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ID PMID Title PublicationDate abstract
34698809 Work participation is reduced during the development of RA, months before clinical arthrit 2022 May 30 OBJECTIVES: We investigated whether work participation is affected in patients with arthralgia during transition to RA. Arthralgia patients with symptom resolution and early RA patients at diagnosis were used as a reference. METHODS: Three groups of patients were studied: arthralgia patients converting to RA (n = 114), arthralgia patients with spontaneous symptom resolution (n = 57), and early RA patients (n = 617). Both presenteeism (i.e. working while sick, scale 0-10) and absenteeism (i.e. sick leave) were taken into account. Work ability 1 year prior to clinical arthritis was estimated (in absolute numbers). The course of work restriction over time was studied using linear mixed models (β coefficient; delta per month) within each patient group. RESULTS: One-year prior to the development of clinical arthritis, mean presenteeism was 7.0 (95% CI 5.8, 8.1) in patients with arthralgia, indicating 30% loss, and further worsened to 6.1 (95% CI 5.3, 6.6) at RA diagnosis, thus indicating 39% loss. In early RA patients, presenteeism improved over time after DMARD initiation (β 0.052 per month 95% CI 0.042, 0.061, P < 0.0001). Presenteeism also improved in arthralgia patients who achieved spontaneous symptom resolution (β 0.063 per month, 95% CI 0.024, 0.10, P = 0.002). Absenteeism did not change significantly in arthralgia patients, but did improve in RA after DMARD-start. ACPA stratification revealed similar results. CONCLUSION: In the months preceding RA, presenteeism was already apparent, and it worsened further during progression to clinical arthritis and diagnosis. This underlines the relevance of the symptomatic pre-RA phase for patients. The observed reversibility in arthralgia patients with symptom resolution may suggest that intervention in pre-RA could improve work participation.
35260022 Current status of shared decision making for rheumatoid arthritis treatment in Japan: a we 2022 May OBJECTIVE: To assess the current status of shared decision making (SDM) in rheumatoid arthritis (RA) clinical practice in Japan from the perspectives of physicians and patients. METHODS: A web-based survey was conducted to recruit patients with RA who were prescribed, for the first time, a conventional synthetic disease-modifying antirheumatic drug (csDMARD) or a biological drug/Janus kinase (JAK) inhibitor, and physicians who prescribed these treatments to patients with RA. The SDM Questionnaire-Physician version (SDM-Q-Doc) and the 9-item SDM Questionnaire (SDM-Q-9) were used to assess the SDM levels of physicians and patients, respectively. The scale ranged from 0 to 100, and higher scores indicated better SDM status. RESULTS: The responses from 107 physicians who treat patients with RA, 107 patients prescribed a csDMARD, and 110 patients prescribed a biological drug/JAK inhibitor were collected. The mean SDM score for SDM-Q-Doc was 74.5 when physicians decided to prescribe a csDMARD and 77.2 when they decided to prescribe a biological drug/JAK inhibitor. However, the mean SDM score for SDM-Q-9 was 62.3 when patients were prescribed csDMARDs and 72.6 when they were prescribed biological drugs/JAK inhibitors. CONCLUSIONS: The results showed differences in SDM level between patients and physicians and, from the patient perspective, between treatment types.
34894248 Impact of social support on severity of depressive symptoms by remission status in patient 2022 Apr 18 OBJECTIVES: We aimed to examine the psychosocial characteristics of patients with rheumatoid arthritis (RA) by remission status and determine the impacts of social support on severity of depressive symptoms. METHODS: We enrolled RA patients aged 40-79 years who visited university hospitals' outpatient clinics. Severity of depressive symptoms (Beck Depression Inventory-II), physical disability (Health Assessment Questionnaire), and support were evaluated. Furthermore, RA disease activity was evaluated by 28-point Disease Activity Score (DAS28) calculation. The independent impacts of instrumental and emotional social support on depressive symptoms by remission status defined as DAS28 score < 2.6 were estimated by multivariable regression analysis. RESULTS: This study included 360 RA patients. In the remission group, emotional support showed a statistically significant negative impact on depressive symptoms, whereas instrumental support had an extremely limited contribution to severity of depressive symptoms. In the non-remission group, instrumental support showed a negative tendency of impact on severity of depressive symptoms, whereas emotional support had a wide range of influence. CONCLUSIONS: Favourable association between emotional support and depressive symptoms is confirmed only among RA patients in remission status. The influence of emotional support in non-remission patients and that of instrumental support regardless of remission status are inconclusive.
