First Depression, Then Rheumatoid Arthritis?


Depression may be linked to an increased risk of rheumatoid arthritis, particularly patients taking antidepressants, shows a new study.

First depression, then rheumatoid arthritis

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Patients with depression, particularly those taking antidepressants, may be susceptible to developing seronegative rheumatoid arthritis years later, suggests the first study to look at a potential link between depression and risk of rheumatoid arthritis by serological status.

There is increasing evidence that seropositive rheumatoid arthritis, which is characterized by elevated levels of rheumatoid factor or anti-cyclic citrullinated peptide, and seronegative rheumatoid arthritis may be different diseases that have similar clinical presentations but different etiology.

Many risk factors for rheumatoid arthritis, such as smoking, have been linked specifically to seropositive rheumatoid arthritis, and less is known about seronegative disease.

“Most of the research related to pathogenesis and prevention of rheumatoid arthritis is focused on the seropositive subtype. Research concerning the seronegative rheumatoid arthritis subtype is relatively less developed even though this may encompass up to 40% of patients with rheumatoid arthritis,” said Dr. Jeffrey Sparks, assistant professor of medicine and director of Immuno-Oncology and Autoimmunity at the Division of Rheumatology, Inflammation, and Immunity, at Brigham and Women’s Hospital in Boston. “There are relatively few risk factors identified for seronegative rheumatoid arthritis. It is possible that mental health disorders such as depression may specifically be related to this subtype of rheumatoid arthritis,”

First depression, then rheumatoid arthritis

Dr. Jeffrey Sparks

To investigate, Sparks and colleagues accessed data on 195,358 women from the Nurses’ Health Study (NHS,1992-2014) and NHSII (1993-2015). A total of 858 validated cases of rheumatoid arthritis, of which 65% were seropositive, were identified among these 195,358 women and there was a median follow up period of 19.7 years.

Women with depression were 28% more likely to subsequently be diagnosed with rheumatoid arthritis than those who did not have depression, and they seemed to be particularly at risk of seronegative disease. Women with depression were 63% more likely to have seronegative rheumatoid arthritis than women without depression but were not significantly more likely to have seropositive rheumatoid arthritis.

Women were deemed to have depression if they reporting having received a diagnosis of depression, were taking antidepressants or attained a score of less than 60 on the Mental Health Inventory-5 score.

Regular use of antidepressants was significantly associated with an increased risk of being diagnosed with seronegative rheumatoid arthritis – a 75% increased risk – but not with seropositive rheumatoid arthritis.

“Antidepressant use may be a marker for more severe depression that required treatment.” ― Dr. Jeffrey Sparks.

He added that the association between depression and subsequent diagnosis of rheumatoid arthritis remained after adjustment for pain and was still observed in patients with rheumatoid arthritis who did not have concomitant fibromyalgia.

To reduce the likelihood of reverse causation, where early rheumatoid arthritis symptoms may have lowered mood prior to the patient receiving a formal diagnosis, a time lag of at least 4 years was included between when depression was assessed and RA diagnosis.

Several possible biologic mechanisms could explain the association between depression and rheumatoid arthritis, Sparks said. “For example, depression may lead to changes in the hypothalamic-pituitary-adrenal axis that leads to chronic inflammation.”

Other studies have investigated links between other mental health disorders, such as anxiety and post-traumatic stress disorder, and rheumatoid arthritis, and these disorders have been linked to risk of systemic lupus erythematosus, he said. “Overall, these findings suggest that mental health and autoimmunity may have a connection.”

Further studies were needed to replicate the findings to show that the association also occurred in men and to help understand the biologic mechanism involved, Sparks said. “Depression has been associated with rheumatoid arthritis risk in men, but it is not clear whether the specific association with seronegative rheumatoid arthritis would be observed. This would be an important future direction particularly since most patients with rheumatoid arthritis are women. If there is no association in men, this may help explain some of that imbalance.”


Sparks JA, MalspeisS, Hahn J et al. "Depression and subsequent risk for incident rheumatoid arthritis among women." Arthritis Care Res (Hoboken). 2020 Sep 16. doi: 10.1002/acr.24441.

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