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ID PMID Title PublicationDate abstract
35241141 Safety and efficacy of autologous, adipose-derived mesenchymal stem cells in patients with 2022 Mar 3 OBJECTIVE: The present study is a phase I/IIa non-randomized, open-label study to evaluate safety and efficacy of a single, intravenous infusion of autologous, adipose-derived mesenchymal stem cells (adMSCs) over a period of 52 weeks, in patients with active rheumatoid arthritis (RA). METHODS: 15 eligible RA patients aged 18-65 years were enrolled and followed up at weeks 4, 12, 26 and 52 after receiving a single intravenous dose of 2 × 10(8) adMSCs. Efficacy was examined using American College of Rheumatology (ACR66/68 score) criteria for swollen and tender joint counts (S/TJC), and serum TNF-α, IL-6, CRP, and ESR levels. Safety endpoints included measures of hematologic, hepatic, and renal function. RESULTS: ACR66/68 scores for both S/TJC showed significant improvements with large effect sizes (ES) at week 52 vs baseline (p < 0.01, ES = 0.83 and p < 0.001, ES = 0.93 respectively). Medium to large ES were also obvious for ACR66/68 scores measured at other timepoints. Levels of inflammatory markers, TNF-α, IL-6 and ESR remained unchanged compared to baseline. However, a difference in CRP levels with a small effect size was observed at week 4 (p = 0.229, ES = 0.33) with further improvement at week 52 (p = 0.183, ES = 0.37). Post-intervention, levels of hematologic, hepatic, and renal function remained largely unchanged (p > 0.05). No acute or long-term serious adverse events (AEs) occurred. CONCLUSIONS: The results indicated that a single, intravenous administration of autologous adMSCs is safe and efficacious for improvement in joint function in patients with active RA. Data from the current study supports the exploration of ad-MSCs as a therapeutic intervention for RA. Trial Registration Clinical trial registration number: NCT03691909. Registered September 27, 2018- Retrospectively registered ( https://clinicaltrials.gov/show/NCT03691909 ).
35074100 Biomedical applications of polysaccharide nanoparticles for chronic inflammatory disorders 2022 Apr 1 Polysaccharides are biopolymers distinguished by their complex secondary structures executing various roles in microorganisms, plants, and animals. They are made up of long monomers of similar type or as a combination of other monomeric chains. Polysaccharides are considered superior as compared to other polymers due to their diversity in charge and size, biodegradability, abundance, bio-compatibility, and less toxicity. These natural polymers are widely used in designing of nanoparticles (NPs) which possess wide applications in therapeutics, diagnostics, delivery and protection of bioactive compounds or drugs. The side chain reactive groups of polysaccharides are advantageous for functionalization with nanoparticle-based conjugates or therapeutic agents such as small molecules, proteins, peptides and nucleic acids. Polysaccharide NPs show excellent pharmacokinetic and drug delivery properties, facilitate improved oral absorption, control the release of drugs, increases in vivo retention capability, targeted delivery, and exert synergistic effects. This review updates the usage of polysaccharides based NPs particularly cellulose, chitosan, hyaluronic acid, alginate, dextran, starch, cyclodextrins, pullulan, and their combinations with promising applications in diabetes, organ fibrosis and arthritis.
