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ID PMID Title PublicationDate abstract
34042056 Understanding the Role and Challenges of Patient Preferences in Disparities in Rheumatolog 2021 Feb Evidence suggests patient preferences, including values and perspectives, have affected clinical outcomes, such as compliance, patient well-being, and satisfaction with care. A literature review was conducted with the purpose of exploring the tools used to elicit patients' treatment preferences and their roles in clinical outcomes. This review revealed racial differences in treatment preferences among patients with rheumatic and musculoskeletal diseases. The use of decision aids is a proactive intervention with potential for reducing race disparities and improving clinical outcomes. The utilization of patient preferences and values can improve outcomes by complementing the shared decision-making approach between patients and rheumatologists.
33128166 The inflammation and reactive oxygen species regulated by Nrf2 and NF-κB signaling pathwa 2021 Sep Because of a large number of macrophages and its secreted pro-inflammatory factors in the synovial fluid of patients with rheumatoid arthritis, the present study aimed to investigate the effect and mechanism of 630-nm LED exposure on monocytes/macrophages and its anti-inflammatory effect. The THP-1 monocytes and PMA-induced THP-1 macrophages (THP-1 macrophages) were employed and irradiated by 630-nm LED for different time and times, and then measure the pro-inflammatory cytokines production by RT-qPCR and Milliplex MAP Multiplex assay, the proteins involved in inflammation pathway and reactive oxygen species (ROS) levels in the cells were detected by Western blot and DCFH-DA method. The exposure dose of red LED (15.3 J/cm(2), 30.6 J/cm(2)) were determined as no-influence on the cell proliferation, the pro-inflammatory factors TNF-α and IL-1β mRNAs, and secretions in supernatant of THP-1 macrophages were significantly decreased after LED exposure. The ROS production was blocked in THP-1 monocytes and THP-1 macrophages after treatment of LED. Finally, the phosphorylated NF-κB proteins which involved in inflammation pathway significantly decreased, and its inhibitors Nrf2 were slightly upregulated. The effects of LED anti-inflammation response are dependent on the mechanism of inhibiting ROS level and regulating NF-κB signaling pathways by increasing Nrf2 expression in the cells. It is suggested that 630-nm LED could decrease pro-inflammation in immune cells, and it may be a beneficial adjunct therapy in relieving inflammation of patients with rheumatoid arthritis.
32103630 Physician Prescribing Patterns and Risk of Future Long-Term Opioid Use Among Patients With 2020 Jul OBJECTIVE: To identify the extent to which opioid prescribing rates for patients with rheumatoid arthritis (RA) vary in the US and to determine the implications of baseline opioid prescribing rates on the probability of future long-term opioid use. METHODS: We identified patients with RA from physicians who contributed ≥10 patients within the first 12 months of participation in the Corrona RA Registry. The baseline opioid prescribing rate was calculated by dividing the number of patients with RA reporting opioid use during the first 12 months by the number of patients with RA providing data that year. To estimate odds ratios (ORs) for long-term opioid use, we used generalized linear mixed models. RESULTS: During the follow-up period, long-term opioid use was reported by 7.0% (163 of 2,322) of patients of physicians with a very low rate of opioid prescribing (referent) compared to 6.8% (153 of 2,254) of patients of physicians with a low prescribing rate, 12.5% (294 of 2,352) of patients of physicians with a moderate prescribing rate, and 12.7% (307 of 2,409) of patients of physicians with a high prescribing rate. The OR for long-term opioid use after the baseline period was 1.16 (95% confidence interval [95% CI] 0.79-1.70) for patients of low-intensity prescribing physicians, 1.89 (95% CI 1.27-2.82) for patients of moderate-intensity prescribing physicians, and 2.01 (95% CI 1.43-2.83) for patients of high-intensity prescribing physicians, compared to very low-intensity prescribing physicians. CONCLUSION: Rates of opioid prescriptions vary widely. Our findings indicate that baseline opioid prescribing rates are a strong predictor of whether a patient will become a long-term opioid user in the future, after controlling for patient characteristics.
