Factors that were associated with high levels of fatigue among patients with Sjogren's syndrome included pain, depression, and -- unexpectedly -- low levels of two proinflammatory cytokines, a U.K. study found.
In a logistic regression model, pain, depression, and low levels of interferon (IFN)-γ and IFN-γ-induced protein-10 (IP-10) predicted fatigue in 67% of cases, according to Wan-Fai Ng, PhD, of the Institute of Cellular Medicine at Newcastle University in Newcastle-upon-Tyne in England, and colleagues.
However, clinical disease activity did not appear to correlate with fatigue, the researchers reported online in RMD Open: Rheumatic & Musculoskeletal Diseases.
Inflammation has been postulated to have a central role in fatigue associated with chronic autoimmune disease as part of a phenomenon termed sickness behavior.
"Sickness behavior is considered an evolutionarily adaptive behavioral response to infection facilitating speedy recovery, minimizing energy expenditure, and reducing environmental risks when an organism is in a weakened state during and following an infection," Ng and colleagues explained.
Because this response is mediated by proinflammatory cytokines, it has been assumed that inflammation would be responsible for fatigue in chronic disease.
However, the finding that proinflammatory cytokine levels were lower among patients with high levels of fatigue "does not ... support a simple concept of higher levels of inflammation leading to worse fatigue,"
Previous research has found that inflammatory burden does not necessarily correlate with fatigue scores in diseases such as Sjogren's syndrome, rheumatoid arthritis, and lupus, "suggesting that there may be a complex range of positive and negative feedback loops contributing to fatigue in autoimmune conditions," they wrote.
Sjogren's syndrome is a suitable disease model for investigating fatigue because of its straightforward diagnostic criteria and the fact that patients generally are not receiving potent immunosuppressive drugs that could influence fatigue, according to the authors. There also is a wide variability in the degree of fatigue that patients with this condition report.
Therefore, to explore the potential relationship between inflammation, fatigue, and other disease characteristics, the researchers selected 159 women and 28 healthy controls from the U.K. Primary Sjogren's Syndrome Registry.
Physical fatigue was rated as minimal, mild, moderate, and severe on a 0-7 scale, while depression and anxiety were assessed with the Hospital Anxiety and Depression Score. Clinical assessments included the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index and Patient Reported Index, along with measures of salivary gland function and sicca scores.
Immunoassays for 24 pro- and anti-inflammatory cytokines were performed using specimens from the registry's biobank, and other inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate also were measured.
At baseline, 43% of patients were receiving immunomodulating agents, most often hydroxychloroquine.
Increased fatigue was associated with higher lymphocyte counts and lower IgG levels and also with depression, pain, anxiety, salivary dryness, and overall symptoms.
"As expected," multiple proinflammatory cytokines were present in higher levels among patients with Sjogren's syndrome than among controls, including tumor necrosis factor (TNF)-α, IP-10, interleukin (IL)-6, IL-10, IL-17, and lymphotoxin (LT)-α.
But when levels of those cytokines were analyzed according to levels of fatigue, inverse correlations were seen for IP-10, TNF-α, LT-α, and IFN-γ.
In the logistic regression analysis including all potentially predictive clinical and laboratory parameters plus the 24 cytokines, fatigue was predicted accurately in 67% of cases. Narrowing the analysis to include only the cytokines IFN-γ and IP-10 along with pain and depression, but eliminating clinical measures, resulted in the same "reasonably accurate" predictive value.
"This suggests that measures of disease activity in primary Sjogren's syndrome appear to be less important than cytokines, depression, and pain in accurately predicting fatigue levels," the researchers observed.
As to why lower levels of inflammatory markers would be associated with worse fatigue, the authors suggested that there might be a negative feedback loop where inflammatory markers are reduced but fatigue persists.
"Thus, although fatigue is induced by proinflammatory cytokines as part of an 'adaptive behavior response,' which has evolved as a protective motivational state during and following an infection, a potentially maladaptive immune response may contribute to the maintenance of persistent fatigue after clearance of a pathogen or in a chronic inflammatory state," Ng and colleagues wrote.
In a healthy patient, they explained, exposure to an infectious agent leads to an immune response triggering inflammatory pathways resulting in sickness behavior, followed by restoration of immune homeostasis and normalization of the behavioral response. But in a patient whose immune response is dysregulated, the anti-inflammatory response becomes excessive and continues to upregulate the immune system "in a pathological feedback loop," and the sickness behavior persists.
Limitations of the study included its cross-sectional design and the possibility of additional unmeasured factors contributing to fatigue.
The study was funded by the Medical Research Council, th eNewcastle NIHR Biomedical Research Center for Aging and Chronic Diseases, and the North East and North Cumbria Local Comprehensive Research Network.
Ng and co-authors disclosed financial relationships with Celgene, Eli Lilly, Glenmark, GlaxoSmithKline, Medimmune, Novartis, Ono, Pfizer, Takeda, and UCB.
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