35277175 Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease: mortality 2022 Mar 11 BACKGROUND: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), like those with idiopathic pulmonary fibrosis (IPF), might develop an unexpected acute exacerbation (AE)-a rapidly progressing and deadly respiratory decline. Although AE incidence and risk factors in RA-ILD patients are known, their post-AE clinical course remains unknown owing to the rarity of AE-RA-ILD. This multicentre retrospective study evaluated post-AE mortality and prognostic variables in AE-RA-ILD patients and created a mortality prediction model for AE-RA-ILD. METHODS: This research comprised 58 patients with AE-RA-ILD and 96 with AE-IPF (a control disease). Multivariate Cox regression analysis was performed to identify prognostic variables. A prediction model was created with recursive partitioning (decision tree). RESULTS: The post-AE 90-day mortality rate in the overall AE-RA-ILD group was 48.3%; percent predicted forced vital capacity within 12 months before AE onset (baseline %FVC) and PaO(2)/FiO(2) ratio at AE onset (P/F at AE) were independent predictors of mortality. Post-AE 90-day mortality rates were 40.6% and 43.8%, respectively, in AE-RA-ILD and AE-IPF patients propensity score-matched for age, sex, baseline %FVC and P/F at AE (P = 1.0000). In AE-RA-ILD patients, C-indices of baseline %FVC and P/F at AE to predict post-AE 90-day mortality were 0.604 and 0.623, respectively. A decision tree model based on these prognostic factors classified AE-RA-ILD patients into mild, moderate and severe groups (post-AE 90-day mortality rates: 20.8%, 64.0% and 88.9%, respectively; P = 0.0002); the C-index improved to 0.775. CONCLUSIONS: Post-AE mortality was high in AE-RA-ILD patients similar to AE-IPF patients. The discovered prognostic factors and our mortality prediction model may aid in the management of AE-RA-ILD patients.
34766228 Stachys schtschegleevii tea, matrix metalloproteinase, and disease severity in female rheu 2022 Apr BACKGROUND: Stachys schtschegleevii (SSC) is a herbal medicine used to treat infections. To date, this is the first study aimed to investigate the effects of SSC tea on disease activity score (DAS), serum inflammatory biomarkers and matrix metalloproteinases (MMP-1 and MMP-3) among women with rheumatoid arthritis (RA). METHODS: This pilot, triple-blind, randomized controlled clinical trial was conducted among forty-four women (age: 30-65 years) diagnosed with moderately active RA. Subjects were randomly assigned (1:1 ratio) into either SSC group (2.4 g/day SSC + 2.4 g/day black tea, n=22) or placebo (2.4 g/day black tea, n=22) for 8 weeks. Serum high-sensitivity C-reactive protein (hs-CRP), interleukin-1 beta (IL-1β), and MMPs were measured using ELISA. According to the American College of Rheumatology guideline considering hs-CRP, DAS28 was assessed. RESULTS: Both study groups had respondent rates above 94.9%. The SSC intervention caused significant reductions in the number and the percent changes of the tender joints (SSC: -74.39% vs. placebo: -57.15%, mean differences= -0.77; P<0.05) and DAS28 [SSC: -32.44% vs. placebo: -22.32%, mean differences= -0.41, P<0.05). Unlike the intervention within SSC group that showed significant reductions in the mean serum levels of hs-CRP, IL-1β, and MMP-3, SSC caused significant MMP-3 reductions (SSC: -20.59% vs. placebo: 1.29%, P<0.05). CONCLUSION: The SSC intervention showed an appropriate clinical efficacy for female RA patients, accompanying remarkable reductions in the number of tender and swollen joints, DAS28, and serum levels of MMP-3. This can provide additional insights to the interventional studies controlling RA-related pathological and inflammatory outcomes. Trial registration Prospectively registered at the Iranian Registry of Clinical Trials (IRCT), linked to the WHO Registry Network ( https://en.irct.ir/trial/11602 , IRCT registration number: IRCT2015032011335N5, Registration date:2015-05-12). Key Points • Stachys schtschegleevii improved clinical outcomes and attenuated disease severity in RA patients. • Stachys schtschegleevii ameliorated serum level of MMP-3 in RA patients.