32621699 Pseudorheumatoid nodule: a variant of granuloma annulare? 2020 May 15 We present an adult woman with subcutaneous nodules without any signs or symptoms of rheumatoid arthritis. These nodules are believed to be pseudorheumatoid nodules, which are considered a deep form of granuloma annulare. This case is unique because these are typically found in children and have rarely been reported in adults. These nodules are typically asymptomatic and do not require treatment. However, attempts have been made to treat them with intralesional corticosteroids, cryotherapy, or excision. Owing to the fact that this is considered a deep form of granuloma annulare, they are sometimes treated similarly with a combination of monthly rifampin, ofloxacin, and minocycline.
32295688 Tofacitinib citrate-based liposomes for effective treatment of rheumatoid arthritis. 2020 Apr 6 Low drug concentrations at interest sites and unwanted systemic side effects are major obstacles to effective therapy of rheumatoid arthritis (RA). With the aim of improving the efficacy of tofacitinib citrate (TOF), a liposomal system was developed for targeted delivery to inflamed joints, and this approach was validated in a RA rat model. TOF was effectively loaded into the liposomes (entrapment efficiency: 86.5±1.9%; drug loading: 2.3±0.05%) by a pH gradient method, and these molecules featured sustained drug release behaviour over 48 h. In vitro and in vivo studies showed that TOF loaded liposomes (TOFL) could be selectively taken up by inflamed cells and showed improved accumulation in arthritic paws, demonstrating the superior target ability to RA tissues. Moreover, compared to free TOF, TOFL significantly improved the therapeutic efficacy, reduced the inflammatory cytokine expression and lipid peroxidation in synovial cells in the joint tissue of RA rats. Overall, these results indicate that TOFL served as the useful nanocarriers for RA-targeted therapy.
31504937 Cytopenias among patients with rheumatic diseases using methotrexate: a meta-analysis of r 2020 Apr 1 OBJECTIVE: To conduct a systematic literature review and meta-analysis to estimate the incidence of anaemia, leucopoenia, neutropenia and thrombocytopenia associated with MTX plus folic acid among patients with rheumatic diseases. METHODS: We searched MEDLINE, PubMed and EMBASE through August 2016 for all randomized controlled clinical trials with a MTX monotherapy arm. We excluded randomized controlled clinical trials for cancer and included only double-blind studies that reported on haematologic adverse events. Studies were excluded if patients did not receive folic acid or leucovorin supplementation. Full text articles were assessed by two independent reviewers. Incidence estimates were calculated using random-effects models. RESULTS: Of 1601 studies identified, 30 (1.87%) were included, representing 3858 patients; all had RA. Seventeen trials reported on anaemia (n = 2032), 17 reported on leucopoenia (n = 2220), 16 reported on neutropenia (n = 2202) and 12 reported on thrombocytopenia (n = 1507). The incidence for any anaemia was 2.55% (95% CI 0.60-5.47%), any leucopoenia 1.17% (95% CI 0.16-2.80%), any neutropenia 1.77% (95% CI 0.33-4.00%), and any thrombocytopenia 0.19% (95% CI 0.00-0.86%). Four cases of severe anaemia were reported, as defined by authors, along with three cases of severe neutropenia. No cases of severe leucopoenia, severe thrombocytopenia or pancytopenia were reported. CONCLUSION: Cytopenias are an uncommon side effect of low-dose MTX with folic acid supplementation among RA patients. Further research is needed to reach a more precise estimate.