35379246 Expression profile of circRNA in peripheral blood mononuclear cells of patients with rheum 2022 Apr 4 BACKGROUND: Circular RNAs (circRNAs) is a newly discovered non-coding RNA that can be used as biomarkers in clinical blood samples. This study aims to screen differentially expressed circular RNAs in PBMCs of patients with rheumatoid arthritis (RA) to determine new biomarkers for the diagnosis of RA. METHODS: The differentially expressed circRNAs in peripheral blood mononuclear cells (PBMCs) of 4 RA patients and 4 healthy participants were screened and analyzed by gene microarray technology. We then validated some of the differentially expressed circRNAs in PBMCs of 20 RA patients, 10 systemic lupus erythematosus (SLE) patients and 20 healthy participants using reverse transcription-quantitative polymerase chain reaction amplification (RT-qPCR). Spearman correlation test was performed to analyze the correlation between differentially expressed circRNAs and clinical variables in RA patients. Receiver operating characteristic (ROC) curves were calculated to evaluate the diagnostic value of circRNAs. RESULTS: Differential analysis obtained 149 circRNAs with significant up-regulated expression and 250 circRNAs with significant down-regulated expression, which predicted the miRNA targets and binding sites. Compared with SLE and health control group, hsa_circ_101328 was found to be a common gene with differential expression of RA. Besides, correlation analysis revealed significant correlation between hsa_circ_101328 and positive CRP. ROC curve analysis showed that hsa_circ_101328 has the potential of RA diagnosis. CONCLUSION: We identified some dysregulated circRNAs in PBMCs from RA patients, and hsa_circ_101328 may be a novel and effective biomarker for early diagnosis of RA.
35257247 Associations between inflammation-related LL-37 with subgingival microbial dysbiosis in rh 2022 May OBJECTIVE: This study investigated the subgingival microbial profile of rheumatoid arthritis (RA) patients and its associations with disease parameters and the inflammation-related antimicrobial peptide, LL-37. METHODS: RA and non-RA (NRA) patients were assessed for periodontal status and divided into periodontitis (CP), gingivitis (G), and healthy (H) groups. Subgingival plaque 16s rRNA gene sequencing data was processed and analyzed using the CLC Genomic Workbench (Qiagen). Bacterial diversity and co-occurrence patterns were examined. Differential abundance between groups was also investigated. Associations between bacterial genera with disease parameters and LL-37 levels were explored qualitatively using canonical correlation analysis. RESULTS: Subgingival microbial community clustered in CP status. Co-occurrence network in NRA-H was dominated by health-associated genera, while the rest of the networks' key genera were both health- and disease-associated. RA-CP displayed highly inter-generic networks with a statistically significant increase in periodontal disease-associated genera (p<0.05). In NRA-H, disease parameters and LL-37 were correlated positively with disease-associated genera while negatively with health-associated genera. However, in the remaining groups, mixed positive and negative correlations were noted with genera. CONCLUSION: RA patients demonstrated subgingival microbial dysbiosis where the bacteria networks were dominated by health- and disease-associated genera. Mixed correlations with disease parameters and LL-37 levels were noted. CLINICAL RELEVANCE: The subgingival microbial dysbiosis in RA may predispose these patients to developing periodontal inflammation with an associated detrimental effect on host immune responses. Routine periodontal assessment may allow initiation of treatment strategies to minimize the effects of gingival inflammation on the existing heightened immune response present in RA patients.
