M. Tarazi; R.G. Gaffney; D. Pearson; C.J. Kushner; V.P. Werth
The British Journal of Dermatology. 2019;180(6):1468-1472.
Abstract and Introduction
Abstract
Background: Fatigue is a well-established symptom in systemic lupus erythematosus (SLE), but has not been well characterized in other skin-limited autoimmune diseases such as cutaneous lupus erythematosus (CLE), amyopathic dermatomyositis (ADM) or autoimmune blistering diseases (AIBD).
Objectives: In this retrospective study, we compared fatigue in controls (n = 84) with that in patients enrolled in prospective longitudinal databases with SLE (n = 165), CLE (n = 226), ADM (n = 136) and AIBD (n = 79).
Methods: We used the 36-Item Short Form Survey (SF-36) vitality scale to analyse median scores and the percentages of patients with clinically significant fatigue (defined as a score ≤ 35) between experimental groups and controls.
Results: Median and interquartile range (IQR) vitality scores demonstrated greater fatigue in the experimental groups (SLE 35, IQR 20–55; CLE 50, IQR 30–70; ADM 50, IQR 30–65; AIBD 55, IQR 35–70) than in controls (73, IQR 65–85) (P < 0·05 for each experimental group vs. control). The SLE group had worse fatigue than all of the other groups (P < 0·05 SLE vs. each group), but there was no difference between the CLE, ADM or AIBD groups (all P > 0·05). In addition, the experimental groups had more clinically significant fatigue (score ≤ 35) (SLE 44·2%, CLE 25·2%, ADM 31·6%, AIBD 24·1%) than controls (2%) (P < 0·01 for each experimental group vs. control). The SLE group had more clinically significant fatigue than the CLE group (P < 0·01); however, there was no difference in clinically significant fatigue between SLE and either ADM (P = 0·17) or AIBD (P = 0·055).
Conclusions: These findings demonstrate that patients with skin-limited autoimmune disease experience more fatigue than controls. Fatigue is an important symptom that negatively affects quality of life for patients. It should be addressed by clinicians and measured in future clinical trials.
Introduction
Fatigue is a well-established symptom in systemic lupus erythematosus (SLE) that significantly impacts patients' quality of life and contributes to disease morbidity. It has been described as an abnormal or extreme whole-body tiredness that is disproportionate to activity or exertion.[1] Overall, 53–80% of patients with SLE identified fatigue as one of their primary symptoms, and its aetiology is thought to be multifactorial.[1] Studies aimed at finding a relationship between fatigue and immunological, inflammatory or other disease characteristics have shown inconsistent results. Fatigue strongly correlates with psychosocial factors such as mood disorders, anxiety, poor sleep quality and chronic pain syndromes.[2]
Although patients with skin-limited autoimmune diseases anecdotally report significant fatigue, there are limited data in patients with conditions such as cutaneous lupus erythematosus (CLE), amyopathic dermatomyositis (ADM) and autoimmune blistering diseases (AIBDs). The aim of this study was to compare fatigue severity between patients with these skin-limited autoimmune conditions and those with SLE, as well as with a healthy control group.
Given what is known about fatigue's influence on quality of life in multiple different inflammatory conditions, it is important to gain a better understanding of the prevalence of fatigue in patients with skin-limited autoimmune diseases. In this retrospective study we use median 36-Item Short Form Survey (SF-36) vitality scores to compare fatigue in historical controls with patients enrolled in prospective longitudinal databases with SLE, CLE, ADM and AIBD. We also examined the percentage of patients in each group who experienced 'clinically significant' fatigue.
Patients and Methods
Patients
This study was reviewed and approved by the institutional review board at the University of Pennsylvania. The study population included patients enrolled in prospective longitudinal databases with SLE (n = 165), CLE (n = 226), ADM (n = 136) and AIBD (n = 79). The AIBD database included patients with immunological or histologically proven bullous pemphigoid, pemphigus vulgaris or pemphigus foliaceus. Historical controls (n = 84) were selected from a study performed by Skoie et al. that examined fatigue in patients with psoriasis and consisted of healthy acquaintances of patients with psoriasis from Stavanger University Hospital in Norway.[3] These patients were Norwegian speaking and age 18 years or older; exclusion criteria in that study included a diagnosis of psoriasis, prior history of cancer, chronic inflammatory diseases or untreated hyper- or hypothyroidism.
We collected baseline characteristics including age, sex, smoking status, comorbidities, autoimmune skin disease-related medications in the study population, and disease severity. Disease severity was reported using the following validated measurement instruments: the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and the Bullous/Pemphigus Disease Area Index (B/PDAI). For historical controls, information was not complete regarding certain comorbidities or medications.