32058056 Rheumatoid arthritis downregulates the drug transporter OATP1B1: Fluvastatin as a probe. 2020 Apr 15 AIMS: Rheumatoid arthritis (RA) is a long term autoimmune inflammatory disease characterized by high autoantibody production and cytokine release, especially IL-6 and TNF-α. Some clinical studies have shown the effect of RA on CYP metabolism. However, the effect of RA on the drug transporter OATP1B1 remains a gap. METHODS: Patients with RA under pharmacological treatment (n = 10) and healthy volunteers (n = 15) treated for seven consecutive days with racemic fluvastatin (20, 40, or 80 mg/24 h) were investigated. Serial blood samples were collected during the last dose interval. All participants were assessed for cytokine profile and CYP2C9 genotype. RESULTS: Patients with RA showed increased plasma concentrations of IFN-γ and TNF-α up to two and four times, respectively, when compared to healthy volunteers, whereas CYP2C9 activity based on genotype was considered normal or slightly reduced for both investigated groups. When compared to healthy volunteers, patients with RA presented higher values (median and 25th-75th percentiles) of normalized AUC for 20 mg dose (250 [114-405] vs. 96.7 [78.1-131] ng h mL(-1) for (-)-3S,5R-fluvastatin and 163 [96.9-325] vs. 83.1 [61.7-107] ng⋅h⋅mL(-1) for (+)-3R,5S-fluvastatin) and lower values of CL/F (40.9 [24.5-89.1] vs. 103 [75.9-128] L⋅h(-1) for (-)-3S,5R-fluvastatin and 61.4 [30.6-103] vs. 120 [93.0-162] L⋅h(-1) for (+)-3R,5S-fluvastatin) and V/F (73.0 [28.5-117] vs. 143 [108-221] L for (-)-3S,5R-fluvastatin and 93.9 [32.7-116] vs. 153 [122-234] L for (+)-3R,5S-fluvastatin) for both enantiomers. CONCLUSION: The lower values of CL/F and V/F for both fluvastatin enantiomers in RA patients suggest that the inflammatory disease downregulates the sinusoidal drug transporter OATP1B1, the rate-determining step in the hepatic clearance of fluvastatin.
32811969 Identification of heterogenous treatment response trajectories to anti-IL6 receptor treatm 2020 Aug 18 Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed cross-sectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p < 0.001). Class 3 showed significantly higher rates of improvement in DAS28, with 58.1% achieving ACR response levels compared to 2.4% in class 1 (p < 0.0001). Biomarkers of inflammation, MMP-3, CRP, C1M, showed greater reduction in class 3 compared to the other classes. Identification of more homogenous patient sub-populations of drug response may allow for more targeted therapeutic treatment regimens and a better understanding of disease aetiology.
31754044 Citrullinome of Porphyromonas gingivalis Outer Membrane Vesicles: Confident Identification 2020 Jan Porphyromonas gingivalis is a key pathogen in chronic periodontitis and has recently been mechanistically linked to the development of rheumatoid arthritis via the activity of peptidyl arginine deiminase generating citrullinated epitopes in the periodontium. In this project the outer membrane vesicles (OMV) from P. gingivalis W83 wild-type (WT), a W83 knock-out mutant of peptidyl arginine deiminase (ΔPPAD), and a mutant strain expressing PPAD with the active site cysteine mutated to alanine (C351A), have been analyzed using a two-dimensional HFBA-based separation system combined with LC-MS. For optimal and positive identification and validation of citrullinated peptides and proteins, high resolution mass spectrometers and strict MS search criteria were utilized. This may have compromised the total number of identified citrullinations but increased the confidence of the validation. A new two-dimensional separation system proved to increase the strength of validation, and along with the use of an in-house build program, Citrullia, we establish a fast and easy semi-automatic (manual) validation of citrullinated peptides. For the WT OMV we identified 78 citrullinated proteins having a total of 161 citrullination sites. Notably, in keeping with the mechanism of OMV formation, the majority (51 out of 78) of citrullinated proteins were predicted to be exported via the inner membrane and to reside in the periplasm or being translocated to the bacterial surface. Citrullinated surface proteins may contribute to the pathogenesis of rheumatoid arthritis. For the C351A-OMV a single citrullination site was found and no citrullinations were identified for the ΔPPAD-OMV, thus validating the unbiased character of our method of citrullinated peptide identification.
