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ID PMID Title PublicationDate abstract
33546769 Transformation of fibroblast-like synoviocytes in rheumatoid arthritis; from a friend to f 2021 Feb 5 Swelling and the progressive destruction of articular cartilage are major characteristics of rheumatoid arthritis (RA), a systemic autoimmune disease that directly affects the synovial joints and often causes severe disability in the affected positions. Recent studies have shown that type B synoviocytes, which are also called fibroblast-like synoviocytes (FLSs), as the most commonly and chiefly resident cells, play a crucial role in early-onset and disease progression by producing various mediators. During the pathogenesis of RA, the FLSs' phenotype is altered, and represent invasive behavior similar to that observed in tumor conditions. Modified and stressful microenvironment by FLSs leads to the recruitment of other immune cells and, eventually, pannus formation. The origins of this cancerous phenotype stem fundamentally from the significant metabolic changes in glucose, lipids, and oxygen metabolism pathways. Moreover, the genetic abnormalities and epigenetic alterations have recently been implicated in cancer-like behaviors of RA FLSs. In this review, we will focus on the mechanisms underlying the transformation of FLSs to a cancer-like phenotype during RA. A comprehensive understanding of these mechanisms may lead to devising more effective and targeted treatment strategies.
33346009 Ibuprofen-loaded calcium phosphate granules: A new bone substitute for local relieving sym 2021 Mar 1 Musculoskeletal diseases often demand a drug treatment at the specific site of injury or defect site. In this context, the use of calcium phosphates is attractive as it allows both the bone substitution and the local delivery of a drug substance. In this work, we present a drug delivery device that combines calcium phosphate bioceramic granules and ibuprofen, a widely used anti-inflammatory drug. After verifying in vitro biocompatibility of the ibuprofen-loaded calcium phosphate granules on murine preosteoblastic cells (MC3T3), we evaluated in vitro efficiency of the drug substance released from the bioceramic using rheumatoid arthritis synoviocytes. Our data document that ibuprofen-loaded calcium phosphate granules reduced inflammatory response and increased apoptosis of synoviocytes. In vivo study showed that both unloaded, and ibuprofen-loaded calcium phosphate granules induced a progressive osteogenesis, but in the case of ibuprofen-loaded implants, bone ingrowth was more limited in first weeks. However, as far as concerns inflammation, while unloaded granules showed inflammation up to 4 weeks, ibuprofen loaded granules did not show any significant inflammation. Ibuprofen concentration determination in blood samples showed that a very small amount of the drug reached the general circulation which render this drug delivery system suitable for both bone substitution and reduction of inflammation at the implantation site. Thus, this new drug carrier could be used to locally relieve inflammatory bone diseases symptoms including rheumatoid arthritis but, beyond this study, this kind of granules could be considered for the delivery of therapeutic agents such as antibiotic, analgesic or anticancer drugs.
34539818 Presence of anti-acetylated peptide antibodies (AAPA) in inflammatory arthritis and other 2021 AIMS: To determine the diagnostic value of anti-acetylated peptide antibodies (AAPA) in patients with rheumatoid arthritis (RA). METHODS: Three acetylated peptides (ac-lysine, ac-lysine.inv and ac-ornithine) derived from vimentin were employed to measure AAPA by enzyme-linked immunosorbent assay (ELISA) in sera of 120 patients with early RA (eRA), 195 patients with established RA (est RA), 99 healthy controls (HC), and 216 patients with other inflammatory rheumatic diseases. A carbamylated and a citrullinated version of the vimentin peptide were used additionally. Receiver operating characteristics and logistic regression analyses were used to assess the discriminative capacity of AAPA. RESULTS: AAPA were detected in 60% of eRA and 68.7% of estRA patients, 22.2% of HC, and 7.1- 30.6% of patients with other rheumatic diseases. Importantly, AAPA were also present in 40% of seronegative RA patients, while antibodies to the carbamylated peptide were detected less frequently. Diagnostic sensitivity of individual peptides for eRA was 28.3%, 35.8%, and 34% for ac-lysine, ac-ornithine, and ac-lysine.inv, respectively. Positive likelihood ratios (LR+) for eRA versus HC were 14.0, 7.1, and 2.1. While the presence of a single AAPA showed varying specificity (range: 84-98%), the presence of two AAPA increased specificity considerably since 26.7% of eRA, as compared with 6% of disease controls, were double positive. Thus, double positivity discriminated eRA from axial spondyloarthritis with a LR+ of 18.3. Remarkably, triple positivity was 100% specific for RA, being observed in 10% of eRA and 21.5% of estRA patients, even in the absence of RF and ACPA. CONCLUSION: AAPA are highly prevalent in early RA and occur also independently of RF and ACPA, thereby reducing the gap of seronegativity. Furthermore, multiple AAPA reactivity increased the specificity for RA, suggesting high diagnostic value of AAPA testing.
