A Review Article on Rheumatoid Arthritis (RA)
DOI:
https://doi.org/10.22270/ajprd.v14i01.1699Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disorder primarily affecting synovial joints and leading to progressive joint destruction, disability, and reduced quality of life. In addition to joint involvement, RA is associated with multiple extra-articular manifestations involving the cardiovascular, pulmonary, ocular, and nervous systems. The etiology of RA is multifactorial, involving genetic predisposition, environmental factors such as smoking, and immune dysregulation. This review article provides a comprehensive overview of rheumatoid arthritis, including its historical background, etiology, pathophysiology, clinical manifestations, diagnostic criteria, and current therapeutic strategies. Special emphasis is given to the role of cytokines, immune cells, autoantibodies, and inflammatory mediators in disease progression. The review also discusses conventional and biological disease-modifying antirheumatic drugs (DMARDs), their mechanisms of action, and associated adverse effects. Understanding the complex pathogenesis and evolving treatment options of RA is essential for improving disease management, minimizing complications, and enhancing patient outcomes.
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Conforti, A.; di Cola, I.; Pavlych, V.; Ruscitti, P.; Berardicurti, O.; Ursini, F.; Giacomelli, R.; Cipriani, P. Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmun. Rev. 2021, 20, 102735. [Google Scholar] [CrossRef]
Cojocaru, M.; Cojocaru, I.M.; Silosi, I.; Vrabie, C.D.; Tanasescu, R. Extra-articular manifestations in rheumatoid arthritis. Mædica 2010, 5, 286–291. [Google Scholar] [PubMed]
Joseph, A.; Brasington, R.; Kahl, L.; Ranganathan, P.; Cheng, T.P.; Atkinson, J. Immunologic rheumatic disorders. J. Allergy Clin. Immunol. 2010, 125, S20S215. [Google Scholar] [CrossRef]
Kurowska, W.; Kuca-Warnawin, E.H.; Radzikowska, A.; Maśliński, W. The role of anti-citrullinated protein antibodies (ACPA) in the pathogenesis of rheumatoid arthritis. Cent. J. Immunol. 2017, 42, 390–398. [Google Scholar] [CrossRef]
Wegner, N.; Lundberg, K.; Kinloch, A.; Fisher, B.; Malmström, V.; Feldmann, M.; Venables, P.J. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol. Rev. 2010, 233, 34–54. [Google Scholar] [CrossRef]
Chaurasia, N.; Singh, A.; Singh, I.L.; Singh, T.; Tiwari, T. Cognitive dysfunction in patients of rheumatoid arthritis. J. Fam. Med. Prim. Care 2020, 9, 2219–2225. [Google Scholar] [CrossRef]
Lassere, M.N.; Rappo, J.; Portek, I.J.; Sturgess, A.; Edmonds, J.P. How many life years are lost in patients with rheumatoid arthritis? Secular cause-specific and all-cause mortality in rheumatoid arthritis, and their predictors in a long-term Australian cohort study. Intern. Med. J. 2013, 43, 66–72. [Google Scholar] [CrossRef] [PubMed]
Hootman, J.M.; Helmick, C.G.; Brady, T.J. A public health approach to addressing arthritis in older adults: The most common cause of disability. Am. J. Public Health 2012, 102, 426–433. [Google Scholar] [CrossRef] [PubMed]
Theis, K.A.; Steinweg, A.; Helmick, C.G.; Courtney-Long, E.; Bolen, J.A.; Lee, R. Which one? What kind? How many? Types, causes, and prevalence of disability among U.S. adults. Disabil. Health J. 2019, 12, 411–421. [Google Scholar] [CrossRef]
Lanes, S.F.; Lanza, L.L.; Radensky, P.W.; Yood, R.A.; Meenan, R.F.; Walker, A.M.; Dreyer, N.A. Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting. The importance of drug and surgery costs. Arthritis Rheum. 1997, 40, 1475–1481. [Google Scholar] [CrossRef]
Aceves-Avila, F. J., Baez-Molgado, S., Medina, F. & Fraga, A. Paleopathology in osseous remains fromthe 16th century. A survey of rheumatic diseases. J. Rheumatol. 25, 776–782 (1998).
Rothschild, B. M., Turner, K. R. & DeLuca, M. A. Symmetrical erosive peripheral polyarthritis in theLate Archaic Period of Alabama. Science 241, 1498–1501 (1988).
Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, Ollier WE. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993 Oct;32(10):903-7. [PubMed]
Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987 Nov;30(11):1205-13. [PubMed]
Weyand CM, Hicok KC, Conn DL, Goronzy JJ. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med. 1992 Nov 15;117(10):801-6. [PubMed]
Teil Espina M, Gabarrini G, Harmsen HJM, Westra J, van Winkelhoff AJ, van Dijl JM. Talk to your gut: the oral-gut microbiome axis and its immunomodulatory role in the etiology of rheumatoid arthritis. FEMS Microbiol Rev. 2019 Jan 01;43(1):1-18. [PubMed]
Wu H, Liao W, Li Q, Long H, Yin H, Zhao M, Chan V, Lau CS, Lu Q. Pathogenic role of tissue-resident memory T cells in autoimmune diseases. Autoimmun Rev. 2018 Sep;17(9):906-911. [PubMed]
Ciccacci C, Conigliaro P, Perricone C, Rufini S, Triggianese P, Politi C, Novelli G, Perricone R, Borgiani P. Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis. Clin Exp Immunol. 2016 Nov;186(2):157-163. [PMC free article] [PubMed]
Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, Alfredsson L., EIRA study group. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003 Sep;62(9):835-41. [PMC free article] [PubMed]
Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004 Oct;50(10):3085-92. [PubMed]
Linn-Rasker SP, van der Helm-van Mil AH, van Gaalen FA, Kloppenburg M, de Vries RR, le Cessie S, Breedveld FC, Toes RE, Huizinga TW. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis. 2006 Mar;65(3):366-71. [PMC free article] [PubMed]
Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, Rönnelid J, Harris HE, Ulfgren AK, Rantapää-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006 Jan;54(1):38-46. [PubMed]
Lundström E, Källberg H, Alfredsson L, Klareskog L, Padyukov L. Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: all alleles are important. Arthritis Rheum. 2009 Jun;60(6):1597-603. [PMC free article] [PubMed]
Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, Kumagai S. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2010 Jan;69(1):70-81. [PubMed]
Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017 Jun;39(4):437-446. [PMC free article] [PubMed]
Klareskog L, Rönnelid J, Saevarsdottir S, Padyukov L, Alfredsson L. The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis. J Intern Med. 2020 May;287(5):514-533. [PubMed]
Essouma, M.; Noubiap, J.J.N. Is air pollution a risk factor for rheumatoid arthritis? J. Inflamm. 2015, 12, 48. [Google Scholar] [CrossRef] [Green Version]
Choy E. Understanding the dynamics: pathways involved in the pathogenesisof rheumatoid arthritis. Rheumatology. (2012) 51(Suppl. 5):v3–11.doi: 10.1093/rheumatology/kes113
Byng-Maddick R, Ehrenstein MR. The impact of biological therapy onregulatory T cells in rheumatoid arthritis. Rheumatology. (2015) 54:768–75.doi: 10.1093/rheumatology/keu487
Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, FiresteinGS, et al. Rheumatoid arthritis. Nat Rev Dis Prim. (2018) 4:18001.doi: 10.1038/nrdp.2018.1
Tran CN, Lundy SK, Fox DA. Synovial biology and t cellsin rheumatoid arthritis. Pathophysiology. (2005) 12:183–9.doi: 10.1016/j.pathophys.2005.07.005
Bugatti S, Vitolo B, Caporali R, Montecucco C, Manzo A. B cells inrheumatoid arthritis: from pathogenic players to disease biomarkers. ResArticle Bio Med Res Int. (2014) 2014:681678. doi: 10.1155/2014/681678
Silverman GJ, Carson DA. Roles of B cells in rheumatoid arthritis. ArthrResTher. (2003) 5(Suppl. 4):S1–6. doi: 10.1186/ar1010
Boissier MC, Semerano L, Challal S, Saidenberg-Kermanac’h N, FalgaroneG.Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction.JAutoimm. (2012) 39:222–8. doi: 10.1016/j.jaut.2012.05.021
Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol (2017) 39(4):437–46. doi: 10.1007/s00281-017-0627-zPubMed Abstract | CrossRef Full Text | Google Scholar
Giles JT. Extra-articular manifestations and comorbidity in rheumatoid arthritis: Potential impact of pre-rheumatoid arthritis prevention. Clin Ther (2019) 41(7):1246–55. doi: 10.1016/j.clinthera.2019.04.01PubMed Abstract | CrossRef Full Text | Google Scholar
Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016 Oct 22;388(10055):2023-2038. [PubMed]
Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001 Sep 15;358(9285):903-11. [PubMed]
Sparks JA. Rheumatoid Arthritis. Ann Intern Med. 2019 Jan 01;170(1):ITC1-ITC16. [PubMed]
Sayah A, English JC. Rheumatoid arthritis: a review of the cutaneous manifestations. J Am Acad Dermatol. 2005 Aug;53(2):191-209; quiz 210-2. [PubMed]
Bongartz T, Nannini C, Medina-Velasquez YF, Achenbach SJ, Crowson CS, Ryu JH, Vassallo R, Gabriel SE, Matteson EL. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010 Jun;62(6):1583-91. [PMC free article] [PubMed]
