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ID PMID Title PublicationDate abstract
33004333 Dysbiosis in the oral microbiomes of anti-CCP positive individuals at risk of developing r 2021 Feb OBJECTIVES: An increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk). METHODS: Subgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups. RESULTS: At periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis, had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05). CONCLUSION: Anti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation.
33323529 Safety and Efficacy of Poseltinib, Bruton's Tyrosine Kinase Inhibitor, in Patients With Rh 2021 Jul OBJECTIVE: To evaluate the efficacy and safety of poseltinib (formerly LY3337641/HM71224), an irreversible covalent inhibitor of Bruton's tyrosine kinase in a 2-part, phase II trial (RAjuvenate; ClinicalTrials.gov: NCT02628028) in adults with active rheumatoid arthritis (RA). METHODS: In Part A, 36 patients with mildly active RA were randomized 1:1:1:1 to oral poseltinib 5, 10, or 30 mg or placebo once daily for 4 weeks to assess safety and tolerability. No safety signals precluded moving to Part B, where 250 patients with moderate-to-severe RA were randomized 1:1:1:1 to oral poseltinib 5 mg (n = 63), 10 mg (n = 62), or 30 mg (n = 63), or placebo (n = 62) once daily for 12 weeks. Parts A and B permitted stable doses of background disease-modifying antirheumatic drugs. The primary endpoint in Part B was proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 12. Logistic regression compared each poseltinib dose to placebo for primary and secondary endpoints. Nonresponder imputation was used for missing data. RESULTS: After interim analysis showed low likelihood of demonstrating significant efficacy, the sponsor discontinued Part B of the study. One hundred and eighty-nine (76%) patients completed 12 weeks in Part B; 61 discontinued study treatment (27 [44%] due to study termination by sponsor). There was no statistically significant difference in ACR20 response between any dose of poseltinib and placebo at Week 12 (P > 0.05 for all comparisons). Five serious adverse events occurred (n = 2, placebo; n = 3, 30 mg); there was 1 death due to a fall. CONCLUSION: While no safety findings precluded continuation, the study was terminated after interim data demonstrated low likelihood of benefit in RA.
32458235 Correlation of patient preferences to treatment outcomes in patients with rheumatoid arthr 2020 Dec OBJECTIVES: To investigate possible associations between rheumatoid arthritis (RA) patient-expressed preferences over anti-tumour necrosis factor (anti-TNF) treatment and clinical and patient-reported outcomes. METHODS: PANORAMA was a non-interventional, prospective, multicentre, cohort study of 12 months duration, in patients with moderate-to-severe RA who initiated or switched to anti-TNF treatment. After initiation of anti-TNF, patients completed a preferences questionnaire on attributes related to anti-TNF treatment. Satisfaction with treatment was assessed with the Treatment Satisfaction Questionnaire for Medication (TSQM); compliance and persistence to treatment were recorded via a patient diary. Univariate and multivariate analyses were applied to assess correlations between patients' preferences over treatment with clinical and patient-reported outcomes. RESULTS: A total of 254 patients were enrolled; 66.1% (168/254) had highly active disease (DAS28-ESR > 5.1), while 65.4% (166/254) were biological-naïve. The 12-month drug-survival rate was 72.3%, while the respective rates of good EULAR response and remission (DAS28-ESR < 2.6) were 56.5% and 40.8%, respectively. By univariate analysis, fulfilment of patient preferences over treatment was associated with increased probability of remaining on therapy (p = 0.019), good EULAR response (p < 0.001) and satisfaction with treatment (p < 0.001). By multivariate analysis, fulfilment of patient preferences was the most important predictor for good EULAR response (OR 5.56, p < 0.001; finding confirmed and after propensity scoring matching), while seropositivity (HR 1.18, p = 0.047) and a high ESR (> 35 mm/h, HR 1.16, p = 0.071) predicted drug survival. CONCLUSIONS: In anti-TNF-treated RA patients, fulfilment of treatment preferences was independently associated with a good EULAR response and correlated with drug persistence at 12 months, emphasising the importance of patient preferences in treatment outcomes. Key Points • In anti-TNF treated RA patients, fulfilment of patients' treatment preferences is associated with a good clinical response at 12 months. • A shared decision-making process can maximise treatment's outcome in anti-TNF treated patients.
