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

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.

Fig. 1

The figure presents an overview of the pathogenesis of rheumatoid arthritis, beginning with genetic and environmental factors, as well as the gut microbiome and autophagy, which together drive peptide citrullination. This process initiates immune activation, where dendritic cells present citrullinated peptides, leading to the activation and differentiation of naive T cells into Th1 and Th17 subtypes. These T-helper cells release key proinflammatory cytokines (IFN-γ, TNF-α, IL-6, and IL-17) that amplify inflammation. Simultaneously, B cells mature into plasma cells, producing autoantibodies such as rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA), which perpetuate joint inflammation. The elevated cytokine levels also activate macrophages and monocytes, disrupting the blood–brain barrier and potentially leading to neuronal damage, although this is an area of ongoing research. On a systemic level, the inflammation promotes synovial hyperplasia and fibroblast-like synoviocyte activation, leading to pannus formation, bone erosion, cartilage loss, and muscle atrophy. Therapeutic interventions targeting different points in this pathway are illustrated and correspond to treatments listed in Table 1. Created in BioRender. Paolone, G. (2025) https://BioRender.com/o18u392