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Fatigue in rheumatoid arthritis and its relation to interleukin-6 serum level
The Egyptian Rheumatologist (2012) 34, 153–157
Egyptian Society for Joint Diseases and Arthritis
The Egyptian Rheumatologist www.rheumatology.eg.net www.sciencedirect.com
ORIGINAL ARTICLE
Fatigue in rheumatoid arthritis and its relation to interleukin-6 serum level Abdel Moneim H. Helal a, Enas M. Shahine Doaa I. Hashad b, Riham Abdel Moneim a a b
a,*
, Marwa M. Hassan a,
Physical Medicine, Rheumatology and Rehabilitation Department, Faculty of Medicine, Alexandria University, Egypt Clinical and Chemical Pathology Department, Faculty of Medicine, Alexandria University, Egypt
Received 11 July 2012; accepted 26 August 2012 Available online 6 October 2012
KEYWORDS Interleukin-6; Rheumatoid arthritis; Fatigue
Abstract Patients and methods: The study included 30 patients with RA diagnosed according to the 2010 ACR-EULAR classification criteria for RA and 15 healthy controls. Patients were included if they were above 18 years and fulfilled a score P6 over 10 of the 2010 ACR-EULAR classification criteria for RA. Disease activity was assessed using 28 joint disease activity score (DAS28), erythrocytes sedimentation rate (ESR), C-reactive protein (CRP). Fatigue was assessed with the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ) and serum IL-6 level was measured in patients and controls. Results: The BRAF-MDQ was significantly higher among patients (mean = 50.6 ± 15.2) than controls (mean = 7.8 ± 3.7) (p < 0.001). Patients’ mean IL-6 serum level was 35.05 ± 21.23 pg/ml and 4.72 ± 3.09 pg/ml among control subjects (p < 0.001). DAS 28 ranged between 4.33 and 7.67, mean 1st hour ESR was 43.57 mm and CRP was positive in 76.7% of patients. Significant correlations were found between BRAF-MDQ score and serum IL-6 level (r = 0.947, p < 0.001), ESR (r = 0.509, p < 0.001) as well as CRP positivity (r = 0.411, p = 0.005) in RA patients. Serum IL-6 level correlated with ESR (r = 0.463, p < 0.001) and CRP (r = 0.376, p = 0.01) among patients. Conclusion: Fatigue is a common symptom and scores higher among RA patients than healthy controls and should be measured in all RA patients with simple fatigue questionnaires matching with different cultures. Fatigue becomes more prominent as serum IL-6 level increases independently of the disease duration and activity. Ó 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Fax: +20 35437245. E-mail address: [email protected] (E.M. Shahine). Peer review under responsibility of Egyptian Society for Joint Diseases and Arthritis.
Production and hosting by Elsevier
1. Introduction Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder affecting most commonly middle-aged women. It is characterized by inflammation of the synovium, which
1110-1164 Ó 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejr.2012.08.004
154 often leads to the destruction of articular cartilage and juxta-articular bone. It is often accompanied by systemic manifestations such as anemia, fatigue and osteoporosis [1]. Fatigue is a subjective feeling of low vitality that disrupts daily functioning, especially prevalent in chronic inflammatory disorders such as rheumatoid arthritis [2]. Unlike normal tiredness, fatigue is chronic, typically not related to overexertion and poorly relieved by rest. People with RA consider fatigue to be an important physical and cognitive symptom that is overwhelming, uncontrollable and unpredictable that affects every aspect of life [3]. Rheumatoid arthritis fatigue is complex and multicausal. Pain, stress, depression, inflammation, metabolic factors, medications and disability are likely to contribute to the development of RA fatigue in varying degrees at different time [2]. Little attention has been paid by health professional teams to the multidimensional nature of RA related fatigue. International consensus has recommended that RA fatigue should now be measured in RA studies alongside the core set, using a validated instrument [3]. In RA, the cytokine network is complex with numerous cytokines present both in blood and in synovial joints [1,4]. Elevation in pro-inflammatory cytokine levels is capable of promoting fatigue in RA. Also, the hypothalamic pituitary adrenal (HPA) axis abnormality has been linked to the occurrence of RA fatigue [3]. Interleukin 6 (IL-6) is one of the cytokines which play a significant role in RA pathogenesis and promotion of fatigue [1,5]. This work is aimed at the assessment of occurrence and level of fatigue and its relation to IL-6 serum level in RA patients. 