RA Treatment Research Articles

A genome-wide association study identifying single nucleotide polymorphisms in the PPFIBP2 gene was predictive for interstitial lung disease in rheumatoid arthritis patients.

Genetic polymorphisms might serve as useful prognostic markers for the timely diagnosis of RA. The purpose of this study was to identify genomic factors predictive of the occurrence of interstitial lung disease (ILD) in RA by performing a genome-wide association study of genetic variants, including single nucleotide polymorphisms (SNPs). The study population included 306 RA patients. All patients were treated with conventional DMARDs, including 6-16 mg MTX per week. Clinical data and venous blood samples were collected from all patients before administration of DMARDs. A total of 278 347 SNPs were analysed to determine their association with ILD occurrence. Several SNPs were strongly associated with ILD occurrence (P < 10-5). rs6578890, which is located on chromosome11 in the intronic region of the gene encoding tyrosine phosphatase receptor typeF polypeptide-interacting protein-binding protein 2 (PPFIBP2), showed the strongest association with ILD occurrence (odds ratio 4.32, P = 10-7.93). PPFIBP2 could be a useful genetic marker for occurrence of interstitial pneumonia in RA patients and might help to identify the risk of ILD occurrence before RA treatment, thereby improving patient outcomes.

Treating Rheumatoid Arthritis by Genetically Engineered Biological Drugs: A Case Study.

The current modern treatment for Rheumatoid Arthritis is the genetically engineered biological drug rituximab. This drug helps to low the active rheumatoid arthritis. The aim of the study is to find and evaluate the clinical efficacy of rituximab . We present our own clinical observation of rituximab use in RA treatment of a female patient. We made the clinical assessment of the patient's condition with the use of clinical, laboratory and instrumental methods. We made diagnostics with the use of the ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) criteria. ESR, concentration of C-reactive protein, IgM of rheumatoid factor, antibodies to cyclic citrullinated peptide were determined. In 2007 the patient was diagnosed RA. She received the treatment with methotrexate, metipred, sulfasalazine, dexamethasone, cyclophosphamide, leflunomide, diprospan, non-steroidal anti-inflammatory drugs (NSAIDs). There was no effect. She had the total right &amp; left knee joints arthroplasty. In 2009, according to blood tests she had: ESR according to Westegren is 90 mm/h, antibodies to cyclic citrulline-containing peptide (AB-CCP) is 500 U/ml, CRP 121.3 mg/l, RF 125.7 IU / ml. She had the diagnosis of rheumatoid arthritis, seropositive, grade 3 activity according to the DAS activity index 28 = 6.11 points with extra-articular manifestations (rheumatoid nodules) late stage, erosive (radiologically stage III), AB-CCP (+), FTS III. She started to receive rituximab therapy. Due to the durable inflammation, the secondary amyloidosis has started. At the same time the secondary systematic osteoporosis has started. We continued the rituximab therapy &amp; zolendronic acid. The RA activity was low (according to the DAS index 28 = 2.95 points). In our study we found that the genetically engineered biological preparation (GEBP) rituximab is effective in the rheumatoid arthritis modern therapy.

Improvement of recycled aggregate properties through a combined method of mechanical grinding and microbial-induced carbonate precipitation

Due to the shortage of natural aggregates, recycled aggregates are gaining great attention in civil engineering. However, recycled aggregates have lower apparent density and higher water absorption and crushing index as compared to natural aggregates. To enhance the properties of recycled mixed aggregates (RMAs), three different treatment routes were adopted in this work: mechanical grinding, microbial-induced carbonate precipitation (MICP), and a combined method of mechanical grinding and MICP. The apparent density, water absorption, and crushing index of RMAs were examined before and after each treatment, and the slump, apparent density, and compressive strength of recycled concretes (RCs) with treated and untreated RMAs were then investigated. In addition, the micro-mechanism of property improvement due to these treatments was analyzed by scanning electron microscopy (SEM). Experimental results revealed that the combined method, in comparison to the other two methods used separately, led to higher apparent density and lower water absorption and crushing index of RMAs. Moreover, RCs treated with the combined method exhibited greater slump, higher apparent density, and superior compressive strength than untreated RCs. Furtherly, compared with commonly used RA treatment methods presented in recent publications, the proposed combined method shows better influence on compressive strength of RCs.

