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ID PMID Title PublicationDate abstract
32415503 Molecular mechanism of action and pharmacokinetic properties of methotrexate. 2020 Jun Since its discovery in 1945, methotrexate has become a standard therapy for number of diseases, including oncological, inflammatory and pulmonary ones. Major physiological interactions of methotrexate include folate pathway, adenosine, prostaglandins, leukotrienes and cytokines. Methotrexate is used in treatment of pulmonary sarcoidosis as a second line therapy and is drug of choice in patients who are not candidates for corticosteroid therapy, with recommended starting weekly dose of 5-15 mg. Number of studies dealt with methotrexate use in rheumatoid arthritis and oncological patients. Authors are conducting research on oral methotrexate use and pharmacokinetics in chronic sarcoidosis patients and have performed literature research to better understand molecular mechanisms of methotrexate action as well as high level pharmacokinetic considerations. Polyglutamation of methotrexate affects its pharmacokinetic and pharmacodynamic properties and prolongs its effect. Bile excretion plays significant role due to extensive enterohepatic recirculation, although majority of methotrexate is excreted through urine. Better understanding of its pharmacokinetic properties in sarcoidosis patients warrant optimizing therapy when corticosteroids are contraindicated in these patients.
32940216 Prevalence of hepatitis B virus infection and risk of reactivation in rheumatic population 2021 May OBJECTIVES: Hepatitis B (HBV) is a common comorbidity among rheumatic patients. The prevalence of HBV infection and the rate of reactivation remain unclear. The literature data suggested a higher risk in chronic than in past infection. Currently, the literature data are mostly focused on anti-TNF and rituximab. This retrospective observational study aimed to analyse the prevalence of HBV infection and the risk of viral reactivation in a population of rheumatic patients undergoing anti-TNF and non-anti-TNF agents. METHODS: We analysed 1216 rheumatic patients, treated with both csDMARDs and bDMARDs between 2006 and 2017. Serologic markers for HBV (HBsAg, anti-HBs, anti-HBc) were performed prior and during biologic treatment. Patients with chronic or resolved infection were monitored every 3 months. RESULTS: The prevalence of HBV in our cohort was 15.7% (chronic infection: 0.4%, resolved infection: 12.6%, anti-HBc positivity alone: 2.6%). 12 (6.2%) out of 191 HBV infected patients experienced a reactivation. All of them showed markers of past infection. One patient experienced HBV reactivation despite lamivudine. Only one patient experienced acute hepatitis, probably due to the interruption of immunosuppressors in anticipation of surgery, not preceded by any HBV prophylactic treatment. CONCLUSIONS: HBV reactivation is a rare event in patients treated with a bDMARD and it can also occur while taking lamivudine, not only in chronic carriers (as per the literature data) but also in inactive ones. Regular screening followed by prompt treatment can prevent symptoms or complications. Due to the risk of hepatitis following the immune reconstitution, an antiviral therapy should be considered in the case of sudden discontinuation of csDMARDs or bDMARD.
31644465 Deadliest catch: neutrophil extracellular traps in autoimmunity. 2020 Jan PURPOSE OF REVIEW: To summarize recent evidence on the pathogenic effects of neutrophils and neutrophil extracellular traps (NETs) in autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. RECENT FINDINGS: NETs can orchestrate innate and adaptive immune dysregulation through diverse mechanisms. NETs induce potent inflammatory responses and represent sources of many autoantigens, creating a feed-forward loop that may perpetuate disease and lead to organ damage. NETs are also increasingly relevant in atherosclerosis and could contribute to the increased risk of premature cardiovascular disease in patients with autoimmunity. SUMMARY: NET formation is increased in a variety of autoimmune and autoinflammatory diseases and can have remarkable effects on cell and tissue-specific damage. Novel therapeutics that target NET formation or clearance is a promising strategy for clinical management of autoimmune diseases and may prevent chronic complications associated with these conditions.
