Inflammation functions as a key mediator in the link between ACPA and erosion development: an association study in Clinically Suspect Arthralgia

R. M. ten Brinck, R. E. M. Toes, A. H. M. van der Helm–van Mil

Anti-citrullinated protein antibodies (ACPA) are associated with more severe joint erosions in rheumatoid arthritis (RA), but the underlying mechanism is unclear. Recent in vitro and murine studies indicate that ACPAs can directly activate osteoclasts leading to bone erosions and pain. This study sought evidence for this hypothesis in humans and evaluated whether in patients with arthralgia who are at risk of RA, ACPA is associated with erosions (detected by magnetic resonance imaging (MRI)) independent of inflammation, and also independent of the presence of rheumatoid factor (RF). Patients with Clinically Suspect Arthralgia (n = 507) underwent determination of ACPA and RF and 1.5 T contrast-enhanced MRI of the metacarpophalangeal, wrist and metatarsophalangeal joints at baseline. MRIs were scored for presence of local inflammation and erosions. Comparisons of erosion scores were performed using the Kruskal-Wallis test. To evaluate if inflammation is, in statistical terms, intermediary in the causal path of ACPA and erosions, three-step mediation analysis was performed using linear regression. ACPA-positive patients had higher erosion scores than ACPA-negative patients (p = 0.006). ACPA-positive patients without subclinical inflammation did not have higher erosion scores than ACPA-negative patients (p = 0.68), in contrast to ACPA-positive patients with local inflammation (p < 0.001). Mediation analyses suggested that local inflammation is in the causal path of ACPA leading to higher erosion scores. Compared to ACPA-negative/RF-negative patients, ACPA-positive/RF-negative patients did not differ (p = 0.30), but ACPA-positive/RF-positive patients had higher erosion scores (p = 0.006). The effect of ACPA on erosions is mediated by inflammation and is not independent of RF.