New Terpenoids from Potentilla freyniana Bornm. and Their Cytotoxic Activities.

Two new A-ring contracted triterpenoids, madengaisu A and madengaisu B, and one undescribed ent-kaurane diterpenoid, madengaisu C, along with 20 known compounds were isolated from the roots of Potentilla freyniana Bornm. The structures were elucidated using extensive spectroscopic techniques, including 1D and 2D-NMR, HR-ESI-MS, ECD spectra, IR, and UV analysis. Moreover, all isolated constituents were evaluated for their anti-proliferative activity against RA-FLS cells and cytotoxic activities against the human cancer cell lines Hep-G2, HCT-116, BGC-823, and MCF-7. Ursolic acid and pomolic acid displayed moderate inhibitory activity in RA-FLS cells with IC50 values of 24.63 ± 1.96 and 25.12 ± 1.97 μM, respectively. Hyptadienic acid and 2α,3β-dihydroxyolean-12-en-28-oic acid 28-O-β-d-glucopyranoside exhibited good cytotoxicity against Hep-G2 cells with IC50 values of 25.16 ± 2.55 and 17.66 ± 1.82 μM, respectively. In addition, 2α,3β-dihydroxyolean-13(18)-en-28-oic acid and alphitolic acid were observed to inhibit HCT-116 cells (13.25 ± 1.65 and 21.62 ± 0.33 μM, respectively), while madengaisu B and 2α,3β-dihydroxyolean-13(18)-en-28-oic acid showed cytotoxic activities against BGC-823 cells with IC50 values of 24.76 ± 0.94 and 26.83 ± 2.52 μM, respectively, which demonstrated that triterpenes from P. freyniana may serve as therapeutic agents for RA and cancer treatment.

1518-PUB: Role of PPARd in Regulating Autophagy Pathway in Improving Islet ß-Cell Function with GLP-1 Receptor Agonist

Aim: To investigate the effect and mechanism of glucagon-like peptide-1 receptor agonist (GLP-1 RA) on the function of islet β cells. Methods: Type 2 diabetes C57BL/6J mice were successfully induced by high fat diet (HFD) feeding for 12 weeks then were randomly divided into HFD+NaCl group (n=5) , HFD+Exenatide group (n=5, 24 nmol•kg-1­•d‑1) and NC group (n=5) . Tolerance tests and insulin measurement were performed after 8 weeks of drug therapy. Weight was measured weekly and fasting blood glucose was measured every 4 weeks. The pancreas were stained with LC3B Immunofluorescence at the end of the experiment. The PA induced primary islet β cells were treated with exendin-4 and PA induced Min6 cells were treated with exendin-4, GW501516 for 24h, which BSA as the control group, then detected the protein levels of PPARδ, LC3B-II and P62. At the same time, PA induced MIN6 cells were treated with GSIS. What's more, we silenced PPARδ transfected with siRNA to verify the role of PPARδ in GLP-1 receptor agonist activation of β-cell autophagy. Results: Compared with the normal control group, the body weight and fasting blood glucose increase and significant peripheral insulin resistance in the high fat group, while the above indexes are significantly improved in the high-fat fed mice after GLP-1 RA treatment. Immunofluorescence biopsies of pancreatic tissue show that LC3B expression decrease after high fat diet, while GLP-1 RA intervention significantly increase. In addition, GLP-1 RA not only can promote the expression of PPARδ and LC3B-II protein and inhibit the expression of P62 protein in primary islet β cells and MIN6 cells, but also significantly increase glucose stimulation insulin secretion in MIN6 cells. More importantly, GW501516 is found to be consistent with GLP-1 RA in MIN6 cells, while GLP-1 RA promote autophagy disappeare after PPARδ expression is silenced. Conclusion: GLP-1 RA can improve the function of islet β cells by activating the autophagy pathway through PPARδ. Disclosure Y.Su: None. B.Lin: None. Y.Chen: None. Z.Liu: None. L.Gan: None. W.Xu: None. Funding Science &amp; Technology Project of Guangzhou（202102010175）

Real-world evidence on methotrexate-free subcutaneous tocilizumab therapy in patients with rheumatoid arthritis: 24-week data from the SIMPACT study.

