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Rheumatoid arthritis (RA) is an autoimmune disease causing progressive joint damage. Early diagnosis and treatment is critical, but remains challenging due to RA complexity and heterogeneity. Machine learning (ML) techniques may enhance RA management by identifying patterns within multidimensional biomedical data to improve classification, diagnosis, and treatment predictions. In this review, we summarize the applications of ML for RA management. Emerging studies or applications have developed diagnostic and predictive models for RA that utilize a variety of data modalities, including electronic health records, imaging, and multi-omics data. High-performance supervised learning models have demonstrated an Area Under the Curve (AUC) exceeding 0.85, which is used for identifying RA patients and predicting treatment responses. Unsupervised learning has revealed potential RA subtypes. Ongoing research is integrating multimodal data with deep learning to further improve performance. However, key challenges remain regarding model overfitting, generalizability, validation in clinical settings, and interpretability. Small sample sizes and lack of diverse population testing risks overestimating model performance. Prospective studies evaluating real-world clinical utility are lacking. Enhancing model interpretability is critical for clinician acceptance. In summary, while ML shows promise for transforming RA management through earlier diagnosis and optimized treatment, larger scale multisite data, prospective clinical validation of interpretable models, and testing across diverse populations is still needed. As these gaps are addressed, ML may pave the way towards precision medicine in RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shi, Zhou, Chang, Jiang, Wei, Zhao, Shan, Zheng, Zhao, Lv, Guo, Wang and He.)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Macrophages are key effector cells that play a central role in RA pathogenesis through their ability to polarize into distinct functional phenotypes. An imbalance favoring pro-inflammatory M1 macrophages over anti-inflammatory M2 macrophages disrupts immune homeostasis and exacerbates joint inflammation. Multiple signaling pathways, including Notch, JAK/STAT, NF-κb, and MAPK, regulate macrophage polarization towards the M1 phenotype in RA. Metabolic reprogramming also contributes to this process, with M1 macrophages prioritizing glycolysis while M2 macrophages utilize oxidative phosphorylation. Redressing this imbalance by modulating macrophage polarization and metabolic state represents a promising therapeutic strategy. Furthermore, complex bidirectional interactions exist between synovial macrophages and fibroblast-like synoviocytes (FLS), forming a self-perpetuating inflammatory loop. Macrophage-derived factors promote aggressive phenotypes in FLS, while FLS-secreted mediators contribute to aberrant macrophage activation. Elucidating the signaling networks governing macrophage polarization, metabolic adaptations, and crosstalk with FLS is crucial to developing targeted therapies that can restore immune homeostasis and mitigate joint pathology in RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zheng, Wei, Jiang, Zhao, Shan, Shi, Zhao, Chang, Li, Zhou, Lv, Guo and He.)

