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ID PMID Title PublicationDate abstract
31475364 Nrf2-Keap1 pathway-mediated effects of resveratrol on oxidative stress and apoptosis in hy 2019 Dec Resveratrol (Res) is a polyphenolic compound that has a variety of biological functions and activities. This study aimed to explore the mechanisms of the antioxidant and proapoptotic effects of Res in H(2) O(2) -treated rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) by the Nrf2-Keap1 signaling pathway. We found that 5 µM H(2) O(2) promoted cell proliferation and increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content in RA-FLSs. However, Res could reverse these effects in 5 µMH2O2-treated RA-FLSs by (1) promoting expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), (2) reducing expression of Kelch-like ECH-related protein 1 (Keap1), (3) inhibiting production of ROS and MDA, (4) blocking activation of nuclear factor-κB (NF-κB) p65, (5) inhibiting cell proliferation and migration, and (6) activating Bcl-2/Bax to induce apoptosis. After lentiviral silencing of Nrf2 (siNrf2) mRNA expression in RA-FLSs, Res addition did not increase the expression of Nrf2 or HO-1 to reduce the production of mitochondrial ROS caused by 5 µM H(2) O(2) . Res reduced the Bcl-2/Bax ratio, but siNrf2 reduced the ability of Res to promote apoptosis. We conclude that Res inhibits ROS production by activating the Nrf2 pathway, thereby inhibiting activation of NF-κB and proliferation and migration of RA-FLSs, to induce apoptosis. Targeting the Nrf2-Keap1 pathway may be a relevant aim of using Res in the treatment of RA.
30635855 Prolactin, autoimmunity, and motherhood: when should women avoid breastfeeding? 2019 May The sexual dimorphic prevalence of autoimmunity represents one of the most alluring observations among the mosaic of autoimmunity. Sex hormones are believed to be a mainstay of this asymmetry. The greater prevalence of autoimmunity among fertile women, disease onset/relapses during pregnancy, and postpartum are some of the points that support this theory. Undeniably, motherhood represents one of the most remarkable challenges for the immune system that not only has to allow for the conceptus but also deal with extraordinary hormonal alterations. Prolactin has a recognized immune-stimulatory effect, mainly inhibiting the negative selection of autoreactive B lymphocytes. In accordance, hyperprolactinemia has been associated with several autoimmune diseases, interfering with its pathogenesis and activity. During the pregnancy and lactation period, assorted autoimmune patients experience relapses, suggesting an active interference from increased levels of prolactin. This association was found to be significant in systemic lupus erythematosus, rheumatoid arthritis, and peripartum cardiomyopathy. Furthermore, treatment with bromocriptine has shown beneficial effects specially among systemic lupus erythematosus patients. In this review, we attempt to provide a critical overview of the link between prolactin, autoimmune diseases, and motherhood, emphasizing whether breastfeeding should be avoided among women, both with diagnosed disease or high risk for its development.
31183781 A Review of the Totality of Evidence Supporting the Development of the First Adalimumab Bi 2019 Aug ABP 501 [United States: AMJEVITA™ (adalimumab-atto); European Union: AMGEVITA(®) (adalimumab)] is the first approved biosimilar to adalimumab [reference product (RP)], a monoclonal antibody (mAb) targeting tumor necrosis factor-alfa (TNF-α). ABP 501 has received approval for use in indications that adalimumab RP is approved for, except those protected by regulatory exclusivity. A systematic step-wise totality of evidence (TOE) approach formed the basis of approval of ABP 501; this involved methodical accumulation of scientifically robust comparative data supporting similarity in analytical, preclinical, and clinical [pharmacokinetics (PK)], efficacy, safety and immunogenicity) evaluations. As a foundational first step, comprehensive analytical assessments demonstrated that ABP 501 is structurally and functionally similar to adalimumab RP in critical quality attributes. Preclinical assessments confirmed similar activity in assessing mechanisms of action and toxicology. Clinical evaluation included a phase 1 PK equivalence study in healthy subjects and two comparative phase 3 studies that evaluated ABP 501 and adalimumab RP in two sensitive patient populations, plaque psoriasis (PsO) and rheumatoid arthritis (RA). The PK profiles of ABP 501 and adalimumab RP were similar in healthy subjects as well as patients with PsO and RA. The pivotal phase 3 study in patients with PsO demonstrated that ABP 501 was clinically similar to adalimumab RP in terms of efficacy, safety and immunogenicity in both the primary and transition phases. The pivotal phase 3 study in patients with RA also established clinical similarity between ABP 501 and adalimumab RP; an open-label extension of this study demonstrated sustained efficacy over an additional 72 weeks, with no new safety or immunogenicity concerns with ABP 501 treatment. Overall, the TOE supported the conclusion that ABP 501 is highly similar to adalimumab RP and provided scientific justification for extrapolation to all the approved indications of adalimumab RP not protected by exclusivities.Funding: Amgen Inc.