34636880 CXCL13 predicts long-term radiographic status in early rheumatoid arthritis. 2022 May 30 OBJECTIVES: Identification of RA patients at a high risk of joint destruction remains challenging. The C-X-C motif chemokine 13 (CXCL13) has previously been suggested as a marker of disease activity in RA. Here, we investigate the potential of plasma CXCL13 as a marker of long-term radiographic status and progression. METHODS: CXCL13 was measured in plasma from treatment-naïve RA patients (n = 158) with an 11-year follow-up. At baseline, clinical and biochemical DASs were obtained; among these CRP, ESR, DAS in 28 joints with CRP (DAS28CRP), number of swollen joints (SJC28) and radiographic status, evaluated by total Sharp score (TSS). Age- and gender-matched healthy controls (HCs) were included. RESULTS: CXCL13 was significantly increased at baseline and decreased during treatment; however, it was not reduced to the level in HCs. At baseline, CXCL13 was associated with both CRP and ESR, but not with other markers of disease activity. Baseline CXCL13 was correlated with both TSS and radiographic progression (ΔTSS) at 11 years. With an 89% probability, levels of CXCL13 above 85 pg/ml predicted the risk of a TSS of 5 or above, after 11 years of treatment. Compared with CRP, DAS28CRP, SJC28 and ACPA status, CXCL13 was superior in predicting 11-year joint destruction. CONCLUSION: In early RA, one single measurement of plasma CXCL13 at baseline is superior to currently used clinical and serological disease markers in the prediction of long-term radiographic status and progression.
34780107 Effectiveness and cost-effectiveness of longstanding exercise therapy versus usual care in 2022 Jan OBJECTIVES: Research on effectiveness and cost-effectiveness of longstanding exercise therapy in patients with axial SpondyloArthritis (axSpA) or Rheumatoid Arthritis (RA) is scarce, and mainly concerned patients with a relatively favorable health status. We aim to evaluate the effectiveness and cost-effectiveness of longstanding exercise therapy compared to usual care in the subgroup of patients with axSpA or RA and severe limitations in functioning. METHODS: In two separate, parallel randomized controlled trials the effectiveness and cost-effectiveness of longstanding, active exercise therapy (52 weeks) compared with usual care (1:1) will be evaluated. The longstanding, active exercise therapy will focus on improving individual limitations in daily activities and participation and will be given by a trained physical therapist in the vicinity of the participant. For each diagnosis, 215 patients with severe limitations in activities and participation will be included. Assessments are performed at baseline, 12, 26, and 52 weeks. The primary outcome measure of effectiveness is the individual level of functioning (activities and participation), as measured with the Patient-Specific Complaints instrument at 52 weeks. For cost-effectiveness analyses, the EuroQol (EQ-5D-5L) and questionnaires on healthcare use and productivity will be administered. The economic evaluation will be a cost-utility analysis from a societal perspective. After 52 weeks, the patients in the usual care group are offered longstanding, active exercise therapy as well. Follow-up assessments are done at 104, 156, and 208 weeks. CONCLUSION: The results of these studies will provide insights in the effectiveness and cost-effectiveness of longstanding exercise therapy in the subgroup of axSpA and RA patients with severe functional limitations.
34686479 Two-dose COVID-19 vaccination and possible arthritis flare among patients with rheumatoid 2022 Apr OBJECTIVES: To investigate the relationship between COVID-19 full vaccination (two completed doses) and possible arthritis flare. METHODS: Patients with rheumatoid arthritis (RA) were identified from population-based electronic medical records with vaccination linkage and categorised into BNT162b2 (mRNA vaccine), CoronaVac (inactive virus vaccine) and non-vaccinated groups. The risk of possible arthritis flare after vaccination was compared using a propensity-weighted cohort study design. We defined possible arthritis flare as hospitalisation and outpatient consultation related to RA or reactive arthritis, based on diagnosis records during the episode. Weekly prescriptions of rheumatic drugs since the launch of COVID-19 vaccination programme were compared to complement the findings from a diagnosis-based analysis. RESULTS: Among 5493 patients with RA (BNT162b2: 653; CoronaVac: 671; non-vaccinated: 4169), propensity-scored weighted Poisson regression showed no significant association between arthritis flare and COVID-19 vaccination ((BNT162b2: adjusted incidence rate ratio 0.86, 95% Confidence Interval 0.73 to 1.01); CoronaVac: 0.87 (0.74 to 1.02)). The distribution of weekly rheumatic drug prescriptions showed no significant differences among the three groups since the launch of the mass vaccination programme (all p values >0.1 from Kruskal-Wallis test). CONCLUSIONS: Current evidence does not support that full vaccination of mRNA or inactivated virus COVID-19 vaccines is associated with possible arthritis flare.