32708725 Over-Expression of Allograft Inflammatory Factor-1 (AIF-1) in Patients with Rheumatoid Art 2020 Jul 16 Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic protein that is encoded by the AIF1 gene. The main functions of AIF-1 are the activation of macrophages and enhancing the production of pro-inflammatory cytokines. To date, three different AIF-1 isoforms have been identified. In this study, we examined the expression of AIF-1 isoforms on the level of mRNA, and we compared the percentage of AIF-1-positive white blood cells (WBCs) in blood and AIF-1/CD68 cells in the synovial membranes in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). We examined 15 patients with RA and 15 patients with OA who had previously undergone knee arthroplasty. Peripheral blood and synovial membranes (SMs) were collected from these patients during knee arthroplasty. We identified three AIF-1 mRNA expression variants in peripheral mononuclear cells (PBMCs) and SMs from patients in both groups. Spearman's rank correlation coefficient tests showed strong, positive, and significant correlations between the three AIF-1 mRNA expression variants in PBMCs and/or SMs in patients with RA and OA. There were no statistically significant correlations for any of the AIF-1 mRNA expression variants between PBMCs and SMs in patients with RA and OA. We observed a statistically significant increased percentage of AIF-1-positive cells in patients with RA in comparison to patients with OA. The percentage of AIF-1-positive cells in the blood of patients with RA and OA was 1.35 ± 0.81% and 0.71 ± 0.25% (p < 0.01), respectively, whereas the percentage of AIF-1/CD68-positive WBC cells in the SMs was 24.05 ± 7.17% and 4.78 ± 1.52% (p < 0.001), respectively. In conclusion, three AIF-1 mRNA expression variants occurred in PBMCs and SM cells in patients with RA and OA. The AIF-1 mRNA expression levels of the variants correlated with each other in PBMCs and SM cells, but there were no statistically significant correlations for AIF-1 mRNA expression variants between PBMCs and SM cells in patients with RA and OA. Both in the blood and SMs, we observed an increased percentage of AIF-1-positive cells in patients with RA in comparison to patients with OA. The above results suggested that AIF-1 was the cytokine involved in the pathogenesis of RA. The precise knowledge of the role of AIF-1 in RA pathogenesis and the development of inflammatory response requires further investigations.
32429245 Tailoring Tofacitinib Oral Therapy in Rheumatoid Arthritis: The TuTORApp-A Usability Study 2020 May 15 OBJECTIVE: To create a mobile application able to help patients follow medical treatments properly. METHODS: We designed and developed a custom Android/iOS App to remind patients of the pharmaceutical drugs to be taken, of the visits and exams to attend, and to detect their compliance with their personal therapeutic plan. In this paper we describe the App development, UX/UI design, Gamification. TuTOR is an Android and iOS application designed to remind patients of the drugs to be taken, giving them all the information related to their therapeutic plans in a simple and non-invasive way. Thanks to a dedicated back-office, specially designed to meet specific medical information needs, the App can also help physicians detect their patients' compliance with their treatments and modify prescriptions in real time. The App also ensures a state-of-the-art approach to data security and privacy protection. The main feature of TuTOR is the smart therapy assistant, which features dedicated alarms to remind users of taking their prescription drugs. Thanks to the automatic synchronization with a local database, the alert system works even without connection to the Internet. Particular attention was paid during the App's design process: we looked to create an intuitive interface to ensure absolute ease of use, with state-of-the-art visual design aimed at maximizing user experience. Other relevant features include the App's ability to givevisual evidence of the most important drugs to be taken and its note-taking feature, which gives patients the possibility to note down indications on why a specific drug was skipped. The App also keeps track of upcoming medical exams, laboratory tests, and visits on a devoted calendar. It also helps patients by listing therapy contacts, such as physicians' phone numbers, and indicates all medical references by showing, for example, locations of relevant clinics and pharmacies on a map. Thanks to specific visual progress indicators and an innovative gamification approach, the App encourages users to faithfully follow therapy guidelines. With TuTOR, assessing the therapy's state of completion is quick and easy.Thanksto the privacy-by-design approach used, all data managed by the system is compliant with the European Privacy Regulation and it is not available to third parties. EXPECTED RESULTS: A mobile App for medication adherence might increase objectively and subjectively measured adherence.