2. Patients and methods Thirty RA patients diagnosed according to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) classification criteria for RA [6] were enrolled in the study. Patients were included if they were more than 18 years and fulfilled a score P6 over 10 of the 2010 ACR-EULAR classification criteria for RA. Patients with other systemic inflammatory rheumatic diseases, fibromyalgia syndrome and other causes of fatigue as anemia, hepatic diseases, kidney diseases, diabetes mellitus, cardiovascular diseases, psychiatric disorders and malignancy were excluded. Fifteen healthy age and gender matched controls were enrolled in the study. An informed consent has been taken from all patients and control subjects before the beginning of the study which was approved by the local Ethics Committee. Demographic data and disease history regarding onset, duration, course, progression and medications received were obtained from all patients. A thorough clinical examination of the musculoskeletal system was carried out. Disease activity was assessed using the 28 joint disease activity score (DAS28) which was performed bilaterally on the shoulders, the elbows, the wrists, the metacarpophalangeals, the proximal interphalangeals and the knee joints. Tenderness and swelling were assessed separately in each joint. Calculation of DAS28 score entailed: (1) Tender joints count (TJC); it was scored on a 0–1 scale: 0 = no tenderness, 1 = tenderness. The individual joint scores were summed. (2) The swollen joint count (SJC); it was assessed also on a 0–1 scale: 0 = no swelling, 1 = swelling. Then the individual joint scores were summed [7]. (3) Erythrocyte sedimentation rate (ESR). (4) Patient’s assessment of his/her general
A.M.H. Helal et al. health (GH) on a visual analog scale (VAS) (0–100 mm; where ‘‘0’’ represents good general condition and ‘‘100’’ worst condip tion). The DAS 28 formula ‘‘DAS28 = 0.56 (TJC) p + 0.28 (SJC) + 0.70 ln (ESR) + 0.014 (GH)’’ was used. DAS28 is a continuous index ranging from 0 to 9.4. A DAS 28 6 3.2 = low disease activity, DAS 28 > 3.2 to 65.1 = moderate disease activity, DAS28 > 5.1 = high disease activity. A commonly used cutoff point for remission in DAS28 is < 2.6 [8]. Each patient and control subject was assessed with the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ) [9]. The 20 items BRAF-MDQ has 4 distinct dimensions: the physical, living, cognition and emotion dimensions. The physical dimension contains a numerical rating scale and questions on frequency and duration of fatigue, but the response options to all questions of other dimensions are scored as 0–3 (where 0 = not at all, 1 = a little, 2 = quite a bit, and 3 = very much). Simple summation yields a global BRAF-MDQ score of 0–70 (with higher scores indicating worse fatigue), whereas the score for each dimension is different due to the varied number of questions (0–22 for physical, 0–21 for living, 0–15 for cognition, and 0–12 for emotion). Laboratory investigations were carried out for each patient and control subject and included ESR using the standard Westergren method [10], C-reactive protein (CRP) using the nephelometer assay [11] and serum IL-6 level using the enzyme-linked immunosorbent assay (ELISA) technique (AviBion Human IL-6 ELISA Kit, Orgenium Laboratories, Finland). Serum concentration of IL-6 was determined based on a standard concentration curve [12]. Statistical analysis was done using the software Statistical Package for the Social Sciences (SPSS) version 17.0. All of the descriptive variables were expressed as the mean ± standard deviation (SD). For comparison between the two groups, Student’s t test was used. Chi-Square test, Pearson’s correlation coefficient and multiple linear regression were used to assess the association and correlation between variables. A probability (p) value 60.05 was considered statistically significant for all tests. 3. Results The study included 27 women (90%) and 3 men (10%) in patients group and 13 women (86.6%) and 2 men (13.3%) in the control group. Patients’ age ranged between 20 and 64 years (mean ± SD: 45.23 ± 12.34) and the mean age of the control group was 41.22 ± 9.13. The disease duration of RA ranged between 3 months and 360 months (88.5 ± 76.1). All studied patients had high BRAF-MDQ scores which was significantly higher in the studied RA patients than in the control group (p = 0.01). The mean BRAF-MDQ score was 50.6 ± 15.2 among patients. While mean BRAF-MDQ score was 7.8 ± 3.7 among controls (Table 1). The histogram representation of BRAF-MDQ score in the studied RA patients demonstrated that the score had 2 peaks, one at 50 and another at 70; meanwhile, in the control group, the BRAF-MDQ score aggregated between 0 and 20 and peaking near the 10 score point (Fig. 1). The DAS28 score in RA patients ranged between 4.3 and 7.6, with a mean score of 5.3 ± 0.6. The 1st hour ESR ranged between 24 and 113 mm, with a mean level of 43.5 ± 25.6 in RA patients, while in the controls it ranged between 5 and 35 mm, with a mean level of 15.8 ± 8.3 (p < 0.001). The percentage of patients who had positive CRP was significantly higher (76.7%) than those with negative CRP
Fatigue in rheumatoid arthritis and its relation to interleukin-6 serum level Table 1
155
Comparison between patients and control group regarding the BRAF-MDQ score and serum IL-6 level.