Sparks JA, Jin Y, Cho SK, Vine S, Desai R, Doyle TJ, Kim SC. Prevalence, incidence and cause-specific mortality of rheumatoid arthritis-associated interstitial lung disease among older rheumatoid arthritis patients. Rheumatology (Oxford). 2021 Aug 02;60(8):3689-3698. [PMC free article] [PubMed]
Samhouri BF, Vassallo R, Achenbach SJ, Kronzer VL, Davis JM, Myasoedova E, Crowson CS. Incidence, Risk Factors, and Mortality of Clinical and Subclinical Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Population-Based Cohort. Arthritis Care Res (Hoboken). 2022 Dec;74(12):2042-2049. [PMC free article] [PubMed]
Conforti A, Di Cola I, Pavlych V, Ruscitti P, Berardicurti O, Ursini F, Giacomelli R, Cipriani P. Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmun Rev. 2021 Feb;20(2):102735. [PubMed]
Abdulqader Y, Al-Ani M, Parperis K. Rheumatoid vasculitis: early presentation of rheumatoid arthritis. BMJ Case Rep. 2016 Nov 08;2016 [PMC free article] [PubMed]
Aletaha D, Neogi T, Silman A, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis.2010;69:1580-1588. doi:10.1136/ard.2010.138461
Radner H, Neogi T, Smolen JS, AletahaD.Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: a systematic literature review. Ann Rheum Dis. 2014;73(1):114-123. doi:10.1136/annrheumdis-2013-203284
Goekoop-Ruiterman YP, de Vries-BouwstraJK,Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005;52(11):3381-3390. doi:10.1002/art.21405
Fraenkel, L.; Bathon, J.M.; England, B.R.; St. Clair, E.W.; Arayssi, T.; Carandang, K.; Deane, K.D.; Genovese, M.; Huston, K.K.; Kerr, G.; et al. American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2021, 73, 924–939. [Google Scholar] [CrossRef]
Smolen, J.S.; Landewé, R.B.M.; Bijlsma, J.W.J.; Burmester, G.R.; Dougados, M.; Kerschbaumer, A.; McInnes, I.B.; Sepriano, A.; van Vollenhoven, R.F.; de Wit, M.; et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis. 2020, 79, 685–699. [Google Scholar] [CrossRef] [Green Version]
Moura, M.D.G.; Lopes, L.C.; Silva, M.T.; Barberato-Filho, S.; Motta, R.H.L.; Bergamaschi, C.C. Use of steroid and nonsteroidal anti-inflammatories in the treatment of rheumatoid arthritis: Systematic review protocol. Medicine 2018, 97, e12658. [Google Scholar] [CrossRef]
Crofford, L.J. Use of NSAIDs in treating patients with arthritis. Arthritis Res. Ther. 2013, 15, S2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Bullock, J.; Rizvi, S.A.A.; Saleh, A.M.; Ahmed, S.S.; Do, D.P.; Ansari, R.A.; Ahmed, J. Rheumatoid arthritis: A brief overview of the treatment. Med. Princ. Pract. 2019, 27, 501–507. [Google Scholar] [CrossRef]
Monti, S.; Klersy, C.; Gorla, R.; Sarzi-Puttini, P.; Atzeni, F.; Pellerito, R.; Fusaro, E.; Paolazzi, G.; Rocchetta, P.A.; Favalli, E.G.; et al. Factors influencing the choice of first- and second-line biologic therapy for the treatment of rheumatoid arthritis: Real-life data from the Italian LORHEN registry. Clin. Rheumatol. 2017, 36, 753–761. [Google Scholar] [CrossRef] [Green Version]
Bywall, K.S.; Kihlbom, U.; Hansson, M.; Falahee, M.; Raza, K.; Baecklund, E.; Veldwijk, J. Patient preferences on rheumatoid arthritis second-line treatment: A discrete choice experiment of Swedish patients. Arthritis Res. Ther. 2020, 22, 1–10. [Google Scholar] [CrossRef] [PubMed]
Wang, W.; Zhou, H.; Liu, L. Side effects of methotrexate therapy for rheumatoid arthritis: A systematic review. Eur. J. Med. Chem. 2018, 158, 502–516. [Google Scholar] [CrossRef] [PubMed]
Van Vollenhoven, R.F. New therapeutic approaches in rheumatoid arthritis. Presse Med. 2016, 45, 179–192. [Google Scholar] [CrossRef] [PubMed]
Fassmer, A.M.; Garbe, E.; Schmedt, N. Frequency and trends of disease-modifying antirheumatic drug (DMARD) use in Germany. Pharmacol. Res. Perspect. 2016, 4, e00254. [Google Scholar] [CrossRef]
Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. JAMA. 2018 Oct 02;320(13):1360-1372. [PubMed]
Wang W, Zhou H, Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: A systematic review. Eur J Med Chem. 2018 Oct 05;158:502-516. [PubMed]
Oo WM, Yu SP, Daniel MS, Hunter DJ. Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics. Expert Opin Emerg Drugs. 2018 Dec;23(4):331-347. [PubMed]
Hughes CD, Scott DL, Ibrahim F., TITRATE Programme Investigators. Intensive therapy and remissions in rheumatoid arthritis: a systematic review. BMC Musculoskelet Disord. 2018 Oct 30;19(1):389. [PMC free article] [PubMed]
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Copyright (c) 2026 Shaziya Tanzeem .T, Shaguftha .T, Farida Banu .S, Karishma .S, Hina Tousif .S, Banny .S.V, Sameera .P, Meena .G

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