Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
34062592 [Lung involvement in rheumatic diseases]. 2021 Jun Lung involvement is one of the most frequent organ manifestation in rheumatic diseases (CTD-ILD). Especially patients with rheumatoid arthritis, systemic sclerosis, and idiopathic inflammatory myopathies are affected. Interstitial lung diseases (ILD) are still associated with significant morbidity and mortality. The last years have brought advances in management and treatment of ILDs. Methotrexate is probably not a significant cause of lung disease in rheumatoid arthritis but might even delay the presentation of interstitial lung disease (ILD). Tocilizumab could be a treatment option in SSc-ILD, despite the limitations of the current studies. For Systemic Sclerosis-ILD (SSc-ILD) and progressive fibrosing ILD, antifibrotic therapy with nintedanib is now approved.
33179175 Indomethacin loaded dextran stearate polymeric micelles improve adjuvant-induced arthritis 2021 Feb BACKGROUND: Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that can effectively control the pain and inflammation caused by rheumatoid arthritis (RA), but its usage is limited due to severe adverse effects. For this reason, making more specific formulations of this drug can be considered. The aim of the present study was designing a novel nano-sized indomethacin delivery system. MATERIALS AND METHODS: Indomethacin-loaded dextran stearate polymeric micelles were prepared by dialysis method. Particle size and zeta potential of micelles were measured by a zeta sizer instrument. Drug release from micelles was investigated in phosphate buffer medium pH 7.4 and then the best formulation regarding physical properties and drug release was selected for animal studies. Arthritis was induced by complete Freund's adjuvant injection in rats. Then, the animals were randomly assigned into the model, the indomethacin solution and the polymeric micelles groups. The clinical effects of polymeric micelle formulation were assessed by measuring arthritis index, animal paw edema and measuring biochemical parameters including myeloperoxidase (MPO) activity, lipid peroxidation (LPO), glutathione (GSH), total antioxidant capacity (TAC), TNF-α, IL-17 and IL-1β. RESULTS: Paw edema was attenuated following the administration of indomethacin-loaded polymeric micelles. Based on the findings of the present study, the use of indomethacin-loaded polymeric micelles could improve inflammatory symptoms, decrease arthritis index and decrease the diameter of the paw in arthritic rats in a significant manner (p ≤ 0.05). In addition, the use of polymeric micelles like indomethacin solution significantly reduced (p ≤ 0.05) the activity of MPO, LPO, TNF-α, IL-17 and IL-1β, and made a significant increase (p ≤ 0.05) in glutathione and TAC content and ameliorated structural changes in the paw tissue compared to the control group. CONCLUSION: Our findings demonstrated that indomethacin-loaded dextran stearate polymeric micelles can provide more effective therapeutic effects in control of inflammation in arthritis in rat.
34910199 The real-world effectiveness of anti-RANKL antibody denosumab on the clinical fracture pre 2021 Aug 12 OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by localized and generalized bone loss. The risk of fractures is doubled in patients with RA. Denosumab, an anti-RANKL monoclonal antibody, is used for those with osteoporosis at high risk fracture and it has inhibitory effect of progressive bone erosion in patients with RA. While the increase in bone mineral density by denosumab has been reported in patients with RA, preventive effect of fracture by denosumab remains unknown. This study aimed to evaluate the efficacy of denosumab in treating clinical fracture risk in patients with RA. METHODS: Patients with RA who received denosumab treatment between 2013 and 2019 were retrospectively evaluated using the ANSWER (Kansai Consortium for the Well-Being of Rheumatic Disease Patients) cohort data. Fracture rates were evaluated between 0 and 6 months (reference period) versus > 6 months (post-reference period) of denosumab use. RESULTS: A total of 873 patients with RA received denosumab, and their characteristics were as follows: 88% females, mean age 68 years, and average disease duration 14.5 years. The hazard rates of all clinical fractures were 0.69 (per 100 person-years) in the reference period and 0.35 in the post-reference period, indicating a 49.2% decrease (p = 0.03). CONCLUSIONS: Denosumab suppresses the risk of clinical fractures in patients with RA.
