Temporal dynamics of inflammatory proteins in the pre-symptomatic phase of rheumatoid arthritis related to seroconversion

Abstract

Abstract Objective Autoimmune processes in rheumatoid arthritis (RA) begin years before clinical symptom onset. This study aimed to analyse inflammation-related proteins in individuals during the pre-symptomatic phase, in relation to healthy controls and patients with early RA, and their relationship to seroconversion. Methods Plasma samples collected prior to symptom onset from individuals who later developed RA ( n  = 419), healthy population controls ( n  = 49), and patients with early RA at diagnosis ( n  = 68) were obtained from a biobank. All samples were analysed for 92 inflammation-related proteins using a proximity extension assay and for anti-CCP2 antibodies and rheumatoid factor. After quality control 77 proteins remained. To identify differentially expressed proteins and enriched pathways, statistical analyses including logistic regression, generalized additive models, and network enrichment analysis was applied. Results Four proteins (MMP10, IL6, CCL19, and IL10RB) showed a higher concentration in pre-symptomatic individuals compared to controls ( p  < 0.05). Twelve proteins were associated with seropositivity in the pre-symptomatic phase and network enrichment analysis of these revealed associated pathways related to the complement system and cytokine activity. Three proteins (CXCL10, CCL7, and CDCP1) were consistently associated with seroconversion and showed increasing trends approaching symptom onset in individuals who seroconverted, but not in individuals who remained seronegative. Proteins associated with early seroconversion were associated with T-cell activity, whereas many of the proteins associated with late seroconversion were associated with bone remodelling, mineral metabolism, and collagen degradation. Conclusion Proteomic alterations are detectable years before RA onset and linked to autoantibody development. Seroconverters differ from those who remain seronegative even in the pre-symptomatic period, supporting the notion that seropositive and seronegative RA represent biologically distinct entities from the earliest stages of the pathogenesis.