Rheumatoid arthritis (RA) is the most common chronic inflammatory disease that affects about 1% of the population. RA is characterized by symmetric polyarthritis and widespread systemic manifestations lead to joint damage and functional disability.1 Among those manifestations, fatigue is very frequent and present in more than 40% of patients with RA using different diagnostic tools.2,3 Fatigue in RA can be defined as a sustained feeling of generalized exhaustion that interferes with activities, which is different from normal tiredness.4 Fatigue has a meaningful contribution to the impaired quality of life and thus adding to disease burden,5 that can make management of RA more challenging. Even though, patients with RA indicated they are not properly supported in the management of RA-fatigue in the healthcare services.6 In routine daily practice, RA patients are evaluated for their disease activity and treatment response; however, silent comorbidities of the disease such as fatigue, anxiety, depression and poor sleep are usually not addressed and thus not controlled.

Although it is the most prevalent complaint in patients with RA, the cause of fatigue is still unknown. Fatigue appears to be multifactorial and associated with multiple determinants (inflammatory and non-inflammatory factors).2,7 Possible inflammatory causes could be RA disease-related components, including pain and disease activity.8–10 In addition, there are non-specific factors associated with fatigue such as sleep disturbances, depressed mood, and physical inactivity.2,7,9 The majority of studies handled the effect of these variables (disease activity, poor sleep, and mood disturbance) on fatigue separately. There are relatively few data on the impact of these factors together on fatigue in RA.9,11

Cultural and religious aspects are important components that play role in expression of fatigue.12 The country of residence has an important influence on the level of fatigue and fatigue levels known to be variable across countries. Thus the data about fatigue cannot be transferred between different countries.13 Fatigue levels and its effects can be modified by cultural differences.14 Therefore, fatigue in RA remains an “unmet need” and more illustration of the contributing factors especially in different RA populations is required. There are limited studies evaluating the contributors of fatigue among Egyptian RA patients.15 To our knowledge, the contributions of poor sleep quality, mood disturbance, and disease activity altogether on fatigue has not been systematically studied among Egyptian patients with RA. The objective of this study was to investigate the presence of fatigue, poor sleep quality and depression in patients compared to healthy controls. Also, to analyze the possible relationship between sleep, mood status, and disease-specific variables with fatigue in RA patients.

Fatigue is reported to be the most disabling factor by RA patients, with a negative impact on disease outcome and quality of life, therefore examining the factors associated with the levels of fatigue is important in clinical practice. The present study showed that fatigue levels, sleep and mood disturbances are higher in Egyptian patients with RA than healthy subjects. Also, poor sleep, severe depression as long as higher disease activity were significant determinants of fatigue in the RA patients. The current reported mean fatigue score among RA patients was comparable to that observed previously using the same fatigue tool measurement.19,20 There was a wide range of prevalence of RA-fatigue has been reported in the literature, with the difference in assessment tools and the ethnicity of RA populations.3,21 Higher fatigue rate has been found in other rheumatic diseases,22 with depression and sleep disturbances have been reported to influence fatigue. Fibromyalgia, which is known with high fatigue level, poor sleep quality and depression among other factors were common.23

While RA fatigue has been viewed as the byproduct of inflammatory process, others have shown that psychosocial factors may play a role. The inflammatory perspective of depression and fatigue in RA has been investigated. Different inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6 are important proinflammatory cytokines implicated in chronic fatigue and all of these are contributors in the inflammatory state in RA. Furthermore, social, family, work and daily living activities are multiple aspects may have an impact on fatigue.

The relationship between fatigue and examined determinants in RA are variable,2 most likely because of the multifactorial etiology of fatigue (physiological, psychological, as well as the disease aspects). Disease duration was found to be correlated with fatigue. However, Stebbings et al. showed that longer disease duration was associated with severe fatigue,20 a recent systematic review found that RA patients experience greater fatigue in irrespective of disease duration.8 The advanced age was not associated with greater fatigue in RA patients which is corresponding to prior study.20 Association between fatigue and disease activity in RA is controversial. A significant correlation between fatigue and ESR was noted in the RA patients as in other.8 DAS28-ESR has several components and this makes it better than measuring inflammation only. In this study, there was correlation between fatigue and overall DAS28-ESR in accordance with previous studies.10,15,24 In contrary, fatigue was not correlated with the ESR value and disease activity.3,20 Fatigue was reported among RA patients in remission or a low disease activity.25 This difference may be related to differences in the characteristics of the patient cohorts. Moreover, in a large longitudinal study despite decreased inflammation with RA treatment, fatigue severity remained unchanged.24 Specifically tailored interventions to reduce fatigue should be offered to RA patients.

