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Rheumatoid arthritis is a chronic, systemic autoimmune disease manifested primarily as inflammatory arthritis, typically involving the small joints of the hands and feet. It can lead to severe disability and death.

Key Points Along with other 'omics' approaches, metabolomics — the comprehensive analysis of all metabolites in a system — represents a change from the traditional analysis of single genes, transcripts, proteins or metabolites Improvements in analytical techniques and pattern-recognition methods have led to a rise in the numbers of untargeted and targeted metabolic studies that are being performed Understanding metabolic changes that are specifically associated with the pathogenesis of autoimmune diseases should lead to novel insights into disease mechanisms and to new strategies for treatment of rheumatic diseases The feasibility of metabolomics for biomarker discovery in rheumatology is supported by the assumption that metabolites are important players in biological systems and that diseases cause disruption of metabolic pathways In the setting of inflammatory diseases, metabolic profiling has potential applications in diagnosis, monitoring and defining disease pathogenesis. This Review focuses on metabolomic studies in rheumatic diseases, including discussion of state-of-the-art technologies, recent insights into disease mechanisms and treatment targets, and the feasibility of metabolomics for biomarker discovery. Metabolomics enables the profiling of large numbers of small molecules in cells, tissues and biological fluids. These molecules, which include amino acids, carbohydrates, lipids, nucleotides and their metabolites, can be detected quantitatively. Metabolomic methods, often focused on the information-rich analytical techniques of NMR spectroscopy and mass spectrometry, have potential for early diagnosis, monitoring therapy and defining disease pathogenesis in many therapeutic areas, including rheumatic diseases. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanisms are being revealed and are shaping our understanding of cell biology, physiology and medicine. These pathways can potentially be targeted to diagnose and treat patients with immune-mediated diseases.

Risk factors-genetic and environmental-for rheumatoid arthritis (RA) are gradually becoming clear, leading to considerable heterogeneity in the pathological processes and clinical features of this disease. Preclinical abnormalities can precede manifestation of symptoms by a decade. Precisely how endogenous predisposing factors interact with environmental triggers to produce clinical disease remains unclear, but the authors of this Review unite diverse strands of research to present a state-of-the-art mechanism for RA pathogenesis. Multiple proven and potential risk factors for the development of rheumatoid arthritis (RA) have been identified, and represent interactions between genes and the environment. Proven risk factors include genetic influences on the function of the innate and adaptive immune systems, smoking, anti-citrullinated protein antibodies (ACPAs), and rheumatoid factors (RF). Potential risk factors include epigenetic control of gene expression, the microbiome and other environmental factors, Toll-like receptors, cytokines, and Fc receptors. Preclinical abnormalities such as circulating RF and ACPAs may occur more than 10 years prior to the onset of clinical disease. However, the precise mechanisms whereby these risk factors lead to clinical disease remain unclear. It is possible that, combined with activation of the innate immune system, a subset of ACPAs initiates the disease in the cartilage or synovium after binding to endogenous citrullinated proteins. Subsequent engagement of Fc receptors and complement activation would lead to secondary inflammation in the synovium with induction of a perpetuating cycle of chronic synovitis. Key Points Rheumatoid arthritis (RA) exhibits multiple predisposing factors that precede its development Genetic risk factors are prominent, involving genes of the MHC as well as many non-MHC genes associated with immune responses and inflammation The presence of elevated serum levels of autoantibodies such as rheumatoid factors and antibodies to citrullinated proteins may precede the clinical onset of RA by over 10 years and could, in some cases, represent a normal adaptive response to neoantigens The most important environmental risk factor for RA defined to date is smoking The precise mechanism of initiation of the clinical disease is unknown but may involve antibodies directed against specific citrullinated proteins and repeated activation of innate immunity

Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles. Epigenomically similar regions exist in RA cells and are associated with active enhancers and promoters and specific transcription factor binding motifs. Differentially marked genes are enriched for immunological and unexpected pathways, with “Huntington’s Disease Signaling” identified as particularly prominent. We validate the relevance of this pathway to RA by showing that Huntingtin-interacting protein-1 regulates FLS invasion into matrix. This work establishes a high-resolution epigenomic landscape of RA and demonstrates the potential for integrative analyses to identify unanticipated therapeutic targets. Fibroblast-like synoviocytes (FLS) in the intimal layer of the synovium can become invasive and destroy cartilage in patients with rheumatoid arthritis (RA). Here the authors integrate a variety of epigenomic data to map the epigenome of FLS in RA and identify potential therapeutic targets.

