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ID PMID Title PublicationDate abstract
31426355 Myeloid Krüppel-Like Factor 2 Critically Regulates K/BxN Serum-Induced Arthritis. 2019 Aug 16 Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease, and Krüppel-like factor 2 (KLF2) regulates immune cell activation and function. Herein, we show that in our experiments 50% global deficiency of KLF2 significantly elevated arthritic inflammation and pathogenesis, osteoclastic differentiation, matrix metalloproteinases (MMPs), and inflammatory cytokines in K/BxN serum-induced mice. The severities of RA pathogenesis, as well as the causative and resultant cellular and molecular factors, were further confirmed in monocyte-specific KLF2 deficient mice. In addition, induction of RA resulted in a decreased level of KLF2 in monocytes isolated from both mice and humans along with higher migration of activated monocytes to the RA sites in humans. Mechanistically, overexpression of KLF2 decreased the level of MMP9; conversely, knockdown of KLF2 increased MMP9 in monocytes along with enrichment of active histone marks and histone acetyltransferases on the MMP9 promoter region. These findings define the critical regulatory role of myeloid KLF2 in RA pathogenesis.
31481566 Risk factors for Staphylococcus aureus bacteremia in patients with rheumatoid arthritis an 2019 Sep 3 INTRODUCTION: Staphylococcus aureus bacteremia (SAB) is an invasive infection with high mortality and morbidity. Rheumatoid arthritis (RA) is associated with increased risk of infections due to the disease per se and the use of antirheumatic treatments. Few minor studies have previously investigated risk of SAB in patients with RA and indicated increased risk compared with the general population. This nationwide observational study aims to investigate incidence of and risk factors for SAB in adult patients with RA compared with the general population. The effect of disease characteristics (eg, joint erosions, disease duration and activity), different antirheumatic treatments and smoking on SAB risk will be evaluated. METHODS AND ANALYSIS: All adults (>18 years of age) alive and living in Denmark in 1996-2017 will be identified in The Danish Civil Registration System. Incident patients with RA are identified in the Danish National Patient Registry (DNPR) and the nationwide rheumatology registry, DANBIO, in which information on, for example, antirheumatic treatments, disease characteristics and smoking is collected prospectively in routine care. Information on comorbidities, invasive procedures and prescribed drugs are identified in the DNPR and in The Register of Medicinal Product Statistics. Socioeconomic status is evaluated in national registers on income and education. Incident cases of first-time SAB are identified in The Danish National SAB Database. All registers are linked on an individual level by unique civil registration numbers. Incidence rates and incidence rate ratios will be analysed using Poisson regression models and the impact of possible risk factors will be evaluated. ETHICS AND DISSEMINATION: All data will be handled in accordance with the General Data Protection Regulation (EU) 2016/679. No ethical approval is necessary in Denmark when handling registry data only. The results will be presented in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology initiative in international peer-reviewed journals and at medical conferences. TRIAL REGISTRATION NUMBER: NCT03908086.
30637590 Long-Term Efficacy of Tumor Necrosis Factor Inhibitors for the Treatment of Methotrexate-N 2019 Mar INTRODUCTION: Synthesis of evidence on the long-term use of first-line biologic therapy in patients with early rheumatoid arthritis (RA) is required. We compared the efficacy of up to 5 years' treatment with first-line tumor necrosis factor inhibitors (TNFis) versus other treatment strategies in this population. METHODS: Previous systematic reviews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) involving treatment of methotrexate-naïve RA patients with first-line TNFis. Literature was synthesized qualitatively, and a meta-analysis conducted to evaluate American College of Rheumatology (ACR) responses, clinical remission defined by any standard measure, and Health Assessment Questionnaire Disability Index (HAQ) at Years 2 and/or 5. RESULTS: Ten RCTs involving 4306 patients [first-line TNFi, n = 2234; other treatment strategies (control), n = 2072] were included in the meta-analysis. Three studies were double-blind for the first 2 years, while seven were partly/completely open label during this period. Five studies reported data at Year 5; all were open label at this time point. At Year 2, ACR50 response, ACR70 response and remission rates were significantly improved with first-line TNFi versus control in double-blind RCTs [log-odds ratio (OR) 0.32 [95% confidence interval (CI) 0.02, 0.62; p = 0.035], log-OR 0.48 (95% CI 0.20, 0.77; p = 0.001), and log-OR 0.44 (95% CI 0.13, 0.74; p = 0.005), respectively], but not in open-label studies. No significant between-group differences were observed in mean HAQ at Year 2 in double-blind or open-label RCTs or in ACR response or remission outcomes at Year 5. CONCLUSION: In double-blind studies, 2-year efficacy outcomes were significantly improved with first-line TNFi versus other treatment strategies in patients with MTX-naïve RA. No significant differences in these outcomes were observed when data from open-label RCTs were considered on their own. Further data on the efficacy of TNFi therapy over ≥ 2 years in patients with methotrexate-naïve RA are required. Plain language summary available for this article.
