PERSPECTIVES OPINION
The need to define treatment goals for systemic lupus erythematosus Kate Franklyn, Alberta Hoi, Mandana Nikpour and Eric F. Morand Abstract | In the current therapeutic climate, mortality rates from systemic lupus erythematosus (SLE) remain unacceptably high. Although new therapies are on the horizon, pending their emergence and availability, optimization of the currently available therapies is potentially achievable. A ‘treat-to-target’ approach is now considered routine for many diseases, including rheumatoid arthritis, for which it has substantially improved patient outcomes. The heterogeneity of SLE, as well as lack of universal agreement over methods to measure disease activity and treatment responses, has impeded the development of such an approach for this disease. In this article, the potential benefits of a treatment-target definition are explored, obstacles to the development of a treatment target in SLE are identified, and possible strategies to achieve this goal are discussed. Franklyn, K. et al. Nat. Rev. Rheumatol. 10, 567–571 (2014); published online 22 July 2014; doi:10.1038/nrrheum.2014.118
Introduction
Systemic lupus erythematosus (SLE) is the archetypal multisystem autoimmune dis ease, with an estimated incidence of 5–50 cases per 100,000 people.1 The survival rate of patients with SLE has improved progres sively over the past 50 years, owing to the application of synthetic glucocorticoids and immunosuppressive agents, but over the past three decades the rate has plateaued.2 Although no longer thought of as an ‘invari ably fatal condition’,3 the mortality risk from SLE is still unacceptably high, especially in young women. Furthermore, treatmentrelated morbidities have become an increas ing concern for clinicians. Although several biologic agents are currently in clinical trials, for example drugs that target type I interferon responses or the B‑cell marker CD22, the therapeutic landscape in SLE remains an area of great unmet need. ‘Treat-to-target’, in which treatment is adjusted or escalated until a specific target is achieved, is now routine in many areas of medicine, and has been proposed as a strat egy to manage patients with SLE.4 However, Competing interests E.F.M. declares that he has received an unrestricted educational grant from GSK. The other authors declare no competing interests.
in SLE, no treatment target suitable for this approach has yet been proposed or vali dated. Although remission should be aimed for, stringently defined remission from SLE rarely occurs, and a more achievable treat ment endpoint might still confer a favour able outcome. In this article, we discuss the potential development of such targets for the treatment of SLE.
The value of treatment targets
Studies from a range of medical disciplines have demonstrated the benefit of adher ence to disease-specific treatment targets. Empirical measures of effectiveness were initially used to drive adjustments of ther apy for common conditions such as diabetes mellitus and hypertension. For example, tight control of blood pressure, when com pared with usual care, resulted in a 50% reduction in cardiovascular mortality and morbidity in nondiabetic hypertensive patients.5 Subsequently, the application of a goal-based approach has led to a paradigm shift in the treatment of rheumatoid arthri tis (RA). The Tight Control of Rheumatoid Arthritis (TICORA) study demonstrated that, compared with routine care, inten sive management aimed at achieving treat ment targets was considerably more likely to achieve remission, and patients accrued
NATURE REVIEWS | RHEUMATOLOGY
less joint damage as measured by radio graphy.6 Similarly, the Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA) trial revealed that targeted care resulted in lasting remission in more than twice as many patients as routine care. 7 Crucially, new therapies, such as biologic agents, were not used in either of these studies; instead, a rigorous approach to the use of existing therapies was applied. As a result of the demonstration that outcomes were improved by goal-based approaches to treatment, the early institution of targetbased therapy for RA has become the standard of care in clinical practice.
Areas of unmet need in SLE Despite a substantial improvement in the second half of the 20th century, SLE mor tality rates have changed little over the past 3 decades. A multinational study calcu lated a standardized mortality ratio (SMR) of 2.4 for SLE, 8 whereas other studies have reported SMRs ranging from 7.9 in a Chinese hospital-based registry 9 to 12.6 in a Canadian cohort.10 The increased risk of death from atherosclerotic cardiovascular disease in women aged 35–44 years with SLE is 50-fold that of the age and sexmatched general population. 11 Another way of expressing the burden of disease is to examine the 10-year survival rate, which for SLE is estimated to be 90%. This rate means that a 25-year-old woman diagnosed with SLE has ~10% chance of dying before the age of 35,2 a mortality rate comparable to many malignancies. The main risk factor for mortality in SLE is organ damage, which in turn is driven by disease activity.12–15 Current evidence sug gests that lower disease activity is predictive of reduced frequency of flares and reduced cumulative exposure to glucocorticoids, whereas higher disease activity is associ ated with increased accrual of damage.13 In addition to direct effects of active disease on organ damage, medication-related tox icity remains prevalent in SLE cohorts, and glucoc orticoid therapy contributes substantially to the morbidity experienced by patients with SLE.16 Although it has not been proven conclusively that reducing disease activity will reduce SLE-associated cardiovascular mortality, the evidence is that VOLUME 10 | SEPTEMBER 2014 | 567
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PERSPECTIVES Box 1 | Defining a ‘LDA’ target for SLE Benefits ■■ Relative homogeneity of the low disease activity state ■■ Ability to test as an outcome measure in clinical trials of new agents ■■ Less stringent and more achievable than remission ■■ Ability to compare treatment approaches in strategy trials ■■ Applicability to everyday clinical practice Obstacles ■■ Relative heterogeneity of active disease phenotypes ■■ Imperfections of current disease activity measures ■■ Remission remains a clinical goal, but is too infrequent to be a useful clinical measure ■■ No currently available method to compare treatment strategies ■■ No biomarker reliably correlates with treatment outcomes Abbreviations: LDA, low disease activity; SLE, systemic lupus erythematosus.