29563614 A critical epitope in CD147 facilitates memory CD4(+) T-cell hyper-activation in rheumatoi 2019 Jun The abnormal activation of CD4(+)CD45RO(+) memory T (Tm) cells plays an important role in the pathogenesis of rheumatoid arthritis (RA). Previous studies have shown that CD147 participates in T-cell activation. However, it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients. In this study, we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients. The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activation and proliferation and further restrained osteoclastogenesis. Using a structural-functional approach, we depicted the interface between 5A12 and CD147. This allowed us to identify two critical residues, Lys63 and Asp65, as potential targets for RA treatment, as the double mutation K63A/D65A inhibited Tm-cell activation, mimicking the neutralization by 5A12. This study provides not only a theoretical basis for a "CD147-Tm/Osteoclast-RA chain" for the potential prevention and treatment of RA or other T-cell-mediated autoimmune diseases but also a new target for related drug design and development.
30601052 Survivorship and long-term outcome of a consecutive series of 200 Scandinavian Total Ankle 2019 Jan AIMS: We report the long-term clinical and radiological outcomes of a consecutive series of 200 total ankle arthroplasties (TAAs, 184 patients) at a single centre using the Scandinavian Total Ankle Replacement (STAR) implants. PATIENTS AND METHODS: Between November 1993 and February 2000, 200 consecutive STAR prostheses were implanted in 184 patients by a single surgeon. Demographic and clinical data were collected prospectively and the last available status was recorded for further survival analysis. All surviving patients underwent regular clinical and radiological review. Pain and function were assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot scoring system. The principal endpoint of the study was failure of the implant requiring revision of one or all of the components. Kaplan-Meier survival curves were generated with 95% confidence intervals and the rate of failure calculated for each year. RESULTS: A total of 84 patients (87 ankles) were alive by the end of this study. Of the surviving 84 patients (87 ankles; rheumatoid arthritis (RA), n = 40; OA, n = 47), 45 were women and 39 were men, with a mean age of 54 years (18 to 72 years) at the time of surgery. A total of 32 implants failed (16%), requiring revision surgery. The mean time to revision was 80 months (2 to 257). The implant survival at 15.8 years, using revision as an endpoint, was 76.16% (95% confidence interval (CI) 64.41 to 87.91). We found a steady but low decrease in survival over the study period. The mean AOFAS score improved from 28 (10 to 52) preoperatively to 61 (20 to 90) at long-term follow-up. CONCLUSION: STAR prostheses in the United Kingdom have now been largely superseded by newer design TAAs, potentially with improved characteristics and surgical techniques. The long-term survivorship for the STAR prosthesis can provide a benchmark for these later designs of ankle arthroplasty.