34852827 High humidity aggravates the severity of arthritis in collagen-induced arthritis mice by u 2021 Dec 1 BACKGROUND: Humidity was an unfavorable factor for patients with rheumatoid arthritis (RA). RA disease activity was severe in high humidity conditions. However, there is no evidence to demonstrate the effects of humidity on arthritis in the animal experiments and explore its relevant mechanism. METHODS: Using the DBA/1 mice, this study addressed the effects of a high humidity (80 ± 5%) on arthritis in collagen-induced arthritis (CIA) mice. Then, this study used the gas chromatography-mass spectrometer (GC-MS) to explore alterations in serum metabolome caused by the high humidity. Furthermore, xylitol and L-pyroglutamic acid, which were both significantly upregulated by the high humidity, were selected to further study their effects on arthritis in the CIA mice. RESULTS: The high humidity (80 ± 5%) could aggravate arthritis variables including increasing arthritis score and swelling, serum autoantibodies (anti-COII and anti-CCP), and proinflammatory cytokines (IL-6, IL-17A, and G-CSF). In addition, the high humidity could cause significant alterations in serum metabolome in the CIA mice. Xylitol and L-pyroglutamic acid were the representative serum metabolites that were significantly upregulated by the high humidity. Further experiments demonstrated that the supplementation of 0.4 mg/mL xylitol in drinking water after inducing the CIA model and 2.0 mg/mL in drinking water before inducing the CIA model could both aggravate arthritis in the CIA mice. CONCLUSIONS: These data demonstrated that high humidity was not beneficial for arthritis development and its mechanism might be associated with xylitol and L-pyroglutamic acid.
34949931 Jintiange Capsule Alleviates Rheumatoid Arthritis and Reverses Changes of Serum Metabolic 2021 PURPOSE: Jintiange capsule (JTG), an approved drug developed as a substitute for tiger bone (TB), has been clinically applied for osteoporosis therapy since 2003. The drug is composed of bionic TB powder, in which peptides and proteins are primarily enriched from other bone extracts. However, as a precious material of traditional Chinese medicine (TCM), TB has been mainly understood and used in TCM to relieve osteoporosis, rheumatoid arthritis and bone injury. Inspired by those, the purpose of this study was to investigate whether JTG also had an effect on relieving rheumatoid arthritis in collagen-induced arthritic (CIA) rats and explore potential mechanism from the perspective of serum metabolic profile changes. METHODS: JTG was analyzed using Nano LC-MS/MS and orally administered in CIA rats for 6 weeks. After administration, intervention effects of JTG on synovial inflammation, bone micro-architecture and bone metabolism were studied, and the impact of JTG on serum metabolic profiles in CIA rats was investigated by metabolomics. RESULTS: Nine bioactive peptides were identified in JTG. In animal treatments, JTG alleviated paw swelling (P < 0.01), arthritic severity (P < 0.01) and synovial tissue proliferation, as well as inflammatory cell infiltration of ankle joint, decreased bone loss, improved microstructure of bone in CIA rats by regulating bone absorption and formation, specifically increasing bone mineral density (BMD) (P < 0.05), bone volume fraction (BVF) (P < 0.05), trabecular number (Tb.N) (P < 0.05) and decreasing trabecular separation (Tb.Sp) (P < 0.05). Besides, serum IL-6 was down-regulated remarkably in CIA rats (P < 0.05). Furthermore, metabolomics analysis revealed that 32 metabolites were regulated significantly (P < 0.05) by comparison between CIA model and JTG in 360 mg/kg dose. The pathway analysis implied that JTG was involved in regulation of biosynthesis of phenylalanine. CONCLUSION: JTG alleviates rheumatoid arthritis and reverses changes in serum metabolic profile in CIA rats.