Objectives: Rheumatoid arthritis (RA) is a complex disease with a challenging diagnosis, especially in seronegative patients. The aim of this study is to investigate whether the methylation sites associated with the overall immune response in RA can assist in clinical diagnosis, using targeted methylation sequencing technology on peripheral venous blood samples., Methods: The study enrolled 241 RA patients, 30 osteoarthritis patients (OA), and 30 healthy volunteers control (HC). Fifty significant cytosine guanine (CG) sites between undifferentiated arthritis and RA were selected and analyzed using targeted DNA methylation sequencing. Logistic regression models were used to establish diagnostic models for different clinical features of RA, and six machine learning methods (logit model, random forest, support vector machine, adaboost, naive bayes, and learning vector quantization) were used to construct clinical diagnostic models for different subtypes of RA. Least absolute shrinkage and selection operator regression and detrended correspondence analysis were utilized to screen for important CGs. Spearman correlation was used to calculate the correlation coefficient., Results: The study identified 16 important CG sites, including tumor necrosis factort receptor associated factor 5 (TRAF5) (chr1:211500151), mothers against decapentaplegic homolog 3 (SMAD3) (chr15:67357339), tumor endothelial marker 1 (CD248) (chr11:66083766), lysosomal trafficking regulator (LYST) (chr1:235998714), PR domain zinc finger protein 16 (PRDM16) (chr1:3307069), A-kinase anchoring protein 10 (AKAP10) (chr17:19850460), G protein subunit gamma 7 (GNG7) (chr19:2546620), yes1 associated transcriptional regulator (YAP1) (chr11:101980632), PRDM16 (chr1:3163969), histone deacetylase complex subunit sin3a (SIN3A) (chr15:75747445), prenylated rab acceptor protein 2 (ARL6IP5) (chr3:69134502), mitogen-activated protein kinase kinase kinase 4 (MAP3K4) (chr6:161412392), wnt family member 7A (WNT7A) (chr3:13895991), inhibin subunit beta B (INHBB) (chr2:121107018), deoxyribonucleic acid replication helicase/nuclease 2 (DNA2) (chr10:70231628) and chromosome 14 open reading frame 180 (C14orf180) (chr14:105055171). Seven CG sites showed abnormal changes between the three groups (P < 0.05), and 16 CG sites were significantly correlated with common clinical indicators (P < 0.05). Diagnostic models constructed using different CG sites had an area under the receiver operating characteristic curve (AUC) range of 0.64-0.78 for high-level clinical indicators of high clinical value, with specificity ranging from 0.42 to 0.77 and sensitivity ranging from 0.57 to 0.88. The AUC range for low-level clinical indicators of high clinical value was 0.63-0.72, with specificity ranging from 0.48 to 0.74 and sensitivity ranging from 0.72 to 0.88. Diagnostic models constructed using different CG sites showed good overall diagnostic accuracy for the four subtypes of RA, with an accuracy range of 0.61-0.96, a balanced accuracy range of 0.46-0.94, and an AUC range of 0.46-0.94., Conclusions: This study identified potential clinical diagnostic biomarkers for RA and provided novel insights into the diagnosis and subtyping of RA. The use of targeted deoxyribonucleic acid (DNA) methylation sequencing and machine learning methods for establishing diagnostic models for different clinical features and subtypes of RA is innovative and can improve the accuracy and efficiency of RA diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: To assess the differences in circulating DNA methylation levels of CXCR5 between rheumatoid arthritis (RA) and osteoarthritis (OA) and healthy controls (HC), and the correlation of methylation changes with clinical characteristics of RA patients., Methods: Peripheral blood samples were collected from 239 RA patients, 30 patients with OA, and 29 HC. Target region methylation sequencing to the promoter region of CXCR5 was achieved using MethylTarget. The methylation level of cg04537602 and methylation haplotype were compared among the three groups, and the correlation between methylation levels and clinical characteristics of RA patients was performed by Spearman's rank correlation analysis., Results: The methylation level of cg04537602 was significantly higher in the peripheral blood of RA patients compared with OA patients (p = 1.3 × 10 -3 ) and in the HC group (p = 5.5 × 10 - 4 ). The sensitivity was enhanced when CXCR5 methylation level combined with rheumatoid factor and anti-cyclic citrullinated peptide with area under curve (AUC) of 0.982 (95% confidence interval 0.970-0.995). The methylation level of cg04537602 in RA was positively correlated with C-reactive protein (CRP) (r = .16, p = .01), and in RA patients aged 60 years and above, cg04537602 methylation levels were positively correlated with CRP (r = .31, p = 4.7 × 10 - 4 ), tender joint count (r = .21, p = .02), visual analog scales score (r = .21, p = .02), Disease Activity Score in 28 joints (DAS28) using the CRP level DAS28-CRP (r = .27, p = 2.1 × 10 - 3 ), and DAS28-ESR (r = .22, p = .01). We also observed significant differences of DNA methylation haplotypes in RA patients compared with OA patients and HC, which was consistent with single-loci-based CpG methylation measurement., Conclusion: The methylation level of CXCR5 was significantly higher in RA patients than in OA and HC, and correlated with the level of inflammation in RA patients, our study establishes a link between CXCR5 DNA methylation and clinical features that may help in the diagnosis and disease management of RA patients., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by chronic inflammation that affects synovial tissues of multiple joints. Granzymes (Gzms) are serine proteases that are released into the immune synapse between cytotoxic lymphocytes and target cells. They enter target cells with the help of perforin to induce programmed cell death in inflammatory and tumor cells. Gzms may have a connection with RA. First, increased levels of Gzms have been found in the serum (GzmB), plasma (GzmA, GzmB), synovial fluid (GzmB, GzmM), and synovial tissue (GzmK) of patients with RA. Moreover, Gzms may contribute to inflammation by degrading the extracellular matrix and promoting cytokine release. They are thought to be involved in RA pathogenesis and have the potential to be used as biomarkers for RA diagnosis, although their exact role is yet to be fully elucidated. The purpose of this review was to summarize the current knowledge regarding the possible role of the granzyme family in RA, with the aim of providing a reference for future research on the mechanisms of RA and the development of new therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zheng, Zhao, Shan, Guo, Schrodi and He.)

