Rheumatoid arthritis: pathogenesis and therapeutic advances

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the unresolved synovial inflammation for tissues-destructive consequence, which remains one of significant causes of disability and labor loss, affecting about 0.2–1% global population. Although treatments with disease-modifying antirheumatic drugs (DMARDs) are effective to control inflammation and decrease bone destruction, the overall remission rates of RA still stay at a low level. Therefore, uncovering the pathogenesis of RA and expediting clinical transformation are imminently in need. Here, we summarize the immunological basis, inflammatory pathways, genetic and epigenetic alterations, and metabolic disorders in RA, with highlights on the abnormality of immune cells atlas, epigenetics, and immunometabolism. Besides an overview of first-line medications including conventional DMARDs, biologics, and small molecule agents, we discuss in depth promising targeted therapies under clinical or preclinical trials, especially epigenetic and metabolic regulators. Additionally, prospects on precision medicine based on synovial biopsy or RNA-sequencing and cell therapies of mesenchymal stem cells or chimeric antigen receptor T-cell are also looked forward. The advancements of pathogenesis and innovations of therapies in RA accelerates the progress of RA treatments.

Keywords

cellular metabolism / epigenetics / pathogenesis / rheumatoid arthritis / therapy

References

1	RE Domen. The antiquity and origins of rheumatoid arthritis. JAMA. 1992;268(19):2649.
2	FJ Aceves-Avila, F Medina, A Fraga. The antiquity of rheumatoid arthritis: a reappraisal. J Rheumatol. 2001;28(4):751-757.
3	SS Yeap. Rheumatoid arthritis in paintings: a tale of two origins. Int J Rheum Dis. 2009;12(4):343-347.
4	R Jonsson. Erik Waaler (1903-1997): one of the founders of rheumatological immunology who discovered rheumatoid factor. Ann Rheum Dis. 2020;79(9):1141-1142.
5	EM Gravallese, DL Longo, GS Firestein. Rheumatoid arthritis–common origins, divergent mechanisms. N Engl J Med. 2023;388(6):529-542.
6	A Di Matteo, JM Bathon, P Emery. Rheumatoid arthritis. Lancet. 2023;402(10416):2019-2033.
7	MH Smith, JR Berman. What is rheumatoid arthritis? JAMA. 2022;327(12):1194.
8	N Komatsu, H Takayanagi. Mechanisms of joint destruction in rheumatoid arthritis—immune cell-fibroblast-bone interactions. Nat Rev Rheumatol. 2022;18(7):415-429.
9	W Grassi, R De Angelis, G Lamanna, C Cervini. The clinical features of rheumatoid arthritis. Eur J Radiol. 1998;27(1):S18-S24. Suppl.
10	MV Sokolova, G Schett, U Steffen. Autoantibodies in rheumatoid arthritis: historical background and novel findings. Clin Rev Allergy Immunol. 2022;63(2):138-151.
11	CY Wu, HY Yang, SF Luo, JH Lai. From rheumatoid factor to anti-citrullinated protein antibodies and anti-carbamylated protein antibodies for diagnosis and prognosis prediction in patients with rheumatoid arthritis. Int J Mol Sci. 2021;22(2):686.
12	A Conforti, I Di Cola, V Pavlych, et al. Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmun Rev. 2021;20(2):102735.
13	FA Figus, M Piga, I Azzolin, R McConnell, A Iagnocco. Rheumatoid arthritis: extra-articular manifestations and comorbidities. Autoimmun Rev. 2021;20(4):102776.
14	M Akiyama, Y Kaneko. Pathogenesis, clinical features, and treatment strategy for rheumatoid arthritis-associated interstitial lung disease. Autoimmun Rev. 2022;21(5):103056.
15	BN Weber, JT Giles, KP Liao. Shared inflammatory pathways of rheumatoid arthritis and atherosclerotic cardiovascular disease. Nat Rev Rheumatol. 2023;19(7):417-428.
16	A Finckh, B Gilbert, B Hodkinson, et al. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol. 2022;18(10):591-602.
17	GBD 2021 Rheumatoid Arthritis Collaborators. Global, regional, and national burden of rheumatoid arthritis, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5(10):e594-e610.
18	Association CR. 2018 Chinese guideline for the diagnosis and treatment of rheumatoid arthritis. Zhonghua Nei Ke Za Zhi. 2018;57(4):242-251.
19	PH Hsieh, O Wu, C Geue, E McIntosh, IB McInnes, S Siebert. Economic burden of rheumatoid arthritis: a systematic review of literature in biologic era. Ann Rheum Dis. 2020;79(6):771-777.
