Identification of early risk factors for anti-citrullinated-protein-antibody positive rheumatoid arthritis-a prospective cohort study

Abstract

Objective: Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression.

Methods: Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥3 years or until clinical arthritis diagnosis. Blood samples from inclusion were analysed for nine ACPA reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model.

Results: Two hundred and sixty-seven individuals were included with median follow-up of 49 months (interquartile range [IQR]: 22-60); 101 (38%) developed arthritis after a median of 14 months (IQR: 6-27). The analysis identified that presence of at least one ACPA reactivity (hazard ratio [HR] 8.0; 95% CI: 2.9, 22), ultrasound-detected tenosynovitis (HR 3.4; 95% CI: 2.0, 6.0), IL-6 levels (HR 1.5; 95% CI: 1.2, 1.8) and IL-15 receptor α (IL-15Rα) levels (HR 0.6; 95% CI: 0.4, 0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [s.e. 0.02], AUC 0.82 [95% CI: 0.76, 0.89], cross-validated AUC 0.70 [95% CI: 0.56, 0.85]).

Conclusion: We propose a high RA risk phase characterized by presence of ACPA reactivity, tenosynovitis, IL-6 and IL-15Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression.

Keywords: anti-citrullinated protein antibody reactivities; biomarkers; rheumatoid arthritis; risk phase.

Figure 1.

Kaplan–Meier curve showing arthritis free survival time in Risk-RA individuals. Dotted line represents CI 95%

Figure 2.

Anti-citrullinated protein antibodies (ACPA) in individuals who progressed towards arthritis, compared with individuals who remained arthritis free. (A) Anti-CCP levels as measured by anti-CCP test; lower dotted line represents upper limit of normal value and cut-off for positive test, and the upper dotted line represents high level (≥3× upper limit of normal). n = 267, *P = 0.0002, univariate Cox regression. (B) Number of ACPA reactivities (range 0–9). n = 252, *P < 0.001, univariate Cox regression

Figure 3.

Prediction model for arthritis progression. After multivariate Cox regression modelling ACPA reactivity (i.e. positivity for at least one of the nine tested ACPA reactivities targeting Cit-Fil, Cit-Fibβ, Cit-Vim, CEP-1, Cit-TNC1, Cit-TNC5, Cit-His3 peptides), ultrasound-detected tenosynovitis, IL-6 and IL-15Rα (both measured by OLINK inflammatory panel) were found to be significant independent predictors. Two hundred and thirty-two individuals with complete data were used in the model

Figure 4.

A model for progression towards arthritis. Individuals exposed to smoking and certain risk gene alleles (HLA-DRB1) will be predisposed to immune activation at mucosal sites such as lung and gingiva, and the development of systemic autoimmunity with ACPA and RF. Individuals further developing musculoskeletal complaints are at high risk for arthritis, but many of these individuals do not progress. We propose a revised model where certain ACPA reactivities, levels of IL-6 and IL-15Rα and ultrasound-detected tenosynovitis are factors in a stage of very high risk for arthritis. This figure was in part generated using images adapted from Servier Medical Art by Servier, licensed under a Creative Common Attribution 3.0 unsupported licence