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ID PMID Title PublicationDate abstract
30250232 Detection and characterization of bacterial nucleic acids in culture-negative synovial tis 2018 Sep 24 Human intestinal microbes can mediate development of arthritis - Studies indicate that certain bacterial nucleic acids may exist in synovial fluid (SF) and could be involved in arthritis, although the underlying mechanism remains unclear. To characterize potential SF bacterial nucleic acids, we used 16S rRNA gene amplicon sequencing to assess bacterial nucleic acid communities in 15 synovial tissue (ST) and 110 SF samples from 125 patients with rheumatoid arthritis (RA) and 16 ST and 42 SF samples from 58 patients with osteoarthritis (OA). Our results showed an abundant diversity of bacterial nucleic acids in these clinical samples, including presence of Porphyromonas and Bacteroides in all 183 samples. Agrobacterium, Comamonas, Kocuria, Meiothermus, and Rhodoplanes were more abundant in synovial tissues of rheumatoid arthritis (STRA). Atopobium, Phascolarctobacterium, Rhodotorula mucilaginosa, Bacteroides uniformis, Rothia, Megasphaera, Turicibacter, Leptotrichia, Haemophilus parainfluenzae, Bacteroides fragilis, Porphyromonas, and Streptococcus were more abundant in synovial tissues of osteoarthritis (STOA). Veillonella dispar, Haemophilus parainfluenzae, Prevotella copri and Treponema amylovorum were more abundant in synovial fluid of rheumatoid arthritis (SFRA), while Bacteroides caccae was more abundant in the synovial fluid of osteoarthritis (SFOA). Overall, this study confirms existence of bacterial nucleic acids in SF and ST samples of RA and OA lesions and reveals potential correlations with degree of disease.
30229672 The optical coherence tomography angiography findings of rheumatoid arthritis patients tak 2019 Sep PURPOSE: The aim of this study is to measure retinal vessel density and thickness of the macula by optical coherence tomography angiography in patients with rheumatoid arthritis taking hydroxychloroquine. METHODS: The study included 40 patients with rheumatoid arthritis taking hydroxychloroquine and 20 age-, gender-, and axial length-matched control subjects. Patients were divided into two groups according to the duration of hydroxychloroquine use. Twenty four of the patients were taking hydroxychloroquine for more than 5 years (Group 1), and the rest of 16 were taking hydroxychloroquine for less than 5 years (Group 2). A total of 20 age- and gender-matched volunteers with similar axial length were selected as Group 3. All of the patients underwent optical coherence tomography angiography, and 3 mm × 3 mm scanning mode was chosen for analyzing vascular density and morphological characteristics on the choriocapillaris layer. In addition, Humphrey visual field 10-2 was evaluated in each subject. RESULTS: The temporal deep vascular density was measured as 48.13% ± 8.5% in Group 1, 54.42% ± 10.3% in Group 2, and 60.35% ± 13.1% in Group 3. Deep temporal and deep hemi-inferior vascular density was significantly lower in Group 1 in comparison with Group 3 (p = 0.041 and p = 0.046, respectively). Visual field testing was normal in all patients. CONCLUSION: The optical coherence tomography angiography findings showed that the parafoveal deep temporal and deep hemi-inferior vascular plexus density was reduced in patients taking hydroxychloroquine for more than 5 years despite having normal perimetry. This observation, which can be obtained only through optical coherence tomography angiography, may be relevant to the early findings of hydroxychloroquine toxicity.