20	CS Lau. Burden of rheumatoid arthritis and forecasted prevalence to 2050. Lancet Rheumatol. 2023;5(10):e567-e568.
21	D Zhu, W Song, Z Jiang, H Zhou, S Wang. Citrullination: a modification important in the pathogenesis of autoimmune diseases. Clin Immunol. 2022;245:109134.
22	C Ge, R Holmdahl. The structure, specificity and function of anti-citrullinated protein antibodies. Nat Rev Rheumatol. 2019;15(8):503-508.
23	F Apel, A Zychlinsky, EF Kenny. The role of neutrophil extracellular traps in rheumatic diseases. Nat Rev Rheumatol. 2018;14(8):467-475.
24	C Carmona-Rivera, PM Carlucci, E Moore, et al. Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol. 2017;2(10):eaag3358.
25	MAM van Delft, TWJ Huizinga. An overview of autoantibodies in rheumatoid arthritis. J Autoimmun. 2020;110:102392.
26	CM Weyand, JJ Goronzy. Ectopic germinal center formation in rheumatoid synovitis. Ann N Y Acad Sci. 2003;987:140-149.
27	Y Kondo, M Yokosawa, S Kaneko, et al. Review: transcriptional regulation of CD4+ T cell differentiation in experimentally induced arthritis and rheumatoid arthritis. Arthritis Rheumatol. 2018;70(5):653-661.
28	FM Brennan, AL Hayes, CJ Ciesielski, et al. Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells: involvement of phosphatidylinositol 3-kinase and nuclear factor kappaB pathways in tumor necrosis factor alpha production in rheumatoid arthritis. Arthritis Rheum. 2002;46(1):31-41.
29	AH Jonsson, F Zhang, G Dunlap, et al. Granzyme K+CD8 T cells form a core population in inflamed human tissue. Sci Transl Med. 2022;14(649):eabo0686.
30	DA Rao, MF Gurish, JL Marshall, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542(7639):110-114.
31	F Wu, J Gao, J Kang, et al. B cells in rheumatoid arthritis: pathogenic mechanisms and treatment prospects. Front in Immunol. 2021;12:750753.
32	HU Scherer, D van der Woude, REM Toes. From risk to chronicity: evolution of autoreactive B cell and antibody responses in rheumatoid arthritis. Nat Rev Rheumatol. 2022;18(7):371-383.
33	N Meednu, J Rangel-Moreno, F Zhang, et al. Dynamic spectrum of ectopic lymphoid B cell activation and hypermutation in the RA synovium characterized by NR4A nuclear receptor expression. Cell Rep. 2022;39(5):110766.
34	Y Qin, ML Cai, HZ Jin, et al. Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways. Ann Rheum Dis. 2022;81(11):1504-1514.
35	H Yamanaka. TNF as a target of inflammation in rheumatoid arthritis. Endocr Metab Immune Disord Drug Targets. 2015;15(2):129-134.
36	C Gabay, C Lamacchia, G Palmer. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010;6(4):232-241.
37	F Pandolfi, L Franza, V Carusi, S Altamura, G Andriollo, E Nucera. Interleukin-6 in rheumatoid arthritis. Int J Mol Sci. 2020;21(15):5238.
38	LS Taams. Interleukin-17 in rheumatoid arthritis: trials and tribulations. J Exp Med. 2020;217(3):e20192048.
39	N Kondo, T Kuroda, D Kobayashi. Cytokine networks in the pathogenesis of rheumatoid arthritis. Int J Mol Sci. 2021;22(20):10922.
40	G Nygaard, GS Firestein. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat Rev Rheumatol. 2020;16(6):316-333.
41	MA Boutet, G Courties, A Nerviani, et al. Novel insights into macrophage diversity in rheumatoid arthritis synovium. Autoimmun Rev. 2021;20(3):102758.
42	D Kuo, J Ding, IS Cohn, et al. HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness. Sci Transl Med. 2019;11(491):eaau8587.
43	T Hasegawa, J Kikuta, T Sudo, et al. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nat Immunol. 2019;20(12):1631-1643.
44	B Cai, C Kasikara, AC Doran, R Ramakrishnan, RB Birge, I Tabas. MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci Signal. 2018;11(549):eaar3721.
45	S Culemann, A Grüneboom, Já Nicolás-ávila, et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature. 2019;572(7771):670-675.
46	L Zeng, K Yang, T Zhang, et al. Research progress of single-cell transcriptome sequencing in autoimmune diseases and autoinflammatory disease: a review. J Autoimmun. 2022;133:102919.