34791054 mTOR activation in CD8+ cells contributes to disease activity of rheumatoid arthritis and 2021 Nov 13 OBJECTIVE: This study aimed to understand the role of mTOR in CD8+ cells in the pathogenicity of rheumatoid arthritis (RA) and the changes after treatment with biologic drugs. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 17 healthy controls and 86 patients with RA. Phosphorylation of mTOR (p-mTOR) and its clinical relevance were evaluated. The role of mTOR in CD8+ cells was also examined in vitro. RESULTS: Patients with RA who had a moderate or high disease activity, were biologic-naïve, and were refractory to MTX were enrolled in this study. The p-mTOR levels in CD8+ cells were higher in patients with RA than in healthy controls, and they positively correlated with the disease activity in such patients. However, after one year of treatment with TNF inhibitors, the p-mTOR levels in CD8+ cells were suppressed and showed a positive correlation with the treatment response, which was not observed in the abatacept-treatment group. In vitro stimulation of CD8+ cells with anti-CD3 and anti-CD28 antibodies induced mTOR phosphorylation and increased the production of granzyme B, GNLY, TNF-α, and IFN-γ but decreased the production of granzyme K. However, on treatment with TNF inhibitors, p-mTOR levels in CD8+ cells and granzyme B production decreased, while granzyme K production increased. The production of GNLY and IFN-γ was not affected by the TNF inhibitors. CONCLUSION: These results suggested that mTOR activation in CD8+ cells may be a novel evaluation marker for RA disease activity and a predictive marker of therapeutic response to TNF inhibitors.
34765622 Serum Human Epididymis Protein 4 as a Novel Biomarker in Identifying Patients With Interst 2021 Objective: Human epididymis protein 4 (HE4) have been implicated in the pulmonary involvements. We aimed to investigate the clinical utility of HE4 in clinical stratification in patients with rheumatoid arthritis (RA). Methods: This study included a discovery cohort comprising 70 RA patients and 64 healthy controls (HCs), and a validation cohort comprising 98 RA patients and 75 HCs. Human epididymis protein 4 were determined by electrochemical luminescence analyzer. Results: The levels of HE4 were significantly elevated in patients with RA compared to HCs. The positive rates of HE4 in patients with RA and HCs were 50.0% and 0, respectively, in the discovery cohort and 53.1 and 1.3%, respectively, in the validation cohort. When RA patients were subgrouped according to HE4 status, HE4-positive group displayed higher prevalence of interstitial lung disease (ILD) compared to HE4-negative group (28.6 vs. 11.4% in discovery cohort and 57.7 vs. 8.7% in the validation cohort). A positive correlation between the levels of HE4 with the degree of lung impairment was identified. Receiver operating curve (ROC) analysis revealed an optimal cut-off value of 104.3 pmol/L in HE4 for distinguishing RA-ILD from RA-non ILD with the areas under the curve (AUC) of 0.790. Multivariate logistic regression analysis illustrated that high levels of HE4 independently identified patients with RA-ILD (OR, 9.080, p < 0.001). Conclusion: Our findings showed a novel role of HE4 in RA risk stratification, suggest that introducing HE4 to the current RA test panel may serve as an indicator in identifying RA patients for further RA-ILD workups, such as high-resolution computed tomography (HRCT).