BRAF-MDQ Serum IL-6 level (pg/ml)
Patients ‘‘n = 30’’ mean ± SD
Control ‘‘n = 15’’ mean ± SD
t
p
50.6 ± 15.2 35.0 ± 21.2
7.8 ± 3.7 4.7 ± 3.0
10.6 5.47
0.001* 0.001*
P* is significant at 60.05. Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ).
Figure 1 Graphic representation of the distribution of the BRAF-MDQ score among studied rheumatoid arthritis patients and control groups.
(23.3%). Significantly higher percent of RA patients (23 patients) had positive CRP compared to 3 control subjects (20%) (p < 0.001). Serum IL-6 concentration was significantly elevated in RA patients compared to healthy controls (p < 0.001). Serum IL-6 concentrations in the patients group ranged between 5 and 130 pg/ml, with a mean of 35.0 ± 21.2, while in the controls it ranged between 1 and 10 pg/ml, with a mean of 4.7 ± 3.0 (Table 1). Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire correlated with serum IL-6 levels of RA patients (r = 0.947, p < 0.001) (fig. 2). Similarly, BRAF-MDQ score of RA patients correlated with the ESR values (r = 0.509, p < 0.001) and CRP (r = 0.411, p = 0.005), where patients with positive CRP had higher BRAF-MDQ scores (49.95 ± 16.24) and whose CRP was negative had lower fatigue scores (52.85 ± 12.03). There were no significant correlation between BRAF-MDQ score and DAS28 score (r = 0.174, p = 0.358). No significant relationship was found between BRAF-MDQ score and age, gender of RA patients or their disease duration (p > 0.05). Although there was no significant relationship between IL6 cytokine level and DAS28 score, serum IL-6 levels showed a significant correlation with the ESR (r = 0.463, p < 0.001) and CRP of RA patients (r = 0.376, p = 0.01), as patients with positive CRP had higher IL-6 levels and vice versa (35.07 ± 24.87 and 35.60 ± 7.77 pg/ml respectively). 4. Discussion Rheumatoid arthritis fatigue is complex and multicausal. It results from the interaction between disease, cognitive, behav-
Figure 2 The correlation between the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire score and interleukin-6 serum level in the studied RA patients.
ioral factors and personal life issues and so its assessment and management is complex [13]. The current results showed that RA patients had significantly higher fatigue scores and elevated serum IL-6 levels compared to healthy controls. Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire correlated significantly with serum IL-6 levels. Systemic actions of IL-6 include; stimulation of production of acutephase proteins, induction of anemia, and impairment of HPA axis [14]. Hypothalamic–pituitary–adrenal axis abnormality has been linked to the development of fatigue in many diseases [15]. In the central nervous system, IL-6 can modulate the HPA axis. Following IL-6 administration, healthy volunteers recorded increased fatigue, inactivity, lack of concentration and altered sleep architecture and these effects were found to correspond with the HPA axis disturbed function [4]. In this study, the correlations between fatigue scores, ESR level and CRP positivity could be due to the high disease activity of the studied patients. Similarly, Wirnsberger et al. [16] reported that higher fatigue scores of RA patients were linked to high CRP level. The present study found no correlation between DAS28 score and fatigue. Failure to demonstrate such correlation is not to downplay the importance of fatigue in RA but it appears that psychosocial aspects like depression, self-efficacy and lack of social support might be the most important variables in explaining fatigue [17]. Some studies reported correlation between fatigue and patient’s assessment of global health component of the DAS28 score [17–19]. This observation indicates that physician and laboratory components of the DAS28 contribute minimally to fatigue scores. Further, RA and OA patients in the clinical and research
156 settings were found to have similar levels of fatigue [17]. On the contrary, other studies found a significant correlation between fatigue and disease activity and emphasized that lack of fatigue was a feature of clinical remission in RA [20,21]. In the current study, fatigue did not correlate with age or disease duration of the studied patients. Similarly, Pollard et al. [18] have reported no significant correlation between fatigue severity and disease duration or age. They related their findings to the likelihood of central origin of RA fatigue rather than the importance of peripheral features like muscle mass which decreased with age and disease duration. While Nikolaus et al. [22] stated that younger women with multiple roles experience more fatigue and after retirement, people have fewer roles and less expectations from others, so older people might be able to cope with fatigue more easily. Also, fatigue score did not correlate with gender of the studied RA patients. However, fewer men than women participated in this study is considered as one of the study limitations which may reduce the generalizability of the results. On the contrary, Huyser et al. [23] reported that the best predictor of fatigue was being a female. In another