Measures of Fatigue in Patients With Rheumatic Diseases: A Critical Review

Abstract

Fatigue is a common symptom, with reported prevalence in the population ranging from 7% to approximately 45% 1-5. For example, evidence regarding fatigue prevalence among the US adult population dates back to the 1970s and early 1990s 2, 6; a US survey in 1974 showed that 14.3% of men and 20.4% of women reported suffering from frequent fatigue 2, and another study found that 12% of men and 22% of women were considered to have lack of energy 6. The prevalence of fatigue in rheumatic diseases varies significantly. For example, in rheumatoid arthritis (RA), its frequency depends primarily on the criteria used to define it. However, clinically relevant fatigue is reported to occur in 40% to 80% of patients with rheumatic diseases 7-9, with 40% experiencing persistent severe fatigue 10. Around one-third of patients with ankylosing spondylitis (AS) experience severe fatigue 11, with an overall prevalence of 53% to 76% 11-13. In osteoarthritis (OA), the prevalence of fatigue varies between 41% 9 and 56%, with 10% of patients experiencing severe fatigue 14. Fatigue has been described as difficulty in initiating or sustaining voluntary activities 15, 16. It is influenced by several factors, including age, sex, physical condition, food intake type, time elapsing between meals, mental status, psychological conditions, personality type, life experience, and health status 17. Fatigue differs depending on whether the individual is healthy or not 18, 19. In healthy individuals, fatigue is a predictable and transient physiologic reaction to prolonged intense activity that abates significantly with rest 19. In contrast, individuals with diseases describe fatigue as an overwhelming sense of tiredness at rest, exhaustion with activity, and lack of energy that precludes them from performing their daily tasks 18. Fatigue is common in many rheumatic conditions 20-22. Because it is a subjective clinical manifestation, fatigue can only be evaluated using patient-reported outcome measures (PROMs); many measures of fatigue have been used in rheumatology populations 23. The Outcome Measures in Rheumatology consortium 24 endorsed the measurement of fatigue in clinical observational, longitudinal studies 25 and clinical trials, mainly in patients with RA and patients with fibromyalgia syndrome (FMS) 25, 26. Different fatigue measures address different aspects of fatigue. For example, as a screening tool, multi-item PROMs can explore broader fatigue issues to create a global score or multidimensional PROMs can produce subscale scores for a range of different facets or domains of fatigue (eg, cognitive and physical fatigue). Multidimensional PROMs with subscales may be useful for informing or evaluating interventions or exploring fatigue causality. Some fatigue PROMs relate to severity only, whereas others include items of both severity and impact 23. Surprisingly, studies of fatigue in inflammatory rheumatological conditions largely fail to show a correlation with measures of inflammation or disease activity. Studies evaluating the relationship of fatigue PROMs with inflammatory markers have found weak associations 8, 27. Very strong associations (eg, more than 0.75) might be expected when examining criterion validity with other fatigue scales 21, 22. Additionally, reliability of fatigue PROMs can be problematic to evaluate because of the fluctuating and unpredictable nature of fatigue itself 23. The characteristics of an ideal fatigue assessment instrument include being easy to understand and complete, causing minimal burden to users, and being able to discriminate cases from noncases with acceptable levels of sensitivity and specificity. Additionally, it should provide a full description of severity and impact, with the ability to act as an outcome measure sensitive to change regarding disease progression and/or treatment. Moreover, it should be reliable, have good reproducibility, and be stable among raters and over time. It must have a stable structure measuring and reasonable correlation to similar valid tools, and be able to discriminate between different patient groups and symptoms and to capture changes in symptoms over time 28. The importance and relevance of fatigue as an outcome measure has been established. Improved standardized assessments of fatigue and comprehensive studies across a range of rheumatic diseases are needed. We will now describe the different instruments used to assess fatigue in patients with rheumatic diseases; for simplicity, we are listing them alphabetically. They are as follows: the Bristol Rheumatoid Arthritis Fatigue (BRAF) Multidimensional Questionnaire (MDQ), the BRAF Numeric Rating Scale (NRS), the Chalder Fatigue Questionnaire (CFQ), the Checklist Individual Strength fatigue (CIS-fatigue), the Fatigue Assessment Scale (FAS), the fatigue NRS, the Fatigue Severity Inventory (FSI), the Fatigue Severity Scale (FSS), the Fatigue Visual Analog Scale (VAS), the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), the Multidimensional