31404657 Racial and ethnic disparities in utilization of total knee arthroplasty among older women. 2019 Dec OBJECTIVE: To evaluate racial and ethnic disparities in utilization of total knee arthroplasty (TKA) in relation to demographic, health, and socioeconomic status variables. DESIGN: Prospective study of 102,767 Women's Health Initiative postmenopausal women initially aged 50-79, examining utilization rates of primary TKA between non-Hispanic Black/African American, non-Hispanic White, and Hispanic/Latina women (hereafter referred to as Black, White, and Hispanic). A total of 8,942 Black, 3,405 Hispanic, and 90,420 White women with linked Medicare claims data were followed until time of TKA, death, or transition from fee-for-service coverage. Absolute disparities were determined using utilization rates by racial/ethnic group and relative disparities quantified using multivariable hazards models in adjusting for age, arthritis, joint pain, mobility disability, body mass index, number of comorbidities, income, education, neighborhood socioeconomic status (SES), and geographic region. RESULTS: TKA utilization was higher among White women (10.7/1,000 person-years) compared to Black (8.5/1,000 person-years) and Hispanic women (7.6/1,000 person-years). Among women with health indicators for TKA including diagnosis of arthritis, moderate to severe joint pain, and mobility disability, Black and Hispanic women were significantly less likely to undergo TKA after adjusting for age [Black: HR (95% confidence interval) = 0.70 (0.63-0.79); Hispanic: HR = 0.58 (0.44-0.77)]. Adjustment for SES modestly attenuated the measured disparity, but significant differences remained [Black: HR = 0.75 (0.67-0.89); Hispanic: HR = 0.65 (0.47-0.89)]. CONCLUSIONS: Compared to White women, Black and Hispanic women were significantly less likely to undergo TKA after considering need and appropriateness for TKA and SES. Further investigation into personal-level and provider-level factors that may explain these disparities is warranted.
30399360 Dose Optimization of Chloroquine by Pharmacokinetic Modeling During Pregnancy for the Trea 2019 Jan The insidious nature of Zika virus (ZIKV) infections can have a devastating consequence for fetal development. Recent reports have highlighted that chloroquine (CQ) is capable of inhibiting ZIKV endocytosis in brain cells. We applied pharmacokinetic modeling to develop a predictive model for CQ exposure to identify an optimal maternal/fetal dosing regimen to prevent ZIKV endocytosis in brain cells. Model validation used 13 nonpregnancy and 3 pregnancy clinical studies, and a therapeutic CQ plasma window of 0.3-2 μM was derived. Dosing regimens used in rheumatoid arthritis, systemic lupus erythematosus, and malaria were assessed for their ability to target this window. Dosing regimen identified that weekly doses used in malaria were not sufficient to reach the lower therapeutic window; however, daily doses of 150 mg achieved this therapeutic window. The impact of gestational age was further assessed and culminated in a final proposed regimen of 600 mg on day 1, 300 mg on day 2 and 3, and 150 mg thereafter until the end of trimester 2, which resulted in maintaining 65% and 94% of subjects with a trough plasma concentration above the lower therapeutic window on day 6 and at term, respectively.
