Can Studying Genetically Predisposed Individuals Inform Prevention Strategies for RA?

Abstract

Rheumatoid arthritis (RA) is a prevalent autoimmune disorder in which complex genetic predisposition interacts with multiple environmental factors to precipitate chronic and progressive immune-mediated joint inflammation. Currently, in most affected individuals, ongoing suppression of the inflammation is required to prevent irreversible damage and functional loss. The delineation of a protracted preclinical period in which autoimmunity is initially established and then evolves to become pathogenic provides unprecedented opportunities for interventions that have the potential to prevent the onset of this lifelong disease. Clinical trials aimed at assessing the impact of specific prevention strategies require the identification of individuals who are at high risk of future RA development. Currently, these risk factors include a strong family history of RA, and the detection of circulating RA-associated autoantibodies, particularly anti-citrullinated protein antibodies (ACPA). Yet, even in such individuals, there remains considerable uncertainty about the likelihood and the timeframe for future disease development. Thus, individuals who are approached to participate in such clinical trials are left weighing the risks and benefits of the prevention measures, while having large gaps in our current understanding. To address this challenge, we have undertaken longitudinal studies of the family members of Indigenous North American RA patients, this population being known to have a high prevalence of RA, early age of onset, and familial clustering of cases. Our studies have indicated that the concepts of “risk” and “prevention” need to be communicated in a culturally relevant manner, and proposed prevention interventions need to have an appropriate balance of effectiveness, safety, convenience, and cultural acceptability. We have focused our proposed prevention studies on immunomodulatory/anti-inflammatory nutritional supplements that appear to strike such a complex balance.

Precision health equity for racialized communities

“…Second, they must identify and validate genomic markers that existing catalogs do not already document. If such data were incorporated into the deployment of precision medicine, such a tool might afford a diversity of racialized communities vital access to preventative and diagnostic care for whom the current reality is to typically treat health conditions in acute care contexts [6][7][8][9][10].…”

“…Similar to accounts about the sacred nature of blood and DNA to Indigenous communities in Canada or the United States, many racialized communities from the global South—differentiated as they certainly are—attribute special (and varying) meanings to blood and tissue also [ 22 , 45 , 46 ]. Nevertheless, the benefit of access to preventative and diagnostic care which precision medicine can possibly offer makes it of interest to some, but certainly not all, racialized communities based on their health priorities, cultural understandings of health and wellness, and collective decisions [ 8 , 22 , 45 ].…”

A Roadmap for Investigating Preclinical Autoimmunity Using Patient-Oriented and Epidemiologic Study Designs: Example of Rheumatoid Arthritis

“…Researchers at the University of Manitoba have assembled a cohort of Indigenous North Americans (INA) with RA and their relatives since 2005 ( 103 ). This prospective cohort was recruited from Cree and Ojibwe populations at urban and rural medical centers in Manitoba and Saskatchewan, Canada.…”

“…The study population being enriched for RA risk factors such as genetics, smoking, and socioeconomic factors, the investigators were able to focus on a population well at risk for developing RA. Probands had a diagnosis of RA according to the ACR 1987 criteria and both probands and relatives were over the age of 18 and self-identified as Indigenous North Americans ( 103 ). A cohort of controls without RA and with no first-degree relatives with RA was recruited from the same population ( 103 ).…”

“…Probands had a diagnosis of RA according to the ACR 1987 criteria and both probands and relatives were over the age of 18 and self-identified as Indigenous North Americans ( 103 ). A cohort of controls without RA and with no first-degree relatives with RA was recruited from the same population ( 103 ).…”