Assessment of Fatigue (MAF), the Multidimensional Fatigue Inventory (MFI), the Multidimensional Fatigue Symptom Inventory (MFSI) Short Form (SF), the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue scales, the Piper Fatigue Self-Report Scale (PFS), the Profile of Fatigue and Discomfort (PROFAD), the Profile of Mood States subscale fatigue (POMS), the Rheumatoid Arthritis Impact of Disease Fatigue (RAID-F), and the SF-36 Vitality (VT). The most important features of these measuring tools are summarized in Tables 1 and 2. The BRAF-MDQ was developed to evaluate the overall experience and impact of fatigue in 229 patients with RA in its different dimensions. It was published in 2010 29, 30. The BRAF-MDQ covers domains of physical fatigue (eg, average fatigue level in the last 7 days), living with fatigue (eg, has fatigue made it difficult to bathe or shower?), cognitive fatigue (eg, has fatigue made it difficult to concentrate?), and emotional fatigue (eg, has being fatigued bothered you?). Twenty items provide a total fatigue score, which includes four subscale scores for physical fatigue (four items), living with fatigue (seven items), cognitive fatigue (five items), and emotional fatigue (four items). There are four options (not at all, a little, quite a lot, and a lot), except in the first three elements, which are numerical or categorical as appropriate. The preceding week. The BRAF-MDQ is free to use. Available at the following website: https://www1.uwe.ac.uk/hls/research/healthandclinicalresearch/researchareas/complexandlong-termhealthca/fatiguescales/brafscales.aspx. The BRAF-MDQ is a patient self-report completed with pen and paper. Items are scored from 0 to 3, except for items 1 (scored 0-10), two (scored 0-7), and 3 (scored 0-2). A total fatigue score is obtained by adding the scores for the 20 items. The elements of the subscales are added together to produce scores for physical fatigue, living with fatigue, cognitive fatigue, and emotional fatigue. The instructions for the missing data indicate that only three questions in total can be omitted, questions 1 and 2 must be completed, and only one question from each subscale can be omitted (it is replaced with the patient's average score for that subscale). The instructions and scoring template can be downloaded from the developers' website. Higher scores reflect greater fatigue severity. The total fatigue score ranges from 0 to 70; subscale scores range from 0 to 22 for physical fatigue, 0 to 21 for living with fatigue, 0 to 15 for cognitive fatigue, and 0 to 12 for emotional fatigue. The time to complete has not been reported. The time to grade has not been reported. The BRAF-MDQ has been translated using the appropriate linguistic methodology of direct translation, independent reverse translation by several native speakers, consolidation, and then independent reverse translation to consolidate the final version (information available from the developers). Versions in English (United Kingdom, South Africa, United States, Canada, and Australia), Polish, French (Belgium, Switzerland, and Canada), Afrikaan (South Africa), Swedish, Dutch (Belgium), Spanish (United States, Spain, Mexico, and Colombia), German, Portuguese (Portugal and Brazil), Japanese, South Korean, Turkish, Russian, Romanian, Bulgarian, Norwegian, Hungarian, Danish, Czech, Greek, Italian, and Chinese (Taiwan) can be downloaded from the developers' website. Floor effects and ceiling effects are unlikely to be significant. In the 229 patients with RA studied, less than 1% obtained the maximum possible score for total fatigue, 2.7% obtained the maximum score for cognitive and living with fatigue, 4.5% obtained the maximum score for physical fatigue, and 7% obtained the maximum score for emotional fatigue; no patient obtained the lowest possible fatigue score for total and physical fatigue, less than 1% obtained the lowest score for living with fatigue, 5% obtained the lowest score for cognitive fatigue, and 6% obtained the lowest score for emotional fatigue (in patients recruited with VAS of fatigue of more than 5 of 10) 30. In the same 229 patients with RA, Cronbach's α was 0.93 for total fatigue, 0.71 for physical fatigue, 0.91 for living with fatigue, 0.92 for cognitive fatigue, and 0.89 for emotional fatigue; all except one were excellent values. The correlations between total fatigue and the four subscales range from r = 0.75 to 0.88 30 (all very good to excellent). The test-retest was performed 1 to 2 hours apart (n = 50 patients with RA before and after clinic visits); correlations were excellent overall; for total fatigue r = 0.95, for physical fatigue r = 0.94, for living with fatigue r = 0.89, for cognitive fatigue r = 0.89, and for emotional fatigue r = 0.92 31. The items and their wording cover a range of severity and impact of fatigue and were derived from patient interviews, which were then refined with focus groups 29. In the 229 patients with RA studied, total fatigue correlated very strongly with the MAF (specific to RA) at 0.82 and with the FACIT-F at −0.81 and