), and 755 (21.8%) had 0-1, 2, or ≥ 3 PPF, respectively. At baseline, patients with ≥ 3 PPF were older, and had longer RA duration and higher CDAI versus those with 0-1 PPF. In 0-1, 2, and ≥ 3 PPF groups, respectively, 20.9%, 23.2%, and 26.5% of patients received ≥ 1 biologic (p = 0.011). Biologic/targeted synthetic disease-modifying antirheumatic drug (tsDMARD) use was similar in patients with/without PPF (p = 0.57). After adjusting for baseline CDAI, mean (standard error) change in CDAI was -4.95 (0.24), -4.53 (0.27), and -2.52 (0.34) for 0-1, 2, and ≥ 3 PPF groups, respectively. More patients were working at baseline but not at 12-month followup in 2 (13.9%) and ≥ 3 (12.5%) versus 0-1 (7.3%) PPF group. CONCLUSION: Despite high disease activity and worse clinical outcomes, number of PPF did not significantly predict biologic/tsDMARD use. This may warrant reconsideration of the importance of PPF in treat-to-target approaches.
30242110 High-throughput Serum N-Glycomics: Method Comparison and Application to Study Rheumatoid A 2019 Jan N-Glycosylation is a fundamentally important protein modification with a major impact on glycoprotein characteristics such as serum half-life and receptor interaction. More than half of the proteins in human serum are glycosylated, and the relative abundances of protein glycoforms often reflect alterations in health and disease. Several analytical methods are currently capable of analyzing the total serum N-glycosylation in a high-throughput manner.Here we evaluate and compare the performance of three high-throughput released N-glycome analysis methods. Included were hydrophilic-interaction ultra-high-performance liquid chromatography with fluorescence detection (HILIC-UHPLC-FLD) with 2-aminobenzamide labeling of the glycans, multiplexed capillary gel electrophoresis with laser-induced fluorescence detection (xCGE-LIF) with 8-aminopyrene-1,3,6-trisulfonic acid labeling, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) with linkage-specific sialic acid esterification. All methods assessed the same panel of serum samples, which were obtained at multiple time points during the pregnancies and postpartum periods of healthy women and patients with rheumatoid arthritis (RA). We compared the analytical methods on their technical performance as well as on their ability to describe serum protein N-glycosylation changes throughout pregnancy, with RA, and with RA disease activity.Overall, the methods proved to be similar in their detection and relative quantification of serum protein N-glycosylation. However, the non-MS methods showed superior repeatability over MALDI-TOF-MS and allowed the best structural separation of low-complexity N-glycans. MALDI-TOF-MS achieved the highest throughput and provided compositional information on higher-complexity N-glycans. Consequentially, MALDI-TOF-MS could establish the linkage-specific sialylation differences within pregnancy and RA, whereas HILIC-UHPLC-FLD and xCGE-LIF demonstrated differences in α1,3- and α1,6-branch galactosylation. While the combination of methods proved to be the most beneficial for the analysis of total serum protein N-glycosylation, informed method choices can be made for the glycosylation analysis of single proteins or samples of varying complexity.
30474720 Persistence with biological drugs in patients treated in rheumatology practices in Germany 2019 Mar The goal of this study was to investigate the persistence with biological drugs in patients treated in rheumatology practices in Germany. This study included patients diagnosed with rheumatoid arthritis (RA), psoriatic arthritis (PA), or ankylosing spondylitis (AS) who received a first prescription of biological drugs between 2008 and 2016 (index date) in 21 rheumatology practices in Germany (n = 4925; Disease Analyzer database). The main outcome measure was the rate of persistence within 5 years of the index date. Kaplan-Meier analyses were performed to study treatment persistence as a function of diagnosis, gender and age. A Cox proportional hazards regression model was used to estimate the relationship between non-persistence and diagnosis, gender, age, and comorbidities. After 5 years of follow-up, the rate of persistence was 31.8% in patients with RA, 35.2% in those with AS, and 33.2% in those with PA (log-rank p value = 0.028). Furthermore, 33.8% of men and 31.9% of women were persistent (log-rank p value = 0.035). The rate of persistence was 20.8%, 27.9%, 33.0%, 36.6%, 35.2%, and 32.0% in people aged ≤ 30, 31-40, 41-50, 51-60, 61-70, and > 70 years, respectively (log-rank p value = 0.002). The risk of discontinuation was lower in participants diagnosed with AS than in those diagnosed with RA [hazard ratio (HR) = 0.87; 95% confidence interval (CI) 0.79-0.96]. In addition, patients aged ≤ 30 years were more likely to discontinue their biological therapy than those aged > 70 years (HR = 1.29; 95% CI 1.10-1.52). Persistence with biological drugs was low after 5 years of follow-up in rheumatology practices.