study, Nikolaus et al. [22] reported that women experienced more negative emotions and consequently more fatigue compared to men. According to Nikolaus et al., negative emotions related to fatigue might occur when personal abilities do not meet with one’s expectations and wishes, and might be worsened by external demands related to multiple roles. The current study showed a correlation between serum IL-6 levels and ESR level as well as CRP positivity. This is consistent with the known function of IL-6 as a stimulator of hepatic synthesis of acute phase reactants [24]. However, no significant relationship between serum IL-6 levels and the DAS28 score was found. This result agreed with Chung et al. [25], who explained this finding by the difference of involvement of the IL-6 family cytokines in the local and systemic reactions; in the synovium and serum. These cytokines were found to be involved mainly in the local reaction and higher levels are within synovial fluid than in serum so levels of circulating, peripherally produced cytokines may not reflect the local situation in the joints. This may be the reason that the serum concentrations of cytokines do not significantly correlate with the disease activity. In this study, serum IL-6 did not correlate with age, gender or disease duration. Similarly, Madhok et al. [26] confirmed that serum IL-6 values are increased in RA patients and are independent of age, patient’s gender and duration of RA. The low number of patients and controls is one of the limitations of this study. Also, the low number of men included in patient and control groups is another limitation. It is recommended to extend this study in future work to include more patients; particularly men to provide more solid conclusions regarding correlation between fatigue and gender in RA. In conclusion, fatigue is a common symptom and scores higher among RA patients than healthy controls. Thus, its evaluation and treatment should be incorporated in the management of RA. Fatigue becomes more prominent as serum IL-6 level increases independently of the disease duration and activity. Conflict of Interest No conflict of interest is declared by authors.
A.M.H. Helal et al. References [1] Milman N, Karsh J, Booth RA. Correlation of a multi-cytokine panel with clinical disease activity in patients with rheumatoid arthritis. Clin Biochem 2010;43:1309–14. [2] Bax M, van Heemst J, Huizinga TW, Toes RE. Genetics of rheumatoid arthritis: what have we learned? Immunogenetics 2011;63:459–66. [3] Emonts M, Hazes MJ, Houwing-Duistermaat JJ, De Jongh CE, De Vogel L, Han HK, et al. Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study. BMC Med Genet 2011;12:36. [4] Srirangan S, Choy EH. The role of Interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskel Dis 2010;2:247–56. [5] Garnero P, Thompson E, Woodworth T, Smolen JS. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum 2010;62:33–43. [6] Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. Rheumatoid arthritis classification criteria an American college of rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum 2010;9:2569–81. [7] van Riel PLCM, Scott DL. EULAR handbook of clinical assessment in rheumatoid arthritis. Alphen Aan Den Rijn. The Netherlands: Van Zuiden Communications; 2000. [8] Singh H, Kumar H, Handa R, Talapatra P, Ray S, Gupta V. Use of clinical disease activity index score for assessment of disease activity in rheumatoid arthritis patients: an Indian experience. Arthritis 2011;2011:1–5. [9] Nicklin J, Cramp F, Kirwan J, Greenwood R, Urban M, Hewlett S. Measuring fatigue in rheumatoid arthritis: a cross-sectional study to evaluate the Bristol Rheumatoid Arthritis Fatigue MultiDimensional Questionnaire, Visual Analog Scales, and Numerical Rating Scales. Arthritis Care Res 2010;62:1559–68. [10] Dacie JV, lewis SM. Practical haematology. 10th ed. Edinburgh– London: Churchill Livingstone; 2006. [11] John BH. Clinical diagnosis and management by laboratory methods. 20th ed. Saunders: Philadelphia; 2001. [12] Kricka LJ. Principles of immunochemical techniques. In: Burtis CA, Ashwood ER, editors. Teitz textbook of clinical chemistry and molecular diagnostics, 4th ed., vol. 1. Philadelphia: Elsevier Saunders; 2006. p. 219. [13] Hewlett S, Chalder T, Choy E, Cramp F, Davis B, Dures E, et al. Fatigue in rheumatoid arthritis: time for a conceptual model. Rheumatol 2011;50:1004–6. [14] Dayer E, Dayer JM, Roux-Lombard P. Primer: the practical use of biological markers of rheumatic and systemic inflammatory diseases. Nat Clin Pract Rheumatol 2007;3:512–20. [15] Smolen JS, Beaulieu A, Rubbert-Roth A, Ramous-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomized trial. Lancet 2008;371:987–97. [16] Wirnsberger RM, De Vries J, Jansen TLTA, Van Heck GL, Wouters EFM, Drent M. Impairment of quality of life: rheumatoid arthritis versus sarcoidosis. Neth J Med 1999;54:86–95. [17] Bergman MJ, Shahouri SH, Shaver TS, Anderson JD, Weidensaul DN, Busch RE, et al. Is fatigue an inflammatory variable in Rheumatoid Arthritis (RA)? Analyses of fatigue in RA, osteoarthritis, and fibromyalgia. J Rheumatol 2009;36:2788–94.