positively with the SF-36 VT at −0.64 30. A range of moderate to strong correlations was also observed between these measures and the BRAF subscales: physical fatigue (severity) −0.68 to 0.83, living with fatigue −0.54 to −0.74, emotional fatigue −0.50 to 0.66, and cognitive fatigue −0.40 to 0.55 30. The lower levels of association observed in cognitive fatigue may reflect the lack of elements of cognitive fatigue in other fatigue measures. For total fatigue and all subscales, the correlation with SF-36 VT was weaker than with other fatigue scales (see Short Form 36 Vitality). In the same 229 patients with RA, total fatigue correlated positively with depression, anxiety, disability, and impotence (0.50-0.63); physical fatigue (severity) correlated moderately with disability, depression, and impotence (0.37-0.45) and weakly with anxiety (0.26); living with fatigue correlated positively with depression, anxiety, disability, and impotence (0.45-0.61); cognitive fatigue correlated moderately with depression, anxiety, and impotence (0.33-0.49) and weakly with disability (0.21); and emotional fatigue correlated positively with depression and anxiety (0.54 and 0.57, respectively) and moderately with impotence and disability (0.45 and 0.35, respectively). Neither total fatigue nor the subscales were strongly associated with pain (0.14-0.38) 30. In patients with RA receiving an intramuscular glucocorticoid injection (n = 42), effect sizes (ESs) of 0.33 to 0.56 for the total BRAF-MDQ and subscales at 2 weeks (P < 0.04) were observed for all 32. In patients with RA receiving an intramuscular glucocorticoid injection (n = 42), the minimally important differences detected were 17.5% for improvement and 6.1% for fatigue worsening of the pretreatment value of the BRAF-MDQ score 32. The BRAF-MDQ has been developed and used in RA 32-35. This tool has been applied in observational studies as well as in clinical trials 32-36. The BRAF-MDQ is specific for RA and was developed in collaboration with patients and cognitive interviews of draft statements including the word "fatigue" in each statement. Factor analysis shows that the subscales of emotional fatigue, cognitive fatigue, and living with fatigue can help elucidate different causal or perpetuating mechanisms or highlight individual patient dimensions that require specific interventions. Internal consistency, test-retest reliability, and construct validity are good, and the BRAF-MDQ shows criterion validity with other fatigue scales. The available data suggest that the BRAF-MDQ would have a better characterization in those patients with more severe fatigue compared with the SF-36 VT 37. It has not been used in the clinical setting. The data suggest that the BRAF-MDQ is a useful research tool for identifying the general fatigue experience, the different types of fatigue in RA, and, potentially, how these may have different causal factors or responses to treatment. The aim of the BRAF-NRS was to develop a standardized NRS for measuring a range of the following RA fatigue dimensions: severity, effect on life, and coping ability 30, 38. A new version was released in 2018 (the BRAF-NRS version 2) 39. Three items are included; they measure severity, effect, and coping with RA fatigue. Three (one for each dimension). Patients circle the NRS from 0 to 10 for each item. Severity ranges from no fatigue, 0, to totally exhausted, 10. Effect ranges from no effect, 0, to a great deal of effect, 10. Coping ranges from not at all well, 0, to very well, 10. A revision of the BRAF-NRS coping item was developed with a score of 10 as worse coping and ranges from very well, 0, to not at all well, 10. The preceding week. No cost. The BRAF-NRS is available from the website of the University of the West of England Bristol ( https://www1.uwe.ac.uk/hls/research/healthandclinicalresearch/researchareas/complexandlong-termhealthca/fatiguescales/brafscales.aspx). The BRAF-NRS is a patient self-report completed with pen and paper. It uses a Likert scale from 0 to 10 for each item. Scores range from 0 to 10, with higher scores reflecting greater problems for severity and effect NRS but lower scores reflecting greater problems from coping NRS. In the BRAF-NRS version 2, scores range from 0 to 10; higher scores reflect greater problems in all dimensions. In terms of normative data, 1276 patients with RA had a mean (SD) BRAF-NRS severity of 4.8 (2.6), effect of 4.6 (2.7), coping (original) of 6.0 (2.6), and coping (revised) of 4.0 (2.7) 39. Time to complete is probably 1 minute for the three items. In the BRAF-NRS, coping may be a particularly challenging notion to grasp across different cultures 40. Time to score has not been reported. The original language is English (United Kingdom). There are currently 35 translated versions of this scale. Floor effect was almost absent, but there is a ceiling effect. In 588 patients with RA, 11.1% scored at ceiling for severity, 16.8% scored at ceiling for effect, and 17.7% scored at ceiling for coping; 0.2% scored at floor for severity, 0.3% scored at floor for effect, and 1.9% scored