disease activity, organ damage and death are a chain of events that can only be interrupted by better control of disease activity.17,18 Regardless of the evidence-base suggest ing the imperative to aggressively reduce disease activity, levels of disease activity in published SLE cohorts are frequently high. For example, in a cross-sectional study performed in 2010 at the Monash Medical Centre (Melbourne, Australia), the median disease activity score measured using the SLE disease activity index 2000 (SLEDAI2K) instrument indicated that 50% of patients had active disease.19 From an economic perspective, a review of the field in 2012 found that the direct cost of managing a patient with SLE is up to US$27,463 per year, and indirect costs,
defined as a loss of productivity due to dis ease related morbidity, can amount to an additional $16,435 per year. 20 The only report that showed cost-savings associated with lowering disease activity dates from 1996, when Sutcliffe et al. 21 showed that a reduction in disease activity of 1 point, using the Systemic Lupus Activity Measure (SLAM) instrument, resulted in a yearly saving of UK£933 per patient. We hypothesize that better control of dis ease activity through the adoption of treat ment targets, if achieved without substantial medication-related morbidity, has the potential to improve outcomes and reduce the economic burden of SLE. As reviewed elsewhere,4 the adoption of treat-to-target approaches for the management of SLE is a concept with a strong scientific rationale. Adoption of a treat-to-target approach for SLE mandates the objective assessment of whether a patient’s current state of disease activity matches a predetermined target, and making treatment decisions accord ingly. Logically, this approach requires that such a target-state first be defined.
composite activity indices have been vali dated against the physician global assess ment (PGA), and in observational studies have been shown to identify changes in dis ease activity over time. Unfortunately, none of the currently available indices is perfect or adequately encompasses all aspects of disease activity. For example, one of the most widely used measures in clinical trials, SLEDAI2K, does not include information regarding the degree of disease activity within a given organ.22–24 The 2004 British Isles Lupus Assessment Group (BILAG)25 index is a more comprehensive instrument in terms of inclusiveness of clinical features, but its complexity renders it cumbersome for use in everyday practice. Most indices fail to include patient-reported measures, and discordance between patient-reported outcomes and physician-recorded disease activity also presents a challenge.26,27 An important limitation of the existing measures of disease activity is that they were developed for the purpose of describing disease activity in observational studies, not to measure treatment response. In the past decade, several composite measures have been developed to define treatment response in SLE clinical trials (Figure 1 (Timeline)).24 These include the SLE Responder Index (SRI), as used in the belimumab trials,28 and the BILAG-based Combined Lupus Assessment (BICLA), as used in epratu zumab trials.29 These composite responder indices include the same components (PGA, SLEDAI and BILAG), but with varying defi nitions. The complexity of these outcome measures means that they are unlikely to find a place in routine clinical care. Furthermore, in the development of treat ment targets, a disease status definition that is ‘absolute’, rather than describing change relative-to-baseline, is required. Therefore,
Obstacles to an SLE treatment goal
The lack of agreement on measures of dis ease activity and treatment response com plicate SLE research by hindering clinical trial design, and hence drug development and the search for biomarkers (Box 1). A number of published instruments are used to quantify disease states in SLE, many of these tools have parallels in the mea surement of disease in patients with RA. However, the clinical diversity of SLE has impeded agreement on methods for the quantification of disease activity. Exist ing measures have been developed by rheumatologists, using both data-driven and consensus-driven methods. Multiple
Timeline | Evolution of treatment strategies for SLE and RA SLE
SLICC
SLEDAI and BILAG
SRI, BICLA, SRI-50
Association of PAD and flares with damage accrual
ACR20
1992
1993
1996
1995
2003
2004
Association between disease activity and radiographically evident damage
RA
2005
2007
2009
2011
20??
T2T trials demonstrate reduced morbidity
Minimal disease activity and remission defined as outcome measures
DAS-28
2010
Further research needed for SLE treatment target definition
T2T guidelines published
Treatment response index Disease activity scores Damage index
Abbreviations: ACR20, ≥20% improvement according to the ACR criteria; BICLA, BILAG-based Composite Lupus Assessment; BILAG, British Isles Lupus Assessment Group; DAS, disease activity score; PAD, persistently active disease; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SLICC, Systemic Lupus International Collaborating Clinics; SRI-50, SLEDAI 2K responder index-50, T2T, treat-to-target.