47	C Tsai, LA Diaz, NG Singer, et al. Responsiveness of human T lymphocytes to bacterial superantigens presented by cultured rheumatoid arthritis synoviocytes. Arthritis Rheum. 1996;39(1):125-136.
48	K Wei, I Korsunsky, JL Marshall, et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020;582(7811):259-264.
49	DE Orange, V Yao, K Sawicka, et al. RNA identification of PRIME cells predicting rheumatoid arthritis flares. N Engl J Med. 2020;383(3):218-228.
50	CJ Malemud. The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2018;10(5-6):117-127.
51	JH Ju, YJ Heo, ML Cho, et al. Modulation of STAT-3 in rheumatoid synovial T cells suppresses Th17 differentiation and increases the proportion of Treg cells. Arthritis Rheum. 2012;64(11):3543-3552.
52	N Lu, CJ Malemud. Extracellular signal-regulated kinase: a regulator of cell growth, inflammation, chondrocyte and bone cell receptor-mediated gene expression. Int J Mol Sci. 2019;20(15):3792.
53	SS Nah, HJ Won, E Ha, et al. Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis. Rheumatol Int. 2010;30(4):443-449.
54	YP Lin, CC Su, JY Huang, et al. Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas-mediated apoptosis in T cells: implications for rheumatoid arthritis. Mol Immunol. 2009;46(16):3328-3335.
55	S Liu, H Ma, H Zhang, C Deng, P Xin. Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis. Clin Immunol. 2021;230:108793.
56	DV Novack. Role of NF-κB in the skeleton. Cell Res. 2010;21(1):169-182.
57	S Rabelo Fde, LM da Mota, RA Lima, et al. The Wnt signaling pathway and rheumatoid arthritis. Autoimmun Rev. 2010;9(4):207-210.
58	Y Zhuang, W Lu, W Chen, Y Wu, Q Wang, Y Liu. A narrative review of the role of the Notch signaling pathway in rheumatoid arthritis. Ann Transl Med. 2022;10(6):371.
59	T Frisell, S Saevarsdottir, J Askling. Family history of rheumatoid arthritis: an old concept with new developments. Nat Rev Rheumatol. 2016;12(6):335-343.
60	R Busch, S Kollnberger, ED Mellins. HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications. Nat Rev Rheumatol. 2019;15(6):364-381.
61	PK Gregersen, J Silver, RJ Winchester. The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30(11):1205-1213.
62	X Hu, AJ Deutsch, TL Lenz, et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat Genet. 2015;47(8):898-905.
63	J Guo, T Zhang, H Cao, et al. Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population. Ann Rheum Dis. 2019;78(6):773-780.
64	AB Begovich, VE Carlton, LA Honigberg, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75(2):330-337.
65	RM Plenge, L Padyukov, EF Remmers, et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet. 2005;77(6):1044-1060.
66	A Suzuki, R Yamada, X Chang, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34(4):395-402.
67	T Iwamoto, K Ikari, T Nakamura, et al. Association between PADI4 and rheumatoid arthritis: a meta-analysis. Rheumatology (Oxford). 2006;45(7):804-807.
68	WTCC Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661-678.
69	EA Stahl, S Raychaudhuri, EF Remmers, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42(6):508-514.
70	S Eyre, J Bowes, D Diogo, et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44(12):1336-1340.
71	K Ishigaki, S Sakaue, C Terao, et al. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis. Nat Genet. 2022;54(11):1640-1651.
72	Y Shirai, Y Nakanishi, A Suzuki, et al. Multi-trait and cross-population genome-wide association studies across autoimmune and allergic diseases identify shared and distinct genetic component. Ann Rheum Dis. 2022;81(9):1301-1312.
73	H Kallberg, L Padyukov, RM Plenge, et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet. 2007;80(5):867-875.
74	Y Okada, D Wu, G Trynka, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376-381.
75	RM Plenge, M Seielstad, L Padyukov, et al. TRAF1–C5as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J Med. 2007;357(12):1199-1209.
76	D Plant, E Flynn, H Mbarek, et al. Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers. Ann Rheum Dis. 2010;69(8):1548-1553.
77	O Khalifa, YM Pers, R Ferreira, et al. X-linked miRNAs associated with gender differences in rheumatoid arthritis. Int J Mol Sci. 2016;17(11):1852.
78	A Paradowska-Gorycka, E Wojtecka-Lukasik, J Trefler, B Wojciechowska, JK Lacki, S Maslinski. Association between IL-17F gene polymorphisms and susceptibility to and severity of rheumatoid arthritis (RA). Scand J Immunol. 2010;72(2):134-141.