at floor for coping 37. In a study, 50 patients with RA completed the first BRAF-NRS on arrival at the clinic (T1) and the second BRAF-NRS on the same day (T2) after a minimum of 60 minutes. There was a very strong correlation between the following T1 and T2 scores: severity (r = 0.92), effect (r = 0.85), and coping (r = 0.62) 32. The single-item NRS covers aspects of fatigue generated from patient interviews and refined with focus groups 29; fatigue coping is not available as a separate domain in other PROMs 41. In the 229 patients with RA studied, the NRS correlated with the fatigue measures MAF, FACIT-F, and SF-36 VT 30. Lower levels of association have been seen in the coping NRS, which might reflect the lack of coping items in other fatigue measures. For all the NRSs, correlations with the SF-36 VT were weaker than other fatigue scales. Correlation between severity and effect (r = 0.71) was strong, whereas associations between perceived coping and both severity and effect were weak to moderate (r = −0.235 and −0.352, respectively), suggesting that coping is a different concept 30. The construct validity for the original BRAF-NRS coping item was acceptable, but it was better for the revised BRAF-NRS version 2 (revised r = 0.15-0.74, original r = 0.09-0.48) 39. Forty-two patients with RA who were prescribed a single high dose of intramuscular glucocorticoids completed their first BRAF-NRS as part of their clinical care while waiting to have their injection. The second BRAF-NRS was obtained at the patients' homes 2 weeks later. The BRAF-NRS was sensitive to change, severity, and effect (ES 0.46-0.47). The BRAF-NRS coping was not sensitive to change (ES 0.05) 32. Three studies analyzing the minimal clinically important difference (MCID) on a number of fatigue severity scales in RA suggest that a change of between 7% and 11% would be clinically important 42, 43. Thus, 10% RA fatigue severity MCID might represent a meaningful change; this compares with multiple sclerosis, in which an average MCID of approximately 15% 44 was found in two studies. The Reducing Arthritis Fatigue Team (RAFT) program demonstrated an adjusted mean difference of 0.59 in the BRAF-NRS fatigue impact beyond the improvement seen in the usual-care arm, with the RAFT program showing a 19% change from the baseline mean and the control arm showing a 12% change from the baseline mean (fatigue impact improving by 1.36 and 0.88 units, respectively). However, further work to establish the MCID for the BRAF-NRS impact is still needed 45. The BRAF-NRS is used in RA 37, 40. None. The BRAF-NRS was developed for patients with RA. It is free to use and quick to apply. It shows a good method of development, acceptability, reliability, validity, and ability to detect change. Investigators using the original BRAF-NRS coping item in ongoing studies should not be tempted to reverse those scores, because they are not mirror images of each other. Investigators should continue to use the original version for studies currently under way, because its performance is acceptable 39. The available data suggest that the BRAF-NRS may be a useful, quick tool to identify three different concepts of RA fatigue, which might inform individualized self-management interventions, with no significant administrative or respondent burden 23. The available data suggest that the BRAF-NRS may be a useful research tool to screen for entry criteria and to identify different facets of fatigue that might be changed differentially by interventions 23. Sometimes referred to as the Chalder Fatigue Scale, or simply the Questionnaire or Fatigue Scale, the CFQ was developed to assess the severity of disabling fatigue in hospital and community populations and was originally published in with an in 2010 The CFQ covers physical fatigue (eg, lack of of and for and mental fatigue (eg, and items produce an overall score, two domains of physical and mental fatigue. There are four in the last revision than no more than more than and more than The preceding The CFQ is free to use. The CFQ can be obtained from the by at The CFQ is a patient self-report completed with pen and paper. Items can be scored in two The first is on a scale of 0 to 3, with an overall score range of 0 to a physical fatigue domain range of 0 to 21 and a mental fatigue domain range of 0 to 12 the CFQ can be scored as a than and no more than = more than and more than = and then added together to produce an overall score between 0 and No is available on the of missing Higher scores reflect greater fatigue. For the Likert score, a score of of clinically relevant fatigue from relevant fatigue and for the score, an overall score of or more of a fatigue In terms of normative data, the mean (SD) score in healthy (n = was compared with in patients with fatigue syndrome and in patients with (n = and = 30, respectively) studies use the CFQ draft range an average global fatigue score in patients with of 22 range the CFQ draft with an range the overall fatigue in patients with syndrome was in control (P < Time to complete has not been reported. The