Association of Seropositivity and Mortality in Rheumatoid Arthritis and the Impact of Treatment With Disease-Modifying Antirheumatic Drugs: Results From a Real-World Study

Abstract

Objective: Seropositivity for anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) in rheumatoid arthritis (RA) is associated with increased overall mortality; however, the association between antibody titers and mortality is not well established. Investigating relationships between antibody titers and mortality may clarify their role in RA pathogenesis. This study was undertaken to evaluate the association of antibody titers with mortality and its modification by disease-modifying antirheumatic drugs (DMARDs).

Methods: Eligible patients with established RA were identified through administrative claims data linked to laboratory results (2005-2016). Patients were categorized by positivity status for ACPA, RF, or both. Patients were further divided into groups by autoantibody titers. DMARD-exposed patients were categorized into biologic DMARD (bDMARD) and conventional DMARD (cDMARD) subcohorts. Crude mortality rates/1,000 patient-years and Kaplan-Meier curves were compared between antibody categories. Adjusted Cox proportional hazards regression and sensitivity (propensity-matched patients) analyses were conducted.

Results: Overall, 53,849 and 79,926 patients had evaluable ACPA and RF status, respectively. For both autoantibodies, mortality rates were significantly higher in seropositive versus seronegative patients (risk increase of 48.0% and 44.0% in ACPA- and RF-positive patients, respectively; P < 0.001 each). Mortality rates were greatest in patients with higher versus lower autoantibody titers (ACPA hazard ratio [HR] 1.60 [95% confidence interval (95% CI]) 1.45-1.76]; RF HR 1.78 [95% CI 1.66-1.91]). In cDMARD-exposed patients, HRs were higher in seropositive versus seronegative cohorts; in bDMARD-exposed patients, there was no difference in mortality by serostatus.

Conclusion: Elevated ACPA/RF titers were independently associated with increased mortality among patients with RA and persisted in patients treated with cDMARDs but not with bDMARDs.

Figure 1

Analyzed patient population. ACPA = anti–citrullinated protein antibody; RF = rheumatoid factor; bDMARD = biologic disease‐modifying antirheumatic drug; cDMARD = conventional disease‐modifying antirheumatic drug.

Figure 2

Association between anti–citrullinated protein antibody (ACPA) and rheumatoid factor (RF) and mortality in an analysis of data from patients with ACPA and/or RF seropositivity. 95% CI = 95% confidence interval; HR = hazard ratio; BL = baseline (the time period of within 180 days before and 30 days after the index date).

Figure 3

Kaplan‐Meier curve for differences in mortality over time between anti–citrullinated protein antibody (ACPA) positivity/negativity (A and C) and rheumatoid factor (RF) positivity/negativity (B and D) scores (both databases) after 1:1 propensity‐score matching. n = total numbers of patients for the 2 groups. The hazard ratio (HR) is from a Cox model with the ACPA or RF variable only. Propensity scores were calculated for ACPA positivity versus ACPA negativity and RF positivity versus RF negativity based on all covariates. Covariates included age, sex, region, number of physician office visits during the past 3 months, an indicator variable for 714.0x diagnosis, an indicator variable for RA diagnosis before ACPA or RF testing, past hospitalization, use of medications (steroids, nonsteroidal antiinflammatory drugs, salicylates), use of disease‐modifying antirheumatic drugs (if applicable), and comorbidity conditions. 95% CI = 95% confidence interval.

Figure 4

Association between anti–citrullinated protein antibody (ACPA) and rheumatoid factor (RF) and mortality among patients treated with biologic disease‐modifying antirheumatic drugs (bDMARDs) and conventional DMARDs (cDMARDs) and with ACPA or RF seropositivity. 95% CI = 95% confidence interval; HR = hazard ratio.