31087226 Efficacy and safety of secukinumab in active rheumatoid arthritis with an inadequate respo 2019 Oct OBJECTIVES: To address the efficacy and safety of secukinumab in comparison with placebo in active rheumatoid arthritis (RA) patients who had an inadequate response to tumor necrosis factor (TNF) inhibitors. METHODS: Databases of PubMed, Embase, and Web of Science were searched to identify the relevant randomized controlled trials (RCTs). Risk ratio (RR) and 95% confidence interval (95% CI) were calculated with the Mantel-Haenszel random effects method. Statistical heterogeneity was assessed using the Cochran Q and I(2) tests. RESULTS: A total of 1292 patients from three phase III RCT studies were included. Compared with placebo, secukinumab 150 mg was superior at 24 weeks in terms of ACR20 with RR (1.66, 95% CI 1.33, 2.08; P < 0.0001; I(2) = 0%), ACR50 (1.88, 95% CI 1.29, 2.72; P = 0.0009; I(2) = 0%), and ACR70 (2.15, 95% CI 1.15, 4.02; P = 0.02; I(2) = 0%). Consistent effects were also observed in pooled group of 150 mg and 75 mg secukinumab. For secukinumab 75 mg alone, ACR20 response rate was significantly higher compared with placebo (RR 1.62, 95% CI 1.29, 2.03; P < 0.00001; I(2) = 0%). Although ACR50 and ACR70 response rates showed a favorable trend to be higher, no statistical difference was observed (RR 1.68, 95% CI 0.99, 2.85, P = 0.05, I(2) = 47%; RR 1.81, 95% CI 0.78, 4.21, P = 0.17, I(2) = 34%, respectively). Compared with the placebo group, there was no increased risk of adverse effects (AEs) and serious AEs at 16 weeks in the pooled secukinumab group. CONCLUSIONS: In active RA patients with an inadequate response to TNF inhibitors, secukinumab may be a therapeutic option. Secukinumab 150 mg showed significantly better clinical efficacy with no increased risk of AEs and serious AEs compared with placebo. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT01770379, NCT01350804, NCT01377012 Key Points • Secukinumab 150 mg showed significantly better clinical efficacy in active RA patients with an inadequate response to TNF inhibitors. • No increased risk of AEs and serious AEs in secukinumab group compared with placebo.
31808927 Association of Patient, Prescriber, and Region With the Initiation of First Prescription o 2019 Dec 2 IMPORTANCE: Prescribing the first biologic treatment for rheumatoid arthritis (RA) is an important decision for patients, their physicians, and payers, with considerable costs and clinical implications. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) have known effectiveness and safety profiles and are less expensive; therefore, determining the variables contributing to csDMARD treatment duration is an essential question for patients, physicians, and payers. OBJECTIVES: To describe access to the first biologic DMARD prescription in a population of patients with RA and identical comprehensive health insurance coverage in Ontario, Canada, and to explore the associations of patient, prescriber, and geographic region with differences in time to first biologic prescription. DESIGN, SETTING, AND PARTICIPANTS: This cohort study of incident patients with RA used administrative data with surveillance and patient-level data collected at yearly intervals. A total of 17 672 patients were included in the study; they were residents of Ontario, Canada, had an incident RA diagnosis at age 67 or older between 2002 and 2015, and received at least 1 csDMARD. Data were analyzed in November 2017. EXPOSURE: Patient variables were age, sex, disease duration, socioeconomic status, distance to care, and supply of care in the patient's area of residence. Prescriber covariates were year of graduation, specialty of practice, and supply of rheumatologic care in the patient's geographic region. MAIN OUTCOMES AND MEASURES: Time from first csDMARD prescription to receipt of first biologic medication. RESULTS: Of 17 672 patients, 11 598 (65.6%) were women, and the mean (SD) age was 75.2 (5.8) years. Characteristics associated with longer time to receipt of a biologic prescription were older age (HR for every 5-year increase, 0.66; 95% CI, 0.62-0.71; P < .001), male sex (HR, 0.76; 95% CI, 0.66-0.89; P < .001), and distance to the nearest rheumatologist (HR per 10-km increase, 0.99; 95% CI, 0.98-0.99; P < .001). Prescribers were primarily rheumatologists (151 of 214 [70.6%]) and primary care physicians (26 of 214 [12.1%]). After adjusting for the number of patients eligible to receive biologic DMARDs, rheumatologists' preferences (ie, yearly prescription rates) for using biologic DMARDs increased over time, from 1.7% in 2001 to 4.9% in 2015. After adjusting for calendar year and patient-, prescriber-, and region-level characteristics, substantial variation between prescribers in rates of prescribing a first biologic DMARD were found (65% variance). CONCLUSIONS AND RELEVANCE: This study found variation in time to receipt of first biologic DMARD after prescription of first csDMARD in a population with RA after adjustment for individual-level patient, prescriber, and geographic area covariates, despite identical universal health insurance coverage.