30497383 Aggregation of experts: an application in the field of "interactomics" (detection of inter 2018 Nov 21 BACKGROUND: Despite the successful mapping of genes involved in the determinism of numerous traits, a large part of the genetic variation remains unexplained. A possible explanation is that the simple models used in many studies might not properly fit the actual underlying situations. Consequently, various methods have attempted to deal with the simultaneous mapping of genomic regions, assuming that these regions might interact, leading to a complex determinism for various traits. Despite some successes, no gold standard methodology has emerged. Actually, combining several interaction mapping methods might be a better strategy, leading to positive results over a larger set of situations. Our work is a step in that direction. RESULTS: We first have demonstrated why aggregating results from several distinct methods might increase the statistical power while controlling the type I error. We have illustrated the approach using 6 existing methods (namely: MDR, Boost, BHIT, KNN-MDR, MegaSNPHunter and AntEpiSeeker) on simulated and real data sets. We have used a very simple aggregation strategy: a majority vote across the best loci combinations identified by the individual methods. In order to assess the performances of our aggregation approach in problems where most individual methods tend to fail, we have simulated difficult situations where no marginal effects of individual genes exist and where genetic heterogeneity is present. we have also demonstrated the use of the strategy on real data, using a WTCCC dataset on rheumatoid arthritis. Since we have been using simplistic assumptions to infer the expected power of the aggregation method, the actual power we estimated from our simulations has turned out to be a bit smaller than theoretically expected. Results nevertheless have shown that grouping the results of several methods is advantageous in terms of power, accuracy and type I error control. Furthermore, as more methods should become available in the future, using a grouping strategy will become more advantageous since adding more methods seems to improve the performances of the aggregated method. CONCLUSIONS: The aggregation of methods as a tool to detect genetic interactions is a potentially useful addition to the arsenal used in complex traits analyses.
29151519 Tofacitinib Therapy for Rheumatoid Arthritis: A Direct Comparison Study between Biologic-n 2018 Mar 1 Objective This study was designed to directly compare the outcomes of tofacitinib therapy for methotrexate-refractory rheumatoid arthritis (RA) between biologic-naïve patients and patients who had experienced an inadequate response to biological agents. Methods We prospectively enrolled and followed 113 patients who had a high or moderate clinical disease activity index (CDAI) (36 biologic-naïve patients and 77 biologic-experienced patients). Patients received 5 mg of tofacitinib twice daily. Effectiveness and adverse events were examined at month 6 of treatment. Results At month 6, 65 patients (57.5%) reached CDAI50, which is defined as achieving ≥50% improvement. The number of previous biological agents was twice as high in CDAI50 non-responders as in responders (2.2 versus 1.1, p<0.001), but there was no significant difference in the type of previous agents or the reason for discontinuation. According to a multivariate logistic regression analysis, the previous use of biological agents [odds ratio (OR) 4.48, p=0.002] and the concurrent use of prednisolone (OR 2.40, p=0.047) were associated with a failure to achieve a CDAI 50 response. Biologic-naïve patients were more likely to achieve CDAI50 than biologic-experienced patients (80.6% versus 46.8%, p=0.001). Mean CDAI values were higher in biologic-experienced patients (11.4 versus 4.8, p=0.001), and remission rates were higher in biologic-naïve patients (41.7% versus 11.7%, p=0.001). Biologic-naïve patients more rapidly achieved remission. Rates of discontinuation resulting from adverse events were similar in both groups. Conclusion Although tofacitinib can provide an effective treatment option for intractable RA patients, its impact on outcomes is lower in patients with previous biologic failure.
29229311 An extra priming dose of hepatitis A vaccine to adult patients with rheumatoid arthritis a 2018 Jan BACKGROUND: Previous studies have indicated that a pre-travel single dose of hepatitis A vaccine is not sufficient as protection against hepatitis A in immunocompromised travelers. We evaluated if an extra dose of hepatitis A vaccine given shortly prior to traveling ensures seroconversion. METHOD: Patients with rheumatoid arthritis (n = 69, median age = 55 years) treated with Tumor Necrosis Factor inhibitor(TNFi) and/or Methotrexate (MTX) were immunized with two doses of hepatitis A vaccine, either as double dose or four weeks apart, followed by a booster dose at six months. Furthermore, 48 healthy individuals, median age = 60 years were immunized with two doses, six months apart. Anti-hepatitis A antibodies were measured at 0, 1, 2, 6, 7 and 12 months. RESULTS: Two months after the initial vaccination, 88% of the RA patients had protective antibodies, compared to 85% of the healthy individuals. There was no significant difference between the two vaccine schedules. At twelve months, 99% of RA patients and 100% of healthy individuals had seroprotective antibodies. CONCLUSION: An extra priming dos of hepatitis A vaccine prior to traveling offered an acceptable protection in individuals treated with TNFi and/or MTX. This constitutes an attractive pre-travel solution to this vulnerable group of patients.
