Abstract
Rheumatoid arthritis is a systemic chronic polyarticular autoimmune disorder of joints and joint membrane mainly affecting feet and hands. The pathological manifestation of the disease includes infiltration of immune cells, hyperplasia of the lining of synovium, formation of pannus and bone and cartilage destruction. If left untreated, the appearance of small focal necrosis, adhesion of granulation, and formation of fibrous tissue on the surface of articular cartilage is noted. The disease primarily affects nearly 1% of the population globally, women being more affected than men with a ratio 2:1 and can initiate regardless of any age. The synovial fibroblast in rheumatoid arthritis individuals exhibits an aggressive phenotype which upregulates the manifestation of protooncogenes, adhesive compounds, inflammatory cytokines and matrix-deteriorating enzymes. Apart from the inflammatory effects of cytokines, chemokines are also noted to induce swelling and pain in arthritic individuals by residing in synovial membrane and forming pannus. The current treatment of rheumatoid arthritis includes treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, treatment with biologics such as inhibitors of TNF-α, interleukins, platelet activating factor, etc. which provides significant relief from symptoms and aids in management of the disease. The current review highlights the pathogenesis involved in the onset of rheumatoid arthritis and also covers epigenetic, cellular and molecular parameters associated with it to aid better and advanced therapeutic approaches for management of the debilitating disease.
Graphical abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Not applicable.
References
Araki Y, Mimura T (2017) The histone modification code in the pathogenesis of autoimmune diseases. Mediators Inflamm. https://doi.org/10.1155/2017/2608605
Araki Y, Mimura T (2017) Matrix metalloproteinase gene activation resulting from disordred epigenetic mechanisms in rheumatoid arthritis. Int J Mol Sci 18:18. https://doi.org/10.3390/ijms18050905
Atzeni F, Nucera V, Masala IF et al (2019) Il-6 Involvement in pain, fatigue and mood disorders in rheumatoid arthritis and the effects of Il-6 inhibitor sarilumab. Pharmacol Res 149:149. https://doi.org/10.1016/j.phrs.2019.104402
Ballestar E (2011) Epigenetic alterations in autoimmune rheumatic diseases. Nat Rev Rheumatol 7:263–271. https://doi.org/10.1038/nrrheum.2011.16
Barik RR, Bhatt LK (2021) Emerging epigenetic targets in rheumatoid arthritis. Rheumatol Int 41:2047–2067. https://doi.org/10.1007/s00296-021-04951-y
Bauerová K, Bezek Š (1999) Role of reactive oxygen and nitrogen species in etiopathogenesis of rheumatoid arthritis. Gen Physiol Biophys 18:15–20
Bazan NG, Colangelo V, Lukiw WJ (2002) Prostaglandins and other lipid mediators in Alzheimer’s disease. Prostaglandins Other Lipid Mediat 68–69:197–210. https://doi.org/10.1016/S0090-6980(02)00031-X
Behl T, Makkar R, Arora S (2021a) Exploring the effect of Terminalia catappa fruit extract in rheumatoid arthritis: an evaluation of behavioural, hematologiocal and histopathological parameters. Endocr Metab Immune Disord Drug Targets 21:1073–1082. https://doi.org/10.2174/1871530320666200825191804
Behl T, Upadhyay T, Singh S et al (2021b) Polyphenols targeting MAPK mediated oxidative stress and inflammation in rheumatoid arthritis. Molecules 26:6570. https://doi.org/10.3390/molecules26216570
Bottini N, Firestein GS (2013) Epigenetics in rheumatoid arthritis: a primer for rheumatologists. Curr Rheumatol Rep 15:1. https://doi.org/10.1007/s11926-013-0372-9