34830741 Comparison of Indexes to Measure Comorbidity Burden and Predict All-Cause Mortality in Rhe 2021 Nov 22 OBJECTIVES: To examine the comorbidity burden in patients with rheumatoid arthritis (RA) patients using a nationwide population-based cohort by assessing the Charlson Comorbidity Index (CCI), Elixhauser Comorbidity Index (ECI), Multimorbidity Index (MMI), and Rheumatic Disease Comorbidity Index (RDCI) scores and to investigate their predictive ability for all-cause mortality. METHODS: We identified 24,767 RA patients diagnosed from 1998 to 2008 in Taiwan and followed up until 31 December 2013. The incidence of comorbidities was estimated in three periods (before, during, and after the diagnostic period). The incidence rate ratios were calculated by comparing during vs. before and after vs. before the diagnostic period. One- and 5-year mortality rates were calculated and discriminated by low and high-score groups and modified models for each index. RESULTS: The mean score at diagnosis was 0.8 in CCI, 2.8 in ECI, 0.7 in MMI, and 1.3 in RDCI, and annual percentage changes are 11.0%, 11.3%, 9.7%, and 6.8%, respectively. The incidence of any increase in the comorbidity index was significantly higher in the periods of "during" and "after" the RA diagnosis (incidence rate ratios for different indexes: 1.33-2.77). The mortality rate significantly differed between the high and low-score groups measured by each index (adjusted hazard ratios: 2.5-4.3 for different indexes). CCI was slightly better in the prediction of 1- and 5-year mortality rates. CONCLUSIONS: Comorbidities are common before and after RA diagnosis, and the rate of accumulation accelerates after RA diagnosis. All four comorbidity indexes are useful to measure the temporal changes and to predict mortality.
34803668 Higher Risk of Cardiovascular Diseases in Rheumatoid Arthritis Patients Without Methotrexa 2021 Cardiovascular diseases (CVDs) lead to higher morbidity and mortality in rheumatoid arthritis; thus, we aimed to determine whether patients who had discontinued methotrexate treatment before the study enrollment (group MTX 0) were at a higher risk of CVD than patients treated with methotrexate at the time of the data collection (group MTX 1). A retrospective, prospective, observational, cross-sectional study was conducted. A total of 125 patients were enrolled in the study. Patients from the MTX 0 group (n = 35) were not treated with methotrexate for 7.54 (SD ± 4.21) years in average. Medical documentation as well as information taken in patient examinations during regular rheumatologist visits was used to obtain the required data. The composite of any CVD occurred less frequently in patients in the MTX 1 group than in the MTX 0 group (18.8 vs. 40.0%, OR 0.35, 95% CI, 0.15 to 0.83; p = 0.017) with a non-significant trend after adjustment for other treatments, which differed between study groups at the baseline (p = 0.054). Significant difference was found for the reduction of myocardial infarction in the MTX 1 group compared to the MTX 0 group (3.5 vs. 14.3%, OR 0.22, 95% CI, 0.05 to 0.97; p = 0.046). There were 4 deaths (4.7%) in the MTX 1 group as compared with 7 (20.0%) in the MTX 0 group (OR 0.20, 95% CI, 0.05 to 0.73; p = 0.015). Our results demonstrate that patients who discontinued methotrexate treatment are at a significantly higher risk of CVD and all-cause mortality. Based on our findings, we recommend stricter control of CVD in cases of methotrexate discontinuation.
34522114 Erythroferrone Expression in Anemic Rheumatoid Arthritis Patients: Is It Disordered Iron T 2021 PURPOSE: Erythroferrone (ERFE) is well acknowledged for its inhibitory function on hepcidin synthesis in the liver during stress erythropoiesis, thereby ensuring sufficient iron supply to bone marrow erythroblasts. Hepcidin plays an indispensable role in the pathogenesis of anemia of chronic disease (ACD). Thus, ERFE was suggested to protect against ACD in various diseases. Rheumatoid arthritis (RA) is commonly involved with ACD and high hepcidin levels, with a further increase of the latter in active states. The present study is a case-control study that aimed to determine the pattern of ERFE expression in RA patients with concomitant ACD and study its relationship with hepcidin, erythropoietin (EPO) and disease activity. PATIENTS AND METHODS: Fifty-five RA patients with ACD were categorized into active and inactive RA using the disease activity score (DAS28); 15 healthy subjects were included as control subjects. ERFE was measured for patients and control subjects using quantitative real-time polymerase chain reaction, in addition to testing for CBC, ESR, CRP, iron profile parameters and hepcidin. EPO was assessed for patients of both active and inactive RA groups. RESULTS: ERFE and hepcidin showed the highest levels in active RA; ERFE values were similar in control subjects and inactive RA patients, while hepcidin was significantly higher in inactive RA than control subjects. Patients with high ERFE levels had higher RBC, Hct, MCV, hepcidin and EPO levels. Stepwise regression analysis has identified DAS28 and disease duration as the best predictors of ERFE values, whereas ERFE and hepcidin were independent predictors of disease activity. CONCLUSION: We introduce ERFE as a novel marker of RA activity. Although the inhibitory effect of ERFE on hepcidin is not evident, our results still indicate that ERFE may have a beneficial erythropoietic effect in the context of ACD in RA disease activity.