28585869 Postmarketing surveillance evaluating the safety and effectiveness of golimumab in Japanes 2018 Jan OBJECTIVES: The purpose of this study was to evaluate the real-world safety and effectiveness of golimumab (GLM) in Japanese patients with rheumatoid arthritis. METHODS: A postmarketing surveillance of 5154 patients was conducted with a follow-up duration of at least 24 weeks. Patients were divided into four groups based on the initial treatment: 50 mg or 100 mg of GLM with concomitant use of methotrexate (MTX) and 50 mg or 100 mg of GLM monotherapy. Patient characteristics at baseline, safety and effectiveness were assessed for each group. RESULTS: Over 70% of patients received 50 mg of GLM with concomitant MTX, and approximately, 20% received monotherapy. The incidence rate of adverse events was 45.40 per 100 patient-years. The incidence of adverse events including serious adverse events was comparable across all groups. The proportion of patients showing remission or low disease activity increased from 13.69% to 46.21% at the final evaluation, and no differences were observed in the percentage of remission across the four groups. Concomitant MTX use was associated with higher probability of continuing therapy. CONCLUSIONS: GLM showed effectiveness in Japanese rheumatoid arthritis patients with an acceptable safety profile.
30687319 T Cell Response to Infliximab in Exposed Patients: A Longitudinal Analysis. 2018 This study aimed to evaluate the proportion of infliximab (IFX)-exposed patients exhibiting cellular response to the drug in a longitudinal way and to establish whether it is predictive for anti-drug antibodies (ADA) development. Seventeen patients suffering from immuno-mediated disorders were enrolled. Blood was sampled at baseline and before each of the first eight infusions of IFX. The proliferation of PBMCs to 15-mer peptides covering VH/VL frames of IFX was assessed as well as transcription factors and cytokines mRNA expression of memory T cells in IFX-stimulated PBMCs. The number of peptides recognized by T cells after four infusions was higher than those recognized by the same patients before treatment. IFX-stimulated PBMCs from more than 90% of patients were able to express the main regulators and adaptive cytokines of memory T cells. While IFN-γ mRNAs increased after the first infusion and declined during the subsequent ones, IL-10 mRNA was upregulated throughout the treatment. IL-10 was functionally active because its neutralization improved IFN-γ and IL-13 mRNA expression in vitro. The IL-10/IFN-γ ratio was shown to be lower in patients who developed ADAs solely at the early infusions. IL-10 production consistently preceded or paralleled the IFN-γ onset in ADA- patients, while it was not produced or followed IFN-γ onset in ADA+ patients. In conclusion, this study provides evidence that the majority of exposed patients undergo a cellular response to IFX with the upregulation of IL-10. The development of ADA is associated with the early impairment of IL-10 and low levels of the IL-10/IFN-γ ratio.
29668128 Tuberculosis associated with tumor necrosis factor-α antagonists, case description and an 2018 Mar 15 Tumor necrosis factor-α (TNF-α) is an important fundamental cytokine during the immune response against cancer and infections such as tuberculosis. This molecule also plays a key pathogenic role in complex and difficult-to-treat diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis and ulcerative colitis. The treatment of these diseases frequently needs TNF-α antagonists, which has been related to an increased risk of developing tuberculosis, mycoses, and other severe infections.We report the case of a 68-year-old man with Crohn's disease, who developed  disseminated tuberculosis due to anti-TNF-α immunosuppressive therapy. The diagnosis was based on the histopathological findings and molecular biology assays.We discuss the clinical presentation and workup of this case, and we present a comparative analysis of tuberculosis cases associated with anti-TNF-α reported in Colombia during the last 10 years emphasizing on the diagnosis and treatment of latent tuberculosis.
29493381 Comparing the effectiveness of biological disease-modifying antirheumatic drugs using real 2019 Jan OBJECTIVES: The objective of this study is to compare the effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) by analyzing claims data of 13 Japanese national university hospitals. METHODS: We evaluated 4970 cases of rheumatoid arthritis treated with bDMARDs from the Clinical Information Statistical Analysis database, which has collected and integrated 13 Japanese national university hospitals' claims data for 10 years. We surveyed the medications and calculated the retention rates of bDMARDs using the Kaplan-Meier method and differentiated the effectiveness between the two bDMARDs by comparing the retention rates after switching from one drug to another. RESULTS: Of the 4970 cases, 1364 switched bDMARDs at least once. Tocilizumab (TCZ) reported the highest retention rate, whereas abatacept (ABT) revealed a similar rate compared with only naïve cases. The retention rate curves were higher in cases on TCZ that switched from the other bDMARDs than those in the reversed cases. Following TCZ, ABT and etanercept indicated better results than the other bDMARDs. CONCLUSION: We could compare the effectiveness among bDMARDs by differentiating the retention rates from big claims data. TCZ reported higher retention rates in both naïve and switched cases than other bDMARDs.
