Highly inflammatory rheumatoid arthritis patients more susceptible to cognitive impairment

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

Background

Rheumatoid arthritis (RA) is a chronic inflammatory illness that produces joint synovitis, resulting in joint deterioration and functional impairment. Patients frequently develop neurological and cognitive issues.

Despite advances in understanding the causes of RA, there is still a considerable gap in our understanding of how systemic inflammation influences cognitive function. Previous research reveals cognitive impairment in RA patients; however, the associations between inflammatory activity in RA and cognitive function are unclear.

About the study

In the present cross-sectional study, researchers comprehensively evaluated cognitive function among rheumatoid arthritis patients initiating biological treatment, investigating relationships between cognitive impairment in RA and inflammation, psychosocial factors, and life quality.

Between June 2022 and 2023, the researchers recruited RA patients aged 16 years and above, diagnosed using the 2010 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria. Eligible individuals had moderate-severe inflammation according to the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) despite conventional synthetic disease-modifying antirheumatic drug (csDMARD) treatment and did not undergo prior biological treatment. The researchers excluded individuals with rheumatic illnesses apart from RA or prior neurological disorders not related to the RA course.

The researchers matched RA patients started on biological therapy for moderate-severe inflammation to healthy controls (without inflammatory disease) for age, gender, and education. Participants underwent comprehensive neuropsychological evaluations for cognitive impairment, as determined using Montreal Cognitive Assessment (MoCA) scores below 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 below 3.2) and high activities (DAS28 score of 3.2 and above).

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

Results and discussion

The study included 140 individuals, divided equally into the RA and control groups, among whom 81% were female with a mean age of 56 years. Individuals with RA more frequently showed cognitive impairments than healthy controls (60% versus 40%) and lower mean MoCA scores (24 versus 25). Concerning MoCA subtests, the team noted more marked involvement among RA patients than among control individuals for the memory, abstraction, and visuospatial domains. In addition, individuals with RA showed lower executive function (specifically working memory) scores, assessed using the Strrop digit span backward assessment (4.0 versus 4.7).

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

Compared to individuals without cognitive impairment, cognitively impaired RA patients were older and less educated, with higher depression, poorer physical function, and more comorbidities such as dyslipidemia, arterial hypertension, obesity, and chronic inflammation, as indicated by DAS28 scores and CRP and IL-6 levels at follow-up.

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

Chronic systemic inflammation in RA affects the prefrontal cortex and the frontal-parietal-temporal circuit 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 systemic chronic inflammation, metabolic dysfunction, and cerebrovascular adverse effects that enhance pro-inflammatory cytokine production.

Conclusion

The study reveals that RA patients with high inflammatory activity are more likely to experience cognitive deficits, including memory, visuospatial, executive function, and abstraction. The impairment is associated with age, a lower level of education, and fat.

The study underlines the need to control inflammation and comorbidity early in RA care and develop innovative therapeutic techniques to reduce the risk of cognitive impairment. Rheumatoid arthritis requires a comprehensive strategy that considers both clinical and psychological factors. Early diagnosis and monitoring of cognitive function in RA patients are critical.