Rheumatoid arthritis (RA) is a highly disabling chronic autoimmune disease. Multiple factors contribute to the complex pathological process of RA, in which an abnormal autoimmune response, high survival of inflammatory cells, and excessive release of inflammatory factors lead to a severe chronic inflammatory response. Clinical management of RA remains limited; therefore, exploring and discovering new mechanisms of action could enhance clinical benefits for patients with RA. Important bidirectional communication occurs between the brain and immune system in inflammatory diseases such as RA, and circulating immune complexes can cause neuroinflammatory responses in the brain. The gamma-aminobutyric acid (GABA)ergic system is a part of the nervous system that primarily comprises GABA, GABA-related receptors, and GABA transporter (GAT) systems. GABA is an inhibitory neurotransmitter that binds to GABA receptors in the presence of GATs to exert a variety of pathophysiological regulatory effects, with its predominant role being neural signaling. Nonetheless, the GABAergic system may also have immunomodulatory effects. GABA/GABA-A receptors may inhibit the progression of inflammation in RA and GATs may promote inflammation. GABA-B receptors may also act as susceptibility genes for RA, regulating the inflammatory response of RA via immune cells. Furthermore, the GABAergic system may modulate the abnormal pain response in RA patients. We also summarized the latest clinical applications of the GABAergic system and provided an outlook on its clinical application in RA. However, direct studies on the GABAergic system and RA are still lacking; therefore, we hope to provide potential therapeutic options and a theoretical basis for RA treatment by summarizing any potential associations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shan, Zhao, Zheng, Guo, Schrodi and He.)

Introduction: Homeodomain-interacting protein kinase 3 (HIPK3) plays an important role in cell proliferation, apoptosis, and inflammation. Over-expression of HIPK3 in immune cells in rheumatoid arthritis (RA) has been reported. In this study, we investigated blood methylation levels and clinical characteristics of RA in a Chinese population., Methods: A total of 235 patients with RA, 30 with osteoarthritis (OA), and 30 matched healthy controls were recruited. The methylation status of seven CpGs in the differentially methylated region of HIPK3 (cg05501357) was measured using targeted methylation-sequencing technology. The association between methylation haplotypes and the overall methylation status of HIPK3 with clinical characteristics was assessed using generalized linear regression., Results: All seven CpGs showed hypomethylation status in RA blood compared with OA and normal individuals (overall p= 1.143×10 -8 and FDR= 2.799×10 -7 ), which is consistent with the previously reported high expression of HIPK3 in RA immune cells. Among all seven CpGs, 33286785 showed the highest predictive power with an area under the curve (AUC) of 0.829; we received a higher AUC=0.864 when we combined HIPK3 with anti-citrullinated protein antibodies (ACPA -) and rheumatoid factor (RF +) in the prediction model, indicating that when a patient's ACPA is negative, HIPK3 can assist RF as a new clinical index for the diagnosis of RA. We also found that HIPK3 methylation levels were negatively correlated with C-reactive protein (CRP; r= -0.16, p= 0.01). Methylation haplotypes were analyzed, and the full methylation haplotype (FMH; r= 0.16, p= 0.01) and full non-methylation haplotype (FNH; r= 0.18, p= 0.0061) were negatively correlated with CRP., Conclusion: Circulating blood methylation levels in the protein region of HIPK3 can be utilized as a supportive diagnostic biomarker and CRP level indicator for RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jiang, Wei, Xu, Chang, Zhang, Zhao, Jin, Xu, Shi, Qian, Sun, Guo, Wang, Qin and He.)

Objectives: HTR2A is previously identified as a susceptibility gene for rheumatoid arthritis (RA). In this study, we performed the association analysis between DNA methylation of HTR2A with RA within peripheral blood samples., Methods: We enrolled peripheral blood samples from 235 patients with RA, 30 osteoarthritis (OA) patients, and 30 healthy controls. The DNA methylation levels of about 218 bp from chr13: 46898190 to chr13: 46897973 (GRCh38/hg38) around HTR2A cg15692052 from patients were analyzed by targeted methylation sequencing., Results: We measured methylation status for 7 CpGs in the promoter region of HTR2A and obseved overall methylation status are signficantly increased in RA compared with normal inviduals (FDR= 9.05 x 10 -5 ). The average cg15692052 methylation levels (methylation score) showed a positive correlation with CRP (r=0.15, P =0.023). Compared with the OA group or HC group, the proportion of haplotypes CCCCCCC ( FDR =0.02 and 2.81 x 10 -6 ) is signficantly increased while TTTTTCC ( FDR =0.01) and TTTTTTT( FDR =6.92 x 10 -3 ) are significantly decreased in RA. We find methylation haplotypes combining with RF and CCP could signficantly enhance the performance of the diagnosing RA and its comorbidities (hypertension, interstitial lung disease, and osteoporosis), especially in interstitial lung disease., Conclusions: In our study, we found signficant hypermethylation of promoter region of HTR2A which indicates the potential clinical diagnostic role in rheumatoid arthritis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Xu, Chang, Jiang, Wei, Shi, Xu, Zheng, Shan, Bian, Li, Guo, Schrodi, Wang and He.)

