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Fatigue, Common in RA, Traced to Factors Beyond Inflammation

Chronic fatigue, extraordinarily common in autoimmune diseases such as rheumatoid arthritis, remains poorly defined. New studies suggest that disease activity is not the only contributing factor.

Katz P, Margaretten M, Trupin L, et al., Sleep disturbance, depression, obesity, and physical inactivity explain a significant portion of fatigue in rheumatoid arthritis.Arthritis Care & Research. 2015. Accepted article. Online March 16, 2015.

van Steenbergen HW, Tsonaka R, Huizinga TW, et al, Fatigue in rheumatoid arthritis; a persistent problem: a large longitudinal study. RMD Open 2015;1:e000041 doi:10.1136/rmdopen-2014-000041

Almost all patients with rheumatoid arthritis (RA) and other autoimmune diseases experience debilitating fatigue that impacts every aspect of life-even the ability to work, causing 21% to lose their jobs, according to a recent patient survey.   

The online survey of 7,838 patients, conducted in March by the American Autoimmune Disease Related Diseases Association (AARDA), also reveals that while 87% have discussed fatigue with their doctors, more than half say they have not been prescribed or recommended any treatment.

The European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) jointly recommend fatigue be included as a key outcome measure in clinical trials. But the same experts concede that there’s no consistent definition of fatigue and no validated, standard measure for it.

Evidence-based recommendations for the optimal management of fatigue in RA are nonexistent. It's not clear whether disease activity and inflammation are the only causes of RA fatigue or merely contribute to it.

Inflammation and fatigue

The largest longitudinal study on RA fatigue thus far shows that the association between inflammation and fatigue is statistically significant. But effect sizes are small, suggesting that non-inflammatory pathways mediate fatigue as well.

The 8-year study of 626 RA patients in the Leiden Early Arthritis Clinic cohort finds that fatigue levels remain about the same over time, despite treatment with disease-modifying antirheumatic drugs (DMARDs) and methotrexate.

Female gender, higher swollen and tender joint counts, and C-reactive protein (CRP) levels are independently and significantly associated with fatigue severity.

While “persistence of inflammation is associated with persistence of more severe fatigue,” better treatment strategies resulted in less radiographic severity but “did not result in less severe fatigue,” the Dutch researchers write.

Non-RA Risk factors for fatigue

A cross-sectional study examining fatigue severity by researchers at the University of California, San Francisco, also concludes that non-inflammatory factors play a role in RA fatigue.

The study of 158 RA patients used the Fatigue Severity Index (FSI, average fatigue over the past week), as the primary outcome measure.

After accounting for factors considered to be part of the disease process (inflammation, disease activity, joint pain, and swelling), the researchers find that RA fatigue is also linked to obesity, poor sleep quality, and depression.

All of these factors are commonly present in RA and other rheumatic diseases, the UCSF team points out.

Comparing RA-specific and non-RA-specific risk factors, the researchers find that the latter “account for a greater proportion of variance in fatigue.”

Increasing physical activity and addressing obesity or depression may help, they suggest.

In the AARDA survey as in the UCSF study, patients report that their fatigue has resulted in increased emotional distress, a sense of isolation, anxiety and depression.

When asked if their primary care doctor had suggested they contact a mental health professional as a result of their fatigue, 80% of the AARDA survey respondents said no.

However, only 29% say they sought professional mental health treatment for themselves as a result of their fatigue.

Since “persistent fatigue is associated with functional loss, fatigue in RA remains an ‘unmet need,’” the Dutch researchers conclude.