79	S Ramírez-Pérez, M Salazar-Páramo, S Pineda-Monjarás, et al. Association of 86 bp variable number of tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL1RN) with susceptibility and clinical activity in rheumatoid arthritis. Clin Rheumatol. 2017;36(6):1247-1252.
80	H Cen, H Huang, LN Zhang, et al. Associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with genetic susceptibility to rheumatoid arthritis: a meta-analysis. Clin Rheumatol. 2016;36(2):287-297.
81	M Ponomarenko, D Rasskazov, O Arkova, et al. How to use SNP_TATA_Comparator to find a significant change in gene expression caused by the regulatory SNP of this gene's promoter via a change in affinity of the TATA-binding protein for this promoter. Biomed Res Int. 2015;2015:359835.
82	C Potter, HJ Cordell, A Barton, et al. Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways. Ann Rheum Dis. 2010;69(7):1315-1320.
83	Y Okada, C Terao, K Ikari, et al. Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat Genet. 2012;44(5):511-516.
84	ZJ Feng, SL Zhang, HF Wen, Y Liang. Association of rs2075876 polymorphism of AIRE gene with rheumatoid arthritis risk. Hum Immunol. 2015;76(4):281-285.
85	G Orozco, S Eyre, A Hinks, et al. Association of CD40 with rheumatoid arthritis confirmed in a large UK case-control study. Ann Rheum Dis. 2010;69(5):813-816.
86	L Jiang, J Yin, L Ye, et al. Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans. Arthritis Rheumatol. 2014;66(5):1121-1132.
87	SV Hoegh, HM Lindegaard, GL Sorensen, et al. Circulating surfactant protein D is decreased in early rheumatoid arthritis: a 1-year prospective study. Scand J Immunol. 2008;67(1):71-76.
88	JS Smolen, D Aletaha, A Barton, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001.
89	H K?llberg, B Ding, L Padyukov, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 2011;70(3):508-511.
90	K Yamamoto, Y Okada, A Suzuki, Y Kochi. Genetics of rheumatoid arthritis in Asia—present and future. Nat Rev Rheumatol. 2015;11(6):375-379.
91	K Lundberg, N Wegner, T Yucel-Lindberg, PJ Venables. Periodontitis in RA—the citrullinated enolase connection. Nat Rev Rheumatol. 2010;6(12):727-730.
92	XF Li, S Wu, Q Yan, et al. PTEN methylation promotes inflammation and activation of fibroblast-like synoviocytes in rheumatoid arthritis. Front Pharmacol. 2021;12:700373.
93	X Xu, L Zheng, Q Bian, et al. Aberrant activation of TGF-β in subchondral bone at the onset of rheumatoid arthritis joint destruction. J Bone Miner Res. 2015;30(11):2033-2043.
94	K Nakano, JW Whitaker, DL Boyle, W Wang, GS Firestein. DNA methylome signature in rheumatoid arthritis. Ann Rheum Dis. 2013;72(1):110-117.
95	AP Cribbs, A Kennedy, H Penn, et al. Methotrexate restores regulatory T cell function through demethylation of the FoxP3 upstream enhancer in patients with rheumatoid arthritis. Arthritis Rheumatol. 2015;67(5):1182-1192.
96	Y Zhang, Y Gao, Y Ding, et al. Targeting KAT2A inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming. MedComm. 2023;4(3):e306.
97	W Jia, W Wu, D Yang, et al. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis. The FASEB Journal. 2018;32(7):4031-4042.
98	M Xia, J Liu, X Wu, et al. Histone methyltransferase Ash1l suppresses interleukin-6 production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20. Immunity. 2013;39(3):470-481.
99	YK Zhang, Y Gao, Y Jiang, et al. Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription. Cell Death Differ. 2023;30(5):1279-1292.
100	M Trenkmann, M Brock, RE Gay, et al. Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis. Ann Rheum Dis. 2011;70(8):1482-1488.
101	KH Park-Min, E Lim, MJ Lee, et al. Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation. Nat Commun. 2014;5:5418.
102	N Saeki, K Inoue, M Ideta-Otsuka, et al. Epigenetic regulator UHRF1 orchestrates proinflammatory gene expression in rheumatoid arthritis in a suppressive manner. J Clin Invest. 2022;132(11):e150533.
103	Y Yin, X Yang, S Wu, et al. Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis. Nat Immunol. 2022;23(9):1342-1354.
104	M Yan, N Komatsu, R Muro, et al. ETS1 governs pathological tissue-remodeling programs in disease-associated fibroblasts. Nat Immunol. 2022;23(9):1330-1341.
105	I Mitxitorena, D Somma, JP Mitchell, et al. The deubiquitinase USP7 uses a distinct ubiquitin-like domain to deubiquitinate NF-?B subunits. J Biol Chem. 2020;295(33):11754-11763.