Brennan FM, Hayes AL, Ciesielski CJ et al (2002) Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells: Involvement of phosphatidylinositol 3-kinase and nuclear factor κB pathways in tumor necrosis factor α production in rheumatoid arthritis. Arthritis Rheum 46:31–41. https://doi.org/10.1002/1529-0131(200201)46:1%3c31::AID-ART10029%3e3.0.CO;2-5
Bui VL, Brahn E (2019) Cytokine targeting in rheumatoid arthritis. Clin Immunol 206:3–8. https://doi.org/10.1016/j.clim.2018.04.001
Bungau SG, Behl T, Singh A et al (2021) Targeting probiotics in rheumatoid arthritis. Nutrients 13:3376. https://doi.org/10.3390/nu13103376
Campbell J, Ciesielski CJ, Hunt AE et al (2004) A novel mechanism for TNF-α regulation by p38 MAPK: involvement of NF-κB with implications for therapy in rheumatoid arthritis. J Immunol 173:6928–6937. https://doi.org/10.4049/jimmunol.173.11.6928
Cheng Q, Wu H, Du Y (2021) The roles of small-molecule inflammatory mediators in rheumatoid arthritis. Scand J Immunol 93:3. https://doi.org/10.1111/sji.12982
Cho C, Nguyen A, Bryant KJ et al (2016) Prostaglandin D2 metabolites as a biomarker of in vivo mast cell activation in systemic mastocytosis and rheumatoid arthritis. Immunity Inflamm Dis 4:64–69. https://doi.org/10.1002/iid3.94
Choi WT, Duggineni S, Xu Y et al (2012) Drug discovery research targeting the CXC chemokine receptor 4 (CXCR4). J Med Chem 55:977–994. https://doi.org/10.1021/jm200568c
Choy E (2012) Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (United Kingdom) 51:3–11. https://doi.org/10.1093/rheumatology/kes113
Ciechomska M, Roszkowski L, Maslinski W (2019) DNA methylation as a future therapeutic and diagnostic target in rheumatoid arthritis. Cells 8:8. https://doi.org/10.3390/cells8090953
Cooles FA, Isaacs JD (2011) Pathophysiology of rheumatoid arthritis. Curr Opin Rheumatol 23:233–240. https://doi.org/10.1097/BOR.0b013e32834518a3
Cribbs A, Feldmann M, Oppermann U (2015) Towards an understanding of the role of DNA methylation in rheumatoid arthritis: Therapeutic and diagnostic implications. Ther Adv Musculoskelet Dis 7:206–219. https://doi.org/10.1177/1759720X15598307
Davignon JL, Hayder M, Baron M et al (2013) Targeting monocytes/macrophages in the treatment of rheumatoid arthritis. Rheumatology 1:4
De Launay D, Van De Sande MG, De Hair MJ, Grabiec AM, Van De Sande GP, Lehmann KA, Wijbrandts CA, Van Baarsen LG, Gerlag DM, Tak PP, Reedquist KA (2012) Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets. Ann Rheum Dis 1:415–423
Derksen VFAM, Huizinga TWJ, van der Woude D (2017) The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Seminars in immunopathology. Springer, pp 437–446
Doñas C, Carrasco M, Fritz M et al (2016) The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. J Autoimmun 75:105–117. https://doi.org/10.1016/j.jaut.2016.07.011
Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361. https://doi.org/10.1038/nature01661
Fu T, Mohan M, Brennan EP et al (2020) Therapeutic potential of lipoxin A4in chronic inflammation: focus on cardiometabolic disease. ACS Pharmacol Transl Sci 3:43–55. https://doi.org/10.1021/acsptsci.9b00097
García-Giménez JL, Garcés C, Romá-Mateo C, Pallardó FV (2021) Oxidative stress-mediated alterations in histone post-translational modifications. Free Radic Biol Med 170:6–18. https://doi.org/10.1016/j.freeradbiomed.2021.02.027
Gibofsky A (2012) Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care 18:S295-302