ObjectivesThe aim of the SIMPACT study was to evaluate the efficacy and safety of MTX-free s.c. tocilizumab (TCZ) therapy in RA patients.MethodsSIMPACT was an open-label, non-controlled, non-randomized, non-interventional study, in which RA patients for whom the treating physicians ordered s.c. TCZ were observed during a 24-week treatment period in Hungarian centres. Although the use of MTX was avoided during the study period, other conventional synthetic DMARDs, oral CSs and NSAIDs were allowed. Study endpoints included the change in DAS28 and clinical activity index (CDAI) scores, the proportion of patients achieving remission in the whole population and in subgroups defined based on prior RA treatment history, and age, weight or biological sex post hoc. The extent of supplementary medication use was monitored.ResultsThree hundred and thirty-seven RA patients were enrolled in 18 study centres. TCZ therapy significantly decreased the disease activity measured by both DAS28 (P = 0.0001) and CDAI (P = 0.0001). Clinical response was more pronounced in biologic-naïve patients and was lower in patients >75 years of age. In the whole population, DAS28 ESR or CRP and CDAI remission rates were 70.10%, 78.95% and 33.59%, respectively. In patients <45 years of age, the CDAI remission rate doubled (67.86%). A significant decrease in the frequency of co-administered medication was reported, including oral CSs and DMARDs.ConclusionReal-world clinical evidence on s.c. TCZ reported here is in line with the efficacy outcomes of randomized clinical trials. Subgroup analysis revealed that TCZ was more effective in biologic-naïve patients and in those <75 years old.Trial registrationClinicalTrials.gov, http://www.clinicaltrials.gov, NCT02402686.

Effect of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese adults without diabetes: A meta-analysis of placebo-controlled randomized trials.

Our aim was to study the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) on the risk of any cardiovascular event in adults with overweight or obesity and without diabetes. We conducted a random-effects meta-analysis of placebo-controlled randomized controlled trials. Nine trials were eligible and, in total, 11 430 patients were included, of which 7702 (67%) were submitted to treatment with GLP-1 RA. During follow-up, 673 participants receiving GLP-1 RA treatment (8.7%) and 416 participants receiving placebo (11.2%) had a cardiovascular event. Treatment with GLP-1 RA versus placebo resulted in a reduction in the risk of any cardiovascular event (RR=0.81, CI 0.70-0.92; p=.001). In overweight or obese adults without diabetes, treatment with GLP-1 RA reduced the risk of cardiovascular events. Our findings support the use of GLP-1 RA for reducing the cardiovascular risk of these patients.

Suppression of NLRP3 Inflammasome by Dihydroarteannuin via the HIF-1α and JAK3/STAT3 Signaling Pathway Contributes to Attenuation of Collagen-Induced Arthritis in Mice.

Dihydroarteannuin (DHA), the primary element of artemisinin extracted from the traditional Chinese herb Artemisia annua L., has been used in malaria treatment for a long time. Recently, many studies have indicated that DHA also exhibits potent anti-rheumatoid arthritis (RA) activity. In this study, collagen-induced arthritis (CIA) in DBA/1J mice and inflammatory model in THP-1 cells were established to evaluate the modulatory effects of DHA on joint destruction and to explore the underlying mechanisms. Our results showed that DHA decreased the serum levels of IL-1β and IL-6, alleviated paw oedema, and reduced bone destruction in DBA/1J mice with CIA. Further exploration with the inflammatory model in THP-1 cells indicated that DHA reduced the protein expression of hypoxia‐inducible factor (HIF)‐1α and the phosphorylation in Janus kinase (JAK) 3 and signal transducer and activator of transcription (STAT) 3 protein, which resulted in a decrease in NOD-like receptor protein (NLRP) 3 expression and interleukin (IL)-1β release. Consequentially, the inflammatory activation in THP-1 cells was inhibited. Therefore, we concluded that DHA efficiently alleviated the inflammation and arthritic symptoms in CIA mice and downregulated inflammation in part by inhibiting NLRP3 expression via the HIF‐1α and JAK3/STAT3 signaling pathway. Thus, DHA may be considered as a potential therapeutic agent in RA treatment.