30588773 Ten-year observation of patients with primary Sjögren's syndrome: Initial presenting char 2019 May AIM/INTRODUCTION: Primary Sjögren's syndrome (pSS) is a prototypical systemic autoimmune disease that manifests with various signs and symptoms. Although some studies have examined these manifestations over the long-term course of the disease, the association between initial clinical and immunological factors and subsequent long-term manifestations has not been fully elucidated. The aim of this study is to identify initial clinical and immunological factors associated with subsequent manifestations in patients with pSS. METHOD: A retrospective review was performed in pSS patients who were followed up over a 10-year period in our department. Clinical and immunological data, including serum immunoglobulin (Ig) and autoantibody levels, were collected and statistically analyzed. RESULT: We analyzed 91 patients who were followed up in our department. The proportion of patients with extraglandular involvement decreased from 90% to 73%, while eight patients developed extraglandular organ involvement. Extraglandular involvement at 10 years more frequently occurred in patients with hyper-IgG than those without hyper-IgG at initial testing (P < 0.01). Extraglandular organ involvement at 10 years more frequently occurred in rheumatoid factor (RF)-positive patients at the time of SS diagnosis (P < 0.05). Malignancy occurred in 9% of patients. Age, lower CH50 and thrombocytopenia were significantly associated with malignancy. Extraglandular organ involvement was associated with the presence of hyper-IgG and RF positivity (P < 0.01 and P < 0.05). CONCLUSION: Our study identified important initial clinical and immunological factors associated with subsequent manifestations in patients with pSS over a long follow-up period. pSS patients with RF and hyper-IgG at diagnosis may have a higher risk of subsequent extraglandular involvement.
30574867 Comparative efficacy and safety of biosimilar rituximab and originator rituximab in combin 2019 Apr OBJECTIVE: We aimed to assess the relative efficacy and safety of biosimilar rituximab and originator rituximab plus methotrexate (MTX) compared to those of placebo plus MTX in patients with active rheumatoid arthritis (RA). MATERIALS AND METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) that examined the efficacy and safety of biosimilar+MTX and rituximab+MTX versus placebo+MTX (MTX group) in patients with active RA despite treatment with MTX and/or tumor necrosis factor (TNF) blockers. RESULTS: Six RCTs involving 1,747 patients met inclusion criteria. The American College of Rheumatology 20% (ACR20) response rate was significantly higher in the biosimilar+MTX (odds ratio (OR) 4.30, 95% credible interval (CrI) 1.75 - 10.91) and rituximab+MTX (OR 4.07, 95% CrI 2.51 - 7.18) groups than in the MTX group, with no difference in the ACR20 response rate between the biosimilar+MTX and rituximab+MTX groups. The biosimilar+MTX group had the highest probability of being the best treatment based on the ACR20 response rate (surface under the cumulative ranking curve (SUCRA) = 0.7832), followed by rituximab+MTX (SUCRA = 0.7134) and MTX groups (SUCRA = 0.0034). ACR50 and ACR70 response rates showed a distribution pattern similar to ACR20 response rate. Safety based on number of adverse events did not differ significantly among the three interventions after 24 weeks. CONCLUSION: Biosimilar and originator rituximab, combined with MTX, represent an effective intervention for active RA despite treatment with MTX or TNF blockers. No significant difference was found between biosimilar and originator rituximab regarding efficacy and safety.