Grabiec AM, Angiolilli C, Hartkamp LM et al (2015) JNK-dependent downregulation of FoxO1 is required to promote the survival of fibroblast-like synoviocytes in rheumatoid arthritis. Ann Rheum Dis 74:1763–1771. https://doi.org/10.1136/annrheumdis-2013-203610
Grespan R, Fukada SY, Lemos HP et al (2008) CXCR2-specific chemokines mediate leukotriene B4-dependent recruitment of neutrophils to inflamed joints in mice with antigen-induced arthritis. Arthritis Rheum 58:2030–2040. https://doi.org/10.1002/art.23597
Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J (2019) Mesenchymal stem cells for regenerative medicine. Cells 8(8):886. https://doi.org/10.3390/cells8080886
Huber LC, Brock M, Hemmatazad H et al (2007) Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum 56:1087–1093. https://doi.org/10.1002/art.22512
Jin Z, Liu Y (2018) DNA methylation in human diseases. Genes Dis 5:1–8. https://doi.org/10.1016/j.gendis.2018.01.002
Karami J, Aslani S, Tahmasebi MN et al (2020) Epigenetics in rheumatoid arthritis; fibroblast-like synoviocytes as an emerging paradigm in the pathogenesis of the disease. Immunol Cell Biol 98:171–186. https://doi.org/10.1111/imcb.12311
Kim GW, Lee NR, Pi RH et al (2015) IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Arch Pharmacal Res 38:575–584
Kmiołek T, Paradowska-Gorycka A (2022) miRNAs as biomarkers and possible therapeutic strategies in rheumatoid arthritis. Cells 11:452. https://doi.org/10.3390/cells11030452
Koch AE (2005) Chemokines and their receptors in rheumatoid arthritis: future targets? Arthritis Rheum 52:710–721. https://doi.org/10.1002/art.20932
Koga T, Kawakami A, Tsokos GC (2021) Current insights and future prospects for the pathogenesis and treatment for rheumatoid arthritis. Clin Immunol 225:225. https://doi.org/10.1016/j.clim.2021.108680
Lee J, Taneja V, Vassallo R (2012) Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dent Res 91(2):142–149
Ling S, Li Z, Borschukova O et al (2007) The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway. Arthritis Res Ther 9:1–2. https://doi.org/10.1186/ar2111
Lupia E, Montrucchio G, Battaglia E et al (1996) Role of tumor necrosis factor-α and platelet-activating factor in neoangiogenesis induced by synovial fluids of patients with rheumatoid arthritis. Eur J Immunol 26:1690–1694. https://doi.org/10.1002/eji.1830260804
Ma Y, Hong FF, Yang SL (2021) Role of prostaglandins in rheumatoid arthritis. Clin Exp Rheumatol 39:162–172. https://doi.org/10.55563/clinexprheumatol/1jlh15
Maini RN, Taylor PC (1997) Anticytokine therapy for rheumatoid arthritis. Hosp Pract 32:50. https://doi.org/10.1056/nejm199707173370310
Majithia V, Geraci SA (2007) Rheumatoid arthritis: diagnosis and management. Am J Med 120:936–939
Makkar R, Behl T, Bungau S et al (2020a) Understanding the role of inflammasomes in rheumatoid arthritis. Inflammation 43:2033–2047. https://doi.org/10.1007/s10753-020-01301-1
Makkar R, Behl T, Kumar A et al (2020b) Emerging therapeutic effects of herbal plants in rheumatoid arthritis. Endocrine Metab Immune Disord Drug Targets 21:617–625. https://doi.org/10.2174/1871530320666200620232828
Makkar R, Behl T, Kumar A et al (2021) Untying the correlation between apolipoproteins and rheumatoid arthritis. Inflamm Res 70:19–28. https://doi.org/10.1007/s00011-020-01410-5
Malemud CJ, Miller AH (2008) Pro-inflammatory cytokine-induced SAPK/MAPK and JAK/STAT in rheumatoid arthritis and the new anti-depression drugs. Expert Opin Ther Targets 12:171–183. https://doi.org/10.1517/14728222.12.2.171