35603149 Th1-Like Treg Cells Are Increased But Deficient in Function in Rheumatoid Arthritis. 2022 OBJECTIVES: This study aimed to investigate the changes in quantity and function of T helper (Th)-like T regulatory (Treg) cell subsets in peripheral blood (PB) and synovial fluid (SF) of rheumatoid arthritis (RA) patients and to understand their relationship with disease activity. METHODS: A total of 86 RA patients and 76 gender and age-matched healthy controls (HC) were enrolled in this study. Th-like Treg frequency and function were determined using flow cytometry. The inhibitory function of Th-like Treg cells was detected using an in vitro co-culture suppression assay. RESULTS: The proportion and absolute number of Th1-like Treg cells from RA PB and RA SF were significantly higher than those of HC PB. In RA SF, the proportions of Treg cells and Th1-like Treg cells were significantly lower in the elevated erythrocyte sedimentation rate or the C-Reactive Protein group, and in the positive groups of anti-CCP antibody and anti-MCV antibody. Additionally, the proportions of Treg cells and Th1-like Treg cells from RA SF were negatively correlated with disease activity. However, the expression levels of CD73 and TGF-β1 in Th1-like Treg cells were decreased, and these Treg cells could not effectively inhibit the proliferation of effector T (Teff) cells. CONCLUSION: Our data indicate that Th1-like Treg cells are the predominant Treg cell subset in RA SF, but their suppressive function is defective. Improving the function of Th1-like Treg cells may control inflammation in joints and provide new strategies for Treg-targeted therapies in RA.
34864624 Systemic pharmacological verification of Baixianfeng decoction regulating TNF-PI3K-Akt-NF- 2022 Feb Traditional Chinese medicine has a long history of treating complex diseases, especially for the conditioning of systemic diseases. It has been reported that Baixianfeng (BXF) decoction used to treat rheumatoid arthritis (RA) may be due to its systemic regulatory effect, but the specific mechanism still remains to be elucidated. The research philosophy and methods of systemic pharmacology were used to explore the mechanism of BXF decoction in treating RA in this study. TCMSP database was used to search the ingredients of BXF decoction and screen the ADME parameters. The parameter index was set as OB ≥ 30%, DL ≥ 0.18, HL ≥ 4 h. The targets of the screened compounds were searched and predicted by TCMSP and Target-Prediction platforms. The disease targets of RA were obtained through the DisGeNET, OMIM, and PharmGkb databases. A series of network construction and analysis relied on Cytoscape 3.2.1 software, and the DAVID database was used for pathway enrichment. The adjuvant arthritis rat model was used for the verification of animal experiments to verify the predicted pathway results in terms of pathological phenotype, inflammatory factors, and pathway protein expression. The results showed that the related targets of 81 active ingredients in the drug crossed 56 targets of RA, and these common targets were enriched in 83 significant pathways, among which the TNF signaling pathway had research significance. Animal experiments have proved that BXF decoction was effective in treating adjuvant arthritis rats. The drug relieved the pathological phenotype of rats in dose-dependent. It reduced the serum content of TNF-α and IL-1β, and reduced the gene expression of TNF-α and IL-6 in spleen tissue. In the cartilage tissue protein of rats, it inhibited the degradation of collagen Ⅱ protein. Further, BXF decoction reduced the activation of p-PI3K, p-Akt, and p-P65 protein, and decreased the overexpression of apoptotic proteins such as cleaved-caspase8 and cleaved-caspase3 in cartilage tissue. Meanwhile, it inhibited the protein expression of MMP9, TNF-α, IL-6, and IL-1β. In conclusion, this study successfully practiced the combination of systemic pharmacology and experimental verification, and clarified that BXF decoction inhibited the progression of adjuvant arthritis rats through the TNF-PI3K-Akt-NF-κB signal axis. It provides new evidence for the study of the mechanism of BXF decoction in treating RA.
