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.
Highlights
Ongomiizwin Indigenous Institute of Health and Healing, Rady Faculty of Health Sciences, Rheumatic Diseases Unit, Department of Internal Medicine, Rady Faculty of Health Sciences, Manitoba Center for Proteomics and Systems Biology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada; 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
Heritability of this disease, a phenomenon that has been called “missing heritability”. This discrepancy may partially relate to the finding that a substantial proportion of the genetic risk may be found in regulatory genomic segments rather than the expressed genome
Researchers have suggested that it is imperative that national guidelines and methodological processes for conducting randomized clinical trial (RCT) with Indigenous peoples be developed in order to have clearer directives and expectations for all those involved [22]
Summary
Further insights regarding the mechanism by which the positively charged QKRAA, QQRAA, and KKRAA SE sequences increase the risk of RA has come from studies demonstrating that the peptide-binding P4 pocket of the HLA-DRB1 molecule, for which the SE sequence forms the sidewall, presents citrullinated antigens efficiently to T cells [6]. This critical observation serves to mechanistically link the HLA genetic risk to the anti-citrullinated protein antibody [ACPA] response that is known to be the hallmark of seropositive RA. Y Y environmental triggers infections, pregnancy, stress clinical threshold arthralgia, other symptoms
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