34703332 Real-World Treatment Patterns and Outcomes from an Electronic Medical Records Database for 2021 PURPOSE: Repository corticotropin injection (RCI; Acthar(®) Gel) is a naturally sourced mixture of adrenocorticotropic hormone analogs and other pituitary peptides that exerts anti-inflammatory and immunomodulatory properties via melanocortin receptors. RCI is approved as a short-term adjunctive therapy for rheumatoid arthritis (RA) and is typically used in patients with refractory RA. The objective of this study was to describe real-world outcomes of RA patients treated with RCI by retrospective analysis of an electronic medical records (EMR) database. PATIENTS AND METHODS: EMR data were obtained from the United Rheumatology-Normal Integrated Community Evidence (UR-NICE(TM)) data repository for patients who used RCI for the treatment of RA. Demographics, comorbidities, disease history, medications, and laboratory evaluations 365 days prior to and 365 days after initiation of RCI were examined. RESULTS: The patient cohort was predominantly White females with a mean age of 60 years and high RA activity prior to RCI therapy. Clinical measures of disease severity indicated that patients had high RA activity before starting RCI therapy. Clinical Disease Activity Index (CDAI) scores were significantly reduced 365 days post-initiation of RCI. Swollen and tender joint counts and patient-reported outcomes, including Routine Assessment of Patient Index Data 3 (RAPID3), Physician Global Assessment, and patient assessment of pain severity were also significantly lower. The number of patients taking conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), biologic (b) DMARDs, nonsteroidal anti-inflammatory drugs (NSAIDS), and opioids decreased, as did the number of drugs tried within each class for csDMARDs, bDMARDs, NSAIDs, and glucocorticoids. CONCLUSIONS: These findings suggest that RCI significantly improves clinical outcomes of RA and decreases the need for concomitant medications for up to 1 year following initiation of therapy. The study provides valuable insights into the use of RCI and management of these difficult-to-treat RA patients during routine clinical practice.
34349639 The Cardiovascular Risks of Fostamatinib in Patients with Rheumatoid Arthritis: A Systemat 2021 Objective: This systematic review and meta-analysis is aimed at assessing the risks of cardiovascular adverse events in patients with rheumatoid arthritis (RA) who have been treated with fostamatinib. Methods: The electronic databases of OVID Medline, OVID EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science were searched to identify studies that reported cardiovascular events or hypertension in RA patients treated with fostamatinib. Two reviewers separately and simultaneously screened the retrieved studies based on study selection criteria, collected data and performed methodological quality assessments. The effect size of meta-analysis was estimated by the Peto odds ratio (OR) or relative risk (RR) with 95% confidence intervals (95%CI). Funnel plot was used to estimate publication bias and sensitivity analysis was performed to test the robustness of the results. Results: A total of 12 trials composed of 5,618 participants with low to moderate risk of bias were included. In comparison to the placebo, the use of fostamatinib was found to elevate the risk of hypertension (RR=3.82, 95%CI 2.88-5.05) but was not associated with the risks of all-cause death (Peto OR=0.16, 95%CI 0.02-1.24), major adverse cardiovascular events (Peto OR=1.24, 95%CI 0.26-5.97), pulmonary heart disease and disease of pulmonary circulation (Peto OR=1.23, 95%CI 0.13-11.87), in addition to other forms of heart disease (Peto OR=1.96, 95%CI 0.72-5.38). Furthermore, sensitivity analysis showed no significant change in effective trends and no publication bias was found. Conclusion: Fostamatinib is associated with increased risk of hypertension; however, no increased risks of cardiovascular events were observed. Further well-planned cohort studies with large study populations and longer follow-up times are needed to elucidate the outcomes. Systematic Review Registration: [PROSPERO], identifier [CRD42020198217].
34122106 The Therapeutic Landscape of Rheumatoid Arthritis: Current State and Future Directions. 2021 Rheumatoid arthritis (RA) is a debilitating autoimmune disease with grave physical, emotional and socioeconomic consequences. Despite advances in targeted biologic and pharmacologic interventions that have recently come to market, many patients with RA continue to have inadequate response to therapies, or intolerable side effects, with resultant progression of their disease. In this review, we detail multiple biomolecular pathways involved in RA disease pathogenesis to elucidate and highlight pathways that have been therapeutic targets in managing this systemic autoimmune disease. Here we present an up-to-date accounting of both emerging and approved pharmacological treatments for RA, detailing their discovery, mechanisms of action, efficacy, and limitations. Finally, we turn to the emerging fields of bioengineering and cell therapy to illuminate possible future targeted therapeutic options that combine material and biological sciences for localized therapeutic action with the potential to greatly reduce side effects seen in systemically applied treatment modalities.
