The patient experience with fatigue and content validity of a measure to assess fatigue severity: qualitative research in patients with ankylosing spondylitis (AS)

Ankylosing spondylitis (AS) is an autoimmune disorder characterized by inflammation of the spine and large joints. Prevalence rates for AS have been estimated to be 0.2 – 1.2% [1], and historically males have been found to be more predominantly affected than females [2, 3]. However, this historical precedence may have contributed to gender biased research and under-diagnosis in women [4]. It is a chronic condition of young adults that commonly develops in the third decade of life [1]. Common symptoms include joint pain, fatigue, low-grade fever, loss of appetite, and eye inflammation [3]. There is wide inter-individual variability in bearing the burden of AS as some patients experience minor disabilities while others may have severe deformities of the spine. Aspects such as reduction in physical function, withdrawal from activities (including employment), and impairment in quality of life, comprise a significant portion of the disease burden [5].

Although there is variability in the burden of AS, many patients experience fatigue as part of their disease, with severe fatigue reported in 50% of patients with AS [6]. Furthermore, fatigue has been found to be one of the key symptoms that can significantly impact health-related quality of life [7], and patients with AS have reported that fatigue has impacted their social life, relationships, and work [8]. For this reason, researchers have called for both a comprehensive assessment of fatigue as part of routine clinical practice in patients with AS and the development of treatment programs directed at alleviating the fatigue that often accompanies AS [8].

The primary objectives of the qualitative research presented here are to describe the patient’s experience with fatigue with respect to their AS and to evaluate the content validity of a measure of fatigue severity for these patients. Concept elicitation interviews were undertaken to gain insights into patients’ with AS perceptions of the symptoms of their condition, especially fatigue, the importance of those symptoms, and the impacts of AS on patients’ lives. Key insights gleaned from these interviews demonstrated the importance of fatigue in AS and the need for clinical research to capture symptom severity as a means of demonstrating treatment benefit. Subsequently this research led to the development of the Worst Fatigue Numeric Rating Scale (WF-NRS), a single-item patient reported outcome (PRO) measure that assesses the level of worst fatigue severity experienced by the patient during the previous 24 hours. This manuscript presents results from qualitative analyses of the interview data to support conclusions regarding the development and usefulness of the WF-NRS for the assessment of fatigue severity among patients with AS in a clinical trial setting.

A total of thirteen participants completed interviews. After the first three interviews, revisions to the inclusion and exclusion criteria (noted above) were made to enhance recruitment and the next ten participants were recruited under the revised criteria. Table 2 shows the sociodemographic characteristics of the sample. There were eight females and five males, and the mean (SD) age was 47 (13.4) years. The majority (N = 10) of participants rated their current level of AS as “moderate” and the remaining 3 participants rated their current AS level as “severe”. For the last ten participants (i.e., those recruited after the change in eligibility criteria and for whom data are available), the mean spinal pain NRS scores were: 6.0 (SD 1.2) for overall pain and 6.2 (SD 1.8) for nocturnal pain. For the entire sample, the average time since AS diagnosis was 13 years, with a minimum of 1 year and a maximum of 35 years. There were no new concepts reported or codes applied after the 7^th interview transcript, which suggests that saturation was attained by the eighth interview. As a means to gather a more in-depth understanding of the concept(s) being studied, we continued to interview 5 participants beyond the saturation point.

In this study, we intended to capture participant’s experience with having AS. Many were young adults (the youngest was 26 years old) or had lived very active lives (the oldest was a 76-year old competitive triathlete) prior to disease onset. Fatigue and pain were often experienced at extreme levels, and the symptoms affected all areas of participants’ lives: mobility, work, career aspirations, social activities, relationships, and emotional well-being. Although participants typically mentioned chronic, and sometimes excruciating, pain when first asked about their experience of AS, when probed about fatigue, they responded with 'Oh yes, very much so’ and 'Oh, I’m always exhausted’. One participant suggested that one possible explanation for not reporting fatigue spontaneously could be the 'normalization’ of the phenomenon by themselves (i.e., feeling fatigued becomes customary) or others (i.e., 'everybody gets tired’), and hence participants’ omission to report this. Fatigue severity was reported to be highly variable from day-to-day as well as throughout the day, with the evening often cited as the time of worst fatigue severity. Participants mentioned a number of factors influencing fatigue severity, including pain, sleep disturbances (that may be related to pain), exercise or activity, and feeling depressed.