35027028 Serum rheumatoid factor IgA, anti-citrullinated peptide antibodies with secretory componen 2022 Jan 13 OBJECTIVE: Rheumatoid arthritis (RA) is often complicated with chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway disease, which occur as extra-articular manifestations. CLD in RA have been associated with the production of rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), or anti-carbamylated protein (CarP) antibody. However, few validation studies have been performed thus far. In the present study, we investigated the association of RF, ACPA, and anti-CarP antibodies with RA complicated with CLD. METHODS: Sera from RA patients with or without CLD were collected. The levels of serum RF, RF immunoglobulin A (IgA), ACPA IgG, ACPA IgA, and ACPA secretory component (SC) were measured using enzyme-linked immunosorbent assay. RESULTS: The comparison of RA patients with and without CLD showed that RF IgA was associated with ILD (mean ± standard deviation: 206.6 ± 400.5 vs. 95.0 ± 523.1 U/ml, respectively, P = 1.13 × 10(- 8)), particularly usual interstitial pneumonia (UIP) (263.5 ± 502.0 U/ml, P = 1.00 × 10(- 7)). ACPA SC was associated with RA complicated with ILD (mean ± standard deviation: 8.6 ± 25.1 vs. 2.3 ± 3.4 U/ml, respectively, P = 0.0003), particularly nonspecific interstitial pneumonia (NSIP) (10.7 ± 31.5 U/ml, P = 0.0017). Anti-CarP antibodies were associated with RA complicated with ILD (0.042 ± 0.285 vs. 0.003 ± 0.011 U/ml, respectively, P = 1.04X10(- 11)). CONCLUSION: RF IgA and ACPA SC in RA were associated with UIP and NSIP, respectively, suggesting different specificities in patients with RA. Anti-CarP antibodies were associated with ILD in RA. These results may help elucidate the different pathogeneses of UIP and NSIP in RA.
35181688 Syndecan-2 regulates PAD2 to exert antifibrotic effects on RA-ILD fibroblasts. 2022 Feb 18 Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD.
34785170 Carotid Artery Pathology in Inflammatory Diseases. 2022 Mar There is considerable evidence that patients with inflammatory conditions are at higher risk of developing cardiovascular (CV) disease including carotid artery stenosis. CV disease accounts for 35-50% of the excess mortality in patients with inflammatory diseases such as rheumatoid arthritis, with cerebrovascular disease being the second leading cause of death. We review current evidence regarding the association of inflammatory conditions and specifically carotid artery disease. Clinical epidemiological observations suggest that mechanisms other than classic risk factors may promote accelerated atherogenesis in rheumatoid and other inflammatory arthritis and carotid artery disease is increased in individuals with these conditions. Additional studies to better understand the underlying mechanisms and targeted strategies to mitigate such risk are indicated. For now, lifestyle modifications, aggressive treatment of risk factors and lipid lowering therapy in appropriate individuals is indicated.
35014025 A large-scale genetic correlation scan between rheumatoid arthritis and human blood metabo 2022 May BACKGROUND: Rheumatoid arthritis (RA) is a complex disease with several risk factors. The effects of blood metabolites on RA remains elusive. We conducted a genetic correlation scan to explore the relevance of blood metabolism with RA. METHOD: The genome-wide association study (GWAS) dataset of RA(2014) was obtained from a large scale meta-analysis, including 29,880 RA cases and 73,758 controls. The GWAS datasets of 529 blood metabolites were derived from a recently published study. Linkage disequilibrium score regression (LDSC) analysis was performed to evaluate the genetic correlation between each of the blood metabolite and RA(2014). Then we used another GWAS data of RA(2021) and blood metabolites for LDSC analysis to verify whether the same blood metabolites were genetically correlated with RA. Mendelian randomization (MR) analysis was then applied to assess the causal relationship between the significant blood metabolites identified by LDSC and RA(2014). RESULT: Six suggestive blood metabolites were identified for RA(2014), including 10-Undecenoate (correlation coefficient = -0.1686, p value = 0.0394), isovalerylcarnitine (correlation coefficient = 0.1660 p value = 0.0273), proline (correlation coefficient = 0.1647, p value = 0.0145), pantothenate (correlation coefficient = -0.3311, p value = 0.0078), tyrosine (correlation coefficient = 0.1735, p value = 0.0010), X-14057 (correlation coefficient = 0.2695, p value = 0.0373). We identified four blood metabolites may have genetic correlations with RA(2021), including oleoylcarnitine (correlation coefficient = 0.1927, p value = 0.0432), levulinate (correlation coefficient = 0.1008, p value = 0.0413), pantothenate (correlation coefficient = -0.2311, p value = 0.0180), tyrosine (correlation coefficient = 0.1301, p value = 0.0078). There are two identical blood metabolites were found to be related with RA: pantothenate and tyrosine. It was found that there was a significant positive causal relationship between RA (exposure) and 10-Undecenoate (outcome) (β = 0.0077, SE = 0.0033, p = 0.0192) by MR analysis. CONCLUSION: We investigated the genetic correlation and causal relationship between RA and blood metabolites by LDSC and MR analysis. These results may provide novel insights into the genetic mechanism of RA.