34093035 The Impacts of IL1R1 and IL1R2 Genetic Variants on Rheumatoid Arthritis Risk in the Chines 2021 BACKGROUND: Rheumatoid arthritis (RA), an autoimmune systemic inflammatory disease, largely resulted from genetic factor. Our purpose was to explore the association for IL1R1 and IL1R2 genetic variants with RA susceptibility in the Chinese Han population. PATIENTS AND METHODS: A total of 508 RA patients and 494 controls were involved in this case-control study; single-nucleotide polymorphisms (SNPs) genotyping was identified by the Agena MassARRAY platform. The relationship between polymorphisms and RA susceptibility was calculated using the Pearson's Chi-square test with odds ratios and 95% confidence intervals (CIs) in multiple genetic models. The Pearson's Chi-square test and Student's t-test were used for sample basic characteristic analysis. And linkage disequilibrium (LD) analysis and haplotype analysis were performed by logistic regression analysis. RESULTS: The result from this study showed that rs2072472 (IL1R2) was an increased risk factor of RA (adjusted OR = 1.41, p = 0.011). Stratified analysis indicated SNPs rs10490571, rs956730, rs3917318 of IL1R1, and SNPs rs4851527, rs719250, rs3218896, rs3218977, rs2072472 of IL1R2 had impacts on RA risk after stratification based on gender and average age (54 years). Finally, haplotype analysis revealed that A(rs3218977)A(rs2072472) haplotype in IL1R2 was related to a decreased RA risk (adjusted OR = 0.79; 95% CI = 0.65-0.94; p = 0.010). Yet, rs3917225(IL1R1) and rs11674595(IL1R2) were not significant in RA association analysis. CONCLUSION: We determined SNPs (rs3917318, rs956730, rs1049057) of IL1R1 and SNPs (rs3218977, rs719250, rs4851527, rs3218896, rs2072472) of IL1R2 were correlated with the RA susceptibility in the Chinese Han population.
33968956 Real-World Methotrexate Dose on Clinical Effectiveness and Structural Damage of Certolizum 2021 Objective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated-conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF. Patients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25-83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1- <8 mg, n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate. Results: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage. Conclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.
33226566 A Review of the Prevalence and Unmet Needs in the Management of Rheumatoid Arthritis in Af 2021 Mar Estimates of the global prevalence of rheumatoid arthritis (RA) range from 0.24 to 1%, but vary considerably around the globe. A variation in RA prevalence is also expected across Africa and the Middle East, due to ethnic, climate, and socioeconomic differences. To assess the prevalence of RA in Africa and the Middle East, we searched Medline (via PubMed) and databases of major rheumatology conferences. Seventeen journal articles and 0 abstracts met the inclusion criteria. Estimated prevalence ranged from 0.06 to 3.4%. Most studies reported values near or below 0.25%. Consistent with data from other regions, RA was more prevalent among urban than rural populations, and among women than men. The women:men prevalence ratio ranged from 1.3:1 to 12.5:1, which suggests notable differences from the global average of 2:1. Relative increases in prevalence were observed in North Africa and the Middle East (13% since 1990) and Western Sub-Saharan Africa (14%), whereas rates in Eastern, Central, and Southern Sub-Saharan Africa show decreases (4-12%). Low disease awareness, delays to visit rheumatologists, and socioeconomic factors appear to hinder early diagnosis and aggressive treatment. Few countries have developed RA-specific treatment guidelines, and many physicians and patients face limited access to even basic treatments. An improved understanding of the epidemiology and management of RA, and the related socioeconomic consequences is necessary, so that targeted attempts can be made to encourage early diagnosis and treatment.
