Key points

Introduction

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder with variable multi-system involvement. The survival of patients with SLE has significantly improved but like many chronic diseases, there is currently no cure, and morbidity and mortality remain high. Treatment of more severe cases of SLE often involves a balance between managing the manifestations of the disease and minimizing the treatment-related side effects. The disease has a significant impact on many aspects of patients’ lives and their overall well-being, or health-related quality of life (HRQOL) because SLE affects a relatively younger age group and improved survival has translated into longer disease duration. Therefore, patients with SLE must cope with a significant disease burden imposed by the numerous symptoms of the disease itself and its treatment, including fatigue, pain, sleep disturbance, renal and skin problems, and neurologic/psychiatric conditions (eg, anxiety, depression, headaches, motor/sensory deficits, seizures, cognitive impairment, neuropathy). Increasing attention to comorbidities of patients with SLE, which themselves add to the burden of the disease, has a substantial impact on patient outcomes and HRQOL.

Successful management of complex conditions such as SLE and comorbid conditions can benefit significantly from patient-reported outcomes (PRO) instruments that validly and precisely measure the relevant aspects of health status (eg, symptoms) and HRQOL. Physicians focus on disease activity and damage as their primary therapeutic goal ; however, there is a mixed literature with regard to the relationship between disease activity or organ damage and changes in HRQOL in patients with SLE. Discordant perspectives between patient and provider when assessing disease burden and activity can result in treatment nonadherence, treatment interruptions, and misunderstandings in communication between patients and providers. PROs can have a critical role in clinical trials and clinical care assessments because PROs provide relevant yet complementary information to disease activity and damage indices when it comes to prioritizing treatment decisions, managing symptoms, formulating interventions, providing a complete approach to the management of the disease, and possibly justifying the considerable costs of new therapies. HRQOL measures have been recommended for inclusion in core datasets for observational studies and clinical trials by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT). Further, measuring HRQOL and other aspects of health status (eg, symptoms, functioning) with PROs provides patients with an opportunity to participate more fully in their treatment and ultimately facilitate better communication with the multidisciplinary team of health professionals involved in their care. We review both generic and SLE-specific PRO instruments and their use in patients with SLE herein.

Generic patient-reported outcome instruments

Generic PRO tools have been used to assess HRQOL in SLE patients, including the Medical Outcomes Study Short Form 36 (SF-36) and EuroQoL-5 Dimensions (EQ-5D). Although these tools allow HRQOL comparisons between SLE patients and other patients with rheumatic and nonrheumatic diseases, some limitations in assessing SLE-specific outcomes exist.

The SF-36 is among the most widely used generic PRO tool in SLE studies. The 36-item questionnaire evaluates 8 separate HRQOL domains (physical functioning, general health, mental health, vitality, role physical, role emotional, bodily pain, and social functioning) and includes 2 summary scores (the physical component score and the mental component score). Two versions of the SF-36 are available to evaluate health status in 1- or 4-week intervals. The questionnaire is scored from 0 (worse health) to 100 (better health). The SF-36 was originally validated in an SLE sample from the UK and found to have favorable psychometric properties including good internal consistency, criterion validity compared with the Medical Outcomes Study Short Form 20+ (SF20+), good discriminant validity compared with a British control population, and construct validity in comparisons with the British Isles Lupus Activity Group score, but an inverse association with disease damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) was found only for the physical function domain. Responsiveness of SF-36 has since been shown in Canadian and French SLE samples. Minimal clinically important differences (MCIDs) have been established in other rheumatic diseases, and range from 5 to 10 for individual domain scores and from 2.5 to 5 for physical component score and mental component score summary scores.