scoring time is The CFQ items scored from 0 to and has a change in 2010 However, the rheumatology studies the original only three use this version Three use the draft CFQ scores of 0 to in two it is not which version has been used A version the draft CFQ with an better than an overall score of 0 to A significant ceiling effect was found in patients with with to of patients with maximum scores No data on floor effects are Cronbach's α was in general patients for the draft 0.88 to for different items one at a time and and 0.82 for two domain scores and also excellent For the final version of Cronbach's α was 0.89 in patients (n = 0.92 in patients with (n = and 0.88 in a survey of (n = In one study that rheumatological patients Cronbach's α was 0.93 and 0.92 for the of patients with (n = and the of patients with diseases (n The reliability value of the using the correlation of the was 0.55 (P < a value The items were generated by and the final CFQ covers a range of physical and mental fatigue problems and a domain score for each a program of fatigue interviews as a the for a of fatigue was as or more of in the CFQ with sensitivity and In (n = the CFQ draft was strongly associated with the and the Fatigue VAS (r = for In a of patients with RA, and total fatigue and physical CFQ scores were moderately correlated with the Fatigue VAS (r = and r = respectively) A CFQ score of of patients with from the general population in of cases In with the draft mean fatigue was significantly different between patients = and control = However, no differences were found in total CFQ or physical and mental domains between control and patients with or and patients with RA from control in physical fatigue (P < 0.05) In CFQ scores of items were moderately associated with two measures of disease activity, the and the (r = and (r = In pain (n = the CFQ was moderately associated with pain disability (r = and pain (r = In a study of patients with to or control after 12 weeks of there was significant improvement in fatigue using the CFQ The MCID by was The CFQ has been used in RA, and as well as and pain This tool has been applied in observational studies as well as clinical trials The CFQ is a scale of fatigue severity than a measure of impact or and it physical and mental The CFQ has good in populations with and good sensitivity to change in must the version from the Some continue to use the which between studies options include one one and two which may the Likert score the use of the score or to define cases this There are rheumatology data in the two nor test-retest have been The use of the CFQ in has been because patients with the maximum score in most of the a patients can no indicate a worsening of their fatigue The CFQ has been used as an outcome in several trials, including a in multiple among others is an subscale of that measures subjective fatigue. The of 20 statements on the of 24 but after it in patients who from fatigue for more than a four items were The analysis four 60 with the 20 were easy to and were subjective fatigue items), (five items), (four items), and physical activity items). Twenty items provide a total score, including four subscale scores for subjective fatigue experience items), (five items), (four items), and physical activity levels items). the fatigue, the subjective fatigue subscale is the only subscale reported and is referred to as the or Fatigue of statements have and the (see website at of the questions are that the statements indicate of fatigue, and the scoring is that is would then indicate a score of 1 of of statements are or full of (see website at The preceding 2 No cost. The can be obtained from the by The is a patient self-report completed with pen and paper. The of 20 statements on problems might have in the 2 A Likert scoring is each indicate a score from 1 to that is or that is not The uses items. item is scored on a Likert scale. on scores in healthy a score score for healthy 1 was with a experience of fatigue, a score between and moderate fatigue, and a score of 35 or higher severe fatigue A score of 35 or at baseline as well as at 12 was persistent severe fatigue 10. Time to complete has not been reported. Time to score has not been reported. The from the Swedish, and versions are available from the The fatigue severity subscale questions that a score from to healthy score, on and patients with other conditions score patients with or a score For example, in a study of of the of the it was that score an overall and in patients the of its There are no studies on floor and ceiling effects in rheumatic The reliability for the was at baseline and 0.92 at 10, which are In for total score, Cronbach's α was and reliability was Cronbach's α for subscales from to 0.92 In patients with RA (n = Cronbach's α for the subjective fatigue was 0.92 and it was 0.89 in patients with (n = In all these the were In patients with RA, analysis was reported as the four subscales data were (n = In patients with RA, the correlation of subjective fatigue over 1 was

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