30183438 New adalimumab formulation associated with less injection site pain and improved motivatio 2019 Nov Objectives: We aimed to evaluate the effect of change to the existing formulation of adalimumab (ADA) on pain and treatment motivation.Methods: We classified injection pain into the following categories: overall pain, pain at needle insertion, pain during drug injection, and pain 10 min after injection; we evaluated the effect of change to the existing formulation on pain using a visual analogue scale. In addition, a faces pain scale was used to evaluate the effect of change in injection pain intensity on treatment motivation.Results: Compared with the existing ADA formulation, the new formulation was associated with lower scores of overall pain (1.6 vs. 6.7), pain at needle insertion (1.8 vs. 4.7), pain during injection (1.6 vs. 7.0), and pain 10 min after the injection (0.4 vs. 3.1). All results showed a significant difference. p < .001. Paired t-tests were used. In the survey, 68% and 80% of the patients reported injection pain with influenza vaccine and the existing formulation, respectively; however, the proportion of the patients who experienced pain with the new formulation decreased to 20%.Conclusions: The new ADA formulation may alleviate the burden on RA patients and improve the quality of adherence to treatment, thereby influencing the RA treatment outcomes.
30941736 Effectiveness of Certolizumab-Pegol in Rheumatoid Arthritis, Spondyloarthritis, and Psoria 2019 Jun BACKGROUND: Identification of predictors of clinical response to certolizumab-pegol (certolizumab) may aid the decision-making process for treating patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). OBJECTIVE: The aim of our study was to evaluate the effectiveness of certolizumab and identify any predictors of favorable outcome in patients with RA, PsA, or SpA. METHODS: We studied 355 RA, SpA, and PsA patients starting treatment with certolizumab. Endpoints of the study were drug survival and identification of predictors of clinical outcome. Drug retention was analyzed via the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox regression models. RESULTS: Of 355 certolizumab initiators, 178 had RA, 94 had PsA, and 83 had SpA. Biologic-naïve RA patients had significantly higher survival rates (73.3%) than switchers taking certolizumab as a second-line (49.0%) or third- or next-line biologic agent (51.2%; p = 0.0001). Instead, PsA and SpA patients showed similar drug retention rates regardless of the line of treatment. A significant clinical improvement from baseline was seen at 3 months for RA (28 joint-Disease Activity Score [DAS28]; p = 0.001), PsA (Disease Activity Index for PsA [DAPSA]; p = 0.001), and SpA (Bath Ankylosing Disease Index; p = 0.01). Biologic-naïve patients had the lowest HR (0.31; p = 0.001) of discontinuing certolizumab for RA, and the highest HR (7.94; p = 0.01) of achieving minimal disease activity (MDA) for PsA. For PsA, a predictor of late MDA was the achievement of low/remission DAPSA at 3 months, and 3-month low/remission DAS28 predicted late remission for RA. CONCLUSIONS: Our study revealed that the best predictor of certolizumab effectiveness in unselected patients with RA, PsA, or SpA was a biologic-naïve status and achievement of an early response within 3 months.
30880092 Correlation between diabetes mellitus and periodontitis in Taiwan: A nationwide cohort stu 2019 Apr AIMS: The mechanism underlying the association of diabetes mellitus (DM) and periodontitis is not clear. This study aimed to investigate the correlation between DM and periodontitis. METHODS: This study was a retrospective cohort study, which conducted based on the Taiwan National Health Insurance Research Database. The study subjects were 39,384 new-onset DM patients who aged above 20 years old from 2005 to 2012. To avoid selection bias, we applied propensity score matching to obtain patients without DM, as the control group. Cox proportional hazard model was used to analyze the risk of periodontitis in patients with DM. RESULTS: After controlling for related variables, Patients with DM had a higher risk for periodontitis compared with the patients without DM (adjusted hazard ratios [aHR] = 1.04, 95% confidence interval [CI]: 1.01-1.08). Patients with hypertension (HTN) had no higher risk for periodontitis (aHR = 0.96, 95% CI: 0.92-1.00). Patients with dyslipidemia and rheumatoid arthritis (RA) patients both had a higher risk for periodontitis (aHR = 1.26, 95% CI: 1.19-1.34; aHR = 1.41, 95% CI: 1.19-1.67). CONCLUSIONS: There is a correlation between DM and periodontitis. Patients with DM may have a higher risk of incident periodontitis. Besides, age, HTN, dyslipidemia, and RA are also associated with incident periodontitis.