30776642 Anti-hyperalgesia effect of nanchelating based nano particle, RAc1, can be mediated via li 2019 Apr OBJECTIVE: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder accompanied with hyperalgesia, edema and pain. At least 30% of the patients failed to respond to the available treatments and medications, which yet have a lot of serious adverse effects on patients. So, using novel technologies to produce more efficient medications is needed. According to the role of iron manipulation in inflammatory process, we have synthetized RAc1 nano particle, which contains zinc and has iron chelating property. In the present study, we evaluated RAc1 nano particle effects on hyperalgesia and liver hepcidin and serum IL-1β and TNF-α expression levels during acute and chronic phases of adjuvant-induced inflammation in male rats and compared its effects with Deferoxamine. METHODS AND MATERIALS: Complete Freund's adjuvant (CFA)-induced arthritis was caused by single subcutaneous injection of CFA into the rat's hind paw on day zero. RAc1 with 100, 200 and 400 ng/kg doses and deferoxamin with doses of 200 mg/kg after diluting in vehicles were administered daily (i.p.) during the 21 days of the study after CFA injection. Hyperalgesia, Edema, liver hepcidin and serum IL-1β and TNF-α expression levels were assessed on days 0, 7, 14 and 21 of the study. RESULTS: The results of this study indicated the role of RAc1 nano particle administration in reducing paw edema, thermal hyperalgesia, and liver hepcidin and serum IL-1β and TNF-α expression even in comparison with Deferoxamine during different phases of inflammation caused by CFA. CONCLUSION: It seems that RAc1 nano particle exerts its immune modulatory effects by decreasing liver hepcidin expression and serum IL-1β and TNF-α levels.
31559768 Study of APOE Gene and D2S439 Marker in Patients of Rheumatoid Arthritis and their Correla 2019 Jul AIM: To delineate the genetic differences in polymorphism of the APOE and D2S439 marker genes for patients with and without rheumatoid arthritis and to study the distribution frequency of the prevalent alleles of these genes in clinically defined sub groups of patients/controls of Indian origin, specifically and their correlation with severity of disease using DAS score. MATERIAL AND METHODS: This is a case control study where peripheral blood samples 160 cases and 150 controls were collected. RESULTS: We evaluated the association of the tetra nucleotide repeat microsatellite marker D2S439 lying at 231.27cM position on the q arm of chromosome-2. The alleles of this marker ranged in size from 163bp-203bp in PCR product length corresponding to 5-15 (CTAT)n tetra repeats. The allele frequencies for this marker in the North Indian population are different from the CEPH populations. The longer alleles, >199bp (=14 or 15 CTAT repeats) were not observed. The genotypes after bimodal distribution differ significantly among cases and controls (p=0.003). Statistically significant difference was seen between cases and controls for ≥(CTAT) 10 longer allele which was more prevalent in the adult RA cases than in controls. Severity of RA was defined by a DAS28 score of >6 on a scale of ten. No significant association was seen with the APOE polymorphism and disease severity. CONCLUSION: The long allele of D2S439 marker representing an expansion of the CTAT, tetranucleotide repeat doubles an individual's the risk for developing RA.
30922373 An open-label extension study to demonstrate long-term safety and efficacy of ABP 501 in p 2019 Mar 29 BACKGROUND: ABP 501 was evaluated in a phase 3 single-arm, open-label extension (OLE) study to collect additional safety and efficacy data in patients with rheumatoid arthritis (RA). METHODS: Subjects completing the final visit in the parent phase 3 randomized, double-blind, controlled equivalence study comparing the efficacy and safety of the biosimilar ABP 501 with adalimumab reference product (RP) were enrolled in this open-label extension (OLE) study. All subjects received 40 mg ABP 501 every other week for 68 weeks. Key safety endpoints included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and anti-drug antibody (ADA) incidences. Efficacy endpoints included ACR20 (at least 20% improvement in American College of Rheumatology core set measurements from baseline) and Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP) change from baseline. RESULTS: Among 466/467 patients treated with ABP 501, 229 transitioned from the ABP 501 arm of the parent study (ABP 501/ABP 501) and 237 from the adalimumab RP arm (RP/ABP 501); 412/467 (88.2%) patients completed the study. The overall TEAE incidence was 63.7% (297/466); grade ≥ 3 TEAE incidence was 9.0% (42/466). The incidence of TEAEs leading to discontinuation of investigational product was 3.6% (17/466). The SAE incidence was 9.9% (46/466). Overall, 18.2% (85/466) of subjects developed binding ADAs and 6.9% (32/466) developed neutralizing ADAs in the OLE study. The ACR20 response rate was 73.3% (340/464 subjects) at OLE baseline, and 78.8% (327/415 subjects) at week 70 of the OLE study. The overall mean DAS28-CRP change from the parent study baseline was - 2.25 at the OLE study baseline (n = 440), - 2.36 at week 4 (n = 463), - 2.41 at week 24 (n = 450), - 2.55 at week 48 (n = 433), and - 2.60 at week 70 (n = 412). Efficacy was maintained throughout the study. CONCLUSIONS: Efficacy previously demonstrated in the parent study was maintained in this OLE study with no new safety findings. Long-term safety, immunogenicity, and efficacy were similar in the ABP 501/ABP 501 and RP/ABP 501 groups. The single switch from RP to ABP 501 did not impact immunogenicity. TRIAL REGISTRATION: ClinicalTrial.gov, NCT02114931.