34441861 Fatigue in Systemic Lupus Erythematosus and Rheumatoid Arthritis: A Comparison of Mechanis 2021 Aug 13 Fatigue is a common constitutional feature of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). While the two diseases share a common mechanism of autoimmunity, they differ in their clinical manifestations and treatment. Fatigue is one of the most commonly reported symptoms in both groups, associated with pain, depression and anxiety, and affecting function, work and quality of life. Fatigue is not easy to assess or conceptualise. It can be linked to disease activity, although it is not always, and is challenging to treat. Several measures have been trialled in RA and SLE; however, none have been adopted into mainstream practice. Despite being a common symptom, fatigue remains poorly managed in both RA and SLE-more so in the latter, where there have been relatively fewer studies. Additionally, comorbidities contribute to fatigue, further complicating its management. Pain, depression and anxiety also need to be addressed, not as separate entities, but together with fatigue in a holistic manner. Here, we describe the similarities and differences between fatigue in patients with RA and SLE, discuss concepts and practices applicable to both conditions and identify areas for further research. Through this review, we aim to highlight the importance of the holistic management of fatigue in SLE.
33496958 Comparative Cost-Effectiveness of Tofacitinib With Continuing Conventional Synthetic Disea 2021 Mar INTRODUCTION: The objective of this study was to evaluate the cost-effectiveness of initiating treatment with tofacitinib and subsequently incorporating it into a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) treatment sequence and to compare the cost-effectiveness of this sequence with that of continuing csDMARDs alone in patients with active rheumatoid arthritis (RA). METHODS: A cohort-based Markov model was used to evaluate the cost-effectiveness of two tofacitinib treatment sequences compared with that of continuing the csDMARD treatment sequence over a lifetime. Of the two tofacitinib sequences, the first consisted of initial tofacitinib treatment followed by biologic DMARDs (bDMARDs) and the second consisted of csDMARD treatments followed by tofacitinib. A third treatment sequence, continuing the csDMARD treatment sequence before starting bDMARDs, was used as a comparator. Efficacy was assessed using the American College of Rheumatology (ACR) response rates (ACR 20, ACR 50, and ACR 70) after 6 months, which were converted to changes in the health assessment questionnaire-disability index (HAQ-DI) score. Utility was estimated by mapping from the HAQ-DI score, costs were analyzed from a Korean societal perspective, and outcomes were considered in terms of quality-adjusted life-years (QALYs). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the model. RESULTS: The incremental cost-effectiveness ratios over a lifetime for starting with tofacitinib and incorporating tofacitinib into the csDMARD treatment sequence versus continuing csDMARDs only were US$14,537 per QALY and US$7,086 per QALY, respectively. One-way sensitivity analysis and probabilistic sensitivity analysis confirmed the robustness of these results. CONCLUSION: Starting with tofacitinib and incorporating it into a csDMARDs treatment sequence is cost-effective compared to continuing csDMARDs alone in patients with RA.
