Assessment of disease activity, damage and quality of life in systemic lupus erythematosus: New aspects




Abstract


Systemic lupus erythematosus (SLE) is a multisystem auto-immune disorder that results from a combination of genetic, environmental and hormonal factors. The heterogeneity of disease presentation and course in different individuals and the variability in the disease progression/fluctuations within the same patient have made finding a unifying assessment tool difficult. It is currently accepted that assessment of patients with SLE cannot be accomplished with a single index. Formal evaluation of three aspects of the disease, disease activity, disease damage and patient-related quality of life (QoL), is required.


In the recent decade, the pathogenesis of SLE at the cellular and molecular levels has been the subject of much research. Robust assessment tools are needed to correlate the presence of various serological markers with disease activity. In addition, multiple clinical trials of new therapies have necessitated validated measures that can give a sensitive response index. This review focusses on the SLE assessment tools currently in use and their translational application in clinical research and trials.


Introduction


Systemic lupus erythematosus (SLE) has a complex phenotype and a variable disease progression pattern that could involve new organ systems over 10 years post diagnosis . Careful clinical monitoring of these patients is therefore essential. In 1987, members of what was to become the Systemic Lupus International Collaborating Clinics (SLICC) group made several attempts to develop and compare reliable disease activity indices. Several robust, reliable and validated, but distinct, indices for evaluating disease activity have been developed. In addition, a number of patient quality of life (QoL) indices have been implemented . By contrast, a single damage index has been utilised. The indices have mainly been used as research tools for longitudinal observational studies. Their incorporation into clinical practice is hindered by the time needed to complete them. Computer-based calculation programs may be involved in deriving the outcome scores. An objective, easy-to-use assessment score to guide specific management strategies is the holy grail for physicians treating SLE.


Comprehensive disease assessment and response tools are essential for the evolving translational laboratory research, for robust clinical trials of novel therapeutic agents, for comparison of existing management strategies and for our continuing understanding of the disease processes and patterns in different patients. In the recent years, several adjustments to the scores have been made as well as composite scores created to fulfil this need.


Assessing disease activity


Three patterns of disease activity are generally observed in lupus patients: disease flare, chronically active disease and quiescence. Each clinic visit should involve an assessment of disease activity as well as screening for drug adverse events and complications, co-morbidities such as fibromyalgia, thyroid dysfunction, depression or malignancy, cardiovascular risk and implications of events such as pregnancy or stress. Features attributable to active lupus must be distinguished from chronic damage and other causes such as infections, drug toxicities and co-morbid diseases . A comprehensive list of clinical assessment parameters has been previously recommended and includes a history and physical examination, urinalysis and spot protein–creatinine ratio, blood pressure and blood tests .


Laboratory tests help to guide the diagnosis of current or impending flares and organ-specific complications (such as renal or haematological). However, because of the heterogeneity of organ involvement the search for a unifying biomarker of active disease has been challenging.


Anti-double strand DNA (anti-dsDNA) antibodies and complement (C3/C4) levels have long been established as predictors of disease activity. Anti-dsDNA is found in approximately 60% of patients during their disease course. The best predictive effect for rising anti-dsDNA antibodies has been found in association with lupus nephritis, albeit with a low overall likelihood ratio . There is also a known association with falling complement levels and disease activity .


New lupus activity markers are emerging as potential candidates for monitoring active disease. Vitamin D receptors are present on immunomodulatory cells. Recent studies have shown a link between vitamin D deficiency and SLE activity . Anti-nucleosome antibodies are strongly associated with SLE activity and may be useful in anti-dsDNA antibody-negative patients . In addition, antibodies to plasminogen activator inhibitor as well as anti-heparan sulphate and anti-chromatin antibodies have been shown to have a correlation with disease activity in small studies .


Due to the heterogeneity of lupus, autoantibody panels have long been advocated for investigating disease activity. Newer techniques for simultaneous multiple antibody detection are likely to improve the ease with which this is achieved .


Global disease activity assessment tools have been designed to look at the recent changes in disease status. They give a reliable and comparable quantitative assessment of lupus activity, with some of them being more applicable to clinical practice than others. The limitation of any global score is that equal weighting may be given to disease with multiple minor worsening features and one with one or two serious features without consideration for the significance of individual organ involvement. In addition, global score indices do not distinguish patients whose activity in the past month has remained the same, become worse or improved partially .