31672661 Chemical variability of Rhododendron tomentosum (Ledum palustre) essential oils and their 2019 Nov Rhododendron tomentosum (Ledum palustre) is an aromatic plant traditionally used for alleviating rheumatic complaints which makes it a potential candidate for a natural drug in rheumatoid arthritis (RA) treatment. However, the effects of plants' volatiles on apoptosis of synovial fibroblasts and infiltrating leucocytes of RA synovia, have not been reported. Volatile fraction of R. tomentosum is chemically variable and chemotypes of the plants need to be defined if the oil is to be used for therapeutic purposes. In the presented work, cluster analysis of literature data enabled to define 10 chemotypes of the plant. The volatile fractions of known composition were then tested for bioactivity using a RA-specific in vitro models. Essential oils of two wild types (γ-terpineol and palustrol/ledol type) and one in vitro chemotype (ledene oxide type) were obtained by hydrodistillation and their bioactivity was tested in two in vitro models: I - peripheral blood lymphocytes of healthy volunteers and II - synoviocytes and immune cells isolated from synovia of RA patients. The influence of oils on blood lymphocytes' proliferation and apoptosis rates of synovia-derived cells was determined by flow cytometry. Dose-dependent inhibitory effect of the serial dilutions of R. tomentosum oils on proliferation rates of blood lymphocytes was found. At 1:400 dilutions, all the tested oils increased the number of necrotic cells in synovial fibroblasts from RA synovia. Additionally, increased proportions of late apoptotic cells were observed in leucocyte populations subjected to oils at 1:400 dilution.
29794874 Tofacitinib 5 mg Twice Daily in Patients with Rheumatoid Arthritis and Inadequate Response 2019 Apr BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We performed a comprehensive review of phase 3 studies of tofacitinib 5 mg twice daily (BID) (approved dose in many countries) in patients with moderate to severe RA and inadequate response to prior disease-modifying antirheumatic drugs. METHODS: A search of PubMed and ClinicalTrials.gov identified 5 studies: ORAL Solo (NCT00814307), ORAL Sync (NCT00856544), ORAL Standard (included adalimumab 40 mg once every 2 weeks; NCT00853385), ORAL Scan (NCT00847613), and ORAL Step (NCT00960440). Efficacy and safety data for tofacitinib 5 mg BID, placebo, and adalimumab were analyzed. RESULTS: Across the 5 studies, 1216 patients received tofacitinib 5 mg BID, 681 received placebo, and 204 received adalimumab. At month 3, tofacitinib demonstrated significantly higher 20%, 50%, and 70% improvement in American College of Rheumatology response criteria (ACR20, ACR50, and ACR70, respectively) response rates, greater improvement in Health Assessment Questionnaire-Disability Index, and a higher proportion of Disease Activity Score-defined remission than placebo. Frequencies of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar for tofacitinib and placebo at month 3; serious infection events were more frequent for tofacitinib. In ORAL Standard, although not powered for formal comparisons, tofacitinib and adalimumab had numerically similar efficacy and AEs; serious AEs and serious infection events were more frequent with tofacitinib. CONCLUSIONS: Tofacitinib 5 mg BID reduced RA signs and symptoms and improved physical function versus placebo in patients with inadequate response to prior disease-modifying antirheumatic drugs. Tofacitinib 5 mg BID had a consistent, manageable safety profile across studies, with no new safety signals identified.