35570630 [Surgical planning and mid-term effectiveness of four major lower extremity arthroplasties 2022 May 15 OBJECTIVE: To investigate the surgical planning and the mid-term effectiveness of four major lower extremity arthroplasties (4JA) in patients with rheumatoid arthritis (RA). METHODS: A clinical data of 25 patients with RA, who received 4JA and were followed up more than 3 years between June 2012 and September 2018, was retrospectively analyzed. There were 3 males and 22 females, with an average age of 48.6 years (range, 27-80 years). The body mass index ranged from 16.0 to 28.4 kg/m (2), with an average of 20.48 kg/m (2). The duration of RA ranged from 2 to 35 years (median, 21 years). There were 8 cases (12 sides) of knee valgus, 6 cases (12 side) of acetabular retraction, and 5 cases (10 sides) of hip stiffness. Among them, 20 patients underwent hip surgery first, and 5 patients underwent knee surgery first. Hip joint function was evaluated by Harris score, Hip Disability and Osteoarthritis Outcome Score (HOOS), hip range of motion, and Trendelenburg sign; knee joint function was evaluated by American Hospital for Special Surgery (HSS) score, knee range of motion and muscle strength, and a timed up and go (TUG) test was performed at last follow-up. X-ray films were used to observe whether the prosthesis was loose or displaced. RESULTS: All 25 patients completed 4JA. Only 1 patient (1 side) had incision infection after operation, 3 patients (3 sides) had proximal femur fractures during operation. All patients were followed up 3.0-8.8 years, with an average of 5.8 years. At last follow-up, the Harris score, HOOS score, and range of motion of flexion, extension, and abduction of the hip joint significantly improved when compared with those before operation, and the patients with positive Trendelenburg sign decreased. The HSS score and range of motion of flexion and extension of the knee joint also significantly improved when compared with those before operation. There were significant differences in all indexes between pre- and post-operation ( P<0.05). The muscle strength was grade V. The TUG test ranged from 7.8 to 15.34 seconds (mean,10.79 seconds). X-ray films showed the prosthesis was not loose or displaced. CONCLUSION: When RA patients receive 4JA, adequate preoperative evaluation, rational selection of the timing and sequence of surgery, and maximal restoration of lower limb alignment can achieve good mid-term effectiveness.
33565350 Does exercise therapy improve patient-reported outcomes in rheumatoid arthritis? A systema 2022 Jan 5 OBJECTIVES: This study aimed to evaluate the impact of exercise therapy on patient-reported outcomes (PROs) in rheumatoid arthritis (RA) as part of the process of updating the 2020 Japanese guidelines for the management of RA according to the Grading of Recommendations, Assessment, Development, and Evaluation system. METHODS: We searched PubMed, Japana Centra Revuo Medicina Web, and the Cochrane Library (from 2009 to 2018) to identify articles that evaluated PROs of exercise therapy and RA disease activity. RESULTS: A total of 662 articles were identified, including nine RCTs, and meta-analyses were performed on six RCTs on systemic exercise therapy and three RCTs on upper extremity exercise therapy. Analyzed exercise therapies were diverse, differing in target population, intervention method, and duration. Significant improvements were observed in the Health Assessment Questionnaire Disability Index (mean difference -0.35, 95% confidence interval (CI): -0.60 to -0.10), pain (standardized mean difference -2.04, 95% CI: -3.77 to -0.32), and SF-36. For upper extremity exercise therapy, significant improvements in PROs (Disabilities of the Arm, Shoulder, and Hand Questionnaire, Michigan Hand Outcome Questionnaire) were observed. CONCLUSION: Exercise therapy in RA treatment improves patient subjective assessment of pain, physical function, and quality of life.
35380780 Activatable Near-Infrared Fluorescent Organic Nanoprobe for Hypochlorous Acid Detection in 2022 Apr 19 Early diagnosis of rheumatoid arthritis (RA) is crucial to prevent deterioration and improve the prognosis of disease outcome. However, current clinical diagnostic methods are unable to achieve accurate and early detection of RA. In this work, we designed an activatable organic nanoprobe (ONP-CySe) capable of specific and real-time imaging of ClO(-) in early RA. ONP-CySe comprises a near-infrared fluorescent selenomorpholine-caged cyanine dye as the sensing component and an amphiphilic triblock copolymer triphenyl phosphine derivative for mitochondria targeting. Our results showed that ONP-CySe successfully detected elevated levels of ClO(-) in the mitochondria of macrophages with high selectivity, low limit of detection (31.5 nM), excellent photostability, and good biocompatibility. Furthermore, ONP-CySe can also be used to monitor anti-inflammatory responses and efficacies of RA therapeutics, such as selenocysteine and methotrexate, in BALB/c mouse models. Therefore, our research proposes a universal molecular design strategy for the detection of ClO(-), which holds potential for early diagnosis and drug screening for RA.