Rheumatoid arthritis (RA) is an autoimmune disease accompanied by metabolic alterations. The metabolic profiles of patients with RA can be determined using targeted and non-targeted metabolomics technology. Metabolic changes in glucose, lipid, and amino acid levels are involved in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, the arachidonic acid metabolic pathway, and amino acid metabolism. These alterations in metabolic pathways and metabolites can fulfill bio-energetic requirements, promote cell proliferation, drive inflammatory mediator secretion, mediate leukocyte infiltration, induce joint destruction and muscle atrophy, and regulate cell proliferation, which may reflect the etiologies of RA. Differential metabolites can be used as biomarkers for the diagnosis, prognosis, and risk prediction, improving the specificity and accuracy of diagnostics and prognosis prediction. Additionally, metabolic changes associated with therapeutic responses can improve the understanding of drug mechanism. Metabolic homeostasis and regulation are new therapeutic strategies for RA. In this review, we provide a comprehensive overview of advances in metabolomics for RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Chang, Jiang, Wei, Zhang, Jin, Zhao, Xu, Shi, Guo and He.)

Rheumatoid arthritis (RA) is an autoimmune disease that severely affects patients' physical and mental health, leading to chronic synovitis and destruction of bone joints. Although various available clinical treatment options exist, patients respond with varying efficacies due to multiple factors, and there is an urgent need to discover new treatment options to improve clinical outcomes. Cuproptosis is a newly characterized form of cell death. Copper causes cuproptosis by binding to lipid-acylated components of the tricarboxylic acid cycle, leading to protein aggregation, loss of iron-sulfur cluster proteins, and eventually proteotoxic stress. Targeting copper cytotoxicity and cuproptosis are considered potential options for treating oncological diseases. The synovial hypoxic environment and the presence of excessive glycolysis in multiple cells appear to act as inhibitors of cuproptosis, which can lead to excessive survival and proliferation of multiple immune cells, such as fibroblast-like synoviocytes, effector T cells, and macrophages, further mediating inflammation and bone destruction in RA. Therefore, in this study, we attempted to elaborate and summarize the linkage of cuproptosis and key genes regulating cuproptosis to the pathological mechanisms of RA and their effects on a variety of immune cells. This study aimed to provide a theoretical basis and support for translating preclinical and experimental results of RA to clinical protocols., (Copyright © 2022 Zhao, Guo, Schrodi and He.)

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint damage and even disability. Although there are various clinical therapies for RA, some patients still have poor or no response. Thus, the development of new drug targets remains a high priority. In this review, we discuss the role of G-protein-coupled receptors (GPCRs), including chemokine receptors, melanocortin receptors, lipid metabolism-related receptors, adenosine receptors, and other inflammation-related receptors, on mechanisms of RA, such as inflammation, lipid metabolism, angiogenesis, and bone destruction. Additionally, we summarize the latest clinical trials on GPCR targeting to provide a theoretical basis and guidance for the development of innovative GPCR-based clinical drugs for RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Wei, Jiang, Chang, Xu, Xu, Shi, Guo and He.)

Secreted frizzled-related protein 1 (SFRP1) is a member of secretory glycoprotein SFRP family. As a primitive gene regulating cell growth, development and transformation, SFRP1 is widely expressed in human cells, including various cancer cells and fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA). Deletion or silencing of SFRP1 involves epigenetic and other mechanisms, and participates in biological behaviors such as cell proliferation, migration and cell pyroptosis, which leads to disease progression and poor prognosis. In this review, we discuss the role of SFRP1 in the pathogenesis of RA-FLS and summarize different experimental platforms and recent research results. These are helpful for understanding the biological characteristics of SFRP1 in RA, especially the mechanism by which SFRP1 regulates RA-FLS pyroptosis through Wnt/β-catenin and Notch signaling pathways. In addition, the epigenetic regulation of SFRP1 in RA-FLS is emphasized, which may be considered as a promising biomarker and therapeutic target of RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2022 Jiang, Wei, Chang, Zhao, Zhang, Xu, Jin, Xu, Shi, Guo, Schrodi and He.)