The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is one of the simpler tools in use. It consists of 24 organ/system and serological items with differently weighted scores of 2–8 assessed over the last 10 days (original SLEDAI) and validated for a 30-day period (SLEDAI-2K) . A score of 6 is considered clinically important, and a score of over 5 is associated with a >50% probability of initiating therapy. Clinical trials of novel therapeutic agents have been supported by SLEDAI outcome measures . SLEDAI has also been used in the study of novel serum markers such as high-sensitivity C-reactive protein (CRP) in patients with active SLE dominated by serositis, musculoskeletal symptoms as well as certain cardiovascular risk factors and thrombo-embolism . Utility of serum beta-2-microglobulin as an immunological measure of disease activity in SLE has been studied using this index . Angiopoietin- 2 (Ang-2) has been shown to have a significant positive correlation with SLEDAI scores and 24-h urinary proteins . Toll-like receptor (TLR) 9 has been shown to play a crucial role in the pathogenesis of SLE in animal models . TLR9 has been validated as a disease activity marker in a Chinese patient cohort . Anti-C1q antibodies are detected in 34–47% of SLE patients. Recently, an association with active disease and especially with lupus nephritis has been demonstrated .


Another simple tool easily adapted to clinical practice is the Lupus Activity Index (LAI). It is based on four visual analogue scales for fatigue, rash, joint involvement and serositis, and four system-based assessments of neurologic, renal, pulmonary and haematologic involvement. This index is not commonly used on its own, though it may be combined with other more comprehensive tools . This tool is, however, quick to apply and can be useful in busy follow-up clinics.


The European Consensus Lupus Activity Measurement Index (ECLAM) was the result of a consensus study in 1992 involving 704 real patients, whose clinical and laboratory parameters were correlated with the clinician’s assessment of their disease activity . Multivariate regression models were used to assign the relative weight to the serological and clinical variables. Twelve variables (10 organ/system ones plus erythrocyte sedimentation rate (ESR) and complement levels) were validated using data from 75 patients observed twice 3 months apart. ECLAM gives a global patient score that ranges from 0 to 17.5. It attempts to compensate for serious single organ involvement. It is relatively easy to use with clinically applicable parameters and a high sensitivity to change. The caveat is that this, like all global score systems, may miss changes in severity over time.


ECLAM has been used in a limited number of clinical studies. Mycophenolate mofetil is accepted as a potent treatment of SLE, with its efficacy supported by reduction in ECLAM . A correlation between anti-nucleosome antibodies and SLE disease activity as expressed by the higher ECLAM score has been demonstrated . In addition, ECLAM has been found to be a robust tool in retrospective evaluation of disease activity from clinical notes .


The Systemic Lupus Activity Measure, Revised (SLAM-R) is a scoring system published in 1988 and revised in 1991, consisting of 16 categories (nine organ/systems and seven laboratory) with 31 items in total . Each item has a numerical score of 0–3, the total sum indicative of the overall disease severity. Items chosen for the scale were those that are not only frequent but can also be reliably graded and rated. It was based on 25 real patients examined twice by independent physicians. The tool has shown excellent sensitivity and responsiveness to change. One of the disadvantages of this scoring system is in the subjectivity of many items because of patient-lead reporting of the symptoms.


The SLAM-R index has been used successfully in several studies. Improvement in the SLAM-R score has been used to demonstrate the effectiveness of hydroxychloroquine treatment, which correlated with a reduction in circulating interferon-alpha (IFN-α) and tumour necrosis factor-alpha (TNF-α) levels . In addition, SLAM-R scoring has been helpful in identifying factors that affect disease activity decline in various racial groups in the US using the LUpus in MInorities: NAture vs nurture (LUMINA) patient cohort . In this cohort, active renal disease was shown to be the most important predictor of mortality .


Patient-lead global assessment tools have all or most of the symptoms self-reported by the patients themselves.


Systemic Lupus Activity Questionnaire for Population Studies (SLAQ) is a patient questionnaire that can be used to collect data from a large number of SLE patients outside the hospital setting. It is largely based on the SLAM scoring tool but adapted for self-reporting. It involves putting a score of 0–3 (mild–severe, respectively) for 24 items in nine organ/systems. In addition, an overall disease activity score of 0–10 over the last 3 months is recorded. It is useful for large epidemiological studies where physician–patient interaction may be impractical, costly and time consuming. It is a validated initial screening tool for identifying patients who may have new or worsening disease activity . It does not, however, substitute for careful clinical physician assessment of the patient and can be influenced by the patient’s educational levels and disease perceptions. In addition, it does not take into account laboratory data.


