Multiple genetic and environmental factors have been associated with an increased risk for rheumatoid arthritis (RA). Of these, the strongest associations have been seen with female sex, a family history of RA, the genetic factor the "shared epitope," and exposure to tobacco smoke. There is also renewed interest in mucosal inflammation and microbial factors as contributors to the development of RA. However, the identification of a "preclinical" period of RA that can be defined as local or systemic autoimmunity as measured by autoantibodies and other biomarkers prior to the development of clinically apparent synovitis suggests that the risk factors for RA are acting long prior to first clinical evidence of IA. As such, a major challenge to the field will be to investigate the full spectrum of the development of RA, from initiation and propagation of autoimmunity during preclinical RA and transition to clinically apparent synovitis and classifiable RA, to determine which genetic and environmental factors are important at each stage of disease development. Understanding the exact role and timing of action of risk factors for RA is especially important given the advent of prevention trials in RA, and the hope that a full understanding of genetic and environmental factors in RA could lead to effective preventive interventions.

Genetic and environmental risk factors for rheumatoid arthritis

An overview of autoantibodies in rheumatoid arthritis

A key unanswered question in the pathophysiology of rheumatoid arthritis (RA) is how systemic autoimmunity progresses to joint-specific inflammation. In patients with seropositive RA (that is, characterized by the presence of autoantibodies) evidence is accumulating that immunity against post-translationally modified (such as citrullinated) autoantigens might be triggered in mucosal organs, such as the lung, long before the first signs of inflammation are seen in the joints. However, the mechanism by which systemic autoimmunity specifically homes to the joint and bone compartment, thereby triggering inflammation, remains elusive. This Review summarizes potential pathways involved in this joint-homing mechanism, focusing particularly on osteoclasts as the primary targets of anti-citrullinated protein antibodies (ACPAs) in the bone and joint compartment. Osteoclasts are dependent on citrullinating enzymes for their normal differentiation and are unique in displaying citrullinated antigens on their cell surface in a non-inflamed state. The binding of ACPAs to osteoclasts releases the chemokine IL-8, leading to bone erosion and pain. This process initiates a chain of events that could lead to attraction and activation of neutrophils, resulting in a complex series of proinflammatory processes in the synovium, eventually leading to RA.

Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis

Rheumatoid arthritis (RA) is currently diagnosed and treated when an individual presents with signs and symptoms of inflammatory arthritis (IA) as well as other features, such as autoantibodies and/or imaging findings, that provide sufficient confidence that the individual has RA-like IA (eg, meeting established classification criteria) that warrants therapeutic intervention However, it is now known that there is a stage of seropositive RA during which circulating biomarkers and other factors (eg, joint symptoms) can be used to predict if and when an individual who does not currently have IA may develop future clinically apparent IA and classifiable RA Indeed, the discovery of the "pre-RA" stage of seropositive disease has led to the development of several clinical trials in which individuals are studied to identify ways to delay or prevent the onset of clinically apparent IA/RA This review focuses on several issues pertinent to understanding the prevention of RA These include discussion of the pathogenesis of pre-RA development, prediction of the likelihood and timing of future classifiable RA, and a review of completed and ongoing clinical trials in RA prevention Furthermore, this review discusses challenges and opportunities to be addressed to effect a paradigm shift in RA, where in the near future, proactive risk assessment focused on prevention of RA will become a public health strategy in much the same manner as cardiovascular disease is managed today

Rheumatoid Arthritis: Pathogenesis, Prediction and Prevention – An Emerging Paradigm Shift

Introduction Patients with clinically suspect arthralgia (CSA) have, according to their rheumatologists, an increased risk of rheumatoid arthritis (RA), but their actual outcome is unexplored. This longitudinal study investigated (1) progression from CSA to clinically detectable arthritis and (2) associations of clinical factors, serological factors (among which are anticitrullinated peptide antibodies (ACPAs)) and MRI-detected subclinical inflammation with arthritis development. Methods 150 patients with CSA were followed for ≥6 months. At baseline, clinical and serological data were collected and unilateral 1.5 T-MRI of metacarpophalangeal (MCP), wrist and metatarsophalangeal (MTP) joints was made. MRI scoring was done according to the RA MRI scoring system. Subclinical MRI inflammation was defined based on MRI results of 193 symptom-free persons. Results During follow-up (median=75 weeks, IQR=41–106 weeks), 30 patients developed clinical arthritis; 87% did so Conclusions Subclinical MRI inflammation precedes clinical arthritis with a few months. Subclinical MRI inflammation is, independent of other factors such as ACPA, associated with arthritis development.

https://ard.bmj.com/content/annrheumdis/75/10/1824.full.pdf

Clinical factors, anticitrullinated peptide antibodies and MRI-detected subclinical inflammation in relation to progression from clinically suspect arthralgia to arthritis

Objectives To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a pragmatic model to predict development of IA in this patient group. Methods In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation. Findings 100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1–69.0); 50 developed IA after a median 7.9 months (range 0.1–52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1–2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0–1; 0/11 progressed). Conclusions In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention. Trial registration number NCT02012764 at ClinicalTrials.gov.

https://ard.bmj.com/content/annrheumdis/early/2014/04/12/annrheumdis-2014-205227.full.pdf

Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study

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Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study