33144158 Outcomes of Percutaneous Coronary Intervention in Patients With Rheumatoid Arthritis. 2021 Feb 1 Rheumatoid arthritis (RA) is the most common inflammatory arthritis and is associated with increased risk of cardiovascular events and mortality. Evidence regarding outcomes following PCI is limited. This study aimed to assess differences in outcomes following percutaneous coronary intervention (PCI) between patients with and without RA. The Melbourne Interventional Group PCI registry (2005 to 2018) was used to identify 756 patients with RA. Outcomes were compared with the remaining cohort (n = 38,579). Patients with RA were older, more often female, with higher rates of hypertension, previous stroke, peripheral vascular disease, obstructive sleep apnea, chronic lung disease, myocardial infarction, and renal impairment, whereas rates of dyslipidemia and current smoking were lower, all p <0.05. Lesions in patients with RA were more frequently complex (ACC/AHA type B2/C), requiring longer stents, with higher rates of no reflow, all p <0.05. Risk of long-term mortality, adjusted for potential confounders, was higher for patients with RA (hazard ratio 1.53, 95% confidence interval 1.30 to 1.80; median follow-up 5.0 years), whereas 30-day outcomes including mortality, major adverse cardiovascular events, bleeding, stroke, myocardial infarction, coronary artery bypass surgery, and target vessel revascularization were similar. In subgroup analysis, patients with RA and lower BMI (P(for interaction) < 0.001) and/or acute coronary syndromes (P(for interaction) = 0.05) had disproportionately higher risk of long-term mortality compared with patients without RA. In conclusion, patients with RA who underwent PCI had more co-morbidities and longer, complex coronary lesions. Risk of short-term adverse outcomes was similar, whereas risk of long-term mortality was higher, especially among patients with acute coronary syndromes and lower body mass index.
32212002 Fetuin-A and thyroxin binding globulin predict rituximab response in rheumatoid arthritis 2020 Sep OBJECTIVES: Rheumatoid arthritis (RA) is a debilitating disease, but patient management and treatment have been revolutionized since the advent of bDMARDs. However, about one third of RA patients do not respond to specific bDMARD treatment without clear identified reasons. Different bDMARDs must be tried until the right drug is found. Here, we sought to identify a predictive protein signature to stratify patient responsiveness to rituximab (RTX) among patients with an insufficient response to a first anti-TNFα treatment. METHODS: Serum samples were collected at baseline before RTX initiation. A proteomics study comparing responders and nonresponders was conducted to identify and select potential predictive biomarkers whose concentration was measured by quantitative assays. Logistic regression was performed to determine the best biomarker combination to predict good or nonresponse to RTX (EULAR criteria after 6 months' treatment). RESULTS: Eleven biomarkers potentially discriminating between responders and nonresponders were selected following discovery proteomics. Quantitative immunoassays and univariate statistical analysis showed that fetuin-A and thyroxine binding globulin (TBG) presented a good capacity to discriminate between patient groups. A logistic regression analysis revealed that the combination of fetuin-A plus TBG could accurately predict a patient's responsiveness to RTX with an AUC of 0.86, sensitivity of 80%, and a specificity of 79%. CONCLUSION: In RA patients for whom a first anti-TNFα treatment has failed, the serum abundance of fetuin-A and TBG before initiating RTX treatment is an indicator for their response status at 6 months. ClinicalTrials.gov identifier: NCT01000441. Key Points • Proteomic analysis revealed 11 putative predictive biomarkers to discriminate rituximab responder vs. nonresponder RA patients. • Fetuin-A and TBG are significantly differentially expressed at baseline in rituximab responder vs. nonresponder RA patients. • Algorithm combining fetuin-A and TBG accurately predicts response to rituximab in RA patients with insufficient response to TNFi.