Results from the concept elicitation interviews also indicated that all participants clearly understood the term 'fatigue’ and some of them used it spontaneously when describing their condition. It is possible that individuals with AS quickly learn the term because it is used by doctors and other patients when discussing the condition. While participants also used other terms and phrases to describe fatigue, such as tiredness, feeling worn out, exhausted, needing to rest, slowed down, etc., the term 'fatigue’ resonated with participants and was considered clear and appropriate for describing how AS makes them feel.

In summary, the concept elicitation interviews confirmed that fatigue was a key symptom of AS. All participants reported experiencing fatigue at some point during their illness, with all but one participant currently experiencing fatigue. Along with pain, fatigue was considered a bothersome symptom of AS, with one participant reporting that fatigue was the most bothersome symptom.

Although there have been a large number of scales developed with the intent of measuring fatigue [13], the WF-NRS has a number of characteristics that distinguish it from the alternatives. First, the WF-NRS was developed based on qualitative input (concept elicitation interviews and cognitive debriefing of the BFI) from an AS population ensuring the assessment of an important and relevant aspect of fatigue severity. This type of patient input is a key aspect for establishing content validity as the fatigue experience may differ across patient populations and scales developed for one condition may not be appropriate for use in another. Many of the existing fatigue scales were developed in patient populations other than AS, such as those with cancer [10, 14, 15], chronic fatigue syndrome[16‐18], multiple sclerosis [19‐21], rheumatoid arthritis [22], or general medical patients [23, 24]. To the best of our knowledge, content validity in AS has not been established for most of these instruments. Second, the WF-NRS is a single-item, unidimensional instrument inquiring about the worst level of fatigue in a 24 hour period as a measure of fatigue severity, which the interviews revealed to be relevant and understandable in patients with AS. Having respondents answer queries based on their worst experience is consistent with recommendations from PRO development guidelines for using appropriate methods and techniques to enhance the validity and reliability of self-reported data [25]. In contrast, the other measures listed above are all multiple-item tools that assess fatigue as either a unidimensional [10, 14, 16, 19] or a multidimensional [15, 17, 18, 20‐24] construct. The brevity of the WF-NRS may make it particularly suitable for use in clinical trials with a patient population that suffers from fatigue, especially if the trial subjects will be expected to complete a battery of other assessment instruments. Finally, the 24-hour recall period appears to be short enough that patients will not have difficulties in accurately completing the instrument. The study participants suggested that fatigue severity was periodic and therefore other recall periods, such as “at the present time”, may not capture clinical peaks. Additionally, capturing the worst level of fatigue in a short timeframe does not require the patient to average his or her symptom severity over time. Patient responses that rely on memory based on long periods of time, or require the responder to average their response, may introduce recall bias [25]. Moreover, incorporating the WF-NRS in a daily diary may help ensure that day-to-day variability in worst fatigue could be readily captured and addresses participants’ concerns that just one assessment may not accurately characterize their fatigue severity. The addition of a clinical outcome assessment tool to capture cognitive impairment should also be considered as participant comments suggest a mental component of fatigue presenting as a consequence of AS.

A limitation of the study may be that the small sample size allowed participant’s input to be obtained from only three clinical sites, although they were located in separate regions of the country. However, the intention of sampling for qualitative research for the development of a patient-reported outcome measure is not to obtain a representative sample of the epidemiologic profile of the patient population but rather to ensure an enriched diversity in patient and disease characteristics, and the distribution of variables indicated a diverse sample with respect to sociodemographic characteristics was obtained. Also, the recruited participants did not include AS patients with a mild level of severity. While the results of this initial qualitative study of fatigue in AS patients were promising, further quantitative research is indicated. In particular, additional research with the WF-NRS is required in order to assess its test-retest reliability; to examine its concurrent, discriminative, and construct validity; and to determine its sensitivity to change. Additionally, the translatability of the WF-NRS into other languages and cultures would also need to be examined before using the instrument in global clinical trials. Nonetheless, the interviews completed with patients with AS in the present study led to the development of the WF-NRS and ensured that the content was relevant to the AS population and the clarity, interpretation (as intended per judgement of the study team), response scale, and recall period were all appropriate.

The reported prevalence and bothersomeness of fatigue supports the importance of assessing the concept of worst fatigue severity in patients with AS to capture treatment benefit(s) in a trial setting. Results of concept elicitation interviews and cognitive debriefing of the BFI fatigue severity subscale support the development and content validity of the Worst Fatigue – Numeric Rating Scale to assess that aspect of fatigue. Additional research is warranted to further evaluate the psychometric measurement properties of the instrument, including construct validity, reliability, and sensitivity to change, and, thereby, support its use in clinical trials.