33959623 Opposing Trends in Total Knee and Hip Arthroplasties for Patients With Rheumatoid Arthriti 2021 Objective: To determine the trend of incidence rate of total knee arthroplasty (TKA), total hip arthroplasty (THA), and TKA or THA (major joint arthroplasty, MJA) among rheumatoid arthritis (RA) population and compared them with general population (GP) in Taiwan. Methods: Incidence rates and trends of TKA, THA, and MJA were determined over a 14-year period (2000-2013) among RA patients and compared them with GP. RA of patients was diagnosed based on the ACR 1987 criteria and extracted from GP. Subanalyses of incidences of TKA, THA, and MJA by year, 10-year age group, and gender were further conducted for demographic analysis. Patient profiles were extracted from the National Health Insurance Research Database (NHIRD) for interrupted time-series analysis and cohort studies. Results: Patients enrolled were 168,457 receiving TKA, 64,543 receiving THA, and 228,191 receiving MJA surgery. Incidences of TKA, THA, and MJA in RA patients were significantly lower by 49.0, 41.5, and 41.0% compared with concomitantly rises in GP by 131.0, 25.1, and 90.0% among the GP during the study period. The dominant age population for TKA, THA, and MJA were those aged 70-79 years in both GP and RA groups. Conclusions: We found an opposing trend in incidence of TKA, THA, and MJA between RA patients and the GP. The possible influence of pharmacological treatment is implicated for the lower incidence rates of TKA, THA, and MJA surgeries among RA patients.
33767774 MicroRNA-23a-5p regulates cell proliferation, migration and inflammation of TNF-α-stimula 2021 May Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial joint inflammation. RA synovial fibroblasts (RASFs) constitute a major cell subset of the RA synovia. MicroRNAs (miRNAs/miRs) have been reported to serve a role in the activation and proliferation of RASFs. The present study aimed to investigate the effects and underlying mechanisms of miR-23a-5p on RA progression. Peripheral blood was collected from patients with RA (n=20) to analyze the expression levels of miR-23a-5p. The effects of miR-23a-5p on cell apoptosis, proliferation and migration in MH7A cells were determined in TNF-α-treated human fibroblast-like synoviocytes (MH7A cells) by flow cytometry, colony formation assay and Transwell assay, respectively. The cell cycle distribution was evaluated using flow cytometry. The binding relationship between miR-23a-5p and toll-like receptor (TLR) 4 was analyzed using a dual luciferase reporter gene assay. ELISA and reverse transcription-quantitative PCR assays were used to detect the levels of the inflammatory factors IL-6, IL-1β and IL-10. The expression levels of apoptosis- and migration-related proteins were analyzed using western blotting. The results of the present study revealed that the expression levels of miR-23a-5p were significantly downregulated in the plasma of patients with RA and in MH7A cells. In addition, the TNF-α-induced increase in the cell proliferative and migratory rates and the production of IL-6 and IL-1β were markedly inhibited following miR-23a-5p overexpression. The TNF-α-induced decreases in MH7A cell apoptosis were also reversed following miR-23a-5p overexpression. Additionally, transfection with miR-23a-5p mimics significantly inhibited the activation of the TLR4/NF-κB signaling pathway in TNF-α-treated MH7A cells by targeting TLR4. Notably, TLR4 overexpression weakened the effects of miR-23a-5p mimic on cell proliferation, apoptosis, migration, inflammation and the TLR4/NF-κB signaling pathway in TNF-α-induced MH7A cells. In conclusion, the findings of the present study indicated that the miR-23a-5p/TLR4/NF-κB axis may serve as a promising target for RA diagnosis and treatment.
33747759 Soluble neuropilin-1 in gingival crevicular fluid is associated with rheumatoid arthritis: 2021 Apr BACKGROUND: To explore the soluble Neuropilin-1 (sNRP-1) concentrations in gingival crevicular fluid (GCF) and the periodontal clinical status of patients with Rheumatoid Arthritis (RA). MATERIALS AND METHODS: We conducted an exploratory study with 40 study participants, 20 with RA, and 20 healthy controls. Clinical and periodontal data were recorded, and GCF samples were obtained. sNRP-1 levels in GCF were determined by ELISA assay. Descriptive statistics, Mann-Whitney U test, Unpaired t-test, logistic regression model, and Area Under Receiver Operating Characteristic Curve (AUC-ROC) were made to explore the diagnostic performance accuracy. RESULTS: RA patients had significantly higher levels of sNRP-1 in GCF (p ​= ​0.0447). The median levels of GCF-sNRP-1 were 208.85 ​pg/μl (IQR 131.03) in the RA group compared to 81.46 ​pg/μl (IQR 163.73) in the control group. We observed an association between the GCF-sNRP-1 concentrations and the RA diagnosis (OR:1.009; CI 1.00-1.001; p ​= ​0.047). The diagnosis of chronic periodontitis was also associated with RA (OR: 6.9; CI 1.52-31.37; p ​= ​0.012). Moreover, the AUC-ROC of GCF-sNRP-1 concentrations combined with periodontal clinical parameters such as periodontal probing depth and periodontal inflamed surface area was 0.80. CONCLUSION: This exploratory case-control study shows that RA patients had significantly higher levels of sNRP-1 in GCF. New longitudinal studies are necessary to evaluate the role of NRP-1 in periodontal tissues and consider it an oral biomarker with clinical value in RA.