32011082 Occupational balance and its association with life satisfaction in men and women with rheu 2020 Jun INTRODUCTION: Despite improved treatments and reduced disability, people with rheumatoid arthritis (RA) experience difficulties in daily life, which may negatively affect their balance of everyday life activities (occupational balance). The aim of this study was to describe occupational balance and its association with self-rated life satisfaction in men and women with RA. METHODS: A survey, including demographic and health-related questions, was sent to 1,277 people who met the following criteria: with RA >4 years, aged 18-80 years, included in the Swedish Rheumatology Quality Register (SRQ), and had at least one registered visit to the participating rheumatology units in the year before inclusion. The 682 who answered all items in the Occupational Balance Questionnaire (OBQ) were included in the study. Their answers were analysed with descriptive statistics, and logistic regression analyses were conducted on men and women separately. RESULTS: Significantly higher occupational balance was identified in those participants who were >65 years, had no children at home, had a lower disease activity score, were not continuously stressed and reported low pain intensity. The results of the logistic regression analyses of both genders showed that higher occupational balance was significantly associated with a higher probability for rating themselves as being satisfied with life as a whole. CONCLUSION: Occupational balance was identified as related to satisfaction with life as a whole, which is valuable information for health professionals. Enhanced occupational balance may be achieved in people with RA by working towards reducing their stress and pain.
32030635 Levels of satisfaction with rheumatoid arthritis treatment and associated alignment betwee 2020 Jun INTRODUCTION: Discordance (misalignment) regarding treatment satisfaction may exist in real-life clinical practice between patients and their physicians. We aimed to assess physician and patient treatment satisfaction levels and associated degree of misalignment in rheumatoid arthritis (RA). METHOD: A point-in-time, multinational survey of patients and physicians was conducted in Latin America from December 2014 to October 2015. Physician- and patient-reported satisfaction levels with current RA treatment, alignment levels in satisfaction perception, and factors associated with satisfaction misalignment were assessed through bivariate and logistic regression analyses. RESULTS: Participating physicians (N = 114) completed 555 patient record forms (PRFs); 372 patients completed self-complete questionnaires (PSC). A total of 346 physician-patient pairs were analyzed. Physicians reported satisfaction with current disease control in 270/346 (78.0%) PRFs; patients reported such satisfaction in 286/346 (82.7%) PSCs. Physician-patient alignment was observed in 78.6% of pairs. Compared with aligned patients, misaligned patients were younger, more likely to have moderate or severe disease (physician subjectively defined), deteriorating or unstable disease (physician subjectively defined), been exposed to a greater number of advanced therapy lines (biologic or Janus kinase inhibitor), greater current pain, a current acute episode, poorer health, and greater disability and impairment. Misaligned patients were less likely to be in remission. Logistic regression analysis revealed that misaligned patients were more likely to experience greater activity impairment. CONCLUSIONS: High treatment satisfaction and alignment were observed among RA patients and their physicians in Latin America. Misaligned patients were more likely to report more severe disease and were less likely to be in remission. Addressing misalignment may lead to improved RA disease control.Key Points• High treatment satisfaction was observed among RA patients and their treating physicians in Latin America.• One-fifth of physician-patient pairs were misaligned in treatment satisfaction.• Patients misaligned with their physicians reported higher disease activity, lower quality of life, and greater disability than those who were aligned with their physicians.• Understanding and addressing misalignment in treatment satisfaction may improve outcomes in this patient population.
32945465 Identification of pivotal genes and pathways in the synovial tissue of patients with rheum 2020 Oct Rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most common debilitating joint disorders and although both share similar clinical manifestations, the pathogenesis of each is different and remains relatively unclear. The present study aimed to use bioinformatic analysis to identify pivotal genes and pathways involved in the pathogenesis of RA. Microarray datasets from patients with RA and OA were obtained from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified using GEO2R software; Gene Ontology analysis and pathway enrichment were analyzed using the Database for Annotation, Visualization and Integrated Discovery and the Kyoto Encylopedia for Genes and Genomes, respectively; and protein‑protein interaction networks of DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes database, and module analysis and pathway crosstalk of the PPI network was visualized using plugins of Cytoscape. In addition, the prediction of target mRNAs for differentially expressed microRNAs (DEMs) was performing using the starBase database and the identified pivotal genes were verified using reverse‑transcription quantitative PCR in synovial tissue from patients with RA. A total of 566 DEGs were identified in GSE55457, GSE55235 while 23 DEMs were identified in the GSE72564 dataset. Upregulated DEGs were found to be mostly enriched in the 'Cytokine‑cytokine receptor interaction' pathway, whereas downregulated DEGs were discovered to be enriched in the 'PPAR signaling pathway'. The top 25 DEGs were mostly enriched in the 'Chemokine signaling pathway'. In addition, six of the miRNA target genes were selected as potential biomarkers and a total of 24 genes were selected as potential hub genes. Experimental validation demonstrated that the expression levels of Cytotoxic T‑Lymphocyte Associated Protein 4 (CTLA4), Zeta‑chain‑associated protein kinase 70 (ZAP70) and LCK proto‑oncogene (LCK) were significantly increased, whereas HGF expression levels were decreased in RA synovial tissue. In conclusion, these findings suggest that the identified DEGs and pivotal genes in the present study may further enhance our knowledge of the underlying pathways in the pathogenesis of RA. These genes may also serve as diagnostic biomarkers and therapeutic targets for RA; however, further experimental validation is necessary following the bioinformatic analysis to determine our conclusions.
