Depression a warning signal for rheumatoid arthritis

Depression may increase susceptibility to developing subsequent seronegative rheumatoid arthritis (RA), according to a study.

“Ours is the first study suggesting that depression may be a novel risk factor for seronegative RA,” the investigators said. “This excess risk was not explained by measured lifestyle factors or by early RA symptoms occurring within 4 years of clinical diagnosis.”

The analysis included 195,358 women from the Nurses’ Health Study (NHS, 1992‐2014) and NHSII (1993‐2015), among whom 9.4 percent had clinician-diagnosed depression. This group tended to be younger (mean, 52.4 vs 56.1 years), have higher body mass index (obesity: 28.3 percent vs 21.4 percent), lower dietary quality, and greater sedentary time relative to the group without depression.

Over 3,087,556 person‐years (median, 17.9 years per participant), 858 RA cases occurred—558 (65.0 percent) were seropositive and 300 (35.0 percent) were seronegative. Multivariable Cox analysis showed that depression contributed to an increased risk of total RA (hazard ratio [HR], 1.28, 95 percent confidence interval [CI], 1.10–1.48), seropositive RA (HR, 1.12, 95 percent CI, 0.93–1.35), and seronegative RA (HR, 1.63, 95 percent CI, 1.27–2.09). [Arthritis Care Res 2020;doi: 10.1002/ACR.24441]

On further analysis, regular use of antidepressants was strongly related to subsequent development of seronegative RA (HR, 1.75, 95 percent CI, 1.32–2.32) but not seropositive RA (HR, 1.21, 95 percent CI, 0.97–1.49).

The findings contribute to existing literature “by including granular data on many prospectively measured behaviors and health factors, addressing possible reverse causation bias, and investigating RA risk by serologic phenotypes,” the investigators said.

“Since about one-third of patients with RA are seronegative, identification of risk factors and strategies to modify risk are urgently needed,” they added.

Individuals with depression or depressive symptoms exhibit elevated levels of systemic inflammatory markers, including interleukin-6 and C-reactive protein, compared with healthy controls, perhaps due to chronic alterations in the hypothalamic-pituitary-adrenal axis. [Brain Behav Immun 2009;23:936-944; Arch Intern Med 2007;167:174-181; Lancet Psychiatry 2019;6:164-173]

As such, depression has been associated with future risk of chronic inflammatory diseases, including cardiovascular disease, psoriasis, psoriatic arthritis, inflammatory bowel disease, alopecia areata, and systemic lupus erythematosus. [Stroke 2017;48:43-48; J Invest Dermatol 2017;137:828-835; Gut 2019;68:1606-1612; JAMA Dermatol 2019;155:475-479; JAMA Psychiatry 2018;75:1225-1233]

“Thus, it is possible that depression may affect future risk of RA, through increased systemic inflammation,” according to the investigators.

“Future studies may investigate how other aspects of mental health may contribute to the pathogenesis of seronegative RA,” they added.