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PERSPECTIVES definition of a desirable ‘state’ that represents a ‘target’ is necessary.
Remission or low disease activity? The definition of ‘remission’ in SLE remains elusive. One definition, proposed by Urowitz et al.,30 is that remission is the complete absence of clinical and serological disease activity for at least 5 years in patients with SLE who no longer require immuno suppressive drugs (other than chloroquinebased drugs). This definition of remission was achieved in only 1.7% of patients in a Canadian cohort.30 As the pharmacological landscape in SLE evolves, achieving such a stringent goal might become more realistic. Currently, however, this goal is impracti cal for clinical trials and is unrealistic for everyday clinical practice. Another study has defined a subgroup of patients with ‘serologically active but clinically quiescent’ (SACQ) SLE, on the basis that hypocomplementaemia and antidouble-stranded-DNA antibody positivity can occur in the absence of clinical disease activity. 31 In a Toronto cohort, patients who had SACQ disease for up to 10 years accrued substantially less organ damage compared with age-matched, sex-matched and disease duration-matched controls who did not have SACQ disease over the same period of time.32 Although these studies have important implications for SLE pheno types, again, few patients met the defini tion of SACQ in this cohort, reducing the utility of SACQ as a target for treatment. A treatment goal based on low disease activity might be more feasible than one based on remission. Achieving a state of low disease activity in RA is associated not just with functional improvement, but also with a profound reduction in long-term joint damage and functional impairment.33 Notwithstanding that remission should be the goal, if it can be demonstrated that the attainment of low SLE disease activity is associated with a reduction in organdamage accrual, morbidity and mortality, adopting it as a treatment target in clinical practice could result in improved patient outcomes, as seen in patients with RA (Figure 1 (Timeline)). SLE treatment response biomarkers In general, studies to correlate biomarkers with composite measures of disease activity have not yet led to clinically useful predic tors of outcome. Although multiple genes associated with SLE susceptibility have been identified, most loci identified to date
Rash Arthritis Mouth ulcers
Treatment ‘Flaring’ Active SLE Heterogeneous Less easily defined
Nephritis Serositis Thrombocytopaenia
‘Doing well’ Less active SLE More homogeneous More easily defined
Vasculitis CNS disease Haemolysis
Figure 2 | The phenotypic diversity of active and inactive SLE. Active SLE, such as when a patient’s disease is flaring, has a diverse range of clinical phenotypes. Therefore, active SLE is, by definition, a highly heterogeneous state, making empirical description difficult. By contrast, patients who have been treated, have recovered from active disease and are ‘doing well’ are more clinically homogeneous, suggesting that this state of disease might be more easily defined. Abbreviations: CNS, central nervous system; SLE, systemic lupus erythematosus.
account for a small proportion of the herit ability of SLE.34 Consequently, biomarkers that are associated with disease phenotype (in regard to which organs are affected or spared), treatment response and outcome are elusive. For example, although disease severity is increased in patients of AfricanAmerican,35 Hispanic,36 Southeast Asian18 and Indigenous Australian ancestry,37 the biological factors contributing to this pre disposition to severe disease are unknown. Currently used biomarkers, such as antidouble-stranded-DNA antibody and serum complement concentrations, although components of most measures of disease activity, are not always reflective of clinical status. The subgroup of patients with SACQ disease serve to remind us that complement and autoantibody levels do not reliably predict flares or disease activity.32 Given the lack of a definitive biomarker that closely correlates with disease outcomes, clinical measures rather than biomarkers will prob ably be a large part of any def inition of a treatment goal for SLE.
What treatment target in SLE? Defining a treatment goal Experienced clinicians intuitively recog nize a state of low disease activity, in which patients with SLE are ‘doing well’. Moreover,
NATURE REVIEWS | RHEUMATOLOGY
such patients might be a relatively homo genous group, regardless of which manifes tations of SLE were present during earlier flares of disease; as the diverse manifesta tions of active disease come under con trol, a reduction in heterogeneity results. In Figure 2, we illustrate this point with an example of how the heterogeneity of active SLE differs from the relative homo geneity of inactive disease. Building on this concept, we propose that defining a state of low disease activity in SLE is intrinsi cally more achievable than quantifying the diversity of phenomena that manifest in disease flares. However, in order to be applied to clinical practice or clinical trials, the state of ‘doing well’ must be defined using reproducible measures. The development of a low disease activity treatment goal for the management of SLE will depend on defining the relative impor tance of a range of potential measures to the avoidance of organ damage and death (Box 2). Variables would probably include disease activity, previous damage, bio markers, quality-of-life measures, patientreported outcomes and treatment-related variables. This work has yet to be under taken; however, some predictions can be made. Given the association between dis ease activity and organ-damage accrual, VOLUME 10 | SEPTEMBER 2014 | 569
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PERSPECTIVES Box 2 | Inclusions for SLE target definition Low disease activity ■■ Predicted to result in reduced organdamage accrual ■■ Should be measured using a validated instrument Immunosuppressive therapy ■■ Not desirable if achieving low disease activity entails toxic effects (e.g. clinically important bone marrow suppression) Glucocorticoid therapy ■■ Glucocorticoid contribution to organ damage should be considered Quality of life ■■ Not yet demonstrated to be associated with mortality Patient-reported outcomes ■■ Difficult to measure Abbreviation: SLE, systemic lupus erythematosus.
