Psoriasis-Associated Fatigue: Pathogenesis, Metrics, and Treatment

Fatigue is defined as “an overwhelming, sustained sense of exhaustion and decreased capacity for physical and mental work,”¹ and it is experienced by most patients with chronic disease. There are 2 types of fatigue: acute and chronic.² Acute fatigue typically is caused by an identified insult (ie, injury), is self-limited, and is relieved by rest. Chronic fatigue, which may have multiple unknown causes, may accompany chronic illness and lasts longer than 6 months.² In chronic disease, fatigue can originate peripherally (neu romuscular dysfunction outside of the central nervous system) or centrally (neurotransmitter activity within the central nervous system). Generally, central fatigue is more relevant in patients with chronic disease; however, both central and peripheral fatigue frequently coexist.

Fatigue, even with its accepted definition, is a nonspecific symptom, making it difficult to measure. Because of its subjective nature and the lack of effective therapies, clinicians often ignore fatigue. Still, patients with chronic disease continue to cite fatigue as one of the most challenging aspects of their disease that frequently decreases their quality of life (QOL).²

Fatigue has been well recognized in a number of chronic inflammatory diseases such as rheumatoid arthritis,^3,4 systemic lupus erythematosus,⁵ fibromyalgia,⁶ and primary Sjögren syndrome.⁷ Similarly, fatigue is a frequent concern among patients with psoriasis and psoriatic arthritis.⁸ Given the prevalence and significance of psoriasis-associated fatigue,⁹ new efforts are needed to understand its pathophysiology, to develop new metrics for its evaluation, and to investigate therapeutic strategies to target it clinically. The following discussion provides an overview of the association between fatigue and psoriatic disease as well as the commonly used metrics for evaluating fatigue. Possible therapeutic agents with which to manage fatigue in this patient population also are provided.

Pathogenesis of Psoriasis-Associated Fatigue

Immunologic/Molecular Basis for Psoriasis-Associated Fatigue

Several theories aim to explain the pathophysiology of fatigue in patients with psoriatic disease. Psoriasis is a chronic inflammatory disease characterized by sharply demarcated erythematous plaques with adherent scale (Figure 1). Many in vitro studies have demonstrated the complex cytokine network that underlies the histopathologic alterations we observe in psoriatic lesions.^10,11 Until recently, psoriasis was considered a type I autoimmune disease with strong T_H1 signaling, influenced by IFN-γ, IL-2, and IL-12.¹² T_H1-producing proinflammatory cytokines, tumor necrosis factor α (TNF-α), and IFN-γ are elevated in psoriatic lesions.¹³ Studies on the efficacy of ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, demonstrate the integral role of the immune system in psoriasis pathogenesis as the production of IL-12 polarizes T cells into T_H1 cells.^14,15 However, in recent years, T_H17 cells have been linked to autoimmune inflammation¹⁶ and have been localized to the dermis in psoriatic lesions.¹⁷

Figure 1. Broad, pink, well-demarcated plaque with retention hyperkeratosis consistent with plaque psoriasis.

Figure 2. Confluent, erythematous, excoriated psoriasiform plaques on the lower legs.

Among a milieu of inflammatory cytokines, IL-1 is crucial for the early differentiation of T_H17 cells.¹⁸ The IL-1 family of cytokines serve as primary mediators of inflammation with members including the IL-1 agonists (IL-1α, IL-1β),¹⁹ IL-1 receptor antagonist (IL-1RA),²⁰ and IL-1 receptor type II (IL-1RII).²⁰ The latter two inhibit IL-1 agonists from binding to their receptor (IL-1RI).^19,20 A study by Yoshinaga et al²¹ investigated the level of inflammatory cytokines within lesional and nonlesional psoriatic skin, finding elevated levels of IL-1β in lesional skin. Another study found that IL-1β expression was increased 357% within biopsied psoriasiform lesions from flaky-skin mice, a useful model to examine the hyperproliferative alterations in the skin. This same study revealed that in vivo IL-1β neutralization alleviated the psoriasiform features in these same mice, suggesting IL-1β is integral to psoriasis pathogenesis.²²

Evidence indicates that the aforementioned inflammatory mediators may contribute to psoriasis-associated fatigue. When the peripheral immune system is continuously activated, such as in psoriasis, the peripherally produced proinflammatory cytokines and subsequent immune signaling are monitored by the brain via afferent nerves, cytokine transporters at the blood-brain barrier, and IL-1 receptors on macrophages and endothelial cells of brain venules.²³ For example, subseptic doses of lipopolysaccharide injected into rats induced messenger RNA expression of IL-1β in the choroid plexus, circumventricular organs, and the meninges,²⁴ sites where cytokines can enter the blood-brain barrier via diffusion or cytokine transporters.²³ These results may suggest a pathway that relays the peripheral immune signals that underlie psoriatic disease to the brain, resulting in activation of brain circuitry that mediates various negative behavioral responses, including fatigue.²³ Following a central IL-1β infusion in mice, investigators found a significant decrease in the running performance (P<.01)²⁵; the same infusion increased lethargy, malaise, and fatigue in rats.²⁶ Interestingly, administration of IL-1RA significantly increased run time to fatigue (P<.05), supporting the hypothesis that IL-1β plays an important role in fatigue.²⁵ Other investigators found that administration of many cytokines (IL-1β, IL-6, TNF-α) into rats induced depressivelike behaviors²⁷ and suppressed locomotor activity.²⁸ Lastly, another investigation found that IL-1RI knockout mice were resistant to symptoms of sickness, such as social exploration, anorexia, immobility, and weight loss, following IL-1β injections.²⁹ Although the translatability of these studies to humans is not entirely clear, one study found that the proinflammatory cytokines IL-1 and TNF-α were elevated in patients with chronic fatigue syndrome.³⁰ Furthermore, a 2013 systematic review found that several serum inflammatory markers including IL-6 and TNF-α were elevated in patients with severe plaque psoriasis compared to healthy controls.³¹ Therefore, these shared inflammatory cytokines may contribute to and explain the pathogenesis of both fatigue and psoriasis.