Fatigue in rheumatoid arthritis and its relation to interleukin-6 serum level [18] Pollard LC, Choy EH, Gonzalez J, Khoshaba B, Scott DL. Fatigue in rheumatoid arthritis reflects pain, not disease activity. Rheumatol 2006;45:885–9. [19] Repping-Wuts H, Fransen J, Van Achterberg T, Bleijenberg G, Van Riel P. Persistent severe fatigue in patients with rheumatoid arthritis. J Clin Nurs 2007;16:377–83. _ [20] Turan Y, Kocaag˘a Z, Koc¸yig˘it H, Gu¨rgan A, Bayram KB, Ipek S. Correlation of fatigue with clinical parameters and quality of life in rheumatoid arthritis. Turk J Rheumatol 2010;25:63–7. [21] Pinals R, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981;24:1308–15. [22] Nikolaus S, Bode C, Taal E, Van De Laar M. New insights into the experience of fatigue among patients with rheumatoid arthritis: a qualitative study. Ann Rheum Dis 2010;69:895–7.
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[23] Huyser BA, Parker JC, Thoreson R, Smarr KL, Johnson JC, Hoffman R. Predictors of subjective fatigue among individuals with rheumatoid arthritis. Arthritis Rheum 1998;41:2230–7. [24] Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood 1995;86:1243–54. [25] Chung SJ, Kwon YJ, Park MC, Park YB, Lee SK. The correlation between increased serum concentrations of interleukin-6 family cytokines and disease activity in rheumatoid arthritis patients. Yonsei Med J 2011;52:113–20. [26] Madhok R, Crilly A, Watson J, CapelI HA. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 1993;52:232–4.
Egyptian Society for Joint Diseases and Arthritis
The Egyptian Rheumatologist www.rheumatology.eg.net www.sciencedirect.com
ORIGINAL ARTICLE
Fatigue in rheumatoid arthritis and its relation to interleukin-6 serum level Abdel Moneim H. Helal a, Enas M. Shahine Doaa I. Hashad b, Riham Abdel Moneim a a b
a,*
, Marwa M. Hassan a,
Physical Medicine, Rheumatology and Rehabilitation Department, Faculty of Medicine, Alexandria University, Egypt Clinical and Chemical Pathology Department, Faculty of Medicine, Alexandria University, Egypt
Received 11 July 2012; accepted 26 August 2012 Available online 6 October 2012
KEYWORDS Interleukin-6; Rheumatoid arthritis; Fatigue
Abstract Patients and methods: The study included 30 patients with RA diagnosed according to the 2010 ACR-EULAR classification criteria for RA and 15 healthy controls. Patients were included if they were above 18 years and fulfilled a score P6 over 10 of the 2010 ACR-EULAR classification criteria for RA. Disease activity was assessed using 28 joint disease activity score (DAS28), erythrocytes sedimentation rate (ESR), C-reactive protein (CRP). Fatigue was assessed with the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ) and serum IL-6 level was measured in patients and controls. Results: The BRAF-MDQ was significantly higher among patients (mean = 50.6 ± 15.2) than controls (mean = 7.8 ± 3.7) (p < 0.001). Patients’ mean IL-6 serum level was 35.05 ± 21.23 pg/ml and 4.72 ± 3.09 pg/ml among control subjects (p < 0.001). DAS 28 ranged between 4.33 and 7.67, mean 1st hour ESR was 43.57 mm and CRP was positive in 76.7% of patients. Significant correlations were found between BRAF-MDQ score and serum IL-6 level (r = 0.947, p < 0.001), ESR (r = 0.509, p < 0.001) as well as CRP positivity (r = 0.411, p = 0.005) in RA patients. Serum IL-6 level correlated with ESR (r = 0.463, p < 0.001) and CRP (r = 0.376, p = 0.01) among patients. Conclusion: Fatigue is a common symptom and scores higher among RA patients than healthy controls and should be measured in all RA patients with simple fatigue questionnaires matching with different cultures. Fatigue becomes more prominent as serum IL-6 level increases independently of the disease duration and activity. Ó 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Fax: +20 35437245. E-mail address: [email protected] (E.M. Shahine). Peer review under responsibility of Egyptian Society for Joint Diseases and Arthritis.