34896445 Intravenous pegylated liposomal prednisolone outperforms intramuscular methylprednisolone 2022 Jan Glucocorticoids (GCs) are potent anti-inflammatory drugs but their use is limited by systemic exposure leading to toxicity. Targeted GC delivery to sites of inflammation via encapsulation in long-circulating liposomes may improve the therapeutic index. We performed a randomized, double-blind, active-controlled, multi-center study in which intravenously (i.v.) administered pegylated liposomal prednisolone sodium phosphate (Nanocort) was compared to equipotent intramuscular (i.m.) methylprednisolone acetate (Depo-Medrol®; i.e. a current standards-of-care for treating flares in rheumatoid arthritis patients). We enrolled 172 patients with active arthritis who met all eligibility criteria, eventually resulting in 150 patients randomized in three groups: (1) Nanocort 75 mg i.v. infusion plus i.m. saline injection; (2) Nanocort 150 mg i.v. infusion plus i.m. saline injection; and (3) Depo-Medrol® 120 mg i.m. injection plus i.v. saline infusion. Dosing in each group occurred at baseline and on day 15 (week 2). Study visits occurred at week 1, 2, 3, 4, 6, 8 and 12, to assess both efficacy and safety. The primary endpoint was the "European League Against Rheumatism" (EULAR) responder rate at week 1. Safety was determined by the occurrence of adverse events during treatment and 12 weeks of follow-up. Treatment with Nanocort was found to be superior to Depo-Medrol® in terms of EULAR response at week 1, with p-values of 0.007 (good response) and 0.018 (moderate response). Treatments were well tolerated with a comparable pattern of adverse events in the three treatment groups. However, the Nanocort groups had a higher incidence of hypersensitivity reactions during liposome infusion. Our results show that liposomal Nanocort is more effective than Depo-Medrol® in treating patients with rheumatoid arthritis flares and has similar safety. This is the first clinical study in a large patient population showing that i.v. administered targeted drug delivery with a nanomedicine formulation improves the therapeutic index of glucocorticoids.
33152178 Scale Banking for Patient-Reported Outcome Measures That Measure Functioning in Rheumatoid 2022 Apr OBJECTIVE: Functioning is an important outcome for the management of rheumatoid arthritis (RA). Heterogeneity of respective patient-reported outcome measures (PROMs) challenges direct comparisons between their results. This study aimed to standardize reporting of such PROMs measuring functioning in RA to facilitate comparability. METHODS: Common-item nonequivalent group design with the Health Assessment Questionnaire (HAQ) as a common scale across data sets from various countries (including the UK, Turkey, and Germany) to establish a common metric was used. Other PROMs included are the physical function items of the Multidimensional HAQ (MDHAQ), the Disabilities of the Arm, Shoulder, and Hand questionnaire, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the World Health Organization Disability Assessment Schedule II (WHODAS II), the Medical Outcomes Study Short Form 36 (SF-36) health survey, and 4 short forms (20, 10, 6, and 4 physical function items) from the Patient-Reported Outcomes Measurement Information System. As the HAQ includes mobility, self-care, and domestic life items, this study focuses on these 3 domains. PROMs were described using standard error of measurement (SEM) and smallest detectable difference (SDD). A Rasch measurement model was used to create the common metric. RESULTS: The range of the SEM was 0.2 (MDHAQ) to 7.4 (SF-36 health survey physical functioning domain). The SDD revealed a range from 9.7% (WOMAC rating scale) to 33.5% (WHODAS physical functioning domain). PROMs co-calibration revealed fit to the Rasch measurement model. A transformation table was developed to allow exchange between PROM scores. CONCLUSION: Scores between the daily activity PROMs commonly used in RA can now be compared. Factors such as SEM and SDD help to determine the choice of a PROM in clinical practice and research.