Recent studies have shown that scores for patients with non-inflammatory symptoms do not correlate well with physician’s disease activity assessment . Factors such as fibromyalgia had an increased self-reported rate through SLAQ that was unconfirmed by clinicians .


Patient global assessment (PGA) of their disease activity and overall well-being has gained importance as more clinical trials have been emphasising the utility of patient perspective on treatment outcome .


Organ-based disease assessment has arisen from the need for a non-skewed view of individual organ involvement that is not combined into an overall score which can, on occasion, give misleading results.


The British Isles Lupus Assessment Index (BILAG) is the most comprehensive lupus activity index assessing individual organ/system activity with the ‘intention to treat’ principle . Unlike the scoring used in global assessments, systems/organs are scored separately, giving an ‘at-a-glance’ view of individual organ involvement. When compared to SLEDAI, BILAG has been found to be more sensitive in detecting active disease requiring treatment . The score considers activity during the last 4 weeks, thus making it sensitive to detecting activity affected by specific interventions . Unlike the global score systems, it captures (and distinguishes) partial change/improvement and deterioration. This makes BILAG particularly useful in clinical trials especially since no one drug is expected to affect all organ systems. The updated 2004 index assesses nine systems in total (constitutional, neuropsychiatric, musculoskeletal, cardio-respiratory, gastrointestinal, ophthalmic, renal and haematological). The gastrointestinal and ophthalmic sections were newly added in 2004, and the vasculitis section was split up to be organ-specific rather than stand-alone. A vascular necrosis of the hip and tendon contracture were taken out of the score since they represented damage rather than activity . Each question is scored from 0 to 4 (0 = not present in the past month, 1 = improving, 2 = same, 3 = worse and 4 = new), and specific values are recorded for some of the renal and all of the haematologic sections. The physician only records the symptom if it is attributable to SLE activity and not to another process. Traditionally physicians using this system will record concomitant SLE treatment and other relevant medications such as angiotensin-converting enzyme (ACE) inhibitors and antidepressants, noting whether the dose has changed. Furthermore, the activity index can be compared easily with serological tests, for example, anti-dsDNA and C3 levels measured on the same day. The information is processed by computer software (BLIPS; ADS-Limathon Ltd., Sheffield, UK) to give each system an activity score of A (most active; physician expected to treat with prednisolone doses above 20 mg and/or start/increase immunosuppression or anticoagulation), B (moderate known activity; treatment requiring lower-dose prednisolone and/or anti-malarials), C (mild persistent activity; for symptomatic treatment only), D (stable; previous organ involvement but no current activity) or E (the system has never been involved). The score can be converted into a numerical one, originally A = 9, B = 3, C = 1, D and E = 0,39 now optimised as A = 12, B = 5, C = 1, D = 0 and E = 0, which is more sensitive .


BILAG assessment does not take too long to complete and can be used for routine outpatient clinical assessment although the conversion of BILAG assessment to the A–E scoring is done subsequently either by hand or preferably using a computer-based calculation.


Recent clinical trials of the biologics epratuzumab, belimumab, abatacept, atacicept and rituximab have used BILAG to demonstrate treatment ‘end’ points defined as all BILAG A scores reduced to B/C/D and B scores to C/D, no new A and <2 new B scores . Other therapeutic interventions such as supplements of omega-3-polyunsaturated fatty acids and rapamycin have shown BILAG-tested effectiveness . BILAG has been used when comparing different drug treatments to each other, for example, cyclosporine versus azathioprine and mycophenolate mofetil versus cyclophosphamide in lupus nephritis . BILAG has also been used in evaluating the correlation between flare biomarkers such as IFN-α and its response proteins, IP-10 and sialic acid-binding Ig-like lectin 1 (SIGLEC-1) , 2-microglobulin/cystatin C (beta2M/CysC) index and urinary neutrophil gelatinase-associated lipocalin in renal disease with SLE activity.


BILAG has been validated in childhood lupus and in pregnancy .


Responder indices


Clinical trials of novel SLE therapies have pushed for a robust responder instrument that would detect meaningful change and provide a sensitive outcome measure in terms of reduction in disease activity. Failure to set a meaningful trial ‘end’ point can lead to disappointing results. This was highlighted by the rituximab trials where primary ‘end’ points are thought to have been set very high, thus failing to demonstrate efficacy over placebo. Indeed, post hoc analysis of the data from the rituximab The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial has demonstrated a delay in time to first A flare and the overall A flare rate in the rituximab arm compared to placebo .


