Objective: To examine whether depsipeptide (FK228), a histone deacetylase (HDA) inhibitor, has inhibitory effects on the proliferation of synovial fibroblasts from rheumatoid arthritis (RA) patients, and to examine the effects of systemic administration of FK228 in an animal model of arthritis.Methods: Autoantibody‐mediated arthritis (AMA) was induced in 19 male DBA/1 mice (6–7 weeks old); 10 of them were treated by intravenous administration of FK228 (2.5 mg/kg), and 9 were used as controls. The effects of FK228 were examined by radiographic, histologic, and immunohistochemical analyses and arthritis scores. RA synovial fibroblasts (RASFs) were obtained at the time of joint replacement surgery. In vitro effects of FK228 on cell proliferation were assessed by MTT assay. Cell morphology was examined by light and transmission electron microscopy. The effects on the expression of the cell cycle regulators p16^INK4a and p21^WAF1/Cip1 were examined by real‐time polymerase chain reaction and Western blot analysis. The acetylation status of the promoter regions of p16^INK4a and p21^WAF1/Cip1 were determined by chromatin immunoprecipitation assay.Results: A single intravenous injection of FK228 (2.5 mg/ml) successfully inhibited joint swelling, synovial inflammation, and subsequent bone and cartilage destruction in mice with AMA. FK228 treatment induced histone hyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor α and interleukin‐1β in the synovial tissues of mice with AMA. FK228 inhibited the in vitro proliferation of RASFs in a dose‐dependent manner. Treatment of cells with FK228 induced the expression of p16^INK4a and up‐regulated the expression of p21^WAF1/Cip1. These effects of FK228 on p16^INK4a and p21^WAF1/Cip1 were related to the acetylation of the promoter region of the genes.Conclusion: Our findings strongly suggest that systemic administration of HDA inhibitors may represent a novel therapeutic target in RA by means of cell cycle arrest in RASFs via induction of p16^INK4a expression and increase in p21^WAF1/Cip1 expression.

Introduction: The purpose of this study was to investigate the profile of histone deacetylase (HDAC) expression in the synovial tissue of rheumatoid arthritis (RA) compared with that of normal control and osteoarthritis (OA), and to examine whether there is a link between HDAC activity and synovial inflammation. Methods: HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of total synovial tissue surgically obtained from normal, OA and RA joints. The level of cytoplasmic tumor necrosis factor a (TNFα) fraction was measured by ELISA. Total RNA of synovial tissue was used for RT-PCR of HDAC1-8. In synovial fibroblasts from RA (RASFs), the effects of TNFα on nuclear HDAC activity and class I HDACs (1, 2, 3, 8) mRNA expressions were examined by quantitative real-time PCR. The protein expression and distribution of class I HDACs were examined by Western blotting. Results: Nuclear HDAC activity was significantly higher in RA than in OA and normal controls and correlated with the amount of cytoplasmic TNFα. The mRNA expression of HDAC1 in RA synovial tissue was higher than in OA and normal controls, and showed positive correlation with TNFα mRNA expression. The protein level of nuclear HDAC1 was higher in RA synovial tissue compared with OA synovial tissue. Stimulation with TNFα significantly increased the nuclear HDAC activity and HDAC1 mRNA expression at 24 hours and HDAC1 protein expression at 48 hours in RASFs. Conclusions: Our results showed nuclear HDAC activity and expression of HDAC1 were significantly higher in RA than in OA synovial tissues, and they were upregulated by TNFα stimulation in RASFs. These data might provide important clues for the development of specific small molecule HDAC inhibitors.

Objective: The aim of this study was to update the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA; JCR CPG for RA) according to recent changes in the medical environment in Japan. This article is a digest version of the guidance.Methods: We used the Grading of Recommendations, Assessment, Development, and Evaluation method to update the 2014 JCR CPG for RA. A consensus was formed by CPG panel members.Results: We identified 36 important clinical questions regarding drug treatment and developed corresponding recommendations for RA. The recommendations included the following RA medications: non-steroidal anti-inflammatory drugs, corticosteroids, conventional synthetic disease-modifying antirheumatic drugs, biological disease-modifying antirheumatic drugs, anti-receptor activator for nuclear factor-κB ligand antibodies, and Janus kinase inhibitors, as well as the tapering and discontinuation of these medications. Recommendations regarding the efficacy and safety of treatments in the elderly and patients with comorbidities were also developed. Finally, we used these recommendations to create an original algorithm for drug treatment for RA based on the Treat-to-Target approach.Conclusion: The 2020 JCR CPG for RA provides a useful tool for rheumatologists, health care professionals, and patients with RA, enabling shared decision-making in a variety of clinical situations.

Objective: To investigate the prevalence and the risk factors of surgical-site infection (SSI) and delayed wound healing (DWH) in patients with rheumatoid arthritis (RA) underwent orthopedic surgery. Methods: We reviewed the records of 1036 elective orthopedic procedures undertaken in RA patients. Risk factors for SSI and DWH were assessed by logistic regression analysis using age, body mass index, disease duration, pre-operative laboratory data, surgical procedure, corticosteroid use, co-morbidity, and use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and biological DMARDs (bDMARDs) as variables. Results: SSI and DWH were identified in 19 cases and 15 cases, respectively. One case of SSI and three cases of DWH were recorded among 196 procedures in patients using bDMARDs. Foot and ankle surgery was associated with an increased risk of SSI (odds ratio (OR), 3.167; 95% confidence interval (CI), 1.256–7.986; p = 0.015). Total knee arthroplasty (TKA; OR, 4.044; 95% CI, 1.436–11.389; p = 0.008) and disease duration (OR, 1.004; 95% CI, 1.000–1.007; p = 0.029) were associated with an increased risk of DWH. Conclusions: Our results indicated foot and ankle surgery, and TKA and disease duration as risk factors for SSI and DWH, respectively. bDMARDs was not associated with an increased risk of SSI and DWH.