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Drugs & Aging
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Open Access 15-03-2025 | Rheumatoid Arthritis | Review Article

Impact of Disease-Modifying Antirheumatic Drugs on Cognitive Function in Older Adults with Rheumatoid Arthritis

Authors: Seyedeh D. Fazel, Massimo Carollo, Lisanne Tap, Andrea Spini, Gianluca Trifirò, Francesco U. S. Mattace-Raso

Published in: Drugs & Aging | Issue 4/2025

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Abstract

Cognitive impairment poses significant challenges for aging populations. Systemic inflammation, a hallmark of rheumatoid arthritis (RA), has been implicated in neurodegeneration through mechanisms including blood–brain barrier disruption, microglial activation, and cytokine-mediated neuronal damage. This review examines the potential impact of disease-modifying antirheumatic drugs (DMARDs) on cognitive function in RA, focusing on the inflammatory pathways linking systemic inflammation to neuroinflammation and cognitive decline. DMARDs, categorized into conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic (tsDMARDs) classes, modulate immune responses through distinct mechanisms. Evidence suggests that DMARDs, particularly bDMARDs targeting proinflammatory cytokines such as TNF-α and IL-6, may mitigate neuroinflammatory processes and preserve cognitive function. However, the cognitive impact of csDMARDs such as methotrexate is complex, with conflicting reports regarding its role in vascular dementia. Emerging therapies such as Janus kinase inhibitors (JAK-i) offer promise in modulating central inflammation, though clinical evidence remains limited. While some studies highlight protective effects of DMARDs against dementia, findings are inconsistent, hindered by heterogeneity in study design, patient demographics, and cognitive assessment methods. This review underscores the need for personalized treatment strategies, integrating RA management with cognitive health considerations. Future research should prioritize robust, prospective studies with long-term follow-up, incorporating neuroimaging and biomarker analysis to elucidate the mechanisms underpinning DMARD-associated cognitive outcomes. A better understanding of the involved inflammatory pathways in RA and the potential effects of DMARDs could lead to improved therapeutic approaches, enhancing quality of life for patients with RA and potentially benefiting broader strategies in preventing or treating dementia.
Literature
1.
Tahami Monfared AA, Khachatryan A, Hummel N, Kopiec A, Martinez M, Zhang R, Zhang Q. Assessing quality of life, economic burden, and independence across the alzheimer’s disease continuum using patient-caregiver Dyad surveys. J Alzheimers Dis. 2024;99(1):191–206.PubMedPubMedCentralCrossRef
2.
Fulop T, Larbi A, Witkowski JM, McElhaney J, Loeb M, Mitnitski A, Pawelec G. Aging, frailty and age-related diseases. Biogerontology. 2010;11(5):547–63.PubMedCrossRef
3.
4.
Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement. 2015;11(6):718–26.PubMedCrossRef
5.
Evans LE, Taylor JL, Smith CJ, Pritchard HAT, Greenstein AS, Allan SM. Cardiovascular comorbidities, inflammation, and cerebral small vessel disease. Cardiovasc Res. 2021;117(13):2575–88.PubMed
6.
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135–43.PubMedCrossRef
7.
8.
Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, et al. Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2011;127(3):701-21.e170.PubMedCrossRef
9.
Süß P, Rothe T, Hoffmann A, Schlachetzki JCM, Winkler J. The joint-brain axis: insights from rheumatoid arthritis on the crosstalk between chronic peripheral inflammation and the brain. Front Immunol. 2020;11: 612104.PubMedPubMedCentralCrossRef
10.
Mason A, Holmes C, Edwards CJ. Inflammation and dementia: using rheumatoid arthritis as a model to develop treatments? Autoimmun Rev. 2018;17(9):919–25.PubMedCrossRef
11.
Sousa DC, de Almeida SB, Roriz Filho JS, Freitas TH, Braga-Neto P. Cognitive dysfunction biomarkers in patients with rheumatoid arthritis: a systematic review. J Clin Rheumatol. 2023;29(3):159–64.PubMedCrossRef
12.