Production and hosting by Elsevier
1. Introduction Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder affecting most commonly middle-aged women. It is characterized by inflammation of the synovium, which
1110-1164 Ó 2012 Egyptian Society for Joint Diseases and Arthritis. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejr.2012.08.004
154 often leads to the destruction of articular cartilage and juxta-articular bone. It is often accompanied by systemic manifestations such as anemia, fatigue and osteoporosis [1]. Fatigue is a subjective feeling of low vitality that disrupts daily functioning, especially prevalent in chronic inflammatory disorders such as rheumatoid arthritis [2]. Unlike normal tiredness, fatigue is chronic, typically not related to overexertion and poorly relieved by rest. People with RA consider fatigue to be an important physical and cognitive symptom that is overwhelming, uncontrollable and unpredictable that affects every aspect of life [3]. Rheumatoid arthritis fatigue is complex and multicausal. Pain, stress, depression, inflammation, metabolic factors, medications and disability are likely to contribute to the development of RA fatigue in varying degrees at different time [2]. Little attention has been paid by health professional teams to the multidimensional nature of RA related fatigue. International consensus has recommended that RA fatigue should now be measured in RA studies alongside the core set, using a validated instrument [3]. In RA, the cytokine network is complex with numerous cytokines present both in blood and in synovial joints [1,4]. Elevation in pro-inflammatory cytokine levels is capable of promoting fatigue in RA. Also, the hypothalamic pituitary adrenal (HPA) axis abnormality has been linked to the occurrence of RA fatigue [3]. Interleukin 6 (IL-6) is one of the cytokines which play a significant role in RA pathogenesis and promotion of fatigue [1,5]. This work is aimed at the assessment of occurrence and level of fatigue and its relation to IL-6 serum level in RA patients. 2. Patients and methods Thirty RA patients diagnosed according to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) classification criteria for RA [6] were enrolled in the study. Patients were included if they were more than 18 years and fulfilled a score P6 over 10 of the 2010 ACR-EULAR classification criteria for RA. Patients with other systemic inflammatory rheumatic diseases, fibromyalgia syndrome and other causes of fatigue as anemia, hepatic diseases, kidney diseases, diabetes mellitus, cardiovascular diseases, psychiatric disorders and malignancy were excluded. Fifteen healthy age and gender matched controls were enrolled in the study. An informed consent has been taken from all patients and control subjects before the beginning of the study which was approved by the local Ethics Committee. Demographic data and disease history regarding onset, duration, course, progression and medications received were obtained from all patients. A thorough clinical examination of the musculoskeletal system was carried out. Disease activity was assessed using the 28 joint disease activity score (DAS28) which was performed bilaterally on the shoulders, the elbows, the wrists, the metacarpophalangeals, the proximal interphalangeals and the knee joints. Tenderness and swelling were assessed separately in each joint. Calculation of DAS28 score entailed: (1) Tender joints count (TJC); it was scored on a 0–1 scale: 0 = no tenderness, 1 = tenderness. The individual joint scores were summed. (2) The swollen joint count (SJC); it was assessed also on a 0–1 scale: 0 = no swelling, 1 = swelling. Then the individual joint scores were summed [7]. (3) Erythrocyte sedimentation rate (ESR). (4) Patient’s assessment of his/her general
A.M.H. Helal et al. health (GH) on a visual analog scale (VAS) (0–100 mm; where ‘‘0’’ represents good general condition and ‘‘100’’ worst condip tion). The DAS 28 formula ‘‘DAS28 = 0.56 (TJC) p + 0.28 (SJC) + 0.70 ln (ESR) + 0.014 (GH)’’ was used. DAS28 is a continuous index ranging from 0 to 9.4. A DAS 28 6 3.2 = low disease activity, DAS 28 > 3.2 to 65.1 = moderate disease activity, DAS28 > 5.1 = high disease activity. A commonly used cutoff point for remission in DAS28 is < 2.6 [8]. Each patient and control subject was assessed with the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ) [9]. The 20 items BRAF-MDQ has 4 distinct dimensions: the physical, living, cognition and emotion dimensions. The physical dimension contains a numerical rating scale and questions on frequency and duration of fatigue, but the response options to all questions of other dimensions are scored as 0–3 (where 0 = not at all, 1 = a little, 2 = quite a bit, and 3 = very much). Simple