In 2012, belimumab, a fully human monoclonal antibody against the soluble B-cell stimulator, was shown to be an effective therapeutic agent in SLE following phase III trials . The need for an ideal respondent index that would detect early as well as overall organ-specific disease activity change came out of the earlier belimumab phase II trial . This new disease activity index called the Systemic Lupus Erythematosus Responder Index (SRI) is derived from a combination of three indices: the Safety of Estrogen in Lupus Erythematosus National Assessment– Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI), Physician Global Assessment and BILAG 2004 . SRI response is defined as: 1) a ≥4-point reduction in the SELENA–SLEDAI score to demonstrate global improvement; 2) no new BILAG A or no more than one new BILAG B domain score to ensure no significant worsening in any organ systems and 3) no deterioration from baseline in the PGA by ≥0.3 points to make sure the overall patient condition was not sacrificed . Chronic damage and patient-reported outcome are excluded. The use of the combination response index highlights the fact that no one score can encompass all clinically important outcome measures.


SRI was later used to identify patients most likely to respond to belimumab. These are patients with more active disease, anti-dsDNA positivity, low complement or corticosteroid treatment at baseline. Ongoing trials of new SLE agents such as blisibimod and LY2127399 are also using SRI to measure outcome .


Recently, a more organ-specific renal activity/response tool has been developed and is awaiting validation in clinical trials .


Another responder index, a derivative of SLEDAI, SLEDAI-2K Responder Index 50 (SRI-50), has been validated as a tool to identify those patients with a ≥50% recovery/improvement in disease activity, making it more sensitive than simply noting the presence or absence of a clinical feature . It has been successfully used to identify treatment responders in clinical trials but retains the ‘Achilles heel’ of all global score systems in that it does not identify those clinical factors that have got worse in the past 30 days.


In addition, a non-combination purpose-designed response index for SLE has been developed to look at specific organ system improvement and used in clinical trials of novel therapeutic agents and in comparing effectiveness of established treatment approaches .


Assessment of disease flare


Agreeing on the definition of flare in an SLE patient and how best to capture it has proved very challenging. A working party on behalf of the Lupus Foundation of America has defined flare as a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs or symptoms and/or laboratory measurements which would be considered clinically significant and prompt increase or initiation of treatment . Flare in SLE occurs in 65–70% of patients in an average year . Certain serological factors such as levels of dsDNA are predictive of flare risk . Serologically active but clinically quiescent SLE has higher flare rates with 59% of patients flaring over a course of 3 years . Patients from the recent phase III trials of belimumab were evaluated to identify predictors of moderate to severe flare. Renal, neurologic or vasculitic involvement, elevated anti-dsDNA or B-lymphocyte stimulator (BLyS) levels and low C3 were predictive of flaring within 1 year .


Reduction in flare rate is a useful therapeutic trial ‘end’ point. Several measures of flare are currently used. For example, an increase in the global SLEDAI-2K score of ≥4 points has been used in distinguishing patients with persistently active disease versus those having a flare . The SELENA–SLEDAI Flare Index (SFI) came out of the safety of oestrogens national assessment trial . The SFI includes three elements: the SELENA–SLEDAI score (range, 0–105, with 0 indicating inactive disease); an assessment of new or worsening disease activity, medication changes and hospitalisations not captured with the use of the SLEDAI; and the score on the physician’s global assessment visual-analogue scale (range, 0–3, with 0 indicating inactive disease and 3 severe disease). Severe flares are defined as 1 or more of the following: a) SELENA–SLEDAI instrument score >12; b) new or worsening central nervous system involvement, vasculitis, glomerulonephritis, myositis, thrombocytopaenia (platelet count <60 × 10 9 cells l −1 ) or haemolytic anaemia (haemoglobin level <70 g l −1 or decrease in haemoglobin level >30 g l −1 over a 2-week period), each requiring doubling of corticosteroid dosage to a final dosage >0.5 mg kg −1 per day or acute hospitalisation; c) any manifestation requiring an increase in dosage of prednisone or equivalent drug to >0.5 mg kg −1 per day, or initiation of therapy with cyclophosphamide, azathioprine, mycophenolate mofetil or methotrexate; d) hospitalisation for lupus activity and e) change in physician’s global assessment score from baseline to >2.5. More recently, the original SFI was revised to distinguish mild from moderate flare . In this version, the severity of flare was defined according to the intensity of proposed treatment, thus bearing some similarities with BILAG.