low levels of inflammation would seem to be an implicit inclusion in any definition of a treatment goal. We propose that a treat ment goal definition would need to utilize a measure of disease activity that has shown validity in other studies. For example, vari ants of the SLEDAI instrument have had extensive validation, making SLEDAI a suitable candidate for the ‘backbone’ dis ease activity measure for a definition of a treatment-target state. 38 However, the relative contribution of disease activity in different organ systems to morbidity and mortality is not well defined. For example, serological activity in the absence of clini cal activity might affect outcomes distinctly from low levels of clinical disease activity.32 Additionally, disease activity in areas of low ‘threat’, such as the skin and joints, might affect outcomes less than disease activity in vital organs, such as the kidney and brain. As acknowledged by the developers of the SRI28 and BICLA29 composite clinical trial indices, no existing measure records disease activity in all domains, and therefore as a global measure of disease activity a PGA was included by the originators of both these indices. A PGA could capture aspects of disease that are not sufficiently quantified using other disease activity instruments. For many conditions, low disease activity per se is sufficient to define a treatment goal. However, in the management of patients with SLE, unlike hypertension or even RA (which is treated with similar medicines), substantial medication-related morbidity goes hand-in-hand with disease-related morbidity in affecting patient outcomes. Therefore, in defining a desirable target state in SLE, consideration should be given 570 | SEPTEMBER 2014 | VOLUME 10
to the risk of treatment-related toxicity (Box 2). As dose-dependent adverse effects of glucocorticoids have been demonstrated in a number of trials,16 and few physicians would consider the achievement of low dise ase activity while taking high doses of glucocorticoids a treatment success, we believe that a definition of an SLE treatment target would have to include information on concomitant medications, in particular on glucocorticoid doses.
opportunity presents itself to change the way that SLE is managed by defining a treatment goal in this disease (Box 2). Once validated, adapting treatments accordingly should reduce SLE mortality by enabling identification of the subgroup of patients requiring intensive therapy and monitoring. Much work remains to be done to define and validate a treat-to-target approach in SLE. Our contention is that the time for such work to begin has arrived.
Defining low disease activity in SLE In defining a clinical state as a treatment target, the goal is to first formalize a descrip tion of the desired clinical state, and sub sequently to validate it against meaningful outcomes. One methodology, similar to that used for the 28-joint disease activity score (DAS28) and SLEDAI instruments,23,39 is to initially harness the opinion of a panel of experienced SLE physicians using consensus-driven methodology. The valid ity of such an eminence-based consensus definition should subsequently be evalu ated using cohort data and outcomes such as flares, accrual of organ damage, healthrelated quality-of-life, and mortality. An alternative approach would be to use exist ing clinical trial data-sets, but in this case researchers would be restricted to analysis of variables already collected. Subsequently, demonstration of the utility of a consensus definition as a prognostic tool and treat ment goal could be assessed in a prospective study, evaluating outcomes such as mor tality and damage accrual after achievement of the defined clinical state. Such a prospec tive study design would reveal the relative contribution of disease and treatment vari ables to outcomes. Moreover, such a study could generate data suitable for redefinition of a treatment target using methodology similar to that applied in the ACR–EULAR definition of RA remission,40 whereby the clinical characteristics observed during the course of disease that lead to good outcomes were defined as the goal of therapy.
Monash University School of Clinical Sciences, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne, VIC 3168, Australia (K.F., A.H., E.F.M.). Departments of Medicine and Rheumatology, The University of Melbourne at St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, Melbourne, VIC 3065, Australia (M.N.). Correspondence to: E.F.M. [email protected]
Conclusions
In the current therapeutic climate, wherein curative SLE-specific therapy might still be years or even decades away, clinicians need ways to improve outcomes for patients. Optimizing current therapies by adopting a ‘treat-to-target’ approach has been dem onstrated to improve outcomes in other dis eases, and is likely to do so in SLE. Following the example of RA, where treat-to-target approaches are now considered routine, the
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Acknowledgements E.F.M. receives funding support from Arthritis Victoria and the National Health and Medical Research Council, Australia. M.N. receives funding support from the National Health and Medical Research Council, Australia. K.F. receives funding support from Arthritis Australia. Author contributions K.F. researched the data for the article and wrote the manuscript. A.H, M.N. and E.F.M provided a substantial contribution to discussions of the content, and to review and/or editing of the manuscript before submission. M.N. and E.F.M. contributed equally.