31180802 Libman-Sacks endocarditis in a Bangladeshi patient suffering from rhupus. 2019 Oct Libman-Sacks endocarditis (LSE) is one of the most characteristic cardiac lesions in systemic lupus erythematosus (SLE). Patients may remain asymptomatic, while symptomatic patients often suffer with systemic emboli. These commonly test positive for anti-phospholipid antibody (aPA). The association of LSE with an overlap of rheumatoid arthritis (RA) and lupus (also known as 'rhupus') is rare. We report such a patient, who had been diagnosed as having RA seven years before and had suffered an acute ischaemic stroke one year previously and had echocardiographic evidence of LSE found during routine evaluation. However, she tested negative for aPA.
31112139 A Case of Methotrexate-Associated Lymphoproliferative Disorder (Lymphomatoid Granulomatosi 2019 Jun Iatrogenic lymphoproliferative disorder (LPD) can develop in patients treated with immunosuppressive drugs for autoimmune or other inflammatory diseases. Here, we report a case of lymphomatoid granulomatosis of the skin that occurred as a methotrexate (MTX)-associated LPD. We also review the relevant literature. A 73-year-old woman presented to our department with an approximately 10-year history of MTX therapy for rheumatoid arthritis. Three months earlier, she noticed a small nodule in her right upper arm. It gradually enlarged, and the center began to decay. Grossly, the lesion was 40 × 40 mm in size with ulceration, and the surrounding skin presented dark red erythema. A biopsy specimen was taken for definitive diagnosis. Histologically, infiltrating growth of medium-to-large atypical lymphocytes was observed underneath the ulceration and was accompanied by small reactive lymphocytes. The atypical lymphocytes demonstrated a tendency to infiltrate the vessels, which showed an angiocentric pattern. Immunohistochemistry revealed that the atypical lymphoid cells were positive for CD79a, CD20, and CD30. In addition, in situ hybridization for Epstein-Barr virus (EBV) revealed expression of EBV-encoded small RNAs. The patient was diagnosed with MTX-associated LPD (lymphomatoid granulomatosis), owing to her history of MTX treatment, the expression of the atypical lymphocytes for B-cell markers and EBV-encoded small RNA, and the angiocentric infiltrating pattern. The lesion reportedly disappeared after withdrawal of MTX.
31292906 Efficacy and Safety of Etanercept in Elderly Patients with Rheumatoid Arthritis: A Post-Ho 2019 Sep BACKGROUND: Elderly individuals are disproportionately affected by rheumatoid arthritis (RA), but few studies have addressed the efficacy and safety of treatments in this population. OBJECTIVE: Our objective was to assess the efficacy and safety of etanercept in elderly patients (aged ≥ 65 years) with RA. METHODS: The efficacy analysis was a post hoc analysis of data from the open-label period of three phase IV clinical trials of etanercept for RA. Least squares (LS) change from baseline (cfb) in 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and modified Total Sharp Scores (mTSS) were analyzed by age (< 65 vs. ≥ 65 years) for each study. The safety analyses were of data pooled from the double-blind, placebo-controlled periods of 19 phase I-IV randomized studies of etanercept in patients with RA. The percentage occurrence of adverse events (AEs) in placebo- and etanercept-treated patients was analyzed by age (< 65 vs. ≥ 65 years). RESULTS: There were no significant differences in LS mean cfb in DAS28 or mTSS between the two age groups. LS mean cfb in HAQ-DI scores was consistently lower in elderly than in non-elderly patients, although significant differences were not observed in all trials. Overall, AE occurrence was higher in elderly than non-elderly patients, regardless of treatment. In etanercept-treated patients, there were small yet statistically significant increases in the occurrence of congestive heart failure, serious infections, and non-melanoma skin cancers in elderly versus non-elderly patients. For most AEs, occurrence did not significantly differ between elderly and non-elderly patients. CONCLUSION: Overall, there were no substantial differences in the efficacy or safety of etanercept between elderly and non-elderly patients with RA.