P192 Efficacy of filgotinib in rheumatoid arthritis by age, body weight, body mass index: post hoc subgroup analysis of two phase 3 trials

Abstract Background/Aims Filgotinib (FIL), an oral Janus kinase 1 preferential inhibitor, has demonstrated safety and efficacy as treatment for signs and symptoms of RA, and it is approved in Japan and Europe for treatment of RA. Patient characteristics can influence response to RA treatment; this post hoc analysis was performed to determine whether age, body weight (BW), and body mass index (BMI) influenced efficacy. Methods Patients from FINCH 1 (F1, n = 1755, inadequate response to methotrexate [MTX-IR]; NCT02889796) or FINCH 3 (F3, n = 1249, MTX-naïve; NCT02886728) were included for analysis of clinical response at week 12 (F1 primary endpoint) or 24 (F3 primary endpoint). Patients were stratified by age (&amp;lt;65, ≥65 years), BW (&amp;lt;60, 60 to &amp;lt; 100, ≥100 kg), and BMI (&amp;lt;25, ≥25 kg/m2). Efficacy was assessed by ACR20, Disease Activity Score-28 &amp;lt;2.6, Clinical Disease Activity Index ≤2.8, Simple Disease Activity Index ≤3.3, Boolean remission, and change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI). Selected efficacy endpoints are displayed in Table 1. Patients treated with FIL200+MTX were compared with control arms (F1, placebo+MTX; F3, MTX). Fisher’s exact test was used for binary endpoints; mixed-effects model for repeated measures was used for HAQ-DI. P-values were nominal without adjusting for multiplicity. Results FIL200+MTX in MTX-IR patients demonstrated greater efficacy vs placebo+MTX regardless of age, BW, and BMI (Table 1). Apart from the ≥65-year-old subgroup, in which there was no clear pattern, FIL200+MTX in MTX-naïve patients demonstrated greater efficacy vs MTX across subgroups (Table 1). Rates of treatment-emergent adverse events (TEAEs) were greater in the ≥65-year-old subgroup vs the &amp;lt;65-year-old subgroup; there was no discernible pattern between BMI subgroups. Among MTX-naïve patients only, rates of TEAEs were higher in those who weighed ≥100 kg vs lower-weight subgroups. Conclusion This exploratory analysis showed FIL200+MTX was efficacious regardless of subgroup characteristics defined by age, BW, or BMI. Most comparisons of FIL200+MTX vs MTX and vs placebo+MTX favored FIL200+MTX. Disclosure Y. Tanaka: Consultancies; Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK, and AbbVie. Member of speakers’ bureau; Daiichi-Sankyo; Eli Lilly; Novartis; YL Biologics; Bristol-Myers; Eisai; Chugai; AbbVie; Astellas; Pfizer; Sanofi; Asahi-Kasei; GSK; Mitsubishi-Tanabe; Gilead Sciences, Inc.; and Janssen. Grants/research support; AbbVie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, and Daiichi-Sankyo. J. Curtis: Grants/research support; from AbbVie, Amgen, BMS, Corrona, Eli Lilly, Janssen, Myriad, Pfizer, Regeneron, Roche, and UCB. S. Wassenberg: Consultancies; AbbVie; Amgen; BMS; Gilead Sciences, Inc.; Eli Lilly; Hexal; MSD; Nichi-Iko; Pfizer; and Sanofi. P. Kiely: Member of speakers’ bureau; Novartis, Lilly, Galapagos, Sobi, Abbvie. L. Ye: Shareholder/stock ownership; Employee and shareholder of Gilead Sciences, Inc. Z. Yin: Shareholder/stock ownership; Employee and shareholder of Gilead Sciences, Inc. B. Downie: Shareholder/stock ownership; Employee and shareholder of Gilead Sciences, Inc. H. Enomoto: Shareholder/stock ownership; former employee/shareholder of Gilead Sciences, Inc. S. Strengholt: Shareholder/stock ownership; shareholder of and employee of Galapagos BV. A. Akhdar: Shareholder/stock ownership; shareholder of and employee of Galapagos BV. C. Watson: Shareholder/stock ownership; shareholder of and employee of Galapagos BV. T. Atsumi: Honoraria; Gilead Sciences, Inc.; Mitsubishi Tanabe; Chugai; Astellas Pharma; Takeda; Pfizer; AbbVie: Eisai; Daiichi Sankyo Co. Ltd.; BMS; UCB Japan Co. Ltd.; Eli Lilly, Otsuka Pharmaceutical Co. Alexion Inc.