106	X Zhang, X Li, H Jia, G An, J Ni. The m6A methyltransferase METTL3 modifies PGC-1α mRNA promoting mitochondrial dysfunction and oxLDL-induced inflammation in monocytes. J Biol Chem. 2021;297(3):101058.
107	J Tang, Z Yu, J Xia, et al. METTL14-mediated m6A modification of TNFAIP3 involved in inflammation in patients with active rheumatoid arthritis. Arthritis Rheumatol. 2023;75(12):2116-2129.
108	Y Kuang, R Li, J Wang, et al. ALKBH5-mediated RNA m6A methylation regulates the migration, invasion and proliferation of rheumatoid fibroblast-like synoviocytes. Arthritis Rheumatol. 2024;76(2):192-205.
109	RR Jadhav, B Hu, Z Ye, et al. Reduced chromatin accessibility to CD4 T cell super-enhancers encompassing susceptibility loci of rheumatoid arthritis. EBioMedicine. 2022;76:103825.
110	H Zhao, H Wang, Y Qin, et al. CCCTC-binding factor: the specific transcription factor of β-galactoside α-2,6-sialyltransferase 1 that upregulates the sialylation of anti-citrullinated protein antibodies in rheumatoid arthritis. Rheumatology (Oxford). 2023:kead282.
111	Q Zhou, Y Zhang, B Wang, et al. KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling. Cell Mol Immunol. 2020;17(8):834-842.
112	N Petryk, S Bultmann, T Bartke, PA Defossez. Staying true to yourself: mechanisms of DNA methylation maintenance in mammals. Nucleic Acids Res. 2021;49(6):3020-3032.
113	LD Moore, T Le, G Fan. DNA methylation and its basic function. Neuropsychopharmacology. 2012;38(1):23-38.
114	A Corvetta, R Della Bitta, MM Luchetti, G Pomponio. 5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases. J Chromatogr. 1991;566(2):481-491.
115	CJ Nile, RC Read, M Akil, GW Duff, AG Wilson. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 2008;58(9):2686-2693.
116	AP Cribbs, A Kennedy, H Penn, et al. Treg cell function in rheumatoid arthritis is compromised by ctla-4 promoter methylation resulting in a failure to activate the indoleamine 2,3-dioxygenase pathway. Arthritis Rheumatol. 2014;66(9):2344-2354.
117	C Calle-Fabregat, E Niemantsverdriet, JD Ca?ete, et al. Prediction of the progression of undifferentiated arthritis to rheumatoid arthritis using DNA methylation profiling. Arthritis Rheumatol. 2021;73(12):2229-2239.
118	Y Liu, MJ Aryee, L Padyukov, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31(2):142-147.
119	L de la Rica, JM Urquiza, D Gómez-Cabrero, et al. Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. J Autoimmun. 2013;41:6-16.
120	JW Whitaker, R Shoemaker, DL Boyle, et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 2013;5(4):40.
121	E Karouzakis, RE Gay, BA Michel, S Gay, M Neidhart. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol. 2009;60(12):3613-3622.
122	G Millán-Zambrano, A Burton, AJ Bannister, R Schneider. Histone post-translational modifications-cause and consequence of genome function. Nat Rev Genet. 2022;23(9):563-580.
123	Y Li, M Zhou, X Lv, et al. Reduced activity of HDAC3 and increased acetylation of histones H3 in peripheral blood mononuclear cells of patients with rheumatoid arthritis. J Immunol Res. 2018;2018:1-10.
124	LC Huber, M Brock, H Hemmatazad, et al. Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum. 2007;56(4):1087-1093.
125	T Kawabata, K Nishida, K Takasugi, et al. Increased activity and expression of histone deacetylase 1 in relation to tumor necrosis factor-alpha in synovial tissue of rheumatoid arthritis. Arthritis Res Ther. 2010;12(4):R133.
126	S Hawtree, MWilson Muthana, G Anthony. The role of histone deacetylases in rheumatoid arthritis fibroblast-like synoviocytes. Biochem Soc Trans. 2013;41(3):783-788.
127	Y Araki, Y Aizaki, K Sato, H Oda, R Kurokawa, T Mimura. Altered gene expression profiles of histone lysine methyltransferases and demethylases in rheumatoid arthritis synovial fibroblasts. Clin Exp Rheumatol. 2018;36(2):314-316.
128	W Wu, M Qin, W Jia, et al. Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis. Cell Mol Immunol. 2018;16(8):694-705.
129	XY Xiao, YT Li, X Jiang, et al. EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis. J Autoimmun. 2020;108:102404.