Mateen S, Moin S, Khan AQ et al (2016) Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS One 11:11. https://doi.org/10.1371/journal.pone.0152925
Mateen S, Moin S, Shahzad S, Khan AQ (2017) Level of inflammatory cytokines in rheumatoid arthritis patients: correlation with 25-hydroxy vitamin D and reactive oxygen species. PLoS One 12:12. https://doi.org/10.1371/journal.pone.0178879
McCoy JM, Wicks JR, Audoly LP (2002) The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis. J Clin Invest 110:651–658. https://doi.org/10.1172/JCI0215528
McInnes IB, Schett G (2017) Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 389:2328–2337. https://doi.org/10.1016/S0140-6736(17)31472-1
Miloso M, Villa D, Crimi M et al (2004) Retinoic acid-induced neuritogenesis of human neuroblastoma SH-SY5Y Cells Is ERK Independent and PKC dependent. J Neurosci Res 75:241–252. https://doi.org/10.1002/jnr.10848
Mueller AL, Payandeh Z, Mohammadkhani N et al (2021) Recent advances in understanding the pathogenesis of rheumatoid arthritis: new treatment strategies. Cells 10:10. https://doi.org/10.3390/cells10113017
Müller-Ladner U, Pap T, Gay RE et al (2005) Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol 1:102–110. https://doi.org/10.1038/ncprheum0047
Műzes G, Sipos F (2022) Mesenchymal stem cell-derived secretome: a potential therapeutic option for autoimmune and immune-mediated inflammatory diseases. Cells 11:11. https://doi.org/10.3390/cells11152300
Noack M, Miossec P (2017) Selected cytokine pathways in rheumatoid arthritis. Seminars in Immunopathology. Springer, pp 365–383
Pitzalis C, Kelly S, Humby F (2013) New learnings on the pathophysiology of RA from synovial biopsies. Curr Opin Rheumatol 25:334–344. https://doi.org/10.1097/BOR.0b013e32835fd8eb
Pruzanski W, Vadas P (1991) Phospholipase A2—a mediator between proximal and distal effectors of inflammation. Immunol Today 12:143–146. https://doi.org/10.1016/S0167-5699(05)80042-8
Radu A-F, Bungau SG (2023) Nanomedical approaches in the realm of rheumatoid arthritis. Ageing Res Rev 87:101927. https://doi.org/10.1016/j.arr.2023.101927
Roberts CA, Dickinson AK, Taams LS (2015) The interplay between monocytes/macrophages and CD4+ T cell subsets in rheumatoid arthritis. Front Immunol 6:6. https://doi.org/10.3389/fimmu.2015.00571
Roman-Blas JA, Jimenez SA (2006) NF-κB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthr Cartil 14:839–848. https://doi.org/10.1016/j.joca.2006.04.008
Rostami Z, Khorashadizadeh M, Naseri M (2020) Immunoregulatory properties of mesenchymal stem cells: micro-RNAs. Immunol Lett 219:34–45. https://doi.org/10.1016/j.imlet.2019.12.011
Rzodkiewicz P, Gąsińska E, Gajewski M et al (2016) Esculetin reduces leukotriene B4 level in plasma of rats with adjuvant-induced arthritis. Reumatologia 54:161–164. https://doi.org/10.5114/reum.2016.62469
Schett G, Zwerina J, Firestein G (2008) The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis 67:909–916. https://doi.org/10.1136/ard.2007.074278
Serhan CN, Haeggström JZ, Leslie CC (1996) Lipid mediator networks in cell signaling: update and impact of cytokines 1. FASEB J 10:1147–1158. https://doi.org/10.1096/fasebj.10.10.8751717
Smith JB, Haynes MK (2002) Rheumatoid arthritis—a molecular understanding. Ann Intern Med 136:908–922. https://doi.org/10.7326/0003-4819-136-12-200206180-00012
Smolen JS, Steiner G (2003) Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2:473–488. https://doi.org/10.1038/nrd1109
Srirangan S, Choy EH (2010) The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis 2:247–256. https://doi.org/10.1177/1759720X10378372