32595130 Bone marrow involvement with Merkel cell carcinoma. 2020 Jun 28 Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous tumour. Most tumours occur in the head and neck, extremities or torso and 36% of them involve the face. Bone marrow involvement in MCC is rare and to our knowledge only nine cases reported in the English literature. Bone marrow biopsy is not usually performed to stage MCC; thus, the true incidence of bone marrow involvement may be under-reported. The majority of the cases reported in the literature have some form of immunosuppression, which suggests a strong association. We report a case of extensive bone marrow involvement from MCC in an 80-year-old Caucasian woman with a history of rheumatoid arthritis treated with adalimumab, methotrexate and prednisone. It may be prudent to include bone marrow biopsy in the staging of MCC in immune-compromised patients.
32796683 Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Upda 2020 Aug 11 The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.
31902026 Ultra-processed food consumption associates with higher cardiovascular risk in rheumatoid 2020 May To investigate the association between food consumption stratified by processing level and cardiovascular risk factors in rheumatoid arthritis. In this cross-sectional study, 56 patients (age: 62.5 ± 7.9 years, BMI: 28.4 ± 5.1 kg/m(2)) had food consumption evaluated according to the processing level (e.g., unprocessed or minimally processed foods, processed foods, and ultra-processed foods) and associated with cardiovascular risk factors. The most prevalent food processing level was unprocessed or minimally processed foods (42.6 ± 12.6% of total energy intake [TEI]), followed by processed (24.2 ± 11.9%TEI), ultra-processed (18.1 ± 11.8%TEI), and culinary ingredients (15.1 ± 6.4%TEI). Adjusted regression models showed that higher consumption of ultra-processed foods was positively associated with Framingham risk score (β = 0.06, CI: 95% 0.001, 0.11, p = 0.045) and glycated hemoglobin (β = 0.04, CI: 95% 0.01, 0.08, p = 0.021). In contrast, higher consumption of unprocessed or minimally processed foods was associated with lower 10-year risk of developing cardiovascular diseases (β = -0.05, CI: 95% - 0.09, -0.003, p = 0.021) and LDL (β = -1.09, CI: 95% - 1.94, -0.24, p = 0.013). Patients with rheumatoid arthritis consuming more ultra-processed foods showed worse metabolic profile, whereas those consuming more unprocessed or minimally processed foods had lower cardiovascular risks. A food pattern characterized by a high ultra-processed food consumption appears to emerge as a novel, modifiable risk factor for cardiovascular diseases in rheumatoid arthritis. Key-Points • Higher ultra-processed food consumption was associated with worse metabolic profile and increased cardiovascular risk, whereas higher unprocessed or minimally processed food consumption was associated with lower 10-year risk of developing cardiovascular diseases. • A food pattern characterized by a high ultra-processed food consumption appears to emerge as a novel, modifiable risk factor for cardiovascular diseases in rheumatoid arthritis.
32255561 Citrulline Not a Major Determinant in the Recognition of Peptidylarginine Deiminase 2 and 2020 Sep OBJECTIVE: Citrullinated proteins are hallmark targets of autoantibodies in rheumatoid arthritis (RA). Our study was undertaken to determine the effect of autocitrullination on the recognition of peptidylarginine deiminases (PADs) 2 and 4 by autoantibodies in RA. METHODS: Autocitrullination sites in PAD2 and PAD4 were determined by mass spectrometry and literature review. Antibodies against native and autocitrullinated PADs in 184 patients with RA were detected by enzyme-linked immunosorbent assay. Linear regression analysis, outlier calculations, and competition assays were performed to evaluate antibody reactivity to native and citrullinated PADs. RESULTS: Autocitrullination of PAD2 and PAD4 was detected in 16 (48%) of 33 arginine residues and 7 (26%) of 27 arginine residues, respectively. Despite robust autocitrullination, autoantibodies bound similarly to native and citrullinated PAD2 or PAD4 (ρ = 0.927 and ρ = 0.903, respectively; each P < 0.0001). Although subsets of anti-PAD-positive sera were identified as exhibiting preferential recognition of native or citrullinated PAD2 (40.5% or 4.8%, respectively) or PAD4 (11.7% or 10.4%, respectively), competition assays confirmed that the majority of anti-PAD reactivity was attributed to a pool of autoantibodies that bound irrespective of citrullination status. CONCLUSION: Autocitrullination does not affect autoantibody reactivity to PADs in the majority of patients with RA, demonstrating that anti-PAD antibodies are distinct from anti-citrullinated protein antibodies in their dependence on citrullination for binding.