The SF-36 has been used in both SLE clinical research studies (for example in ) and in clinical trials. Further, the SF-36 is frequently used as a legacy HRQOL instrument to validate other tools, including SLE-specific PRO instruments. One criticism of the SF-36 is that it does not assess all dimensions of health status that are important to SLE patients, such as body image and appearance, self-confidence, and social support. Also, there have been concerns about the sensitivity of the SF-36 to capture the frequent changes in health status seen in SLE patients, especially over long periods of time. For example, little change in HRQOL was found in SLE patients who completed the SF-36 instrument over an 8-year period in one study, whereas in another study change in SF-36 was seen only during the first 2 years after a diagnosis of SLE, and then remained stable for the subsequent 3 years of follow-up. In contrast, certain components of the SF-36 have been sensitive to change over shorter periods of time in clinical drug trials. These studies highlight the importance of critically evaluating the use of the SF-36 in certain clinical situations and suggest that use of the SF-36 to evaluate HRQOL may be most appropriate for SLE studies with short-term follow-up or SLE patients early in the disease course.

The EQ-5D has also been used in SLE studies, offering the advantage of allowing for economic evaluation in addition to measuring HRQOL. The 6-item questionnaire assesses health on the day of completion, and assesses 5 dimensions of disability, such as mobility and self-care, with a single visual analog scale score for patient-reported overall health. The disability dimensions have a 3-item response scale and results are reported as a summary score from 0 (death or health worse than death) to 1.0 (best imaginable health). EQ-5D visual analog scale scores range from 0 (worst imaginable health) to 100 (best imaginable health) and can be used to calculate quality-adjusted life-years for economic analysis. When psychometric properties of the EQ-5D in patients with SLE were assessed in a US multiethnic population, no floor or ceiling effects were found. Discriminant validity was detected among patients with high versus low SLE disease activity, but the EQ-5D did not differ among patients with a range of disease damage. Content validity and reliability of the EQ-5D were not assessed. The EQ-5D summary score was sensitive to changes over time when compared with EQ-5D visual analog scale and self-reported improvements, but the overall effect size was small. More recently, construct validity was established in a Chinese sample of SLE patients when compared with the Lupus Quality of Life Questionnaire (LupusQoL), and discriminant validity was seen with both SLE disease activity and damage scores. Additionally, significant ceiling effects were detected in the EQ-5D, with almost one-half of participants reporting no problems in some disability domains including self-care. The EQ-5D has been used primarily in clinical SLE research studies. For example, Strand and colleagues found that SLE patients taking corticosteroids had lower HRQOL, measured by the EQ-5D, than those who were not taking corticosteroids, and concluded that medication side effects contribute to poorer HRQOL in these patients. EQ-5D was also included in the belimumab clinical trials, with changes in patient-reported pain/discomfort domain noted.

The National Institutes of Health initiative Patient-Reported Outcomes Measurement Information System™ (PROMIS™) was established to develop self-report measures of adult and pediatric health status across a range of areas, or domains (eg, fatigue, pain) that are applicable to a broad array of health conditions. PROMIS is domain specific but is not disease specific.

Computerized adaptive testing (CAT) enables precise and efficient estimation of a person’s trait levels with only a subset of items from the item pool or “bank,” and not all participants answer the same items. This efficiency and precision have been demonstrated with PROMIS CATs in Dutch patients with rheumatoid arthritis and in US patients with rheumatoid arthritis, osteoarthritis, and normal aging cohorts comparing PROMIS Physical Function short forms and CATs relative to existing “legacy” measures (eg, HAQ-DI, SF-36).

The content relevance of PROMIS to SLE has been evaluated in a qualitative study of multiethnic Asian individuals with SLE, which confirmed that PROMIS domains (eg, physical function, pain, fatigue, sleep disturbance, sleep-related impairment, anger, anxiety, and depression) address the priority domains identified by these patients and could reasonably serve as a core set of HRQOL instruments, although some content gaps remain to be filled.

The body of literature demonstrating the validity of PROMIS measures in specific clinical populations remains very much in a nascent stage, but has included several studies in patients with SLE, including one with juvenile-onset SLE and several studies of adults with SLE described elsewhere in this paper. A cross-sectional study of SLE patients recruited through an Internet panel company used measures from PROMIS and another National Institutes of Health-funded initiative, the Quality of Life in Neurologic Disorders, to assess the PRO measures’ associations with patient-reported SLE disease severity (Lai J-S, Jensen SE, Kaiser K, et al. An evaluation of health-related quality of life in patients with systemic lupus erythematosus using PROMIS, unpublished.). The PROMIS measures included the PROMIS-29 health profile, a measure composed of 4 items from each of 7 domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities) and a 0 to 10 pain intensity item, and the psychosocial illness impact-negative short form. Compared with the general population norms, nearly all scores were at least one-half of a standard deviation worse (ie, 5 T-score units) with fatigue, pain interference, physical function, and psychosocial illness impact being the worst (ie, 1 standard deviation worse than the norms). Acceptable test–retest reliability (>0.7) was found on all instruments (range, 0.78–0.94).

The Activity in Lupus to Energize and Renew study was a cross-sectional study designed to test the relationship between subjective fatigue and objectively measured physical activity in patients with SLE. The study included PROMIS measures (PROMIS Version 1.0; 8-item short forms for fatigue, pain interference, anxiety, depression, sleep disturbance, sleep-related impairment, and physical function), and accelerometer-based physical activity in patients with SLE. All PROMIS short forms demonstrated excellent internal consistency reliability (Cronbach alpha, all >0.90). Results demonstrated significant negative correlations between minutes of bouted moderate-to-vigorous physical activity and physical function, fatigue, and pain interference. Bouted moderate/vigorous physical activity minutes correlated with lower PROMIS-measured fatigue ( r = -0.20; P = .03). Both light physical activity and moderate/vigorous physical activity minutes correlated with better physical function ( r = 0.19 [ P = .04] and r = 0.25 [ P = .006], respectively). Mean PROMIS T-scores for fatigue, pain interference, anxiety, sleep disturbance, sleep-related impairment, and physical function were each one-half of a standard deviation worse than the general US population mean.

PROMIS allows for standardized comparison of health status across chronic disease populations in addition to comparing with population-normed data; PROMIS measures are disease agnostic. For example, comparisons of the PROMIS scores reported by SLE patients in this study to a large sample of individuals with arthritis (either rheumatoid arthritis or osteoarthritis) who completed the same PROMIS measures demonstrated that anxiety, depression, fatigue, and pain Interference scores were worse in this SLE sample, whereas physical function and satisfaction with social role scores were similar. Studies of rheumatic disease patients incorporating PROMIS measures have also shown that, compared with patients with systemic sclerosis, patients with SLE reported similar fatigue, more sleep disturbance, and better physical function. Compared with patients with osteoarthritis, SLE patients had more fatigue but better physical function.

PROMIS measures offer several advantages, including brevity and reduced burden; improved measurement with increased precision, allowing for increased power and reduced sample sizes; and flexible administration (established short forms of various lengths, custom short forms, CATs). They are domain specific rather than disease specific, and have a standardized scoring/metric, with a mean of 50 and standard deviation of 10, with most domains centered around the US general population, allowing for comparability across short forms and CATs and across studies and clinical conditions. Users of PROMIS measures have the ability to transform scores from other measures to the PROMIS score metric through PROsetta Stone linking methodology, and the measures are psychometrically sound, developed using state-of-the-science methods.

Although studies using PROMIS measures in people with SLE are only just emerging, these measurement tools seem to be appropriate for use in this population. The evidence to date suggests that PROMIS represents a system of valid and psychometric robust measurement tools that can provide brief yet precise scores for monitoring patients’ HRQOL across relevant domains with minimal respondent burden. Additional research is needed to contribute to the evidence supporting the validity of the PROMIS measures in SLE. There is a need for studies to focus on the development of interpretive aids for PROMIS measures so researchers, clinicians, and patients can better understand what the scores and score changes mean in an informative, clinical context.