130	R Ai, T Laragione, D Hammaker, et al. Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun. 2018;9(1):1921.
131	T Nakasa, S Miyaki, A Okubo, et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheumatol. 2008;58(5):1284-1292.
132	J Stanczyk, C Ospelt, E Karouzakis, et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheumatol. 2011;63(2):373-381.
133	N Mu, JT Gu, TL Huang, et al. Blockade of discoidin domain receptor 2 as a strategy for reducing inflammation and joint destruction in rheumatoid arthritis via altered interleukin-15 and Dkk-1 signaling in fibroblast-like synoviocytes. Arthritis Rheumatol. 2020;72(6):943-956.
134	Y Wang, L Hou, X Yuan, et al. LncRNA NEAT1 targets fibroblast-like synoviocytes in rheumatoid arthritis via the miR-410-3p/YY1 axis. Front Immunol. 2020;11:1975.
135	Y Rao, Y Fang, W Tan, et al. Delivery of long non-coding RNA NEAT1 by peripheral blood monouclear cells-derived exosomes promotes the occurrence of rheumatoid arthritis via the MicroRNA-23a/MDM2/SIRT6 axis. Front Cell Dev Biol. 2020;8:551681.
136	S Zhong, Q Ouyang, D Zhu, et al. Hsa_circ_0088036 promotes the proliferation and migration of fibroblast-like synoviocytes by sponging miR-140-3p and upregulating SIRT 1 expression in rheumatoid arthritis. Mol Immunol. 2020;125:131-139.
137	J Yang, M Cheng, B Gu, J Wang, S Yan, D Xu. CircRNA_09505 aggravates inflammation and joint damage in collagen-induced arthritis mice via miR-6089/AKT1/NF-κB axis. Cell Death Dis. 2020;11(10):833.
138	CM Weyand, JJ Goronzy. Immunometabolism in early and late stages of rheumatoid arthritis. Nat Rev Rheumatol. 2017;13(5):291-301.
139	CM Weyand, JJ Goronzy. Immunometabolism in the development of rheumatoid arthritis. Immunol Rev. 2020;294(1):177-187.
140	PG de Oliveira, M Farinon, E Sanchez-Lopez, S Miyamoto, M Guma. Fibroblast-like synoviocytes glucose metabolism as a therapeutic target in rheumatoid arthritis. Front Immunol. 2019;10:1743.
141	B Wu, TV Zhao, K Jin, et al. Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation. Nat Immunol. 2021;22(12):1551-1562.
142	CM McGrath, SP Young. Lipid and metabolic changes in rheumatoid arthritis. Curr Rheumatol Rep. 2015;17(9):57.
143	Q Lei, J Yang, L Li, et al. Lipid metabolism and rheumatoid arthritis. Front Immunol. 2023;14:1190607.
144	G Robinson, I Pineda-Torra, C Ciurtin, EC Jury. Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies. J Clin Invest. 2022;132(2):e148552.
145	FM Sladek. What are nuclear receptor ligands? Mol Cell Endocrinol. 2011;334(1-2):3-13.
146	KW Frommer, A Sch?ffler, S Rehart, A Lehr, U Müller-Ladner, E Neumann. Free fatty acids: potential proinflammatory mediators in rheumatic diseases. Ann Rheum Dis. 2015;74(1):303-310.
147	ZK Chen, HS Lv, J Jiang. LTB4 can stimulate human osteoclast differentiation dependent of RANKL. Artif Cells Blood Substit Immobil Biotechnol. 2010;38(1):52-56.
148	HJ Kim, B Ohk, HJ Yoon, et al. Docosahexaenoic acid signaling attenuates the proliferation and differentiation of bone marrow-derived osteoclast precursors and promotes apoptosis in mature osteoclasts. Cell Signal. 2017;29:226-232.
149	E Panfili, R Gerli, U Grohmann, MT Pallotta. Amino acid metabolism in rheumatoid arthritis: friend or foe? Biomolecules. 2020;10(9):1280.
150	AE Papathanassiu, JH Ko, M Imprialou, et al. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. Nat Commun. 2017;8:16040.
151	LO Tykocinski, AM Lauffer, A Bohnen, et al. Synovial fibroblasts selectively suppress Th1 cell responses through IDO1-mediated tryptophan catabolism. J Immunol. 2017;198(8):3109-3117.
152	NT Nguyen, T Nakahama, T Kishimoto. Aryl hydrocarbon receptor and experimental autoimmune arthritis. Semin Immunopathol. 2013;35(6):637-644.