Rheumatoid arthritis (RA), one of the most common immune system diseases, mainly affects middle-aged and elderly individuals and has a serious impact on the quality of life of patients. Pain and disability caused by RA are significant symptoms negatively affecting patients, and they are especially seen when inappropriate treatment is administered. Effective therapeutic strategies have evolved over the past few decades, with many new disease-modifying antirheumatic drugs (DMARDs) being used in the clinic. Owing to the breakthrough in the treatment of RA, the symptoms of patients who could not be treated effectively in the past few years have been relieved. However, some patients complain about symptoms that have not been reported, implying that there are still some limitations in the RA treatment and evaluation system. In recent years, biomarkers, an effective means of diagnosing and evaluating the condition of patients with RA, have gradually been used in clinical practice to evaluate the therapeutic effect of RA, which is constantly being improved for accurate application of treatment in patients with RA. In this article, we summarize a series of biomarkers that may be helpful in evaluating the therapeutic effect and improving the efficiency of clinical treatment for RA. These efforts may also encourage researchers to devote more time and resources to the study and application of biomarkers, resulting in a new evaluation system that will reduce the inappropriate use of DMARDs, as well as patients' physical pain and financial burden., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wei, Jiang, Zhao, Jin, Zhang, Chang, Xu, Xu, Shi, Guo and He.)

MicroRNAs (miRNAs) play crucial roles in regulating the transcriptome and development of rheumatoid arthritis (RA). Currently, a comprehensive map illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interactions with terminal cells such as fibroblast-like synoviocytes (FLS), immune-cells, osteoblasts, and osteoclasts are still laking. In this review, we summarize the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA and regulate target genes and pathways, including NF-κB, Fas-FasL, JAK-STAT, and mTOR pathways. We outline how functional genetic variants of miR-499 and miR-146a partly explain susceptibility to RA. By regulating gene expression, miRNAs affect T cell differentiation into diverse cell types, including Th17 and Treg cells, thus constituting promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the opportunity to combine these miRNAs with antibodies to cyclic citrullinated peptide (ACCP) to allow accurate diagnosis and prognosis, particularly for seronegative patients. Furthermore, we review the evidence implicating miRNAs as promising biomarkers of efficiency and response of, and resistance to, disease-modifying anti-rheumatic drugs and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chang, Xu, Zhang, Jin, Jiang, Wei, Xu, Shi, Zhao, Xiong, Guo and He.)

Rheumatoid arthritis (RA) is an autoimmune disease that can cause joint damage and disability. Epigenetic variation, especially DNA methylation, has been shown to be involved in almost all the stages of the pathology of RA, from autoantibody production to various self-effector T cells and the defects of protective T cells that can lead to chronic inflammation and erosion of bones and joints. Given the critical role of T cells in the pathology of RA, the regulatory functions of DNA methylation in T cell biology remain unclear. In this review, we elaborate on the relationship between RA pathogenesis and DNA methylation in the context of different T cell populations. We summarize the relevant methylation events in T cell development, differentiation, and T cell-related genes in disease prediction and drug efficacy. Understanding the epigenetic regulation of T cells has the potential to profoundly translate preclinical results into clinical practice and provide a framework for the development of novel, individualized RA therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Wei, Chang, Xu, Jiang, Guo, Schrodi and He.)

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases. Its leading features include chronic synovial inflammation and degeneration of the bones and joints. In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs). Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease. Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA. Its dysregulation in various associated cell types contributes to the development of RA. In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Jiang, Guo, Schrodi and He.)

Rheumatoid arthritis is an autoimmune disease that exhibits significant clinical heterogeneity. There are various treatments for rheumatoid arthritis, including disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), and inflammatory cytokine inhibitors (ICI), typically associated with differentiated clinical effects and characteristics. Personalized responsiveness is observed to the standard treatment due to the pathophysiological heterogeneity in rheumatoid arthritis, resulting in an overall poor prognosis. Understanding the role of individual variation in cellular and molecular mechanisms related to rheumatoid arthritis will considerably improve clinical care and patient outcomes. In this review, we discuss the source of pathophysiological heterogeneity derived from genetic, molecular, and cellular heterogeneity and their possible impact on precision medicine and personalized treatment of rheumatoid arthritis. We provide emphasized description of the heterogeneity derived from mast cells, monocyte cell, macrophage fibroblast-like synoviocytes and, interactions within immune cells and with inflammatory cytokines, as well as the potential as a new therapeutic target to develop a novel treatment approach. Finally, we summarize the latest clinical trials of treatment options for rheumatoid arthritis and provide a suggestive framework for implementing preclinical and clinical experimental results into clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Guo, Schrodi and He.)