According to our results, RA therapy that is based on the administration of disease-modifying anti-rheumatic drugs (DMARDs), immunosuppressant drugs, has no impact on fatigue level in consistent with Abdel-Magied et al.15 However previous work showed some evidence that TNF-inhibitors and to lesser extent DMARDs can reduce fatigue,3 there are relatively few data on whether conventional DMARDs only improve fatigue. Those authors present a different view when it comes to the importance of the type of therapy in the severity of fatigue. They claim that methods of treatment have an impact on decreased fatigue perception among RA patients. Furthermore, longitudinal studies focusing on the effectiveness of DMARDs and new therapies on fatigue seem to be necessary.

A high percentage RA patients have low quality of sleep, in accordance with the authors,21,26 with more than half of RA patients were poor sleepers. In our study, overall PSQI score (6.4±3.6) was similar to Elazeem et al. findings in Egyptian RA patients using PSQI (6.9±2.8).26 Sleep disturbance was strongly associated with fatigue in RA patients.11,27 While fatigue may disturb sleep quality, the disturbance in the sleep may also lead to greater fatigue and thus vicious cycle. The significant association between total PSQI score and DAS28-ESR score is observed in this study which emphasizes that painful joints and inflammation precipitate poor sleep and decreased alertness.7,20,28 In agreement with other authors,26 we found no significant association between PSQI and the use of DMARDs or NSAIDs (data not shown). From another prospect, depression represents a component of the vicious cycle of RA constitutional symptoms and can impede the remission of the disease.24 The medical literature suggests heterogeneous prevalence rates of depression in RA.21 Depression score recorded in RA study population is comparable to the literature.27 Presence of severe fatigue, high disease activity as well as poor sleep in RA patients could explain the higher number of RA cases with depression. Depression has been found to be associated with the fatigue within the RA cohort in previous studies.3,20

There are limited integrative data aiming at characterizing RA-related fatigue from a whole viewpoint. Fatigue, poor sleep, depression and disease activity can be the cause and the outcome in this viscous cycle. These findings support the results reported in different RA ethnic population.11,22,26 In a recent review by Katz,7 an empirical model of the causes of RA fatigue showed that these variables had direct and indirect effects on fatigue and explained the majority of variation in fatigue.

The major strengths of this study are the multiple multidimensional measurements used in the assessment of the variables, which all had been validated in RA. However, being cross-sectional design, the causality of the relationships cannot be determined. Some of the measure used may be affected by each other. Further research is needed to investigate whether improvements in sleep, depression and disease activity can reduce fatigue. Some other variables such as levels of pain did not included; which have been shown to have strong associations with fatigue.29 Stebbing et al. found that fatigue in RA patients had no significant association with pain but was associated with depression and anxiety.20 Despite these limitations, though, our findings were consistent with other research. Most of the studies about fatigue in patients with RA have been done in western countries and very few from developing countries. If we consider cultural differences, research from developing countries would be helpful to reveal ethnic differences. Future research in this field should aim at finding instruments covering all related dimensions of fatigue in patients with RA. Furthermore, the future investigations able to understand the underlying pathophysiological mechanisms of fatigue are needed.

In conclusion, severe fatigue, poor sleep and depression are more common in Egyptian patients with RA. The results of this study would suggest that fatigue may not solely result of RA disease activity, but may be the result of a constellation of multiple factors that include depression, and poor sleep. That is to say, evaluation of the fatigue and its determinants in RA assessment must be included in clinical practice. These results will be better to validate and replicate in RA patients from different ethnic origin.

The study was not funded by grant.

None.