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Rheumatoid Arthritis and Cognition: Is There a Genetic Link?

Noted genetic risks behind RA offer insight into the connections between the immune system and mental health and encourage clinicians to assess for such issues.

with Tiziano Marovino, DPT, MPH, DAIPM, and Hannah Jones, PhD

Scientists and clinicians have long recognized the association between rheumatoid arthritis (RA) and cognitive and psychiatric problems, although research is lacking on what may account for this link. Some have theorized that medications and other direct or indirect effects of RA—such as pain, decreased activity, or social isolation—play a role.1,2

Unfortunately, testing for any potential links is problematic; when the disease is active, it can be difficult to isolate the factors involved. “Most studies have looked at RA populations and correlated [them] with cognitive disorders, [but it has not been made clear whether] the correlations were confounded by specific disease effects and/or effects from RA treatments, such as corticosteroids,” explained Tiziano Marovino, DPT, MPH, DAIPM, Chief of Health Strategy and Innovation at the Biogenesis Group and a member of the PPM editorial board.

Recently, however, a team of researchers3 from the University of Bristol and Cardiff University used a novel approach to simplify these factors. What they found raises interesting and potentially useful insight into the emerging links between mental health and the immune system.

Researchers tested IQ scores in children using a short form of the Wechsler Intelligence Scale for Children. (Source: 123RF)

Data Assessed in Childhood

Researchers analyzed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a study designed to examine how genetics and environment influence health. ALSPAC data includes health assessments from birth for all children in the cohort. In addition, genetic data was available for 7,977 of the children and adolescents.4

“We focused on studying these relationships in childhood, as we were interested in associations prior to the clinical onset of disease and therefore in the absence of disease-related factors,” lead author Hannah Jones, PhD, senior research associate in epidemiology at Bristol University, told PPM.

Using an ALSPAC searchable database, the researchers were able to construct polygenic risk scores (PRS) for three autoimmune illnesses: RA, multiple sclerosis (MS), and inflammatory bowel disease (IBD). Risks for MS and IBD were included in order to examine the selectivity of the results to RA. The team then compared the information on subjects’ symptoms for these three conditions from testing conducted at clinical visits related to cognitive and psychiatric illness (ie, anxiety, depression, psychotic experiences, attention-deficit/hyperactivity disorder).

The team also tested children using a short form of the Wechsler Intelligence Scale for Children (total IQ, performance IQ, verbal IQ, working memory, verbal learning, processing speed, and problem solving; an additional measure of IQ was also captured at age 15 years using the Wechsler Abbreviated Scale of Intelligence) and Test of Everyday Attention for Children (selective attention and attentional control).

Genetic Risks Found with RA

The study found that, at 8 years old, the PRS for RA was associated with a lower IQ, particularly in verbal function, a finding which fits with previous studies.2 There was, however, little evidence of an association between lower IQ scores and PRS for MS or IBD. In children age 4 to 16, a genetic predisposition for RA was associated with increased odds of hyperactive and inattentive symptoms, the strongest evidence of the association being at age 13.

The researchers wrote in their published report that these findings support, “a primary etiological association between genetic risk for RA and neural phenotypes that [are] not simply secondary to disease-related processes or reverse causation.” They added that their “results are also broadly in keeping with the finding that attention is a domain of cognition particularly affected in patients with RA, although the current findings suggest a particularly strong association of genetic risk for RA with attention during childhood development.”

The team found little association between anxiety and depression among subjects with rheumatoid arthritis PRS. However, these symptoms are common in patients with RA, which suggests that anxiety and depression may be caused by disease-associated factors, such as pain, social isolation, and certain medications.

Implications for Clinicians

Rheumatoid arthritis is generally considered a connective-tissue disorder and not a disorder of the brain, despite evidence of its effect on neurological function.1 These new findings indicate that clinicians should take central nervous system (CNS) function into account as part of evaluation and management of the disease.

“The study does lend support to the notion that RA is perhaps not just a connective tissue disorder,” Dr. Marovino said, “and providers should consider the CNS ramifications given the evidence we do have, including this study, that supports a link between cognitive disorder and RA through immune system functions.”

Added Dr. Jones, “Our results suggest that cognitive difficulties should be considered as a component of RA that are not just secondary to disease-related factors. It may also be important to assess and monitor cognitive impairment in patients with RA, especially as cognitive factors impact activities of daily living.”

In addition to highlighting the need for taking cognitive function into account when treating RA, this research may provide insight and future direction for the study of the immune system’s role in cognitive function. “One benefit from this study is that it provides more evidence for the role of the immune system in pathologies that we did not know might be related, which also provides investigators other areas for research to identify novel treatment strategies aimed at ameliorating psychological impairments,” Dr. Marovino noted.

Last updated on: October 11, 2019
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