32141631 Increased IgA anti-citrullinated protein antibodies in the periodontal inflammatory exudat 2020 May AIM: To assess rheumatoid arthritis (RA)-associated autoantibodies in the gingivocrevicular fluid (GCF) of RA patients and healthy controls with or without periodontal disease, as chronic mucosal inflammation in periodontal disease is hypothesized to contribute to the formation of these autoantibodies. MATERIALS AND METHODS: Anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), and their IgA isotypes were assessed in the serum and GCF of RA patients (n = 72) and healthy controls (HC, n = 151). The presence and levels of these antibodies were studied in relation to interleukin (IL)-8 and periodontal disease. RESULTS: In contrast to the HC, the levels of ACPA and RF in the serum and GCF of the RA patients were strongly correlated (p < .0001). The HC with high levels of IgA-ACPA (n = 27) also had significantly higher levels of total IgG, total IgA, and IL-8 in the GCF than the HC with low levels of IgA-ACPA in the GCF (n = 124). Periodontal inflammation and smoking were seen more frequently in the group with high levels of IgA-ACPA compared to the group with low IgA-ACPA. CONCLUSION: The IgA-ACPA in the GCF of HC may be associated with periodontal inflammation and smoking, and could be involved in the progression to RA.
32979413 Sesquiterpene lactones; Damsin and neoambrosin suppress cytokine-mediated inflammation in 2021 Feb 10 ETHNOPHARMACOLOGIAL RELEVANCE: Although Damsissa (Ambrosia maritima) is traditionally used as anti-inflammatory and diuretic, the biological activity and mechanism of action of its major constituents are to be elucidated. AIM: to decipher the anti-arthritic potential of damsin (DMS) and neoambrosin (NMS) and to unfold their molecular signaling in complete Freund's adjuvant (CFA)-induced arthritis model. MATERIALS AND METHODS: the right hind paw was inoculated with CFA (0.1 ml) at day 0 and 7 while treatments were started from the 14(th) day and continued for 2 weeks. Rats were randomly assigned into 4 groups; normal group (NRML), CFA-induced arthritis group, CFA-induced arthritis treated with DMS and NMS (10 mg/kg/day) as 3(rd) and 4(th) group; respectively. RESULTS: Throughout experimental period, treatments ameliorated the increase of paw volume, knee joint diameter and nociception tests as reflected in open field arena. Also, DSM and NMS suppressed phosphorylation of Akt, STAT-3, ERK1/2 which was further mirrored by inactivation of GSK3β and downregulation of MCP-1 together with CCN1 and NF-kβ in hind paw tissue. Concomitantly, inflammation markers; TNF-α, IL-6, -12 were lowered as confirmed microscopically during examination of hind paw tissue. CONCLUSION: DSM and NMS-induced suppression of NF-kβ subdues clinical features of RA most probably through repression of Akt/ERK1/2/STAT3 pathway. Therefore, DMS and NMS can serve as safe and effective treatment for rheumatoid arthritis, one of the most disabling chronic, inflammatory and painful autoimmune disease.
33060309 Benefits of Methotrexate Use on Cardiovascular Disease Risk Among Rheumatoid Arthritis Pat 2021 Jun OBJECTIVE: Methotrexate (MTX) has been associated with reduced risk for cardiovascular disease (CVD) events among patients with rheumatoid arthritis (RA) not exposed to biologic disease-modifying antirheumatic drugs (bDMARDs). The effect of concomitant MTX on CVD risk among RA patients initiating bDMARDs remains unknown. METHODS: A retrospective cohort study was conducted to assess the effect of MTX on CVD risk using 2006-2015 Medicare claims data for patients with RA initiating bDMARD. The main exposure was current use of MTX, updated in a time-varying fashion. The primary outcome was a composite of incident myocardial infarction (MI), stroke, and fatal CVD. Secondary outcomes were each event that comprised the primary outcome. Incidence rates (IR) and 95% CI were calculated using Poisson regression. Associations between MTX and risk of CVD were assessed using Cox regression. RESULTS: A total of 88,255 bDMARD initiations and 1861 CVD events were included in this study. Mean age was 64.6 (12.3) years, 84.0% were female, and 68.2% were non-Hispanic White. The crude IRs (95% CI) for CVD were 17.9 (16.9-18.8) and 12.1 (11.1-13.2) per 1000 patient-years among MTX unexposed and exposed, respectively. The multivariable adjusted HR (95% CI) for CVD events associated with MTX was 0.76 (0.68-0.85). Multivariable adjusted HRs were 0.78 (0.66-0.91), 0.74 (0.62-0.88), 0.77 (0.68-0.86), and 0.82 (0.73-0.93) for MI, stroke, MI or stroke, and a composite CVD outcome, respectively. Results were robust in sensitivity and subgroup analyses. CONCLUSION: Among patients with RA receiving biologics, concomitant MTX use was associated with a 24% lower risk for CVD events.