32019572 Thrombotic microangiopathy and liver toxicity due to a combination therapy of leflunomide 2020 Feb 5 BACKGROUND: Treatment of active rheumatoid arthritis may necessitate a methotrexate mono- or combination therapy. As in the present case, novel side effects may occur, when escalating therapy. CASE PRESENTATION: A 63-year-old Caucasian female patient with rheumatoid arthritis on methotrexate for 8 years and on leflunomide for 6 years was admitted for weakness, edema, ascites, and petechiae of the lower legs. Comorbidities included a urinary tract infection, metabolic syndrome with obesity, type-2 diabetes without necessity for insulin or oral antidiabetics, and non-alcoholic fatty liver disease. Laboratory results showed acute liver failure, oliguric acute kidney injury, thrombocytopenia, and schistocyte-positive, Coombs-negative hemolytic anemia. On admission, her ADAMTS13 activity was decreased, and her leflunomide plasma level was elevated (120 μg/l). Due to severe hypoalbuminemia, an intravascular hypovolemia, and severe metabolic alcalosis with hypokalemia were found. For the newly diagnosed thrombotic microangiopathy, leflunomide and methotrexate were discontinued, and 4 units of fresh-frozen plasma were given. Steroid therapy was administered for 5 days, until thrombotic thrombocytopenic purpura was excluded. Intravenous human albumin, oral vitamin K, and cholestyramine were administered for liver failure and leflunomide overdosage, respectively. Liver biopsy revealed a non-alcoholic fatty liver disease transforming into liver cirrhosis. After 2 weeks, our patient was discharged. However, within 3 weeks after discharge, our patient was rehospitalized for a relapse of acute liver failure, urinary tract infection, and influenza. Leflunomide and methotrexate were not reintroduced before or thereafter. Over a period of 11 months after discharge, her thrombotic microangiopathy subsided, and her renal and liver function fully recovered. CONCLUSIONS: Under a combination of leflunomide and methotrexate, liver toxicity and, for the first time, thrombotic microangiopathy occurred as side effects. Non-alcoholic fatty liver disease may have predisposed for the drug-induced liver toxicity.
32723749 Genome-wide association study in a Korean population identifies six novel susceptibility l 2020 Nov OBJECTIVE: Genome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case-control population. METHODS: We newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations. RESULTS: We identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with p(meta)<5×10(-8) and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases. CONCLUSION: This study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.
