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 (RF). This period prior to 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 that should normally be transient, but instead is followed by systemic spread of the autoimmunity as manifest by serum autoantibody elevations, and ultimately drives 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.

Keywords: Autoimmune disease; Inflammation; Mucosa; Prevention; Rheumatoid arthritis.

Figure 1.. Natural history of RA development.

RA progresses through a series of stages first identified in first-degree relatives (FDR) by evidence of local mucosal ACPA production and inflammation at distinct sites in the absence of systemic autoantibodies, and is next characterized in a subset of those individuals by development of detectable circulating RA-specific autoimmunity, with or without arthralgias. The presence of systemic ACPA is followed by eventual progression in a very high proportion of individuals to symptoms and signs of joint involvement, and eventually clinically diagnosed and classifiable RA. Notably, there is the possibility of reversion at each step, although the likelihood diminishes as clinical disease further evolves.

Figure 2.. Model of RA development transitioning from local immune responses to systemic autoimmunity to inflammatory arthritis.

RA progresses through a process originating in mucosal sites (periodontum, mouth, intestine, lung, likely others) (A) where ACPA are produced locally, followed by spread to a systemic immune response identified through serum RA-related autoantibodies, IgA plasmablasts, and both B and T cell immune reactivity (B). This is followed by the development of arthritis (C).

Figure 3.. “Failed checkpoint” model of RA development as disease evolves from local immune responses to systemic autoimmunity and then inflammatory arthritis.

Shown are key steps during RA evolution where it appears that drivers of disease overcome normal mechanisms that restrain autoimmune disease development. Checkpoint #1: Mucosal microbiome homeostasis. Checkpoint #2: Mucosal barrier and cellular responses. Checkpoint #3. Adaptive immunity and expansion/spreading of autoimmune response. Checkpoint #4: Synovial inflammation and persistence thereof.