Measurement of Fatigue
The SF-36 is a 36-item patient-reported survey that measures different aspects of health status through the following subscales: physical functioning, role limitations due to physical problems, social functioning, bodily pain, general mental health, role limitations due to emotional problems, vitality, and general health perceptions. Scores are between 0 and 100, with a higher score defining a more favourable health state. Fatigue severity was assessed with the vitality subscale, and general mental health was assessed with the mental health subscale using patients' scores recorded from their first visit.[4] Clinically significant fatigue was defined as a score ≤ 35.[3,5] This cut-off point was used by Dagfinrud et al. in their investigation of fatigue in patients with ankylosing spondylitis (AS).[5] They assigned vitality scores below the 10th percentile of the general population to the 'low vitality' group, suggesting that 'clinically significant' fatigue occurs in 10% of the general population.
Statistical Analysis
We compared the median SF-36 vitality scores between our skin disease groups and the control group using the Kruskal–Wallis test and post hoc Dunn's multiple comparison test. We also compared the percentages of patients with clinically significant fatigue (score ≤ 35) in each group through the Fisher's exact test. Using the Bonferroni correction for multiple comparisons, P-values < 0·05 were considered statistically significant.
Univariate and multivariate logistic regression analyses were performed comparing the presence of clinically significant fatigue and covariates such as age, sex, smoking status, comorbidities, medications and SF-36 mental health score (; see Supporting Information). Variables with P-values < 0·25 in the univariate analysis were retained in the multivariable model for SLE, CLE, ADM and AIBD. In the final model, P-values < 0·05 were considered statistically significant.
Table S1. Associations between fatigue and selected variables in patients with autoimmune skin diseases.
(Missing)
Results
Fatigue Severity Between Groups
The majority of patients in our autoimmune skin disease groups were female, and the mean ages were 45 ± 14·0, 48·8 ± 14·6, 40·1 ± 13·0, 55·4 ± 13·0 and 65·1 ± 16·1 years in controls and patients with CLE, SLE, ADM and AIBD, respectively. The average CLASI, CDASI or B/PDAI scores were 9·9 for SLE, 9·7 for CLE, 19·4 for ADM and 9·6 for AIBD. The baseline characteristics of the control and autoimmune skin disease groups are presented in (see Supporting Information).
Table S2. Demographic and clinical characteristics of the patients
(Missing)
Patients with autoimmune skin diseases demonstrated greater fatigue measured by median and interquartile range (IQR) vitality scores (SLE 35, IQR 20–55; CLE 50, IQR 30–70; ADM 50, IQR 30–65; AIBD 55, IQR 35–70) compared with controls (73, IQR 65–85) (P < 0·05 for the SLE, CLE, ADM and AIBD groups vs. control) (Figure 1). Among patients with autoimmune skin disease, the SLE group had significantly worse fatigue than all of the other groups (P < 0·05 for SLE vs. CLE, ADM and AIBD). There was no difference in median vitality scores between the CLE, ADM or AIBD groups (all P > 0·05).
Figure 1.
(Missing)
Median 36-Item Short Form Survey (SF-36) vitality scores between patients in the autoimmune skin disease groups and controls. SLE, systemic lupus erythematosus; CLE, cutaneous lupus erythematosus; ADM, amyopathic dermatomyositis; AIBD, autoimmune blistering disease.
After examining median vitality scores, we then assessed which groups had the most patients with clinically significant fatigue (score ≤ 35). We found that the groups with autoimmune skin disease had more clinically significant fatigue – SLE, 73 of 165 (44·2%); CLE, 57 of 226 (25·2%); ADM, 43 of 136 (31·6%); AIBD, 19 of 79 (24.1%) – than controls (two of 84, 2%). The P-values were all < 0·01 between each experimental group and the controls (Figure 2). Among patients with autoimmune skin disease, those with SLE had more clinically significant fatigue than those with CLE (P < 0·01). However, there was no difference in clinically significant fatigue for SLE vs. ADM (P = 0·17) or AIBD (P = 0·06).
Figure 2.
(Missing)
Percentage of patients with clinically significant fatigue between the autoimmune skin disease groups and controls. SLE, systemic lupus erythematosus; CLE, cutaneous lupus erythematosus; ADM, amyopathic dermatomyositis; AIBD, autoimmune blistering disease.