32162022 [Evaluation of the trabecular bone score (TBS) in routine clinical care of patients with i 2020 Dec BACKGROUND: Osteoporosis-related fractures are common in patients with rheumatoid arthritis (RA). Bone mineral density (BMD) measurements using dual-energy x‑ray absorptiometry (DXA) alone has only a limited value for predicting the risk of fractures. The trabecular bone score (TBS) is a surrogate parameter for trabecular microarchitecture of bone and a predictor of fracture risk independent of BMD. AIM: To examine the prevalence of BMD, TBS and osteoporosis-related vertebral fractures (VF) in patients with RA in comparison to controls with non-inflammatory musculoskeletal diseases. METHODS: Data from patients with RA diagnosed by a rheumatologist and with TBS and DXA measurements, who were assessed in this hospital between 2006 and 2014 were retrospectively analyzed. The RA patients were matched with controls with non-inflammatory musculoskeletal diseases. "Reduced bone health" was defined as a T‑score <-1.0 and/or a TBS value <-1.31. Statistical analyses were carried out using the Mann-Whitney test and the Wilcoxon test. RESULTS: Data from 143 patients with RA (age 72.1 ± 11.1 years, 72% female) and 106 controls (age 69.6 ± 12.6 years, 75% female) were included. The RA patients more frequently had low BMD (n = 102, 71.3%) and low TBS values (n = 125, 87.4%) compared to controls (n = 63, 59.4% and n = 79, 74.5%, p = 0.049 and p = 0.009, respectively). The RA patients had more VF (n = 52, 36.4%) than controls (n = 24, 22.6%, p = 0.02). A total of 20 patients with VF (26.3%) had normal lumbar spine BMD and 9 (11.8%) also had a normal hip BMD. In patients with VF the combination of low TBS with normal spine BMD was more common than a normal TBS and low spine BMD (p = 0.008 for patients with RA, p = 0.025 for controls). DISCUSSION: It is known that VF can occur in patients with normal BMD. In patients with VF, a low TBS with normal spine BMD is found more frequently than normal TBS and low spine BMD. These results suggest that measurement of the TBS has the potential to be a useful tool to detect increased fracture risk in patients with RA and normal spine BMD.
32160284 Stromal Cells in the Pathogenesis of Inflammatory Bowel Disease. 2020 Jul 30 Up till now, research on inflammatory bowel disease [IBD] has mainly been focused on the immune cells present in the gastrointestinal tract. However, recent insights indicate that stromal cells also play an important and significant role in IBD pathogenesis. Stromal cells in the intestines regulate both intestinal epithelial and immune cell homeostasis. Different subsets of stromal cells have been found to play a role in other inflammatory diseases [e.g. rheumatoid arthritis], and these various stromal subsets now appear to carry out also specific functions in the inflamed gut in IBD. Novel potential therapies for IBD utilize, as well as target, these pathogenic stromal cells. Injection of mesenchymal stromal cells [MSCs] into fistula tracts of Crohn's disease patients is already approved and used in clinical settings. In this review we discuss the current knowledge of the role of stromal cells in IBD pathogenesis. We further outline recent attempts to modify the stromal compartment in IBD with agents that target or replace the pathogenic stroma.
33156836 Liposome/gold hybrid nanoparticle encoded with CoQ10 (LGNP-CoQ10) suppressed rheumatoid ar 2020 Coenzyme Q10 (CoQ10), also known as ubiquinone, is a fat-soluble antioxidant. Although CoQ10 has not been approved as medication by the Food and Drug Administration, it is widely used in dietary supplements. Some studies have shown that CoQ10 has anti-inflammatory effects on various autoimmune disorders. In this study, we investigated the anti-inflammatory effects of liposome/gold hybrid nanoparticles encoded with CoQ10 (LGNP-CoQ10). Both CoQ10 and LGNP-CoQ10 were administered orally to mice with collagen-induced arthritis (CIA) for 10 weeks. The inflammation pathology of joint tissues of CIA mice was then analyzed using hematoxylin and eosin and Safranin O staining, as well as immunohistochemistry analysis. We obtained immunofluorescence staining images of spleen tissues using confocal microscopy. We found that pro-inflammatory cytokines were significantly decreased in LGNP-CoQ10 injected mice. Th17 cell and phosphorylated STAT3-expressed cell populations were also decreased in LGNP-CoQ10 injected mice. When human peripheral blood mononuclear cells (PBMCs) were treated with CoQ10 and LGNP-CoQ10, the IL-17 expression of PBMCs in the LGNP-CoQ10-treated group was significantly reduced. Together, these results suggest that LGNP-CoQ10 has therapeutic potential for the treatment of rheumatoid arthritis.