31916502 Molecular modeling studies of pyrrolo[2,3-d]pyrimidin-4-amine derivatives as JAK1 inhibito 2021 Feb Rheumatoid Arthritis (RA) is an autoimmune disease caused by overproduction of pro-inflammatory cytokines. Janus Kinases (JAKs) mediate cytokines signaling through the Janus Kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways. Clinical studies have shown that Janus kinase 1 (JAK1) mediated signaling plays a key role in synovial response in rheumatoid arthritis. Hence, the inhibition JAK1 is considered as an important therapeutic route for treatment of rheumatoid arthritis. In this study, we have performed three-dimensional quantitative structure-activity relationship (3 D-QSAR), molecular docking, molecular dynamics (MD) and free energy calculations on a series of pyrrolo[2,3-d]pyrimidin-4-amine JAK1 inhibitors. Molecular docking studies of the compounds 03, 13, 36 and 49 with JAK1 were performed to study the binding interactions. The binding conformations of the compounds from docking studies were selected based on binding energy and H-bond interactions and were used as initial structure for MD simulations. Using 3 D-QSAR techniques, a ligand-based comparative molecular field analysis (CoMFA) model (q(2) = 0.5, r(2) = 0.96) and a receptor-based CoMFA model (q(2) = 0.78, r(2) = 0.98) were developed. Analysis of the MD results of the most active compound (compound 49) with JAK1 showed the formation of H-bond interactions with residues Glu957, Leu959 and Gly887 and water-mediated H-bond interaction with Gly887 and His885. Based on the contour map analyses of the receptor-based CoMFA, a design strategy was proposed and was used for designing new JAK1 inhibitors. Four of the designed compounds (D57, D58, D98 and D99) showed predicted activity values (pIC(50)> 8.8) greater than the most active compound for JAK1. MM-PBSA based free energy calculations indicated that the designed compounds were able to form stable binding with JAK1 primarily through electrostatic interactions and van der Waal interactions. Collectively, the outcome of this study can be used to further the progress of JAK1 inhibition for the treatment of rheumatoid arthritis. Communicated by Ramaswamy H. Sarma.
34802464 Association between ultrasound images and patient-reported outcomes in the treatment of rh 2021 Nov 22 BACKGROUND: Improvements in the treatment of rheumatoid arthritis (RA) have made it possible to achieve treatment goals. It has been reported that both residual synovitis caused by RA and the patients' subjective symptoms remain even after achieving the treatment goals; however, there are limited reports showing a relationship between them. Furthermore, no studies have evaluated the relationship between patient-reported outcomes (PROs) and subclinical synovitis measured by musculoskeletal ultrasonography (MSUS) in the treatment of RA. This study aimed to investigate residual symptoms and residual synovitis due to remission (REM) or low disease activity (LDA). METHODS: We performed MSUS on 300 patients with RA who attended our hospital for routine care, and we analysed them cross-sectionally by disease activity. Grayscale (GS) and power Doppler (PD) synovitis was evaluated in 22 bilateral hand joints using MSUS. We first performed univariate and multivariate analysis by dividing the data by disease activity. Next, we analysed each PRO in the obtained MSUS results. RESULTS: A multivariate analysis of high disease activity (HDA)/moderate disease activity (MDA) vs. LDA/ REM group identified tender joint count (TJC), pain visual analog scale (VAS) score, and presence or absence of GS score ≥ 2. The one-way analysis of the relationship between the presence or absence of GS score ≥ 2 and each PRO showed a significant difference. In contrast, a multivariate analysis of LDA vs. REM group identified TJC and fatigue VAS score. In REM, PROs alone were relevant, and there was no correlation with MSUS. CONCLUSION: We found that the residual inflammation in the ultrasound images was associated with PROs in the LDA group, but not in the REM group. Trial registration Retrospectively registered.