32025851 Circadian fluctuations of endothelial nitric oxide synthase activity in females with rheum 2020 Apr Rheumatoid arthritis (RA) is a disease associated with circadian disorders of steroid hormones or cytokine secretion which induce inflammatory, destructive and proliferative processes in the synovial joints. Angiogenesis plays an important role in RA, but circadian rhythms of the angiogenic mediator production, especially endothelial nitric oxide synthase (NOS3), are still unclear. NOS3 takes part in regulation of endothelial functions, inflammation, and bone remodeling process. Studying circadian rhythms of NOS3 production in RA patients will make an improvement in understanding the angiogenic-inflammatory pathways relevant to rheumatic diseases. The aim of the study was to test the hypothesis of a diurnal variation in circulating levels of NOS3 in RA patients. A cross-sectional monocentric pilot study of circadian variability of endothelial nitric oxide synthase in a Ukrainian population was conducted between March and July 2017. We examined 36 RA patients (100% women) and 34 age-matched healthy women without joint diseases and autoimmune diseases (control). Blood samples were collected four times per day (at 08:00; 14:00; 20:00 and 02:00) for two consecutive days. Serum NOS3 concentration was measured by ELISA (Cloud-Clone Corp kit). The study was conducted in compliance with bioethical standards. The SPSS22 software package was used for statistical processing of the results. A diurnal variation in circulating levels of NOS3 in healthy women was established, with peak values appearing in the evening and acrophase at 20:00, and low values in the morning, with batiphase at 08:00. In patients with RA serum, NOS3 levels were substantially decreased throughout the day compared to the control. In RA patients, a diurnal variation in circulating levels of NOS3 was also established. However, the variability of NOS3 production was higher in RA patients than in the control group. For example, in RA patients the difference between morning/evening values of NOS3 was 1.3 times higher (p < 0.05) than in the control. Negative correlations were found between the morning NOS3 levels and RA activity markers such as DAS28 and the number of tender and swollen joints. The diurnal variation in circulating levels of NOS3 in women with RA as well as in healthy women was found. However, in RA patients, a decrease in NOS3 production was observed, especially in the morning, which was associated with an increase in the disease activity. Thus, the circadian rhythm of circulating NOS3 can be opposite to the circadian rhythm of secretion of main inflammatory regulators in RA.
32532307 Predicting the treatment response of certolizumab for individual adult patients with rheum 2020 Jun 12 BACKGROUND: A model that can predict treatment response for a patient with specific baseline characteristics would help decision-making in personalized medicine. The aim of the study is to develop such a model in the treatment of rheumatoid arthritis (RA) patients who receive certolizumab (CTZ) plus methotrexate (MTX) therapy, using individual participant data meta-analysis (IPD-MA). METHODS: We will search Cochrane CENTRAL, PubMed, and Scopus as well as clinical trial registries, drug regulatory agency reports, and the pharmaceutical company websites from their inception onwards to obtain randomized controlled trials (RCTs) investigating CTZ plus MTX compared with MTX alone in treating RA. We will request the individual-level data of these trials from an independent platform (http://vivli.org). The primary outcome is efficacy defined as achieving either remission (based on ACR-EULAR Boolean or index-based remission definition) or low disease activity (based on either of the validated composite disease activity measures). The secondary outcomes include ACR50 (50% improvement based on ACR core set variables) and adverse events. We will use a two-stage approach to develop the prediction model. First, we will construct a risk model for the outcomes via logistic regression to estimate the baseline risk scores. We will include baseline demographic, clinical, and biochemical features as covariates for this model. Next, we will develop a meta-regression model for treatment effects, in which the stage 1 risk score will be used both as a prognostic factor and as an effect modifier. We will calculate the probability of having the outcome for a new patient based on the model, which will allow estimation of the absolute and relative treatment effect. We will use R for our analyses, except for the second stage which will be performed in a Bayesian setting using R2Jags. DISCUSSION: This is a study protocol for developing a model to predict treatment response for RA patients receiving CTZ plus MTX in comparison with MTX alone, using a two-stage approach based on IPD-MA. The study will use a new modeling approach, which aims at retaining the statistical power. The model may help clinicians individualize treatment for particular patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number pending (ID#157595).
