The Complex Network of Potential Fatigue Causes in IMIDs

During his presentation at the 2022 Interdisciplinary Autoimmune Summit, Wan-Fai Ng, PhD, stated, “The key to managing fatigue is using a personalized approach, tailored to counteract the contributing mechanism of fatigue in order to address the underlying problem.”

Dr Ng is a rheumatologist at Newcastle University in Newcastle upon Tyne, UK.

Discovering the contributing mechanism of fatigue can be difficult, as there is a complex network of systems and mechanisms within any individual patient, all of which have the potential to influence fatigue, he said.

Even larger is the issue of the conception challenge of fatigue. Dr Ng stated that, to date, there is no consensus definition or measurement method for fatigue. There are many unknowns when it comes to fatigue: Is fatigue experienced by patients with immune-mediated inflammatory diseases (IMIDs) the same fatigue experienced by healthy people? Are there different types of fatigue or merely different aspects (such as physical and mental)? Is fatigue a continuum or a dichotomy?

Dr Ng offered a working definition for fatigue as “a multi-dimensional phenomenon in which the biophysical cognitive, motivational, and emotional state of the body is affected, resulting in significant impairment of the individual’s ability to function in their normal capacity.”

Despite the uncertainty that surrounds fatigue, Dr Ng stated, “it is undisputable that the prevalence and the impact of fatigue is significant.” It is a common symptom among patients with IMIDs, with a 50%-75% prevalence among patients with such conditions as Sjögren syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease.

Fatigue is also “a very high unmet need to both the patient and society,” Dr Ng said. Participants in many studies have reported fatigue symptoms as “most burdensome,” a “top priority in need of improvement,” and the “key limiting factor on social activity.” These reports from patients are also supported by objective data through health-related quality of life measurements. In addition, fatigue is associated with more adverse health outcomes, such as mortality, hospitalization, disability in activities of daily living, limitation of physical functioning, and risk of cardiovascular system (CVS) disease. Economically, fatigue is associated with both direct and indirect health costs. In 2007, one US study found there was an annual excess of $100 billion attributed to direct and indirect costs related to fatigue.

While the cause of fatigue is unclear, Dr Ng stated that it is fair to assume that “inflammation and immune dysregulation contribute to the pathogenesis of fatigue” but that those 2 conditions are “neither sufficient nor necessary for the pathogenesis of fatigue.” While data has shown that fatigue is more prevalent among patients with active IMIDs and that often treatment of the underlying IMID can resolve fatigue, this is not always the case. Fatigue also persists in a significant proportion of patients who have entered remission for their IMIDs, and not all patients with IMIDs experience fatigue, he explained. This implies that there are additional mechanisms involved in the pathogenesis of fatigue; perhaps, he suggested, there are different mechanisms operating in different individuals or operating at different stages of disease.

Dr Ng also argued that “understanding fatigue that persists in patients in remission of their underlying IMID” is a “far more important unmet need,” since fatigue associated with inflammation or disease activity would improve as the underlying IMID is treated.

Patients with IMIDs have a chronic phenomenon of inflammation which likely results in the development of an immune regulatory or other adaptive mechanism. Dr Ng stated that while it is likely that those mechanisms contribute to fatigue, it is also possible that those adaptive mechanisms become “maladaptive” and continue to contribute to fatigue even while the patient is in remission from their IMID.

Inflammation is the primary consideration for contribution to fatigue in patients with IMIDs. Inflammation causes cytokines and pattern recognition receptors to communicate with the brain and coordinate “sickness behavior,” or a “constellation of nonspecific symptoms of sickness” that includes weakness, malaise, fatigue, aches, inability to concentrate, depression, and lethargy, Dr Ng said. Inflammation can also indirectly disrupt circadian rhythms, lead to sleep disturbances, increase oxidative stress, induce depression-like symptoms, and potentially blunt the hypothalamus-pituitary-adrenal (HPA) axis responses — all of which can contribute to fatigue.

Neuroendocrine factors, like HPA axis behavior, can also affect fatigue. The HPA axis responds to stress, whether that is environmental, physiological, or from inflammation, Dr Ng explained. The pathways of this axis eventually lead to the secretion of cortisol, which regulates and affects other functions, like mood and metabolism. Evidence of HPA axis involvement in fatigue in IMIDs includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and reduce responsivity to challenges.

Autonomic dysfunction may also play a role in fatigue in IMID, indicated by self-reported symptoms from patients, tilt tests, heart rate and blood pressure variability, sweet responses, and plasma levels of catecholamines.

In the event of stress or inflammation, the parasympathetic nervous system may help to reduce inflammation, while the sympathetic nervous system can also affect the patient’s emotions, metabolism, and CVS, which are all relevant to fatigue.

Patients with IMIDs often report problems with sleep. Sleep disturbances can result in nonrestorative sleep and changes in objective sleep parameters. Dr Ng pointed out that the impact of sleep disturbances on a patient with chronic disease would be “very different” than that for a patient with acute disturbances.

There is also the potential of excess oxidation produced in response to inflammation in stress. This can affect metabolic efficiency, and neurotransmitters like tryptophan, which could in turn affect a patient’s sleep and mood. Current studies are investigating the potential of genetics to influence fatigue through polymorphisms, gene expression, and epigenetics. Other determinants of fatigue include pain, cardio-respiratory fitness, obesity, mood, coping strategies and illness perception, comorbid conditions.

All of these possibilities illustrate that the pathogenesis of fatigue is incredibly complex, Dr Ng explained. While inflammation plays a central role, many systems become involved, all of which can influence fatigue.

Dr Ng also stated that at different stages of the disease, different systems may contribute to fatigue. At the onset of fatigue, inflammation may be the main culprit. Once inflammation becomes more chronic, however, additional mechanisms may cause and be more important in the management of fatigue.

As “there are many bio-psychological mechanisms that can contribute to fatigue in IMID,” Dr Ng suggested attempting to determine what the most predominant mechanism for the individual patient is, and then targeting that mechanism with an appropriate therapy.

If inflammation is the primary driver of fatigue, then optimizing immunomodulatory therapies to achieve clinical remission of the underlying IMID may be the best way to reduce fatigue. Dr Ng also suggested nonpharmacological interventions such as physical activity, exercise, and cognitive behavioral therapy (CBT) may improve fatigue, though it is unclear how long this benefit may be sustained.

For unresolved pain or an associated mood disorder, Dr Ng suggested analgesics, CBT, antidepressants, or acupuncture, to resolve fatigue. In the case of metabolic dysregulation, exercise and physical therapy, and supplements such as antioxidants or coenzyme Q10, may be beneficial. If sleep changes are the main culprit, sleep education, CBT for insomnia, and exercise and physical training may help. When neurotransmitter metabolism and central nervous system changes may be in play, psychostimulants, modafinil, selective serotonin reuptake inhibitors, and mind-body therapy could be the best course, he said. Low-dose hydrocortisone, herbal medicines, and psychological medicine may help with HPA axis involvement, and vagus nerve stimulation may be a solution for autonomic dysfunction.

For patients whose fatigue continues despite the treatment of their inflammation, “it may be that…inflammation is not the key mechanism of fatigue,” Dr Ng stated.

—Allison Casey

Reference:
Ng W. Advances in understanding fatigue in IMIDs. Presented at: Interdisciplinary Autoimmune Summit; April 21, 2022. Virtual.