Fatigue and Inflammation Explored


Founder of Health Rising and Phoenix Rising
Staff member
In this review article inflammation is postulated to be the link between fatigue, pain and depression. This is a freebie article by the way.
Arthritis Res Ther. 2015 Oct 5;17(1):254. doi: 10.1186/s13075-015-0784-1.Fatigue in chronic inflammation - a link to pain pathways.
Louati K1,2, Berenbaum F3,4.Author information

Some highlights:

What is fatigue? This is fatigue

Fatigue is usually defined as a state of exhaustion and decreased strength accompanied by a feeling of weariness, sleepiness, and irritability, with a cognitive component [1]. A physiological fatigue state, occurring after strong physical effort, sends a signal to the body to bring it to rest to rescue the exhausted tissues (that is, the muscles). Unlike normal fatigue, pathological fatigue does not improve with rest. This kind of fatigue is seen in most acute and chronic inflammatory diseases, including arthritis.

It is similar but different from weakness in that fatigue brings along these added symptoms I think: weariness, sleepiness, and irritability and cognitive problems.
  • Fatigue is common in chronic illnesses - particularly inflammatory illnesses.
  • Fatigue is correlated with inflammatory cytokines in some diseases not others; in other words it can be generated in a number of ways
  • Fatigue is well correlated with cytokines in post-cancer states: "A recent review described fatigue occurring with inflammation before, during and after treatment with several cancers. Fatigue was well correlated with high levels of inflammatory peripheral cytokines (IL-6, IL-1 and TNF), which could signal the central nervous system (CNS) and generate fatigue or other behavioral symptoms.
  • Fatigue is common in rheumatic disorders such as RA, SpA, Sjögren syndrome, systemic lupus erythematosus and vasculitis and can be severe: "For 75 % of patients with ankylosing arthritis and 50 % of those with RA, fatigue was considered severe". (Do they experience post-exertional malaise?)
  • In general biotherapies (including Rituximab) have had, however, only small to moderate effects on fatigue: anti-TNF (infliximab, adalimumab, etanercept, golimumab and certolizumab), anti-IL-6 (tocilizumab), CTLA4 immunoglobulin (abatacept) and anti-CD20 (rituximab) " the overall effect size of biotherapies on fatigue was small"
  • New drugs, however, seem to be more effective in fighting fatigue: FACIT-Fatigue and SF-36 vitality scales were improved with secukinumab, an antibody against IL-17, and tofacitinib, an oral Janus kinase inhibitor
  • They are obviously missing some immune tests because when immune drugs affect fatigue standard inflammation tests don't indicate how: After 3 months of anti-TNF therapy for RA, fatigue was decreased in patients but was independent of the level of CRP: on multiple regression, only global health and tender joint count explained 34 % of the variance in fatigue
  • Exercise helps RA patients improve fatigue scores:
  • There is a high correlation between the amount of fatigue and pain people with fibromyalgia and RA experience.
Then they go on to pathway and mention what could be happening in ME/CFS:

Another model of the association of fatigue, pain and depression is CFS. Recently, a review showed that chronic inflammation could explain, in part, the sickness behavior [57]. In this pathology, with increased sensitivity to pain and with sickness behavior, inflammatory cytokines could have an effect on nociception. Such cytokines appeared to be critical mediators of hyperalgesia in a lipopolysaccharide-induced animal model [82, 83]. In CFS, the levels of neopterin, a marker of cellular immune system activation, IL-1 and TNF were correlated with fatigue and depression [84].

Brain inflammation could have a role in CFS, in part by activating microglia or astrocytes. Indeed, the density of 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide, a marker of neuroinflammation, was increased in some areas of the brain, in particular the cingulate cortex, in patients with CFS compared with healthy patients. Its increased level in the thalamus was correlated but not significantly with pain score and fatigue sensation (P = 0.0683) [85].

We have emerging evidence of the role of microbiota in the pathogenesis of autoimmune disease, particularly in rheumatologic disease [86]. Recently, Galland [87] proposed a schema in which the gut microbiome could affect CFS or fibromyalgia: the bacterial components could excessively stimulate the innate immune system and induce systemic and CNS inflammation by producing neurotoxic metabolites or could directly stimulate afferent neurons of the nervous system to send signals to the brain via the vagus nerve. Then, the gut microbiome could affect the HPA axis and be responsible for fatigue and pain in these diseases.


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