34830541 The Relationship between Platelet Indices and Ultrasound, Clinical, Laboratory Parameters 2021 Nov 12 (1) Background: A proper assessment of disease activity is crucial for the management of a patient with rheumatoid arthritis (RA). Platelets seem to be involved in joint inflammation pathophysiology. Platelet indices (PIs) are markers of platelet activation, and include platelet count (PC), mean platelet volume (MPV), platelet distribution width (PDW) and plateletcrit (PCT). The purpose of the study was to assess the relationship between PIs and disease activity markers, both systemic (clinical, laboratory) and local (ultrasound, US), in patients with RA; (2) Methods: The study group consisted of 131 consecutive RA patients. The following assessments were performed: joint counts, Disease Activity Score (DAS28), complete blood cell counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and US of 24 small joints; (3) Results: Mean values of PIs remained within the normal reference ranges. Values of PC, PCT, PDW were significantly associated with disease activity markers, both clinical (DAS28, joint counts) and laboratory (CRP, ESR). In patients with high disease activity, PC, PCT were significantly higher and PDW lower. PC was positively correlated with Power Doppler US (PDUS) score. In patients with features of RA severity (antibodies positivity, extra-articular manifestations) PC and PCT were positively associated with all US parameters (Grey Scale US, PDUS, Global scores); (4) Conclusions: In patients with RA, PC and PCT may serve as positive disease activity markers and PDW may serve as a negative marker. PIs may be used as reliable, inexpensive markers of RA systemic activity; they may also serve as markers of local inflammation in the joints affected by RA.
34668452 Diet quality and disease activity in rheumatoid arthritis. 2021 Oct 20 Objective:This study examined associations between diet quality and disease activity in adults with rheumatoid arthritis (RA). Perceived stress was also compared to diet and disease activity. Methods: In a cross-sectional design, 50 adults with RA were recruited. The Arizona Food Frequency Questionnaire was used to measure dietary intake (four weeks) and diet quality scores were calculated with the Healthy Eating Index - 2015. Perceived stress was measured with the Perceived Stress Scale. Disease activity was measured with the Health Assessment Questionnaire-Disability Index and Pain Scale, erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein, and Disease Activity Score Including 28 Joints-ESR. Results: Diet quality (56; SD ± 12) in participants was lower than the national mean (59). Age (p = 0.015) and gender (p = 0.003) were associated with higher diet quality. The belief that diet affects RA disease activity was reported by 44% of the participants, and these participants were significantly more likely to report dietary changes (p < 0.0001). Higher educational level (at least some college) was associated with this belief (B = -1.535, p = 0.023). Participants with lower diet quality also had significantly higher pain (B = -0.396, p = 0.022) and ESR scores (p = 0.019). Women were more likely to have higher HAQ-DI scores (B = 0.570, p = 0.001). Perceived stress was significantly associated with HAQ-DI and pain scores (B = 0.445, p = 0.001 and B = 0.289, p = 0.042, respectively). Medical cannabis was reportedly used by 8% of participants. Conclusion: In RA patients, lower diet quality may be associated with more pain and inflammation, and perceived stress may be associated with higher disability and disease activity.
34366836 Switching and Discontinuation Pattern of Biologic Disease-Modifying Antirheumatic Drugs an 2021 Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease characterized by persistent joint synovial inflammation and swelling, leading to cartilage damage and bone erosion. This retrospective, longitudinal study is to evaluate the treatment patterns of biologic-naïve RA patients receiving index biologic disease-modifying antirheumatic drug (bDMARD) and tofacitinib by the data of Taiwan National Healthcare Insurance Claims and the Death Registry between 2012 and 2017. Drug survival and treatment patterns were determined by investigating the occurrence of switching and discontinuation from index treatment. At baseline, 70.0% of patients used tumor necrosis factor inhibitors (TNFi) bDMARD with the majority taking etanercept (27.0%) or adalimumab (26.2%). During the follow-up period, 40.0% (n = 3,464) of index users switched (n = 1,479) or discontinued (n = 1,985) the treatment with an average incidence rate of 0.18 per patient-year. Among the six index treatment groups, drug survival was the lowest for adalimumab and highest for tocilizumab. When compared with etanercept, only adalimumab had a higher cumulative probability of switching/discontinuation (adjusted HR = 1.17, 95% CI: 1.08-1.28), whereas golimumab, non-TNFi bDMARDs and tofacitinib were significantly less probable to switch or discontinue. For patients switching the index treatment, tocilizumab (31.2%) and tofacitinib (23.4%) were the main regimens being switched to. In addition, 48.2% of patients who discontinued the index treatment received further retreatment, and 63.8-77.0% of them were retreated with same agent. In conclusion, this population-based study found that TNFi were the preferred agents as the index treatments during 2012-2017. Non-TNFi and tofacitinib were more common second-line agents being switched to. Nearly half of discontinued patients received retreatment, with a majority receiving the same agent.
34325604 Circ_0003972 Promotes the Proliferation and Inflammation of Fibroblast-like Synovial Cells 2021 Jul 29 BACKGROUND: Circular RNAs (circRNAs) have been shown to play an important role in rheumatoid arthritis (RA) progression. This study aims to explore the role and mechanism of circ_0003972 in RA progression. METHODS: Quantitative real-time PCR was used to determine gene expression. The proliferation and apoptosis of human RA fibroblast-like synovial (HFLS-RA) cells were measured using cell counting kit 8 assay, EdU staining and flow cytometry. Western blot analysis was performed to measure protein expression, and ELISA assay was used to examine the concentrations of inflammation factors. The interaction between miR-654-5p and circ_0003972 or FZD4 was confirmed by dual-luciferase reporter assay and RIP assay. RESULTS: Circ_0003972 was highly expressed in RA patients and HFLS-RA cells. Circ_0003972 knockdown inhibited the proliferation, inflammation, while promoted the apoptosis of TNFα-induced HFLS-RA cells. MiR-654-5p was downregulated in RA patients and HFLS-RA cells, and it could be sponged by circ_0003972. MiR-654-5p inhibitor reversed the effect of circ_0003972 silencing on the proliferation, inflammation, and apoptosis of TNFα-induced HFLS-RA cells. Frizzled-4 (FZD4) could be targeted by miR-654-5p, and its expression was positively regulated by circ_0003972. Furthermore, FZD4 overexpression also reversed the effects of miR-654-5p on proliferation, inflammation and apoptosis in TNFα-induced HFLS-RA cells. CONCLUSION: Our data suggested that circ_0003972 might promote the proliferation and inflammation of HFLS-RA cells to accelerate RA progression via regulating miR-654-5p/FZD4.
33604347 The Association Between CTLA-4, CD80/86, and CD28 Gene Polymorphisms and Rheumatoid Arthri 2021 Background: Rheumatoid arthritis (RA) is related to several pivotal susceptibility genes, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and costimulatory molecule (CD80/CD86) genes. Although the connection between polymorphisms of CTLA-4 and CD86 genes in different populations of RA have been studied extensively, the results are controversial. Objective: To clarify the correlation in the Chinese Han population between CTLA-4, CD80/86, and CD28 gene polymorphisms, and RA susceptibility. Methods: A case-control study (574 RA patients and 804 controls) was conducted to determine the correlation between CTLA-4 rs231775 and rs16840252 gene polymorphisms, CD86 rs17281995 gene polymorphisms, and the risk of RA for the Chinese Han population. Furthermore, an additional meta-analysis, including three single nucleotide polymorphisms (SNPs) (CTLA-4 rs231775, CTLA-4 rs3087243, and CTLA-4 rs5742909) from 32 citations, including 43 studies, 24,703 cases and 23,825 controls was performed to elucidate the relationship between known SNPs in the CTLA-4 genes and RA for more robust conclusions. Results: The results showed that CTLA-4 rs231775 gene polymorphism decreased the RA risk (GA vs. AA, OR = 0.77, P = 0.025), whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA susceptibility. Stratification analyses by RF, ACPA, CRP, ESR, DAS28, and functional class identified significant associations for CTLA-4 rs231775 and rs16840252 gene polymorphisms in the RF-positive and RF-negative groups. A meta-analysis of the literature on CTLA-4 gene polymorphisms and RA risk revealed that the risk of RA was decreased by CTLA-4 rs231775 gene polymorphisms. Conclusions: The CTLA-4 rs231775 gene polymorphism decreased the risk of RA, whereas CTLA-4 rs16840252 and CD86 rs17281995 gene polymorphisms were not related to RA risk. A meta-analysis indicated that CTLA-4 rs231775 and rs3087243 gene polymorphisms decreased the risk of RA. To support these analytical results, additional clinical cases should be investigated in further studies.