Objectives The objective of this study was to investigate the effect of the novel Janus kinase inhibitor CP-690,550 in fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). Methods RA FLSs were isolated from tissue obtained by arthroplasty, cultured and serum-starved 48 h prior to stimulation. Messenger RNA and protein levels were determined by quantitative PCR and ELISA or multiplex bead assay, respectively. Phosphorylation of STAT (signal transducers and activators of transcription) proteins was determined by western blot. Results Interleukin-6-induced phosphorylation of STAT1 and STAT3 was inhibited by CP-690,550 with IC50 values of 23 and 77 nM, respectively. Unexpectedly, although tumour necrosis factor (TNF) did not induce immediate phosphorylation of either STAT, CP-690,550 inhibited TNF-induced expression of several chemokines (IP-10, RANTES and MCP1) at the messenger RNA and protein levels. Chemokine expression was inhibited by cycloheximide, implying a need for de novo protein synthesis, and cycloheximide abolished the effect of CP-690,550 (tofacitinib). TNF induced early interferon (IFN) β expression and STAT1 phosphorylation beginning at 3 h, which was blocked by CP-690,550. The dependence of TNF-induced chemokine expression on type I IFN was confirmed in FLSs from mice lacking type I IFN receptors (IFNARs) and in RA FLSs using an IFNAR blocking antibody. Conclusions The Janus kinase/STAT pathway in FLS is indirectly activated by TNF through autocrine expression of type I IFN, resulting in IFNAR engagement and production of T cell chemokines. These findings illuminate a novel role of CP-690,550 in the treatment of RA: the reduction of chemokine synthesis by FLS, thereby limiting recruitment of T cells and other infiltrating leucocytes.

Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients. Rheumatoid arthritis is an inflammatory disease that selectively affects different joints. Here the authors show that gene expression and DNA methylation patterns of fibroblast-like synoviocytes differ between hip and knee joints in patients with RA, thus providing epigenetic and transcriptomic evidence for this anatomic selectivity of inflammation.

Rheumatoid arthritis (RA) is an immune-mediated disease affecting diarthrodial joints that remains an unmet medical need despite improved therapy. This limitation likely reflects the diversity of pathogenic pathways in RA, with individual patients demonstrating variable responses to targeted therapies. Better understanding of RA pathogenesis would be aided by a more complete characterization of the disease. To tackle this challenge, we develop and apply a systems biology approach to identify important transcription factors (TFs) in individual RA fibroblast-like synoviocyte (FLS) cell lines by integrating transcriptomic and epigenomic information. Based on the relative importance of the identified TFs, we stratify the RA FLS cell lines into two subtypes with distinct phenotypes and predicted active pathways. We biologically validate these predictions for the top subtype-specific TF RARα and demonstrate differential regulation of TGFβ signaling in the two subtypes. This study characterizes clusters of RA cell lines with distinctive TF biology by integrating transcriptomic and epigenomic data, which could pave the way towards a greater understanding of disease heterogeneity. Fibroblast-like synoviocytes (FLS) are used as a model of rheumatoid arthritis synoviocytes, although cell lines derived from individual patients can have heterogeneous biology. Here the authors use a Taiji computational approach to analyze gene expression, chromatin accessibility and functional differences between individual patient-derived RA FLS lines.