35246023 The influences of perfluoroalkyl substances on the rheumatoid arthritis clinic. 2022 Mar 4 BACKGROUND: The effect of environmental factors on genetically susceptible individuals is a basic link in the pathogenesis of rheumatoid arthritis. Perfluoroalkyl substances (PFASs) are a class of synthetic organic fluorine chemicals, which have been mass-produced and widely used in the past 60 years, and also have been shown to be one of the major pollutants affecting human health. The impact of fluoride on the development of Rheumatoid Arthritis (RA) is unclear. This study explored the relationship between common fluoride and clinical manifestations of rheumatoid arthritis. RESULTS: A cohort of 155 patients with RA and 145 health controls in Second Affiliated Hospital of Zhejiang University School of Medicine were investigated. Serum concentrations of all fluoride detected were higher in RA patients than in healthy controls. There were 43 male patients and 112 female patients in the RA cohort. Some of perfluoroalkyl substances (perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorotrdecanoate (PFTrA), perfluorooctanesulfonate (PFOS)) were correlated negatively with the Body Mass Index (BMI); some of them (PFOA, PFNA, PFTrA, PFOS, 8:2 Chlorinated polyfluorinated ether sulfonate (8:2Cl-PFESA)) were correlated positively with the Disease Activity Score 28 (DAS28); two (PFOA, PFOS) of them were correlated positively with the white blood cell count, and one (Perfluoroundecanoate (PFUnA)) of them was correlated negatively with the hemoglobin; two (Perfluorodecanoate (PFDA), PFUnA) of them were correlated negatively with the presence of interstitial lung disease. CONCLUSION: These data suggest that exposure to perfluoroalkyl substances may promote the disease activity of rheumatoid arthritis and the visceral lesions.
35027405 Tofacitinib and risk of cardiovascular outcomes: results from the Safety of TofAcitinib in 2022 Jun OBJECTIVES: Recent results from 'ORAL Surveillance' trial have raised concerns regarding the cardiovascular safety of tofacitinib in patients with rheumatoid arthritis (RA). We further examined this safety concern in the real-world setting. METHODS: We created two cohorts of patients with RA initiating treatment with tofacitinib or tumour necrosis factor inhibitors (TNFI) using deidentified data from Optum Clinformatics (2012-2020), IBM MarketScan (2012-2018) and Medicare (parts A, B and D, 2012-2017) claims databases: (1) A 'real-world evidence (RWE) cohort' consisting of routine care patients and (2) A 'randomised controlled trial (RCT)-duplicate cohort' mimicking inclusion and exclusion criteria of the ORAL surveillance trial to calibrate results against the trial findings. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate HR and 95% CIs for composite outcome of myocardial infarction and stroke and accounting for 76 potential confounders. Database-specific effect estimates were pooled using fixed effects models with inverse-variance weighting. RESULTS: In the RWE cohort, 102 263 patients were identified of whom 12 852 (12.6%) initiated tofacitinib. The pooled weighted HR (95% CI) comparing tofacitinib with TNFI was 1.01 (0.83 to 1.23) in RWE cohort and 1.24 (0.90 to 1.69) in RCT-duplicate cohort which aligned closely with ORAL-surveillance results (HR: 1.33, 95% CI 0.91 to 1.94). CONCLUSIONS: We did not find evidence for an increased risk of cardiovascular outcomes with tofacitinib in patients with RA treated in the real-world setting; however, tofacitinib was associated with an increased risk of cardiovascular outcomes, although statistically non-significant, in patients with RA with cardiovascular risk factors. TRIAL REGISTRATION NUMBER: NCT04772248.