30316209 Studies on prevalence of infection with Trichomonas tenax identified by molecular techniqu 2018 Trichomonas tenax, cosmopolitan flagellate inhabiting human oral cavity, is the etiological agent of oral trichomonosis associated with gingival and periodontium deterioration. Purpose of this studies was to investigate the prevalence of infection with Trichomonas tenax identified by molecular techniques amplifying the region of ITS1-5.8S rRNA-ITS2 specific for T. tenax. The study included 498 persons: diabetic, renal transplant, rheumatoid arthritis patients and the control group. Prevalence of T. tenax in oral cavity was 10.2% in control group, 14.1% in diabetics, 12.0% in renal transplant patients and 14.0% in rheumatoid arthritis patients. Comparative assessment of results showed symptoms of gingiva and periodontium deteriorations, at varying intensity in patients with various systemic diseases; higher prevalence of the trichomonad infection was revealed in adults in all groups. Simultaneously, renal transplantation, diabetes, rheumatoid arthritis and related therapy do not affect T. tenax incidences and no increased risk of the infection has been observed in the patients; the permanent medication used due to main disease should be taken into consideration as likely inhibitory factor.
30096961 In Vivo and In Vitro Anti-Arthritic Effects of Cardenolide-Rich and Caffeoylquinic Acid-Ri 2018 Aug 9 Periploca forrestii Schltr. (P. forrestii) is a species used in Traditional Chinese Medicine (TCM) known as "Miao medicine", and has a long history of use in the treatment of rheumatism, rheumatoid arthritis (RA), and joint pain. The present study aimed to evaluate the anti-arthritis effects of the cardenolide-rich and caffeoylquinic acid-rich fractions (CDLFs and CQAFs) of P. forrestii in collagen-induced arthritic (CIA) rats, and defined the mechanisms of therapeutic action in MH7A cells treated with TNF-α. Serum rheumatoid factor (RF), TNF-α, IL-6, IL-1β, PGE₂, NO, SOD, and MDA were determined by ELISA or other commercially assay kits. Histopathological changes in ankle joint tissues were examined. The mRNA expressions of IL-1β, IL-6, COX-2, and iNOS in MH7A cells were measured by qRT-PCR assays. In addition, the expressions of iNOS, COX-2, and p65 proteins, and the phosphorylation of IκBα, p38, ERK(1/2), and JNK proteins in MH7A cells were analyzed by Western blot. The results showed that CDLF and CQAF could suppress the paw swelling in CIA rats at different doses (125 mg/kg, 250 mg/kg, and 500 mg/kg). Histopathological examination suggests that the CDLF and CQAF significantly relieved the damage of the structure of the ankle joint in CIA rats. In addition, serum RF, TNF-α, IL-6, IL-1β, PGE₂, NO, and MDA were decreased, along with increased activity of serum SOD. Furthermore, CDLF and CQAF downregulated the expressions of IL-1β, IL-6, COX-2, iNOS, and p65, and inhibited the phosphorylation of IκBα, p38, ERK(1/2), and JNK in MH7A cells treated with TNF-α. These findings demonstrated that both CDLF and CQAF exhibited anti-arthritic activity, which might be associated with their inhibitory effects on the NF-κB and MAPK signaling pathways.
