Daily stresses can lead to fatigue in people with rheumatoid arthritis (RA), but worrying can make a range of symptoms worse, according to a new Dutch study published online in the Annals of the Rheumatic Diseases.

“Patients who have a tendency for more worrying reported slightly more disease activity, more swollen joints and more pain one month later,” explains lead author Andrea W. M. Evers, PhD, a clinical psychologist and coordinator at Radboud University Nijmegen Medical Centre in the Netherlands.

The researchers were trying to understand how daily stressors and worrying impact symptoms and disease activity in RA, an autoimmune form of arthritis that affects 1.5 million people in the U.S.

To find out, they gathered data from 80 RA patients once a month for six months. Patients answered questions about daily stressors (for example, long appointment wait times or losing something valuable), level of worry, and symptoms of pain, fatigue and disease activity.

Researchers also took blood samples to measure levels of the stress hormone cortisol as well as inflammatory cytokines (molecules) that are believed to play a key role in RA severity, including TNF-alpha and interleukin-1 beta (IL-1β). (Some biologics, including etanercept (Enbrel) and adalimumab (Humira) are TNF inhibitors, while anakinra (Kineret) is an IL-1 inhibitor.)

Researchers found that worrying led to higher self-reported disease activity, more pain and more swollen joints one month later, while daily stressors predicted greater fatigue one month later.

They also found that patients with a higher level of certain cytokines – specifically IL-1β and interferon gamma – were also likely to experience more fatigue a month later.

“These findings suggest that fatigue might have an important role in both stress-related factors and inflammatory processes, but the precise relationships are unknown and the exact mechanisms need to be disentangled in future research,” Evers says.

Although worrying led to worse symptoms, it did not lead changes in specific cytokine and cortisol levels – but that doesn’t mean that there isn’t a physical connection, just that the researchers might have been looking at the “wrong” pathway.

The researchers say their findings point to the need for more studies about exactly how worrying impacts the disease process. They say there are several possible explanations. For example, because worrying affects emotional well-being and behavior, Evers says it could lead to less treatment adherence – and thus more pain.

Terry L. Moore, MD, director of the division of rheumatology at St. Louis University School of Medicine in Missouri, says while there is a growing body of evidence indicating stress and fatigue can affect the immune system, he questions the findings of this particular study because he says it had too many difficult-to-measure variables at play.

“Self-reported disease activity, pain and fatigue – some of the things they were monitoring are very subjective,” Dr. Moore says. “You are relying on patients to tell you what went on during the day. Fatigue varies – what one says is fatigue another might not view that way.”

While the medical community continues to search for answers, Evers says there is no question patients with the tendency to worry extensively can be helped with psychological interventions like cognitive-behavioral therapy.