34069878 The Preparation of a Novel Poly(Lactic Acid)-Based Sustained H(2)S Releasing Microsphere f 2021 May 18 Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that mainly erodes joints and surrounding tissues, and if it is not treated in time, it can cause joint deformities and loss of function. S-propargyl-cysteine (SPRC) is an excellent endogenous hydrogen sulfide donor which can relieve the symptoms of RA through the promotion of H(2)S release via the CSE/H(2)S pathway in vivo. However, the instant release of H(2)S in vivo could potentially limit its further clinical use. To solve this problem, in this study, a SPRC-loaded poly(lactic acid) (PLA) microsphere (SPRC@PLA) was prepared, which could release SPRC in vitro in a sustained manner, and further promote sustained in vivo H(2)S release. Furthermore, its therapeutical effect on RA in rats was also studied. A spherical-like SPRC@PLA was successfully prepared with a diameter of approximately 31.61 μm, yielding rate of 50.66%, loading efficiency of 6.10% and encapsulation efficiency of 52.71%. The SPRC@PLA showed significant prolonged in vitro SPRC release, to 4 days, and additionally, an in vivo H(2)S release around 3 days could also be observed. In addition, a better therapeutical effect and prolonged administration interval toward RA rats was also observed in the SPRC@PLA group.
33792526 Brassica juncea (L.) Czern. leaves alleviate adjuvant-induced rheumatoid arthritis in rats 2021 Apr 1 Brassica juncea (BJ) is a familiar edible crop, which has been used as a dietary ingredient and to prepare anti-inflammatory/anti-arthritic formulations in Ayurveda. But, the scientific validation or confirmation of its therapeutic properties is very limited. This study was performed to determine the efficiency of BJ leaves for the treatment of Rheumatoid arthritis using in vivo and in silico systems. Standard in vitro procedures was followed to study the total phenolic, flavonoid contents and free radical scavenging ability of the extracts of BJ. The effective extract was screened and the presence of bioactive chemicals was studied using HPLC. Further, the possible therapeutic actions of the BJ active principles against the disease targets were studied using PPI networking and docking analysis. IL2RA, IL18 and VEGFA are found to be the potential RA target and the compounds detected from BJ extract have shown great binding efficiency towards the target from molecular docking study. The resulting complexes were then subject to 100 ns molecular dynamics simulation studies with the GROMACS package to analyze the stability of docked protein-ligand complexes and to assess the fluctuation and conformational changes during protein-ligand interactions. To confirm the anti-arthritic activity of BJ, the extract was tested in CFA-induced arthritic Wistar rats. The test groups administered with BJ extract showed retrieval of altered hematological parameters and substantial recovery from inflammation and degeneration of rat hind paw.Communicated by Ramaswamy H. Sarma.
34919213 Post Hoc Analysis of the Correlation Between Patient-Reported Outcomes and Clinical Respon 2022 Apr PURPOSE: Approximately 6% of patients with rheumatoid arthritis (RA) in the USA have refractory disease that is resistant to standard-of-care therapies. A recent phase IV clinical trial affirmed the safety and efficacy of repository corticotropin injection (RCI; Acthar® Gel) for refractory RA. This post hoc analysis of the clinical trial data assessed whether changes in clinical measures correlated with patient-reported outcome (PRO) improvements. METHODS: Data were assessed from the trial's open-label period when patients received RCI (80 U) twice weekly for 12 weeks. Clinical assessments included hemoglobin A1c, C-reactive protein, erythrocyte sedimentation rate (ESR), total joint count (TJC), swollen joint count (SJC), Disease Activity Score with 28 joint count and ESR (DAS28-ESR), and Clinical Disease Activity Index (CDAI). PROs included pain (Visual Analog Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), disability (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and activity impairment (Work Productivity and Activity Impairment [WPAI] questionnaire). Patients grouped by minimal clinically important difference (MCID) improvement vs no improvement in PROs were compared with clinical measures at week 12. Correlations were determined by multivariable linear regression analysis and standardized coefficient estimates. RESULTS: RCI responders, defined as patients with DAS28-ESR < 3.2 at week 12, reported significantly greater PRO improvements for pain, disability, fatigue, activity impairment, current work impairment, and overall work impairment than nonresponders. Patients with MCID improvements in all PROs showed significantly greater decreases in mean values for TJC, DAS28-ESR, and CDAI, whereas those with pain, fatigue, and disability improvements had significantly greater SJC and ESR reductions. Multivariable linear regression analysis determined that improvement from baseline in all PROs correlated with significant decreases in TJC, DAS28-ESR, and CDAI. ESR reduction significantly correlated with improvements in pain and disability, but not fatigue or WPAI. CONCLUSIONS: These results confirm that clinical responses to RCI were directly correlated with patient perception of improvement.
