Elicitation of health state utilities associated with varying severities of flares in Systemic Lupus Erythematosus

The objective of this study was to elicit six utility values associated with increasing severity of flare. A decrease in utility was observed with increasing severity of flare. These data suggest, based on valuation by the general population, that flares of any severity are seen to have a disutility over the anchor HS (minimal disease activity).

The lowest utility scores were recorded for the severe generalised flare HS, rather than the severe renal flare HS or severe CNS flare HS. Previously studies have reported no significant difference in HRQoL between SLE patients with and without renal involvement [9]. The clinical severity of severe CNS and severe renal flares is substantial; however clinical measures are based on physiological or pathological measurements and may have only little relationship to patients’ feeling of well-being [11, 24, 14]. These findings are consistent with insights from patient experiences gathered during HS development, as the most bothersome symptoms during flare reported by patients (e.g. joints, pain, fatigue) did not always correlate with clinical severity. These findings highlight the importance of including patient perspective/patient-reported outcomes alongside clinical outcomes in the development of new treatments for SLE.

Furthermore, these results are consistent with the existing literature. The severe generalised HS presented in this study included more severe musculoskeletal, fatigue and pain manifestations versus the severe renal flare HS and severe CNS flare HS. Additionally, the severe generalised HS description included more descriptive statements highlighting the emotional impact of these manifestations e.g. depression and anxiety associated with an inability to carry out daily activities and the perception of being a burden to family and friends. Previous reports suggest that SLE patients experiencing high levels of pain were also burdened with greater fatigue, anxiety and depression, and as a result had a significantly lower HRQoL [12, 14]. Patient-reported fatigue has been shown to have a significant impact on multiple aspects of an SLE patients’ life (emotion, cognition, work, activities of daily living, social activities etc.) [13, 14]. Increased treatment and subsequent cumulative organ damage have been shown to be significant predictors of lower HRQoL scores [25], and treatment-related adverse events have been found to have a negative impact on patient HRQoL in approximately 70 % of patients [26]. Increased medication and hospital visits were included within the flare HS descriptors. Further research to quantify the impact of these factors on the general population’s valuation of the HS descriptions is needed.

Within our study the lowest utility scores were often observed in the Japanese cohort, with the exception of the severe renal flare HS and the severe CNS flare HS. Previous studies, not specific to SLE, have shown EQ-5D derived utility scores vary on average by 0.24 between Japan and the UK – this may be due to cultural disparities [27, 28]. Differences observed in utility scores may be reflective of differences in social preference weights between populations. These variations could be due to the general population’s perception of disease severity and impact [29]; descriptors within the HS may have resonated more with the general population in Japan.

The TTO methodology is a standardised tool for HS valuations by Health Technology Assessment (HTA) bodies [18]. The six HS were developed using interviews with physicians and patients as recommended by NICE; furthermore the HS were validated by independent expert rheumatologists from 5 different countries (AU, CA, ES, FR, JPN) [18]. Previously large differences in elicited utility values have been observed for the same HS when using different interviewers, due to methodological inconsistencies in the TTO exercise [30]. The utility scores elicited within this study are consistent across six countries, suggesting methodical limitations were minimal.

It is acknowledged, despite being a widely accepted method, there are some limitations to the TTO technique. Some authors have raised doubts over willingness to trade life for improved health and whether it reveals true preferences [31]. Although not observed within this study, ease of discussing trading off years has been identified as problematic particularly in religious or elderly populations [18, 32]. In addition, this TTO method did not allow for HS to be valued as worse than dead.

The HS may fail to capture all aspects of HRQoL which may influence valuation by the general public [33]. Descriptors within the HS may resonate differently with members of the general public, therefore it is acknowledged there may be a difference in the interpretation of the HS. However, during the development of the HS, pain and fatigue were both cited as the most bothersome by the patients; this was also reflected in some participants’ TTO scores whereby the moderate HS was ranked as more severe than the severe CNS or severe renal HS. The authors observed during the patient interviews that clinical severity may not correlate with patients HRQoL. For example patients with severe underlying disease activity i.e. severe renal flare, may also experience mild skin and joint manifestations in addition to some indicative symptoms of kidney involvement such as headaches and swollen legs which were often cited as less bothersome.

Due to the heterogeneous nature of SLE, not all organ manifestations could be captured, therefore utility values derived from this study may not be applicable to other SLE manifestations of similar overall clinical severity. The HS did not capture the length or frequency of flares, as this is highly variable by patient, and the standard 10 year timeframe for the TTO exercise did not reflect the variation in actual survival between HS. SLE patients have previously reported considerable uncertainty surrounding their condition in particular relating to the timing, severity and future consequences of flare [34]. Uncertainty is closely related to increased anxiety and a negative impact on patient HRQoL [34]. Younger age is a significant predictor of uncertainty and subsequently of a lower HRQoL for SLE patients, as SLE may affect career development, fertility and ability to raise a family; these consequences have not been explored within this study [34]. Furthermore, a large SLE cohort study demonstrated that over the course of one year patients were more likely to experience periods of persistently active disease (PAD) than a flare episode [22]. The reported frequency of PAD compared to flare warrants further investigation into the disutility associated with PAD.

Utility values have been derived from the general population, in line with HTA guidance, rather than from patients with SLE. To ensure a demographic representation of society a 50:50, female to male ratio was used for utility elicitation, therefore gender neutral HS were developed. SLE predominantly affects females, 90:10 female to male ratio, as such health state development was guided by only female SLE patients. Further analyses by gender may elucidate any differences in perception of the HS by male and female members of the general public.

As a representative sample of the general population was recruited, the distribution of participants’ age differs from that of a typical SLE population. Age has previously been found to have an impact on valuation of HS by the general public [18]. Within the utility elicitation participants must imagine they are a 41 year old SLE patient; however, it is acknowledged that participants will draw upon their own experiences and descriptors within the HS may resonate differently with members of the general public. Own health has also been found to have an impact on valuation of HS [18], although in our sample mean VAS scores for own health were higher than the anchor HS in all countries [35]. Age and own health may be a contributing factor for any differences in perception and willingness to trade.

Despite these limitations this study shows that from a societal perspective increasing severity of flare is associated with a decrease in utility scores. The impact of flare on HRQoL, particularly of certain organ manifestations (e.g. musculoskeletal) is consistent with results reported in the literature. These results can be applied in future cost-utility analyses of healthcare interventions which aim to reduce the frequency and or severity of flares in SLE.