Value of Biomarkers in the Prevention of Rheumatoid Arthritis A Finckh 1 , D Alpizar-Rodriguez 1 and P Roux-Lombard 2 Recent diagnostic advances allow to identify persons in a pre- symptomatic stage of rheumatoid arthritis (RA), opening the way for a preventive therapeutic intervention, which may potentially be curative. We review and discuss existing biomarkers predictive of future onset of RA. A responsible use of biomarkers in clinical settings will require an integration of blood-based tests, imaging techniques, clinical history, environmental risk factors, and family history. Rheumatoid arthritis (RA), leads to progressive joint destruction, disability, and increased mortality. The disease, once fully devel- oped, is difficult to treat and generally requires lifelong therapy. The earlier effective antirheumatic therapy is initiated, the more likely a favorable response to therapy, a concept sometimes coined the “therapeutic window of opportunity.” Epidemiologic studies have revealed that the joint involvement in RA is pre- ceded by a long “preclinical” period. Recent diagnostic advances allow identifying persons in the presymptomatic stages (Figure 1), opening the way for therapeutic interventions in the very early phases of the disease, which may potentially be curative. Most preventive interventions in this population have so far focused on secondary prevention in patients with undifferentiated arthri- tis, but several trials are ongoing to evaluate the efficacy of thera- peutic intervention at an earlier stage. Thus, once viewed as inexorably progressive, RA has become a potentially curable dis- ease with early, aggressive use of antirheumatic drugs. Therefore, diagnosing preclinical RA as accurately as possible has become a high-stakes undertaking. 1 Markers of systemic autoimmunity and inflammation can pre- cede the diagnosis of RA by many years. Autoantibodies such as IgM-rheumatoid factor (IgM-RF) and anti-citrullinated peptide antibodies (ACPAs) can be found in the serum of blood donors up to 20 years before the onset of the disease. However, isolated ACPA positivity leads only to a 5% increased risk of developing RA within the next 5 years and RF alone is not clearly associated with an increased risk of RA in the general population. Nevertheless, in a high-risk population, such as individuals who have at least two first-degree relatives with RA, the presence of RF or ACPAs increases the risk of developing RA by up to 38% and 69%, respectively. Similarly, ACPA-positive individuals expe- riencing arthralgias have a 6-fold increased risk of developing arthritis within 12 months. ACPAs seem to develop before RF, and immunoglobulin (Ig)M and IgA subtypes of RF seem to appear before IgG subtypes of RF, even if the precise timing appears to be quite variable. ACPAs can be directed towards sev- eral different citrullinated targets (ACPA fine specificities), which are combined in the commercially available ACPA tests (the so- called anti-CCP tests). Typically, the immune response starts with reactivity to only a few epitopes and then spreads over time to a variety of citrullinated peptides. So far, there is no evidence of a particular sequence of development in ACPA fine specific- ities, and there is no confirmation for a higher risk of RA with specific ACPAs. The expansion of ACPA specificity often comes with RF positivity, which may explain why the simultaneous presence of both autoantibodies is highly predictive of RA devel- opment within the next 5 years. Other autoantibodies such as anti-carbamylated proteins, anti-peptidylarginine deiminase (PAD-4), anti-collagen type II, and anti-IgG hinge are also often present during the preclinical stage, but their additive predictive value is still unclear. 2 Not only autoantibodies, but various cytokines and acute phase reactants increase before the clinical onset of RA. Increased levels of C-reactive protein (CRP) are detected in sera of blood donors who later develop RA, most commonly within 2 years of onset of symptoms. The CRP levels increase until RA onset. A preclinical rise of CRP is observed in subjects both with and without auto- antibodies, but levels are slightly higher in seropositive patients. 3 A large variety of cytokines and chemokines reflecting inflamma- tion (interleukin (IL)-1b, IL-1Ra, tumor necrosis factor alpha (TNFa), IL-6, IL-15, monocyte chemoattractant protein (MCP)- 1, granulocyte macrophage colony-stimulating factor (GM-CSF)) and the activation of the adaptive immune system, such as 1 Division of Rheumatology, Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva, Switzerland; 2 Division of Immunology and Allergy, Department of Internal Medicine Specialties, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland. Correspondence: A Finckh (axel.finckh@hcuge.ch) Received 15 March 2017; accepted 25 April 2017; advance online publication 00 Month 2017. doi:10.1002/cpt.727 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2017 1 TRANSLATION