153	CD Mills. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol. 2012;32(6):463-488.
154	JS Smolen, RBM Landewé, SA Bergstra, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18.
155	Z Zhao, Z Hua, X Luo, et al. Application and pharmacological mechanism of methotrexate in rheumatoid arthritis. Biomed Pharmacother. 2022;150:113074.
156	G Smedeg?rd, J Bj?rk. Sulphasalazine: mechanism of action in rheumatoid arthritis. Br J Rheumatol. 1995;34(2):7-15. Suppl.
157	E Schrezenmeier, T D?rner. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-166.
158	RI Fox, ML Herrmann, CG Frangou, et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin Immunol. 1999;93(3):198-208.
159	SM Naguwa. Tumor necrosis factor inhibitor therapy for rheumatoid arthritis. Ann N Y Acad Sci. 2005;1051:709-715.
160	D Tracey, L Klareskog, EH Sasso, JG Salfeld, PP Tak. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244-279.
161	K Chaabo, B Kirkham. Rheumatoid Arthritis—Anti-TNF. Int Immunopharmacol. 2015;27(2):180-184.
162	H Mitoma, T Horiuchi, H Tsukamoto, N Ueda. Molecular mechanisms of action of anti-TNF-α agents-Comparison among therapeutic TNF-α antagonists. Cytokine. 2018;101:56-63.
163	T Tanaka, M Narazaki, T Kishimoto. Interleukin (IL-6) immunotherapy. Cold Spring Harb Perspect Biol. 2018;10(8):a028456.
164	EH Choy, F De Benedetti, T Takeuchi, M Hashizume, MR John, T Kishimoto. Translating IL-6 biology into effective treatments. Nat Rev Rheumatol. 2020;16(6):335-345.
165	TW Huizinga, RM Fleischmann, M Jasson, et al. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014;73(9):1626-1634.
166	JL Barnas, RJ Looney, JH Anolik. B cell targeted therapies in autoimmune disease. Curr Opin Immunol. 2019;61:92-99.
167	MA Lopez-Olivo, M Amezaga Urruela, L McGahan, EN Pollono, ME Suarez-Almazor. Rituximab for rheumatoid arthritis. Cochrane Database Syst Rev. 2015;1:CD007356.
168	V Reddy, LN Dahal, MS Cragg, M Leandro. Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer? Drug Discov Today. 2016;21(8):1330-1338.
169	M Bonelli, C Scheinecker. How does abatacept really work in rheumatoid arthritis? Curr Opin Rheumatol. 2018;30(3):295-300.
170	HA Blair, ED Deeks. Abatacept: a review in rheumatoid arthritis. Drugs. 2017;77(11):1221-1233.
171	P Mohammadi, M Hesari, M Chalabi, F Salari, F Khademi. An overview of immune checkpoint therapy in autoimmune diseases. Int Immunopharmacol. 2022;107:108647.
172	Y Tanaka, Y Luo, JJ O'Shea, S Nakayamada. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol. 2022;18(3):133-145.
173	KL Winthrop, SB Cohen. Oral surveillance and JAK inhibitor safety: the theory of relativity. Nat Rev Rheumatol. 2022;18(5):301-304.
174	DP McLornan, JE Pope, J Gotlib, CN Harrison. Current and future status of JAK inhibitors. Lancet. 2021;398(10302):803-816.
175	LI Sakkas, A Mavropoulos, DP Bogdanos. Phosphodiesterase 4 inhibitors in immune-mediated diseases: mode of action, clinical applications, current and future perspectives. Curr Med Chem. 2017;24(28):3054-3067.
176	L Crocetti, G Floresta, A Cilibrizzi, MP Giovannoni. An overview of PDE4 inhibitors in clinical trials: 2010 to early 2022. Molecules. 2022;27(15):4964.
177	P Miossec, JK Kolls. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov. 2012;11(10):763-776.
178	T Pérez-Jeldres, M Alvarez-Lobos, J Rivera-Nieves. Targeting sphingosine-1-phosphate signaling in immune-mediated diseases: beyond multiple sclerosis. Drugs. 2021;81(9):985-1002.
179	N Burg, JE Salmon, T Hla. Sphingosine 1-phosphate receptor-targeted therapeutics in rheumatic diseases. Nat Rev Rheumatol. 2022;18(6):335-351.
180	M Bigaud, Z Dincer, B Bollbuck, et al. Pathophysiological consequences of a break in S1P1-dependent homeostasis of vascular permeability revealed by S1P1 competitive antagonism. PLoS One. 2016;11(12):e0168252.
181	JT Bagdanoff, MS Donoviel, A Nouraldeen, et al. Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932). J Med Chem. 2010;53(24):8650-8662.