VOLUME 10 | SEPTEMBER 2014 | 571 © 2014 Macmillan Publishers Limited. All rights reserved
The need to define treatment goals for systemic lupus erythematosus Kate Franklyn, Alberta Hoi, Mandana Nikpour and Eric F. Morand Abstract | In the current therapeutic climate, mortality rates from systemic lupus erythematosus (SLE) remain unacceptably high. Although new therapies are on the horizon, pending their emergence and availability, optimization of the currently available therapies is potentially achievable. A ‘treat-to-target’ approach is now considered routine for many diseases, including rheumatoid arthritis, for which it has substantially improved patient outcomes. The heterogeneity of SLE, as well as lack of universal agreement over methods to measure disease activity and treatment responses, has impeded the development of such an approach for this disease. In this article, the potential benefits of a treatment-target definition are explored, obstacles to the development of a treatment target in SLE are identified, and possible strategies to achieve this goal are discussed. Franklyn, K. et al. Nat. Rev. Rheumatol. 10, 567–571 (2014); published online 22 July 2014; doi:10.1038/nrrheum.2014.118
Introduction
Systemic lupus erythematosus (SLE) is the archetypal multisystem autoimmune dis ease, with an estimated incidence of 5–50 cases per 100,000 people.1 The survival rate of patients with SLE has improved progres sively over the past 50 years, owing to the application of synthetic glucocorticoids and immunosuppressive agents, but over the past three decades the rate has plateaued.2 Although no longer thought of as an ‘invari ably fatal condition’,3 the mortality risk from SLE is still unacceptably high, especially in young women. Furthermore, treatmentrelated morbidities have become an increas ing concern for clinicians. Although several biologic agents are currently in clinical trials, for example drugs that target type I interferon responses or the B‑cell marker CD22, the therapeutic landscape in SLE remains an area of great unmet need. ‘Treat-to-target’, in which treatment is adjusted or escalated until a specific target is achieved, is now routine in many areas of medicine, and has been proposed as a strat egy to manage patients with SLE.4 However, Competing interests E.F.M. declares that he has received an unrestricted educational grant from GSK. The other authors declare no competing interests.
in SLE, no treatment target suitable for this approach has yet been proposed or vali dated. Although remission should be aimed for, stringently defined remission from SLE rarely occurs, and a more achievable treat ment endpoint might still confer a favour able outcome. In this article, we discuss the potential development of such targets for the treatment of SLE.
The value of treatment targets
Studies from a range of medical disciplines have demonstrated the benefit of adher ence to disease-specific treatment targets. Empirical measures of effectiveness were initially used to drive adjustments of ther apy for common conditions such as diabetes mellitus and hypertension. For example, tight control of blood pressure, when com pared with usual care, resulted in a 50% reduction in cardiovascular mortality and morbidity in nondiabetic hypertensive patients.5 Subsequently, the application of a goal-based approach has led to a paradigm shift in the treatment of rheumatoid arthri tis (RA). The Tight Control of Rheumatoid Arthritis (TICORA) study demonstrated that, compared with routine care, inten sive management aimed at achieving treat ment targets was considerably more likely to achieve remission, and patients accrued
NATURE REVIEWS | RHEUMATOLOGY
less joint damage as measured by radio graphy.6 Similarly, the Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA) trial revealed that targeted care resulted in lasting remission in more than twice as many patients as routine care. 7 Crucially, new therapies, such as biologic agents, were not used in either of these studies; instead, a rigorous approach to the use of existing therapies was applied. As a result of the demonstration that outcomes were improved by goal-based approaches to treatment, the early institution of targetbased therapy for RA has become the standard of care in clinical practice.
Areas of unmet need in SLE Despite a substantial improvement in the second half of the 20th century, SLE mor tality rates have changed little over the past 3 decades. A multinational study calcu lated a standardized mortality ratio (SMR) of 2.4 for SLE, 8 whereas other studies have reported SMRs ranging from 7.9 in a Chinese hospital-based registry 9 to 12.6 in a Canadian cohort.10 The increased risk of death from atherosclerotic cardiovascular disease in women aged 35–44 years with SLE is 50-fold that of the age and sexmatched general population. 11 Another way of expressing the burden of disease is to examine the 10-year survival rate, which for SLE is estimated to be 90%. This rate means that a 25-year-old woman diagnosed with SLE has ~10% chance of dying before the age of 35,2 a mortality rate comparable to many malignancies. The main risk factor for mortality in SLE is organ damage, which in turn is driven by disease activity.12–15 Current evidence sug gests that lower disease activity is predictive of reduced frequency of flares and reduced cumulative exposure to glucocorticoids, whereas higher disease activity is associ ated with increased accrual of damage.13 In addition to direct effects of active disease on organ damage, medication-related tox icity remains prevalent in SLE cohorts, and glucoc orticoid therapy contributes substantially to the morbidity experienced by patients with SLE.16 Although it has not been proven conclusively that reducing disease activity will reduce SLE-associated cardiovascular mortality, the evidence is that VOLUME 10 | SEPTEMBER 2014 | 567
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PERSPECTIVES Box 1 | Defining a ‘LDA’ target for SLE Benefits ■■ Relative homogeneity of the low disease activity state ■■ Ability to test as an outcome measure in clinical trials of new agents ■■ Less stringent and more achievable than remission ■■ Ability to compare treatment approaches in strategy trials ■■ Applicability to everyday clinical practice Obstacles ■■ Relative heterogeneity of active disease phenotypes ■■ Imperfections of current disease activity measures ■■ Remission remains a clinical goal, but is too infrequent to be a useful clinical measure ■■ No currently available method to compare treatment strategies ■■ No biomarker reliably correlates with treatment outcomes Abbreviations: LDA, low disease activity; SLE, systemic lupus erythematosus.