31330824 Myeloid Dendritic Cells Are Enriched in Lymph Node Tissue of Early Rheumatoid Arthritis Pa 2019 Jul 20 Lymph nodes (LNs) are highly organized structures where specific immune responses are initiated by dendritic cells (DCs). We investigated the frequency and distribution of human myeloid (mDCs) and plasmacytoid (pDCs) in LNs and blood during the earliest phases of rheumatoid arthritis (RA). We included 22 RA-risk individuals positive for IgM rheumatoid factor and/or anti-citrullinated protein antibodies, 16 biological-naïve RA patients and 8 healthy controls (HCs). DC subsets (CD1c(+) mDCs and CD304(+) pDCs) in LN tissue and paired peripheral blood were analyzed using flow cytometry and confocal microscopy. In blood of RA patients a significant decreased frequency of pDCs was found, with a similar trend for mDCs. In contrast, mDC frequencies were higher in RA compared with HCs and RA-risk individuals, especially in LN. Frequency of mDCs seemed higher in LNs compared to paired blood samples in all donors, while pDCs were higher in LNs only in RA patients. As expected, both mDCs and pDCs localized mainly in T-cell areas of LN tissue. In conclusion, compared with RA-risk individuals, mDCs and pDCs were enriched in the LN tissue of early-RA patients, while their frequency in RA-risk individuals was comparable to HCs. This may suggest that other antigen-presenting cells are responsible for initial breaks of tolerance, while mDCs and pDCs are involved in sustaining inflammation.
31471299 Integrin and transcriptomic profiles identify a distinctive synovial CD8+ T cell subpopula 2019 Nov OBJECTIVES: Current evidence suggests that immune events in the gut may impact joint inflammation in ankylosing spondylitis (AS) but the expression of gut-related trafficking molecules in the inflammed joint is poorly characterised. We aimed to (1) assess differential expression patterns of trafficking molecules between patients and controls, (2) generate joint-specific cellular signatures and (3) obtain transcriptomic profiles of noteworthy cell subpopulations. METHODS: Male subjects under 40 years of age fulfilling the mNY criteria were recruited. The following cells were surface stained using a 36-marker mass cytometry antibody panel: (1) peripheral blood mononuclear cells from AS patients, and healthy controls; (2) synovial fluid mononuclear cells from AS and rheumatoid arthritis (RA) patients. Additionally, RNA-seq was performed on CD8+ T cell subpopulations from the synovial fluid (SF). RESULTS: Mature CD8+ T cells were enriched in AS SF, with a distinct pattern of integrin expression (β7, CD103, CD29 and CD49a). RNA-seq analysis of SF-derived CD103+CD49a+CD8+ T cells revealed elevated TNFAIP3, GZMB, PRF1 and IL-10. CONCLUSIONS: We have identified a novel integrin-expressing mature CD8+ T cell population (CD49a+CD103+β7+CD29+) that appears to be more prevalent in AS SF than RA SF. These cells seem to possess dual cytotoxic and regulatory profiles which may play a role in AS pathogenesis.