Effect of glucagon-like peptide-1 receptor agonists on renal function: A meta-analysis of randomized controlled trials.

The objective of this meta-analysis was to examine the impact of the GLP-1 RA on renal function parameters in randomized controlled trials. A systematic search was performed in PubMed-MEDLINE, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases. Meta-analysis was performed using a random-effects model and sensitivity analysis. Data from 18 randomized controlled trials involving 12 192 subjects, showed that treatment with GLP-1 RA had no effect on serum creatinine levels (weighted mean difference [WMD]: 0.00 mg/mL, 95% confidence interval [CI]: -0.01, 0.01, P = .83, I2 = 0%) and glomerular filtration rate (WMD: 1.01 mL/min/1.73 m2 , 95% CI: -1.61, 3.63, P = .45, I2 = 75%). On the other hand, a significant reduction in urinary albumin excretion (WMD: -18.01 mg/day, 95% CI: -31.20, -4.82, P = .007, I2 = 23%) and albumin-to-creatinine ratio (WMD: -6.74 mg/g, 95% CI: -12.64, -0.85, P = .03, I2 = 68%) was detected after GLP-1 RA therapy. Results of our meta-analysis revealed that GLP-1 RA treatment decreases urinary albumin excretion and albumin-to-creatinine ratio but it did not cause significant changes in creatinine levels and glomerular filtration rate.

Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial.ObjectiveTo evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations.Data SourcesMEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions.Study SelectionRandomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non−GLP-1 RA drugs in adults.Data Extraction and SynthesisTwo reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework.Main Outcomes and MeasuresThe primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021.ResultsA total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction).Conclusions and RelevanceThis systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.Trial RegistrationPROSPERO Identifier: CRD42021271599

7-deacetyl-gedunin suppresses proliferation of Human rheumatoid arthritis synovial fibroblast through activation of Nrf2/ARE signaling

BackgroundRheumatoid arthritis (RA) is an chronic autoimmune disease and characterized by high incidence. However, there is no effective therapies for RA. Therefore, it is urgent to discover new drugs for RA treatment. Nuclear factor erythroid 2 (NF-E2)-related factor (Nrf2) can effectively protect against arthritic inflammatory diseases through diverse stages, such as regulating redox balance, detoxification, metabolism and inflammation. Dimethyl fumarate (DMF), targets the Nrf2 pathway, was approved by FDA for the clinical treatment of multiple sclerosis (MS), which is another autoimmune disease. The latest report shown that DMF ameliorates complete Freund's adjuvant-induced arthritis in rats through activation of the Nrf2/HO-1 signaling pathway. Hence, Nrf2 serves as an important target for inflammation interference and oxidative stress of macrophages and RASFs in RA; therefore, it can be adopted as an effective therapeutic approach in the future.Rheumatoid arthritis synovial fibroblasts (RASFs) play crucial roles in the RA pathogenesis. Our results revealed that 7-deacetyl-gedunin (7-d-GDN), derived from fruits of Toona sinensis (A. Juss.) Roem, significantly inhibited RASFs proliferation in dose- and time- dependent manners and inhibited cell viability in MH7A cells, which is a kind of immortal cell line from joints of patients with RA. Additionally, 7-d-GDN remarkably down-regulated MMP-1/3/9/13 in RASFs, IL-6 and IL-33 in MH7A cells. Besides, 7-d-GDN sharply inhibited reactive oxygen species (ROS) in RASFs. Further mechanistic study demonstrated that 7-d-GDN induced heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone 1(NQO1), which all participated in suppressing of oxidative stress. Additionally, 7-d-GDN increased sequestosome 1 (SQSTM1, p62), causing down-regulating Kelch-like ECH-associated protein 1 (Keap1), which resulting in NF-E2-related factor 2 (Nrf2) cytoplasm accumulation and subsequently translocation into nucleus. Collectively, 7-d-GDN exerts the anti-inflammatory effect through regulating anti-oxidative enzymes via p62/ Nrf2/ARE signaling. All suggest that the potential of 7-d-GDN in suppression of inflammation, especially antagonizing RA severity. Our works support for drugs discovery in RA treatment.