Stańczyk J, Kowalski ML (2001) The role of cyclooxygenase and prostaglandins in the pathogenesis of rheumatoid arthritis. Pol Merkur Lekarski 11:438–443
Sujitha S, Rasool M (2017) MicroRNAs and bioactive compounds on TLR/MAPK signaling in rheumatoid arthritis. Clin Chim Acta 473:106–115. https://doi.org/10.1016/j.cca.2017.08.021
Szekanecz Z, Koch AE (2016) Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat Rev Rheumatol 12:5–13. https://doi.org/10.1038/nrrheum.2015.157
Toussirot E, Abbas W, Khan KA et al (2013) Imbalance between HAT and HDAC activities in the PBMCs of patients with ankylosing spondylitis or rheumatoid arthritis and influence of HDAC inhibitors on TNF alpha production. PLoS One 8:8. https://doi.org/10.1371/journal.pone.0070939
Toussirot É, Michel F, Binda D, Dumoulin G (2015) The role of leptin in the pathophysiology of rheumatoid arthritis. Life Sci 140:29–36
Udalova IA, Mantovani A, Feldmann M (2016) Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol 12:472–485. https://doi.org/10.1038/nrrheum.2016.91
Vargaftig BB, Singer M (2003) Leukotrienes mediate part of Ova-induced lung effects in mice via EGFR. Am J Physiol Lung Cell Mol Physiol 285:L808–L818. https://doi.org/10.1152/ajplung.00377.2002
Viatte S, Plant D, Raychaudhuri S (2013) Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 9:141–153. https://doi.org/10.1038/nrrheum.2012.237
Wada TT, Araki Y, Sato K et al (2014) Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts. Biochem Biophys Res Commun 444:682–686. https://doi.org/10.1016/j.bbrc.2014.01.195
Wang L, Ding Y, Guo X, Zhao Q (2015) Role and mechanism of vascular cell adhesion molecule-1 in the development of rheumatoid arthritis. Exp Ther Med 10:1229–1233. https://doi.org/10.3892/etm.2015.2635
Xu S, Lu H, Lin J et al (2010) Regulation of TNFα and IL1β in rheumatoid arthritis synovial fibroblasts by leukotriene B4. Rheumatol Int 30:1183–1189. https://doi.org/10.1007/s00296-009-1125-y
Yang CM, Luo SF, Hsieh HL et al (2010) Interleukin-1β induces ICAM-1 expression enhancing leukocyte adhesion in human rheumatoid arthritis synovial fibroblasts: Involvement of ERK, JNK, AP-1, and NF-κB. J Cell Physiol 224:516–526. https://doi.org/10.1002/jcp.22153
Zhu H, Wu LF, Mo XB, Lu X, Tang H, Zhu XW, Xia W, Guo YF, Wang MJ, Zeng KQ, Wu J (2019) Rheumatoid arthritis–associated DNA methylation sites in peripheral blood mononuclear cells. Ann Rheum Dis 78:36–42
Acknowledgements
This study is supported via funding from Prince Sattam bin Abdulaziz University project number (PSAU/2023/R/1444).
Funding
This study is supported via funding from Prince Sattam bin Abdulaziz University project number (PSAU/2023/R/1444).
Author information
Authors and Affiliations
Contributions
Conceptualization: RM and TB; investigation: AS, SS, NS and SR; writing—original draft preparation: RR; revision: AS and TB; figure making: CVDLC and SY; literature collection: TB, RS and NS; proofreading: TB and SGB.
Corresponding authors
Ethics declarations
Conflict of interest
The author declare that they have no conflict of interest.
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent to publish
All authors have given consent for publication of the current article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Makkar, R., Sehgal, A., Singh, S. et al. Current trends in epigenetic, cellular and molecular pathways in management of rheumatoid arthritis. Inflammopharmacol 31, 1577–1588 (2023). https://doi.org/10.1007/s10787-023-01262-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-023-01262-5