Fatigue in psoriasis: prevalence and biological mechanisms
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Background: Fatigue is prevalent in patients with chronic inflammatory diseases and often rated as the most troublesome aspect of their disease. Clinical experience indicates that fatigue is common also in patients with psoriasis, but studies are sparse. A model for understanding fatigue is the "sickness behavior model" in animals. Following the onset of an infection a coordinated set of behavioral changes occurs in the sick animal, commonly recognized as lethargy, depression, loss of thirst, hunger, and reduction in grooming. Fatigue is a prominent and dominant feature of this response. This behavior is signaled by interleukin (IL)-1β in the brain, and has many similarities with chronic fatigue in humans. Chronic inflammatory disease resembles a "chronic infection". Thus, fatigue is continuously induced through "danger signals" triggering the innate immune system and leading to a “sickness behavior response”. Although activation of the innate immune system and IL-1β play pivotal roles in generation of fatigue, other immune regulatory mechanisms have been suggested as potential mediators. The frequent reported lack of association between disease activity and fatigue in chronic inflammatory diseases is a paradox that could be explained by involvement of down-regulatory immune mechanisms and responses involved in protection against cellular stress. However, the entire biological mechanisms of fatigue are yet poorly understood. Fatigue can be challenging for the patients to live with and for the clinicians to treat. There is a lack of management guidelines. Evidence suggest that biological drugs could be effective, however this effect has not been systematically evaluated. Main objectives: • Write a review article with focus on current knowledge, biological mechanisms and identifying research gaps on fatigue in psoriasis • Investigate and describe fatigue in chronic plaque-type psoriasis patients and compare with age- and gender matched healthy subjects to obtain a better understanding of the extent and severity of this phenomenon • Estimate the efficacy of biological drugs on fatigue in psoriasis • Uncover biological processes and signaling pathways that cause fatigue in psoriasis: - Investigate plasma levels of markers of oxidative stress in psoriasis patients compared to healthy subjects, and explore the associations with fatigue - Investigate plasma levels of selected cytokines in psoriasis patients compared to healthy subjects, and explore the association with fatigue - Compare gene expression of selected heat shock protein genes in psoriasis patients with high and low fatigue levels Subject and methods: Fatigue was measured in 84 patients with chronic plaque-type and 84 age- and gender-matched healthy subjects. The patients were recruited from the Department of Dermatology, Stavanger University Hospital and the healthy subjects were predominantly recruited form acquaintances of the patients. Fatigue severity was assessed using three different generic fatigue instruments: the fatigue Visual Analog Scale (fVAS), the Fatigue Severity Scale (FSS), and the Short Form 36 (SF-36) vitality scale. Cut-off scores were defined as ≥50 for fVAS, ≥4 for FSS, and ≤35 for SF-36 vitality scale. Disease activity was evaluated using the Psoriasis Area and Severity Index (PASI), and the impact on quality of life (QoL) with the Dermatology Life Quality Index (DLQI). To investigate oxidative stress, we measured plasma levels of advanced oxidation protein products (AOPP) and malondialdehyde (MDA) in plasma using UV-spectrophotometry and high performance liquid chromatography connected to a fluorescence detector. Plasma levels of IL-1β, IL-1Rα, IL-6, and IL-10 were measured by electrochemiluminescence based Meso Scale Discovery assay, IL-1RII by sandwich enzyme-linked immunosorbent assay. Peripheral blood transcriptional profiles of HSP genes from 10 patients with high fatigue and 10 patents with low fatigue were compared. The expression levels of four of these genes (HSPB11, HSPA14, HSP90B1, HSP90AB1) were re-evaluated by reverse transcription quantitative real-time polymerase reaction in 20 patients with high and 20 patients with low fatigue. Results: We found that: • Fatigue is overlooked and an under-researched phenomenon in psoriasis. • Nearly 50% of psoriasis patients suffer from clinically important fatigue. Fatigue severity is associated with pain, depression and smoking, but not with psoriasis disease severity • Biological drugs have a small to moderate effect on fatigue in psoriasis • Plasma concentrations of AOPP and MDA are not associated with fatigue in psoriasis patients. These biomarkers of oxidative stress are not increased in psoriasis patients compared to healthy subjects. Plasma AOPP and MDA are strongly dependent on gender and other non-disease related factors. Several physiological and methodological factors influence concentrations of AOPP and MDA • Plasma concentrations of IL-1β, IL-1Rα, IL-1RII, IL-6, and IL-10 are not associated with fatigue. Plasma concentrations of IL-1Ra and IL-6 were influenced by BMI, not disease severity in psoriasis patients • Fatigue is associated with altered expression of some HSPs. A tendency to higher expression levels of HSPB11 and lower expression of HSP90B1 is 9demonstrated in patients with high fatigue scores compared to those with low fatigue scores. Conclusions: Fatigue is common and severe in psoriasis patients. Fatigue is strongly associated with pain and depression, but not with disease activity. There is a modest positive effect of biological drugs. Fatigue is not related to plasma markers of oxidative stress or selected cytokines, but associations to gene expression levels of selected HSPs are evident.
Has partsPaper I: Skoie IM, Ternowitz T, Jonsson G, Norheim K, Omdal R. Fatigue in psoriasis: a phenomenon to be explored. Br J Dermatol. 2015;172(5):1196-203. The article is available at: https://hdl.handle.net/1956/10287
Paper II: Skoie IM, Dalen I, Ternowitz T, Jonsson G, Kvivik I, Norheim K, Omdal R. Fatigue in psoriasis: a controlled study. Br J Dermatol. 2017 Aug;177(2):505-512. The article is available in the thesis file. The article is also available at: https://doi.org/10.1111/bjd.15375
Paper III: Skoie IM, Dalen I, Omdal R, Jonsson G. Malondialdehyde and advanced Oxidation protein products are not increased in psoriasis: a controlled study. Arch Dermatol Res. 2019 May;311(4):299-308. The article is not available in BORA due to publisher restrictions. The published version is available at: https://doi.org/10.1007/s00403-019-01903-2
Paper IV: Skoie IM, Dalen I, Kvivik I, Bardsen K, Omdal R. Fatigue in patients with plaque-type psoriasis: lack of an association with plasma cytokines. Eur J Dermatol. 2020 Feb 1;30(1):16-23. The article is not available in BORA due to publisher restrictions. The published version is available at: https://doi.org/10.1684/ejd.2020.3701
Paper V: Skoie IM, Dalen I, Omdal R. Effect of Biological Treatment on Fatigue in Psoriasis: A Systematic Review and Meta-Analysis. Am J Clin Dermatol. 2019 Aug;20(4):493-502. The article is not available in BORA due to publisher restrictions. The published version is available at: https://doi.org/10.1007/s40257-019-00434-w
Paper VI: Skoie IM, Bardsen K, Nilsen M, Eidem L, Dalen I, Omdal R. Heat shock genes in peripheral blood mononuclear cells are differently expressed in psoriasis patients with high and low fatigue. The article is not available in BORA.