Factors Associated With Fatigue
We examined potential influential factors on fatigue through multivariate logistic regression for each autoimmune skin disease group (). In all of these groups, patients with higher mental health scores were less likely to have clinically significant fatigue. Patients with CLE taking immunosuppressant medications were more likely to have clinically significant fatigue [odds ratio (OR) 2·62, 95% confidence interval (CI) 1·20–5·74; P = 0·016]; however, this association was not seen in the other autoimmune skin disease groups. The multivariable logistic regression revealed that female patients with SLE and patients with ADM with hypothyroid disease were more likely to have clinically significant fatigue (OR 6·45, 95% CI 1·14–36·5; P = 0·035 and OR 4·21, 95% CI 1·31–13·5; P = 0·016, respectively) than patients without these covariables.
Table 1. Multivariate logistic regression
(Missing)
Discussion
In this study we examined the prevalence of fatigue in patients with SLE, CLE, ADM and AIBD compared with healthy controls. Our results demonstrate that patients with skin-limited autoimmune disease have significantly worse fatigue than healthy controls. When examining fatigue between the autoimmune skin disease groups, we found that patients with SLE had worse fatigue scores than those with CLE, ADM and AIBD, which is expected given the systemic nature of the disease. However, surprisingly there was no significant difference in the prevalence of clinically significant fatigue between the SLE and ADM or AIBD groups. While patients with SLE had worse fatigue scores overall, there was a similar prevalence of clinically significant fatigue in patients with cutaneous-limited disease. This finding has critical implications for future clinical trials, which should consider fatigue outcomes when assessing the efficacy of a new therapy.
The second goal of this study was to identify and quantify associations between clinical variables and fatigue using a multivariate model. The variables identified are inconsistent between SLE, CLE, ADM and AIBD, which is likely due to the demographic heterogeneity between the groups and the relatively small sample size. However, the influential variables found in this study are still of clinical importance and should be explored to understand better the nature of fatigue in this population. Furthermore, these variables can help physicians to identify and counsel patients who are more likely to experience clinically significant fatigue in their clinic.
Across all patients with autoimmune skin diseases, fatigue was influenced by mental health score, which we used as a surrogate for depressed mood and emotional well-being.[6] Postulated mechanisms propose that chronic inflammatory states can lead to cytokine-induced 'sickness behaviour', which shares many features with depression, such as fatigue and anhedonia. There is also evidence to suggest that major depression is associated with proinflammatory cytokines, and this relationship may therefore be bidirectional.[7–9] This finding is further supported by clinical studies in SLE that have shown a relationship between fatigue and mood disorders.[2]
The association between immunosuppressants and fatigue was seen only in CLE and can be explained by the treatment algorithm for the disease. Patients with CLE are placed on immunosuppressants when their disease is severe with widespread skin manifestations and is refractory to topical steroids and antimalarials.[10,11] Although disease activity was not examined in the multivariate analysis, patients with CLE on immunosuppressants may have more debilitating disease that could be contributing to their fatigue. If, on the other hand, the medications contribute to patients' fatigue, it is important for clinical trials to consider fatigue as an outcome measure when assessing new treatment options.
The fatigue-associated variables such as thyroid disease in ADM and female sex in SLE are consistent with past studies. Fatigue is a hallmark symptom in thyroid disease, and autoimmune thyroid dysfunction is particularly common in dermatomyositis.[12,13] Fatigue has also been found to be more prevalent in women.[14]
The results of this study suggest that having an autoimmune skin condition significantly contributes to fatigue. This finding has been seen in other inflammatory diseases such as ankylosing spondylitis (AS) psoriasis.[3,5] A study performed by Dagfinrud et al. showed that a median of 30% of patients with AS experienced clinically significant fatigue, compared with 10% of the general population.[5] Although patients with AS have significant limitation of movement and pain, which could be contributing to their fatigue, the percentage of patients with clinically significant fatigue is comparable with those seen in our autoimmune skin disease population. Similarly, Skoie at al examined fatigue in psoriasis and found that 42% of patients experienced clinically significant fatigue, compared with 2% of healthy controls.[3] As mentioned earlier, proinflammatory cytokines generated by the innate immune system may cross the blood–brain barrier and generate an adaptive response, termed 'sickness behaviour', which acts to conserve energy and cause fatigue.[3,7,15]
This study had several limitations. It is a retrospective study of prospectively collected data at a single institution comparing patients with autoimmune skin disease with historical controls. Our groups were not matched by age and sex, which impacts the internal validity of the study; however, these variables were included in the multivariate analysis and their effects are included in the results. The control group consisted of healthy individuals living in Norway, which has a predominantly white population. Although dermatomyositis usually presents in white female patients, SLE/CLE is a more racially heterogeneous group. These inherent differences were not controlled for in this study. Additionally, our control group was not included in our multivariate analysis due to missing data on thyroid disease in this group, as well as information on their mental health scores.