Effect of glucagon-like peptide-1 receptor agonists on body weight in adults with obesity without diabetes mellitus-a systematic review and meta-analysis of randomized control trials.

Clinical trials have investigated the weight loss effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in adults with obesity without diabetes mellitus, but results for weight loss efficacy were varied. We aimed to provide an up-to-date systematic review and meta-analysis for overall weight loss effect of GLP-1 RA in adults with obesity and overweight without diabetes mellitus. We retrieved eligible randomized control trials that assessed the weight loss effect of GLP-1 RA in adults (≥18 years old) without type 1/type 2 diabetes up to September 30, 2021, using Pubmed and Embase. Of 36 clinical trials assessed for eligibility, 12 trials were included, with a combined total of 11,459 participants. Compared with control groups, a more significant weight loss was seen in GLP-1 RA groups with an overall mean difference of -7.1kg (95% CI -9.2 to -5.0) (I2 = 99%). The overall analysis results showed that GLP-1 RA improved glycemic control without increasing the risk of hypoglycemic events. Better control of blood pressure and plasma levels of LDL, HDL, and triglycerides was seen with GLP-1 RA treatment. Subgroup analysis showed greater treatment effect of semaglutide than liraglutide. Vomiting, nausea, dyspepsia, diarrhea, constipation, and abdominal pain were GLP-1 RA-associated common adverse effects.

SIX1 attenuates inflammation and rheumatoid arthritis by silencing MyD88-dependent TLR1/2 signaling

ObjectivesRheumatoid arthritis (RA) is a chronic autoimmune disease that severely affects the patients' quality of life. Sine oculis homeobox 1 (SIX1) has been reported as a key regulator of organogenesis and inflammation. This study aimed to explore the effects of SIX1 on RA. MethodsWistar rats were immunized with type II collagen to induce an animal model of RA. RA synovial fibroblasts (RASFs) were isolated from the rats. SIX1 expression in RA rats and RASFs was detected by qRT-PCR and western blot. CCK-8, EdU, transwell, flow cytometer, and ELISA were conducted to assay the effects of SIX1 on RASFs. The effects of SIX1 on RA rats were studied by Safranin O staining, H&E staining, and ELISA. Besides, GSEA and KEGG analysis were used to predict the underlying signaling pathways. ResultsSIX1 was low expressed in synovial tissue of RA rats and RASFs. SIX1 overexpression inhibited the proliferation, invasion, and levels of TNF-α, IL-6, and IL-8 in RASFs. However, SIX1 overexpression promoted the apoptosis of RASFs. SIX1 overexpression enhanced body weight, and attenuated the cartilage damage, pathological injury, and pro-inflammatory cytokine release of RA rat model. MyD88-dependent TLR1/2 might be a downstream signaling of SIX1. RelA acted as a transcription factor of TLR1/2, and SIX1 inhibited TLR1/2 signaling possibly via interaction with RelA. Adding with Pam3CSK4, a specific agonist of TLR1/2 signaling, attenuated the effects of SIX1 on RASFs. ConclusionSIX1 attenuated inflammation and RA by silencing MyD88-dependent TLR1/2 signaling. SIX1 may be a promising target for RA treatment.