34798162 Intestinal metabolism and absorption mechanism of multi-components in Gaultheria leucocarp 2022 Mar 25 ETHNOPHARMACOLOGICAL RELEVANCE: Dianbaizhu (Gaultheria leucocarpa var. yunnanensis) as a Chinese folk medicine exerts significant treatment effects on rheumatoid arthritis (RA) with a long historical time. Our previous reports showed that the anti-rheumatic arthritis fraction (ARF) extracted and enriched from Dianbaizhu possessed good druggability, which was better than its single active ingredients. However, the intestinal transport characteristics and mechanism of ARF have not been elucidated to date. AIM OF THE STUDY: In order to illustrate the role of active ingredients of ARF in alleviating RA and promoting the development of dosage forms, the intestinal metabolism, absorption properties and mechanism of ARF in vitro and in situ models were investigated. MATERIALS AND METHODS: Firstly, after incubating with 4 intestinal segments (duodenum, jejunum, ileum, and colon), 7 key components in ARF, including MATG-B, (+)-catechin, MSTG-A, Gaultherin, chlorogenic acid, quercetin, and kaempferol were quantitatively analyzed by a high-performance liquid chromatography (HPLC). Secondly, combining the physiological and pathological rats, the in situ single-pass intestinal perfusion and in vitro everted gut sacs of rats were performed to investigate the absorption features and transport mechanisms of ARF using HPLC and HPLC-Q-TOF-MS/MS. Subsequently, in situ studies were employed to determine the effect of P-glycoprotein (P-gp) inhibitor (verapamil) on the transport characteristics of ARF in RA model rats. RESULTS: Comparing the absorption parameters of ARF incubated in different intestinal segments, data showed that the absorption of ARF in the small intestine was significantly stronger than that of the colon (P < 0.01). The number of characterized prototype components was subjected to the incubation time, drug concentration and rat body condition, but not the intestinal segments. There were no significant differences in the number of metabolites among different intestinal segments, administration concentrations and incubation time. The best small intestinal absorption site of ARF was duodenum and ileum in normal and model rats, respectively. The P(eff) values of 7 index compounds were all higher than 0.2 × 10(-4)cm/s, and the F(a) values of 7 index compounds were all greater than 20% in the in situ perfusion investigation. The results showed that MSTG-B, MSTG-A and Gaultherin were likely to be substrates of P-gp as verapamil significantly enhanced their P(eff) and K(a) values, while other ingredients were not P-gp substrates. CONCLUSIONS: The intestinal membrane permeability of ARF was good. Its intestinal absorption mechanisms mainly involved active transportation processes and passive diffusion. Besides, this report provided data support and basis for clinical development, bioavailability improvement and formulation design.
34772862 The effects of acupuncture and related techniques on patients with rheumatoid arthritis: A 2022 Mar 1 BACKGROUND: One new type of acupuncture and related techniques (ACNRT) is increasingly used by rheumatoid arthritis (RA) patients to control their disease and improve their quality of life. However, the efficacy of using ACNRT in combination with western medicine (WM) for this purpose remains unknown. METHODS: Randomized controlled trials of ACNRT and WM treatments for RA from January 1, 2000, to January 31, 2021, were searched for in the databases PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials, as well as in three Chinese databases: China National Knowledge Infrastructure, Wanfang Data, and Airiti Library. The primary outcomes consisted of inflammatory markers including C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor. The secondary outcomes were clinical characteristics including pain visual analog scale (VAS) score, Disease Activity Score (DAS-28), swollen joints count (SJC), tender joints count (TJC), morning stiffness, and the results of a health assessment questionnaire. The three types of ACNRT used in the focal trials were acupuncture, moxibustion, and electro-acupuncture. Two qualified researchers extracted data from these trials' results and independently assessed their risk of bias. Statistical analyses were performed using Comprehensive Meta-Analysis V3 software. RESULTS: A total of 12 RCTs with 874 patients met the inclusion criteria. As compared with the patients who received WM treatment alone, those who were given integrated ACNRT/WM treatment showed greater reductions in CRP (weighted mean difference [WMD]: -6.299; 95% CI: -9.082 to -3.517), ESR (WMD: -6.563; 95% CI: -8.604 to -4.522), VAS (WMD: -1.089; 95% CI: -1.575 to -0.602), DAS-28 (WMD: -0.633; 95% CI: -1.006 to -0.259), SJC (WMD: -1.921; 95% CI: -3.635 to -0.207), and TJC (WMD: -1.491; 95% CI: -2.941 to -0.042). CONCLUSION: This meta-analysis of RA provides reliable evidence in favor of ACNRT plus WM. However, longer term, high-quality, repeatable, multicenter randomized controlled trials with larger sample sizes are needed.