33355913 How to Define Boolean Low Disease Activity in Rheumatoid Arthritis: Experience from a Larg 2021 Mar INTRODUCTION: The aim of this work is to propose Boolean-defined low disease activity (LDA) and to test its utility in rheumatoid arthritis (RA). METHODS: We used data from a longitudinal academic clinical database of RA in Peking University First Hospital over a decade. The initial proposal of Boolean-defined LDA was proposed with ascending thresholds from 2 to 5 in steps of 1 (referred to as Boolean-LDA2/3/4/5). Agreement and residual swollen joint count (SJC) pattern with the index-based [Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)] LDA was analyzed. To confirm discovery, we randomly classified RA patients in a 3:2 ratio into either analysis cohort or validation cohort. RESULTS: In total, 4881 visits of 672 patients were included in the analysis cohort. Of these visits, the frequencies of achieving LDA were 71.9% (SDAI), 73.6% (CDAI), 52.8% (Boolean-LDA2), 65.2% (Boolean-LDA3), 73.5% (Boolean-LDA4), and 80.7% (Boolean-LDA5). High consistency and similar SJC pattern with SDAI-LDA or CDAI-LDA were observed in Boolean-LDA3 (kappa = 0.796, 0.771). Further analysis found meeting SDAI-LDA but not Boolean-LDA3 was largely attributable to higher patient's global assessment (PGA) scores (62.9%). In further modification of Boolean-LDA3, better agreement with SDAI-LDA or CDAI-LDA was reached when exclusively increasing PGA cutoffs to 4.0, 4.5 or replacing PGA by evaluator's global assessment (EGA) with cutoff to 3.0. These findings were further replicated in randomly generated validation cohort of 449 patients with 3306 clinic visits. CONCLUSIONS: Using cutoff of 3 to Boolean-LDA provides great clinical utility with index-based LDA, especially when exclusively increasing PGA cutoffs to 4.0, 4.5 or replacing PGA by EGA with cutoffs to 3.0. This may deserve being considered in clinical practice.
33246122 Dendropanax dentiger (Harms) Merr. root and its major constituents exert therapeutic effec 2021 Mar 1 ETHNOPHARMACOLOGICAL RELEVANCE: The root of Dendropanax dentiger (Harms) Merr. is a pivotal folk Chinese medicine against rheumatoid arthritis (RA) with no scientific validation. AIM OF THE STUDY: This study was conducted to explore the anti-RA effect of the D. dentiger extract on complete Freund's adjuvant-induced arthritis (AIA) in rats and identified its major bio-constituents. MATERIALS AND METHODS: Dendropanax dentiger roots extracts (127.5, 255.0 and 510.0 mg/kg, once daily) were orally at day 7 post-administration adjuvant and lasting for 22 days. The therapeutic effects of D. dentiger roots extract on AIA rats were investigated by body weight growth, arthritis score, thymus and spleen indices, and histopathological analysis. Moreover, the levels of rheumatoid factor (RF), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-4, IL-6, IL-10, IL-17, cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and matrix metalloproteinase-2 (MMP-2) were also evaluated. Finally, the major constituents were isolated and identified from D. dentiger roots extract with COX-2 inhibitory and antioxidant activities. RESULTS: Dendropanax dentiger roots extract remarkably alleviated the histological lesions of knee joint, increased body weight growth, decreased arthritis score, and reduced thymus and spleen indices in model rats. In parallel, the levels of RF, CRP, TNF-α, IL-1β, IL-6, IL-17, COX-2, 5-LOX and MMP-2 were observably downregulated, while the levels of IL-4 and IL-10 were prominently upregulated in D. dentiger roots extract-treated rats. Meanwhile, 14 compounds were isolated and identified from D. dentiger roots extract, and four phenol derivatives (1, 4, 6 and 7) exhibited remarkable COX-2 inhibitory and antioxidant activities. CONCLUSIONS: Dendropanax dentiger roots extract possessed persuasive anti-RA effect may be partly responsible for phenol derivatives via modulation of inflammatory biomarkers, and supports the traditional folk use of D. dentiger in China.