35624488 Fibronectin extra domain A as a drug delivery targeting epitope for rheumatoid arthritis. 2022 May 27 OBJECTIVES: To assess the ability of monoclonal antibodies (mAbs) specific for fibronectin extra-domain A (FnEDA) to target diseased tissues of mouse collagen induced arthritis (mCIA) models. To explore the parameters of the targeting exhibited by anti-FnEDA mAbs including timing and location. METHODS: Targeting capabilities of anti-FnEDA mAbs were demonstrated by biodistribution study where i.v. injected antibodies were detected by conjugated near-infrared (NIR) fluorophore, (125)I label and immunohistochemistry (IHC) of the injected antibody. Location of FnEDA expression in both mCIA and human RA tissue were mapped by IHC. Quantification of anti-FnEDA mAbs targeted to disease tissue was measured by whole-body autoradiography (WBA). Timing of the targeting was interrogated with fluorescent and confocal microscopy using anti-FnEDA mAbs labeled with different fluorophores and injected at different times. RESULTS: Anti-FnEDA mAbs show specific targeting to diseased paws of mCIA animal. The targeting was focused on inflamed synovium which is consistent with FnEDA expression profile in both mCIA and human RA tissues. Anti-FnEDA mAbs accumulated in diseased tissue at pharmacologically relevant concentrations, the targeting was sustained for up to 14 days and FnEDA was able to support targeting of multiple doses of anti-FnEDA mAbs given 5 days apart. CONCLUSION: FnEDA is specifically upregulated in the inflamed tissues of mCIA. Antibodies specific for FnEDA can be useful as molecular delivery vehicles for disease specific targeting of payloads to inflamed joint tissue.
35147113 Serum irisin concentrations and osteoporotic vertebral fractures in women with rheumatoid 2022 Feb 11 Irisin stimulates osteoblast differentiation increasing bone mass a decreasing in irisin levels might contribute to osteoporotic fractures in inflammatory diseases. To date, there is controverted whether irisin levels are associated with osteoporotic fractures in rheumatoid arthritis (RA). Therefore, we evaluate the association of serum irisin with osteoporotic Vertebral Fractures (VFs) in women with RA.A total of 148 women with RA was included in the study.Clinical characteristics and risk factors of VFs was evaluated. For measurement of bone mineral density we included the assessment of lumbar spine (AP L1-L4) and Femoral Neck by dual-energy X-ray absorptiometry (DXA). VFs were evaluated by lateral vertebral assessment (LVA) of the dorsal and lumbar regions using X-ray and digital vertebral morphometry by DXA, using the Genant scale. Serum irisin levels were measured by ELISA. A reference group of 97 women with non-rheumatic diseases were included to compare irisin levels.RA patients had a median age of 59 years and 41% had osteoporosis. Seventy three (49%) had VFs. Lower irisin levels were observed in RA patients compared to controls (94 ± 74 vs 135 ± 103, P < .001). Irisin concentrations were lower in RA + VFs than RA non-VFs (74 ± 42 vs 113 ± 92 ng/mL, P = .001). In the multivariable logistic regression analysis the low 50 percentile irisin levels < 73 ng/mL (OR:3.1, 95% CI:1.55-6.2, P = .001), and disease duration of RA (OR:1.04, 95% CI:1.001-1.08, P = .04) were associated with an increase in the risk of VFs.A decrease of irisin levels is associated to VFs in RA. These results are valuable to consider that RA patients with low levels of irisin are in a potential risk of VFs.
35634335 The Regulatory Role of MicroRNAs on Phagocytes: A Potential Therapeutic Target for Chronic 2022 An effective acute inflammatory response results in the elimination of infectious microorganisms, followed by a smooth transition to resolution and repair. During the inflammatory response, neutrophils play a crucial role in antimicrobial defense as the first cells to reach the site of infection damage. However, if the neutrophils that have performed the bactericidal effect are not removed in time, the inflammatory response will not be able to subside. Anti-inflammatory macrophages are the main scavengers of neutrophils and can promote inflammation towards resolution. MicroRNAs (miRNAs) have great potential as clinical targeted therapy and have attracted much attention in recent years. This paper summarizes the involvement of miRNAs in the process of chronic diseases such as atherosclerosis, rheumatoid arthritis and systemic lupus erythematosus by regulating lipid metabolism, cytokine secretion, inflammatory factor synthesis and tissue repair in two types of cells. This will provide a certain reference for miRNA-targeted treatment of chronic diseases.
35177450 RetINal Toxicity And HydroxyChloroquine Therapy (INTACT): protocol for a prospective popul 2022 Feb 17 PURPOSE: Hydroxychloroquine (HCQ) is an important medication for patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and other rheumatic diseases. Although it is well-tolerated and cost-effective, the risk of HCQ retinal toxicity is of increasing concern. The aim of this study is to re-examine the HCQ retinal toxicity incidence rate, risk factors and clinical course after discontinuation. METHODS: We designed a prospective population-based cohort study in adult patients with SLE or RA, currently receiving HCQ for five or more years, who are residents of British Columbia (BC), Canada. Based on administrative data, we identified 5508 eligible participants (1346 SLE and 4162 RA). They will participate in annual or biannual retinal screening over 5 years in alignment with the recently revised American Academy of Ophthalmology guidelines. To standardise procedures for retinal screening, imaging, diagnostic criteria, severity staging and data transfer, a consensus meeting was convened in December 2019 with participation of BC retinal specialists and the research team. Agreement was attained on: use of spectral domain-optical coherence tomography as the primary objective screening modality; classification of images into categories of normal, equivocal or abnormal; and transferring the equivocal and abnormal images plus corresponding subjective test results via cloud-based server from each clinic to a reading centre. Confirmation of HCQ retinal toxicity diagnoses and severity staging will be performed by three independent and masked reviewers. The incidence of HCQ retinal toxicity will be calculated, accounting for the competing risk of death. Hazard ratios for each risk factor will be calculated for the risk of HCQ retinopathy, after adjusting for confounders. We will also estimate the risk of HCQ retinal toxicity progression over 5 years. ETHICS AND DISSEMINATION: This study has received approval from the University of British Columbia Clinical Research Ethics Board (H20-00736) and the Vancouver Coastal Health Research Institute.
33878168 Patient and rheumatologist perspectives on tapering DMARDs in rheumatoid arthritis: a qual 2022 Feb 2 OBJECTIVES: To understand the perspectives of patients and rheumatologists for tapering DMARDs in RA. METHODS: Using semi-structured interview guides, we conducted individual interviews and focus groups with RA patients and rheumatologists, which were audiotaped and transcribed. We conducted a pragmatic thematic analysis to identify major themes, comparing and contrasting different views on DMARD tapering between patients and rheumatologists. RESULTS: We recruited 28 adult patients with RA (64% women; disease duration 1-54 y) and 23 rheumatologists (52% women). Attitudes across both groups towards tapering DMARDs were ambivalent, ranging from wary to enthusiastic. Both groups expressed concerns, particularly the inability to 'recapture' the same level of disease control, while also acknowledging potential positive outcomes such as reduced drug harms. Patient tapering perspectives (whether to and when) changed over time and commonly included non-biologic DMARDs. Patient preferences were influenced by lived experiences, side effects, previous tapering experiences, disease trajectory, remission duration and current life roles. Rheumatologists' perspectives varied on timing and patient profile to initiate tapering, and were informed by both data and clinical experience. Patients expressed interest in shared decision-making (SDM) and close monitoring during tapering, with ready access to their health-care team if problems arose. Rheumatologists were generally open to tapering (not stopping), though sometimes only when requested by their patients. CONCLUSION: The perspectives of patients and rheumatologists on tapering DMARDs in RA vary and evolve over time. Rheumatologists should periodically discuss DMARD tapering with patients as part of SDM, and ensure monitoring and flare management plans are in place.