30443897 Patient Perspectives on the Value of Patient Preference Information in Regulatory Decision 2019 Jun BACKGROUND: There is increasing interest in involving patient preferences for benefits and risks in regulatory decision making. Therefore, it is essential to identify patient perspectives regarding the value of patient preference information (PPI). OBJECTIVES: The aim of this study was to explore how patients with rheumatoid arthritis (RA) value the use of PPI in regulatory decision making regarding medical products. METHODS: Regulators and patients with RA were interviewed to gather initial insights into opinions on the use of PPI in regulatory decisions regarding medical products. The interviews were used to draft and validate the interview guide for focus groups with patients with RA. Participants were purposively sampled in collaboration with the Swedish Rheumatism Association in Stockholm and Uppsala. Each focus group consisted of three to six patients (18 in total). All interviews were audio-recorded, transcribed verbatim, and analysed using content analysis. RESULTS: According to the participants, PPI could lead to regulators considering patients' needs, lifestyles and well-being when making decisions. PPI was important in all stages of the medical product lifecycle. Participants reported that, when participating in a preference study, it is important to be well-informed about the use of the study and the development, components, administration, and risks related to the medical products. CONCLUSIONS: Patients thought PPI could be valuable to consider in regulatory decisions. It is essential for patients to be well-informed when asked for their preferences. Research on information materials to inform patients in preference studies is needed to increase the value of PPI in regulatory decision making.
30320628 An Immune Suppression-associated EBV-positive Anaplastic Large Cell Lymphoma With a BRAF V 2019 Jan Iatrogenic lymphoproliferative disorders have been described in patients receiving immunosuppressive/immunomodulatory agents outside the transplantation setting. Novel biological agents such as TNF-α blockers and JAK-inhibitors have also proven to be effective in many disorders including rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis and Crohn disease), psoriasis, and others. A significant dilemma exists in those lymphoproliferative disorders associated with immunosuppressants and rheumatologic conditions, that relies on whether the association of the process is with the medication or the underlying autoimmune condition. In the current case report, we describe an extraordinary case of Epstein-Barr virus-positive anaplastic large cell lymphoma, in association with rheumatoid arthritis and the use of JAK-inhibitors. Comprehensive molecular testing (fluorescence in situ hybridization, OncoScan microarray, pyrosequencing) was done comparing sequential biopsies in this patient from skin and lung, which revealed a driving mutation in the BRAF V600E gene, a crucial finding, given the potential use of targeted therapy in this pathway.
31187337 Characterization of senescence biomarkers in rheumatoid arthritis: relevance to disease pr 2019 Oct Rheumatoid arthritis (RA) has been associated with early senescent features. However, the effects of disease progression on senescence markers are largely unknown. Here, we evaluated key senescence markers in RA, including telomere length and T cell differentiation stages as well as cytomegalovirus (CMV) serology, previously associated with premature aging. In a cross-sectional study, 44 patients with active (Ac-RA), 26 patients with controlled (Co-RA), and 30 healthy controls were recruited. Peripheral blood was collected and differentiation stages of T cells analyzed by multi-color flow cytometry. Enzyme-linked immunosorbent assays were used to evaluate the CMV serology. The telomere length was measured by multiplex quantitative PCR. Patients with Ac-RA presented lower percentage of intermediate-differentiated T cells (CD4+CD27-CD28+ and CD8+CD27-CD28+; p < 0.001). All patients had a reduced proportion of cytotoxic T cells, and higher CD4/CD8 ratio compared with controls (p < 0.001). A lower proportion of CMV IgG+ subjects was found in the Co-RA group, (P < 0.001), although no differences in the CMV IgG titers were observed between groups. The groups had similar leukocyte telomere length. In addition, age was negatively correlated with CD8+CD27+CD28+ T (early-differentiated) cells (P < 0.05). Positive correlations between CMV IgG titers and age (P < 0.05) and CD4+CD27-CD28- T (late-differentiated) cells (P < 0.01) were observed. Furthermore, disease duration was correlated with CD4+CD27+CD28+ T cells (r = - 0.318, p < 0.05) and CD4+CD27-CD28- T cells (r = 0.308, p < 0.05). Our findings indicate that CMV and age may have a similar impact on T cells in both RA patients and controls. KEY POINTS: • Patients and controls were homogenous regarding CMV IgG titers and TL. • A lower proportion of CMV IgG+ subjects was found in the Co-RA group. • Anti-CMV levels were positively correlated with age and percentage of CD4+CD27-CD28- (late-differentiated) T cells.