disease activity, organ damage and death are a chain of events that can only be interrupted by better control of disease activity.17,18 Regardless of the evidence-base suggest ing the imperative to aggressively reduce disease activity, levels of disease activity in published SLE cohorts are frequently high. For example, in a cross-sectional study performed in 2010 at the Monash Medical Centre (Melbourne, Australia), the median disease activity score measured using the SLE disease activity index 2000 (SLEDAI2K) instrument indicated that 50% of patients had active disease.19 From an economic perspective, a review of the field in 2012 found that the direct cost of managing a patient with SLE is up to US$27,463 per year, and indirect costs,
defined as a loss of productivity due to dis ease related morbidity, can amount to an additional $16,435 per year. 20 The only report that showed cost-savings associated with lowering disease activity dates from 1996, when Sutcliffe et al. 21 showed that a reduction in disease activity of 1 point, using the Systemic Lupus Activity Measure (SLAM) instrument, resulted in a yearly saving of UK£933 per patient. We hypothesize that better control of dis ease activity through the adoption of treat ment targets, if achieved without substantial medication-related morbidity, has the potential to improve outcomes and reduce the economic burden of SLE. As reviewed elsewhere,4 the adoption of treat-to-target approaches for the management of SLE is a concept with a strong scientific rationale. Adoption of a treat-to-target approach for SLE mandates the objective assessment of whether a patient’s current state of disease activity matches a predetermined target, and making treatment decisions accord ingly. Logically, this approach requires that such a target-state first be defined.
composite activity indices have been vali dated against the physician global assess ment (PGA), and in observational studies have been shown to identify changes in dis ease activity over time. Unfortunately, none of the currently available indices is perfect or adequately encompasses all aspects of disease activity. For example, one of the most widely used measures in clinical trials, SLEDAI2K, does not include information regarding the degree of disease activity within a given organ.22–24 The 2004 British Isles Lupus Assessment Group (BILAG)25 index is a more comprehensive instrument in terms of inclusiveness of clinical features, but its complexity renders it cumbersome for use in everyday practice. Most indices fail to include patient-reported measures, and discordance between patient-reported outcomes and physician-recorded disease activity also presents a challenge.26,27 An important limitation of the existing measures of disease activity is that they were developed for the purpose of describing disease activity in observational studies, not to measure treatment response. In the past decade, several composite measures have been developed to define treatment response in SLE clinical trials (Figure 1 (Timeline)).24 These include the SLE Responder Index (SRI), as used in the belimumab trials,28 and the BILAG-based Combined Lupus Assessment (BICLA), as used in epratu zumab trials.29 These composite responder indices include the same components (PGA, SLEDAI and BILAG), but with varying defi nitions. The complexity of these outcome measures means that they are unlikely to find a place in routine clinical care. Furthermore, in the development of treat ment targets, a disease status definition that is ‘absolute’, rather than describing change relative-to-baseline, is required. Therefore,
Obstacles to an SLE treatment goal
The lack of agreement on measures of dis ease activity and treatment response com plicate SLE research by hindering clinical trial design, and hence drug development and the search for biomarkers (Box 1). A number of published instruments are used to quantify disease states in SLE, many of these tools have parallels in the mea surement of disease in patients with RA. However, the clinical diversity of SLE has impeded agreement on methods for the quantification of disease activity. Exist ing measures have been developed by rheumatologists, using both data-driven and consensus-driven methods. Multiple
Timeline | Evolution of treatment strategies for SLE and RA SLE
SLICC
SLEDAI and BILAG
SRI, BICLA, SRI-50
Association of PAD and flares with damage accrual
ACR20
1992
1993
1996
1995
2003
2004
Association between disease activity and radiographically evident damage
RA
2005
2007
2009
2011
20??
T2T trials demonstrate reduced morbidity
Minimal disease activity and remission defined as outcome measures
DAS-28
2010
Further research needed for SLE treatment target definition
T2T guidelines published
Treatment response index Disease activity scores Damage index
Abbreviations: ACR20, ≥20% improvement according to the ACR criteria; BICLA, BILAG-based Composite Lupus Assessment; BILAG, British Isles Lupus Assessment Group; DAS, disease activity score; PAD, persistently active disease; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SLICC, Systemic Lupus International Collaborating Clinics; SRI-50, SLEDAI 2K responder index-50, T2T, treat-to-target.