Effect of a 3-Week Treatment with GLP-1 Receptor Agonists on Vasoactive Hormones in Euvolemic Participants

Glucagon-like-peptide-1 receptor agonists (GLP-1 RAs) exert cardiovascular benefits by reducing plasma glucose, body weight, and blood pressure. The blood pressure-lowering effect may be mediated by angiotensin II (ANG II) suppression and consecutive natriuresis. However, the role of ANG II and other vasoactive hormones on GLP-1 RA treatment has not been clearly defined. This work aimed to investigate the effect of a 3-week treatment with the GLP-1 RA dulaglutide on vasoactive hormones, that is, renin, ANG II, aldosterone, mid-regional proatrial natriuretic peptide (MP-proANP), and natriuresis in euvolemic participants. Randomized, double-blinded, placebo-controlled, crossover trials were conducted at University Hospital Basel, Switzerland. A total of 54 euvolemic participants, including 20 healthy individuals and 34 patients with primary polydipsia, received a subcutaneous injection of dulaglutide (Trulicity) 1.5 mg and placebo (0.9% sodium chloride) once weekly over a 3-week treatment phase. After a 3-week treatment phase, dulaglutide showed no effect on plasma renin, plasma ANG II, or plasma aldosterone levels in comparison to placebo. Natriuresis remained unchanged or decreased on dulaglutide depending on the measured parameter. Dulaglutide significantly decreased plasma MR-proANP levels (treatment effect: 10.60 pmol/L; 95% CI, -14.70 to -7.90; P < .001) and systolic blood pressure (median: 3 mm Hg; 95% CI, -5 to 0; P = .036), whereas heart rate increased (median: 5 bpm; 95% CI, 3-11; P < .001). In euvolemic participants, a 3-week treatment of dulaglutide reduced systolic blood pressure independently of plasma renin, ANG II, or aldosterone levels and urinary sodium excretion. The reduction in MR-proANP might be secondary to reduced arterial pulse pressure.

Real-world effectiveness of liraglutide versus dulaglutide in Japanese patients with type 2 diabetes: a retrospective study

Real-world data comparing the effectiveness of various glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in type 2 diabetes mellitus (T2DM) are limited. We investigated the clinical effectiveness of liraglutide and dulaglutide in Japanese T2DM in a real-world setting. This retrospective study included 179 patients with T2DM who were treated with GLP-1 RA for at least 12 months (liraglutide, n = 97; dulaglutide, n = 82). We used stabilized propensity score-based inverse probability of treatment weighting (IPTW) to reduce selection bias and confounding by observed covariates. Changes in glycated hemoglobin (HbA1c) at the end of the 12-month treatment were evaluated. After adjustment by stabilized propensity score-based IPTW, no significant differences were observed in patient characteristics between the liraglutide and dulaglutide groups. HbA1c was significantly lower at 12 months in both groups (liraglutide, 8.9 to 7.4%; dulaglutide, 8.7 to 7.5%). Multivariate linear regression analysis showed no differences in the extent of changes in HbA1c at 12 months between the two agents. High baseline HbA1c, the addition of GLP-1 RA treatment modality, and in-hospital initiation of GLP-1 RA treatment were identified as significant contributing factors to HbA1c reduction. The effects of liraglutide and dulaglutide on lowering HbA1c levels at 12 months were comparable in a real-world setting.

Folic Acid Modified Glucosamine/Methotrexate Polymer Targeted Therapy for Rheumatoid Arthritis

Objective. To develop a targeted drug for the treatment of rheumatoid arthritis. Methods. In this study, methotrexate (MTX) was combined with glucosamine (Glu) and modified with folic acid (FA) to prepare folic acid‐glucosamine/methotrexate polymer (FA‐Glu/MTX). The stability, sustained release, cytotoxicity, and therapeutic effect were evaluated based on in vitro and in vivo experiments. Results. FA‐Glu/MTX had good stability, sustained release, and low cytotoxicity. In addition, the results of in vivo experiments proved that compared with MTX, FA‐Glu/MTX has a stronger therapeutic effect on RA and has certain targeting properties. Conclusion. FA‐Glu/MTX is expected to become a new option for RA treatment.

Nanoparticle conjugated with aptamer anti-MUC1/Y for inflammatory arthritis

Aptamers may form well-defined three-dimensional structures binding with high affinity and stability to a specific receptor. The aptamer anti-MUC1 isoform Y is one the most used due the affinity to MUC1, which is overexpressed in several types of cancer and inflammation process. In this study we have developed, characterized, in vitro as in vivo evaluated a nanoaptamer (anti-MUC1/Y) as a nanoagent for rheumatoid arthritis treatment. The results showed that a nanoaptamer with a size range of 241 nm was produced. The entrapment efficacy was 90% with a biodistribution showing a high hepatic uptake (>98%). The results in vivo showed a potent effect in arthritis experimental model, especially in low doses. The results corroborate the applicability of this nanosystem for RA treatment.