32417912 Circulating CD19+CD24hiCD38hi regulatory B cells as biomarkers of response to methotrexate 2020 Oct 1 OBJECTIVE: The protagonism of regulatory B cells seems to vary along the course of the disease in murine models of inflammatory conditions. Decreased numbers of circulating regulatory CD19+CD24hiCD38hi transitional (cTr) B cells have been described in patients with long-standing RA, thus our objective was to examine the frequency and evolution of cTr B cells in the peripheral blood of early RA (ERA) patients. METHODS: Freshly isolated peripheral blood mononuclear cells from 48 steroid- and DMARD-naïve ERA patients with a disease duration of <24 weeks and 48 healthy controls (HCs) were examined by flow cytometry. Co-cultures of isolated memory B cells were established with autologous T cells in the absence or presence of Tr B cells. RESULTS: As compared with HCs, ERA patients demonstrated an increased frequency of cTr B cells. cTr B cells of ERA patients and HCs displayed an anti-inflammatory cytokine profile and were able to downregulate T cell IFN-γ and IL-21 production, together with ACPA secretion in autologous B/T cell co-cultures. Basal frequencies of cTr B cells above the median value observed in HCs were associated with a good EULAR response to MTX at 12 months [relative risk 2.91 (95% CI 1.37, 6.47)]. A significant reduction of cTr B cells was observed 12 months after initiating MTX, when the cTr B cell frequency was no longer elevated but decreased, and this was independent of the degree of clinical response or the intake of prednisone. CONCLUSION: An increased frequency of regulatory cTr B cells is apparent in untreated ERA and the baseline cTr B cell frequency is associated with the clinical response to MTX at 12 months.
33054815 The role of EMMPRIN/CD147 in regulating angiogenesis in patients with psoriatic arthritis. 2020 Oct 14 BACKGROUND: Angiogenesis plays a central role in the pathophysiology of rheumatic diseases. Patients with psoriatic arthritis (PsA) demonstrate increased vascularity over patients with rheumatoid arthritis (RA), with unknown mechanisms. METHODS: We evaluated the serum levels of several pro- and anti-angiogenic factors in 62 PsA patients with active disease, 39 PsA patients in remission, 33 active RA patients, and 33 healthy controls (HC). Additionally, we used an in vitro co-culture system of fibroblast (HT1080) and monocytic-like (MM6) cell lines, to evaluate how their interactions affect the secretion of angiogenic factors and angiogenesis promoting abilities using scratch and tube formation assays. RESULTS: PsA patients, regardless of disease activity, exhibited higher levels of EMMPRIN/CD147, IL-17, and TNF-α relative to RA patients or HC. Factors, such as IL-6, and the ratio between CD147 and thrombospondin-1, exhibited elevated levels in active PsA patients relative to PsA patients in remission. Secretion of CD147, VEGF, and MMP-9 was increased in vitro. CD147 neutralization with an antibody reduced these levels and the ability of endothelial cells to form tube-like structures or participate in wound healing. CONCLUSIONS: CD147 plays a role in mediating angiogenesis in PsA, and the therapeutic possibilities of neutralizing it merit further investigation.
32873834 Accumulation of synovial fluid CD19(+)CD24(hi)CD27(+) B cells was associated with bone des 2020 Sep 1 Regulatory CD19(+)CD24(hi)CD27(+) B cells were proved to be numerically decreased and functionally impaired in the peripheral blood (PB) from rheumatoid arthritis (RA), with the potential of converting into osteoclast-priming cells. However, the distribution and function of CD19(+)CD24(hi)CD27(+) B cells in RA synovial fluid (SF) were unclear. In this study, we investigated whether RA SF CD19(+)CD24(hi)CD27(+) B cells were increased and associated with bone destruction. We found that the proportion of RA SF CD19(+)CD24(hi)CD27(+) B cells was increased significantly, and was positively correlated with swollen joint counts, tender joint counts and disease activity. CXCL12, CXCL13, CCL19 contributed to the recruitment of CD19(+)CD24(hi)CD27(+) B cells in RA SF. Notably, CD19(+)CD24(hi)CD27(+) B cells in the SF from RA expressed significantly more RANKL compared to OA and that in the PB from RA. Critically, RA CD19(+)CD24(hi)CD27(+) B cells promoted osteoclast (OC) differentiation in vitro, and the number of OCs was higher in cultures with RA SF CD19(+)CD24(hi)CD27(+) B cells than in those derived from RA PB. Collectively, these findings revealed the accumulation of CD19(+)CD24(hi)CD27(+) B cells in SF and their likely contribution to joint destruction in RA. Modulating the status of CD19(+)CD24(hi)CD27(+) B cells might provide novel therapeutic strategies for RA.