33226693 Impact of systemic factors in shaping the periodontal microbiome. 2021 Feb Since 2010, next-generation sequencing platforms have laid the foundation to an exciting phase of discovery in oral microbiology as it relates to oral and systemic health and disease. Next-generation sequencing has allowed large-scale oral microbial surveys, based on informative marker genes, such as 16S ribosomal RNA, community gene inventories (metagenomics), and functional analyses (metatranscriptomics), to be undertaken. More specifically, the availability of next-generation sequencing has also paved the way for studying, in greater depth and breadth, the effect of systemic factors on the periodontal microbiome. It was natural to investigate systemic diseases, such as diabetes, in such studies, along with systemic conditions or states, , pregnancy, menopause, stress, rheumatoid arthritis, and systemic lupus erythematosus. In addition, in recent years, the relevance of systemic "variables" (ie, factors that are not necessarily diseases or conditions, but may modulate the periodontal microbiome) has been explored in detail. These include ethnicity and genetics. In the present manuscript, we describe and elaborate on the new and confirmatory findings unveiled by next-generation sequencing as it pertains to systemic factors that may shape the periodontal microbiome. We also explore the systemic and mechanistic basis for such modulation and highlight the importance of those relationships in the management and treatment of patients.
32172207 Phytoestrogens protect joints in collagen induced arthritis by increasing IgG glycosylatio 2020 Jun Based on previous studies, we know that estrogen can protect the joints from arthritis development by increasing IgG glycosylation and inhibiting osteoclast activation. Phytoestrogens, especially genistein and daidzein, are structurally similar to estradiol that can bind to estrogen receptors (ERs). However, how phytoestrogens affect IgG glycosylation and osteoclast activation in vivo are not investigated so far. In this study, we used 20 mg/kg genistein or daidzein to gavage the female DBA1/J mice in collagen induced arthritis (CIA). We assessed arthritis and bone erosion by clinical scores, histopathology, and micro-CT analysis. Inflammatory cells such as neutrophils, B cells, macrophages and T cells in the peripheral blood were analyzed by flow cytometry. Phagocytic function of peritoneal macrophages was assessed by using FITC-labeled Escherichia coli. New monoclonal antibodies against CII were produced, purified and analyzed. Glycosylation levels of polyclonal and monoclonal IgG were detected by lectin-ELISA. Quantitative PCR was used to analyze the genes related to IgG glycosylation (B4galt1, St6gal1) and osteoclasts (TRAP, NFATC1, c-Fos). Expression of NF-κB and Akt signaling pathways as well as downstream transcription factors NFATc1 and c-Fos was studied by Western blot. Our results show that phytoestrogens protect mice from CIA by increasing IgG glycosylation leading to amelioration of inflammation and inhibiting the NF-κB pathway and NFATc1/c-Fos to decrease the activity of osteoclasts. In conclusion, phytoestrogens can protect bone and joints in CIA mice by increasing IgG glycosylation and inhibiting osteoclast activity.
32389171 [Interleukin-37 inhibits proliferation, migration and induces apoptosis of rheumatoid arth 2020 Mar Objective To investigate the effect of interleukin-37 (IL-37) on the proliferation, apoptosis and migration ability of rheumatoid arthritis fibroblast-like synoviocytes (RAFLS) induced by lipopolysaccharide (LPS) and its underlying mechanism. Methods RAFLS were cultured in vitro and divided into the blank control group, LPS group and LPS combined with (50, 100, 200) ng/mL IL-37 groups. The CCK-8 assay was used to detect the proliferation of RAFLS. The apoptosis of RAFLS was detected by flow cytometry and the migration ability by cell wound scratch assay. After screening the treatment dose of IL-37 (100 ng/mL), RAFLS were divided into the blank control group, LPS group, LPS combined with 100 ng/mL IL-37 treatment group, and LPS combined with IL-37 and STA-21 group. The expression levels of apoptosis-related proteins like BAX, Bcl2, c-caspase-3 and signal transducers and activators of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3) were detected by Western blotting. Results Compared with the model group, IL-37 treatment inhibited the proliferation and migration of RAFLS and promoted the apoptosis of RAFLS. BAX, c-caspase-3 protein levels increased, Bcl2 and p-STAT3 protein levels decreased. Compared with the LPS combined with IL-37 group, STAT3 specific inhibitor STA-21 increased significantly the protein expression levels of BAX and c-caspase-3, while decreased distinctly the levels of Bcl2 and p-STAT3. Conclusion IL-37 can inhibit the proliferation and migration of RAFLS and induces cell apoptosis by inhibiting the STAT3 pathway.
32675025 The first knee prosthesis to go through beyond compliance: A new standard for the safe int 2020 Dec INTRODUCTION: Beyond Compliance (BC) was introduced in 2012 to improve the monitoring and regulation of new medical devices and techniques, ensuring patient safety whilst promoting innovation through an evidence based appraisal of devices during their introduction. This study reports the 2 year outcomes of the first Total Knee Replacement (TKR) implant to be assessed through the BC process. METHODS: 100 consecutive patients undergoing primary knee arthroplasty were enrolled. All patients received a single radius cruciate retaining TKA (Unity, Corin), and the patella was resurfaced in all cases. Patients were followed up at 6 weeks, 3, 6, 12 and 24 months post operatively. Pre-and post-operative range of movement (ROM) as well as outcome scores including OKS, KOOS, EQ5D index and EQ5D VAS were recorded. RESULTS: 100 patients with a mean age 73.6 (SD = 8.7) were included. 2 patients died during the follow-up period due to unrelated reasons. Overall satisfaction rates were 96%. Complications included ongoing pain (5 patients), and a periprosthetic fracture (1 patient) nine months post-surgery (traumatic). No knees were revised during the follow-up period. Significant improvements were observed in all outcomes measures (OKS, KOOS, EQ5D, and EQ5D VAS). The mean added ROM was 13.2°. DISCUSSION: This knee prosthesis has been demonstrated to be safe and effective with excellent early outcomes. The careful regulated introduction of this device through BC has ensured patients safety while supporting innovation in knee arthroplasty. The success of BC requires surgeons to insist industry fully engage with the process for all new devices or techniques.
32145090 Adipose-derived mesenchymal stromal cells suppress osteoclastogenesis and bone erosion in 2020 Aug Osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA), and adipose-derived mesenchymal stromal cells (ADSCs) can inhibit experimental collagen-induced arthritis model. This study aims to determine whether ADSCs also suppresses osteoclastogenesis and bone erosion in collagen-induced arthritis (CIA). Osteoclasts were induced from bone marrow-derived CD11b(+) cells with receptor activator of nuclear factor-κ B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) stimulation and assessed with tartrate-resistant acid phosphatase (TRAP) staining. For human cells, osteoclasts were produced from human CD14(+) cells. ADSCs were generated and added to cultures with different ratios with CD11b(+) cells. Transwell and antibody blockade experiments were performed to define the mechanism of action. NF-κB and RANKL expression were determined by Western blotting and RT-qPCR. About 2 × 10(6) ADSCs or fibroblast cells were adoptively transferred to DBA1/J mice on day 14 after immunization with type II collagen/complete Freund's adjuvant (CII/CFA) while the onset and severity of the CIA were monitored. Adipose-derived mesenchymal stromal cells but not fibroblast cells completely suppressed osteoclastogenesis in vitro for human and mice. ADSCs injected after immunization and before of onset of CIA significantly suppressed disease development. Treatment with ADSCs dramatically decreased the levels of NF-κB p65/p50 in osteoclasts in vitro and P65/50 and RANKL expression by synovial tissues in vivo. We have demonstrated that ADSCs can inhibit RANKL-induced osteoclasts genesis via CD39 signals. Our findings also suggest that ADSCs can inhibit osteoclasts genesis without the involvement of regulatory T cells. ADSCs might represent a promising strategy for stem cell-based therapies for RA. Thus, manipulation of ADSCs may have therapeutic effects on RA and other bone erosion-related diseases.