Rheumatoid arthritis (RA) is a systemic immune-mediated disease characterized by joint inflammation and destruction. The disease typically affects small joints in the hands and feet, later progressing to involve larger joints such as the knees, shoulders, and hips. While the reasons for these joint-specific differences are unclear, distinct epigenetic patterns associated with joint location have been reported. In this study, we evaluated the unique epigenetic landscapes of fibroblast-like synoviocytes (FLS) from hip and knee synovium in RA patients, focusing on the expression and regulation of Homeobox (HOX) transcription factors. These highly conserved genes play a critical role in embryonic development and are known to maintain distinct expression patterns in various adult tissues. We found that several HOX genes, especially HOXD10, were differentially expressed in knee FLS compared with hip FLS. Epigenetic differences in chromatin accessibility and histone marks were observed in HOXD10 promoter between knee and hip FLS. Histone modification, particularly histone acetylation, was identified as an important regulator of HOXD10 expression. To understand the mechanism of differential HOXD10 expression, we inhibited histone deacetylases (HDACs) with small molecules and siRNA. We found that HDAC1 blockade or deficiency normalized the joint-specific HOXD10 expression patterns. These observations suggest that epigenetic differences, specifically histone acetylation related to increased HDAC1 expression, play a crucial role in joint-specific HOXD10 expression. Understanding these mechanisms could provide insights into the regional aspects of RA and potentially lead to therapeutic strategies targeting specific patterns of joint involvement during the course of disease.

Identifying novel therapeutic targets for the treatment of disease is challenging. To this end, we developed a genome-wide approach of candidate gene prioritization. We independently collocated sets of genes that were implicated in rheumatoid arthritis (RA) pathogenicity through three genome-wide assays: (i) genome-wide association studies (GWAS), (ii) differentially expression in RA fibroblast-like synoviocytes (FLS), and (iii) differentially methylation in RA FLS. Integrated analysis of these complementary data sets identified a significant enrichment of multi-evidence genes (MEGs) within pathways relating to RA pathogenicity. One MEG is Engulfment and Cell Motility Protein-1 (ELMO1), a gene not previously considered as a therapeutic target in RA FLS. We demonstrated in RA FLS that ELMO1 is: (i) expressed, (ii) promotes cell migration and invasion, and (iii) regulates Rac1 activity. Thus, we created links between ELMO1 and RA pathogenicity, which in turn validates ELMO1 as a potential RA therapeutic target. This study illustrated the power of MEG-based approaches for therapeutic target identification.

Background Cadherins (CDH), such as CDH11, are glycoprotein adhesion molecules contributing to cell-cell interactions in health and disease. CDH11 has demonstrated important functions in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). In transcriptome expression studies, we observed that Cadherin 6 (CDH6) expression was higher in RA compared to osteoarthritis (OA). CDH6 is associated with cancer progression, but little information is known on the role of CDH6 in RA. The present study investigates CDH6 expression, regulation, function in FLS, and distribution in RA synovia. Methods Synovial tissue and FLS were obtained from RA or OA patients undergoing joint replacement. CDH6 epigenetic marks and expression in RA and OA FLS were evaluated using public databases. CDH6 expression was determined by RT-PCR, Western blot, and immunostaining. RA and OA FLS were stimulated with cytokines and growth factors, and CDH6 mRNA expression was determined. CDH6 was silenced using siRNA, and the effect on migration, cell growth, apoptosis, autophagy, cell cycle, and signaling was studied. Results In our analysis of cadherin family expression, CDH6 expression was higher in RA than OA FLS. This was associated with differential chromatin accessibility and histone marks in the CDH6 promoter of RA FLS. H3K27ac was identified as an important regulator of CDH6 expression in RA FLS based on experiments using histone deacetylase inhibitors. TGFß, but not IL-1β, TNF, IL-17A, IFNγ, IL-6, or PDGF, increased CDH6 expression of cultured RA FLS. CDH6 knockdown significantly decreased RA FLS migration and cell growth. The latter was associated with increased apoptosis in CDH6 deficient FLS. Immunofluorescence showed CDH6 protein distribution in the membrane, perinuclear, and nuclear regions of cultured FLS. In RA synovial tissue, CDH6 expression was noted in FLS and macrophages within the lining and sublining regions. Conclusions CDH6 expression is elevated in RA FLS due to epigenetic and local conditions of synovitis promoting migration, survival and cell growth, which are characteristic features of aggressive RA FLS. The intracellular distribution suggests additional functions beyond adhesion and homotypic aggregation, such as signaling and gene regulation. These data suggest CDH6 contributes to RA pathogenesis by influencing pathologic FLS behavior and could be a therapeutic target.