29683364 Inflammatory biomarkers in saliva and serum of patients with rheumatoid arthritis with res 2018 Jun OBJECTIVE: To study prospectively the association of salivary and serum matrix metalloproteinase (MMP)-8, tissue inhibitor of MMPs (TIMP)-1 and interleukin (IL)-6 with periodontal and systemic inflammation in rheumatoid arthritis (RA). We hypothesized that biomarker concentrations reflect inflammation. METHODS: Fifty three early untreated RA (ERA) and 28 chronic RA (CRA) patients, underwent rheumatological and dental examinations at baseline and one year later after starting first conventional or biological disease modifying antirheumatic drug. We included 43 control subjects. Saliva and serum samples were analyzed for MMP-8, TIMP-1 and IL-6. Periodontal health was assessed by bleeding on probing (BOP), pocket depth (PD) and periodontal inflammatory burden index (PIBI); RA disease activity was assessed by disease activity score DAS28. Joint destruction was analyzed by the modified Sharp-van der Heijde (SHS) method. RESULTS: Serum MMP-8 (p < .001; p < .001) and IL-6 (p < .001; p = .002) were significantly higher in CRA vs. other study groups during the study. Salivary MMP-8 (p = .010) and IL-6 (p = .010) were significantly higher in ERA vs. other study groups at baseline. Salivary MMP-8 was associated with periodontal parameters. CONCLUSION: Elevated serum concentrations of MMP-8 and IL-6 in CRA patients reflected chronic RA, while elevated salivary concentrations of MMP-8 levels in ERA patients reflected increased periodontal inflammation. Key messages Concentrations of inflammatory biomarkers in serum and saliva were different between patients with RA and healthy controls. Concentrations of MMP-8 and of IL-6 in serum were elevated in patients with chronic RA reflecting joint inflammation and the burden of established RA. Concentrations of MMP-8 in saliva was elevated already at the early stage of RA and the level of salivary MMP-8 was associated with poor periodontal health both in patients with early and in those with chronic RA.
29532748 A2A Adenosine Receptor Agonists and their Potential Therapeutic Applications. An Update. 2018 BACKGROUND: Adenosine is an endogenous purine nucleoside, which mediates a variety of important biological processes and diseases, such as vasodilation, inflammation, cancer, wound healing, ischemia reperfusion injury, Parkinson disease, infectious diseases, and other CNS disorders. Particularly important are the A2A receptors that have been expressed in the lung, liver, heart, cardiovascular tissues, leukocytes, neutrophils, and endothelial cells. This review provides an update of the latest A2A receptor agonists developed in the period 2005-2017, their selectivity regarding other adenosine receptors and their potential therapeutic applications. METHODS: I have conducted an extensive search from the most common bibliographic databases for critically review the most recent works on the A2A receptor agonists and their therapeutic applications in inflammation, asthma and chronic obstructive pulmonary disease, myocardial perfusion imaging, sepsis, rheumatoid arthritis, and wound healing, among others. RESULTS: In the last decade, a great deal of effort has been devoted to develop adenosine receptor agonists and antagonists for treatment of a number of diseases. Thus, for A2A receptor agonists more than 130 papers and reviews have been found, many of them highlighting the usefulness of these compounds in the field. CONCLUSIONS: Although so far many of the A2A receptor agonists have failed in clinical trials due to their side effects, some of them have been approved for protection against cardiac ischemia-reperfusion injury and anemia. The recently reported crystal structure of the human A2A receptor in complex with the agonist UK-432097 is a fundamental keystone for the development of new and selective A2A ligands with new therapeutic applications.