32911135 The potential utility of anterior upper lobe honeycomb-like lesion in interstitial lung di 2020 Oct BACKGROUND: Interstitial lung disease (ILD) is associated with high morbidity and mortality in patients with connective tissue disease (CTD). Because some patients with CTD overlap present with ILD first, with CTD diagnosed later, specific radiologic signs are needed to help differentiate each CTD or CTD-ILD from idiopathic ILD. OBJECTIVES: To determine whether specific CT findings can help differentiate CTD as rheumatoid arthritis (RA), systemic sclerosis (SSc), or polymyositis/dermatomyositis (PM/DM). METHODS: We analyzed 143 consecutive ILD patients with RA, SSc, or PM/DM. We assessed diagnostic accuracy of CT findings of CTD-ILD, CT pattern, and signs including "anterior upper lobe honeycomb-like lesion" and "low attenuation area (LAA) within an interstitial abnormality" for each CTD-ILD. Prognostic predictors were determined using Cox regression models. RESULTS: Subjects were 78 patients with RA-ILD, 38 with SSc-ILD, 24 with PM/DM-ILD, and 3 with overlapping CTD-ILD. High frequency of anterior upper lobe honeycomb-like lesion suggests that CTD-ILD is due to RA-ILD (22%) rather than SSc-ILD (8%) or PM/DM-ILD (8%), whereas LAA within an interstitial abnormality suggests that CTD-ILD is due to SSc-ILD (26%) rather than RA-ILD (4%) or PM/DM-ILD (0%). Multivariate analysis showed that while not associated with survival, current or ex-smoker, honeycombing, and acute exacerbation were negative prognostic factors of mortality. CONCLUSIONS: The tendency is high for RA-ILD, in which anterior upper lobe honeycomb-like lesion is a specific feature, to show UIP or NSIP/UIP pattern, combined emphysema, and honeycombing; SSc-ILD to show NSIP pattern and LAA within an interstitial abnormality; and PM/DM-ILD to show NSIP pattern and non-honeycombing.
32007797 Elevated levels of soluble Endothelial protein C receptor in rheumatoid arthritis and bloc 2020 Apr BACKGROUND: Endothelial protein C receptor (EPCR) is a membranous protein that can be combined with a variety of ligands and plays important roles in anticoagulant and anti-inflammation. Recent reports have shown that surface EPCR expression on T cells is negatively associated with Th17 differentiation and is co-expressed with other immunosuppressive molecules, such as The programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Hence, we hypothesized that EPCR may play a critical role in rheumatoid arthritis (RA) disease progression that is mediated by Th17 differentiation. In order to explore the role of EPCR on RA disease pathogenesis, we detected membranous EPCR (mEPCR) expression in CD4(+) T cells and soluble EPCR (sEPCR) expression in the sera of RA patients. METHODS: The proportion of CD4(+)/EPCR(+) T cells in the peripheral blood of RA patients was detected by flow cytometry, and the expression of sEPCR in the sera of RA patients was detected by enzyme-linked immunosorbent assay (ELISA). For in vitro experiments, protein C (PC) and EPCR recombinant proteins were used to block peripheral blood mononuclear cell (PBMC) activation and to detect Th17 differentiation. For in vivo experiments in DBA/1 mice with collagen-induced arthritis (CIA), we administered PC and EPCR recombinant proteins, monitored disease progression, and evaluated the role of EPCR in disease progression. RESULTS: The proportion of CD4(+)/EPCR(+) T cells in the peripheral blood of RA patients was lower than that of osteoarthritis (OA) patients, while the expression level of sEPCR in the sera of RA patients was concomitantly higher than that in OA patients. Subsequent analysis revealed that sEPCR expression was positively correlated with rheumatoid factors (RF) and other inflammatory indicators in RA patients. Further studies confirmed that sEPCR administration alleviated the progression of collagen-induced arthritis and partially blocked the therapeutic effect of PC in CIA mice. CONCLUSION: Soluble EPCR is associated with RA disease progression and induces disease remission in CIA mice by inhibiting Th17 differentiation.
32029712 Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution 2020 Feb 6 Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC(1)), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC(1), not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC(1) leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC(1) is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.