summation yields a global BRAF-MDQ score of 0–70 (with higher scores indicating worse fatigue), whereas the score for each dimension is different due to the varied number of questions (0–22 for physical, 0–21 for living, 0–15 for cognition, and 0–12 for emotion). Laboratory investigations were carried out for each patient and control subject and included ESR using the standard Westergren method [10], C-reactive protein (CRP) using the nephelometer assay [11] and serum IL-6 level using the enzyme-linked immunosorbent assay (ELISA) technique (AviBion Human IL-6 ELISA Kit, Orgenium Laboratories, Finland). Serum concentration of IL-6 was determined based on a standard concentration curve [12]. Statistical analysis was done using the software Statistical Package for the Social Sciences (SPSS) version 17.0. All of the descriptive variables were expressed as the mean ± standard deviation (SD). For comparison between the two groups, Student’s t test was used. Chi-Square test, Pearson’s correlation coefficient and multiple linear regression were used to assess the association and correlation between variables. A probability (p) value 60.05 was considered statistically significant for all tests. 3. Results The study included 27 women (90%) and 3 men (10%) in patients group and 13 women (86.6%) and 2 men (13.3%) in the control group. Patients’ age ranged between 20 and 64 years (mean ± SD: 45.23 ± 12.34) and the mean age of the control group was 41.22 ± 9.13. The disease duration of RA ranged between 3 months and 360 months (88.5 ± 76.1). All studied patients had high BRAF-MDQ scores which was significantly higher in the studied RA patients than in the control group (p = 0.01). The mean BRAF-MDQ score was 50.6 ± 15.2 among patients. While mean BRAF-MDQ score was 7.8 ± 3.7 among controls (Table 1). The histogram representation of BRAF-MDQ score in the studied RA patients demonstrated that the score had 2 peaks, one at 50 and another at 70; meanwhile, in the control group, the BRAF-MDQ score aggregated between 0 and 20 and peaking near the 10 score point (Fig. 1). The DAS28 score in RA patients ranged between 4.3 and 7.6, with a mean score of 5.3 ± 0.6. The 1st hour ESR ranged between 24 and 113 mm, with a mean level of 43.5 ± 25.6 in RA patients, while in the controls it ranged between 5 and 35 mm, with a mean level of 15.8 ± 8.3 (p < 0.001). The percentage of patients who had positive CRP was significantly higher (76.7%) than those with negative CRP
Fatigue in rheumatoid arthritis and its relation to interleukin-6 serum level Table 1
155
Comparison between patients and control group regarding the BRAF-MDQ score and serum IL-6 level.
BRAF-MDQ Serum IL-6 level (pg/ml)
Patients ‘‘n = 30’’ mean ± SD
Control ‘‘n = 15’’ mean ± SD
t
p
50.6 ± 15.2 35.0 ± 21.2
7.8 ± 3.7 4.7 ± 3.0
10.6 5.47
0.001* 0.001*
P* is significant at 60.05. Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ).
Figure 1 Graphic representation of the distribution of the BRAF-MDQ score among studied rheumatoid arthritis patients and control groups.
(23.3%). Significantly higher percent of RA patients (23 patients) had positive CRP compared to 3 control subjects (20%) (p < 0.001). Serum IL-6 concentration was significantly elevated in RA patients compared to healthy controls (p < 0.001). Serum IL-6 concentrations in the patients group ranged between 5 and 130 pg/ml, with a mean of 35.0 ± 21.2, while in the controls it ranged between 1 and 10 pg/ml, with a mean of 4.7 ± 3.0 (Table 1). Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire correlated with serum IL-6 levels of RA patients (r = 0.947, p < 0.001) (fig. 2). Similarly, BRAF-MDQ score of RA patients correlated with the ESR values (r = 0.509, p < 0.001) and CRP (r = 0.411, p = 0.005), where patients with positive CRP had higher BRAF-MDQ scores (49.95 ± 16.24) and whose CRP was negative had lower fatigue scores (52.85 ± 12.03). There were no significant correlation between BRAF-MDQ score and DAS28 score (r = 0.174, p = 0.358). No significant relationship was found between BRAF-MDQ score and age, gender of RA patients or their disease duration (p > 0.05). Although there was no significant relationship between IL6 cytokine level and DAS28 score, serum IL-6 levels showed a significant correlation with the ESR (r = 0.463, p < 0.001) and CRP of RA patients (r = 0.376, p = 0.01), as patients with positive CRP had higher IL-6 levels and vice versa (35.07 ± 24.87 and 35.60 ± 7.77 pg/ml respectively). 4. Discussion Rheumatoid arthritis fatigue is complex and multicausal. It results from the interaction between disease, cognitive, behav-
Figure 2 The correlation between the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire score and interleukin-6 serum level in the studied RA patients.