30224512 Therapeutic Potential of Mesenchymal Cell-Derived miRNA-150-5p-Expressing Exosomes in Rheu 2018 Oct 15 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial tissue inflammation and joint destruction associated with the activation of angiogenesis. Exosomes, which play a role in cell-to-cell communication as carriers of genetic information, transfer microRNAs (miRNAs or miRs) between cells and have been studied as delivery vehicles for therapeutic molecules. The aim of the current study was to investigate the therapeutic effect of mesenchymal stem cell (MSC)-derived miR-150-5p exosomes on joint destruction in RA. The expression and secretion of miR-150-5p, matrix metalloproteinase (MMP) 14, and vascular endothelial growth factor (VEGF) in RA patients and fibroblast-like synoviocytes (FLS) were examined by quantitative RT-PCR, ELISA, and Western blotting. Immunohistochemistry was used to assess angiogenesis. MSCs were transfected with an miR-150-5p expression plasmid, and MSC-derived exosomes were harvested. The effect of MSC-derived miR-150-5p exosomes (Exo-150) on MMP14 and VEGF expression was examined. The effects of Exo-150 on cell migration and invasion in cytokine-stimulated FLS from RA patients were examined by HUVEC tube formation and transwell assays. The effect of Exo-150 in vivo was examined in a collagen-induced arthritis mouse model. Exo-150 decreased migration and invasion in RA FLS and downregulated tube formation in HUVECs by targeting MMP14 and VEGF. Injection of Exo-150 reduced hind paw thickness and the clinical arthritic scores in collagen-induced arthritis mice. Exo-150 reduced joint destruction by inhibiting synoviocyte hyperplasia and angiogenesis. Exosomes facilitate the direct intracellular transfer of miRNAs between cells and represent a potential therapeutic strategy for RA.
30091313 Generation, Characteristics and Clinical Trials of Ex Vivo Generated Tolerogenic Dendritic 2018 Sep Dendritic cells (DCs) play a key role not only in the initiation of primary immune responses, but also in the development and maintenance of immune tolerance. Numerous protocols have been developed to generate tolerogenic DCs (tolDCs) ex vivo, and the therapeutic efficacy of ex vivo-generated tolDCs has been demonstrated in autoimmune disease animal models. Based on successes in small animal models, several clinical trials have been completed or are on-going in patients with autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and Crohn's disease. Here we describe the methods used to generate tolDCs ex vivo, and the common features shared by tolDCs. In addition, we overview five completed clinical trials with reported outcomes and summarize the tolDC-based clinical trials that are currently registered with the U.S. National Institutes of Health. Although the number of tolDC-based clinical trials is much smaller than the hundreds of clinical trials using immunogenic DCs, tolDC-based treatment of autoimmune diseases is becoming a reality, and could serve as an innovative cellular therapy in the future.
30509328 Regulatory role of capsaicin-sensitive peptidergic sensory nerves in the proteoglycan-indu 2018 Dec 3 OBJECTIVE: The regulatory role of capsaicin-sensitive peptidergic sensory nerves has been shown in acute inflammation, but little is known about their involvement in T/B-cell driven autoimmune arthritis. This study integratively characterized the function of these nerve endings in the proteoglycan-induced chronic arthritis (PGIA), a translational model of rheumatoid arthritis. METHODS: Peptidergic afferents were defunctionalized by resiniferatoxin (RTX) pretreatment in BALB/c mice, PGIA was induced by repeated antigen challenges. Hind paw volume, arthritis severity, grasping ability and the mechanonociceptive threshold were monitored during the 17-week experiment. Myeloperoxidase activity, vascular leakage and bone turnover were evaluated by in vivo optical imaging. Bone morphology was assessed using micro-CT, the intertarsal small joints were processed for histopathological analysis. RESULTS: Following desensitization of the capsaicin-sensitive afferents, ankle edema, arthritis severity and mechanical hyperalgesia were markedly diminished. Myeloperoxidase activity was lower in the early, but increased in the late phase, whilst plasma leakage and bone turnover were not altered. Desensitized mice displayed similar bone spurs and erosions, but increased trabecular thickness of the tibia and bony ankylosis of the spine. Intertarsal cartilage thickness was not altered in the model, but desensitization increased this parameter in both the non-arthritic and arthritic groups. CONCLUSION: This is the first integrative in vivo functional and morphological characterization of the PGIA mouse model, wherein peptidergic afferents have an important regulatory function. Their overall effect is proinflammatory by increasing acute inflammation, immune cell activity and pain. Meanwhile, their activation decreases spinal ankylosis, arthritis-induced altered trabecularity, and cartilage thickness in small joints.