30558548 Anti-SIRT1 autoantibody is elevated in ankylosing spondylitis: a potential disease biomark 2018 Dec 17 BACKGROUND: Little is known about the presence of specific autoantibodies in ankylosing spondylitis (AS), an immune-mediated inflammatory disease. The object of this study was to explore potential autoantibody profiles in AS patients. RESULTS: Levels of anti-SIRT1 autoantibodies were significantly higher in AS (P < 0.001) and psoriatic arthritis (PsA) (P < 0.01) patients but not rheumatoid arthritis (RA) patients compared with healthy controls. Additionally, titers of anti-NAD-dependent protein deacetylase sirtuin-1(SIRT1) antibodies were significantly higher in AS patients than in RA (P < 0.05) and PsA (P < 0.05) patients. Moreover, levels of anti-SIRT1 (P < 0.001) antibodies were significantly higher during the first year in patients with hip joint involvement. The anti-SIRT1 antibody positivity rate was 18.9% in AS patients. CONCLUSIONS: Our findings indicate that anti-SIRT1 autoantibodies may serve as a marker for diagnosing AS and predicting hip joint involvement at an early stage.
29406256 Males With Rheumatoid Arthritis Often Evidence Carotid Atheromas on Panoramic Imaging: A R 2018 Jul PURPOSE: Males with rheumatoid arthritis (RA) are at an exceedingly high risk of adverse intraoperative ischemic events, given the role of systemic inflammation in the atherogenic process. We hypothesized that their panoramic images would demonstrate calcified carotid artery atheromas (CCAPs) significantly more often than those from a general population of similarly aged men. PATIENTS AND METHODS: We implemented a retrospective observational study. The sample was composed of male patients older than 55 years of age who had undergone panoramic imaging studies. The predictor variable was the diagnosis of RA confirmed by a positive rheumatoid factor (RF) titer, and the outcome variable was the prevalence rate of CCAPs. The other major study variable was the level of RF among the patients evidencing CCAPs. The prevalence of CCAPs among the patients with RA was then compared with that of a historical general population of similarly aged men. Descriptive and bivariate statistics were computed, and the P value was set at .05. RESULTS: Of the 100 men (mean age 69.89 ± 8.927 years) with RA, 29 (29%; mean age 72.10 ± 7.68 years) had atheromas (CCAP+). Of these 29 men, 25 (86%; mean age 71.88 ± 7.43 years) had a RF titer of ≥41 IU/mL, twice that of normal. A statistically significant (P < .05) association was found between a diagnosis of RA and the presence of an atheroma on the panoramic image compared with the 3% rate found in the historical cohort. CONCLUSIONS: The results of the present study suggest that CCAP, a risk indicator of future adverse cardiovascular events, is frequently seen on panoramic images of male patients with RA and that these individuals routinely manifest high titer levels of RF, a biologic marker of inflammation. Oral and maxillofacial surgeons planning surgery for male patients with RA must be uniquely vigilant for the presence of these lesions.
29069471 Serious infusion-related reaction after rituximab, abatacept and tocilizumab in rheumatoid 2018 Jan 1 OBJECTIVE: The aim was to evaluate the incidence of serious infusion-related reactions (SIRRs) in RA treated by non-TNF-targeted biologics. METHODS: We analysed data from three independent prospective registers, namely autoimmunity and rituximab, Orencia (abatacept) and RA (ORA) and Registry RoAcTEmra (tocilizumab), promoted by the French Society of Rheumatology and including patients with RA. SIRRs were defined by an occurrence during or within 24 h of an infusion and requiring discontinuation of treatment. Characteristics of patients with SIRRs were extracted from the electronic database. RESULTS: Among the 4145 patients, SIRRs occurred in 100 patients: 56 patients with the rituximab cohort (2.8% or 0.7/100 patient-years), 15 with the abatacept cohort (1.5% or 0.6/100 patient-years) and 29 with tocilizumab (1.9% or 1/100 patient-years). No fatal SIRR occurred. A previous mild infusion reaction to non-TNF-targeted biologics was observed in a quarter of patients with SIRRs. After pooled multivariate analysis, positive anti-CCP was associated with a higher risk of SIRR (odds ratio = 2.5; 95% CI: 1.01, 6.17). Absence of concomitant treatment with a synthetic DMARD tended to be associated with a higher risk of SIRR (odds ratio = 1.67; 95% CI: 1.00, 2.86). CONCLUSION: In daily practice, SIRRs are slightly more frequent than in clinical trials and rarely life threatening. In common practice, serological status (anti-CCP positivity) and absence of concomitant treatment with a synthetic DMARD increase the risk of SIRR.