BILAG 2004 is well suited for identifying flares. It defines a severe flare as one new category A item and a moderate flare as ≥2 new category B items. The SLICC group has conducted a study comparing flares defined using BILAG and SFI, demonstrating higher physician consistency with the former index .


Assessment of SLE chronic damage


The life expectancy of patients with SLE has been improving substantially over the last 50 years . However, increased evidence has been emerging for the impact of end-organ damage on patient morbidity and mortality. The damage is permanent and can be caused by the disease itself, its treatment or a co-morbidity. In order to have a measure of this long-term damage the Systemic Lupus International Collaborating Clinics group, endorsed by the American College of Rheumatology (ACR), developed an instrument known as SLICC/ACR . Twelve systems with 41 individual items are assessed for damage since the onset of SLE, not attributable to active inflammation and present for at least 6 months. A maximum score is 47, with higher scores predicting poorer outcome . Several robust cohort studies have established the link between SLE disease activity, organ damage and risk of death . One of the original cohort studies from Toronto demonstrated a 10-year mortality of 25% in patients exhibiting at least one item of damage in the first year of diagnosis compared to 7.3% in patients with no early damage . A 5-year prospective cohort study based on 141 of our own clinic patients showed that an increase in the average BILAG score or the presence of A flares was strongly predictive of damage and overall mortality . More recently, data from a large lupus cohort enrolled in 1991 and followed up for 10 years demonstrated that disease activity measured using global BILAG predicted subsequent organ damage and mortality after adjusting for key covariates such as demographics, disease duration, treatment regimens and lupus serology . Premature atherosclerotic cardiovascular disease has received a lot of attention with up to a 50-fold increase in risk compared with non-SLE patients . Damage accrual in SLE measured by SLICC/ACR has also been found to correlate with age at disease onset, disease duration and frequent flares . Renal damage has been shown to be the most important single predictor of mortality within the damage index .


Assessing health-related patient quality of life (HRQoL)


SLE is a complex chronic disease, and even though survival continues to improve, while there is no cure, the patients often demonstrate lifelong symptoms and have a long-term need for medical attention. Chronic disease tends to have significant implications for the physical, social and psychological aspects of patients’ life. Measuring the health-related patient quality of life (HRQoL) enables patients to put across their take on the disease and treatment, providing a better overall picture for the clinicians. In addition, recent specific recommendation has been made regarding the use of HRQoL assessments as therapeutic trial ‘end’ points .


Assessment of disease impact on HRQoL from the patients’ perspective used to be most commonly done using a generic Short-Form-36 (SF-36) questionnaire. It is not specific for SLE, having been devised in 1992 for a general Medical Outcomes Study . The questionnaire asks the patients to rate the limitations in their physical and social activities because of physical and emotional problems, overall body pain, general mental health, vitality and general health perceptions.


Multiple studies have found the overall HRQoL to be poorer in SLE . Fatigue has been shown to have the biggest impact on mental and physical components of the SF-36 . Two specific measures of fatigue, Krupp Fatigue Severity Scale and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, as well as SF-36 have been used in more recent clinical trials of belimumab and epratuzumab . Interestingly, there seems to be little correlation between disease activity scores and HRQoL scores. Part of the reason could be that some of the most important aspects of SLE HRQoL such as sleep disturbance and sexual function are not assessed by the standard SF-36. In addition, few of the standard disease activity scores take account of subjective patient-reported symptoms. In summary, it has become clear that while useful for comparing QoL between different conditions, the generic questionnaires needed to be adjusted in order to capture SLE-specific health implications.


More recently, lupus-specific QoL measures have been developed and validated. Notably, the LupusQoL includes 34 sections across eight domains and incorporates more disease-specific items such as fatigue and intimate relationship scores to make it relevant for SLE assessment. It uses the Likert response format and gives an overall adjusted score out of 100 (100 = best HRQoL) . It has been demonstrated that LupusQoL is an independent outcome measure with no correlation with patient demographics and clinical variables such as disease activity, duration or damage .


The Systemic Lupus Erythematosus-specific QoL (SLEQoL) questionnaire was developed in Singapore and consists of 40 items including physical functioning, activities, symptoms, treatment, mood and self-image. A minimal clinically important difference in scores has been calculated for this index in order to increase its sensitivity in detecting significant change .


Another SLE Quality of Life questionnaire (L-QoL) is based on the concept that the ability and capacity of individuals to satisfy their needs improves their QoL .


Both SLEQoL and L-QoL are yet to be validated in clinical trials .

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Nov 11, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Assessment of disease activity, damage and quality of life in systemic lupus erythematosus: New aspects

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