34406722 2021 Aug BACKGROUND: Rheumatoid arthritis is a major inflammatory disorder and causes substantial disability. Treatment goals span minimising disease activity, achieving remission and decreasing disability. In active rheumatoid arthritis, intensive management achieves these goals. As many patients with established rheumatoid arthritis have moderate disease activity, the TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis ThErapy) programme assessed the benefits of intensive management. OBJECTIVES: To (1) define how to deliver intensive therapy in moderate established rheumatoid arthritis; (2) establish its clinical effectiveness and cost-effectiveness in a trial; and (3) evaluate evidence supporting intensive management in observational studies and completed trials. DESIGN: Observational studies, secondary analyses of completed trials and systematic reviews assessed existing evidence about intensive management. Qualitative research, patient workshops and systematic reviews defined how to deliver it. The trial assessed its clinical effectiveness and cost-effectiveness in moderate established rheumatoid arthritis. SETTING: Observational studies (in three London centres) involved 3167 patients. These were supplemented by secondary analyses of three previously completed trials (in centres across all English regions), involving 668 patients. Qualitative studies assessed expectations (nine patients in four London centres) and experiences of intensive management (15 patients in 10 centres across England). The main clinical trial enrolled 335 patients with diverse socioeconomic deprivation and ethnicity (in 39 centres across all English regions). PARTICIPANTS: Patients with established moderately active rheumatoid arthritis receiving conventional disease-modifying drugs. INTERVENTIONS: Intensive management used combinations of conventional disease-modifying drugs, biologics (particularly tumour necrosis factor inhibitors) and depot steroid injections; nurses saw patients monthly, adjusted treatment and provided supportive person-centred psychoeducation. Control patients received standard care. MAIN OUTCOME MEASURES: Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)-categorised patients (active to remission). Remission (DAS28-ESR < 2.60) was the treatment target. Other outcomes included fatigue (measured on a 100-mm visual analogue scale), disability (as measured on the Health Assessment Questionnaire), harms and resource use for economic assessments. RESULTS: Evaluation of existing evidence for intensive rheumatoid arthritis management showed the following. First, in observational studies, DAS28-ESR scores decreased over 10–20 years, whereas remissions and treatment intensities increased. Second, in systematic reviews of published trials, all intensive management strategies increased remissions. Finally, patients with high disability scores had fewer remissions. Qualitative studies of rheumatoid arthritis patients, workshops and systematic reviews helped develop an intensive management pathway. A 2-day training session for rheumatology practitioners explained its use, including motivational interviewing techniques and patient handbooks. The trial screened 459 patients and randomised 335 patients (168 patients received intensive management and 167 patients received standard care). A total of 303 patients provided 12-month outcome data. Intention-to-treat analysis showed intensive management increased DAS28-ESR 12-month remissions, compared with standard care (32% vs. 18%, odds ratio 2.17, 95% confidence interval 1.28 to 3.68; p = 0.004), and reduced fatigue [mean difference –18, 95% confidence interval –24 to –11 (scale 0–100); p < 0.001]. Disability (as measured on the Health Assessment Questionnaire) decreased when intensive management patients achieved remission (difference –0.40, 95% confidence interval –0.57 to –0.22) and these differences were considered clinically relevant. However, in all intensive management patients reductions in the Health Assessment Questionnaire scores were less marked (difference –0.1, 95% confidence interval –0.2 to 0.0). The numbers of serious adverse events (intensive management n = 15 vs. standard care n = 11) and other adverse events (intensive management n = 114 vs. standard care n = 151) were similar. Economic analysis showed that the base-case incremental cost-effectiveness ratio was £43,972 from NHS and Personal Social Services cost perspectives. The probability of meeting a willingness-to-pay threshold of £30,000 was 17%. The incremental cost-effectiveness ratio decreased to £29,363 after including patients’ personal costs and lost working time, corresponding to a 50% probability