32993800 Rheumatoid arthritis patients on persistent moderate disease activity on biologics have ad 2020 Sep 29 BACKGROUND: The long-term outcome of rheumatoid arthritis (RA) patients who in clinical practice exhibit persistent moderate disease activity (pMDA) despite treatment with biologics has not been adequately studied. Herein, we analyzed the 5-year outcome of the pMDA group and assessed for within-group heterogeneity. METHODS: We included longitudinally monitored RA patients from the Hellenic Registry of Biologic Therapies with persistent (cumulative time ≥ 50% of a 5-year period) moderate (pMDA, 3.2 < DAS28 ≤ 5.1) or remission/low (pRLDA, DAS28 ≤ 3.2) disease activity. The former was further classified into persistent lower-moderate (plMDA, DAS28 < 4.2) and higher-moderate (phMDA, DAS28 ≥ 4.2) subgroups. Five-year trajectories of functionality (HAQ) were the primary outcome in comparing pRLDA versus pMDA and assessing heterogeneity within the pMDA subgroups through multivariable mixed-effect regression. We further compared serious adverse events (SAEs) occurrence between the two groups. RESULTS: We identified 295 patients with pMDA and 90 patients with pRLDA, the former group comprising of plMDA (n = 133, 45%) and phMDA (n = 162, 55%). pMDA was associated with worse 5-year functionality trajectory than pRLDA (+ 0.27 HAQ units, CI 95% + 0.22 to + 0.33; p < 0.0001), while the phMDA subgroup had worse 5-year functionality than plMDA (+ 0.26 HAQ units, CI 95% 0.18 to 0.36; p < 0.0001). Importantly, higher persistent disease activity was associated with more SAEs [pRLDA: 0.2 ± 0.48 vs pMDA: 0.5 ± 0.96, p = 0.006; plMDA: 0.32 ± 0.6 vs phMDA: 0.64 ± 1.16, p = 0.038]. Male gender (p = 0.017), lower baseline DAS28 (p < 0.001), HAQ improvement > 0.22 (p = 0.029), and lower average DAS28 during the first trimester since treatment initiation (p = 0.001) independently predicted grouping into pRLDA. CONCLUSIONS: In clinical practice, RA patients with pMDA while on bDMARDs have adverse long-term outcomes compared to lower disease activity status, while heterogeneity exists within the pMDA group in terms of 5-year functionality and SAEs. Targeted studies to better characterize pMDA subgroups are needed, in order to assist clinicians in tailoring treatments.
32741960 Retinoic Acid-Platinum (II) Complex [RT-Pt(II)] Protects Against Rheumatoid Arthritis in M 2020 Aug 3 BACKGROUND Rheumatoid arthritis (RA) is an inflammatory disorder that is present in approximately 1% of the world's population. This study was aimed to investigate the effect of retinoic acid-platinum (II) complex [RT-Pt(II)] on rheumatoid arthritis (RA) and to explore the mechanism involved. MATERIAL AND METHODS MH7A cell viability was determined by MTT assay and apoptosis was assessed using FACSCalibur flow cytometry. RT-PCR and Western blot assays were used for assessment of mRNA and proteins levels. RESULTS Treatment of rheumatoid arthritis with RT-Pt(II) significantly reduced the levels of IL‑1ß, IL-6, IL-8, MMP-1, and MMP-13 in synovial fluid of mice in a dose-dependent manner. The expression of iNOS and COX-2 mRNA and protein in rheumatoid arthritis rats was also significantly inhibited by treatment with RT-Pt(II). The TNF-alpha-induced proliferation of MH7A cells was alleviated by RT-Pt(II) treatment in a concentration-dependent manner. Moreover, RT-Pt(II) treatment induced apoptosis and caused arrest of cell cycle in MH7A cells. The activation of MEK/NF-kappaB pathway was downregulated by RT-Pt(II) treatment in MH7A cells. CONCLUSIONS In summary, the present study demonstrated that RT-Pt(II) inhibits TNF-alpha-induced inflammatory response, suppresses cell viability, and induces apoptosis in rheumatoid arthritis synovial cells. Moreover, RT-Pt(II) exhibited its effect through targeting the MEK/NF-kappaB pathway. Therefore, RT-Pt(II) can be used for the development of treatments for rheumatoid arthritis.