31411001 LncRNA MEG3 inhibits rheumatoid arthritis through miR-141 and inactivation of AKT/mTOR sig 2019 Oct Rheumatoid arthritis (RA) is a chronic inflammation mediated by autoimmune responses. MEG3, a kind of long noncoding RNA (lncRNA), participates in cell proliferation in cancer tissues. However, the correlation between MEG3 and RA is yet unclear. Therefore, to clarify how MEG3 works in RA, we performed a series of experiments using RA samples. We found that MEG3 was downregulated in the fibroblast-like synoviocytes of RA patients (RA-FLS), in comparison with healthy subjects. MEG3 was also down-regulated evidently in lipopolysaccharide (LPS)-treated chondrocyte. As part of our experiments, MEG3 was overexpressed in chondrocyte by transfection with lentivirus containing sequences encoding MEG3. In addition, in presence of LPS, reductions were identified not only in the cell proliferation, but also in the generation of interleukin-23 (IL-23), which, however were reversed in the lentivirus (containing MEG3-encoding sequences)-transfected chondrocytes. Up-regulated MEG3 resulted in an increase the level of Ki67. Moreover, MEG3 was negatively correlated with miR-141, and miR-141 was up-regulated in LPS-treated chondrocyte. Inhibitory effects of MEG3 overexpression, mentioned above, were partially abolished by overexpressed miR-141. Further, animal experiment also showed the inhibitory effect of MEG3 in overexpression on the AKT/mTOR signaling pathway. In-vivoexperiments also showed that cell proliferation was facilitated by MEG3 overexpression with inhibited inflammation. In summary, the protective role of MEG3 in RA was proved to be exerted by the increase in the rate of proliferation, which might correlate to the regulatory role of miR-141 and AKT/mTOR signal pathway, suggesting that MEG3 holds great promise as a therapeutic strategy for RA.
31403345 Factors influencing physician decisions to discontinue treatment after onset of liver dysf 2020 Jul Objectives: Adverse drug reactions (ADRs) related to liver dysfunction are a common problem in patients with rheumatoid arthritis (RA) receiving iguratimod, but which patient subgroups go on to discontinue iguratimod treatment is unclear. A post-hoc analysis of a post-marketing surveillance study was performed to investigate factors influencing treatment continuation after the onset of liver dysfunction.Methods: Types of ADR were compared between patients in whom iguratimod treatment was discontinued or continued in accordance with the judgment of the patient's physician after the patient developed liver dysfunction as an ADR. Stepwise logistic regression analysis was also conducted to investigate factors associated with treatment discontinuation.Results: The multivariate analysis found that concomitant use of methotrexate (MTX) at >8 mg/week (vs. no use) was associated with a significantly lower risk of discontinuation (OR: 0.136; 95%CI: 0.030-0.620), and previous treatment with MTX (vs. no use) was associated with a significantly higher discontinuation risk (OR: 4.045; 95%CI: 1.098-14.908).Conclusion: Although concomitant use of MTX during iguratimod treatment does not appear to influence treatment discontinuation due to abnormal liver function, liver function tests are of importance to continued treatment in patients receiving iguratimod who have a history of MTX use.
30618151 MRI of synovitis and joint fluid. 2019 Jun Synovitis and joint effusion are common manifestations of rheumatic disease and play an important role in the disease pathophysiology. Earlier detection and accurate assessment of synovial pathology, therefore, can facilitate appropriate clinical management and hence improve prognosis. Magnetic resonance imaging (MRI) allows unparalleled assessment of all joint structures and associated pathology. It has emerged as a powerful tool, which enables not only detection of synovitis and effusion, but also allows quantification, detailed characterization, and noninvasive monitoring of synovial processes. The purpose of this article is to summarize the pathophysiology of synovitis and to review the role of qualitative, semiquantitative, and quantitative MRI in the assessment of synovitis and joint fluid. We also discuss the utility of MRI as an outcome measure to assess treatment response, particularly with respect to osteoarthritis and rheumatoid arthritis. Emerging applications such as hybrid positron emission tomography / MRI and molecular imaging are also briefly discussed. Level of Evidence: 5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019.