34998422 Hyaluronidase treatment of synovial fluid is required for accurate detection of inflammato 2022 Jan 8 BACKGROUND: Synovial fluid (SF) is commonly used for diagnostic and research purposes, as it is believed to reflect the local inflammatory environment. Owing to its complex composition and especially the presence of hyaluronic acid, SF is usually viscous and non-homogeneous. In this study, we investigated the importance of homogenization of the total SF sample before subsequent analysis. METHODS: SF was obtained from the knee of 29 arthritis patients (26 rheumatoid arthritis, 2 osteoarthritis, and 1 juvenile idiopathic arthritis patient) as part of standard clinical care. Synovial fluid was either treated with hyaluronidase as a whole or after aliquoting to determine whether the concentration of soluble mediators is evenly distributed in the viscous synovial fluid. Cytokine and IgG levels were measured by ELISA or Luminex and a total of seven fatty acid and oxylipin levels were determined using LC-MS/MS in all aliquots. For cell analysis, synovial fluid was first centrifuged and the pellet was separated from the fluid. The fluid was subsequently treated with hyaluronidase and centrifuged to isolate remaining cells. Cell numbers and phenotype were determined using flow cytometry. RESULTS: In all patients, there was less variation in IgG, 17-HDHA, leukotriene B(4) (LTB(4)), and prostaglandin E(2) (PGE(2)) levels when homogenization was performed before aliquoting the SF sample. There was no difference in variation for cytokines, 15-HETE, and fatty acids arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Between 0.8 and 70% of immune cells (median 5%) remained in suspension and were missing in subsequent analyses when the cells were isolated from untreated SF. This percentage was higher for T and B cells: 7-85% (median 22%) and 7-88% (median 23 %), respectively. CONCLUSIONS: Homogenization of the entire SF sample leads to less variability in IgG and oxylipin levels and prevents erroneous conclusions based on incomplete isolation of synovial fluid cells.
34623640 Semi-Mechanistic PK/PD Modeling and Simulation of Irreversible BTK Inhibition to Support D 2022 Feb Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.
34897499 Efficacy and safety of abatacept in biologic-naïve patients with active rheumatoid arthri 2022 Apr 18 OBJECTIVES: The objective of this study is to evaluate efficacy and safety of abatacept in biologic-naïve, anti-citrullinated protein antibody (ACPA)-positive Japanese patients with active rheumatoid arthritis (RA) by background methotrexate (MTX) dose. METHODS: In this post hoc analysis of a randomized, double-blind, placebo-controlled phase 4 study (NCT01758198), patients received intravenous abatacept (∼10 mg/kg) or placebo both with MTX (≥6 mg/week). Efficacy (Disease Activity Score 28 using C-reactive protein [DAS28 (CRP)] and Health Assessment Questionnaire-Disability Index [HAQ-DI]) was assessed by baseline MTX dosage (≤8 and >8 mg/week) to week 16; safety was assessed by MTX dosage ≤8 and >8 mg/week. Change from baseline in DAS28 (CRP) and HAQ-DI was assessed using longitudinal repeated measures analysis. RESULTS: Overall, 101 and 102 patients received abatacept + MTX ≤8 and >8 mg/week, while 96 and 106 patients received placebo + MTX ≤8 and >8 mg/week, respectively. Regardless of baseline MTX dose received, mean changes from baseline in DAS28 (CRP) and HAQ-DI in abatacept groups were similar; repeated measures analysis showed similar trends in changes from baseline in DAS28 (CRP) and HAQ-DI. Abatacept safety profile was consistent with previous observations. CONCLUSIONS: Post hoc analysis demonstrated similar efficacy and safety of abatacept in biologic-naïve ACPA-positive Japanese patients with RA regardless of baseline MTX dose.