Ungprasert P, Wijarnpreecha K, Thongprayoon C. Rheumatoid arthritis and the risk of dementia: a systematic review and meta-analysis. Neurol India. 2016;64(1):56–61.PubMedCrossRef
13.
Mena-Vázquez N, Ortiz-Márquez F, Ramírez-García T, Cabezudo-García P, García-Studer A, Mucientes-Ruiz A, et al. Impact of inflammation on cognitive function in patients with highly inflammatory rheumatoid arthritis. RMD Open. 2024;10(2): e004422.PubMedPubMedCentralCrossRef
14.
Mueller AL, Payandeh Z, Mohammadkhani N, Mubarak SMH, Zakeri A, Alagheband Bahrami A, et al. Recent advances in understanding the pathogenesis of rheumatoid arthritis: new treatment strategies. Cells. 2021;10(11):3017.PubMedPubMedCentralCrossRef
15.
Basile MS, Ciurleo R, Bramanti A, Petralia MC, Fagone P, Nicoletti F, Cavalli E. Cognitive decline in rheumatoid arthritis: insight into the molecular pathogenetic mechanisms. Int J Mol Sci. 2021;22(3):1185.PubMedPubMedCentralCrossRef
16.
17.
Chi GC, Fitzpatrick AL, Sharma M, Jenny NS, Lopez OL, DeKosky ST. Inflammatory biomarkers predict domain-specific cognitive decline in older adults. J Gerontol A Biol Sci Med Sci. 2017;72(6):796–803.PubMed
18.
McDowell B, Marr C, Holmes C, Edwards CJ, Cardwell C, McHenry M, et al. Prevalence of cognitive impairment in patients with rheumatoid arthritis: a cross sectional study. BMC Psychiatry. 2022;22(1):777.PubMedPubMedCentralCrossRef
19.
Cooper J, Pastorello Y, Slevin M. A meta-analysis investigating the relationship between inflammation in autoimmune disease, elevated CRP, and the risk of dementia. Front Immunol. 2023;14:1087571.PubMedPubMedCentralCrossRef
20.
Wang YC, Lin MS, Huang AP, Wu CC, Kung WM. Association between systemic rheumatic diseases and dementia risk: a meta-analysis. Front Immunol. 2022;13:1054246.PubMedPubMedCentralCrossRef
21.
Zhang C, Wang Y, Wang D, Zhang J, Zhang F. NSAID exposure and risk of Alzheimer’s disease: an updated meta-analysis from cohort studies. Front Aging Neurosci. 2018;10:83.PubMedPubMedCentralCrossRef
22.
Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320(13):1360–72.PubMedCrossRef
23.
Feely MG, O’Dell JR. Update on the use of conventional disease-modifying antirheumatic drugs in the management of rheumatoid arthritis. Curr Opin Rheumatol. 2010;22(3):316–20.PubMedCrossRef
24.
25.
Tanaka Y. Recent progress in treatments of rheumatoid arthritis: an overview of developments in biologics and small molecules, and remaining unmet needs. Rheumatology (Oxford). 2021;60(Suppl 6):vi12–20.PubMedCrossRef
26.
Kerschbaumer A, Sepriano A, Bergstra SA, Smolen JS, van der Heijde D, Caporali R, et al. Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2023;82(1):95–106.PubMedCrossRef
27.
Sramek M, Neradil J, Veselska R. Much more than you expected: the non-DHFR-mediated effects of methotrexate. Biochim Biophys Acta Gen Subj. 2017;1861(3):499–503.PubMedCrossRef
28.
Riksen NP, Barrera P, van den Broek PH, van Riel PL, Smits P, Rongen GA. Methotrexate modulates the kinetics of adenosine in humans in vivo. Ann Rheum Dis. 2006;65(4):465–70.PubMedPubMedCentralCrossRef
29.
van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ, Thomas CM, et al. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford). 2002;41(6):658–65.PubMedCrossRef
30.
