Objective: We have previously reported that stimulation of mouse bone marrow–derived macrophages with tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) induces differentiation of osteoclast‐like cells. We undertook this study to clarify the characterization and function of human TNF and IL‐6–induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors.Methods: Peripheral blood monocytes were cultured with a combination of TNF and IL‐6, TNF alone, IL‐6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL‐6–induced osteoclasts or RANKL‐induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole‐body bone mineral density (BMD) was examined.Results: Peripheral blood monocytes stimulated with a TNF and IL‐6–induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL‐6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL‐6–induced osteoclast formation. Expression levels of IL1β, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL‐6–induced osteoclasts, but not in RANKL‐induced osteoclasts. The number of TNF and IL‐6–induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL‐induced osteoclast numbers negatively correlated with the whole‐body BMD of the same patients.Conclusion: Our results demonstrate that TNF and IL‐6–induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.

Matrix metalloproteinases (MMPs) are implicated in the degradation of extracellular matrix (ECM). Rheumatoid arthritis (RA) synovial fibroblasts (SFs) produce matrix-degrading enzymes, including MMPs, which facilitate cartilage destruction in the affected joints in RA. Epigenetic mechanisms contribute to change in the chromatin state, resulting in an alteration of gene transcription. Recently, MMP gene activation has been shown to be caused in RASFs by the dysregulation of epigenetic changes, such as histone modifications, DNA methylation, and microRNA (miRNA) signaling. In this paper, we review the role of MMPs in the pathogenesis of RA as well as the disordered epigenetic mechanisms regulating MMP gene activation in RASFs.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that is characterized by synovial hyperplasia and progressive joint destruction. The activation of RA synovial fibroblasts (SFs), also called fibroblast-like synoviocytes (FLS), contributes significantly to perpetuation of the disease. Genetic and environmental factors have been reported to be involved in the etiology of RA but are insufficient to explain it. In recent years, accumulating results have shown the potential role of epigenetic mechanisms, including histone modifications, DNA methylation, and microRNAs, in the development of RA. Epigenetic mechanisms regulate chromatin state and gene transcription without any change in DNA sequence, resulting in the alteration of phenotypes in several cell types, especially RASFs. Epigenetic changes possibly provide RASFs with an activated phenotype. In this paper, we review the roles of epigenetic mechanisms relevant for the progression of RA.

Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of autoimmune diseases. Histone modifications regulate the chromatin states and gene transcription without any change in the DNA sequence, possibly resulting in phenotype alteration in several different cell types. In this paper, we discuss the significant roles of histone modifications involved in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, and type 1 diabetes.

Objectives: Using an expert- and data-driven methodology, we have constructed the first clinical practice guidelines (CPGs) for adult Still’s disease (ASD) after complete systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. Methods: The CPG committee for ASD organized by the Research Team for Autoimmune Diseases, the Research Program for Intractable Disease of the Japanese Ministry of Health, Labour, and Welfare has developed CPG for ASD 2017, according to the procedure proposed by Minds. The CPG development process includes (1) clarification of the purpose of CPG, (2) organization of the steering committee, (3) organization of the CPG committee and secretariat, (4) defining the scope (setting of clinical questions (CQs)), (5) SR, (6) development of recommendations, (7) drafting the CPG, (8) external evaluation and public comments, and (9) release. Because we wanted to construct CPG for ASD to encompass both adult-onset Still’s disease (AOSD) and adult patients with systemic juvenile idiopathic arthritis (sJIA), we also included SR data from sJIA in this study. Results: Twenty-six CQs were selected and roughly divided into the following items: (1) clinical findings (CQs 1–4), (2) laboratory findings (CQs 5–8), (3) complications (CQs 9–13), (4) treatment with oral medicine (CQs 14–19), (5) treatment with biological reagents (CQs 20–23), and (6) treatments for sJIA (CQs 25–26). Recommendations and the strength of the recommendations for these CQs were decided by a modified Delphi method. Conclusion: We have developed the first published CPG for ASD including AOSD and sJIA, which includes 26 CQs and recommendations. This guideline will help rheumatologists, non-specialized physicians, other healthcare providers, medical and health-related students, and patients and their family members to understand and treat ASD.