34302478 Predictors of poor function in RA based on two prospective UK inception cohorts. Do comorb 2022 Apr 11 OBJECTIVES: Evidence suggests that factors beyond disease activity associate with functional disability in RA. The primary study objective was to explore associations between comorbidities, sociodemographic factors and functional outcomes at five and 10 years. METHODS: RA patients from two UK prospective cohorts were grouped into low (<1.5) and high (≥1.5) five- and 10-year health assessment questionnaire (HAQ) score. Clinical variables (e.g. disease activity, rheumatoid nodules, erosions) and sociodemographic factors (e.g. ethnicity, deprivation) were recorded at baseline and yearly thereafter. Comorbidity was measured using the Rheumatic Diseases Comorbidity Index (RDCI). Binary logistic regression models were fitted using multiple imputation. RESULTS: In total, 2701 RA patients were recruited (mean age 56.1 years, 66.9% female). A total of 1718 (63.4%) had five-year and 820 (30.4%) 10-year follow-up data. In multivariable analysis, no association was found between RDCI and HAQ ≥ 1.5 at five or 10 years. Sociodemographic factors (increased age at disease onset, female gender, minority ethnicity) were associated with higher odds of HAQ ≥ 1.5 at five and 10 years, with worse deprivation additionally associated with HAQ ≥ 1.5 at 10 years (OR 0.79, 95% CI: 0.69, 0.90). CONCLUSION: Comorbidities at baseline have not been found to be associated with worse RA functional outcome in the long-term. On the other hand, sociodemographic factors, independently of disease measures, are associated with worse functional outcome in RA at five and 10 years, in models adjusting for comorbidity burden. Tailoring management interventions according to not only clinical disease parameters but also patient sociodemographic factors may improve long-term outcomes including functional disability.
34228594 Rhupus: dual rheumatic disease. 2022 Mar 4 Autoimmune disorders are typically categorized into systematic and local diseases that affect a single organ or tissue. Organs and tissues affected by autoimmune disorders include components of the endocrine system, such as thyroid, pancreas, and adrenal glands; blood, such as red blood cells; and the connective tissues, skin, muscles, and joints. Rhupus is a complex musculoskeletal autoimmune disease (AD) in which features of both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are simultaneously present. The cause and trigger of rhupus is still unknown, suggesting the role of genetic, immunological, hormonal, and environmental factors in the initiation and progression of the disease. The role of immune system has been established by the presence of specific autoantibodies as markers for diagnosis of rhupus and the formation of immune complex in serum. The complications of rhupus include the presence of rheumatoid factor (RF) and nodules and the involvement of nervous and renal systems that complicates its diagnosis and prognosis. The rhupus arthritis resembles RA-like pathophysiology and leads to inflammation, deformation, and disability. Due to the heterogeneity and rarity of the disease, the prevalence, pathophysiology, and natural history as well as radiological and immunological profiles of rhupus are still not properly understood.
35180623 SIX1 attenuates inflammation and rheumatoid arthritis by silencing MyD88-dependent TLR1/2 2022 May OBJECTIVES: Rheumatoid 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. METHODS: Wistar 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. RESULTS: SIX1 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 Pam(3)CSK(4), a specific agonist of TLR1/2 signaling, attenuated the effects of SIX1 on RASFs. CONCLUSION: SIX1 attenuated inflammation and RA by silencing MyD88-dependent TLR1/2 signaling. SIX1 may be a promising target for RA treatment.