Mahadeo KM, Dhall G, Panigrahy A, Lastra C, Ettinger LJ. Subacute methotrexate neurotoxicity and cerebral venous sinus thrombosis in a 12-year-old with acute lymphoblastic leukemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: homocysteine-mediated methotrexate neurotoxicity via direct endothelial injury. Pediatr Hematol Oncol. 2010;27(1):46–52.PubMedCrossRef
31.
Chou MH, Wang JY, Lin CL, Chung WS. DMARD use is associated with a higher risk of dementia in patients with rheumatoid arthritis: a propensity score-matched case-control study. Toxicol Appl Pharmacol. 2017;1(334):217–22.CrossRef
32.
Leitner GR, Wenzel TJ, Marshall N, Gates EJ, Klegeris A. Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders. Expert Opin Ther Targets. 2019;23(10):865–82.PubMedCrossRef
33.
Zhou Y, Chen Y, Xu C, Zhang H, Lin C. TLR4 Targeting as a promising therapeutic strategy for alzheimer disease treatment. Front Neurosci. 2020;14: 602508.PubMedPubMedCentralCrossRef
34.
Varma VR, Desai RJ, Navakkode S, Wong LW, Anerillas C, Loeffler T, et al. Hydroxychloroquine lowers Alzheimer’s disease and related dementias risk and rescues molecular phenotypes related to Alzheimer’s disease. Mol Psychiatry. 2023;28(3):1312–26.PubMedCrossRef
35.
36.
Hamm BS, Rosenthal LJ. Psychiatric Aspects of chloroquine and hydroxychloroquine treatment in the wake of coronavirus disease-2019: psychopharmacological interactions and neuropsychiatric sequelae. Psychosomatics. 2020;61(6):597–606.PubMedPubMedCentralCrossRef
37.
Alamri RD, Elmeligy MA, Albalawi GA, Alquayr SM, Alsubhi SS, El-Ghaiesh SH. Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: a comprehensive review. Int Immunopharmacol. 2021;93: 107398.PubMedPubMedCentralCrossRef
38.
Garnock-Jones KP. Teriflunomide: a review of its use in relapsing multiple sclerosis. CNS Drugs. 2013;27(12):1103–23.PubMedCrossRef
39.
Cronstein BN, Montesinos MC, Weissmann G. Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFkappaB. Proc Natl Acad Sci U S A. 1999;96(11):6377–81.PubMedPubMedCentralCrossRef
40.
Jørgensen KA, Koefoed-Nielsen PB, Karamperis N. Calcineurin phosphatase activity and immunosuppression: a review on the role of calcineurin phosphatase activity and the immunosuppressive effect of cyclosporin A and tacrolimus. Scand J Immunol. 2003;57(2):93–8.PubMedCrossRef
41.
Anstey A, Lear JT. Azathioprine: clinical pharmacology and current indications in autoimmune disorders. BioDrugs. 1998;9(1):33–47.PubMedCrossRef
42.
Karlsson M, Pukenas B, Chawla S, Ehinger JK, Plyler R, Stolow M, et al. Neuroprotective effects of cyclosporine in a porcine pre-clinical trial of focal traumatic brain injury. J Neurotrauma. 2018;36(1):14–24.PubMedPubMedCentralCrossRef
43.
44.
Patocka J, Nepovimova E, Kuca K, Wu W. Cyclosporine A: chemistry and toxicity—A review. Curr Med Chem. 2021;28(20):3925–34.PubMedCrossRef
45.
Huang LC, Chang YH, Yang YH. Can disease-modifying anti-rheumatic drugs reduce the risk of developing dementia in patients with rheumatoid arthritis? Neurotherapeutics. 2019;16(3):703–9.PubMedPubMedCentralCrossRef
46.
Kodishala C, Hulshizer CA, Kronzer VL, Davis JM 3rd, Ramanan VK, Vassilaki M, et al. Risk factors for dementia in patients with incident rheumatoid arthritis: a population-based cohort study. J Rheumatol. 2023;50(1):48–55.PubMedCrossRef
47.
