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The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity. We investigated the relevance of this new classification of HLA-DRB1 SE+ alleles in terms of rheumatoid factor (RF) and ACPA production in a sample of French RA patients. We studied 160 early RA patients included in a prospective longitudinal cohort of French Caucasian patients with recent-onset arthritis. RF, anticyclic citrullinated peptide 2 (anti-CCP2) and antideiminated human fibrinogen autoantibodies (AhFibA) were assessed in all patients at inclusion. The HLA-DRB1 gene was typed by PCR-sequence specific oligonucleotides probes (PCR-SSOP), and SE+ alleles were classified into four groups (S1, S2, S3P, S3D) according to the new classification. The new classification of HLA-DRB1 SE+ alleles distinguishes predisposing and protective alleles for RF, anti-CCP2 or AhFibA production. The presence of S2 or S3P alleles is associated with both RF, anti-CCP2 or AhFibA positivity, whereas the presence of S3D or S1 alleles appears to be protective for RF, anti-CCP2 or AhFibA positivity. The new classification of HLA-DRB1 SE+ alleles is relevant in terms of autoantibody production in early RA patients by differentiating predisposing and protective alleles for RF or ACPA production.

Increased osteoclastogenesis is a common feature of bone erosion, notably in osteoporosis but also in inflammatory diseases such as rheumatoid arthritis (RA) and osteoarticular infections. Human cytomegalovirus (HCMV) infection has been described to impair monocyte differentiation into macrophages and dendritic cells. However, its effect on monocyte‐derived osteoclasts is yet to be determined. We showed here that in vitro HCMV infection is associated with an inhibition of osteoclastogenesis through decreased expression of colony stimulating factor 1 receptor (CSF‐1R) and RANK in monocytes, which was mediated by an upregulation of quaking I‐5 protein (QKI‐5), a cellular RNA‐interacting protein. We found that deliberate QKI5 overexpression in the absence of HCMV infection is able to decrease CSF‐1R and RANK expression, leading to osteoclastogenesis inhibition. Finally, by using lentiviral vectors in a calvarial bone erosion mouse model, we showed that QKI5 inhibits bone degradation. This work identifies QKI5 as a strong inhibitor of bone resorption. Future research will point out whether QKI5 could be a target for bone pathologies. © 2019 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objectives: To compare two strategies-a hydrocortisone replacement strategy and a prednisone tapering strategy-for their success in glucocorticoid discontinuation in patients with rheumatoid arthritis (RA) with low disease activity (LDA)., Methods: The Strategies for glucocorticoid TApering in Rheumatoid arthritis (STAR) study was a double-blind, double-placebo randomised controlled trial including patients with RA receiving a stable dose of glucocorticoid 5 mg/day for ≥3 months and were in LDA for ≥3 months. Patients were randomly assigned in a 1:1 ratio to either replace prednisone with 20 mg/day of hydrocortisone for 3 months, then reduce to 10 mg/day for 3 months before discontinuation or to taper prednisone by 1 mg/day every month until complete discontinuation, contingent on maintaining LDA. The primary outcome was the percentage of patients achieving glucocorticoid discontinuation at 12 months. Other secondary outcomes were proportion of flares, need for additional glucocorticoid use, disease activity, patient-reported outcomes and the results of adrenocorticotropic hormone (ACTH) stimulation tests., Results: Of the 102 patients randomised in the trial (mean age 62.4 years, 70.6% females), 53 had hydrocortisone replacement and 49 tapered prednisone. At 12 months, 29 patients (55%) in the hydrocortisone replacement group and 23 patients (47%) in the prednisone tapering group achieved glucocorticoid discontinuation (p=0.4). No difference was observed between groups in the secondary outcomes. No cases of acute adrenal insufficiency were observed; however, 17 patients still had an abnormal ACTH stimulation test at 12 months, with no differences between arms., Conclusion: A hydrocortisone replacement strategy was not superior to a prednisone tapering strategy for achieving glucocorticoid discontinuation success in patients with RA in LDA., Trial Registration Number: NCT02997605., Competing Interests: Competing interests: AR-W, CB, MM, VB, MN, ChR, AS, PV-S, RMF, MP, J-EG, MS, PD, SL, LZ, GC, JFB, BJ, YD and AC declare no competing interests. HM declared to have received grants from Celltrion, Healthcare, Lilly, Nordic Pharma, Medac, consulting fees from AbbVie, Accord, CellTrion HealthCare, Johnson & Johnson, UCB, honoraria for presentation from AbbVie, Bristol Myers Squibb, CellTrion HealthCare, Fresenius Kabi, Galapagos, Medac, Nordic Pharma, Novartis, Sanofi, UCB, support for attending meeting from CellTrion HealthCare, Fresenius Kabi, UCB, participated in advisory board for Lilly, Pfizer. CS received grant from Novartis, Roche-Chugai, honoraria for presentations from Novartis, Galapagos, Pfizer, Lilly and support for attending meetings from Lilly, Novartis, Galapagos. JM received grants from Bristol Myers Squib, Fresenius Kabi Novartis, Roche Chugai, Pfizer and Lilly, received honoraria for presentation from AbbVie, Boehringer Ingelheim, Biogen, Lilly, Viatris, Pfizer, Sanofi, from Bristol Myers Squib, Fresenius Kabi, Galapagos, Medac, Novartis, Roche Chugai, support for attending meetings from Bristol Myers Squib, Fresenius Kabi, Lilly, participated in advisory boards for AbbVie, Pfizer, Theramex, Galapagos, Fresenius Kabi and Sanofi. CR received grants from Biogen, Lilly, Nordic Pharma, consulting fees from Novartis, Lilly, AstraZeneca, AbbVie, Pfizer and GSK, received honoraria for presentations from AbbVie, Boehringer Ingelheim, Novartis, Lilly, Galapagos, Pfizer, UCB, support for attending meeting from UCB, Novartis and AstraZeneca. LG received grants from AbbVie, Biogen, Lilly, Novartis, UCB, consulting fees from AbbVie, Amgen, BMS, Celltrion, Janssen, Novartis, Pfizer, UCB, honoraria for presentations from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB, support for attending meeting from MSD, Novartis, Pfizer, participated in advisory boards for Janssen, Pfizer, UCB., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

In chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic inflammation appears as an independent risk factor, contributing to increased cardiovascular mortality. This high cardiovascular mortality reveals the existence of accelerated atherosclerosis, the pathogenesis of which may be associated with traditional risk factors such as smoking, hypertension, dyslipidemia, deterioration of insulin sensitivity, and less traditional risk factors such as hyperhomocysteinemia, inflammatory conditions and endothelial dysfunction. Control of systemic inflammation theoretically provides a means of preventing this higher cardiovascular mortality among RA patients. In this review we address the question of the impact of anti-rheumatic drugs currently used in RA, such as non-steroidal anti-inflammatory drugs (e.g. non-selective or cyclooxygenase-2 selective inhibitors), steroidal anti-inflammatory drugs (glucocorticoids), traditional disease-modifying anti-rheumatic drugs (e.g. methotrexate) or biologics (e.g. anti-tumour necrosis factor alpha anti-tumour necrosis factor alpha) on cardiovascular diseases in RA patients. We also discuss the specific mechanisms involved in the differential cardiovascular effects of these therapeutic agents.

In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFalpha), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFalpha and adalimumab, a human anti-TNFalpha monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFalpha or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)gamma in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFalpha inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARgamma activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFalpha and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis.