Curr Rheumatol Rep (2013) 15:380 DOI 10.1007/s11926-013-0380-9

SYSTEMIC LUPUS ERYTHEMATOSUS (M PETRI, SECTION EDITOR)

Top 10 Recent Developments in Health-Related Quality of Life in Patients with Systemic Lupus Erythematosus Anisha B. Dua & Zahi Touma & Sergio Toloza & Meenakshi Jolly

Published online: 1 November 2013 # Springer Science+Business Media New York 2013

Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that has major implications for healthrelated quality of life (HRQoL). Improvements in the monitoring and management of SLE improves survival; however, improvement of HRQoL remains of paramount importance among these patients. Measurement of HRQoL has been recommended in clinical practice and research including drug development and testing in clinical trials. Both generic and disease specific instruments have been developed to ascertain HRQoL. In an increasingly global collaborative environment, the importance of assessing HRQoL across nations, acknowledgment of their confounders, and limitations of used instruments are critical. Here, we review selected major developments in the past 5 years highlighting: the importance of measuring HRQoL in SLE patients, the benefits and limitations of instruments that exist, and their application in research settings. Keywords Systemic lupus erythematosus . Quality of life . Patient-reported outcomes . Health-related quality of life . QoL . Clinical trials . Modifiers . Confounders This article is part of the Topical Collection on Systemic Lupus Erythematosus A. B. Dua Allegheny Health Network, Pittsburgh, PA, USA Z. Touma University of Toronto, Toronto, ON, Canada S. Toloza Hospital San Juan Bautista, Catamarca, Argentina M. Jolly (*) Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 West Harrison, Suite 510, Chicago, IL 60612, USA e-mail: [email protected]

Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects primarily women with implications in terms of morbidity, survival, and health related quality of life (HRQoL). HRQoL represents the state of one’s physical and functional health, but also a global view of the patients’ social environment and psychological status that may influence their response to illness. HRQoL includes symptoms, functional status, general health perceptions, and may also be influenced by disadvantaged socioeconomic status as well as ethnicity [1]. Survival of SLE patients has significantly improved over the past few decades, from less than 50 % at 5 years in 1955 to 85 % at 10 years and 75 % at 20 years in recent studies [2]. Despite improvements in survival and better understanding of the disease itself, an SLE patients Quality of life (QoL) is significantly worse than someone in the general population and in some cases worse than those with other chronic medical conditions [3, 4]. The Outcome Measures in Rheumatology Clinical Trials (OMERACT) group and the US Food and Drug administration have highlighted the importance of measuring and reporting the patient’s experience with the disease through self-reported HRQoL instruments and defined it as an independent domain [5, 6]. The measurement of HRQoL has been studied in observational studies and determined in an increasing number of SLE clinical trials. A better understanding of importance and recent developments in measuring HRQoL in SLE will aid patients, physicians, and third party payers in management decision making, through justification of benefits, risks and costs assessments, and potentially help improve health outcomes. Herein, we summarize significant HRQoL developments (in the past 5 years) that were published in peer reviewed English language literature. The search and quality selection of papers was made using consensus approach by the authors.

380, Page 2 of 11

Recognition of the Need to Measure QoL in SLE The need to measure HRQoL in SLE has been recognized as increasingly important by patients, physicians, researchers and industry [6–9]. While strides have been made in the management of disease activity in SLE patients, it is clear that QoL does not always or significantly correlate with disease activity and accrued damage [7–9].Furthermore, physiciancentered assessment of SLE patients does not always reflect patients’ self-perceived QoL. The goal of improving patient care and HRQoL is central to all practicing physicians caring for SLE patients. Efficient and cost effective management of chronic disease requires competing treatment regimens to be evaluated in terms of their ability both to control the disease and improve QoL[10]. Furthermore, flares in disease activity, especially musculoskeletal, also contribute towards poor HRQoL in SLE [11]. While the measurement of disease activity and damage is fundamental in the management of SLE patients, it does not inform on the patient’s QoL [10] Disease activity and damage showed weak correlation with HRQoL measures [9, 11]. HRQoL is a determinant of adherence in patients and health care utilization [12]. It is therefore important to acknowledge HRQoL as an independent health outcome in the assessment of SLE patients.

Generic HRQoL Measurement is not Sufficient in SLE SLE impacts HRQoL in many ways that another chronic condition might. Hence, instruments adopted in the assessment of HRQoL in SLE have more frequently included generic rather than disease specific questionnaires (Table 1). Though Medical Outcomes Study Short Form 36 (SF-36) has several advantages due to it being a generic HRQoL questionnaire, it is not disease-specific; it lacks items deemed important by SLE patients [8, 13, 14•]. Advantages of generic instruments are that they allow for the comparison of HRQoL between different diseases [15], thereby allowing appropriation of disease burden and health resources allocation. It is important to be aware of the psychometric properties (reliability, validity, and responsiveness) of the patient reported outcome (e.g. QoL) instrument before they can be fully applied effectively to assess QoL in any situation. SF-36 and EuroQoL-5D, generic HRQoL tools, have been shown to be valid and reliable measures of HRQoL in SLE [16]. Aggarwal et al. found pertinent domains of these HRQoL tools and their summary scores (EQ-5D index, EQ-5D visual analog scale, and SF-6D) to be strongly correlated with each other [16]. However, domains and summary indices of SF-36 were unable to differentiate among patients of varied disease activity, and were insensitive to change in disease activity longitudinally [16]. This finding has also been reported by others [17]. Domains that are important to SLE patients are notably absent

Curr Rheumatol Rep (2013) 15:380

from SF-36 or EQ5D [8, 13, 14•].The need for use of a disease-specific QoL instrument is also evident from poor correlations between SF-6D (a health utility index) with aspects of intimate relationships and body image [18], issues that are noted to be important in SLE. Furthermore, SF-36 scales may include items that are of limited relevance to SLE patients. In a study comparing generic [Quality of Life Scale (QoLS-S), EQ-5D, SF-6D, SF-36) and SLE specific HRQoL instruments (SLE Quality of Life Questionnaire (L–QoL), Lupus-QoL Scale (LupusQoL), SLE Symptom Checklist (SSC), and Systemic Lupus Erythematosus-Specific QoL (SLEQoL)], moderate evidence for generic measures, but strong evidence for content validity and internal consistency reliability for disease-specific measures were reported [19, 20•].

Identification of Domains of Importance in SLE Based on semi-structured interviews with female SLE patients, 11 HRQoL themes emerged as important: prognosis and course of disease; body image; effects of treatment; emotional difficulties; inability to plan due to disease unpredictability; fatigue; pain; career prospects and loss of income; memory loss/concentration; reliance on others to assist with everyday tasks; and pregnancy [8]. Similar themes were chosen by other SLE patients in other studies [10, 14•, 21, 22]. Body image is an important theme in SLE that is affected by mucocutaneous manifestations of lupus and skin scars, in particular with discoid lupus, obesity, alopecia, glucocorticoid exposure, skin hyperpigmentation, and from anti-malarial drugs [23]. A preliminary study revealed body image to be poor among SLE patients, and to be associated with a lower HRQoL [24]. Besides body image, other important issues identified by SLE patients that impact their daily QoL include sleep disturbances, planning, intimate relationships, procreation, medication side effects, effects on concentration, sexual functioning, contraception, family/friends support, career/vocation, and personal and environmental issues [8, 13, 14•]. The development of lupus-specific HRQoL instruments has been undertaken in an attempt to more accurately measure HRQoL variables important to SLE patients. These domains are not included in SF-36. Ow et al. identified four domains (family, relationships, freedom, and stigma and discrimination) that are important in Asian SLE patients [21]. Two of these domains, family and stigma and discrimination, may be accentuated in the Asian sociocultural context [21]. All four of these problems were identified as important during generation of the item pool for LupusPRO, and some were retained while others were dropped in further iterations, based on patient feedback (clinimetric and field testing) and further refinement of the tool.

Specific

Generic

Boston, MA

United Kingdom

USA Developed in Europe

Blackburn, UK Chicago, USA Spain

Singapore

United Kingdom

SF-36

SF-6D

EQ-5D

LupusQoL LupusQoL-US LupusQoL (Spanish, French)

SLE specific Quality of Life instrument (SLEQOL) (English, Portuguese and Thai, Chinese)

L-QoL (English, Estonian)

Instruments Where developed

Patient interviews

Rheumatologist and nurse clinician consensus

Expert input and semi-structured qualitative patient interview

EuroQOL scientists

Members of the general UK population interview

Developed by RAND as part of the Medical Outcomes Study

Theme identification

Table 1 Characteristics of various generic and disease-specific QoL tools used in SLE

0–25

0–240

*0–100a *0–100a *0–100a

Index score −0.11–1 Visual Analog 0–100

Profile score: 5 digit descriptor ranging from 1 to 3 in each dimensiona

Reliability Y Validity Y Responsiveness Y Cross-cultural adaptation and validation Y Internal consistency Y Reliability Y Validity Y Responsiveness N Cross-cultural adaptation and validation Y

Internal consistency Y Reliability N Validity N Responsiveness Cross-cultural adaptation and validation Y Internal consistency N Reliability N Validity N Responsiveness Y Cross-cultural adaptation and validation Y Internal consistency N Reliability N Validity N Responsiveness Y Cross-cultural adaptation and validation N Internal consistency Y Reliability Y Validity Y Responsiveness N Cross-cultural adaptation and validation Y Internal consistency Y

*0–100a

*0–1.0a

Psychometric and clinimetrics properties

Score range

Not given

One week

Previous month Previous month Previous month

Not stated

Previous month

Previous month

Time frame

[10]

[22]

[38]

[85]

[84]

[83]

Ref.

Curr Rheumatol Rep (2013) 15:380 Page 3 of 11, 380

[14•] Previous month Internal consistency Y Reliability Y Validity Y Responsiveness Y Cross-cultural adaptation and validation Y

Curr Rheumatol Rep (2013) 15:380

Recently Developed Disease Specific QoL Tools in SLE

Y Yes; N no; a higher score=better QoL

LupusPRO (English, Tagalog, Spanish, French, Turkish, Chinese)

Instruments Where developed

Table 1 (continued)

Chicago, USA

Patient interviews

0–100a

Ref. Psychometric and clinimetrics properties Theme identification

Score range

Time frame

380, Page 4 of 11

Here, we summarize only the more recently developed SLEspecific instruments published in the past 5 years. Other tools and their features are discussed in the subsequent section (Table 1). QoL tool for SLE (L-QoL) (2009), a 25-item questionnaire, was designed through qualitative interviews of male and female SLE patients, with the intent of providing a unidimensional index of SLE impact [10]. This questionnaire provides a score from 0 to 25, with higher scores indicating worse HRQoL. L-QoL is a reliable and valid questionnaire. It was validated against patient perceived disease activity, health status, and Nottingham Health Profile. The ethnic background of the patients from which the questionnaire was generated, floor/ceiling effects, responsiveness to change against physician assessment of disease activity, and cross-cultural validation information are not available [14•, 25]. Lupus Patient-Reported Outcomes (Lupus-PRO) (2013) is a disease-targeted QoL instrument that was developed in the United States and is based on both male and female ethnically diverse SLE patient interviews [14•]. It measures both lupusspecific HRQoL (symptoms, lupus medications, physical health, emotional health, pain, vitality, procreation, cognition, and body image) and non-HRQoL (desires-goals, coping, social support, satisfaction with care). LupusPRO has been validated against SF 36, EQ5D, Lupus Quality of Life tool (LupusQoL), generic body image tools, depression, and physician-assessed disease activity and damage measures. It has been found to be responsive to changes in patient-reported changes in health status [26], have measurement equivalence [27] in cross-cultural adaptation, and validation studies in other languages or countries [28–33]. Lupus Impact Tracker (LIT) is a 10-item one-dimensional tool that was derived from the LupusPRO, and provides an overall summary score (0–100, where higher scores imply greater impact of the disease on their QoL). This has been developed using psychometric, statistical methods from the LupusPRO, and feedback from focus groups [34]. It has been validated against the SF-36, LupusQoL, disease activity, and damage measures [35, 36]. It has been found to be responsive to systemic lupus erythematosus responder index (SRI) and self-reported change in health status [35]. The SLE-specific body image tool (BILS) was developed from SLE patients and found to have good reliability and validity (against generic body image tools) among 233 SLE patients [37].

Features of Various Lupus Specific QoL Instruments Direct comparison of the validity of QoL tools is difficult because of the different methodologies employed in the development and evaluation of these tools. However, there is

Curr Rheumatol Rep (2013) 15:380

supportive evidence that multidimensional disease-specific measures are the most suitable in terms of content and internal reliability for use in studies of adult patients with SLE [19]. The validity and reliability of these HRQoL measurement tools is critical for truly reflecting an SLE patient’s QoL at a given point in time. SLE-specific health-related PRO measures (Table 1) currently available for use in the adult SLE population include the Systemic Lupus Erythematosus–Specific QoL (SLE-QoL) [22], the Lupus-QoL Scale (LupusQoL) [38], the SLE QoL Questionnaire (L-QoL[10], SLE Symptoms Checklist (SSC), the Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY) [39], and LupusPRO [14•]. Comparison of some of these tools has been published before [19, 25]. The SSC contains a list of symptoms and is not considered to be a HRQoL measure. The SLEQoL was developed in Singapore by rheumatologists and nurse clinicians without formal patient input during item pool development. The validity of this tool against generic HRQoL tools is poor. Floorceiling effects data is not available, but responsiveness assessments are available for SLEQoL. The L-QoL, developed by Doward et al., was derived from in-depth interviews of SLE patients and measures the impact of the disease and its treatments; however, most patients were in fair to excellent health [10]. It lacks responsiveness and floor–ceiling effects information. This tool was tested against self-reported disease activity assessments and a generic HRQOL tool that is not frequently used in Rheumatologic literature (Nottingham Health Profile). The Lupus-QoL was derived from semistructured interviews with predominantly Caucasian SLE women from the United Kingdom. It has good psychometric properties, and provides information on ceiling and floor effects. Responsiveness to change in some of the LupusQoL domains to significant change in disease activity at monthly intervals was noted in a study comparing SF-36 and LupusQoL. This tool does report floor–ceiling effects information. LupusPRO, as noted above is also developed from SLE patients (male and female) in the US, has good psychometric properties, includes HRQoL (Domains Lupus symptoms, medication side effects, procreation, cognition are unique to LupusPRO) and Non-HRQoL (Coping, Social Support, Desires-Goals and Satisfaction with care are unique to LupusPRO) constructs. It is responsive to changes in disease and health status [26] and has floor–ceiling effects data available. LIT has good validity and reliability against SF-36 as well as Lupus-QoL, and is responsive to self-reported changes in health status [35] and SRI [37].

Lupus Specific QoL Tools and Cross Cultural Adaptations A validated HRQoL instrument in SLE that can be used in multicenter, multinational, multiethnic SLE patients and

Page 5 of 11, 380

clinical trials is necessary and requires careful crosscultural adaptation and validation. Certain domains of QoL may be of more or less importance based on a given sociocultural context, and the importance of having one instrument that is valid and reliable across varied groups of SLE patients (based on ethnicity, sociocultural status), and that retains its measurement equivalence, is paramount in efforts at the understanding, measurement, and improvement of HRQoL in SLE. QoL tools development in SLE patients has been conducted largely in Western societies and mostly in the English language. Cultural adaptation of these QoL measures is very important to prevent selection bias associated with studies that might selectively exclude non-English-speaking patients during pivotal clinical trials [25]. Though some changes in item functioning of the QOL tool is bound to occur in varied cultural contexts, significant changes in the properties of most of the items are not expected if the tool is appropriately translated using cross-cultural adaptations and standardized techniques. Psychometric studies (validity, reliability, Differential Item Functioning for Measurement equivalence) of translated or cross-cultural adaptations are important to confirm their functioning before they can be widely used across cultures or languages. These limitations can be further addressed through validation studies of cross-cultural and translated questionnaires. This need has been recognized and studies are underway to assess the psychometric properties of the different instruments in special groups after translations and cross-cultural adaptations. SLE-QoL that was developed in Singapore has been adapted for Chinese-speaking SLE patients in Singapore; the instrument has also undergone preliminary validation testing in Thai [40•], Chinese [41]v and Brazilian-Portuguese [42]. The L-QoL [10], produced in the UK has been translated into Estonian, but has not been validated further. The LupusQoL has been adapted for cross-cultural use and validated and evaluated for use in the United States [43]. It has also been translated into Dutch, Greek, Hungarian, Italian, Portuguese, Swedish, and Chinese, but validation results are available only for the Spanish [44] and French [45] translations. LupusPRO, has been translated and validated in the Spanish language among Hispanic SLE patients from the US, Puerto Rico, Mexico, and South America [46], and in English in the Philippines [30], English in Canada [31] Canadian-French [31],Turkish [33], and Tagalog [29]. The tool shows measurement equivalence in all these validation studies [27]. It has been cross-culturally adapted/translated (and pretested) into Italian, German, Dutch, Swedish, Polish, and Hindi. Lupus Impact Tracker has been validated in North America. It has undergone cross-cultural adaptation for use in German, Italian, French, Polish, and Spanish, and validation studies are ongoing.

380, Page 6 of 11

Recent Observational HRQoL Studies in SLE Patients Several studies have previously noted the importance of HRQoL as an independent outcome measure in SLE, as it provides unique patient information that is not captured by disease activity and damage assessments. In a study evaluating 125 Caucasian and Hispanic SLE patients, depression but not disease activity (measured by Systemic Lupus Erythematosus Disease Activity Index) correlated with worse HRQoL. Depression was the only predictor of self-reported disease activity longitudinally [47, 48]. HRQoL of SLE patients was not associated with disease activity or damage in other studies [49, 50]. SLE is experienced as a more severe illness than other chronic illnesses by the patients [51]. Domains of QoL that were most affected in SLE patients were role emotional and role physical [50]. In a Canadian study with 33 SLE patients with active renal disease, worse HRQoL (physical function, Role Physical, Social Function) was found in comparison with SLE patients without active renal disease, after adjusting for demographics, non-renal disease activity, and non-renal damage [52] . Depression was noted to be the major determinant of QoL in all domains of SF-36 in this cohort [47, 48]. In two other studies, HRQoL of SLE patients was found to be associated with daily glucocorticoid dose, depression, and fatigue [49]. Psychological distress and coping capacities were strongly associated with most aspects of HRQoL in SLE, while sense of coherence mediated the relationship of psychological distress with physical HRQoL [53]. Satisfaction with life was noted to be low by 62 % of the SLE patients [50]. The authors reported moderate to strong correlations between all the HRQoL domains and satisfaction with life. Furthermore, type of treatment received by SLE patients with proliferative lupus nephritis (National Institutes of Health regimen for cyclophosphamide or the Euro Lupus Protocol) may influence patients perceptions of treatment effectiveness [51]. Few observational studies have been published using disease-specific QOL instruments in SLE. Fatigue was the most impaired, while body image was the least impaired domain in SLE among 322 SLE subjects from the UK on the LupusQoL [54]. There were no clinically important associations between the 8 domains of the LupusQoL and clinical or demographic variables in this group of patients [54]. Using the LupusQoL-US [43] tool among 185 US patients (60 % African American) with SLE, fatigue and physical health were the two most affected domains, while intimate relationships was the least impaired domain. Differences in LupusQoL-US scores were observed based on age, sex, and marital status, but not ethnicity [55].Body image is affected in SLE patients [24], and it is an important domain for patients, especially in women and in growing children. A study comparing body image between SLE with age/gender-matched non-SLE patients in a

Curr Rheumatol Rep (2013) 15:380

self-administered questionnaire [37] reported body image to be significantly worse in SLE patients [24]. Body image in SLE patients correlated inversely with overall damage, irreversible cutaneous damage, alopecia, and self-reported depression. This shows that manifestations of a certain organ system can impact patients HRQoL in several ways. The importance of cutaneous manifestations on HRQoL was also corroborated in a study of 31 patients with cutaneous lupus. Cutaneous activity in visible areas (Cutaneous Lupus Disease Area and Severity Index, CLASI) (activity on the face and nose) was associated with worse body image [56].

QoL in Intervention Based Clinical Trials in SLE The benefit/s of an effective health intervention in SLE should be perceptible to the patient. The role of non-medical interventions is also important in discovering ways to improve HRQoL in SLE patients. Navarette-Navarette et al. studied the role of cognitive behavioral therapy (CBT) in a randomized controlled trial that included 34 SLE patients followed over 15 months, with high levels of daily stress. They found significant reductions in levels of anxiety, depression, and daily stress in the CBT group compared to controls, but no significant differences in disease activity [57]. The role of controlling disease activity, tailoring the dosage of glucocorticoids to the lowest possible dose or stopping it and life-style modifications in gaining QoL, have been examined in two studies. The first showed that, over a 5-year period, patients with SLE had improvements in SF-6D scores with gains in HRQoL when they obtained better disease control, by reducing or stopping steroid therapy, and through smoking cessation [18]. The second indicated better effectiveness of physical activity by endurance training over cardiovascular fitness in improving QoL and physiologic status in patients with SLE [58]. Inclusion of the impact of medications on HRQoL in SLE has recently received some attention as an endpoint in SLE trials [59]. The study by Daleboudt et al. compared the effect of two different cyclophosphamide regimens in 32 patients with lupus nephritis on HRQoL. The Euro Lupus protocol group patients showed higher HRQoL on four of seven scales of SF-36, and less symptomatic burden from either nausea or vomiting than the ones receiving the National Institute of Health cyclophosphamide regimen [51]. Fatigue was the most disturbing symptom in both groups. Use of dehydroepiandrosterone use was found to be equally effective as placebo in improving fatigue in SLE patients [60]. Griffiths et al. evaluated whether low-dose cyclosporine was a more effective corticosteroid-sparing agent than azathioprine in 80 SLE patients over 12 months. Both drugs were found to be effective corticosteroid-sparing agents, but there was no significant difference found in HRQoL or adverse events between the

Curr Rheumatol Rep (2013) 15:380

two groups [61]. Use of hydroxychloroquine and HRQoL was analyzed in a cross-sectional study that involved 230 SLE patients using the LupusQoL and LupusPRO, and no association between its use and HRQoL was noted [62]. Patients with relatively well-controlled SLE may not recognize or reflect changes in measurements of HRQoL in a given timeframe. There has been much research evaluating B cells as therapeutic targets in SLE. However, when specifically looking at HRQoL, the randomized controlled trial evaluating rituximab versus placebo in moderate to severe SLE did not find any significant difference in SF-36 HRQoL measures [63]. Trials evaluating belimumab had HRQoL parameters as part of the outcomes measures. Vollenhoven et al. reported an improvement in SF-36 physical component score and mental component scores at week 52, as well as improvement in fatigue as early as week 8, among seropositive SLE responders receiving belimumab [64]. Increased use of HRQoL measurements in major trials reflects the growing emphasis and importance of addressing HRQoL as a separate domain, especially because it does not always parallel disease activity or flares.

Recognition of Modifiers and Confounders in QoL Measurement in SLE The study of HRQoL in SLE patients is complicated by the chronic waxing and waning nature of the disease and the fact that multiple factors outside the disease itself can influence and change a patient’s self-perceived QoL. Domains of HRQoL of particular importance to SLE patients include fatigue, ability to work, good health, independence, social and family life, learned helplessness (reflecting the unpredictability of lupus), pain, and the home environment [65], and can be confounded by fatigue, depression, and fibromyalgia [66, 67]. Anxiety and depression may be associated with neurocognitive manifestations that result in poor HRQoL. Hanley et al. compared cognitive function between SLE and RA patients and found self-reported cognitive symptoms to not reliably screen for efficiency of cognitive processing in patients with SLE. Self-reported cognitive complaints were instead influenced by the presence of anxiety and depression [68]. Not only depression and anxiety may cause cognitive dysfuction but also the disease itself. In the study by Peretti et al. of 31 Caucasian SLE patients (who did not meet ACR criteria for neuropsychiatric SLE) and 23 controls, a high prevalence of cognitive deficits was found in SLE women compared to normal women, which included impairment in cognitive domains important for daily activities. Elevated autoantibodies tended to correlate with cognitive dysfunction [69]. As we have previously stated, concomitant fibromyalgia, anxiety, or depression in SLE patients can significantly impact health status and HRQoL. In a study by Torrente-Sergarra of 84 SLE patients, 35.7 % had fibromyalgia, 19 % clinical signs

Page 7 of 11, 380

of depression, and 35.7 % had anxiety [67]. There was a significant association between fibromyalgia with anxiety and depression symptoms. The high prevalence of fibromyalgia in SLE is associated with depression and anxiety and worsening health status in SLE patients. Disease activity had little to no impact on psychiatric or fibromyalgia symptoms [6]. This was supported by another study that showed that changes in SF-36 in SLE patients with established disease were not affected by disease activity, steroids, or damage accrual during the interval, but were affected by the presence of fibromyalgia [17]. The roles of socio-economic status, comorbidties (diabetes), and disease activity were found to be predictive of development of depression in SLE [70]. Other confounding factors such as socioeconomic status and poor education can also influence self-perceived HRQoL and can impact a patient’s access to care and health outcomes. Among 211 SLE patients, higher socioeconomic status was associated with HRQoL; zip code-based annual household income, independent of education, was predictive of HRQoL [71]. Variable effects on patient HRQoL must be studied further and understood in order to accurately measure QoL outcomes (accounting for significant confounders) in clinical practice as well as controlled trials.

Use of QoL to Improve Health Care Services in SLE The role of the physician-patient relationship, access to health services, and modes of communicating health-related information may also significantly influence HRQoL in SLE patients. Patient perceptions of physician quality of care and their satisfaction with care were found to be associated with better HRQoL [72] Physician quality of care is affected by the “perception of doctor’s understanding of impact of SLE on patient’s life”, as well as “providing educational information to understand their disease.” Bennett et al. tested the hypothesis that patients’ working alliance with treating physicians and patients’ attachment styles would be associated with patients’ adherence, satisfaction, and HRQoL. In this study of 193 SLE patients, the working alliance was significantly and positively associated with variables of adherence, satisfaction, and HRQoL [73]. Severity of depression symptoms was found to be associated with medication adherence difficulties, which in turn led to more health care utilization [12]. This suggests that screening for depression using patient-reported measures, and addressing depression, may be a way to improve adherence and/or health care utilization in SLE. The ability to maximize the patient–physician interaction in the clinical setting is key to enhancing HRQoL, and a way to measure HRQoL in each clinical encounter is needed so that HRQoL can be followed longitudinally. The Lupus Impact Tracker was developed to allow patient–physician

380, Page 8 of 11

communication and to serve as a means to convey the impact of SLE or its treatment on the patient’s life. Patients are able to track the impact of the symptoms routinely, and participate by following a summation score longitudinally to address how their disease is doing. This tool was found to be feasible and acceptable to implement by both physicians and patients during routine clinical care setting, without placing significant burden on the patient, office staff, or physician schedule [35].

Conclusions: Where Do We Go from Here and What Is on the Horizon? HRQoL has been found to be predictive of mortality in chronic diseases [74–76], including rheumatoid arthritis [77]. In SLE, SF-6D was found to be predictive of mortality [78]; however, after adjustment for age, ethnicity, poverty, disease activity, and damage, it did not remain an independent predictor of mortality. This is quite understandable, as all variables included in this multivariate model are associated with HRQoL. However, by itself, HRQoL was predictive of mortality in SLE. Further research is urgently needed in this area, so we can begin to understand the importance of including HRQoL as an important endpoint in all clinical research in SLE. Though we now have disease targeted PRO tools in SLE, important work must be completed before these tools can become mainstream. QOL tools being used in SLE need to attain/complete cross-cultural adaptation, validation, and measurement equivalence determination across countries, so they can be used by all SLE patients, thus allowing them to be included in clinical trials. Thus far, measurement equivalence for LupusPRO and SLE-QOL has been reported. Also, responsiveness to change for LupusQoL, SLEQOL, and LupusPRO has been suggested, but further work is ongoing to ascertain the minimally important differences for these tools. Finally, consensus needs to be reached on the tool/s best suited for further study and inclusion into clinical research in SLE. Use of free or for charge electronic/Web-based applications is being explored in various chronic diseases to allow patients (and communicated to physicians) to track their health status in real time. Since HRQoL represents a dynamic state, it is suggested that it be assessed outside of the clinical settings, and within the patients’ real day-to-day environment. This can be achieved through hand-held phone applications [79, 80] or websites [81]. Formal validation or testing of effectiveness these resources in clinical trials and longitudinal observational studies are needed. Another concern is that current instruments available for measuring HRQoL may better reflect changes in disease activity among patients with moderate/large-sized improvement or worsening rather than small (yet significant) changes. A 4week period may not be sufficient time to resume daily activities in response to moderate/large changes in disease activity,

Curr Rheumatol Rep (2013) 15:380

and thus be reflected in HRQoL. On the other hand, changes in daily HRQoL in response to mild changes in disease activity may either not be valued as “significant” or may be valued variedly based on individual’s processing and preferences. Furthermore, use of a 4-week recall-based tool to reflect cumulative HRQoL of the period in between the clinic visits (usually more than 4 weeks) may also result in poor correlation between physician assessed disease activity (usually 10 days or 4 weeks recall) performed at varied time intervals and HRQoL. Reiterating this point, Touma et al. found both SF-36 and LupusQoL to be responsive to flares and improvement when both disease activity and HRQOL assessments were performed at monthly intervals [82]. We have yet to determine what is the best way to monitor for HRQoL changes longitudinally in SLE patients, especially for those in remission or mild disease. Through optimization of (1) patient–physician interaction and (2) screening for poor HRQoL or its predictors, through the use of cross-culturally adapted, validated, and responsive questionnaires in settings of both patient care, and testing/ comparison of effective treatments for SLE, we may be able to improve patient care, foster adherence, and health care utilization, and improve HRQoL in SLE. Compliance with Ethics Guidelines Conflict of Interest Anisha B. Dua has served on a national advisory board for Amgen. Zahi Touma has received honoraria from and is a consultant for GlaxoSmithKline and Janssen Research and Development, and has received royalties from www.sledai-2k.com and www.s2k-ri.50.com. Meenakshi Jolly holds the copyrights to LupusPRO and LIT, has served as a consultant for GlaxoSmithKline, has received grant support from GlaxoSmithKline/The Binding Site, has received honoraria from GlaxoSmithKline, has received royalties from GlaxoSmithKline and MedImmune, has received payment for development of educational presentations (including service on speakers bureaus) from GlaxoSmithKline, and has had travel/accommodations expenses covered/reimbursed by GlaxoSmithKline. Sergio Toloza declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular interest, published recently, have been highlighted as: • Of importance

1. Wilson IB, Cleary PD. Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA. 1995;273(1):59–65. 2. Urowitz MB, Gladman DD, Tom BD, Ibanez D, Farewell VT. Changing patterns in mortality and disease outcomes for patients

Curr Rheumatol Rep (2013) 15:380

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

with systemic lupus erythematosus. J Rheumatol. 2008;35(11):2152– 8. Jolly M. How does quality of life of patients with systemic lupus erythematosus compare with that of other common chronic illnesses? J Rheumatol. 2005;32(9):1706–8. Smolen JS, Strand V, Cardiel M, Edworthy S, Furst D, Gladman D, et al. Randomized clinical trials and longitudinal observational studies in systemic lupus erythematosus: consensus on a preliminary core set of outcome domains. J Rheumatol. 1999;26(2):504–7. FDA Guidance on Patient Reported Outcomes. “http://wwwfdagov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM193282pdf” [Internet]. 2010. Strand V, Gladman D, Isenberg D, Petri M, Smolen J, Tugwell P. Endpoints: consensus recommendations from OMERACT IV. Outcome measures in rheumatology. Lupus. 2000;9(5):322–7. Alarcon GS, McGwin Jr G, Uribe A, Friedman AW, Roseman JM, Fessler BJ, et al. Systemic lupus erythematosus in a multiethnic lupus cohort (LUMINA).XVII. Predictors of self-reported health-related quality of life early in the disease course. Arthritis Rheum. 2004;51(3):465–74. McElhone K, Abbott J, Gray J, Williams A, Teh LS. Patient perspective of systemic lupus erythematosus in relation to health-related quality of life concepts: a qualitative study. Lupus. 2010;14:1640–7. Jolly M, Utset TO. Can disease specific measures for systemic lupus erythematosus predict patients health related quality of life? Lupus. 2004;13(12):924–6. Doward LC, McKenna SP, Whalley D, Tennant A, Griffiths B, Emery P, et al. The development of the L-QoL: a quality-of-life instrument specific to systemic lupus erythematosus. Ann Rheum Dis. 2009;68(2):196–200. Erratum appears in Ann Rheum Dis. 2011 Aug;70(8):1519. Zhu TY, Tam LS, Lee VW, Lee KK, Li EK. Relationship between flare and health-related quality of life in patients with systemic lupus erythematosus. J Rheumatol. 2010;37(3):568–73. Julian LJ, Yelin E, Yazdany J, Panopalis P, Trupin L, Criswell LA, et al. Depression, medication adherence, and service utilization in systemic lupus erythematosus. Arthritis Rheum. 2009;61(2):240–6. Stamm TA, Bauernfeind B, Coenen M, Feierl E, Mathis M, Stucki G, et al. Concepts important to persons with systemic lupus erythematosus and their coverage by standard measures of disease activity and health status. Arthritis Rheum. 2007;57(7):1287–95. • Jolly M, Pickard AS, Block JA, Kumar RB, Mikolaitis RA, Wilke CT, et al. Disease-specific patient reported outcome tools for systemic lupus erythematosus. Semi Arthritis Rheum. 2012;42(1):56–65. This article describes the development, reliabililty and validity of LupusPRO; a disease-targeted patient-reported health outcome tool. Burckhardt CS, Archenholtz B, Bjelle A. Quality of life of women with systemic lupus erythematosus: a comparison with women with rheumatoid arthritis. J Rheumatol. 1993;20(6):977–81. Aggarwal R, Wilke CT, Pickard AS, Vats V, Mikolaitis R, Fogg L, et al. Psychometric properties of the EuroQol-5D and Short Form-6D in patients with systemic lupus erythematosus. J Rheumatol. 2009;36(6):1209–16. Kuriya BGD, Ibañez D, Urowitz MB. Quality of Life over time in patients with systemic Lupus Erythematosus. Arthritis Rheum. 2008;59(2):181–5. Harrison MJ, Ahmad Y, Haque S, Dale N, Teh LS, Snowden N, et al. Construct and criterion validity of the short form-6D utility measure in patients with systemic lupus erythematosus. J Rheumatol. 2012;39(4):735–42. Yazdany J. Health-related quality of life measurement in adult systemic lupus erythematosus: Lupus Quality of Life (LupusQoL), Systemic Lupus Erythematosus-Specific Quality of Life Questionnaire (SLEQOL), and Systemic Lupus Erythematosus Quality of Life Questionnaire (L-QoL). Arthritis Care Res. 2011;63 Suppl 11:S413– 9. Review.

Page 9 of 11, 380 20. • Castelino M, Abbott J, McElhone K, LS T. Comparison of the psychometric properties of health-related quality of life measures used in adults with systemic lupus erythematosus: a review of the literature. Rheumatology (Oxford). 2013;52(4):684–96. This article compares the psychometric properties of different HRQoL questionnaires. 21. Ow YLM, Thumboo J, Cella D, Cheung YB, Yong Fong K, Wee HL. Domains of health-related quality of life important and relevant to multiethnic English-speaking Asian systemic lupus erythematosus patients: a focus group study. Arthritis Care Res. 2011;63(6):899– 908. 22. Leong KP, Kong KO, Thong BY, Koh ET, Lian TY, Teh CL, et al. Development and preliminary validation of a systemic lupus erythematosus-specific quality-of-life instrument (SLEQOL). Rheumatology. 2005;44(10):1267–76. 23. Body Image: A handbook of theory, Research, & Clinical Practice. NY: Guilford Press; 2002, 2002. 24. Jolly M, Pickard AS, Mikolaitis RA, et al. Body image in patients with systemic Lupus Erythematosus. Int J Behav Med. 2012;19(2): 157–64. 25. Toloza SM, Jolly M, Alarcon GS. Quality-of-life measurements in multiethnic patients with systemic lupus erythematosus: crosscultural issues. Curr Rheumatol Rep. 2010;12(4):237–49. Review. 26. Jolly M, Cornejo J, Mikolaitis RA, JA B. LupusPRO and responsiveness to changes in health status and disease activity over time. Arthritis Rheum. 2011;63(10s):S898-S. 27. Jolly M, Kosinski M, SM T, al e. Equivalence of various language versions of Lupus Specific Patient Reported Outcome Measure: LupusPRO. Arthritis & Rheum. 2012;4(10):S607-S. 28. Jolly M, Block JA, RA M, al e. Spanish LupusPRO: cross cultural validation study for lupus. Arthritis & Rheumatism. 2011;63(10s): S725. 29. Salvador M, Tananguan RM, Jolly M, Navarra SV. Validation of the Filipino version of LupusPro(R) questionnaire among Filipino patients with systemic lupus erythematosus: APLAR-0471. Int J Rheum Dis. 2013;16(Supplement 1):82. Abstract. 30. Navarra SV, Tanangunan RM, Mikolaitis-Preuss RA, Kosinski M, Block JA, Jolly M. Cross-cultural validation of a disease-specific patient-reported outcome measure for lupus in Philippines. Lupus. 2013;22(3):262–7. 31. Bourre-Tessier J, Clarke AE, Mikolaitis-Preuss RA, Kosinski M, Bernatsky S, Block JA, et al. Cross-cultural validation of a diseasespecific patient-reported outcome measure for systemic Lupus Erythematosus in Canada. J Rheumatol. 2013;40(8):1327–33. 32. Bourré-Tessier J, Clarke AE, Mikolaitis-Preuss RA, Kosinski M, Block JA, M J. Validation of French version of LupusPRO among Canadian Lupus patients. Arthritis & Rheumatism. 2012;64(10s): S947-S. 33. Kaya A, Goker B, Cura ES, Tezcan ME, Tufan A, al e. Turkish lupusPRO: cross-cultural validation study for lupus. Clin Rheumatol 2013 Aug 11[Epub ahead of print]. 2013. 34. Jolly M, Kosinski M, Garris CP, et al. Development of the Lupus Impact Tracker: a tool for patients and physicians to assess and monitor the impact of systemic lupus erythematosus. Value Health. 2011;14(3):A 65–A6. Abstract. 35. Jolly M, Kosinski M, Garris CP, Ogelsby A. Validation of the Lupus Impact Tracker (LIT), a patient reported outcome tool, in a prospective multicenter longitudinal study of systemic lupus erythematosus patients. Value Health. 2012;15(7):A 515. 36. Jolly M, Kosinski M, Garris CP. Validation of the Lupus Tracker. Value in Health. Value Health. 2011;14(3):A 65. 37. Jolly M, Pickard AS, Sequeira W, Wallace DJ, Solem CT, et al. A brief assessment tool for body image in systemic lupus erythematosus. Body Image. 2012;9(2):279–84. 38. McElhone K, Abbott J, Shelmerdine J, Bruce IN, Ahmad Y, Gordon C, et al. Development and validation of a disease-specific health-

380, Page 10 of 11 related quality of life measure, the LupusQol, for adults with systemic lupus erythematosus. Arthritis Rheum. 2007;57(6):972–9. 39. Moorthy LN, Peterson MG, Baratelli MJ, al e. Preliminary crosscultural adaptation of a new pediatric health-related quality of life scale in children with systemic lupus erythematosus: an international effort. Lupus. 2010. p. 83–8. 40. • Kasitanon N, Wangkaew S, Puntana S, Sukitawut W, Leong KP, TTSHLS Group, et al. The reliability, validity and responsiveness of the Thai version of Systemic Lupus Erythematosus quality of life (SLEQOL-TH) instrument. Lupus. 2013;22(3):289–96. This article highlights the psychometric properties of the Thai version of SLEQOL-TH questionnaire. 41. Kong KO, Ho HJ, Howe HS, Thong BY, Lian TY, Chng HH, et al. Cross-cultural adaptation of the systemic Lupus Erythematosus quality of life questionnaire into Chinese. Arthritis Rheum. 2007;57(6):980–5. 42. Freire EA, Bruscato A, Leite DR, Sousa TT, Ciconelli RM. Translation into Brazilian Portuguese, cultural adaptation and validatation of the systemic lupus erythematosus quality of life questionnaire (SLEQOL). Acta Reumatologica Portuguesa. 2010;35(3): 334–9. 43. Jolly M, Pickard AS, Wilke C, Mikolaitis RA, Teh LS, McElhone K, et al. Lupus-specific health outcome measure for US patients: the LupusQoL-US version. Ann Rheum Dis. 2009;69:29–33. 44. Gonzalez-Rodriguez V, Peralta-Ramirez MI, Navarrete-Navarrete N, Callejas-Rubio JL, Santos Ruiz AM, Khamashta M. Adaptation and validation of the Spanish version of a disease-specific quality of life measure in patients with systemic lupus erythematosus: the Lupus quality of life. Med Clin. 2010;134(1):13–6. Spanish. 45. Devilliers H, Amoura Z, Besancenot JF, Bonnotte B, Pasquali JL, Wahl D, et al. LupusQoL-FR is valid to assess quality of life in patients with systemic lupus erythematosus. Rheumatology. 2012;51(10):1906–15. 46. Jolly M, Toloza S, Block J, Mikolaitis R, Kosinski M, Wallace D, et al. Spanish LupusPRO: cross-cultural validation study for lupus. Lupus. 2013;22(5):431–6. 47. Moldovan I, Katsaros E, Carr FN, Cooray D, Torralba K, Shinada S, et al. The patient reported outcomes in Lupus (PATROL) study: role of depression in health-related quality of life in a Southern California lupus cohort. Lupus. 2011;12:1285–92. 48. Carr FN, Nicassio PM, Ishimori ML, Moldovan I, Katsaros E, Torralba K, et al. Depression predicts self-reported disease activity in systemic lupus erythematosus. Lupus. 2011;20(1):80–4. 49. Choi ST, Kang JI, Park IH, Lee YW, Song JS, Park YB, et al. Subscale analysis of quality of life in patients with systemic lupus erythematosus: association with depression, fatigue, disease activity and damage. Clin Exp Rheumatol. 2012;30(5):665–72. 50. Kulczycka L, Sysa-Jedrzejowska A, Robak E. Quality of life and satisfaction with life in SLE patients-the importance of clinical manifestations. Clin Rheumatol. 2010;29(9):991–7. 51. Daleboudt GM, Broadbent E, Berger SP, Kaptein AA. Illness perceptions in patients with systemic lupus erythematosus and proliferative lupus nephritis. Lupus. 2011;3:290–8. 52. Appenzeller S, Clarke AE, Panopalis P, Joseph L, St Pierre Y, Li T. The relationship between renal activity and quality of life in systemic lupus erythematosus. J Rheumatol. 2009;36(5):947–52. 53. Hyphantis T, Palieraki K, Voulgari PV, Tsifetaki N, Drosos AA. Coping with health-stressors and defence styles associated with health-related quality of life in patients with systemic lupus erythematosus. Lupus. 2011;9:893–903. 54. McElhone K, Castelino M, Abbott J, Bruce IN, Ahmad Y, Shelmerdine J, et al. The LupusQoL and associations with demographics and clinical measurements in patients with systemic lupus erythematosus. J Rheumatol. 2010;37(11):2273–9. 55. Jolly M, Pickard SA, Mikolaitis RA, Rodby RA, Sequeira W, Block JA. LupusQoL-US benchmarks for US patients with systemic lupus erythematosus. J Rheumatol. 2010;37(9):1828–33.

Curr Rheumatol Rep (2013) 15:380 56. Jolly M, Kazmi N, Mikolaitis RA, Sequeira W, JA B. Validation of the Cutaneous Lupus Disease Area and Severity Index (CLASI) using physician- and patient-assessed health outcome measures. J Am Acad Dermatol. 2012. 57. Navarrete-Navarrete N, Peralta-Ramírez MI, Sabio-Sánchez JM, et al. Efficacy of cognitive behavioural therapy for the treatment of chronic stress in patients with lupus erythematosus: a randomized controlled trial. Psychother Psychosom. 2010;79(2):107–15. 58. Abrahao MI, Montenegro-Rodrigues R, Marangoni RG. et al. Impact of physical activity program in systemic Lupus Erythematosus. Arthritis & Rheum. 2009;60(10 S):1123-. 59. Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12): 3918–30. 60. Hartkamp A, Geenen R, Godaert GL, Bijl M, Bijlsma JW, Derksen RH. Effects of dehydroepiandrosterone on fatigue and well-being in women with quiescent systemic lupus erythematosus: a randomised controlled trial. Ann Rheum Dis. 2010;69(6):1144–7. 61. Griffiths B, Emery P, Ryan V, Isenberg D, Akil M, Thompson R, et al. The BILAG multi-centre open randomized controlled trial comparing ciclosporin vs azathioprine in patients with severe SLE. Rheumatology. 2010;49(4):723–32. Erratum appears in Rheumatology (Oxford). 2011 Mar;50(3):634. 62. Jolly M, Sandler DS, Sequeira W, Block JA. Hydroxy-Chloroquine Use and Disease Specific Health Related Quality of Life in Systemic Lupus Erythematosus. Arthritis Rheum. 2010;60(10s):S108. 63. Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-toseverely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222–33. 64. van Vollenhoven RF, Petri MA, Cervera R, Roth DA, Ji BN, Kleoudis CS, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71(8):1343–9. 65. Thumboo J, Strand V. Health-related quality of life in patients with systemic lupus erythematosus: an update. Ann Acad Med Singap. 2007;36(2):115–22 [Review] [56 refs]. 66. Bruce IN, Mak VC, Hallett DC, Gladman DD, Urowitz MB. Factors associated with fatigue in patients with systemic lupus erythematosus. Ann Rheum Dis. 1999;58(6):379–81. 67. Torrente-Segarra V, Carbonell-Abello J, Castro-Oreiro S, Manresa Dominguez JM. Association between fibromyalgia and psychiatric disorders in systemic lupus erythematosus. Clin Exp Rheumatol. 2010;28(6 Suppl 63):S22–6. 68. Hanly JG, Su L, Omisade A, Farewell VT, Fisk JD. Screening for cognitive impairment in systemic lupus erythematosus. J Rheumatol. 2012;39(7):1371–7. 69. Peretti CS, Peretti CR, Kozora E, Papathanassiou D, Chouinard VA, Chouinard G. Cognitive impairment in systemic lupus erythematosus women with elevated autoantibodies and normal single photon emission computerized tomography. Psychother Psychosom. 2012;81(5): 276–85. 70. Julian LJ, Tonner C, Yelin E, Yazdany J, Trupin L, Criswell LA, et al. Cardiovascular and disease-related predictors of depression in systemic lupus erythematosus. Arthritis Care Res. 2011;63(4):542–9. 71. Jolly M, Mikolaitis RA, Shakoor N, Fogg LF, Block JA. Education, zip code-based annualized household income, and health outcomes in patients with systemic lupus erythematosus. J Rheumatol. 2010;37(6): 1150–7. 72. Dua AB, Aggarwal R, Mikolaitis RA, Sequeira W, Block JA, Jolly M. Rheumatologists’ quality of care for lupus: comparison study between a university and county hospital. Arthritis Care Res. 2012;64(8):1261–4.

Curr Rheumatol Rep (2013) 15:380 73. Bennett JK, Fuertes JN, Keitel M, Phillips R. The role of patient attachment and working alliance on patient adherence, satisfaction, and health-related quality of life in lupus treatment. Patient Educ Couns. 2011;85(1):53–9. 74. Zuluaga MC, Guallar-Castillon P, Lopez-Garcia E, Banegas JR, Conde-Herrera M, Olcoz-Chiva M, et al. Generic and diseasespecific quality of life as a predictor of long-term mortality in heart failure. Eur J Heart Fail. 2010;12(12):1372–8. 75. Kanwal F, Gralnek IM, Hays RD, Zeringue A, Durazo F, Han SB, et al. Health-related quality of life predicts mortality in patients with advanced chronic liver disease. Clin Gastroenterol Hepatol. 2009;7(7): 793–9. 76. Issa SM, Hoeks SE, Scholte op Reimer WJ, Van Gestel YR, Lenzen MJ, Verhagen HJ, et al. Health-related quality of life predicts longterm survival in patients with peripheral artery disease. Vasc Med. 2010;15(3):163–9. 77. Michaud K, Vera-Llonch M, Oster G. Mortality risk by functional status and health-related quality of life in patients with rheumatoid arthritis. J Rheumatol. 2012;39(1):54–9. 78. Fernandez M, Alarcon GS, McGwin Jr G, Sanchez ML, Apte M, Vila LM, et al. Using the Short Form 6D, as an overall measure of health, to predict damage accrual and mortality in patients with systemic

Page 11 of 11, 380

79.

80. 81.

82.

83.

84.

85.

lupus erythematosus: XLVII, results from a multiethnic US cohort. Arthritis Rheum. 2007;57(6):986–92. Lupus Applications for Android. Internet [Internet]. 2013 9/13/13 AD. Available from: http://blog.laptopmag.com/best-lupus-apps? slide=1. Healthy Tweeting. Internet [Internet]. 2013; Last accessed 09/13/ 2013. Available from: http://www.healthytweeting.com/. USinLUPUS. Lupus Impact Tracker. Last lvisited 12/11/12 [Internet]. 2012. Available from: http://www.usinlupus.com/content/dam/ usinlupus/. Touma Z, Gladman DD, Ibanez D, Urowitz MB. Is there an advantage over SF-36 with a quality of life measure that is specific to systemic Lupus Erythematosus? J Rheumatol. 2011;38:1898– 905. Ware JE. The SF-36 Health Survey. In: B S, editor. Quality of life and pharmacoeconomics in clinical trials. Second ed. Philadelphia: Lippincott-Raven; 1996. p. 337–45. Brazier JE, Tsuchiya A, Roberts J, J B. A comparison of the EQ-5D and the SF-6D across seven patient groups. Health Economics. 2004;13:873–84. Group E. EuroQol: a new facility for the measurement of healthrelated quality of life. Health Pol. 1990;16:199–208.