Patients with highly inflammatory rheumatoid arthritis are more susceptible to cognitive impairment

In a recent study published in RMD openResearchers assessed cognitive function in rheumatoid arthritis (RA) patients with ongoing inflammatory activity.

Background

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes inflammation of the synovial membrane of the joints, leading to joint deterioration and functional impairment. Patients often develop neurological and cognitive problems.

Despite advances in understanding the causes of RA, there is still a significant gap in our understanding of how systemic inflammation affects cognitive function. Previous studies have revealed impaired cognitive function in RA patients; however, the links between inflammatory activity in RA and cognitive function are unclear.

About the study

In this cross-sectional study, researchers performed a comprehensive assessment of cognitive function in patients with rheumatoid arthritis starting biologic therapy, examining the associations between cognitive impairment in RA and inflammation, psychosocial factors, and quality of life.

From June 2022 to 2023, researchers recruited patients with RA aged 16 years and older diagnosed according to the 2010 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria. Eligible individuals had moderately severe inflammation according to the 28-joint Disease Activity Score with ESR (DAS28-ESR) despite conventional treatment with synthetic disease-modifying antirheumatic drugs (csDMARDs) and no prior biologic therapy. Researchers excluded individuals with rheumatic diseases other than RA or previous neurological disorders unrelated to RA.

The researchers matched RA patients who were started on biologic therapy to control moderate to severe inflammation with vigorous controls (without inflammatory disease) for age, sex, and education. Participants underwent comprehensive neuropsychological assessments for cognitive impairment, defined by Montreal Cognitive Assessment (MoCA) scores of less than 26. Other assessments included the Stroop cognitive test, Hospital Anxiety and Depression Scale (HADS), Quality of Life-RA Scale II (QOL-RA II), and the 28-joint Disease Activity Score (DAS28)—C-reactive protein (CRP) levels as low (DAS28 score less than 3.2) and high (DAS28 score 3.2 or higher).

The team used multivariate logistic regressions to determine odds ratios (ORs) for analysis. Study variables included race, date of birth, and comorbidities such as smoking, alcohol consumption, hypertension, obesity, diabetes, dyslipidemia, and previous cardiovascular disease. The researchers also recorded symptom onset, date of diagnosis, disease duration, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, interleukin 6 (IL-6), Health Assessment Questionnaire, Spanish version (HAQ) scores, and erosions.

Results and discussion

The study included 140 people, evenly divided into RA and control groups, 81% of whom were women with an average age of 56. People with RA were more likely to have cognitive impairment than vigorous controls (60% vs. 40%) and lower average MoCA scores (24 vs. 25). When it came to MoCA subtests, the team noted more pronounced engagement in RA patients than in control subjects in the domains of memory, abstraction, and visuospatial. In addition, people with RA showed lower executive function scores (particularly working memory), as assessed by Strap’s backward digit span (4.0 vs. 4.7).

RA patients were more depressed and had a poorer quality of life. The team observed frail and negative but significant correlations between MoCA scores, age, HAQ, DAS28-CRP, IL-6, and CRP, while moderate and positive correlations were observed with cognitive tests. They also observed statistically significant correlations between the Stroop finger span reverse test and mean levels of DAS28-CRP, IL-6, and CRP.

Compared with individuals without cognitive impairment, patients with rheumatoid arthritis and cognitive impairment were older and less educated, more likely to suffer from depression, had poorer physical function, and more comorbidities, such as dyslipidemia, hypertension, obesity, and chronic inflammation, as evidenced by DAS28 scores and CRP and IL-6 levels during follow-up.

Logistic regressions showed that older RA patients (OR, 1.0) and lower MoCA scores (OR, 3.0) had a higher risk of cognitive impairment, and those with a secondary education or higher had a lower risk (OR, 0.2). However, limiting the study sample to RA patients showed that the factors contributing most to the risk of cognitive impairment were obesity (OR, 6.0) and inflammation during the course of the disease, as indicated by DAS28 scores (OR, 2.4) and mean CRP (OR, 1.1). Modeling with IL-6 expression yielded similar results.

Chronic systemic inflammation in RA affects the prefrontal cortex and frontal-parietal-temporal circuit of the brain, leading to neuroinflammation, endothelial dysfunction, and cognitive decline. IL-6 potentiates neuroinflammation by activating glial cells, increasing blood-brain barrier (BBB) ​​permeability, and modulating neurotransmission. Obesity in RA patients leads to cognitive impairment due to chronic systemic inflammation, metabolic dysfunction, and cerebrovascular side effects that raise the production of proinflammatory cytokines.

Application

The study reveals that RA patients with high inflammatory activity are more likely to experience cognitive deficits, including memory, visuospatial, executive, and abstract functions. Impairment is associated with age, lower education level, and obesity.

The study highlights the need to control inflammation and comorbidities early in the course of RA treatment and to develop creative therapeutic techniques to reduce the risk of cognitive impairment. Rheumatoid arthritis requires a comprehensive strategy that addresses both clinical and psychological factors. Early diagnosis and monitoring of cognitive function in RA patients is crucial.