Abstract
Rheumatoid arthritis (RA) is characterised by severe joint and bone damage due to heightened autoimmune response at the articular sites. Worldwide annual incidence and prevalence rate of RA is 3 cases per 10,000 population and 1%, respectively. Several genetic and environmental (microbiota, smoking, infectious agents) factors contribute to its pathogenesis. Although convention treatment strategies, predominantly Disease Modifying Anti Rheumatic Drugs (DMARDs) and Glucocorticoids (GC), are unchanged as the primary line of treatment; novel strategies consisting of biological DMARDs, are being developed and explored. Personalized approaches using biologicals targetspecific pathways associated with disease progression. However, considering the economic burden and side-effects associated with these, there is an unmet need on strategies for early stratification of the inadequate responders with cDMARDs. As RA is a complex disease with a variable remission rate, it is important not only to evaluate the current status of drugs in clinical practice but also those with the potential of personalised therapeutics. Here, we provide comprehensive data on the treatment strategies in RA, including studies exploring various combination strategies in clinical trials. Our systematic analysis of current literature found that conventional DMARDs along with glucocorticoid may be best suited for early RA cases and a combination of conventional and targeted DMARDs could be effective for treating seronegative patients with moderate to high RA activity. Clinical trials with insufficient responders to Methotrexate suggest that adding biologicals may help in such cases. However, certain adverse events associated with the current therapy advocate exploring novel therapeutic approaches such as gene therapy, mesenchymal stem cell therapy in future.
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References
Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J (2018) Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 6(1):1–4. https://doi.org/10.1038/s41413-018-0016-9
Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis.Erratum. Lancet 388(10055):2023–2038. https://doi.org/10.1016/S0140-6736(16)30173-8. Epub 2016 May. PMID: 27156434.
Yap H-Y, Tee S, Wong M, Chow S-K, Peh S-C, Teow S-Y (2018) Pathogenic role of immune cells in rheumatoid arthritis: implications in clinical treatment and biomarker development. Cells 7(10):161. https://doi.org/10.3390/cells7100161
Kurkó J, Besenyei T, Laki J, Glant TT, Mikecz K, Szekanecz Z (2013) Genetics of rheumatoid arthritis—a comprehensive review. Clin Rev Allergy Immunol 45(2):170–179. https://doi.org/10.1007/s12016-012-8346-7
Jeffery RC (2014) Clinical features of rheumatoid arthritis. Medicine (United Kingdom) 42(5):231–236. https://doi.org/10.1016/j.mpmed.2014.02.011
Friedman B, Cronstein B (2019) Methotrexate mechanism in treatment of rheumatoid arthritis. Jt Bone Spine 86(3):301–307. https://doi.org/10.1016/j.jbspin.2018.07.004
Schrezenmeier E, Dörner T (2020) Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16(3):155–166. https://doi.org/10.1038/s41584-020-0372-x
Dhillon S (2017) Tofacitinib: a review in rheumatoid arthritis. Drugs 77(18):1987–2001. https://doi.org/10.1007/s40265-017-0835-9
Al-Salama ZT, Scott LJ (2018) Baricitinib: a review in rheumatoid arthritis. Drugs 78(7):761–772. https://doi.org/10.1007/s40265-018-0908-4
Zhao S, Mysler E, Moots RJ (2018) Etanercept for the treatment of rheumatoid arthritis. Immunotherapy 10(6):433–445. https://doi.org/10.2217/imt-2017-0155
Radner H, Aletaha D (2015) Anti-TNF therapie in der rheumatoiden Arthritis—ein Überblick. Wien Med Wochenschr 165(1–2):3–9. https://doi.org/10.1007/s10354-015-0344-y
Novella-Navarro M, Plasencia C, Tornero C et al (2020) Clinical predictors of multiple failure to biological therapy in patients with rheumatoid arthritis. Arthritis Res Ther 22(1):1–8. https://doi.org/10.1186/s13075-020-02354-1