29081378 TNFα blockade mediates bone protection in antigen-induced arthritis by reducing osteoclas 2018 Feb Bone protective effects of TNFα inhibition in rheumatoid arthritis are thought to be mediated by inhibiting synovial osteoclast differentiation and activity. However, it has not been addressed, if TNFα inhibitors alter the pool of peripheral osteoclast precursor cells (OPCs). Here, we blocked TNFα function in C57BL/6 mice with antigen induced arthritis (AIA) using the soluble TNFα receptor etanercept. Synovial bone lesions and osteoclasts were markedly reduced upon Etanercept in the early chronic phase of AIA. Unexpectedly this was not associated with a reduced recruitment of circulating OPCs to the arthritic joint nor to reduced synovial inflammation. In contrast we found that OPC numbers in bone marrow and blood were significantly reduced. Overall our study suggests that arrest of osteoclast mediated bone lesions upon inhibition of TNFα is, at least initially, based on reduced OPC availability in the periphery, and not on OPC recruitment or local anti-inflammatory effects in the arthritic joint.
30291236 Bone protection by inhibition of microRNA-182. 2018 Oct 5 Targeting microRNAs recently shows significant therapeutic promise; however, such progress is underdeveloped in treatment of skeletal diseases with osteolysis, such as osteoporosis and rheumatoid arthritis (RA). Here, we identified miR-182 as a key osteoclastogenic regulator in bone homeostasis and diseases. Myeloid-specific deletion of miR-182 protects mice against excessive osteoclastogenesis and bone resorption in disease models of ovariectomy-induced osteoporosis and inflammatory arthritis. Pharmacological treatment of these diseases with miR-182 inhibitors completely suppresses pathologic bone erosion. Mechanistically, we identify protein kinase double-stranded RNA-dependent (PKR) as a new and essential miR-182 target that is a novel inhibitor of osteoclastogenesis via regulation of the endogenous interferon (IFN)-β-mediated autocrine feedback loop. The expression levels of miR-182, PKR, and IFN-β are altered in RA and are significantly correlated with the osteoclastogenic capacity of RA monocytes. Our findings reveal a previously unrecognized regulatory network mediated by miR-182-PKR-IFN-β axis in osteoclastogenesis, and highlight the therapeutic implications of miR-182 inhibition in osteoprotection.
30553912 Betulinic acid inhibits the migration and invasion of fibroblast-like synoviocytes from pa 2019 Feb The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) contributes to cartilage and bone destruction in rheumatoid arthritis (RA). Betulinic acid has been demonstrated to have a positive therapeutic effect on tumor, inflammation and immune disorder, however, the effects of betulinic acid on RA FLSs have not been verified. Therefore, in the present study, we observed the effect of betulinic acid on the migration and invasion of RA FLSs and explored its underlying signal mechanisms. Our results showed that betulinic acid treatment suppressed the migration, invasion and reorganization of the actin cytoskeleton of RA FLSs. In addition, we found that the mRNA expression of IL-1β, IL-6, IL-8 and IL-17A were markedly down-regulated by treatment with betulinic acid in TNF-α-induced RA FLSs. To gain insight into the molecular mechanisms, we evaluated the effect of betulinic acid on NF-κB activation in RA FLSs. The results indicated that betulinic acid treatment reduced the TNF-α-induced activation of NF-κB signal pathway and the NF-κB nuclear accumulation. We also observed that treatment with betulinic acid attenuated synovial inflammation and joint destruction in mice with CIA. Taken together, these results suggest that betulinic acid inhibits the migration and invasion of RA FLSs by blocking NF-κB signal pathway activation.