31823689 Assessing the Association of Formulary Copayment Changes with Real-World Treatment Pattern 2020 Feb BACKGROUND: Rheumatoid arthritis (RA) is a chronic disease that requires long-term treatment to improve or maintain stable disease activity. Tumor necrosis factor inhibitors (TNFi), a class of biologic disease-modifying antirheumatic drugs (bDMARD), are effective at treating symptoms and inhibiting joint progression. Although treatment changes are not recommended in patients with stable disease, health plans have recently enacted formulary changes with higher copayments that could disrupt patient access to TNFis. OBJECTIVE: To assess the association of formulary copayment changes with real-world treatment patterns, treatment effectiveness, and health care costs among bDMARD-naive patients with RA receiving the TNFi etanercept. METHODS: This retrospective observational cohort analysis used the IBM Watson Health MarketScan Commercial Claims and Encounters Database. Adult patients with RA with 6 months of stable etanercept use (no refill gap ≥ 45 days) from January 1, 2013, through December 31, 2015, were selected and the index date was set to the first fill date after the stable-use period. Average etanercept copayment was calculated at the drug-plan level. Copayment change was defined as a monthly increase of at least $40 to account for copayment changes attributable to etanercept wholesale acquisition costs between 2014 and 2015. This amount also corresponded to the 90th percentile of average plan-level changes in etanercept copayments in the database, representing an average change in copayment by a payer. Patients were followed ≥ 12 months before and after the index date to track etanercept treatment changes and ≥ 12 months after a treatment change to track costs after etanercept copayment changes. Etanercept persistence, bDMARD switching, refill gaps, and treatment effectiveness (using a validated effectiveness algorithm) were described for patients with or without copayment change during the 12 months post-index or postchange. We also assessed the mean total of all-cause and RA-related expenditure during the 12-month post-index (or postchange) period. RESULTS: 1,970 stable patients met study inclusion criteria (mean [standard deviation] age: 50.3 [9.5] years; 77.8% female) and were evaluated. Of these, 133 (6.8%) patients had a copayment change ≥$40 during follow-up. Overall, most patients (60.3%) persisted on etanercept for the 12-month follow-up period, while 13.0% switched from etanercept, and 8.1% discontinued (refill gap of ≥ 45 days). Nearly half (48.0%) of all patients were considered effectively treated according to a validated algorithm. Compared with patients without a copayment change, those with a copayment change were more likely to switch biologics (19.5% vs. 12.6%; P = 0.021). Although statistical significance was not reached, patients with a copayment change were less likely to be persistent (54.1% vs. 60.7%; P = 0.135), and less likely to be effectively treated (42.1% vs. 48.4%; P = 0.161) than patients without a copayment change. All-cause and RA-related expenditures at baseline and post-copayment change were similar between patients with and without a copayment change. CONCLUSIONS: Changing formulary copayment of etanercept was associated with higher switching without difference in costs or health care utilization between copayment and no copayment change groups. DISCLOSURES: This study was sponsored by Amgen. Bonafede, Manjelievskaia, and Lopez-Gonzalez are employees of IBM Watson Health, which received funding from Amgen to conduct this study. Oko-osi, Collier, and Stolshek are employees and shareholders of Amgen. Gharaibeh was an employee of Amgen at the time of study execution and manuscript drafting. The authors have no other relationships that present a potential conflict of interest. Data pertaining to this study were presented in a poster at the 2018 ACR/ARHP Annual Meeting; October 19-24, 2018; Chicago, IL.
32213077 Prevalence of coexisting autoimmune thyroidal diseases in coeliac disease is decreasing. 2020 Mar BACKGROUND: Coeliac disease (CD) is associated with an increased risk of other immune-mediated conditions. Aim: To investigate the prevalence of coexistent immune-mediated diseases in CD patients, and changes in the prevalence of autoimmune thyroidal diseases over the last 50 years. METHODS: Medical record data were collected retrospectively from 749 CD patients in Ireland. Prevalence of autoimmune diseases was compared with previously published results from general populations. Patients were divided into four groups based on the year of diagnosis to analyse changes in the prevalence of autoimmune thyroidal disease over time. RESULTS: Median age at the time of CD diagnosis was 56 years (range 18-91 years). A total of 233 (31.1%) patients had a coexistent immune-mediated condition (IMC). Autoimmune thyroidal diseases were seen in 149 (19.9%) patients, hypothyroidism in 110 (14.7%), type 1 diabetes in 27 (3.6%), psoriasis in 20 (2.7%), inflammatory bowel disease in 14 (1.9%) and rheumatoid arthritis in 12 (1.6%). All conditions were more common in CD patients than in the general population. Type 1 diabetes was diagnosed mainly before CD, whereas there was no such trend in other conditions. Autoimmune thyroidal diseases became less common in female CD patients over time. CONCLUSIONS: Prevalence of autoimmune diseases is increased in adult CD patients compared with the general population. However, concomitant autoimmune thyroidal diseases became less common over time in women.
