Why does malaise/fatigue occur? Underlying mechanisms and potential relevance to treatments in rheumatoid arthritis

ABSTRACT

Introduction

Fatigue and malaise are commonly associated with a wide range of medical conditions, including rheumatoid arthritis (RA). Evidence suggests that fatigue and malaise can be overwhelming for patients, yet these symptoms remain inadequately-managed, largely due to an incomplete elucidation of the underlying causes.

Areas covered

In this assessment of the published literature relating to the pathogenesis of fatigue or malaise in chronic conditions, four key mechanistic themes were identified. Each theme (inflammation, hypothalamic-pituitary-adrenal axis, dysautonomia, and monoamines) is discussed, as well as the complex network of interconnections between themes which suggests a key role for inflammatory cytokines in the development and persistence of fatigue.

Expert opinion

Fatigue is multifaceted, poorly defined, and imperfectly comprehended. Moreover, the cause and severity of fatigue may change over time, as a consequence of the natural disease course or pharmacologic treatment. This detailed synthesis of available evidence permits us to identify avenues for current treatment optimization and future research, to improve the management of fatigue and malaise in RA. Within the development pipeline, several new anti-inflammatory therapies are currently under investigation, and we anticipate that the next five years will herald much-needed progress to reduce the debilitating nature of fatigue in patients with RA.

KEYWORDS:

• Fatigue
• hypothalamus
• inflammation
• malaise
• monoamines
• rheumatoid arthritis
• sympathetic and parasympathetic nerves

Article highlights

• Fatigue and malaise are common, and often overwhelming, symptoms associated with a wide range of medical conditions, including rheumatoid arthritis.

• There is currently no cure for fatigue/malaise, which is partly due to fact that the underlying pathophysiology remains incompletely understood.

• We undertook an assessment and synthesis of the published literature relating to the pathogenesis of fatigue/malaise in chronic conditions.

• We were able to identify four key mechanistic themes in the development and persistence of fatigue/malaise (inflammation, hypothalamic-pituitary-adrenal axis, dysautonomia, and monoamines), all of which can be linked to the actions of inflammatory cytokines.

• Several new anti-inflammatory therapies are currently under investigation for the treatment of rheumatoid arthritis, bringing hope to patients that new drugs may soon become available to reduce the debilitating symptoms of fatigue/malaise and allowing them to resume normal daily activities.

Declaration of interest

Y Tanaka has received speaker fees and/or honoraria from Eli Lilly, AstraZeneca, Abbvie, Asahi-kasei, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Gilead, GlaxoSmithKline, Pfizer, Taiho, and Taisho, and research grants from Asahi-kasei, Chugai, Eisai, Mitsubishi-Tanabe, and TK Ikeda has received speaker fees from Abbvie, Asahi-kasei, Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Kyowa Kirin, Novartis, Mitsubishi-Tanabe, Pfizer, Taiho, and UCB, and research grant from Mitsubishi-Tanabe. Y Kaneko has received speaker fees from Abbvie, Asahi-kasei, Astellas, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Taisho, and UCB, and research grants from Abbvie, Asahi-kasei, Boehringer-Ingelheim, Chugai, Eisai, Gilead, Mitsubishi-Tanabe, and UCB. N Ishiguro has received speaker fees and/or honoraria from Abbvie, Eisai, Eli Lilly, and Gilead. T Takeuchi has received grants from AbbVie, Asahi-kasei, AYUMI, Chugai, Eli Lilly, Mitsubishi-Tanabe, and Ono, and honoraria from AbbVie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai., Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe, and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

All articles used to inform the discussion in this manuscript are in the published domain, and are cited in the reference list.

Acknowledgments

The authors thank SA Mitchell, PhD (McCann Healthcare Worldwide Japan Inc.) for providing editorial assistance, which was funded by Eli Lilly and Company.

Additional information

Funding

This paper was funded by Eli Lilly and Company, who supported the literature search, but played no role in data collection and analysis.