182	J Tuttle, E Drescher, JA Simón-Campos, et al. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. N Engl J Med. 2023;388(20):1853-1862.
183	C Gabay, B Fautrel, J Rech, et al. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease. Ann Rheum Dis. 2018;77(6):840-847.
184	F Behrens, PP Tak, M ?stergaard, et al. MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial. Ann Rheum Dis. 2015;74(6):1058-1064.
185	M Galeazzi, L Bazzichi, GD Sebastiani, et al. A phase IB clinical trial with Dekavil (F8-IL10), an immunoregulatory ‘armed antibody’ for the treatment of rheumatoid arthritis, used in combination wiIh methotrexate. Isr Med Assoc J. 2014;16(10):666.
186	Y Tanaka, T Takeuchi, H Yamanaka, et al. Long-term safety and efficacy of E6011, an anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis inadequately responding to methotrexate. Mod Rheumatol. 2023;34(1):37-44.
187	Y Li, F Ramírez-Valle, Y Xue, et al. Population pharmacokinetics and exposure response assessment of CC-292, a potent BTK inhibitor, in patients with chronic lymphocytic leukemia. J Clin Pharmacol. 2017;57(10):1279-1289.
188	A Winkler, W Sun, S De, et al. The interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 blocks inflammation in preclinical models of rheumatic disease and in humans enrolled in a randomized clinical trial. Arthritis Rheumatol. 2021;73(12):2206-2218.
189	DM Tóth, T Ocskó, A Balog, et al. Amelioration of autoimmune arthritis in mice treated with the DNA methyltransferase inhibitor 5'-azacytidine. Arthritis Rheumatol. 2019;71(8):1265-1275.
190	GH Yang, C Zhang, N Wang, Y Meng, YS Wang. Anacardic acid suppresses fibroblast-like synoviocyte proliferation and invasion and ameliorates collagen-induced arthritis in a mouse model. Cytokine. 2018;111:350-356.
191	Z Zhao, Y Zhang, D Gao, et al. Inhibition of histone H3 lysine-27 demethylase activity relieves rheumatoid arthritis symptoms via repression of IL6 transcription in macrophages. Front Immunol. 2022;13:818070.
192	L G?schl, T Preglej, N Boucheron, et al. Histone deacetylase 1 (HDAC1): a key player of T cell-mediated arthritis. J Autoimmun. 2020;108:102379.
193	J Fri??i?, C Reinwald, M B?ttcher, et al. Reset of inflammatory priming of joint tissue and reduction of the severity of arthritis flares by bromodomain inhibition. Arthritis Rheumatol. 2023;75(4):517-532.
194	H Wang, T Li, S Chen, Y Gu, S Ye. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 2015;67(12):3190-3200.
195	TLW Muskardin, JL Paredes, S Appenzeller, TB Niewold. Lessons from precision medicine in rheumatology. Mult Scler. 2020;26(5):533-539.
196	JS Smolen, P Emery, GF Ferraccioli, et al. Certolizumab pegol in rheumatoid arthritis patients with low to moderate activity: the CERTAIN double-blind, randomised, placebo-controlled trial. Ann Rheum Dis. 2015;74(5):843-850.
197	R Klaasen, CA Wijbrandts, DM Gerlag, PP Tak. Body mass index and clinical response to infliximab in rheumatoid arthritis. Arthritis Rheum. 2011;63(2):359-364.
198	KL Hyrich, KD Watson, AJ Silman, DP Symmons. British Society for Rheumatology Biologics Register. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford). 2006;45(12):1558-1565.
199	TLW Muskardin, P Vashisht, JM Dorschner, et al. Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis. Ann Rheum Dis. 2016;75(10):1757-1762.
200	Jr Dennis G, CT Holweg, SK Kummerfeld, et al. Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics. Arthritis Res Ther. 2014;16(2):R90.
201	F Rivellese, AEA Surace, K Goldmann, et al. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial. Nat Med. 2022;28(6):1256-1268.
202	F Humby, P Durez, MH Buch, et al. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial. Lancet. 2021;397(10271):305-317.
203	M Lopez-Santalla, JA Bueren, MI Garin. Mesenchymal stem/stromal cell-based therapy for the treatment of rheumatoid arthritis: an update on preclinical studies. EBioMedicine. 2021;69:103427.
204	D Mougiakakos, G Kr?nke, S V?lkl, et al. CD19-targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med. 2021;385(6):567-569.
205	B Zhang, Y Wang, Y Yuan, et al. In vitro elimination of autoreactive B cells from rheumatoid arthritis patients by universal chimeric antigen receptor T cells. Ann Rheum Dis. 2021;80(2):176-184.