31239367 Down-regulation of microRNA-142-3p inhibits the aggressive phenotypes of rheumatoid arthri 2019 Jul 31 The present study aimed to investigate the regulatory roles of miR-142-3p on the aggressive phenotypes of rheumatoid arthritis (RA) human fibroblast-like synoviocytes (RA-HFLSs), and reveal the potential mechanisms relating with nuclear factor-κB (NF-κB) signaling. miR-142-3p expression was detected in RA synovial tissues and RA-HFLSs by quantitative real-time PCR (qRT-PCR) and Northern blot analysis. RA-HFLSs were transfected with miR-142-3p inhibitor and/or treated with 10 µg/l tumor necrosis factor α (TNF-α). The viability, colony formation, apoptosis, migration, invasion, and the levels of interleukin (IL)-6, and matrix metalloproteinase 3 (MMP-3) were detected. The mRNA expressions of B-cell lymphoma-2 (Bcl-2), Bax, Bad, IL-6, and MMP-3 were detected by qRT-PCR. Moreover, the expression of Bcl-2, IL-1 receptor-associated kinase 1 (IRAK1), Toll-like receptor 4 (TLR4), NF-κB p65, and phosphorylated NF-κB p65 (p-NF-κB p65) were detected by Western blot. The interaction between IRAK1 and miR-142-3p was identified by dual luciferase reporter gene assay. MiR-142-3p was up-regulated in RA synovial tissues and RA-HFLSs. TNF-α activated the aggressive phenotypes of RA-HFLSs, including enhanced proliferation, migration, invasion, and inflammation, and inhibited apoptosis. miR-142-3p inhibitor significantly decreased the cell viability, the number of cell clones, the migration rate, the number of invasive cells, the contents and expression of IL-6 and MMP-3, and increased the apoptosis rate and the expressions of Bax and Bad, and decreased Bcl-2 expression of TNF-α-treated RA-HFLSs. MiR-142-3p inhibitor significantly reversed TNF-α-induced up-regulation of IRAK1, TLR4, and p-NF-κB p65 in TNF-α-treated RA-HFLSs. Besides, IRAK1 was a target of miR-142-3p. The down-regulation of miR-142-3p inhibited the aggressive phenotypes of RA-HFLSs through inhibiting NF-κB signaling.
30189019 The effects of methotrexate and hydroxychloroquine combination therapy vs methotrexate mon 2019 Jan 1 OBJECTIVES: To investigate the added value of MTX-HCQ combination therapy (CTG) in early RA in a controlled cohort study. MTX monotherapy (MTG) is recommended as (part of) first choice treatment but no head-to-head comparisons are available comparing MTX-HCQ CTG with MTG. METHODS: RA patients from the Sint Maartenskliniek and Radboudumc Nijmegen who started MTX with or without concomitant HCQ from April 2010 to October 2015 were included. The primary outcome was the between-group ΔDAS28-CRP at 6 months, and secondary outcomes were ΔDAS28-CRP at 12 months, EULAR response at 6 and 12 months, and treatment intensification. Regression modelling was used to correct for confounding. RESULTS: We included 325 patients, with only small between-group differences at baseline. The DAS28-CRP improvement at 6 months was larger in the CTG (Δ = 0.38 (CI: 0.01, 0.76)), and the difference between groups in DAS28-CRP improvement was smaller at 12 months (Δ = 0.22 points (CI:-0.19, -0.62)). At 6 months, a higher percentage of patients had a good EULAR response in the CTG (Δ = 15% (CI: 2.7%, 27%)). This difference was reduced at 12 months (Δ = 6% (CI -6.4%, 19%)). Treatment intensification with conventional synthetic DMARDs was more likely in the MTG (Δ = 31% (CI: -43%, 19%)). The proportion of patients starting biologic DMARD treatment during the observation period was comparable (Δ = 2% (CI: -8%, 12%)). DISCUSSION: In contrast to indirect comparison review data, MTX-HCQ seems somewhat more effective after 6 months than MTX monotherapy in early RA patients. After 12 months, we observed no significant differences between the two strategies, probably due to treat-to-target efforts.