35219101 Glycerophospholipid metabolism is involved in rheumatoid arthritis pathogenesis by regulat 2022 Apr 16 To explore the metabolic mechanism of differential plasma interleukin (IL)-6 expression in patients with rheumatoid arthritis (RA). A total of 240 RA patients were enrolled in the non-target metabolomics study cohort and 69 healthy volunteers were included as healthy controls (HCs). Plasma IL-6 levels were detected by electrochemiluminescence assay. Plasma metabolites were detected by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Patients with active RA (n = 20) and remissive RA (n = 20) and 20 HCs were enrolled in the targeted validation cohort. Metabolites identified by non-target metabolomics were quantitatively analyzed by ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry. Effects of 1-oleoyl-sn-glycero-3-phosphocholine (OGPC) associated with IL-6 on MH7A cells were assessed. After 24-h or 48-h induction by TNF-α, the supernatants were collected for IL-6 quantification by enzyme-linked immunosorbent assay. Furthermore, Western blot was performed to investigate the relative JAK2 and p-JAK2 expressions. With an increasing IL-6 level, OGPC shown to be related to the glycerophospholipid metabolism pathway by Kyoto Encyclopedia of Genes and Genomes analysis displayed a significant decrease. In the validating RA cohort, the OGPC concentrations in remissive RA group and active RA group decreased compared with HC group. OGPC down-regulated IL-6 secretion and p-JAK2 expression in TNF-α-induced MH7A cells in vitro. In conclusion, glycerophospholipid metabolism is the main metabolic pathway associated with the differential IL-6 expression in RA patients. The down-regulated OGPC is a promoting factor for the increased IL-6 plasma level in RA patients, which further affects the downstream JAK signaling pathway.
35358709 Circular RNA circ_0130438 suppresses TNF-α-induced proliferation, migration, invasion and 2022 Jun BACKGROUND: Circular RNAs (circRNAs) can play a critical role in rheumatoid arthritis (RA) pathogenesis by involving gene regulation by competing for shared microRNAs (miRNAs), a family of small noncoding RNAs. MiR-130a-3p is a disease-related miRNA and Kruppel-like factor 9 (KLF9) is a zinc finger transcription factor, which are involved in RA pathogenesis. Here, we identified the action of circRNA circ_0130438 in regulating fibroblast-like synoviocytes (FLSs) stimulated by tumor necrosis factor α (TNF-α). METHODS: The direct relationship between miR-130a-3p and circRNA circ_0130438 or KLF9 was predicted by bioinformatics analysis and examined by a dual-luciferase reporter or RNA immunoprecipitation (RIP) assay. CircRNA circ_0130438, miR-130a-3p and KLF9 factor expression levels were gauged by a quantitative real-time PCR (qRT-PCR) or a western blot method. Cell proliferation ability was analyzed by a 5-Ethynyl-2'-Deoxyuridine (EdU) staining assay. The transwell assay was used to evaluate cell migration and invasion capacities. The production levels of interleukin-1β (IL)-1β, IL-6 and IL-8 were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The level of circRNA circ_0130438 was reduced in RA tissues (P = 0.0001) and FLSs isolated from RA tissues (P = 0.0001) compared with corresponding normal controls. Exposure of human fibroblast-like MH7A synoviocytes to TNF-α suppressed circRNA circ_0130438 expression (P < 0.0001). In contrast, the elevated expression of circRNA circ_0130438 suppressed the TNF-α-induced proliferation (P = 0.0047) and migration (P = 0.0023) of MH7A cells, as well as their pro-inflammatory cytokines (IL-1β, IL-6 and IL-8) production (P < 0.0001, P < 0.0001 and P < 0.0001). The circRNA circ_0130438 contained a miR-130a-3p binding site. Furthermore, the increase of miR-130-3p in TNF-α-stimulated MH7A cells reversed the effects of circRNA circ_0130438 elevation on cell proliferation (P = 0.0006), migration (P = 0.0406) and pro-inflammatory cytokines (IL-1β, IL-6 and IL-8) production (P = 0.0036, P < 0.0001 and P = 0.0004), indicating that miR-130a-3p was a functional mediator of circRNA circ_0130438 regulation. We also documented that KLF9 was a direct target and downstream effector of miR-130a-3p. Importantly, circRNA circ_0130438 enhanced KLF9 expression (P < 0.0001) in TNF-α-stimulated MH7A cells by functioning as a competing endogenous RNA (ceRNA) for miR-130a-3p (P = 0.0004). CONCLUSION: Our findings demonstrate that the elevated expression of circRNA circ_0130438 suppresses TNF-α-induced migration, proliferation and pro-inflammatory cytokines (IL-1β, IL-6 and IL-8) production of human MH7A cells by enhancing KLF9 expression by operating as a ceRNA for miR-130a-3p.