32401927 Rhoifolin regulates oxidative stress and proinflammatory cytokine levels in Freund's adjuv 2020 Rheumatoid arthritis (RA) is an autoimmune disease of knee joints involving pain and inflammation. Rhoifolin is a plant flavonoid known to have antioxidant and anti-inflammatory properties. This study was taken to identify the effect of rhoifolin on complete Freund's adjuvant (CFA)-induced arthritis in the rat model. Treatment with rhoifolin (10 and 20 mg/kg) showed a significant improvement in the overall health parameters such as paw edema and weight loss. This improvement in morphological parameters corroborated the findings with gross morphological changes observed in the histopathological analysis. Rhoifolin treatment also caused a significant decrease in oxidative stress, evident from changes in intracellular levels of glutathione, glutathione peroxidase, malondialdehyde, and superoxide dismutase in the articular cartilage tissue. Moreover, proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin(IL)-1β, and IL-6 showed a significant downregulation of gene expression and intracellular protein concentration levels. The NF-κB pathway showed a significant attenuation as evident in the significant reduction in the levels of NF-κB p65 and p-IκB-α. These results indicated that rhoifolin can be a natural therapeutic alternative to the extant regimens, which include non-steroidal anti-inflammatory drugs and immunosuppressants. Additionally, the antioxidant and anti-inflammatory action of rhoifolin was probably mediated by the NF-κB pathway. However, the exact target molecules of this pathway need to be determined in further studies.
31207152 Live Zoster Vaccine in Patients With Rheumatoid Arthritis Treated With Tofacitinib With or 2020 Mar OBJECTIVE: To explore herpes zoster (HZ) rates and live zoster vaccine (LZV) safety in a subset of patients with rheumatoid arthritis who received LZV before tofacitinib ± methotrexate (MTX), or adalimumab (ADA) plus MTX in the ORAL Strategy. METHODS: ORAL Strategy was a 1-year, phase IIIb/IV, randomized, triple-dummy, active-comparator-controlled study. MTX-inadequate responder patients received tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID plus MTX, or ADA 40 mg every other week plus MTX (1:1:1 randomization). Eligible patients age ≥50 years could opt to receive LZV 28 days before initiating study treatment. HZ incidence rates (IRs; patients with events per 100 patient-years) were calculated. Opportunistic HZ infections (multidermatomal/disseminated), serious HZ events, and LZV-related adverse events were monitored. RESULTS: In ORAL Strategy, 216 of 1,146 patients (18.8%) received LZV. Overall, 18 patients (1.6%) developed HZ (vaccinated: n = 3; nonvaccinated: n = 15). HZ IRs were 1.1 (95% confidence interval [95% CI] 0.3-2.9), 2.3 (95% CI 1.0-4.6), and 1.7 (95% CI 0.6-3.7) for tofacitinib monotherapy, tofacitinib plus MTX, and ADA plus MTX, respectively, and were generally similar between vaccinated and nonvaccinated patients. Three multidermatomal, 1 disseminated, and 2 serious HZ events occurred. No vaccinated patients had zoster-like lesions within 42 days of vaccination; 1 patient had vaccination-site erythema. CONCLUSION: LZV was well tolerated, and HZ IRs were generally similar between treatment groups and vaccinated versus nonvaccinated patients. However, ORAL Strategy was not powered for comparisons between vaccinated and nonvaccinated patients because <20% of all patients were vaccinated. Furthermore, LZV has been shown to be effective only in ~50% of individuals.
33258021 [Calcium, phosphate and the calcium-sensing receptor : A proinflammatory combination in r 2021 Feb Calcium and phosphate are necessary for the functionality of the organism and the cellular metabolism. In the form of hydroxyapatite, calcium and phosphate stabilize bone and teeth, but deposition of calcium phosphate in soft tissue or the vasculature can have devastating consequences. To prevent ectopic calcification, calcium and phosphate are stabilized by fetuin-A/alpha-2-HS-glycoprotein as non-crystalline, 60-100 nm-sized calciprotein particles (CPP) in extracellular fluids. An increase of the CPP concentration in the extracellular fluid beyond a certain threshold results in pro-inflammatory responses in monocytes and macrophages, which includes the activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome resulting in the release of interleukin-1β and interleukin-18. The release of pro-inflammatory cytokines as a result of increased CPPs is enhanced in rheumatoid arthritis (RA). The calcium-sensing receptor plays a major role in this mechanism by modulating the uptake (macropinocytosis) of CPPs and thereby increasing the pro-inflammatory potential. Bone erosion and subsequent release of calcium and phosphate during the etiopathology of RA can therefore aggravate the joint inflammation in this disease.