30148437 Can switching to abatacept therapy in patients with rheumatoid arthritis on background met 2019 Jan OBJECTIVES: To explore antinuclear autoantibody (ANA) and anti-double-stranded DNA (anti-dsDNA) autoantibody development during abatacept and tumour necrosis factor inhibitor (TNFi) treatment, and effects of switching from TNFi to abatacept in ANA/anti-dsDNA autoantibody-positive patients. METHODS: This was a post hoc analysis of biologic-naïve patients with active RA in ATTEST and AMPLE. In AMPLE, patients received subcutaneous abatacept or adalimumab (2 years). In ATTEST, patients received intravenous abatacept or infliximab (1 year), or placebo (6 months) then abatacept (6 months); at 1 year, all patients could receive abatacept (open-label long-term extension). Serum ANA/anti-dsDNA autoantibody levels were measured at baseline, Month 6 (ATTEST only), Years 1 and 2. RESULTS: At baseline, 25.7 and 0.9% (AMPLE), and 21.6 and 8.4% of patients (ATTEST) were ANA/anti-dsDNA autoantibody positive, respectively. More baseline ANA/anti-dsDNA autoantibody-negative patients became positive during TNFi than abatacept treatment. In ATTEST (TNFi group), 48.5% (48/99; ANA) and 48.3% (57/118; anti-dsDNA) of patients seroconverted to positive status by Year 1, falling to 22.4% (22/98 ANA) and 13.3% (15/113; anti-dsDNA) by Year 2 after switching to abatacept. Of ANA/anti-dsDNA autoantibody-positive patients at Year 1, 41.9% and 68.9%, were negative at Year 2. CONCLUSIONS: ANA/anti-dsDNA seroconversion was more frequent with TNFi than abatacept therapy; TNFi-associated seroconversion decreased after switching from TNFi to abatacept.
31268376 Sarilumab monotherapy or in combination with non-methotrexate disease-modifying antirheuma 2020 Mar Objectives: To determine long-term safety and efficacy of sarilumab as monotherapy or with non-methotrexate (MTX) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in Japanese patients with active rheumatoid arthritis (RA).Methods: In this double-blind, randomized study (NCT02373202), patients received subcutaneous sarilumab 150 mg q2w (S150) or 200 mg q2w (S200) as monotherapy or with non-MTX csDMARDs for 52 weeks. The primary endpoint was safety.Results: Sixty-one patients received monotherapy (S150, n = 30; S200, n = 31) and 30 received combination therapy (S150 + csDMARDs, n = 15; S200 + csDMARDs, n = 15). Rates of treatment-emergent adverse events (TEAEs) were 83.3%/90.3%/93.3%/86.7% for S150/S200/S150 + csDMARDs/S200 + csDMARDs, respectively. Nasopharyngitis and neutropenia were the most frequently reported TEAEs. One serious infection was reported in each monotherapy group and in the S200 + csDMARDs group. There were no cases of grade 4 neutropenia; no patients with grade 3 neutropenia experienced associated serious infection. Improvements in ACR20/50/70 response rates were generally similar between the two monotherapy groups and between the two combination groups; improvements in physical function (Health Assessment Questionnaire-Disability Index, HAQ-DI) and DAS28-CRP were observed at weeks 24 and 52 (all groups).Conclusion: The safety profile of sarilumab was consistent with known class effects of interleukin-6 signaling blockade therapeutics. Sarilumab as mono- or combination therapy improved clinical signs/symptoms and physical function in Japanese RA patients.
30009649 Effectiveness and safety of initiating adalimumab plus ≥12 mg/week methotrexate with a 2019 Jul Objectives: This real-world study assessed the effectiveness and safety outcomes of initiating adalimumab and methotrexate (≥12 mg/week) with adjustable dosing in Japanese patients with early rheumatoid arthritis (RA). Methods: This single-arm, prospective postmarketing observational study (conducted from September 2012 to March 2017 at 119 sites) enrolled biologic-naïve patients with early RA (≤2 years duration) and a Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) >3.2 who were treated with methotrexate for ≥3 months and had initiated treatment with adalimumab and methotrexate (≥12 mg/week). This report presents 52-week data. The primary outcome was the proportion of patients who achieved DAS28-CRP scores <2.6 at week 52. Results: Overall, 293 of 346 enrolled patients were included in the effectiveness population: women, 73%; mean (standard deviation) age, 54.3 (13.9) years; DAS28-CRP score, 4.51 (0.90); and modified total Sharp score (mTSS), 7.69 (9.98). At week 52, 77% of patients achieved clinical remission (DAS28-CRP <2.6), 92.3% achieved low disease activity (DAS28-CRP ≤3.2), and 86% of evaluable patients experienced structural remission (ΔmTSS ≤0.5). Conclusion: Adalimumab plus methotrexate (≥12 mg/week) with adjustable dosing was well tolerated, and could be a beneficial treatment option for Japanese patients with early RA.