van Vollenhoven R (2019) Treat-to-target in rheumatoid arthritis—are we there yet? Nat Rev Rheumatol 15(3):180–186. https://doi.org/10.1038/s41584-019-0170-5
Arora S, Rafiq A, Jolly M (2016) Management of rheumatoid arthritis: review of current guidelines. J Arthrosc Jt Surg 3(2):45–50. https://doi.org/10.1016/j.jajs.2016.07.002
Lau CS, Chia F, Dans L et al (2019) 2018 update of the APLAR recommendations for treatment of rheumatoid arthritis. Int J Rheum Dis 22(3):357–375. https://doi.org/10.1111/1756-185X.13513
Aletaha D, Smolen J, Ward MM (2006) Measuring function in rheumatoid arthritis: identifying reversible and irreversible components. Arthritis Rheum 54(9):2784–2792. https://doi.org/10.1002/art.22052
Smolen JS, Aletaha D, Grisar JC, Stamm TA, Sharp JT (2010) Estimation of a numerical value for joint damage-related physical disability in rheumatoid arthritis clinical trials. Ann Rheum Dis 69(6):1058–1064. https://doi.org/10.1136/ard.2009.114652
Aletaha D, Alasti F, Smolen JS (2016) Optimisation of a treat-to-target approach in rheumatoid arthritis: strategies for the 3-month time point. Ann Rheum Dis 75(8):1479–1485. https://doi.org/10.1136/annrheumdis-2015-208324
van Drongelen V, Holoshitz J (2017) Human leukocyte antigen-disease associations in rheumatoid arthritis. Rheum Dis Clin North Am 43(3):363–376. https://doi.org/10.1016/j.rdc.2017.04.003
Fugger L, Svejgaard A (2000) Association of MHC and rheumatoid arthritis HLA-DR4 and rheumatoid arthritis: studies in mice and men. Arthritis Res 2(3):208–211. https://doi.org/10.1186/ar89
Nemtsova MV, Zaletaev DV, Bure IV et al (2019) Epigenetic changes in the pathogenesis of rheumatoid arthritis. Front Genet 14(10):1–13. https://doi.org/10.3389/fgene.2019.00570
Karouzakis E, Raza K, Kolling C et al (2018) Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis. Sci Rep 8(1):1–6. https://doi.org/10.1038/s41598-018-24240-2
Karouzakis E, Gay RE, Gay S, Neidhart M (2012) Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 64(6):1809–1817. https://doi.org/10.1002/art.34340
Ahmed S, Riegsecker S, Beamer M et al (2013) Largazole, a class I histone deacetylase inhibitor, enhances TNF-α-induced ICAM-1 and VCAM-1 expression in rheumatoid arthritis synovial fibroblasts. Toxicol Appl Pharmacol 270(2):87–96. https://doi.org/10.1016/j.taap.2013.04.014
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(3):1229–1233. https://doi.org/10.3892/etm.2015.2635
Ai R, Laragione T, Hammaker D et al (2018) Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun 9(1):1–1. https://doi.org/10.1038/s41467-018-04310-9
Chang K, Yang SM, Kim SH, Han KH, Park SJ, Il SJ (2014) Smoking and rheumatoid arthritis. Int J Mol Sci 15(12):22279–22295. https://doi.org/10.3390/ijms151222279
Ozguner F, Koyu A, Cesur G (2005) Active smoking causes oxidative stress and decreases blood melatonin levels. Toxicol Ind Health 21(10):21–26. https://doi.org/10.1191/0748233705th211oa
Bijl M, Horst G, Limburg PC, Kallenberg CGM (2001) Effects of smoking on activation markers, Fas expression and apoptosis of peripheral blood lymphocytes. Eur J Clin Invest 31(6):550–553. https://doi.org/10.1046/j.1365-2362.2001.00842.x
Shizu M, Itoh Y, Sunahara R et al (2007) Cigarette smoke condensate upregulates the gene and protein expression of proinflammatory cytokines in human fibroblast-like synoviocyte line. J Interferon Cytokine Res 28(8):509–521. https://doi.org/10.1089/jir.2007.0081
Lee J, Taneja V, Vassallo R (2012) Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dent Res 91(2):142–149. https://doi.org/10.1177/0022034511421200
Xue M, McKelvey K, Shen K et al (2014) Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammation and cartilage degradation. Rheumatol (United Kingdom) 53(12):2270–2279. https://doi.org/10.1093/rheumatology/keu254
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(5):206–219. https://doi.org/10.1177/1759720X15598307
Lu B, Solomon DH, Costenbader KH, Karlson EW (2014) Alcohol consumption and risk of incident rheumatoid arthritis in women: a prospective study. Arthritis Rheumatol 66(8):1998–2005. https://doi.org/10.1002/art.38634
Forsyth C, Kouvari M, D’Cunha NM et al (2018) The effects of the mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies. Rheumatol Int 38(5):737–747. https://doi.org/10.1007/s00296-017-3912-1
Khanna S, Jaiswal KS, Gupta B (2017) Managing rheumatoid arthritis with dietary interventions. Front Nutr. https://doi.org/10.3389/fnut.2017.00052
Kostoglou-Athanassiou I, Athanassiou P, Lyraki A, Raftakis I, Antoniadis C (2012) Vitamin D and rheumatoid arthritis. Ther Adv Endocrinol Metab 3(6):181–187. https://doi.org/10.1177/2042018812471070
Smolen JS, Steiner G (2003) Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2(6):473–488. https://doi.org/10.1038/nrd1109
Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A et al (2020) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease- modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 79(6):S685–S699
Mazouyès A, Clay M, Bernard AC, Gaudin P, Baillet A (2017) Efficacy of triple association methotrexate, sulfasalazine and hydroxychloroquine in early treatment of rheumatoid arthritis with insufficient response to methotrexate: meta-analysis of randomized controlled trials. Jt Bone Spine 84(5):563–570. https://doi.org/10.1016/j.jbspin.2016.10.010
Herrmann ML, Schleyerbach R, Kirschbaum BJ (2000) Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology 47(2–3):273–289. https://doi.org/10.1016/S0162-3109(00)00191-0
Hirohata S, Ohshima N, Yanagida T, Aramaki K (2002) Regulation of human B cell function by sulfasalazine and its metabolites. Int Immunopharmacol 2(5):631–640. https://doi.org/10.1016/S1567-5769(01)00186-2
Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF (2015) Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 23(5):231–269. https://doi.org/10.1007/s10787-015-0239-y
Taylor PC, Abdul Azeez M, Kiriakidis S (2017) Filgotinib for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs 26(10):1181–1187. https://doi.org/10.1080/13543784.2017.1372422
Jegatheeswaran J, Turk M, Pope JE (2019) Comparison of Janus kinase inhibitors in the treatment of rheumatoid arthritis: a systemic literature review. Immunotherapy 11(8):737–754. https://doi.org/10.2217/imt-2018-0178
Bernal J, Vela P, Ruiz García V, Burls A, Cabello J, Bort-Martí S (2017) FRI0199 systematic review and meta-analysis on certolizumab pegol for rheumatoid arthritis in adults. Rheum Dis. https://doi.org/10.1136/annrheumdis-2017-eular.6433
Jones G, Wallace T, McIntosh MJ, Brockwell L, Gomez-Reino JJ, Sebba A (2017) Five-year efficacy and safety of tocilizumab monotherapy in patients with rheumatoid arthritis who were methotrexate-and biologic-naive or free of methotrexate for 6 months: the ambition study. J Rheumatol 44(2):142–146. https://doi.org/10.3899/jrheum.160287
Ruscitti P, Cipriani P, Liakouli V et al (2018) The emerging role of IL-1 inhibition in patients affected by rheumatoid arthritis and diabetes. Rev Recent Clin Trials 13(3):210–214. https://doi.org/10.2174/1574887113666180314102651
Blair HA, Deeks ED (2017) Abatacept: a review in rheumatoid arthritis. Drugs 77(11):1221–1233. https://doi.org/10.1007/s40265-017-0775-4
Chiu YG, Ritchlin CT (2017) Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis. Expert Opin Biol Ther 17(1):119–128. https://doi.org/10.1080/14712598.2017.1263614
It T, Effects S. Denosumab (Prolia)
Crotti C, Raimondo MG, Becciolini A, Biggioggero M, Favalli EG (2017) Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date. Drug Des Devel Ther 11:211–223. https://doi.org/10.2147/DDDT.S104233
Sherbini AA, Gwinnutt JM, Hyrich KL et al (2022) Rates and predictors of methotrexate-related adverse events in patients with early rheumatoid arthritis: results from a nationwide UK study. Rheumatology. https://doi.org/10.1093/rheumatology/keab917
Yan H, Su R, Xue H, Gao C, Li X, Wang C (2021) Pharmacomicrobiology of methotrexate in rheumatoid arthritis: gut microbiome as predictor of therapeutic response. Front Immunol 12:1–15. https://doi.org/10.3389/fimmu.2021.789334
Sergeant JC, Hyrich KL, Anderson J et al (2018) Prediction of primary non-response to methotrexate therapy using demographic, clinical and psychosocial variables: results from the UK Rheumatoid Arthritis Medication Study (RAMS). Arthritis Res Ther 20(1):1–11. https://doi.org/10.1186/s13075-018-1645-5
Artacho A, Isaac S, Nayak R et al (2021) The pretreatment gut microbiome is associated with lack of response to methotrexate in new-onset rheumatoid arthritis. Arthritis Rheumatol 73(6):931–942. https://doi.org/10.1002/art.41622
Hambardzumyan K, Bolce RJ, Wallman JK, Van Vollenhoven RF, Saevarsdottir S (2019) Serum biomarkers for prediction of response to methotrexate monotherapy in early rheumatoid arthritis: results from the SWEFOT trial. J Rheumatol 46(6):555–563. https://doi.org/10.3899/jrheum.180537
Fragoulis GE, Mcinnes IB, Siebert S (2019) JAK-inhibitors. new players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology (United Kingdom) 58:i43–i54
Harigai M (2019) Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis. Rheumatology (United Kingdom) 58(1):i34–i42. https://doi.org/10.1093/rheumatology/key287
Lunzer R (2014) Tofacitinib versus methotrexate in rheumatoid arthritis: kommentar. J Miner 21(4):157. https://doi.org/10.1056/NEJMoa1310476
Fleischmann R, Mysler E, Hall S et al (2017) Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 390(10093):457–468. https://doi.org/10.1016/S0140-6736(17)31618-5
Mogul A, Corsi K, McAuliffe L (2019) Baricitinib: the second FDA-approved JAK inhibitor for the treatment of rheumatoid arthritis. Ann Pharmacother 53(9):947–953. https://doi.org/10.1177/1060028019839650
Hernández-Cruz B, Rosas J, Díaz-Torné C et al (2022) Real-world treatment patterns and clinical outcomes of baricitinib in rheumatoid arthritis patients in spain: results of a multicenter, observational study in routine clinical practice (The ORBIT-RA Study). Rheumatol Ther 9(2):589–608. https://doi.org/10.1007/s40744-021-00423-8
Taylor PC, Takeuchi T, Burmester GR et al (2022) Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis 81(3):335–343. https://doi.org/10.1136/annrheumdis-2021-221276
Kaneko Y, Murakami T, Nishitsuka K, Takakubo Y, Takagi M, Yamashita H (2022) Effectiveness of baricitinib in refractory seronegative rheumatoid arthritis and uveitis: a case report. Front Med 8:1–6. https://doi.org/10.3389/fmed.2021.764067
Westhovens R, Taylor PC, Alten R et al (2017) Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis 76(6):998–1008. https://doi.org/10.1136/annrheumdis-2016-210104
Westhovens R, Rigby WFC, Van Der Heijde D et al (2021) Filgotinib in combination with methotrexate or as monotherapy versus methotrexate monotherapy in patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: the phase 3, randomised controlled FINCH 3 trial. Ann Rheum Dis 80(6):727–738. https://doi.org/10.1136/annrheumdis-2020-219213
Kavanaugh A, Westhovens RR, Winthrop KL et al (2021) Safety and efficacy of filgotinib: Up to 4-year results from an open-label extension study of phase II rheumatoid arthritis programs. J Rheumatol 48(8):1230–1238. https://doi.org/10.3899/jrheum.201183
Winthrop KL, Tanaka Y, Takeuchi T et al (2022) Integrated safety analysis of filgotinib in patients with moderately to severely active rheumatoid arthritis receiving treatment over a median of 1.6 years. Ann Rheum Dis 81(2):184–192. https://doi.org/10.1136/annrheumdis-2021-221051
Fleischmann R, Mysler E, Bessette L et al (2022) Long-term safety and efficacy of upadacitinib or adalimumab in patients with rheumatoid arthritis: results through 3 years from the SELECT-COMPARE study. RMD Open 8(1):1–12. https://doi.org/10.1136/rmdopen-2021-002012
Conaghan P, Cohen S, Burmester G et al (2022) Benefit-risk analysis of upadacitinib compared with adalimumab in the treatment of patients with moderate-to-severe rheumatoid arthritis. Rheumatol Ther 9(1):191–206. https://doi.org/10.1007/s40744-021-00399-5
Koch AE (2007) The pathogenesis of rheumatoid arthritis. Am J Orthop (Belle Mead NJ) 36(7):5–8
Tilders FJ, DeRuk RH, Van Dam AM, Vincent VA, Schotanus K, Persoons JH (1994) Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: routes and intermediate signals. Psychoneuroendocrinology 19(2):209–232
Haworth C, Brennan FM, Chantry D, Turner M, Maini RN, Feldmann M (1991) Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-α. Eur J Immunol 21(10):2575–2579. https://doi.org/10.1002/eji.1830211039
Suematsu S, Matsuda T, Aozasa K et al (1989) IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 86(19):7547–7551. https://doi.org/10.1073/pnas.86.19.7547
Suzuki M, Hashizume M, Yoshida H, Mihara M (2010) Anti-inflammatory mechanism of tocilizumab, a humanized anti-IL-6R antibody: effect on the expression of chemokine and adhesion molecule. Rheumatol Int 30(3):309–315. https://doi.org/10.1007/s00296-009-0953-0
Nestorov I (2005) Clinical pharmacokinetics of TNF antagonists: how do they differ? Semin Arthritis Rheum 34(5):12–18. https://doi.org/10.1016/j.semarthrit.2005.01.004
Voulgari PV, Drosos AA (2006) Adalimumab for rheumatoid arthritis. Expert Opin Biol Ther 6(12):1349–1360. https://doi.org/10.1517/14712598.6.12.1349
He B, Li Y, Luo W et al (2022) The risk of adverse effects of TNF-α inhibitors in patients with rheumatoid arthritis: a network meta-analysis. Front Immunol 13:1–16. https://doi.org/10.3389/fimmu.2022.814429
Hirose T, Kawaguchi I, Murata T, Atsumi T (2022) Cost-effectiveness analysis of etanercept 25 mg maintenance therapy after treatment with etanercept 50 mg for moderate rheumatoid arthritis in the PRESERVE trial in japan. Value Heal Reg Issues 28:105–111. https://doi.org/10.1016/j.vhri.2021.06.012
Cai Y, Xu K, Aihaiti Y et al (2022) Derlin-1, as a potential early predictive biomarker for nonresponse to infliximab treatment in rheumatoid arthritis is related to autophagy. Front Immunol 12:1–15. https://doi.org/10.3389/fimmu.2021.795912
Tasaki S, Suzuki K, Kassai Y et al (2018) Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission. Nat Commun 9(1):2755. https://doi.org/10.1038/s41467-018-05044-4
Pelechas E, Voulgari PV, Drosos AA (2019) Golimumab for rheumatoid arthritis. J Clin Med 8(3):387. https://doi.org/10.3390/jcm8030387
Tanaka Y, Senoo A, Fujii H, Baker D (2016) Evaluation of golimumab for the treatment of patients with active rheumatoid arthritis. Expert Opin Drug Metab Toxicol 12(3):319–326. https://doi.org/10.1517/17425255.2016.1146682
Theunssens X, Bricman L, Dierckx S et al (2022) Anti-TNF induced sarcoidosis-like disease in rheumatoid arthritis patients: review cases from the RA UCLouvain brussels cohort. Rheumatol Ther 9(2):763–770. https://doi.org/10.1007/s40744-022-00424-1
Park JW, Kim MJ, Kim H-A, Kim JH, Lee EB, Shin K (2022) The aftermath of tapering tocilizumab after achieving treatment target in patients with rheumatoid arthritis: a nationwide cohort study. Front Med 9:1–9. https://doi.org/10.3389/fmed.2022.839206
Tony H-P, Feist E, Aries PM et al (2022) Sarilumab reduces disease activity in rheumatoid arthritis patients with inadequate response to janus kinase inhibitors or tocilizumab in regular care in Germany. Rheumatol Adv Pract 6(1):1–7. https://doi.org/10.1093/rap/rkac002
Humby F, Durez P, Buch MH et al (2021) 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 397(10271):305–317. https://doi.org/10.1016/S0140-6736(20)32341-2
Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA (2006) Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 180(1–2):63–70. https://doi.org/10.1016/j.jneuroim.2006.06.029
Pollastro S, Klarenbeek PL, Doorenspleet ME et al (2019) Non-response to rituximab therapy in rheumatoid arthritis is associated with incomplete disruption of the B cell receptor repertoire. Ann Rheum Dis 78(10):1339–1345. https://doi.org/10.1136/annrheumdis-2018-214898
Oldroyd AGS, Symmons DPM, Sergeant JC et al (2018) Long-term persistence with rituximab in patients with rheumatoid arthritis. Rheumatology (United Kingdom) 57(6):1089–1096. https://doi.org/10.1093/rheumatology/key036
Wang Z, Bao HW, Ji Y, Li Y (2020) A systematic review and meta-analysis of rituximab combined with methotrexate versus methotrexate alone in the treatment of rheumatoid arthritis. Medicine (United States) 99(8):e19193. https://doi.org/10.1097/MD.0000000000019193
Norris-Grey C, Cambridge G, Moore S, Reddy V, Leandro M (2022) Long-term persistence of rituximab in patients with rheumatoid arthritis: an evaluation of the UCL cohort from 1998 to 2020. Rheumatology (Oxford) 61(2):591–596. https://doi.org/10.1093/rheumatology/keab248
Behrens F, Koehm M, Rossmanith T et al (2021) Rituximab plus leflunomide in rheumatoid arthritis: a randomized, placebo-controlled, investigator-initiated clinical trial (AMARA study). Rheumatology 60(11):5318–5328. https://doi.org/10.1093/rheumatology/keab153
Scher JU (2012) B-cell therapies for rheumatoid arthritis. Bull NYU Hosp Jt Dis 70(3):200–203
Cron RQ (2005) Editorial: a signal achievement in the treatment of arthritis. Arthritis Rheum 52(8):2229–2232. https://doi.org/10.1002/art.21206
Pombo-Suarez M, Gomez-Reino JJ (2019) Abatacept for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol 15(4):319–326. https://doi.org/10.1080/1744666X.2019.1579642
Kremer JM, Dougados M, Emery P et al (2005) Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 52(8):2263–2271. https://doi.org/10.1002/art.21201
Pascart T, Philippe P, Drumez E et al (2019) Abatacept monotherapy versus abatacept plus methotrexate for treatment-refractory rheumatoid arthritis. Am J Ther 26(3):E358–E363. https://doi.org/10.1097/MJT.0000000000000645
Tamura N, Azuma T, Misaki K et al (2021) Effectiveness and safety of subcutaneous abatacept in biologic-naïve RA patients at Week 52: a japanese multicentre investigational study (ORIGAMI study). Mod Rheumatol 32(3):1–11. https://doi.org/10.1093/mr/roab090
Tanaka Y, Matsubara T, Hashizume K, Amano N, Takeuchi T (2021) Efficacy and safety of abatacept in biologic-naïve patients with active rheumatoid arthritis by background methotrexate dose: post hoc analysis of a randomized, placebo-controlled, phase 4 study. Mod Rheumatol 32(3):1–8. https://doi.org/10.1093/mr/roab029
Takeuchi T, Tanaka Y, Soen S et al (2019) Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase. Ann Rheum Dis 78(7):899–907. https://doi.org/10.1136/annrheumdis-2018-214827
Tanaka S, Kobayashi M, Saito K, Takita A (2022) Correction to: impact of denosumab discontinuation on changes in bone mineral density and bone erosion in rheumatoid arthritis patients. Mod Rheumatol 32(2):292–295. https://doi.org/10.1093/mr/roab102
Mirzaei A, Jahed SA, Kadijani AA, Zabihiyeganeh M (2021) Risk of infection in postmenopausal women with rheumatoid arthritis and osteoporosis taking denosumab and bDMARDS. Med J Islam Repub Iran 35(1):1–4. https://doi.org/10.47176/mjiri.35.12
Smolen JS, Pangan AL, Emery P et al (2019) Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet 393(10188):2303–2311. https://doi.org/10.1016/S0140-6736(19)30419-2
Strand V, Mysler E, Moots RJ et al (2019) Patient-reported outcomes for tofacitinib with and without methotrexate, or adalimumab with methotrexate, in rheumatoid arthritis: a phase IIIB/IV trial. RMD Open 5(2):1–10. https://doi.org/10.1136/rmdopen-2019-001040
NCT01202760. A Rheumatoid Arthritis Study in Participants [Internet], 2010. http://cochranelibrarywiley.com/o/cochrane/clcentral/articles/205/CN-01524205/frame.html
Weinblatt ME, Baranauskaite A, Dokoupilova E et al (2018) Switching from reference adalimumab to SB5 (Adalimumab Biosimilar) in Patients With rheumatoid arthritis: fifty-two–week phase III randomized study results. Arthritis Rheumatol 70(6):832–840. https://doi.org/10.1002/art.40444
A Study of Certolizumab Pegol as Additional Therapy in Chinese Patients With Active Rheumatoid Arthri- tis (RAPID-C), NCT02151851. 2018.
Study to Assess the Short- and Long-term Efficacy of Certolizumab Pegol Plus Methotrexate Compared to Adalimumab Plus Methotrexate in Subjects With Moderate to Severe Rheumatoid Arthritis (RA) Inadequately Responding to Methotrexate.
Burmester GR, Kaeley GS, Kavanaugh AF et al (2017) Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab. RMD Open 3(2):1–9. https://doi.org/10.1136/rmdopen-2017-000465
Verschueren P, De Cock D, Corluy L et al (2015) Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial. Ann Rheum Dis 74(1):27–34. https://doi.org/10.1136/annrheumdis-2014-205489
Huang Y, Fan Y, Liu Y, Xie W, Zhang Z (2019) Efficacy and safety of secukinumab in active rheumatoid arthritis with an inadequate response to tumor necrosis factor inhibitors: a meta-analysis of phase III randomized controlled trials. Clin Rheumatol 38(10):2765–2776. https://doi.org/10.1007/s10067-019-04595-1
Bessette L, Haraoui B, Chow A et al (2019) Effectiveness and safety of certolizumab pegol in rheumatoid arthritis patients in canadian practice: 2-year results from the observational FαsT-CAN study. Ther Adv Musculoskelet Dis. https://doi.org/10.1177/1759720x19831151
Strand V, Tundia N, Song Y, Macaulay D, Fuldeore M (2016) Economic burden of non-responders to biologic DMARD treatments in rheumatoid arthritis. Arthritis Rheumatol 68:9–10
Thomson TM, Lescarbeau RM, Drubin DA et al (2015) Blood-based identification of non-responders to anti-TNF therapy in rheumatoid arthritis. BMC Med Genomics. https://doi.org/10.1186/s12920-015-0100-6
Yokoyama-Kokuryo W, Yamazaki H, Takeuchi T et al (2020) Identification of molecules associated with response to abatacept in patients with rheumatoid arthritis. Arthritis Res Ther 22(1):1–8. https://doi.org/10.1186/s13075-020-2137-y
Raterman HG, Vosslamber S, de Ridder S et al (2012) The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. Arthritis Res Ther 14(2):R95. https://doi.org/10.1186/ar3819
Kneepkens EL, Pascual-Salcedo D, Plasencia C et al (2013) Golimumab levels, anti-drug antibodies and clinical response in rheumatoid arthritis Patients at 28 week of follow-up: 1456. Arthritis Rheum 65:S618–S619. https://doi.org/10.1002/art.38216%0A
Benjamin O, Bansal P, Goyal A, Lappin SL (2021) Disease modifying anti-rheumatic drugs (DMARD). StatPearls Publishing, Treasure Island
Cho SK, Kim D, Won S et al (2017) Safety of resuming biologic DMARDs in patients who develop tuberculosis after anti-TNF treatment. Semin Arthritis Rheum 47(1):102–107. https://doi.org/10.1016/j.semarthrit.2017.01.004
Berger JR, Malik V, Lacey S, Brunetta P, Lehane PB (2018) Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event. J Neurovirol 24(3):323–331. https://doi.org/10.1007/s13365-018-0615-7
Aslani S, Mahmoudi M, Karami J, Jamshidi AR, Malekshahi Z, Nicknam MH (2016) Epigenetic alterations underlying autoimmune diseases. Autoimmunity 49(2):69–83. https://doi.org/10.3109/08916934.2015.1134511
Nile CJ, Read RC, Akil M, Duff GW, Wilson AG (2008) Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 58(9):2686–2693. https://doi.org/10.1002/art.23758
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(4):1087–1093. https://doi.org/10.1002/art.22512
Grabiec AM, Korchynskyi O, Tak PP, Reedquist KA (2012) Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay. Ann Rheum Dis 71(3):424–431. https://doi.org/10.1136/ard.2011.154211
Choo QY, Ho PC, Tanaka Y, Lin HS (2010) Histone deacetylase inhibitors MS-275 and SAHA induced growth arrest and suppressed lipopolysaccharide-stimulated NF-ΚB p65 nuclear accumulation in human rheumatoid arthritis synovial fibroblastic E11 cells. Rheumatology 49(8):1447–1460. https://doi.org/10.1093/rheumatology/keq108
Miao CG, Huang C, Huang Y et al (2013) MeCP2 modulates the canonical Wnt pathway activation by targeting SFRP4 in rheumatoid arthritis fibroblast-like synoviocytes in rats. Cell Signal 25(3):598–608. https://doi.org/10.1016/j.cellsig.2012.11.023
Steen-Louws C, Hartgring SAY, Popov-Celeketic J et al (2019) IL4-10 fusion protein: a novel immunoregulatory drug combining activities of interleukin 4 and interleukin 10. Clin Exp Immunol 195(1):1–9. https://doi.org/10.1111/cei.13224
Thiolat A, Denys A, Petit M et al (2014) Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice. Cytokine 69(1):87–93. https://doi.org/10.1016/j.cyto.2014.05.015
Ceribelli A, Nahid MA, Satoh M, Chan EKL (2011) MicroRNAs in rheumatoid arthritis. FEBS Lett 585(23):3667–3674. https://doi.org/10.1016/j.febslet.2011.05.020
Therapy AG, Deviatkin AA, Vakulenko YA, Akhmadishina LV, Tarasov VV (2020) Emerging concepts and challenges in rheumatoid. Biomedicines 8(1):9
Payet M, Dargai F, Gasque P, Guillot X (2021) Epigenetic regulation (Including micro-rnas, dna methylation and histone modifications) of rheumatoid arthritis: a systematic review. Int J Mol Sci 22(22):12170. https://doi.org/10.3390/ijms222212170
Li J, Song Q, Shao L, Zhang LL, Guo XH, Mao YJ (2018) MiR-124A inhibits proliferation and invasion of rheumatoid arthritis synovial fibroblasts. Eur Rev Med Pharmacol Sci 22(14):4581–4588
Ye Y, Gao X, Yang N (2018) LncRNA ZFAS1 promotes cell migration and invasion of fibroblast-like synoviocytes by suppression of miR-27a in rheumatoid arthritis. Hum Cell 31(1):14–21. https://doi.org/10.1007/s13577-017-0179-5
Zou Y, Xu S, Xiao Y et al (2018) Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation. J Clin Invest 128(10):4510–4524. https://doi.org/10.1172/JCI97965
Shui X, Chen S, Lin J, Kong J, Zhou C, Wu J (2019) Knockdown of lncRNA NEAT1 inhibits Th17/CD4+ T cell differentiation through reducing the STAT3 protein level. J Cell Physiol 234(12):22477–22484. https://doi.org/10.1002/jcp.28811
Zhang J, Huang X, Wang H et al (2015) The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Res Ther 6(1):1–7. https://doi.org/10.1186/s13287-015-0240-9
Causton B, Pardo-Saganta A, Gillis J et al (1998) Page 1 of 47 1. 409
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Prasad, P., Verma, S., Surbhi et al. Rheumatoid arthritis: advances in treatment strategies. Mol Cell Biochem 478, 69–88 (2023). https://doi.org/10.1007/s11010-022-04492-3
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DOI: https://doi.org/10.1007/s11010-022-04492-3