32711802 Continuing versus tapering glucocorticoids after achievement of low disease activity or re 2020 Jul 25 BACKGROUND: Patients with inflammatory diseases, such as rheumatoid arthritis, often receive glucocorticoids, but long-term use can produce adverse effects. Evidence from randomised controlled trials to guide tapering of oral glucocorticoids is scarce. We investigated a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids in patients with rheumatoid arthritis. METHODS: The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was a double-blind, multicentre, two parallel-arm, randomised controlled trial done at 39 centres from six countries (France, Germany, Italy, Russia, Serbia, and Tunisia). Adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5-15 mg per day for 24 weeks or more were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activaity, confirmed by a Disease Activity Score for 28 joints-erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less 4-6 weeks before and on the day of randomisation. Patients were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16. All patients received tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks) with or without csDMARDs maintained at stable doses during the entire 24-week study. The primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0·6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group. The trial is registered with ClinicalTrials.gov, NCT02573012. FINDINGS: Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 (200 [77%] women and 59 [23%] men) were recruited onto the trial. In all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen; the estimated mean change in DAS28-ESR from baseline to week 24 was 0·54 (95% CI 0·35-0·73) with tapered prednisone and -0·08 (-0·27 to 0·12) with continued prednisone (difference 0·61 [0·35-0·88]; p<0·0001), favouring continuing prednisone 5 mg per day for 24 weeks. Treatment was regarded as successful (defined as low disease activity at week 24, plus absence of rheumatoid arthritis flare for 24 weeks and no confirmed adrenal insufficiency) in 99 (77%) patients in the continued-prednisone group versus 85 (65%) patients in the tapered-prednisone group (relative risk 0·83; 95% CI 0·71-0·97). Serious adverse events occurred in seven (5%) patients in the tapered-prednisone group and four (3%) patients in the continued-prednisone group; no patients had symptomatic adrenal insufficiency. INTERPRETATION: In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose. FUNDING: F Hoffmann-La Roche.
33359861 Polysaccharides and glycosides from Aralia echinocaulis protect rats from arthritis by mod 2021 Apr 6 ETHNOPHARMACOLOGICAL RELEVANCE: Aralia echinocaulis has been used in traditional medicines in China and exhibits good effects on rheumatoid arthritis (RA). AIM OF THE STUDY: Aralia echinocaulis is rich in polysaccharides and glycosides. This study aims to explore the effect of total polysaccharide and glycoside (TPG) from A. echinocaulis on an RA rat model and the role of alterations in gut microbes mediated by TPG. MATERIALS AND METHODS: In this study, a collagen-induced arthritis (CIA) rat model was constructed and used to evaluate the effects of TPG in vivo. 16S rRNA sequencing was used to detect the changes in the gut microbiota. A cooccurrence analysis was conducted by calculating Spearman's rank correlations. Microbial functions were predicted using PICRUSt with the KEGG and COG databases. RESULTS: The results showed that TPG from A. echinocaulis could inhibit arthritis, reduce serum IL-1β and TNF-α levels, and improve synovial pathology in the RA rat model but failed to produce the same results in a pseudoaseptic RA rat model. 16S rRNA sequencing verified that TPG could modulate the gut microbiota community structure of RA rats. The cooccurrence analysis found 19 out of the 50 most abundant genera in a cooccurrence network, of which 16 showed a positive correlation and 3 showed a negative correlation. KEGG pathway and COG function analyses found that TPG-induced alterations in the gut microbiota might be correlated with the circulatory system, excretory system, metabolic diseases, signaling molecules and interactions, coenzyme transport and metabolism, and nucleotide transport and metabolism. CONCLUSIONS: TPG from A. echinocaulis had significant effects on the RA rat model, which are related to the modulation of the gut microbiota. These results are useful to better understanding the mechanisms of TPG in RA.