Mechanism‐driven strategies for prevention of rheumatoid arthritis

Abstract

In seropositive rheumatoid arthritis (RA), the onset of clinically apparent inflammatory arthritis (IA) is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor. This period before clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA, and an "at-risk" status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA. With the goal of developing RA prevention strategies, studies have characterized immune phenotypes of preclinical RA/at-risk states. From these studies, a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production, which should normally be transient, but instead is followed by a systemic spread of the autoimmunity as manifested by serum autoantibody elevations, ultimately driving the development of clinically identified joint inflammation. This model can be envisioned as the progression of disease development through serial "checkpoints" that in principle should constrain or resolve autoimmunity; however, instead, the checkpoints "fail" and clinical RA develops. Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay, diminish, halt, or even reverse the progression to clinical RA. Notably, these prevention strategies could utilize existing therapies approved for clinical RA, therapies approved for other diseases that target relevant pathways in the preclinical/ at-risk state, or approaches that target novel pathways.

Alterações intestinais em pessoas com artrite reumatoide

“…Como a AR é uma doença inflamatória e autoimune, em que quadros de disfunção e/ou inflamação intestinal podem ser determinantes para sua expressão, dados respectivos à presença de muco e/ou coloração escura nas fezes foram colhidos para verificar fatores complementares que pudessem contribuir com a apresentação da enfermidade. O perfil sintomatológico fecal constitui importante cofator para auxiliar na determinação da presença ou ausência de quadros disbióticos, doenças e/ou outras disfunções intestinais que possam provocar liberação de biomarcadores pró-inflamatórios (Holers et al, 2022;Swidsinski et al, 2008;Cafiero et al, 2020). Entretanto, a maioria dos participantes relatou ausência de muco e/ou coloração escura nas fezes.…”

Editorial: The interplay between the oral Microbiota and rheumatoid arthritis

“…The detection of ACPAs in individuals devoid of articular symptoms suggests that these autoantibodies originate at extra-articular sites, and mucosal surfaces affected by an overlying dysbiosis were specifically incriminated. This is referred to as the "mucosal origins hypothesis" (22). In the case of periodontitis, this model is particularly supported by the finding that several periodontal pathogens can either citrullinated bacterial and host peptides as in the case of Porphyromonas gingivalis, or cause leukocyte hypercitrullination as in the case of Aggregatibacter actinomycetemcomitans, and thereby contribute to initiating an immune response against citrullinated epitopes.…”

Low-Intensity Physical Exercise Decreases Inflammation and Joint Damage in the Preclinical Phase of a Rheumatoid Arthritis Murine Model

“…Subsequently, active elements of the innate and adaptative immune response access the synovium, resulting in overt synovitis that is clinically detectable. The period before clinical inflammatory arthritis is designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA, and an at-risk status in those who exhibit predictive biomarkers of RA but have not developed inflammatory arthritis [ 2 , 3 , 4 , 5 ].…”