Getting grip on preclinical rheumatoid arthritis

This thesis focused on prediction and prevention of rheumatoid arthritis (RA). Part I starts with a review of RA risk factors and their combination into prediction models. Next, we further studied the preclinical phase of RA and concluded that HLA-shared epitope-alleles (HLA-SE) and smoking, the most prominent genetic and environmental risk factors for RA, act at different preclinical stages: smoking confers risk for anti-citrullinated protein antibodies (ACPA)- and symptom-development, whereas HLA-SE mediates symptom- and inflammatory arthritis (IA)-development. Furthermore, in individuals at risk of RA, lipid abnormalities are already present, and are associated with ACPA positivity, regardless of arthritis development. Next, we aimed to improve RA prediction in at-risk individuals using clinical risk factors. Using the Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire, we showed that certain self-reported symptoms can provide useful information to estimate a person’s risk of developing RA, also in addition to rheumatoid factor (RF) and ACPA status. Conversely, it is unlikely that optimal spectral transmission (OST) imaging can contribute to the diagnosis and prediction of arthritis in persons at risk of RA. Finally, we concluded that replacing clinical arthritis with imaging-detected subclinical synovitis for diagnosing RA introduced a high false-positive rate, which implies that starting disease-modifying anti-rheumatic drug (DMARD) treatment in these patients would lead to considerable overtreatment.
In part II, we studied opportunities for preventive intervention. We showed that individuals at risk of RA and axial spondyloarthritis (axSpA) seem highly willing to make lifestyle changes, while most rheumatologists do not advise at-risk patients to do so, mostly due to a current lack of evidence. In contrast, rheumatologists are more willing to prescribe preventive medication than at-risk individuals are to use it. Next, the randomized, double-blind, placebo-controlled STAtins to Prevent Rheumatoid Arthritis (STAPRA) trial could not provide evidence regarding the preventive efficacy of atorvastatin, mainly due to a high reluctance to participate. Finally, we identified factors that were important in at-risk individuals’ decision about prevention trial participation. The prospect of personal benefit, the acknowledgement of symptoms and the desire to contribute to society stimulated trial participation, while misconception about the trial aim or about being at risk, negative views on trial medication, and a low perceived urgency to act versus a high perceived burden of trial participation discouraged participation. Addressing these factors could improve inclusion in trials aimed to prevent RA onset.