Elevations in adipocytokines and mortality in rheumatoid arthritis

Abstract

Objectives: This study assessed whether circulating levels of adiponectin and leptin are associated with higher mortality in patients with RA.

Methods: Participants were adults from the Veterans Affairs RA Registry. Adipokines and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum at enrolment. Dates and causes of death were derived from the Corporate Data Warehouse and the National Death Index. Covariates were derived from medical record, biorepository and registry databases. Multivariable Cox proportional hazard models evaluated associations between biomarkers and all-cause and cause-specific mortality.

Results: A total of 2583 participants were included. Higher adiponectin levels were associated with older age, male sex, white race, lower BMI, autoantibody seropositivity, radiographic damage, longer disease duration, prednisone use and osteoporosis. Higher adiponectin concentrations were also associated with higher levels of inflammatory cytokines but not higher disease activity at enrolment. Leptin was primarily associated with greater BMI and comorbidity. The highest quartile of adiponectin (vs lowest quartile) was associated with higher all-cause mortality [hazard ratio (HR): 1.46 (95% CI: 1.11, 1.93), P = 0.009] and higher cardiovascular mortality [HR: 1.85 (95% CI: 1.24, 2.75), P = 0.003], after accounting for covariates. Higher leptin levels were also associated with greater all-cause and cancer mortality.

Conclusions: Elevations in adipokines are associated with age, BMI, comorbidity and severe disease features in RA and independently predict early death. Associations between adiponectin and inflammatory cytokines support the hypothesis that chronic subclinical inflammation promotes metabolic changes that drive elevations in adipokines and yield adverse health outcomes.

Keywords: RA; cardiovascular disease; disease activity; mortality.

Fig. 1

Adiponectin levels by weight and percentage change from maximum BMI, adjusting for age, sex and race

Fig. 2

Line plots showing inflammatory cytokine levels by adiponectin quartile (A) and leptin quartile (B) (unadjusted) *P < 0.05 compared with third quartile; †P < 0.05 compared with second quartile; ‡P < 0.05 compared with first quartile.

Fig. 3

All-cause and cause-specific mortality in adjusted models by adiponectin quartile (A) and leptin quartile (B) Adjusted for: age, age², sex, race, BMI, smoking, disease duration category, TNFi use, methotrexate use, prednisone use, hydroxychloroquine use, ACPA status, RF status, DAS28, MD-HAQ category, RDCI, erosive disease, hypertension, diabetes, hyperlipidaemia, heart failure, coronary artery disease, cerebrovascular disease, other vascular disease, venous thrombosis, osteoarthritis, osteoporosis, spine disease, liver disorder, any neoplasm, skin cancer, date of enrolment and date of enrollment². DAS28: DAS in 28 joints; MD-HAQ: Multidimensional Health Assessment Questionnaire; RDCI: Rheumatic Disease Comorbidity Index.