Study Validates Link Between Some Pro-inflammatory Molecules, Less Fatigue in pSS

Higher levels of some inflammatory signaling molecules are associated with less fatigue in people with primary Sjögren’s syndrome, challenging prior thoughts that inflammatory molecules directly mediate fatigue in chronic autoimmune conditions, a recent validation study found.

The study, “Fatigue in primary Sjögren’s syndrome (pSS) is associated with lower levels of proinflammatory cytokines: a validation study,” was published in the journal Rheumatology International.

People who are sick often get tired. Sometimes, this is actually an adaptive response, termed “sickness behavior” — if there’s an infection, it makes sense to conserve energy so the body can better fight it off — but in autoimmune diseases such as Sjögren’s syndrome, this fatigue usually does little more than make a person feel … well, sick and tired.

Fatigue is influenced by many factors, one of which is cytokines — a class of molecules that the immune system uses to send signals throughout the body. Because many cytokines can be measured with relative ease via a blood test, these molecules are attractive candidates as prognostic markers that doctors can measure objectively in order to assess a patient’s state.

It’s a common assumption that pro-inflammatory cytokines would induce more fatigue, because both tend to occur when the immune system is being more active. Paradoxically, though, a previous study suggested that, in primary Sjögren’s syndrome patients, higher levels of certain pro-inflammatory cytokines are associated with less fatigue.

In the new study, the same researchers set out to validate their previous finding — no single study can be infallible; replication studies are crucial for good science.

To do this, the researchers analyzed blood samples and self-reported fatigue for 120 primary Sjögren’s syndrome patients and 30 controls (who didn’t have Sjögren’s syndrome and weren’t experiencing notable fatigue) from the United Kingdom Primary Sjögren’s Syndrome Registry.

The researchers measured seven pro-inflammatory cytokines: interferon-γ-induced protein 10 (IP-10), tumor necrosis factor-α (TNF-α), lymphotoxin-α (LT-α), interferon-γ (IFN-γ), interferon-α (IFN-α), interleukin-12p70 (IL-12p70), and interleukin-17 (IL-17).

Levels of five of these cytokines — IP-10, TNF-α, LT-α, IFN-y, and IFN-α — were significantly higher in patients than in controls.

Higher levels of two of the cytokines, TNF-α and LT-α, showed a statistically significant link to lower reported fatigue. These two cytokines both showed a comparable significant association in the previous study as well, so the new results validated the previous findings.

For two additional cytokines, IP-10 and IFN-y, higher levels were associated with lower fatigue. But while this association reached statistical significance in the previous study, it didn’t in this study; therefore, only the previous results for TNF-α and LT-α, independently, were validated.

The researchers then developed a statistical model using TNF-α and LT-α levels, as well as depression, anxiety, and pain score. This model was able to accurately predict fatigue scores in 85% of the primary Sjögren’s syndrome patients in the study.

Although this study does suggest that some pro-inflammatory cytokines are linked to less fatigue, the relationship isn’t nearly so simple as that. Instead, the researchers propose, these higher levels are probably indicative of a more abnormally regulated immune system.

“In other words,” the researchers stated, “we postulated that the exaggerated or inappropriate immune regulation turns what was an adaptive behavioral response, sickness behavior, into a persistent, pathological response resulting in chronic fatigue with or without concomitant pain and depression.”

They added, “Identifying such anti-inflammatory mechanisms may give clue to treatment of fatigue in pSS.”

More research will be needed to fully understand such mechanisms, as well as how cytokines and fatigue are interconnected, and how this connection could be therapeutically exploited.