Development, psychometric evaluation and cognitive debriefing of the rheumatoid arthritis symptom and impact questionnaire (RASIQ)

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease often associated with persistent pain. There is a need for a patient-reported outcome measure (PROM) that is rooted in the patient experience and psychometrically validated. We describe the development of the Rheumatoid Arthritis Symptom and Impact Questionnaire (RASIQ), a novel PROM with potential to record key symptoms and impacts of RA with a 24-h recall period.ResultsA literature review identified RA concepts that patients considered most important to their disease experience, including pain, fatigue, joint swelling and stiffness. From this, an initial item pool (33 items; 27 related to symptoms, 6 related to impacts) was developed with a recall period of 24 h. Two rheumatologists evaluated each item’s relevance, and the second version of the RASIQ was refined (29 items; 21 related to symptoms, 8 related to impacts). Next, three rounds of cognitive debriefing interviews were conducted with patients with RA (n = 15 overall). The RASIQ was revised to remove items deemed irrelevant or redundant, leaving 16 items measuring symptoms (joint pain, energy/tiredness, joint stiffness) and impacts (rest, sleep). A parallel series of semi-structured concept elicitation interviews (n = 30) facilitated the design of a conceptual model of RA symptoms, impacts and treatment experiences. Post-hoc comparison of the model with RASIQ revealed that all items selected were among the most important and relevant symptoms and impacts for patients. A final round of cognitive debriefing interviews (n = 12) confirmed that the final 16-item RASIQ was relevant and easy to understand, with no further changes recommended. Psychometric evaluation using data from two Phase II RA clinical trials confirmed a 3-factor structure, as well as the reliability and validity of the scale scores, and the ability of RASIQ to detect changes in symptoms and impacts when administered at specific study timepoints, using a 24-h recall period.ConclusionsRASIQ is a novel, 16-item PROM developed with substantial patient input. Results from concept elicitation, cognitive debriefing, and psychometric evaluation confirmed the validity of the instrument, which has the potential to measure symptoms and impacts through a 24-h recall period and complement existing disease activity instruments with longer recall periods.

Pain as a mediator in the temperament-alexithymia relationship in individuals suffering from rheumatoid arthritis.

The study aims to establish a relationship between temperament traits, symptoms of alexithymia, and pain intensity in rheumatoid arthritis. Despite the significant progress seen in the area of RA treatment, pain, often life-long, remains the predominant symptom. This constant pain and progressing disability, as well as dependence upon other people cause RA patients to experience psychological stress that can be modified by individual patient traits. Recently, several authors have underlined the need to relate personality and temperament constructs to neurobiological processes that may underlie individual differences. It seems then that patient characteristics may play a significant role in the course of the disease. The study was performed on a group of patients (N=317) with rheumatoid arthritis diagnosed according to the current criteria of the American-European Consensus of 2010. All patients expressed voluntary consent to participate, and the study protocol was approved by the Local Ethics Committee. This was a survey-based study. It involved the application of the adult version of the Buss and Plomin EAS Temperament Questionnaire (EAS-D), which tests 3 main temperament domains: sociability, activity, and emotionality. The pain was measured on the Visual Analogue Scale (VAS). VAS is used to measure pain intensity. The level of alexithymia was tested using the Toronto Alexithymia Scale-20. The scale consists of 20 statements and includes 3 subscales that measure difficulty in describing feelings/emotions, difficulty in identifying feelings/emotions, and operational externally oriented thinking. The analysis revealed that alexithymia is positively correlated only with one dimension of temperament, i.e., emotionality, and with pain intensity. Moreover, high emotionality was positively correlated with pain. A simple mediation analysis revealed that pain intensity functioned as a mediator in the emotionality-alexithymia relationship. The observed correlations indicate that RA patients with a high level of emotionality exhibit high alexithymia as they perceive pain related to the disease symptoms more intensely. The observed mediation is partial, meaning that there are also other mediating factors in this relationship.