Kern DM, Lovestone S, Cepeda MS. Treatment with TNF-α inhibitors versus methotrexate and the association with dementia and Alzheimer’s disease. Alzheimers Dement (N Y). 2021;7(1): e12163.PubMedCrossRef
48.
Marr C, McDowell B, Holmes C, Edwards CJ, Cardwell C, McHenry M, et al. The RESIST study: examining cognitive change in rheumatoid arthritis patients with mild cognitive impairment being treated with a TNF-inhibitor compared to a conventional synthetic disease-modifying anti-rheumatic drug. J Alzheimers Dis. 2024;99(1):161–75.PubMedCrossRef
49.
Smolen JS, Landewé RBM, Bergstra SA, Kerschbaumer A, Sepriano A, Aletaha D, 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.PubMedCrossRef
50.
Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, Carandang K, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021;73(7):924–39.PubMedCrossRef
51.
Newby D, Prieto-Alhambra D, Duarte-Salles T, Ansell D, Pedersen L, van der Lei J, et al. Methotrexate and relative risk of dementia amongst patients with rheumatoid arthritis: a multi-national multi-database case-control study. Alzheimers Res Ther. 2020;12(1):38.PubMedPubMedCentralCrossRef
52.
Zhou M, Xu R, Kaelber DC, Gurney ME. Tumor necrosis factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS ONE. 2020;15(3): e0229819.PubMedPubMedCentralCrossRef
53.
Sattui SE, Navarro-Millan I, Xie F, Rajan M, Yun H, Curtis JR. Incidence of dementia in patients with rheumatoid arthritis and association with disease modifying anti-rheumatic drugs: analysis of a national claims database. Semin Arthritis Rheum. 2022;57: 152083.PubMedCrossRef
54.
Zafeiridi E, McMichael A, Mirakhur A, McHenry M, Holmes C, McGuinness B. Are tumour necrosis factor inhibitor drugs associated with a lower risk of dementia? Int J Geriatr Psychiatry. 2020;35(7):802–3.PubMedCrossRef
55.
Meade T, Manolios N, Cumming SR, Conaghan PG, Katz P. Cognitive Impairment in rheumatoid arthritis: a systematic review. Arthritis Care Res (Hoboken). 2018;70(1):39–52.PubMedCrossRef
56.
Oláh C, Schwartz N, Denton C, Kardos Z, Putterman C, Szekanecz Z. Cognitive dysfunction in autoimmune rheumatic diseases. Arthritis Res Ther. 2020;22(1):78.PubMedPubMedCentralCrossRef
57.
Shao Y, Tan B, Shi J, Zhou Q. Methotrexate induces astrocyte apoptosis by disrupting folate metabolism in the mouse juvenile central nervous system. Toxicol Lett. 2019;301:146–56.PubMedCrossRef
58.
McGuinness B, Holmes C, Mirakhur A, Kearsley-Fleet L, Vieira R, Watson K, et al. The influence of TNF inhibitors on dementia incidence in patients with rheumatoid arthritis; an analysis from the BSRBR-RA. Int J Geriatr Psychiatry. 2018;33(3):556–8.PubMedCrossRef
59.
Chou RC, Kane M, Ghimire S, Gautam S, Gui J. Treatment for rheumatoid arthritis and risk of Alzheimer’s disease: a nested case-control analysis. CNS Drugs. 2016;30(11):1111–20.PubMedPubMedCentralCrossRef
60.
Zheng C, Fillmore NR, Ramos-Cejudo J, Brophy M, Osorio R, Gurney ME, et al. Potential long-term effect of tumor necrosis factor inhibitors on dementia risk: a propensity score matched retrospective cohort study in US veterans. Alzheimers Dement. 2022;18(6):1248–59.PubMedCrossRef
61.
Desai RJ, Varma VR, Gerhard T, Segal J, Mahesri M, Chin K, et al. Comparative risk of alzheimer disease and related dementia among medicare beneficiaries with rheumatoid arthritis treated with targeted disease-modifying antirheumatic agents. JAMA Netw Open. 2022;5(4): e226567.PubMedPubMedCentralCrossRef
62.
