The pathophysiology is incompletely understood, but some individuals develop autoantibodies characteristic of RA, rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA). The presence of such antibodies puts individuals at increased risk of disease development, although some test positive for such antibodies without symptoms for many years, and individuals with seronegative RA never develop such antibodies.5
Some individuals eventually develop joint symptoms but without clear-cut synovitis that can be identified on exam. For some, these symptoms can be quite significant, potentially affecting their employment. A subset of these individuals have subclinical joint inflammation (e.g., low levels of inflammation that can be detected on ultrasound or magnetic resonance imaging [MRI]), although this is sometimes transient.6
Most individuals who eventually develop seropositive RA go through this initial period of elevated antibodies and joint symptoms before they develop clinically apparent RA with synovitis. These early stages (before clinically apparent RA) involve limited systemic inflammation, which in some patients is followed by expansion of innate and adaptive immune responses and consequent tissue injury.5
The terminology surrounding these disease states will probably evolve and become more formalized. A EULAR study group suggested that the term “pre-RA” should be used only retrospectively to describe any of these earlier phases of disease in someone who has developed clinically apparent RA, but the term is also sometimes applied non-retrospectively.7
Some groups prefer the term preclinical RA to describe people who, to varying degrees, are at high risk of progression to clinically apparent RA. Individuals can also be described as being at high risk for RA, which can be quantified via scoring systems.8 EULAR has defined a phenotype based on clinical characteristics, clinically suspected arthralgia (CSA), which is characterized by joint symptoms without clinically apparent synovitis.9
Existing intervention trials in patients at high risk for clinically defined RA have used slightly different criteria for inclusion (e.g., in terms of whether joint pain must be present, antibody positivity and imaging criteria). These differences can complicate interpretation and comparisons among studies.10
High-Risk RA/Pre-RA Trials
Several trials have explored whether early interventions in groups at high risk for RA may delay or prevent the development of clearly apparent synovitis and the definite diagnosis of RA as defined by current classification criteria. They have also explored the effectiveness of decreasing existing symptom burden in such patients. But before APIPPRA and ARIAA, none had met their clinical end points.1,2