30634456 A Disintegrin and Metalloprotease 15 is Expressed on Rheumatoid Arthritis Synovial Tissue 2019 Jan 9 A disintegrin and metalloprotease 15 (ADAM15) is involved in several malignancies. In this study, we investigated the role of ADAM15 in rheumatoid arthritis (RA) angiogenesis. Soluble ADAM15 (s-ADAM15) in serum from RA and normal (NL) subjects was measured using ELISA. To determine membrane-anchored ADAM15 (ADAM15) expression in RA synovial tissues, immunohistochemistry was performed. To examine the role of ADAM15 in angiogenesis, we performed in vitro Matrigel assays and monocyte adhesion assays using human umbilical vein endothelial cells (HUVECs) transfected with ADAM15 siRNA. Finally, to investigate whether angiogenic mediators were affected by ADAM15, cytokines in ADAM15 siRNA-transfected HUVEC-conditioned medium were measured. ADAM15 was significantly higher in RA serum than in NL serum. ADAM15 was also expressed on RAST endothelial cells. ADAM15 siRNA-treated HUVECs had decreased EC tube formation in response to RA synovial fluids compared with non-treated HUVECs. The adhesion index of ADAM15 siRNA-transfected HUVECs was significantly lower than the adhesion index of control siRNA-transfected HUVECs. ENA-78/CXCL5 and ICAM-1 were decreased in tumor necrosis factor (TNF)-α-stimulated ADAM15 siRNA-transfected HUVEC-conditioned medium compared with TNF-α-stimulated control siRNA-transfected HUVEC-conditioned medium. These data show that ADAM15 plays a role in RA angiogenesis, suggesting that ADAM15 might be a potential target in inflammatory diseases such as RA.
31207549 Complement and its environmental determinants in the progression of human rheumatoid arthr 2019 Aug Rheumatoid arthritis (RA) is a complex autoimmune disease with an etiology that is not yet well understood, disproportionally affects women and also varies in incidence and prevalence by population. The presence of anti-citrullinated protein antibodies (ACPA) is a highly specific biomarker for the diagnosis of clinically apparent RA. ACPA are also present in the serum for an average of 3-5 years prior to the onset of RA during an asymptomatic period characterized by mucosal inflammation and local ACPA production at these sites. We hypothesized that systemic complement activation products might be generated during the pre-clinical initiation of RA and/or provide a second hit that promotes subsequent arthritis development in the joints. In addition, we evaluated which demographic and genetic features and environmental exposures could influence the complement activation process. We analyzed plasma from healthy subjects, subjects at-risk for the development of RA based on serum ACPA positivity in absence of inflammatory arthritis (IA), and ACPA positive RA subjects by Multiplex Assay and ELISA for eighteen complement system components, factors and activation products belonging to the classical, lectin and alternative pathways. By using regression models, associations between complement proteins and various demographic, genetic, and environmental factors previously found to be associated with RA, including sex, smoking, shared epitope, and oral contraceptive use, were examined. We found no evidence of systemic complement activation in ACPA positive subjects without IA, but in contrast found evidence of systemic involvement of the both classical and alternative pathways during the stage of the disease where classified RA is present, (i.e. during joint inflammation and damage). With regard to the demographic, genetic, and environmental variables, females who reported current or past oral contraceptive use and subjects with current tobacco exposure demonstrated alterations of the alternative pathway of complement. Furthermore, RA subjects with established disease who have a body mass index categorized as obese demonstrated higher levels of C2 compared to RA subjects who are not considered obese. In sum, the complement system may be involved in the pathogenesis of RA, with only localized mucosal effects during the preclinical period in those at-risk for RA but in the joint as well as systemically in those who have developed clinically apparent arthritis.