29198077 Fibroblast-like synoviocyte migration is enhanced by IL-17-mediated overexpression of L-ty 2018 Feb In rheumatoid arthritis (RA), activated synovial fibroblasts have the ability to invade joint cartilage, actively contributing to joint destruction in RA. The mechanisms underlying this cell migration and invasion remain unclear. Our previous results and data from the GEO profile indicate that the L-type amino acid transporter gene, LAT1, is overexpressed in the synovium of RA. To identify its potential role in RA, fibroblast-like synoviocytes (FLS) from patients with RA were used to determine the effects of suppressing the LAT1 genes using RNA interference and the LAT inhibitor, BCH. We found that BCH exposure reduced the phosphorylation of mTOR and its downstream target 4EBP1, radiolabeled leucine uptake, and migration of RA FLS. LAT1 silencing by siRNA presented effects similar to BCH inhibition. Treatment of cells with IL-17 stimulated the expression of LAT1. In contrast, applying an inhibitor of mTOR pathway, temsirolimus, or silencing eIF4E neutralized the stimulation of IL-17 on LAT1. BCH and siLAT1 also resulted in lower IL-17-stimulated leucine uptake and cell migration. These results suggest that the migration of RA FLS is aggravated by IL-17-mediated overexpression of LAT1 via mTOR/4E-BP1 pathway. In conclusion, further investigation is warranted into LAT1 as a potential target for drug therapies aimed at attenuating migration of transformed-appearing fibroblasts and subsequently preventing further erosion of bone and cartilage.
29901636 Male patients with rheumatoid arthritis have an increased risk of osteoporosis: Frequency 2018 Jun Most previous research investigating osteoporosis in rheumatoid arthritis (RA) has focused on female patients and there is a lack of data regarding clinical characteristics of osteoporosis in male patients with RA.The aim of this study was to compare the frequency of osteoporosis between male patients with RA and healthy patients, and to identify the risk factors for osteoporosis and low bone mineral density (BMD) in male patients with RA.We conducted a retrospective, cross-sectional study including 76 South Korean male patients with RA aged over 50 years and 76 age-matched male healthy individuals. BMD was measured at the lumbar spine (L1-4) and left hip (femoral neck and total hip) using dual energy X-ray absorptiometry. Osteoporosis was defined as a T-score of ≤ -2.5 according to the World Health Organization (WHO) classification.The frequency of osteoporosis at either the spine or the hip among male patients with RA was significantly higher than that among controls (22.4% vs 10.5%, P = .049) and RA patients had a significantly lower total hip BMD than healthy individuals (0.92 ± 0.14 vs 0.96 ± 0.1 g/cm, P = .027). For male RA patients, the mean 28-joint Disease Activity Scores using erythrocyte sedimentation rate (DAS28-ESR) and body mass index (BMI) were 3.28 and 22 kg/m, respectively. In multivariable logistic regression models, BMI ≤ 22 kg/m (odds ratio = 3.43, P = .043) and DAS28-ESR > 3.2 (odds ratio = 3.85, P = .032) were independent risk factors for osteoporosis at either site in male patients with RA.Our data demonstrate that male patients with RA had a 2.1 times higher risk for osteoporosis compared with healthy individuals. This suggests that appropriate management of osteoporosis in patients with RA is crucial not only for postmenopausal women but also for men aged over 50 years, especially those with low BMI and higher disease activity.
29511118 Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signal 2018 Mar 6 Rheumatoid arthritis (RA) is a chronic inflammatory disorder that causes joint pain, swelling, and loss of function. Development of effective new drugs has proven challenging in part because of the complexities and interconnected nature of intracellular signaling networks that complicate the effects of pharmacological interventions. We characterized the kinase signaling pathways that are activated in RA and evaluated the multivariate effects of targeted inhibitors. Synovial fluids from RA patients activated the kinase signaling pathways JAK, JNK, p38, and MEK in synovial fibroblasts (SFs), a stromal cell type that promotes RA progression. Kinase inhibitors enhanced signaling of "off-target" pathways in a manner dependent on stimulatory context. Inhibitors of p38, which have been widely explored in clinical trials for RA, resulted in undesirable increases in nuclear factor κB (NF-κB), JNK, and MEK signaling in SFs in inflammatory, but not mitogenic, contexts. This was mediated by the transcription factor CREB, which functions in part within a negative feedback loop in MAPK signaling. CREB activation was induced predominately by p38 in response to inflammatory stimuli, but by MEK in response to mitogenic stimuli; hence, the effects of drugs targeting p38 or MEK were markedly different in SFs cultured under mitogenic or inflammatory conditions. Together, these findings illustrate how stimulatory context can alter dominance in pathway cross-talk even for a fixed network topology, thereby providing a rationale for why p38 inhibitors deliver limited benefits in RA and demonstrating the need for careful consideration of p38-targeted drugs in inflammation-related disorders.