Santoro A, Bientinesi E, Monti D. Immunosenescence and inflammaging in the aging process: age-related diseases or longevity? Ageing Res Rev. 2021;71: 101422.PubMedCrossRef
63.
Zhang W, Sun HS, Wang X, Dumont AS, Liu Q. Cellular senescence, DNA damage, and neuroinflammation in the aging brain. Trends Neurosci. 2024;47(6):461–74.PubMedCrossRef
64.
Wang Y, Kuca K, You L, Nepovimova E, Heger Z, Valko M, et al. The role of cellular senescence in neurodegenerative diseases. Arch Toxicol. 2024;98(8):2393–408.PubMedPubMedCentralCrossRef
65.
West E, Stuckelberger A, Pautex S, Staaks J, Gysels M. Operationalising ethical challenges in dementia research: a systematic review of current evidence. Age Ageing. 2017;46(4):678–87.PubMed
66.
Ingrasciotta Y, Spini A, L’Abbate L, Fiore ES, Carollo M, Ientile V, et al. Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: an external validity analysis of 66,639 biologic users from the Italian VALORE project. Pharmacol Res. 2024;200: 107074.PubMedCrossRef
67.
Götzelmann TG, Strech D, Kahrass H. The full spectrum of ethical issues in dementia research: findings of a systematic qualitative review. BMC Med Ethics. 2021;22(1):32.PubMedPubMedCentralCrossRef
68.
Teague S, Youssef GJ, Macdonald JA, Sciberras E, Shatte A, Fuller-Tyszkiewicz M, et al. Retention strategies in longitudinal cohort studies: a systematic review and meta-analysis. BMC Med Res Methodol. 2018;18(1):151.PubMedPubMedCentralCrossRef
69.
Abshire M, Dinglas VD, Cajita MI, Eakin MN, Needham DM, Himmelfarb CD. Participant retention practices in longitudinal clinical research studies with high retention rates. BMC Med Res Methodol. 2017;17(1):30.PubMedPubMedCentralCrossRef
70.
Miranda A, Rubovits E, Mudar R, Leung V, Raj M. Where are caregivers in the clinical trial? Evaluation of caregiver responsibilities in Alzheimer’s disease and related dementias clinical trials. Alzheimers Dement. 2023;19(11):5316–22.PubMedCrossRef
71.
72.
van der Togt CJT, Van den Bemt B, Aletaha D, Alten R, Chatzidionysiou K, Galloway J, et al. Points to consider for cost-effective use of biological and targeted synthetic DMARDs in inflammatory rheumatic diseases: results from an umbrella review and international Delphi study. RMD Open. 2023;9(1): e002898.PubMedPubMedCentralCrossRef
73.
Prawjaeng J, Leelahavarong P, Budtarad N, Pilasant S, Chanjam C, Katchamart W, et al. Cost-utility analysis of biologic disease-modifying antirheumatic drugs (bDMARDs), targeted synthetic DMARDs (tsDMARDs) and biosimilar DMARDs (bsDMARDs) combined with methotrexate for Thai rheumatoid arthritis patients with high disease activity. BMC Health Serv Res. 2023;23(1):561.PubMedPubMedCentralCrossRef
74.
Berger S, Moseholm KF, Hegelund ER, Tesch F, Nguyen MCS, Mortensen LH, et al. Association of tumor necrosis factor-α inhibitors with incident dementia: analysis based on population-based cohort studies. Drugs Aging. 2024;41(5):423–30.PubMedPubMedCentralCrossRef
Metadata
Title
Impact of Disease-Modifying Antirheumatic Drugs on Cognitive Function in Older Adults with Rheumatoid Arthritis
Authors
Seyedeh D. Fazel
Massimo Carollo
Lisanne Tap
Andrea Spini
Gianluca Trifirò
Francesco U. S. Mattace-Raso
Publication date
15-03-2025
Publisher
Springer International Publishing
Published in
Drugs & Aging / Issue 4/2025
Print ISSN: 1170-229X
Electronic ISSN: 1179-1969
DOI
https://doi.org/10.1007/s40266-025-01190-9

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