Another limitation is that the study was conducted at a quaternary referral centre, and the patients included may have more refractory or severe disease. Studies examining the relationship between fatigue and disease activity in patients with SLE have failed to demonstrate a conclusive association between these two factors.[1] However, patients' interpretation of more severe disease status and feelings of hopelessness towards their condition may contribute to greater fatigue. Finally, fatigue is a multifactorial symptom and therefore all contributing factors, such as employment type and socioeconomic status, were not controlled for or evaluated.
In conclusion, the results of this study indicate that fatigue is more prevalent in patients with SLE, CLE, ADM and AIBD than in healthy controls. Interestingly, we found that patients with skin-limited disease, such as ADM and AIBD, had the same prevalence of clinically significant fatigue as those with SLE, while patients with CLE had less fatigue. Fatigue is a debilitating symptom that significantly contributes to lower quality of life in patients with inflammatory conditions. It is important for physicians to recognize and address this symptom in patients with both skin-limited and systemic autoimmune diseases, and perhaps to refer them for counselling or offer interventions for fatigue and coexisting mood disorders. Moreover, fatigue should be investigated further in these conditions to determine its effect on patients' quality of life and its potential as an outcome measure in clinical trials for patients with skin-limited autoimmune diseases.
What's Already Known About This Topic?
Fatigue is a well-established symptom of systemic lupus erythematosus, but has not been well characterized in skin-limited autoimmune diseases.
What Does This Study add?
This study aims to examine fatigue in patients with cutaneous lupus erythematosus, amyopathic dermatomyositis and autoimmune blistering diseases.
References
Ahn, GE, Ramsey-Goldman, R. Fatigue in systemic lupus erythematosus. Int J Clin Rheumatol2012; 7:217–27.
Omdal, R, Waterloo, K, Koldingsnes, W et al. Fatigue in patients with systemic lupus erythematosus: the psychosocial aspects. J Rheumatol 2003; 30:283–7.
Skoie, IM, Dalen, I, Ternowitz, T et al. Fatigue in psoriasis: a controlled study. Br J Dermatol 2017; 177:505–12.
Ingves, C, Jemec, GB. Combined imiquimod and acitretin for non-surgical treatment of basal cell carcinoma. Scand J Plast Reconstr Surg Hand Surg 2003; 37:293–5.
Dagfinrud, H, Vollestad, NK, Loge, JH et al. Fatigue in patients with ankylosing spondylitis: a comparison with the general population and associations with clinical and self-reported measures. Arthritis Rheum 2005; 53:5–11.
McHorney, CA, Ware, JE, Raczek, AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993; 31:247–63.
Dantzer, R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am 2009; 29:247–64.
Maes, M, Bosmans, E, Meltzer, HY. Immunoendocrine aspects of major depression. Relationships between plasma interleukin-6 and soluble interleukin-2 receptor, prolactin and cortisol. Eur Arch Psychiatry Clin Neurosci 1995; 245:172–8.
Kiecolt-Glaser, JK, Glaser, R. Depression and immune function: central pathways to morbidity and mortality. J Psychosom Res 2002; 53:873–6.
Okon, LG, Werth, VP. Cutaneous lupus erythematosus: diagnosis and treatment. Best Pract Res Clin Rheumatol 2013; 27:391–404.
Kuhn, A, Ruland, V, Bonsmann, G. Cutaneous lupus erythematosus: update of therapeutic options: part I. J Am Acad Dermatol 2011; 65:e179–93.
Wang, H, Tao, L, Li, H, Deng, J. Dermatomyositis related to autoimmune thyroiditis. J Eur Acad Dermatol Venereol 2011; 25:1085–93.
Lukjanowicz, M, Bobrowska-Snarska, D, Brzosko, M. [Coexistence of hypothyroidism with polymyositis or dermatomyositis]. Ann Acad Med Stetin 2006; 52 ( Suppl. 2):49–55. (in Polish).
Engberg, I, Segerstedt, J, Waller, G et al. Fatigue in the general population – associations to age, sex, socioeconomic status, physical activity, sitting time and self-rated health: the northern Sweden MONICA study 2014. BMC Public Health 2017; 17:654.
Dantzer, R, O'Connor, JC, Freund, GG et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9:46–56.
Acknowledgments
The authors would like to thank Dr Inger Marie Skoie and Dr Roald Omdal of Stavanger University Hospital, Stavanger, Norway for generously sharing their data.
Funding sources
This work was supported by the United States Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development and Biomedical Laboratory Research and Development) Merit Review 5 I01 BX000706-04 (principle investigator V.P.W.) and by the United States Department of Health and Human Services and the National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases) R21 AR066286 (principle investigator V.P.W.).
The British Journal of Dermatology. 2019;180(6):1468-1472. © 2019 Blackwell Publishing
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