32224046 Mechanisms determining the amelioration of rheumatoid arthritis in pregnancy: A systematic 2020 Dec BACKGROUND: The phenomenon of pregnancy-induced remission of rheumatoid arthritis (RA) was first reported by Philip Hench in 1938. Despite extensive efforts, the underlying scientific basis has remained elusive. A number of different potential mechanisms have been investigated. We have undertaken a systematic review of the available peer-reviewed articles involving pregnant patients with RA in order to establish the depth of current scientific understanding of this important topic. METHODS: This review was conducted according to guidelines of preferred reporting items for systematic reviews and meta-analyses. Studies were identified by a thorough search of multiple databases including Medline, PubMed and EMBASE. Search terms used were different combinations of the keywords: rheumatoid arthritis, inflammatory arthritis, pregnancy, mechanisms, disease activity, relapse and remission. Non-English language articles and studies that were not directly relevant were excluded. Two independent reviewers (CR and KA) screened the retrieved articles by reading the title and abstract to identify studies that addressed potential mechanisms determining RA activity in pregnancy. Articles were further refined after reading the full text. A data extraction sheet was developed for the purpose of this review and used by the independent reviewers. RESULTS: After exclusion of irrelevant, duplicate and foreign language articles, a final total of 37 original articles were identified. The largest body of literature concerned glycosylation of immunoglobulins, with 9 published articles. There is evidence of an association between increasing levels of galactosylation of immunoglobulins and reduced RA disease activity in pregnancy. Other identified articles comprised 5 on cytokine changes in pregnancy, 5 on human leucocyte antigen (HLA) incompatibility, 5 on changes in peripheral blood mononuclear cell (PBMC) gene expression; 4 on changes in corticosteroids; 3 on pregnancy associated α2-glycoprotein; 2 on changes in rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA); and 1 each on microchimerism, gamma delta T cells, regulatory T cells, and mannose-binding lectin. The results of these studies were heterogenous and occasionally conflicting. Selected studies varied greatly in terms of population size, methodology and use of controls and disease activity assessments. CONCLUSION: This systematic review has found that the cause of the pregnancy-induced amelioration of RA remains to be determined, despite extensive efforts. It is unclear which of the various transitory changes in pregnancy may be responsible for initiating downstream anti-inflammatory immunological mechanisms. We discuss limitations of the current literature and suggest areas for future study.
31820726 Validation of new classification criteria of rheumatoid arthritis in an international mult 2020 Sep OBJECTIVES: Early identification of patients with rheumatoid arthritis (RA) is essential to allow prompt therapy. In this study, we aimed to evaluate the performance of the newly proposed ERA criteria, compared to the 1987 ACR and 2010 ACR/EULAR criteria in an international multicentre study. METHODS: A total of 606 patients with disease duration ≤2 years and age ≥16 years who were diagnosed as RA or non-RA were enrolled from China, Sweden and India. The clinical and laboratory parameters were recorded. We compared the sensitivity, specificity, predictive value, likelihood ratio (LR), and the area under the ROC curve (AUC) of three criteria in these cohorts. Concordance between the three criteria was calculated with the Kappa coefficient. RESULTS: Three hundred and twelve RA and 294 non-RA patients were included. The Early Rheumatoid Arthritis (ERA) criteria had significantly higher specificity compared to the 2010 ACR/ EULAR criteria (83.7% vs. 78.2%, p=0.02) and sensitivity were similar (79.2% vs. 78.5%, p=0.883). In comparison with the 1987 ACR criteria, the ERA criteria had higher sensitivity (79.2% vs. 54.5%, p<0.001) but lower specificity (83.7% vs. 89.1%, p<0.001), and the AUC of the ERA criteria (0.878) was comparable to the 2010 ACR/EULAR criteria (0.849) and higher than the 1987 ACR criteria (0.791, p<0.0001). Patients from the three countries, seronegative and very early arthritis cohorts yielded consistent results. CONCLUSIONS: The ERA criteria demonstrate a better performance across ethnics in early RA diagnosis, and is more feasible in daily practice.