Elevated anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) titers have been independently associated with increased mortality in patients with rheumatoid arthritis (RA), according to research published in Arthritis Care & Research.

Researchers conducted a retrospective real-world study examining the role of ACPA and RF seropositivity in risk prediction for mortality in RA. Investigators also studied the association between ACPA and RF titers and all-cause mortality, examining whether the use of disease-modifying antirheumatic drugs (DMARDs) affected these associations.

Study data were obtained from 2 US administrative claims databases linked to laboratory data. Patients were followed from the date of the analysis-specific index until death, end of health plan enrollment, or the end of the study period (June 2016).

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In total, 133,775 patients with RA were included from both databases (ACPA n=53,849; RF n=79,926). Baseline characteristics were generally balanced between groups, with DMARD use, RA diagnoses, previous or current positive smoking status, and the presence of chronic obstructive pulmonary disease “significantly elevated” in seropositive patients (P <.001).

The ACPA group had 184,170 patient-years of follow-up. In this group, 5.7% of patients died, and the mortality incidence rate was 16.7 per 1000 patient-years (95% CI, 16.1-17.3). The RF group had 297,830 patient-years of follow-up; 6.5% of patients died, and the mortality incidence rate was 17.5 per 1000 patient-years (95% CI, 17-18). Both ACPA and RF positivity were associated with a significant increase in mortality risk (P <.0001 for both).

In the ACPA group with baseline RF data, ACPA positivity was associated with increased mortality compared with RF positivity; double ACPA and RF positivity were associated with the highest mortality risk (hazard ratio [HR] 1.61; 95% CI, 1.45-1.79). Single ACPA positivity was associated with a higher risk compared with single RF positivity.

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In the RF group with baseline ACPA data, the highest mortality risk was also noted in the ACPA and RF double-positive group (HR 1.22; 95% CI, 1.09-1.36). According to the investigators, “all other combinations of the presence of ACPA and RF were associated with a significantly increased mortality risk compared with ACPA and/or RF seronegativity.”

Also, mortality risk positively correlated with ACPA and RF titers and was the highest in groups of patients with the highest titers for both ACPA and RF (HR 1.60 and 1.78, respectively; 95% CI, 1.45-1.76 and 1.66-1.91). The findings were consistent when the groups were combined.

Survival curves comparing patients with ACPA and RF serostatus showed similar patterns of divergence. Compared with single ACPA and RF positivity, single ACPA and RF negativity was associated with a higher survival rate.

Both ACPA and RF single-positive patients who received conventional synthetic DMARD (csDMARD) therapies had a statistically significant increase in mortality risk (ACPA HR 1.52; RF HR 1.47). Patients who had single ACPA or RF positivity who received csDMARDs had a 46% and 62% increased mortality risk vs patients with double ACPA and RF negativity. No increase in mortality risk was noted in patients receiving biologic DMARDs.

Study limitations included those inherent to the nature of observational studies, including the absence of randomization.

“Elevated ACPA and RF titers were independently associated with increased mortality among patients diagnosed with RA,” the researchers concluded. “Additional analyses are warranted, including evaluation of the association of disease activity and mortality.”

Disclosure: This clinical trial was supported by Bristol-Myers Squibb. Multiple authors report affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Alemao E, Bao Y, Weinblatt ME, Shadick N. Association of seropositivity and mortality in rheumatoid arthritis and the impact of treatment with disease-modifying antirheumatic drugs [published online September 17, 2019]. Arthritis Care Res. doi: 10.1002/acr.24071