ioral factors and personal life issues and so its assessment and management is complex [13]. The current results showed that RA patients had significantly higher fatigue scores and elevated serum IL-6 levels compared to healthy controls. Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire correlated significantly with serum IL-6 levels. Systemic actions of IL-6 include; stimulation of production of acutephase proteins, induction of anemia, and impairment of HPA axis [14]. Hypothalamic–pituitary–adrenal axis abnormality has been linked to the development of fatigue in many diseases [15]. In the central nervous system, IL-6 can modulate the HPA axis. Following IL-6 administration, healthy volunteers recorded increased fatigue, inactivity, lack of concentration and altered sleep architecture and these effects were found to correspond with the HPA axis disturbed function [4]. In this study, the correlations between fatigue scores, ESR level and CRP positivity could be due to the high disease activity of the studied patients. Similarly, Wirnsberger et al. [16] reported that higher fatigue scores of RA patients were linked to high CRP level. The present study found no correlation between DAS28 score and fatigue. Failure to demonstrate such correlation is not to downplay the importance of fatigue in RA but it appears that psychosocial aspects like depression, self-efficacy and lack of social support might be the most important variables in explaining fatigue [17]. Some studies reported correlation between fatigue and patient’s assessment of global health component of the DAS28 score [17–19]. This observation indicates that physician and laboratory components of the DAS28 contribute minimally to fatigue scores. Further, RA and OA patients in the clinical and research
156 settings were found to have similar levels of fatigue [17]. On the contrary, other studies found a significant correlation between fatigue and disease activity and emphasized that lack of fatigue was a feature of clinical remission in RA [20,21]. In the current study, fatigue did not correlate with age or disease duration of the studied patients. Similarly, Pollard et al. [18] have reported no significant correlation between fatigue severity and disease duration or age. They related their findings to the likelihood of central origin of RA fatigue rather than the importance of peripheral features like muscle mass which decreased with age and disease duration. While Nikolaus et al. [22] stated that younger women with multiple roles experience more fatigue and after retirement, people have fewer roles and less expectations from others, so older people might be able to cope with fatigue more easily. Also, fatigue score did not correlate with gender of the studied RA patients. However, fewer men than women participated in this study is considered as one of the study limitations which may reduce the generalizability of the results. On the contrary, Huyser et al. [23] reported that the best predictor of fatigue was being a female. In another study, Nikolaus et al. [22] reported that women experienced more negative emotions and consequently more fatigue compared to men. According to Nikolaus et al., negative emotions related to fatigue might occur when personal abilities do not meet with one’s expectations and wishes, and might be worsened by external demands related to multiple roles. The current study showed a correlation between serum IL-6 levels and ESR level as well as CRP positivity. This is consistent with the known function of IL-6 as a stimulator of hepatic synthesis of acute phase reactants [24]. However, no significant relationship between serum IL-6 levels and the DAS28 score was found. This result agreed with Chung et al. [25], who explained this finding by the difference of involvement of the IL-6 family cytokines in the local and systemic reactions; in the synovium and serum. These cytokines were found to be involved mainly in the local reaction and higher levels are within synovial fluid than in serum so levels of circulating, peripherally produced cytokines may not reflect the local situation in the joints. This may be the reason that the serum concentrations of cytokines do not significantly correlate with the disease activity. In this study, serum IL-6 did not correlate with age, gender or disease duration. Similarly, Madhok et al. [26] confirmed that serum IL-6 values are increased in RA patients and are independent of age, patient’s gender and duration of RA. The low number of patients and controls is one of the limitations of this study. Also, the low number of men included in patient and control groups is another limitation. It is recommended to extend this study in future work to include more patients; particularly men to provide more solid conclusions regarding correlation between fatigue and gender in RA. In conclusion, fatigue is a common symptom and scores higher among RA patients than healthy controls. Thus, its evaluation and treatment should be incorporated in the management of RA. Fatigue becomes more prominent as serum IL-6 level increases independently of the disease duration and activity. Conflict of Interest No conflict of interest is declared by authors.
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