Patients with rheumatoid arthritis (RA) are two to four times more likely than the general population to have depression. This has posed an interesting question among researchers: Does body-wide inflammation, seen in RA, lead directly to depression or does inflammation increase disease activity, which in turn can result in depression?

“We know that traditional risk factors, such as pain and disability, cause depression in RA, but there is this novel idea that inflammation plays a role as well. This idea that inflammation contributes to depression in RA is gaining more acceptance,” says Mary Margaretten, MD, a rheumatologist at the University of California San Francisco (UCSF).

“There is a body of literature recognizing depression as an inflammatory state. There is a well-documented event called cytokine-induced depression, where cytokines are increased and depression occurs,” explains Patricia Katz, PhD, a professor of medicine at the University of California San Francisco (UCSF) whose research has focused on the relationship between function and psychological status among adults with chronic health conditions like RA. “However, there are some people who think that…the depression causes the inflammation. There is some evidence going that way, too. But I think in a disease that has an inflammatory underpinning as RA does, there is more work needed,” she says. 

Which comes first: depression or RA?

Katz and her colleague Mary Margaretten, MD, co-authored a 2011 report in the International Journal of Clinical Rheumatology that reviewed what is currently known about the link between RA and depression and what role inflammation might play. “It’s analogous to cardiovascular disease in RA. There is this high risk of heart disease in patients with RA due to traditional risk factors and novel risk factors like inflammation. Similarly, there is a disproportionate burden of depression in our patients,” explains Dr. Margaretten, an assistant professor of medicine in the division of rheumatology at UCSF. 

Studies have reported a general link between inflammation and depression.  Johns Hopkins University researchers reported in the Archives of Internal Medicine in 2004 that major depression in men was strongly associated with increased levels of a marker of inflammation called C-reactive protein (CRP). Researchers say C-reactive protein (CRP) is helpful to study because it’s an objective marker of inflammation that is easily measured in clinical practice. 

A 2009 study published in Arthritis & Rheumatism reported a similar association. The study researchers analyzed CRP levels and self-reported questionnaires from 218 RA patients and found that inflammation and depression independently increased the likelihood that someone was experiencing severe pain. When inflammation and depression occurred together, the risk of severe pain increased even more. 

“With that study, one does not know what came first. Based on that study you can say depression and inflammation are associated, but you can’t say inflammation causes depression,” Dr. Margaretten explains.