Impact of Cyclic Citrullinated Peptide Antibody Level on Progression to Rheumatoid Arthritis in Clinically Tested Cyclic Citrullinated Peptide Antibody-Positive Patients Without Rheumatoid Arthritis

Abstract

Objective: To investigate the risk of progression to rheumatoid arthritis (RA) in patients who were cyclic citrullinated peptide (CCP) antibody positive without RA at initial presentation.

Methods: We performed a retrospective cohort study of CCP+ individuals seen at a US tertiary care system between 2009 and 2018 who were without RA or other systemic rheumatic disease by medical record review at the time of CCP antibody positivity. Progression to classifiable RA was determined through medical record review. We investigated the risk of progression to RA overall and stratified by CCP antibody level (low: >1 to 2× the upper limit of normal [ULN]; medium: >2 to 3× ULN; high: >3× ULN). Multivariable Cox regression estimated the hazard ratio (HR) and 95% confidence interval (95% CI) for RA by CCP antibody level.

Results: We identified 340 CCP+ patients who were without RA or other rheumatic disease at baseline. During 1,047 person-years of follow-up, 73 patients (21.5%) developed RA. The risk of progression to RA increased with CCP antibody level, with 46.0% (95% CI 34.7-55.3) of patients with high-level CCP antibodies progressing to RA by 5 years. Compared to low CCP antibody level, medium (HR 3.00 [95% CI 1.32-6.81]) and high (HR 4.83 [95% CI 2.51-9.31]) CCP antibody levels were strongly associated with progression to RA, adjusting for age, sex, body mass index, smoking, family history of RA, and rheumatoid factor level.

Conclusion: Among CCP+ patients without RA, the risk for progression to RA increased substantially with increasing CCP antibody level. This study provides further support for close monitoring for development of RA among CCP+ patients and identifying strategies to mitigate this risk.

Figure 1.

Flow diagram of study sample. CCP= cyclic citrullinated peptide antibody; RA= rheumatoid arthritis; SRD= systemic rheumatic disease; ACR/EULAR= American College of Rheumatology and European League Against Rheumatism. *Other SRD= systemic lupus erythematosus, scleroderma, dermatomyositis, polymyositis, seronegative spondyloarthropathies (including ankylosing spondylitis, reactive arthritis, psoriatic arthritis), antiphospholipid syndrome, mixed connective tissue disease, Sjögren’s syndrome, systemic vasculitis (including Takayasu arteritis, giant cell arteritis, polyarteritis nodosa, Behçet’s disease, Henoch-Schönlein purpura, ANCA-associated vasculitis), polymyalgia rheumatica, dermatomyositis, and juvenile idiopathic arthritis.

Figure 2.

Kaplan-Meier curves for rheumatoid arthritis-free survival after index date of initial CCP positivity according to: A) CCP (cyclic citrullinated peptide) in 3 levels. B) CCP binary level and rheumatoid factor (RF) status. C) CCP binary level and presence/absence of family history of RA. D) CCP binary level and presence/absence of symptoms (pain, stiffness, or both) in RA-specific joints. RA-specific joints were defined as metacarpophalangeal joints, proximal interphalangeal joints, metatarsophalangeal joints, thumb interphalangeal joints, wrists, and elbows.