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PERSPECTIVES definition of a desirable ‘state’ that represents a ‘target’ is necessary.
Remission or low disease activity? The definition of ‘remission’ in SLE remains elusive. One definition, proposed by Urowitz et al.,30 is that remission is the complete absence of clinical and serological disease activity for at least 5 years in patients with SLE who no longer require immuno suppressive drugs (other than chloroquinebased drugs). This definition of remission was achieved in only 1.7% of patients in a Canadian cohort.30 As the pharmacological landscape in SLE evolves, achieving such a stringent goal might become more realistic. Currently, however, this goal is impracti cal for clinical trials and is unrealistic for everyday clinical practice. Another study has defined a subgroup of patients with ‘serologically active but clinically quiescent’ (SACQ) SLE, on the basis that hypocomplementaemia and antidouble-stranded-DNA antibody positivity can occur in the absence of clinical disease activity. 31 In a Toronto cohort, patients who had SACQ disease for up to 10 years accrued substantially less organ damage compared with age-matched, sex-matched and disease duration-matched controls who did not have SACQ disease over the same period of time.32 Although these studies have important implications for SLE pheno types, again, few patients met the defini tion of SACQ in this cohort, reducing the utility of SACQ as a target for treatment. A treatment goal based on low disease activity might be more feasible than one based on remission. Achieving a state of low disease activity in RA is associated not just with functional improvement, but also with a profound reduction in long-term joint damage and functional impairment.33 Notwithstanding that remission should be the goal, if it can be demonstrated that the attainment of low SLE disease activity is associated with a reduction in organdamage accrual, morbidity and mortality, adopting it as a treatment target in clinical practice could result in improved patient outcomes, as seen in patients with RA (Figure 1 (Timeline)). SLE treatment response biomarkers In general, studies to correlate biomarkers with composite measures of disease activity have not yet led to clinically useful predic tors of outcome. Although multiple genes associated with SLE susceptibility have been identified, most loci identified to date
Rash Arthritis Mouth ulcers
Treatment ‘Flaring’ Active SLE Heterogeneous Less easily defined
Nephritis Serositis Thrombocytopaenia
‘Doing well’ Less active SLE More homogeneous More easily defined
Vasculitis CNS disease Haemolysis
Figure 2 | The phenotypic diversity of active and inactive SLE. Active SLE, such as when a patient’s disease is flaring, has a diverse range of clinical phenotypes. Therefore, active SLE is, by definition, a highly heterogeneous state, making empirical description difficult. By contrast, patients who have been treated, have recovered from active disease and are ‘doing well’ are more clinically homogeneous, suggesting that this state of disease might be more easily defined. Abbreviations: CNS, central nervous system; SLE, systemic lupus erythematosus.
account for a small proportion of the herit ability of SLE.34 Consequently, biomarkers that are associated with disease phenotype (in regard to which organs are affected or spared), treatment response and outcome are elusive. For example, although disease severity is increased in patients of AfricanAmerican,35 Hispanic,36 Southeast Asian18 and Indigenous Australian ancestry,37 the biological factors contributing to this pre disposition to severe disease are unknown. Currently used biomarkers, such as antidouble-stranded-DNA antibody and serum complement concentrations, although components of most measures of disease activity, are not always reflective of clinical status. The subgroup of patients with SACQ disease serve to remind us that complement and autoantibody levels do not reliably predict flares or disease activity.32 Given the lack of a definitive biomarker that closely correlates with disease outcomes, clinical measures rather than biomarkers will prob ably be a large part of any def inition of a treatment goal for SLE.
What treatment target in SLE? Defining a treatment goal Experienced clinicians intuitively recog nize a state of low disease activity, in which patients with SLE are ‘doing well’. Moreover,
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such patients might be a relatively homo genous group, regardless of which manifes tations of SLE were present during earlier flares of disease; as the diverse manifesta tions of active disease come under con trol, a reduction in heterogeneity results. In Figure 2, we illustrate this point with an example of how the heterogeneity of active SLE differs from the relative homo geneity of inactive disease. Building on this concept, we propose that defining a state of low disease activity in SLE is intrinsi cally more achievable than quantifying the diversity of phenomena that manifest in disease flares. However, in order to be applied to clinical practice or clinical trials, the state of ‘doing well’ must be defined using reproducible measures. The development of a low disease activity treatment goal for the management of SLE will depend on defining the relative impor tance of a range of potential measures to the avoidance of organ damage and death (Box 2). Variables would probably include disease activity, previous damage, bio markers, quality-of-life measures, patientreported outcomes and treatment-related variables. This work has yet to be under taken; however, some predictions can be made. Given the association between dis ease activity and organ-damage accrual, VOLUME 10 | SEPTEMBER 2014 | 569
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PERSPECTIVES Box 2 | Inclusions for SLE target definition Low disease activity ■■ Predicted to result in reduced organdamage accrual ■■ Should be measured using a validated instrument Immunosuppressive therapy ■■ Not desirable if achieving low disease activity entails toxic effects (e.g. clinically important bone marrow suppression) Glucocorticoid therapy ■■ Glucocorticoid contribution to organ damage should be considered Quality of life ■■ Not yet demonstrated to be associated with mortality Patient-reported outcomes ■■ Difficult to measure Abbreviation: SLE, systemic lupus erythematosus.
low levels of inflammation would seem to be an implicit inclusion in any definition of a treatment goal. We propose that a treat ment goal definition would need to utilize a measure of disease activity that has shown validity in other studies. For example, vari ants of the SLEDAI instrument have had extensive validation, making SLEDAI a suitable candidate for the ‘backbone’ dis ease activity measure for a definition of a treatment-target state. 38 However, the relative contribution of disease activity in different organ systems to morbidity and mortality is not well defined. For example, serological activity in the absence of clini cal activity might affect outcomes distinctly from low levels of clinical disease activity.32 Additionally, disease activity in areas of low ‘threat’, such as the skin and joints, might affect outcomes less than disease activity in vital organs, such as the kidney and brain. As acknowledged by the developers of the SRI28 and BICLA29 composite clinical trial indices, no existing measure records disease activity in all domains, and therefore as a global measure of disease activity a PGA was included by the originators of both these indices. A PGA could capture aspects of disease that are not sufficiently quantified using other disease activity instruments. For many conditions, low disease activity per se is sufficient to define a treatment goal. However, in the management of patients with SLE, unlike hypertension or even RA (which is treated with similar medicines), substantial medication-related morbidity goes hand-in-hand with disease-related morbidity in affecting patient outcomes. Therefore, in defining a desirable target state in SLE, consideration should be given 570 | SEPTEMBER 2014 | VOLUME 10
to the risk of treatment-related toxicity (Box 2). As dose-dependent adverse effects of glucocorticoids have been demonstrated in a number of trials,16 and few physicians would consider the achievement of low dise ase activity while taking high doses of glucocorticoids a treatment success, we believe that a definition of an SLE treatment target would have to include information on concomitant medications, in particular on glucocorticoid doses.
opportunity presents itself to change the way that SLE is managed by defining a treatment goal in this disease (Box 2). Once validated, adapting treatments accordingly should reduce SLE mortality by enabling identification of the subgroup of patients requiring intensive therapy and monitoring. Much work remains to be done to define and validate a treat-to-target approach in SLE. Our contention is that the time for such work to begin has arrived.
Defining low disease activity in SLE In defining a clinical state as a treatment target, the goal is to first formalize a descrip tion of the desired clinical state, and sub sequently to validate it against meaningful outcomes. One methodology, similar to that used for the 28-joint disease activity score (DAS28) and SLEDAI instruments,23,39 is to initially harness the opinion of a panel of experienced SLE physicians using consensus-driven methodology. The valid ity of such an eminence-based consensus definition should subsequently be evalu ated using cohort data and outcomes such as flares, accrual of organ damage, healthrelated quality-of-life, and mortality. An alternative approach would be to use exist ing clinical trial data-sets, but in this case researchers would be restricted to analysis of variables already collected. Subsequently, demonstration of the utility of a consensus definition as a prognostic tool and treat ment goal could be assessed in a prospective study, evaluating outcomes such as mor tality and damage accrual after achievement of the defined clinical state. Such a prospec tive study design would reveal the relative contribution of disease and treatment vari ables to outcomes. Moreover, such a study could generate data suitable for redefinition of a treatment target using methodology similar to that applied in the ACR–EULAR definition of RA remission,40 whereby the clinical characteristics observed during the course of disease that lead to good outcomes were defined as the goal of therapy.
Monash University School of Clinical Sciences, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne, VIC 3168, Australia (K.F., A.H., E.F.M.). Departments of Medicine and Rheumatology, The University of Melbourne at St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, Melbourne, VIC 3065, Australia (M.N.). Correspondence to: E.F.M. [email protected]
Conclusions
In the current therapeutic climate, wherein curative SLE-specific therapy might still be years or even decades away, clinicians need ways to improve outcomes for patients. Optimizing current therapies by adopting a ‘treat-to-target’ approach has been dem onstrated to improve outcomes in other dis eases, and is likely to do so in SLE. Following the example of RA, where treat-to-target approaches are now considered routine, the
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Acknowledgements E.F.M. receives funding support from Arthritis Victoria and the National Health and Medical Research Council, Australia. M.N. receives funding support from the National Health and Medical Research Council, Australia. K.F. receives funding support from Arthritis Australia. Author contributions K.F. researched the data for the article and wrote the manuscript. A.H, M.N. and E.F.M provided a substantial contribution to discussions of the content, and to review and/or editing of the manuscript before submission. M.N. and E.F.M. contributed equally.
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