32999362 Efficacy and safety of a single switch from etanercept originator to etanercept biosimilar 2020 Sep 30 AntiTNF-α biosimilars are broadly available for the treatment of inflammatory arthritis. There are a lot of data concerning the maintenance of clinical efficacy after switching from originators to biosimilars; therefore, such a transition is increasingly encouraged both in the US and Europe. However, there are reports about flares and adverse events (AE) as a non-medical switch remains controversial due to ethical and clinical implications (efficacy, safety, tolerability). The aim of our work was to evaluate the disease activity trend after switching from etanercept originator (oETA-Enbrel) to its biosimilar (bETA-SP4/Benepali) in a cohort of patients in Turin, Piedmont, Italy. In this area, the switch to biosimilars is stalwartly encouraged. We switched 87 patients who were in a clinical state of stability from oETA to bETA: 48 patients were affected by Rheumatoid Arthritis (RA),26 by Psoriatic Arthritis (PsA) and 13 by Ankylosing Spondylitis (AS).We evaluated VAS-pain, Global-Health, CRP, number of swollen and tender joints, Disease Activity Score on 28 joints (DAS28) for RA, Disease Activity in Psoriatic Arthritis (DAPSA) for PsA, Health Assessment Questionnaire (HAQ) and Health Assessment Questionnaire for the spondyloarthropathies (HAQ-S),Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS patients. 11/85 patients (12.6%) stopped treatment after switching to biosimilar etanercept. No difference was found between oETA and bETA in terms of efficacy. However, some arthritis flare and AE were reported. Our data regarding maintenance of efficacy and percentage of discontinuation were in line with the existing literature.
31493964 Increased adenosine-to-inosine RNA editing in rheumatoid arthritis. 2020 Jan OBJECTIVE: Adenosine-to-inosine (A-to-I) RNA editing of Alu retroelements is a primate-specific mechanism mediated by adenosine deaminases acting on RNA (ADARs) that diversifies transcriptome by changing selected nucleotides in RNA molecules. We tested the hypothesis that A-to-I RNA editing is altered in rheumatoid arthritis (RA). METHODS: Synovium expression analysis of ADAR1 was investigated in 152 RA patients and 50 controls. Peripheral blood mononuclear cells derived from 14 healthy subjects and 19 patients with active RA at baseline and after 12-week treatment were examined for ADAR1p150 and ADAR1p110 isoform expression by RT-qPCR. RNA editing activity was analysed by AluSx(+) Sanger-sequencing of cathepsin S, an extracellular matrix degradation enzyme involved in antigen presentation. RESULTS: ADAR1 was significantly over-expressed in RA synovium regardless of disease duration. Similarly, ADAR1p150 isoform expression was significantly increased in the blood of active RA patients. Individual nucleotide analysis revealed that A-to-I RNA editing rate was also significantly increased in RA patients. Both baseline ADAR1p150 expression and individual adenosine RNA editing rate of cathepsin S AluSx(+) decreased after treatment only in those patients with good clinical response. Upregulation of the expression and/or activity of the RNA editing machinery were associated with a higher expression of edited Alu-enriched genes including cathepsin S and TNF receptor-associated factors 1,2,3 and 5. CONCLUSION: A previously unrecognized regulation and role of ADAR1p150-mediated A-to-I RNA editing in post-transcriptional control in RA underpins therapeutic response and fuels inflammatory gene expression, thus representing an interesting therapeutic target.