that intensive management is cost-effective at English willingness-to-pay thresholds. Analysing trial baseline predictors showed that remission predictors comprised baseline DAS28-ESR, disability scores and body mass index. A 6-month extension study (involving 95 intensive management patients) showed fewer remissions by 18 months, although more sustained remissions were more likley to persist. Qualitative research in trial completers showed that intensive management was acceptable and treatment support from specialist nurses was beneficial. LIMITATIONS: The main limitations comprised (1) using single time point remissions rather than sustained responses, (2) uncertainty about benefits of different aspects of intensive management and differences in its delivery across centres, (3) doubts about optimal treatment of patients unresponsive to intensive management and (4) the lack of formal international definitions of ‘intensive management’. CONCLUSION: The benefits of intensive management need to be set against its additional costs. These were relatively high. Not all patients benefited. Patients with high pretreatment physical disability or who were substantially overweight usually did not achieve remission. FUTURE WORK: Further research should (1) identify the most effective components of the intervention, (2) consider its most cost-effective delivery and (3) identify alternative strategies for patients not responding to intensive management. TRIAL REGISTRATION: Current Controlled Trials ISRCTN70160382. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.
33863841 The arthritis connection to inflammatory bowel disease (IBD): why has it taken so long to 2021 Apr Inflammatory bowel disease (IBD) associated arthritis is a subgroup of spondyloarthritis (SpA) that has suffered from lack of recognition in rheumatology clinical and research circles for over 100 years. Although clinically distinguishable from rheumatoid arthritis and ankylosing spondylitis, it took advances in detection systems in the middle of the last century (rheumatoid factor, HLA-B27) to convincingly make the final separations. We now know that significant numbers of patients with SpA have associated clinical IBD and almost half of them show subclinical gut inflammation, yet the connection between the gut and the musculoskeletal system has remained a vexing problem. Two publications from Nathan Zvaifler (one in 1960, the other in 1975) presciently described the relationship between the gut and the spine/peripheral joints heralding much of the work present today in laboratories around the world trying to examine basic mechanisms for the connections (there are likely to be many) between the gut, the environment (presumably our intestinal flora) and the downstream effect on the musculoskeletal system. The role of dysregulated microbiome along with microbiome-driven T helper 17 cell expansion and immune cell migration to the joints has been recognised, all of which occur in the appropriate context of genetic background inside and outside of the human leucocyte antigen system. Moreover, different adhesion molecules that mediate immune cells homing to the gut and joints have been noted. In this review, we studied the origins and evolution of IBD-arthritis, proposed pathogenic mechanisms and the current gaps that need to be filled for a complete understanding of IBD-arthritis.
33995414 Insulin Signaling in Arthritis. 2021 Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.
33897428 Combined Cornus Officinalis and Paeonia Lactiflora Pall Therapy Alleviates Rheumatoid Arth 2021 Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to cartilage destruction and bone erosion. In-depth exploration of the pathogenesis of RA and the development of effective therapeutic drugs are of important clinical and social value. Herein, we explored the medicinal value of Cornus officinalis Sieb. and Paeonia lactiflora Pall. in RA treatment using a rat model of collagen-induced arthritis (CIA). We compared the therapeutic effect of Cornus officinalis and Paeonia lactiflora with that of their main active compounds, ursolic acid and paeoniflorin, respectively. We demonstrated that the combination of Cornus officinalis and Paeonia lactiflora effectively inhibited the release of factors associated with oxidative stress and inflammation during RA, therein ameliorating the symptoms and suppressing the progression of RA. We further showed that the underlying mechanisms may be related to the regulation of apoptosis in synovial tissues, and we investigated the potential involvement of AMPK-mediated mitochondrial dynamics in the therapeutic action of the two drugs and their active components.