Background/Purpose: Persons with rheumatoid arthritis (RA) have an increased risk of mortality compared to the general population. Seropositivity has been shown to be associated with development of extraarticular manifestations of RA and higher mortality risk. The role of seropositivity on cause-specific mortality by sex in RA has not been investigated in population-based cohorts. The aims of this study were to investigate the effect of seropositivity on overall and cause-specific mortality in RA by sex.

Methods: The study population consisted of adult (age ≥18 years) residents of a geographically defined area who first met >4 American College of Rheumatology 1987 criteria for RA in 1980-2019, and non-RA persons from the same population matched 3:1 to RA participants by age and sex.  All participants were followed until death, migration, or December 31^st, 2022. Underlying cause of death was obtained from death certificates. Competing risks/cumulative incidence methods were used to compare cause-specific mortality incidence between participants with and without RA. Additionally, Cox models were used to estimate the effect of RA on risk of cause-specific mortality, adjusting for sex, age and calendar year of index date. Interactions for RA with sex, age, seropositivity, and diagnosis date were also explored.

Results: The study included 1,337 participants with RA and 4,011 comparators without RA (mean age 56.0, SD 15.6 years, 69% female for both groups, 64% seropositive RA). During a median of 16.8 years of follow-up, 496 RA and 1,269 non-RA died. All-cause mortality was significantly increased in both women and men with RA. The increased risk of death due to respiratory causes in patients with RA was significantly different (interaction p-value < 0.001) depending on seropositive (HR 2.24; 95% CI 1.55, 3.25) versus seronegative (HR 0.48; 95% CI 0.21, 1.09) status. Seropositive RA patients also had increased risk of death due to coronary heart disease (CHD), non-cardiac circulatory, neoplasms, digestive, and GU (genitourinary) related causes, but interaction tests vs seronegative RA were non-significant (Table1). 

Mortality due to CHD, non-cardiac circulatory, respiratory, neoplasms, and GU related causes was higher in women with RA vs women with no RA, but not in men with RA vs men with no RA, though interaction tests were non-significant.

Mortality due to non-CHD circulatory causes was increased in seronegative RA vs controls and in men with RA vs men with no RA, but not in women with RA vs women with no RA (interaction tests non-significant).

While the effect of seropositive RA tended to be greater in women than in men for most causes of death, none of the tests of interaction between sex and seropositivity were significant (Table 2).

Conclusion: Seropositivity in persons with RA associates with a significantly increased risk of death due to respiratory causes, while seronegativity may associate in no such increased risk. The seropositive effect may be greater in women than in men, though larger studies are needed to confirm.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cause-specific-mortality-differs-in-rheumatoid-arthritis-by-sex-and-seropositivity/